WO1986004894A1 - Lipid derivatives - Google Patents

Lipid derivatives Download PDF

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Publication number
WO1986004894A1
WO1986004894A1 PCT/JP1985/000062 JP8500062W WO8604894A1 WO 1986004894 A1 WO1986004894 A1 WO 1986004894A1 JP 8500062 W JP8500062 W JP 8500062W WO 8604894 A1 WO8604894 A1 WO 8604894A1
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WO
WIPO (PCT)
Prior art keywords
silica gel
compound
methyl
concentrated
reaction
Prior art date
Application number
PCT/JP1985/000062
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/JP1985/000062 priority Critical patent/WO1986004894A1/en
Priority to EP85302202A priority patent/EP0157609B1/en
Priority to DE8585302202A priority patent/DE3586746D1/en
Priority to AT85302202T priority patent/ATE81501T1/en
Priority to DE8585302202T priority patent/DE3586746T2/en
Priority to JP60069628A priority patent/JPH0745454B2/en
Priority to CA000478129A priority patent/CA1281324C/en
Priority to KR1019850002240A priority patent/KR930004361B1/en
Publication of WO1986004894A1 publication Critical patent/WO1986004894A1/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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    • C07D211/06—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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    • C07D213/04—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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    • C07D239/24—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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    • C07D295/04—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
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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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Definitions

  • the present invention relates to a novel lipid derivative useful as a medicine
  • P AF P latelet Activating Factor
  • PAF has a phospholipid structure and is a chemical messenger present in vivo. 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.
  • finger derivatives having an ether bond or a viruvayl bond have Enzymes that break the bond are inadequate, especially in cancer cells, so they can easily accumulate in cells, alter lipid metabolism in cancer cells, and cause cancer cells to die. Have.
  • the present inventors have a PAF inhibitory effect, and have various circulatory disorders,
  • 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 a bond or substituted.
  • R + represents hydrogen, alkyl or aralkyl
  • X and Y each represent 0
  • Y When Y is an imino group, Y may form a ring with the imino group represented by X or R + and Z represents an optionally substituted imino or nitrogen-containing heterocyclic ring. Lipid derivatives and salts thereof.
  • the alkyl group represented by R 1 may be either straight-chain or branched, such as decyl ,,, decinyl, tridecyl, tetradecyl pentadecyl, hexadecyl, heptadecyl octadecyl, nonadecyl, eicosanyl Alkyl groups having about 0 to 30 carbon atoms, such as, henicosanyl, docosanil, tricosanil, tetracosanyl, pentacosanyl, hexacosanyl, heptacosanyl, octacosanyl, nonacosanyl, triacontanyl, pharmanesyl, dihydrophytyl and the like.
  • R 1 represents an alkyl group
  • the R 1 is a group represented by the formula
  • R 5 HC 0-(E).
  • R 5 can be 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 alkyl group is an alkyl group having 14 to 20 carbon atoms.
  • 2i l 5 o 1- is preferably an alkyl group having 14 to 18 carbon atoms, more preferably an alkyl group having 15 to 18 carbon atoms, and still more preferably an alkyl group having 15 to 18 carbon atoms. Most preferred are those having 16 to 18 alkyl groups.
  • R 2 examples include, for example, hydroxy, alkoxy, aralkyloxy, acyloxy or the formula
  • W represents an oxygen atom or a sulfur atom
  • RS and R 7 also represent hydrogen or alkyl, respectively, or both represent 0 with an adjacent nitrogen atom.
  • Examples of the alkoxy group represented by R 2 include lower alkoxy groups having about 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoquine, butoxy, isobutoxy, and pentoxy.
  • the aralkyloxy group represented by R 2 includes phenyl-lower (C 5 ) alkoxy, such as benzyloxy, phenethyloxy, ⁇ -methylbenzyloxy, ⁇ -methylphenethyloxy, and 5-methylphenethyloxy. .
  • acyloxy group represented by R 2 examples include a lower alkanoyloxy group having about 1 to 5 carbon atoms, such as formyloxy, acetyloquine, propionyloquine, petyryloxy, isoptyryloxy, valeryloxy, and isopareryloxy.
  • Benzoiruokishi phenoxyethanol carbonyl O carboxymethyl, Cal Pokishiokishi, lower (C -! 5) alkoxy force Ruboniruokishi (main Tokishikaru Boniruokishi, E butoxycarbonyl O carboxymethyl, propoxycarbonyl O alkoxy, butoxycarbonyl O carboxymethyl) is Ashiruokishi groups such like Can be
  • examples of the alkyl group represented by R s or R 7 include: Examples thereof include lower alkyl groups having about 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, and pentyl.
  • examples of the ring constituted by R 8 and R 7 together with the adjacent nitrogen atom include, in addition to the nitrogen atom, a 3- to 7-membered heterocyclic ring which may have a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom.
  • R 2 examples include, for example, amino, acylamino and the like.
  • Examples of the amino group represented by R 2 include lower alkanol amino groups having about 5 to about 5 carbon atoms, such as formamide, acetate amide, bu pionamide, butane amide, isobutanamide dolamide, and isovaleramide. And acylamino groups such as nzylamino.
  • Examples of the cyclic amino represented by R 2 include triaziridinyl, 1-azetidinyl, 1-pi- ⁇ -ridinyl.piperidino, 1- ⁇ -hydroazepinyl, 1-piverazinyl, morpholino, thiomorpholino, 1-perhydrodiazepinyl, 4 —A 3- to 7-membered monocyclic heterocyclic ring such as perhydroxoxazepinyl and 4-hydroxythiazepinyl, for example, a fused ring having about 8 to 9 carbon atoms such as 2-isoindolinidyl.
  • the monocyclic heterocyclic ring and the condensed ring-' may have a substituent such as oxo at a substitutable position.
  • substituent such as oxo at a substitutable position.
  • substituted monocyclic heterocyclic ring and unsubstituted ring include 2 , 5-dioxopyrrolidinyl, 1,3-dioxoisoindolinyl and the like.
  • R 2 is more preferably alkoxy.
  • alkylene chain represented by R 3 examples include straight-chain or branched alkylene chains having about 1 to 8 carbon atoms, such as methylene, ethylene, and trialkylene. 1 Methylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and the like, and the alkylene ⁇ ':
  • alkoxycarbonyl e.g., main butoxycarbonyl, Etokinkarubo two Le
  • DOO carboxylase
  • R 3 is preferably methylene, ethylene or trimethylene, and more preferably methylene or ethylene.
  • alkyl group represented by R 4 Echiru, propyl, isopropyl, butyl, Isobuchiru, sec- butyl, t Ert- butyl, pentyl, exemplified by lower alkyl groups having about 1 to 6 carbon atoms such as hexyl 0 It is.
  • the aralkyl group represented by R + includes, for example, phenyl lower (C 1-8 ) alkyl groups such as benzyl, phenethyl, phenylpropyl, phenylbutyl, ⁇ -methylphenethyl and ⁇ -methylphenethyl.
  • R 8 represents hydrogen, optionally substituted alkyl, acyl or optionally substituted rubamoyl.
  • examples of the alkyl group represented by R 8 include an alkyl group having about 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl and the like. , ig class (C t - 5) Al Kirukarubo alkenyl (e.g., main butoxycarbonyl, ethoxy Kin carbonyl, Provo Kin, butoxycarbonyl, ben butoxycarbonyl) or the like location
  • Examples of the acyl group represented by R 8 include lower aliphatic groups having about 1 to 5 carbon atoms.
  • Rukano I le eg, formyl, Asechiru, propionyl, Puchiriru, Isopuchi Li Runoku Rerizore, isovaleryl
  • Benzoiru phenoxyethanol carbonyl
  • Cal Bokishiru glare class (C Bok 5) alkoxycarbonyl (Kiyoshi, main butoxycarbonyl, ethoxycarbonyl Carbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl) and the like.
  • Examples of the optionally substituted carbamoyl group represented by R 8 include carbamoyl, glazed (C 5 ) alkyl levamoyl (eg, methylcarbamoyl, ethyl carbamoyl, propyl carbamoyl, butylcarbamoyl), Di-lower (C 5 ) alkyl rubamoyl (eg, dimethylcarbamoyl, methylethylcarbamoyl, getylcarbamoyl, methylbutyryl rubamoyl), 3- to 7-membered cyclic amino (eg, (aziridinyl)) Rubonyl, (azetidine-1-yl) carbonyl, (pyrrolidin-1-yl) power Luponyl, pyridino-force carbonyl, (perhydrazazepine-1-yl) carbonyl, (piperazine-1-yl) Le) carbonyl, morpholino-carbon
  • examples of the group represented by R 3 include the same groups as R 8 .
  • R 8 and R 3 may be the same or different, and _R 8 and R 3 are linked to form alkenylene or alkylene May be.
  • alkylene bridges include, for example, methylene, ethylene, trimethylene, tetramethylene, vinylene And lower alkylene having about 1 to 4 carbon atoms such as propenylene and alkylene bridges, and may have a substituent such as oxo at a substitutable position and may have o.
  • substituted alkylene and alkenylene for example,
  • Examples include 1-oxoethylene, 3-oxoprobenylene, and 1,2-dioxoethylene. Specifically, the expression
  • R 3 and R + may form a ⁇ Rekiren, Aruke two Le emissions which R 3 and R + is formed by communicating Yui, alkylene ⁇
  • examples include: lower alkylene having 1 to 4 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, vinylene, and ⁇ -benylene, and alkylene. It may have a g-substituent such as oxo at a possible position.
  • the substituted alkylene and alkenylene include reoxoethylene, 3-oxo sigma-benylene, and 2-dioxoethylene. Specifically, the formula Y _ R 3 - ⁇ -R +
  • ⁇ is preferred.
  • an optionally substituted imino group is preferable, a substituted imino group is more preferable, and an imino group substituted with lower alkylcarbonyl is more preferable.
  • Examples of the optionally substituted imino group represented by Z include an imino group and a lower alkyl group having about L to 6 carbon atoms which may be substituted with a lower (CL ⁇ + ) alkoxycarbonyl.
  • g-substituted imino groups eg, methyl imino, ethyl imino, propyl imino, isop sigma pilimino, butyl imino, isobbutyl imino, sec-butyl imino, tert-butyl imino
  • Imino groups substituted with an aralkyl group such as phenyl, pentylimino, heximimino, ethoxycarbonylmethylimino), phenyl-lower (Ct-8) alkyl (benzylimino, phenethylimino) Mino, phenylp sigma pyrimino, phenylbutylimino,
  • the imino group represented by Z may be quaternized to form an imino group, and the imimino group may be substituted with a lower (C t -J alkoxycarbonyl) or carboquinate.
  • Ararukiru group e.g., phenylene Lou lower (C t - s) alkyl] in may be substitution for the substituent Lee Minio group:.
  • Matatoeba Dimethyliminio, Methylethyliminio, Methylp ⁇ pylyminio, Methylbutyliminio, Methylbenguiluminio, Methylhexylinominio, Jethyriminio, Ethylpropylyminio, Echitylbutyrimino, Ethilben
  • Examples of the nitrogen-containing heterocyclic ring represented by Z include a heterocyclic ring containing at least one nitrogen atom.
  • a nitrogen atom, an oxygen atom or ' A monocyclic or bicyclic heterocyclic ring which may be contained as a ring-constituting atom is exemplified.
  • the heterocyclic ring may be saturated, partially saturated, or a fully hydrogenated heterocyclic ring such as a heteroaromatic ring, for example, azetidinyl, pyrrolidinyl, piberidinyl, perhydridyl. Droazepinii, pyrinyl, virazolinyl.
  • Pyril pyridyl, oxazolyl. Tizoril, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, morpholinyl tiomo 'refolini / re, pirazini ⁇ , Virazolidinyl, indolyl, isoindolinole, 1-indazolyl, purinyl, isoindrillyl, quinolinyl, isoquinolinyl, 1,2.3,4-tetrahydroquinolinyl, perhydrindolyl, Examples include groups such as ⁇ -hydroisoquinolinyl.
  • a 4- to 7-membered ring is preferred, and a 5- or 6-membered ring is preferred.
  • Most preferred arbitrariness is rather, thiazol Le or pyridyl which favored.
  • These groups may be substituted at a substitutable position with a lower (C + ) alkyl group (clear, methyl, ethyl, propyl, and butyl), a hydroquinone group, an amino (imino) group, a mono- or di-lower group.
  • (C + :) alkylamino eg, methylamino, dimethylamino
  • rubamoyl group permutation A lower (CL-4) alkyl group (eg, hydroxyxethyl, aminoethyl), carboxyl, carboxylate, lower (C alkoxycarbonyl (eg, methoxy) Carbonyl) and the like; for example, ⁇ -methylperforinyl, ⁇ -'methylbiperidinyl, ⁇ -methylpiperazinyl, ⁇ -methylbi-siglidinyl, ⁇ -ethylpyrrolidinyl, ⁇ - And groups such as ethoxycarbonylmethylpyridinio.
  • the nitrogen atom in the nitrogen-containing heterocyclic ring may be quaternized by R + , for example, ⁇ , ⁇ -dimethylpyrrolidinio, ⁇ -methylpyridinio, ⁇ -ethylpyridinio, ⁇ -propylpyridinio , ⁇ -butylpyridinio, ⁇ -methyl- ⁇ ethylpyridino, 3-methylthiazolio, 3-ethylthiazolio, 3-propylthiazolio, 3-butylthiazolio, and the like. Further, the nitrogen atom may be quaternized by bonding to R 3.
  • heterocyclic ring containing a quaternized nitrogen atom examples include, for example, pyridinio-1-yl, oxazolio-3 —Yl.thiazolio— 3-yl, pyridazinyl-1-yl, pyridimidin-1-yl, virazin-1-yl, quinolinio-1-yl, isoquinolinolin-1-2-yl, 4-Methylmorpholinio-1-yl, 1-methylbiperidinyl-1-yl, 1-methylpiperazinio-i-yl, 1-methylbirolidine di-n-yl, 1-ethylpyrroli 3-Dimethylthiazolio-1 2-yl, 1-methylimidazolio-1-yl, 3-carboxyla-topyridinyl-11-yl, 3-methoxycarbonylpyridinio-1 Groups such as 1-yl and 4-dimethylaminopyridinyl-1-yl can
  • a heterocyclic ring containing a quaternary nitrogen atom is more preferable.
  • 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.
  • Z has a quaternized nitrogen atom: well, chloride ions, bromide ions, iodine ions; acid anions such as sulfate ions, nitrate ions, phosphate ions, and sulphate ions;
  • a salt may be formed with anion such as an ion, or a salt may be formed in a molecule.
  • the compound (I) may have an asymmetric carbon in the molecule depending on the type of the substituent represented by R 2 , but when two stereoisomers of R—coordination and S coordination exist, 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 blood loss), myocardial infarction, angina thrombotic vein Diseases associated with inflammation, glomerulonephritis, shock (eg, endotoxin shock, intravascular coagulation caused by endotoxin, anaphylactic shock, hemorrhagic shock) and allergies (eg, It is useful as a preventive and therapeutic agent for bronchial asthma) and an antitumor agent.
  • PAF thrombosis
  • stroke eg, cerebral hemorrhage, cerebral blood loss
  • myocardial infarction e.g., myocardial infarction
  • angina thrombotic vein Diseases associated with inflammation glomerulonephritis
  • shock eg, endotoxin shock, intravascular coagulation caused by endotoxin, anaphylactic shock, hemo
  • Compound (I) and its salts have excellent properties in both hydrophilicity and lipophilicity and low toxicity. Therefore, they can be used as a powder or as a pharmaceutical composition in a suitable dosage form. It can be safely administered in a targeted or non-perfusion manner.
  • the dosage varies depending on the administration target, target disease, illness, administration route, etc., for example, when used for prevention and treatment of shock in adults: well, administration by intravenous injection
  • compound (I) or a salt thereof is generally used in a single dose of about 0.02 to 20 mg / kg body weight, preferably Q.l to 10 mg Zkg body weight, and more preferably l to '2 mg_kg body weight.
  • the compound (I) or a salt thereof may be administered at a rate of about G.01 to 1.0 g / kg body weight / min. For about 1 hour, about i to 5 times a day, preferably 1 to 3 times. It can also be administered by multiple infusions. In the case of other non-radial administration and oral administration, the same amount can be administered. If the shock symptoms are particularly severe, the dose may be increased according to the symptoms.
  • the compound (I) or a salt thereof is usually 0.1 to 20 mgZ kg in a single dose. It is convenient to administer severely, about 1 to 5 times a day, preferably about 1 to 3 times a day. More specifically, for the prevention of thrombosis, a single dose of about 0.5 to 4 mg Zkg body weight, and for the purpose of treatment, a single dose of about 4 to 10 mg / lig body weight, 1 to 4 times daily Preferably, it is administered about three times. 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 pharmaceutically acceptable carrier or excipient.
  • the composition is administered orally or parenterally.
  • compositions for oral administration include, for example, solid or liquid dosage forms, specifically tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, forcepsels (soft capsules). ), 'N a' soaps, emulsions, suspending agents and the like.
  • Such a composition is produced by a method known per se, and contains a carrier or a carrier commonly used in the pharmaceutical field.
  • carriers for tablets and pills 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, and instillation. Dosage forms such as agents.
  • Such injections are produced 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 liquid usually used for injections. You.
  • Aqueous solutions for injection include physiological saline, isotonic solutions containing glucose and other auxiliaries, and suitable dissolution aids such as alcohol (eg, ethanol), polyalcohols (eg, Propylene glycol, polyethylene glycol), nonionic surfactant [eg, polysorbate 80, HC 0-50 (polyoxyethylene (50 (no l) adduc t of hydrogenat ed cas toroi 1)
  • suitable dissolution aids such as alcohol (eg, ethanol), polyalcohols (eg, Propylene glycol, polyethylene glycol), nonionic surfactant [eg, polysorbate 80, HC 0-50 (polyoxyethylene (50 (no l) adduc t of hydrogenat ed cas toroi 1)
  • Oily liquids include sesame oil and soybean oil.
  • 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 base for suppositories 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.
  • Q t is easily substituted to group and nitrogen (e.g., chlorine, bromine, C androgenic such as iodine, OTosyl, etc. OMesyl group), and the other symbols the same meaning as defined] compounds I tables in And optionally substituted amine () or nitrogen-containing cyclic compound ( ⁇ 1) to obtain compound (I).
  • nitrogen e.g., chlorine, bromine, C androgenic such as iodine, OTosyl, etc. OMesyl group
  • the solvent examples include toluene, benzene, ether, dioxane, tetrahydrofuran and the like, and compound (VI) or (VI) itself can be used as the solvent.
  • the reaction Under ripening, the reaction may be performed in a sealed tube. Also, the expression
  • R 1Q represents lower alkyl
  • R 3 ′ represents a bond or alkylene
  • 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].
  • the reaction between (IX) and (X) can be carried out in the presence or absence of a solvent at ⁇ 10 to + 150 ° C.
  • a solvent such as toluene, benzene, ether, dioxane, tetrahydrofuran, chloroform can be used, and a base such as triethylamine or pyridine may be added to promote the reaction.
  • (X) may be reacted with sodium hydride, ⁇ -butyllithium, or the like in the above-mentioned solvent, converted into a metal salt, and then reacted with compound (IX).
  • the compound is, for example, a compound represented by the formula H 2 N—R 3 —Z—R + (XV), wherein each symbol is as defined above, to which diphosgene has been added in the absence of a catalyst or methylene chloride, chloroform, benzene, In an inert solvent such as tetrahydrofuran or toluene, the reaction is carried out at 120 to +120, or by the formula H 00 C -R 3 -Z -R + (XVI) Is the same as defined above), and tertiary amines such as triethylamine and tributylamine in solvents such as chloroform, toluene, benzene, dic ⁇ ⁇ methane and tetrahydropropane. Easily synthesized by reacting at 0-150 ° C in the presence of min and then 0- + 1500 in the presence of a tertiary amine such as pyridine. Can be.
  • 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 that is cored to R 8 or R 3 .
  • a compound in which X, Z or Y is a substituted imino group can be obtained.
  • the reaction is carried out in a solvent (eg, benzene, toluene, chloroform, dichloromethane, ether, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide) and the reaction temperature is reduced from itrc to about 150C. Proceed by keeping.
  • 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 a primary, secondary, or tertiary amine is reacted with, for example, an alkyl halide to obtain a compound represented by the formula (I). It is also possible to obtain a compound in which the nitrogen atoms contained in the groups represented by Z and Z are secondary, tertiary and quaternary amines. This reaction proceeds in a solvent such as ether, chloroform, tetrahide-mouth furan, benzene, toluene, etc. in the presence of an equivalent or large excess of alkyl halide at 0 ° to 10 ° C. I do.
  • the reaction can be carried out after the group is eliminated, and another substituent can be introduced.
  • R 2 is a benzyloxy group in the formula (I)
  • catalytic reduction can be performed, and after R 2 has been converted to a hydroxy group, acylation and rubamoylation can be performed.
  • X and or Y can be simultaneously acylated or levamoylated during the above acylation or levamoylation.
  • Catalytic return in this reaction The primary reaction can be carried out by using a catalyst such as platinum oxide, palladium carbon, Raney nickel, etc., and keeping the solution at room temperature to + 100 ° C in a solvent such as alcohol, tetrahydrofuran, water, or acid. it can.
  • the acylation reaction of (XW) is carried out by reacting (XVI) with an active derivative of carboxylic acid (acid anhydride, acid halide, etc.) in an inert solvent (ether, ethanol, benzene, toluene, dichlor- This can be achieved by maintaining the temperature between 10 ° C and + 150 ° C, such as methane, tetrahedral furan, and dimethylformamide. At this time, tertiary amine (triethylamine, pyridine, dimethylaminopyridine) or the like may be added to promote the reaction.
  • the reaction of (XVH) into a compound (XDO) can be carried out according to a compound reaction (production method of XUO) described below.
  • the starting material (VI) can be produced, for example, according to the following reaction formula.
  • Q t represents a tosyl or mesyl
  • THP represents a Tetorahi Doropi run one 2 _ I Le
  • Q + represents a Tetorahi Doropi run one 2 _ I Le
  • Q + represents a Tetorahi Doropi run one 2 _ I Le
  • Q + represents a Tetorahi Doropi run one 2 _ I Le
  • Q + represents a Tetorahi Doropi run one 2 _ I Le
  • Q + represents a Tetorahi Doropi run one 2 _ I Le
  • Q + represents a Tetorahi Doropi run one 2 _ I Le
  • Q + represents a Tetorahi Doropi run one 2 _ I Le
  • Q + represents a Tetorahi Doropi run one 2 _ I Le
  • Q + represents a Tetorahi Doropi run one 2 _ I Le
  • Q + represents a Tetorahi Doropi run one 2
  • (IX) and (XI) can be synthesized by reacting (XI) or (X) with, for example, chlorophenyl carbonate, phosgene or diphosgene.
  • Compound (a) used as a raw material in the above reaction can be synthesized, for example, by the following method.
  • R 2a represents an acyloxy group and R L has the same meaning as described above].
  • the compound can be produced, for example, according to the following reaction formula.
  • R 2b represents an acylamino group, and R 1 has the same meaning as described above]
  • R 1 has the same meaning as described above
  • R 2 C ′ represents a group represented by the formula (IE), and R 1 has the same meaning as described above]
  • R 1 has the same meaning as described above
  • Q s represents a halogen atom, and the others are as defined above.
  • reaction of (XXX YI) ⁇ (XL VI) is carried out without solvent or in an inert solvent (eg, It is preferably carried out at 0 to 150 ° C. in the presence of tertiary amines such as tosoleene, benzene, chloroform, dichloromethane, tetrahydrofuran), preferably pyridine, triethylamine, dimethylaminopyridine and the like. .
  • tertiary amines such as tosoleene, benzene, chloroform, dichloromethane, tetrahydrofuran
  • reaction (XL YI) ⁇ (XL) can usually be carried out in water or alcohol at +10 to 110 in the presence of an acid (eg, hydrochloric acid J).
  • an acid eg, hydrochloric acid J
  • reaction of (XXXVI) ⁇ (XL 1) can be carried out without solvent or in an inert solvent such as benzene, toluene, ethanol, dic ⁇ ⁇ methane, or tetrahydrofuran, and preferably a tertiary amine such as pyridine.
  • the reaction is preferably carried out at 0 to + 150 ° C.
  • 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 according to the following reaction formula. CH2OR 1 CH.OR 1 CHzOR 1
  • R 1 are as defined above
  • R 2e represents a cyclic amino radical compounds represented by may be prepared for example according to the following reaction scheme n
  • R 2e represents a cyclic amino group
  • Ts.Tri represents tosyl and trityl, respectively.
  • R and R 2 are as defined above] can be produced, for example, according to the following reaction formula.
  • compounds having a group that may hinder the reaction are used as protective groups known per se (eg, benzyl, tosyl, trityl, phthalimid, succinimide, benzyloxycarbonyl, tert-carbonyl).
  • the reaction can be carried out by protecting the group with -butoxycarbonyl) and, after the reaction, subjecting to a deprotection reaction known per se to obtain the desired compound.
  • the salt of compound (II) may be obtained, for example, by the above-mentioned method for producing compound (I) itself. However, if necessary, compound (I) can be produced by adding an acid or a base to compound (I). The salt form can also be converted using an ion exchange resin.
  • Examples 1 to 105 are the same as those disclosed in International Application PCT / JP84 / 04676.
  • This isocyanate compound was dissolved in chloroform (2 ml), and 2- (aminomethyl) pyridine 61 [0.6 mimol] was added thereto under ice-cooling, followed by stirring at room temperature for 17.5 hours.
  • the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography [silica gel: 20 g; eluent: chloroform: methanol-20: 1] to give the target compound 206 mg ( Colorless solid; 77.0%). ⁇ *
  • Example 80 1.0 g [2.5 mimol] of the amino compound prepared in Example 80 was dissolved in 25 ml of toluene, and diphosgene 905 92 [7.5 mimol] was added. The mixture was ripened at C for 5 hours, cooled, and concentrated under reduced pressure to obtain a crude isocyanate.
  • IR [filrnjcm] 1 3070, 3030. 2940, 2875, 1775, 1720, 1600,
  • I RCKBi cnT 1 3325, 2925, 2850, 1697, 1540, 1470, 1270
  • Example 11-iii 130 mg of the compound obtained in Example 11-iii) was dissolved in 0.5 ml of iodide chill and heated under reflux for 27 hours. The residue was purified by silica gel chromatography [eluent, black-mouthed form ⁇ black-mouthed form-methanol (20: 1)] to obtain 103 mg of the desired product.
  • Example 118 320 mg (0.613 mimol) of the pyridine derivative obtained in Example 118 was dissolved in a mixture of 3 ml of pyridine and 0.5 ml of acetic anhydride, and the mixture was refluxed for ripening for 3 hours.
  • the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel (5 g). The eluate was used to form a colorless solid (203 mg, yield 58.7%). .
  • Example 1 200 mg (0.35 mmol) of the acetate obtained in 20 was dissolved in a mixed solution of 1 mi of dichloromethane and 2 ml of methyl iodide, and allowed to stand at room temperature for 2 days.
  • reaction solution was concentrated to dryness under reduced pressure, and the residue was washed with n-hexane to obtain 246 mg of a colorless powder (100% yield).
  • IR (Br) cm _1 3400, 2920, 2850, 1760, 1720, 1500, 1470,
  • Example 1 was prepared using 1.23 g (10 mimol) of ⁇ -picolinic acid, 3.03 g (11 mimol) of diphenylphosphoryl azide, 1.2 g of triethylamine and 20 mi of toluene. By treating in the same manner as in 18, a colorless crystal (2.7 g, yield 83%) was obtained.
  • Example 12 Dissolve 300 mg of the ester obtained in 23 in 1.56 ml of t-butanol, add 26 mg of powdered potassium hydroxide, stir at room temperature for 1 hour, and then add concentrated hydrochloric acid. Neutralize and add 10 mi of ice water and 10 ml of dichloromethane, stir and separate the organic layer, dry with sodium sulfate, and then reduce to dryness under reduced pressure. (5 g) (developing solvent: chloroform, methanol, water (65/24/4)) to give 216 mg of a colorless powder (80.0% yield).
  • TL C silica gel, CHC1 3 , MeOH, H 2 0 (65: 25: 4)
  • Example 1 1.2 g (2.72 mmol) of the peracyl derivative obtained in 25 and 1.04 g (8.15 mmol) of 2-chloromethylpyridine hydrochloride were added to powdered potassium hydroxide 1 In the presence of 12 g, dimethyl sulfoxide was dissolved in 6 mU, and the mixture was stirred for 50 hours. The reaction mixture was poured into 60 ml of water, adjusted to pH 7.0, extracted with 60 ml of ether, and the ether layer was dried with sodium sulfate and replaced. Concentrated to dryness under pressure. The residue was purified by silica gel (10 g) [developing solvent, ethyl acetate, n-hexane (2 : 1)] to give a colorless solid 1.42 (yield 96.5%).
  • Example 12 1.4 g (2.62 mmol) of the trityl form obtained in 26 was dissolved in a mixture of 40 ml of methanol, 5 ml of water and 3 ml of concentrated hydrochloric acid, and stirred at room temperature for 1 hour. The resulting solution was cooled, and the precipitated crystals were filtered off. The mother liquor was neutralized with 1N-sodium hydroxide and concentrated to dryness under reduced pressure. The residue was dissolved in a mixture of 19 ml of chloroform and methanol in, and the insoluble matter was removed. The residue was again concentrated to dryness under reduced pressure, and the residue was silica gel (1 Og) [developing solvent, chloroform, Methanol (19: 1)] to give 729 mg (100% yield) of a colorless solid.
  • Example 12 729 mg (2.65 mmol) of the hydroxy compound obtained in 27 and 0.8 g (2.65 mmol) of octadecyl isocyanate were dissolved in 1 mU of pyridine. Aged at 105 ° C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel (15 g) [eluent, chloroform, methanol (49: 1)]. Then, 1.2 g (yield: 77.2%) of a colorless powder was obtained.
  • Example 128 700 mg (1.19 millimoles) of the pyridine derivative obtained in Example 128 was used in 0.5 ml of dichloromethane, and 338.6 mg of methyl iodide (2.386 millimoles). The reaction mixture was allowed to stand overnight at room temperature, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was recrystallized from a mixture of dichloromethane, dichloromethane 1.5 ml, and n-hexane 15 ml. 88 Omg of a colorless powder (100% yield) was obtained.
  • IR (nim) cm _1 3300, 2940, 2850, 1710, 1660, 1515, 1455,
  • Example 13 A mixture of 1.78 g (3.08 mimol) of the trityl form obtained in 30 was mixed with 4 Oml of methanol, 5 Oml of water, 10 ml of dichloro sigmamethane and 3 mi of concentrated hydrochloric acid. And stirred at room temperature for 1.5 hours. Neutralized with sodium bicarbonate and concentrated to dryness under reduced pressure. The residue was purified with silica gel (15 g) [eluent, chloroform, methanol (19 :) to give 973 mg of a colorless candy substance (yield 94.
  • Example 13 970 mg (2.9 mmol) of the hydroquine compound obtained in 31 and 857 mg (2.9 mmol) of octadecyl isocyanate were dissolved in 1 ml of pyridine. Heated at 120 ° C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel (17 g) [eluent, chloroform, ethyl acetate, ⁇ -hexane (48: 2: 50)] to give a colorless product 1.59 g (yield 87.0%) of a solid was obtained. TLC .silica gel, CHC1 3, eOH (19: 1)
  • Example 13 1.59 g (2.5 mmol) of the benzyl compound obtained in 32 was dissolved in 50 ml of 70% acetic acid and stirred in a hydrogen stream for 16 hours in the presence of 300 mg of palladium carbon. .
  • Example 13 1.16 g (2.15 mimol) of the hydroxy compound obtained in Example 3 and 574 mg (3.01 mimol) of tosyl chloride were dissolved in 3 ml of dichloromethane. Then, 104 mg of triethylamine was added, and the mixture was stirred for 3 hours.
  • Example 134 135 mg of the mixture obtained in Example 134 was dissolved in 5 ml of 20% trimethylamine-toluene (vZv) and left at room temperature for 4 days. The reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in 70% methanol (10 ml). IRA—410 [C1 type] was passed through 7 ml. The residue was purified by silica gel (2.5 g) [eluent, chloroform, methanol, water (65: 25: 4)] to give 83 mg of a colorless solid ( Yield 62.5%).
  • Example 13 mg of the mixture obtained in Example 13 was dissolved in 3 ml of N-methylpyrrolidine, and heated at 100 ° C for 2 days. The reaction solution was treated in the same manner as in Example 13 to obtain 56 mg of a colorless solid (yield: 40.5%).
  • IR (f ilm) ci _1 3350, 2920, 2850, 2700, 2620, 1710, 1660,
  • Example 108 108 mg (0.2 mmol) of the thiazole compound obtained in 38, dimethyl Luminopyridine (122 mg, 1.0 millimol) and acetic anhydride (102 mg, 1.0 millimol) were dissolved in toluene (0.5 oil) and ripened at 80 ° C for 4 hours.
  • the reaction mixture was concentrated to dryness under reduced pressure, and the residue was subjected to silylation gel (3 g) [eluate, porcine form, methanol (39: D), and silica gel (3 g) [eluate , ⁇ -hexane, ethyl acetate (1: 1)] to give 11 Omg of a colorless solid (yield 78.1%).
  • IR (film) cnT 1 3350, 2930, 2850, 1745, 1715, 1525, 1470,
  • Example t38 100 mg (0.18 ⁇ millimol) of the thiazole derivative obtained in Example t38 was dissolved in 1.5 ml of methyl iodide and ripened at 70 ° C for 8 hours. The reaction solution was concentrated to dryness under intimidation to obtain 124 mg (yield: 100%) of a pale yellow solid.
  • Example 13 39 100 mg (0.185 mmol) of the acetate obtained in Example 13 39 was dissolved in 0.5 ml of methyl iodide and heated at 50 ° C for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel (2 g) [eluent, CHCl 3 , MeOH, H 20 (65: 25: 4)] to give a pale yellow powder. 16 mg (100% yield) was obtained.
  • Example 13 39 117 mg (0.2 millimoles) of the acetate obtained in Example 13 39 was dissolved in 1.0 ml of pill having an iodide and heated at 90 ° C. for 5 hours.
  • the reaction mixture concentrated Chijimiinui solidified under ⁇ , the residue silica force gel (2 g) [eluent CHC1 3 - CHCl 3, MeOH. (19: l)]
  • IR (f ilm) cm _1 3340, 2925, 2855, 1755, 1700, 1535, 1470,
  • Example 1 46 2 mg (0.3 mmol) of the thiazole compound obtained in 46, dimethylaminopyridine 244 mg (2.0 mmol), acetic anhydride 204 mg (2.0 mol) (Millimol) in 1.Oml of toluene. C, heated overnight. The reaction mixture was concentrated to dryness under intimidation and the residue was subjected to silylation gel (2 g) [eluate, chromium ⁇ -form], followed by silyri gel (2 g) [eluate, ⁇ -hexane, ethyl acetate (1: 1)] to give 84 mg of a colorless solid (yield 48.0%).
  • Example 14 4.5 mg of the acetate obtained in 47 was dissolved in 0.5 ml of methyl iodide and heated at 60 ° C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel (0.5 g) [eluent, CHCl 3 , MeOH (65:25)] to give 85 mg to a pale yellow powder. Obtained.
  • Example 1447 The acetate (79. ⁇ mgCO.136 millimol) obtained in Example 1447 was dissolved in 1.0 mL of thiol chill, and the mixture was ripened overnight for 90. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel (1.7 g) [eluent, CHCl 3 ⁇ CHCl 3 , MeOH (l 9: 1)] to give a pale yellow solid. mg (43.7% yield).
  • IR (fUm) cm- 1 3350, 2925, 2855, 1750, 1705, 1525, 1465,
  • reaction solution was concentrated to dryness under reduced pressure, and the residue was purified with silica gel (5 g) [eluent, ⁇ -hexane, ethyl diethyl ester (1)] to obtain 34.5 mg of a pale yellow powder (yield) 73.6%).
  • Example 150 100 mg (0.18 mmol) of the thiazole derivative obtained in 50 was dissolved in 1.5 ml of methyl iodide and heated at 70 C for 8 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain 128 mg (yield: 100%) of a pale yellow solid.
  • Example 150 190 mg (0.341 mmol) of the thiazole obtained in 50, 244 mg (2.0 mmol) of dimethylaminopyridine, 204 mg (2 (1.0 mmol) was dissolved in 1 ml of toluene, heated to 100, and heated for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was subjected to silylation gel (2 g) [eluent, chloroform.methanol (39: 1)]. —Hexane, ethyl acetate (1: 1)] to give 20 mg of a colorless oil (9.8% yield).
  • Example 152 20 mg (0.033 mimol) of the acetate obtained in Example 152 was dissolved in 1 mU of methyl iodide and left at room temperature for 16 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain 25 mg of the desired product (yield: 100%).
  • IR (KBr) cm _1 3330, 2920, 2850, 1730, 1700, 1520, 1470, 1370, 1325, 1270, 1250, 1200, 1150, 1100, 1060, 1040, 975, 920
  • Example 156 1.80 g of the N-methyl compound obtained in Example 154 was dissolved in 20 ml of ether, and 2.86 g of methyl iodide was added thereto, followed by stirring at room temperature for 20 hours. The reaction solution was concentrated to dryness to obtain 2.26 g of the target compound as a colorless powder.
  • Exchange Example 156 1.80 g of the N-methyl compound obtained in Example 154 was dissolved in 20 ml of ether, and 2.86 g of methyl iodide was added thereto, followed by stirring at room temperature for 20 hours. The reaction solution was concentrated to dryness to obtain 2.26 g of the target compound as a colorless powder.
  • Example 15 Iodide 2. Og obtained in 55 was ion-exchanged with an Amberlite IRA-410 (C) ion exchange resin to obtain chloride. Further purification was carried out by silica gel chromatography (eluent: liquid form: mouth-methanol / water 65: 25: 4) to obtain 1.57 g of the target compound as a colorless powder.
  • Example 15 18 mg of the compound obtained in 59 was dissolved in 5 ml of ether, 0.2 ml of methyl iodide was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated to dryness to obtain the desired compound (146 mg). Light brown powder.
  • Example 160 14 ⁇ mg of the iodide obtained in Example 160 was subjected to ion exchange using an Amberlite IRA-410 ion exchange resin (CI type 1) to obtain 120 mg of chloride. Light brown solid ⁇ .
  • Amberlite IRA-410 ion exchange resin CI type 1
  • 1-octadecylcarbamoyl-2-methylglycerin 2.4 1 g 0.96 ml of diglycol methane solution and triethylamine were added dropwise to 15 ml of dichloromethane in which 0.833 ml of diphosgene was dissolved under ice-cooling. After stirring at room temperature for 40 minutes, the reaction solution was concentrated to dryness under reduced pressure to obtain a crude ester carbonate product.
  • Example 16 1.24 g of the benzyl derivative obtained in 63 was dissolved in a mixture of 14 ml of acetic acid, 4 ml of water and 2 nd of ethanol, and a hydrogen stream was flown using palladium carbon as a catalyst. Medium and catalytic reduction was performed. After the catalyst was filtered off, the filtrate was concentrated to dryness, and the residue was recrystallized from n-hexane to obtain 1.1 Og of the target compound as a colorless powder.
  • I RC Br.cm -1 3330, 2930, 2855, 1745, 1700, 1550, 1540, 1475, 1265, 1080, 790, 730
  • Example 1 To 18.4 mg (4 Xl0 mole) of alcohol 2 obtained in 64, 18.3 mg (9.6 x 10-mole) of tosyl chloride, 0.13 ml of triethylamine (9.6 xl (T * mole) and stirred for 3 days at room temperature.Then the reaction solution was mixed with chloroform and washed with water and aqueous sodium hydrogen carbonate, dried, concentrated and purified by silica gel chromatography. : N-hexane-ethyl acetate
  • Example 1 67 46 mg of the methyl ester obtained in Example 1 67 was added with 2 mU of tetrahydrofuran, and 0.2 ml of concentrated hydrochloric acid was added thereto, followed by stirring at room temperature for 4 hours. After the reaction solution was neutralized with sodium bicarbonate, the solvent was distilled off, the residue was purified by silica gel chromatography, and the residue was reprecipitated from formaldehyde-acetone to give 10 mg of the desired product. Obtained.
  • the resultant was dissolved in 1 and 2.35 ml (2.9.4 millimoles) of acetic anhydride was added, followed by heating at 110 C for 60 hours in a nitrogen stream.
  • the reaction solution was concentrated to dryness, and a 5% aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted with a stoichiometric solution.
  • the organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure.
  • step 2 To the compound synthesized in step 2) (365 mg CO.70 millimol) was added 3 ml of thiol iodide, and the mixture was heated to reflux in a nitrogen stream for 2 days under light shielding. After cooling, the reaction solution was concentrated to dryness, and the obtained iodide salt was washed with IRA-410 (Cr) [30 ml; eluent: 7

Abstract

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

Description

明 加 脂 体  Light fat body
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 a novel lipid derivative useful as a medicine
背景技術 Background art
P A F [P latelet A ct ivat i ng 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 AF [P latelet Activating Factor] has a phospholipid structure and is a chemical messenger present in vivo. 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 ック症伏を呈し、 死に至ることもある。 P A Fによるショッ クはェンドトキシンによるショック症伏に似ており、エンドトキシンショ 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 an animal, these effects combine to cause the animal to exhibit shock shock and even death. The shock caused by PAF resembles shock caused by endotoxin, and it is thought 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 する指質誘導体は、 これらの結合を切断する酵素が特にがん钿胞では不 足しているため、 がん:钿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 thought to be involved at the stage of implantation of cancer cells. In addition, finger derivatives having an ether bond or a viruvayl bond have Enzymes that break the bond are inadequate, especially in cancer cells, so they can easily accumulate in cells, alter lipid metabolism in cancer cells, and cause cancer cells to die. Have.
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 The present inventors have a PAF inhibitory effect, and have various circulatory disorders,
-性疾患の予防♦治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、 慶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。 -Prevention of sexual diseases ♦ As a result of intensive search for a lipid derivative useful as a therapeutic agent and an antitumor agent, we succeeded in producing a lipid derivative having an excellent effect and completed the present invention.
発明の開示 Disclosure of the invention
本発明は式  The present invention uses the formula
差換え C H 2 0 R 1 Replacement CH 2 0 R 1
C H R 2 ( I )CHR 2 (I)
C H 2 X - C - Y一 R 3— Z— R + CH 2 X-C-Y-R 3 — Z— R +
II  II
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ァミノまたは環状 ァミノを示し、 R 3は結合手または置換されていてもよいアルキレンを、[In the formula, R 1 represents alkyl or alkyl rubamoyl, R 2 represents hydrogen, optionally substituted hydroxy, optionally substituted amino or cyclic amino, and R 3 represents a bond or substituted. Alkylene which may be
R +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 0R + represents hydrogen, alkyl or aralkyl, and X and Y each represent 0
(酸素原子）， S (硫黄原子）または置換されていてもよいィミノ基を示し、(Oxygen atom), S (sulfur atom) or an imino group which may be substituted,
Yがィミノ基である場合、 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イミノまたは含窒素 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。 When Y is an imino group, Y may form a ring with the imino group represented by X or R + and Z represents an optionally substituted imino or nitrogen-containing heterocyclic ring. Lipid derivatives and salts thereof.
上記式（ I )に関し、 R 1で示されるアルキル基としては直鎖伏もしく は分枝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 オクタデシル， 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， テトラコサニル,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， トリアコンタニル，フアルネシ一ル，ジヒ ドロ フイチルなど炭素数 i 0 ~ 30程度のアルキル基があげられ、 なかでも炭素 数 14〜20のアルキル基が好ましく、 炭素数 14〜18のアルキル基がより好 ましく、 炭素数 15〜18のアルキル基がさらに好ましく、 炭素数 16〜18の アルキル基が最も好ましい。 また、 R 1がアルキル力ルバモイル基を示 す場合には、 R 1は式 In the above formula (I), the alkyl group represented by R 1 may be either straight-chain or branched, such as decyl ,,, decinyl, tridecyl, tetradecyl pentadecyl, hexadecyl, heptadecyl octadecyl, nonadecyl, eicosanyl Alkyl groups having about 0 to 30 carbon atoms, such as, henicosanyl, docosanil, tricosanil, tetracosanyl, pentacosanyl, hexacosanyl, heptacosanyl, octacosanyl, nonacosanyl, triacontanyl, pharmanesyl, dihydrophytyl and the like. However, an alkyl group having 14 to 20 carbon atoms is preferable, an alkyl group having 14 to 18 carbon atoms is more preferable, an alkyl group having 15 to 18 carbon atoms is more preferable, and an alkyl group having 16 to 18 carbon atoms is most preferable. When R 1 represents an alkyl group, the R 1 is a group represented by the formula
R 5 H C 0 - ( E ) として表わすことができ、 式（H )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 アルキル力ルバモイル基のアルキル基が炭素数 14〜 20のアルキル基であ R 5 HC 0-(E). In the formula (H), R 5 can be an alkyl group having about 10 to 30 carbon atoms, similar to the alkyl group of R 1 described above. In particular, the alkyl group of the alkyl group is an alkyl group having 14 to 20 carbon atoms.
差換え Replacement
2i l 5 o 一 3 - る ものが好ま し く、 炭素数 14〜18のアルキル基であるものがより好まし く、炭素数 15~ 18のアルキル基である ものがさ らに好ま しく、炭素数 16〜 18のアルキル基である ものが最も好ましい。 2i l 5 o 1-is preferably an alkyl group having 14 to 18 carbon atoms, more preferably an alkyl group having 15 to 18 carbon atoms, and still more preferably an alkyl group having 15 to 18 carbon atoms. Most preferred are those having 16 to 18 alkyl groups.
R 2で示される g換されていてもよいヒ ドロキン基としては、 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
Figure imgf000005_0001
Examples of the optionally substituted hydroxy group represented by R 2 include, for example, hydroxy, alkoxy, aralkyloxy, acyloxy or the formula
Figure imgf000005_0001
[式中、 Wは酸素原子または硫黄原子を示し、 R Sおよび R 7はそれぞれ 水素またはアルキルも示すか、 または両者が隣接する窒素原子とと もに 0 [Wherein, W represents an oxygen atom or a sulfur atom, and RS and R 7 also represent hydrogen or alkyl, respectively, or both represent 0 with an adjacent nitrogen atom.
環を形成する]で表わされる基などがあげられる。  Which forms a ring].
R 2で示されるアルコキシ基としては炭素数 1〜5程度の低級アルコキ シ基があげられ、 たとえばメ トキシ，エ トキシ，プロボキシ，イソプロボ 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。 Examples of the alkoxy group represented by R 2 include lower alkoxy groups having about 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoquine, butoxy, isobutoxy, and pentoxy.
R 2で示されるァラルキルォキシ基としてはフエニル—低級（C 5 ) 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， α —メチルベンジルォキン， α—メチルフエネチルォキシ， 5—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-lower (C 5 ) alkoxy, such as benzyloxy, phenethyloxy, α-methylbenzyloxy, α-methylphenethyloxy, and 5-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 チルォキン，プロピオニルォキン，プチリルォキシ，ィソプチリルォキシ， バレリルォキシ，イソパレリルォキシなどの炭素数 1〜5程度の低級アル カノ 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 ポキシォキシ，低級（ C !- 5)アルコキシ力ルボニルォキシ（メ トキシカル ボニルォキシ，ェトキシカルボニルォキシ，プロポキシカルボニルォキシ， 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 a lower alkanoyloxy group having about 1 to 5 carbon atoms, such as formyloxy, acetyloquine, propionyloquine, petyryloxy, isoptyryloxy, valeryloxy, and isopareryloxy. , Benzoiruokishi, phenoxyethanol carbonyl O carboxymethyl, Cal Pokishiokishi, lower (C -! 5) alkoxy force Ruboniruokishi (main Tokishikaru Boniruokishi, E butoxycarbonyl O carboxymethyl, propoxycarbonyl O alkoxy, butoxycarbonyl O carboxymethyl) is Ashiruokishi groups such like Can be
25 twenty five
式（ )に関して、 R s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，プチル，ィソプチル，ペンチル などの炭素数 1〜 5程度の低級アルキル基があげられる。 R 8および R 7が 隣接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、 たとえば丄—アジリジニル， 1—ァゼチジニル，] _一 ピ σリジニル，ピペリ ジノ， 1一パーヒ 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，丄一パ一ヒ ドロジァゼピニル， 4—パーヒ ド' 口才キサゼピニル， 4一パーヒ ドロチアゼピニルなどがあげられる。 Regarding the formula (), examples of the alkyl group represented by R s or R 7 include: Examples thereof include lower alkyl groups having about 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, and pentyl. Examples of the ring constituted by R 8 and R 7 together with the adjacent nitrogen atom include, in addition to the nitrogen atom, a 3- to 7-membered heterocyclic ring which may have a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom. For example, 丄 -aziridinyl, 1-azetidinyl,] _-pi-σ-ridinyl, piperidino, 1-perhydro-droazepinyl, 1-piperazinyl, morpholino, thiomorpholino, 1-hydroxyl-drosazepinyl, 4-perhydrodoxazepinyl , 41-perhydrothiazepinyl and the like.
R 2で示される置換されていてもよいアミノ としてはたとえばァミ ノ， ァシルアミノなどがあげられる。 Examples of the optionally substituted amino represented by R 2 include, for example, amino, acylamino and the like.
R 2で示されるアンルァミノ基としてはたとえばホルムアミ ド，ァセト アミ ド，ブ σ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，イソバレルアミ ドなどの炭素数 ί〜5程度の低級アルカノィルアミ 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 amino group represented by R 2 include lower alkanol amino groups having about 5 to about 5 carbon atoms, such as formamide, acetate amide, bu pionamide, butane amide, isobutanamide dolamide, and isovaleramide. And acylamino groups such as nzylamino.
R 2で示される環状ァミノとしてはたとえば卜ァジリジニル，1ーァゼ チジニル， 1—ピ σリ ジニル.ピペリ ジノ ， 1 -ぺ一ヒ ドロアゼピニル， 1 -ピ ベラジニル，モルホリノ ，チオモルホリ ノ ， 1—パーヒ ドロジァゼピニル， 4 —パーヒ ドロォキサゼピニル， 4 -パ一ヒ ドロチアゼピニルなどの 3ないし 7員の単環式複素環，たとえば 2—イソィン ドリ二ルなどの炭素数 8〜 9程 度の縮合環があげられる。 該単環式複素環および縮合環-':ま置換可能な位 置に、 たとえばォキソなどの置換基を有していてもよく、 置換された単 環式複素環および綰合環としてはたとえば 2 , 5—ジォキソピロリ ジ二ル， 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 triaziridinyl, 1-azetidinyl, 1-pi-σ-ridinyl.piperidino, 1- ぺ -hydroazepinyl, 1-piverazinyl, morpholino, thiomorpholino, 1-perhydrodiazepinyl, 4 —A 3- to 7-membered monocyclic heterocyclic ring such as perhydroxoxazepinyl and 4-hydroxythiazepinyl, for example, a fused ring having about 8 to 9 carbon atoms such as 2-isoindolinidyl. The monocyclic heterocyclic ring and the condensed ring-'may have a substituent such as oxo at a substitutable position. Examples of the substituted monocyclic heterocyclic ring and unsubstituted ring include 2 , 5-dioxopyrrolidinyl, 1,3-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伏もしくは分技状の炭素数 1 ~ 8程度のアルキレン鎮があげられ、 たとえばメチレン，エチレン， ト リ 1 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、該アルキレン鑌':またとえば低級（CExamples of the alkylene chain represented by R 3 include straight-chain or branched alkylene chains having about 1 to 8 carbon atoms, such as methylene, ethylene, and trialkylene. 1 Methylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and the like, and the alkylene 鑌 ':
! -+)アルコキシカルボニル [例、 メ トキシカルボニル，エトキンカルボ二 ル] ,カルボキシラー トなどで置換されていてもよく、該置換基は基 Zと ό 結合する基 R 3中の炭素原子の隣接位に結合している場合が望ましい。 ! - +) alkoxycarbonyl [e.g., main butoxycarbonyl, Etokinkarubo two Le], may be substituted with such carboxylase DOO, the substituent adjacent position to a carbon atom in the radicals R 3 to the bonding group Z and ό It is desirable to be connected to.
なかでも R 3としては好ま しく はメチレン，ェチレン， ト リメチレンがぁ げられ、 より好まし く はメチレンまたはェチレンがあげられる。 Among them, R 3 is preferably methylene, ethylene or trimethylene, and more preferably methylene or ethylene.
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，ィソブチル， sec—ブチル， t ert—ブチル，ペンチル， 0 へキシルなどの炭素数 1 ~ 6程度の低級アルキル基があげ れる。 Methyl example, the alkyl group represented by R 4, Echiru, propyl, isopropyl, butyl, Isobuchiru, sec- butyl, t Ert- butyl, pentyl, exemplified by lower alkyl groups having about 1 to 6 carbon atoms such as hexyl 0 It is.
R +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， フエ二ルブロピル，フエニルブチル， α —メチルフエネチル， ^ 一メチル フエネチルなどのフエ二ルー低級（C 1 - 8 )アルキル基があげられる。 The aralkyl group represented by R + includes, for example, phenyl lower (C 1-8 ) alkyl groups such as benzyl, phenethyl, phenylpropyl, phenylbutyl, α-methylphenethyl and ^ -methylphenethyl.
Xが置換されていてもよいイ ミ ノ基である場合、 Xとして：またとえば When X is an optionally substituted imino group, as X:
L 5 式 L 5 formula
一 X一  One X one
(IV' )  (IV ')
R 8 R 8
：式中、 R 8は水素，置換されていて 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 rubamoyl].
20 上記式（ )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 ピル，プチル，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、 該アルキル基は、 たとえばカルボキシル， ig級（C t - 5)アル キルカルボ二ル（例、 メ トキシカルボニル，エトキンカルボニル，プロボ キンカルボニル，ブトキシカルボニル，ベン トキシカルボニル）などで置20 In the above formula (), examples of the alkyl group represented by R 8 include an alkyl group having about 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl and the like. , ig class (C t - 5) Al Kirukarubo alkenyl (e.g., main butoxycarbonyl, ethoxy Kin carbonyl, Provo Kin, butoxycarbonyl, ben butoxycarbonyl) or the like location
25 換されていてもよい。 25 may have been replaced.
R 8で示されるァシル基としてはたとえば、 炭素数 1~ 5程度の低級ァ ルカノ ィル（例、 ホルミル，ァセチル，プロピオニル，プチリル，イソプチ リ ルノくレリゾレ，イソバレリル），ベンゾィル，フエノキシカルボニル，カル ボキシル，眩級（C卜 5 )アルコキシカルボニル（冽、 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 lower aliphatic groups having about 1 to 5 carbon atoms. Rukano I le (eg, formyl, Asechiru, propionyl, Puchiriru, Isopuchi Li Runoku Rerizore, isovaleryl), Benzoiru, phenoxyethanol carbonyl, Cal Bokishiru, glare class (C Bok 5) alkoxycarbonyl (Kiyoshi, main butoxycarbonyl, ethoxycarbonyl Carbonyl, 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 ば、 力ルバモイル，眩級（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 ィル）， ジ—低級（C 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 ，ジェチルカルバモイル ，メチルブ 口ピル力ルバモイル）， 3~ 7員環状ァミノ [例、 （ァジリ ジン一 ィル）力 ルボニル，（ァゼチジン— 1—ィル）カルボニル，（ピロ リ ジン— 1 -ィル）力 ルポニル，ピぺリ ジノ力ルボニル，（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 力ルボニル，チオモル ホリ ノ 力ルボニル]などがあげられる。 Examples of the optionally substituted carbamoyl group represented by R 8 include carbamoyl, glazed (C 5 ) alkyl levamoyl (eg, methylcarbamoyl, ethyl carbamoyl, propyl carbamoyl, butylcarbamoyl), Di-lower (C 5 ) alkyl rubamoyl (eg, dimethylcarbamoyl, methylethylcarbamoyl, getylcarbamoyl, methylbutyryl rubamoyl), 3- to 7-membered cyclic amino (eg, (aziridinyl)) Rubonyl, (azetidine-1-yl) carbonyl, (pyrrolidin-1-yl) power Luponyl, pyridino-force carbonyl, (perhydrazazepine-1-yl) carbonyl, (piperazine-1-yl) Le) carbonyl, morpholino-carbonyl, thiomorpholino-carbonyl, and the like.
Yが置換されていてもよいィ 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,
- X一  -X
( V )  (V)
R 9 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。 And the group represented by 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 3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レ 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 3 may be the same or different, and _R 8 and R 3 are linked to form alkenylene or alkylene May be.
R 8および R 9が連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 1〜4程度の低級アルケニレン，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 o ί 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、Alkenylene formed by linking R 8 and R 9 ; alkylene bridges include, for example, methylene, ethylene, trimethylene, tetramethylene, vinylene And lower alkylene having about 1 to 4 carbon atoms such as propenylene and alkylene bridges, and may have a substituent such as oxo at a substitutable position and may have o. As the substituted alkylene and alkenylene, for example,
1 -ォキソエチレン， 3 -ォキソプロべ二レン， 1 , 2—ジォキソエチレンなど があげられる。 具体的には式 Examples include 1-oxoethylene, 3-oxoprobenylene, and 1,2-dioxoethylene. Specifically, the expression
- X - C - Y - 0  -X-C-Y-0
として表わされる基として、 As a group represented as
Figure imgf000009_0001
Figure imgf000009_0001
どがあげられる。  Throw.
Yがィ ミ ノ基である場合、 R 3および R +は連锆してアルケニレン，ァ レキレンを形成してもよく、 R 3および R +が連结して形成するァルケ二 レ ン，アルキレン撟と して：またとえば、 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，ブ σベニレンなどの炭素数 1〜4程度の低 級ァルケ二レン，アルキレン撟があげられ、 これらの基は置換可能な位 置に、 たとえばォキソなどの g換基を有していてもよい。 置換されたァ ルキレン，アルケニレンとしてはたとえば、 レオキソエチレン， 3 -ォキソ ブ σベニレン，し 2—ジォキソェチレンなどがあげられる。 具体的には式 一 Y _ R 3 - Ζ - R + If a Y Gai Mi amino group, R 3 and R + is Ren锆to alkenylene, it may form a § Rekiren, Aruke two Le emissions which R 3 and R + is formed by communicating Yui, alkylene撟Examples include: lower alkylene having 1 to 4 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, vinylene, and σ-benylene, and alkylene. It may have a g-substituent such as oxo at a possible position. Examples of the substituted alkylene and alkenylene include reoxoethylene, 3-oxo sigma-benylene, and 2-dioxoethylene. Specifically, the formula Y _ R 3 -Ζ-R +
として表わされる基として、 As a group represented as
¾換 ∑ Exchange ∑
: :
Figure imgf000010_0001
Figure imgf000010_0001
などがあげられる。 And so on.
としては〇が好ま しい。  〇 is preferred.
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 ノ基がより好まし く、 低級アルキルカルボニルで置換されたィ ミ ノ基 がさらに好ま しい。  As Y, an optionally substituted imino group is preferable, a substituted imino group is more preferable, and an imino group substituted with lower alkylcarbonyl is more preferable.
Zで示される置換されていてもよいイ ミ ノ基としてはたとえば、 イ ミ ノ基，低級（ C L - +)アルコキシ力ルボニルで置換されていてもよい炭素数 L〜6程度の低級アルキル基で g換されたイ ミ ノ基（例、 メチルイ ミ ノ ，ェ チルイ ミ ノ ，プロピルイ ミ ノ ，イソプ σピルイ ミ ノ ，プチルイ ミ ノ ，ィソブ チルイ ミ ノ ，sec—プチルイ ミ ノ ，t ert—プチルイ ミ ノ ，ペンチルイ ミ ノ ， へキシルイ ミ ノ ，ェトキシカルボニルメチルイ ミ ノ），フエニル—低級（C t - 8 )アルキルなどのァラルキル基で置換されたィ ミ ノ基（ 、 ベンジル ィ ミ ノ ，フエネチルイ ミ ノ ，フエニルプ σピルイ ミ ノ ，フエ二ルブチルイ ミ ノ ，（ —メチルフエネチル）ィ ミ ノ ，（,S —メチルフエネチル）ィ ミ ノ） があげられる。 また、 Zで示されるイ ミ ノ基は 4級化されてイ ミ ニォ基 を形成してもよく、 該ィ ミニォ基は低級（C t -Jアルコキシカルボニル もしく ：まカルボキンラー トで置換されていて &よい炭素数 1〜 6程度の低 級アルキル基，ァラルキル基 [例、 フエ二ルー低級（ C t - s )アルキル]で置 換されていてもよい。 該置換イ ミニォ基として:またとえば、 ジメチルイ ミニォ，メチルェチルイ ミニォ，メチルプ σピルィ ミニォ，メチルブチル イ ミニォ，メチルベンチルイ ミニォ，メチルへキシルイ ミニォ，ジェチル ィ ミニォ，ェチルプロピルィ ミニォ，ェチルブチルイ ミニォ，ェチルベン Examples of the optionally substituted imino group represented by Z include an imino group and a lower alkyl group having about L to 6 carbon atoms which may be substituted with a lower (CL − + ) alkoxycarbonyl. g-substituted imino groups (eg, methyl imino, ethyl imino, propyl imino, isop sigma pilimino, butyl imino, isobbutyl imino, sec-butyl imino, tert-butyl imino Imino groups substituted with an aralkyl group such as phenyl, pentylimino, heximimino, ethoxycarbonylmethylimino), phenyl-lower (Ct-8) alkyl (benzylimino, phenethylimino) Mino, phenylp sigma pyrimino, phenylbutylimino, (—methylphenethyl) imino, (, S—methylphenethyl) imino). Further, the imino group represented by Z may be quaternized to form an imino group, and the imimino group may be substituted with a lower (C t -J alkoxycarbonyl) or carboquinate. Te & good carbon number 1-6 about lower alkyl group, Ararukiru group [e.g., phenylene Lou lower (C t - s) alkyl] in may be substitution for the substituent Lee Minio group:. Matatoeba , Dimethyliminio, Methylethyliminio, Methylp σpylyminio, Methylbutyliminio, Methylbenguiluminio, Methylhexylinominio, Jethyriminio, Ethylpropylyminio, Echitylbutyrimino, Ethilben
差換え チルイ ミ ニォ，ェチルへキシルイ ミニォ，ジプロピルィ ミ ニォ，プロピル プチルイ ミニォ，プロピルペンチルイ ミニォ，プロピルへキシルイ ミニォ， ジブチルイ ミ ニォ，プチルぺンチルイ ミニォ，プチルへキシルイ ミニォ， ジペンチルイ ミニォ，ペンチ レへキシルイ ミニォ，ジへキシルイ 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， X—エトキシカルボニルメチル— —メチル ィ ミ ニォ， N—力ルポキシラー トメチル _ N—メチルイ ミニォなどがあ げられる。 なかでも Zがジメチルイ ミニォであり、 R +がメチルである 場合が好ま しい。 Replacement Chiliminio, ethylheximini, dipropylimino, propyl petitimini, propylpentyliminio, propylheximini, dibutylimimino, butylpentilymini, butylheximini, dipentyliminio, pentyliximinio, Dihexyliminio, benzylmethyliminio, dibenzyliminino, phenethylmethyliminio, diphenethyliminio, X-ethoxycarbonylmethyl-—methyliminio, N-methyloxypropylmethyl-N-methyliminio can give. Among them, it is preferred that Z is dimethyliminio and R + 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':ま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 式葰素環があげられる。 該複素環は飽和したもの、 部分飽和した .の、 あ'るいは複素芳香環のような最 ί氐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，ピベリ ジニル，パーヒ ドロアゼピ 二^ ,ピ リニル，ビラゾリニル .ピ リル，ピリ ジル，ォキサゾリ ル.チゾ リ ル ,ピリ ダジニル，ピリ ミ ジル，ピラジニル，ィ ミ ダゾリ ル，モルホリニ ル チォモ 'レホリニ/レ，ピぺラジニ^ ,ビラゾリ ジニル，イン ドリル，ィソ イン ドリ ノレ， 1 Η—イ ンダゾリル，プリニル，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，パーヒ ドロイ ン ド リル，ぺ―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：ま 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 く、 チアゾリ ルまたはピリ ジルが最も好ま しい。 これらの基は置換可 能な位置に低級（C + )アルキル基（冽、 メチル，ェチル，プロピル，プチ ル），ヒ ドロキン基，ァミ ノ （ィ ミ ノ）基，モノ もしく はジ低級（C +：)アル キルァミ ノ （例、 メチルアミ ノ ，ジメチルアミ ノ），力ルバモイル基，ゥレ 差換え ィ ド基，ヒ ド σキシもしくはアミノ基で置換された低級（C L -4 )アルキル 基（例、 ヒ ドロキシェチル，アミ ノエチル），カルボキシル，カルボキシラ ― ト，低級（ C 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 Ν—メチル乇ルホリニル， Ν— ' メチルビペリ ジニル，Ν—メチルピペラジニル，Ν—メチルビ σリジニル， Ν—ェチルピロリジニル，Ν—ェトキシカルボニルメチルピリジニォな どの基があげられる。 Examples of the nitrogen-containing heterocyclic ring represented by Z include a heterocyclic ring containing at least one nitrogen atom. For example, in addition to the nitrogen atom, a nitrogen atom, an oxygen atom or ': A monocyclic or bicyclic heterocyclic ring which may be contained as a ring-constituting atom is exemplified. The heterocyclic ring may be saturated, partially saturated, or a fully hydrogenated heterocyclic ring such as a heteroaromatic ring, for example, azetidinyl, pyrrolidinyl, piberidinyl, perhydridyl. Droazepinii, pyrinyl, virazolinyl. Pyril, pyridyl, oxazolyl. Tizoril, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, morpholinyl tiomo 'refolini / re, pirazini ^, Virazolidinyl, indolyl, isoindolinole, 1-indazolyl, purinyl, isoindrillyl, quinolinyl, isoquinolinyl, 1,2.3,4-tetrahydroquinolinyl, perhydrindolyl, Examples include groups such as ぺ -hydroisoquinolinyl. Among them, in the case of a monocyclic heterocycle: a 4- to 7-membered ring is preferred, and a 5- or 6-membered ring is preferred. Most preferred arbitrariness is rather, thiazol Le or pyridyl which favored. These groups may be substituted at a substitutable position with a lower (C + ) alkyl group (clear, methyl, ethyl, propyl, and butyl), a hydroquinone group, an amino (imino) group, a mono- or di-lower group. (C + :) alkylamino (eg, methylamino, dimethylamino), rubamoyl group, permutation A lower (CL-4) alkyl group (eg, hydroxyxethyl, aminoethyl), carboxyl, carboxylate, lower (C alkoxycarbonyl (eg, methoxy) Carbonyl) and the like; for example, Ν-methylperforinyl, Ν-'methylbiperidinyl, Ν-methylpiperazinyl, Ν-methylbi-siglidinyl, Ν-ethylpyrrolidinyl, Ν- And groups such as ethoxycarbonylmethylpyridinio.
該含窒素複素環における窒素原子は R +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—ェチ ルピリジニォ， Ν—プロピルピリジニォ， Ν—ブチルピリジニォ， Ν—メ チル— —ェチルピ口リジニォ， 3—メチルチアゾリオ， 3—ェチルチア ゾリオ， 3—プロピルチアゾリオ， 3—プチルチアゾリォなどの基があげ 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— 3—ィル.チアゾリオ— 3 -ィル，ピリダ ジニルオー 1 —ィル，ピリ ミ ジニォ一 1—ィル，ビラジニォ一 1一ィル，キ ノ リニォー 1—ィル，イソキノ リニォ一 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—メチルピペラジニォ— i一ィル， 1 -メチルビロリ ジニォー丄-ィル， 1一ェチルピロリジニォー i一 . ィル. 3—メチルチアゾリオ一 2 —ィル， 1 -メチルイミダゾリオ— 1—ィル， 3—カルボキシラ一 トピリジニォ一 1一ィル， 3—メ トキシカルボニルピ リ ジニォ一 1—ィル， 4—ジメチルアミノ ピリ ジニォ一 1—ィルなどの基 があげられる。 The nitrogen atom in the nitrogen-containing heterocyclic ring may be quaternized by R + , for example, Ν, Ν-dimethylpyrrolidinio, Ν-methylpyridinio, Ν-ethylpyridinio, Ν-propylpyridinio , Ν-butylpyridinio, Ν-methyl- ェ ethylpyridino, 3-methylthiazolio, 3-ethylthiazolio, 3-propylthiazolio, 3-butylthiazolio, and the like. Further, the nitrogen atom may be quaternized by bonding to R 3. Examples of the heterocyclic ring containing a quaternized nitrogen atom include, for example, pyridinio-1-yl, oxazolio-3 —Yl.thiazolio— 3-yl, pyridazinyl-1-yl, pyridimidin-1-yl, virazin-1-yl, quinolinio-1-yl, isoquinolinolin-1-2-yl, 4-Methylmorpholinio-1-yl, 1-methylbiperidinyl-1-yl, 1-methylpiperazinio-i-yl, 1-methylbirolidine di-n-yl, 1-ethylpyrroli 3-Dimethylthiazolio-1 2-yl, 1-methylimidazolio-1-yl, 3-carboxyla-topyridinyl-11-yl, 3-methoxycarbonylpyridinio-1 Groups such as 1-yl and 4-dimethylaminopyridinyl-1-yl can give.
また、 R 4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 4 is linked to the imino group represented by Y are specifically the formulas
- Y - R 3 - Z - R + で表わされる基として. -Y-R 3 -Z-R + As a group represented by
H ノ H no
CH 5 CH 5
C! Η 0  C! Η 0
などの基があげられる。 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：ま拮合可能な位置であれば 、ずれでもよ Position of the heterocyclic ring that binds to the R 3: or if拮合possible position, even shift
C  C
t、 [例、 N —メチルピリ ジニォー 2 —ィル， X —メチルピリジニォ— 3 — ィル， N ェチルピリ ジニォ一 2 —ィル， N - I t, [eg, N —Methylpyridinio 2 —yl, X —Methylpyridinio — 3 —yl, N-ethylpyridinio-1 2 —yl, N-I
— 一プチルピリ ジニォ一 2 —ィ ル， N —メ トキシカルボニルメチルピリ ジニォ— 2 —ィル， N —ェチルピ σ リ ジン— 2 —ィル， N —メチルー N —ェチルピロ リ ジニォ一 2 —ィル， X —ェチルビべリ ジン 3 ィル， >：一メチル一 X —ェチルピぺリ ジ二 ォ— 3 —ィル， 3—メチルチアゾリオ 2 —ィル， 3 —ェチルチアゾリオ - 2 一ィル， 3 プロピルチアゾリオ一 2 —ィ ， 3 —プチルチアゾリォ — 2 —ィル， 3—メチルチアゾリオ一 4 ィル， 3 ェチルチアゾリオ 4 —ィル， 3 , 4—ジメチルチアゾリオ一 5—ィル：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。  — 1-Phtylpyridinone 1-2 —yl, N —Methoxycarbonylmethylpyridinio — 2 —yl, N —Ethylpy σ resin —2 —yl, N —Methyl-N —ethylpyridininone 2 —yl, X—Ethylbiberidine 3 yl,>: Monomethyl X—Ethylpyridinyl 3 —yl, 3-Methylthiazolio 2-yl, 3 —Ethylthiazolio-2-yl, 3-propylthiazolio 1 2 — i, 3 — butyl thiazolio — 2 — yl, 3-methylthiazolio 1 -4 yl, 3 ethyl thiazolio 4 — yl, 3, 4-dimethylthiazolio 1 -5-yl: is a nitrogen atom or its adjacent position (Position next to the nitrogen atom) is more preferred.
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:ま、 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，詐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 R 2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 一配位の 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ち 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. When Z has a quaternized nitrogen atom: well, chloride ions, bromide ions, iodine ions; acid anions such as sulfate ions, nitrate ions, phosphate ions, and sulphate ions; A salt may be formed with anion such as an ion, or a salt may be formed in a molecule. The compound (I) may have an asymmetric carbon in the molecule depending on the type of the substituent represented by R 2 , but when two stereoisomers of R—coordination and S coordination exist, 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、 たとえば血栓症，脳卒中（例、 脳出血，脳血拴），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—ショ ッ ク，出血性ショ ッ 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 blood loss), myocardial infarction, angina thrombotic vein Diseases associated with inflammation, glomerulonephritis, shock (eg, endotoxin shock, intravascular coagulation caused by endotoxin, anaphylactic shock, hemorrhagic shock) and allergies (eg, It is useful as a preventive and therapeutic agent for bronchial asthma) and an 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、.そのまま玢末剤として、 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柽ロ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，症伏，投与ルー'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 用する場合に:ま、 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. 0丄〜 20mg/kg体重程度、 好ましくは Q . l〜10mg Zkg体重程度、 さ に好ましくは l~ '2mg_ kg体重程度、 1 日丄〜 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回あたり G . 01〜1. 0 g/kg体'重/ m in . 程度を約 1時間 程度、 1 日 i〜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。 他の非径ロ投与および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。 ショ ック症状が特に重 場 にはその症状に 応じて増量して用いて bよい。  Compound (I) and its salts have excellent properties in both hydrophilicity and lipophilicity and low toxicity. Therefore, they can be used as a powder or as a pharmaceutical composition in a suitable dosage form. It can be safely administered in a targeted or non-perfusion manner. The dosage varies depending on the administration target, target disease, illness, administration route, etc., for example, when used for prevention and treatment of shock in adults: well, administration by intravenous injection In this case, compound (I) or a salt thereof is generally used in a single dose of about 0.02 to 20 mg / kg body weight, preferably Q.l to 10 mg Zkg body weight, and more preferably l to '2 mg_kg body weight. It is convenient to administer about 5 to 5 times a day, preferably about 1 to 3 times. Further, the compound (I) or a salt thereof may be administered at a rate of about G.01 to 1.0 g / kg body weight / min. For about 1 hour, about i to 5 times a day, preferably 1 to 3 times. It can also be administered by multiple infusions. In the case of other non-radial administration and oral administration, the same amount can be administered. If the shock symptoms are particularly severe, the dose may be increased according to the symptoms.
また、 たとえば成人の血栓症に対する予防♦治療のために径ロ投与す る場合、 化合物（ I )またはその塩を 1回量として通常 0. 1~ 20mgZ 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 mgZkg体重程度、 治療を目的とする場合、 1回量 4~ 10mg/ lig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。 In addition, for example, when the drug is administered for the prevention or treatment of thrombosis in adults, the compound (I) or a salt thereof is usually 0.1 to 20 mgZ kg in a single dose. It is convenient to administer severely, about 1 to 5 times a day, preferably about 1 to 3 times a day. More specifically, for the prevention of thrombosis, a single dose of about 0.5 to 4 mg Zkg body weight, and for the purpose of treatment, a single dose of about 4 to 10 mg / lig body weight, 1 to 4 times daily Preferably, it is administered about three times. 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も含む、ものであり、 該組 成物は S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 pharmaceutically acceptable carrier or excipient. The composition is administered orally or parenterally. Provided in a dosage form suitable for
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，フィルムコーテング錠を含む），丸剤，顆粒剤，散 剤，力プセル剤（ソフ トカプセル剤を含む）， 'ン a 'ソプ剤，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陚形剤を含有するものである。 たとえば錠剤用の担体，陚形剤として:ま乳糖，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, specifically tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, forcepsels (soft capsules). ), 'N a' soaps, emulsions, suspending agents and the like. Such a composition is produced by a method known per se, and contains a carrier or a carrier commonly used in the pharmaceutical field. For example, carriers for tablets and pills include lactose, starch, sucrose, magnesium stearate and the like.
非経口投与のための組成物として：ま、 たとえば注射剤.坐剤などがあ ■f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 )またはその塩を通常注射剤に用いら れる無菌の水性 しくは油性液に溶解、 懸'蜀または乳化することによつ て謂製される。 注射用の水溶液としては生理食塩水，ブドウ糖やその他 の浦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， ポリエチレングリコ—ル），非イオン性界面活性剤 [例、ポリソルべ— ト 80 , H C 0 - 50 (po l yoxyethy l ene(50(no l) adduc t of hydrogenat ed cas tor o i 1) ]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  Compositions for parenteral administration include, for example, injections, suppositories, etc. Examples of injections include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, and instillation. Dosage forms such as agents. Such injections are produced 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 liquid usually used for injections. You. Aqueous solutions for injection include physiological saline, isotonic solutions containing glucose and other auxiliaries, and suitable dissolution aids such as alcohol (eg, ethanol), polyalcohols (eg, Propylene glycol, polyethylene glycol), nonionic surfactant [eg, polysorbate 80, HC 0-50 (polyoxyethylene (50 (no l) adduc t of hydrogenat ed cas toroi 1) Oily liquids include sesame oil and soybean oil.
差換え げられ、 溶解捕助剤として安息香酸ベンジル，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ァンプルに充塡され、 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 ることによつて調製される。 Replacement Benzyl benzoate, benzyl alcohol and the like may be used in combination as a dissolution aid. The prepared injection is usually filled in a suitable sample and provided as an 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 base for suppositories 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)(R3と桔合する Z中の原子が窒素原子である場合） A) (when the atom in Z that combines with R 3 is a nitrogen atom)
式  Expression
C H20 R 1 CH 2 0 R 1
C H R 2 CHR 2
· - (VI) ·-(VI)
CH2- X- C-Y-R3-Q1 * CH 2 -X- CYR 3 -Q 1 *
0  0
[式中、 Q t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ァミ ン（ )または含窒素環状化合 物（\1)を反応させて化合物（ I )を得る。 化合物（VI)と（VI)または（ ）と の反応は化合物（VI)に対し、 化合物（W)または（VI)を 1当量ないし大過 剰加え、 ！]〜 ÷ 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，エーテル，ジォキサン，テ トラヒ ド σフランなどがあげられ、 また化合物（VI)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 そ'反応を行ってもよい。 また、 式 Wherein, Q t is easily substituted to group and nitrogen (e.g., chlorine, bromine, C androgenic such as iodine, OTosyl, etc. OMesyl group), and the other symbols the same meaning as defined] compounds I tables in And optionally substituted amine () or nitrogen-containing cyclic compound (\ 1) to obtain compound (I). In the reaction of compound (VI) with (VI) or (), 1 equivalent or a large excess of compound (W) or (VI) is added to compound (VI), and! ] ~ ÷ The reaction can be carried out at 200 ° C in the presence or absence of a solvent. Examples of the solvent include toluene, benzene, ether, dioxane, tetrahydrofuran and the like, and compound (VI) or (VI) itself can be used as the solvent. Under ripening, the reaction may be performed in a sealed tube. Also, the expression
C H20 R CH 2 0 R
C H R 2 CHR 2
(Via)  (Via)
C H2— X C - Y-R3' - CHC H2Ql CH 2 — XC-YR 3 '-CHC H 2 Q l
〇 C 00 R 10 〇 C 00 R 10
[式中、 R 1Qは低級アルキルを、 R3'は結合手またはアルキレンを示し、 他の記号は前記と同意義]で表わされる化合物を自体公知の方法で式 [Wherein, R 1Q represents lower alkyl, R 3 ′ represents a bond or alkylene, and the other symbols are as defined above].
C H20 R 1 CH 2 0 R 1
5Five
Figure imgf000017_0001
Figure imgf000017_0001
[式中、 各記号は前記と同意義]で表わされる化合物（VI b)に導いた後、 化合物（"VI b)と（W )または（VI)を、 化合物（ VI )と（W )または（VI)の反応 に準じて反応させることにより式 ， ' - [Wherein each symbol is as defined above], the compound ("VI b) and (W) or (VI) are replaced with the compound (VI) and (W) or By reacting according to the reaction of (VI), the formula
C H20 R 1 CH 2 0 R 1
I - I-
C H R 2 CHR 2
； (l a)  ; (L a)
CHa- X - C - Y -R3' - CH CH2Z - R + CHa- X-C-Y -R 3 '-CH CH 2 Z-R +
0 C 00 R 10 - 二式中、 各記号は前記と同意義]で表わされる化合物を得ることもできる: B)式 0 C 00 R 10- wherein each symbol is as defined above] can also be obtained:
C H20 R 1 CH 2 0 R 1
C HR2 (IX) C H2 - X C - Q2 C HR 2 (IX) CH 2 -XC-Q 2
〇  〇
[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 HY-R3- Z-R4 (X) [式中、各記号は 記と同じ]で表わされる化合物を反応させて化合物 [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-R 3 -ZR 4 (X) wherein each symbol is the same as above.
[I ]を得る。 （IX)と（X)の反応は、 溶媒の存在下もしくは無溶媒下、 — 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，クロ口ホルムなどを用いる 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 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 η—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（IX)と 反応させてもよい。  Get [I]. The reaction between (IX) and (X) can be carried out in the presence or absence of a solvent at −10 to + 150 ° C. As the solvent, toluene, benzene, ether, dioxane, tetrahydrofuran, chloroform can be used, and a base such as triethylamine or pyridine may be added to promote the reaction. Alternatively, (X) may be reacted with sodium hydride, η-butyllithium, or the like in the above-mentioned solvent, converted into a metal salt, and then reacted with compound (IX).
C)式  C) formula
C H2〇 R 1 CH 2 〇 R 1
CHR2 (XI) C H2X H CHR 2 (XI) CH 2 XH
[式中、 R R2':ま前記と同意義]で表わされる化合物に、 式 -[Wherein, RR 2 ': also as defined above], a compound represented by the formula-
Q3- C- Y-R3- Z-R + Q 3 -C- YR 3 -ZR +
」 ( ) 0  '' () 0
[式中、 G はカルボ二ル基を活性化する基 ヽロゲン（例、 塩素，フエノ キンなど））を示し、 他は前記と同意義]で表わされる化合物を反応させ て化合物 [ ΐ ]を得る。 化合物（XI )と（U)の反応は Β )における化合物（IX) と（X )の反応に準じておこなうことができる。  [Wherein, G represents a group (eg, chlorine, phenoquine, etc.) that activates a carbonyl group, and the others have the same meanings as above.] obtain. The reaction between compound (XI) and (U) can be carried out according to the reaction between compound (IX) and (X) in ii).
D)式  D) Formula
C H20 R 1 CH 2 0 R 1
CHR2 . 一 （xm)CHR 2. One (xm)
C H 2 C = 0 C H 2 C = 0
[式中、 R R2は前記と同じ]で表わされる化合物に、 式（X)で表わされ る化合物も反応させて（ I )(X=M)を得る。 反応は（DOと（X)の反応に The compound represented by the formula (X) is reacted with the compound represented by the formula (wherein RR 2 is as defined above) to obtain (I) (X = M). The reaction is the (DO and (X) reaction
差換え 準じて行うことができる。 Replacement It can be performed according to it.
E)式  E) Formula
0 = C = N- R3- Z -R4 (XIV) [式中、 略号は前記と同じ]で表わされる化合物に、 式（2)で表わされる 化合物を反応させて（ I )(Y==NH)を得る。 反応は（Ώ)と（: )の反応に準 じて行う ことができる。 0 = C = NR 3 -Z -R 4 (XIV) wherein the abbreviations are the same as described above, and the compound represented by the formula (2) is reacted with (I) (Y = = NH). The reaction can be carried out according to the reaction of (Ώ) and (:).
化合物 はたとえば式 H2N— R3— Z— R+(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無触媒あるいは塩 化メチレン，クロ口ホルム，ベンゼン，テ トラヒ ドロフラン， トルエンなど の不活性溶媒中、 一 2 0〜+ 1 2 0てで反応させることにより、 または 式 H 00 C -R3- Z - R+(X VI) [式中、 各記号は前記と同意義]で表わ される化合物に D P PAをクロ口ホルム， トルエン，ベンゼン，ジク σ σ メタ ン，テ トラヒ ドロフ ンなどの溶媒中トリェチルァミ ン， トリブチル ァミ ンなどの三級ァミ ンの存在下、 0〜一 1 5 0 °Cにて反応後、 さらに ピリ ジンなどの三級ァミ ンの存在下、 0〜+ 1 5 0てで反応させること により容易に合成することができる。 The compound is, for example, a compound represented by the formula H 2 N—R 3 —Z—R + (XV), wherein each symbol is as defined above, to which diphosgene has been added in the absence of a catalyst or methylene chloride, chloroform, benzene, In an inert solvent such as tetrahydrofuran or toluene, the reaction is carried out at 120 to +120, or by the formula H 00 C -R 3 -Z -R + (XVI) Is the same as defined above), and tertiary amines such as triethylamine and tributylamine in solvents such as chloroform, toluene, benzene, dic σ σ methane and tetrahydropropane. Easily synthesized by reacting at 0-150 ° C in the presence of min and then 0- + 1500 in the presence of a tertiary amine such as pyridine. Can be.
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 R8あるいは R3に対!芯する酸無水物，酸ハライ ド，アル キルハライ ドと反応させて、 式（ I )中、 Xおよび Z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 σ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— itrcから 15O°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、 トリエチルアミ ン，ピリ ジン，ジメチルァ ミノ ピリ ジン，水酸化ナトリゥム，水素化ナトリゥム）を反応中に共存さ せることもできる。 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 that is cored to R 8 or R 3 . In the formula (I), a compound in which X, Z or Y is a substituted imino group can be obtained. In general, the reaction is carried out in a solvent (eg, benzene, toluene, chloroform, dichloromethane, ether, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide) and the reaction temperature is reduced from itrc to about 150C. Proceed by keeping. At this time, a base (eg, triethylamine, pyridine, dimethylaminopyridine, sodium hydroxide, sodium hydride) can be co-present during the reaction for the purpose of accelerating the reaction rate.
差換え 式（I )中、 Zで示される基の中に含まれる窒素原子が、 1級， 2級， 3 級ァミ 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 σ口ホルム，テトラハイ ド-口フラン，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° 〜十 150°Cに保つこ とによって進行する。 Replacement In the formula (I), a compound in which the nitrogen atom contained in the group represented by Z is a primary, secondary, or tertiary amine is reacted with, for example, an alkyl halide to obtain a compound represented by the formula (I). It is also possible to obtain a compound in which the nitrogen atoms contained in the groups represented by Z and Z are secondary, tertiary and quaternary amines. This reaction proceeds in a solvent such as ether, chloroform, tetrahide-mouth furan, benzene, toluene, etc. in the presence of an equivalent or large excess of alkyl halide at 0 ° to 10 ° C. I do.
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がベンジルォキジ基の場合、 接触還元をおこない、 R 2を ヒ ドロキシ基とした後、 ァシル化，力ルバモイ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 contained in the formula (I), the reaction can be carried out after the group is eliminated, and another substituent can be introduced. For example, when R 2 is a benzyloxy group in the formula (I), catalytic reduction can be performed, and after R 2 has been converted to a hydroxy group, acylation and rubamoylation can be performed.
化 Conversion
Figure imgf000020_0001
Figure imgf000020_0001
この反応の際、 Xおよび Z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および 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 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—ル，テ トラハイ ドロフラン，水， §乍酸などの溶媒中、 室温から + 100°Cに保つことによつておこなうことができる。 （X W)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° 〜 + 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 するため、 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 VH)を力ルバモイル化して（X DO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（XUOの 製造法]に準じておこなうことができる。 In this reaction, when X, Z or Y is an unsubstituted imino group, X and or Y can be simultaneously acylated or levamoylated during the above acylation or levamoylation. Catalytic return in this reaction The primary reaction can be carried out by using a catalyst such as platinum oxide, palladium carbon, Raney nickel, etc., and keeping the solution at room temperature to + 100 ° C in a solvent such as alcohol, tetrahydrofuran, water, or acid. it can. The acylation reaction of (XW) is carried out by reacting (XVI) with an active derivative of carboxylic acid (acid anhydride, acid halide, etc.) in an inert solvent (ether, ethanol, benzene, toluene, dichlor- This can be achieved by maintaining the temperature between 10 ° C and + 150 ° C, such as methane, tetrahedral furan, and dimethylformamide. At this time, tertiary amine (triethylamine, pyridine, dimethylaminopyridine) or the like may be added to promote the reaction. The reaction of (XVH) into a compound (XDO) can be carried out according to a compound reaction (production method of XUO) described below.
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 きる。  The starting material (VI) can be produced, for example, according to the following reaction formula.
差換え 20—
Figure imgf000022_0001
Replacement 20—
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000023_0001
OMes l 上 E式中、 Q t 'はトシルまたはメシルを示し、 T H Pはテトラヒ ドロピ ラン一 2 _ィルを示し、 Q + ,QSはハロゲン（冽、クロル，ブロム，ョー ド） OTosyl, OMesylを示す。 他の記号は前記と同意義。 差換え ' 0
Figure imgf000022_0002
Figure imgf000023_0001
During OMes l on E-type, Q t 'represents a tosyl or mesyl, THP represents a Tetorahi Doropi run one 2 _ I Le, Q +, Q S is halogen (Kiyoshi, chloro, bromo, ® over de) OTosyl, OMesyl Is shown. Other symbols are as defined above. Replacement '0
II  II
この方法は式 HX— 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，パルビツール酸など）の場合に用いると良 い。  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, parbituric acid, etc.).
(IX)および（XI)は（XI)または（X)にたとえばクロ 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 (XI) can be synthesized by reacting (XI) or (X) with, for example, chlorophenyl carbonate, phosgene or diphosgene.
前記反応において原料として用いられた化合物（a)はたとえば以下の 方法で合成できる。  Compound (a) used as a raw material 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）  (I will explain separately when X is 0, S, ΝΗ)
10 式 10 expressions
C H20 R 1 CH 2 0 R 1
C H R 2 a CHR 2a
！ (XXXV)  ! (XXXV)
C H20 H CH 2 0 H
[式中、 R2aはァシルォキシ基を示し、 R L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 L has the same meaning as described above]. The compound can be produced, for example, according to the following reaction formula.
Figure imgf000024_0001
CHR2a
Figure imgf000024_0001
CHR 2a
CH20Tri CH20Tri CH20H CH 2 0Tri CH 2 0Tri CH 2 0H
(XXXI) (X X )  (XXXI) (X X)
20  20
式 formula
Figure imgf000024_0002
Figure imgf000024_0002
C HR 2¾ C HR 2 ¾
ί  ί
C H20 H CH 2 0 H
[式中、 R2bはァシルアミノ基を示し、 R 1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 2b represents an acylamino group, and R 1 has the same meaning as described above], for example, can be produced according to the following reaction formula.
差換え (X XXIX) (XL) (XL I ) Ph Replacement (X XXIX) (XL) (XL I) Ph
Figure imgf000025_0001
Figure imgf000025_0001
式  Expression
C H20 R 1 CH 2 0 R 1
C HR 0 C HR 0
(Xし IV)  (X then IV)
C H20 H CH 2 0 H
[式中、 R2 C ':ま式（IE)で表わされる基を示し、 R 1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つて製造できる。 [Wherein R 2 C ′: represents a group represented by the formula (IE), and R 1 has the same meaning as described above], for example, can be produced according to the following reaction formula.
Figure imgf000025_0002
Figure imgf000025_0002
(XL VI)  (XL VI)
[式中、 Qsはハロゲン原子を示し、 他は前記と同意義] [Wherein, Q s represents a halogen atom, and the others are as defined above.]
(XXX YI)→(X L VI)の反応は、 無溶媒あるいは不活性溶媒中（例, トゾレエン，ベンゼン，クロ口ホルム，ジクロロメタン，テ トラヒ ドロフラン） 、 好ましくはピリジン， トリェチルァミ ン，ジメチルァミノ ピリ ジンなど の三級ァミ ンの存在下、 0〜十 1 5 0 °Cにて行うことが好ましい。 The reaction of (XXX YI) → (XL VI) is carried out without solvent or in an inert solvent (eg, It is preferably carried out at 0 to 150 ° C. in the presence of tertiary amines such as tosoleene, benzene, chloroform, dichloromethane, tetrahydrofuran), preferably pyridine, triethylamine, dimethylaminopyridine and the like. .
(XL YI)→(XL の反応は通常、 水またはアルコール中、 酸（例、 塩酸 J乍酸）の存在下、 + 1 0〜十 1 1 0てにて進行させることができ る。  The reaction (XL YI) → (XL) can usually be carried out in water or alcohol at +10 to 110 in the presence of an acid (eg, hydrochloric acid J).
CH20R; (XL VH) CH20R1 CHsOR1 CH 2 0R; (XL VH) CH20R 1 CHsOR 1
R6K I I R 6 KII
CH0H CHOCNHR6 - CHOCiiHR8 CH0H CHOCNHR 6 -CHOCiiHR 8
！ !1  ! ! 1
CH20Tri ！ W (XL IT ) CH 20 Tri! W (XL IT)
(XXXVI) (XXXVI)
Figure imgf000026_0001
Figure imgf000026_0001
f  f
I CH20Rl CHsOR1 I CH 2 0R l CHsOR 1
！ ClCOOPh i  ! ClCOOPh i
1 > CHOCOOPh
Figure imgf000026_0002
CH0C?i<S (L I ) 1 > CHOCOOPh
Figure imgf000026_0002
CH0C? I < S (LI)
CH20Tri (I D CH20Tri CH 20 Tri (ID CH 20 Tri
Figure imgf000026_0003
Figure imgf000026_0003
(XXXVI)→(XL 1)の反応は無溶媒あるいはベンぜン， トルエン，ク 口口ホルム，ジク σ σメタン，テトラヒ ドロフランなどの不活性溶媒中、 好ましくは、 ピリ ジンなどの三級ァミ ンの存在下、 0〜+ 1 5 0°Cにて 行うことが好ましく、 また、 （XXXVI)→(L I )の反応は、 （XXXVI) とクロ口炭酸フエニルを不活性溶媒（例、 クロ口ホルム，ジクロロメタン ベンゼン， トルエン，ジェチルエーテル）中、 0〜+ 1 0 0°Cにて反応さ せて生成する化合物（ I L)に、 無溶媒またはベンゼン， トルエン,ク σ口 ホルム，ジクロ σメタ ン，テトラヒ ドロフラン等の不活性溶媒中、 化合物 (L)を 0〜+ 1 5 0 °Cにて反応させるのが好ましい。 The reaction of (XXXVI) → (XL 1) can be carried out without solvent or in an inert solvent such as benzene, toluene, ethanol, dic σ σ methane, or tetrahydrofuran, and preferably a tertiary amine such as pyridine. The reaction is preferably carried out at 0 to + 150 ° C. in the presence of a solvent, and (XXXVI) → (LI) is obtained by reacting (XXXVI) with phenyl phenyl carbonate in an inert solvent (eg, Formaldehyde, dichloromethane, benzene, toluene, and getyl ether) in a solvent at 0 to + 100 ° C (IL). Compounds in an inert solvent such as methane, tetrahydrofuran, etc. (L) is preferably reacted at 0 to + 150 ° C.
式 C H  Formula C H
C o H20 R 1 C o H 2 0 R 1
C HR2d C HR 2d
I (L E)  I (L E)
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.
CH20 ハロゲン化アルキル CH20 CH 2 0 alkyl halide CH 2 0
έκθΗ VPh ハロゲン化ァラルキ ^ έκθΗ V Ph halogenated ^
\ CHR2d ph (L D \ CHR 2d ph (LD
H I / 、 H  H I /, H
CH20 CH 2 0
CH20H ハロゲン化アルキル C OR1 CH 2 0H Alkyl halide C OR 1
加水分解 > iHn.2d アルキルイソシァネ -ト、 HR2d (し Π) Hydrolysis> i H n. 2 d Alkyl isocyanate , HR2d ( し )
CH20H CH20H CH 2 0H CH 2 0H
am  am
式  Expression
C Η20 R 1 C Η 20 R 1
C HR2 C HR 2
(L V)  (L V)
C H2S H CH 2 SH
[式中、 R 1および R2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。 CH2OR1 CH.OR1 CHzOR1 [Wherein R 1 and R 2 are as defined above] can be produced according to the following reaction formula. CH2OR 1 CH.OR 1 CHzOR 1
I TsCl ！ PhCH2SH ! I TsCl! PhCH 2 SH!
CHR2 - CHR2 ■ CHR2 CHR 2 -CHR 2 ■ CHR 2
CH20H CH2OTs CH2SCH2Ph CH 2 0H CH 2 OTs CH 2 SCH 2 Ph
a VI) (L )
Figure imgf000028_0001
a VI) (L)
Figure imgf000028_0001
式  Expression
C H20 R 1 CH 2 0 R 1
C HR2e CLVI) (C HR 2e CLVI)
C H20 H CH 2 0 H
[式中、 R1は前記と同意義、 R2e は環状アミノ基を示す]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 n [In the formula, R 1 are as defined above, R 2e represents a cyclic amino radical compounds represented by may be prepared for example according to the following reaction scheme n
CH20 l CH20R】 CH 2 0 l CH 2 0R]
十 CHaOR1 Ten CHaOR 1
CHOTs > CHR2e ■ CHR2e CHOTs> CHR 2e ■ CHR 2e
I I
CH OTri CH20Tri CH2OH CH OTri CH 2 0Tri CH2OH
(XXXK) (LDO (L I)  (XXXK) (LDO (L I)
上記各反応式中、 R2eは環状アミノ基を、 記号 Ts.Triはそれぞれ トシル， トリチルを示す。 In each of the above reaction formulas, R 2e represents a cyclic amino group, and the symbol Ts.Tri represents tosyl and trityl, respectively.
式  Expression
C H2〇 R 1 CH 2 〇 R 1
CHR2 x) CHR 2 x)
C H 2 H 2  C H 2 H 2
[式中、 R およぴ 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。
Figure imgf000029_0001
[Wherein R and R 2 are as defined above] can be produced, for example, according to the following reaction formula.
Figure imgf000029_0001
CH20 ' CH 2 0 '
CHR2 (L X) CHR 2 (LX)
CH2NH2 上己各反応式中、 記号 Ph, Ts, T および D P 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ァジ ドを示す。 In each reaction formula of CH 2 NH 2 , the symbols Ph, Ts, T and DPPA 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。  Among the compounds used in each reaction, compounds having a group that may hinder the reaction are used as protective groups known per se (eg, benzyl, tosyl, trityl, phthalimid, succinimide, benzyloxycarbonyl, tert-carbonyl). The reaction can be carried out by protecting the group with -butoxycarbonyl) and, after the reaction, subjecting to a deprotection reaction known per se to obtain the desired compound.
化合物（〖）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 らあるが、 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、 また、 イオン交換樹脂を用いて、 塩形を変換する こともできる。  The salt of compound (II) may be obtained, for example, by the above-mentioned method for producing compound (I) itself. However, if necessary, compound (I) can be produced by adding an acid or a base to compound (I). The salt form can also be converted using an ion exchange resin.
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 〜 1 0 5は国際出願 P C T/J P 8 4 /0 0 4 7 6に開示し たものと同じである。  Examples 1 to 105 are the same as those disclosed in International Application PCT / JP84 / 04676.
実施例 106 Example 106
1 —メチルー 2—[N—ァセチルー N'—（3 —才クタデシルカルバモ ィルォキシ一 2—メ トキシプロピル）ゥレイ ド]メチルピリ ジニゥム ク 口ライ ド、 1—Methyl-2— [N-Acetyl-N '— (3—Ctadecylcarbamoyloxy-1-2-methoxypropyl) -Reid] Methylpyridinium Mouth ride,
i ) 2— [Ν'—（3—才クタデシルカルバモイルォキシー 2—メ トキ シプロピル）ゥレイ ド]メチルピリ ジン  i) 2— [Ν '— (3-tactadecylcarbamoyloxy-2-methoxypropyl) perido] methylpyridine
実施例 8 0で製造したァミノ体 2 0 0 mg[0. 5 ミ リモル]をトルエン 5 mlに溶解し、 ジホスゲン 1 8 1 〃 [1 . 5 ミ リモル]を加えた後、 窒 素気流中 1 0分間室温にて攪拌し、 更に 7 9 °Cにて 5時間攪拌した。 冷 後、 反応液を減圧濃縮し、 粗イソシァネート体を得た。  200 mg [0.5 mimol] of the amino compound produced in Example 80 was dissolved in 5 ml of toluene, and diphosgene 18 1〃 [1.5 mimol] was added thereto. The mixture was stirred at room temperature for 0 minutes, and further stirred at 79 ° C for 5 hours. After cooling, the reaction solution was concentrated under reduced pressure to obtain a crude isocyanate compound.
このイソシァネート体をクロロホルム 2 mlに溶解し、 氷冷下 2—（ァ ミ ノメチル）ピリ ジン 6 1 [0. 6 ミ リモル]を加え、 室温にて 1 7. 5時間攪拌した。 反応液を減圧濃縮し、 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： 2 0g;溶出液：クロ口ホルム：メタノール- 2 0 : 1 ]にて精製し、 目的化合物 2 0 6 mg (無色固体； 7 7. 0 %)を得 た。 · *  This isocyanate compound was dissolved in chloroform (2 ml), and 2- (aminomethyl) pyridine 61 [0.6 mimol] was added thereto under ice-cooling, followed by stirring at room temperature for 17.5 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography [silica gel: 20 g; eluent: chloroform: methanol-20: 1] to give the target compound 206 mg ( Colorless solid; 77.0%). · *
T L C [Silica Gel； CHCl3/ eOH(20/l)j： Rf = 0.27 TLC [Silica Gel; CHCl 3 / eOH (20 / l) j: Rf = 0.27
NMR [90MHz, CDC ] .δ : 0.86(3H,t), 1.25(32H,s), 3.12(2H,q),NMR [90MHz, CDC] .δ: 0.86 (3H, t), 1.25 (32H, s), 3.12 (2H, q),
3.37(3H,s), 3.30~3.55(3H,m)， 4丄 2(2H，m), 4.47(2H,d), 5.25 (lH.br.), o.58(lH,br.t), 6.04(1H, br. t) , 7.18(2H, ), 7.62(1H, d,t), 8.47(lH,br.d) 3.37 (3H, s), 3.30 ~ 3.55 (3H, m), 4 丄 2 (2H, m), 4.47 (2H, d), 5.25 (lH.br.), O.58 (lH, br.t) , 6.04 (1H, br.t), 7.18 (2H,), 7.62 (1H, d, t), 8.47 (lH, br.d)
I R[KBr]cm一1: 3330, 2920, 2855, 1695, 1635, 1590, 1539, IR [KBr] cm- 1 : 3330, 2920, 2855, 1695, 1635, 1590, 1539,
1478, 1442, 1290, 1280, 1262, 1251, 1235, 1139, 1105, 1055 ii ) 2— [N—ァセチルー N'— (3—ォクタデシルカルバモイルォキ シー 2—メ トキシプロピル）ウレイ ド]メチルピリ ジン  1478, 1442, 1290, 1280, 1262, 1251, 1235, 1139, 1105, 1055 ii) 2— [N-acetyl-N '— (3-octadecylcarbamoyloxy 2-methoxypropyl) ureido] methylpyri gin
i ) で得た化合物 2 0 0 mg[0 3 7 4 ミ リモル]をク口口ホルム 5 ml に溶解し、 トリェチルァミ ン 3. 8m.l，無水酢酸 0. 7 mlを加えた後、 窒素気流中にて 2日間還流した。 冷後、 反応液に 3 %NaH C 03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、 溶媒を減圧留去した。 得られた祖生成物をカラムクロマトグラフィー [シ リ力ゲル： 1 0 g;溶出液： n—へキサン 乍酸ェチル = 1/2]にて精製し、目 的化合物 1 5 8mg (淡褐色固体； 7 3. 2 %)を得た。 i) The compound obtained in 200) [200 mg] was dissolved in 5 ml of porcine, and 3.8 ml of triethylamine and 0.7 ml of acetic anhydride were added. Refluxed in the medium for 2 days. After cooling, a 3% aqueous solution of NaHCO 3 was added to the reaction solution, and the mixture was extracted with chloroform.The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting crude product was purified by column chromatography [silica gel: 10 g; eluent: n-hexane / ethyl = 1/2] to give the desired compound (158 mg, pale brown solid). 73.2%).
T L C [Silica Gel； n-hexane/AcOEt (1/2)]： Rf=0.32 TLC [Silica Gel; n-hexane / AcOEt (1/2)]: Rf = 0.32
NMR [90MHz,CDCl3] δ： 0.87(3H,t), 1.26(32H,s), 2.31(3H,s), NMR [90MHz, CDCl 3 ] δ: 0.87 (3H, t), 1.26 (32H, s), 2.31 (3H, s),
3.15(2H,q), 3.26〜3.72(3H,m) , 3.43(3H,s), 4.18(2H,m)> 5.05 (2H,s), 5.14(lH,br.), 7.09〜7.37(2H, m) , 7.67(1H, d. t) , 8.51(1 H.m), 9.S8(lH,br.) 3.15 (2H, q), 3.26〜3.72 (3H, m), 3.43 (3H, s), 4.18 (2H, m) > 5.05 (2H, s), 5.14 (lH, br.), 7.09〜7.37 (2H , m), 7.67 (1H, d.t), 8.51 (1 Hm), 9.S8 (lH, br.)
I R[KBr]cm-1: 3320, 2920, 2850, 1717, 1698, 1660, 1530, IR [KBr] cm -1 : 3320, 2920, 2850, 1717, 1698, 1660, 1530,
1395, 1275, 1262, 1200  1395, 1275, 1262, 1200
iii) 1 —メチルー 2— [N—ァセチル一 N'— (3—ォクタデシルカル バモイルォキン一 2—メ トキシプロピル）ゥレイ ド]メチルピリ ジニゥム クロライ ド（ 4 ) ' , iii) 1-Methyl-2— [N-Acetyl-1-N '— (3-octadecylcarbamoylquin-2--1-methoxypropyl) -reido] methylpyridinium chloride (4)',
Π )で得た化合物 1 5 0 mg(0. 2 6 ミ リモル）にメチルョージ ド 2 ml を加え、 窒素気流中、 遮光して 3 日間還流した。 冷後、 反応液を濃縮乾 固し、 残渣を I R A - 1 0 [〇1-型](1 5 ml;溶出液： 7 0 %メタノー ルノ水）にて処理し、 得られた粗ク口ライ ド体をァセトン ·石油ェ一テ ルょり再沈澱法により精製し目的化合物 1 3 1 mg (無色固体； 8 0. 3 %) を得た。 To 150 mg (0.26 mimol) of the compound obtained in Π), 2 ml of methyl chloride was added, and the mixture was refluxed for 3 days in a nitrogen stream, protected from light. After cooling, the reaction solution was concentrated to dryness, and the residue was treated with IRA-10 [〇1-type] (15 ml; eluent: 70% methanolic water). The purified product was purified by acetone / petroleum ether reprecipitation method to obtain 131 mg of the desired compound (colorless solid; 80.3%).
T L C [Silica Gel； AcOEt/AcOH/H20(3/l/l)]： R f = 0.26TLC [Silica Gel; AcOEt / AcOH / H 2 0 (3 / l / l)]: R f = 0.26
R [90MHz, CDC 13] δ 0.87(3H,t), 1.24(32H,s), 2.o5(3H,s), 3.10(2H,q), 3.27〜3.65(3H,m), 3.38(3H,s), 4.08(2H,m), 4.71 (3H,s), 5.10(lH,br.), 5.62 (2H, br . s) , 7.66(lH,m), 7.85(lH,m), 8.30(lH,m), 9.27(lH,br.t), 9.48(lH，m) R [90MHz, CDC 1 3] δ 0.87 (3H, t), 1.24 (32H, s), 2.o5 (3H, s), 3.10 (2H, q), 3.27~3.65 (3H, m), 3.38 ( 3H, s), 4.08 (2H, m), 4.71 (3H, s), 5.10 (lH, br.), 5.62 (2H, br.s), 7.66 (lH, m), 7.85 (lH, m), 8.30 (lH, m), 9.27 (lH, br.t), 9.48 (lH, m)
I R [ Brlcm- 1: 3400, 2923, 2850, 1710, 1635, 1530, 1470 IR [Brlcm -1 : 3400, 2923, 2850, 1710, 1635, 1530, 1470
差換え 実施例 107 Replacement Example 107
[N—ァセチル一 N'—（3—ォクタデシルカルバモイルォキシー 2— メ ト丰シ）プロピル]ゥレイ ドエチルジメチルアン乇ニゥム クロライ ド i ) N—（ジメチルァミ ノ）ェチルー Ν' (3—ォクタデシルカルバモ ィルォキシー 2—メ トキシ）プロピルウレァ  [N-Acetyl-1-N '-(3-octadecylcarbamoyloxy-2-methoxy) propyl] ゥ raidethyldimethyldimethylanimide chloride i) N- (dimethylamino) ethyl チ ル' (3—o Kutadecylcarbamoyloxy 2-methoxy) propylurea
実施例 8 0で製造したアミ ノ体 1 . 0 0g[2. 5 ミ リモル]を トルェ ン 2 5mlに溶解し、 ジホスゲン 9 0 5〃 2 [7. 5 ミ リモル]を加えた後 8 0 °Cにて 5時間加熟し、 冷後反応液を减圧濃縮し、 粗イソシァネー ト 体を得た。  1.0 g [2.5 mimol] of the amino compound prepared in Example 80 was dissolved in 25 ml of toluene, and diphosgene 905 92 [7.5 mimol] was added. The mixture was ripened at C for 5 hours, cooled, and concentrated under reduced pressure to obtain a crude isocyanate.
このイソシァネー ト体をクロ口ホルム 1 Omlに溶解し、 氷冷下 asym— ジメチルェチレンジァミ ン 3 3 1 mg[3. 7 5 ミ リモル]を加え、 室温に て 1 6時間攪拌し、 更に 2時間還流した。 反応液を减圧濃縮し、 得られ た粗生成物もカラムク口マトグラフィ ー [シリ力ゲル： 5 0 g;溶出液：ク σ口ホルム Zメタノール =20/丄→3/1]にて精製し、目的物 4 7 0 mg (無色 固体： 3 6. 5 %)を得た。  This isocyanate form was dissolved in 1 mL of chloroform in form, and 33.1 mg [3.75 mimol] of asym-dimethylethylenediamine was added under ice-cooling, followed by stirring at room temperature for 16 hours. The mixture was refluxed for another 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (column gel: 50 g; eluent: Sigma-mouth form Z methanol = 20 / 丄 → 3/1). This gave 470 mg of the desired product (colorless solid: 36.5%).
Tし C [Silica Gel ;CHCl3/MeOH(3/l)]： R f- 0.26T then C [Silica Gel; CHCl 3 / MeOH (3 / l)]: R f- 0.26
R [90MHz, CDC 131 δ： 0.87(3H,t), i.24(32H,s), 2.37(6H,s), 2.61(2H,t), 3.U(2H，q). 3.20〜3.63(5il,m), 3.4i(3H,s), 4.15 C2H,br.), 5.42(lH,br.), 5.84(2H, r . t) R [90MHz, CDC 1 3 1 δ:. 0.87 (3H, t), i.24 (32H, s), 2.37 (6H, s), 2.61 (2H, t), 3.U (2H, q) 3.20 ~ 3.63 (5il, m), 3.4i (3H, s), 4.15 C2H, br.), 5.42 (lH, br.), 5.84 (2H, r.t)
I R [KB rjcm-1： 3350, 2925, 2850, 1695, 1630, 1590, 1540, IR [KB rjcm -1 : 3350, 2925, 2850, 1695, 1630, 1590, 1540,
1470  1470
ii ) N一ァセチルー N—（ジメチルァミ ノ）ェチルー N'— (3—ォクタ デシルカルバモイルォキシー 2—メ トキシ）プロピルウレァ  ii) N-acetyl-N- (dimethylamino) ethyl-N '-(3-octadecylcarbamoyloxy-2-methoxy) propylurea
i )で合成した化合物 1 2 9 mg[0. 2 5 ミ リモル]に無水酢酸 0. 5 m 1,トリェチルァミ ン 3 miを加え、 窒素気流中 4時間還流した。 反応液に クロ口ホルムを加え、 5 %NaH C〇3溶液で洗浄後、 有機層を硫酸ナト リウムにて乾燥し、 威圧濃縮した。 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： 8 g;溶出液：ァセトン]にて精製し、 目的物 1 3 9 mg (無色油状物， 1 0 0 %)を得た。 ― To 129 mg [0.25 mmol] of the compound synthesized in i), 0.5 m1 of acetic anhydride and 3 mi of triethylamine were added, and the mixture was refluxed for 4 hours in a nitrogen stream. To the reaction mixture was added chloroform, washed with 5% NaH 3 solution, and the organic layer was washed with sodium sulfate. It was dried over helium and concentrated under pressure. The obtained crude product was purified by column chromatography [silica gel: 8 g; eluent: acetone] to obtain 139 mg of the desired product (colorless oil, 100%). ―
T L C [Silica Gel;acetone]： Rf = 0.13 TLC [Silica Gel; acetone]: Rf = 0.13
NMR [90MHz, CDC ] δ ： 0.87(3H,t), 1.26(32H,s), 2.28(6H,s), NMR [90MHz, CDC] δ: 0.87 (3H, t), 1.26 (32H, s), 2.28 (6H, s),
2.33(3H,s), 2.50(2H, t), 3.i5(2H,q), 3.36〜3.63(3H, m) , 3.43 (3H.s), 3.76(2H,t), 4.16(2H,d), 5.03(1H, br . ) , 9.68(lH,br.) I R [f ilmlcm"1： 3320, 2930, 2855, 1708, 1660, 1539, 1470, 2.33 (3H, s), 2.50 (2H, t), 3.i5 (2H, q), 3.36 ~ 3.63 (3H, m), 3.43 (3H.s), 3.76 (2H, t), 4.16 (2H, d), 5.03 (1H, br.), 9.68 (lH, br.) IR [filmcm] 1 : 3320, 2930, 2855, 1708, 1660, 1539, 1470,
1370, 1250  1370, 1250
iii) [N—ァセチルー NT—（3—ォクタデシルカルバモイルォキン一 iii) [N-acetyl-NT- (3-octadecylcarbamoyl-quinone)
2—メ トキシ）プロピル]ゥレイ ドエチルト リメチルアンモニゥム クロ ライ ド' 2-Methoxy) propyl] ゥ Reid ethyltrimethylammonium chloride '
n )で合成した化合物 1 3 9 mg[0. 2 5 ミ リモル]にヨウ化メチル 2 m 1を加え、 室温にて遮光して 2日間攪拌した。 反応液を减圧濃縮し、'得 れた粗生成物をァセトンー石油エーテルより再沈殺させョージド体 1 5 0 mgを得た。 このョージド体を I R A - 1 0 [C ( 1 0 nd;溶出 液： 7 0 %メタノ一ル 水）にて処理し、 目的物 1 3 5 mg [無色粉末， 8 8. 9 %]を得た。  To 39 mg [0.25 mimol] of the compound synthesized in n), 2 ml of methyl iodide was added, and the mixture was stirred at room temperature under light shielding for 2 days. The reaction solution was concentrated under reduced pressure, and the obtained crude product was reprecipitated from acetone-petroleum ether to obtain 150 mg of an ozyed compound. The forged compound was treated with IRA-10 [C (10 nd; eluent: 70% methanol in water)] to obtain 135 mg of the desired product [colorless powder, 88.9%]. .
T L C [Silica Gel； cOEt/AcOH/H20(3/l/l)]： Rf = 0.69 TLC [Silica Gel; cOEt / AcOH / H 2 0 (3 / l / l)]: Rf = 0.69
NMR [90MHz, CDCU] δ 0.86(3H, t), 1.2o(32H,s), 2.55(3H,s), NMR [90MHz, CDCU] δ 0.86 (3H, t), 1.2o (32H, s), 2.55 (3H, s),
3.12(2H,q), 3.32〜3.72 (3H, m) , 3.42(3H,s), 3.49(9H,s), 3.82 〜4.45(6H,ni), 5. HClH.br.), 9.30(lH,br.)  3.12 (2H, q), 3.32-3.72 (3H, m), 3.42 (3H, s), 3.49 (9H, s), 3.82-4.45 (6H, ni), 5.HCl.br.), 9.30 (lH , br.)
I R [KBrjcm-1 : 3431, 2925, 2855, 1710, 1668, 1540, 1468, IR [KBrjcm -1 : 3431, 2925, 2855, 1710, 1668, 1540, 1468,
1390, 1259, 1200  1390, 1259, 1200
実施例 108 Example 108
1 ーェチルー 2— [N—ァセチルー N—（3—ォクタデシルカルバモイ ルォキシー 2—メ トキシプロピルォキシ）カルボニルァミ ノ ]メチルピリ ジニゥム クロライ ド 1-ethyl-2— [N-acetyl-N— (3-octadecylcarbamoy Roxy 2-Methoxypropyloxy) carbonylamino] methylpyridinium chloride
実施例 1 0 3で製造した化合物 1 4 0 mg[0. 243 ミ リモル]にョ— ドエタン 3mlを加え、 窒素気流中 3日間還流した。 冷後、 反応液を濃縮 乾固し、 残渣を I R A— 4 1 0 [Cl ](l 5 ml:溶出液： 7 0 %メタノ ール 水）にて処理し、 粗クロライ ド体 1 9 2mgを得た。 この粗クロラ イ ド体をアセ トンに溶解した後氷冷し、 折出した沈澱をろ取し、 目的物 1 2 0 mg (無色粉末， 7 6. 9%)を得た。  To 140 mg [0.243 mimol] of the compound produced in Example 103, 3 ml of ethane was added, and the mixture was refluxed for 3 days in a nitrogen stream. After cooling, the reaction solution was concentrated to dryness, and the residue was treated with IRA-410 [Cl] (5 ml: eluent: 70% aqueous methanol) to give 192 mg of a crude chloride. Obtained. This crude chloride was dissolved in acetone, cooled on ice, and the precipitated precipitate was collected by filtration to obtain 120 mg of the desired product (colorless powder, 76.9%).
T L C [Silica Gel ;CHCl3/ eOH(3/l)]： Rf = 0.32 TLC [Silica Gel; CHCl 3 / eOH (3 / l)]: Rf = 0.32
NMR [90MHz, CDCls] δ ： 0.88(3H,t), 1.25(32H,s), i.71(3H,t), NMR [90MHz, CDCls] δ: 0.88 (3H, t), 1.25 (32H, s), i.71 (3H, t),
2.65(3H,s), 3.12(2H,q), 3.38(3H,s), 3.66(1H, quint) , 4.02C2H, br.d), 4.37C2H,m)> 5.20(2H,q), 5.31(1H, r . ) , 5.48(2H, br. s) , 7.75(lH,br.d), 8.06(1H, r . t) , 8. 7(1H, br.t) , 10.00(1H, br. d) I R[ Br]cm_1: 3405, 2930, 2850, 1754, 1700, 1638, 1224 製造例 109 ' 2.65 (3H, s), 3.12 (2H, q), 3.38 (3H, s), 3.66 (1H, quint), 4.02C2H, br.d), 4.37C2H, m) > 5.20 (2H, q), 5.31 ), 5.48 (2H, br.s), 7.75 (lH, br.d), 8.06 (1H, rt.), 8.7 (1H, br.t), 10.00 (1H, br.t) d) IR [Br] cm _1 : 3405, 2930, 2850, 1754, 1700, 1638, 1224 Production example 109 '
1—エトキシカルボニルメチルー 2— [N—ァセチル一 N—（ 3—ォク タデシルカルバモイルォキン一 2—メ トキシプロピルォキン）カルボ二 ルァミ ノ ]メチルピリ ジニゥム クロライ ド  1-Ethoxycarbonylmethyl-2- [N-acetyl-1-N- (3-octadecylcarbamoylquinine-2-methoxypropylquinone) carbonilumina] methylpyridinium chloride
実施例 1 0 3で製造した化合物 1 7 3mg[0. 3 ミ リモル]にェチル クロ口アセテー ト 1 mlを加え、 5 0 °Cにて 2時間更に 9 0 °Cにて 24時 間加熟した。 冷後、 反応液を減圧濃縮し、 得られた粗生成物をカラムク 口マトグラフィ一 [シリ力ゲル： 1 0 g;溶出液：ク口口ホルム/メタノ一 ル = 4ノ 1 ]にて精製し、 目的物 6 2 mg (淡褐色粉末.2 9. 5 %)を得た。 T L C [Silica Gel ;CHCl3/MeOH(3/l)]： Rf=0.30 To the compound (173 mg [0.3 millimol]) prepared in Example 103, 1 ml of ethyl ethyl acetate was added, and the mixture was ripened at 50 ° C for 2 hours and further at 90 ° C for 24 hours. did. After cooling, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography [Sili-force gel: 10 g; eluent: porcine form / methanol = 4-1]. 62 mg (light brown powder; 2.9.5%) of the desired product was obtained. TLC [Silica Gel; CHCl 3 / MeOH (3 / l)]: Rf = 0.30
NMR [90MHz, CDC13] <5： 0.86(3H,t), 1.24(32H,s), 1.37(3H,m), NMR [90MHz, CDC1 3] < 5: 0.86 (3H, t), 1.24 (32H, s), 1.37 (3H, m),
2.59(3H,s), 3.13(2H,q), 3.37(3H,s), 3.70 (1H, m) , 3.89〜4.5S (6H,m), 5.3K3H.br.), 6.32(2H, br.) , 7.86, 8.10, 8.55, 9.902.59 (3H, s), 3.13 (2H, q), 3.37 (3H, s), 3.70 (1H, m), 3.89-4.5S (6H, m), 5.3K3H.br.), 6.32 (2H, br.), 7.86, 8.10, 8.55, 9.90
(each 1H, m) (each 1H, m)
I R [K B r]cm_1 : 3380, 2925, 2850, 1750, 1700, 1627, 1525, IR [KB r] cm _1 : 3380, 2925, 2850, 1750, 1700, 1627, 1525,
1465, 1420, 1375, 1348， 1220  1465, 1420, 1375, 1348, 1220
実施例 110 Example 110
1一 [(2—メ トキシー 3—ォクタデシルカルバモイルォキシ）プロピ ル]一 3— ( 2—チアゾリオェチル）ヒダン トイン クロライ ド  1-[(2-Methoxy-3-octadecylcarbamoyloxy) propyl] -1-3- (2-thiazolioethyl) hydantoin chloride
i ) 2—メチルー 3—ト リチルグリセリ ン  i) 2-Methyl-3-tritylglycerin
1一ベンゾィル一 2—メチルグリセリ ン 1 3. 6 0 g[64. 7ミ リモ ル],ピリ ジン 1 0. 2 3 g[ 1 2 9. 4 ミ リ乇ル]を塩化メチレン 1 5 0 m 1 Benzoyl-1-methylglycerin 13.60 g [64.7 mimol], pyridine 10.2 3 g [129.4 miril] in methylene chloride 150 m
1に溶解し、 氷冷下トリチルクロライ ド 2 7. 0 5 g[9 7. 0ミ リモル] を加えた後、 室温にて I 8時間攪拌した。 反応液を水洗後、 有機層を無 水炭酸カリ ウムに,て乾燥し、 溶媒を'减圧留去した。 The mixture was dissolved in 1 and triethyl chloride (2.70 g [97.0 mimol]) was added under ice-cooling, followed by stirring at room temperature for 8 hours. After washing the reaction solution with water, the organic layer was dried over anhydrous potassium carbonate, and the solvent was distilled off under reduced pressure.
得られた残渣をジォキサン 3 Oml,エタノール 2 δ Omlに溶解し、 1 0 %水酸化ナトリゥム水溶液を加えて 2 0時間還流した。 冷後、 反応液 を'减圧濃縮し、 残渣に水を加えてクロ口ホルム抽出。 有機層を無水炭酸 カリ ウムにて乾燥後、 溶^を减圧留去し、 得られた粗生成物をカラムク σマトグラフィー [シリ力ゲル： 3 0 0 g;溶出液： η—へキサン/酢酸ェチ ル = 3ノ 1 ]にて精製し、 目的物 2 2. 4 8 g (淡黄油状物， 9 9. 7 %) を得た。  The obtained residue was dissolved in dioxane (3 Oml) and ethanol (2δOml), and a 10% aqueous sodium hydroxide solution was added thereto, followed by refluxing for 20 hours. After cooling, the reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with chloroform. After the organic layer was dried over anhydrous potassium carbonate, the solvent was distilled off under reduced pressure, and the obtained crude product was subjected to column chromatography σ chromatography [silica gel: 300 g; eluent: η-hexane / The residue was purified with ethyl acetate = 3 1] to obtain 2.48 g of the desired product (pale yellow oil, 99.7%).
T L C [Silica Gel； n—へキサン/酢酸ェチル（ 3： 1 )]： Rf = 0.17 MR [90MHz, CDC ] δ 2.13(1Η, br . ) , 3.22(2H,m), 3.38(3H,s), TLC [Silica Gel; n-hexane / ethyl acetate (3: 1)]: Rf = 0.17 MR [90MHz, CDC] δ 2.13 (1Η, br.), 3.22 (2H, m), 3.38 (3H, s) ,
3.67(2H,m)) 7.19〜7.54(15H, m) 3.67 (2H, m) ) 7.19 ~ 7.54 (15H, m)
I R [filmlcm-1： 3420, 3025, 2940, 2875, 2830, 1600, 1490, IR [filmlcm- 1 : 3420, 3025, 2940, 2875, 2830, 1600, 1490,
1220, 1132, 1080, 1040, 780, 768, 750, 710  1220, 1132, 1080, 1040, 780, 768, 750, 710
ii ) 2—メチルー 3— p— トルエンスルホニル一 1—ト リチルグリセ 差換 リ ン ii) 2-Methyl-3-p-Toluenesulfonyl-1- 1-tritylglycere Replacement Rin
i )で合成したアルコール体 3. 4 84g[l 0 ミ リモル], ト リエチル ァミ ン 3. 0 3 6 g[3 0ミ リモル]を塩化メチレン 4 0 miに溶解し、 氷 冷下 p—トルエンスルホン酸ク口ライ ド 2. 47 8 g[l 3 ミ リモル]を加 えた後、 室温にて 1 7時間攪拌した。 反応液に 1 N塩酸を加えてクロ口 ホルム抽出し、 有機層を硫酸マグネシウムにて乾燥後、 溶媒を減圧留去 した。 得られた粗生成物をカラムク口マトグラフィ一 [シリ力ゲル： 1 7 Og;溶出液： n—へキサン/酢酸ェチル = 5/1—3/1]にて精製し、 目的物 4. 49 I g (無色固体； 8 9. 4%)を得た。  3.4 84 g [10 mimol] of the alcohol compound synthesized in i) and 3.036 g [30 mimol] of triethylamine were dissolved in 40 mi of methylene chloride, and p- After adding 2.478 g [l 3 mimol] of toluenesulfonic acid mouth light, the mixture was stirred at room temperature for 17 hours. The reaction mixture was added with 1 N hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography [Sili-force gel: 17 Og; eluent: n-hexane / ethyl acetate = 5 / 1-3 / 1] to obtain the desired product 4.49 I g (colorless solid; 89.4%).
T L C [Silica Gel;n—へキサン Z酢酸ェチル（3/1)]: Rf = 0.43T L C [Silica Gel; n—Hexane Z Ethyl acetate (3/1)]: Rf = 0.43
NMR [90MHz, CDC13] δ ： 2.37(3H,s), 3.12(2H,d), 3.22(3H,s), 3.40(lH,quint), .13(2H, m) , 7.04〜7.48(ΠΗ, m) , 7.73(2H,d) I REKBrlcm'1 : 3060, 2930, 2890, 2870, 2820, 1599, 1450, NMR [90MHz, CDC1 3] δ : 2.37 (3H, s), 3.12 (2H, d), 3.22 (3H, s), 3.40 (lH, quint), .13 (2H, m), 7.04~7.48 (ΠΗ , m), 7.73 (2H, d) I REKBrlcm ' 1 : 3060, 2930, 2890, 2870, 2820, 1599, 1450,
1370, 1190, 1180, 1100, 1080, 980, 790, 770, 715  1370, 1190, 1180, 1100, 1080, 980, 790, 770, 715
iii) 3—（2—ベンジルォキシェチル）一 1一 [1—(2—メ トキシー 3 一ト リチルォキン）プロピル]ヒダン トイン  iii) 3- (2-Benzyloxethyl) 1- [1— (2-Methoxy-3-trityloxy) propyl] hydantoin
ii)で合成したトシル体 6. 0 3 1 g〔i 2 ミ リモル]及び 3—（2—ベ ンジルォキシェチル）ヒダン トイン 1 . 4 0 6g[6 ミ リモル]をジメチル スルホキサイ ド 1 2 mlに溶解し、 粉末水酸化力リウム 673 mg[l 2 ミ リモル]を加えた後、 室温にて 1 7. 5時間攪拌した。 反応液に I N塩 酸（1 2 ml)を加えて酢酸ェチル抽出し、 有機層は水洗後硫酸マグネシゥ ムにて乾燥し、 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： 2 5 0 g;溶出液： n—へキサン/酢酸ェチル = 1.5/1]にて精製し、目的物 2.7 9 3 g(台伏物質： 8 2. 4 %)を得た。 T L C [Silica Gei;n—へキサン Z詐酸ェチル（1/1)]： Rf = 0.49 NMR [90MHz, CDC13] 5： 3.18(2Η,πι), 3.28(3H,s), 3.48(2H，m), 6.031 g [i 2 mimol] of the tosyl compound synthesized in ii) and 1.46 g [6 mimol] of 3- (2-benzyloxyshethyl) hydantoin were added to dimethyl sulfoxide 12 The mixture was dissolved in water, and after adding 673 mg [l 2 mimol] of powdered lithium hydroxide, the mixture was stirred at room temperature for 17.5 hours. The reaction solution was added with IN hydrochloric acid (12 ml), extracted with ethyl acetate, the organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography [silica gel: 250 g; eluent: n-hexane / ethyl acetate = 1.5 / 1], and 2.793 g of the target product (pillow substance) : 82.4%). TLC [Silica Gei; n- hexane Z詐酸Echiru (1/1)]: Rf = 0.49 NMR [90MHz, CDC1 3] 5: 3.18 (2Η, πι), 3.28 (3H, s), 3.48 (2H, m),
差換え 3.67(4H,t), 3.75ClH,ni), 3.87C2H, ABq) , 4.48(2H(s), 7.12〜7.S9Replacement 3.67 (4H, t), 3.75ClH, ni), 3.87C2H, ABq), 4.48 (2H ( s), 7.12 ~ 7.S9
(20H,m) (20H, m)
I R [f ilrnjcm"1： 3070, 3030. 2940, 2875, 1775, 1720, 1600, IR [filrnjcm] 1 : 3070, 3030. 2940, 2875, 1775, 1720, 1600,
1470, 1115, 1080, 760, 710  1470, 1115, 1080, 760, 710
iv) 3—（2—ベンジルォキシェチル）一 1 —[(3—ヒ ドロキン一 2— メ トキシ）プロピル]ヒダン トイン  iv) 3- (2-benzyloxyshethyl) 1-1 — [(3-hydroquinone-2-methoxy) propyl] hydantoin
iii)で合成した化合物 2. 2 5 9 g[4 ミ リモル]もテトラハイ ドロフラ ン 6 5mUこ溶解し、 水 5 ml,濃塩酸 5 mlを加えて 1時間 2 0分還流した。 冷後、 反応液を減圧濃縮し、 1 N水酸化ナトリウム溶液にて中和後、 ク ロロホルム抽出し、 有機層を硫酸マグネシウムにて乾燥し、 溶媒を減圧 留去した。 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： 5 Og;溶出液： S乍酸ェチル]にて精製し、 目的物 1 . 0 9 3 g (無色油状物 ; 8 4. 8 %)を得た。  2.59 g [4 mimol] of the compound synthesized in iii) was also dissolved in 65 mU of tetrahydrofuran, 5 ml of water and 5 ml of concentrated hydrochloric acid were added, and the mixture was refluxed for 1 hour and 20 minutes. After cooling, the reaction solution was concentrated under reduced pressure, neutralized with 1 N sodium hydroxide solution, extracted with chloroform, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography [silica gel: 5 Og; eluent: ethyl ether S] to obtain 1.093 g of the desired product (colorless oil; 84.8%). ).
T L C [Silica Gel;AcOEt]： Rf = 0.30TLC [Silica Gel; AcOEt]: Rf = 0.30
MR [90MHz, CDC13] δ： 2.90(1H, t), 3.38(3H,s), 3.41〜3.65 MR [90MHz, CDC1 3] δ : 2.90 (1H, t), 3.38 (3H, s), 3.41~3.65
(4H,m), 3.70(4H, t), 3.80(lH,m). 3.98(2H, Bq) , 4.50(2H,s), 7.28(5H,s) (4H, m), 3.70 (4H, t), 3.80 (lH, m). 3.98 (2H, Bq), 4.50 (2H, s), 7.28 (5H, s)
I R： film]cm~l： 3450, 2940, 2870, 1765, 1710, 1470, 1110, 760 v ) 3—（2—ベンジルォキシェチル）一 ί一 [(2—メ トキシ一 3—才 クタデシルカルバモイルォキシ）プロピル]ヒダン トイン IR: film] cm ~ l : 3450, 2940, 2870, 1765, 1710, 1470, 1110, 760 v) 3— (2-benzyloxyshetyl) 1- (1— (2-methoxy-1 3-year-old) Decylcarbamoyloxy) propyl] hydantoin
iv)で合成したアルコール体 1 . 0 9 3 g〔3. 3 9 1 ミ リモル]をピリ ジン 2 0 mlに溶解し、 ステアリ ルイソシァネー ト 2. 0 0 g[6. 7 8 1 ミ リモル]を加えた後、 7 0°Cにて 2 2時間加温した。 反応液に n—へキ サン Z g乍酸ェチル（1/ 1.5)混液を加えて沈澱物をろ別後、 母液を減圧濃 縮した。 得られた粗生成物を力ラムクロマトグラフィー [シリカゲル： 8 Og;溶出液 '.η—へキサン/昨酸ェチル = 1/1.5]にて精製し、目的物 1 .9 差換え i 1 4 g (飴状物質； 9 1 .4 %)を得た。 1.093 g [3.391 mimol] of the alcohol synthesized in iv) was dissolved in 20 ml of pyridine, and 2.0 g of stearyl isocyanate [6.781 mimol] was added. After the addition, the mixture was heated at 70 ° C for 22 hours. To the reaction mixture was added a mixture of n-hexane Z g and ethyl (1 / 1.5), the precipitate was filtered off, and the mother liquor was concentrated under reduced pressure. The obtained crude product was purified by force column chromatography [silica gel: 8 Og; eluent '.η-hexane / ethyl acetate = 1 / 1.5], and the target product was replaced by 1.9. i 14 g (candy-like substance; 91.4%) was obtained.
T L C [Silica Gel; n—へキサン Z酢酸ェチル（1/1.5)]： Rf = 0.39 N MR [90MHz, CDC13] δ ： 0.89(3Η, t), 1.28(32H,s), 3.13(2H,q), TLC [Silica Gel; hexane Z acetate Echiru (1 / 1.5) to n-]: Rf = 0.39 N MR [90MHz, CDC1 3] δ: 0.89 (3Η, t), 1.28 (32H, s), 3.13 (2H, q),
3.29(3H,s), 3.47〜3.68(2H，fli), 3.72(4H,t), 3.80(lH,m), 3.97 5- (2H,s), 4.12(2H,d), 4.53(2H,s), 4.90(iH, br. ) , 7.30(5H,s)  3.29 (3H, s), 3.47 to 3.68 (2H, fli), 3.72 (4H, t), 3.80 (lH, m), 3.97 5- (2H, s), 4.12 (2H, d), 4.53 (2H, s), 4.90 (iH, br.), 7.30 (5H, s)
I R [f ilm] cm"1： 3320, 2920, 2850, 1765, 1700, 1525, 1462, IR [f ilm] cm " 1 : 3320, 2920, 2850, 1765, 1700, 1525, 1462,
1245, 1110  1245, 1110
vi) 3—（2—ヒ ドロキシェチル）一 1— [1 ー（2—メ トキシー 3—才 クタデシルカルバモイルォキシ）プロピル]ヒダン トイン vi) 3- (2-Hydroxyshetyl) 1-1- [1- (2-Methoxy-3-year-old Cutadecylcarbamoyloxy) propyl] hydantoin
0 V )で合成した化合物 1 .8 5 3 g[3 ミ リモル]及び 1 0 Pd/C 6 0 0 mgに 9 0 %舴酸水溶液を加え、 室温にて 1 4時間接触還元を行なつた。 触媒をろ別後、 母液を'减圧濃縮し、 得られた粗生成物をカラムクロマト グラフィ一 [シリ力ゲル： 5 0 g;溶出液：酉乍酸ェチル]にて精製し、 目的物 1 . 4 2 9 g (無色粉末， 9 0. 3 %)を得た。90 V aqueous acid solution was added to 1.853 g [3 mimol] and 10 Pd / C 600 mg of the compound synthesized by the above method, and the mixture was subjected to catalytic reduction at room temperature for 14 hours. . After the catalyst was removed by filtration, the mother liquor was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography [silica gel: 50 g; eluent: ethyl acetate] to obtain the desired product 1 429 g (colorless powder, 90.3%) were obtained.
5 T L C [Silica Gel;AcOEt]： R f = 0.47 5 T L C [Silica Gel; AcOEt]: R f = 0.47
N R :90MHz,CDCl3] δ ： 0.89(3H,t), 1.28(32H,s), 3.i6(2H,q), NR: 90MHz, CDCl 3 ] δ: 0.89 (3H, t), 1.28 (32H, s), 3.i6 (2H, q),
3.41(3H,s), 3.50〜3.70(2H,m), 3.76(4H,m), 3.83(lH,m), 4.03(2 H,s), 4.16C2H,m), 5.00(iH,br.)  3.41 (3H, s), 3.50-3.70 (2H, m), 3.76 (4H, m), 3.83 (lH, m), 4.03 (2H, s), 4.16C2H, m), 5.00 (iH, br. )
I RCKBr]cm-t: 3430, 2930, 2850, 1765, 1710, 1690, 1542,I RCKBr] cm -t : 3430, 2930, 2850, 1765, 1710, 1690, 1542,
0 1480 0 1480
vii) 1 —[(2—メ トキシー 3—才クタデシルカルバモイルォキシ）プ αピル]— 3 - (2 -Ρ- トルエンスルホニルォキシェチル）ヒダン トイン vi)で合成したアルコール体， 1 . 4 2 9 g[2. 7 0 8 ミ リモル]及び ト リェチルァミ ン 3 0 mlを塩化メチレン 1 0 mlに溶解し、 氷冷下 p— ト5 ルエンスルホニルクロライ ド 6 1 9 mg[ 3. 2 4 9 ミ リモル]を加えた後、 室温にて 3 日間攙拌した。 反応液に 1 N塩酸溶液を加えてク σ σホルム  vii) 1-[(2-Methoxy-3-butadecylcarbamoyloxy) -α-pill] —alcohol synthesized with 3- (2-Ρ-toluenesulfonyloxicetyl) hydantoin vi), 1. Dissolve 42.9 g [2.708 mimol] and 30 ml of triethylamine in 10 ml of methylene chloride and p-toluenesulfonyl chloride 6 19 mg [3.2 And then stirred at room temperature for 3 days. Add 1 N hydrochloric acid solution to the reaction mixture and add σ σ form
差換え 抽出し、 有機層を硫酸マグネシウムにて乾燥し、 溶媒を减圧留去した。 得られた粗生成物を力ラムクロマ トグラフィ ー [シリカゲル： 8 0 g；溶出 液：n -へキサン/ ϊ乍酸ェチル = 1/1.5]にて精製し、 目的物 1 . 8 4 6 g (飴 伏物質； 1 0 0 %)を得た。 Replacement After extraction, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by force chromatography (silica gel: 80 g; eluent: n-hexane / ethyl acetate = 1 / 1.5), and 1.846 g of the desired product (candy) (100%).
T L C [Silica Gel;n—へキサン 酢酸ェチル α/1.5)]： Rf = 0.31 T L C [Silica Gel; n-hexane ethyl acetate α / 1.5)]: Rf = 0.31
MR [90MHz ,CDC13] δ： 0.88(3H,t), 1.28(32H,s), 2.43(3H,s), 3.i6(2H,q), 3.40(3H,d), 3.45〜 3.68(2H, m) , 3.75(2H,t), 3.70- 3.88(lH，m), 3.98(2H,ABq), 4.12(2H,d), 4.25(2H,t), .85(1H, br . ) , 7.32(2H,d), 7.78(2H,d) MR [90MHz, CDC1 3] δ : 0.88 (3H, t), 1.28 (32H, s), 2.43 (3H, s), 3.i6 (2H, q), 3.40 (3H, d), 3.45~ 3.68 ( 2H, m), 3.75 (2H, t), 3.70-3.88 (lH, m), 3.98 (2H, ABq), 4.12 (2H, d), 4.25 (2H, t), .85 (1H, br.) , 7.32 (2H, d), 7.78 (2H, d)
I R [film]cm-1： 3330, 2920, 2850, 1770, 1710, 1598, 1525, 1465,IR [film] cm- 1 : 3330, 2920, 2850, 1770, 1710, 1598, 1525, 1465,
1360, 1240, 1190, 1180, 760 1360, 1240, 1190, 1180, 760
viii) 1 — [(2—メ トキシー 3—才クタデシルカルバモイルォキシ）プ 口ピル]— 3— ( 2—チアゾリオェチル）ヒダン トイ ン クロライ ド vii)で合成したトシル体、 4 4mg[0. 0 6 5 ミ リモル]にチアゾール 0. 5 mlを加え、 8 8〜 9 0てにて窒素気流中 4 0時間加熱した。 反応 液を減圧濃縮し、 残留物を I R A— 4 1 0 [C 1型] (5 ml:溶出液：メタノ —ル /水 = 7/3)にて処理し、得られた粗ク口ライ ド体をカラムクロマ ト グラフィ ー（シリカゲル： 4 g;溶出液：クロロホルムノメ タノ 一ル /水 =6 5/25/1)にて精製し、目的物 12mg (無色粉末、 29.2%)を得た。  viii) 1-[(2-Methoxy 3-butadecyl carbamoyloxy) lip]-Tosyl compound synthesized with 3- (2-thiazolioethyl) hydantoin chloride chloride, 4 mg [0.0 0.5 mol of thiazole was added to the mixture, and the mixture was heated in a nitrogen stream at 40 to 90 hours for 40 hours. The reaction mixture was concentrated under reduced pressure, and the residue was treated with IRA-410 [C1 type] (5 ml: eluent: methanol / water = 7/3). The product was purified by column chromatography (silica gel: 4 g; eluent: chloroform / ethanol / water = 65/25/1) to obtain 12 mg of the desired product (colorless powder, 29.2%).
T L C [Silica Gel； CHCl3/MeOH/H20(65/25/l)]： Rf = 0.13TLC [Silica Gel; CHCl 3 / MeOH / H 20 (65/25 / l)]: Rf = 0.13
MR :90皿 z,CDCl3] 5： 0.85(3H,t), 1.23(32H,s), 3.09(2H,q),MR: 90 dishes z, CDCl 3 ] 5: 0.85 (3H, t), 1.23 (32H, s), 3.09 (2H, q),
3.38(3H,s), 3.41〜4.28(liH,m), 5.04(1H, br. ) , 8.21， 8.76, il.05(eachlH,br.) 3.38 (3H, s), 3.41 ~ 4.28 (liH, m), 5.04 (1H, br.), 8.21, 8.76, il.05 (eachlH, br.)
I R [filmjcm-1 : 3300, 2920, 2850, 1763, 1700, 1520, 1485 実施例 ill IR (filmjcm -1 : 3300, 2920, 2850, 1763, 1700, 1520, 1485 Example ill
1 一 [(2—メ トキシー 3—才クタデシルカルバモイルォキシ）プロピ  1 1 [(2-Methoxy 3-Kutadecylcarbamoyloxy) prop
差換え ル]一 3— [2—(1 —メチルイ ミ ダゾリオ）ェチル]ヒダン トイン クロ ライ ド Replacement 1] 3— [2— (1—Methylimidazolio) ethyl] hydantoin chloride
i ) 3—（2—ョー ドエチル）一 1一 [(2—メ トキシー 3—ォクタデシ ルカルバモイルォキシ）プロピル]ヒダン トイン  i) 3- (2-iodoethyl) -1-1 [(2-methoxy-3-octadecylcarbamoyloxy) propyl] hydantoin
実施例 110— vii)で合成した化合物、 1 .8 4 6g[2. 7 0 8 ミ リモル] 及びヨウ化ナ ト リ ウム 6 0 9 mg[4. 0 6 2 ミ リモル]をアセトン 3 0 ml に溶解し、 3 1時間遮光して還流した。 冷後、 反応液を威圧濃縮し、 残 渣にクロ口ホルムを加えて沈澱をろ別後、 母液を滅圧濃縮した。 得られ た粗生成物をカラムクロマトグラフィ ー [シリカゲル： 5 5 g;溶出液：ii— へキサンノ詐酸ェチル = 1 / 11にて精製し、 目的物し 4 1 8g (無色 固体： 8 2. 1 %)を得た。  Example 110—The compound synthesized in vii), 1.846 g [2.708 mmol] and sodium iodide 600 mg [4.062 mmol] in acetone 30 ml And refluxed for 31 hours in the dark. After cooling, the reaction solution was concentrated under pressure, and the residue was mixed with chloroform to remove the precipitate. The mother liquor was concentrated under reduced pressure. The crude product obtained was purified by column chromatography [silica gel: 55 g; eluent: ii-ethyl ethyl hexanoate = 1/11] to give the desired product, 4 18 g (colorless solid: 82.1 %).
T L C [Silica Gel； n—へキサン //酢酸ェチル（ 1 1 )]： Rf=0.32 NMR [90MHz, CDCls] δ 0.88(3H,s), 1.25(32H,s), 3.16(2H,q), TLC [Silica Gel; n-hexane // ethyl acetate (1 1)]: Rf = 0.32 NMR [90MHz, CDCls] δ 0.88 (3H, s), 1.25 (32H, s), 3.16 (2H, q),
3.33(2H,t), 3.40(3H,s), 3.53(2H,m), 3. - 72(lH,m) , 3.89(2H,t), 4.03(2H,s), 4.14(2H,d) , 4.81(lH,br.) 3.33 (2H, t), 3.40 (3H, s), 3.53 (2H, m), 3.-72 (lH, m), 3.89 (2H, t), 4.03 (2H, s), 4.14 (2H, d ), 4.81 (lH, br.)
I R [ Brjcm-1 : 3330, 2920, 2850, 1770, 1718, 1698, 1540, IR [Brjcm -1 : 3330, 2920, 2850, 1770, 1718, 1698, 1540,
1480, 1277, 1265, 1250, 1125  1480, 1277, 1265, 1250, 1125
Π) 1 — [(2—メ 卜キン一 3—ォクダデシルカルバモイルォキシ）プ σピル]一 3— [ 2— ( 1 —メチルイ ミ ダゾリォ）ェチル]ヒダン トイン クロライ ド  Π) 1 — [(2-methodin-1-3-octadecylcarbamoyloxy) p σ pill] -1 3— [2- (1—methylimidazolyo) ethyl] hydantoin chloride
ί )で合成した化合物、 1 2 8 mg[0. 2 ミ リモル]に 1一メチルイ ミ ダゾール i 6 4mg[2 ミ リモル]を加え、 6 0てにて窒素気流中 2 4時間 加熱した。 反応液を减圧濃縮し、 残留物を I R A— 4 1 0 [01型](6(111 ；溶出液：メタノール Z水 = 7/3)にて処理し、 得られた粗グロライ ド体を カラムクロマトグラフィ一（シリ力ゲル： 6 g;溶出液：ク σ口ホルム/メ タノ ール/水 = 65/25/1)にて精製し、目的物 1 1 5mg (無色粉末、 9 1 . 差; beん 5 %)を得た。 To the compound synthesized in ί), 128 mg [0.2 mmol], 1-methylimidazole i64 4 mg [2 mmol] was added, and the mixture was heated in a nitrogen stream at 60 and heated for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was treated with IRA-410 [01] (6 (111; eluent: methanol / Z water = 7/3). Purify by chromatography (silica gel: 6 g; eluent: sigma-form / methanol / water = 65/25/1) to obtain 115 mg of the desired product (colorless powder, 91. be 5%).
Tし C [Silica Gel :CHCl3/MeOH/H20(65/25/i)]： Rf = 0.29T then C [Silica Gel: CHCl 3 / MeOH / H 20 (65/25 / i)]: Rf = 0.29
MR [90MHz, CDC13] <5： 0.88(3H,t), 1.27(32H,s), 3.15(2H,q), 3.42(3H,s), 3.58(2H,m), 3.73(lH,tn), 3.89-4.30 (9H, m) , 4.68 (2H,br.), 5.38(lH,br.)( 7.43 and 7.75(each lH.br. s), 10.36 MR [90MHz, CDC1 3] < 5: 0.88 (3H, t), 1.27 (32H, s), 3.15 (2H, q), 3.42 (3H, s), 3.58 (2H, m), 3.73 (lH, tn ), 3.89-4.30 (9H, m), 4.68 (2H, br.), 5.38 (lH, br.) ( 7.43 and 7.75 (each lH.br.s), 10.36
(lH.br. s) (lH.br.s)
I R [ Brlcm-1： 3425, 2925, 2850, 1770, 1710, 1530, 1470, IR [Brlcm -1 : 3425, 2925, 2850, 1770, 1710, 1530, 1470,
1252  1252
実施例 U2 Example U2
1 — [(2—メ トキシー 3—才クタデシルカルバモイルォキン）プロピ ル]— 3— [ 2—（ 1 —メチルピロ リ ジノ）ェチル]ヒダン トイン クロラ ィ ド  1 — [(2-Methoxy 3-butadecyl carbamoyl quine) propyl] — 3 -— [2- (1-Methylpyrrolidino) ethyl] hydantoin chloride
実施例 1 1 i — i )で合成した化合物、 1 2 8nig[0. 2 ミ リ.モル]に i 一メチルピロリ ジン 1 Ί 0 mg[2 ミ リモル]を加え、 6 0。Cにて窒素気流 中 2 4時間加熟した。 反応液を減圧濃縮し、 残留物を I R A— 4 1 0 [C 1型 (6 ml:溶出液：メタノールノ水 =7/3)にて処理し、得られた粗ク口ラ ィ ド体を力ラムクロマトグラフィー（シリカゲル： 6 g;溶出液：クロロホ ルム /メ タノ ール /水 = 65/25/1)にて精製し、目的物 1 2 0 mg (無色粉末、 9 5. 0 %)を得た。  Example 11 1Ί0 mg [2 millimoles] of i-methylpyrrolidine was added to 128 nig [0.2 millimoles] of the compound synthesized in 1i-i), and the mixture was added to the mixture. The mixture was ripened in a nitrogen stream at C for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was treated with IRA-410 (C1 type (6 ml: eluent: methanolic water = 7/3)). Purification by column chromatography (silica gel: 6 g; eluent: chloroform / methanol / water = 65/25/1) yielded 120 mg of the desired product (colorless powder, 95.0%) I got
T L C [Silica Gel； CHCl3/MeOH/H20(65/25/l)]： Rf = 0.24TLC [Silica Gel; CHCl 3 / MeOH / H 20 (65/25 / l)]: Rf = 0.24
' R [90MHz,CDCl3] δ： 0.88(3H, t), 1.26(32H,s), 2.29(4H, br.) , 3.15(2H,q), 3.40(3H,s), 3.42(3H,s), 3.57(2H>m), 3.72(lH,m), 3.78〜4.33(12H,m), 5.48(1H, br. t) 'R [90MHz, CDCl 3 ] δ: 0.88 (3H, t), 1.26 (32H, s), 2.29 (4H, br.), 3.15 (2H, q), 3.40 (3H, s), 3.42 (3H, s), 3.57 (2H > m), 3.72 (lH, m), 3.78 to 4.33 (12H, m), 5.48 (1H, br.t)
I R [ Br]cm_1: 3460, 2920, 2853, 1765, 1702, 1539, 1470, IR [Br] cm _1 : 3460, 2920, 2853, 1765, 1702, 1539, 1470,
1255 実施例 113 1255 Example 113
3— [2 3—メ トキシカルボニルピリジニォ）ェチル]一 1一 [(2— メ トキシー 3—ォクタデシルカルバモイルォキシ）プロピル]ヒダン トイ ン ョージ ド及び 3 - [2 - (3—カルボキシレイ トピリ ジニォ）ェチル] 一 1一 [(2—メ トキシー 3—ォクタデシルカルバモイルォキシ）プロピ ル]ヒダン トイン ョージ ド  3- [23-Methoxycarbonylpyridinio) ethyl] 1-111 [(2-Methoxy-3-octadecylcarbamoyloxy) propyl] hydantoinode and 3- [2- (3-carboxy) Laytopyridinyl) ethyl] 1 1 1 [(2-Methoxy 3- octadecylcarbamoyloxy) propyl]
実施例 1 1 1一 i )で合成した化合物、 3 1 9mg[0. 5 ミ リモル]に メチルニコチネ— ト 6 8 6 mg[5 ミ リモル]も加え、 8 0。Cにて窒素気流 中 2 4時間加熟した。 反応液を減圧濃縮し、 得られた粗生成物をカラム クロマ トグラフィ一（シリ力ゲル： 3 0 g;溶出液：グロ口ホルム Zメタノ ール- 5ゾ 1 )にて分離精製し前期溶出部よりカルボキシレート体 9 4 mg (黄色粉末）、 後期溶出部よりメ トキシカルボニル体 1 9 7mg (黄色粉 末、 5 0. 9 %)を得た。  To the compound synthesized in Example 1 1 1 1 i), 319 mg [0.5 mimol], methylnicotinate 686 mg [5 mimol] was also added, and the yield was 80. The mixture was ripened in a nitrogen stream at C for 24 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was separated and purified by column chromatography (silica gel: 30 g; eluent: Glo-mouth form Z methanol-5 zo 1). 94 mg of the carboxylate compound (yellow powder) was obtained, and 197 mg of the methoxycarbonyl compound (yellow powder, 50.9%) was obtained from the late elution part.
[メ トキシカルボニル体] [Methoxycarbonyl compound]
T L C [Silica Gel； CHCl3/MeOH(5/l)]： Rf = 0.24 TLC [Silica Gel; CHCl 3 / MeOH (5 / l)]: Rf = 0.24
N' R :90MHz,CDCl3] (5： 0.85(3H, t), 1.24(32H,s), 3. li(2H,q), N 'R: 90MHz, CDCl 3 ] (5: 0.85 (3H, t), 1.24 (32H, s), 3.li (2H, q),
3.40(3H,s), 3.50(2H,tn), 3.66(iH,m), 3.95〜4.38(9H, ra) . 5.13 (iH.br.), 5.41(2H,br.), 8.30(lH,t), 8.92(lH.d), 9.85(lH,s), 9.98(lH,d)  3.40 (3H, s), 3.50 (2H, tn), 3.66 (iH, m), 3.95-4.38 (9H, ra) .5.13 (iH.br.), 5.41 (2H, br.), 8.30 (lH, t), 8.92 (lH.d), 9.85 (lH, s), 9.98 (lH, d)
I R [K B r^cm-1： 3450, 2920, 2850, 1770, 1710, 1640, 1535, 1470,IR [KB r ^ cm -1 : 3450, 2920, 2850, 1770, 1710, 1640, 1535, 1470,
1440, 1308, 1248, 1205, 1160, 1130, 759 1440, 1308, 1248, 1205, 1160, 1130, 759
[カルボキシレート体] [Carboxylate form]
T L C [Silica Gel； CHCl3/ eOH(5/l)]： Rf = 0.37 TLC [Silica Gel; CHCl 3 / eOH (5 / l)]: Rf = 0.37
MR [90MHz, CDC 13] δ ： 0.88(3H,t)， 1.28(32H,s), 3.14(2H,q), 3.35〜3.81(6H，m), 3.89〜4.40(6H, m) , 4.55(lH,m), 5.29(2H, br.), MR [90MHz, CDC 1 3] δ: 0.88 (3H, t), 1.28 (32H, s), 3.14 (2H, q), 3.35~3.81 (6H, m), 3.89~4.40 (6H, m), 4.55 (lH, m), 5.29 (2H, br.),
8.29(lH,m), 8.95(lH,m), 9.63〜10. Q2(2H, m) I R [ B r]cm_1： 3400, 2920, 2850, 1770, 1710, 1530, 1470, 1475, 1250 8.29 (lH, m), 8.95 (lH, m), 9.63-10.Q2 (2H, m) IR [ Br ] cm_1 : 3400, 2920, 2850, 1770, 1710, 1530, 1470, 1475, 1250
実施.例 114 Example 114
3 - [2 -(4 -ジメチルァミノ ピリジニォ）ェチル]一 1一 [(2—メ ト キシ一 3—才クタデシルカルバモイルォキシ）プロピル]ヒダン トイン ョ一ジ ド  3- [2- (4-Dimethylaminopyridinio) ethyl] 1-11-1 ((2-Methoxy-1-3-tacutadecylcarbamoyloxy) propyl] hydantoinodide
実施例 1 1 1一 i )で合成した化合物、 1 2 8mg[0. 2 ミ リモル]及 び 4一ジメチルァミ ノ ピリ ジン 2 4 4 mg[2 ミ リモル]をク口口ホルム 2 mlに溶解し、 2 8 4時間加熟還流した。 冷後、 反応液を減圧濃縮し、 残 留物を力ラムクロマトグラフィ ー（シリカゲル： 1 2 g;溶出液：クロロホ ルム Zメタノ ール /水 = 65/25八）にて精製し、前期溶出部より目的物 7mg (無色粉末、 4. 6 %)、 後期溶出部より目的物及び 4ージメチルァミ ノ ピリジンの混合物 1 8 8 mgを得た。  Example 11 111 mg [0.2 mimol] and 41-dimethylaminopyridine 244 mg [2 mimol] of the compound synthesized in Example 11) were dissolved in 2 ml of ostium. The mixture was refluxed for aging for 284 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: 12 g; eluent: chloroform Z methanol / water = 65/258). 7 mg (colorless powder, 4.6%) of the desired product was obtained, and 188 mg of a mixture of the desired product and 4-dimethylaminopyridine was obtained from the late elution part.
T L C [Silica Gel； CHCl3/ eOH/H20(65/25/l)]： Rf = 0.54TLC [Silica Gel; CHCl 3 / eOH / H 20 (65/25 / l)]: Rf = 0.54
R :90MHz,CDCl3] δ： 0.88(3H,t), 1.25(32H,s), 3.13(2H,q),R: 90MHz, CDCl 3 ] δ: 0.88 (3H, t), 1.25 (32H, s), 3.13 (2H, q),
3.28(6H,s), 3.42(3H,s), 3.59(2H,m), 3.70(1H. m) , 3.88〜4.28 (6H,tn), 4.62(2H,ni), 5.05(1H, br . ) , 6.99 and 8.43(eac 2H,d) I R 1 B r]cm-1: 3400, 2920, 2850, 1770, 1710, 1650, 1570, 3.28 (6H, s), 3.42 (3H, s), 3.59 (2H, m), 3.70 (1H.m), 3.88-4.28 (6H, tn), 4.62 (2H, ni), 5.05 (1H, br. ), 6.99 and 8.43 (eac 2H, d) IR 1 B r) cm -1 : 3400, 2920, 2850, 1770, 1710, 1650, 1570,
1540, 1470, 1250  1540, 1470, 1250
実施例 115 Example 115
1 一 [(2—メ トキシー 3—才クタデシルカルバモイルォキシ）プロピ ル]— 3— [2— (ト リメチルァンモニォ）ェチル]ヒダン トイン クロラ ィ ド、  1 [(2-Methoxy 3- octadecyl carbamoyloxy) propyl] — 3— [2- (trimethylammonio) ethyl] hydantoin chloride,
実施例 1 1 1— i )で合成した化合物、 2 3 0 mg[ 0.3 6 2 ミ リモル] に 2 0 %トリメチルァミ ン一トルエン溶液 1 Omlを加え、 室温にて 2週 間放置した。 折出したョード塩を I R A— 4 1 0 [C1型] (1 5 ml;溶出 差換え 液：メタノ ール/水 = 7ノ 3 )にて処理し、 目的物 2 1 9 mg (無色粉末、 1 0 0 %)を得た。 To the compound synthesized in Example 11-11-i), 230 mg [0.362 mmol], 20% trimethylamine-toluene solution (1 Oml) was added and left at room temperature for 2 weeks. Replace the evoked salt with IRA-410 [C1] (15 ml; elution replacement) Liquid: methanol / water = 7-3) to give 219 mg of the desired product (colorless powder, 100%).
T L C [Silica Gel； CHCl3/Me0H/H20C65/25/l)]： Rf = 0.35TLC [Silica Gel; CHCl 3 / Me0H / H 2 0C65 / 25 / l)]: Rf = 0.35
MR [90MHz, CDC13] δ 0.87(3H,t), 1.26(32H,s), 3.i3(2E,q), 3.40〜3.79(3H,m), 3.42(3H,s), 3.49(9H, br. s) , 3.89〜4.26(8H, m), S.42(lH,br.t) MR [90MHz, CDC1 3] δ 0.87 (3H, t), 1.26 (32H, s), 3.i3 (2E, q), 3.40~3.79 (3H, m), 3.42 (3H, s), 3.49 (9H , br. s), 3.89 to 4.26 (8H, m), S.42 (lH, br.t)
I R [KBrlcm"1 : 3415, 2930, 2855, 1768, 1710, 1540, 1473, IR [KBrlcm] 1 : 3415, 2930, 2855, 1768, 1710, 1540, 1473,
1255  1255
実施例 116 Example 116
2— [N - (3—ォクタデシルカルバモイルォキシー 2—ェトキシプロ ピルォキシカルボニル）ァミ ノ ]メチル一 N—メチルピリ ジニゥム ク口 リ ド、 - i ) 2— 0—ェチル一 3—〇一 [N— (ピリ ジン一 2—ィル）メチル]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  2— [N- (3-octadecylcarbamoyloxy 2-—ethoxypropylpyroxycarbonyl) amino] methyl-1-N-methylpyridinium oxalate, -i) 2—0—ethyl-1 3-—1 [N— (pyridin-2-yl) methyl] force rubamoyl-1 1 0-octadecylcarbamoylglycerin
2 - 0—ェチルー 1一 0—ォクタデシルカルバモイルグリセリ ン（mp. δ 5〜5 6 °C) 8 3 0 rag [ 2 ミ リモル],フヱニルク σ σホルメー ト 3 4 4 mg[2. 2 ミ リモル]，ピリ ジン 3 2 0 mg及び塩化メチレン 1 0 mlより合 成したカーボネー ト体に 2—〔アミ ノ メチル）ピリ ジン 2 6 0 mg,ク σ σ ホルム 5 mlを加え、 1 2時間加熱還流した。 反応液を濃縮乾固し、 得ら れた生成物を力ラムクロマ トグラフィ,一 [シリ力ゲル： 4 0 g;溶出液，η— へキサン一酢酸ェチル（1 ： 3)]にて精製し、 目的物 7 2 7 mg(6 6 %)を 得た。  2-0-ethyl-11-0-octadecylcarbamoylglycerin (mp. Δ 5 to 56 ° C) 830 rag [2 mimol], finilk σ σ formate 3 4 4 mg [2.2 mi Rimole], 320 mg of pyridine and 10 ml of methylene chloride, 260 mg of 2- [aminomethyl) pyridine and 5 ml of σσ-form were added to the carbonate, and heated for 12 hours Refluxed. The reaction solution was concentrated to dryness, and the obtained product was purified by force chromatography, and purified by HPLC [silica gel: 40 g; eluate, η-hexane monoethyl acetate (1: 3)]. 727 mg (66%) of the desired product was obtained.
I RCKBi cnT1: 3325, 2925, 2850 , 1697, 1540, 1470, 1270 I RCKBi cnT 1 : 3325, 2925, 2850, 1697, 1540, 1470, 1270
NMR (60MHz,CDCl3) δ： 0.87(3Η), 1.08(3Η,ί), 1.27(32H,s), NMR (60MHz, CDCl 3 ) δ: 0.87 (3Η), 1.08 (3Η, ί), 1.27 (32H, s),
3.16(2H,q), 3.3〜4.0 (3Η, m) , 4.18(4H,m), 4.50(2H,d), 4.80 3.16 (2H, q), 3.3 ~ 4.0 (3Η, m), 4.18 (4H, m), 4.50 (2H, d), 4.80
(lH.br. ), 5.90(lH,brJ, 7.20(2H,m), 7.65(lH,m), 8.50(lH,m) 差換え ii ) 2—〇—ェチルー 3— 0— [N—ァせチル一 N—（ピリ ジン一 2— ィル）メチル]力ルバモイル一 1— 0—ォクタデシルカルバモイルグリセ リ ン (lH.br.), 5.90 (lH, brJ, 7.20 (2H, m), 7.65 (lH, m), 8.50 (lH, m) ii) 2—〇—Ethyl-3—0— [N—acetyl-N— (pyridin-2-yl) methyl] methyl-l-bamoyl-1—0—Octadecylcarbamoylglycerin
ί )で得た力ルバモイル体 2 8 5 mgをピリジン 5 mlに溶解し、 無水酢 酸 2 mlを加えて 1 0 0 °Cにて 2 3時間加熱した。 濃縮乾固し、 残渣をシ リ力ゲルク口マ トグラフィ一（展開溶媒，η—へキサン一蚱酸ェチル， 1 ： 1 )で精製し、 目的物 2 2 8 mg(7 5 %)を得た。  285 mg of the rubamoyl compound obtained in ί) was dissolved in 5 ml of pyridine, 2 ml of acetic anhydride was added, and the mixture was heated at 100 ° C. for 23 hours. After concentrating to dryness, the residue was purified by silica gel chromatography (developing solvent, η-hexane monoethyl ester, 1: 1) to obtain 228 mg (75%) of the desired product .
I R( Br)cm-1: 3350, 2930, 2855, 1742, 1705, 1698, 1598, 1532, 1370, 1115, 1080, 980, 778, 760IR (Br) cm -1 : 3350, 2930, 2855, 1742, 1705, 1698, 1598, 1532, 1370, 1115, 1080, 980, 778, 760
MR (90MHz, CDC13) δ： 0.87(3H,t), 1.07(3H,t), 1.23(32H,s) , MR (90MHz, CDC1 3) δ : 0.87 (3H, t), 1.07 (3H, t), 1.23 (32H, s),
2.60(3H(s,Ac), 3.U(2H,q), 3.3〜3.7(3H,m) , 3.97(2H,d), 4.21 (2H, ), 4.83(lH,br,NH), 5.08(2H, s , CH2 , Py) , 7.iO(2H), 7.60 (1H) , 8.48(1H) 2.60 (3H ( s, Ac), 3.U (2H, q), 3.3-3.7 (3H, m), 3.97 (2H, d), 4.21 (2H,), 4.83 (lH, br, NH), 5.08 (2H, s, CH 2 , Py), 7.iO (2H), 7.60 (1H), 8.48 (1H)
iii) 2— [N—（ 3—ォクタデシルカルバモイルォキシー 2—ェトキ シプロピルォキシカルボニル）ァミ ノ ]メチル一 ΝΪ—メチルピリ ジニゥム クロ リ ド  iii) 2- [N- (3-octadecylcarbamoyloxy-2-ethoxypropyloxycarbonyl) amino] methyl-1-methylpyridinium chloride
Π )で得た化合物 2 2 2 mgに沃化メチル 1 . 5 mlを加え、 2日間加熱 還流した。 冷後、 反応液を減圧濃縮し、 残渣を I R A - 4 1 0 [01型]( 1 5 ml:溶出液： MeOH— H20, 7： 3)にて処理した。 得られたク口ライ ド体を カラムクロマ トグラフィ ー [シリカゲル， 1 5 g，溶出液：クロ口ホルム一 メタノール， 4： 1 ]にて精製し、 目的物 1 2 5 mgを得た。1.5 mg of methyl iodide was added to 222 mg of the compound 222 obtained in Π), and the mixture was heated under reflux for 2 days. After cooling, the reaction solution was concentrated under reduced pressure, the residue IRA - 4 1 0 [01 inch] (1 5 ml: eluent: MeOH- H 2 0, 7: 3) was treated with. The obtained closed mouth was purified by column chromatography [silica gel, 15 g, eluent: chloroform-form-methanol, 4: 1] to obtain 125 mg of the desired product.
R(60MHz,CDCl3)<5： 0.87(3H,t), 1.12(3H), 1.25(32H,s), 2.64R (60MHz, CDCl 3 ) <5: 0.87 (3H, t), 1.12 (3H), 1.25 (32H, s), 2.64
(3H,s,Ac), 3.14C2H), 3.60(2H,q), 3.8〜4.S(6H), 4.72(3H, s , NMe) ,(3H, s, Ac), 3.14C2H), 3.60 (2H, q), 3.8-4.S (6H), 4.72 (3H, s, NMe),
5.45(2H,br-s,C|2-Py), 7.6~8.6(3H, m) , 9.60(1H) 5.45 (2H, br-s, C | 2 -Py), 7.6 ~ 8.6 (3H, m), 9.60 (1H)
実施例 117 Example 117
2— [N—（ 3—ォクタデシルカルバモイルォキシ一 2—エ トキンプロ 差換え ピルォキシカルボニル）ァミ ノ ]メチル一 N—ェチルピリ ジニゥム ョ一 ジ ド 2— [N— (3-octadecylcarbamoyloxy-2-etinopro) Replacement Pyroxycarbonyl) amino] methyl-1-N-ethylpyridinidine
実施例 1 1 6 - iii)で得た化合物 1 3 0 mgを沃化工チル 0. 5 mlに溶 解し、 2 7時間加熱還流した。 シリカゲルクロマ トグラフィ ー [溶出液 , クロ口ホルム→クロ口ホルム一メタノール（2 0： 1 )]で精製し、 目的物 1 0 3 mgを得た。  130 mg of the compound obtained in Example 11-iii) was dissolved in 0.5 ml of iodide chill and heated under reflux for 27 hours. The residue was purified by silica gel chromatography [eluent, black-mouthed form → black-mouthed form-methanol (20: 1)] to obtain 103 mg of the desired product.
I R ( Br)cm-1： 3420, 2925, 2850, 1738, 1700, 1628, 1530, IR (Br) cm -1 : 3420, 2925, 2850, 1738, 1700, 1628, 1530,
1465, 1370, 1220, 1160, 985, 778  1465, 1370, 1220, 1160, 985, 778
NMR (90MHz, CDC13)<5： 0.87(3H,t), i.l5(3H,t), 1.25(32H,s), NMR (90MHz, CDC1 3) < 5: 0.87 (3H, t), i.l5 (3H, t), 1.25 (32H, s),
1.73(3H,t), 2.66(3H,s, -Ac), 3.1l(2H,q), 3.61(2H,q), 3.85 1.73 (3H, t), 2.66 (3H, s, -Ac), 3.1l (2H, q), 3.61 (2H, q), 3.85
(lH,m), 4.02C2H), 4.39(2H), 4.93(1H, br, , 5.- 08(2H, q,I-CH2) , 5.47(2H,s,CH2-Py)> 7.84(1H), 8.05(1H), 8.41(1K), 9.64(1H) 実施例 U8 . (lH, m), 4.02C2H) , 4.39 (2H), 4.93 (1H, br,, 5.- 08 (2H, q, I-CH 2), 5.47 (2H, s, CH 2 -Py)> 7.84 (1H), 8.05 (1H), 8.41 (1K), 9.64 (1H) Example U8.
3ーォクタデシルカルバモイルー 2—メチルー 1—(ピリ ジン一 2— ィル）カルパ'モイルグリセロール  3-octadecylcarbamoyl-2-methyl-1- (pyridin-1-yl) carpa'moylglycerol
tn-力ルボキシピリ ジン 0. 6 1 δ g(-5 ミ リモル），ジフエニルホスホ リルアジ ド し 5 1 5g(5. 0 5 ミ リモル）， ト リェチルァミ ン 0. 6 g をトルエン 1 Omlに溶かし、 室温にて 2時間かきまぜてから、 1時間加 熟還流した。 反応液を約半分まで濃縮してから、 3—才クタデシルカル バモイルー 2—メチルダリセロール 1 . 9 g(4. 7 4 ミ リモル）を加え て、 1 0 0て，一夜加熱し、 反応液を減圧下に濃縮乾固して、 残渣をシ リカゲル（2 D g)溶出液，クロロホルムにて精製して無色結晶 1 . 7 4 g (収 率 7 0. 4 %)を得た。  Dissolve 0.61 δg (-5 mimol) of tn-potassyl oxypyridine, 5 g (5.05 mimol) of diphenylphosphoryl azide and 0.6 g of triethylamine in 1 Oml of toluene and bring to room temperature. After stirring for 2 hours, the mixture was refluxed for aging for 1 hour. After concentrating the reaction solution to about half, add 1.9 g (4.74 mimol) of 3-methyltadecylcarbamoyl-2-methyldaricerol, heat it up to 100, and heat it overnight. The residue was concentrated to dryness under reduced pressure, and the residue was purified with silica gel (2 Dg) eluate and chloroform to obtain 1.74 g of colorless crystals (yield: 70.4%).
T L C .Silica gel , CHC , MeOH(i9： 1) T L C .Silica gel, CHC, MeOH (i9: 1)
Rf=0.27, 単一スポヅ ト  Rf = 0.27, single spot
N RC60MC,CDC13)5： 0.97(3H), 1.25(32H), 3.17C2H), 3.47(3H), 3.67C1H), 4.23C2H), 4.33(2H), 7.23C1H), 7.9δ(1Η) N RC60MC, CDC1 3 ) 5: 0.97 (3H), 1.25 (32H), 3.17C2H), 3.47 (3H), 3.67C1H), 4.23C2H), 4.33 (2H), 7.23C1H), 7.9δ (1Η)
実施例； 9 Example; 9
3— [(3—ォクタデシルカルバモイルォキシ一 2—メ トキシプロポキ シ）カルボニルアミ ノ ]一 1一メチルピリ ジニゥム ィォダイ ド  3-[(3-octadecylcarbamoyloxy-l- 2-methoxypropoxy) carbonylamino] -l-methylpyridinidine iodide
実施例 1 1 8で得たピリ ジン誘導体 3 0 0 mg( 0. 5 7 ミ リモル）をョ ゥ化メチル 2 mしジクロロメタ ン 2 mlに溶かし室温にて 2日間放置した。 反応液を減圧下に濃縮乾固して、 残渣を η—へキサンにて洗って無色 粉末 3 7 5mg (収率 1 0 0 %)を得た。  300 mg (0.557 mmol) of the pyridine derivative obtained in Example 118 was dissolved in 2 ml of methyl chloride and 2 ml of dichloromethane, and left at room temperature for 2 days. The reaction solution was concentrated to dryness under reduced pressure, and the residue was washed with η-hexane to obtain 37.5 mg of a colorless powder (yield: 100%).
I R (KBr)cm-1： 3310, 2920, 2850, 1730, 1695， 1550, 1510, IR (KBr) cm- 1 : 3310, 2920, 2850, 1730, 1695, 1550, 1510,
1460, 1270, 1240, 1160, 1060  1460, 1270, 1240, 1160, 1060
NMR(60 C,CDC13)<5： 0.87(3H), 1.25(32H), 3.17(2H), 3.45(3H), 3.70(1H), 4.20(4H), 4.50(3H), 5.13(1H), 7.90(1H), 8.70(1H), 8.87(1H), 9.38(1H), 9.93(1Η)· . 実施例 o NMR (60 C, CDC1 3) <5: 0.87 (3H), 1.25 (32H), 3.17 (2H), 3.45 (3H), 3.70 (1H), 4.20 (4H), 4.50 (3H), 5.13 (1H) , 7.90 (1H), 8.70 (1H), 8.87 (1H), 9.38 (1H), 9.93 (1Η) .Example o
3—ォクタデシルカルバモイルー 2—メチル一 1一（N—ァセチルー 3-octadecylcarbamoyl 2-methyl-1- (N-acetyl
N一ピリ ジン一 3—ィル）力ルバモイルグリセリ ン N-pyridin-1-3-yl) l-rubamoylglycerin
実施例 1 1 8で得たピリ ジン誘導体 3 2 0 mg( 0. 6 1 3 ミ リモル）を ピリ ジン 3 ml,無水酢酸〖 . 5mlの混液に溶かし、 3時間加熟還流した。 反応液を減圧下に濃縮乾固して、 残渣をシリ力ゲル（5g)溶出液ク口 口ホルムにて精製して無色固形物 2 0 3 mg (収率 5 8. 7 %)を得た。 320 mg (0.613 mimol) of the pyridine derivative obtained in Example 118 was dissolved in a mixture of 3 ml of pyridine and 0.5 ml of acetic anhydride, and the mixture was refluxed for ripening for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel (5 g). The eluate was used to form a colorless solid (203 mg, yield 58.7%). .
T L C .Silica gel , CHC , MeOH(19： i) T L C .Silica gel, CHC, MeOH (19: i)
Rf = 0.52, 単一スポヅ ト Rf = 0.52, single spot
R(60MC,CDC13)<5： 0.92(3H), 1.23(32H), 2.65(3H), 3.07(2H), 3.25C3H), 3.40C1H), 3.90(2H), 4.20(2H), 4.90(lH), 7.43(2H), 8.40(1H), 8.57(1H) R (60MC, CDC1 3 ) <5: 0.92 (3H), 1.23 (32H), 2.65 (3H), 3.07 (2H), 3.25C3H), 3.40C1H), 3.90 (2H), 4.20 (2H), 4.90 ( lH), 7.43 (2H), 8.40 (1H), 8.57 (1H)
実施例 121 3— [N— ( 3—ォクタデシルカルバモイルォキシー 2—メ トキシプロ ポキシカルボ二ル）一 N—ァセチル]アミ ノ一 1一メチルピリ ジニゥム ィォダイ ド Example 121 3— [N— (3-octadecylcarbamoyloxy) 2-methoxypropoxycarbonyl) -N-acetyl] amino-1 1-methylpyridinimide
実施例 1 2 0で得たアセテート 2 0 0 mg( 0. 3 5 ミ リモル）をジクロ ロメタン 1 mi,ヨウ化メチル 2 mlの混液に溶かし、 室温にて 2日間放置 した。  Example 1 200 mg (0.35 mmol) of the acetate obtained in 20 was dissolved in a mixed solution of 1 mi of dichloromethane and 2 ml of methyl iodide, and allowed to stand at room temperature for 2 days.
反応液を減圧下に濃縮乾固して、 残渣を n -へキサンにて洗い無色粉 末 24 6 mg (収率 1 0 0 %)を得た。  The reaction solution was concentrated to dryness under reduced pressure, and the residue was washed with n-hexane to obtain 246 mg of a colorless powder (100% yield).
T L C .Silica gel , CHC , MeOH, H20(65： 25： ) TLC .Silica gel, CHC, MeOH, H 20 (65:25:)
Rf = 0.50, 単一スポヅ ト  Rf = 0.50, single spot
I R( Br)cm_1: 3400, 2920, 2850, 1760, 1720, 1500, 1470, IR (Br) cm _1 : 3400, 2920, 2850, 1760, 1720, 1500, 1470,
1370, 1250, 1100, 1045, 915  1370, 1250, 1100, 1045, 915
NMR(60MC,CDC13)5： 0.92(3H), 1.25(32H), 2.72(3H), 3.05(2H), NMR (60MC, CDC1 3) 5 : 0.92 (3H), 1.25 (32H), 2.72 (3H), 3.05 (2H),
3.37C3H), 3.60(1H), 3.89(2H), 4.28(2H), 4.63(3H), 5.00(1H), 8.G〜8.5(2H), 9.1'7〜9.47(2H) 3.37C3H), 3.60 (1H), 3.89 (2H), 4.28 (2H), 4.63 (3H), 5.00 (1H), 8.G ~ 8.5 (2H), 9.1'7 ~ 9.47 (2H)
実施例 122 Example 122
3—ォクタデシルカルバモイルー 2—メチルー 1— (ピリ ジン一 2— ィル）力ルバモイルグリセリ ン  3-Octadecylcarbamoyl-2-methyl-1- (pyridin-2-yl) capable rubamoylglycerin
α—ピコリ ン酸 1. 2 3 g( 1 0 ミ リモル），ジフエ二ルホスホリルアジ ド 3. 0 3 g( 1 1 ミ リモル）， トリェチルァミ ン 1 . 2 gとトルエン 2 0 miを実施例 1 1 8と同様に処理して、 無色結晶 2. 7 g (収率 83 %)を 得た。  Example 1 was prepared using 1.23 g (10 mimol) of α-picolinic acid, 3.03 g (11 mimol) of diphenylphosphoryl azide, 1.2 g of triethylamine and 20 mi of toluene. By treating in the same manner as in 18, a colorless crystal (2.7 g, yield 83%) was obtained.
T L C .Silica gel , CHC13 , MeOH(L9： 1) TLC .Silica gel, CHC1 3, MeOH (L9: 1)
Rf = 0.51, 単一スポヅ ト  Rf = 0.51, single spot
NMR (60MC,CDC13) <5： 0.92(3H), 1.25(32H), 3.13(2H), 3.47(3H), 3.70C1H), 4.20(2H),_ 4.30(2H), 4.73(1H), 6.90(1H), 7.65(1H), 差換え 7.90C1H), 8.33C1H), 8.83(lfl) NMR (60MC, CDC1 3) < 5: 0.92 (3H), 1.25 (32H), 3.13 (2H), 3.47 (3H), 3.70C1H), 4.20 (2H), _ 4.30 (2H), 4.73 (1H), 6.90 (1H), 7.65 (1H), Replacement 7.90C1H), 8.33C1H), 8.83 (lfl)
実施例 123 Example 123
N— [ 2— [ 3— (ォクタデシルカルバモイルォキン一 2—メ トキシプ ロポキシ）カルボニルァミ ノ ]ェチル]一 N—ェトキシカルボニルメチル — N , N—ジメチルアンモニゥム クロリ ド  N— [2 -— [3 -— (octadecylcarbamoylquinone-2- (methoxypropoxy) carbonylamino] ethyl] -1-N-ethoxycarbonylmethyl—N, N-dimethylammonium chloride
実施例 9で得たジメチル体 1 . 0 3 g(2 ミ リモル）をモノ ク口ロ蚱酸 ェチルエステル 2 mlに溶かし 1 6時間室温にて放置した。 反応液を減圧 下に留去し、 残渣を酢酸ェチル 6 tnlより熱時再結晶して無色針状結晶 1 . 2 g (収率 9 4. 0 %)を得た。  1.03 g (2 mmol) of the dimethyl compound obtained in Example 9 was dissolved in 2 ml of monomethyl ethyl ester and left at room temperature for 16 hours. The reaction solution was distilled off under reduced pressure, and the residue was recrystallized from 6 tnl of ethyl acetate under heating to obtain 1.2 g of colorless needle crystals (yield 94.0%).
T L C .silica gel , CHC13. eOH, H20(65： 24： ) . TLC .silica gel, CHC1 3 eOH , H 2 0 (65: 24:)
R f-0.37  R f-0.37
I R (nim)cnT1 3350, 2920, 2850, 1775, 1710, 1520, 1470, IR (nim) cnT 1 3350, 2920, 2850, 1775, 1710, 1520, 1470,
1450, 1260, 1150, 1030 1450, 1260, 1150, 1030
MR(60MC,CDC13) δ ： 0.83C6H), 1.27 (32H), 3.13(2H), 3.60(6H), 4.13(6H), 5.13(1H), 7.33(1H), 3.2〜4.3(5H) MR (60MC, CDC1 3) δ : 0.83C6H), 1.27 (32H), 3.13 (2H), 3.60 (6H), 4.13 (6H), 5.13 (1H), 7.33 (1H), 3.2~4.3 (5H)
実施例 124 Example 124
N - [2— [( 3—ォクタデシルカルバモイルォキシ一 2—メ トキシプ ロボキシ）力ルポニルァミ ノ：!ェチル]— N—力ルボキシレー トメチルー N , N—ジメチルアンモニゥム  N- [2 -— ((3-octadecylcarbamoyloxy-1-2-methoxypropyl) amino !! ethyl] —N-nitrocarboxylate Methyl N, N-dimethylammonium
実施例 1 2 3で得たエステル 3 0 0 mgを t—ブタノ ール 1 . 5 6 mlに 溶かし、 粉末水酸化カリ ウム 2 6 mgを加え、 1時間室温にてかきまぜた 後、 濃塩酸にて中和して氷水 1 0 mi,ジクロロメタ ン 1 0 mlを加えて、 かきまぜ有機層を分取して、 硫酸ナトリウムにて乾かしてから、 減圧下 に囊縮乾固し、 残渣をシリ力ゲル（5 g) (展開溶媒クロロホルム，メ タノ ール，水（65/24/4))にて精製し、無色粉末 2 1 6 mg (収率 8 0. 0 %)を得 た。 TL C , silica gel , CHC13 , MeOH, H20(65： 25： 4) Example 12 Dissolve 300 mg of the ester obtained in 23 in 1.56 ml of t-butanol, add 26 mg of powdered potassium hydroxide, stir at room temperature for 1 hour, and then add concentrated hydrochloric acid. Neutralize and add 10 mi of ice water and 10 ml of dichloromethane, stir and separate the organic layer, dry with sodium sulfate, and then reduce to dryness under reduced pressure. (5 g) (developing solvent: chloroform, methanol, water (65/24/4)) to give 216 mg of a colorless powder (80.0% yield). TL C, silica gel, CHC1 3 , MeOH, H 2 0 (65: 25: 4)
Rf = 0.31 単一スポ ヅ ト  Rf = 0.31 single spot
I R(KBr)cm~1: 3450, 2930, 2850, 1710, 1640, 1540, 1470, IR (KBr) cm ~ 1 : 3450, 2930, 2850, 1710, 1640, 1540, 1470,
1400, 1270, 1140, 1050  1400, 1270, 1140, 1050
NMRCeOMC.CDCla) δ ： 0.83(3H), 1.25(32H), 3.10(2H), 3.32(3H),NMRCeOMC.CDCla) δ: 0.83 (3H), 1.25 (32H), 3.10 (2H), 3.32 (3H),
3.40C6H), 4.08(4H), 5.30C1H), 7.60(1H), 2.9〜4.G(5H) 3.40C6H), 4.08 (4H), 5.30C1H), 7.60 (1H), 2.9 ~ 4.G (5H)
実施例 125 Example 125
1 — ( 3—ト リチルォキシ一 2—メ トキシプロピル）ゥラシル  1 — (3-trityloxy 2- 2-methoxypropyl) peracil
ゥラシル 2. 2 4 g(2 0 ミ リモル）， 3—ト リチル 2—メチルダリセ口 ール 5. 0 3 g( 1 0 ミ リモル）を炭酸ソーダ 4. 2 4 g存在下、 ジメチル ホルムァミ ド 2 0 mlに懸蜀して 1 0 5。C , 1 6時間かきまぜた。 反応液 を減圧下に濃縮乾固して、 残渣に水 1 0 0 ml,クロ口ホルム 1 0 0 を 加えて、 g乍酸にて水層を ΡΗ 7. 0に調整して、 激しくふりまぜてから、 有機層を分取して、 硫酸ナトリウムで乾かしてから、 減圧下に 縮乾固 する。 残渣をシリカゲル（3 Og) [溶出液，クロ口ホルム，酢酸ェチル ,η— へキサン（4 ： 1 ： 3 )；；にて精製して、 無色粉末 2. 6 7g (収率 6 0. 5 %)を得た。  Peracil 2.24 g (20 mmol), 3-trityl 2-methyldariceol 5.03 g (10 mmol) in the presence of 4.24 g of sodium carbonate in dimethylformamide 20 Shut to the ml and 105. C, stirred for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, 100 ml of water and 100 ml of chloroform were added to the residue, and the aqueous layer was adjusted to ΡΗ7.0 with acid while stirring vigorously. Then, the organic layer is separated, dried over sodium sulfate, and then reduced to dryness under reduced pressure. The residue was purified by silica gel (3 Og) [eluent, ethyl acetate, ethyl acetate, η-hexane (4: 1: 3); 2.67 g of colorless powder (yield 60.5). %).
T L C .silica gel , CHC , eOH(19： 1) , Rf = 0.44  T L C .silica gel, CHC, eOH (19: 1), Rf = 0.44
実施例 126 Example 126
1 — (3—ト リチルォキシ一 2—メ トキシプロピル）一 3 - (ピリ ジン 1 — (3-trityloxy 2- 2-methoxypropyl) -1- 3- (pyridine
— 2—ィル）メチルゥラシル — 2-yl) methylperacyl
実施例 1 2 5で得たゥラシル誘導体 1 . 2g(2. 7 2 ミ リモル）， 2— クロロメチルピリ ジン塩酸塩 1 . 0 4g(8. 1 5 ミ リモル）を粉末水酸 化カリ ウム 1 . 1 2 g存在下，ジメチルスルホキシ ド 6 mUこ溶かし、 5 0 ， 1時間かきまぜた。 反応液を水 6 0 mlにあけ pH 7. 0に調整した後、 エーテル 6 0 mlにて抽出し、 エーテル層は硫酸ナ ト リ ゥムにて乾かし減 差換え 圧下に濃縮乾固した。 残渣をシリカゲル（1 0 g) [展開溶媒，詐酸ェチル， n—へキサン（2 : 1 )]にて精製して無色固形物 1 . 42(収率9 6 . 5 %) を得た。 Example 1 1.2 g (2.72 mmol) of the peracyl derivative obtained in 25 and 1.04 g (8.15 mmol) of 2-chloromethylpyridine hydrochloride were added to powdered potassium hydroxide 1 In the presence of 12 g, dimethyl sulfoxide was dissolved in 6 mU, and the mixture was stirred for 50 hours. The reaction mixture was poured into 60 ml of water, adjusted to pH 7.0, extracted with 60 ml of ether, and the ether layer was dried with sodium sulfate and replaced. Concentrated to dryness under pressure. The residue was purified by silica gel (10 g) [developing solvent, ethyl acetate, n-hexane (2 : 1)] to give a colorless solid 1.42 (yield 96.5%).
T L C .silica gel , n- Hexane, EtOAc(l:2), R f = 0.14  T L C .silica gel, n- Hexane, EtOAc (l: 2), R f = 0.14
NMR(60MC,CDC13) <5： 3.22(1H), 3.28(3H), 3.60(2H), 4.05(2H), NMR (60MC, CDC1 3) < 5: 3.22 (1H), 3.28 (3H), 3.60 (2H), 4.05 (2H),
5.23(2H), 7.0〜8.0(18H), 8.27(lH) 5.23 (2H), 7.0〜8.0 (18H), 8.27 (lH)
実施例 127 Example 127
1 一（ 3—ハイ ドロキシー 2—メ トキシプロピル）一 3—（ピリ ジン一 2—ィル）メチルゥラシル  1- (3-hydroxy-2-methoxypropyl) -3- (pyridin-2-yl) methylperacyl
実施例 1 2 6で得たトリチル体 1 . 4 g(2 . 6 2 ミ リモル）をメタノ ール 4 0 ml，水 5 ml,濃塩酸 3 mlの混液に溶かし、 室温にて 1時間かきま ぜ 4てに冷却し、 折出する結晶をろ去し、 母液は 1 N—水酸化ナトリウ ムにて中和後減圧下に濃縮乾固した。 残渣をクロ口ホルム 1 9 ml,メタ ノール i n の混液に溶かし、 不溶物を除いてから再び'减圧下に濃縮乾固 して、 残渣をシリカゲル（1 O g) [展開溶媒，クロ口ホルム，メタノール（ 1 9 ： 1 )]にて精製して無色固形物 7 2 9 mg (収率 1 0 0 %)を得た。  Example 12 1.4 g (2.62 mmol) of the trityl form obtained in 26 was dissolved in a mixture of 40 ml of methanol, 5 ml of water and 3 ml of concentrated hydrochloric acid, and stirred at room temperature for 1 hour. The resulting solution was cooled, and the precipitated crystals were filtered off. The mother liquor was neutralized with 1N-sodium hydroxide and concentrated to dryness under reduced pressure. The residue was dissolved in a mixture of 19 ml of chloroform and methanol in, and the insoluble matter was removed. The residue was again concentrated to dryness under reduced pressure, and the residue was silica gel (1 Og) [developing solvent, chloroform, Methanol (19: 1)] to give 729 mg (100% yield) of a colorless solid.
T L C , silica gel , CHC13 , eOH(19： 1) , Rf = 0.25 TLC, silica gel, CHC1 3, eOH (19: 1), Rf = 0.25
R(60MC,CDCl3)(5 ： 2.8δ(1Η), 3.88(3Η), 3.60(3Η), 3.93(2Η), 5.27(2Η), 5.73(1Η), 7.23(3Η), 7.60(1Η), 8.30(1Η)  R (60MC, CDCl3) (5: 2.8δ (1Η), 3.88 (3Η), 3.60 (3Η), 3.93 (2Η), 5.27 (2Η), 5.73 (1Η), 7.23 (3Η), 7.60 (1Η), 8.30 (1Η)
実施例 128 Example 128
1 一（ 3—ォクタデシルカルバモイルォキン一 2—メ トキシ）プロピル 一 3—（ピリ ジン一 2—ィル）メチルウランル  1- (3-octadecylcarbamoyl-quin-1--2-methoxy) propyl 1-3- (pyridin-2-yl) methyluran
実施例 1 2 7で得たハイ ドロキシ体 7 2 9 mg( 2 . 6 5 ミ リモル），ォ クタデシルイソシアナート 0 . Ί 8 g(2 . 6 5 ミ リモル）をピリ ジン 1 m Uこ溶かし、 1 0 5 °C, 1 6時間加熟した。 反応液を減圧下に濃縮乾固し て、 残渣をシリカゲル（1 5 g) [溶出液，クロ口ホルム，メタノール（49:1)] 差 にて精製して、無色粉末 1 .2g (収率 7 7. 2 %)を得た。 Example 12 729 mg (2.65 mmol) of the hydroxy compound obtained in 27 and 0.8 g (2.65 mmol) of octadecyl isocyanate were dissolved in 1 mU of pyridine. Aged at 105 ° C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel (15 g) [eluent, chloroform, methanol (49: 1)]. Then, 1.2 g (yield: 77.2%) of a colorless powder was obtained.
T L C .silica gel, CHC13 ,MeOH(19： 1) , Rf=0.42 TLC .silica gel, CHC1 3, MeOH (19: 1), Rf = 0.42
N R(60MC,CDC13)<5： 0.87(3H), 1.23(32H), 3.38(3H), 3.63(1H), 4.11C2H), 4.15C2H), 5.08(LH). 5.27(2H). 5.72(1H), 7.17(2fi), 7.23(1H), 7.58C1H), 8.45(1H) NR (60MC, CDC1 3) < 5:.. 0.87 (3H), 1.23 (32H), 3.38 (3H), 3.63 (1H), 4.11C2H), 4.15C2H), 5.08 (LH) 5.27 (2H) 5.72 ( 1H), 7.17 (2fi), 7.23 (1H), 7.58C1H), 8.45 (1H)
実施例 129 Example 129
2 - [ 1 一（3—ォグタデシルカルバモイルォキシ一 2—メ トキシプロ ピル）ゥラシルー 3—ィル]メチルー 1一メチルピリ ジニゥム ィォダイ ド、  2-[1- (3-Ogutadecylcarbamoyloxy-1-2-methoxypropyl) ゥ lacyl-3-yl] methyl-1-methylpyridinidine iodide,
実施例 1 2 8で得たピリ ジン誘導体 7 0 0 mg( 1 . 1 9 ミ リモル）をジ クロロメタ ン 0. 5 ml,ヨウ化メチル 3 3 8. 6 mg(2. 3 8 6 ミ リモル） の混液に溶かし、 室温にて一夜放置し、 反応液を减圧下に濃縮乾固して、 残渣をジクロ,ロメタン 1 . 5 ml，n—へキサン 1 5 mlの混液より再桔晶し て、 無色粉末 8 8 Omg (収率 1 0 0 %)を得た。  700 mg (1.19 millimoles) of the pyridine derivative obtained in Example 128 was used in 0.5 ml of dichloromethane, and 338.6 mg of methyl iodide (2.386 millimoles). The reaction mixture was allowed to stand overnight at room temperature, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was recrystallized from a mixture of dichloromethane, dichloromethane 1.5 ml, and n-hexane 15 ml. 88 Omg of a colorless powder (100% yield) was obtained.
T L C .silica gel , CHC13 , eOH, H20(65： 25： 4) , Rf = 0.33 TLC .silica gel, CHC1 3, eOH , H 2 0 (65: 25: 4), Rf = 0.33
I R (nim)cm_1： 3300, 2940, 2850, 1710, 1660, 1515, 1455, IR (nim) cm _1 : 3300, 2940, 2850, 1710, 1660, 1515, 1455,
1400, 1370, 1250"1 1400, 1370, 1250 " 1
MR (60MC.CDC ) δ 0.90(3H), 1.25(32H), 6.48(2H), 3.40C3H), 3.70(1H), 4.1δ(4Η), 4.72(3H), 5.15(lH), 5.25(2H), 5.80(1H), 7.5Q(1H), 7.97(2H), 8.43(1H), 9.35(1H)  MR (60MC.CDC) δ 0.90 (3H), 1.25 (32H), 6.48 (2H), 3.40C3H), 3.70 (1H), 4.1δ (4Η), 4.72 (3H), 5.15 (lH), 5.25 (2H ), 5.80 (1H), 7.5Q (1H), 7.97 (2H), 8.43 (1H), 9.35 (1H)
元素分折： C 3 + HS7N + 05 I ♦ 2 H20 (764.79) Elemental folding: C 3 + H S7 N + 0 5 I ♦ 2 H 2 0 (764.79)
C , 53.40; H , 8.04; N , 7.33  C, 53.40; H, 8.04; N, 7.33
C , 53.40; H, 7.89; N , 7.43  C, 53.40; H, 7.89; N, 7.43
実施例 130 . Example 130.
1 — (3—ト リチルォキシー 2—メ トキシプロピル）一 3— (2—ベン ジルォキシェチル）ゥラシル 実施例 1 2 5で得たゥラシル誘導体 1 . 3 6g(3. 0 8 ミ リモル）， 21 — (3—Trityloxy 2—Methoxypropyl) 1 3— (2—Benziloxityl) ゥ racil Example 1 1.36 g (3.08 mimol) of peracyl derivative obtained in 25, 2
—ベンジル一 1一トシルエチレングリ コール 2. 8 3 g(9. 2 4 ミ リモ ル）をジメチルスルホキシ ド 6 mlに溶かし、 粉末水酸化力リウム 6 9 0 m gを加えて、 5 0 °C, 2時間かきまぜた。 反応液を氷水 6 0 mlにあけ酢酸 にて pH 7. 0に調整して、 エーテル 1 0 0 mlにて抽出し、 エーテル層 は硫酸ナトリゥムにて乾かし、 减圧下に濃縮乾固して残渣をシリカゲル (1 5g) [溶出液， η—へキサン，詐酸ェチル（2： 1 )]にて精製して、 詒状 物質に 7 8 g (収率 1 0 0 %)を得た。 —Dissolve benzyl-1-tosylethylene glycol (2.83 g, 9.24 millimol) in dimethyl sulfoxide (6 ml), add powdered hydroxide hydroxide (690 mg), and add the solution at 50 ° C. , Stir for 2 hours. The reaction solution was poured into 60 ml of ice water, adjusted to pH 7.0 with acetic acid, extracted with 100 ml of ether, the ether layer was dried over sodium sulfate, and concentrated to dryness under reduced pressure to remove the residue. Purification with silica gel (15 g) [eluent, η-hexane, ethyl sulphate (2: 1)] gave 78 g (yield 100%) of a toluene-like substance.
T L C .silica gel , n- Hexane, EtOAc(l:l) T L C .silica gel, n- Hexane, EtOAc (l: l)
Rf = 0.50, 単一スポヅ ト Rf = 0.50, single spot
R(60MC,CDC13)(5： 3.25(3H), 3.23(1H), 3.52(2H), 3.70(2H),R (60MC, CDC1 3 ) (5: 3.25 (3H), 3.23 (1H), 3.52 (2H), 3.70 (2H),
4.13C4H), 4.50C2H), 5.53(1H), 6.7〜8J(2H) 4.13C4H), 4.50C2H), 5.53 (1H), 6.7-8J (2H)
実施例 Ul , . -Example Ul, .-
1 一（ 3—ハイ ドロキシー 2—メ トキシプロピル）一 3— ( 2—ベンジ ルォキシェチル）ウランル 1 1 (3—hydroxy 2-methoxypropyl) 1 3— (2-benzyloxystil) uranium
実施例 1 3 0で得たトリチル体 1 . 7 8 g(3. 0 8 ミ リモル）をメタ ノ ール 4 Oml,水 5 Oml,ジクロ σメ タ ン 1 0 ml，濃塩酸 3 miの混液に溶 かし、 室温 1 . 5時間かきまぜた。 炭酸水素ナ ト リ ウムにて中和して、 '减圧下に濃縮乾固した。 残渣をシリカゲル（1 5 g) [溶出液，クロ口ホル ム，メタノール（19: ]にて精製して無色飴伏物質 9 7 3 mg (収率 9 4.  Example 13 A mixture of 1.78 g (3.08 mimol) of the trityl form obtained in 30 was mixed with 4 Oml of methanol, 5 Oml of water, 10 ml of dichloro sigmamethane and 3 mi of concentrated hydrochloric acid. And stirred at room temperature for 1.5 hours. Neutralized with sodium bicarbonate and concentrated to dryness under reduced pressure. The residue was purified with silica gel (15 g) [eluent, chloroform, methanol (19 :) to give 973 mg of a colorless candy substance (yield 94.
5 %)を得た。  5%).
T L C .silica gel , CHC , ¾eOH(19： i) , R f-0.33  T L C .silica gel, CHC, ¾eOH (19: i), R f-0.33
iN'MR(60MC,CDCl3)(5： 2.75(1H), 3.33(3H), 3.53(2H), 3.70(2H), iN'MR (60MC, CDCl 3 ) (5: 2.75 (1H), 3.33 (3H), 3.53 (2H), 3.70 (2H),
3.83C2H), 4.22C2H), 4.50(2H), 5.65(1H), 7.13(1H), 7.24(5H) 実施例 132  3.83C2H), 4.22C2H), 4.50 (2H), 5.65 (1H), 7.13 (1H), 7.24 (5H) Example 132
1 — (3—ォクタデシルカルバモイルォキシー 2—メ トキシプロピル） 差換え 一 3—（2—ベンジルォキシェチル）ゥラシル 1 — (3-octadecylcarbamoyloxy 2-methoxypropyl) Replacement One 3- (2-benzyloxyshethyl) チ ル racil
実施例 1 3 1で得たハイ ドロキン体 9 7 0 mg(2. 9 ミ リモル），ォク タデシルイソシアナー ト 8 5 7 mg(2. 9 ミ リモル）をピリ ジン 1 mlに溶 かし、 1 2 0°C, 1 6時間加熱した。 反応液を減圧下に濃縮乾固して、 残渣をシリカゲル（1 7g) [溶出液，クロ口ホルム，酢酸ェチル，η—へキサ ン（48:2:50)]にて精製して、無色固形物 1 .5 9 g (収率 8 7.0 %)を得た。 T L C .silica gel , CHC13 , eOH(19： 1) Example 13 970 mg (2.9 mmol) of the hydroquine compound obtained in 31 and 857 mg (2.9 mmol) of octadecyl isocyanate were dissolved in 1 ml of pyridine. Heated at 120 ° C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel (17 g) [eluent, chloroform, ethyl acetate, η-hexane (48: 2: 50)] to give a colorless product 1.59 g (yield 87.0%) of a solid was obtained. TLC .silica gel, CHC1 3, eOH (19: 1)
Rf-0.74, 単一スポッ ト  Rf-0.74, single spot
NMR(60MC,CDC13)(5： 0.83(3H). 1.22(32H), 3.17(2H), 3.30(3H), 3.62(1H), 3.73C2H), 4.0〜 4(6H) , 4.55(2H), 4.97(1H), 5.67(1 NMR (60MC, CDC1 3) ( 5:. 0.83 (3H) 1.22 (32H), 3.17 (2H), 3.30 (3H), 3.62 (1H), 3.73C2H), 4.0~ 4 (6H), 4.55 (2H) , 4.97 (1H), 5.67 (1
H), 7.17(1H), 7.27C5H) H), 7.17 (1H), 7.27C5H)
実施例 133 Example 133
1 一（ 3—才クタデシルカルバモイルォキン一 2—メ トキシプロピル） 一 3—（ 2—ハイ ドロキシェチル）ウランル  1 1- (3-year-old octadecyl carbamoyl quinone 2-methoxypropyl) 1 3- (2-hydroxyshethyl) uranium
実施例 1 3 2で得たベンジル体 1 . 5 9g(2. 5 ミ リモル）を 7 0 % 酢酸 5 0 mlに溶かしパラジウム炭素 3 0 0 mg存在下に水素気流中 1 6時 間ふりまぜた。  Example 13 1.59 g (2.5 mmol) of the benzyl compound obtained in 32 was dissolved in 50 ml of 70% acetic acid and stirred in a hydrogen stream for 16 hours in the presence of 300 mg of palladium carbon. .
不溶物をろ去して、 母液を減圧下に濃縮乾固し、 残渣をメタノール 1 0 mlより再锆晶して、 無色結晶し 1 62(収率8 5. 2 %)を得た。  The insolubles were removed by filtration, the mother liquor was concentrated to dryness under reduced pressure, and the residue was recrystallized from 10 ml of methanol to give colorless crystals, yielding 162 (yield: 85.2%).
T L C .silica gel , CHC13 , MeOH(19： 1) TLC .silica gel, CHC1 3, MeOH (19: 1)
Rf = 0.28, 単一スポヅ ト  Rf = 0.28, single spot
NTMR(60MC,CDC13)<5： 0.92(3H), 1.25(32H), 2.30(1H), 3.13(2H), 3.38C3H), 3.63C3H), 3.87(2H), .15(4H), 4.97(1H), 5.68(1H), 7.20C1H) . N T MR (60MC, CDC1 3 ) <5: 0.92 (3H), 1.25 (32H), 2.30 (1H), 3.13 (2H), 3.38C3H), 3.63C3H), 3.87 (2H), .15 (4H) , 4.97 (1H), 5.68 (1H), 7.20C1H).
実施例 134 Example 134
1 - (3—ォクタデシルカルバモイルォキシー 2—メ トキシプロピル） 一 3—（2— トルエンスルホニルォキシェチル）ゥラシル 1- (3-octadecylcarbamoyloxy 2-methoxypropyl) One 3- (2-toluenesulfonyloxityl) ゥ racil
実施例 1 3 3で得たハイ ド口キシ体 1 . 1 6 g( 2. 1 5 ミ リモル）， ト シルクロリ ド 5 7 4 mg( 3. 0 1 ミ リモル）をジクロロメタ ン 3 mlに溶か し、 トリェチルァミ ン 4 0 4 mgを加えて、 3時間かきまぜた。  Example 13 1.16 g (2.15 mimol) of the hydroxy compound obtained in Example 3 and 574 mg (3.01 mimol) of tosyl chloride were dissolved in 3 ml of dichloromethane. Then, 104 mg of triethylamine was added, and the mixture was stirred for 3 hours.
反応液にジクロロメタン 2 Oml,氷水 2 0 mlを加えて、 激しくふりま ぜてから、 有機層を分取し、 硫酸ナトリウムにて乾かし减圧下に濃縮乾 固し、 残渣をシリカゲル（1 3 g) [溶出液， n—へキサン，酢酸ェチル，クロ 口ホルム，メタノ一ル（50 :50:98: 2)]にて精製し、目的トシレート体，およ びクロリ ドの混合物 1 .3 5 gを得た。  To the reaction mixture, add 2 Oml of dichloromethane and 20 ml of ice water, shake vigorously, separate the organic layer, dry over sodium sulfate, concentrate to dryness under reduced pressure, and concentrate the residue on silica gel (13 g). Purify with [eluate, n-hexane, ethyl acetate, chloroform form, methanol (50: 50: 98: 2)], and obtain 1.35 g of a mixture of the target tosylate and chloride. I got
T L C .silica gel . n- Hexane, EtOAc(l:l) T L C .silica gel .n- Hexane, EtOAc (l: l)
Rf= 0.12, 0.26 2スポッ ト  Rf = 0.12, 0.26 2 spots
実施例 135 Example 135
N - [ 2 - { 1 一（3—才クタデシルカルバ乇ィルォキシ一 2—メ トキ シ）プロピルゥラシルー 3—ィル]エチル]チアゾリゥム クロリ ド 実施例 1 3 4で得た混合物 1 . 0 8- gをチアゾール 3 mlに溶かし 1 0 N- [2- [1- (3- (octadecadecylcarbazyloxy-2- (2-methoxy)) propylperacyl-3-yl] ethyl] thiazolym chloride The mixture obtained in Example 13 34 1.0 8- g in 3 ml of thiazole 10
0 °C，3 日間加熱した。 反応液を減圧下に濃縮乾固して、 残渣を 7 0 % メタノール 5 0 miに溶かし、 I R A— 4 1 0こ C 1_型] 2 5 mlのカラムを 通過させ、 少量の 7 0 %メタノ ールにて洗い通過液洙液を合せて、 減圧 下に濃縮乾固して、 残渣をシリカゲル（2. 5 g) [溶出液，クロ口ホルム， メタノール，水（65 :24:0]にて精製して、無色固形物 6 2 5 mg (収率 5 6.Heated at 0 ° C for 3 days. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in 70% methanol 5 0 mi, IRA- 4 1 0 This C 1 _ type] passed through a column of 2 5 ml, a small amount of 70% methanol Wash with sodium chloride solution, combine the filtrate, concentrate to dryness under reduced pressure, and concentrate the residue on silica gel (2.5 g) [eluent, chloroform, methanol, water (65: 24: 0)]. To give a colorless solid, 6 25 mg (yield 56.
5 %)を得た。 5%).
T L C .silica gel , CHC13 , eOH, H20(65： 25： 4) TLC .silica gel, CHC1 3, eOH , H 2 0 (65: 25: 4)
Rf = 0.37 単一スポヅ ト  Rf = 0.37 single spot
I R(film)cm一1: 3350, 2920, 2850, 1710, I860, 1540, 1460, IR (film) cm 1 : 3350, 2920, 2850, 1710, I860, 1540, 1460,
1400, 1250, 1150, 1050  1400, 1250, 1150, 1050
NMR(60MC,CDC13)(5： 0.93C3H), 1.23(32H), 3.10(2H), 3.38(3H), NMR (60MC, CDC1 3) ( 5: 0.93C3H), 1.23 (32H), 3.10 (2H), 3.38 (3H),
差換え 3.63C1H), 4.10C4H). 4.57(2H), 5.20(2H), 5.60C1H). 5.77(1H),Replacement 3.63C1H), 4.10C4H) .4.57 (2H), 5.20 (2H), 5.60C1H). 5.77 (1H),
7.43(1H), 8.30(1H), 8.85(1H), 10.93(1H) 7.43 (1H), 8.30 (1H), 8.85 (1H), 10.93 (1H)
実施例 136 Example 136
N - [ 2 - { 1 - (3一才クタデシルカルバモイルォキシー 2—メ トキ シプロピル）ゥラシルー 3—ィル }ェチル]一 N , N , N— トリメチルアン モニゥム クロリ ド  N- [2- {1-(3-year-old octadecylcarbamoyloxy-2-methoxypropyl) peracyl-3-yl} ethyl] -1-N, N, N-trimethylammonium chloride
実施例 1 3 4で得た混合物 1 3 5 mgを 2 0 %ト リメチルァミ ン一 トル ェン（vZv) 5 mlに溶かし、 室温にて 4日間放置した。 反応液を減圧下に 濃縮乾固して、 残渣を 7 0 %メタノール 1 0 mlに溶かし I R A— 4 1 0 [C1一型] 7 mlを通過させ、 通過液，水洗液合せて、 减圧下に濃縮乾固し て、 残渣をシリカゲル（2. 5 g) [溶出液，クロ口ホルム，メタノ ール，水（6 5:25:4)]にて精製して、無色固形物 8 3 mg (収率 6 2. 5 %)を得た。  135 mg of the mixture obtained in Example 134 was dissolved in 5 ml of 20% trimethylamine-toluene (vZv) and left at room temperature for 4 days. The reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in 70% methanol (10 ml). IRA—410 [C1 type] was passed through 7 ml. The residue was purified by silica gel (2.5 g) [eluent, chloroform, methanol, water (65: 25: 4)] to give 83 mg of a colorless solid ( Yield 62.5%).
T L C .silica gel , CHC13 ,MeOH. H20(65： 25 :4) . TLC .silica gel, CHC1 3, MeOH H 2 0 (65: 25: 4)
Rf = 0.27 単一スポヅ ト  Rf = 0.27 single spot
I R (film)cm~1： 3350, 2920, 2850, 171.0, 1660, 1530, 1460, IR (film) cm ~ 1 : 3350, 2920, 2850, 171.0, 1660, 1530, 1460,
1380, 1250, 1140, 1055, 930 1380, 1250, 1140, 1055, 930
MR (60MC,CDC13) δ 0.89(3Η), 1.23C32H), 3.18(2Η), 3.38(3Η), 3.53C9H), 3.72C1H), 3.90(2Η), 4.12C4H), 4.40(2Η), 5.57(1Η), 5.77CLH), 7.43C1H) MR (60MC, CDC1 3) δ 0.89 (3Η), 1.23C32H), 3.18 (2Η), 3.38 (3Η), 3.53C9H), 3.72C1H), 3.90 (2Η), 4.12C4H), 4.40 (2Η), 5.57 (1Η), 5.77CLH), 7.43C1H)
実施例丄 37 Example 丄 37
Ν - Γ 1 一（ 3—才クタデシルカルバモイルォキシー 2—メ トキシプロ ピル）ゥラシルー 3—ィル]ェチル一 Ν—メチルピロ リ ジニゥム クロリ Κ  Ν-Γ 1 (3-year-old octadecylcarbamoyloxy 2-methoxypropyl) ゥ lacyl 3-yl] ethyl-1 Ν—methylpyrrolidinidine chloride Κ
実施例 1 3 4で得た混合物 1 3 5 mgを N—メチルピロリ ジン 3 mlに溶 かし 1 0 0 °C， 2日間加熱した。 反応液を実施例 1 3 6と同様に処理し て、 無色固形物 5 6mg (収率 4 0. 5 %)を得た。 T L C .silica gel , CHC13 , eOH, H20(65： 25： ) 13 mg of the mixture obtained in Example 13 was dissolved in 3 ml of N-methylpyrrolidine, and heated at 100 ° C for 2 days. The reaction solution was treated in the same manner as in Example 13 to obtain 56 mg of a colorless solid (yield: 40.5%). TLC .silica gel, CHC1 3, eOH , H 2 0 (65: 25:)
Rf = 0.35 単一スポヅ ト  Rf = 0.35 single spot
I R (f ilm)ci_1： 3350, 2920, 2850, 2700, 2620, 1710, 1660, IR (f ilm) ci _1 : 3350, 2920, 2850, 2700, 2620, 1710, 1660,
1530, 1460, 1390, 1250, 1100, 1040  1530, 1460, 1390, 1250, 1100, 1040
NMR(60MC(CDC13) δ ： 0.90(3Η), 1.23(32Η), 2.27(4Η), 3.07(2Η), NMR (60MC (CDC1 3) δ : 0.90 (3Η), 1.23 (32Η), 2.27 (4Η), 3.07 (2Η),
3.37C3H). 3.40C3H), 3.S2(1H), 3.75(4Η), 4.10(2Η), 4.33C4H), δ.58(1Η), 5.77C1H), 7.43(1Η) 3.37C3H). 3.40C3H), 3.S2 (1H), 3.75 (4Η), 4.10 (2Η), 4.33C4H), δ.58 (1Η), 5.77C1H), 7.43 (1Η)
実施例 138 Example 138
2 - (3ーォクタデシルカルバモイルォキシー 2—メ トキシプロポキ シカルボニル）アミ ノメチルチアゾール  2- (3-octadecylcarbamoyloxy-2-methoxypropoxycarbonyl) aminomethylthiazole
実施例 9と同様にして合成した 3—才クタデシルカルバモイルー 2— メチル一 1一フエノキシカルボニルグリセリ ン 2. 3 3 g(4. 4 7 ミ リ モル）， 2—ァミ ノチアゾール 0. 7 7g(6. 1 3 ミ リモル）， ト リメチル アミ ン 2 mlをトルエン 2 mlに溶かし、 室温にて 1 日放置した。 反応液を 減圧下に濃縮乾固して ¾渣をシリカゲル（2 5 g) [溶出液，η—へキサン， S乍酸ェチル（1:1)]にて精製して、淡黄色粉末 1 .3 5 g (収率 55.7%)を得 た。  3-tactadecylcarbamoyl-2-methyl-11-phenoxycarbonylglycerin synthesized in the same manner as in Example 9 2.33 g (4.47 mimol), 2-aminothiazole 0 .77 g (6.13 mimol) and trimethylamine (2 ml) were dissolved in toluene (2 ml) and allowed to stand at room temperature for 1 day. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified with silica gel (25 g) [eluent, η-hexane, ethyl ethyl sulphate (1: 1)] to give a pale yellow powder. 35 g (55.7% yield) was obtained.
T L C .silica gel , n- Hexan, EtOAc (1： 1)  T L C .silica gel, n- Hexan, EtOAc (1: 1)
Rf = 0.37 単一スポッ ト Rf = 0.37 single spot
R(60MC,CDC13)<5： 0.90(3H), 1.25(32H), 3.丄 3(2H), 3.47(3H), R (60MC, CDC1 3) < 5: 0.90 (3H), 1.25 (32H), 3.丄3 (2H), 3.47 (3H ),
3.62(1H), 4.17C2H), 4.67(2H), 4.80(1H), 5.63(1H), 7.27(1H), 7.67(1H) 3.62 (1H), 4.17C2H), 4.67 (2H), 4.80 (1H), 5.63 (1H), 7.27 (1H), 7.67 (1H)
実施例 139 Example 139
2— [N—ァセチルー N—（3—ォクタデシルカルバモイルォキシー 2 ーメ トキシプロポキシカルボニル）ァミ ノメチル]チアゾール  2- [N-acetyl-N- (3-octadecylcarbamoyloxy-2-methoxypropoxycarbonyl) aminomethyl] thiazole
実施例 1 3 8で得たチアゾ一ル体 1 0 8 mg( 0. 2ミ リモル），ジメチ ルァミ ノ ピリ ジン 1 2 2 mg( 1 . 0 ミ リモル），無水酢酸 1 0 2 mg( 1 . 0 ミ リモル）をトルエン 0. 5 oilに溶かし、 8 0°C，4時間加熟した。 反応液を减圧下に濃縮乾固して、 残渣をシリ力ゲル（ 3 g) [溶出液，ク 口口ホルム，メタノ ール（39: D]、さ らにシリカゲル（3 g) [溶出液，η—へ キサン，酢酸ェチル（1:1)]にて、 精製して、 無色固形物 1 1 Omg (収率 7 8. 1 %)を得た。 Example 108 108 mg (0.2 mmol) of the thiazole compound obtained in 38, dimethyl Luminopyridine (122 mg, 1.0 millimol) and acetic anhydride (102 mg, 1.0 millimol) were dissolved in toluene (0.5 oil) and ripened at 80 ° C for 4 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was subjected to silylation gel (3 g) [eluate, porcine form, methanol (39: D), and silica gel (3 g) [eluate , Η-hexane, ethyl acetate (1: 1)] to give 11 Omg of a colorless solid (yield 78.1%).
Tし C .silica gel , n- Hexan, EtOAc(l： 2)  T then C .silica gel, n- Hexan, EtOAc (l: 2)
Rf = 0.43 単一スポヅ ト  Rf = 0.43 single spot
I R (film)cnT1： 3350, 2930, 2850, 1745, 1715, 1525, 1470, IR (film) cnT 1 : 3350, 2930, 2850, 1745, 1715, 1525, 1470,
1430, 1375, 1345, 1210, 1145, 1080, 920  1430, 1375, 1345, 1210, 1145, 1080, 920
NMR(60MC,CDC13) δ： 0.92(3H), i.23(32H), 2.6(3H), 3.08(2H), 3.37C3H), 3.57C1H), 4.10(2H), 4.27(2H), 4.90(1H), 5.27(2H), 7.23C1H), 7.67(1H) _ NMR (60MC, CDC1 3) δ : 0.92 (3H), i.23 (32H), 2.6 (3H), 3.08 (2H), 3.37C3H), 3.57C1H), 4.10 (2H), 4.27 (2H), 4.90 (1H), 5.27 (2H), 7.23C1H), 7.67 (1H) _
実施例 140 Example 140
2— [N— (3—ォクタデシルカルバモイルォキシ一 2—メ トキシプロ ポキシカルボニル）アミ ノ ]メチルー 3—メチルチアゾリ ゥム ィォダイ ド'  2- [N- (3-octadecylcarbamoyloxy-2- (methoxypropoxycarbonyl) amino] methyl] -3-methylthiazolidimide
実施例 t 3 8で得たチアゾール体 1 0 0 mg( 0. 1 8 δ ミ リモル）をョ ゥ化メチル 1 . 5 mlに溶かし 7 0 °C, 8時間加熟した。 反応液を '威圧下 に濃縮乾固し、 淡黄色固形物 1 2 4mg (収率 1 0 0 %)を得た。  100 mg (0.18 δmillimol) of the thiazole derivative obtained in Example t38 was dissolved in 1.5 ml of methyl iodide and ripened at 70 ° C for 8 hours. The reaction solution was concentrated to dryness under intimidation to obtain 124 mg (yield: 100%) of a pale yellow solid.
T L C .silica gel,CHCl3,Me0H,H20(65:25:4) TLC .silica gel, CHCl 3 , Me0H, H 20 (65: 25: 4)
Rf = 0.35 単一スボッ ト  Rf = 0.35 single slot
I R (film)cm"1： 3340, 2930, 2850, 1700, 1520, 1470, 1250, IR (film) cm " 1 : 3340, 2930, 2850, 1700, 1520, 1470, 1250,
1140, 1050  1140, 1050
NMR(60MC,CDC13)(5： 0.88(3Η), 1.2δ(32Η), 3.15(2Η), 3.45(3Η), NMR (60MC, CDC1 3) ( 5: 0.88 (3Η), 1.2δ (32Η), 3.15 (2Η), 3.45 (3Η),
3.65C1H), 4.I3C2H), 4.23(2Η), 5.08(3Η), 8.27(1Η), 8.45(1Η) 実施例 Ul 3.65C1H), 4.I3C2H), 4.23 (2Η), 5.08 (3Η), 8.27 (1Η), 8.45 (1Η) Example Ul
2— [N— (3—才クタデシルカルバモイルォキン一 2—メ トキシプロ ポキシカルボニル）ァミ ノ ]メチルー 3—ェチルチアゾリ ゥム ィォダイ 実施例 1 3 8で得たチアゾール体 1 0 0 mg(0. 1 8 5 ミ リモル）をョ ゥ化工チル 1 . Oralに溶かし 8 0°C,—夜加熱した。 反応液を减圧下に 濃縮乾固し、 残渣をシリ力ゲル（2 g) [溶出液， CHCl3→CHCl3,MeOH(i9:l)] にて精製して、淡黄色固形物 9 1 mg (収率 7 0. 5 %)を得た。 2 -— [N— (3-year-old octadecylcarbamoylquinone-2-methoxypropoxycarbonyl) amino] methyl-3-ethylthiazolidimodidai 100 mg of the thiazole derivative obtained in Example 13 (0. 185 mmol) was dissolved in 1. Oral and heated at 80 ° C overnight. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel (2 g) [eluent, CHCl 3 → CHCl 3 , MeOH (i9: l)] to give 9 1 mg of a pale yellow solid (Yield: 70.5%).
T L C .silica gel , CHC13 , MeOH, H20(65： 25： ) TLC .silica gel, CHC1 3, MeOH , H 2 0 (65: 25:)
Rf = 0.66 単一スポッ ト  Rf = 0.66 single spot
I R (f ilra)cm"1： 3320, 2920, 2850, 1720, 1520, 1465, 1240, IR (filra) cm " 1 : 3320, 2920, 2850, 1720, 1520, 1465, 1240,
1140, 1050, 910 1140, 1050, 910
MR(60MC,CDC13)<5： 0.88(3H), 1.27 (32H), 1.67(3H), 3.13(2H), 3.45C3H), 3.63(1H), 4.13(2H), 4.25(2H), 4.73(2H), 4.98(lH), 5.10C2H), 7.33(iH), 8.25(1H), 8.45(1H) MR (60MC, CDC1 3) < 5: 0.88 (3H), 1.27 (32H), 1.67 (3H), 3.13 (2H), 3.45C3H), 3.63 (1H), 4.13 (2H), 4.25 (2H), 4.73 (2H), 4.98 (lH), 5.10C2H), 7.33 (iH), 8.25 (1H), 8.45 (1H)
実施例 142 Example 142
2一 [ —ァセチルー N— (3—ォクタデシルカルバモイルォキシー 2 —メ トキシプロポキシカルボニル）ア ミ ノ メチル ]一 3—メチルチアゾリ ゥム ィォダイ ド  21-[-Acetyl-N- (3-octadecylcarbamoyloxy 2-methoxypropoxycarbonyl) aminomethyl] -1-3-methylthiazolidimide
実施例 1 3 9で得たアセテー ト 1 0 0 mg(0. 1 8 5 ミ リモル）をヨウ 化メチル 〖 . 5 mlに溶かし 5 0 °C, 1 6時間加熱した。 反応液を减圧下 に濃縮乾固し、 残渣をシリ力ゲル（2 g) [溶出液， CHCl3，MeOH,H20(65:25: 4)]にて精製して、淡黄色粉末 i 1 6 mg (収率 1 0 0 %)を得た。 100 mg (0.185 mmol) of the acetate obtained in Example 13 39 was dissolved in 0.5 ml of methyl iodide and heated at 50 ° C for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel (2 g) [eluent, CHCl 3 , MeOH, H 20 (65: 25: 4)] to give a pale yellow powder. 16 mg (100% yield) was obtained.
Tし C .silica gel , CHC13 , MeOH. H20(65： 25： ) . T and C .silica gel, CHC1 3, MeOH H 2 0 (65: 25:)
Rf = 0.25 単一スポヅ ト  Rf = 0.25 single spot
I R (f ilm)cm~1： 3400, 2930, 2850, 1700, 1560, 1530, 1470, 差換え 1375, 1330, 1250, 1200, 1140, 1075 IR (f ilm) cm ~ 1 : 3400, 2930, 2850, 1700, 1560, 1530, 1470, replacement 1375, 1330, 1250, 1200, 1140, 1075
NMR(60 C,CDC13)(5： 0.92(3H), 1.25(32H), 2.62(3H), 3.08C2H), 3.48C3H), 3.80C1H), 4.17(2H), 4.45(2H), 4.52(3H), 5.33(1H), 5.59C2H), 8.43(1H), 8.58(iH) NMR (60 C, CDC1 3) (5: 0.92 (3H), 1.25 (32H), 2.62 (3H), 3.08C2H), 3.48C3H), 3.80C1H), 4.17 (2H), 4.45 (2H), 4.52 ( 3H), 5.33 (1H), 5.59C2H), 8.43 (1H), 8.58 (iH)
実施例 143  Example 143
2— [N—ァセチルー N— ( 3—ォクタデシルカルバモイルォキシ一 2 ーメ トキシプロポキシカルボニル）ァミ ノ ]メチルー 3—ェチルチアゾリ ゥム ィオダイ ド  2- [N-Acetyl-N- (3-octadecylcarbamoyloxy-1--2-methoxypropoxycarbonyl) amino] methyl-3-ethylthiazolidiomide
実施例 1 3 9で得たアセテー ト 1 1 7 tng(0. 2ミ リモル）をヨウ化工 チル 1. 0 mUこ溶かし 9 0 °C, 5時間加熱した。 反応液を威圧下に濃縮 乾固し、 残渣をシリ力ゲル（2 g) [溶出液. CHCl3→CHCl3,MeOH,(19:l)]に て精製して、 淡黄色粉末 1 1 6mg (収率 5 0. 7 %)を得た。 11.7 tng (0.2 millimol) of the acetate obtained in Example 13 39 was dissolved in 1.0 mU of iodide and heated at 90 ° C. for 5 hours. The reaction mixture was concentrated under pressure to dryness, and the residue was purified by silica gel (2 g) [eluent. CHCl 3 → CHCl 3 , MeOH, (19: l)] to give a pale yellow powder (1 16 mg). (Yield 50.7%).
Tし C .silica gel , CHC13 , eOH, H20(65： 25： 4) T and C .silica gel, CHC1 3, eOH , H 2 0 (65: 25: 4)
Rf = 0.71 単一スポッ ト  Rf = 0.71 single spot
I R (film)cm~l： 3300, 2920, 2850, 1750, 1700, 1525, 1465, IR (film) cm ~ l : 3300, 2920, 2850, 1750, 1700, 1525, 1465,
1370, 1340, 1240, 1205, 1140, 1105, 1070, 990  1370, 1340, 1240, 1205, 1140, 1105, 1070, 990
： R (60MC,CDC13) <5： 0.83(3H) , 1.23C32H), 1.69(3H) , 2.62(3H), 3.13(2H), 3.47(3H), 3.80(1H), 4.17(2H), 4.46(2H), 4.92(2H), 5.10C1H), 5.63C2H), 8.43(1H), 8.67(1H) : R (60MC, CDC1 3) <5: 0.83 (3H), 1.23C32H), 1.69 (3H), 2.62 (3H), 3.13 (2H), 3.47 (3H), 3.80 (1H), 4.17 (2H), 4.46 (2H), 4.92 (2H), 5.10C1H), 5.63C2H), 8.43 (1H), 8.67 (1H)
実施例 U4  Example U4
2— [N—ァセチルー N— (3—ォクタデシルカルバモイルォキシー 2 —メ トキシプロポキシカルポニル）ァミ ノ ]メチルー 3—プロピルチアゾ リウム ィォダイ ド  2- [N-acetyl-N- (3-octadecylcarbamoyloxy 2 -methoxypropoxycarbonyl) amino] methyl-3-propylthiazolium iodide
実施例 1 3 9で得たアセテー ト 1 1 7 mg( 0. 2 ミ リモル）をヨウ化プ 口ピル 1 . 0 mlに溶かし 9 0 °C, 5時間加熱した。 反応液を减圧下に濃 縮乾固し、 残渣をシリ力ゲル（2g) [溶出液. CHC13— CHCl3,MeOH(19:l)] 117 mg (0.2 millimoles) of the acetate obtained in Example 13 39 was dissolved in 1.0 ml of pill having an iodide and heated at 90 ° C. for 5 hours. The reaction mixture concentrated Chijimiinui solidified under减圧, the residue silica force gel (2 g) [eluent CHC1 3 - CHCl 3, MeOH. (19: l)]
差換え にて精製して、淡黄色粉末 1 1 6mg (収率 5 0. 7 %)を得た。 Replacement Then, 116 mg (yield: 50.7%) of pale yellow powder was obtained.
T L C .silica gel,CHCl3,MeOH,H20(65:25:4) TLC .silica gel, CHCl 3 , MeOH, H 20 (65: 25: 4)
Rf = 0.73 単一スポ 'ソ ト  Rf = 0.73 Single spot
I R (film) cm-1: 3350, 2920, 2850, 1750, 1700, 1535, 1470, IR (film) cm -1 : 3350, 2920, 2850, 1750, 1700, 1535, 1470,
1375, 1340, 1240, 1205, 1150, 1100, 1070, 990  1375, 1340, 1240, 1205, 1150, 1100, 1070, 990
iN'MR (60MCCDC13) δ： 0.88(3Η), 1.08(3Η), 1.23(32Η), 2.16(2Η), 2.62C3H), 3.15C2H), 3.45(3Η), 3.83(1Η), 5.62(2Η), 8.43C1H), 8.67C1H) iN'MR (60MCCDC13) δ: 0.88 (3Η), 1.08 (3Η), 1.23 (32Η), 2.16 (2Η), 2.62C3H), 3.15C2H), 3.45 (3Η), 3.83 (1Η), 5.62 (2Η) , 8.43C1H), 8.67C1H)
実施例 U5 Example U5
2— [Ν—ァセチルー Ν— (3—才クタデシルカルバモイルォキン一 2 ーメ トキシプロポキシカルボニル）ァミ ノ ]メチルー 3—プチルチアゾリ ゥム ィオダイ ド  2- [Ν-Acetyl- ー-(3-year-old octadecylcarbamoyl-quinone-2-methylethoxypropoxycarbonyl) amino] methyl-3-methylbutyldiazomidiodide
実施例 1.3 9で得たアセテー ト 1 1 7 mg( 0. 2 ミ リモル）をヨウ化ブ チル 1 . O mlに溶かし 9 0°C, 5時間加熟した。 反応液を威圧下に濃縮 乾固し、 残渣をシリカゲル（2g) [溶出液， CHC13— CHCl3,MeOH(19:l)]、さ らにシリ力ゲル（2g) [溶出液，ァセ ト ン，酢酸ェチル（1:1)にて精製して、 淡褐色固形物 4 7 mg (収率 3 0. 5 %)を得た。 117 mg (0.2 mmol) of the acetate obtained in Example 1.39 was dissolved in 1.0 mL of butyl iodide and ripened at 90 ° C. for 5 hours. The reaction mixture was concentrated to dryness under intimidating and the residue was purified on silica gel (2 g) [eluent, CHC1 3 - CHCl 3, MeOH (19: l)], silica force gel (2 g) in the al [eluent, § Se The residue was purified with tones and ethyl acetate (1: 1) to obtain 47 mg of a light brown solid (yield: 30.5%).
T L C .silica gel , CHCU , eOH, H20(65： 25： 4) TLC .silica gel, CHCU, eOH, H 20 (65: 25: 4)
Rf-0.7 単一スポヅ ト  Rf-0.7 Single spot
I R (f ilm)cm_1： 3340, 2925, 2855, 1755, 1700, 1535, 1470, IR (f ilm) cm _1 : 3340, 2925, 2855, 1755, 1700, 1535, 1470,
1430, 1375, L340, 1240, 1205, 1150, 1110, 1070, 1040, 985 N R (60MC,CDC13) δ 0.88(3Η), 1.00(3Η), 1.25(32Η), 2.00(4Η), 2.65(311), 3.10C2H), 3.45(3Η), 3.78(1Η), 5.12(1Η), 5.δ8(2Η), 8.42C1H), 8.62(1Η) 1430, 1375, L340, 1240, 1205, 1150, 1110, 1070, 1040, 985 NR (60MC, CDC1 3) δ 0.88 (3Η), 1.00 (3Η), 1.25 (32Η), 2.00 (4Η), 2.65 (311 ), 3.10C2H), 3.45 (3Η), 3.78 (1Η), 5.12 (1Η), 5.δ8 (2Η), 8.42C1H), 8.62 (1Η)
実施例 146 Example 146
4一（3—ォクタデシルカルバモイルォキシー 2—メ トキシプロポキ シカルボニル）アミ ノメチルチアゾール 4- (3-octadecylcarbamoyloxy 2-methoxypropoxy) Cicarbonyl) aminomethylthiazole
実施例 9と同様にして合成した 3—ォクタデシルカルバモイル一 2— メチルー 1一フエノキシカルボニルグリセリ ン 2. 6 0 g(5. 0 ミ リ乇 ル）， 4ーァミ ノチアゾール 0. 5 7g(5. 0 0 ミ リモル）， ト リェチルァ ミ ン 1 mlをジクロロメタン 5 mlに溶かし、 5 0 °Cにて一夜加熱した。 反 応液を減圧下に濃縮乾固して残渣をシリカゲル（2 5 g) [溶出液， n—へキ サン，胙酸ェチル（1:1)]にて精製して、淡黄色粉末 4 4 0 mg (収率 1 6. 3-Octadecylcarbamoyl-12-methyl-11-phenoxycarbonylglycerin synthesized in the same manner as in Example 9. 2.60 g (5.0 milliliters), 4-aminothiazole 0.57 g (5.0 mmol) and 1 ml of triethylamine were dissolved in 5 ml of dichloromethane and heated at 50 ° C overnight. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel (25 g) [eluent, n-hexane, ethyl ethyl syrup (1: 1)] to give a pale yellow powder. 0 mg (Yield 16.
0 %)を得た。 0%).
T L C .silica gel , n- Hexan. EtOAc(l： 1)  T L C .silica gel, n- Hexan. EtOAc (l: 1)
Rf=0.51 単一スポッ ト  Rf = 0.51 Single spot
実施冽 147 Conducted 147
4— [N—ァセチルー N—（3—ォクタデシルカルバモイルォキン一 2 ' メ トキシプロポキシカルボニル）ァミ ノメチル]チアゾール  4— [N-Acetyl-N- (3-octadecylcarbamoylquinone 2 'methoxypropoxycarbonyl) aminomethyl] thiazole
実施例 1 4 6で得たチアゾ一ル体 1 6 2 mg(0. 3 ミ リモル），ジメチ ルァミ ノ ピリ ジン 2 44 mg( 2. 0 ミ リモル），無水酢酸 2 0 4 mg( 2. 0 ミ リモル）をトルエン 1 . Omlに溶かし、 1 1 0。C,一夜加熱した。 反応 液を威圧下に濃縮乾固して、 残渣をシリ力ゲル（2 g) [溶出液，クロ σホ ルム]，ついでシリ力ゲル（2 g) [溶出液，η—へキサン，酢酸ェチル（1:1)] にて、 精製して、 無色固形物 8 4 mg (収率 4 8. 0 %)を得た。  Example 1 46 2 mg (0.3 mmol) of the thiazole compound obtained in 46, dimethylaminopyridine 244 mg (2.0 mmol), acetic anhydride 204 mg (2.0 mol) (Millimol) in 1.Oml of toluene. C, heated overnight. The reaction mixture was concentrated to dryness under intimidation and the residue was subjected to silylation gel (2 g) [eluate, chromium σ-form], followed by silyri gel (2 g) [eluate, η-hexane, ethyl acetate (1: 1)] to give 84 mg of a colorless solid (yield 48.0%).
TL C . silica gel , n- Hexan. EtOAc(l： 2)  TL C. Silica gel, n- Hexan. EtOAc (l: 2)
Rf=0.63 単一スポッ ト  Rf = 0.63 Single spot
1 R (f ilm)cm-1： 3350, 2920, 2850, 1740, 1705, 1535, 1465, 1 R (f ilm) cm- 1 : 3350, 2920, 2850, 1740, 1705, 1535, 1465,
1435, 1370, 1350, 1200, 1140, 1080, 980, 950 1435, 1370, 1350, 1200, 1140, 1080, 980, 950
MR(60MC,CDC13) δ ： 0.88C3H), 1.25(32Η), 2.57(3Η), 3.18C2H), 3.38C3H), 3.67(1Η), 4.12(2Η), 4.24(2Η), 4.92(1Η), 5.14(2Η), MR (60MC, CDC1 3) δ : 0.88C3H), 1.25 (32Η), 2.57 (3Η), 3.18C2H), 3.38C3H), 3.67 (1Η), 4.12 (2Η), 4.24 (2Η), 4.92 (1Η) , 5.14 (2Η),
7.17C1H), 8.73C1H) 実施例 148 7.17C1H), 8.73C1H) Example 148
4一 [ —ァセチルー N—（3—ォクタデシルカルバモイルォキシ一 2 ーメ トキシプロポキシカルボニル）ァミ ノメチル ]— 3—メチルチアゾリ ゥム ィオダイ ド  4-1-[— Acetyl-N— (3-octadecylcarbamoyloxy-1-2-methoxypropoxycarbonyl) aminomethyl] —3-methylthiazolodiiodide
実施例 1 4 7で得たアセテー ト 4. 5 mgをヨウ化メチル 0. 5 mlに溶 かし 6 0°C, 1 6時間加熱した。 反応液を减圧下に濃縮乾固し、 残渣を シリ力ゲル（0. 5 g) [溶出液， CHCl3,MeOH(65:25)]にて精製して、淡黄色 粉末に 8 5 mgを得た。 Example 14 4.5 mg of the acetate obtained in 47 was dissolved in 0.5 ml of methyl iodide and heated at 60 ° C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel (0.5 g) [eluent, CHCl 3 , MeOH (65:25)] to give 85 mg to a pale yellow powder. Obtained.
T L C .silica gel , CHC13 , eOH, H20(65： 25： ) TLC .silica gel, CHC1 3, eOH , H 2 0 (65: 25:)
Rf = 0.69 単一スポッ ト  Rf = 0.69 single spot
実施例] L49 Example] L49
4— [N—ァセチルー N— ( 3—ォクタデシルカルバモイルォキシー 2 —メ トキシプロポキシカルボニル）ァミ ノ ]メチルー 3—ェチルチアゾリ ゥム ィオダイ ド  4— [N-Acetyl-N— (3-octadecylcarbamoyloxy 2—methoxypropoxycarbonyl) amino] methyl-3-ethylthiazolidimiodide
実施例 1 4 7で得たアセテー ト 7 9. δ mgCO . 1 3 6 ミ リモル）をョ ゥ化工チル 1 . 0 mLに溶かし 9 0 ，一夜加熟した。 反応液を减圧下に 濃縮乾固し、 残渣をシリカゲル（1 . 7 g) [溶出液， CHCl3→CHCl3,MeOH(l 9:1)]にて精製して、淡黄色固形物 4 4 mg (収率 4 3.7 %)を得た。 The acetate (79.δmgCO.136 millimol) obtained in Example 1447 was dissolved in 1.0 mL of thiol chill, and the mixture was ripened overnight for 90. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel (1.7 g) [eluent, CHCl 3 → CHCl 3 , MeOH (l 9: 1)] to give a pale yellow solid. mg (43.7% yield).
T L C .silica gel , CHC13 , eOH, H20(65： 25： ) TLC .silica gel, CHC1 3, eOH , H 2 0 (65: 25:)
Rf = 0.72 単一スポッ ト  Rf = 0.72 single spot
I R(fUm)cm一1: 3350, 2925, 2855, 1750, 1705, 1525, 1465, IR (fUm) cm- 1 : 3350, 2925, 2855, 1750, 1705, 1525, 1465,
1370, 1335, 1240. 1205, 1140, 1105, 1070, 1040, 995， 940 MR (6QMC,CDC13) δ： 0.87(3Η) , 1.23(32Η), 1.72(3Η), 2.60C3H), 3.08(2Η), 3.45C3H), 3.79(1Η), 4.14(2Η), 4.42(2Η), 4.87(2Η), 5.07(1Η), 5.20(2Η), 8.25(1Η), 10.80(1Η) 1370, 1335, 1240. 1205, 1140 , 1105, 1070, 1040, 995, 940 MR (6QMC, CDC1 3) δ: 0.87 (3Η), 1.23 (32Η), 1.72 (3Η), 2.60C3H), 3.08 (2Η ), 3.45C3H), 3.79 (1Η), 4.14 (2Η), 4.42 (2Η), 4.87 (2Η), 5.07 (1Η), 5.20 (2Η), 8.25 (1Η), 10.80 (1Η)
実施例 15Q 差換え 4ーメチルー 5—（3—ォクタデシルカルバモイルォキシー 2—メ ト キシプロポキシカルボニル）ァミ ノェチルチアゾール Example 15Q Replacement 4-methyl-5- (3-octadecylcarbamoyloxy) 2-methoxypropoxycarbonyl) aminoethylthiazole
実施例 9と同様にして合成した 3—才クタデシルカルバモイルー 2— メチルー 1一フヱノキシカルボニルグリセリ ン 4 3 9 mg( 1. 2 6 ミ リ モル）， 4ーメチルー 5—アミ ノエチルチアゾール 1 7 9. 5 rag( 1 . 2 6 ミ リモル）， ト リエチルァミ ン 1 mlをトルエン 1 mUこ溶かし、 5 0 °C , 4時間加熟した。 反応液を減圧下に濃縮乾固して残渣をシリカゲル（5 g) [溶出液，η—へキサン，舴酸ェチル（ 1)]にて精製して、 淡黄色粉末 3 4 5 mg (収率 7 3. 6 %)を得た。  3-year-old octadecylcarbamoyl-2-methyl-1-phenyloxycarbonylglycerin synthesized in the same manner as in Example 9 43 mg (1.26 mmol), 4-methyl-5-aminoethylthiazole 17.5.5 rag (1.26 mimol) and 1 ml of triethylamine were dissolved in 1 mU of toluene and ripened at 50 ° C for 4 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified with silica gel (5 g) [eluent, η-hexane, ethyl diethyl ester (1)] to obtain 34.5 mg of a pale yellow powder (yield) 73.6%).
T L C .silica gel, n- Hexan, EtOAc(l： i) T L C .silica gel, n- Hexan, EtOAc (l: i)
Rf=0.21 単一スポッ ト  Rf = 0.21 Single spot
N R (60MC,CDCL3) <5： 0.80(3H), 1.25(32H), 2.46(3H), 2.52(3H), 3.07(2H), 3.13(2H), 3.47(3·Η), 3.63(1H), 4.16(2H), 4.23(1H), . 4.'97(1H), 8.50C1H) NR (60MC, CDCL 3 ) <5: 0.80 (3H), 1.25 (32H), 2.46 (3H), 2.52 (3H), 3.07 (2H), 3.13 (2H), 3.47 (3Η), 3.63 (1H ), 4.16 (2H), 4.23 (1H), .4'97 (1H), 8.50C1H)
実施例 151 Example 151
3 , 4—ジメチルー 5—[2 _ (3—ォクタデシルカルバ乇ィルォキシ 一 2—メ トキシプロポキシカルボニル）ァミ ノ ]ェチルチアゾリ ゥム ィ ォダイ ド  3,4-dimethyl-5- [2 _ (3-octadecylcarbazyloxy-l- 2-methoxypropoxycarbonyl) amino] ethylthiazolidimide
実施例 1 5 0で得たチアゾール体 1 0 0 mg( 0. 1 8 ミ リモル）をョゥ 化メチル 1 . 5 mlに溶かし 7 0 C.8時間加熱した。 反応液を減圧下に 濃縮乾固し、 淡黄色固形物 1 2 8mg (収率 1 0 0 %)を得た。  Example 150 100 mg (0.18 mmol) of the thiazole derivative obtained in 50 was dissolved in 1.5 ml of methyl iodide and heated at 70 C for 8 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain 128 mg (yield: 100%) of a pale yellow solid.
Tし C .silica gel, CHC13 , MeOH, H20(65： 25： ) T and C .silica gel, CHC1 3, MeOH , H 2 0 (65: 25:)
R f =0.39 単一スポヅ ト  R f = 0.39 single spot
NMR(60 C(CDC13) δ 0.87C3H), 1.27(32Η), 2.52(3Η), 3.18(4Η), 3.45(3Η), 3.58(3Η), 4.17(4Η), 4.27(3Η), δ.06(1Η), 6.27(1Η), NMR (60 C (CDC1 3) δ 0.87C3H), 1.27 (32Η), 2.52 (3Η), 3.18 (4Η), 3.45 (3Η), 3.58 (3Η), 4.17 (4Η), 4.27 (3Η), δ. 06 (1Η), 6.27 (1Η),
10.45C1H) 実施例 152 (10.45C1H) Example 152
4—メチルー 5— [N—ァセチルー N— ( 3—ォクタデシルカルバモイ ルォキシ一 2—メ トキシプロ^キシカルボニル）ァミ ノ ]ェチルチアゾー ル  4-Methyl-5- [N-acetyl-N- (3-octadecylcarbamoyloxy-2- (2-methoxypropyl) carbonyl] amino] ethylthiazole
実施例 1 5 0で得たチアゾ一ル体 1 9 0 mg( 0. 3 4 1 ミ リモル），ジ メチルァミ ノ ピリ ジン 24 4 mg( 2. 0 ミ リモル），無水酢酸 2 0 4 mg( 2. 0 ミ リモル）をトルエン 1 mlに溶かし、 1 0 0て， 1 6時間加熱した。 反 応液を減圧下に濃縮乾固して残渣をシリ力ゲル（2 g) [溶出液，クロロホ ルム.メタノ ール（39:1)]さらにシリ力ゲル（2 g) [溶出液. n—へキサン， 酢酸ェチル（1:1)]にて精製して、 無色油状物 2 0 mg (収率 9. 8 %)を得 た。  Example 150 190 mg (0.341 mmol) of the thiazole obtained in 50, 244 mg (2.0 mmol) of dimethylaminopyridine, 204 mg (2 (1.0 mmol) was dissolved in 1 ml of toluene, heated to 100, and heated for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was subjected to silylation gel (2 g) [eluent, chloroform.methanol (39: 1)]. —Hexane, ethyl acetate (1: 1)] to give 20 mg of a colorless oil (9.8% yield).
T L C .silica gel , n-Hexan,EtOAc(l: 1)  T L C .silica gel, n-Hexan, EtOAc (l: 1)
Rf = 0.21 単一スポッ ト Rf = 0.21 single spot
MR(60MC,CDC13) δ 0.80(3H), 1.25C32H), '2.46(3Η), 2.52(3Η), 3.07C2H), 3.13(2Η), 3.47(3Η), 3.63(1Η), 4.16(2Η), 4.23(1Η), MR (60MC, CDC1 3) δ 0.80 (3H), 1.25C32H), '2.46 (3Η), 2.52 (3Η), 3.07C2H), 3.13 (2Η), 3.47 (3Η), 3.63 (1Η), 4.16 (2Η ), 4.23 (1Η),
4.97(1Η), 8.50(1Η) 4.97 (1Η), 8.50 (1Η)
実施例 1· 53 Example 1 53
3 , 4—ジメチル一 5— —ァセチル一 Ν—（ 3—才クタデシルカル バモイルォキシ一 2—メ トキシプロポキシ力ルボニル）ァミ ノ ]ェチルチ ァゾリ ゥム ィオダイ ド  3,4-Dimethyl-1-5-acetyl-1- (3-year-old octadecylcarbamoyloxy-2-methoxypropoxyl-carbonyl) amino] ethylthiazomidiodide
実施例 1 5 2で得たァセテ一ト 2 0 mg( 0. 0 3 3 ミ リモル）をョゥ化 メチル 1 mUこ溶かし室温、 1 6時間放置した。 反応液を减圧下に濃縮乾 固し、 目的物 2 5 mg (収率 1 0 0 %)を得た。  20 mg (0.033 mimol) of the acetate obtained in Example 152 was dissolved in 1 mU of methyl iodide and left at room temperature for 16 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain 25 mg of the desired product (yield: 100%).
T L C .silica gel, CHC13 , eOH, H20(65： 25： ) TLC .silica gel, CHC1 3, eOH , H 2 0 (65: 25:)
R f =0.42 単一スポッ ト  R f = 0.42 Single spot
I R(KBr)cm_1: 3330, 2920, 2850, 1730, 1700, 1520, 1470, 1370, 1325, 1270, 1250, 1200, 1150, 1100, 1060, 1040, 975, 920 IR (KBr) cm _1 : 3330, 2920, 2850, 1730, 1700, 1520, 1470, 1370, 1325, 1270, 1250, 1200, 1150, 1100, 1060, 1040, 975, 920
NMR(60MC,CDC13)5： 0.87C3H), 1.23(32H). 2.52(3H), 2.59(3H), 3.72(1H), 3.97(2H), 4.22(4H), 4,40(3H), 5.10(1H), 10.88(1H) 実施例 154 NMR (60MC, CDC1 3) 5 :. 0.87C3H), 1.23 (32H) 2.52 (3H), 2.59 (3H), 3.72 (1H), 3.97 (2H), 4.22 (4H), 4,40 (3H), 5.10 (1H), 10.88 (1H) Example 154
1ーォクタデシルカルバモイルー 2—メチル一 3—（4ーメチルピぺ ラジノ）カルボニルグリセリ ン  1-octadecylcarbamoyl-2-methyl-1- (4-methylpyrazino) carbonylglycerin
3—ォクタデシルカルバモイルー 2—メチルグリセリ ン 2. 0 1 gを ジクロルメタン 2 0 mlに溶解し、 氷冷下クロルギ酸フヱニル 0 , 9 4 1 g,ピリ ジン 0. 4 7 gを加えた。 室温にて 3 0分間かきまぜた後クロ口 ホルム 4 Omlを加え、 水，重曹水で洗い、 乾燥，濃縮して、 炭酸エステル 体を得た。 これに N—メチルピペラジン 2 mlを加え、 6 0°C, 1時間加 熟した。 冷後、 反応液をシリカゲルクロマ トグラフィ ーに付して精製を おこない、 （溶出液，酢酸ェチル—メタノ ール 10:1)目的物（無色，固体） 2. 1 0 gを得た。  2.0 g of 3-octadecylcarbamoyl-2-methylglycerin was dissolved in 20 ml of dichloromethane, and 0,941 g of phenyl chloroformate and 0.447 g of pyridine were added under ice cooling. After stirring at room temperature for 30 minutes, 4 Oml of chloroform was added, and the mixture was washed with water and aqueous sodium hydrogen carbonate, dried and concentrated to obtain a carbonate. 2 ml of N-methylpiperazine was added thereto, and the mixture was ripened at 60 ° C for 1 hour. After cooling, the reaction solution was purified by silica gel chromatography to obtain (eluate, ethyl acetate-methanol 10: 1) 2.10 g of the desired product (colorless, solid).
I RCKBr.Cm"1): 3340, 2930, 2850, 2800, 1748, 1698, 1536, 1470,I RCKBr.Cm " 1 ): 3340, 2930, 2850, 2800, 1748, 1698, 1536, 1470,
1450, 1300, 1260, 1240, 11501450, 1300, 1260, 1240, 1150
MR (90MHz, CDC13) δ： 0.87(3H,t), 1.25, 1.70 (32H, m) , 2.28 MR (90MHz, CDC1 3) δ : 0.87 (3H, t), 1.25, 1.70 (32H, m), 2.28
(3H,s), 2.25-2.5C4H), 3.15C2H,q), 3.44(3H,s), 3.5- 3.7(5H, m) , 5.18(4H,m)> 4.72(lH,m) (3H, s), 2.25-2.5C4H), 3.15C2H, q), 3.44 (3H, s), 3.5-3.7 (5H, m), 5.18 (4H, m) > 4.72 (lH, m)
T L C Rf = 0.24 (AcOEt- eOH 10:1) T L C Rf = 0.24 (AcOEt- eOH 10: 1)
実施例 155 Example 155
4— (3—才クタデシルカルバモイルォキシー 2—メ トキシプロポキ シカルボ二ル）一 1 , 1一ジメチルビペラジニゥム ョージ ド  4— (3—Ctadecylcarbamoyloxy 2—Methoxypropoxycarbyl) 1-1,1-Dimethylbiperazinoxide
実施例 1 5 4で得られた N—メチル体 1 . 8 0 gをエーテル 2 0 mlに 溶解し、 ヨウ化メチル 2. 8 6 gを加えて室温で 2 0時間かきまぜた。 反応液を濃縮乾固し、 無色粉末状の目的物 2. 2 6gを得た。 換ん 実施例 156 1.80 g of the N-methyl compound obtained in Example 154 was dissolved in 20 ml of ether, and 2.86 g of methyl iodide was added thereto, followed by stirring at room temperature for 20 hours. The reaction solution was concentrated to dryness to obtain 2.26 g of the target compound as a colorless powder. Exchange Example 156
4一（3—ォクタデシルカルバモイルォキシー 2—メ トキシプロポキ シ力ルボニル）一 1 , 1 ージメチルピペラジニゥム クロライ ド  4- (3-octadecylcarbamoyloxy-2-methoxypropoxycarbonyl) 1-1,1-dimethylpiperazinium chloride
実施例 1 5 5で得られたヨウ化物 2. Ogをアンバーライ ト I RA— 4 1 0 (C ）イオン交換樹脂を用いてイオン交換をおこない塩化物とし た。さらにシリカゲルクロマトグラフィーに付して精製をおこない（溶出 液 クロ口ホルム—メ タノール一水 65 :25 :4)無色粉末状の目的物 1 . 5 7gを得た。  Example 15 Iodide 2. Og obtained in 55 was ion-exchanged with an Amberlite IRA-410 (C) ion exchange resin to obtain chloride. Further purification was carried out by silica gel chromatography (eluent: liquid form: mouth-methanol / water 65: 25: 4) to obtain 1.57 g of the target compound as a colorless powder.
I R(KBr,cm— ： 3400, 2925, 2850, 1702, 1550, 1470, 1260, 1190, 1020  I R (KBr, cm—: 3400, 2925, 2850, 1702, 1550, 1470, 1260, 1190, 1020
NMR C90MHz,CDCl3) δ： 0.87(3H,t), 1.25(32H,s), 3.12(2H,q), 3.43(3H,s), 3„61(6H,s), 3.5- .0(9H, m) , 4.05- .3(4H,m) , 5.09(lH,br). NMR C90MHz, CDCl 3) δ: 0.87 (3H, t), 1.25 (32H, s), 3.12 (2H, q), 3.43 (3H, s), 3 "61 (6H, s), 3.5- .0 ( 9H, m), 4.05- .3 (4H, m), 5.09 (lH, br).
実施例 157 Example 157
1—ォクタデシルカルバモイルー 2—メチルー 3—( 1—ェチルピぺ リ ジン一 3—ィル）力ルバモイル グリセリ ン  1-octadecylcarbamoyl-2-methyl-3- (1-ethylpyridin-1-3-yl) force rubamoyl glycerin
1 ^ォクタデシルカルバモイル一 2—メチルー 3—フヱノキシカルボ ニル グリセリ ン 1 . 3 gに 3—アミノー 1—ェチルビペリ ジン 1 mlを 加え、 6 0 °Cで 1時間加熟した。 反応液をシリカゲルクロマトグラフィ 一に付して精製をおこない（g乍酸ェチル—メタノール L0:D目的物 1 . To 1.3 g of 1 ^ octadecylcarbamoyl-1-methyl-3-phenyloxycarbonyl glycerin was added 1 ml of 3-amino-1-ethylpyperidine, and the mixture was ripened at 60 ° C for 1 hour. The reaction mixture was purified by silica gel chromatography (ethyl acetate-methanol L0: D.
1 3gを得た。 乳白色固体。 13 g were obtained. Milky white solid.
MR (90MHz, CDC13) δ： 0.87(3H,t), 1.02(3H. t), 1.25(32H, m) , 1.57(4H,m), 2.34(6H,m), 3.14(2H,m), 3.43(3H,s), 3.57(lH,m), 3.77(lH,m), 4.16(4H,m), 4.73(lH,br), 5.25(lH,br) MR (90MHz, CDC1 3) δ : 0.87 (3H, t), 1.02 (. 3H t), 1.25 (32H, m), 1.57 (4H, m), 2.34 (6H, m), 3.14 (2H, m) , 3.43 (3H, s), 3.57 (lH, m), 3.77 (lH, m), 4.16 (4H, m), 4.73 (lH, br), 5.25 (lH, br)
T L C Rf=0.16 (AcOEt- eOH 10:1) T L C Rf = 0.16 (AcOEt- eOH 10: 1)
実施例 15δ 差換え 3—（3—ォクタデシルカルバモイルォキシー 2—メ トキシプロポキ シカルボニル）ァミ ノ ー 1 ーェチルー 1ーメチルピぺリ ジニゥム ョ一 ジド、 Example 15 δ Replacement 3- (3-octadecylcarbamoyloxy-2-methoxypropoxycarbonyl) amine 1-ethyl-1-methylpyridinyl amide,
実施例 1 5 7で得られる N -ェチル体 2 0 Omgをエーテル 1 Omlに溶 解し、 ヨウ化メチル 0. 5 mlを加えて室温で 2 日間かきまぜた。 反応液 を濃縮乾固して、 淡褐色粉末の目的物 2 5 O mgを得た。  20 mg of the N-ethyl compound obtained in Example 157 was dissolved in 1 ml of ether, and 0.5 ml of methyl iodide was added thereto, followed by stirring at room temperature for 2 days. The reaction solution was concentrated to dryness to obtain 25 O mg of the desired product as a light brown powder.
I RCKBr.cm-1): 3460, 3330 , 2925, 2852, 1702, 1530, 1472,I RCKBr.cm -1 ): 3460, 3330, 2925, 2852, 1702, 1530, 1472,
1260, 1140, 1060, 782, 730 1260, 1140, 1060, 782, 730
NMR(90MHz,CDCl3)<5： 0.87(3H,t), 1.25(32H, m) , 1.45(3H,t), 2.10(4H,m), 3.13(2H,m), 4.18, 4.38(3H,s), 3.43(3H,s), 3.5-NMR (90 MHz, CDCl 3 ) <5: 0.87 (3H, t), 1.25 (32H, m), 1.45 (3H, t), 2.10 (4H, m), 3.13 (2H, m), 4.18, 4.38 (3H , s), 3.43 (3H, s), 3.5-
4. l(8H,m), 4.14(4H,m), 4.91(lH,br), 5.8(lH,br) 4.l (8H, m), 4.14 (4H, m), 4.91 (lH, br), 5.8 (lH, br)
T L C Rf = 0.25 CCHCls-MeOH 5:1) (TLC Rf = 0.25 CCHCls-MeOH 5: 1)
実施例 159 . Example 159.
1 ーォクタデシルカルバモイルー 2—メチルー 3— [N—ァセチルー Ν— ( ί —ェチルビべリ ジン一 3—ィル）]力ルバモイル グリセリ ン 実施例 1 5 7で得られる化合物 6 0 0 mgをピリジン 5 ml ,無水詐酸 2 mlの混液に溶解し、 1 8時間加熟還流した。 反応液を濃縮乾固し、 残渣 をシリカゲルクロマ トグラフィ一に付して精製して、 淡褐色固体の目的 物 1 2 5 mgを得た。  1-octadecylcarbamoyl-2-methyl-3— [N-acetyl-Ν— (ί—ethylveveridin-13-yl)] potassium glycerin 600 mg of the compound obtained in Example 157 The mixture was dissolved in a mixture of 5 ml of pyridine and 2 ml of anhydrous acid, and the mixture was refluxed for 18 hours. The reaction solution was concentrated to dryness, and the residue was purified by silica gel chromatography to obtain 125 mg of the desired product as a light brown solid.
I RCKBr.cm-'): 3350. 2930, 2855, 1740, 1710, 1530, 1460,I RCKBr.cm- '): 3350.2930, 2855, 1740, 1710, 1530, 1460,
1378, 1230, 1220. 1145, 780 1378, 1230, 1220.1145, 780
MR (90MHz, CDC13) <5： 0.87(3H,t), 1.03(3H,t), 1.25(32H. m) , 1.5— 2.1(4H,m), 2.25 - 3.0 (6H, m) , 2.40(3H,s), 3.14(2H, m) , 3.45(3H,s), 3.64(lH,m), 4.25(4H,m), 4.60(lH,m), 5.10(lH,br) T L C Rf=0.19 (AcOEt-MeOH 10:1) MR (90MHz, CDC1 3) < 5: 0.87 (3H, t), 1.03 (3H, t), 1.25 (. 32H m), 1.5- 2.1 (4H, m), 2.25 - 3.0 (6H, m), 2.40 (3H, s), 3.14 (2H, m), 3.45 (3H, s), 3.64 (lH, m), 4.25 (4H, m), 4.60 (lH, m), 5.10 (lH, br) TLC Rf = 0.19 (AcOEt-MeOH 10: 1)
実施例 ISO 差挾 3— [N—ァセチルー N— ( 3—ォクタデシルカルバモイルォキシー 2Working example ISO 3— [N—acetyl-N— (3-octadecylcarbamoyloxy 2
—メ トキシプロポキシカルボニル）ァミ ノ一 1ーェチルー 1ーメチルピ ペリ ジニゥム ョージ ド —Methoxypropoxycarbonyl) amino 1-ethyl-1-methylpiperidine
実施例 1 5 9で得られる化合物 1 1 8 mgをエーテル 5 mlにとかし、 ョ ゥ化メチル 0. 2 mlを加えて、 室温で 3日間かきまぜた。 反応液を濃縮 乾固し、 目的の化合物 1 4 6 mgを得た。 淡褐色粉末。  Example 15 18 mg of the compound obtained in 59 was dissolved in 5 ml of ether, 0.2 ml of methyl iodide was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated to dryness to obtain the desired compound (146 mg). Light brown powder.
I RCKBr.cm-1): 3420, 2925, 2852, 1738, 1700, 1535, 1470,I RCKBr.cm -1 ): 3420, 2925, 2852, 1738, 1700, 1535, 1470,
1372, 1325, 1240, 1180 1372, 1325, 1240, 1180
実施例 161 Example 161
3— [N—ァセチル一 N— (3—ォクタデシルカルバモイルォキシ一 2 3— [N—acetyl-1 N— (3-octadecylcarbamoyloxy-1 2
—メ トキシプロポキシカルボ二ル）]ァミ ノ一 1 ーェチルー 1—メチルピ ペリ ジニゥム クロライ ド —Methoxypropoxycarbonyl)] amino 1 1-ethyl 1-methylpiperidinium chloride
実施例 1 6 0で得たョゥ化物 1 4 δ mgをアンバーライ ト I R A— 4 1 0イオン交換樹脂（CI一型）を用いてイオン交換をおこなって塩化物 1 2 0 mgを得た。淡褐色固^。  14 δ mg of the iodide obtained in Example 160 was subjected to ion exchange using an Amberlite IRA-410 ion exchange resin (CI type 1) to obtain 120 mg of chloride. Light brown solid ^.
I RC Br.ctn-1): 3400, 2925, 2850, 1735, 1698, 1538, 1470,I RC Br.ctn -1 ): 3400, 2925, 2850, 1735, 1698, 1538, 1470,
1372, 1325, 1240, 1178, 780, 7251372, 1325, 1240, 1178, 780, 725
R (90MHz, CDC )<5： 0.87(3H,t), 1.25(32H, m) , 1.70(3H,t), R (90MHz, CDC) <5: 0.87 (3H, t), 1.25 (32H, m), 1.70 (3H, t),
2.02(4H,m)> 2.44(3H,s), 3.12(2H,m), 3.3- 3.85(4H,m) , 3.45 (3H,s) , 3.65-4.1(4H,m). 4.19(2H,d), 4.40(2H.m), 4.9(lH,br),2.02 (4H, m) > 2.44 (3H, s), 3.12 (2H, m), 3.3- 3.85 (4H, m), 3.45 (3H, s), 3.65-4.1 (4H, m). d), 4.40 (2H.m), 4.9 (lH, br),
5.15(lH,br) 5.15 (lH, br)
T L C Rf = 0.2 (CHC - eOH 5:1) T L C Rf = 0.2 (CHC-eOH 5: 1)
実施例 162 Example 162
1 —ォクタデシルカルバモイルー 2—メチルー 3—ト リ クロロメチル ォキシカルボニル グリセリ ン  1-octadecylcarbamoyl-2-methyl-3-trichloromethyloxycarbonyl glycerin
1ーォクタデシルカルバモイルー 2—メチルグリセリ ン 2. 4 1 gお よびト リェチルァミ ン 0. 9 6 mlのジグロルメタ ン溶液を氷冷下ジホス ゲン 0. 8 3 3 mlを溶解したジクロルメタン 1 5 ml中に滴下した。 室温 で 4 0分間かきまぜたのち、 反応液を减圧下濃縮乾固して、 炭酸エステ ル体の粗生成物を得た。 1-octadecylcarbamoyl-2-methylglycerin 2.4 1 g 0.96 ml of diglycol methane solution and triethylamine were added dropwise to 15 ml of dichloromethane in which 0.833 ml of diphosgene was dissolved under ice-cooling. After stirring at room temperature for 40 minutes, the reaction solution was concentrated to dryness under reduced pressure to obtain a crude ester carbonate product.
T L C Rf=0.45 (n-Hexane-AcOEt 3:1) T L C Rf = 0.45 (n-Hexane-AcOEt 3: 1)
実施例 163 Example 163
1ーォクタデシルカルバモイルー 2—メチルー 3—（2—ベンジルォ キシ一 1 ーメ トキシカルポニルェチル）カルパモイル グリセリ ン  1-octadecylcarbamoyl-2-methyl-3- (2-benzyloxy-1-methoxypropyl) carbamoyl glycerin
0—ベンジルー D L—セリ ンメチルエステル塩酸塩 1 . 0 1 g(4. 1 2 mmole)およびト リェチルァミ ン 4 1 6 mg(4. 1 2 mmole)のジクロル メタ ン溶液（2 ml)を、 実施例 1 6 2で得られる粗エステル体 1 . 5 0 g のジクロルメタン溶液（&ml)に加えた。 室温で 2時間かきまぜた後、 溶 媒を留去し、 残留物をシリカゲルクロマトグラフィーに,付して精製をお - こなつた。 [溶出液： n—へキサン一酢酸ェチル（2:1)]無色固体の目的物 1 .2 8 gを得た。 A solution of 1.01 g (4.12 mmole) of 0-benzyl-DL-serine methyl ester hydrochloride and 416 mg (4.12 mmole) of triethylamine in dichloromethane (2 ml) was prepared. example 1 6 crude ester body 1 obtained in 2. was added to 5 0 g of dichloromethane solution (& m l). After stirring at room temperature for 2 hours, the solvent was distilled off, and the residue was purified by silica gel chromatography. [Eluent: n-hexane monoethyl acetate (2: 1)] 1.28 g of the target compound as a colorless solid was obtained.
I RC Br.cm-1): 3340, 2925, 2852, 1752, 1698, 1535, 1472, I RC Br.cm -1 ): 3340, 2925, 2852, 1752, 1698, 1535, 1472,
1262, 1118, 1080, 790, 740, 702 " 1262, 1118, 1080, 790, 740, 702 "
MR (90MHz, CDC13)<5： 0.87(3H,t), i.25(32H,m)1 3.14(2H,m), 3.43(3H,s), 3.57(lH,m), 3.73(3H,s), 3.6- 3.95(2H,m) , 4.17 (4H,m)( 4.35-4.5(lH,m), 4.50(2H,s), 4.76(lH,br), 5.60(iH,br) MR (90MHz, CDC1 3) < 5: 0.87 (3H, t), i.25 (32H, m) 1 3.14 (2H, m), 3.43 (3H, s), 3.57 (lH, m), 3.73 (3H , s), 3.6- 3.95 (2H, m), 4.17 (4H, m) ( 4.35-4.5 (lH, m), 4.50 (2H, s), 4.76 (lH, br), 5.60 (iH, br)
T L C Rf = 0.5 (n-Hexane- AcOEt 1:1) T L C Rf = 0.5 (n-Hexane- AcOEt 1: 1)
実施例 164 Example 164
1一才クタデシルカルバモイルー 2—メチルー 3—（2—ヒ ドロキシ 一 1ーメ トキシカルボニルェチル）カルパモイル グリセリ ン  1-year-old kutadecylcarbamoyl-2-methyl-3- (2-hydroxy-1-1-methoxycarbonylethyl) carbamoyl glycerin
実施例 1 6 3で得られるベンジル体 1 . 2 4 gを酢酸 1 4 ml,水 4 ml, エタノール 2 ndの混液にとかし、 パラジウム炭素を触媒にして水素気流 中、 接触還元をおこなった。 触媒をろ別したのち、 ろ液を濃縮乾固し、 残渣を n—へキサンより再結晶して無色粉末の目的物 1 . 1 Ogを得た。 I RC Br.cm-1): 3330, 2930, 2855, 1745, 1700, 1550, 1540, 1475, 1265, 1080, 790, 730Example 16 1.24 g of the benzyl derivative obtained in 63 was dissolved in a mixture of 14 ml of acetic acid, 4 ml of water and 2 nd of ethanol, and a hydrogen stream was flown using palladium carbon as a catalyst. Medium and catalytic reduction was performed. After the catalyst was filtered off, the filtrate was concentrated to dryness, and the residue was recrystallized from n-hexane to obtain 1.1 Og of the target compound as a colorless powder. I RC Br.cm -1 ): 3330, 2930, 2855, 1745, 1700, 1550, 1540, 1475, 1265, 1080, 790, 730
MR (90MHz, CDC ) <5： 0.87(3H,t), 1.25(32H, m) , 2.78(lH,br), MR (90MHz, CDC) <5: 0.87 (3H, t), 1.25 (32H, m), 2.78 (lH, br),
3.15(2H,m), 3.44(3H,s), 3.59(lH,m), 3.77(3H,s), 3.95(2H,m), 4.15(4H,m), 4.4(lH,m), 4.86(lH,br), 5.78(lH,br) 3.15 (2H, m), 3.44 (3H, s), 3.59 (lH, m), 3.77 (3H, s), 3.95 (2H, m), 4.15 (4H, m), 4.4 (lH, m), 4.86 (lH, br), 5.78 (lH, br)
in. . 59. 5° 一 61°C in. .59.5 ° one 61 ° C
実施例 165 Example 165
i一才クタデシルカルバモイルー 2—メチルー 3—（ 1ーメ トキシカ ルポ二ルビニル）力ルバモイル グリセリ ン  1-year-old kutadecylcarbamoyl-2-methyl-3- (1-methoxyvinylvinyl) rubumoyl glycerin
実施例 1 64で得られるアルコール体 2 1 8.4mg(4 Xl0 mole)に ト シルクロ リ ド 1 8 3 mg(9. 6x 10- mole),ト リェチルァミ ン 0. 1 3 ml(9. 6xl(T*mole)を加えて、室温で 3日間かきまぜた。 反応液にクロ 口ホルムを加え水，重曹水で洗ったのち、 乾燥，濃縮し、 シリカゲルクロ マ トグラフィ 一に付して精製した。 （溶媒： n—へキサン—酢酸ェチル Example 1 To 18.4 mg (4 Xl0 mole) of alcohol 2 obtained in 64, 18.3 mg (9.6 x 10-mole) of tosyl chloride, 0.13 ml of triethylamine (9.6 xl (T * mole) and stirred for 3 days at room temperature.Then the reaction solution was mixed with chloroform and washed with water and aqueous sodium hydrogen carbonate, dried, concentrated and purified by silica gel chromatography. : N-hexane-ethyl acetate
3 ： 1 )無色粉末伏の目的物 1 Ί 5 mgを得た。 3: 1) 1 to 5 mg of a colorless powdery target product was obtained.
I RCKBr.cm-1): 3335, 2970, 2925, 2851, 1735, 1710, 1692, 1640, 1540, 1472, 1450, 1350, 1270, 1250, 1218, 1140, 1095, 1070, 902, 810, 715I RCKBr.cm -1 ): 3335, 2970, 2925, 2851, 1735, 1710, 1692, 1640, 1540, 1472, 1450, 1350, 1270, 1250, 1218, 1140, 1095, 1070, 902, 810, 715
R(90 Hz,CDCl3)(5： 0.87(3H,t), 1.25(32H,m), 3.15(2H,m), 3.46(3H,s), 3.61(lH(m), 3.83(3H,s), 4.21(4H, m) , 4.70(lH,br), 5.79(lH,d), 6.27(lH,s) R (90 Hz, CDCl 3 ) (5: 0.87 (3H, t), 1.25 (32H, m), 3.15 (2H, m), 3.46 (3H, s), 3.61 (lH ( m), 3.83 (3H, s), 4.21 (4H, m), 4.70 (lH, br), 5.79 (lH, d), 6.27 (lH, s)
T L C Rf = 0.65 (n-hexane-AcOEt 1:1) T L C Rf = 0.65 (n-hexane-AcOEt 1: 1)
実施例 166 Example 166
1一才クタデシルカルバモイルー 2—メチルー 3—（ 2—ジメチルァ ミ ノー 1—メ トキシカルボニルェチル）力ルバモイル グリセリ ン 実施例 1 6 5で得られる化合物 3 0 mgをジメチルアミ ン 6 0 mgを含む トルエン 0. 3 mlに溶解し、 室温で 3時間かきまぜた。 减圧下、 反応液 を濃縮乾固し、 無色固体の目的物 3 2. 5 (ngを得た。 1-year-old Kutadecylcarbamoyl-2-methyl-3- (2-dimethyla Minnow 1-methoxycarbonylethyl) rubamoyl glycerin 30 mg of the compound obtained in Example 1 65 was dissolved in 0.3 ml of toluene containing 60 mg of dimethylamine, and stirred at room temperature for 3 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain 32.5 (ng) of the target compound as a colorless solid.
I RCKBr.cin"1): 3325, 2925, 2850, 1750, 1695, 1550, 1470,I RCKBr.cin " 1 ): 3325, 2925, 2850, 1750, 1695, 1550, 1470,
1275, 1260, 1150, 1075, 1035, 785, 7251275, 1260, 1150, 1075, 1035, 785, 725
MR (90MHz,CDCl3) δ： 0.87(3H,t), 1.25(32H,m), 2.22(6H,s), 2.63(2H,d), 3.14(2H,m), 3.43(3H,s), 3.57(lH,m), 3.73(3H,s), 4.17(4H,in)> 4.30(lH,t), 4.84(lH,br), 5.68(lH,br) MR (90MHz, CDCl 3 ) δ: 0.87 (3H, t), 1.25 (32H, m), 2.22 (6H, s), 2.63 (2H, d), 3.14 (2H, m), 3.43 (3H, s) , 3.57 (lH, m), 3.73 (3H, s), 4.17 (4H, in) > 4.30 (lH, t), 4.84 (lH, br), 5.68 (lH, br)
T L C Rf = 0.58 (AcOEt- Acetone 1:1) T L C Rf = 0.58 (AcOEt- Acetone 1: 1)
実施例 167 Example 167
1ーォクタデシルカルバモイルー 2—メチルー 3—（1 ーメ トキシカ ルポ二ルー 2— ト リメチルァン乇ニォェチル）力ルバ乇ィル グリセリ ン ョージ ド  1-octadecylcarbamoyl-2-methyl-3- (1-methoxypropanol-2—trimethylpanenyl) capillary glyceride
■実施例 1 6 6で得られるジメチルァミノ体 2 6 mgをエーテル 2 mlにと かし、 ヨウ化メチル 0. 2 mlを加えて 1 5時間かきまぜた。 反応液を濃 縮乾固し、 残渣をエーテルで洗って、 無色粉末の目的物 3 2 nigを得た。 I R(KBr,cm一1): 3350, 2925, 2850, 1740, 1700, 1530, 1470, . 1315, 1262, 1140, 1080, 788, 735 (1) 26 mg of the dimethylamino compound obtained in Example 16 was dissolved in 2 ml of ether, and 0.2 ml of methyl iodide was added thereto, followed by stirring for 15 hours. The reaction solution was concentrated to dryness, and the residue was washed with ether to obtain 32 nig of the desired product as a colorless powder. IR (KBr, cm- 1 ): 3350, 2925, 2850, 1740, 1700, 1530, 1470,. 1315, 1262, 1140, 1080, 788, 735
N R C90MHz,CDCl3) <5： 0.87(3H,t), 1.25(32H, m) , 3.13(2H, m) ,NR C90MHz, CDCl 3 ) <5: 0.87 (3H, t), 1.25 (32H, m), 3.13 (2H, m),
3.43C3H,s), 3.53(9H,s), 3. - 3.6(1Η, m) , 3.80(3H,s), 3.9- 4.4(6H,m), 4.92ClH.br) , 5.07(lH,br), 6.97(lH,br) 3.43C3H, s), 3.53 (9H, s), 3.-3.6 (1Η, m), 3.80 (3H, s), 3.9- 4.4 (6H, m), 4.92ClH.br), 5.07 (lH, br ), 6.97 (lH, br)
T L C Rf-0.4 (CHCl3-MeOH-H20 65:25:2) TLC Rf-0.4 (CHCl 3 -MeOH-H 2 0 65: 25: 2)
実施例 168 Example 168
2— [(3—ォクタデシルォキシカルバモイルォキシー 2—メ トキシ） プロポキシカルボニルァミ ノ ]一 3— ト リメチルアン乇ニオブ σピオナ 一ト 2-[(3-octadecyloxycarbamoyloxy 2-methoxy) propoxycarbonylamino] -1 3-trimethylamponiobium piona One
実施例 1 6 7で得られるメチルエステル体 4 6 mgをテ トラヒ ドロフラ ン 2 mUことかし、 濃塩酸 0. 2 mlを加えて室温で 4時間かきまぜた。 反 応液を重曹で中和したのち、 溶媒を留去し、 残渣をシリカゲルクロマト グラフィ一に付して精製し、 さらにクロ口ホルム一アセ トンから再沈澱 をおこなって、 目的物 1 0 mgを得た。  46 mg of the methyl ester obtained in Example 1 67 was added with 2 mU of tetrahydrofuran, and 0.2 ml of concentrated hydrochloric acid was added thereto, followed by stirring at room temperature for 4 hours. After the reaction solution was neutralized with sodium bicarbonate, the solvent was distilled off, the residue was purified by silica gel chromatography, and the residue was reprecipitated from formaldehyde-acetone to give 10 mg of the desired product. Obtained.
I RC Br.cm" 1): 3390, 2930, 2852, 1695, 1632, 1540, 1470, I RC Br.cm " 1 ): 3390, 2930, 2852, 1695, 1632, 1540, 1470,
1270, 1070  1270, 1070
T L C Rf-0.28 (CHCl3- eOH-H20 65:25:2) TLC Rf-0.28 (CHCl 3 -eOH-H 2 0 65: 25: 2)
マススペク トル m/e: 574(M+ 1 ) Mass spectrum m / e: 574 (M + 1)
実施例 169 Example 169
3一 [N—ァセチル— N— (Ν'ーェチルビリ ジニォ一 2—ィル）メチル] カルバ乇ィル一 1 一へキサデシルカルバモイルー 2—メチルダリセリ ン クロライ ド'  3- [N-Acetyl-N- (Ν'-Ethylviridine-1-2-yl) methyl] carbazyl-1 1-Hexadecylcarbamoyl-2-methylmethalyserine chloride '
0 2—メチル一 3—（2 ' —ピリ ジルメチル）力ルバモイルー 1 一へキ サデシルカルバモイルグリ セリ ン 0 2-Methyl-1 3- (2'-pyridylmethyl) rubamoyl-1 1-hexadecylcarbamoylglycerin
1 —へキサデシルカルバモイルー 2—メチルグリセリ ン 5 6 7 mg( 1 . 1-Hexadecylcarbamoyl-2-methylglycerin 566 mg (1.
5 2 ミ リモル）及びピリ ジン 2 4 0 mg(3. 0 4 ミ リモル）を塩化メチレ ン 4 mlに溶解し、 氷冷下フヱニルクロロフオルメート 2 6 1 mg(l . 6 7 ミ リモル）を滴下した後、 室温にて 1時間攪拌した。 反応液に 5 %炭 酸水素ナトリゥム水溶液を加えてク口口ホルム抽出し、 有機層は硫酸ナ ト リ ウムで乾燥後、 溶媒を減圧留去した。 25.2 mg) and 240 mg (3.04 mmol) of pyridine were dissolved in 4 ml of methylene chloride, and the solution was cooled under ice-cooling to give 26 mg of phenylchloroformate (1.67 mmol). ) Was added dropwise, followed by stirring at room temperature for 1 hour. A 5% aqueous solution of sodium hydrogencarbonate was added to the reaction solution, and the mixture was extracted with stomal form. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
得られた粗カーボネートに 2—（アミノメチル）ピリジン 0. 1 8 5 ml ( 1 0.1-85 ml of 2- (aminomethyl) pyridine was added to the obtained crude carbonate.
. 8 2 ミ リモル）を加え 9 0てにて 3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： 0 g:溶出液： n—へキサン 乍 酸ェチル = 1/4)にて精製し、目的物 6 3 3 mg(8 2. 1 %，無色固形物）を 得た。 .82 mmol) and heated at 90 ° C. for 3 hours. After cooling, the crude product was purified by column chromatography (silica gel: 0 g, eluent: n-hexane and ethyl acetate = 1/4), and the desired product was 633.3 mg (82.1%, colorless) Solids) Obtained.
T L C (Silica Gel； n- hexane/AcOEt = 1/4)： Rf=0.25  TLC (Silica Gel; n-hexane / AcOEt = 1/4): Rf = 0.25
NMR(90MHz,CDCl3) <5： 0.87(3H,t), 1.24(28H,s), 3.15(2H,q), . NMR (90MHz, CDCl 3) < 5: 0.87 (3H, t), 1.24 (28H, s), 3.15 (2H, q),.
3.44(3H,s), 3.60(lH,quint), 4.i8(4H,m), 4.50(2H,d), 4.85 (lH.br), 5.95(lH,br), 7.23(2H,m), 7.67(1H, d. t) , 8.53(lH,d.d) 3.44 (3H, s), 3.60 (lH, quint), 4.i8 (4H, m), 4.50 (2H, d), 4.85 (lH.br), 5.95 (lH, br), 7.23 (2H, m) , 7.67 (1H, d.t), 8.53 (lH, dd)
' I R(KBr)cm-1： 3325, 2922, 2850, 1692, 1596, 1539, 1466， '' IR (KBr) cm -1 : 3325, 2922, 2850, 1692, 1596, 1539, 1466,
1265, 1250 、  1265, 1250,
2) 3— [N—ァセチルー N—（2 '—ピリ ジルメチル）]力ルバモイルー 2—メチルー 1一へキサデシルカルバモイルグリセリ ン  2) 3— [N-Acetyl-N— (2′-pyridylmethyl)]-rubumoyl-2-methyl-11-hexadecylcarbamoylglycerin
1)で合成した化合物 6 3 3 mg (し 2 5 ミ リモル）をピリジン 1 2. 5 m The compound synthesized in 1) 6 3 3 mg (25 mol) was added to pyridine 12.5 m
1に溶解し、 無水酢酸 2. 3 5 ml(2 4. 9 4 ミ リモル）を加えた後、 窒 素気流中 1 1 0 Cにて 6 0時間加熱した。 反応液を濃縮乾固し、 残留物 に 5 %炭酸水素ナト リ ゥム水溶液を加えてク口口ホルム抽出し、 有機層 は硫酸ナ小リウムで乾燥後、 溶媒を減圧留去した。 得られた粗生成物を カラムクロマ トグラフィ一（シリ力ゲル： 2 7 g;溶出液： n—へキサンノ酢 酸ェチル = 1/2)にて精製し、目的物 4 1 5 tng(6 0. 5 %,淡黄色固形物） を得た。 The resultant was dissolved in 1 and 2.35 ml (2.9.4 millimoles) of acetic anhydride was added, followed by heating at 110 C for 60 hours in a nitrogen stream. The reaction solution was concentrated to dryness, and a 5% aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted with a stoichiometric solution. The organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography (silica gel: 27 g; eluent: n-hexane ethyl acetate = 1/2), and the desired product (4,15 tng (60.5)) was purified. %, Pale yellow solid).
T L C (Silica Gel； ti- hexane/AcOEt = i/3)： R f = 0.47 T L C (Silica Gel; ti-hexane / AcOEt = i / 3): R f = 0.47
MR(90MHz.CDCl3) <5： 0.87(3H,t), 1.25(28H,s), 2.62(3H.s), 3.14(2H,q), 3.30(3H,s), 3. 7 ClH, qui nt) , 4.00(2H,d), 4.24MR (90MHz.CDCl 3 ) <5: 0.87 (3H, t), 1.25 (28H, s), 2.62 (3H.s), 3.14 (2H, q), 3.30 (3H, s), 3.7 ClH, qui nt), 4.00 (2H, d), 4.24
(2H,d.d), 4.83(lH,br), 5.09(2H,s), 7.17(2H，m), 7.62(lH,d. t) ,(2H, d.d), 4.83 (lH, br), 5.09 (2H, s), 7.17 (2H, m), 7.62 (lH, d.t),
8.49(lH,d.d) 8.49 (lH, d.d)
I R(KBr)cm"1: 3352, 2920, 2848, 1738, 1694, 1590, 1532, IR (KBr) cm " 1 : 3352, 2920, 2848, 1738, 1694, 1590, 1532,
1365, 1226  1365, 1226
3) 3— [N—ァセチル— N—（Ν'—ェチルピリ ジニォ一 2—ィル）メチ ル]力ルバモイルー 1 一へキサデシルカルバモイルー 2—メチルグリセ リ ン クロライ ド 3) 3— [N-Acetyl—N— (Ν'-Ethylpyridinio-1-yl) methyl] force rubamoyl-1 Hexadecylcarbamoyl-2-methylglycer Link chloride
2)で合成した化合物 3 8 5 mg(0. 7 0 ミ リモル）にヨウ化工チル 3 ml を加え、 窒素気流中 2日間遮光して加熱還流した。 冷後、 反応液を濃縮 乾固し、 得られたヨウ ド塩を I R A— 4 1 0 (C Γ)[3 0 ml;溶出液： 7 0 %メタノ ール 水]にて処理し、 目的物 4 3 0 mg( 1 0 0 %,淡黄粉末） を得た。  To 38.5 mg (0.70 mmol) of the compound synthesized in 2) was added 3 ml of thiol iodide, and the mixture was heated and refluxed in a nitrogen stream for 2 days under light shielding. After cooling, the reaction solution was concentrated to dryness, and the obtained iodine salt was treated with IRA-410 (CΓ) [30 ml; eluent: 70% aqueous methanol] to obtain the target compound. There were obtained 400 mg (100%, pale yellow powder).
T L C (Silica Gel ;CHCl3/ eOH= 3/1)： Rf = 0.i2 TLC (Silica Gel; CHCl 3 / eOH = 3/1): Rf = 0.i2
NMR(90MHz,CDCl3) 5： 0.87(3H,t), 1.24(28H,s), 1.7L(3H,t), NMR (90MHz, CDCl 3 ) 5: 0.87 (3H, t), 1.24 (28H, s), 1.7L (3H, t),
2.64(3H,s), 3.10(2H,q), 3.37(3H,s), 3.66(1H, quint) , 4.00(2H,d), 4.37(2H,m), 5.22(2H,q and lH.br), 5.47(2H,s), 7.7δ(1Η, br . d) , 2.64 (3H, s), 3.10 (2H, q), 3.37 (3H, s), 3.66 (1H, quint), 4.00 (2H, d), 4.37 (2H, m), 5.22 (2H, q and lH. br), 5.47 (2H, s), 7.7δ (1Η, br.d),
8.05(lH,br.t), 8. 9(1H, br. t) , 10.07(1H, br.d) 8.05 (lH, br.t), 8.9 (1H, br.t), 10.07 (1H, br.d)
I R(KBr)cm-!: 3425, 2925, 2851, 1750, 1700, 1629, 1532,  I R (KBr) cm- !: 3425, 2925, 2851, 1750, 1700, 1629, 1532,
1466, 1371, 1220  1466, 1371, 1220
実施例 170 Example 170
3— [N—ァセチルー N—〔N '—ェチルピリ ジニォ一 2—ィル）メチル] 力ルバモィル一 2—メチルー 3—テ トラデシルカルバモイルグリセリ ン クロライ ド'  3— [N-Acetyl-N— [N'-Ethylpyridinio-l-2-yl) methyl] rubamoyl-l-Methyl-3-tetradecylcarbamoylglycerin chloride
1) 2—メチル一 3—（ 2 '—ピリ ジルメチル）力ルバモイルー 1 ーテ ト ラデシルカルバモイルグリセリ ン  1) 2-Methyl-1- 3- (2'-pyridylmethyl) rubamoyl 1-tetradecylcarbamoylglycerin
1 ーテ トラデシルカルバモイルー 2—メチルグリセリ ン 5 1 8 mg( 1 . 1-Tetradecylcarbamoyl-2-methylglycerin 5 18 mg (1.
5 0 ミ リモル）及びピリ ジン 2 3 7 mg(3. 0 0 ミ リモル）を塩化メチレ ン 4 mlに溶解し、 氷冷下フヱニルク口口フオルメー ト 2 5 8 g(l .6 5 ミ リモル）を滴下した後、 室温にて 3 0分間攪拌した。 反応液に 5 %炭 酸水素ナトリゥ厶水溶液を加えてク口口ホルム抽出し、 有機層は硫酸ナ ト リ ウムで乾燥後、 溶媒を减圧留去した。 50 millimoles) and pyridine (237 mg, 3.0 millimoles) were dissolved in 4 ml of methylene chloride, and cooled under ice-cooling. After dropwise addition, the mixture was stirred at room temperature for 30 minutes. A 5% aqueous solution of sodium hydrogencarbonate was added to the reaction solution, and the solution was extracted with stomal form. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
得られた粗力ーボネー トに 2—（アミ ノメチル）ピリ ジン 0. 1 8 3 mi 差換え (1 . 8 0 ミ リモル）を加え 9 0てにて 3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（シリ力ゲル： 2 0 g;溶出'液：n—へキサン/ 酢酸ェチル = 1/4)にて精製し、目的物（ ） 5 9 1 mg(8 2.1 %，無色固 形物）を得た。 2- (aminomethyl) pyridine 0.183 mi (1.80 mmol) was added and heated at 90 ° C. for 3 hours. After cooling, the crude product was purified by column chromatography (silica gel: 20 g; eluate: n-hexane / ethyl acetate = 1/4), and the desired product () 591 mg (8 2.1%, colorless solid).
T L C (Silica Gel； n- hexane/AcOEt = 1/4) Rf = 0.20 T L C (Silica Gel; n-hexane / AcOEt = 1/4) Rf = 0.20
NMRC90MHz,CDCl3)(5： 0.87(3H,t), 1.24(24H,s), 3.15(2H,q), 3.44(3H,s), 3.59(lH,quint), 4.18(4H,m), 4.50(2H(d), 4.82 ClH.br), 5.92ClH.br), 7.22(2H,m), 7.66(1H, d. t) , 8.53(lH,d.d) NMRC90MHz, CDCl 3) (5: 0.87 (3H, t), 1.24 (24H, s), 3.15 (2H, q), 3.44 (3H, s), 3.59 (lH, quint), 4.18 (4H, m), 4.50 (2H ( d), 4.82ClH.br), 5.92ClH.br), 7.22 (2H, m), 7.66 (1H, d.t), 8.53 (lH, dd)
1 R( Br)cm_1: 3320, 2924, 2850, 1690, 1592, 1542， 1465, 1 R (Br) cm _1 : 3320, 2924, 2850, 1690, 1592, 1542, 1465,
1270  1270
2) 3— [N _ァセチルー N '— ( 2 '—ピリ ジルメチル）]力ルバモイルー 2) 3— [N_acetyl-N '-(2'-pyridylmethyl)]
2—メチルー 1 —テ トラデシルカルバモイルグリセリ ン 2-Methyl-1—Tetradecylcarbamoylglycerin
1)で合成した化合物 5 6 2 mg( 1 . 1 7 ミ リモル）をピリ ジン 1 1 . 7 mUこ溶解し、 無水酢酸 2. 2 1 ml(2 3. 4 3 ミ リモル）を加えた後、 窒 素気流中 1 1 0°Cにて 6 0時間加熱した。 反応液を濃縮乾固し、 残留物 に 5 %炭酸水素ナトリゥム水溶液を加えてク口口ホルム抽出し、 有機層 ；ま硫酸ナト リ ゥムで乾燥後、 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（シリカゲル： 2 5 g:溶出液： ti—へキサンノ胙 酸ェチル = 1/2)にて精製し、目的物（ ）3 7 6 mg(6 1 .5 %,淡黄色固 形物）を得た。  After dissolving 56.2 mg (1.17 mmol) of the compound synthesized in 1) in 11.7 mU of pyridine, add 2.21 ml (2.4.33 mmol) of acetic anhydride Then, it was heated at 110 ° C. for 60 hours in a nitrogen stream. The reaction solution was concentrated to dryness, and a 5% aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted with stomal form. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by column chromatography (silica gel: 25 g; eluent: ti-hexane ethyl ether = 1/2), and the desired product () (376 mg, 61.5) was obtained. %, Pale yellow solid).
T L C (Silica Gel； n- exane/AcOEt - 1/3) Rf = 0.46  T L C (Silica Gel; n-exane / AcOEt-1/3) Rf = 0.46
NMR (90MHz, CDCla) δ ： 0.87(3H,t), 1.24(24H,s), 2.80(3H,s), 3.l3(2H,q), 3.28(3H,s), 3.47 (1H, quint) , 4.00(2H,d), 4.23 C2H,d.d), 4.88(lH,br), 5.08(2H,s), 7.17(2H, m) , 7.61(1H, d. t) , 8.48(lH,d.d) NMR (90MHz, CDCla) δ: 0.87 (3H, t), 1.24 (24H, s), 2.80 (3H, s), 3.l3 (2H, q), 3.28 (3H, s), 3.47 (1H, quint ), 4.00 (2H, d), 4.23 C2H, dd), 4.88 (lH, br), 5.08 (2H, s), 7.17 (2H, m), 7.61 (1H, d.t), 8.48 (lH, dd) )
I R(KBr)cm"1: 3352, 2920, 2850, 1738, 1694, 1590, 1532, 2 ~ . I 255 一 75— IR (KBr) cm " 1 : 3352, 2920, 2850, 1738, 1694, 1590, 1532, 2 ~. I 255 one 75—
1365, 1225  1365, 1225
3) 3— [N—ァセチル— Ν— (Ν'—ェチルピリ ジニォ一 2—ィル）メチ ル]力ルバモイル一 2—メチルー 3—テトラデシルカルバモイルグリセ リ ン ク σライ ド  3) 3— [N-Acetyl—Ν— (Ν'-Ethylpyridininone-2-yl) methyl] -rubumoyl-1-methyl-3--3-tetradecylcarbamoylglycerin σ-lide
2)で合成した化合物 3 6 5 mgCO . 7 0 ミ リモル）にヨウ化工チル 3 ml を加え、 窒素気流中 2 日間遮光して加熱還流した。 冷後、 反応液を濃縮 乾固し、 得られたヨウ ド塩を I R A- 4 1 0 (C r)[3 0 ml;溶出液： 7 To the compound synthesized in step 2) (365 mg CO.70 millimol) was added 3 ml of thiol iodide, and the mixture was heated to reflux in a nitrogen stream for 2 days under light shielding. After cooling, the reaction solution was concentrated to dryness, and the obtained iodide salt was washed with IRA-410 (Cr) [30 ml; eluent: 7
0 %メ タノ ールノ水]にて処理し、 目的物 4 0 2mg(9 8. 0 %,淡黄粉 末）を得た。 0% methanol water] to obtain 402 mg (98.0%, pale yellow powder) of the desired product.
10 Tし C (Silica Gel ;CHCl3/MeOH= 3/1) Rf = 0.13 10 T and C (Silica Gel; CHCl 3 / MeOH = 3/1) Rf = 0.13
NMR(90MHz,CDCl3)(5： 0.87(3H,t), 1.25(24H,s), 1.71(3H,t), NMR (90 MHz, CDCl 3 ) (5: 0.87 (3H, t), 1.25 (24H, s), 1.71 (3H, t),
2.65(3H,s), 3.11(2H,q), 3.37(3H,s), 3.66(1H, quint) , 4.01 (2H,d), 4.38(2H,m), 5.20(2H,q and lH.br), 5.48(2H,s), 7.77 (lH.br.d), 8.06(lH,br.t), 8.49(1H, r . t) , 10.00(1H, br .d)  2.65 (3H, s), 3.11 (2H, q), 3.37 (3H, s), 3.66 (1H, quint), 4.01 (2H, d), 4.38 (2H, m), 5.20 (2H, q and lH. br), 5.48 (2H, s), 7.77 (lH.br.d), 8.06 (lH, br.t), 8.49 (1H, r.t), 10.00 (1H, br.d)
1 R( Br)cra-1: 3390, 2920, 2850, 1750, 1700, 1625, 1524, 1 R (Br) cra -1 : 3390, 2920, 2850, 1750, 1700, 1625, 1524,
1450, 1370, 1215  1450, 1370, 1215
以下に実施例 i 0 6〜 1 7 0で合成した化合物の構造式を参考のため 己載する。 The structural formulas of the compounds synthesized in Examples i06 to 170 are described below for reference.
実施例 106 CH20C0NHC18H37 i Example 106 CH 2 0C0NHC 18 H 37 i
Figure imgf000078_0001
実施例丄 07 CH20C0MCi8H:
Figure imgf000078_0001
Example 丄 07 CH 2 0C0MCi 8 H:
I I
CHOMe CHOMe
+  +
CH,NHCOfiCH,CH2Me3 CI" 一 I CH, NHCOfiCH, CH 2 Me 3 CI "I
Ac 実施例 108 CH20C0NHC18Hi Ac Example 108 CH 2 0C0NHC 18 Hi
CHOMe
Figure imgf000078_0002
実施列 109 CH20CC 8H: CHOMe
Figure imgf000078_0002
Implementation row 109 CH 2 0CC 8 H:
CHOMe  CHOMe
CH20C0NCHs CH 2 0C0NCH s
！ cr! cr
Ac Ac
CH2COOEt 実施伊 U 10 CH20C0MHC18H37 CH 2 COOEt implementation U 10 CH 2 0C0 MHC 18 H 3 7
CHOMe  CHOMe
I 人  I people
CH2 CH2CH2 W. cr 0 実施例 111 CH 2 CH 2 CH 2 W. cr 0 Example 111
Figure imgf000079_0001
Figure imgf000079_0001
実施例 U2 CH20C0NHC18H37 Example U2 CH 2 0C0NHC 18 H 37
I I
CHOMe CHOMe
Θ Θ
実施例 113 Example 113
CH2 CH 2
I I
CHO CH2 CHO CH 2
Figure imgf000079_0002
実施例 114 CH20C0NHC18H
Figure imgf000079_0002
Example 114 CH 2 0C0NHC 18 H
CHOMe  CHOMe
i 0  i 0
1 Λ 1 Λ
CH2 NCH2CH2 / 0 CH 2 NCH 2 CH 2/0
実施例 115 CH20C0MCi8H; Example 115 CH 2 0C0MCi 8 H ;
I I
CHOMe CHOMe
I 0  I 0
+ cr + cr
CH2 N- CH2CH2NMes 0 CH 2 N- CH 2 CH 2 NMe s 0
実施例 116 CH20C0NHC18H37 Example 116 CH 2 0C0NHC 18 H 3 7
CHOEt  CHOEt
CH20C0NCHi crCH 2 0C0NCH i cr
I I
Ac  Ac
差換え 実施例 117 Replacement Example 117
Figure imgf000080_0001
実施例 118 CH20C0fiHC18H37
Figure imgf000080_0001
Example 118 CH 2 0C0fiHC 18 H 3 7
I I
CHOMe CHOMe
CH2OCONH Ui  CH2OCONH Ui
実施例 U9 CH20C0NHCi8H37 Example U9 CH 2 0C0NHCi 8 H 3 7
CHOMe  CHOMe
CH20C0iiH ^ -N l' CH 2 0C0iiH ^ -N l '
実施例 120 CH20C0 C18H3 Example 120 CH 2 0C0 C 18 H 3
CHOMe
Figure imgf000080_0002
実施例 121 CH20C0NHC18H3 CHOMe
Figure imgf000080_0002
Example 121 CH 2 0C0NHC 18 H 3
I I
CHOMe
Figure imgf000080_0003
実施例 122 CHzOCONHCtsHj CHOMe
Figure imgf000080_0003
Example 122 CHzOCONHCtsHj
CHOMe  CHOMe
CH2OCONH Ύ  CH2OCONH Ύ
差換え 実施例 123 CHaOCONHCisHsv Replacement Example 123 CHaOCONHCisHsv
I I
CHOMe Me CHOMe Me
CHaOCONHCH2CH2 NCH2C00Et CHaOCONHCH 2 CH 2 NCH 2 C00Et
I  I
Me 実施例 124 CH20C0fiHC18H3. Me Example 124 CH 2 0C0fiHC 18 H 3 .
CHOMe Me  CHOMe Me
4-1  4-1
CH2OCONHCH2CH2 SCH2C00' CH 2 OCONHCH 2 CH 2 SCH 2 C00 '
Me 実施例 125 CH2OTrityl Me Example 125 CH 2 OTrityl
CHOMe
Figure imgf000081_0001
CHOMe
Figure imgf000081_0001
実施例 Π6 CH20Trityl Example Π6 CH 2 0 Trityl
CHOMe  CHOMe
I 0  I 0
CH2 Ϊ人? fCH2丄 実施例 127 CH20H CH 2 Ϊ people? FCH 2実 施 Example 127 CH 2 0H
CHOMe
Figure imgf000081_0002
CHOMe
Figure imgf000081_0002
実施例 128 CH20C0MCl8H37 Example 128 CH 2 0C0MC l8 H 3 7
CHOMe
Figure imgf000081_0003
CHOMe
Figure imgf000081_0003
差換え 実施例 129 CH20C0NHCi8H37 Replacement Example 129 CH 2 0C0NHCi 8 H 3 7
I I
CHOMe
Figure imgf000082_0001
CHOMe
Figure imgf000082_0001
実施例 130 CH20Tri 1 Example 130 CH 20 Tri 1
i
Figure imgf000082_0002
実施例 131 CH20H i
Figure imgf000082_0002
Example 131 CH 2 0H
CHOMe
Figure imgf000082_0003
実施例 132 CH20C0NHCt8H37 CHOMe
Figure imgf000082_0003
Example 132 CH 2 0C0NHCt 8 H 3 7
CHOMe I 0 CHOMe I 0
CK2 N^MCH2CH20CH2Ph 実施例 133 CH20C0SHC1 8H37 CK 2 N ^ MCH 2 CH 2 0CH 2 Ph Example 133 CH 2 0C0SHC 1 8 H37
I I
CHOMe CHOMe
1 o 1 o
CH2 N^ CHaCHzOH 実施列 134 CH20C0SHC18H; CH 2 N ^ CHaCHzOH Implementation 134 CH 2 0C0SHC 18 H ;
CHOMe  CHOMe
0  0
CH2 ^ CH2CH2OTs 実施例 135 CH20C0NHCt8H37 CH 2 ^ CH 2 CH 2 OTs Example 135 CH 2 0C0NHC t8 H 3 7
CHOMe
Figure imgf000083_0001
CHOMe
Figure imgf000083_0001
実施例 136 CH20C0NHC18H37 Example 136 CH 2 0C0NHC 18 H 37
CHOMe  CHOMe
： 0 ^  : 0 ^
CH2 ίί CH2CH2¾e3 ci- 実施伊 U37 CH20C0 HC18H37 CH 2 ίί CH 2 CH 2 ¾e 3 ci- Implemented U37 CH 2 0C0 HC 18 H 3 7
CHOMe  CHOMe
ί 0 Me  ί 0 Me
CH2 ^- CH2CH2 crCH 2 ^-CH 2 CH 2 cr
" o +\ 実施判 138 CH20C0 HCiaH37 "o + \ execution decision 138 CH 2 0C0 HC ia H 3 7
CHOMe  CHOMe
CH20C0,雷 H: CH 2 0C0, Lightning H :
Figure imgf000083_0002
実施例 139 CH20C0 HCl8H37
Figure imgf000083_0002
Example 139 CH 2 0C0 HC l8 H 3 7
CHOMe
Figure imgf000083_0003
CHOMe
Figure imgf000083_0003
実施例 UO CH20C0 HCl8H37 Example UO CH 2 0C0 HC 18 H 3 7
CHOMe
Figure imgf000083_0004
CHOMe
Figure imgf000083_0004
差換え 実施例 141 Replacement Example 141
実施例 142 Example 142
p Γ 実施例 U3 p Γ Example U3
Figure imgf000084_0001
Figure imgf000084_0001
実施例 144 CH20C0 HC18E37 Example 144 CH 2 0C0 HC 18 E 3 7
CHOMe CHOMe
！ S— CH20C0 CH2 ! S— CH 2 0C0 CH 2
Ac 実施例 U5 CH20C0NHC18H37 Ac Example U5 CH 2 0C0NHC 18 H 3 7
Figure imgf000084_0002
実施例 146 CH20C0fiHCl8H37
Figure imgf000084_0002
Example 146 CH 2 0C0fiHC l8 H 3 7
CHOMe  CHOMe
CH20C0NHCH: , 実施例 147 CH 2 0C0NHCH:, Example 147
実施例 148 Example 148
Figure imgf000085_0001
Figure imgf000085_0001
実施例 149 CH2OCONHC18H37 Example 149 CH2OCONHC18H37
CHOMe  CHOMe
CH20C0CH 2 0C0
Figure imgf000085_0002
Figure imgf000085_0002
実施冽 150 CH20C0NHC18H37 Implemented cool 150 CH 2 0C0NHC 18 H 3 7
CHOMe
Figure imgf000085_0003
実施 ί列 i51 CH2OCO HC18H3, CHOMe
Figure imgf000085_0003
Implementation ί Row i51 CH2OCO HC18H3,
CHOMe  CHOMe
i  i
CH20C0NHCH2CH5 -S 久 Me CH 2 0C0NHCH 2 CH 5 -S
Me 実施冽 152 CH20C0NHCl 8H37 Me practice cold 152 CH 2 0C0NHC l 8 H37
CHOMe
Figure imgf000085_0004
CHOMe
Figure imgf000085_0004
―.差換え 実施例 153 CH20C0NHC18H37 ― Replacement Example 153 CH 2 0C0NHC 18 H 3 7
CHOMe
Figure imgf000086_0001
CHOMe
Figure imgf000086_0001
実施例 154 CH20C0NHC1 8H37 Example 154 CH 2 0C0NHC 1 8 H37
CHOMe
Figure imgf000086_0002
実施例 155 CH20C0 18H3. CHOMe
Figure imgf000086_0002
Example 155 CH 2 0C0 18 H 3.
i  i
CHOMe  CHOMe
+  +
.Me  .Me
.CH2OCO '一'"く Me 実施例 156 CH20C0 HC18H3 .CH 2 OCO 'one'"ku Me Example 156 CH 2 0C0 HC 18 H 3
CHOMe  CHOMe
i  i
Me  Me
CH,OCO 'N<; CI  CH, OCO 'N <; CI
Me 実施 l列 157 CH20C0 C18H: Me Implementation l row 157 CH 2 0C0 C 18 H:
CHOMe  CHOMe
CH20C0M^N-Et 実施例 158 CH20C0 HCt8H3' CH 2 0C0M ^ N-Et Example 158 CH 2 0C0 HC t8 H 3 '
CHOMe
Figure imgf000086_0003
CHOMe
Figure imgf000086_0003
差換え 実施例 159 CH20C0NHCl8H: Replacement Example 159 CH 2 0C0NHC l8 H:
1  1
CHOMe  CHOMe
CH20C0 4 - Et CH 2 0C0 4-Et
Ac 実施例 160 CH20C( Cl8H37 Ac Example 160 CH 2 0C (C l8 H 37
CHOMe  CHOMe
Et Et
CHaOCOlJ CHaOCOlJ
+ Me Ac 実施例 161 CH20C0NHC18H3. + Me Ac Example 161 CH 2 0C0NHC 18 H 3 .
CHOMe  CHOMe
1 -H P 0Γ 1 -H P 0Γ
CH20C0 ^ <^ し1 Ac ' 実施例 162 CH20C0NHC18H37 CH 2 0C0 ^ <^ Shi 1 Ac 'Example 162 CH 2 0C0NHC 18 H 3 7
CHOMe  CHOMe
CH20C00CC13 実施例 163 CH20C0SHC1 8H37 CH 2 0C00CC1 3 Example 163 CH 2 0C0SHC 18 H37
CHOMe  CHOMe
CH20C0eCHCH20CH2Ph CH 2 0C0eCHCH 2 0CH 2 Ph
COOMe 実施例 164 CH20C0 HC18H37 COOMe Example 164 CH 2 0C0 HC 18 H 3 7
CHOMe  CHOMe
CH20C0NHCHCH20H CH 2 0C0NHCHCH 2 0H
COOMe  COOMe
差換え 実施例 165 CH20C0MHC18H37 Replacement Example 165 CH 2 0C0MHC 18 H 3 7
C I丽 e C I 丽 e
CH20C0fiHC=CH2 CH 2 0C0fiHC = CH 2
COOMe 実施例 166 CH20C0iiHCt8H37 COOMe Example 166 CH 2 0C0iiHC t8 H 37
CHO e A  CHO e A
c  c
CH20C0¾THCHCH2NMe: CH 2 0C0¾ T HCHCH 2 NMe :
COOMe -NEi  COOMe -NEi
z t 実施例 167 CH20C0NHCisH3' zt Example 167 CH 2 0C0NHCisH 3 ′
I I
CHOMe CHOMe
+ CH2OCONHCHCH2NMe3 + CH 2 OCONHCHCH 2 NMe 3
COOMe 実施例 1δ8 CH20C0'HC18H37 COOMe Example 1δ8 CH 2 0C0'HC 18 H 3 7
CHOMe  CHOMe
I " 十 I "ten
CH20C0SHCHCH2SMe3 CH 2 0C0SHCHCH2SMe 3
COO" 実施例 169 CH 2OC JNHC 16^33  COO "Example 169 CH 2OC JNHC 16 ^ 33
CHOMe  CHOMe
CH2OCONCH2 crCH 2 OCONCH 2 cr
Figure imgf000088_0001
Figure imgf000088_0001
実施例 170 CH20C0 HC"H23 Example 170 CH 2 0C0 HC "H 23
j  j
CHOMe ！  CHOMe!
CH2OCO H,. -J ci' 上記構造式中、 Acはァセチルを、 Buはブチルを、 Etはェチルを、 Meはメチルを、 Phはフヱニルを、 Prはプロピルを、 Tritylはトリチ ルを、 Tsはトシルを示す。 CH2OCO H, .- J ci ' In the above structural formula, Ac represents acetyl, Bu represents butyl, Et represents ethyl, Me represents methyl, Ph represents phenyl, Pr represents propyl, Trityl represents trityl, and Ts represents tosyl.
実験例 6 Experiment 6
血小板凝集抑制作用  Platelet aggregation inhibitory action
[試験方法] [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分間違心分離することにより多血小板血漿（P R P： latelet 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扳血漿（P P P :platelet poor plasma)を分離した。 P P Pで P R Pを希釈して血小板数を約 50万個/ 1に調整した。 この P RP 250 1を 37°Cで 2分攪拌後、 被験薬物を加えさらに 2分間攪拌 後に P AF 1 X 10_8Mを加えた。 血小板凝集は凝集計（理化電機製）で測 定し 。 被験薬物の凝集抑制活性は、 対照 P R P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。 Blood was directly collected from male male herons using a syringe containing 3.15% citric acid (1 to 9 blood) as an anticoagulant. Then, platelet-rich plasma (PRP: latelet rich plasma) was obtained by eccentric separation 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. The PRP was diluted with PPP to adjust the platelet count to about 500,000 / l. After the P RP 250 1 for 2 minutes at 37 ° C, was added P AF 1 X 10_ 8 M after stirring for an additional 2 minutes adding the test drug. 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.
二锆果] Two hundred fruits]
表 6に示す。 Table 6 shows.
表 6 P AFによるゥサギ血小板凝集抑制作用 Table 6.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 TO.) 3X10~8M 3X10— 7M 3X 10"eM (Example TO.) 3X10 ~ 8 M 3X10— 7 M 3X 10 " e M
108 100 100 100  108 100 100 100
110 34 100 100  110 34 100 100
115 9 100 100  115 9 100 100
116 100 100 100  116 100 100 100
117 100 100  117 100 100
136 丄 1 100 100  136 丄 1 100 100
140 18 100 100 100  140 18 100 100 100
142 25 100 , 100 100  142 25 100, 100 100
143 100 100  143 100 100
144 9 100 100  144 9 100 100
145 100 100 X  145 100 100 X
148 42 100  148 42 100
149 78 100 100  149 78 100 100
i 161 6 100 100 実験例 7  i 161 6 100 100 Experimental example 7
ラッ トにおける Ρ AF降圧に対する抑制作用  Suppressive effect on 降 AF pressure drop in rat
[試験方法]  [Test method]
体重約 4 0 0 gの雄性 Sprague-Dawleyラッ トをぺントパルビタール · ナトリウム（5 0 mg/kg,静脈内投与）麻酔下に用いた。 血圧測定のために 一側股動脈およぴ薬液投与のために一側股静脈内に力ニューレを掙入固 定した。 血圧は圧トランスジューサーを介して測定し、 ポリグラフに記 録した。 先づ F AF 0 . 3 gZkgを静脈内（i.v.)投与して血圧下降度 差換 もしらベた後、 被験薬物を静脈内投与しその 5および 6 0分後に P AF を 0. 3 gZkg静脈内投与して血圧下降度をしらべた。 A male Sprague-Dawley rat weighing about 400 g was used under anesthesia with sodium pertalbital (50 mg / kg, iv). For measurement of blood pressure, a force neura was inserted and fixed in the unilateral hip artery and the unilateral hip vein for administration of the drug solution. Blood pressure was measured via a pressure transducer and recorded on a polygraph. Administer F AF 0.3 gZkg intravenously (iv) to replace blood pressure drop After the test, the test drug was intravenously administered, and 5 and 60 minutes later, 0.3 gZkg of PAF was intravenously administered to examine the degree of decrease in blood pressure.
[結果] [Result]
P A F降圧に対する抑制作用は、 被験薬物投与前の P A Fによる降圧 度（AmmHg)に対する薬物投与後の P AF降圧度（AmmHg)の比率として 表示（％抑制）した。 锆果を表 7に示す。  The inhibitory effect on PAF hypotension was expressed (% suppressed) as the ratio of the PAF hypotensive (AmmHg) after drug administration to the PAF hypotensive (AmmHg) before test drug administration. Table 7 shows the results.
表 7 P A F降圧に対する回復作用  Table 7 Recovery effect on P AF pressure drop
試験化合物 ί 投与量 回復率（％)  Test compound ί Dose Recovery rate (%)
！  !
(実験例 o) mg/kg, i . v. 5分後 6 0分後  (Experimental example o) mg / kg, i.v. 5 minutes later 60 minutes later
116 j 1 100 77  116 j 1 100 77
108 ！ 1 100 丄 00  108! 1 100 丄 00
108 j 0.1 100 55  108 j 0.1 100 55
142 1 1 100 100  142 1 1 100 100
143 ί 100 100  143 ί 100 100
π7 ！ 1 100 100 π 7 ! 1 100 100
！  !
： 149 1 100 100  : 149 1 100 100
149 ； 0.1 100 39  149; 0.1 100 39
実験例 8 Experiment 8
ラ ッ トにおけるエン ドトキシンショ ッ ク防止作用  Endotoxin shock prevention in rats
こ試験方法] This test method]
体重約 4 0 0 gの雄性 Sprague- Dawleyラッ トをべントバルピタール♦ ナトリゥム（50mg/kg,i.v.)麻酔下に用いた。血圧測定のために一側股動 脈におよび薬液投与のために一側股静脈内力二ュ一レを掙入固定した。 血圧は圧トランスジューサーを介して測定しポリグラフに記録した。 先 づエン ドトキシン（Lipopo saccharide W.E.coli 0111: B4,和光純薬） を生理食塩水に懸蜀して 1 5 nig/ kg ,静脈内投与し、 その 3〜 5分後に みられる最大の血圧下降反応（A mm H g)を記録した。 同時に実施例 1 0 8の化合物を生理食塩水に溶解して 1〜 1 0 0 gZkgの用量で静脈内 投与し、 その 1分後のェンドトキシン降圧に対する回復率を算出した。 回復率の強弱によりェンドトキシンショ ッ クに対する防止作用の有無を 判定した。 Male Sprague-Dawley rats weighing about 400 g were used under anesthesia with Bentovalpital sodium (50 mg / kg, iv). The unilateral hip vein was inserted and fixed in the unilateral venous vein for blood pressure measurement, and the unilateral venous force in the unilateral venous vein was used for drug solution administration. Blood pressure was measured via a pressure transducer and recorded on a polygraph. Endotoxin (Lipopo saccharide WEcoli 0111: B4, Wako Pure Chemical Industries) Was suspended in saline and administered intravenously at 15 nig / kg, and the maximum hypotensive response (AmmHg) observed 3-5 minutes after that was recorded. At the same time, the compound of Example 108 was dissolved in physiological saline and administered intravenously at a dose of 1 to 100 gZkg, and the recovery rate from the endotoxin hypotension 1 minute after that was calculated. The presence or absence of an endotoxin shock inhibitory effect was determined based on the strength of the recovery rate.
[結果] [Result]
锆果を表 8に示す。  Table 8 shows the results.
表 8 ラッ トにおけるエンドトキシン降圧に対する抑制  Table 8 Inhibition of endotoxin hypotension in rats
Figure imgf000092_0001
Figure imgf000092_0001
:'平均値士標準誤差 : 'Standard error
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 derivatives provided by the present invention are useful as pharmaceuticals
差換え Replacement

Claims

91  91
請 求 の 範 囲  The scope of the claims
式  Expression
C H20 R 1 CH 2 0 R 1
C HR2 C HR 2
CH2 - X - C— Y - R3 - Z— R + CH 2 -X-C— Y-R 3 -Z— R +
〇  〇
[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 ドロキン，置換されていてもよいアミノまたは環状 ァミ ノを示し、 R 3は結合手または置換されていてもよいアルキレンを、 R +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で示されるィミノ基または R +とともに環も形成してもよく、 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。 [Wherein, R 1 represents alkyl or alkyl rubamoyl, R 2 represents hydrogen, an optionally substituted hydroquine, an optionally substituted amino or cyclic amino, and R 3 represents a bond or a substituent. R + 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 represents May form a ring together with the imino group represented by X or R + , and Z represents an optionally substituted imino or nitrogen-containing heterocyclic ring] or a salt thereof.
PCT/JP1985/000062 1984-04-03 1985-02-15 Lipid derivatives WO1986004894A1 (en)

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Application Number Priority Date Filing Date Title
PCT/JP1985/000062 WO1986004894A1 (en) 1985-02-15 1985-02-15 Lipid derivatives
EP85302202A EP0157609B1 (en) 1984-04-03 1985-03-29 Lipid derivatives their production and use
DE8585302202A DE3586746D1 (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.
DE8585302202T DE3586746T2 (en) 1984-04-03 1985-03-29 LIPID DERIVATIVES, YOUR 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
WO1991009837A1 (en) * 1989-12-22 1991-07-11 Commonwealth Scientific And Industrial Research Organisation Amino acids, peptides or derivatives thereof coupled to fats

Citations (3)

* 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

Patent Citations (3)

* 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

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991009837A1 (en) * 1989-12-22 1991-07-11 Commonwealth Scientific And Industrial Research Organisation Amino acids, peptides or derivatives thereof coupled to fats

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