WO1985004398A1 - Lipid derivatives - Google Patents

Lipid derivatives Download PDF

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Publication number
WO1985004398A1
WO1985004398A1 PCT/JP1984/000163 JP8400163W WO8504398A1 WO 1985004398 A1 WO1985004398 A1 WO 1985004398A1 JP 8400163 W JP8400163 W JP 8400163W WO 8504398 A1 WO8504398 A1 WO 8504398A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
formula
alkyl
silica gel
Prior art date
Application number
PCT/JP1984/000163
Other languages
French (fr)
Japanese (ja)
Inventor
Hiroaki Nomura
Kohei Nishikawa
Susumu Tsushima
Original Assignee
Takeda Chemical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to PCT/JP1984/000163 priority Critical patent/WO1985004398A1/en
Priority to DE8585302202T priority patent/DE3586746T2/en
Priority to DE8585302202A priority patent/DE3586746D1/en
Priority to EP85302202A priority patent/EP0157609B1/en
Priority to AT85302202T priority patent/ATE81501T1/en
Priority to JP60069628A priority patent/JPH0745454B2/en
Priority to CA000478129A priority patent/CA1281324C/en
Priority to KR1019850002240A priority patent/KR930004361B1/en
Publication of WO1985004398A1 publication Critical patent/WO1985004398A1/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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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/40—Acylated substituent nitrogen atom
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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
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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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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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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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    • C07D277/22—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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    • C07D295/16—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

  • P A F Platinum Act ivating Factor
  • platelet aggregation is considered to be involved at the stage of implantation of cancer cells.
  • lipid derivatives having ether bonds or rubamoyl bonds cleave these bonds.
  • Enzymes are deficient, especially in cancer cells, so they are easily accumulated in cancer cells, alter lipid metabolism in cancer cells, and have the effect of causing cancer cells to die.
  • the present inventors have a PAF inhibitory effect and are useful as a prophylactic / therapeutic agent and antitumor agent for various circulatory disorders and allergic sexual diseases.
  • the production was successful and the present invention was completed.
  • the present invention uses the formula
  • W represents a group represented by W (wherein W represents an oxygen atom or a sulfur atom, and R 5 represents a hydrogen or an alkyl group, or both form a ring together with an adjacent nitrogen atom), R 3 represents an alkylene chain; X and Y each represent an oxygen atom or a sulfur atom; the other represents an optionally substituted imino group; and Z represents an optionally substituted amino group or an ammonium group. Which may form ⁇ ) or a salt thereof.
  • the alkyl group having 10 to 30 carbon atoms represented by R 1 may be linear or branched.
  • R 1 represents an alkyl group If R 1 is the formula
  • R 6 can be the same group as the alkyl group of R 1 described above.
  • the alkyl group of the alkylcarbamoyl group is an alkyl group having 14 to 20 carbon atoms, more preferably an alkyl group having 15 to 18 carbon atoms.
  • alkoxy group represented by are alkoxy groups having about 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isop D-poxy, butoxy, isobutoxy, and pentoxy.
  • Examples of the aralkyloxy group represented by R 2 include phenyloxy 15 alkoxy, such as benzyloxy, phenethyloxy, ffi-methinolepentinoleoxy, (methinolephenetinoleoxy, and ⁇ 3-methinolenetoxy).
  • examples of the alkyl group represented by R 4 or R 5 include Examples thereof include alkyl groups having about 1 to 5 carbon atoms, such as methinole, ethinole, provinole, isopropinole, butynole, isobutinole, and pentyl.
  • R 4 and R 5 may be formed together with an adjacent nitrogen atom as a 3 to 7-membered complex which may have a heteroatom such as a nitrogen atom, an oxygen atom and a sulfur atom in addition to the nitrogen atom.
  • Examples are 1-azeridinyl, 1-aditidinyl, 1-pyrrolidininole, piperidino, 1-perhydrodroazepinyl, 1-piperazininole, monoreholino, thiomosleholino; 1-ha. -Hydrozinze pininole, 4-no, Lohi droxazebininole,) Ichino. ⁇ Hydrothiazepininole fried.
  • Examples of the alkylene chain represented by R 3 include linear or branched alkylene chains having about 1 to 8 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, And octamethylene.
  • Examples of the optionally substituted imino group represented by X or Y include an imino group and an alkyl group having about 1 to 5 carbon atoms (eg, methyl, ethyl, propyl, butyl, pentyl). Imino group, and anorecanoinole group having about 1 to 5 carbon atoms (honoleminole, acetinole, propioninole, butylinole, isoptyryl, valeryl, isopareryl).
  • alkyl group as a substituent of the amino group is substituted with, for example, carboxyl, alkylcarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl) and the like. May be.
  • Substituted is also a good Amino groups and Anmonio group optionally Amino groups represented by Z, Anmonio group, Amino group (for example substituted with one stone two ( ⁇ _ 6 alkyl group, Mechiruamino, Echiruami Bruno, Puropiruami No, replace Sopropinoreamino, butinoleamino, isobutinoreamino, sec-butinoreamino, tert-butinoreamino, pentinoreamino, hexinoreamino, dimetinoreamino, methinoleetinoreamino, methinolepropinoreamininomeinoleminoreminoreminoremeinoleme Pentinoleamino, Methynorhexenoleamino, Jetinoreamino, Etinolepropinoreamino, Etinolebutinoreamino, Etinolepentinoreamino, Etinolehexinorea
  • the ring formed by z may be any ring as long as it is a heterocyclic ring containing at least one nitrogen atom and has a bond in which the nitrogen atom is bonded to a group.
  • a monocyclic or bicyclic heterocyclic ring which may contain a nitrogen atom, an oxygen atom or a sulfur atom as a ring-constituting atom in addition to the atom is mentioned.
  • the complex ⁇ is saturated, partially saturated, and replaced (c ::? I, ⁇ : Or any of the lowest hydrogenated rings such as heteroaromatics.
  • alkyl group eg, methinole, ethinole, propynole, butynole
  • a hydroxy group an amino (imino) group
  • carbamoyl group e.g., a clade group
  • a substituent such as a substituted 4- alkyl group ( ⁇ , hydroxyxethyl, aminoethyl), for example, ⁇ -methylmorpholino ⁇ -methylbiperidinio, ⁇ -methylbipe Radino, ⁇ -methylpyrrolidine, and the like.
  • Examples of the salt of the compound (I) include pharmacologically acceptable salts such as hydrochloride, hydrobromide, hydrobromide, sulfate, nitrate, and phosphate. Addition salts are preferred.
  • ⁇ has a quaternized nitrogen atom, chloride ion, bromine ion, iodine ion, sulfate ion, nitrate ion, phosphate ion , which acid anion or hydroxide ion 3 ⁇ 4 which ion A salt may be formed, or a salt may be formed in the molecule.
  • ⁇ '3 ⁇ 4 Compound (I) has an asymmetric carbon in the molecule and has two kinds of stereoisomers, R-coordination and S-coordination, and each of them or a mixture thereof is included in the present invention. Things.
  • Compound (I) and its salts have excellent PAF inhibitory effects, and PAF-induced circulatory disorders such as thrombosis, stroke (eg, cerebral hemorrhage, cerebral thrombosis), myocardial infarction, angina, thrombotic phlebitis, thread Diseases associated with spherical nephritis, shock (eg, due to endotoxin shock, endotoxin!), Intravascular blood coagulation caused by anaphylactic shock, and allergy (eg, bronchial asthma). It is useful as a prophylactic and therapeutic agent and an antitumor agent.
  • PAF-induced circulatory disorders such as thrombosis, stroke (eg, cerebral hemorrhage, cerebral thrombosis), myocardial infarction, angina, thrombotic phlebitis, thread Diseases associated with spherical nephritis, shock (eg, due to endotoxin shock, endotoxi
  • compound (I) and its salt have excellent properties both in hydrophilicity and lipophilicity and low toxicity, they can be orally administered to mammals as powders or as pharmaceutical compositions in appropriate dosage forms. Or it can be safely administered orally.
  • the dosage varies depending on the administration subject, target disease, symptoms, administration route, and the like.
  • compound (I) when used for the prevention or treatment of adult shock, when administered by intravenous injection, compound (I)
  • it is convenient to administer the salt thereof as a single dose usually in the range of about 0.1 to 20 body weight, preferably in the range of about 1 to 10 Zf ⁇ body weight, and about 1 to 3 times a day.
  • the compound (I) or a salt thereof may be administered by intravenous injection at a dose of about 0.07 to 0.7 Z body weight Z min. For about 1 hour or about 1 to 3 times a day. it can. In the case of other parenteral administration and oral administration, an equivalent dose can be administered. If the shock symptoms are particularly severe, the dose may be increased according to the symptoms.
  • compound (I) or a salt thereof when administered orally for the prevention or treatment of thrombosis in adults, is usually 0.1 to 2 Q'mg as a single dose, about 1 to 3 Q'mg, body weight, 1 to 3 times a day. It is convenient to administer about once. Further details
  • the pharmaceutical composition used for administration contains an effective amount of compound (I) or a salt thereof and a pharmacologically acceptable carrier or excipient, and the composition is suitable for oral or parenteral administration. It is provided as a dosage form.
  • compositions for oral administration include, for example, solid or liquid dosage forms, such as tablets (including sugar-coated tablets and filmco-tablets), pills, granules, powders, and forcepsels (soft power). Capsules), syrups, emulsions and suspensions.
  • Such a composition is produced by a method known per se and contains a carrier or excipient usually used in the field of pharmaceuticals.
  • carriers and excipients for tablets include lactose, starch, sucrose, magnesium stearate and the like.
  • compositions for parenteral administration include injections, suppositories, etc.
  • injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, infusions, and the like. Dosage form.
  • Such injections are prepared by a method known per se, for example, by dissolving, suspending or emulsifying compound (I) or a salt thereof in a sterile aqueous or oily liquid commonly used for injections.
  • Saline is a solution for injection, such as isotonic solution can be mentioned including Budoku sugar and its other auxiliary agents, appropriate solubilizing agents, for example Anorekonore (eg, Etano one Honoré), E 0 Li Anorekonore (eg , Propylene glycol, polyethylene glycol), nonionic surfactants [eg, polysonoate 80, HC 0- 50 (polyoxyethylene (.5 Omol) adduct of hydrogenated castor oil)] Any combination may be used.
  • Anorekonore eg, Etano one Honoré
  • E 0 Li Anorekonore eg , Propylene glycol, polyethylene glycol
  • nonionic surfactants eg, polysonoate 80, HC 0- 50 (polyoxyethylene (.5 Omol) adduct of hydrogenated castor oil)
  • Any combination may be used.
  • oily liquid-? I Sesame oil, soybean oil, etc.
  • Suppositories 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.
  • each of the above-mentioned compositions may contain other active ingredients as long as it does not produce a favorable interaction (by compounding with compound (I) or a salt thereof).
  • Compound (I) or a salt thereof can be produced, for example, by the following method.
  • one of X 'and Y' represents an oxygen atom or a sulfur atom, the other represents an unsubstituted imino group, Q represents a halogen (eg, chlorine, bromine, or iodine); Is the same as defined above), and reacting the optionally substituted amine (V) or cyclic compound (VI) with a compound represented by the formula
  • Solvents such as toluene and benzene
  • the compound in which one of X and Y is a substituted imino group is, for example, a compound (W) and an acid anhydride #r ( ⁇ ), an acid halide (K) or an alkyl halide (X).
  • W a compound
  • ⁇ an acid anhydride #r
  • K an acid halide
  • X alkyl halide
  • the starting compound (IV) can be produced, for example, according to the following reaction formula.
  • R 23 ⁇ represents acyloxy, and R 1 is as defined above
  • R 1 is as defined above
  • R 2b represents acylamino, and R 1 has the same meaning as described above] can be produced, for example, according to the following reaction formula.
  • R 2e represents a group represented by the formula ( ⁇ ), and R 1 has the same meaning as described above].
  • the compound represented by the following formula can be produced, for example, according to the following reaction formula.
  • R 2a represents alkyne or aralkyloxy
  • R 1 has the same meaning as described above, for example, according to the following reaction scheme.
  • the salt of the compound (I) may be obtained, for example, by the method for producing the compound (I) described above, but may be produced by adding an acid or a base to the compound (I), if necessary.
  • T L C Silica genole, black mouth honole.
  • Carpamoyl 2 0—methyl 1-octadecinolecanoleno, 'moinoleglycerin
  • the precipitated precipitate is collected and purified by column chromatography using a silica gel column eluting with formaldehyde, methanol and water (65: 25: 1) to elute the desired product (colorless powder) 8 9 7 (Yield 74.3%) was obtained.
  • Example 1 2-tosyl body 3.8 8 6 prepared in (6.0 4 5 Mi Rimoru) and bromide Richikumu (LiBr'H 2 0) 1.2 6 7 ⁇ (1 2.0 8 9 Mi Rimoru) dimethyl Chiruhorumuami de (3 7 ) Dissolve in 60. For 42 hours.
  • the crude product obtained by treatment in the same manner as in Example 7 was purified by silica gel column chromatography using ethyl hexane monoacetate (3: 2) as an eluent to obtain the desired product (colorless solid). 0 ⁇ (93% yield) was obtained.
  • TLC sica gel, ethyl hexyl monate ()]: R f 0.45
  • the benzyl derivative 2.0 ⁇ (3.34 mmol) obtained in Example 15 was converted to 70% acetic acid.
  • IRCKB r 3 aiT 1 3330, 2925, 2850, 1580, 1470, 1370, 1120, 1700, 1404 , 7 2 2
  • IRC KBr 1 3470, 3620, 2920, 2850, 1715, 1665, 1645, 1-5300, 1470, 1 3 8 0, 1 2 6 0, 1 1 2 0, 9 7 0, 9 2 0, 7 2 0
  • 3- octadecyloxy- 2 -phthalylimidopropan-1-ol used as a raw material was 3-octadecyloxy1-2-aminoprono obtained in Example 18-II). It was synthesized by reacting canolevoethoxyphthalone amide with 1-one. ii) 1-octadecyloxy-1 2-amino-3— — N, dimethinoleaminoethynole) Canolebamoinolexyproha. -The above carbonate is dissolved in asym.-dimethylethylenediamine ( 2 ⁇ ), 70. , 4 o'clock mixed.
  • IRC KB r W 3280, 2920, 2850, 1740, 1715, 1655, 1550, 1470, 1370, 1 3 0 0, 1 2 5 0, 1 1 8 5, 1 1 3 0, 9 8 0
  • the compound 138 was dissolved in ether (5), and methyl oxalate 109 was added. The mixture was stirred overnight at room temperature, and when it was cool, the solid that had been separated out was collected. The desired product (colorless powder) 144 was obtained. '

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Abstract

Novel compounds of formula (I), wherein R1 represents C10-30 alkyl or alkylcarbonyl, R2 represents hydrogen, hydroxy, alkoxy, aralkyloxy, acyloxy, acylamino or a group represented by formula (II), (wherein W represents oxygen or sulfur, and R4 and R5 each represents hydrogen or alkyl or, when taken together, R4 and R5 form a ring together with the adjacent nitrogen atom), R3 represents an alkylene chain, one of X and Y represents an oxygen or sulfur atom and the other represents an optionally substituted imino group, and Z represents an optionally substituted amino group or ammonio group optionally forming a ring, and salts thereof show the effect of depressing PAF and are useful for prophylaxis and treatment of various circulatory troubles and allergic diseases and useful as oncostatic agents.

Description

明 細  Details
脂 体  Fat body
技術分野  Technical field
本発明は医薬として有用 新規脂質誘導体に関する <  The present invention relates to a novel lipid derivative useful as a medicament.
P A F〔 Platelet Act ivating Factor〕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 ラキシ一および炎症、 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 、 また、 強力 血圧下降作用 を有することも知られている。 P A F (Platelet Act ivating Factor) is a chemical messenger that has a phospholipid structure and exists in living organisms. It has been clarified that PAF is closely related to allergy, anaphylaxis and inflammation as well as to platelet aggregation as its in vivo function, and it is also known to have a strong blood pressure lowering action.
—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、 動物がショッグ症状を呈し、 死に至ることもある。 P A Fによるショ ッ クはエン ド トキシンによるショ ック症状 'に似てお 、 エン ド トキシンシ ョックに P A Fが関与しているのでは 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 shogg symptoms and even death. The shock caused by PAF is similar to the shock symptom caused by endotoxin, and it is considered that PAF is 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モイル結合を有 する脂質誘導体は、 これらの結合を切断する酵素が特にがん細胞では不 足しているため、 がん.細胞内に蓄積されやすく、 がん細胞内の脂質代謝 に変化を与え、 がん細胞を死に至らしめる作用を有する。  In cancer translocation, platelet aggregation is considered to be involved at the stage of implantation of cancer cells.Furthermore, lipid derivatives having ether bonds or rubamoyl bonds cleave these bonds. Enzymes are deficient, especially in cancer cells, so they are easily accumulated in cancer cells, alter lipid metabolism in cancer cells, and have the effect of causing cancer cells to die.
本発明者らは P A F抑制作用を有し、 種々の循環障害疾患、 アレルギ —性疾患の予防 ·治療剤および抗腫瘍剤として有用 ¾脂質誘導体を鋭意 探索した結果、 優れた作用を有する脂質誘導体の製造に成功し、 本発明 を完成した。  The present inventors have a PAF inhibitory effect and are useful as a prophylactic / therapeutic agent and antitumor agent for various circulatory disorders and allergic sexual diseases. The production was successful and the present invention was completed.
発明の開示 Disclosure of the invention
本発明は式  The present invention uses the formula
差換え ί ΟΜΡΙ C¾ORx . Replacement ί ΟΜΡΙ C¾OR x .
CHR2 o ( I ) CHR 2 o (I)
I it  I it
CH2 - X - C - Y - R3 - Z CH 2 -X-C-Y-R 3 -Z
〔式中、 R1は炭素欽1 0 〜 3 0のアルキルもしくはアルキルカルパモ ィル基を、 R2は水素， 水酸基， アルコキシ基， ァラルキルォキシ基， ァ シルォキシ基， ァシルァミノ基または式
Figure imgf000004_0001
[Wherein, R 1 represents an alkyl or alkylcarbamoyl group having 10 to 30 carbon atoms, and R 2 represents hydrogen, a hydroxyl group, an alkoxy group, an aralkyloxy group, an acyloxy group, an acylamino group, or a compound represented by the formula
Figure imgf000004_0001
W (式中、 Wは酸素原子または硫黄原子を示し、 および R5はそれぞれ 水素またはアルキル基を示すか、 または両者が隣接する窒素原子ととも に環を形成する）で表わされる基を示し、 R3はアルキレン鎖を示し、 X および Yはその一方が酸素原子もしくは硫黄原子を、 他方が置換されて いてもよいィミノ基を示し、 Zは置換されていてもよいアミノ基もしく はアンモニォ基を示し、 それは璟を形成していてもよい〕で表わされる 化合物またはその塩に関する。 W represents a group represented by W (wherein W represents an oxygen atom or a sulfur atom, and R 5 represents a hydrogen or an alkyl group, or both form a ring together with an adjacent nitrogen atom), R 3 represents an alkylene chain; X and Y each represent an oxygen atom or a sulfur atom; the other represents an optionally substituted imino group; and Z represents an optionally substituted amino group or an ammonium group. Which may form 璟) or a salt thereof.
上記式（ I )に関し、 R1で示される炭素数 1 0 〜 3 0のアルキル基と しては直鎖状もしくは分枝状のいずれでもよく、 たとえばデシル， クン デシノレ， ト リデシノレ， テトラデシノレ， ペンタデシノレ， へキサデシノレ， へ プタデシノレ， ォクタデシノレ， ノナデシノレ， エイ コサニノレ， へネィコサニ ノレ， ドコサ二ゾレ， ト リコサニノレ， テトラコサ二ノレ， ペンタコサ二ノレ， へ キサコサニノレ, ヘプタコサ二ノレ， ォクタコサニノレ， ノナコサニノレ， ト リ アコンタニル， フアルネシール， ジヒ ドロフイチルなど力 ίあ-げられ、 かでも炭素数 1 4 〜 2 0のアルキル基が好ましく、 ^素数 1 5 〜 1 8の アルキル基がさらに好ましい。 また、 R1がアルキル力ルバモイル基を示 す場合には、 R1は式 In the above formula (I), the alkyl group having 10 to 30 carbon atoms represented by R 1 may be linear or branched. For example, decyl, kundesinole, tridecinole, tetradecinole, pentadecinole , Hexadesinore, Heptadesinole, Octadesinole, Nonadesinole, Eikosaninore, Heinekosaninore, Dokosanizore, Tricosaninole, Tetracosanore, Pentacosaninole, Hexakosanoreno, Heptakosanore, Heptakosanore , Dihydrophytyl and the like, preferably an alkyl group having 14 to 20 carbon atoms, more preferably an alkyl group having a prime number of 15 to 18. R 1 represents an alkyl group If R 1 is the formula
R6 NHCO」 ( ΙΠ ) R 6 NHCO ”(ΙΠ)
として表わすことができ、 式（ ΠΙ )中、 R6は上記の R1のアルキル基と同 様 ¾基をあげることができる。 ¾かでもアルキルカルパモイル基のアル キル基が炭素数 1 4〜2 0のアルキル基であるものが好ましく、 炭素飲 1 5〜 1 8のアルキル基であるものがさらに好ましい。 In the formula (II), R 6 can be the same group as the alkyl group of R 1 described above. Preferably, the alkyl group of the alkylcarbamoyl group is an alkyl group having 14 to 20 carbon atoms, more preferably an alkyl group having 15 to 18 carbon atoms.
で示されるアルコキシ基としては炭素数 1〜 5程度のアルコキシ基 があげられ、 たとえばメ トキシ， エトキシ， プロポキシ， イ ソプ Dポキ シ， ブトキシ， イ ソブトキシ， ペン トキシ どがあげられる。 Examples of the alkoxy group represented by are alkoxy groups having about 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isop D-poxy, butoxy, isobutoxy, and pentoxy.
R2で示されるァラルキルォキシ基としてはフヱニルー 一 5 アルコキ シがあげられ、 たとえばベンジルォキシ， フヱネチルォキシ， ffi—メチ ノレペンジノレオキシ， （¾ーメチノレフエ ネチノレオキシ， <3—メチノレフ ヱ ネチ ルォキシ¾どがあげられる。 Examples of the aralkyloxy group represented by R 2 include phenyloxy 15 alkoxy, such as benzyloxy, phenethyloxy, ffi-methinolepentinoleoxy, (methinolephenetinoleoxy, and <3-methinolenetoxy).
R2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 ， ァセチ ルォキ ， プロ ピオニルォキシ, ブチ リルォキシ， イ ソブチリルォキン， パレ リルォキシ， イ ソパレ リルォキシ どの炭素数 1〜 5程度のアル力 ノイノレオキシ， ベンゾイノレオキシ， カノレポキシォキシ， C^sァノレコキシ 力ノレボ^ノレオキシ ( メ トキシカノレポニノレオキシ， エ トキシカノレボニノレオ キシ， プロポキシカノレポニノレオキシ， ブトキシカノレボニノレオキシ ) 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, for example, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxine, parerylloxy, isopalyloxy, and any of those having about 1 to 5 carbon atoms such as innoleoxy, benzoinoleoxy, and canolepoxy. Oxy, C ^ s anolecoxy, olevo ^ norreoxy (methoxycanoleponinoleoxy, ethoxycanolevoninoleoxy, propoxycanoleponinoleoxy, butoxycanoleboninoleoxy) and the like.
がで示されるァシ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， プロピオンアミ ド， ブタンアミ ド， イ ソブタンアミ ド， ハ *レノレ アミ ド， イソバレルアミ ド どの炭素数:！〜 5程度のアルカノィルアミ ノゃベンゾィルァミ ノなどのァシルブミ ノ基があげられる。  Examples of the acylamino group represented by are, for example, formamide, acetoamide, propionamide, butanamide, isobutaneamide, ha * renoleamide, and isovaleramide. Up to about 5 alkanoylaminobenzoylamino and other acylamino groups.
式（ Π )に関して、 R4または R5で示されるアルキル基としてはたとえ ばメチノレ， ェチノレ， プロビノレ， イソプロピノレ， ブチノレ， ィソブチノレ， ぺ ンチルなどの炭素数 1〜 5程度のアルキル基があげられる。 R4および R5 が隣接する窒素原子とともに構成する瑷としては、 該窒素原子の他に窒 素原子， 酸素原子， 硫黄原子るどの異種原子を有していてもよい3 い し 7員の複素瑗があげられ、 たとえば 1ーァゼリジニル， 1一アジチジ ニル， 1一ピロリジニノレ， ピペリジノ， 1一パーヒ ドロアゼピニル， 1 ーピペラジニノレ， モノレホリノ， チォモスレホリ ノ； 1 ーハ。ーヒ ドロジァゼ ピニノレ， 4 ーノ、ローヒ ドロォキサゼビニノレ， )一ノ、。ーヒ ドロチアゼピニノレ るどがあげられる。 Regarding the formula (Π), examples of the alkyl group represented by R 4 or R 5 include Examples thereof include alkyl groups having about 1 to 5 carbon atoms, such as methinole, ethinole, provinole, isopropinole, butynole, isobutinole, and pentyl. R 4 and R 5 may be formed together with an adjacent nitrogen atom as a 3 to 7-membered complex which may have a heteroatom such as a nitrogen atom, an oxygen atom and a sulfur atom in addition to the nitrogen atom. Examples are 1-azeridinyl, 1-aditidinyl, 1-pyrrolidininole, piperidino, 1-perhydrodroazepinyl, 1-piperazininole, monoreholino, thiomosleholino; 1-ha. -Hydrozinze pininole, 4-no, Lohi droxazebininole,) Ichino.ー Hydrothiazepininole fried.
R3で示されるアルキレン鎖としては直鎖状もしくは分枝状の炭素数 1 〜 8程度のアルキレン鎖があげられ、 たとえばメチレン， エチレン， ト リメチレン， テト ラメチレン， ペンタメチレン， へキサメチレン， ヘプ タメチレン， ォクタメチレンなどがあげられる。 Examples of the alkylene chain represented by R 3 include linear or branched alkylene chains having about 1 to 8 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, And octamethylene.
Xまたは Yで示される置換されていてもよいィ ミノ基としてはたとえ ばィ ミノ基， 炭素数 1〜 5程度のアルキル基（例、 メチル， ェチル， プ 口ピル， ブチル， ペンチル）で置換されたィ ミノ基， 炭素数 1〜 5程度 のァノレカノイ ノレ基 ( ホノレミノレ， ァセチノレ， プロピオ二ノレ， ブチリノレ， ィ ソプチリル, バレリル， ィ ソパレリル） どのァシル基で置換されたィ ミ ノ基 どがあげられる。 該ィ ミノ基の置換分としてのアルキル基は、 たとえばカルボキシル， アルキルカルボニル（例、 メ トキシカルボ 二ノレ， エ トキシカノレポ二ノレ， プロポキシカルボ二ノレ， ブトキシカノレポ二 ノレ， ペントキシカルポニル）などで置換されていてもよい。  Examples of the optionally substituted imino group represented by X or Y include an imino group and an alkyl group having about 1 to 5 carbon atoms (eg, methyl, ethyl, propyl, butyl, pentyl). Imino group, and anorecanoinole group having about 1 to 5 carbon atoms (honoleminole, acetinole, propioninole, butylinole, isoptyryl, valeryl, isopareryl). The alkyl group as a substituent of the amino group is substituted with, for example, carboxyl, alkylcarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl) and the like. May be.
Zで示される置換されていてもよいァミノ基およびアンモニォ基とし てはァミノ基， アンモニォ基， 1 いし 2個の (^_6アルキル基で置換さ れ ァミノ基（例、 メチルァミノ， ェチルァミ ノ， プロピルァミ ノ， ィ 差換え ソプロピノレアミ ノ， ブチノレアミノ， ィ ソブチノレアミ ノ， sec —ブチノレア ミ ノ， tert—ブチノレア ミ ノ， ペンチノレアミ ノ， へキシノレアミ ノ， ジメチ ノレアミ ノ， メチノレエチノレアミ ノ， メチノレプロピノレアミ ノ， メチノレブチノレ ァミノ， メチノレペンチノレアミノ， メチノレへキシノレアミノ， ジェチノレアミ ノ， ェチノレプロ ピノレアミ ノ， ェチノレブチノレア ミ ノ， ェチノレペンチノレア ミ ノ， ェチノレへキシノレア ミ ノ， ジプロ ピノレアミ ノ， プロ ピノレブチノレアミ ノ， プロピノレペンチノレアミノ， プロピノレへキシノレアミノ， ジブチノレアミノ， ブチノレペンチノレアミノ， ブチノレへキシノレアミ ノ， ジペンチノレアミ ノ， ぺ ンチルへキシノレアミ ノ， ジへキシノレアミ ノ ）、 3個の Cい sアルキル基で 置換されたアンモニォ基（例、 ト リメチルアンモニォ， ジメチルェチル アンモニォ， ジメチノレプロピノレアンモニォ， ジメチノレブチノレアンモニォ， ジメチノレペンチノレアンモニォ， ジメチノレへキシノレアンモニォ， メチノレジ ェチノレアンモニォ， メ チノレエチノレプロピノレアンモニォ， メ 'チノレエチノレブ チノレアンモニォ， メチノレエチノレペンチノレアンモニォ， メ チノレエチノレへキ シノレアンモニォ， ト リェチノレアンモニォ， ジェチノレフ。口 ピノレアンモニォ， ジェチノレブチノレアンモニォ， ジェチノレペンチノレアンモニォ， ェチノレジプ 口 ピノレアンモニォ， ェチノレプロピノレフ、、チノレアンモニォ， ト リプロピノレア ンモニォ， ジブ口ピノレブチノレアンモニォ， プロピノレブチノレペンチノレアン モニォ， ト リ ブチノレアンモニォ， ト リペンチノレアンモニォ， ト リへキシ ルアンモニォ ） どがあげられる。 Substituted is also a good Amino groups and Anmonio group optionally Amino groups represented by Z, Anmonio group, Amino group (for example substituted with one stone two (^ _ 6 alkyl group, Mechiruamino, Echiruami Bruno, Puropiruami No, replace Sopropinoreamino, butinoleamino, isobutinoreamino, sec-butinoreamino, tert-butinoreamino, pentinoreamino, hexinoreamino, dimetinoreamino, methinoleetinoreamino, methinolepropinoreamininomeinoleminoreminoreminoremeinoleme Pentinoleamino, Methynorhexenoleamino, Jetinoreamino, Etinolepropinoreamino, Etinolebutinoreamino, Etinolepentinoreamino, Etinolehexinoreamino, Dipropinoreaminino, Propinolebutinoreamino Norepentinoreamino, Propinorehexinoreamino, Dibutinoreamino, Butinorepentinoreamino, Butinorehexinoreamino, Dipentinoreamino, Pentylhexinoreamino, Dihexinole Mi Bruno), Anmonio group (eg substituted with three C have s alkyl group, preparative trimethyl ammonium Nio, Jimechiruechiru Anmonio dimethylol Honoré prop Honoré ammoxidation Nio, dimethylcarbamoyl Norev Chino les ammoxidation Nio, dimethylcarbamoyl Honoré pliers Honoré amm Nio , Dimethinore Hexinoreammonio, Mechinorezietinoreammonio, Mechinoreetinorepropinoreammonio, Mechinoreetinoreb Chinoreammonio, Mechinoleetinole Pentinoreammonio, Mechinoleemonemoreimore Mouth Pinoreammonio, Mouth Pinoleammonio, Metinolebutinoreammonio, Metinorepentinoreammonio, Etinolesip Mouth Pinoreammonio, Metinolepropinolev, Mouth-Tinoleammonio, Tripropinorea, Monipio Les butyrate Norre ammoxidation Nio, prop Norev Chino les pliers Honoré en Monio, Application Benefits butyrate Honoré ammoxidation Nio, Application Benefits pliers Honoré ammoxidation Nio, the Application Benefits carboxymethyl Ruanmonio) etc. can be mentioned.
zが形成する環としては、 少なくとも 1個の窒素原子を含む複素環で あ 、 かつ該窒素原子が基 と結合する結合手を有するものであればい かなるものであってもよく、 たとえば該窒素原子の他に窒素原子， 酸素 原子または硫黄原子を環構成原子として含んでいてもよい単環式もしく は二環式複素環があげられる。 該複素璦は飽和したもの、 部分飽和した 差換 ( c::?i 、Λ : もの、 あるいは複素芳香瑷のよう ¾最低水素化^素環のいずれであ て もよく、 たとえば 1ーァゼチジニル， 1一ピロ リジニル， ピペリジノ， 1一 —ヒ ドロアセ、、ピニノレ， 1—ピロリニノレ， 1ーピラゾリ二ノレ， 1— ピロ リル， ピリジニォ， ォキサゾリオ， チアゾリオ， ピリダジニォ， ピ リ ミジニォ， ピラジニォ， 1一イ ミダゾリノレ， モルホリ ノ， チオモルホ リノ， 1—ピペラジニノレ， 1—ビラゾリジニノレ， 1—イ ン ド リル， 2— イソイ ンドリノレ， 1 H イ ンダゾーノレ— 1ーィノレ， 8—プリ二ノレ， 1— イ ソイ ン ド リル， 2—イ ソイ ン ド リル， キノ リニォ， イ ソキノ リニォ， 1 , 2 , 3 , 4—テトラヒ ドロキノ リ ン一 1—ィ ル， 1 2 3 , 4 - テトラ匕 ドロイソキノ リ ン一 2 —ィ ノレ， ーヒ ドロイ ン ドーノレ一 1 —ィ ノレ， パーヒドロイ ソキノ リ ン一 2—ィル どの基があげられ、 ¾かでも 単環式複素環の場合には 4 いし7員環が好ましく、 5または6員瑗が さらに好ましい。 これらの基は置換可能な位置に アルキル基（例、 メチノレ， ェチノレ， プロピノレ， ブチノレ ) ， ヒ ドロキシ基， ァミノ (ィ ミノ )基， 力ルバモイル基， クレイ ド基， ヒ ドロキシもしくはァミ ノ基で置 - 换されたじぃ4アルキル基（ · 、 ヒ ドロキシェチル， アミ ノエチル）など の置換基を有していてもよく、 たとえば Ν—メチルモルホリニォ Ν— メチルビペリジニォ， Ν—メチルビペラジニォ， Ν—メチルピロ リジニ ォなどの基があげられる。 The ring formed by z may be any ring as long as it is a heterocyclic ring containing at least one nitrogen atom and has a bond in which the nitrogen atom is bonded to a group. A monocyclic or bicyclic heterocyclic ring which may contain a nitrogen atom, an oxygen atom or a sulfur atom as a ring-constituting atom in addition to the atom is mentioned. The complex 璦 is saturated, partially saturated, and replaced (c ::? I, Λ: Or any of the lowest hydrogenated rings such as heteroaromatics. For example, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 11-hydroace, pininole, 1-pyrrolininole, 1-pyrazolini Nore, 1-pyrrolyl, pyridinio, oxazolio, thiazolio, pyridazino, pyrimidinio, pyrazinio, 11-imidazolinole, morpholino, thiomorpholino, 1-piperazinole, 1-virazolidinole, 1-inylone Ndrinole, 1H Indazonole 1-Innole, 8-Prininole, 1-Isoindolil, 2-Isoindolyl, Quinolinio, Isoquinolino, 1,2,3,4, Tetrahydroquinolori 1-yl, 1 2 3, 4-Tetora-Doroisoquinoline 1 2 1 - I Honoré, Pahidoroi Sokino Li down one 2-I le which group and the like, preferably 4 insulators 7-membered ring in the case of a monocyclic heterocyclic ring with or ¾, more preferably 5 or 6-membered瑗. These groups may be substituted at any substitutable position with an alkyl group (eg, methinole, ethinole, propynole, butynole), a hydroxy group, an amino (imino) group, a carbamoyl group, a clade group, a hydroxy or amino group. It may have a substituent such as a substituted 4- alkyl group (·, hydroxyxethyl, aminoethyl), for example, Ν-methylmorpholino Ν-methylbiperidinio, Ν-methylbipe Radino, ジ -methylpyrrolidine, and the like.
化合物（ I )の塩としては、 たとえば塩酸塩， 臭化水素酸塩， ョク化 水素酸塩， 硫酸塩， 硝酸塩， リン酸塩 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。 Ζが 4級化された窒素原子 を有する場合には、 塩素イオン， 臭素イ オン， ヨウ素イ オン， 硫酸ィォ ン， 硝酸イオン， リン酸イオン ¾どの酸のァニオンや水酸イオン ¾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。  Examples of the salt of the compound (I) include pharmacologically acceptable salts such as hydrochloride, hydrobromide, hydrobromide, sulfate, nitrate, and phosphate. Addition salts are preferred. When Ζ has a quaternized nitrogen atom, chloride ion, bromine ion, iodine ion, sulfate ion, nitrate ion, phosphate ion ， which acid anion or hydroxide ion ¾ which ion A salt may be formed, or a salt may be formed in the molecule.
ζ'¾ 化合物（ I )は分子内に不斉炭素を有し、 R—配位， S—配位の2種 の立体異性体が存在するが、 その各々あるいはその混合物のいずれも本 発明に包含されるものである。 ζ'¾ Compound (I) has an asymmetric carbon in the molecule and has two kinds of stereoisomers, R-coordination and S-coordination, and each of them or a mixture thereof is included in the present invention. Things.
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， 脳血栓 ) , 心筋梗塞， 狭心症， 血栓性静脈炎， 糸球体腎炎， ショ ック（例、 ェ ン ド トキシンショ ック， エン ド トキシンによ！)生じる血管内血液凝固症 侯群， アナフィ ラキシーショック）やアレルギーに関連する疾病（例、 気管支喘息） ¾どの予防 ·治療剤および抗腫瘰剤として有用である。  Compound (I) and its salts have excellent PAF inhibitory effects, and PAF-induced circulatory disorders such as thrombosis, stroke (eg, cerebral hemorrhage, cerebral thrombosis), myocardial infarction, angina, thrombotic phlebitis, thread Diseases associated with spherical nephritis, shock (eg, due to endotoxin shock, endotoxin!), Intravascular blood coagulation caused by anaphylactic shock, and allergy (eg, bronchial asthma). It is useful as a prophylactic and therapeutic agent 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、 そのまま粉末剤として、 .または適当 剤形の医薬組^ 物として、 哺乳動物に対して経口的または 経口的に安全に投与するこ とができる。 投与量は投与対象， 対象疾患， 症状， 投与ルート どによ つても異 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 使用する場合には、 静脈注射によ 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. 1〜 2 0 体重程度、 好ましくは 1〜 1 0 Zf ^体重程度、 レ日 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 た 0. 0 7〜 0. 7 Z 体重 Z min . 程度を約 1時間程度、 1日 1〜 3回程度点滴注射によ ?投与する こともできる。 他の非経口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い場合にはその症状に 応じて増量して用いてもよい。  Since compound (I) and its salt have excellent properties both in hydrophilicity and lipophilicity and low toxicity, they can be orally administered to mammals as powders or as pharmaceutical compositions in appropriate dosage forms. Or it can be safely administered orally. The dosage varies depending on the administration subject, target disease, symptoms, administration route, and the like. For example, when used for the prevention or treatment of adult shock, when administered by intravenous injection, compound (I) Alternatively, it is convenient to administer the salt thereof as a single dose usually in the range of about 0.1 to 20 body weight, preferably in the range of about 1 to 10 Zf ^ body weight, and about 1 to 3 times a day. The compound (I) or a salt thereof may be administered by intravenous injection at a dose of about 0.07 to 0.7 Z body weight Z min. For about 1 hour or about 1 to 3 times a day. it can. In the case of other parenteral administration and oral administration, an equivalent dose 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 *治療のために経口投与す る場合、 化合物（ I )またはその塩を 1回量として通常 0. 1 ~ 2 Q'mg, 体重程度、 1日 1〜 3回程度投与するのが好都合である。 さらに詳し  Also, for example, when administered orally for the prevention or treatment of thrombosis in adults, compound (I) or a salt thereof is usually 0.1 to 2 Q'mg as a single dose, about 1 to 3 Q'mg, body weight, 1 to 3 times a day. It is convenient to administer about once. Further details
ϋ 差換え f OiVPI くは、 血栓症の予防を目的とする場合、 1回量 0. 5〜 4 Wノ^体重程度、 治療を目的とする場合、 1回量4〜 1 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力;できる。 ϋ Replacement f OiVPI In the case of thrombosis prevention, a single dose of about 0.5 to 4 W ^ body weight; for the purpose of treatment, a single dose of about 4 to 1 body weight each day Preferably, it is administered about three times. In the case of other parenteral administration, it is possible to administer an equivalent amount.
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賦形剤とを含むものであ 、 該 組成物は経口または非経口投与に適する剤形として提供される。  The pharmaceutical composition used for administration contains an effective amount of compound (I) or a salt thereof and a pharmacologically acceptable carrier or excipient, and the composition is suitable for oral or parenteral administration. It is provided as a dosage form.
経口投与のための組成物としてはたとえば、 固体または液体の剤形、 具体的には錠剤（糖衣錠， フィ ルムコ—テング錠を含む）， 丸剤， 顆粒 剤， 散剤， 力プセル剤（ ソフ ト力プセル剤を含む）， シコップ剤， 乳剤， 懸濁剤 どがあげられる。 かかる組成物は自体公知の方法によって製造 され、 製剤分野において通常用いられる担体もしくは賦形剤を含有する ものである。 たとえば錠剤用の担体， 賦形剤としては乳糖， でんぷん， ショ糖， ステアリン酸マグネシウム ¾どがあげられる。  Compositions for oral administration include, for example, solid or liquid dosage forms, such as tablets (including sugar-coated tablets and filmco-tablets), pills, granules, powders, and forcepsels (soft power). Capsules), syrups, emulsions and suspensions. Such a composition is produced by a method known per se and contains a carrier or excipient usually used in the field of pharmaceuticals. For example, carriers and excipients for tablets include lactose, starch, sucrose, magnesium stearate and the like.
非経口投与のための組成物としては、 たとえば注射剤， 坐剤 どがあ げられ、 注射剤としてはたとえば静脈注射剤， 皮下注射剤， 皮内注射剤， 筋肉内注射剤， 点滴注射剤などの剤形があげられる。 かかる注射剤は自 体公知の方法、 たとえば化合物（ I )またはその塩を通常注射剤に用い られる無菌の水性もしくは油性液に溶解、 懸濁または乳化することによ つて調製される。 注射用の水溶液としては生理食塩水， ブドク糖やその 他の補助薬を含む等張液などがあげられ、 適当な溶解補助剤， たとえば ァノレコーノレ (例、 ェタノ 一ノレ ) ， ホ0リ アノレコーノレ (例、 プロ ピレングリ コール， ポリ エチレングリ コール） ， 非イ オン性界面活性剤〔例、 ポリ ソノレべ一ト 8 0， H C 0— 5 0 ( polyoxyethylene (· 5 O mol ) adduct of hydrogenated castor oi l ) 〕 どと併用してもよい。 油性液とし -? I てはゴマ油， 大豆油などがあげられ、 溶解補助剤として安息香酸ベンジ Examples of compositions for parenteral administration include injections, suppositories, etc. Examples of injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, infusions, and the like. Dosage form. Such injections are prepared by a method known per se, for example, by dissolving, suspending or emulsifying compound (I) or a salt thereof in a sterile aqueous or oily liquid commonly used for injections. Saline is a solution for injection, such as isotonic solution can be mentioned including Budoku sugar and its other auxiliary agents, appropriate solubilizing agents, for example Anorekonore (eg, Etano one Honoré), E 0 Li Anorekonore (eg , Propylene glycol, polyethylene glycol), nonionic surfactants [eg, polysonoate 80, HC 0- 50 (polyoxyethylene (.5 Omol) adduct of hydrogenated castor oil)] Any combination may be used. As oily liquid-? I Sesame oil, soybean oil, etc.
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 アンプルに充填され、 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、 成型することによって調製される。  Benzyl alcohol and the like. The prepared injection is usually filled in an appropriate ampoule and provided as an injection. Suppositories 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.
るお、 上記各組成物は化合物（ I )またはその塩との配合によ )好ま しく い相互作用を生じ い限り、 他の活性成- を含有していてもよい。  In addition, each of the above-mentioned compositions may contain other active ingredients as long as it does not produce a favorable interaction (by compounding with compound (I) or a salt thereof).
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。  Compound (I) or a salt thereof can be produced, for example, by the following method.
まず、 式  First, the expression
CH, OR1 CH, OR 1
CER' 0 (IV)'  CER '0 (IV)'
II II
CH2— X -C-Y R3-Q CH 2 — X -CY R 3 -Q
〔式中、 X'および Y'はその一方が酸素原子または硫黄原子を、 他方が無 置換イ ミノ基を示し、 Qはハロゲン（例、 塩素， 臭素， ョ ク素）を示し、 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 （ V )または環式化合物（ VI )を反応させ、 式 [In the formula, one of X 'and Y' represents an oxygen atom or a sulfur atom, the other represents an unsubstituted imino group, Q represents a halogen (eg, chlorine, bromine, or iodine); Is the same as defined above), and reacting the optionally substituted amine (V) or cyclic compound (VI) with a compound represented by the formula
CHaOR1 CHaOR 1
CHR2 0 (1) CHR 2 0 (1)
I , II ,  I, II,
CH9-X -C-Y— R3— Z CH 9 -X -CY— R 3 — Z
〔式中、 各記号は前記と同意義〕で表わされる化合物を得る。 化合物（ Wherein each symbol is as defined above. Compound(
IV ) と（ V )または（ W )との反応は化合物（ IV )に対し、 化合物（ V IV) and (V) or (W) react with compound (IV) to compound (V
)または（ VI：)を 1当量ないし大過剎加え、 0〜200てで溶媒の存在  ) Or (VI :) is added in an amount of 1 equivalent to a large excess.
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 It can be performed under or without solvent. Solvents such as toluene and benzene
ゼン， エーテル， ジォキサン， テトラヒ ドロフランなどがあげられ、 ま n^^ ゝ 、， f vv:r s た化合物（ v )または（ I )自体を溶媒として用いることもできる。 加 熱下においては封管中で反応を行ってもよい。 Zen, ether, dioxane, tetrahydrofuran, etc., and n ^^ ゝ, fvv: rs Compound (v) or (I) itself can also be used as a solvent. The reaction may be performed in a sealed tube under heating.
式（ I )中、 Xおよび Yの一方が置換されたィミノ基である化合物は、 たとえば化合物（ W )と酸無水 #r (观 ) , 酸ハライ ド（ K )またはアル キルハラィ ド（ X )とを ¾Sさせることによって製造することができる。  In the formula (I), the compound in which one of X and Y is a substituted imino group is, for example, a compound (W) and an acid anhydride #r (观), an acid halide (K) or an alkyl halide (X). Can be produced by making ¾S
3  Three
反応は一股に溶媒（例、 ベンゼン， トルエン， ジメチルスルホキシド， ジメチルホルムアミ ド， テo )ト ラヒドロフラン ）中、 反応温度を。〜 1 0 0 。(：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のた め、 塩基（例、 ト リェチルァミン， ピリジン， ジメチルァミノ ピリジン, 水酸化力リゥム， 水素化ナトリクム ）を反応^中に共存させることもで The reaction can be performed in a solvent (eg, benzene, toluene, dimethylsulfoxide, dimethylformamide, tetrahydrofuran) at a reaction temperature. ~ 100. (: Proceeding by keeping the temperature at this level. In this case, a base (eg, triethylamine, pyridine, dimethylaminopyridine, hydroxylated water, sodium hydrogen) is coexisted in the reaction for the purpose of accelerating the reaction rate. With things
§ α § α
出発原枓である化合物（ IV )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 compound (IV) can be produced, for example, according to the following reaction formula.
I) 式（ ）中、 Xが 0または Sの場合  I) In the formula (), when X is 0 or S
CH2OR3 CHsOR1 CH 2 OR 3 CHsOR 1
CHR2 CHR2 C m) (CHR 2 CHR 2 C m)
CH2XH cx n CH2XCNH-R°-Q CH 2 XH cx n CH 2 XCNH-R ° -Q
II  II
0  0
Ci^OR1 CHaOR1 Ci ^ OR 1 CHaOR 1
C^COOPh(XY) H2N—R3_0H(X1) C ^ COOPh (XY) H 2 N--R 3 _0H (X1)
CHR CHR2 (XVI) CHR CHR 2 (XVI)
I I
CHpOH Xff CH2OCOPii CHpOH Xff CH 2 OCOPii
CHaOR1 CHaOR 1
TsC (XK)  TsC (XK)
CHR2 (S¾ CHR 2 (S¾
CH2OCONH-R3 -OH CH 2 OCONH-R 3 -OH
差換え CH.OR1 Replacement CH.OR 1
L i Q (XXI )  L i Q (XXI)
CHR2 (XX) CHR 2 (XX)
C OCONH— R3— OTs C OCONH— R 3 — OTs
CHpOR1 CHpOR 1
CHR' (XI)  CHR '(XI)
〔X = 0〕  (X = 0)
CH2OCONH-R -Q CH 2 OCONH-R -Q
Π) 式（ IV )中、 Yが 0または Sの場合 Π) When Y is 0 or S in formula (IV)
CHゥ OR1 CH2ORi CHaOR1 CH ゥ OR 1 CH 2 ORi CHaOR 1
酸化 DPPA(X )  Oxidized DPPA (X)
CHR" CHR2 CHR2 CHR "CHR 2 CHR 2
(XXV)  (XXV)
CH2OH COOH CH2NCO CH 2 OH COOH CH 2 NCO
(XIV) (ΧΧΙΠ)
Figure imgf000013_0001
(XIV) (ΧΧΙΠ)
Figure imgf000013_0001
CH2NHCO— Y— R3— Q 式 CH 2 NHCO— Y— R 3 — Q formula
CH2ORx CH 2 OR x
CHR2a (XlVa) CH2OH CHR 2a (XlVa) CH 2 OH
〔式中、 R23^:ァシルォキシを示し、 R1は前記と同意義〕の化合物はたと えば次の反応式に従つて製造できる。 [Wherein, R 23 ^ represents acyloxy, and R 1 is as defined above], for example, can be produced according to the following reaction formula.
CE OR1 CE OR1 CE OR 1 CE OR 1
I ァシル化 I  I acylated I
CHOH (im) > CHR2a (XlVa) CHOH (im)> CHR 2a (XlVa)
CH2OTri CH2OTri CH 2 OTri CH 2 OTri
(XXK) 差換え O PI 式 (XXK) Replacement O PI formula
C^OR1 C ^ OR 1
CHR 2b (XIVrb ) CHR 2b (XIV r b)
CH2OH CH 2 OH
C式中、 R2bはァシルァミノを示し、 R1は前記と同意義〕の化合物はたと えば次の反応式に従って製造できる。 In the formula C, R 2b represents acylamino, and R 1 has the same meaning as described above] can be produced, for example, according to the following reaction formula.
CH2ORl (ΧΠΙ) C^OR1 CH2ORl CH 2 OR l (ΧΠΙ) C ^ OR 1 CH 2 OR l
I PhCH2NH9 I H I PhCH 2 NH 9 IH
CHOTs > CHNHCH, Ph CHNHCH2Ph CHOTs> CHNHCH, Ph CHNHCH 2 Ph
CH2OTri CH2OTri (im CH2OH CH 2 OTri CH 2 OTri (im CH 2 OH
(XXX) (nxm)  (XXX) (nxm)
CHsOR1 CHsOR 1
接敏還元 ァシル化  Intimate reduction acylation
CHNH。  CHNH.
CH2OH CH 2 OH
(XXXIV) (XXXIV)
>  >
CH^OR1 CH ^ OR 1
CHR2C (Wc ) CHR 2C (Wc)
CH2OH CH 2 OH
〔式中、 R2eは式（ Π )で表わされる基を示し、 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 2e represents a group represented by the formula (Π), and R 1 has the same meaning as described above]. The compound represented by the following formula can be produced, for example, according to the following reaction formula.
(X c )
Figure imgf000014_0001
(X c)
Figure imgf000014_0001
差換え Replacement
, _ O Pl ヽ ), _ O Pl ヽ )
)  )
Figure imgf000015_0001
Figure imgf000015_0001
CH2OH (XIVc") CH 2 OH (XIVc ")
(W=0) 式  (W = 0) formula
CH.OR1
Figure imgf000015_0002
CH.OR 1
Figure imgf000015_0002
CH2OH CH 2 OH
〔式中、 R2aはアルコキン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つて製造できる。 Wherein R 2a represents alkyne or aralkyloxy, and R 1 has the same meaning as described above, for example, according to the following reaction scheme.
Figure imgf000015_0003
Figure imgf000015_0003
; VjRじ Λ( "vvit-o 式
Figure imgf000016_0001
; VjR Λ ("vvit-o formula
Figure imgf000016_0001
CH2 SH CH 2 SH
〔式中、 R1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。 ' _[Wherein R 1 and R 2 are as defined above] can be produced according to the following reaction formula. '_
CH2ORx (XIX) CH OR1 (XLV I )- CHgOR1 CH 2 OR x (XIX) CH OR 1 (XLV I)-CHgOR 1
I TsC^ PhCH2SH I TsC ^ PhCH 2 SH
CHR2 CHR2 » CHR2 CHR 2 CHR 2 »CHR 2
CH2OH CH2OTs CH2SCH2Ph CH 2 OH CH 2 OTs CH 2 SCH 2 Ph
( XIV ) ( XLV ) (XLVD )  (XIV) (XLV) (XLVD)
CH OR1 CH OR 1
Na/NH.  Na / NH.
CHR' (XI ' )  CHR '(XI')
CH2 SH 上記各反応式中、 記号 Ph， Ts ， Tr iおよび D P P Aはそれぞれフエ二 ノレ ， トシノレ ， トリチルおよびジフエ二ルホスホリ ルアジドを示す。 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 ， フタノレィ ミ ド， ペンジノレオキシカノレポ二ノレ ， t ert—ブトキシカノレポ二ノレ CH 2 SH In the above reaction formulas, the symbols Ph, Ts, Tri and DPPA represent phenyl, tosinole, trityl and diphenylphosphoryl azide, respectively. Among the compounds used in each reaction, compounds having a group that may hinder the reaction may be selected from protecting groups known per se (eg, benzyl, tosyl, trityl, phthalonimide, penzinoleoxycanoleponinole, tert). —Butoxycanole Ponore
)で該基を保護して反応を行 ¾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。 また、 式（ I )中、 R2がァシルォキシ ，ァシルァミノである化合物は、 式（ W )中、 R2が水酸基，了ミノ基である化合物を（ W )— ( I )への 反応に用いれば、 式（ I )中、 Xまたは Yで示されるィ ミ ノ基の置換分 としてのァシルと R2で示されるァシルォキシまたはァシルァミノ中のァ シルが同じ化合物を製造することもできる。 で -- え i さらに、 式（ I )中、 Zがアルキルで置換された非環状アンモニォで ある化合物は、 たとえば化合物（ IV )とジアルキルアミンを反応させて 式（ W )中、 Zがジアルキルアミノ基である化合物を得、 これを（ VK ) - ( I )の反応に付した後、 アルキルハラィ ドを反応させて製造するこ ともできる。 ) To protect the group and carry out the reaction, and after the reaction, subject it to a deprotection reaction known per se to obtain the desired compound. In the formula (I), the compound in which R 2 is acyloxy or acylamino is obtained by using the compound in which R 2 is a hydroxyl group or an amino group in the formula (W) for the reaction to (W) — (I). In the formula (I), the compound represented by X as a substituent of the imino group represented by X or Y and the acyl represented by R 2 by acyloxy or acylamino can also be produced. De-eh i Further, a compound in which Z is an acyclic ammonium substituted with alkyl in the formula (I) can be obtained, for example, by reacting a compound (IV) with a dialkylamine to obtain a compound in which Z is a dialkylamino group in the formula (W). It can also be produced by subjecting it to the reaction of (VK)-(I) and then reacting it with an alkyl halide.
また、 式（ I )中、 Zがァミノ ， アルキルァミノ ，ジアルキルァミノ である化合物はたとえば次の反応式に従つて製造することができる。  In the formula (I), a compound wherein Z is amino, alkylamino, dialkylamino can be produced, for example, according to the following reaction formula.
CHgOR1 (XLVDI) R R CHゥ OR1 CHgOR 1 (XLVDI) RR CH ゥ OR 1
H,N-R3-N: H, NR 3 -N:
CHR2(XVI) CHR2 (ID CHR 2 (XVI) CHR 2 (ID
/ R，  / R,
CH2OCOPh CHpOCONH-Re一 NCH 2 OCOPh CHpOCONH-R e- N
Figure imgf000017_0001
酸無水物. CH2OR]
Figure imgf000017_0001
Acid anhydride. CH 2 OR ]
酸ハライ ド  Acid halide
ァノ レ、ライド CHR2 (L) Fanore, Ride CHR 2 (L)
CHoOCO-Y-R3-N CHoOCO-YR 3 -N
CHsOR1 (LI ) CHgOR1 CHsOR 1 (LI) CHgOR 1
I HY-R3 -Q I HY-R 3 -Q
CHR2 CHR2 (LEO CHR 2 CHR 2 (LEO
/R，  / R,
CH2NC0 CH NHCO-Y-R3-N CH 2 NC0 CH NHCO-YR 3 -N
(XXV) 'ヽ R' 酸無水物 CHaOR1 (XXV) 'ヽ R' acid anhydride CHaOR 1
酸ノヽライ ド  Acid noride
ァノ 1 ^ルハライド CHR2 0 Fano 1 ^ Le Halide CHR 2 0
I II q /R， I II q / R,
CH ι。*>一 X - C一 Y - R上、3 - N丄 ' (. Lm j CH ι. *> One X-C one Y-R, three-N 丄 '(. Lm j
Figure imgf000017_0002
Figure imgf000017_0002
( Υ = oまたは s ) - 上記反応式中、 および R"はそれぞれアルキルまたは保護基（例、 ぺ ンジル.）を示すか、 R，および R"が隣接する窒素原子とともに環を形成し、 差換え フタルイミ ド， スクシンィミ ドるどの保護基を示す。 R，および R"のうち、 少 くとも一方が保護基である場合には、 該保護基を有する化合物を脱 保護反応に付し、 目的とする化合物を得ることができる。 (Υ = o or s)-where R and R "each represent an alkyl or a protecting group (eg, benzyl), or R and R" form a ring with an adjacent nitrogen atom, and Phthalimid, succinimide, etc. When at least one of R and R "is a protecting group, the compound having the protecting group can be subjected to a deprotection reaction to obtain a desired compound.
化合物（ I )の塩はたとえば上記した化合物（ I )の製造方法自体で 得られることもあるが、 必耍に応じて、 化合物（ I )に酸または塩基を 加えて製造することもできる。 発明を実施するための最良の形態  The salt of the compound (I) may be obtained, for example, by the method for producing the compound (I) described above, but may be produced by adding an acid or a base to the compound (I), if necessary. BEST MODE FOR CARRYING OUT THE INVENTION
実施例 1 Example 1
2—0—べンジルー 3— 0— ( 2'—ジメチルァミ ノエチル） カノレバモ ィル一 1一 0—ォクタデシルグリ セ リ ン  2—0—Benziru 3—0— (2′—Dimethylaminoethyl) Canolebamoyl 1 1 1 0—Octadecylglycerin
2 -0一ベンジブレ一 1— 0—ォクタデシルグリセリン 1.8 8 (.4.3 2 5 ミ リモル） ， ピリジン ， 0.6 8 4 ^ ( 8.6 5 ミ リモル）をジクロノレ メ タン （ 1 2 ）に溶解し、 クロ口炭酸フヱニノレ 0.7 45 ^ ( 4.7 5 6 ミリモル）を氷冷下滴下した後，室温にて 1.5時間攪拌した。 反応液を 1 %炭酸水素ナトリクム溶液で洗浄後，有機層を硫酸マグネシクムで乾 燥し、 溶媒を減圧留去した。 得られたカーボネートを精製すること く asym.—ジメチノレエチレンジァミン ， 4 5 7身（ 5.1 9 ミ リモル）を加 え， 70。にて5時間加熱し，冷後クロ口ホルム一メ タノール（ 1 9 : 1 )を溶出液とするシリ カゲルカラムクロマトグラフィ 一にて精製し，目 的物（無色固形物） 2.3 7 （収率 9 9.8 % )を得た。 2 -0-1-0-Octadecylglycerin 1.88 (.4.3 25 millimoles), pyridine, 0.684 ^ (8.65 millimoles) are dissolved in dichloronorethane (12), and After the addition of 0.745 ^ (4.756 mmol) of phenol carbonate, which was added dropwise under ice-cooling, the mixture was stirred at room temperature for 1.5 hours. After washing the reaction solution with 1% sodium hydrogen carbonate solution, the organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting carbonate was purified without adding asym.-dimethinoleethylenediamine, 457 (5.19 mmol), 70. After heating for 5 hours at room temperature, the mixture was cooled and purified by silica gel column chromatography using chloroform-methanol (19: 1) as eluent to obtain the target substance (colorless solid) 2.37 (yield 9%). 9.8%).
T L C〔シリカゲノレ， クロ口ホノレ .ム一メ タノーノレ （ 1 4 : 1 ) 〕 R f T L C [Silica genole, black mouth honole.
= 0.1 5 = 0.1 5
NMR 9 0 ΜΗ ζ C D C 3〕 ^ : 0.87 ( 3 H ) , 1.2 8 ( 3 2 Η ) ， 2.2 0 ( 6 Η ) 2.3 7 ( 2 H ) , 3.2 3 ( 2 H ) , 3.4 2 ( 2 差換え H ) , 3.5 3 ( 2 H ) , 3.7 6 ( 1 H ) , 4.2 0 ( 2 H ) , 4.6 8 ( 2 H ) , 5.2 7 ( 1 H ) , 7.3 2 ( 5 H ) NMR 90 ΜΗ ζ CDC 3 ] ^: 0.87 (3 H), 1.28 (32 Η), 2.20 (6)) 2.37 (2 H), 3.2 3 (2 H), 3.4 2 (2 H), 3.5 3 (2 H), 3.76 (1 H), 4.20 (2 H), 4.68 (2 H), 5.2 7 (1 H), 7.32 (5 H)
1 R〔 filmDc^1 : 3 3 3 0 , 2 9 2 0 , 2 8 5 0 , 2 8 1 5 , 1 7 2 5 , 1 5 0 0 , 1 4 6 8 , 1 2 5 5 , 1 1 2 0 , 1 0 6 0 実施例 2 1 R [filmDc ^ 1 : 3 3 3 0, 2 9 2 0, 2 8 5 0, 2 8 1 5, 1 7 2 5, 1 5 0 0, 1 4 6 8, 1 2 5 5, 1 1 2 0, 1 0 6 0 Example 2
2— 0—ァセチルー 3— 0—〔 N—ァセチル Ν— ( 2'—ジメチルァ ミノェチル ) 〕カルパモイノレ一 1一 0—ォクタテ"シルグリセリン  2—0—Acetyl-3—0— [N-Acetyl Ν— (2'-Dimethylaminominethyl)] Carpamoinole 1 1 0—Octate “Sylglycerin
エタノール（ 5 ）および 9 0 酢酸水溶液（ 5 0 ^ )の混液に、 実 '施例 1で製造したベンジルエーテル体 1.0 9 7 ^ ( 2 ミ リモル）および 1.0%パラジウム炭素 2 5 0 を加え、 室温にて 2時間接触環元を行な つた。 反応終了後，触媒を^別し、 液を減圧濃縮して、 粗アルコール 体 9 5 8 を得た。 このアルコール体に、 クロ口ホルム （ .1 0 ) ， ト リエチルァミ ン （ 2 0 ^ ) ,無水酢酸 ( 3 mりを加えた後，室温にて 1 3時間放置し、 反応液を減圧濃縮した。 残渣を酢酸ェチル—アセ ト ン （ 5 : 1 )を溶出液とするシリ力ゲルカラムクロマ トグラフィ 一にて精製 し、 目的物（無色油状物質） 40 6？ ^(収率 3 7.4 % )を得た。  To a mixture of ethanol (5) and an aqueous solution of 90 acetic acid (50 ^) were added 1.097 ^ (2 mmol) of the benzyl ether compound produced in Example 1 and 1.0% palladium carbon 250, and the mixture was stirred at room temperature. The contact reduction was carried out for 2 hours. After completion of the reaction, the catalyst was separated, and the solution was concentrated under reduced pressure to obtain a crude alcohol derivative 958. To this alcohol compound were added chloroform (.10), triethylamine (20 ^), and acetic anhydride (3 m), and the mixture was allowed to stand at room temperature for 13 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate-acetate (5: 1) as an eluent to obtain the target compound (colorless oily substance) 406? ^ (37.4% yield). Was.
T L C〔シリカゲル， クロ口ホルム一メタノール（ 5 ： 1 ) 〕 ： R f = 0.6 6  TLC [silica gel, chloroform-form-methanol (5: 1)]: Rf = 0.66
NMR C 9 0 MHz C D C 3〕 5 ： 0.8 8 ( 3 H ) , 1.2 7 ( 3 2NMR C 90 MHz CDC 3 ] 5: 0.88 (3 H), 1.27 (3 2
H ) , 2.1 0 ( 3 H ) 2.2 3 ( 6 H ) ， 2.4 0 ( 2 H ) , 2.5 0 ( 3H), 2.10 (3H), 2.23 (6H), 2.40 (2H), 2.50 (3H)
H ) ， 3.46 ( 2 H ) 3.5 8 ( 2 H ) , 3.8 5 ( 2 H ) , 4, 4 2 ( 2H), 3.46 (2H) 3.58 (2H), 3.85 (2H), 4, 4 2 (2
H ) , 5.2 9 ( 1 H ) H), 5.2 9 (1 H)
I R C film 3cm ： 2 9 2 4 , 2 8 5 0 ， 1 7 4" 5 , 1 7 1 0 ， 1 4 6 0 , 1 3 7 2 , 1 2 3.4 , 1 1 8 0 錢ぇ' Ί 実施例 3 IRC film 3cm: 29 24, 28 50, 17 4 "5, 17 10 0, 14 60, 13 72, 1 2 3.4, 1 18 0 Example 3
？,—0—ァセチノレ— 3— 0—！： N—ァセチノレ一 N— ( 2'— ト リメチノレ アンモニォェチノレ） _〕カノレノ、 -モイルー 1— 0—ォクタデシルグリセリン 一。 ョージド  ? , —0—Acetinole—3—0—! : N—Acetinole N— (2'—Trimetinole Ammoniechinore) _] Canoleno, -Moyru 1-0—Octadecylglycerin. Forged
実施例 2で製造したジメチルァミノ体 3 5 5 OT （ 0.7 0 9 ミ リモル ） およびョク化メチル 2 0 1 M （ 1.4 1 8 ミ リモル）をエーテル 1 5 に 溶解して、 室温にて 2 2時間攪拌した。 氷冷下.，析出した ¾澱を 取し、 目的物（無色粉末） 4 2 (収率 8 7.3 ^ )を得た。 The Jimechiruamino body 3 5 5 OT prepared in Example 2 (0.7 0 9 Mi Rimoru) and ® click methyl 2 0 1 M (1.4 1 8 Mi Rimoru) was dissolved in ether 1 5, 2 for 2 hours at room temperature Stirred. The resulting precipitate was collected under ice-cooling to give the desired product (colorless powder) 42 (yield: 87.3 ^).
T L C〔シリ カゲル，酢酸ェチル一酢酸一水（ 3 ： 1 ： 1 ) 〕 ： R f = 0.3 9  TLC [silica gel, ethyl acetate-monoacetate-water (3: 1: 1)]: R f = 0.39
NMR C 9 0 MHz ， C D C£3 D <5 : 0.8 9 ( 3 H ) , 1.2 7 ( 3 2 H ) , 2.1 2 ( 3 H ) , 2.5 2 ( 3 H ) , 3.4 7 ( 2 H ) ， 3.4 8 ~ 3. 7 1 ( 1 1 H ) , 3.8 0 ( 2 H ) , 4.2 2 ( 2 H ) , 4.5 1 ( 2 H ) , 5.4 2 ( 1 H ) NMR C 90 MHz, CDC £ 3 D <5: 0.89 (3H), 1.27 (32H), 2.12 (3H), 2.52 (3H), 3.47 (2H), 3.4 8 to 3.7 1 (1 1 H), 3.80 (2 H), 4.2 2 (2 H), 4.5 1 (2 H), 5.4 2 (1 H)
I R C KB r Dm1: 3 4 5 0 , 2 9 2 0 , 2 8 4 0 , 1 7 4 0 , 1 6IRC KB r Dm 1 : 3 4 5 0, 2 9 2 0, 2 8 4 0, 1 7 4 0, 1 6
8 0 , 1 4 6 5 , 1 3 7 1 , 1 2 3 2 , 1 2 0 0 実施例 4 8 0, 1 4 6 5, 1 3 7 1, 1 2 3 2, 1 2 0 0 Example 4
2—0—ベンジル一 1— 0—ォク デシノレ一 3—0— ( 2'- ト リメチ ノレアンモニォェチソレ ) カノレノ モイ ノレグリ セ リ ン 。 ョージド  2-0—Benzyl 1—0—Octodecino 3—0— (2'-Trimetin-Noreammonjöchisole) Canoleno Moi Noregri Serine. Forged
実施例 1で製造したジメチルァミノ体 9 0 6 ^ ( 1.6 5 1 ミ リモル） およびヨウ化メチノレ 4 6 9mg( 3.3 0 2 ミ リモノレ ）をエーテル（ 2 0 mi )に溶解し、 室温にて 2日間攪拌した。 折出した ¾澱を 取し、 目的物 (無色粉末） 1.0 2 4 （収率 8 9.8 % )を得た。  The dimethylamino derivative (906 ^ (1.651 mimol)) and methinole iodide (4.69 mg, 3.302 mirimonele) prepared in Example 1 were dissolved in ether (20 mi) and stirred at room temperature for 2 days. did. The precipitated precipitate was collected to obtain 1.024 of the desired product (colorless powder) (yield: 89.8%).
T L C〔シリ カゲル ，酢酸ェチルー酢酸一水（ 3 ： 1 ： 1 ) 〕 ： R f = 0.43 TLC [silica gel, ethyl acetate-acetic acid monohydrate (3: 1: 1)]: R f = 0.43
NMR C 9 0 MH z , C D C£3 + CD3OD〕 δ ： 0.8 9 ( 3 H ) ， 1. 2 5 ( 32 H ) , 3.2 7 ( 9 H ) , 3.43 ( 2 H ) , 3.5 3 ( 2 H ) ， 3.60〜3·9 1 ( 5 Η ) , 4.23 ( 2 H ) , 4.68 ( 2 H ) ， 6.7 1 ( 1 H ) , 7.3 6 ( 5 H ) NMR C 90 MHz, CDC £ 3 + CD 3 OD] δ: 0.89 (3H), 1.25 (32H), 3.27 (9H), 3.43 (2H), 3.53 (2 H), 3.60 to 3 · 91 (5 Η), 4.23 (2H), 4.68 (2H), 6.7 1 (1H), 7.36 (5H)
I R C KBr^ cm"1 : 3 3 5 5 , 2 9 2 7 , 2 8 5 0 , 1 7 3 0 , 1 5 3 9 , 1 4 7 3 , 1 2 5 5 , 1 1 3 0 , 1 0 4 4 , 7 5 9 , 7 0 3 IRC KBr ^ cm " 1 : 3 3 5 5, 2 9 2 7, 2 8 5 0, 1 7 3 0, 1 5 3 9, 1 4 7 3, 1 2 5 5, 1 1 3 0, 1 0 4 4, 7 5 9, 7 0 3
実施例 5 Example 5
2—0—ペンジノレー 3— 0— ( 2'—ハイ ドロキシェチノレ ） カルパモイ ノレ一 1— 0—オケタテ"シノレク *リセリ ン  2-0—Penzinole 3—0— (2'—Hydroxyschinore) Carpamoy Nore 1 1-0—Okate “Sinorek * Lyserine”
2—0—ベンジル- 1— 0—ォクタテ"シノレク *リ セ リ ン 1.7.3 9 （ 4 ミ リモル） ， ピリジン 6 3 2 （ 8 ミ リモル） ， ク ロ 口炭酸フエニル 6 8 9 （ 4.4 ミ リモル） ， ジクロロメタン （ 1 0 m ） よ 、 実施例 1 と 同様にして得られたカーボネートをクロ口ホルム ( 1 0 m ）に溶解し、 ェタノールァミ ン 293 ( 4.8 ミ リモル）を加えて 2 1時間還流した c 反応液を減圧濃縮し、 残渣をへキサン—酢酸ェチル（ 1 ： 1 )を溶出液 と.するシリカゲルカラムクロマトグラフィ一にて精製し、 目的物（無色 固形物） 1.941 ^ (収率 9 3.0 % )を得た。 2-0-Benzyl-1-0-octate "cinorek * lyserine 1.7.39 (4 mimol), pyridine 632 (8 mimol), phenyl chlorocarbonate 689 (4.4 mimol) ), Dichloromethane (10 m), and the carbonate obtained in the same manner as in Example 1 was dissolved in chloroform (10 m). Ethanolamine 293 (4.8 mmol) was added, and the mixture was refluxed for 21 hours. c The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (1: 1) as an eluent to give the desired product (colorless solid) 1.941 ^ (93.0% yield) ).
' T L C〔シリ力ゲル，へキサン一酢酸ェチル（ 1 ： 1 ) 〕 ： R f = 0· 1 8  'TLC [silicone gel, ethyl hexane monoacetate (1: 1)]: R f = 0 · 18
NMR.〔 90MHz，CDC^3〕3 : 0.8 7 ( 3 H ) ， 1.2 7 ( 3 2 H ) , 2.82 ( 1 H ) ， 3·1 5〜3.9 1 ( 9 Η ) , 4.2 2 ( 2 Η ) ， 46 8 ( 2 Η ) , 5.3 7 ( 1 Η ) , 7.33 ( 5 Η ) NMR. [90MHz, CDC ^ 3 ] 3: 0.87 (3H), 1.27 (32H), 2.82 (1H), 3.15 to 3.91 (9 9), 4.22 (2Η) , 468 (2 Η), 5.37 (1 Η), 7.33 (5 Η)
I R C Κ Β r 1 ： 333 5 , 29 20 , 2 8 5 0 ， 1 7 00 ， 1 5 30 , 1465 , 12 59 , 1 IRC Κ Β r 1 : 333 5, 29 20, 28 50, 17 00, 15 30, 1465, 12 59, 1
C31H55N05 C 31 H 55 N0 5
計算値： C， 7 1.3 6 ; H , 0.6 2 ； Ν , 2.6 8  Calculated values: C, 71.36; H, 0.62; Ν, 2.68
実測値： C , 7 1.6 5 ； Η， 0.6 2 ； Ν , 2.4 0 実施例 6 - Measured value: C, 71.65; Η, 0.62; Ν, 2.40 Example 6-
2一 0—ペンジノレー 1—0—ォクタデシノレ一 3一 0一 ( 2'- ρ—ト ノレ エンスノレホニノレォキシェチノレ ) 力ルバモイルグリセ リ ン 2-1 0—Penzinole 1—0—Octadesinole 3 1 0 1 (2'- ρ— レ レ ス ス ス 力 力 ル ル ル ル バ バ ル)
実施例 5で製造したアルコール体 1.841 ^ ( 3.5 28ミリモル）を ト リェチルァミ ン （ 1 0 m ）に溶解し、 氷^下に p -トルエンスルホニ ルクロライ ド 0- 8 7 5 ^ ( 5 8 7ミリモル）を加えた後、 室温にて 1 2時間攪拌した。 氷冷下反応液に 5 %塩酸水溶液を加え、 クロ口ホルム にて抽出し、 有機層は硫酸マグネシゥムにて乾燥後、 .溶媒を減圧留去し た。 残渣はへキサン—酢酸ェチル（ 2.5 ： 1 )を溶出液とするシリカゲ ルカラムクロマトグラフィ一にて精製し、 目的物（無色油状物質） 2·3 6 g- (収率 99.0%)を得た。 1.841 ^ (3.528 mmol) of the alcohol compound produced in Example 5 was dissolved in triethylamine (10 m), and p-toluenesulfonyl chloride 0-875 ^ (587 mmol) was dissolved on ice under ice. ), And the mixture was stirred at room temperature for 12 hours. A 5% aqueous hydrochloric acid solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue hexane - acetic Echiru (2 5:. 1) was purified by silica gel gel column chromatography one to eluent to give the desired product (colorless oil) 2 · 3 6 g- (99.0 % yield) Was.
T L C〔シリカゲル，へキサン一酢酸ェチル（ 2 : l ) 〕 ： R f = 0. 29  TLC [silica gel, ethyl hexane monoacetate (2: l)]: Rf = 0.29
N MR〔 90MH z ，CDC 〕 0.88 ( 3 H ) ， 1.23 ( 3 2 H ) ， 41 ( 3 H ) ， ·3.28〜 3.5 8 ( 6 H ) ， 3.7 2 ( 1 H ) ， 3. 9 7〜4.3 7 ( 4H ) ， 4.64 ( 2 H ) 5.02 ( 1 H ) ， 7.42〜 7. 2 2 ( 7 H ) , 7.7 9 ( 2H )  N MR [90MHz, CDC] 0.88 (3H), 1.23 (32H), 41 (3H), · 3.28 to 3.58 (6H), 3.72 (1H), 3.97 to 4.3 7 (4H), 4.64 (2H) 5.02 (1H), 7.42 to 7.22 (7H), 7.79 (2H)
I R〔film〕c^ : 333 0 , 293 0 , 28 5 0 , 17 28 , 1 6 I R [film] c ^: 333 0, 293 0, 285 0, 17 28, 1 6
00 , 1 5 2 5 , 146 5 , 1 36 5 , 125 5 , 90 , 80， 1 120 , 1100 , 7 60 実施例 7 00, 15 25, 146 5, 1 365 5, 125 5, 90, 80, 1 120, 1100, 760 Example 7
2—0—ベンジノレ— 3— 0— ( 2,ーブロモ-ェチノレ ) 力ノレノ、 *モイ ノレ一 1 一 0一才クタデシルグリセリン  2-0—benzinole—3—0— (2, -bromo-ethynole) * no * 1 1 0 1 year old Kutadecyl glycerin
実施例 6で製造したトシル体 2.3 6 0 ^ ( 3.4 9 1 ミ リモル）および 臭化リチウム（ LiBr ·Η20 ) 0.732 （ 6.9 8 3 ミ リモル）をジメチ ルホルムア ミ ド （ 2 に加え、 60°にて 2時間加熱した。 冷後、 反 応液に水を加えてエーテル抽出し、 有機層は硫酸マグネシクムで乾燥後、 溶媒を減圧留去した。 残渣はへキサン一酢酸ェチル（ 4 ： 1 )を溶出液 とするシリカゲルカラムクロマトグラフィ 一にて精製し、 目的物（無色 固形物） 1.8 5 5 （収率 9 0.9 % )を得た。 Added Example 6 tosyl body 2.3 6 0 ^ (3.4 9 1 Mi Rimoru) prepared in and lithium bromide (LiBr · Η 2 0) 0.732 (6.9 8 3 Mi Rimoru) in dimethylol Ruhorumua Mi de (2, 60 ° After cooling, water was added to the reaction solution, and the mixture was extracted with ether. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.The residue was ethyl hexane monoacetate ( 4 : 1). The purified product was purified by silica gel column chromatography using as an eluent to obtain 1.855 (yield 90.9%) of the target product (colorless solid).
T L C〔シリ力ゲル，へキサン一酢酸ェチル（ 2 ： 1 ) 〕 ： R f = 0. 5 1  TLC [silicone gel, ethyl hexane monoacetate (2: 1)]: Rf = 0.51
NMR C 9 0 MH z ， COC£3〕 j ： 0.8 7 ( 3 H ) ， 1.2 6 ( 3 2 H ) , 3.2 9〜- 3.9 2 ( 9 Η ) , 4.2 2 ( 2 Η ) , 4.6 6 ( 2 Η ) ， 5. 0 6 ( 1 Η ) , 7 30 ( 5 Η ) , NMR C 90 MHz, COC £ 3 ] j: 0.87 (3 H), 1.26 (32 H), 3.29--3.92 (9 Η), 4.2 2 (2 Η), 4.6 6 (2 Η), 5.06 (1 1), 730 (5Η),
-ι  -ι
I R〔 Κ Β cm 3 3 3 0 , 2 9 2 0 , 2 8 5 0 , 1 7 2 0 , 1 5  I R 〔Κ Βcm 3 3 3 0, 2 9 2 0, 2 8 5 0, 1 7 2 0, 1 5
3 8 , 1 4 7 0 , 1 2 5 0 , 1 2 1 5 3 5 , 2 5 3 8, 1 4 7 0, 1 2 5 0, 1 2 1 5 3 5, 2 5
元素分折： C31 H54N04Br Elemental fold: C 31 H 54 N0 4 Br
計算値： C ， 6 3.6 8 ； H， 9.3 1 ； N， 2.4 0  Calculated values: C, 63.68; H, 9.31; N, 2.40
実測値： C ， 6 3.9 8 ； H , 9.3 7 ； N， 2.2 2  Obtained values: C, 63.98; H, 9.37; N, 2.22
実施例 8 Example 8
— 2— 0—ベンジル一 1—0—ォクタデシノレ一 3— 0—（ 2'—チアゾリ _ ォェチノレ )カノレハ'モイノレク *リセ リン * ブロマイ ド 実施例 7で製造したブロム体 8 7 7 （ 1.5ミ リモル）にチアゾ―ル 差換え - 5 I 1 （ 6.0ミリモノレ）を加え、 110°にて 1 2時間加熱した。 反応 液を濃縮乾固し、 残渣はク onホルムーメタノール（ 3 ： 1 )を溶出液 とするシリ力ゲルカラムクロマトグラフィ 一にて精製し、 目的物（無色 粉末） 7 8 1 （収率 7 7.7 ¾ )を得た。 — 2— 0—Benzyl 1—0—Octadecinole 1 3—0— (2′-thiazoli_oetinole) kanoreha'moinolek * lyserin * bromide Bromide produced in Example 7 8 7 7 (1.5 mimol) Thiazole replacement- 5 I 1 (6.0 millimono) was added, and the mixture was heated at 110 ° for 12 hours. The reaction mixture was concentrated to dryness, and the residue was purified by silica gel column chromatography using quonformumethanol ( 3 : 1) as eluent to obtain the target compound (colorless powder). ¾) was obtained.
T L C〔シリ力ゲル，酢酸ェチル一酢酸一水（ 3 ： 1 ： 1 ) 〕 ： R f = 0.41  TLC [silicone gel, ethyl acetate-monoacetate-water (3: 1: 1)]: R f = 0.41
NMR C 90 MHz , COC£3〕 <? : 0.88 ( 3 Η ) , 1.26 ( 32 H ) ， 3.42 ( 2 H ) ， 3.5 0 ( 2 H ) , 3.60- 438 ( 5 H ) ， 4.NMR C 90 MHz, COC £ 3 ] <?: 0.88 (3Η), 1.26 (32H), 3.42 (2H), 3.50 (2H), 3.60-438 (5H), 4.
6 7 ( 2 Η ) , ?.9 2 ( 2 Η ) ， 6.8 5 ( 1 Η ) , 7.3 5 ( 5 Η ) , 8. 0 4 ( 1 Η ) , 8.43 ( 1 Η ) , 1 0.6 2 ( 1 Η ) 6 7 (2 Η),? .92 (2 Η), 6.85 (1 Η), 7.35 (5 Η), 8.04 (1 Η), 8.43 (1 Η), 1 0.62 (1 Η)
I C Κ Β r D οί"1： 3 3 8 0 ， 2 9 2 0 ， 2 8 5 0 , 1 7 0 1 ， 1 5 2 5 , 1 2 6 2. , 1 2 5 0 , 1 1 5 3 , 1 1 2 0 , 1 1 0 5 , 7 5'3 ,IC Κ Β r D ο 1 " 1 : 3380, 2920, 2850, 1701, 1525, 1226., 1250, 11553, 1 1 2 0, 1 1 0 5, 7 5'3,
7 0 0 実施例 9 7 0 0 Example 9
_3— 0— Γ 2'ージメチルァミ ノェチル） カルパモイルー 2— 0—メチ ルー 1ーォクタデシノレカノレノ、 'モイノレグリセリン  _3—0—Γ2'-dimethylaminoethyl) Carpamoyl 2—0—methyl 1-octadecinolecanoleno, 'moinoleglycerin
2― 0—メチル一 1— 0—ォクタデシルカルパモイルグリセリン 1.6 0 7 ^ ( 4ミリモル ） ， ピリジン 6 3 2 （ 8ミリモル ） ，クロ口炭酸 フヱ二ノレ 6 8 97^( 4.4ミ リモノレ） ， ジクロ ηメタン（ 1 0 mi) よ 、 実施例 1および5 と同様にして得られたカーボネートに asym.—ジメチ ルエチレンジァミン 44 5 ( .8 ミ リモル）を加え 70°にて 5時間加 熱した。 冷後、 粗生成物をクロ口ホルム一メタノール（ 1 0 ： 1 )を溶 出液とするシリカゲルカラムクロマトグラフィ一にて精製し、 目的物（ 無色固形物） 1.8 9 5 （収率 9 1.9 % )を得た。 2-0-Methyl-1-O-octadecylcarpamoylglycerin 1.607 ^ (4 mmol), pyridine 632 (8 mmol), chlorophenol carbonate 6 8 97 ^ (4.4 mi monole) , Dichloromethane methane (10 mi), asym.-dimethylethylenediamine 445 (.8 mimol) was added to the carbonate obtained in the same manner as in Examples 1 and 5, and the mixture was heated at 70 ° for 5 hours. Heated. After cooling, the crude product was purified by silica gel column chromatography using chloroform-methanol (10: 1) as eluent, and the desired product (colorless solid) 1.895 (yield 91.9%) I got
, Ο 'ΡΙ T L C〔 シ リ カゲル ， クロ口ホルムーメ タノ一ル（ 5 ： 1 ) 〕 ： R f, Ο 'ΡΙ TLC [silica gel, black mouth form mutanol (5: 1)]: R f
= 0.3 1 = 0.3 1
NMR C 9 0 MHz ， CDC 〕 δ ： 0.8 8 ( 3 Η ) , 1.2 7 ( 3 2 Η ) ， 2.2 0 ( 6 Η ) ， 2.3 9 ( 2 Η ) ， 3.0 2〜 3·3 4 ( 4 Η ) ， 3. 4 3 ( 3 Η ) , 3.5 8 ( 1 Η ) , 1 6 ( 4 Η ) , 5.0 0 ( 1 Η ) , 5. 4 5 ( 1 Η ) ,  NMR C 90 MHz, CDC] δ: 0.88 (3Η), 1.27 (32Η), 2.20 (6Η), 2.39 (2Η), 3.02 to 3 3.034 (4Η) , 3.43 (3Η), 3.58 (1Η), 16 (4Η), 5.00 (1Η), 5.45 (1Η),
I R〔 KBr〕c^ : 3 3 0 0 , 2 9 2 5 , 2 8 5 0 ， 1 6 9 5 ， 1 5 3 5 , 1 4 7 0 , 1 2 8 0 , 1 2 6 0 , 1 1 1 5 , 1 0 7 5 実施例 1 0 ·  IR [KBr] c ^: 3300, 2925, 2850, 1695, 1535, 1470, 1280, 1260, 1111 5, 1 0 7 5 Example 10
_2— 0—メチル一 1— 0—ォクタテ"シルカルバモイルー 3 -0 - ( 2' ― ト リメチノレアンモニォェチノレ ) カノレハ 'モイノレク *リセ リ ン ， ョ一ジ ド 実施例 9で製造したジメチルァミ ノ体 9 4 7 （ 1.8 3 6 ミ リモル） およびヨウ化メチル 3 3 9 mg ( 2.3 8 7 ミ リモル）をエーテル（ 2 0 ηί )に溶解し、 室温にて 2日間攪拌した。 析出した ¾澱を 取し、 クロ口 ホルムーメ タノ一ルー水（ 6 5 : 2 5 : 1 )を溶出液とするシリ力ゲル カラムクロマトグラフィ一にて精製して、 目的物（無色粉末） 8 9 7 (収率 7 4.3 % )を得た。 _2— 0—Methyl 1—0—Octate “Silcarbamoyl 3 -0-(2 '-Trimethinoleammonyechinole) Kanoleha' Moinolek * Lyserine, forged Manufactured in Example 9 Jimechiruami Bruno member 9 4 7 was dissolved in (1.8 3 6 Mi Rimoru) and methyl iodide 3 3 9 mg (2.3 8 7 Mi Rimoru) ether (2 0 ηί), and stirred at room temperature for 2 days. The precipitated precipitate is collected and purified by column chromatography using a silica gel column eluting with formaldehyde, methanol and water (65: 25: 1) to elute the desired product (colorless powder) 8 9 7 (Yield 74.3%) was obtained.
T L C〔シリカゲル ， クロ口ホルムーメ タノール一水（ 6 5 : 2 5 : 4 ) ： R f = 0.4 1  TLC [silica gel, black mouth formum methanol monohydrate (65: 25: 4): Rf = 0.41
NMR〔 9 0 MHz ， CDC^3〕 S ： 0.8 9 ( 3 H ) ， 1.2 7 ( 3 2 H ) , 3.1 3 ( 2 H ) , 3.5 0 ( 1 2 H ) , 3.6 2〜4.5 2 ( 9 H ) , 5.5 0 ( 1 H ) ， 6.8 1 ( 1 H ) NMR [90 MHz, CDC ^ 3 ] S: 0.89 (3H), 1.27 (32H), 3.13 (2H), 3.50 (12H), 3.62-4.52 (9H ), 5.50 (1H), 6.81 (1H)
I R C K B r 3 OT1： 3 49 8 , 2 9 2 0 , 2 8 5 0 ， 1 7 0 8 ， 1 5 3 0 , 1 4 7 0 , 1 2 6 0 実施例 1 1 . IRCKB r 3 OT 1 : 349 8, 292 0, 2850, 1708, 1530, 1470, 1260 Example 11 1.
3一 0— ( 2,—ハイ—ド ロキシェチノレ ) カノレノ、 'モイ—ノレ一 2— 0—メチノレ 一：！ 一 0—ォクタデシル力ルバモイルグリセリン  3-1 0— (2, —high Lokishechnole) Canoleno, 'Moi-noke 1 2-0—Mechinore 1! One 0-octadecyl potato rubamoyl glycerin
2— 0—メチノレー 1— 0—オタタデシルカルバモイノレグリ セリ ン 3.2 1 3 ^ ( 8 ミ リモル） ， ピリジン 1.2 6 6 ^ ( 1 6 ミ リモル） ， クロ口炭酸 7ェニル 1· 3 7 8 ^ ( 8.8 ミ リモル） ， ジクロノレメ タン （ 2 0 m ） よ 、 実施例 9と同様にして得られたカーボネー トをクロ口ホルム （ 1 6 ^ ) に溶解し、 ェタノ ールァミン 5 8 6 W ( 9.6ミリモル）を加えて 1 5時 間還流した。 反応液を濃縮乾固し、 残渣をへキサン一酢酸ェチル（ 1 ： 2—0—Methinole 1—0—Ottatadecylcarbamoinoleglycerin 3.2 13 ^ (8 mimol), pyridine 1.266 ^ (16 mimol), 7-phenyl carbonate 1,3 7 8 ^ (8.8 millimoles), dichloronomethane (20 m), and the carbonate obtained in the same manner as in Example 9 were dissolved in black-mouthed form ( 16 ^), and ethanol 586 W (9.6 millimoles) was dissolved. ) And refluxed for 15 hours. The reaction mixture is concentrated to dryness, and the residue is purified with hexane monoethyl acetate (1: 1).
4 )を溶出液とするシリ力ゲルカラムクロマトグラフィ 一にて精製し、 目的物（無色固形物 ) 3.6 8 9 (収率 9 4.4 % )を得た。 Purification was performed by silica gel column chromatography using 4) as an eluent to obtain 3.689 (yield 94.4%) of the target product (colorless solid).
T L C〔シリカゲル，へキサン—酢酸ェチル（ 1 ： 4 ) 〕 ： R'f = 0. TLC [silica gel, hexane-ethyl acetate (1: 4)]: R'f = 0.
1 9 1 9
NMR C 9 0 MHz ， CDC 〕 S： 0.8 8 ( 3 H ) ， 1.2 8 ( 3 2 H ) , 3.0 0〜 3.8 0 ( 1 0 H ) , 4.1 8 ( 4 H ) , 5； 1 3 ( 1 Η ) ， 5.6 9 ( 1 Η )  NMR C 90 MHz, CDC] S: 0.88 (3H), 1.28 (32H), 3.00 to 3.80 (10H), 4.18 (4H), 5; 13 (1Η) ), 5.6 9 (1Η)
I R C Κ Β r D csT1 ： 3 3 2 4 , 2 9 2 0 , 2 8 5 0 , 6 9 5 , 1 5 4 5 , 1 2 7 5 IRC Κ Β r D csT 1 : 3 3 2 4, 2 9 2 0, 2 8 5 0, 6 9 5, 1 5 4 5, 1 2 7 5
元素分折： C26H52N206 Elemental analysis: C 26 H 52 N 2 0 6
計算値： C , 6 3.9 0 ； H , 1 0.7 2 ； N , 5.7 3  Calculated values: C, 63.90; H, 10.72; N, 5.73
実測値： C ， 6 3 5 7 ； H ， 1 0.7 3 ； N， 5.8 4 実施例 1 2  Measured values: C, 6357; H, 10.73; N, 5.8 4 Example 12
2一 0—メチノレ— 1_一 0一ォクタデシノレカノレバモイ ノレ一 3—0— _( 2' — D—トノレエンスノレホニノレオキシェチゾレ ) 力ノレノ、'モイノレク *リセ リ ン  2 1 0—Metinore— 1_-1 0 1—Octodesinorenokanorebamoi Nore 1 3—0— _ (2 '— D—Tonoreensunorehoninoleoxyetizole) N
じ The
-1 実施例 1 1で製造したアルコール体 3.539 （ 7.2 4 2 ミ リモル）を ト リェチルァミン （ 2 2 ^ )に溶解し、 氷冷下に Ρ—トルエンスルホニ ルクロライ ド 1.7 9 3 ^ ( 9.40 6ミ リモル）を加えた後、 室温にて 8 時間攪拌した。 実施例6と同様に処理し、 得られた粗生成物をへキサン —酢酸ェチル（ 1 : 1 )を溶出液とするシリ力ゲルカラムクロマトグラ フィ一にて精製し、 目的物（無色固形物） 4.0 3 9 （収率， 8 6.8 % )を得た。 -1 3.539 (7.242 mmol) of the alcohol compound produced in Example 11 was dissolved in triethylamine (22 ^), and 9-toluenesulfonyl chloride 1.973 ^ (9.406 mmol) under ice cooling. After the addition, the mixture was stirred at room temperature for 8 hours. The crude product obtained was treated in the same manner as in Example 6, and the crude product was purified by silica gel chromatography using hexane-ethyl acetate (1: 1) as an eluent. 4.039 (yield, 86.8%).
T L C〔シリ 力ゲル ， へキサン一酢酸ェチル（ 1 ： 1 ) 〕 ： R f = 0. 2 1  TLC [silica gel, ethyl hexane monoacetate (1: 1)]: Rf = 0.21
NMR C 9 0 MHz ， CDC^3〕 δ ： 0.8 8 ( 3 Η ) ， 1.2 5 ( 3 2 Η ) , 2.43 ( 3 Η ) , 3.1 6 ( 2 Η ) ， 3.3 0〜 3.7 0 ( 6 Η ) , 4. 1 3 ( 6 Η ) ， 4.8 6 ( 1 Η ) ^ 5.2 5 ( 1 Η ) , 7.3 2 ( 2 Η ) ， 7. · 8 0 ( 2 Η ) NMR C 90 MHz, CDC ^ 3 ] δ: 0.88 (3Η), 1.25 (32 2), 2.43 (3Η), 3.16 (2Η), 3.30 to 3.70 (6Η), 4.13 (6 Η), 4.86 (1 Η) ^ 5.25 (1 Η), 7.32 (2 Η), 7. · 80 (2 Η)
I R C Κ Β r 3 CTT1 ： 3 3 8 0 , 2 9 2 0 , 2 8 5 0 ， 1 6 9 5 ， 1 5 40 , 1 4 6 8 , 1 3 6 5 , 1 2 6 0 , 1 1 8 0 IRC Κ Β r 3 CTT 1 : 3380, 2920, 2850, 1695, 1540, 1468, 1365, 1260, 1188 0
実施例 1 3 Example 13
3— 0一 (2'—ブロモェチノレ ) 力ノレノ、'モイノレ一 2— 0—メチノレ— 1— 0—ォクタテシノレカノレノ、 *モイノレク *リセ リ ン  3-0-1 (2'-Bromochinore) Power Noreno, Moinore 1 2-0-Metinore 1-0 0-Octateshinorekanoreno, * Moinolek * Lyserine
実施例 1 2で製造したトシル体 3.8 8 6 （ 6.0 4 5 ミ リモル）およ び臭化リチクム （ LiBr'H20 ) 1.2 6 7 ^ ( 1 2.0 8 9 ミ リモル）ジメ チルホルムアミ ド（ 3 7 )に溶解し、 60。にて 4 2時間加熱した。 実 施例 7と同様に処理して得られた粗生成物をへキサン一酢酸ェチル（ 3 ： 2 )を溶出液とするシリカゲルカラムクロマト ラフィ一にて精製し、 目的物〔無色固形物〕 3.1 0 ^ (収率 9 3 % )を得た。 T L C〔シリ カゲル， へキサン一 酸ェチル（ ) 〕 ： R f 0. 4 5 Example 1 2-tosyl body 3.8 8 6 prepared in (6.0 4 5 Mi Rimoru) and bromide Richikumu (LiBr'H 2 0) 1.2 6 7 ^ (1 2.0 8 9 Mi Rimoru) dimethyl Chiruhorumuami de (3 7 ) Dissolve in 60. For 42 hours. The crude product obtained by treatment in the same manner as in Example 7 was purified by silica gel column chromatography using ethyl hexane monoacetate (3: 2) as an eluent to obtain the desired product (colorless solid). 0 ^ (93% yield) was obtained. TLC [silica gel, ethyl hexyl monate ()]: R f 0.45
NMR C 90MHz ， CDC^3〕 S ： 0.88 ( 3 H ) , 1.2 7 ( 32 H ) , 3.1 7 ( 2 H ) , 3.34〜； 3· 7 3 ( 8 H ) , · 1 8 ( 4 H ) ， 4. 9 0 ( 1 Η ) , 5.40 ( 1 Η ) NMR C 90MHz, CDC ^ 3 ] S: 0.88 (3H), 1.27 (32H), 3.17 (2H), 3.34 ~; 3 · 73 (8H), · 18 (4H), 4.90 (1Η), 5.40 (1Η)
I R〔 KBr〕 ： 3 330 , 2920 , 28 5 0 , 1 695 ， 1 5 40 , 147 0 , 13 10 , 12 75 , 11 52. , 1 1 20  I R [KBr]: 3330, 2920, 2850, 1695, 1540, 1470, 1310, 1275, 1152., 1120
元素分折 C26H51N205Br Elemental analysis C 26 H 51 N 2 0 5 Br
計算値 C , 5 6.6 1 ； H , 9.32 ； N , 5.08  Calculated C, 5 6.6 1; H, 9.32; N, 5.08
実測値 C ,.5 6.38 ； H , 9.28 ； N , 4.9 5 実施例 14  Found C, .5 6.38; H, 9.28; N, 4.95 Example 14
2— 0—メチル一 1― 0—ォクタデシルタルバモ 'ィルー 3— 0— ( 2' —チアゾリォェチノレ ) カノレバモイノレク，リ セリ ン ' ブロマイ ド  2—0—Methyl 1—0—Octadecyl tarbamo 'Iru 3–0— (2'—Thiazoryechnole) Canolebamoinolek, Liserin' Bromide
実施例 13で製造したブロム体 1.103 （ 2 ミリモル）にチアゾ— ル 68 1 ( 8ミリモル）を加え、 1 10。にて 12時間加熱した。 反応 液を濃縮乾固し、 残渣は、 クロ口ホルム一メ タノール一水（ 6 5 ： 2 5 ： 1 )を溶出液とするシリカゲルカラムクロマトグラアイ一にて精製し、 目的物〔淡褐色粉末〕 847 （収率 66.5%)を得た。 Thiazole Example 1 3 bromo member 1.10 3 prepared in (2 mmol) - Le 68 1 (8 mmol) was added, 1 10. For 12 hours. The reaction mixture was concentrated to dryness, the residue is black port Holm Ichime methanol monohydrate (6 5: 2 5: 1) was purified by silica gel column chromatograph eye one to eluent, the desired product [a pale brown powder 847 (66.5% yield).
T L C〔シリ カゲル，酢酸ェチル—酢酸一水（ 3 ： Ϊ ： 1 ) 〕 ： R f TLC [silica gel, ethyl acetate-acetic acid monohydrate (3: Ϊ: 1)]: R f
= 0.34 = 0.34
NMR C 90 MHz ， CDC 3 D ^ ： 0.88 ( 3 H ) , 1.2 5 ( 32 H ) , 3.1 2 ( 2 H ) , 3.40 ( 3 H ) , 3.68 ( 1 H ) ， 3.82 ( 2 H ) , 4.1 5 ( 4 H ) ， 5, 06 ( 2 H ) ， 5.48 ( 1 H ) ， 7.0 6 ( 1 H ) , 8.38 ( 1 H ) , 8.68 ( 1 H ) ， 10.7 4 ( 1 H ) 差換え · I R〔 KBr〕 e^ : 3 3 7 0 ， 2 9 2 0 ， 2 8 5 0 ， 】 7 0 2 ， 1 5 3 4 , 1 4 7 0 , 1 2 5 5 NMR C 90 MHz, CDC 3 D ^: 0.88 (3 H), 1.2 5 (32 H), 3.1 2 (2 H), 3.40 (3 H), 3.68 (1 H), 3.82 (2 H), 4.1 5 (4H), 5,06 (2H), 5.48 (1H), 7.06 (1H), 8.38 (1H), 8.68 (1H), 10.74 (1H) IR [KBr] e ^: 3370, 2920, 2850,] 702, 1534, 1470, 1255
実施例 1 5 Example 15
2 ― 0一ペンジノレー 1 — 0ー ( 2' — ト リメチノレアンモニォェチノレ ) 力 ルバモイル一 3 — 0—ォクタテ"シルグリセリン 。 _クロライ ド  2-0-Penzinole 1-0-(2 '-Trimethinoleammoniechinole) Power Lubamoyl 3-0-Octate "Sylglycerin. _ Chloride
2 — 0—ベンジルー 3 — 0—ォクタテ"シルグリセリ ン 2. 6 7 . （ 6. 1 4 ミ リモル） ， 2—クロロェチルイ ソシァネート 0. 8 4 ^ ( 8 ミ リモノレ 2-0-benzyl-3-0-octate "sylglycerin 2.67. (6.14 mimol), 2-chloroethylysocyanate 0.84 ^ (8 milimonole
)をジクコルメタン （ 6 rf )に溶解し、 一夜室温にてかきまぜた。 反応 液を減圧下に濃縮乾固し、 残渣をクロ口ホルムを溶出液とするシ リ カゲ ルカラムクロマ トグラフィ一にて精製し、 得られたク口ル体をさらに 2 0 %ト リ メチルァ ミ ン一トルエン （ 2 0 m£ )に溶.解し、 封管中、 1 6 0。 2 4時間加熱.した。 反応液を減圧下に濃縮乾固し、 残渣にァセ ト ン （ 1 0 mi )を加えて洗い、 無色粉末 2. 0 （収率 8 5. 0 ^ )を得た。  ) Was dissolved in dichloromethane (6 rf) and stirred overnight at room temperature. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography using chloroform as an eluent. The obtained closate was further purified with 20% trimethylamine. Dissolve in toluene (20 ml) and in a sealed tube, 160. Heated for 24 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was washed with aceton (10 mi) to obtain colorless powder 2.0 (yield 85.0 ^).
T L C〔シリ力ゲル， n— BuOH— AcOH—水（ 4 ： 1 ： 1 ) 〕 ： R f = 0. 3 6  TLC [silicone gel, n-BuOH-AcOH-water (4: 1: 1)]: Rf = 0.36
I R〔 KBr〕e^ : 3 3 5 0 ， 2 9 3 0 ， 2 8 5 0 ， 1 7 2 5. , 1 4 6 5 , 1 2 5 0 , 1 1 2 0 , 1 0 6 0  I R [KBr] e ^: 3350, 2930, 2850, 1725, 1465, 1250, 1120, 1600
実施例 1 6 Example 16
1 — 0一（2' — ト リメチノレアンモニォェチノレ ）力ルバモイノレ一 3 — 0 —ォクタテ"シルグリセリン 。 クロライ ド 1-0-1 (2 '-Trimethylino-ammonechinore) Power 3-0-Octatate "Sylglycerin. Chloride
実施例 1 5で得たベンジル体 2. 0 ^ ( 3. 3 4ミ リモル）を 7 0 %酢酸  The benzyl derivative 2.0 ^ (3.34 mmol) obtained in Example 15 was converted to 70% acetic acid.
( 3 に溶解し、 1 0 %パラジウム炭素 2 0 0 を加え、 水素気流 中、 4時間激しくかきまぜた。 不溶物を 去し、 母液は減圧下に濃縮乾 (Dissolved in 3 and added 100% palladium on carbon and stirred vigorously in a stream of hydrogen for 4 hours. Remove insolubles and concentrate mother liquor under reduced pressure to dryness
¾'ύ '< -Λし' "~ 固し、 残渣をク口口ホルムーアセ ト ン （ 1 : 1 ) ( 1 0 ）よ 熱時再 結晶し、 無色結晶性粉末 1.7 （収率 1 0 0 % )を得た。 ¾'ύ '<- Λ Mr.'"~ Solidified, the residue click every mouth Horumuase tons (1: 1) (1 0) good recrystallization when hot, to obtain a colorless crystalline powder 1.7 the (1 0 0% yield).
T L C〔シリカゲル， n - BuOH-AcOH一水（ 4 ： 1 ·· 1 ) ： R f = 0.2 1  TLC [silica gel, n-BuOH-AcOH monohydrate (4: 1 ··· 1): R f = 0.21
I R C K B r D «ί1： 3 4 0 0 , 2 9 3 5 , 2 8 5 0 , 1 7 1 0 ， 1 5 3 0 , 1 4 8 0 , 1 2 7 0 , 1 1 3 0 , 9 6 0 実施例 1 7 IRCKB r D «ί 1 : 3 4 0 0, 2 9 3 5, 2 8 5 0, 1 7 1 0, 1 5 3 0, 1 4 8 0, 1 2 7 0, 1 1 3 0, 9 6 0 Example 17
2— 0—メ チノレカルバモイルー 1— 0— f — ト リ メチノレアンモニォ ェチル )カノレバモイノレ一 3— 0—ォクタデシルグリセリン ' クロライ ド 実施例 1 6で得たハイ ド口キシ体 2 0 0 ( 0.3 9 ミ リモル）をピリ ジン （ 2 mi ).， クロ口ホル A ( 1 ^ ) 混液に溶解し、 メ チルイ ソシァ ネー ト 6 0 0 ^を加え、 50°で一夜かきまぜた。 反応液を減圧下に濃縮 乾固し、 残渣をクロ口ホルム （ 0.5 ) ， アセ ト ン （ 5 ^ )の混液よ 熱時再結晶し、 目的物（無色粉末） 1 9 8 を得た。  2—0—Methinolecarbamoyl 1—0—f—Trimethylinoammonioethyl) Canolebamoinole 3—0—Octadecylglycerin 'chloride Hydroxyl oxy compound obtained in Example 16 20 0 (0.39 mimol) was dissolved in a mixture of pyridine (2 mi). And black mouth phor A (1 ^), and methyl thiocyanate 600 ^ was added, followed by stirring at 50 ° overnight. The reaction solution was concentrated to dryness under reduced pressure, and the residue was recrystallized from a mixed solution of chloroform (0.5) and acetate (5 ^) under heating to obtain the desired product (colorless powder) 198.
TL C〔シリ力ゲル， n— BuOH— AcOH—水（ 4 ： 1 ： 1 ) 〕 ： R  TLC [silicone gel, n-BuOH-AcOH-water (4: 1: 1)]: R
0.2  0.2
I R〔 KBr〕 ： 3 4 0 0 , 2 9 2 0 , 2 8 5 0 , 1 7 2 0 ， 1 5 4- 0 , 1 4 7 0 , 1 2 7 0 , 1 1 5 5 , 1 1 2 5 , 7 7 0  IR [KBr]: 3400, 2920, 2850, 1720, 154-0, 1470, 1270, 1155, 1125 , 7 7 0
NMR C 6 0 MHz ， COC£3〕 <5 ： 0.8 8 ( 3 H ) , 1.2 5 ( 3 2 H ) , 2.7 8 ( 3 H ) ， 3.1 0〜4·0 0 ( 1 5 Η ) , 4.2 8 ( 4 Η ) ， 4.0 7 ( 1 Η ) , 5.7 2 ( 2 Η ) NMR C 60 MHz, COC £ 3 ] <5: 0.88 (3H), 1.25 (32H), 2.78 (3H), 3.10 to 4.00 (15Η), 4.28 (4 Η), 4.0 7 (1 Η), 5.7 2 (2 Η)
元素分析： C29H60N3O5C^ '3H2O Elemental analysis: C 29 H 60 N 3 O 5 C ^ '3H 2 O
計算値： C , 5 6.1 5 ； H , 1 0.7 2 ； N , 6.7 7  Calculated values: C, 56.15; H, 10.72; N, 6.77
実測値： C , 5 6.2 5 ； H , 1 0.40 ； N , 6.9 9 ―  Measured value: C, 5 6.25; H, 10.40; N, 6.9 9 ―
Aひ 実施例 1 8 A Example 18
1—ォクタデシルォキシー 2—ァセトアミ ドー 3— ( 2'—ジメチルァ ノェチル）カルパモイクレオキシブロノ、0ン 1-octadecyloxy 2-acetamide 3- (2'-dimethylanoethyl) carpamoicoleoxybrono, 0
j) 3—ォクタデシノレォキシ一 2—アミノ_プロノ、。ン一 1—ォーノレ 1一 0—ォクタテ'、シノレ一 2— 0一トシノレ一 3—0—ト リチッレク *リセロ 一ノレ 8.6 7 （ 1 1.7 ミ リ モル）にベンジルァミ ン （ 1 2 ^ )をカロえ、 120°で 8時間加熟したのち、 減圧下、 過剰のベンジルアミンを留去し た。 残渣に n—へキサンを加えて不溶物を^去し、 ^液は濃縮乾固した。 ¾渣に Ί 0 酢酸（ 5 0 )を加えて 100°、 2時間加熱かくはんした。 冷後、 析出結晶を 去し、 ^液にパラジウム炭素を加えて接触還元した 後、 過、 濃縮乾固した。 残渣をク n oホルムに溶解し、 重曹水で洗つ た後、 乾燥、 濃縮し、 シリ力ゲルク口マトグラフィ一によつて精製した (溶出液，ク。口ホルム一メタノール（ 1 0 : 1 ) )。 目的物（無色粉 末） 3.1 3 ^ (収率 7 8 % )を得た。  j) 3-octadecinoleoxy 2-amino-prono. 1-one-one-one-one-one-one-one-one-two-one-one-one-one-three-one-three-three-liter-rethello-one-one 8.6 7 (11.7 millimoles) of benzylamine (1 2 ^) After ripening at 120 ° for 8 hours, excess benzylamine was distilled off under reduced pressure. N-Hexane was added to the residue to remove insolubles, and the solution was concentrated to dryness. Acetic acid (50) was added to the residue and stirred at 100 ° for 2 hours. After cooling, the precipitated crystals were removed, and the solution was subjected to catalytic reduction by adding palladium carbon, and then concentrated to dryness. The residue was dissolved in chloroform, washed with aqueous sodium bicarbonate solution, dried, concentrated, and purified by silylation gel chromatography (eluent, c. Mouth-form-methanol (10: 1)). . The desired product (colorless powder) 3.1 3 ^ (yield 78%) was obtained.
I R C K B r 3 aiT1： 3 3 3 0 , 2 9 2 5 ， 2 8 5 0 ， 1 5 8 0 ， 1 4 7 0 , 1 3 7 0 , 1 1 2 0 , 1 0 7 0 , 1 0 4 0 , 7 2 2 IRCKB r 3 aiT 1 : 3330, 2925, 2850, 1580, 1470, 1370, 1120, 1700, 1404 , 7 2 2
NMR C 9 0 MHz ， CDC^3〕 <5 : 0.8 7 ( 3 H ， t ) , l.2 5 ( 3 2 H , m ) , 3.0 5 ( 1 H , m ) ， 3.4 1 ( 2 H , d ) , 3.4 2 ( 2 H , t ) ， 3.5〜 3.7 ( 2 H ， m ) NMR C 90 MHz, CDC ^ 3 ] <5: 0.87 (3H, t), l.25 (32H, m), 3.05 (1H, m), 3.41 (2H, d ), 3.4 2 (2 H, t), 3.5 to 3.7 (2 H, m)
I]) 3—ォクタデシルォキシ一 2—ァセトアミ ドプロパン一 1—ォ一 ノレ I]) 3-octadecyloxy 2-acetamide propane 1-1
前記ァミノアルコール体 8 5 7.5 （ 2.5 ミ リ モル） ， ァセチノレク口 リ ド 1 9 7 ^ ( 2.5 ミ リモル） ， 4ージメチルァミノピリジン 3 0 5 mg ( 2.5ミリモル）をクロ口ホルム （ 3 5 )に溶解し、 室温で 2 8時間 かきまぜた。 反応液を減圧下に濃縮乾固し、 残渣をシリカゲルクロマト グラフィ 一で精製し（溶出液、 クロ口ホルム一メタノール ， 2 0 ： 1 )， 目的物（無色粉末） 8 6 8 W (収率 9 0% )を得た。 ' NMR C 9 0 MHz , CDC^3〕 ^： 0.8 7 ( 3 H , t ) , 1.2 5 ( 3 2 H , m ) , 2.0 1 ( 3 Η , s ) , 2.9 ( l H ) , 3.43 ( 2 Η , t ) , 3.6 0 ( 2 Η , d ) , 3.7 7 ( 2 Η , m ) , 4.0 5 ( 1 Η , m ) , 6.1 ( 1 Η , b r , ΝΗ ) The above amino alcohol derivative 857.5 (2.5 millimoles), acetinolec chloride 197 ^ (2.5 millimoles), 4-dimethylaminopyridine 305 mg (2.5 millimoles) were added to chloroform form (35 ) And 28 hours at room temperature I stirred it. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent, chloroform-form-methanol, 20 : 1) to give the desired product (colorless powder) 868 W (yield 9 0%). 'NMR C 90 MHz, CDC ^ 3 ] ^: 0.87 (3H, t), 1.25 (32H, m), 2.01 (3Η, s), 2.9 (lH), 3.43 (2 Η, t), 3.6 0 (2Η, d), 3.7 7 (2Η, m), 4.05 (1Η, m), 6.1 (1Η, br, ΝΗ)
_ίϋ) 1—ォクタデシルォキシ一 2—ァセトアミ ド一 3— ( 2'—ジメチ ノレアミ ノエチノレ ) カノレノ、*モイノレォキシプロノヽ。ン _ίϋ) 1-octadecyloxy 2- 2-acetamide 1 3- (2'-dimethylmethamine) canoleno, * moinoleoxyprono ヽ. In
前記アルコール体 3 8 5 W ( 1 ミ リモル） ， ピリジン 1 5 877^ ( 2 ミ リモノ ）をジクロルメタン（ 1 0 ）に溶解し、 氷冷下、 クロ口炭酸フ ニル 1 5 6 （ 1 ミリモル）を加えた。 室温にて 1時間かきまぜた後、 反応液にク口口ホルム、 水を加えて分液し、 有機層を希塩酸、 重曹水で 洗い、 乾燥、 濃縮してフヱニル炭酸エステル体を得た。 炭酸エステル体 を asym.—ジメチルエチレンジァミン（ 1.5 )に溶解し、 70。、 4時 間加熱した。 反応液をシリ力ゲルクロマトグラアイ一 付して精製し（ 溶出液、 ク口 σホルムーメタノール， 5 : 1 ) ,目的物（無色粉末） 3 Q ng(収率， 7 2% )を得た。 The alcohol 38.5 W (1 mmol) and pyridine 15877 ^ (2 mmol) were dissolved in dichloromethane (10), and under ice-cooling, phenyl carbonate 1556 (1 mmol) was dissolved. added. After stirring at room temperature for 1 hour, the reaction solution was mixed with water and water, and the organic layer was washed with diluted hydrochloric acid and aqueous sodium bicarbonate, dried and concentrated to obtain a phenyl carbonate. The carbonate was dissolved in asym.-dimethylethylenediamine (1.5), 70. Heated for 4 hours. The reaction mixture was purified by silica gel chromatography (eluent, sulphate σ-formumethanol, 5 : 1) to give 3 Q ng (yield, 72%) of the target compound (colorless powder). Was.
I R KBr D effl^ S S S O , 3 2 8 0 , 2 9 2 0 , 28 5 0 , 1 6 I R KBr D effl ^ S S S O, 3 2 8 0, 2 9 2 0, 28 5 0, 1 6
9 5 , 1 6 5 5 , 1 4- 6 2 , 1 3 7 8 , 1 3 1 0 , 1 2 7 8 , 1 1 3 0 NMR C 9 0 MHz ， CDC 3 D ^： 0.8 7 ( 3 H , t ) , 1.2 5 ( 3 2 H , m ) ， 1.9 7 ( 3 H , s ) ， 2.2 0 ( 6 H , s , N M e 2 ) , 2.8 8 ( 2 H , t ) ， 3.1〜3.5 ( 4 H ， m ) , 3.40 ( 2 H , t ) ， 0 ( 1 H , m ) , 4.1 7 C 2 H , m ) , 5.2 , 6.0 ( N H ) 差換え T L C〔シリ力ゲル， CHC 3— MeOH R f = 0.2 0 9 5, 1 6 5 5, 1 4- 6 2, 1 3 7 8, 1 3 1 0, 1 2 7 8, 1 1 3 0 NMR C 9 0 MHz, CDC 3 D ^: 0.8 7 (3 H, t), 1.2 5 (3 2 H, m), 1.9 7 (3 H, s), 2.2 0 (6 H, s, NM e 2), 2.8 8 (2 H, t), 3.1~3.5 (4 H , M), 3.40 (2 H, t), 0 (1 H, m), 4.17 C 2 H, m), 5.2, 6.0 (NH) TLC [silicone gel, CHC 3 — MeOH R f = 0.20
実施例 1 9 Example 19
] —ォクタデシルォキシー 2—ァセトアミ ドー 3—（2'— ト リメチル アンモニォェチノレ ) カルパモイルォキシプ ン 。 _ョージド - 実施例 1 8で得られたジメチルァミノ体 3 0 0 ( 0, 6ミリモル）を エーテル（ 3 0 ) ， クロ口ホルム （ 3 ^ )の混液に溶解し、 ョク化メ チル 4 2 0^( 3ミ リモル）を加えて、 室温で 1日かきまぜた。 圻出し た粉末を 取して、 エーテル一クロ πホルム混液で洗い、 目的物（無色 粉末） 2 5 8 W (収率 6 7 % )を得た。  ] —Octadecyloxy 2-acetamide 3— (2'-trimethylammoniochinole) Carpamoyloxypne. ___ Ozide-The dimethylamino derivative 300 (0.6 mmol) obtained in Example 18 was dissolved in a mixture of ether (30) and black form (3 ^), and methyl octylate 420 ^ (3 mmol) was added and stirred at room temperature for 1 day. The powder thus obtained was collected and washed with a mixed solution of ether and π-form to obtain the desired product (colorless powder), 258 W (yield: 67%).
I R C KBr 1 : 3 4 7 0 ， 3 6 2 0 , 2 9 2 0 ， 2 8 5 0 ， 1 7 1 5 , 1 6 6 5 , 1 6 4 5 , 1-5 3 0 , 1 4 7 0 , 1 3 8 0 , 1 2 6 0 , 1 1 2 0 , 9 7 0 , 9 2 0 , 7 2 0 IRC KBr 1 : 3470, 3620, 2920, 2850, 1715, 1665, 1645, 1-5300, 1470, 1 3 8 0, 1 2 6 0, 1 1 2 0, 9 7 0, 9 2 0, 7 2 0
NMR〔 9 0 MHz ， CDC 3.〕 <5 ： 0.8 7 ( 3 H , t ) , 1.2 5 ( NMR [90 MHz, CDC 3. ] <5: 0.87 (3H, t), 1.25 (
+ 3 2 H , m ) , 2.0 0 ( 3 H , s , NHA c ; , 3.4 3 C 9 H , s , Ν Me3 ) , 3.4 0 ( 2 H , t , CH20) ， 3.6 5〜 0 ( 4 H , m ) , 4. 0〜4.3 5 ( 3 H , m ， 〉 CHN， CH2 OCO ) + 3 2 H, m), 2.0 0 (3 H, s, NHA c;, 3.4 3 C 9 H, s, Ν Me 3), 3.4 0 (2 H, t, CH 2 0), 3.6 5~ 0 (4 H, m), 4. 0~4.3 5 (3 H, m,> CHN, CH 2 OCO)
実施例 2 0 Example 20
1—ォクタデシノレォキシ一 2—ァセトアミ ドー 3—〔 N—ァセチノレー Ν— ( 2'— ト リ メチノレアンモニォェチル ) 〕 力ルバモイノレォキシプロノ、0 ン 。 ョージド 1-O Kuta Desi Honoré O carboxymethyl one 2- Asetoami dough 3- [N- Asechinore Ν- (2'- Application Benefits methylate Honoré amm Nio E chill)] force Luba Moi Honoré O carboxymethyl pro Roh, 0 emissions. Forged
I) ォクタデシルォキシ一 2—フタルイ ミ ド一 3—7エノキシカ ノレボニノレオキシプ 、'ン I) Octadecyloxy-1 2-phthalimid 3-7 Enoxyka olevoninoleoxyp
3—ォクタデシノレォキシ一 2—フタノレイ ドプ 0ン一 1ーォ一ノレ 9 3-O Kuta Desi Honoré O carboxymethyl one 2- Futanorei de-flop 0 down one 1 over O one Honoré 9
ΟΓ'ΡΙ 5 2 ミ リモル）をジクロルメ タン （ 2 0 mi )に溶解し、 氷冷下ピ リジン 3 1 6 W( 4ミ リモル）およびクロル炭酸フエニル 3 1 3^( 2 ミリモル）を加えた。 氷冷下で 1 5分、 室温で4 5分かきまぜた後、 反 応液にクロ °ホルム（ 40 ^ )を加えて、 希塩酸，重曹水で洗い、 乾燥， 濃縮して目的の炭酸エステル体を得た。 ΟΓ'ΡΙ (5.2 mmol) was dissolved in dichloromethane ( 20 mi), and pyridine 3 16 W (4 mmol) and phenyl chlorocarbonate 3 13 ^ (2 mmol) were added under ice cooling. 1 5 minutes under ice-cooling, followed by stirring 4 5 minutes at room temperature, the reaction solution was added a black ° Holm (4 0 ^), dilute hydrochloric acid, washed with aqueous sodium bicarbonate solution, dried, carbonate of concentrated to purpose I got
お、 原料として用いた3—ォクタデシルォキシ一 2—フタルイミ ド プロパン一 1—オールは、 実施例 1 8 - ί)て得た 3—ォクタデシルォキ シ一 2—ア ミ ノプロノ、。ン一 1—ォーノレにカノレボェ トキシフタ一ノレイ ミ ド を反応させて合成した。 ϋ) 1—ォクタデシルォキシ一 2—ァミノ一 3— — N， ジメ チノレアミノェチノレ )カノレバモイノレォキシプロハ。ン - 前記炭酸エステル体を asym.—ジメチルエチレンジァミン（ 2 ^ )に 溶解し、 70。， 4時閭かきまぜた。 反応液に n—へキサンを加えて不溶 物を 去し、 液をシリカゲルクロマトグラフィ一で精製した（溶出液， ク口 口ホルムーメタノ一ノレ一水， 6 5 : 2 5 : 4 )。 目的物（無色固体 ) 4 6 6 ¾ た。 Here, 3- octadecyloxy- 2 -phthalylimidopropan-1-ol used as a raw material was 3-octadecyloxy1-2-aminoprono obtained in Example 18-II). It was synthesized by reacting canolevoethoxyphthalone amide with 1-one. ii) 1-octadecyloxy-1 2-amino-3— — N, dimethinoleaminoethynole) Canolebamoinolexyproha. -The above carbonate is dissolved in asym.-dimethylethylenediamine ( 2 ^), 70. , 4 o'clock mixed. N-Hexane was added to the reaction solution to remove insolubles, and the solution was purified by silica gel chromatography (eluent, octamethylformone monohydrate, 65: 25: 4). The desired product (colorless solid) was obtained.
T L C〔シリカゲノレ ， CHC 3—1^6011—水， 6 5 : 2 5 : 4 ) : 1^ f = 0.2 TLC [Silica phenol, CHC 3 —1 ^ 6011—water, 65: 25: 4): 1 ^ f = 0.2
I R C KBr D m1: 3 3 3 0 ， 2 9 2 0 ， 2 8 5 0 ， 1 6 9 0 ， 1 5 5 0 , 1 4 6 5 , 1 2 7 8 , 1 1 3 0 , 1 0 3 0 IRC KBr D m 1 : 3330, 2920, 2850, 1690, 1550, 1465, 1279, 1130, 1300
_iii) 1ーォクタデシルォキシ一 2—ァセトアミ ドー 3 - c N—ァセチ ノレ一 N— ( 'ージメチノレアミノェチノレ ) 〕 カノレノ、 ·モイ ノレォキシプロハ。ン 前記の方法で得た 2ーァミノ体 1 7 5 ^をクロ口ホルム （ 3 )に溶 え 解し、 ト リエチルァミ ン （ 1 ） ，無水酢酸（ 0.3 ^ )を加えて室温で 1夜かきまぜた。 反応液を濃縮し、 シリカゲルクロマトグラフィーで精 製した（溶出液， クロロホルム一メタノール， 1 0 ： 1 )。 目的物（無 色固体）を 1 48 W得た。 _iii) 1-octadecyloxy 2-acetamide 3-cN—acetinolone N — ('dimethinoleaminoethynole)] canoleno, moi noreoxyproha. Dissolve the 2-amino form, 175 ^, obtained by the above method in black-mouthed form (3). Construed, Doo Riechiruami switch (1), was stirred overnight at room temperature was added acetic anhydride (0.3 ^). The reaction solution was concentrated and purified by silica gel chromatography (eluent, chloroform-methanol, 10: 1). 148 W of the target product (colorless solid) was obtained.
I R C KB r W: 3 2 8 0 ， 2 9 2 0 , 2 8 5 0 ， 1 7 4 0 ， 1 7 1 5 , 1 6 5 5 , 1 5 5 0 , 1 4 7 0 , 1 3 7 0 , 1 3 0 0 , 1 2 5 0, 1 1 8 5 , 1 1 3 0 , 9 8 0  IRC KB r W: 3280, 2920, 2850, 1740, 1715, 1655, 1550, 1470, 1370, 1 3 0 0, 1 2 5 0, 1 1 8 5, 1 1 3 0, 9 8 0
NMR C 9 0 MHz , CDC^3〕 <5 ： 0.8 7 ( 3 H , t ) , 1. Ε 5 ( 3 2 Η , m ) ， 2.0 0 ( 3 Η , s ) ， 2.4 5 ( 6 Η , s ) , 2.5 0 ( 3Η, s ) , 2.6 8 ( 2 Η , t ) ， 3.3〜 3.6 ( 4 H ， m ) , 3.9 8 ( 2 Η , t ) ， 4. l 5〜4.6 0 ( 3 H , m ) NMR C 90 MHz, CDC ^ 3 ] <5: 0.87 (3H, t), 1. 1.5 (32Η, m), 2.00 (3Η, s), 2.45 (6Η, s) ), 2.50 (3Η, s), 2.68 (2Η, t), 3.3 to 3.6 (4H, m), 3.98 (2Η, t), 4.l5 to 4.60 (3H, m) )
— iV) _ 1—ォクタデシルォキシ一 2—ァセ トアミ ドー 3—〔 N—ァセチ ノレ一 N— ( 2'— h リメチノレアンモニォェチノレ ) 〕 カノレハ 'モイノレォキシプ ロノ ·？ン · ョージ ド — IV) _ 1—Octadecyloxy 2—Acetamide 3— [N—Acetinolone N— (2'—h Limetinoleammonjechinore)) Kanoleha 'Moinoleoxyprono? N / A
前記化合物 1 3 8 をエーテル（ 5 )に溶解し、 ョク化メチル 1 0 9 を加えた。 室温で 1夜攪拌し、 冷時，折出固体を 取した。 目的物 (無色粉末） 1 4 1 を得た。 '  The compound 138 was dissolved in ether (5), and methyl oxalate 109 was added. The mixture was stirred overnight at room temperature, and when it was cool, the solid that had been separated out was collected. The desired product (colorless powder) 144 was obtained. '
I R C KB c^"1 : 3 4 5 0 ， 2 9 2 0 , 2 8 5 0 ， 1 7 5 5 ， 1 6 7 0 , 1 5 40 , 1 4 7 0 , 1 3 7 5 , 1 2 6 0 , 1 2 0 5 , 1 1 6 5 NMR〔 9 0 MHz , CDC 3〕 S ： 0.8 7 ( 3 H , t ) ， 1.2 5 ( 3 2 H , m ) , 2.0 3 ( 3 H , s ) , 2.5 2 ( 3 H , s ) , 3.4 5 ( 9 H ， s ) , 3.3〜3.7 ( 4 H , m ) ， 3.7〜4.0 ( 2 H ， m ) ， 0 7 〜 3 ( 2 H ， m ) ， 4·4〜4ί.6 ( 3 H ， m ) IRC KB c ^ " 1 : 3450, 2920, 2850, 1755, 1670, 1540, 1470, 1375, 1260 , 1 2 0 5, 1 1 6 5 NMR [9 0 MHz, CDC 3] S: 0.8 7 (3 H, t), 1.2 5 (3 2 H, m), 2.0 3 (3 H, s), 2.5 2 (3H, s), 3.45 (9H, s), 3.3 to 3.7 (4H, m), 3.7 to 4.0 (2H, m), 07 to 3 (2H, m), 4 4 to 4ί.6 (3H, m)
差換え 血小板凝集抑制作用 Replacement Platelet aggregation inhibitory action
〔試験方法〕 〔Test method〕
雄性クサギよ 血液凝固防止剤として、 3.1 5%クニン酸（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、 800 rpmで 10分間遠心分離することによ 多血小板血漿（ P R P ： platelet rich plasma ) を得た。 残 の血液をさらに 3000 rpm で 1 0分間遠心して上清液として乏血小板血漿（ P P P： latelet 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5 0万 個 Z ^ に調製した。 この PRP 2 50 を 37°で2分攪拌後、 被検 薬物を加えさらに 2分間攪拌後に P A F 1 X 10_8Mを加えた。 血小板凝 集は凝集計（理化電機製 )で測定した。 被験薬物の凝集抑制活性は、 対 照 P R Pにおける P A F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。 As male clerodendrum trichotomum by blood coagulation preventing agent, using a syringe containing 3.1 5% Kunin acid (ratio of 1 for the blood 9) it was bled directly. Subsequently, platelet-rich plasma (PRP) was obtained by centrifuging at 800 rpm for 10 minutes at room temperature. The remaining blood was further centrifuged at 3000 rpm for 10 minutes to separate latelet poor plasma (PPP) as a supernatant. To prepare a platelet count to about 5 0 million units Z ^ by diluting the PRP with PPP. The PRP 2 5 0 to 2 minutes After stirring at 3 7 °, was added PAF 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 ratio of PAF to the maximum light transmittance (maximum aggregation ratio) in the control PRP.
(：結果:）  (: Result :)
第 1表に示す。 第 1表 PAFによるクサギ血小板凝集抑制作用 試験化合物 試験薬物濃度と抑制率（ ）  It is shown in Table 1. Table 1. Inhibitory effect of PAF on rabbit platelet aggregation Test compound Test drug concentration and inhibition rate ()
(実施例 ) 1X10 M 3X10 M 3X10 M  (Example) 1X10 M 3X10 M 3X10 M
3 86 100 100  3 86 100 100
8 100  8 100
10 82  10 82
14 52 100  14 52 100
19 72  19 72
20 100 100 実験例 2 20 100 100 Experimental example 2
マウスにおける P A F致死に対する防止作用  Preventive effect on PAF lethality in mice
試験方法〕  Test method〕
雄性 J c 一 I CRマウスに P A F
Figure imgf000037_0001
ノ の生理食塩 水溶液として v.投与した場合の 3 0分以内のショック死に対する被験 薬物 5分前 i .v.投与による防止作用を調べた。 PAF in male Jc-I CR mice
Figure imgf000037_0001
The preventive effect of i.v. administration 5 minutes before the test drug against shock death within 30 minutes when v. Administration as a physiological saline solution was examined.
〔結果〕  [Result]
表 2に示す。 PAFの投与によ マウスの生存率は 1 9 %であったが 実施例 3の化合物の 0.1および 1 K?i.v.前処置によ 、 生存率はそ れぞれ 3 8および 1 0 0 %と著明に改善され、 本化合物は強力 ¾PAF 致死防止薬である。 表 2 マクスにおける P A F致死に対する防止作用  See Table 2. Although the survival rate of the mice was 19% by the administration of PAF, the survival rates of the compound of Example 3 were 38 and 100%, respectively, by the pretreatment with 0.1 and 1 K? Iv, respectively. Clearly improved, this compound is a potent ¾PAF lethal inhibitor. Table 2 Preventive effects on PAF lethality in Max
Figure imgf000037_0002
製剤例 1
Figure imgf000037_0002
Formulation Example 1
2— 0—ァセ'チル一 3— 0—〔 N—ァセチルー N—（ 2，一ト '人メチル アンモニォェチノレ ) 〕 カノレパモイノレ一 1一 0—ォクタデシノレグリ セ リ ン 。 ョージド 1 0 ^を蒸留水 1.0 に溶解し、 無菌^過後、 無菌条件下に 1 ^ずつ 1 0 0 0本のバイアルに分注し、 凍結乾燥を行い、 密栓する。 差換え —方、 マンニトール 1 0 0 ^を含有する 2 の注射用蒸留水を無菌的 に 2 ^ずつ注射用アンプルに分注後、 熔閉し、 1 0 0 0本に調製する。 用時、 注射用マンニ ト ール液に前者 1パイ アル分の粉末を溶解して用 いる。 2-0-acetyl-1-3-0- [N-acetyl-N- (2,1'-methylammoniochinole)] Canolepamoinole 1-10-octadecinoleglycerin. Dissolve 10 ^ in distilled water 1.0, aseptically filter, pipette 1 ^ each into 100 vials under aseptic conditions, freeze-dry, and stopper tightly. Replacement On the other hand, 2 蒸 留 of distilled water for injection containing 100 ^ of mannitol is aseptically dispensed into 2 ず つ ampules for injection, and then sealed to prepare 100 本. At the time of use, the powder for the former, 1 pir, is dissolved in mannitol solution for injection.
製剤例 2 Formulation Example 2
1錠あた の使用量として As the amount of one tablet used
(1) 2一 0—ァセチノレ— 3—ひ一（： N—ァセチル一 N— ( 2，一ト リメ チソレアンモニォェチノレ ) 〕 カノレノ、-モイノレ— 1― 0ーォクタデシノレ ク'リセ リ ン · 三 ジド 1 0 0 m  (1) 21-0—Acetinole—3—Hiichi (: N—Acetyl-1-N— (2,1-trimethylisolemmonyochinore)) Canoreno, -Moinore—1-0 · Three-zid 100 m
(2) 乳糖 2 0 O mg(2) Lactose 20 O mg
(3) コーンスターチ 5 1 mq(3) Corn starch 5 1 mq
(4) ヒ ドロキシプロピノレセノレロース 9 mg を常法によ 混合、 顆粒化し、 コーンスターチ（ 8 W ) ステアリン酸 マグネシウム（ 2 m と混和後、 打錠して 1錠3 7 0 ,直径9. 5 舰の 錠剤とする。 (4) hydroxycarboxylic pro Pinot receptacle Honoré loin 9 mg mixed by the conventional method, granulated cornstarch (8 W) after mixing with magnesium stearate (2 m, 1 tablet 3 7 0 tabletted, diameter 9. 5舰 tablets.
製剤例 3 Formulation Example 3
製剤例 2の錠剤を 1錠あた の使用量として、 ヒ ドロキシプロピルメ チルセルロースフタ レー ト （ 1 とヒマシ油（ ΐ ττ )を濃度 7 %と るるように溶解したアセ ト ン一エタノール（ 4 ： 6 )混液を用いてコー ティングを施すことによ 腸溶性の被覆錠とする。 産業上の利用可能性  Assuming that the tablet of Formulation Example 2 is used in an amount of 1 tablet per tablet, hydroxypropyl methylcellulose phthalate (1 and castor oil (ΐττ) dissolved in acetonitrile (ethanol) to a concentration of 7% 4: 6) Coated tablets are used to make enteric coated tablets.
本発明によって提供される新規脂質誘導体は医薬として有用である <  The novel lipid derivative provided by the present invention is useful as a medicine <

Claims

請 求 の 範 囲 式  Scope of claim
C H2 O R 1 C HR2 CH 2 OR 1 C HR 2
o =  o =
C H2— X— C一 Y— R3— Z CH 2 — X— C-I Y— R 3 — Z
〔式中、 R1は炭素数 1 0〜3 0のアルキルもしくはアルキル力ルバモイ ル基を、 R2は水素，水酸基，アルコキシ基，ァラルキルォキシ基，ァシ ルォキシ基，ァシルァミノ基または式 [Wherein, R 1 represents an alkyl or alkyl group having 10 to 30 carbon atoms, and R 2 represents hydrogen, a hydroxyl group, an alkoxy group, an aralkyloxy group, an acyloxy group, an acylamino group, or a compound represented by the formula
R4 R 4
一 O CN  One O CN
II ヽ R5 II ヽ R 5
W  W
(式中、 Wは酸素原子または硫黄原子を示し、 R4および R5はそれぞれ水 素またはアルキル基を示すか、 または両者が隣接する窒素原子とともに 環を形成する）で表わされる基を示し、 R3はアルキレン鎖を示し、 Xお よび Yはその一方が酸素原子もしくは硫黄原子を、 他方が置換されてい てもよぃィ ミノ基を示し、 Zは置換されていてもよいアミノ基もしくは アンモニォ基を示し、 それは瑷を形成していてもよい〕で表わされる化 合物またはその塩。 (Wherein W represents an oxygen atom or a sulfur atom, R 4 and R 5 each represent a hydrogen or an alkyl group, or both form a ring together with an adjacent nitrogen atom), R 3 represents an alkylene chain; X and Y each represent an oxygen atom or a sulfur atom; the other represents a substituted or unsubstituted amino group; and Z represents an optionally substituted amino group or ammonium group. Or a group thereof, which may form 瑷) or a salt thereof.
一1 One 1
ΟΛ^ΡΙ 差換え  ΟΛ ^ ΡΙ Replacement
PCT/JP1984/000163 1984-04-03 1984-04-03 Lipid derivatives WO1985004398A1 (en)

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DE8585302202A DE3586746D1 (en) 1984-04-03 1985-03-29 LIPID DERIVATIVES, YOUR PRODUCTION AND USE.
EP85302202A EP0157609B1 (en) 1984-04-03 1985-03-29 Lipid derivatives their production and use
AT85302202T ATE81501T1 (en) 1984-04-03 1985-03-29 LIPID DERIVATIVES, THEIR PRODUCTION AND USE.
JP60069628A JPH0745454B2 (en) 1984-04-03 1985-04-01 Lipid derivative
CA000478129A CA1281324C (en) 1984-04-03 1985-04-02 Lipid derivatives, their production and use
KR1019850002240A KR930004361B1 (en) 1984-04-03 1985-04-03 Method for producing lipid derivatives
US06/906,310 US4737518A (en) 1984-04-03 1986-09-12 Lipid derivatives, their production and use
US07/556,280 US5025005A (en) 1984-04-03 1990-07-23 Lipid derivatives, their production and use
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Cited By (2)

* 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
WO2022249069A1 (en) * 2021-05-26 2022-12-01 Vyluma Inc. Low-dose carbachol ophthalmic compositions with cumulative effect

Citations (1)

* 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

Patent Citations (1)

* 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

Cited By (2)

* 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
WO2022249069A1 (en) * 2021-05-26 2022-12-01 Vyluma Inc. Low-dose carbachol ophthalmic compositions with cumulative effect

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