WO1998017629A1 - 1,4-benzoquinone derivatives - Google Patents

1,4-benzoquinone derivatives Download PDF

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Publication number
WO1998017629A1
WO1998017629A1 PCT/JP1997/003873 JP9703873W WO9817629A1 WO 1998017629 A1 WO1998017629 A1 WO 1998017629A1 JP 9703873 W JP9703873 W JP 9703873W WO 9817629 A1 WO9817629 A1 WO 9817629A1
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compound
mmol
fabms
substituted
unsubstituted
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PCT/JP1997/003873
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French (fr)
Japanese (ja)
Inventor
Hitomi Hamai
Yutaka Maeda
Yutaka Kanda
Mitsunobu Hara
Kazuhito Akasaka
Shiro Akinaga
Chikara Murakata
Shun-Ichi Ikeda
Kendo Shono
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Kyowa Hakko Kogyo Co., Ltd.
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Priority to AU47238/97A priority Critical patent/AU4723897A/en
Publication of WO1998017629A1 publication Critical patent/WO1998017629A1/en

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    • C07D213/00—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
    • 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
    • C07D213/60—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
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    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/32—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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    • C07C323/35—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group
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    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
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    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/28—Sulfur 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
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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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    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—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 separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to a novel 1,4-benzoquinone derivative or a pharmaceutically acceptable salt thereof, which has a pharmacotransferase inhibitory activity and is useful as an antitumor agent.
  • the ras oncogene is point-mutated in many human tumor tissues and is detected in an active form that can transform normal cells.
  • binding to the cell membrane by pharmacosylation of cysteine residues present in the C-terminal region is essential. is there.
  • This reaction is catalyzed by pharmacotransferase. Therefore, it is expected that the pharmacologic inhibitor of pharmacosyltransferase will suppress the function of the ras oncogene product, and can be expected to have an antitumor effect [Gibbs et al. (Cell), Vol. 77, pp.
  • An epoxycyclohexene derivative is known as a pharmacophorase inhibitor (WO95Z085646).
  • X and Y are both hydrogen atoms
  • R 1 and R 2 are taken together as an oxygen atom
  • R 3 is 2,6,10 -Trimethyl-1,5,9-indene force
  • a compound represented by trienyl is described.
  • the present invention provides a compound of the formula (I)
  • X and Y are the same or different and each represents a hydrogen atom, halogen, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower Alkoxy, lower alkanoyl, amino, substituted or unsubstituted mono- or di-lower alkylamino, arylamino, aralkylamino, lower alkenylamino, substituted or unsubstituted heterocyclic amino, substituted or unsubstituted alkylthio, substituted or unsubstituted heterocyclic Thio, substituted or unsubstituted arylthio, substituted or unsubstituted aralkylthio, lower alkenylthio, lower alkenyloxy, substituted or unsubstituted aryloxy, aralkyloxy, Z (CH 2 CH 2 ⁇ ) n R 4 (where n is represents an integer of 2 ⁇ 5, Z is an oxygen atom, NH
  • halogen means each atom of iodine, bromine, chlorine or fluorine.
  • alkyl moiety of the alkylthio include linear or branched alkyl having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isobenzyl, Hexyl, heptyl, octyl, nonyl, decyl, pendecyl, dodecyl, pencil decyl and the like.
  • the lower alkenyl moiety in lower alkenyloxy, lower alkenylthio and lower alkenylamino is a straight or branched chain having 2 to 6 carbon atoms, for example, vinyl, aryl, crotyl, prenyl, 3-butenyl, 2-pentenyl. , 4-pentenyl, 2-hexenyl, 5-hexenyl and the like.
  • the aralkyl moiety in aralkyloxy, aralkylamino and aralkylthio includes, for example, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like having 7 to 15 carbon atoms.
  • the aryl portion in aryloxy, arylamino and arylthio includes phenyl, naphthyl, biphenyl, anthryl and the like.
  • Examples of the alicyclic heterocyclic group include pyrrolidinyl, piberidinyl, piperidino, N-methylbiperidino, piperazinyl, morpholino, thiomorpholino, homopiberidinyl, homopiperazinyl, tetrahydropyranyl and the like.
  • Examples of the heterocyclic group of the heterocyclic thio and heterocyclic amino are the following: Examples include an aromatic complex group and an alicyclic heterocyclic group as defined above.
  • Substituents for substituted lower alkyl, substituted lower alkoxy, substituted mono- or di-lower alkylamino, and substituted alkylthio include halogens having 1 to 3 substituents, hydroxy, ethoxylated, ethoxylated carbamoyl, mercapto, amino, and lower alkoxy. And lower alkoxy propyl, lower alkylthio, lower alkanol, lower alkanol, mono- or di-lower alkylamino, hydroxy lower alkyl, trialkylsilyl, and heterocyclic groups.
  • Substituent aryloxy, substituted arylthio, substituted aralkylthio, substituted heterocyclic thio, substituted heterocyclic amino, and substituted alicyclic heterocyclic groups may be the same or different, and may have 1 to 4 hydroxy, halogen, and nitro substituents. , Amino, mono- or di-lower alkylamino, carboxy, lower alkyl, lower alkoxy, lower alkoxyl propyl, lower alkanoyl, lower alkanoyloxy, lower alkanoylamino, lower alkanoyloxymethyl and the like.
  • each substituent lower alkyl, hydroxy lower alkyl, mono- or di-lower alkylamino, lower alkylthio, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, lower alkanoylamino and lower alkanoyl
  • the lower alkyl moiety and the halogen in xmethyl have the same meanings as described above, respectively, and the heterocyclic group has the same meaning as the heterocyclic group of the heterocyclic thio and the heterocyclic amino.
  • Pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts.
  • Acid salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, and phosphate, formate, acetate, benzoate, maleate, fumarate, succinate, and tartrate.
  • organic acid salts such as citrate, oxalate, methanesulfonate, P-toluenesulfonate, aspartate, and glutamate.
  • the metal salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt.
  • ammonium salt examples include ammonium and tetramethyl.
  • the organic amine addition salts include addition salts such as morpholine and piperidine, and the amino acid addition salts include addition salts such as glycine, phenylalanine, glutamic acid, and lysine.
  • Compound (I) can be produced, for example, by the following reaction step.
  • R 5 represents a hydrogen atom or lower alkyl
  • R 6 represents lower alkyl
  • R la and R 2a are the same or different and represent lower alkoxy
  • X, Y, and R 3 have the same meanings as defined above. Is.
  • the lower alkoxy has the same meaning as the lower alkoxy.
  • Compound (III) can be synthesized by reducing nitro group of known compound (II) with an appropriate reducing agent.
  • the reducing agent to be used may be any method as long as it is a method usually used for reduction of a nitro group, for example, a method by hydrogenation or hydrazine treatment in the presence of a catalyst such as palladium or platinum, zinc, tin under acidic conditions, etc.
  • the reduction method using a single metal is used.
  • the reaction temperature is preferably from 0 to 150 ° C. in the presence of 0.1 to 1 equivalent of the catalyst, and the reaction time is usually from 10 minutes to 5 hours.
  • the reaction temperature is preferably 0 to 100 ° C. in the presence of 1 to 50 equivalents of a reducing agent, and the reaction time is usually 10 minutes to 10 hours.
  • the compound (IV) represents the compound (III) or its hydrochloride by 1 to 10 equivalents of the formula R 3 C ⁇ Hal (wherein R 3 has the same meaning as described above, and Hal represents chlorine or bromine). It can be synthesized by reacting with an acid halide to be used in the presence of 1 to 10 equivalents of a base such as pyridine, triethylamine, N, N-dimethylaniline and the like. The reaction can be carried out in an inert solvent such as dichloromethane, chloroform and tetrahydrofuran. The reaction temperature is preferably from 130 to 150, and the reaction time is usually from 5 minutes to 5 hours.
  • compound (III) is obtained by mixing 1 to 10 equivalents of a carboxylic acid represented by the formula R 3 CO 2 H (wherein R 3 has the same meaning as described above) with 1 to 50 equivalents of ⁇ , ⁇ ′. It can also be synthesized by reacting in the presence of a condensing agent such as -dicyclohexylcarposimide.
  • a condensing agent such as -dicyclohexylcarposimide.
  • the compound (I) a in which R 1 and R 2 are the same or different and are lower alkoxy is a compound (IV) obtained by converting 1 to 10 equivalents of rhodobenzene in a lower alcohol such as methanol or ethanol. It can be obtained by treating with oxidizing agents such as diacetate and bis (trifluoroacetoxy) chloride.
  • the reaction temperature is preferably from ⁇ 30 to 100 ° C., and the reaction time is usually from 10 minutes to 5 hours.
  • (I) b can be synthesized by subjecting compound (IV) to the same oxidation reaction as in step 3 in a water-containing solvent such as water-containing acetonitrile as a solvent.
  • a water-containing solvent such as water-containing acetonitrile
  • the oxidizing agent 1 to 10 equivalents of benzenebenzene acetic acid, bis (trifluoroacetoxy) benzene or the like is used.
  • the reaction temperature is preferably 130 to 100 ° C, and the reaction time is usually 10 minutes to 5 hours. is there.
  • Compound (I) b is obtained by converting compound (I) a obtained in step 3 to an inorganic acid such as sulfuric acid, perchloric acid, hydrochloric acid, hydrobromic acid or acetic acid in a solvent such as tetrahydrofuran, furan, dioxane, or acetonitrile. It can also be synthesized by treating with an organic acid such as trifluoroacetic acid, p-toluenesulfonic acid and the like. Usually, 0.1 to 100 equivalents of an inorganic acid or an organic acid are used, the reaction temperature is preferably -80 to 50 ° C, and the reaction time is usually 10 minutes to 10 hours.
  • an inorganic acid such as sulfuric acid, perchloric acid, hydrochloric acid, hydrobromic acid or acetic acid in a solvent such as tetrahydrofuran, furan, dioxane, or acetonitrile. It can also be synthesized by treating with an organic
  • the compound (I) b—2 having a functional group at the X or Y site is the compound (I) b — 1 in which R 1 and R 2 are in the form of It can also be manufactured by a process.
  • R 3 is as defined above, X a and X b are as defined above X, although Y a and Y b have the same meanings as defined above Y, when X a is the same as X b at the same time Y a is never the same as Y b.
  • Compound (I) b_2 is compound (I) b-1 with acetonitrile and tetrahydride
  • an inert solvent such as furan, ether, dioxane, dimethylformamide, chloroform, and dichloromethane
  • it can be obtained by addition reaction or substitution reaction of 1 to 10 equivalents of the corresponding alcohol, amine, or thiol.
  • the alcohol itself may be used as the solvent, and 1 to 10 equivalents of a base such as sodium hydrogencarbonate, potassium carbonate, sodium hydroxide, pyridine, triethylamine, or 0.001.
  • the reaction can also be promoted by adding a palladium catalyst such as ⁇ 1 equivalent of tetrakis (triphenylphosphine) palladium (o).
  • a palladium catalyst such as ⁇ 1 equivalent of tetrakis (triphenylphosphine) palladium (o).
  • the oxidation reaction to quinone can also be performed by adding 1 to 10 equivalents of an oxidizing agent such as cerium ammonium nitrate or potassium nitrosodisulfonate to the reaction system after the addition reaction. Can be promoted.
  • the position and number of addition or substitution vary depending on the compound (I) b-1 used and the type of alcohol, amine or thiol to be added or substituted, as well as the reaction temperature, reaction time and the type of base used.
  • the reaction temperature is preferably from 120 to 150 ° C, and the reaction time is usually completed in 10 minutes to 40 hours.
  • Compound (I) b-2 in which Y is a hydroxyl group can also be synthesized by demethylation of compound (I) b-1 in which Y is methoxy using lithium iodide or the like.
  • X c represents a group obtained by removing a hydrogen atom from the definition of X, and Y, R la , R 2a and R 3 are as defined above. )
  • Compound (I) d is Asetonitoriru Compound (I) c, tetrahydrofuran, ether, Jiokisan, dimethylformamide, black hole Holm, an inert solvent such as Jikurorome evening down from 1 to 1 0 equivalents of the formula X e -H
  • X e has the same meaning as described above, and can be obtained by an addition reaction of a thiol, alcohol, or amine represented by the formula:
  • the reaction can also be promoted by adding 1 to 10 equivalents of a base such as sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, pyridine, and triethylamine.
  • the reaction temperature is preferably 120 to 150, and the reaction time is usually completed in 10 minutes to 40 hours.
  • the isolation and purification of the product in the above production method can be carried out by appropriately combining methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, and the like.
  • the intermediate can be subjected to the next reaction without purification.
  • the compound (I) may have isomers such as positional isomers, geometric isomers or optical isomers, but the possible isomers and mixtures of the isomers in any ratio are also included in the present invention. .
  • the compound (I) may be purified as it is when the salt of the compound (I) is obtained, or may be dissolved or suspended in an appropriate solvent when the salt of the compound (I) is obtained in a free form.
  • a salt may be formed by adding a base.
  • Compound (I) or a pharmaceutically acceptable salt thereof may be present in the form of an adduct with water or various solvents, and such adducts are also included in the present invention.
  • Table 1 shows the structures of typical examples of the compound (I).
  • the extract obtained by crushing bovine brain is applied to DEAE-Sephacel (manufactured by Pharmacia) column chromatography, and the active fraction is subjected to ultrafiltration.
  • [20 mM Tris-HCl (pH 8.0), 50 mM sodium chloride (NaCl), 20 mM zinc chloride (ZnCl 2 ), ImM dithiothreitol (DTT) and 0.2 mM phenylmethylsulfonyl fluoride (PMSF)] was used as a crude enzyme solution.
  • Activity measurement is as above The measurement was carried out by measuring the amount of the enzyme obtained by the method, which transfers [ 3 H] pharynesyl pyrophosphate to Ras protein produced in Escherichia coli.
  • Cytostatic activity was measured using 3Y1-B cells (hereinafter, HR-3Y1 cells) transformed with the oncogene vH-ras.
  • HR-3Y1 cells 3Y1-B cells transformed with the oncogene vH-ras.
  • DMEM medium containing 10% fetal bovine serum [Nissui] (hereinafter, the medium will leave A) 1.0 X 10 4 cells in / ml of HR-3Y1 cells adjusted to 0.1ml was dispensed.
  • Compound (I) or a pharmaceutically acceptable salt thereof may be administered as it is or orally or parenterally as various pharmaceutical compositions.
  • dosage form of such a pharmaceutical composition include tablets, pills, powders, granules, capsules, suppositories, injections, and drops.
  • the usual methods are applied for formulating the above dosage forms, for example, containing various excipients, lubricants, binders, disintegrants, suspending agents, isotonic agents, emulsifiers, absorption promoters, etc. It may be.
  • Carriers used in pharmaceutical compositions include, for example, water, distilled water for injection, physiological saline, glucose, fructoses, sucrose, mannitol, lactose, starch, corn * starch, cellulose, methylcellulose, carboxy Methylcellulose, hydroxypropylcellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogen phosphate, magnesium stearate, urea, silicone resin, sorbitol fatty acid ester, glycerin fatty acid ester, etc. Is appropriately selected according to the conditions.
  • the dosage and frequency of administration vary depending on the desired therapeutic effect, administration method, treatment period, age, body weight, etc., but oral or parenteral (eg, injection, infusion, rectal administration by suppository, skin patch, etc.) It is usually 0.01 to 200 mg / kg per adult, depending on the method of administration.
  • ordinary post-treatment means the following post-reaction treatment.
  • Example 14 Using the same method as in Example 13, 1.37 g of compound 6 obtained in Example 6 was dissolved in 50 ml of tetrahydrofuran, and 418 mg (2.2 mmol) of P-toluenesulfonic acid monohydrate and 3N hydrochloric acid 15 ml was added, and the mixture was stirred at room temperature for 6 hours. After usual post-treatment, recrystallization from chloroform-methanol-hexane gave 1.13 g (92%) of compound 14.
  • Example 33 N- ⁇ 4- [2- (2-methoxyethoxy) ethoxy] -3,6-dioxocyclohexa-1,4-genyl ⁇ -4-benzyloxyphenoxyacetamide (compound 3 3) 22.0 mg (0.055 mm) of compound 14 obtained in Example 14 in the same manner as in Example 24 01), 1 ml of 2- (2-methoxyethoxy) ethanol and 32.4 mg (0.40 mmol) of titanium bicarbonate gave 5.5 mg (21%) of compound 33.
  • Example 29 Using a method similar to that in Example 29, the compound was obtained from 26.7 mg (0.071 mmol) of compound 13 obtained in Example 13, 18.0 mg (0.21 mmol) of sodium hydrogen carbonate, and 2.0 ml of triethylene glycol. 24.9 mg (72%) of 34 were obtained.
  • Example 40 Using the same method as in Example 40, the compound was obtained from 20.5 mg (0.047 mmol) of compound 15 obtained in Example 15 and 0.5 ml (5.3 mmol) of diethylene glycol and 4.4 mg (0.052 mmol) of sodium hydrogen carbonate. 4 1 was obtained in an amount of 14.5 mg (61%).
  • Example 48 N- [4-forcerubamoylmethylamino-3,6-dioxocyclohexa-1,4 -Genenyl] -3,7,11-trimethyl-2,6,10-dodecatrienamide (Compound 48) Using a method similar to that of Example 45, compound 13 obtained in Example 13 From 22.5 mg (0.060 mmol), 13.3 mg (0.12 mmol) of glycinamide hydrochloride, and 10.2 mg (0.13 mmol, 2.2 eq) of sodium hydrogen carbonate, 3.8 mg (15%) of compound 48 was obtained.
  • Example 50 N- [4- (2-methoxyethylamino) -3,6-dioxocyclohexa-1,4-genyl] -3,7,11-trimethyl-2,6,10-dodeca Trienamide (Compound 50) Using the same method as in Example 45, 22.1 mg (0.059 mmol) of compound 13 obtained in Example 13 and 10 PLl (0.12 mmol) of 2-methoxyethylamine were used. mmol), 13.7 mg (56%) of compound 50 was obtained.
  • Example 51 1 N- ⁇ 4- [2- (N, N-dimethylamino) ethylamino 3,6-dioxocyc-hexa-1,4-genyl ⁇ -3,7,11-trimethyl-2,6,10 -Dodecatrienamide (Compound 51)
  • Example 53 Using a method similar to that of Example 52, 26.1 mg (0.066 mmol) of compound 14 obtained in Example 14, 17.4 mg (0.12 mmol) of / 3-alanine methyl ester hydrochloride, and triethylamine 10 From Hl (0.066 mmol), 14.9 mg (49%) of a compound 53 was obtained.
  • Example 45 Using a method similar to that in Example 45, a compound was obtained from 24.5 mg (0.065 mmol) of compound 13 obtained in Example 13 and 10 l (O.lOmmol) of 2- (2-aminoethoxy) ethanol. 12.7 mg (44%) of 54 were obtained.
  • Example 45 Using the same method as in Example 45, 18.5 mg (0.049 mmol) of the compound 13 obtained in Example 13 was dissolved in 3 ml of methanol, and 10 l (0.15 mmol) of pyrrolidine was added to the solution. 7.4 mg (37%) was obtained.
  • Example 62 N- [4- (N-methylbiperazino) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide hydrochloride (compound 62)
  • Example 65 N- (4-ethylthio-3,6-dioxocyclohexa-1,4-genyl) -4-benzyloxyphenoxyacetamide (compound 65) and N- [4,5 -Bis (ethylthio) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 66)
  • Example 66 N- (4-chloro-5-decane-3,6-dioxocyclohexa-1,4-phenyl) _4-benzyloxyphenoxyacetamide (compound 67) and N- [4,5-bis (decanethio) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (compound 68)
  • Example 75 N- [4- (2,3-dihydroxypropylthio) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 78) ) Using the same method as in Example 64, 21.3 mg (0.054 mmol) of compound 14 obtained in Example 14, 4.5 til (0.054 mmol) of 3-mercapto-1-propanediol and 8.1 l of triethylamine (0.054 mmol), 6.5 mg (25%) of compound 78 was obtained.
  • Example 88 N- [4- (3,4,5-triacetoxy-6-acetoxymethyltetrahydropyran-2-ylthio) -3,6-dioxocyclohexa-1,4-genyl] -4- Benzyloxy phenoxyacetamide (Compound 91) Using a method similar to that of Example 64, 6.9 mg (0.043 mmol) of compound 14 obtained in Example 14 and 15.5 mg of 1-thio-; 3-D-glucose tetraacetate (0.043 mmol) ) And 6.4 l (0.043 mmol) of triethylamine to give 25.3 mg (82%) of compound 91.
  • Example 64 Using a method similar to that in Example 64, 20.8 mg (0.052 mmol) of compound 14 obtained in Example 14, 7.0 mg (0.056 mmol) of 4-aminothiophenol and 7.9 l (0.053 mmol) of triethylamine were used. As a result, 16.2 mg (64%) of compound 94 was obtained.
  • Example 95 N- (6,6-dimethoxy 5-benzylthio-3-oxocyclohex-1-enyl) -4-benzyloxyphenoxyacetamide (compound 98), N- ⁇ 6, 6-Dimethoxy 5- (4-acetamidophenyl) thio-3-oxocyclohex-1-enyl ⁇ -4-benzyldioxyphenoxyacetamide (Compound 101), N- (6,6 -Dimethoxy-5-carboxyphenylthio-3-oxocyclohex-1-enyl) -4-benzyloxyphenoxyacetamide (Compound 104), N- ⁇ 6,6-dimethoxy 5- (4-pyridylthio ) -3-Oxocyclohexoxyenyl ⁇ -4-benzyloxyphenoxyacetamide (Compound 105), N- ⁇ 6,6-dimethoxy 5- (2-pyridylthio) -3-oxocyclo Xyl
  • Example 97 N- ⁇ 6,6-dimethoxy-5- (4-hydroxyphenyl) thio-3-oxosic-hexoxy-1-enyl ⁇ -4-benzyloxyphenoxyacetamide (Compound 1 0 2) Similarly to Example 96, 410 mg (1.00 mmol) of compound 2 obtained in Example 2 and 4- From 206 mg (1.63 mmol) of hydroxythiophenol, 452 mg (84.2%) of compound 102 was obtained.
  • Example 98 N- ⁇ 6,6-dimethoxy-5- (4-methoxyphenyl) thio-3-oxocyclohex-1-enyl ⁇ -4-benzyloxyphenoxyacetamide (Compound 10 3)
  • Compound 103 was obtained from 14.9 mg (0.036 mmol) of Compound 2 obtained in Example 2 and 4.5 Hl (0.037 mmol) of P-methoxythiophenol. (5 0.5%).
  • Example 99 N- ⁇ 6,6-dimethoxy-5- (2,5-dichlorophenyl) thio-3-oxosic-hexoxy-1-enyl ⁇ -4-benzyloxyphenoxyacetamide ( Compound 1 15)
  • 25.9 mg (0.063 mmol) of compound 2 obtained in Example 2 and 18.4 mg (0.103 mmol) of 2,5-dichlorothiophenol were used to obtain 27.3 of compound 115. mg (73.3%).
  • Example 96 22.8 mg (90.0%) of compound 122 was obtained from 21.6 mg (0.049 mmol) of compound 6 obtained in Example 6 and 3.5 l (0.049 mmol) of mercaptophenol. Obtained.
  • Example 104 N- ⁇ 4-chloro-6,6-dimethoxy-5- (4-ethylthio) -3-oxocyclohexyl-1-enyl ⁇ -4-benzyloxyphenoxyacetamide (Compound 12 9)
  • Example 105 N- (6,6-dimethoxy-5-aminophenylthio-3-oxocyclohex-1-enyl) -4-benzyloxyphenoxyacetamide (Compound 130) 9.6 mg (24.3%) of Compound 130 from 18.0 mg (0.041 mmol) of Compound 6 obtained in Example 6 and 5.8 mg (0.046 mmol) of p-aminothiophenol obtained in Example 6 using the same method as 96. Obtained.
  • Example 13 Using a method similar to that of Example 13, the compound was obtained from 12 mg (0.032 mmol) of Compound 1331 obtained in Example 106 and 6.0 mg (0.032 mmol) of p-toluenesulfonic acid monohydrate. 4.5 mg (43%) of product 132 were obtained.
  • Example 108 N- (3,6-dioxo-4-trimethylsilylethylthiocyclohexa-1,4-genyl) -4-benzyloxyphenoxyacetamide (Compound 133) and N- [3,6-Dioxo-4,5-bis (trimethylsilylethylthio) cyclohexa-1,4-genenyl] -4-benzyloxyphenoxyacetamide (Compound 134) From 18.0 mg (0.045 mmol) of compound 14 obtained in Example 14 and 7.3 l (0.046 mmol) of 2-trimethylsilylethanethiol obtained in Example 14 using the same method as in 64, thin layer chromatography after usual post-treatment (Only in the form of black mouth) to obtain 19.8 mg (88.3%) of compound 133 and 1.8 mg (6.3%) of compound 134.
  • Example 14 From the compound 14 obtained in Example 14 23.5 mg (0.059 mmol), methyl thioglycolate 5.3 Hl (0.059 mmol) and triethylamine 9.8 l (0.059 mmol) using the same method as in Example 64. 13.5 mg (48.9%) of compound 135 was obtained.
  • Example 114 N- [3,6-dioxo-4- (4-methoxyphenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 144) ) 16.4 mg (0.042 mmol) of compound 14 obtained in Example 14 and 5.2-H p-methoxybenzenethiol (0.042 mmol) obtained in Example 14 using the same method as in Example 6 mg (68.5%).
  • Example 115 N- [3,6-dioxo-5- (4-methoxyphenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 14 1 ) 23.4 mg (0.043 mmol) of compound 14 obtained in Example 14 was dissolved in 3 ml of tetrahydrofuran using a method similar to that of Example 64, and 17 mg (0.090 mmol) of p-toluenesulfonic acid monohydrate was dissolved. Was added, and then 3.0 ml (3.0 mmol) of 1N hydrochloric acid was added, followed by stirring at room temperature for 7 days.
  • Example 1 16 N- [3,6-dioxo-4- (2-methoxyphenylthio) cyclohexa-1,4-genenyl] -4-benzyloxyphenoxyacetamide (Compound 144) ) From 21.6 mg (0.054 mmol) of compound 14 obtained in Example 14 and 6.6 l (0.054 mmol) of o-methoxybenzenethiol obtained in Example 14 using the same method as in Example 6, 25.0 mg of compound 14 2 (91.8%).
  • Example 1 222 N- [3,6-dioxo-4- (2-chlorophenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 1 4 8)
  • Example 124 N- [3,6-dioxo-4- (3-bromophenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 150 ) From 15.8 mg (0.040 mmol) of the compound 14 obtained in Example 14 and 4.1 Hl (0.040 mmol) of 3-bromothiophenol obtained in Example 14 using the same method as in Example 64, 17.8 mg of Compound 150 was obtained. (81.4%).
  • Example 1 25 N- [3,6-dioxo-4- (2-bromophenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 15 1 )
  • Reference Example 4 Compound d 495 mg (2.1 mmol) of 3,7,11-trimethyl-2,6,10-dodecatrienoic acid was dissolved in 5 ml of toluene, 0.5 ml of oxalyl chloride was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure to obtain a crude product of 3,7,11-trimethyl-2,6,10-dodecatrienic chloride.
  • the compound g was obtained from 433 mg (l.7 mmol) of 4-benzyloxyphenoxyacetic acid and 300 mg (1.4 mmol) of 3,2-dimethoxy-2,5-dimethoxynitrobenzene. 523 mg (89%) were obtained.
  • Example 2 Using the same method as in Example 1, the compound was prepared from 488 mg (1.8 mmol) of 2,3-bis (methoxymethoxy) -5-methoxynitrobenzene and 557 mg (2.0 mmol) of 4-benzyloxyphenoxyacetic acid. 567 mg (66%) of S was obtained.
  • the present invention provides a 1,4-benzoquinone derivative or a pharmacologically acceptable salt thereof, which has a pharmacotransferase inhibitory activity and is useful as an antitumor agent.

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Abstract

1,4-Benzoquinone derivatives represented by general formula (I) or pharmacologically acceptable salts thereof: (I) wherein ----- represents a single or double bond; X and Y each represents hydrogen, halogeno, etc.; R?1 and R2¿ each represents lower alkoxyl, or both represent oxygen; and R3 represents 2,6,10-trimethyl-1,5,9-undecatrienyl represented by formula (A) or aryloxymethyl represented by formula (B) where W represents hydrogen, halogeno, etc. The compounds have a farnesyl transferase inhibitory activity and are useful as an antitumor agent.

Description

明細  Statement
1,4-ベ ン誘導体  1,4-ben derivative
技 術 分 野 Technical field
本発明は、 フアルネシルトランスフェラーゼ阻害活性を有し、 抗腫瘍剤とし て有用な新規 1，4-ベンゾキノン誘導体またはその薬理的に許容される塩に関す る。  The present invention relates to a novel 1,4-benzoquinone derivative or a pharmaceutically acceptable salt thereof, which has a pharmacotransferase inhibitory activity and is useful as an antitumor agent.
背 景 技 術 Background technology
ras癌遺伝子は、 ヒトの多くの腫瘍組織で点突然変異を受け、 正常細胞をト ランスフォームできる活性型で検出される。 ras癌遺伝子産物のトランスフォ —メ一シヨン活性の発現には、 12、 13もしくは 61番目のアミノ酸突然変異に 加え、 C末端領域に存在するシスティン残基のフアルネシル化による細胞膜へ の結合が必須である。 本反応は、 フアルネシルトランスフェラーゼにより触媒 を受ける。 従って、 フアルネシルトランスフェラ一ゼ阻害物質は、 ras 癌遺伝 子産物の機能を抑制することが予想され、 抗腫瘍作用を有することが期待でき る [ギブスら （Gibbs, et al.) 、 セル （Cell) 、 77卷、 175-178頁 （1994年） ]。 フアルネシルトランスフェラ一ゼ阻害剤として、 エポキシシクロへキセン誘 導体が知られている （WO 9 5 Z 0 8 5 4 6 ) 。 またその合成中間体として、 後述する式 （I ) 中、 Xおよび Yがいずれも水素原子であり、 R 1および R 2 が一緒になつて酸素原子であり、 かつ R 3が 2,6,10-トリメチル -1,5,9-ゥンデ力 トリエニルで表される化合物が記載されている。 The ras oncogene is point-mutated in many human tumor tissues and is detected in an active form that can transform normal cells. In order to express the trans-measuring activity of the ras oncogene product, in addition to the amino acid mutation at positions 12, 13 or 61, binding to the cell membrane by pharmacosylation of cysteine residues present in the C-terminal region is essential. is there. This reaction is catalyzed by pharmacotransferase. Therefore, it is expected that the pharmacologic inhibitor of pharmacosyltransferase will suppress the function of the ras oncogene product, and can be expected to have an antitumor effect [Gibbs et al. (Cell), Vol. 77, pp. 175-178 (1994)]. An epoxycyclohexene derivative is known as a pharmacophorase inhibitor (WO95Z085646). Further, as a synthetic intermediate thereof, in the formula (I) described below, X and Y are both hydrogen atoms, R 1 and R 2 are taken together as an oxygen atom, and R 3 is 2,6,10 -Trimethyl-1,5,9-indene force A compound represented by trienyl is described.
発 明 の 開 示 Disclosure of the invention
本発明は、 式 （ I )  The present invention provides a compound of the formula (I)
[式中、 は単結合ま
Figure imgf000003_0001
[Wherein is a single bond
Figure imgf000003_0001
たは二重結合を表し、 Xおよび Yは同一または異なって、 水素原子、 ハロゲン、 ヒドロキシ、 置換もしくは非置換の低級アルキル、 置換もしくは非置換の低級 アルコキシ、 低級アルカノィル、 ァミノ、 置換もしくは非置換のモノまたはジ 低級アルキルァミノ、 ァリールァミノ、 ァラルキルァミノ、 低級アルケニルァ ミノ、 置換もしくは非置換の複素環ァミノ、 置換もしくは非置換のアルキルチ ォ、 置換もしくは非置換の複素環チォ、 置換もしくは非置換のァリールチオ、 置換もしくは非置換のァラルキルチオ、 低級アルケニルチオ、 低級アルケニル ォキシ、 置換もしくは非置換のァリールォキシ、 ァラルキルォキシ、 Z ( C H 2 C H 2〇） n R 4 (式中、 nは 2 〜 5の整数を表し、 Zは酸素原子、 N Hまた は N C H 3を表し、 R 4は水素原子または低級アルキルを表す。 ) または置換 もしくは非置換の脂環式複素環基を表し、 R 1および R 2は同一または異なつ て低級アルコキシを表すか、 一緒になつて酸素原子を表し、 尺 3は式(八）
Figure imgf000004_0001
X and Y are the same or different and each represents a hydrogen atom, halogen, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower Alkoxy, lower alkanoyl, amino, substituted or unsubstituted mono- or di-lower alkylamino, arylamino, aralkylamino, lower alkenylamino, substituted or unsubstituted heterocyclic amino, substituted or unsubstituted alkylthio, substituted or unsubstituted heterocyclic Thio, substituted or unsubstituted arylthio, substituted or unsubstituted aralkylthio, lower alkenylthio, lower alkenyloxy, substituted or unsubstituted aryloxy, aralkyloxy, Z (CH 2 CH 2 〇) n R 4 (where n is represents an integer of 2 ~ 5, Z is an oxygen atom, NH or represents NCH 3, R 4 represents a representative.) or a substituted or unsubstituted alicyclic heterocyclic group in which a hydrogen atom or a lower alkyl, R 1 And R 2 are the same or different and represent lower alkoxy, or together form an acid It represents atom, scale 3 has the formula (eight)
Figure imgf000004_0001
で表される 2,6,10-トリメチル -1,5,9-ゥンデカトリェニルまたは式（B)
Figure imgf000004_0002
（式中、 Wは水素原子、 ハロゲン、 カルボキシ、 低2,6,10-trimethyl-1,5,9-ndecatrienyl represented by the following formula (B)
Figure imgf000004_0002
(Where W is a hydrogen atom, halogen, carboxy, low
B  B
級アルキル、 低級アルカノィル、 低級アルカノィルォキシ、 低級アルカノィル ォキシアルキル、 ヒドロキシ、 低級アルコキシ、 低級アルコキシアルコキシ、 低級アルケニルォキシ、 置換もしくは非置換のァリールォキシ、 ァラルキルォ キシ、 ニトロ、 ァミノ、 モノまたはジ低級アルキルァミノ、 ァラルキルァミノ、 低級アルケニルァミノ、 置換もしくは非置換のァリールァミノ、 置換もしくは 非置換の複素環ァミノ、 アルキルチオ、 低級アルケニルチオ、 置換もしくは非 置換のァリ一ルチオ、 ァラルキルチオまたは置換もしくは非置換の複素環チォ を表す。 ） で表されるァリールォキシメチル基を表す。 ただし、 Xおよび Yが いずれも水素原子であり、 R 1および R 2が一緒になつて酸素原子の場合、 R 3は式 （B ) を表す。 ] で表される 1,4-ベンゾキノン誘導体またはその薬理的 に許容される塩に関する。 以下、 式 （ I ) で表される化合物を化合物 （ I ) という。 他の式番号の化合 物についても同様である。 Lower alkyl, lower alkanoyl, lower alkanoyloxy, lower alkanoyloxyalkyl, hydroxy, lower alkoxy, lower alkoxyalkoxy, lower alkenyloxy, substituted or unsubstituted aryloxy, aralkyloxy, nitro, amino, mono- or di-lower alkylamino, Aralkylamino, lower alkenylamino, substituted or unsubstituted arylamino, substituted or unsubstituted heterocyclic amino, alkylthio, lower alkenylthio, substituted or unsubstituted arylthio, aralkylthio or substituted or unsubstituted heterocyclic thio. Represent. ) Represents an aryloxymethyl group. However, when X and Y are both hydrogen atoms and R 1 and R 2 are together and are an oxygen atom, R 3 represents the formula (B). And a pharmacologically acceptable salt thereof. Hereinafter, the compound represented by the formula (I) is referred to as compound (I). The same applies to compounds having other formula numbers.
式 （ I ) の各基の定義において、 ハロゲンは、 ヨウ素、 臭素、 塩素またはフ ッ素の各原子を意味する。 アルキルチオのアルキル部分としては、 炭素数 1〜 2 0の直鎖または分岐状のアルキル、 例えばメチル、 ェチル、 プロピル、 イソ プロピル、 ブチル、 イソブチル、 sec-ブチル、 tert-ブチル、 ペンチル、 イソべ ンチル、 へキシル、 ヘプチル、 ォクチル、 ノニル、 デシル、 ゥンデシル、 ドデ シル、 ペン夕デシル等があげられる。 低級アルキルおよび低級アルコキシ、 低 級アルカノィル、 低級アルコキシアルコキシ、 モノまたはジ低級アルキルアミ ノ、 低級アル力ノィルォキシおよび低級アル力ノィルォキシアルキルの低級ァ ルキル部分は、 前記アルキルのうち、 炭素数 1〜8のものを包含する。 低級ァ ルケニルォキシ、 低級アルケニルチオおよび低級アルケニルァミノにおける低 級アルケニル部分としては、 炭素数 2〜 6の直鎖または分岐状の、 例えばビニ ル、 ァリル、 クロチル、 プレニル、 3—ブテニル、 2 —ペンテニル、 4—ペン テニル、 2—へキセニル、 5 —へキセニル等があげられる。 ァラルキルォキシ、 ァラルキルァミノおよびァラルキルチオにおけるァラルキル部分としては、 炭 素数 7〜 1 5の、 例えばベンジル、 フエネチル、 ベンズヒドリル、 ナフチルメ チル等があげられる。 ァリールォキシ、 ァリールァミノおよびァリールチオに おけるァリール部分としては、 フエニル、 ナフチル、 ビフエ二ル、 アントリル 等があげられる。 脂環式複素環基としてはピロリジニル、 ピベリジニル、 ピぺ リジノ、 N-メチルビペリジノ、 ピペラジニル、 モルホリノ、 チオモルホリノ、 ホモピベリジニル、 ホモピペラジニル、 テトラヒドロピラニル等があげられる。 複素環チォおよび複素環ァミノの複素環基としてはフリル、 チェニル、 ピロリ ル、 イミダゾリル、 トリァゾリル、 テトラゾリル、 チアジアゾリル、 ピリジル、 インドリル、 キノリル、 イソキノリル、 キノキサリニル、 キナゾリニル、 チア ゾリル、 ベンゾチアゾリル、 ベンゾイミダゾリル、 ォキサゾリル等の芳香族複 素環基および前記と同義の脂環式複素環基があげられる。 置換低級アルキル、 置換低級アルコキシ、 置換モノま-たはジ低級アルキルァ ミノ、 置換アルキルチオの置換基としては、 置換数 1〜3のハロゲン、 ヒドロ キシ、 力ルポキシ、 力ルバモイル、 メルカプト、 ァミノ、 低級アルコキシ、 低 級アルコキシ力ルポニル、 低級アルキルチオ、 低級アルカノィル、 低級アル力 ノィルォキシ、，モノまたはジ低級アルキルァミノ、 ヒドロキシ低級アルキル、 トリアルキルシリル、 複素環基等があげられる。 In the definition of each group in formula (I), halogen means each atom of iodine, bromine, chlorine or fluorine. Examples of the alkyl moiety of the alkylthio include linear or branched alkyl having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isobenzyl, Hexyl, heptyl, octyl, nonyl, decyl, pendecyl, dodecyl, pencil decyl and the like. Lower alkyl and lower alkoxy, lower alkanol, lower alkoxyalkoxy, mono- or di-lower alkylamino, lower alkyloxy and lower alkyloxyalkyl, the lower alkyl moiety of the above alkyl has 1 to 8 carbon atoms. Includes The lower alkenyl moiety in lower alkenyloxy, lower alkenylthio and lower alkenylamino is a straight or branched chain having 2 to 6 carbon atoms, for example, vinyl, aryl, crotyl, prenyl, 3-butenyl, 2-pentenyl. , 4-pentenyl, 2-hexenyl, 5-hexenyl and the like. The aralkyl moiety in aralkyloxy, aralkylamino and aralkylthio includes, for example, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like having 7 to 15 carbon atoms. The aryl portion in aryloxy, arylamino and arylthio includes phenyl, naphthyl, biphenyl, anthryl and the like. Examples of the alicyclic heterocyclic group include pyrrolidinyl, piberidinyl, piperidino, N-methylbiperidino, piperazinyl, morpholino, thiomorpholino, homopiberidinyl, homopiperazinyl, tetrahydropyranyl and the like. Examples of the heterocyclic group of the heterocyclic thio and heterocyclic amino are the following: Examples include an aromatic complex group and an alicyclic heterocyclic group as defined above. Substituents for substituted lower alkyl, substituted lower alkoxy, substituted mono- or di-lower alkylamino, and substituted alkylthio include halogens having 1 to 3 substituents, hydroxy, ethoxylated, ethoxylated carbamoyl, mercapto, amino, and lower alkoxy. And lower alkoxy propyl, lower alkylthio, lower alkanol, lower alkanol, mono- or di-lower alkylamino, hydroxy lower alkyl, trialkylsilyl, and heterocyclic groups.
置換ァリールォキシ、 置換ァリールチオ、 置換ァラルキルチオ、 置換複素環 チォ、 置換複素環ァミノおよび置換脂環式複素環基の置換基としては、 同一ま たは異なって、 置換数 1〜4のヒドロキシ、 ハロゲン、 ニトロ、 ァミノ、 モノ またはジ低級アルキルァミノ、 カルボキシ、 低級アルキル、 低級アルコキシ、 低級アルコキシ力ルポニル、 低級アルカノィル、 低級アルカノィルォキシ、 低 級アルカノィルァミノ、 低級アルカノィルォキシメチル等があげられる。  Substituent aryloxy, substituted arylthio, substituted aralkylthio, substituted heterocyclic thio, substituted heterocyclic amino, and substituted alicyclic heterocyclic groups may be the same or different, and may have 1 to 4 hydroxy, halogen, and nitro substituents. , Amino, mono- or di-lower alkylamino, carboxy, lower alkyl, lower alkoxy, lower alkoxyl propyl, lower alkanoyl, lower alkanoyloxy, lower alkanoylamino, lower alkanoyloxymethyl and the like.
各置換基の定義において、 低級アルキル、 ヒドロキシ低級アルキル、 モノま たはジ低級アルキルァミノ、 低級アルキルチオ、 低級アルコキシ、 低級アルコ キシカルポニル、 低級アルカノィル、 低級アルカノィルォキシ、 低級アルカノ ィルァミノおよび低級アルカノィルォキシメチルにおける低級アルキル部分お よびハロゲンはそれぞれ前記と同義であり、 複素環基は前記複素環チォおよび 複素環ァミノの複素環基と同義である。  In the definition of each substituent, lower alkyl, hydroxy lower alkyl, mono- or di-lower alkylamino, lower alkylthio, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, lower alkanoylamino and lower alkanoyl The lower alkyl moiety and the halogen in xmethyl have the same meanings as described above, respectively, and the heterocyclic group has the same meaning as the heterocyclic group of the heterocyclic thio and the heterocyclic amino.
化合物 （I )の薬理的に許容される塩は、 薬理的に許容される酸付加塩、 金 属塩、 アンモニゥム塩、 有機アミン付加塩、 アミノ酸付加塩を包含する。 酸付 加塩としては塩酸塩、 臭化水素酸塩、 硫酸塩、 リン酸塩等の無機酸塩、 ギ酸塩、 酢酸塩、 安息香酸塩、 マレイン酸塩、 フマル酸塩、 コハク酸塩、 酒石酸塩、 ク ェン酸塩、 しゅう酸塩、 メタンスルホン酸塩、 P-トルエンスルホン酸塩、 ァス パラギン酸塩、 グルタミン酸塩等の有機酸塩があげられる。 金属塩としてはリ チウム塩、 ナトリウム塩、 カリウム塩等のアルカリ金属塩、 マグネシウム塩、 カルシウム塩等のアルカリ土類金属塩、 アルミニウム塩、 亜鉛塩等があげられ、 アンモニゥム塩としてはアンモニゥム、 テトラメチルアンモニゥム塩等があげ られ、 有機アミン付加塩としてはモルホリン、 ピぺリジン等の付加塩、 ァミノ 酸付加塩としてはグリシン、 フエ二ルァラニン、 グルタミン酸、 リジン等の付 加塩があげられる。 Pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts. Acid salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, and phosphate, formate, acetate, benzoate, maleate, fumarate, succinate, and tartrate. And organic acid salts such as citrate, oxalate, methanesulfonate, P-toluenesulfonate, aspartate, and glutamate. Examples of the metal salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt. Examples of the ammonium salt include ammonium and tetramethyl. Ammonium salt etc. The organic amine addition salts include addition salts such as morpholine and piperidine, and the amino acid addition salts include addition salts such as glycine, phenylalanine, glutamic acid, and lysine.
次に、 化合物 （ I ) の製造法について説明する。 化合物 （ I )は、 例えば次 の反応工程により製造することができる。  Next, a method for producing the compound (I) will be described. Compound (I) can be produced, for example, by the following reaction step.
なお、 以下に示す製造法において、 定義した基が実施方法の条件下で変化す るかまたは方法を実施するのに不適切な場合、 有機合成化学で常用される保護 基の導入および脱離方法 [例えば、 プロテクティブ ·グループス ·イン ·ォー ガニック · シンセシス (Protective Groups in Organic Synthesis), グリーン (T.W. Greene)著、 ジョン ·ヮイリ一 ·アンド 'サンズ ·ィンコーポレイテツド (John Wiley & Sons, Inc.) ( 1 9 8 1年） 参照] を用いることにより、 目的化合物を 得ることができる。 また、 必要に応じて置換基導入等の反応工程の順序を変え ることもできる。  In the following production methods, when the defined groups change under the conditions of the method or are inappropriate for carrying out the method, methods for introducing and removing protecting groups commonly used in organic synthetic chemistry are used. [For example, Protective Groups in Organic Synthesis, by TW Greene, John Wiley & Sons, John Wiley & Sons, Inc.) (1989)] can be used to obtain the desired compound. In addition, the order of the reaction steps such as introduction of a substituent can be changed as necessary.
製造法 1 Manufacturing method 1
Figure imgf000007_0001
Figure imgf000007_0001
(式中、 R 5は水素原子または低級アルキルを表し、 R 6は低級アルキルを表 し、 R laおよび R 2aは同一または異なって低級アルコキシを表し、 X、 Y、 および R 3 は前記と同義である。 ） (Wherein, R 5 represents a hydrogen atom or lower alkyl, R 6 represents lower alkyl, R la and R 2a are the same or different and represent lower alkoxy, and X, Y, and R 3 have the same meanings as defined above. Is.)
ここで、 低級アルコキシは前記低級アルコキシと同義である。  Here, the lower alkoxy has the same meaning as the lower alkoxy.
(工程 1 ) 化合物 （ I I I ) は、 公知の化合物 （ I I) を適当な還元剤によりニトロ基 を還元することより合成できる。 用いられる還元剤は通常二ト口基の還元に用 いられる方法であればいずれでもよく、 例えばパラジウム、 白金等の触媒存在 下水素添加またはヒドラジン処理による方法、 酸性条件下での亜鉛、 スズ等の 単体金属による還元法等が用いられる。 水素添加反応では 0. 1〜1当量の触 媒存在下、 反応温度は 0〜1 50°Cが好ましく、 反応時間は通常 1 0分〜 5時 間である。 また、 単体金属による還元反応においては、 1〜50当量の還元剤 存在下、 反応温度は 0〜 100°Cが好ましく、 反応時間は通常 10分〜 10時 間である。 (Process 1) Compound (III) can be synthesized by reducing nitro group of known compound (II) with an appropriate reducing agent. The reducing agent to be used may be any method as long as it is a method usually used for reduction of a nitro group, for example, a method by hydrogenation or hydrazine treatment in the presence of a catalyst such as palladium or platinum, zinc, tin under acidic conditions, etc. The reduction method using a single metal is used. In the hydrogenation reaction, the reaction temperature is preferably from 0 to 150 ° C. in the presence of 0.1 to 1 equivalent of the catalyst, and the reaction time is usually from 10 minutes to 5 hours. In the reduction reaction using a simple metal, the reaction temperature is preferably 0 to 100 ° C. in the presence of 1 to 50 equivalents of a reducing agent, and the reaction time is usually 10 minutes to 10 hours.
(工程 2)  (Process 2)
化合物 （ I V) は、 化合物 （ I I I) またはその塩酸塩を、 1〜 10当量 の式 R 3C〇Hal (式中、 R 3は前記と同義であり、 Halは塩素または臭素を 表す） で表される酸ハライドと 1〜： 10当量のピリジン、 トリェチルァミン、 N，N-ジメチルァニリン等の塩基存在下、 反応させることにより合成できる。 反応は、 ジクロロメタン、 クロ口ホルム、 テトラヒドロフラン等の不活性溶媒 中でも行うことができる。 反応温度は一 30〜 1 50 が好ましく、 反応時間 は通常 5分〜 5時間である。 また、 化合物 （ I I I ) を 1〜1 0当量の式 R 3 CO 2H (式中、 R 3は前記と同義である） で表されるカルボン酸と、 1〜5 0当量の Ν,Ν' -ジシクロへキシルカルポジイミド等の縮合剤存在下で反応さ せることによつても合成できる。 The compound (IV) represents the compound (III) or its hydrochloride by 1 to 10 equivalents of the formula R 3 C〇Hal (wherein R 3 has the same meaning as described above, and Hal represents chlorine or bromine). It can be synthesized by reacting with an acid halide to be used in the presence of 1 to 10 equivalents of a base such as pyridine, triethylamine, N, N-dimethylaniline and the like. The reaction can be carried out in an inert solvent such as dichloromethane, chloroform and tetrahydrofuran. The reaction temperature is preferably from 130 to 150, and the reaction time is usually from 5 minutes to 5 hours. Further, compound (III) is obtained by mixing 1 to 10 equivalents of a carboxylic acid represented by the formula R 3 CO 2 H (wherein R 3 has the same meaning as described above) with 1 to 50 equivalents of Ν, Ν ′. It can also be synthesized by reacting in the presence of a condensing agent such as -dicyclohexylcarposimide.
(工程 3)  (Process 3)
化合物 （ I ) のうち、 R 1および R 2が同一または異なって低級アルコキシ である化合物 （ I ) aは、 化合物 （ I V) を、 メタノール、 エタノール等の低 級アルコール中、 1〜 10当量のョードベンゼン二酢酸、 ビス （トリフルォロ ァセトキシ） ョ一ドベンゼン等の酸化剤で処理することにより得ることができ る。 反応温度は— 30〜100°Cが好ましく、 反応時間は通常 10分〜 5時間 である。 (工程 4) " Among the compounds (I), the compound (I) a in which R 1 and R 2 are the same or different and are lower alkoxy is a compound (IV) obtained by converting 1 to 10 equivalents of rhodobenzene in a lower alcohol such as methanol or ethanol. It can be obtained by treating with oxidizing agents such as diacetate and bis (trifluoroacetoxy) chloride. The reaction temperature is preferably from −30 to 100 ° C., and the reaction time is usually from 10 minutes to 5 hours. (Step 4) "
化合物 （ I ) のうち、 R 1および R 2が一緒になつて酸素原子である化合物Compound (I) wherein R 1 and R 2 are taken together to form an oxygen atom
(I) bは、 溶媒として含水ァセトニトリル等含水溶媒中で、 化合物 （ I V) を工程 3と同様の酸化反応を行うことにより合成できる。 酸化剤としては 1〜 1 0当量のョードベンゼン二酢酸、 ビス （トリフルォロアセトキシ） ョードベ ンゼン等を用い、 反応温度は一 30〜 100°Cが好ましく、 反応時間は通常 1 0分〜 5時間である。 (I) b can be synthesized by subjecting compound (IV) to the same oxidation reaction as in step 3 in a water-containing solvent such as water-containing acetonitrile as a solvent. As the oxidizing agent, 1 to 10 equivalents of benzenebenzene acetic acid, bis (trifluoroacetoxy) benzene or the like is used. The reaction temperature is preferably 130 to 100 ° C, and the reaction time is usually 10 minutes to 5 hours. is there.
(工程 5 )  (Process 5)
化合物 （ I ) bは、 工程 3により得られる化合物 （ I ) aを、 テトラヒド 口フラン、 ジォキサン、 ァセトニトリル等の溶媒中、 硫酸、 過塩素酸、 塩酸、 臭化水素酸等の無機酸、 あるいは酢酸、 トリフルォロ酢酸、 パラトルエンスル ホン酸等の有機酸で処理することによつても合成できる。 通常 0. 1~100 当量の無機酸または有機酸が用いられ、 反応温度は— 80〜50°Cが好ましく、 反応時間は通常 10分〜 10時間である。  Compound (I) b is obtained by converting compound (I) a obtained in step 3 to an inorganic acid such as sulfuric acid, perchloric acid, hydrochloric acid, hydrobromic acid or acetic acid in a solvent such as tetrahydrofuran, furan, dioxane, or acetonitrile. It can also be synthesized by treating with an organic acid such as trifluoroacetic acid, p-toluenesulfonic acid and the like. Usually, 0.1 to 100 equivalents of an inorganic acid or an organic acid are used, the reaction temperature is preferably -80 to 50 ° C, and the reaction time is usually 10 minutes to 10 hours.
製造法 2 Manufacturing method 2
化合物 （ I) のうち、 Xまたは Y部位に官能基を有する化合物 （ I ) b— 2 は、 R 1および R2がー体となって酸素原子を表す化合物（I)b_ 1から、 次 の工程によっても製造することができる。 Among the compounds (I), the compound (I) b—2 having a functional group at the X or Y site is the compound (I) b — 1 in which R 1 and R 2 are in the form of It can also be manufactured by a process.
Figure imgf000009_0001
Figure imgf000009_0001
(式中、 R 3は前記と同義であり、 X aおよび X bは前記 Xと同義であり、 Y a および Y bは前記 Yと同義であるが、 X aが Xbと同一である場合、 同時に Ya が Ybと同一であることはない。 ） (Wherein, R 3 is as defined above, X a and X b are as defined above X, although Y a and Y b have the same meanings as defined above Y, when X a is the same as X b at the same time Y a is never the same as Y b.)
(工程 6)  (Step 6)
化合物 （ I) b_ 2は、 化合物 （ I) b— 1をァセトニトリル、 テトラヒド 口フラン、 エーテル、 ジォキサン、 ジメチルホルムアミド、 クロ口ホルム、 ジ クロロメタン等の不活性溶媒中、 1〜 1 0当量の対応するアルコール、 ァミン， チオール等の付加反応または置換反応により得ることができる。 アルコールと の反応の場合には、 アルコールそのものを溶媒に用いてもよく、 また 1〜； 10 当量の炭酸水素ナトリウム、 炭酸カリウム、 水酸化ナトリウム、 ピリジン、 ト リエチルァミン等の塩基あるいは 0 . 0 0 1〜 1当量のテトラキス （トリフエ ニルホスフィン） パラジウム （o ) 等のパラジウム触媒を加えることによって も反応を促進することができる。 また、 付加反応の場合には、 付加反応終了後、 反応系中に 1〜 1 0当量の硝酸セリウムアンモニゥム、 ニトロソジスルホン酸 カリウム等の酸化剤を添加することによってもキノンへの酸化反応を促進する ことができる。 付加または置換の位置および数は用いる化合物 （ I ) b— 1 および付加または置換するアルコール、 ァミン、 チオールの種類、 さらには反 応温度、 反応時間および用いる塩基の種類により異なる。 反応温度は一 2 0〜 1 5 0 °Cが好ましく、 反応時間は通常 1 0分〜 4 0時間で終了する。 Compound (I) b_2 is compound (I) b-1 with acetonitrile and tetrahydride In an inert solvent such as furan, ether, dioxane, dimethylformamide, chloroform, and dichloromethane, it can be obtained by addition reaction or substitution reaction of 1 to 10 equivalents of the corresponding alcohol, amine, or thiol. In the case of reaction with an alcohol, the alcohol itself may be used as the solvent, and 1 to 10 equivalents of a base such as sodium hydrogencarbonate, potassium carbonate, sodium hydroxide, pyridine, triethylamine, or 0.001. The reaction can also be promoted by adding a palladium catalyst such as ~ 1 equivalent of tetrakis (triphenylphosphine) palladium (o). In addition, in the case of the addition reaction, the oxidation reaction to quinone can also be performed by adding 1 to 10 equivalents of an oxidizing agent such as cerium ammonium nitrate or potassium nitrosodisulfonate to the reaction system after the addition reaction. Can be promoted. The position and number of addition or substitution vary depending on the compound (I) b-1 used and the type of alcohol, amine or thiol to be added or substituted, as well as the reaction temperature, reaction time and the type of base used. The reaction temperature is preferably from 120 to 150 ° C, and the reaction time is usually completed in 10 minutes to 40 hours.
また、 Yが水酸基である化合物 （ I ) b— 2は、 Yがメトキシの化合物 ( I ) b - 1をヨウ化リチウム等を用いた脱メチル化反応によっても合成でき る。  Compound (I) b-2 in which Y is a hydroxyl group can also be synthesized by demethylation of compound (I) b-1 in which Y is methoxy using lithium iodide or the like.
製造法 3 Manufacturing method 3
化合物 （ I ) のうち、 = が単結合であり、 Xが水素原子以外であり、 R 1 および R 2 が同一または異なって低級アルコキシである化合物 （I ) d は Xが水素原子であり、 R 1および R 2が同一または異なって低級アルコキシ である化合物 （ I ) じから、 次の工程によっても製造することができる。 Among the compounds (I), = is a single bond, X is other than a hydrogen atom, and R 1 and R 2 are the same or different and are lower alkoxy, and (I) d is a compound wherein X is a hydrogen atom; Compounds (1) in which 1 and R 2 are the same or different and are lower alkoxy can also be produced by the following steps.
Figure imgf000010_0001
Figure imgf000010_0001
(式中、 X cは、 前記 Xの定義より水素原子を除いた基を表し、 Y、 R la、 R 2aおよび R 3は前記と同義である。 ） (Wherein, X c represents a group obtained by removing a hydrogen atom from the definition of X, and Y, R la , R 2a and R 3 are as defined above. )
(工程 7 )  (Step 7)
化合物 （ I) dは、 化合物 （ I) cをァセトニトリル、 テトラヒドロフラン、 エーテル、 ジォキサン、 ジメチルホルムアミド、 クロ口ホルム、 ジクロロメ夕 ン等の不活性溶媒中、 1〜 1 0当量の式 Xe-H (式中、 Xeは前記と同義であ る。 ） で表されるチオール、 アルコール、 またはァミンの付加反応により得る ことができる。 1〜 10当量の炭酸水素ナトリウム、 炭酸カリウム、 水酸化ナ トリウム、 ピリジン、 トリェチルァミン等の塩基を加えることによつても反応 を促進することもできる。 - 反応温度は一 20〜 1 50 が好ましく、 反応時間 は通常 10分〜 40時間で終了する。 Compound (I) d is Asetonitoriru Compound (I) c, tetrahydrofuran, ether, Jiokisan, dimethylformamide, black hole Holm, an inert solvent such as Jikurorome evening down from 1 to 1 0 equivalents of the formula X e -H ( In the formula, X e has the same meaning as described above, and can be obtained by an addition reaction of a thiol, alcohol, or amine represented by the formula: The reaction can also be promoted by adding 1 to 10 equivalents of a base such as sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, pyridine, and triethylamine. -The reaction temperature is preferably 120 to 150, and the reaction time is usually completed in 10 minutes to 40 hours.
上記製造法における生成物の単離、 精製は、 通常の有機合成で用いられる方 法、 例えば濾過、 抽出、 洗浄、 乾燥、 濃縮、 結晶化、 各種クロマトグラフィー 等を適宜組み合わせて行うことができる。 また、 中間体においては、 特に精製 することなく次の反応に供することも可能である。  The isolation and purification of the product in the above production method can be carried out by appropriately combining methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, and the like. In addition, the intermediate can be subjected to the next reaction without purification.
化合物 （ I) には、 位置異性体、 幾何異性体または光学異性体のような異性 体が存在し得るが、 可能な異性体および該異性体のいかなる比率における混合 物も本発明に包含される。  The compound (I) may have isomers such as positional isomers, geometric isomers or optical isomers, but the possible isomers and mixtures of the isomers in any ratio are also included in the present invention. .
化合物 （ I) の塩を取得したい場合には、 化合物 （I ) の塩が得られる時は そのまま精製すればよく、 また遊離の形で得られる時は適当な溶媒に溶解また は懸濁し、 酸または塩基を加え塩を形成させればよい。  When it is desired to obtain a salt of compound (I), the compound (I) may be purified as it is when the salt of the compound (I) is obtained, or may be dissolved or suspended in an appropriate solvent when the salt of the compound (I) is obtained in a free form. Alternatively, a salt may be formed by adding a base.
また、 化合物 （ I ) またはその薬理的に許容される塩は、 水あるいは各種溶 媒との付加物の形で存在することもあるが、 それら付加物も本発明に包含され る。  Compound (I) or a pharmaceutically acceptable salt thereof may be present in the form of an adduct with water or various solvents, and such adducts are also included in the present invention.
化合物 （ I) の代表例の構造を第 1表に示す。 第 1表 （ 1 ) ：化合物 （I) の具体例 Table 1 shows the structures of typical examples of the compound (I). Table 1 (1): Specific examples of compound (I)
Figure imgf000012_0001
Figure imgf000012_0001
化合物番号 X Y R  Compound number X Y R
H H A  H H A
2 H II B  2 H II B
3 C1 H A  3 C1 H A
4 C1 H B  4 C1 H B
H C1 A  H C1 A
6 H CI B  6 H CI B
C1 CI B  C1 CI B
8 CH3CO II A 8 CH 3 CO II A
9 CH30 H B 9 CH 3 0 HB
131 H CI  131 H CI
CH3 CH 3
W W
：化合物 （I) の具体例 : Specific examples of compound (I)
Figure imgf000013_0001
化合物番 X Y R3 ri H
Figure imgf000013_0001
Compound number XYR 3 ri H
11 CI H A 11 CI H A
12 CI II B12 CI II B
13 H CI A13 H CI A
14 H CI B14 H CI B
15 CI CI B15 CI CI B
16 Br H A16 Br H A
17 Br H B17 Br H B
18 CH2OH H A18 CH 2 OH HA
19 CH(OH)CH3 H A19 CH (OH) CH 3 HA
20 OCH3 H A20 OCH 3 HA
21 OCH2OCH3 H B21 OCH 2 OCH 3 HB
22 H OCH3 A22 H OCH 3 A
23 H OH A23 H OH A
24 H OCH3 B24 H OCH 3 B
25 H OCH2CH3 A25 H OCH 2 CH 3 A
26 H OCH2C02H A26 H OCH 2 C0 2 HA
27 H OCH2CH2SCH3 B27 H OCH 2 CH 2 SCH 3 B
28 H 0(CH2)4OH A28 H 0 (CH 2 ) 4 OH A
29 H OCH2CH2OCH3 A29 H OCH 2 CH 2 OCH 3 A
30 H 0(CH2CH20)2H A30 H 0 (CH 2 CH 2 0) 2 HA
31 H 0(CH2CH20)2H B 第 1表 （3 ) ：化合物 （I) の具体例
Figure imgf000014_0001
31 H 0 (CH 2 CH 2 0) 2 HB Table 1 (3): Specific examples of compound (I)
Figure imgf000014_0001
化合物番号 X Y R3
Figure imgf000014_0002
Compound number XYR 3
Figure imgf000014_0002
56 H NHCH(CH2OH)C02CH3 A 第 1表 (4) 化合物 （I) の具体例
Figure imgf000015_0001
 56 H NHCH (CH 2 OH) C0 2 CH 3 A Table 1 (4) Specific examples of compound (I)
Figure imgf000015_0001
化合物番号 X Y Compound number X Y
Figure imgf000015_0002
化合物 (I)の具体例
Figure imgf000015_0002
Specific examples of compound (I)
Figure imgf000016_0001
化合物番号 X Y R3 =、
Figure imgf000016_0001
Compound number XYR 3 =,
7〜-  7-
Figure imgf000016_0002
Figure imgf000016_0002
83 H B  83 H B
84 H s B 84 H s B
s CH3 s CH 3
ヽ  ヽ
N-N  N-N
85 H 。J[ \\ B  85H. J [\\ B
"\ 2 第 1表 (6) 化合物 (I)の具体例 "\ 2 Table 1 (6) Specific examples of compound (I)
Figure imgf000017_0001
化合物番号 X Y
Figure imgf000017_0001
Compound number XY
Figure imgf000017_0002
Figure imgf000017_0002
95 H  95 H
NH2 NH 2
96 H 96 H
HO,C 第 1表 （7 ) ：化合物 （I) の具体 HO, C Table 1 (7): Specifics of compound (I)
Figure imgf000018_0001
Figure imgf000018_0001
化合物番号 X YCompound number X Y
97 S H 97 S H
Figure imgf000018_0002
Figure imgf000018_0002
101 H  101 H
-NHCOCH,  -NHCOCH,
102 OH H  102 OH H
Figure imgf000018_0003
Figure imgf000018_0003
106 s- H 106 s-H
107 H 化合物 （I) の具体例
Figure imgf000019_0001
化合物番号 X Y 107 H Specific examples of compound (I)
Figure imgf000019_0001
Compound number XY
108 S- F H  108 S- F H
Figure imgf000019_0002
第 1表 （9 ) ：化合物 （I) の具体例
Figure imgf000019_0002
Table 1 (9): Specific examples of compound (I)
Figure imgf000020_0001
Figure imgf000020_0001
γ YL口  γ YL mouth
116 SCH2C02H H116 SCH 2 C0 2 HH
117 SCII2CO2CH3 H117 SCII2CO2CH3 H
118 SCH2C02CH2CH3 H118 SCH 2 C0 2 CH 2 CH 3 H
119 SCH2C02CH2CH3 CI119 SCH 2 C0 2 CH 2 CH 3 CI
120 SCH2CH3 CI120 SCH 2 CH 3 CI
121 SCII2CH2OH H121 SCII 2 CH 2 OH H
122 SCII2CH2OH CI122 SCII 2 CH 2 OH CI
123 SCH2CII2SH II123 SCH2CII2SH II
124 SCH2CH(OH)CH2OH H124 SCH 2 CH (OH) CH 2 OH H
125 SCH2CH2C02H H125 SCH 2 CH 2 C0 2 HH
126 SCH2CH2C02CH2CH3 H126 SCH 2 CH 2 C0 2 CH 2 CH 3 H
127 SCII2CH2NH2 H127 SCII 2 CH 2 NH 2 H
128 SCH2CH2N(CH3)2 H128 SCH 2 CH 2 N (CH 3 ) 2 H
129 SCII2CH3 H129 SCII2CH3 H
130 CI （10) ：化合物 Iの 130 CI (10): Compound I
Figure imgf000021_0001
Figure imgf000021_0001
化合物番号 X Y Compound number X Y
132 H C1 c 133 H SCH2CH2Si(CH3)3 B 134 SCH2CH2Si(CH3)3 SCH2CH2Si(CH3)3 B 135 H SCH2C02CH3 B
Figure imgf000021_0002
132 H C1 c 133 H SCH 2 CH 2 Si (CH 3 ) 3 B 134 SCH 2 CH 2 Si (CH 3 ) 3 SCH 2 CH 2 Si (CH 3 ) 3 B 135 H SCH 2 C0 2 CH 3 B
Figure imgf000021_0002
137 H S'  137 H S '
Figure imgf000021_0003
Figure imgf000021_0003
144 H S- HCOCH3 B 第 1表 (11) 化合物 (I)の具体例 144 H S- HCOCH3 B Table 1 (11) Specific examples of compound (I)
o  o
X、 义 ,  X, 义,
、0- -0  , 0- -0
化合物番号 X Y Compound number X Y
145 H 145 H
S- F  SCIENCE FICTION
146 H S CI 146 H S CI
Figure imgf000022_0001
Figure imgf000022_0001
149 H δ / Br 149 H δ / Br
Figure imgf000022_0002
Figure imgf000022_0002
化合物 （ I V) の製造法および物性値を参考例に示した。 参考例中の化合物 の構造および化合物番号を第 2表に示す。 98/17629 The production method and physical properties of compound (IV) are shown in Reference Examples. Table 2 shows the structures and compound numbers of the compounds in Reference Examples. 98/17629
第 2表：参考例中の化合物の構造Table 2: Structures of compounds in Reference Examples
Figure imgf000023_0001
U 物番号 X Y R9 R:
Figure imgf000023_0001
U Object number XYR 9 R :
a H H H B  a H H H B
b H H CH3 A b HH CH 3 A
C H H CH3 B CHH CH 3 B
d CI H H A  d CI H H A
e CI H II B  e CI H II B
f CI H CH3 A f CI H CH 3 A
8 CI H CH3 B 8 CI H CH 3 B
h H CI CH3 A h H CI CH 3 A
H CI CH3 B j CI CI CH3 B H CI CH 3 B j CI CI CH 3 B
k Br H H A  k Br H H A
m Br H H B  m Br H H B
n CH(OH)CH3 H H A n CH (OH) CH 3 HHA
P COCFI3 II CH3 A P COCFI 3 II CH 3 A
q CH2OH H H A q CH 2 OH HHA
r H CH3 B r H CH 3 B
s OCH2OCH3 II CH2OCH3 B s OCH 2 OCH 3 II CH 2 OCH 3 B
t H CI CH3 t H CI CH 3
へ O-" " CH, 次に、 化合物 （ I ) の薬理活性について試験例で説明する。  Next, the pharmacological activity of compound (I) will be described in Test Examples.
試験例 1 ： フアルネシルトランスフェラ一ゼ阻害活性 Test Example 1: Inhibitory activity of fuarnesyltransferase
フアルネシルトランスフェラ一ゼ （FTase) は、 牛の脳を破砕して得られた 抽出液を DEAE-セファセル (Sephacel) [フアルマシア社製] カラムクロマトグ ラフィ一にかけ、 その活性画分を限外濾過で濃縮し、 透析 [20mM トリス塩酸 (Tris-HCl) pH8.0、 50mM塩化ナトリウム (NaCl)、 20mM塩化亜鉛 (ZnCl2)、 ImM ジチオスレィ トール （DTT) および 0.2mMフエ二ルメチルスルホニルフルォ ライド （PMSF) ] したものを粗酵素液として用いた。 活性測定は、 上記の方 法で得た酵素が、 [3 H ] フアルネシルピロリン酸を大腸菌で生産した Ras蛋 白に転移する量を測定することにより行った。 酵素阻害活性に関しては、 上記 の反応系を用いて、 テストサンプルによる Ras蛋白へのフアルネシル化阻害を 測定した。 非処理群と既知濃度の検体で処理した群の酵素阻害活性を比較する ことにより、 検体濃度 （11.1 β Μ, 3.7 L M) でのフアルネシル化の阻害活性 (% ) を算出した。 The extract obtained by crushing bovine brain is applied to DEAE-Sephacel (manufactured by Pharmacia) column chromatography, and the active fraction is subjected to ultrafiltration. [20 mM Tris-HCl (pH 8.0), 50 mM sodium chloride (NaCl), 20 mM zinc chloride (ZnCl 2 ), ImM dithiothreitol (DTT) and 0.2 mM phenylmethylsulfonyl fluoride (PMSF)] was used as a crude enzyme solution. Activity measurement is as above The measurement was carried out by measuring the amount of the enzyme obtained by the method, which transfers [ 3 H] pharynesyl pyrophosphate to Ras protein produced in Escherichia coli. Regarding the enzyme inhibitory activity, inhibition of pharmacosylation to Ras protein by a test sample was measured using the above reaction system. By comparing the enzyme inhibitory activities of the untreated group and the group treated with a sample of known concentration, the inhibitory activity (%) of pharmacosylation at the sample concentration (11.1 βΜ, 3.7 LM) was calculated.
結果を第 3表に示す。  Table 3 shows the results.
第 3表 （ 1 ) ： フアルネシルトランスフェラーゼ阻害活性 化合物番号 フアルネシルトランスフ cラーゼ （阻害％) Table 3 (1): Inhibitory activity of pharmacosyltransferase Compound No. pharmacosyltransferase (% inhibition)
11.1 μΜ 3.7 μΜ  11.1 μΜ 3.7 μΜ
4 48 21  4 48 21
10 60 18  10 60 18
11 58 20  11 58 20
14 90 52  14 90 52
15 98 81  15 98 81
17 100 73  17 100 73
20 31 8  20 31 8
24 55 53  24 55 53
31 80 68  31 80 68
33 100 100  33 100 100
35 100 99  35 100 99
65 48 2  65 48 2
69 99 90  69 99 90
70 99 96  70 99 96
71 98 90  71 98 90
73 94 87  73 94 87
75 98 83  75 98 83
83 97 93  83 97 93
93 96 76  93 96 76
94 100 77  94 100 77
96 92 47 第 3表 （2 ) ： フアルネシルトランスフェラーゼ阻害活性 化合物番号 フアルネシルトランスフェラ一ゼ （阻害％) 96 92 47 Table 3 (2): Inhibitory activity of pharmacosyltransferase Compound No. Calcium pharmacophorase (% inhibition)
11.1 μΜ 3.7 μΜ  11.1 μΜ 3.7 μΜ
130 72 52  130 72 52
132 94 44  132 94 44
133 78 78  133 78 78
135 91 53  135 91 53
137 91 91  137 91 91
138 87 57  138 87 57
139 99 73  139 99 73
140 92 67  140 92 67
141 91 62  141 91 62
142 89 59  142 89 59
143 91 54  143 91 54
144 97 94  144 97 94
145 99 76  145 99 76
146 98 76  146 98 76
147 99 66  147 99 66
148 100 78  148 100 78
149 100 90  149 100 90
150 98 68  150 98 68
151 98 80 試験例 2 ：細胞増殖抑制活性  151 98 80 Test example 2: Cell proliferation inhibitory activity
細胞増殖抑制活性は、 発癌遺伝子 v-H-rasで形質転換した 3Y1-B細胞 （以下、 HR-3Y1細胞という） を用いて測定した。 96穴マイクロ夕イタ一プレートの各 穴に、 10%牛胎児血清を含む DMEM培地 [ニッスィ] (以下、 培地 Aとい う） で 1.0 X 104個/ mlに調整した HR-3Y1細胞を 0.1mlずつ分注した。 該プレ ートを炭酸ガスインキュベーター内で 37°C、 24時間培養後、 これに培地 Aに より適宜希釈した検体 （試験化合物） 50mlずつを加え、 さらに炭酸ガスイン キュベ一夕一内で 37°C、 72時間培養した。 培養上清を除去後、 培地 Aで lmg /mlに希釈した 3-(4，5-ジメチルチアゾ一ル -2-ィル) -2,5-ジフエ二ルテトラゾリ ゥムブロミド（MTT)[Sigma]を 50ml添加し、 インキュベーター内に 5時間静置 した。 ジメチルスルフォキシド [関東化学] を 150ml添加し細胞を完全に溶 解させた後、 マイクロプレートリーダ一により 550nmの吸光度を測定した。 無処理細胞と既知濃度の検体で処理した細胞の吸光度を比較することにより 細胞の増殖を 50%阻害する検体濃度 (IC50)を算出した。 Cytostatic activity was measured using 3Y1-B cells (hereinafter, HR-3Y1 cells) transformed with the oncogene vH-ras. To each well of a 96-well micro evening Ita first plate, DMEM medium containing 10% fetal bovine serum [Nissui] (hereinafter, the medium will leave A) 1.0 X 10 4 cells in / ml of HR-3Y1 cells adjusted to 0.1ml Was dispensed. After culturing the plate in a carbon dioxide gas incubator at 37 ° C for 24 hours, add 50 ml of a sample (test compound) appropriately diluted with medium A, and further add the plate at 37 ° C in a carbon dioxide gas incubator overnight. And cultured for 72 hours. After removing the culture supernatant, add 50 ml of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolidine bromide (MTT) [Sigma] diluted to 1 mg / ml with medium A. Then, it was left still in the incubator for 5 hours. After adding 150 ml of dimethyl sulfoxide [Kanto Chemical] to completely dissolve the cells, the absorbance at 550 nm was measured using a microplate reader. By comparing the absorbance of untreated cells and cells treated with a sample of known concentration, the concentration of the sample that inhibits cell growth by 50% (IC 50 ) was calculated.
結果を第 4表に示す。 第 4表：細胞増殖抑制活性  The results are shown in Table 4. Table 4: Cell proliferation inhibitory activity
化合物番号 細胞增殛抑制活性 （HR3Y1細胞)  Compound No. Cytotoxic activity (HR3Y1 cells)
(IC50； μΜ) (IC 50 ; μΜ)
1 2.2  1 2.2
3 2.1  3 2.1
4 0.14  4 0.14
10 3.3  10 3.3
20 5.6  20 5.6
22 5.4  22 5.4
25 6.3  25 6.3
31 5.3  31 5.3
32 9.1  32 9.1
33 4.1  33 4.1
34 5.6  34 5.6
35 4.5  35 4.5
50 2.8  50 2.8
55 6.6  55 6.6
58 0.8  58 0.8
60 4.6  60 4.6
65 0.43  65 0.43
66 0.67  66 0.67
70 6.4 化合物 （ I ) またはそれらの薬理的に許容される塩は、 そのままあるいは各 種の医薬組成物として経口的または非経口的に投与される。 このような医薬組 成物の剤形としては、 例えば錠剤、 丸薬、 散剤、 顆粒剤、 カプセル剤、 坐剤、 注射剤、 点滴剤等が挙げられる。  70 6.4 Compound (I) or a pharmaceutically acceptable salt thereof may be administered as it is or orally or parenterally as various pharmaceutical compositions. Examples of the dosage form of such a pharmaceutical composition include tablets, pills, powders, granules, capsules, suppositories, injections, and drops.
上記剤形の製剤化には、 通常の方法が適用され、 例えば各種の賦形剤、 潤滑 剤、 結合剤、 崩壊剤、 懸濁化剤、 等張化剤、 乳化剤、 吸収促進剤等を含有して いてもよい。 医薬組成物に使用される担体としては、 例えば水、 注射用蒸留水、 生理食塩 水、 グルコース、 フラクト一ス、 白糖、 マンニット、 ラクト一ス、 澱粉、 コー ン *スターチ、 セルロース、 メチルセルロース、 カルボキシメチルセルロース、 ヒドロキシプロピルセルロース、 アルギン酸、 タルク、 クェン酸ナトリウム、 炭酸カルシウム、 リン酸水素カルシウム、 ステアリン酸マグネシウム、 尿素、 シリコーン樹脂、 ソルビ夕ン脂肪酸エステル、 グリセリン脂肪酸エステル等が 挙げられ、 これらは製剤の種類に応じて適宜選択される。 The usual methods are applied for formulating the above dosage forms, for example, containing various excipients, lubricants, binders, disintegrants, suspending agents, isotonic agents, emulsifiers, absorption promoters, etc. It may be. Carriers used in pharmaceutical compositions include, for example, water, distilled water for injection, physiological saline, glucose, fructoses, sucrose, mannitol, lactose, starch, corn * starch, cellulose, methylcellulose, carboxy Methylcellulose, hydroxypropylcellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogen phosphate, magnesium stearate, urea, silicone resin, sorbitol fatty acid ester, glycerin fatty acid ester, etc. Is appropriately selected according to the conditions.
投与量および投与回数は、 目的とする治療効果、 投与方法、 治療期間、 年齢、 体重等により異なるが、 経口もしくは非経口 （例えば、 注射、 点滴、 座剤によ る直腸投与、 皮膚貼付等） 的投与方法により、 通常成人 1 日当り 0.01〜200mg /kgである。  The dosage and frequency of administration vary depending on the desired therapeutic effect, administration method, treatment period, age, body weight, etc., but oral or parenteral (eg, injection, infusion, rectal administration by suppository, skin patch, etc.) It is usually 0.01 to 200 mg / kg per adult, depending on the method of administration.
以下に、 本発明の実施例および参考例を示す。  Hereinafter, examples and reference examples of the present invention will be described.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
以下の実施例および参考例において、 通常の後処理とは下記の反応後処理を 表す。  In the following Examples and Reference Examples, ordinary post-treatment means the following post-reaction treatment.
各工程の反応終了後、 必要に応じて反応液に水、 酸、 緩衝液等を加え、 酢酸 エヂル、 クロ口ホルム、 エーテル等の非水溶性溶媒で抽出する。 抽出液は水、 食塩水等で洗浄後、 無水硫酸ナトリウム等で乾燥し、 溶媒留去する。  After completion of the reaction in each step, if necessary, add water, acid, buffer, etc. to the reaction solution, and extract with a non-aqueous solvent such as ethyl acetate, chloroform, and ether. The extract is washed with water, saline, etc., dried over anhydrous sodium sulfate, etc., and the solvent is distilled off.
実施例 1 ： N-(6，6-ジメトキシ -3-ォキソシクロへキサ -1,4-ジェニル) -3,7,11-ト リメチル -2,6,10-ドデカトリェンアミド （化合物 1 ) Example 1: N- (6,6-dimethoxy-3-oxocyclohexa-1,4-genenyl) -3,7,11-trimethyl-2,6,10-dodecatrienamide (Compound 1)
参考例 2で得られる化合物 bの 766mg(2.1mmol)をメタノール 10mlに溶解し、 ョードベンゼン二酢酸 904mg(2.1mmol)をメタノール 10mlに溶解して加え、 室温で 2時間攪拌した。 通常の後処理後、 残渣をシリカゲルカラムクロマトグ ラフィ一 [へキサン/酢酸ェチル = 70 / 30 (v/v)] で精製し、 化合物 1を 609 mg(76%) 得た。  766 mg (2.1 mmol) of the compound b obtained in Reference Example 2 was dissolved in 10 ml of methanol, 904 mg (2.1 mmol) of benzenebenzeneacetic acid was dissolved in 10 ml of methanol, and the mixture was stirred at room temperature for 2 hours. After usual post-treatment, the residue was purified by silica gel column chromatography [hexane / ethyl acetate = 70/30 (v / v)] to obtain 609 mg (76%) of compound 1.
1H NMR (500MHz, CDC13) δ ppm ； 7.45 (d, J=2.1Hz, IH), 7.32 (br s， 1H)， 6. 52 (d, J=10.4Hz, IH), 6.43 (dd, J=10.4 2.1Hz, IH), 5.69 (d, J=l.lHz, IH), 5.1 0-5.07 (m, 2H), 3.26 (s, 6H), 2.22 (d, J=1.3Hz, 3H), 2.21-2.18 (m, 4H), 2.10-1. 97 (m, 4H)， 1.68 (d, J=1.2Hz， 3H), 1.62 (d, J=l.lHz, 3H), 1.60 (br s, 3H) FABMS m/z; 388 (M+H)+ 1H NMR (500MHz, CDC1 3) δ ppm; 7.45 (d, J = 2.1Hz, IH), 7.32 (br s, 1H), 6. 52 (d, J = 10.4Hz, IH), 6.43 (dd, J = 10.4 2.1Hz, IH), 5.69 (d, J = l.lHz, IH), 5.1 0-5.07 (m, 2H), 3.26 (s, 6H), 2.22 (d, J = 1.3Hz, 3H), 2.21-2.18 (m, 4H), 2.10-1.97 (m, 4H), 1.68 ( d, J = 1.2Hz, 3H), 1.62 (d, J = l.lHz, 3H), 1.60 (br s, 3H) FABMS m / z; 388 (M + H) +
実施例 2 ： N-(6，6-ジメトキシ -3-ォキソシクロへキサ -1，4-ジェニル) -4-ベンジ ルォキシフエノキシァセトアミド （化合物 2 ) Example 2: N- (6,6-dimethoxy-3-oxocyclohexa-1,4-genenyl) -4-benzyloxyphenoxyacetamide (Compound 2)
実施例 1と同様の方法を用いて、 参考例 3で得られる化合物 cの 139.1mg(0. 35mmol)とョードベンゼン二酢酸 170.9mg(0.53mmol)より、 化合物 2を 175.6mg (47%)得た。  Using the same method as in Example 1, 175.6 mg (47%) of compound 2 was obtained from 139.1 mg (0.35 mmol) of compound c obtained in Reference Example 3 and 170.9 mg (0.53 mmol) of eodobenzenediacetate. .
1H NMR (400MHz, CDC13) δ ppm ； 8.58 (br s, 1H)， 7.42-7.30 (m， 6H), 6.99-6. 88 (m, 4H)， 6.59-6.56 (m, IH), 6.44 (m， IH), 5.03 (s, 2H), 4.56 (s, 2H), 3.19 1H NMR (400MHz, CDC1 3) δ ppm;. 8.58 (br s, 1H), 7.42-7.30 (m, 6H), 6.99-6 88 (m, 4H), 6.59-6.56 (m, IH), 6.44 ( m, IH), 5.03 (s, 2H), 4.56 (s, 2H), 3.19
(s, 6H) (s, 6H)
FABMS m/z ； 410(M+H)+ FABMS m / z; 410 (M + H) +
実施例 3 ： N-(5-クロ口- 6,6-ジメトキシ -3-ォキソシクロへキサ -1，4-ジェニル) - 3,7,11-トリメチル -2,6,10-ドデカトリェンアミド (化合物 3 ) Example 3: N- (5-chloro-6,6-dimethoxy-3-oxocyclohexa-1,4-genenyl) -3,7,11-trimethyl-2,6,10-dodecatrienamide ( Compound 3)
実施例 1と同様の方法を用いて、 参考例 6で得られる化合物 f の 47mg(0.12 mmol)と、 ョードベンゼン二酢酸 41mg(0.128mmol)より、 化合物 3を 21mg(4 2%)得た。  Using a method similar to that in Example 1, 21 mg (42%) of compound 3 was obtained from 47 mg (0.12 mmol) of compound f obtained in Reference Example 6 and 41 mg (0.128 mmol) of p-benzenediacetic acid.
1H NMR (400MHz, CDC13) δ ppm ； 7.56 (d， J=2.0Hz, H)， 7.39 (br s, IH), 6.6 8 (d, J=2.0Hz, IH), 5.70 (br s， IH), 5.09-5.06 (m， 2H), 3.22 (s, 6H)， 2.23 (d, J=1.2Hz, 3H), 2.20 (m, 4H), 2.13-2.04 (m, 4H), 1.68 (d, J=1.0Hz, 3H), 1.62 (d, 1H NMR (400MHz, CDC1 3) δ ppm; 7.56 (d, J = 2.0Hz, H), 7.39 (br s, IH), 6.6 8 (d, J = 2.0Hz, IH), 5.70 (br s, IH ), 5.09-5.06 (m, 2H), 3.22 (s, 6H), 2.23 (d, J = 1.2Hz, 3H), 2.20 (m, 4H), 2.13-2.04 (m, 4H), 1.68 (d, J = 1.0Hz, 3H), 1.62 (d,
J=1.2Hz, 3H), 1.60 (br s， 3H) J = 1.2Hz, 3H), 1.60 (br s, 3H)
FABMS m/z ； 422 (M+H)+ FABMS m / z; 422 (M + H) +
実施例 4 ： N-(5-クロ口- 6，6-ジメトキシ -3-ォキソシクロへキサ -1,4-ジェニ ル )_4-ベンジルォキシフエノキシァセトアミド （化合物 4 ) Example 4: N- (5-chloro-6,6-dimethoxy-3-oxocyclohexa-1,4-genyl) _4-benzyloxyphenoxyacetamide (compound 4)
実施例 1と同様の方法を用いて、 参考例 7で得られる化合物 gの 523mg(1.2 mmol)とビス（トリフルォロァセトキシ）ョ一ドベンゼン 401mg(1.2mmol)より、 化合物 4を 324mg(60%)得た。 ぐN：：寸.：,.----- -- .- Using the same method as in Example 1, 324 mg (60 mmol) of Compound 4 was obtained from 523 mg (1.2 mmol) of Compound g obtained in Reference Example 7 and 401 mg (1.2 mmol) of bis (trifluoroacetoxy) chlorobenzene. %)Obtained. N :: Dimensions ::, .------.-
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£LS£0/L6dr/∑Dd 6Z9 /86 OAV 溶解し、 p-トルエンスルホン酸一水和物 0.57g (3.00mmol)を加え、 25分間加熱 還流した。 室温まで冷却し、 通常の後処理後、 残渣をシリカゲルカラムクロマ トグラフィ一 [へキサンノ酢酸ェチル = 90 I 10 (v/v)] で精製し、 化合物 1£ LS £ 0 / L6dr / ∑Dd 6Z9 / 86 OAV After dissolution, 0.57 g (3.00 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was heated under reflux for 25 minutes. After cooling to room temperature and usual post-treatment, the residue was purified by silica gel column chromatography [ethyl ethyl hexanoacetate = 90 I 10 (v / v)] to give Compound 1.
3を 1.51g (95%)得た。 1.51 g (95%) of 3 were obtained.
1H NMR (500MHz, CDC13) δ ppm ； 7.92 (br s, 1H)， 7.78 (s, 1H), 6.99 (s, 1H), 5.75 (d, J=1.0Hz, 1H), 5.10-5.06 (m， 2H), 2.23 (d, J=1.2Hz， 3H), 2.22-2.20 (m, 4H), 2.07-1.98 (m, 4H), 1.67 (d, J=1.0Hz, 3H), 1.62 (d, J=1.0Hz， 3H), 1.5 9 (d, J=0.5Hz， 3H) 1H NMR (500MHz, CDC1 3) δ ppm; 7.92 (br s, 1H), 7.78 (s, 1H), 6.99 (s, 1H), 5.75 (d, J = 1.0Hz, 1H), 5.10-5.06 (m , 2H), 2.23 (d, J = 1.2Hz, 3H), 2.22-2.20 (m, 4H), 2.07-1.98 (m, 4H), 1.67 (d, J = 1.0Hz, 3H), 1.62 (d, (J = 1.0Hz, 3H), 1.59 (d, J = 0.5Hz, 3H)
FABMS m/z ； 378 (M+3H)+ FABMS m / z; 378 (M + 3H) +
実施例 1 4 ： N-(4-ク口口- 3,6-ジォキソシクロへキサ -1，4-ジェニル) -4-ベンジ ルォキシフエノキシァセトアミド （化合物 1 4 ) Example 14: N- (4-co-mouth-3,6-dioxocyclohexa-1,4-genyl) -4-benzyloxyphenoxyacetamide (compound 14)
実施例 1 3と同様の方法を用いて、 実施例 6で得られる化合物 6の 1.37gを テトラヒドロフラン 50mlに溶解し、 P-トルエンスルホン酸一水和物 418mg(2.2 mmol)と、 3 Nの塩酸 15mlを加え、 室温で 6時間攪拌した。 通常の後処理後、 クロ口ホルム-メタノール-へキサンより再結晶し、 化合物 1 4を 1.13g (92%) 得た。  Using the same method as in Example 13, 1.37 g of compound 6 obtained in Example 6 was dissolved in 50 ml of tetrahydrofuran, and 418 mg (2.2 mmol) of P-toluenesulfonic acid monohydrate and 3N hydrochloric acid 15 ml was added, and the mixture was stirred at room temperature for 6 hours. After usual post-treatment, recrystallization from chloroform-methanol-hexane gave 1.13 g (92%) of compound 14.
1H NMR (400MHz, CDC13) δ ppm ； 9.29 (br s， 1H), 7.80 (s, 1H), 7.43-7.30 (m， 5H)， 7.03 (s, 1H)， 6.97-6.91 (m, 4H), 5.03 (s, 2H), 4.58 (s, 2H) 1H NMR (400MHz, CDC1 3) δ ppm; 9.29 (br s, 1H), 7.80 (s, 1H), 7.43-7.30 (m, 5H), 7.03 (s, 1H), 6.97-6.91 (m, 4H) , 5.03 (s, 2H), 4.58 (s, 2H)
FABMS m/z ； 400 (M+3H)+ FABMS m / z; 400 (M + 3H) +
実施例 1 5 ： N-(4,5-ジクロロ- 3,6-ジォキソシクロへキサ -1,4-ジェニル) -4-ベ ンジルォキシフエノキシァセトアミド （化合物 1 5 ) Example 15: N- (4,5-dichloro-3,6-dioxocyclohexa-1,4-genenyl) -4-benzyloxyphenoxyacetamide (Compound 15)
実施例 1 0と同様の方法を用いて、 参考例 1 0で得られる化合物 jの 104mg (0.23mmol)とビス（トリフルォロアセトキシ）ョードベンゼン 198mg(0.46mmol) より、 化合物 1 5を 60mg(61%)得た。  Using the same method as in Example 10, 60 mg (61 mg) of compound 15 was obtained from 104 mg (0.23 mmol) of compound j obtained in Reference Example 10 and 198 mg (0.46 mmol) of bis (trifluoroacetoxy) odobenzene. %)Obtained.
1H NMR (400MHz, CDC13) δ ppm ； 9.39 (br s， 1H), 7.84 (s， 1H), 7.43-7.30 (m, 5H)， 6.99-6.90 (m， 4H), 5.03 (s, 2H), 4.60 (s, 2H) 1H NMR (400MHz, CDC1 3) δ ppm; 9.39 (br s, 1H), 7.84 (s, 1H), 7.43-7.30 (m, 5H), 6.99-6.90 (m, 4H), 5.03 (s, 2H) , 4.60 (s, 2H)
FABMS m/z ； 432 (M+H)+ 実施例 1 6 ： N-(5-ブロモ -3,6-ジォキソシクロへキサ -1,4-ジェニル) -3,7,11- トリメチル -2,6,10-ドデカトリェンアミド （化合物 1 6 ) FABMS m / z; 432 (M + H) + Example 16: N- (5-bromo-3,6-dioxocyclohexa-1,4-genenyl) -3,7,11-trimethyl-2,6,10-dodecatrienamide (compound 16)
実施例 1 0と同様の方法を用いて、 参考例 1 1で得られる化合物 kの 156mg (0.357mmol)とビス（トリフルォロアセトキシ）ョードベンゼン 162mg(0.38mmol) より、 化合物 1 6を 57mg(38%)得た。  Using the same method as in Example 10, 57 mg (38 mg) of compound 16 was obtained from 156 mg (0.357 mmol) of compound k obtained in Reference Example 11 and 162 mg (0.38 mmol) of bis (trifluoroacetoxy) odobenzene. %)Obtained.
1H NMR (400MHz, CDC13) δ ppm ； 7.97 (br s, IH), 7.70 (d， J=2.4Hz, IH), 7.22 (d, J=2.4Hz, IH), 5.75 (d， J=1.0Hz， IH), 5.10-5.06 (m， 2H), 2.23-1.97 (m, 1H NMR (400MHz, CDC1 3) δ ppm; 7.97 (br s, IH), 7.70 (d, J = 2.4Hz, IH), 7.22 (d, J = 2.4Hz, IH), 5.75 (d, J = 1.0 Hz, IH), 5.10-5.06 (m, 2H), 2.23-1.97 (m,
11H), 1.68 (d， J=1.0Hz, 3H)， 1.62 (d, J=1.2Hz, 3H)， 1.60 (d， J=0.7Hz, 3H) FABMS m/z ； 422 (M+3H)+ 11H), 1.68 (d, J = 1.0Hz, 3H), 1.62 (d, J = 1.2Hz, 3H), 1.60 (d, J = 0.7Hz, 3H) FABMS m / z; 422 (M + 3H) +
実施例 1 7 ： N-(5-ブロモ -3,6-ジォキソシクロへキサ -1,4-ジェニル) -4-ベンジ ルォキシフエノキシァセトアミド （化合物 1 7 ) Example 17: N- (5-bromo-3,6-dioxocyclohexa-1,4-genenyl) -4-benzyloxyphenoxyacetamide (compound 17)
実施例 1 0と同様の方法を用いて、 参考例 1 2で得られる化合物 mの 126mg (0.27mmol)とビス（トリフルォロアセトキシ）ョードベンゼン 118mg(0.27mmol) より、 化合物 1 7を 88mg(72%)得た。  Using a method similar to that of Example 10, 88 mg (72 mg) of compound 17 was obtained from 126 mg (0.27 mmol) of compound m obtained in Reference Example 12 and 118 mg (0.27 mmol) of bis (trifluoroacetoxy) odobenzene. %)Obtained.
1H NMR (500MHz, CDCI3) δ ppm ； 9.36 (br s, IH), 7.71 (d, J=2.4Hz, 1H)， 7. 43-7.29 (m， 5H), 7.26 (d, J=2.4Hz, IH), 6.95-6.92 (m, 4H)， 5.03 (s, 2H), 4.59 (s, 2H)  1H NMR (500 MHz, CDCI3) δ ppm; 9.36 (br s, IH), 7.71 (d, J = 2.4 Hz, 1H), 7.43-7.29 (m, 5H), 7.26 (d, J = 2.4 Hz, IH), 6.95-6.92 (m, 4H), 5.03 (s, 2H), 4.59 (s, 2H)
FABMS m/z ； 443 (M+2H)+  FABMS m / z; 443 (M + 2H) +
実施例 1 8 ： N-(5-ヒドロキシメチル -3,6-ジォキソシクロへキサ -1,4-ジェニ ル) -3，7，11-トリメチル -2,6,10-ドデカトリェンアミド （化合物 1 8 ) Example 18: N- (5-hydroxymethyl-3,6-dioxocyclohexa-1,4-genenyl) -3,7,11-trimethyl-2,6,10-dodecatrienamide (Compound 1 8)
実施例 1 0と同様の方法を用いて、 参考例 1 5で得られる化合物 Qの 489mg (1.3mmol)とビス（トリフルォロアセトキシ）ョードベンゼン 666mg(1.5rnmol)よ り、 化合物 1 8を 209mg(45%)得た。 Using the same method as in Example 10, 209 mg of compound 18 was obtained from 489 mg (1.3 mmol) of compound Q obtained in Reference Example 15 and 666 mg (1.5 rnmol) of bis (trifluoroacetoxy) odobenzene. (45%).
1H NMR (500MHz, CDCI3) δ ppm ； 7.92 (br s, IH), 7.62 (d, J=2.5Hz, 1H)， 6. 76 (dd, J=4.2, 1.9Hz, 1H)， 5.75 (d, J=0.8Hz, IH), 5.08 (m, 2H)， 4.56 (br s, 2 H)， 2.22 (d, J=1.2Hz, 3H), 2.21 (m, 4H), 2.08-1.98 (m, 4H)， 1.67 (d, J=l.lHz, 3H), 1.62 (d, J=1.0Hz, 3H), 1.59 (s, 3H) 6Z9卜 Ϊ/ OAV一 1H NMR (500 MHz, CDCI3) δ ppm; 7.92 (br s, IH), 7.62 (d, J = 2.5 Hz, 1H), 6.76 (dd, J = 4.2, 1.9 Hz, 1H), 5.75 (d, J = 0.8Hz, IH), 5.08 (m, 2H), 4.56 (br s, 2H), 2.22 (d, J = 1.2Hz, 3H), 2.21 (m, 4H), 2.08-1.98 (m, 4H ), 1.67 (d, J = l.lHz, 3H), 1.62 (d, J = 1.0Hz, 3H), 1.59 (s, 3H) 6Z9 Ϊ / OAV one
Figure imgf000034_0001
Figure imgf000034_0001
Qo9 ΐ 9Uοョ日I $ヽ ν ()9一dl s ml(l.Ommol)とョードベンゼン二酢酸 252mg(0.783mmol)を塩化メチレン 3ml溶 解したものを加え、 5時間加熱還流した。 通常の後処理の後、 薄層クロマトグ ラフィ一 [トルエン Z酢酸ェチル = 80 / 20 (v/v)] で精製し、 化合物 2 1を 1 5.5mg(14%)得た。 Qo9 ΐ 9Uο Day I $ ヽ ν () 9 dl s ml (l.O mmol) and 252 mg (0.783 mmol) of odobenzene diacetate dissolved in 3 ml of methylene chloride were added, and the mixture was heated under reflux for 5 hours. After usual post-treatment, purification was performed using thin-layer chromatography [toluene Z-ethyl acetate = 80/20 (v / v)] to obtain 15.5 mg (14%) of compound 21.
1H NMR (400MHz, CDC13) 6 ppm ； 9.29 (br s, IH), 7.56 (d, J=2.4Hz, IH), 7. 43-7.32 (m, 5H)， 6.96-6.91 (m, 4H), 6.19 (d, J=2.4Hz, IH), 5.22 (s, 2H), 5.03, 1H NMR (400MHz, CDC1 3) 6 ppm; 9.29 (br s, IH), 7.56 (d, J = 2.4Hz, IH), 7. 43-7.32 (m, 5H), 6.96-6.91 (m, 4H) , 6.19 (d, J = 2.4Hz, IH), 5.22 (s, 2H), 5.03,
(s, 2H)， 4.58 (s, 2H), 3.50 (s, 3H) (s, 2H), 4.58 (s, 2H), 3.50 (s, 3H)
FABMS m/z ； 424 (M+H)+ FABMS m / z; 424 (M + H) +
実施例 2 2 ： N-(4-メトキシ -3,6-ジォキソシクロへキサ -1,4-ジェニル) -3,7,11- トリメチル -2,6，10-ドデカトリェンアミド （化合物 2 2 ) Example 22: N- (4-methoxy-3,6-dioxocyclohexa-1,4-genenyl) -3,7,11-trimethyl-2,6,10-dodecatrienamide (compound 22)
実施例 1 3で得られる化合物 1 3の 5.4mg(0.014mmol)をテトラヒドロフラ ン 5mlとメタノール 5mlの混合溶媒に溶解し、 1規定の炭酸水素ナトリウム 水溶液 0.1mlを加え、 10分間加熱還流した。 通常の後処理の後、 薄層クロマ トグラフィ一 [へキサン/酢酸ェチル = 70 I 30 (v/v)] で精製し、 化合物 2 2を 2.2mg(41%)得た。  5.4 mg (0.014 mmol) of the compound 13 obtained in Example 13 was dissolved in a mixed solvent of 5 ml of tetrahydrofuran and 5 ml of methanol, 0.1 ml of a 1 N aqueous sodium hydrogen carbonate solution was added, and the mixture was heated under reflux for 10 minutes. After ordinary post-treatment, purification was performed by thin-layer chromatography [hexane / ethyl acetate = 70I30 (v / v)] to obtain 2.2 mg (41%) of compound 22.
1H NMR (400MHz, CDC13) δ ppm ； 8.11 (br s, IH), 7.56 (s, IH), 5.89 (s, 1H)， 5.75 (d, J=1.2Hz， 1H)， 5.10-5.06 (m, 2H), 3.86 (s, 3H)， 2.22 (d, J=1.2Hz, 3H), 2.21-2.20 (m, 4H)， 2.13-1.97 (m, 4H), 1.68 (d, J=1.0Hz, 3H), 1.62 (d, J=1.2H z, 3H)， 1.59 (br s, 3H) 1H NMR (400MHz, CDC1 3) δ ppm; 8.11 (br s, IH), 7.56 (s, IH), 5.89 (s, 1H), 5.75 (d, J = 1.2Hz, 1H), 5.10-5.06 (m , 2H), 3.86 (s, 3H), 2.22 (d, J = 1.2Hz, 3H), 2.21-2.20 (m, 4H), 2.13-1.97 (m, 4H), 1.68 (d, J = 1.0Hz, 3H), 1.62 (d, J = 1.2H z, 3H), 1.59 (br s, 3H)
FABMS m/z ； 372 (M+H)+ FABMS m / z; 372 (M + H) +
実施例 2 3 ： N-(4-ヒドロキシ -3,6-ジォキソシクロへキサ -1，4-ジェニル) -3,7,1 1-トリメチル -2,6,10-ドデカトリェンアミド （化合物 2 3 ) Example 23: N- (4-hydroxy-3,6-dioxocyclohexa-1,4-genenyl) -3,7,11-trimethyl-2,6,10-dodecatrienamide (compound 23 )
実施例 2 2で得られる化合物 2 2の 5.8mg(0.0086mmol)をピリジン 2mlに溶 解し、 ヨウ化リチウム 3.0mg(0.0226mmol)を加え 4日間加熱還流した。 室温ま で冷却し、 通常の後処理後、 薄層クロマトグラフィー [クロ口ホルム Zメ夕ノ —ル =90 I 10 (v/v)] で精製し、 化合物 2 3を 2.5mg(45%) 得た。  5.8 mg (0.0086 mmol) of compound 22 obtained in Example 22 was dissolved in 2 ml of pyridine, and 3.0 mg (0.0226 mmol) of lithium iodide was added, followed by heating under reflux for 4 days. After cooling to room temperature and purifying by ordinary work-up, the product was purified by thin-layer chromatography [form: Z-form = 90 I 10 (v / v)] to give 2.5 mg (45%) of compound 23. Obtained.
1H NMR (100MHz, CDCI3) <5 ppm ； 8.12 (br s, 1H)， 7.55 (s, IH), 5.89 (s, IH), 6S/86卜 1 OAV 1H NMR (100 MHz, CDCI3) <5 ppm; 8.12 (br s, 1H), 7.55 (s, IH), 5.89 (s, IH), 6S / 86 1 OAV
Figure imgf000036_0001
Figure imgf000036_0001
ニル) -3,7,11-トリメチル- 2,6,10-ドデカトリェンアミド （化合物 2 6 ) Nyl) -3,7,11-trimethyl-2,6,10-dodecatrienamide (Compound 26)
実施例 1 3で得られる化合物 1 3の 24.4mg(0.065mmol)をジメチルホルムァ ミド 4.5mlに溶解し、 グリコール酸 15.7mg(0.21mmol)、 次いで水素化ナトリウ ム 9.9mg(0.41mmol)を加え、 室温で 3日間攪拌した。 通常の後処理後、 薄層ク 口マトグラフィ一 [クロ口ホルム Zメタノール =90 / 10 (v/v) ] で精製し、 化合物 2 6を 6.2mg(23%) 得た。  24.4 mg (0.065 mmol) of compound 13 obtained in Example 13 was dissolved in 4.5 ml of dimethylformamide, and 15.7 mg (0.21 mmol) of glycolic acid and then 9.9 mg (0.41 mmol) of sodium hydride were added. The mixture was stirred at room temperature for 3 days. After ordinary post-treatment, the product was purified by thin-layer gel chromatography [cloform form Z methanol = 90/10 (v / v)] to obtain 6.2 mg (23%) of compound 26.
1H NMR (500MHz, CDC13) δ ppm ； 8.11 (br s, 1H), 7.35 (s, 1H)， 5.87 (s, 1 1H NMR (500MHz, CDC1 3) δ ppm; 8.11 (br s, 1H), 7.35 (s, 1H), 5.87 (s, 1
H)， 5.72 (s, 1H)， 5.11-5.06 (m, 2H), 4.10-4.36 (m, 2H), 2.16 (s, 3H), 2.16-1.96 (m, 8H), 1.66 (s， 3H), 1.60 (s, 3H), 1.58 (s, 3H) H), 5.72 (s, 1H), 5.11-5.06 (m, 2H), 4.10-4.36 (m, 2H), 2.16 (s, 3H), 2.16-1.96 (m, 8H), 1.66 (s, 3H) , 1.60 (s, 3H), 1.58 (s, 3H)
FABMS m/z ； 418 (M+3H)+ FABMS m / z; 418 (M + 3H) +
実施例 2 7 ： N-[4-(2-メチルチオエトキシ) -3，6-ジォキソシクロへキサ -1,4-ジ ェニル ]-4-ベンジルォキシフエノキシァセトアミド （化合物 2 7 ) Example 27: N- [4- (2-methylthioethoxy) -3,6-dioxocyclohexa-1,4-dienyl] -4-benzyloxyphenoxyacetamide (Compound 27)
実施例 2 4と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 25.2 mg(0.063mmol)と、 メチルチオエタノール lml、 炭酸水素ナトリウム 9.9mg(0.1 2mmol)より、 化合物 2 7を 19.7mg(34%)得た。  Using the same method as in Example 24, Compound 27 was obtained from 25.2 mg (0.063 mmol) of Compound 14 obtained in Example 14 and 1 ml of methylthioethanol and 9.9 mg (0.12 mmol) of sodium hydrogen carbonate. 19.7 mg (34%) were obtained.
1H NMR (100MHz, CDC13) δ ppm ； 9.53 (br s, 1H)， 7.69 (s, 1H), 7.52-7.30 (m, 5H), 6.95 (s, 4H), 5.03 (s, 2H)， 4.59 (s, 2H)， 4.16 (t, J=6.8Hz, 2H), 2.95 (t, J=6.8Hz, 2H), 2.24 (s, 3H) 1H NMR (100MHz, CDC1 3) δ ppm; 9.53 (br s, 1H), 7.69 (s, 1H), 7.52-7.30 (m, 5H), 6.95 (s, 4H), 5.03 (s, 2H), 4.59 (s, 2H), 4.16 (t, J = 6.8Hz, 2H), 2.95 (t, J = 6.8Hz, 2H), 2.24 (s, 3H)
FABMS m/z ； 455 (M+3H)+ FABMS m / z; 455 (M + 3H) +
実施例 2 8 ： N-[4-(4-ヒドロキシブトキシ) -3,6-ジォキソシクロへキサ -1,4-ジ ェニル ]-3,7,11-トリメチル -2,6,10-ドデカトリェンアミド (化合物 2 8 ) Example 28: N- [4- (4-hydroxybutoxy) -3,6-dioxocyclohexa-1,4-dienyl] -3,7,11-trimethyl-2,6,10-dodecatriene Amide (Compound 28)
実施例 1 3で得られる化合物 1 3の 25.5mg(0.067mmol)をテトラヒドロフラ ン 1.5mlに溶解し、 炭酸水素ナトリウム 17.3mg(0.21mmol)を加え、 次いで 1，4- ブタンジオール 1.5mlを加え、 5時間加熱還流した。 室温まで冷却し一晩攪拌 した後、 通常の後処理を行い、 薄層クロマトグラフィー [クロ口ホルム Zメタ ノール =97 I 3 (v/v) ] で精製し、 化合物 2 8を 7.1mg(24%)得た。 25.5 mg (0.067 mmol) of the compound 13 obtained in Example 13 was dissolved in 1.5 ml of tetrahydrofuran, 17.3 mg (0.21 mmol) of sodium hydrogen carbonate was added, and then 1.5 ml of 1,4-butanediol was added. The mixture was refluxed for 5 hours. After cooling to room temperature and stirring overnight, perform the usual post-treatment and purify by thin-layer chromatography [cloform form Z methanol = 97 I 3 (v / v)] to obtain 7.1 mg of compound 28 ( 24%).
1H NMR (500MHz, CDCI3) <5 ppm ； 8.12 (br s, 1H)， 7.54 (s, 1H)， 5.87 (s, 1H)， 5.75 (d, J=l.lHz, 1H)， 5.09-5.08 (m, 2H), 4.12-3.63 (m, 8H), 2.22 (d, J=1.1H z， 3H), 2.20-1.97 (m, 8H), 1.67 (d, J=1.2Hz， 3H), 1.62 (d, J=1.0Hz， 3H), 1.59 (s, 3H) 1H NMR (500 MHz, CDCI3) <5 ppm; 8.12 (br s, 1H), 7.54 (s, 1H), 5.87 (s, 1H), 5.75 (d, J = l.lHz, 1H), 5.09-5.08 (m, 2H), 4.12-3.63 (m, 8H), 2.22 (d, J = 1.1Hz, 3H), 2.20-1.97 (m, 8H), 1.67 (d, J = 1.2Hz, 3H), 1.62 (d, J = 1.0Hz, 3H), 1.59 (s, 3H)
FABMS m/z ； 430 (M+H)+ FABMS m / z; 430 (M + H) +
実施例 2 9 ： N-[4-(2-メトキシェトキシ) -3,6-ジォキソシクロへキサ -1,4-ジェ ニル] -3,7,11-トリメチル -2，6，10-ドデカトリェンアミド （化合物 2 9 ) Example 29: N- [4- (2-methoxyethoxy) -3,6-dioxocyclohexa-1,4-phenyl] -3,7,11-trimethyl-2,6,10-dodecato Lienamide (Compound 29)
実施例 1 3で得られる化合物 1 3の 21.5mg(0.057mmol)をテトラヒドロフラ ン 3mlに溶解し、 2-メトキシェタノ一ル 1.5mlと炭酸水素ナトリウム 4.7mg(0. 056mmol)を加え、 7時間加熱還流した。 通常の後処理の後、 薄層クロマトダラ フィ一 [クロ口ホルム/メタノール =99 / 1 (v/v)] で精製し、 化合物 2 9を 1 0.2mg(43%)得た。  21.5 mg (0.057 mmol) of compound 13 obtained in Example 13 was dissolved in 3 ml of tetrahydrofuran, 1.5 ml of 2-methoxyethanol and 4.7 mg (0.056 mmol) of sodium hydrogen carbonate were added, and the mixture was heated under reflux for 7 hours. did. After the usual post-treatment, purification was performed using thin-layer chromatographic chromatography (cloth form / methanol = 99/1 (v / v)) to obtain 10.2 mg (43%) of compound 29.
1H NMR (500MHz, CDC13) δ ppm ； 8.10 (br s, 1H)， 7.55 (s, IH), 5.91 (s, IH), 5.75 (d, J=l.lHz, 1H)， 5.09-5.06 (m, 2H), 4.10-4.08 (m, 2H), 3.81-3.79 (m, 2 H), 3.43 (s, 3H)， 2.22 (d, J=1.2Hz, 3H)， 2.21-1.97 (m, 8H), 1.67(d， J=1.2Hz, 3 H), 1.62 (d, J=l.lHz, 3H), 1.59 (s, 3H) 1H NMR (500MHz, CDC1 3) δ ppm; 8.10 (br s, 1H), 7.55 (s, IH), 5.91 (s, IH), 5.75 (d, J = l.lHz, 1H), 5.09-5.06 ( m, 2H), 4.10-4.08 (m, 2H), 3.81-3.79 (m, 2H), 3.43 (s, 3H), 2.22 (d, J = 1.2Hz, 3H), 2.21-1.97 (m, 8H ), 1.67 (d, J = 1.2Hz, 3H), 1.62 (d, J = l.lHz, 3H), 1.59 (s, 3H)
FABMS m/z ； 416 (M+H)+ FABMS m / z; 416 (M + H) +
実施例 3 0 ： N-{4-[2-(2-ヒドロキシエトキシ)エトキシ] - 3,6-ジォキソシクロ へキサ -1,4-ジェニル}-3，7，11-トリメチル -2,6,10-ドデカトリェンアミド （化合物 3 0 ) Example 30: N- {4- [2- (2-hydroxyethoxy) ethoxy] -3,6-dioxocyclohexa-1,4-genyl} -3,7,11-trimethyl-2,6,10 -Dodecatrienamide (Compound 30)
実施例 2 9と同様の方法を用いて、 実施例 1 3で得られる化合物 1 3の 26.1 mg(0.070mmol)と炭酸水素ナトリゥム 17.5mg(0.21mmol)、 ジエチレングリコ一 ル 2.0mlより、 化合物 3 0を 20.8mg(67%)得た。  Using a method similar to that of Example 29, Compound 30 was obtained from 26.1 mg (0.070 mmol) of Compound 13 obtained in Example 13, 17.5 mg (0.21 mmol) of sodium hydrogen carbonate, and 2.0 ml of diethylene glycol. Was obtained in 20.8 mg (67%).
1H NMR (500MHz, CDCI3) δ ppm ； 8.10 (br s， 1H)， 7.55 (s, IH), 5.90 (s, 1H)， 5.75 (d, J=1.0Hz, IH), 5.10-5.06 (m, 2H)， 4.11-4.10 (m, 2H), 3.94-3.93 (m, 2 H), 3.67 (br s, 3H), 3.69-3.67 (m， 2H), 2.22 (d， J=1.2Hz, 3H)， 2.21-1.97 (m， 8 H)， 1.67 (d, J=l.lHz, 3H), 1.62 (d， J=1.0Hz, 3H)， 1.59 (s， 3H)  1H NMR (500 MHz, CDCI3) δ ppm; 8.10 (br s, 1H), 7.55 (s, IH), 5.90 (s, 1H), 5.75 (d, J = 1.0 Hz, IH), 5.10-5.06 (m, 2H), 4.11-4.10 (m, 2H), 3.94-3.93 (m, 2H), 3.67 (br s, 3H), 3.69-3.67 (m, 2H), 2.22 (d, J = 1.2Hz, 3H) , 2.21-1.97 (m, 8H), 1.67 (d, J = l.lHz, 3H), 1.62 (d, J = 1.0Hz, 3H), 1.59 (s, 3H)
FABMS m/z ； 447 (M+H)+ 実施例 3 1 ： N-{4-[2-(2-ヒドロキシエトキシ)エトキ^] -3,6-ジォキソシクロ へキサ -1,4-ジェニル}-4-ベンジルォキシフエノキシァセトアミ ド （化合物 3 1 ) FABMS m / z; 447 (M + H) + Example 31 1: N- {4- [2- (2-hydroxyethoxy) ethoxy ^]-3,6-dioxocyclohexa-1,4-genyl} -4-benzyloxyphenoxyacetamide ( Compound 31)
実施例 1 4で得られる化合物 1 4の 21.7mg(0.055mmol)， をクロ口ホルム 2.0 mlに溶解し、 ジエチレングリコール lml、 次いで炭酸カリウム 4.6mg(0.033mm ol)を加え、 室温で 1時間攪拌した。 通常の後処理の後、 薄層クロマトグラフ ィー [クロ口ホルム/ メタノール =98 / 2 (v/v)] で精製し、 化合物 3 1を 2.7 mg(ll%)得た。  21.7 mg (0.055 mmol) of compound 14 obtained in Example 14 was dissolved in 2.0 ml of chloroform, lml of diethylene glycol and then 4.6 mg (0.033 mmol) of potassium carbonate were added, and the mixture was stirred at room temperature for 1 hour. . After ordinary post-treatment, the product was purified by thin-layer chromatography [form: methanol / methanol = 98/2 (v / v)] to obtain 2.7 mg (ll%) of Compound 31.
1H NMR (400MHz, CDC13) δ ppm ； 9.42 (br s, IH), 7.58 (s, IH), 7.43-7.29 (m, 5H), 6.94 (d, J=0.7Hz, 4H), 5.95 (s, 1H)， 5.03 (s, 2H), 4.57 (s, 2H), 4.13- 4.11 (m, 2H), 3.95-3.93 (m, 2H), 3.76 (br s， 2H), 3.69-3.67 (m, 2H) 1H NMR (400MHz, CDC1 3) δ ppm; 9.42 (br s, IH), 7.58 (s, IH), 7.43-7.29 (m, 5H), 6.94 (d, J = 0.7Hz, 4H), 5.95 (s , 1H), 5.03 (s, 2H), 4.57 (s, 2H), 4.13- 4.11 (m, 2H), 3.95-3.93 (m, 2H), 3.76 (br s, 2H), 3.69-3.67 (m, 2H)
FABMS m/z ； 469 (M+2H)+ FABMS m / z; 469 (M + 2H) +
実施例 3 2 ： N-{4-[2-(2-メトキシェトキシ)エトキシ] -3,6-ジォキソシクロへ キサ -1，4-ジェニル}-3,7，11-トリメチル -2，6，10-ドデカトリェンアミド (化合物 3 2 ) Example 32: N- {4- [2- (2-methoxyethoxy) ethoxy] -3,6-dioxocyclohexa-1,4-genenyl} -3,7,11-trimethyl-2,6, 10-Dodecatrienamide (Compound 32)
実施例 2 9と同様の方法を用いて、 実施例 1 3で得られる化合物 1 3の 150 mg(0.40mmol) と炭酸水素ナトリウム 234.5mg(2.79mmol)、 2-(2-メトキシエト キシ)エタノール 6.0mlより、 化合物 3 2を 106mg(58%)得た。  Using the same method as in Example 9, 150 mg (0.40 mmol) of compound 13 obtained in Example 13 and 234.5 mg (2.79 mmol) of sodium hydrogen carbonate, 2- (2-methoxyethoxy) ethanol 6.0 106 mg (58%) of Compound 32 was obtained from the ml.
1H NMR (500MHz, CDCI3) δ ppm ； 8.10 (br s， IH), 7.54 (s, IH), 5.90 (s, IH), 5.75 (d, J=l.lHz, IH), 5.10-5.06(m, 2H), 4.10(dd, J=4.2, 5.6Hz, 2H)， 3.91 (dd, J=4.2, 5.6Hz， 2H), 3.72-3.70 (m, 2H)， 3.56-3.54 (m, 2H), 3.38 (s, 3H), 2.22 (d, J=1.2Hz, 3H)， 2.20-1.97 (m, 8H), 1.67 (d, J=1.2Hz, 3H)， 1.62 (d, J=l.lHz， 3H), 1.59 (s, 3H) 1H NMR (500MHz, CDCI3) δ ppm; 8.10 (br s, IH), 7.54 (s, IH), 5.90 (s, IH), 5.75 (d, J = l.lHz, IH), 5.10-5.06 (m , 2H), 4.10 (dd, J = 4.2, 5.6Hz, 2H), 3.91 (dd, J = 4.2, 5.6Hz, 2H), 3.72-3.70 (m, 2H), 3.56-3.54 (m, 2H), 3.38 (s, 3H), 2.22 (d, J = 1.2Hz, 3H), 2.20-1.97 (m, 8H), 1.67 (d, J = 1.2Hz, 3H), 1.62 (d, J = l.lHz, 3H), 1.59 (s, 3H)
FABMS m/z ； 461 (M+2H)+ FABMS m / z; 461 (M + 2H) +
実施例 3 3 ： N-{4-[2-(2-メトキシェトキシ)エトキシ] -3,6-ジォキソシクロへ キサ -1，4-ジェニル}-4-ベンジルォキシフエノキシァセトアミド （化合物 3 3 ) 実施例 2 4と同様に、 実施例 1 4で得られる化合物 1 4の 22.0mg (0.055mm 01)と 2-(2-メトキシェトキシ）エタノール lml、 炭酸水素チトリゥム 32.4mg(0.40 mmol)より、 化合物 3 3を 5.5mg(21%)得た。 Example 33: N- {4- [2- (2-methoxyethoxy) ethoxy] -3,6-dioxocyclohexa-1,4-genyl} -4-benzyloxyphenoxyacetamide (compound 3 3) 22.0 mg (0.055 mm) of compound 14 obtained in Example 14 in the same manner as in Example 24 01), 1 ml of 2- (2-methoxyethoxy) ethanol and 32.4 mg (0.40 mmol) of titanium bicarbonate gave 5.5 mg (21%) of compound 33.
1H NMR (400MHz, CDC13) δ ppm ； 9.42 (br s, 1H)， 7.56 (s, IH), 7.43-7.30 (m， 5H), 6.94 (d, J=0.7Hz, 4H)， 5.95 (s, IH), 5.03 (s, 2H)， 4.57 (s, 2H)， 4.14- 4.12 (m, 2H), 3.93-3.90 (m, 2H), 3.72-3.70 (m， 2H), 3.57-3.54 (m, 2H)， 3.38 (s, 3H) 1H NMR (400MHz, CDC1 3) δ ppm; 9.42 (br s, 1H), 7.56 (s, IH), 7.43-7.30 (m, 5H), 6.94 (d, J = 0.7Hz, 4H), 5.95 (s , IH), 5.03 (s, 2H), 4.57 (s, 2H), 4.14-4.12 (m, 2H), 3.93-3.90 (m, 2H), 3.72-3.70 (m, 2H), 3.57-3.54 (m , 2H), 3.38 (s, 3H)
FABMS m/z ； 483 (M+2H)+ FABMS m / z; 483 (M + 2H) +
実施例 3 4 ： N-{4-[2-[2-(2-ヒドロキシエトキシ)エトキシ]エトキシ] -3，6-ジォ キソシクロへキサ -1,4-ジェニル}-3，7,11-トリメチル -2,6,10-ドデカトリェンアミ ド （化合物 3 4 ) Example 34: N- {4- [2- [2- (2-hydroxyethoxy) ethoxy] ethoxy] -3,6-dioxocyclohexa-1,4-genyl} -3,7,11- Trimethyl-2,6,10-dodecatrienamide (Compound 34)
実施例 2 9と同様の方法を用いて、 実施例 1 3で得られる化合物 1 3の 26.7 mg(0.071mmol)と炭酸水素ナトリウム 18.0mg(0.21mmol)、 トリエチレングリコ ール 2.0mlより、 化合物 3 4を 24.9mg(72%)得た。  Using a method similar to that in Example 29, the compound was obtained from 26.7 mg (0.071 mmol) of compound 13 obtained in Example 13, 18.0 mg (0.21 mmol) of sodium hydrogen carbonate, and 2.0 ml of triethylene glycol. 24.9 mg (72%) of 34 were obtained.
1H NMR (500MHz, CDC13) 6 ppm ； 8.10 (br s, IH), 7.54 (s, 1H)， 5.93 (s, IH), 5.75 (d, J=0.9Hz, IH), 5.10-5.06 (m, 2H)， 4.13-3.60 (m, 13H), 2.22 (d, J=1.2 Hz, 3H)， 2.21-1.98 (m, 8H)， 1.67 (d, J=l.lHz, 3H), 1.62 (d, J=1.0Hz, 3H), 1.6 0 (s, 3H) 1H NMR (500MHz, CDC1 3) 6 ppm; 8.10 (br s, IH), 7.54 (s, 1H), 5.93 (s, IH), 5.75 (d, J = 0.9Hz, IH), 5.10-5.06 (m , 2H), 4.13-3.60 (m, 13H), 2.22 (d, J = 1.2 Hz, 3H), 2.21-1.98 (m, 8H), 1.67 (d, J = l.lHz, 3H), 1.62 (d , J = 1.0Hz, 3H), 1.6 0 (s, 3H)
FABMS m/z ;489(M+H)+ FABMS m / z; 489 (M + H) +
実施例 3 5 ： N-{4-[2-[2-(2-ヒドロキシエトキシ)エトキシ]エトキシ] -3，6-ジォ キソシクロへキサ -1,4-ジェニル) -4-ベンジルォキシフエノキシァセトアミド (化合物 3 5 ) Example 35: N- {4- [2- [2- (2-hydroxyethoxy) ethoxy] ethoxy] -3,6-dioxocyclohexa-1,4-genenyl) -4-benzyloxyf Enoxyacetamide (Compound 35)
実施例 2 4と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 21.9 mg(0.055mmol)、 トリエチレンダリコール 1mlおよび炭酸水素ナトリウム 14.0 mg(0.17mmol)より、 化合物 3 5を 3.3mg(12%)得た。  Using a method similar to that in Example 24, Compound 3 5 was obtained from 21.9 mg (0.055 mmol) of Compound 14 obtained in Example 14, 1 ml of triethylenedalicol and 14.0 mg (0.17 mmol) of sodium hydrogen carbonate. 3.3 mg (12%) was obtained.
1H NMR (400MHz, CDC13) δ ppm ； 9.42 (br s， IH), 7.57 (s, 1H)， 7.43-7.29 (m, 5H), 6.94 (d, J=0.7Hz, 4H)， 5.97 (s, IH), 5.03 (s, 2H), 4.57 (s, 2H), 4.14- 3.60 (m, 12H) /一 ί6ά£/1υά β OAV 1H NMR (400MHz, CDC1 3) δ ppm; 9.42 (br s, IH), 7.57 (s, 1H), 7.43-7.29 (m, 5H), 6.94 (d, J = 0.7Hz, 4H), 5.97 (s , IH), 5.03 (s, 2H), 4.57 (s, 2H), 4.14- 3.60 (m, 12H) / One ί6ά £ / 1υά β OAV
Figure imgf000041_0001
Figure imgf000041_0001
S 6卜 OAV Q s S 6 OAV Q s
き日 ε Day ε
(％9 。  (% 9.
X X
)s)) ς or)6sォίH自 00寸 i s s-. ) s)) ς or) 6sίH self 00 inch i s s-.
) 8rs寸)9 HZ)ρ τζτ mi ΗHs- " ) 8rs dimension) 9 HZ) ρ τζτ mi ΗHs- "
) () s( £( sΗΪH86ε: LΗs  ) () s (£ (sΗΪH86ε: LΗs
2； 2;
m m
Figure imgf000042_0001
Figure imgf000042_0001
(ζ)Η ss) ()寸Z ςε H £ 9s. FABMS m/z ； 428 (M+H)+ (ζ) Η ss) () Dimension Z ςε H £ 9s. FABMS m / z; 428 (M + H) +
実施例 4 1 N-{5-クロ口- 4-[2-(2-ヒドロキシエトキシ)エトキシ] -3,6-ジォキソ シクロへキサ -1,4-ジェニル}-4-ベンジルォキシフエノキシァセトアミド （化合 物 4 1 ) Example 4 1 N- {5-chloro-4-4- [2- (2-hydroxyethoxy) ethoxy] -3,6-dioxocyclohexa-1,4-genyl} -4-benzyloxyphenoxy Cetamide (Compound 41)
実施例 4 0と同様の方法を用いて、 実施例 1 5で得られる化合物 1 5の 20.5 mg(0.047mmol)とジエチレングリコール 0.5ml(5.3mmol)、 炭酸水素ナトリウム 4.4mg(0.052mmol)より、 化合物 4 1を 14.5mg(61%)得た。  Using the same method as in Example 40, the compound was obtained from 20.5 mg (0.047 mmol) of compound 15 obtained in Example 15 and 0.5 ml (5.3 mmol) of diethylene glycol and 4.4 mg (0.052 mmol) of sodium hydrogen carbonate. 4 1 was obtained in an amount of 14.5 mg (61%).
1H NMR (400MHz, CDC13) δ ppm ； 9.45 (br s, 1H)， 7.52 (s， 1H)， 7.43-7.30 (m， 5H)， 6.96-6.90 (m, 4H), 5.03 (s, 2H), 4.75 (m, 2H), 4.58 (s, 2H), 3.80 (m, 1H NMR (400MHz, CDC1 3) δ ppm; 9.45 (br s, 1H), 7.52 (s, 1H), 7.43-7.30 (m, 5H), 6.96-6.90 (m, 4H), 5.03 (s, 2H) , 4.75 (m, 2H), 4.58 (s, 2H), 3.80 (m,
2H)， 3.70 (m, 2H), 3.61 (m, 2H) 2H), 3.70 (m, 2H), 3.61 (m, 2H)
FABMS m/z ； 502 (M+H)+ FABMS m / z; 502 (M + H) +
実施例 4 2 ： N-(4-ァミノ- 3,6-ジォキソシクロへキサ -1，4-ジェニル) -3,7，11- トリメチル -2,6,10-ドデカトリェンアミド （化合物 4 2 ) Example 42: N- (4-amino-3,6-dioxocyclohexa-1,4-genyl) -3,7,11-trimethyl-2,6,10-dodecatrienamide (compound 42)
実施例 1 3で得られる化合物 4 2の 19.5mg(0.052mmol)を 1 Mアンモニア Z メタノール溶液 lOOml(lOOmmol)に溶解し、 室温で 20分間攪拌した後、 減圧下 で溶媒を除去し、 残渣を薄層クロマトグラフィー [へキサン Z酢酸ェチル =80 / 20 (v/v) ] で精製し、 化合物 4 2を 7.5mg(41%)得た。  19.5 mg (0.052 mmol) of compound 42 obtained in Example 13 was dissolved in 1 M ammonia Z methanol solution lOOml (lOOmmol), stirred at room temperature for 20 minutes, and the solvent was removed under reduced pressure. Purification by thin layer chromatography [hexane Z ethyl acetate = 80/20 (v / v)] afforded 7.5 mg (41%) of compound 42.
1H NMR (500MHz, CDC13) δ ppm ； 8.42 (s, IH), 7.44 (s, 1H)， 5.77 (d, J=l.l Hz, IH), 5.67 (s, IH), 5.35 (br s, IH), 5.09-5.06 (m, 2H), 2.22 (d, J=1.3Hz, 3 H)， 2.12-1.97 (m, 8H), 1.67 (d, J=l.lHz, 3H), 1.62 (d, J=l.lHz， 3H), 1.60 (s, 3H) 1H NMR (500MHz, CDC1 3) δ ppm; 8.42 (s, IH), 7.44 (s, 1H), 5.77 (d, J = ll Hz, IH), 5.67 (s, IH), 5.35 (br s, IH ), 5.09-5.06 (m, 2H), 2.22 (d, J = 1.3Hz, 3H), 2.12-1.97 (m, 8H), 1.67 (d, J = l.lHz, 3H), 1.62 (d, J = l.lHz, 3H), 1.60 (s, 3H)
FABMS m/z ； 357 (M+H)+ FABMS m / z; 357 (M + H) +
実施例 4 3 ： N-[4- (メチルァミノ） -3,6-ジォキソシクロへキサ -1，4-ジェニル] -3， 7，11-トリメチル -2,6,10-ドデカトリェンアミド （化合物 4 3 ) Example 43: N- [4- (methylamino) -3,6-dioxocyclohexa-1,4-genyl] -3,7,11-trimethyl-2,6,10-dodecatrienamide (Compound 4 3)
実施例 1 3で得られる化合物 1 3の 17.5mg(0.047mmol)をメタノール 6mlに 溶解し、 塩酸メチルァミン 12.8mg(0.19mmol)、 次いで卜リエチルァミン 7 2 1 (0.050mmol)を加え、 室温で 10分間攪拌した後、 通常の後処理の後、 薄層ク 口マトグラフィ一 [へキサンノ酢酸ェチル =75 I 25 (v/v) ] で精製し、 化合 物 4 3を 9.5mg(55%)得た。 17.5 mg (0.047 mmol) of the compound 13 obtained in Example 13 was dissolved in 6 ml of methanol, and 12.8 mg (0.19 mmol) of methylamine hydrochloride and then 7221 (0.050 mmol) of triethylamine were added, and the mixture was added at room temperature for 10 minutes. After stirring, after normal post-treatment, Purification by oral chromatography [ethyl hexanoacetate = 75 I 25 (v / v)] gave 9.5 mg (55%) of compound 43.
1H NMR (400MHz, CDC13) δ ppm ； 8.55 (br s, IH), 7.42 (s, IH), 6.20 (br s, IH), 5.78 (s, IH), 5.40 (s， IH), 5.08 (br s, 2H)， 2.90 (d, J=5.4Hz, 3H), 2.22 (d, J=1.2Hz, 3H)， 2.20-1.97 (m, 8H)， 1.67 (s, 3H), 1.62 (s， 3H)1.60 (s， 3H) FABMS m/z ； 371 (M+H)+ 1H NMR (400MHz, CDC1 3) δ ppm; 8.55 (br s, IH), 7.42 (s, IH), 6.20 (br s, IH), 5.78 (s, IH), 5.40 (s, IH), 5.08 ( br s, 2H), 2.90 (d, J = 5.4Hz, 3H), 2.22 (d, J = 1.2Hz, 3H), 2.20-1.97 (m, 8H), 1.67 (s, 3H), 1.62 (s, 3H) 1.60 (s, 3H) FABMS m / z; 371 (M + H) +
実施例 4 4 ： N-(4-メチルァミノ- 3,6-ジォキソシクロへキサ -1,4-ジェニル) -4- ベンジルォキシフエノキシァセトアミド （化合物 4 4 ) Example 44: N- (4-methylamino-3,6-dioxocyclohexa-1,4-genyl) -4-benzyloxyphenoxyacetamide (compound 44)
実施例 1 4で得られる化合物 1 4の 104mg(0.26mmol)を 10%メタノール-ク ロロホルムの混合溶媒 11mlに溶解し、 メチルヒドラジン硫酸塩 151mg (1.1m mol)、 次いで炭酸水素ナトリウム 88mg(l.lmmol)を加え、 室温で 15時間攪拌 した。 通常の後処理の後、 薄層クロマトグラフィー [クロ口ホルム メタノー ル =98 I 2 (v/v)] で精製し、 化合物 4 4を llmg(ll%)得た。  104 mg (0.26 mmol) of compound 14 obtained in Example 14 was dissolved in 11 ml of a 10% methanol-chloroform mixed solvent, and 151 mg (1.1 mmol) of methylhydrazine sulfate was added, followed by 88 mg (l. lmmol), and the mixture was stirred at room temperature for 15 hours. After usual work-up, the product was purified by thin-layer chromatography [clonal form methanol = 98 I 2 (v / v)] to obtain llmg (ll%) of compound 44.
1H NMR (400MHz, CDC13) δ ppm ； 9.78 (br s， IH), 7.44 (s, IH), 7.43-7.30 (m, 5H), 6.94 (s, 4H)， 6.16 (br s， IH), 5.43 (s, 1H)， 5.03 (s, 2H)， 4.57(s, 2H)， 1H NMR (400MHz, CDC1 3) δ ppm; 9.78 (br s, IH), 7.44 (s, IH), 7.43-7.30 (m, 5H), 6.94 (s, 4H), 6.16 (br s, IH), 5.43 (s, 1H), 5.03 (s, 2H), 4.57 (s, 2H),
2.90 (d, J=5.6Hz, 3H) 2.90 (d, J = 5.6Hz, 3H)
FABMS m/z ； 393 (M+H)+ FABMS m / z; 393 (M + H) +
実施例 4 5 ： N-[4-(tert-ブチルァミノ） -3,6-ジォキソシクロへキサ -1,4-ジェニ ル] -3,7,11-トリメチル -2，6，10-ドデカトリェンアミ ド （化合物 4 5 ) Example 45: N- [4- (tert-butylamino) -3,6-dioxocyclohexa-1,4-genyl] -3,7,11-trimethyl-2,6,10-dodecatriamine (Compound 45)
実施例 2 2で得られる化合物 2 2の 9.5mg(0.026mmol)をメタノール lmlに 溶解し、 tert-プチルァミン 10 l(O.lOmmol)を室温で加え、 4時間 30分攪拌し た。 反応終了後、 反応溶液より減圧下で溶媒を除去し、 残渣を薄層クロマトグ ラフィ一 [へキサン Z酢酸ェチル = 80Z20 (v/v)] で精製し、 化合物 4 5を 3.3 mg(31%)得た。  9.5 mg (0.026 mmol) of compound 22 obtained in Example 22 was dissolved in 1 ml of methanol, and 10 l (0.1 mmol) of tert-butylamine was added at room temperature, followed by stirring for 4 hours and 30 minutes. After completion of the reaction, the solvent was removed from the reaction solution under reduced pressure, and the residue was purified by thin-layer chromatography [hexane Z-ethyl acetate = 80Z20 (v / v)] to give 3.3 mg of compound 45 (31%). Obtained.
1H NMR (500MHz, CDCI3) δ ppm ； 8.54 (br s， 1H)， 7.41 (s, 1H)， 6.27 (br s, 1H)， 5.78 (d， J=1.0Hz, IH), 5.63 (s, IH), 5.09-5.07 (m, 2H)， 2.22 (d， J=1.2Hz, 3H)， 2.20-1.97 (m, 8H), 1.67 (d, J=l.lHz, 3H), 1.62 (d, J=1.0Hz, 3H)， 1.56 (s, 3H)， 1.40 (s, 9H) 1H NMR (500 MHz, CDCI3) δ ppm; 8.54 (br s, 1H), 7.41 (s, 1H), 6.27 (br s, 1H), 5.78 (d, J = 1.0 Hz, IH), 5.63 (s, IH ), 5.09-5.07 (m, 2H), 2.22 (d, J = 1.2Hz, 3H), 2.20-1.97 (m, 8H), 1.67 (d, J = l.lHz, 3H), 1.62 (d, J = 1.0Hz, 3H), 1.56 (s, 3H), 1.40 (s, 9H)
FABMS m/z ； 413 (M+H)+ FABMS m / z; 413 (M + H) +
実施例 4 6 ： N-[4-力ルポキシメチルァミノ- 3，6-ジォキソシクロへキサ -1，4- ジェニル] -3,7,11-トリメチル -2,6,10-ドデカトリェンアミド (化合物 4 6 ) 実施例 1 3で得られる化合物 1 3の 25.0mg(0.066mmol)をメタノール 3mlに 溶解し、 ダリシン 15.4mg(0.21mmol)、 次いで炭酸水素ナトリウム 12.0mg(0.14 mmol)を加え、 室温で 1時間攪拌した。 通常の後処理の後、 薄層クロマトダラ フィ一 [クロ口ホルム/メタノール =90 I 10 (v/v)]で精製し、 化合物 4 6を 4.8 mg(17%)得た。 Example 46: N- [4-potoxymethylamino-3,6-dioxocyclohexa-1,4-genyl] -3,7,11-trimethyl-2,6,10-dodecatrienamide (Compound 46) 25.0 mg (0.066 mmol) of compound 13 obtained in Example 13 was dissolved in 3 ml of methanol, and 15.4 mg (0.21 mmol) of daricin and then 12.0 mg (0.14 mmol) of sodium hydrogen carbonate were added. The mixture was stirred at room temperature for 1 hour. After usual post-treatment, purification was performed using thin-layer chromatographic chromatography (cloth form / methanol = 90 I 10 (v / v)) to obtain 4.8 mg (17%) of compound 46.
1H NMR (500MHz, CDC13) δ ppm ； 8.44 (br s, 1H)， 6.82 (br s， IH), 5.74 (s, IH), 5.07-5.05 (m, 2H)， 3.79 (br s, 2H), 2.22 (d, J=1.2Hz, 3H), 2.20-1.97 (m, 8H), 1.67 (s, 3H)， 1.62 (d, J=l.lHz, 3H)， 1.59 (s, 3H) 1H NMR (500MHz, CDC1 3) δ ppm; 8.44 (br s, 1H), 6.82 (br s, IH), 5.74 (s, IH), 5.07-5.05 (m, 2H), 3.79 (br s, 2H) , 2.22 (d, J = 1.2Hz, 3H), 2.20-1.97 (m, 8H), 1.67 (s, 3H), 1.62 (d, J = l.lHz, 3H), 1.59 (s, 3H)
FABMS m/z ； 414 (M+H)+ FABMS m / z; 414 (M + H) +
実施例 4 7 ： N-[4-エトキシカルポニルメチルァミノ- 3，6-ジォキソシクロへ キサ -1,4-ジェニル] -3，7，11-トリメチル -2,6,10-ドデカトリェンアミド (化合物 4 7 ) Example 47: N- [4-ethoxycarbonylmethylamino-3,6-dioxocyclohexa-1,4-genyl] -3,7,11-trimethyl-2,6,10-dodecatrienamide ( Compound 47)
実施例 1 3で得られる化合物 1 3の 23.9mg(0.064mmol)を tert-ブタノ一ル 2m 1に溶解し、 ダリシンェチルエステル塩酸塩 17.5mg(0.13mmol)、 次いで炭酸水 素ナトリゥム lO.Omg(O.llmmol)を加え、 1時間 30分加熱還流した。 通常の後 処理の後、 薄層クロマトグラフィー [クロ口ホルムノメタノール =97 I 3 (v/v)] で精製し、 化合物 4 7を 4.2mg(15%)得た。  23.9 mg (0.064 mmol) of the compound 13 obtained in Example 13 was dissolved in 2 ml of tert-butanol, and 17.5 mg (0.13 mmol) of daricinethyl ester hydrochloride was added, followed by sodium hydrogen carbonate. Omg (O.llmmol) was added, and the mixture was heated under reflux for 1 hour and 30 minutes. After usual post-treatment, purification was performed by thin-layer chromatography [form-formomethanol = 97 I 3 (v / v)] to obtain 4.2 mg (15%) of compound 47.
1H NMR (500MHz, CDCI3) δ ppm ； 8.46 (br s, 1H)， 7.46 (s, IH), 6.60 (br s, IH), 5.77 (s, IH), 5.34 (s, 1H)， 5.09-5.06 (m， 2H), 4.29 (q, J=7.1Hz, 2H), 3.8 8 (d, J=5.4Hz, 2H), 2.22 (d, J=1.2Hz, 3H), 2.20-1.97 (m, 8H)， 1.67 (d, J=1.1H z, 3H), 1.62 (d, J=1.0Hz, 3H)， 1.59 (s, 3H), 1.32 (t, J=7.1Hz, 3H) 1H NMR (500 MHz, CDCI3) δ ppm; 8.46 (br s, 1H), 7.46 (s, IH), 6.60 (br s, IH), 5.77 (s, IH), 5.34 (s, 1H), 5.09-5.06 (m, 2H), 4.29 (q, J = 7.1Hz, 2H), 3.88 (d, J = 5.4Hz, 2H), 2.22 (d, J = 1.2Hz, 3H), 2.20-1.97 (m, 8H ), 1.67 (d, J = 1.1Hz, 3H), 1.62 (d, J = 1.0Hz, 3H), 1.59 (s, 3H), 1.32 (t, J = 7.1Hz, 3H)
FABMS m/z ； 443 (M+H)+ FABMS m / z; 443 (M + H) +
実施例 4 8 ： N-[4-力ルバモイルメチルァミノ- 3,6-ジォキソシクロへキサ -1,4 -ジェニル] -3，7，11-トリメチル -2,6，10-ドデカトリェンアミド （化合物 4 8 ) 実施例 4 5と同様の方法を用いて、 実施例 1 3で得られる化合物 1 3の 22.5 mg(0.060mmol)とグリシンアミド塩酸塩 13.3mg(0.12mmol)、 炭酸水素ナトリウ Λ 10.2mg(0.13mmol, 2.2eq)より、 化合物 4 8を 3.8mg(15%)得た。 Example 48: N- [4-forcerubamoylmethylamino-3,6-dioxocyclohexa-1,4 -Genenyl] -3,7,11-trimethyl-2,6,10-dodecatrienamide (Compound 48) Using a method similar to that of Example 45, compound 13 obtained in Example 13 From 22.5 mg (0.060 mmol), 13.3 mg (0.12 mmol) of glycinamide hydrochloride, and 10.2 mg (0.13 mmol, 2.2 eq) of sodium hydrogen carbonate, 3.8 mg (15%) of compound 48 was obtained.
1H NMR (400MHz, CDC13) δ ppm ； 8.44 (br s, IH), 7.47 (s, 1H、， 6.71 (br s, IH), 5.77 (s， IH), 5.67 (s, 1H)， 5.40 (br s， 2H)， 5.08-5.06 (m, 2H), 3.85 (d, J =4.6Hz, 2H)， 2.22 (d, J=1.0Hz， 3H)， 2.20-1.97 (m, 8H), 1.67 (s， 3H), 1.62 (s, 3H), 1.60 (s, 3H) 1H NMR (400MHz, CDC1 3) δ ppm; 8.44 (br s, IH), 7.47 (s, 1H ,, 6.71 (br s, IH), 5.77 (s, IH), 5.67 (s, 1H), 5.40 ( br s, 2H), 5.08-5.06 (m, 2H), 3.85 (d, J = 4.6 Hz, 2H), 2.22 (d, J = 1.0 Hz, 3H), 2.20-1.97 (m, 8H), 1.67 ( s, 3H), 1.62 (s, 3H), 1.60 (s, 3H)
FABMS m/z ； 414 (M+H)+ FABMS m / z; 414 (M + H) +
実施例 4 9 ： N-{4-[N-(2-ヒドロキシェチル) -N-メチルァミノ] -3，6-ジォキソシ クロへキサ -1,4-ジェニル}-3，7，11-トリメチル -2,6,10-ドデカトリェンアミド （化 合物 4 9 ) Example 49: N- {4- [N- (2-hydroxyethyl) -N-methylamino] -3,6-dioxocyclohexa-1,4-genenyl} -3,7,11-trimethyl- 2,6,10-dodecatrienamide (compound 49)
実施例 4 5と同様の方法を用いて、 実施例 1 3で得られる化合物 1 3の 24.1 mg(0.064mmol)と N-メチルエタノールァミン 8.0 l(O.lOmmo)より、 化合物 4 9を 16.0mg(60%)得た。  Using a method similar to that of Example 45, Compound 4 9 was obtained from 24.1 mg (0.064 mmol) of Compound 13 obtained in Example 13 and 8.0 l (O.lOmmo) of N-methylethanolamine to obtain 16.0 of compound 49. mg (60%).
1H NMR (500MHz, CDC13) 6 ppm ； 8.38 (br s, IH), 7.34 (s, 1H)， 5.77 id. J= 1.1Hz, IH), 5.10-5.07 (m, 2H), 3.90 (br s, 2H), 3.83 (t, J=5.1Hz, 2H), 3.08 (s, 3H), 2.22 (d, J=1.2Hz, 3H), 2.21-1.97 (m, 8H)， 1.67 (d, J=l.lHz, 3H), 1.62 (d, J=1.0Hz, 3H), 1.60 (d, J=0.7Hz, 3H) 1H NMR (500MHz, CDC1 3) 6 ppm;. 8.38 (br s, IH), 7.34 (s, 1H), 5.77 id J = 1.1Hz, IH), 5.10-5.07 (m, 2H), 3.90 (br s , 2H), 3.83 (t, J = 5.1Hz, 2H), 3.08 (s, 3H), 2.22 (d, J = 1.2Hz, 3H), 2.21-1.97 (m, 8H), 1.67 (d, J = l.lHz, 3H), 1.62 (d, J = 1.0Hz, 3H), 1.60 (d, J = 0.7Hz, 3H)
FABMS m/z ； 415 (M+H)+ FABMS m / z; 415 (M + H) +
実施例 5 0 ： N-[4-(2-メトキシェチルァミノ） -3,6-ジォキソシクロへキサ -1,4- ジェニル] -3,7,11-トリメチル -2,6，10-ドデカトリェンアミド （化合物 5 0 ) 実施例 4 5と同様の方法を用いて、 実施例 1 3で得られる化合物 1 3の 22.1 mg(0.059mmol)と 2-メトキシェチルァミン 10 PL l(0.12mmol)より、 化合物 5 0 を 13.7mg(56%)得た。 Example 50: N- [4- (2-methoxyethylamino) -3,6-dioxocyclohexa-1,4-genyl] -3,7,11-trimethyl-2,6,10-dodeca Trienamide (Compound 50) Using the same method as in Example 45, 22.1 mg (0.059 mmol) of compound 13 obtained in Example 13 and 10 PLl (0.12 mmol) of 2-methoxyethylamine were used. mmol), 13.7 mg (56%) of compound 50 was obtained.
1H NMR (500MHz, CDC13) δ ppm ； 8.53 (br s, IH), 7.43 Cs. 1H)， 6.42 (br s, 1H)， 5.77 (d, J=l.lHz, IH), 5.42 (s, IH), 5.09-5.06 (m, 2H), 3.60 (t, J=5.2Hz, 2H), 3.39 (s, 3H)， 3.30 (dt, J=5.2, 10.7Hz， 2H), 2.22 (d, J=1.2Hz, 3H), 2.20-1. 97 (m, 8H), 1.67 (d, J=l.lHz, 3H)， 1.62 (d， J=l.lHz, 3H), 1.59 (s， 3H) 1H NMR (500MHz, CDC1 3) δ ppm;. 8.53 (br s, IH), 7.43 Cs 1H), 6.42 (br s, 1H), 5.77 (d, J = l.lHz, IH), 5.42 (s, IH), 5.09-5.06 (m, 2H), 3.60 (t, J = 5.2Hz, 2H), 3.39 (s, 3H), 3.30 (dt, J = 5.2, 10.7Hz, 2H), 2.22 (d, J = 1.2Hz, 3H), 2.20-1.97 (m, 8H), 1.67 (d , J = l.lHz, 3H), 1.62 (d, J = l.lHz, 3H), 1.59 (s, 3H)
FABMS m/z ； 415 (M+H)+ FABMS m / z; 415 (M + H) +
実施例 5 1 ： N-{4-[2-(N，N-ジメチルァミノ）ェチルアミノト 3，6-ジォキソシク 口へキサ -1,4-ジェニル}-3，7，11-トリメチル -2,6,10-ドデカトリェンアミド （化合 物 5 1 ) Example 51 1: N- {4- [2- (N, N-dimethylamino) ethylamino 3,6-dioxocyc-hexa-1,4-genyl} -3,7,11-trimethyl-2,6,10 -Dodecatrienamide (Compound 51)
実施例 4 5と同様の方法を用いて、 実施例 1 3で得られる化合物 1 3の 25.6 mg(0.068mmol)と N，N-ジメチルエチレンジァミン 16 l(0.13mmol)より、 化合 物 5 1を 3.7mg(13%)得た。  Using a method similar to that of Example 45, Compound 5 was obtained from 25.6 mg (0.068 mmol) of Compound 13 obtained in Example 13 and 16 l (0.13 mmol) of N, N-dimethylethylenediamine. 3.7 mg (13%) of 1 was obtained.
1H NMR (400MHz, CDC13) δ ppm ； 8.55 (br s， IH), 7.42 (s, IH), 6.73 (br s, 1H)， 5.78 (d， J=1.0Hz, 1H)， 5.39 (s, 1H)， 5.10-5.06 (m, 2H)， 3.16 (dt, J=5.9, 5. 4Hz， 2H), 2.58 (d, J=6.1Hz, 2H), 2.26 (s， 6H)， 2.22 (d, J=1.2Hz， 3H)， 2.20-1.9 7 (m， 8H), 1.67 (d， J=1.0Hz, 3H)， 1.62 (d, J=1.0Hz， 3H), 1.60 (s, 3H) 1H NMR (400MHz, CDC1 3) δ ppm; 8.55 (br s, IH), 7.42 (s, IH), 6.73 (br s, 1H), 5.78 (d, J = 1.0Hz, 1H), 5.39 (s, 1H), 5.10-5.06 (m, 2H), 3.16 (dt, J = 5.9, 5.4Hz, 2H), 2.58 (d, J = 6.1Hz, 2H), 2.26 (s, 6H), 2.22 (d, J = 1.2Hz, 3H), 2.20-1.9 7 (m, 8H), 1.67 (d, J = 1.0Hz, 3H), 1.62 (d, J = 1.0Hz, 3H), 1.60 (s, 3H)
FABMS m/z ； 428 (M+H)+ FABMS m / z; 428 (M + H) +
実施例 5 2 ： N-[4-(2-力ルポキシェチルァミノ） -3,6-ジォキソシクロへキサ -1， 4-ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 5 2 ) Example 52: N- [4- (2-caprolactoxy) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 5 2)
実施例 1 4で得られる化合物 1 4の 39.4mg(0.099mmol)を 2%メ夕ノ一ル-ク ロロホルムの混合溶媒 5.0mlに溶解し、 /3 -ァラニン 19.5mg(0.22mmol)、 次い でトリェチルァミン 70 H l(0.50mmol)を加え、 室温で 30時間攪拌した。 通常 の後処理の後、 薄層クロマトグラフィー [クロ口ホルム Zメタノール = 90 I 10 (v/v)]で精製し、 化合物 5 2を 2.0mg(4.5%)得た。  39.4 mg (0.099 mmol) of compound 14 obtained in Example 14 was dissolved in 5.0 ml of a 2% methanol-chloroform mixed solvent, and 19.5 mg (0.22 mmol) of / 3-alanine was added. Then, 70 Hl (0.50 mmol) of triethylamine was added thereto, followed by stirring at room temperature for 30 hours. After the usual post-treatment, purification was performed by thin-layer chromatography [clonal form Z methanol = 90 110 (v / v)] to obtain 2.0 mg (4.5%) of compound 52.
1H NMR (400MHz, CDC13 / CD3OD = 9 / 1) δ ppm ； 7.33 (s， IH), 7.32-7.24 (m, 5H)， 6.87 (s, 4H)， 5.41 (s, 1H)， 4.95 (s， 2H)， 4.50 (s, 2H), 3.38 (t， J=6.4H z, 2H), 2.56 (t, J=6.4Hz, 2H) 1H NMR (400MHz, CDC1 3 / CD 3 OD = 9/1) δ ppm; 7.33 (s, IH), 7.32-7.24 (m, 5H), 6.87 (s, 4H), 5.41 (s, 1H), 4.95 (s, 2H), 4.50 (s, 2H), 3.38 (t, J = 6.4Hz, 2H), 2.56 (t, J = 6.4Hz, 2H)
FABMS m/z ； 451 (M+H)+ FABMS m / z; 451 (M + H) +
実施例 5 3 ： N-[4-(2-メトキシカルポニルェチルァミノ） -3,6-ジォキソシクロ へキサ -1,4-ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 5 3 ) Example 53: N- [4- (2-methoxycarbonylethylamino) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (compound 5 3)
実施例 5 2と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 26.1 mg(0.066mmol)と、 /3 -ァラニンメチルエステル塩酸塩 17.4mg(0.12mmol)、 トリ ェチルァミン 10 H l(0.066mmol)より、 ィ匕合物 5 3を 14.9mg(49%)得た。  Using a method similar to that of Example 52, 26.1 mg (0.066 mmol) of compound 14 obtained in Example 14, 17.4 mg (0.12 mmol) of / 3-alanine methyl ester hydrochloride, and triethylamine 10 From Hl (0.066 mmol), 14.9 mg (49%) of a compound 53 was obtained.
1H NMR (500MHz, CDC13) δ ppm ； 9.75 (br s, IH), 7.45 (s, 1H)， 7.43-7.31 (m， 5H)， 6.94 (s, 4H)， 6.37 (br t, J=6.4Hz, 1H)， 5.47 (s, IH), 5.03 (s, 2H), 4. 57 (s, 2H)， 3.73 (s, 3H)， 3.48 (dt， J= 6.4Hz, 2H), 2.66 (t, J=6.4Hz, 2H) 1H NMR (500MHz, CDC1 3) δ ppm; 9.75 (br s, IH), 7.45 (s, 1H), 7.43-7.31 (m, 5H), 6.94 (s, 4H), 6.37 (br t, J = 6.4 Hz, 1H), 5.47 (s, IH), 5.03 (s, 2H), 4.57 (s, 2H), 3.73 (s, 3H), 3.48 (dt, J = 6.4Hz, 2H), 2.66 (t , J = 6.4Hz, 2H)
FABMS m/z ； 465 (M+H)+ FABMS m / z; 465 (M + H) +
実施例 5 4 ： N-{4-[2-(2-ヒドロキシエトキシ)ェチルァミノ] -3，6-ジォキソシ クロへキサ -1,4-ジェニル}-3,7，11-トリメチル -2,6,10-ドデカトリェンアミド (化 合物 5 4 ) Example 54: N- {4- [2- (2-hydroxyethoxy) ethylamino] -3,6-dioxocyclohexa-1,4-genyl} -3,7,11-trimethyl-2,6, 10-Dodecatrienamide (compound 54)
実施例 4 5と同様の方法を用いて、 実施例 1 3で得られる化合物 1 3の 24.5 mg(0.065mmol)と 2-(2-アミノエトキシ)エタノール 10 l(O.lOmmol)より、 化合 物 5 4を 12.7mg(44%)得た。  Using a method similar to that in Example 45, a compound was obtained from 24.5 mg (0.065 mmol) of compound 13 obtained in Example 13 and 10 l (O.lOmmol) of 2- (2-aminoethoxy) ethanol. 12.7 mg (44%) of 54 were obtained.
1H NMR (500MHz, CDCI3) δ ppm ； 8.52 (br s， IH), 7.43 (s, IH), 6.50-6.49 (t, J=5.0Hz, 1H)， 5.78 (d, J=l.lHz, 1H)， 5.43 (s, IH), 5.10-5.06 (m, 2H), 3.78 (d, J=3.8Hz, 2H)， 3.73 (d， J=5.3Hz, 2H), 3.62-3.60 (m， 2H)， 3.34 (q, J=5.4Hz, 2 1H NMR (500 MHz, CDCI3) δ ppm; 8.52 (br s, IH), 7.43 (s, IH), 6.50-6.49 (t, J = 5.0 Hz, 1H), 5.78 (d, J = l.lHz, 1H ), 5.43 (s, IH), 5.10-5.06 (m, 2H), 3.78 (d, J = 3.8Hz, 2H), 3.73 (d, J = 5.3Hz, 2H), 3.62-3.60 (m, 2H) , 3.34 (q, J = 5.4Hz, 2
H)， 2.22 (d, J=1.2Hz, 3H), 2.20-1.97 (m, 8H), 1.67 (d, J=1.2Hz, 3H), 1.62 (d,H), 2.22 (d, J = 1.2Hz, 3H), 2.20-1.97 (m, 8H), 1.67 (d, J = 1.2Hz, 3H), 1.62 (d,
J=l.lHz, 3H), 1.60 (s, 3H) J = l.lHz, 3H), 1.60 (s, 3H)
FABMS m/z ； 445 (M+H)+ FABMS m / z; 445 (M + H) +
実施例 5 5 ： N-{4-[N-(2-(2-ヒドロキシエトキシ)ェチル) -N-メチルァミノ] -3， 6-ジォキソシク口へキサ -1，4-ジェニル}- 3,7,11-トリメチル -2,6,10-ドデカトリエ ンアミド （化合物 5 5 ) Example 55: N- {4- [N- (2- (2-hydroxyethoxy) ethyl) -N-methylamino] -3,6-dioxocyclohexa-1,4-genyl} -3,7, 11-trimethyl-2,6,10-dodecatrienamide (compound 55)
実施例 1 3で得られる化合物 1 3の 10.9mg(0.029mmol)をテトラヒドロフラ ン lmlに溶解し、 2-(2-メチルアミノエトキシ)エタノール 2mlを加え、 室温で 1分間攪拌した。 通常の後処理の後、 薄層クロマトグラフィー [クロ口ホルム メタノ一ル = 98 I 2 (v/v)]で精製し、 化合物 5 5を 4.1mg(31%)得た。 1H NMR (400MHz, CDC13) δ ppm ； 8.36 (br s， 1H)， 7.32 (s, 1H)， 5.77 (d, J= 0.7Hz, 1H)， 5.57 (s, 1H)， 5.10-5.06 (m, 2H), 3.92-3.55 (m, 8H)， 3.12 (s, 3H), 2.22 (d, J=1.2Hz, 3H), 2.20-1.99 (m, 8H), 1.67 (s, 3H), 1.62 (s, 3H), 1.60 (s, 3H) 10.9 mg (0.029 mmol) of compound 13 obtained in Example 13 was dissolved in 1 ml of tetrahydrofuran, 2 ml of 2- (2-methylaminoethoxy) ethanol was added, and the mixture was stirred at room temperature for 1 minute. After usual work-up, the product was purified by thin-layer chromatography [form-form methanol = 98 I 2 (v / v)] to obtain 4.1 mg (31%) of compound 55. 1H NMR (400MHz, CDC1 3) δ ppm; 8.36 (br s, 1H), 7.32 (s, 1H), 5.77 (d, J = 0.7Hz, 1H), 5.57 (s, 1H), 5.10-5.06 (m , 2H), 3.92-3.55 (m, 8H), 3.12 (s, 3H), 2.22 (d, J = 1.2Hz, 3H), 2.20-1.99 (m, 8H), 1.67 (s, 3H), 1.62 ( s, 3H), 1.60 (s, 3H)
FABMS m/z ； 459 (M+H)+ FABMS m / z; 459 (M + H) +
実施例 5 6 ： N-[4-(2-ヒドロキシ小メトキシカルボニルェチルァミノ）—3,6-ジ ォキソシクロへキサ -1,4-ジェニル] -3,7,11-トリメチル -2,6,10-ドデカトリエンァ ミド （化合物 5 6 ) Example 56: N- [4- (2-hydroxy small methoxycarbonylethylamino) -3,6-dioxocyclohexa-1,4-genyl] -3,7,11-trimethyl-2,6 , 10-Dodecatrienamide (compound 56)
実施例 4 5と同様の方法を用いて、 実施例 1 3で得られる化合物 1 3の 24.1 mg(0.064mmol) と L-セリンメチルエステル塩酸塩 12.1mg(0.078mmol)、 炭酸水 素ナトリウム 6.7mg(0.080mmol)より、 化合物 5 6を 3.4mg(12%)得た。  Using the same method as in Example 45, 24.1 mg (0.064 mmol) of compound 13 obtained in Example 13 and 12.1 mg (0.078 mmol) of L-serine methyl ester hydrochloride, 6.7 mg of sodium hydrogen carbonate (0.080 mmol), 3.4 mg (12%) of compound 56 was obtained.
1H NMR (500MHz, CDC13) δ ppm ； 8.43 (br s， IH), 7.47 (s, IH), 6.80 (d， J= 7.8Hz, 1H)， 5.77 (d, J=l.lHz, IH), 5.42 (s, IH), 5.09-5.06 (m, 2H), 3.83 (s, 3 H)， 2.22 (d, J=1.2Hz, 3H), 2.15-1.97 (m， 8H)， 1.67 (d, J=1.0Hz, 3H), 1.62 (d， J=l.lHz, 3H), 1.59 (s, 3H) 1H NMR (500MHz, CDC1 3) δ ppm; 8.43 (br s, IH), 7.47 (s, IH), 6.80 (d, J = 7.8Hz, 1H), 5.77 (d, J = l.lHz, IH) , 5.42 (s, IH), 5.09-5.06 (m, 2H), 3.83 (s, 3 H), 2.22 (d, J = 1.2 Hz, 3H), 2.15-1.97 (m, 8H), 1.67 (d, J = 1.0Hz, 3H), 1.62 (d, J = l.lHz, 3H), 1.59 (s, 3H)
FABMS m/z ； 459 (M+H )+ FABMS m / z; 459 (M + H) +
実施例 5 7 ： N-(4-フルフリルァミノ- 3,6-ジォキソシクロへキサ -1,4-ジェニ ル) -3,7,11-トリメチル -2，6，10-ドデカトリェンアミド （化合物 5 7 ) Example 57: N- (4-furfurylamino-3,6-dioxocyclohexa-1,4-genenyl) -3,7,11-trimethyl-2,6,10-dodecatrienamide (compound 57 )
実施例 4 5と同様の方法を用いて、 実施例 1 3で得られる化合物 1 3の 27.6 mg(0.074mmol)、 フルフリルァミン 10 l(O.llmmol)より、 化合物 5 7を 8.0m g(30%)得た。  Using a method similar to that of Example 45, 27.6 mg (0.074 mmol) of compound 13 obtained in Example 13 and 10 l (O.llmmol) of furfurylamine gave 8.0 mg (30%) of compound 57. Obtained.
1H NMR (500MHz, CDC13) δ ppm ； 8.49 (br s， IH), 7.44 (s, IH), 7.40-7.39 (m, IH), 6.38 (br t， J=5.8Hz, IH), 6.36-6.35 (m, 1H)， 6.31-6.30 (m， IH), 5.77 (d, J=0.9Hz, 1H)， 5.54 (s, IH), 5.09-5.06 (m, 2H), 4.32 (d, J=5.8Hz, 2H), 2.22 1H NMR (500MHz, CDC1 3) δ ppm; 8.49 (br s, IH), 7.44 (s, IH), 7.40-7.39 (m, IH), 6.38 (br t, J = 5.8Hz, IH), 6.36- 6.35 (m, 1H), 6.31-6.30 (m, IH), 5.77 (d, J = 0.9Hz, 1H), 5.54 (s, IH), 5.09-5.06 (m, 2H), 4.32 (d, J = 5.8Hz, 2H), 2.22
(d, J=1.2Hz， 3H), 2.20-1.97 (m, 8H)， 1.67 (d, J=1.0Hz, 3H), 1.62 (d， J=0.9Hz,(d, J = 1.2Hz, 3H), 2.20-1.97 (m, 8H), 1.67 (d, J = 1.0Hz, 3H), 1.62 (d, J = 0.9Hz,
3H), 1.60 (s, 3H) 3H), 1.60 (s, 3H)
FABMS m/z ； 437 (M+H)+ 実施例 5 8 ： N-[3，6-ジォキソ -4-(N-フエニルァミノ） シクロへキサ -1,4-ジェ ニル] -3,7,11-トリメチル -2,6,10-ドデカトリェンアミド (化合物 5 8 ) FABMS m / z; 437 (M + H) + Example 58: N- [3,6-dioxo-4- (N-phenylamino) cyclohexa-1,4-genenyl] -3,7,11-trimethyl-2,6,10-dodecatriene Amide (compound 58)
実施例 4 5と同様の方法を用いて、 実施例 1 3で得られる化合物 1 3の 22.0 mg(0.059mmol)とァニリン 10 l(O.llmmol)より、 化合物 5 8を 14.8mg(59 ) 得た。  Using a method similar to that in Example 45, 14.8 mg (59) of compound 58 was obtained from 22.0 mg (0.059 mmol) of compound 13 obtained in Example 13 and 10 l (O.ll mmol) of aniline. Was.
1H NMR (500MHz, CDC13) δ ppm ； 8.47 (s, IH), 7.76 (br s， 1H)， 7.53 (s, IH), 7.45-7.39 (m, 2H), 7.24-7.21 (m， 3H), 6.08 (s， IH), 5.78 (d, J=1.0Hz， 1H)， 5. 09-5.06 (m, 2H), 2.23 (d, J=1.2Hz, 3H), 2.21-1.97 (m, 8H)， 1.68(d, J=1.0Hz, 3 H)， 1.62 (d, J=1.0Hz, 3H), 1.60 (s, 3H) 1H NMR (500MHz, CDC1 3) δ ppm; 8.47 (s, IH), 7.76 (br s, 1H), 7.53 (s, IH), 7.45-7.39 (m, 2H), 7.24-7.21 (m, 3H) , 6.08 (s, IH), 5.78 (d, J = 1.0Hz, 1H), 5.09-5.06 (m, 2H), 2.23 (d, J = 1.2Hz, 3H), 2.21-1.97 (m, 8H ), 1.68 (d, J = 1.0Hz, 3H), 1.62 (d, J = 1.0Hz, 3H), 1.60 (s, 3H)
FABMS m/z ； 433 (M+H)+ FABMS m / z; 433 (M + H) +
実施例 5 9 ： N-[3,6-ジォキソ -4-(l-ピロリジノ） シクロへキサ -1，4-ジェニル] - 3,7,11-トリメチル -2,6,10-ドデカトリェンアミド （化合物 5 9 ) Example 59: N- [3,6-dioxo-4- (l-pyrrolidino) cyclohexa-1,4-genenyl] -3,7,11-trimethyl-2,6,10-dodecatrienamide (Compound 59)
実施例 4 5と同様の方法を用いて、 実施例 1 3で得られる化合物 1 3の 18.5 mg(0.049mmol)をメタノール 3mlに溶解し、 ピロリジン 10 l(0.15mmol)をカロ え、 化合物 5 9を 7.4mg(37%)得た。  Using the same method as in Example 45, 18.5 mg (0.049 mmol) of the compound 13 obtained in Example 13 was dissolved in 3 ml of methanol, and 10 l (0.15 mmol) of pyrrolidine was added to the solution. 7.4 mg (37%) was obtained.
1H NMR (500MHz, CDC13) δ ppm ； 8.50 (br s, 1H)， 7.34 (s, 1H)， 5.78 (d, J= 1.1Hz, IH), 5.46 (s, IH), 5.09-5.06 (m, 2H), 3.93 (br s， 4H), 3.34 (br s, 4H)， 2.22 (d, J=1.2Hz， 3H), 2.20-1.97 (m, 8H), 1.67 (d, J=l.lHz, 3H)1.62 (d, J=l.l Hz, 3H)， 1.60 (d, J=0.3Hz, 3H) 1H NMR (500MHz, CDC1 3) δ ppm; 8.50 (br s, 1H), 7.34 (s, 1H), 5.78 (d, J = 1.1Hz, IH), 5.46 (s, IH), 5.09-5.06 (m , 2H), 3.93 (br s, 4H), 3.34 (br s, 4H), 2.22 (d, J = 1.2Hz, 3H), 2.20-1.97 (m, 8H), 1.67 (d, J = l.lHz , 3H) 1.62 (d, J = ll Hz, 3H), 1.60 (d, J = 0.3Hz, 3H)
FABMS m/z ； 411 (M+H)+ FABMS m / z; 411 (M + H) +
実施例 6 0 ： N-[4-(N-メチルビペラジノ） -3,6-ジォキソシクロへキサ -1,4-ジェ ニル] -3,7,11-トリメチル -2,6,10-ドデカトリェンアミド (化合物 6 0 ) Example 60: N- [4- (N-methylbiperazino) -3,6-dioxocyclohexa-1,4-genenyl] -3,7,11-trimethyl-2,6,10-dodecatrenamide (Compound 60)
実施例 4 5と同様の方法を用いて、 実施例 1 3で得られる化合物 1 3の 23.9 mg(0.064mmol)、 1-メチルピペラジンフ β l(0.063mmol)より、 化合物 6 0を 12. 9mg(46%)を得た。  Using a method similar to that of Example 45, 12.9 mg of compound 60 was obtained from 23.9 mg (0.064 mmol) of compound 13 obtained in Example 13 and 1-methylpiperazinef βl (0.063 mmol). (46%).
1H NMR (500MHz, CDC13) δ ppm ； 8.28 (s, IH), 7.35 (s, 1H)， 5.76 (d， J=1.0 Hz, 1H)， 5.68 (s, IH), 5.09-5.06 (m， 2H), 3.62 (t, J=5.0Hz, 4H), 2.52 (t, 3=5.0 Hz, 4H), 2.32 (s, 3H)， 2.21 (d， J=1.2Hz, 3H)， 2.20-1.97 (m， 8H)， 1.67 (d， J=l. 1Hz, 3H), 1.61 (d, J=l.lHz, 3H), 1.59 (s, 3H) 1H NMR (500MHz, CDC1 3) δ ppm; 8.28 (s, IH), 7.35 (s, 1H), 5.76 (d, J = 1.0 Hz, 1H), 5.68 (s, IH), 5.09-5.06 (m, 2H), 3.62 (t, J = 5.0Hz, 4H), 2.52 (t, 3 = 5.0 Hz, 4H), 2.32 (s, 3H), 2.21 (d, J = 1.2Hz, 3H), 2.20-1.97 (m, 8H), 1.67 (d, J = l. 1Hz, 3H), 1.61 (d, J = l.lHz, 3H), 1.59 (s, 3H)
FABMS m/z ； 442 (M+3H)+ FABMS m / z; 442 (M + 3H) +
実施例 6 1 ： N-[4-(N-メチルビペラジノ） -3,6-ジォキソシクロへキサ -1,4-ジェ ニル ]_4-ベンジルォキシフエノキシァセトアミド （化合物 6 1 ) Example 61: N- [4- (N-methylbiperazino) -3,6-dioxocyclohexa-1,4-phenyl] _4-benzyloxyphenoxyacetamide (Compound 61)
実施例 1 4で得られる化合物 1 4の 21.9mg(0.055mmol) を 2 %メタノール のクロ口ホルム溶液に溶解し、 1-メチルピペラジン 12.0 l(O.l lmmol)を加え、 室温で 1 時間攪拌した後、 薄層クロマトグラフィー [クロ口ホルムノメ夕ノー ル = 98 I 2 (v/v)]で精製し、 化合物 6 1を 18.0mg(71%)得た。  After dissolving 21.9 mg (0.055 mmol) of compound 14 obtained in Example 14 in 2% methanol in chloroform, add 12.0 l (Ol lmmol) of 1-methylpiperazine and stir at room temperature for 1 hour. The resultant was purified by thin-layer chromatography [form-form-form no .: 98 I 2 (v / v)] to obtain 18.0 mg (71%) of compound 61.
1H NMR (500MHz, CDC13) <5 ppm ； 9.53 (br s, 1H)， 7.38 (s, 1H), 7.43-7.36 (m， 5H)， 6.93 (s, 5H), 5.71 (s, 1H), 5.02 (s, 2H)， 4.56 (s, 2H), 3.61-3.59 (m, 4H)， 2.54-2.52 (m, 4H), 2.32 (s, 3H) 1H NMR (500MHz, CDC1 3) <5 ppm; 9.53 (br s, 1H), 7.38 (s, 1H), 7.43-7.36 (m, 5H), 6.93 (s, 5H), 5.71 (s, 1H), 5.02 (s, 2H), 4.56 (s, 2H), 3.61-3.59 (m, 4H), 2.54-2.52 (m, 4H), 2.32 (s, 3H)
FABMS m/z ； 462 (M+H)+ FABMS m / z; 462 (M + H) +
実施例 6 2 ： N-[4-(N-メチルビペラジノ） -3,6-ジォキソシクロへキサ -1,4-ジェ ニル] -4-ベンジルォキシフエノキシァセトアミド塩酸塩 （化合物 6 2 ) Example 62: N- [4- (N-methylbiperazino) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide hydrochloride (compound 62)
実施例 6 1で得られる化合物 6 1を酢酸ェチルに溶解し、 0.88規定塩化水素 ノ酢酸ェチル溶液を加え、 生じた固体をろ別した後に、 真空乾燥し、 化合物 6 2を得た。  Compound 61 obtained in Example 61 was dissolved in ethyl acetate, a 0.88 N hydrogen chloride / ethyl acetate solution was added, and the resulting solid was filtered off, followed by vacuum drying to obtain compound 62.
1H NMR (500MHz, DMSO-d6) δ ppm ； 9.65 (s, 1H), 7.60-7.39 (m， 5H), 7.20 (s, 1H), 6.98-6.93 (m, 4H)， 5.98 (s， 1H), 5.04 (s, 2H), 4.79 (s, 2H), 4.20 (br s,1H NMR (500 MHz, DMSO-d 6 ) δ ppm; 9.65 (s, 1H), 7.60-7.39 (m, 5H), 7.20 (s, 1H), 6.98-6.93 (m, 4H), 5.98 (s, 1H ), 5.04 (s, 2H), 4.79 (s, 2H), 4.20 (br s,
2H), 3.41 (br s, 4H)， 3.14 (br s, 2H), 2.79 (s, 3H) 2H), 3.41 (br s, 4H), 3.14 (br s, 2H), 2.79 (s, 3H)
FABMS m/z ； 462 (M+H-HC1)+ FABMS m / z; 462 (M + H-HC1) +
実施例 6 3 ： N-(4-ァミノ- 5-クロ口- 3,6-ジォキソシクロへキサ -1,4-ジェエル)- 3，7，11-トリメチル -2,6,10-ドデカトリェンアミド (化合物 6 3 ) Example 63: N- (4-amino-5-chloro-3,6-dioxocyclohexa-1,4-jeel) -3,7,11-trimethyl-2,6,10-dodecatrienamide (Compound 63)
実施例 1 1で得られる化合物 1 1の 52mg(0.14mmol)をメタノール 2mlに溶 解し、 1規定アンモニア Zメタノール溶液を 0.5ml(0.5mmol)加えた。 室温で 1 0分間攪拌し、 減圧下に溶媒を留去した。 残渣を薄層クロマトグラフィー [ク ロロホルムノメタノール =99 I 1 (v/v)]で精製し、 化合物 6 3を 8.9mg(16%)得 た。 52 mg (0.14 mmol) of the compound 11 obtained in Example 11 was dissolved in 2 ml of methanol, and 0.5 ml (0.5 mmol) of a 1N ammonia Z methanol solution was added. The mixture was stirred at room temperature for 10 minutes, and the solvent was distilled off under reduced pressure. The residue is purified by thin-layer chromatography. [Roloformomethanol = 99 I 1 (v / v)] to obtain 8.9 mg (16%) of compound 63.
1H NMR (400MHz, CDC13) δ ppm ； 8.43 (br s， IH), 7.47 (s, IH), 6.10 (br s, IH), 5.77 (d, J=l.lHz, 1H)， 5.38 (br s, 1H)， 5.10-5.06 (m, 2H), 2.24-2.18 (m, 7H), 2.10-1.95 (m, 4H), 1.67 (d， J=l.lHz, 3H)， 1.62 (d, J=0.9Hz, 3H)， 1.59 (s, 3H) 1H NMR (400MHz, CDC1 3) δ ppm; 8.43 (br s, IH), 7.47 (s, IH), 6.10 (br s, IH), 5.77 (d, J = l.lHz, 1H), 5.38 (br s, 1H), 5.10-5.06 (m, 2H), 2.24-2.18 (m, 7H), 2.10-1.95 (m, 4H), 1.67 (d, J = l.lHz, 3H), 1.62 (d, J = 0.9Hz, 3H), 1.59 (s, 3H)
FABMS m/z ； 391 (M+H)+ FABMS m / z; 391 (M + H) +
実施例 6 4 ： N-(4-ェチルチオ- 3,6-ジォキソシクロへキサ -1,4-ジェニル) -3,7,1 1-トリメチル -2,6,10-ドデカトリェンアミド （化合物 6 4 ) Example 64: N- (4-Ethylthio-3,6-dioxocyclohexa-1,4-genenyl) -3,7,11-trimethyl-2,6,10-dodecatrienamide (Compound 64 )
実施例 1 3で得られる化合物 1 3の 21.0mg(0.056mmol)を塩化メチレン 30ml に溶解し、 エタンチオール 4.1 l(0.056mmol)、 次いでトリェチルァミン 8.4 l(0.056mmol)を加え、 室温で 1分間攪拌した。 通常の後処理の後、 薄層クロ マトグラフィ一（クロ口ホルム)で精製し、 化合物 6 4を 11.4mg(51%)得た。  Dissolve 21.0 mg (0.056 mmol) of compound 13 obtained in Example 13 in 30 ml of methylene chloride, add 4.1 l (0.056 mmol) of ethanethiol and then 8.4 l (0.056 mmol) of triethylamine, and stir at room temperature for 1 minute. did. After usual post-treatment, the product was purified by thin-layer chromatography (black-mouthed form) to obtain 11.4 mg (51%) of compound 64.
1H NMR (400MHz, CDC13) 6 ppm ； 8.08 (br s， IH), 7.63 (s, IH), 6.33 (s, 1H)， 1H NMR (400MHz, CDC1 3) 6 ppm; 8.08 (br s, IH), 7.63 (s, IH), 6.33 (s, 1H),
5.75 (d, J=1.0Hz, IH), 5.10-5.06 (br s， 2H)， 2.80 (q, J=7.4Hz, 2H)， 2.22 (d, J =1.2Hz, 3H)， 2.20-1.97 (m, 8H), 1.67 (d， J=1.2Hz, 3H), 1.61 (d, J=1.2Hz, 3H)，5.75 (d, J = 1.0Hz, IH), 5.10-5.06 (br s, 2H), 2.80 (q, J = 7.4Hz, 2H), 2.22 (d, J = 1.2Hz, 3H), 2.20-1.97 ( m, 8H), 1.67 (d, J = 1.2Hz, 3H), 1.61 (d, J = 1.2Hz, 3H),
1.60 (s, 3H), 1.40 (t, J=7.4Hz， 3H) 1.60 (s, 3H), 1.40 (t, J = 7.4Hz, 3H)
FABMS m/z ； 403 (M+2H)+ FABMS m / z; 403 (M + 2H) +
実施例 6 5 ： N-(4-ェチルチオ- 3,6-ジォキソシクロへキサ -1，4-ジェニル) -4-ベ ンジルォキシフエノキシァセトアミド （化合物 6 5 ) および N-[4,5-ビス（ェチ ルチオ) -3，6-ジォキソシクロへキサ -1,4-ジェニル] -4-ベンジルォキシフエノキシ ァセトアミド （化合物 6 6 ) Example 65: N- (4-ethylthio-3,6-dioxocyclohexa-1,4-genyl) -4-benzyloxyphenoxyacetamide (compound 65) and N- [4,5 -Bis (ethylthio) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 66)
実施例 1 4で得られる化合物 1 4の 73.1mg(0.18mmol) をァセトニトリル 24 mlに溶解し、 0.45%エタンチォ一ルのァセトニトリル溶液 6.0ml(0.365mmol)、 次いでリン酸バッファ一 (pH7.0)lmlを加え、 室温で 20時間攪拌した。 通常の 後処理の後、 薄層クロマトグラフィー [ クロ口ホルム/メタノール =98 / 2 (V /V)]で精製し、 化合物 6 5を 19.4mg(25%)および化合物 6 6を 15.6mg(18%)得た。 化合物 6 5 -73.1 mg (0.18 mmol) of compound 14 obtained in Example 14 was dissolved in 24 ml of acetonitrile, and a solution of 0.45% ethanethiol in acetonitrile 6.0 ml (0.365 mmol), and then phosphate buffer (pH 7.0) lml was added and the mixture was stirred at room temperature for 20 hours. After the usual work-up, the product was purified by thin-layer chromatography [closed-form / methanol = 98/2 (V / V)] to obtain 19.4 mg (25%) of compound 65 and 15.6 mg (18%) of compound 66. %)Obtained. Compound 6 5-
1H NMR (400MHz, CDC13) δ ppm ； 9.40 (br s， IH), 7.65 (s, 1H)， 7.43-7.29 1H NMR (400MHz, CDC1 3) δ ppm; 9.40 (br s, IH), 7.65 (s, 1H), 7.43-7.29
(m, 5H)， 6.94 (s, 4H)， 6.36 (s, IH), 5.03 (s, 2H), 4.57 (s， 2H)， 2.82 (q, 1=7.5(m, 5H), 6.94 (s, 4H), 6.36 (s, IH), 5.03 (s, 2H), 4.57 (s, 2H), 2.82 (q, 1 = 7.5
Hz, 2H)， 1.41 (t， J=7.5Hz, 3H) Hz, 2H), 1.41 (t, J = 7.5Hz, 3H)
FABMS m/z ； 425 (M+2H)+  FABMS m / z; 425 (M + 2H) +
化合物 6 6 Compound 6 6
1H NMR (400MHz, CDC13) δ ppm ； 9.42 (br s, 1H)， 7.59 (s, IH), 7.43-7.30 (m, 5H), 6.94 (br s, 4H)， 5.03 (s, 1H)， 4.57 (s, 2H), 3.27 (q, J=7.4Hz, 2H), 3. 05 (q, J=7.4Hz, 2H), 1.24 (t, J=7.3Hz, 3H), 1.22 (t, J=7.3Hz, 3H) 1H NMR (400MHz, CDC1 3) δ ppm; 9.42 (br s, 1H), 7.59 (s, IH), 7.43-7.30 (m, 5H), 6.94 (br s, 4H), 5.03 (s, 1H), 4.57 (s, 2H), 3.27 (q, J = 7.4Hz, 2H), 3.05 (q, J = 7.4Hz, 2H), 1.24 (t, J = 7.3Hz, 3H), 1.22 (t, J = 7.3Hz, 3H)
FABMS m/z ； 484 (M+H)+ FABMS m / z; 484 (M + H) +
実施例 6 6 ： N-(4-クロ口- 5-デカンチォ -3,6-ジォキソシクロへキサ -1，4-ジェ ニル )_4-ベンジルォキシフエノキシァセトアミド （化合物 6 7 ) および N-[4，5- ビス (デカンチォ) -3,6-ジォキソシクロへキサ -1，4-ジェニル] -4-ベンジルォキシ フエノキシァセトアミド （化合物 6 8 ) Example 66: N- (4-chloro-5-decane-3,6-dioxocyclohexa-1,4-phenyl) _4-benzyloxyphenoxyacetamide (compound 67) and N- [4,5-bis (decanethio) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (compound 68)
実施例 1 4で得られる化合物 1 4の 23.9mg(0.060mmol)をテトラヒドロフラ ン 10mlに溶解し、 デカンチオール 12.5 ii l(0.060mmol)、 次いでリン酸バッフ ァ一 （pH7.0)lmlを加え、 室温で 10分間攪拌した。 通常の後処理の後、 薄層ク 口マトグラフィ一（ク口口ホルム)で精製し、 化合物 6 7を 13.8mg(12%)および 化合物 6 8を 13.2mg(7.7%)得た。  23.9 mg (0.060 mmol) of compound 14 obtained in Example 14 was dissolved in 10 ml of tetrahydrofuran, and 12.5 il (0.060 mmol) of decanethiol was added thereto, followed by 1 ml of phosphate buffer (pH 7.0). Stirred at room temperature for 10 minutes. After usual work-up, purification was performed by thin-layer mouth chromatography (Kokuguchi-Horme) to obtain 13.8 mg (12%) of compound 67 and 13.2 mg (7.7%) of compound 68.
化合物 6 7 Compound 6 7
1H NMR (400MHz, CDCI3) δ ppm ； 9.36 (br s, IH), 7.75 (s, IH), 7.44-7.30 (m, 5H)， 6.95 (s, 4H)， 5.04 (s, 2H), 4.58 (s, 2H)， 3.24 (t, J=7.4Hz, 2H), 1.66- 0.80 (m, 19H)  1H NMR (400 MHz, CDCI3) δ ppm; 9.36 (br s, IH), 7.75 (s, IH), 7.44-7.30 (m, 5H), 6.95 (s, 4H), 5.04 (s, 2H), 4.58 ( s, 2H), 3.24 (t, J = 7.4Hz, 2H), 1.66- 0.80 (m, 19H)
FABMS m/z ； 572 (M+3H)+ FABMS m / z; 572 (M + 3H) +
化合物 6 8 Compound 6 8
1H NMR (400MHz, CDCI3) δ ppm ； 9.42 (br s, IH), 7.59 (s, IH), 7.44-7.29 (m, 5H)， 6.94 (s, 1H)， 5.03 (s, 2H), 4.57 (s, 2H), 3.23 (t, J=7.5Hz, 2H), 3.07 (d, J=7.3Hz, 2H), 1.66-0.80 (m, 38H) 1H NMR (400 MHz, CDCI3) δ ppm; 9.42 (br s, IH), 7.59 (s, IH), 7.44-7.29 (m, 5H), 6.94 (s, 1H), 5.03 (s, 2H), 4.57 ( s, 2H), 3.23 (t, J = 7.5Hz, 2H), 3.07 (d, J = 7.3Hz, 2H), 1.66-0.80 (m, 38H)
FABMS m/z ； 707 (M+3H)+ FABMS m / z; 707 (M + 3H) +
実施例 6 7 ： N-(4-エトキシカルボ二ルメチルチオ- 3,6-ジォキソへキサ -1,4- ジェニル) -4-ベンジルォキシフエノキシァセトアミド （化合物 6 9 ) および N- [4,5-ビス（エトキシカルボ二ルメチルチオ) -3,6-ジォキソへキサ -1，4-ジェニル 4- ベンジルォキシフエノキシァセトアミド （化合物 7 0 ) Example 67: N- (4-ethoxycarbonylmethylthio-3,6-dioxohexa-1,4-genyl) -4-benzyloxyphenoxyacetamide (compound 69) and N- [4 , 5-Bis (ethoxycarbonylmethylthio) -3,6-dioxohexa-1,4-genenyl 4-benzyloxyphenoxyacetamide (Compound 70)
実施例 1 4で得られる化合物 1 4の 27.5mg(0.069mmol)をァセトニトリル 30 mlに溶解した後、 0.75%のチォグリコール酸ェチルエステルのァセトニトリル 溶液 1.0ml(0.068mmol)を加え、 室温で 1 時間攪拌した。 フレミ一塩 28.7mg(0.1 1 mol)を加えて 10分間攪拌し、 通常の後処理を行った。 残渣を薄層クロマト グラフィ一 [ クロ口ホルム Zメタノール =98 I 2 (v/v)]で精製し、 化合物 6 9 を 7.0mg(21%)および化合物 7 0を 3.5mg(8.4%)得た。  After dissolving 27.5 mg (0.069 mmol) of compound 14 obtained in Example 14 in 30 ml of acetonitrile, 1.0 ml (0.068 mmol) of a 0.75% solution of ethyl thioglycolate in acetonitrile was added and stirred at room temperature for 1 hour. did. 28.7 mg (0.1 1 mol) of Fremi monosalt was added, and the mixture was stirred for 10 minutes, followed by ordinary post-treatment. The residue was purified by thin-layer chromatography [Cross-form-form Z methanol = 98 I 2 (v / v)] to obtain 7.0 mg (21%) of compound 69 and 3.5 mg (8.4%) of compound 70. .
化合物 6 9 Compound 6 9
1H NMR (400MHz, CDC13) d ppm ； 9.37 (br s, IH), 7.66 (s, 1H)， 7.43-7.30 (m, 5H), 6.96-6.90 (m, 4H), 6.48 (s, 1H)， 5.03 (s, 2H)， 4.57 (s, 2H), 4.24 (q, J=7.1Hz， 2H), 3.61 (s, 2H), 1.30 (t, J=7.1Hz， 3H) 1H NMR (400MHz, CDC1 3) d ppm; 9.37 (br s, IH), 7.66 (s, 1H), 7.43-7.30 (m, 5H), 6.96-6.90 (m, 4H), 6.48 (s, 1H) , 5.03 (s, 2H), 4.57 (s, 2H), 4.24 (q, J = 7.1Hz, 2H), 3.61 (s, 2H), 1.30 (t, J = 7.1Hz, 3H)
FABMS m/z ； 483 (M+3H)+ FABMS m / z; 483 (M + 3H) +
化合物 7 0 Compound 7 0
1H NMR (400MHz, CDC13) δ ppm ； 9.37 (br s， 1H)， 7.62 (s, IH), 7.43-7.30 (m, 5H), 6.96-6.91 (m, 4H), 5.03 (s, 2H)， 4.56 (s, 2H), 4.23-4.09 (m， 4H), 4.0 5 (s, 2H)， 3.82 (s, 2H), 1.29-1.22 (m, 6H) 1H NMR (400MHz, CDC1 3) δ ppm; 9.37 (br s, 1H), 7.62 (s, IH), 7.43-7.30 (m, 5H), 6.96-6.91 (m, 4H), 5.03 (s, 2H) , 4.56 (s, 2H), 4.23-4.09 (m, 4H), 4.05 (s, 2H), 3.82 (s, 2H), 1.29-1.22 (m, 6H)
FABMS m/z ； 601 (M+2H)+ FABMS m / z; 601 (M + 2H) +
実施例 6 8 ： N-(5-クロ口- 4-エトキシカルポ二ルメチルチオ- 3，6-ジォキソ -1，4 -ジェニル) -4-ベンジルォキシフエノキシァセトアミド （化合物 7 1 ) Example 68: N- (5-chloro-4-ethoxycarbonylmethylthio-3,6-dioxo-1,4-genenyl) -4-benzyloxyphenoxyacetamide (Compound 71)
実施例 6 5と同様の方法を用いて、 実施例 1 5で得られた化合物 1 5と 5% のチォグリコール酸ェチルエステルのァセトニトリル溶液 55 l(0.025mmol) より、 化合物 7 1を 4.7mg(38%)得た。
Figure imgf000055_0001
Using a method similar to that of Example 65, 4.7 mg (38%) of Compound 71 was obtained from 55 l (0.025 mmol) of a compound 15 obtained in Example 15 and 5% of ethyl thioglycolate in acetonitrile. %)Obtained.
Figure imgf000055_0001
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6·6 ミ ^ェ Γι 4 :β £Τ £LS£0/L6dr/lDd 6Ζ9.Ϊ/86 OAV ジェニル] -4-ベンジルォキシフエノキシァセトアミド （ィ匕合物 7 7 )
Figure imgf000056_0006
6 ・ 6 ^ ι 4ι 4: β £ Τ £ LS £ 0 / L6dr / lDd 6Ζ9.Ϊ / 86 OAV Genyl] -4-benzyloxyphenoxyacetamide
実施例 6 4と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 22.3 mg(0.056mmol)、 2-メルカプトプロピオン酸 4.9 H l(0.056mmol)およびトリェチ ルァミン 8.4 l(0.056mmol)より、 化合物 7 7を 6.2mg(24%)得た。  Using the same method as in Example 64, 22.3 mg (0.056 mmol) of compound 14 obtained in Example 14, 4.9 Hl (0.056 mmol) of 2-mercaptopropionic acid and 8.4 l (0.056 mmol) of triethylamine ), 6.2 mg (24%) of compound 77 was obtained.
1H NMR (400MHz, CDC13) δ ppm ； 12.4 (br s， IH), 9.73 (br s， 1H)， 7.44-7.30 1H NMR (400MHz, CDC1 3) δ ppm; 12.4 (br s, IH), 9.73 (br s, 1H), 7.44-7.30
(m, 6H), 6.98-6.91 (m, 4H), 6.63 (s, IH), 5.04 (s, 2H), 4.81 (s, 2H)， 3.09 (t,(m, 6H), 6.98-6.91 (m, 4H), 6.63 (s, IH), 5.04 (s, 2H), 4.81 (s, 2H), 3.09 (t,
J=7.0Hz, 2H), 2.67-2.64 (m, 2H) J = 7.0Hz, 2H), 2.67-2.64 (m, 2H)
FABMS m/z ； 469 (M+2H)+ FABMS m / z; 469 (M + 2H) +
実施例 7 5 ： N-[4-(2，3-ジヒドロキシプロピルチオ) -3，6-ジォキソシクロへキ サ -1,4-ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 7 8 ) 実施例 6 4と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 21.3 mg(0.054mmol)、 3-メルカプト- 1-プロパンジオール 4.5 ti l(0.054mmol)および トリェチルァミン 8.1 l(0.054mmol)より、 化合物 7 8を 6.5mg(25%)得た。 1H NMR (400MHz, DMSO-d6) 6 ppm ； 9.72 (br s, 1H)， 7.38 (s, IH), 7.46-7.30 (m, 5H)， 6.98-6.79 (m, 4H), 6.63 (s, 1H)， 5.20 (d, J=5.1Hz, IH), 5.04 (s, 2H), 4.81 (s， 2H), 4.78 (t, J=6.1Hz, 1H)， 3.70 (br s, 1H)， 3.47-3.38(m, IH), 3.37-3. 32 (m, IH), 3.12-3.06 (m, IH), 2.86-2.80 (m, IH) Example 75: N- [4- (2,3-dihydroxypropylthio) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 78) ) Using the same method as in Example 64, 21.3 mg (0.054 mmol) of compound 14 obtained in Example 14, 4.5 til (0.054 mmol) of 3-mercapto-1-propanediol and 8.1 l of triethylamine (0.054 mmol), 6.5 mg (25%) of compound 78 was obtained. 1H NMR (400 MHz, DMSO-d 6 ) 6 ppm; 9.72 (br s, 1H), 7.38 (s, IH), 7.46-7.30 (m, 5H), 6.98-6.79 (m, 4H), 6.63 (s, 1H), 5.20 (d, J = 5.1Hz, IH), 5.04 (s, 2H), 4.81 (s, 2H), 4.78 (t, J = 6.1Hz, 1H), 3.70 (br s, 1H), 3.47 -3.38 (m, IH), 3.37-3.32 (m, IH), 3.12-3.06 (m, IH), 2.86-2.80 (m, IH)
FABMS m/z ； 472 (M+3H)+ FABMS m / z; 472 (M + 3H) +
実施例 7 6 ： N-(3，6-ジォキソ -4-プロピルチオシクロへキサ -1,4-ジェニル) -4- ベンジルォキシフエノキシァセトアミド （化合物 7 9 ) Example 76: N- (3,6-Dioxo-4-propylthiocyclohexa-1,4-genenyl) -4-benzyloxyphenoxyacetamide (Compound 79)
実施例 6 4と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 21.3 mg(0.054mmol)、 1-プロパンチオール 4.9 l(0.054mmol)およびトリェチルアミ ン 8.1 H l(0.054mmol)より、 化合物 7 9を 17.4mg(74%)得た。  Using a method similar to that of Example 64, 21.3 mg (0.054 mmol) of compound 14 obtained in Example 14, 4.9 l (0.054 mmol) of 1-propanethiol and 8.1 Hl of triethylamine (0.054 mmol) were used. As a result, 17.4 mg (74%) of compound 79 was obtained.
1H NMR (400MHz, CDC13) δ ppm ； 9.40 (br s， IH), 7.65 (s， 1H)， 7.45-7.30 (m, 5H), 6.94 (br s, 4H), 6.35 (s, 1H)， 5.03 (s, 2H), 4.57 (s, 2H), 2.76(t, 3=7. 3Hz, 2H), 1.83-1.74 (m， 2H), 1.09 (t， J=7.3Hz, 3H) 1H NMR (400MHz, CDC1 3) δ ppm; 9.40 (br s, IH), 7.65 (s, 1H), 7.45-7.30 (m, 5H), 6.94 (br s, 4H), 6.35 (s, 1H), 5.03 (s, 2H), 4.57 (s, 2H), 2.76 (t, 3 = 7.3 Hz, 2H), 1.83-1.74 (m, 2H), 1.09 (t, J = 7.3 Hz, 3H)
FABMS m/z ； 439 (M+2H)+ /卜一 FABMS m / z; 439 (M + 2H) + / Uruichi
Figure imgf000058_0001
+
Figure imgf000058_0001
+
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寸 Q LΙΛ- ムs「寸:(l 8ς£i日- ,·  Dimension Q LΙΛ- m s `` Dimension: (l 8ς £ i day-,
(I¾寸2S ¾¾(6寸~S = 30 (m， 6H), 6.97-6.89 (m, 4H), 6.29 (s, 1H), 5.04 (s, 2H), 4.83 (s, 2H), 3.10 (s, 3H) (I¾2S¾¾ (6 寸 ~ S = 30 (m, 6H), 6.97-6.89 (m, 4H), 6.29 (s, 1H), 5.04 (s, 2H), 4.83 (s, 2H), 3.10 (s, 3H)
FABMS m/z ； 495 (M+3H)+ FABMS m / z; 495 (M + 3H) +
実施例 8 0 ： N-[4-(l-メチル -1H-テトラゾ一ル -5-ィルチオ) -3,6-ジォキソシク 口へキサ -1,4-ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 8 3 ) Example 80: N- [4- (l-methyl-1H-tetrazol-5-ylthio) -3,6-dioxocyclohexahexa-1,4-genyl] -4-benzyloxyphenoxy Cetamide (compound 83)
実施例 6 5と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 21.7 mg(0.055mmol)と 5-メルカプト- 1-メチルテトラゾール 6.3mg(0.054mmol)より、 化合物 8 3を 18.3mg(70%)得た。  Using a method similar to that of Example 65, Compound 83 was obtained from 21.7 mg (0.055 mmol) of Compound 14 obtained in Example 14 and 6.3 mg (0.054 mmol) of 5-mercapto-1-methyltetrazole. 18.3 mg (70%) was obtained.
1H NMR (400MHz, CDC13) δ ppm ； 9.35 (br s, 1H)， 7.77 (s, 1H), 7.43-7.29 (m， 5H), 6.93 (m, 4H)， 6.82 (s, 1H)， 5.03 (s, 2H)， 4.58 (s, 2H)， 4.13 (s, 3H) FABMS m/z ； 480 (M+3H)+ 1H NMR (400MHz, CDC1 3) δ ppm; 9.35 (br s, 1H), 7.77 (s, 1H), 7.43-7.29 (m, 5H), 6.93 (m, 4H), 6.82 (s, 1H), 5.03 (s, 2H), 4.58 (s, 2H), 4.13 (s, 3H) FABMS m / z; 480 (M + 3H) +
実施例 8 1 ： N-{4-[5-メチル -(1，3，4)チアジアゾ一ル -2-ィルチオ] -3,6-ジォキ ソシクロへキサ -1,4-ジェニル}-4-ベンジルォキシフエノキシァセトアミド （化 合物 8 4 ) Example 81: N- {4- [5-methyl- (1,3,4) thiadiazol-2-ylthio] -3,6-dioxocyclohexa-1,4-genyl} -4-benzyl Oxyphenoxyacetamide (compound 84)
実施例 6 5と同様の方法をより、 実施例 1 4で得られる化合物 1 4の 21.0m g(0.053mmol)と 5-メチル -1,3,4-チアジアゾ一ル -2-チオール 5.6mg(0.056mmol)よ り、 化合物 8 4を 19.1mg(73%) 得た。  According to the same method as that of Example 65, 21.0 mg (0.053 mmol) of compound 14 obtained in Example 14 and 5.6 mg of 5-methyl-1,3,4-thiadiazol-2-thiol (0.056 mmol), 19.1 mg (73%) of compound 84 was obtained.
1H NMR (400MHz, CDCI3 I CD3OD = 9 / 1) δ ppm ； 7.63 (s， 1H), 7.35-7.28 (m, 5H), 6.86 (m, 4H), 6.48 (s, 1H), 4.95 (s, 2H), 4.52 (s, 2H)， 2.81 (s, 3H) FABMS m/z ； 496 (M+3H)+ 1H NMR (400MHz, CDCI3 I CD 3 OD = 9/1) δ ppm; 7.63 (s, 1H), 7.35-7.28 (m, 5H), 6.86 (m, 4H), 6.48 (s, 1H), 4.95 ( s, 2H), 4.52 (s, 2H), 2.81 (s, 3H) FABMS m / z; 496 (M + 3H) +
実施例 8 2 ： N-{4-[5-ァミノ -(1,3,4)チアジァゾール -2-ィルチオ] -3,6-ジォキ ソシクロへキサ -1，4-ジェニル}-4-ベンジルォキシフエノキシァセトアミド （ィ匕 合物 8 5 ) Example 82: N- {4- [5-amino- (1,3,4) thiaziazol-2-ylthio] -3,6-dioxocyclohexa-1,4-genyl} -4-benzyloxy Phenoxyacetamide
実施例 1 4で得られる化合物 1 4の 15.0mg(0.038mmol) を塩化メチレン 30 mlに溶解し、 5-ァミノ- 2-メルカプト- 1,3,4-チアジアゾ一ル 5.2mg(0.039mmol)、 トリェチルァミン 5.7 a l(0.038mmol)を加え、 室温で 10分間攪拌した。 生じ
Figure imgf000060_0001
15.0 mg (0.038 mmol) of compound 14 obtained in Example 14 was dissolved in 30 ml of methylene chloride, and 5-amino-2-mercapto-1,3,4-thiadiazol 5.2 mg (0.039 mmol), 5.7 al (0.038 mmol) of triethylamine was added, and the mixture was stirred at room temperature for 10 minutes. Arising
Figure imgf000060_0001
実施例 6 4と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 18.4 mg(0.046mmol)、 2-メルカプトべンゾチアゾ一ル 7.7mg(0.046mmol)およびトリ ェチルァミン 6.9 β l(0.046mmol)より、 化合物 8 8を 16.8mg(69%)得た。 Using a method similar to that of Example 64, 18.4 mg (0.046 mmol) of compound 14 obtained in Example 14, 7.7 mg (0.046 mmol) of 2-mercaptobenzothiazole and 6.9 βl of triethylamine ( 0.046 mmol) to give 16.8 mg (69%) of compound 88.
1H NMR (400MHz, CDC13) δ ppm ； 9.34 (br s， 1H)， 8.14-7.49 (m, 4H), 7.74 (s, 1H)， 7.42-7.29 (m, 5H), 6.92 (m， 4H)， 6.90 (s, 1H), 5.02 (s, 2H), 4.58 (s, 2H) 1H NMR (400MHz, CDC1 3) δ ppm; 9.34 (br s, 1H), 8.14-7.49 (m, 4H), 7.74 (s, 1H), 7.42-7.29 (m, 5H), 6.92 (m, 4H) , 6.90 (s, 1H), 5.02 (s, 2H), 4.58 (s, 2H)
FABMS m/z ； 530 (M+2H)+ FABMS m / z; 530 (M + 2H) +
実施例 8 6 ： N-[3，6-ジォキソ -4-(4-ピリジルチオ） シクロへキサ -1,4-ジェニ ル] -4-ベンジルォキシフエノキシァセトアミド （化合物 8 9 ) Example 86: N- [3,6-dioxo-4- (4-pyridylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 89)
実施例 6 5と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 20.7 mg(0.052mmol)と、 4-メルカプトピリジン 5.8mg(0.052mmol)より、 化合物 8 9 を 8.4mg(34%)得た。  Using a method similar to that of Example 65, 8.4 mg of compound 89 was obtained from 20.7 mg (0.052 mmol) of compound 14 obtained in Example 14 and 5.8 mg (0.052 mmol) of 4-mercaptopyridine. 34%).
1H NMR (500MHz, CDC13) 6 ppm ； 9.33 (br s， 1H), 8.76-8.75 (m, 2H), 7.46-7. 44 (m, 2H), 7.72 (s, 1H), 7.42-7.32 (m， 5H), 6.94-6.90 (m, 4H), 5.99 (s, 1H), 5.02 (s, 2H)， 4.47 (s, 2H) 1H NMR (500MHz, CDC1 3) 6 ppm;. 9.33 (br s, 1H), 8.76-8.75 (m, 2H), 7.46-7 44 (m, 2H), 7.72 (s, 1H), 7.42-7.32 ( m, 5H), 6.94-6.90 (m, 4H), 5.99 (s, 1H), 5.02 (s, 2H), 4.47 (s, 2H)
FABMS m/z ； 475 (M+3H)+ FABMS m / z; 475 (M + 3H) +
実施例 8 7 ： N-[3，6-ジォキソ -4-(2-ピリジルチオ） シクロへキサ -1,4-ジェニ ル ]_4-ベンジルォキシフエノキシァセトアミド （化合物 9 0 ) Example 87: N- [3,6-dioxo-4- (2-pyridylthio) cyclohexa-1,4-phenyl] _4-benzyloxyphenoxyacetamide (Compound 90)
実施例 6 5と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 21.7 mg(0.055mmol)と 2-メルカプトピリジン 6.0mg(0.054mmol)より、 化合物 9 0を 2.0mg(7.8%)得た。  Using a method similar to that of Example 65, 2.0 mg (7.8 mg) of compound 90 was obtained from 21.7 mg (0.055 mmol) of compound 14 obtained in Example 14 and 6.0 mg (0.054 mmol) of 2-mercaptopyridine. %)Obtained.
1H NMR (400MHz, CDCI3) δ ppm ； 9.35 (br s, 1H), 8.74-7.16 (m, 11H), 6.95 (s, 4H)， 5.99 (s, 1H), 5.04 (s， 2H), 4.59 (s, 2H)  1H NMR (400 MHz, CDCI3) δ ppm; 9.35 (br s, 1H), 8.74-7.16 (m, 11H), 6.95 (s, 4H), 5.99 (s, 1H), 5.04 (s, 2H), 4.59 ( s, 2H)
FABMS m/z ； 475 (M+3H)+ FABMS m / z; 475 (M + 3H) +
実施例 8 8 ： N-[4-(3，4,5-トリァセトキシ -6-ァセトキシメチルテトラヒドロ ピラン- 2-ィルチオ) -3,6-ジォキソシクロへキサ -1,4-ジェニル] -4-ベンジルォキシ フエノキシァセトアミド （化合物 9 1 ) 実施例 6 4と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 6.9 mg(0.043mmol)、 1-チォ - ;3 -D-グルコーステトラァセテ一ト 15.5mg(0.043mmol) およびトリェチルアミン 6.4 l(0.043mmol)より、 化合物 9 1を 25.3mg(82%) 得た。 Example 88: N- [4- (3,4,5-triacetoxy-6-acetoxymethyltetrahydropyran-2-ylthio) -3,6-dioxocyclohexa-1,4-genyl] -4- Benzyloxy phenoxyacetamide (Compound 91) Using a method similar to that of Example 64, 6.9 mg (0.043 mmol) of compound 14 obtained in Example 14 and 15.5 mg of 1-thio-; 3-D-glucose tetraacetate (0.043 mmol) ) And 6.4 l (0.043 mmol) of triethylamine to give 25.3 mg (82%) of compound 91.
1H NMR (400MHz, CDC13) δ ppm ； 9.34 (br s， IH), 7.68 (s， IH), 7.43-7.30 (m, 5H), 6.94 (m， 4H), 6.66 (s, 1H)， 5.33-5.21 (m， 2H)， 5.12-5.06 (m, 1H)， 5.0 3 (s, 2H), 4.88 (d， J=1.0Hz, 1H)， 4.57 (s， 2H), 4.24-4.10 (m, 2H)， 3.88-3.83 (m, IH), 2.12 (s, 3H), 2.06 (s, 3H), 2.05 (s， 3H)， 2.02 (s, 3H) 1H NMR (400MHz, CDC1 3) δ ppm; 9.34 (br s, IH), 7.68 (s, IH), 7.43-7.30 (m, 5H), 6.94 (m, 4H), 6.66 (s, 1H), 5.33 -5.21 (m, 2H), 5.12-5.06 (m, 1H), 5.03 (s, 2H), 4.88 (d, J = 1.0Hz, 1H), 4.57 (s, 2H), 4.24-4.10 (m, 2H), 3.88-3.83 (m, IH), 2.12 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H)
FABMS m/z ； 728 (M+3H)+ FABMS m / z; 728 (M + 3H) +
実施例 8 9 ： N-(3，6-ジォキソ -4-フエ二ルチオシクロへキサ -1,4-ジェニル) -4- ベンジルォキシフエノキシァセトアミド （化合物 9 2 ) Example 89: N- (3,6-dioxo-4-phenylthiocyclohexa-1,4-genyl) -4-benzyloxyphenoxyacetamide (compound 92)
実施例 6 5と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 24.2 mg(0.061mmol)と 0.63 %のチォフエノールのァセトニトリル溶液 1.0ml(0.061m mol)より、 化合物 9 2を 117.5mg(61%)得た。  Using the same method as in Example 65, Compound 9 2 was obtained from 24.2 mg (0.061 mmol) of compound 14 obtained in Example 14 and 1.0 ml (0.061 mmol) of 0.63% thiophenol in acetonitrile. 117.5 mg (61%) were obtained.
1H NMR (400MHz, CDC13) δ ppm ； 9.32 (br s, IH), 7.67 (s, IH), 7.52-7.49 (m, 5H), 7.42-7.29 (m， 5H), 6.94-6.88 (m, 4H), 5.86 (s, IH), 5.02 (s, 2H), 4.5 6 (s, 2H) 1H NMR (400MHz, CDC1 3) δ ppm; 9.32 (br s, IH), 7.67 (s, IH), 7.52-7.49 (m, 5H), 7.42-7.29 (m, 5H), 6.94-6.88 (m, 4H), 5.86 (s, IH), 5.02 (s, 2H), 4.5 6 (s, 2H)
FABMS m/z ； 473 (M+2H)+ FABMS m / z; 473 (M + 2H) +
実施例 9 0 ： N-[4-(4-ヒドロキシフエ二ルチオ) -3，6-ジォキソシクロへキサ -1， 4-ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 9 3 ) Example 90: N- [4- (4-hydroxyphenylthio) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (compound 93)
実施例 6 5と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 19.6 mg(0.049mmol)と 4-ヒドロキシチオフエノ一ル 8.0mg(0.063mmol)より、 化合物 9 3を 9.7mg(40%)得た。  Using a method similar to that of Example 65, Compound 93 was obtained from 19.6 mg (0.049 mmol) of Compound 14 obtained in Example 14 and 8.0 mg (0.063 mmol) of 4-hydroxythiophenol. 9.7 mg (40%) were obtained.
1H NMR (400MHz, CDC13) δ ppm ； 9.32 (br s, 1H)， 7.66 (s, IH), 7.40-7.30 (m, 5H)， 6.96-6.91 (m, 8H), 5.86 (s, IH), 5.29 (br s， 1H)， 5.02 (s, 2H), 4.56 (s, 2H) 1H NMR (400MHz, CDC1 3) δ ppm; 9.32 (br s, 1H), 7.66 (s, IH), 7.40-7.30 (m, 5H), 6.96-6.91 (m, 8H), 5.86 (s, IH) , 5.29 (br s, 1H), 5.02 (s, 2H), 4.56 (s, 2H)
FABMS m/z ； 489 (M+2H)+ 実施例 9 1 ： N-[4-(4-ァミノフエ二ルチオ) -3,6-ジォキゾシクロへキサ -1,4-ジ ェニル ]-4-ベンジルォキシフエノキシァセトアミド （化合物 9 4 ) FABMS m / z; 489 (M + 2H) + Example 91: N- [4- (4-aminophenylthio) -3,6-dioxocyclohexa-1,4-dienyl] -4-benzyloxyphenoxyacetamide (compound 94)
実施例 6 4と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 20.8 mg(0.052mmol)、 4-アミノチオフエノ一ル 7.0mg(0.056mmol)およびトリエチル ァミン 7.9 l(0.053mmol)より、 化合物 9 4を 16.2mg(64%)得た。  Using a method similar to that in Example 64, 20.8 mg (0.052 mmol) of compound 14 obtained in Example 14, 7.0 mg (0.056 mmol) of 4-aminothiophenol and 7.9 l (0.053 mmol) of triethylamine were used. As a result, 16.2 mg (64%) of compound 94 was obtained.
1H NMR (400MHz, CDC13) δ ppm ； 9.31 (br s, IH), 7.62 (s, IH), 7.41-7.28 (m, 5H)， 7.23-7.19 (m, 2H)， 6.93-6.88 (m, 4H)， 6.74-6.71 (m, 2H), 5.89 (s, 1 H)， 5.00 (s, 2H), 4.54 (s， 2H)， 4.01 (br s， 2H) 1H NMR (400MHz, CDC1 3) δ ppm; 9.31 (br s, IH), 7.62 (s, IH), 7.41-7.28 (m, 5H), 7.23-7.19 (m, 2H), 6.93-6.88 (m, 4H), 6.74-6.71 (m, 2H), 5.89 (s, 1H), 5.00 (s, 2H), 4.54 (s, 2H), 4.01 (br s, 2H)
FABMS m/z ； 488 (M+2H)+ FABMS m / z; 488 (M + 2H) +
実施例 9 2 ： N-[4-(3-ァミノフエ二ルチオ) -3,6-ジォキソシクロへキサ- 1,4-ジ ェニル ]-4-ベンジルォキシフエノキシァセトアミド （化合物 9 5 ) Example 92: N- [4- (3-aminophenylthio) -3,6-dioxocyclohexa-1,4-dienyl] -4-benzyloxyphenoxyacetamide (Compound 95)
実施例 6 4と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 16.1 mg(0.041mmol)、 3-ァミノベンゼンチオール 4.3 l(0.041mmol)およびトリェチ ルァミン 6.1 l(0.041mmol)より、 化合物 9 5を 10.0mg(51%) 得た。  Using the same method as in Example 64, 16.1 mg (0.041 mmol) of compound 14 obtained in Example 14, 4.3 l (0.041 mmol) of 3-aminobenzenethiol and 6.1 l (0.041 mmol) of triethylamine were obtained. ), 10.0 mg (51%) of compound 95 was obtained.
1H NMR (400MHz, CDC13) δ ppm ； 9.33 (br s, IH), 7.66 (s, IH), 7.42-7.27 (m， 5H), 6.99-6.90 (m, 4H)， 6.87-6.76 (m, 4H)， 5.99 (s, IH), 5.02 (s, 2H), 4.5 6 (s, 2H), 3.82 (br s， 2H) 1H NMR (400MHz, CDC1 3) δ ppm; 9.33 (br s, IH), 7.66 (s, IH), 7.42-7.27 (m, 5H), 6.99-6.90 (m, 4H), 6.87-6.76 (m, 4H), 5.99 (s, IH), 5.02 (s, 2H), 4.5 6 (s, 2H), 3.82 (br s, 2H)
FABMS m/z ； 488 (M+2H)+ FABMS m / z; 488 (M + 2H) +
実施例 9 3 ： N-[4-(2-カルポキシフエ二ルチオ) -3，6-ジォキソシクロへキサ -1， 4-ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 9 6 ) Example 93: N- [4- (2-carboxyphenylthio) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 96)
実施例 6 4と同様の方法を用いて、 実施例 1 4で得られる化合物 1 4の 15.3 mg(0.038mmol)、 チォサリチル酸 5.8mg(0.038mmol)およびトリェチルァミン 5. 8 l(0.039mmol)より、 化合物 9 6を 2.4mg(12%)得た。  Using a method similar to that of Example 64, from 15.3 mg (0.038 mmol) of compound 14 obtained in Example 14, 5.8 mg (0.038 mmol) of thiosalicylic acid, and 5.8 l (0.039 mmol) of triethylamine, 2.4 mg (12%) of compound 96 was obtained.
1H NMR (400MHz, CDC13) δ ppm ； 9.29 (br s, 1H)， 8.05 (s, 1H)， 7.62 (s, IH), 7.59 (s, 3H), 7.41-7.29 (m, 5H)， 6.93-6.87 (m, 4H)， 5.81 (m, IH), 5.00 (s, 2 H), 4.54 (s, 2H) 1H NMR (400MHz, CDC1 3) δ ppm; 9.29 (br s, 1H), 8.05 (s, 1H), 7.62 (s, IH), 7.59 (s, 3H), 7.41-7.29 (m, 5H), 6.93 -6.87 (m, 4H), 5.81 (m, IH), 5.00 (s, 2 H), 4.54 (s, 2H)
FABMS m/z； 517 (M+2H)+ W 実施例 9 4 ： N-(6，6-ジメトキシ -5-フエ二ルチオ- 3-ォキソシクロへキシ -1-ェ ニル )_4-ベンジルォキシフエノキシァセトアミド (化合物 9 7 )、 N-{6,6-ジメト キシ 5-(3-ァミノフエニル)チォ -3-ォキソシク口へキシ -1-ェニル }-4-ベンジルォ キシフエノキシァセトアミド (化合物 1 0 0 )、 N-{6，6-ジメトキシ 5-(4-フルォ 口フエニル)チォ -3-ォキソシクロへキシ -1-ェニル }-4-ベンジルォキシフエノキ シァセトアミド (化合物 1 0 8 )、 N-{6，6-ジメトキシ 5-(3-ブロモフエニル)チォ- 3-ォキソシクロへキシ -1-ェニル }-4-ベンジルォキシフエノキシァセトアミド (化 合物 1 1 0 )、 N-{6,6-ジメトキシ 5-(2-ブロモフエニル)チォ -3-ォキソシクロへ キシ -1-ェニル }-4-ベンジルォキシフエノキシァセトアミド (化合物 1 1 1 )、 N- {6，6-ジメトキシ 5-(3-クロロフェニル)チォ -3-ォキソシクロへキシ -1-ェニル }-4- ベンジルォキシフエノキシァセトアミド (化合物 1 1 3 )、 N-{6，6-ジメトキシ 5- (2-クロ口フエニル)チォ -3-ォキソシク口へキシ -1-ェニル }-4-ベンジルォキシフ エノキシァセトアミド (化合物 1 1 4 )、 N-(6，6-ジメトキシ -5-カルボキシメチル チォ -3-ォキソシク口へキシ -1-ェニル )-4-ベンジルォキシフエノキシァセ卜アミ ド (化合物 1 1 6 )、 N-(6,6-ジメトキシ -5-メトキシカルポ二ルメチルチオ- 3-ォキ ソシク口へキシ -1-ェニル )-4-ベンジルォキシフエノキシァセトアミド (化合物 1 1 7 )、 N-{6，6-ジメトキシ 5-(2-ヒドロキシェチル)チォ -3-ォキソシクロへキ シ小ェ二ル}-4-ベンジルォキシフエノキシァセトアミド (化合物 1 2 1 )、 N-{6, 6-ジメトキシ 5-(2-メルカプトェチル)チォ -3-ォキソシクロへキシ -1-ェニル }-4- ベンジルォキシフエノキシァセトアミド (化合物 1 2 3 )、 N-{6，6-ジメトキシ 5- (2,3-ジヒドロキシプロピル)チォ -3-ォキソシクロへキシ -1-ェニル }-4-ベンジル ォキシフエノキシァセトアミド (化合物 1 2 4 )、 N-(6，6-ジメトキシ- 5-カルポキ シェチルチオ- 3-ォキソシク口へキシ -1-ェニル )-4-ベンジルォキシフエノキシァ セトアミド (化合物 1 2 5 )および N-(6,6-ジメトキシ -5-エトキシカルポニルェ チルチオ- 3-ォキソシク口へキシ -1-ェニル )-4-ベンジルォキシフエノキシァセト アミド (化合物 1 2 6 ) FABMS m / z; 517 (M + 2H) + W Example 94: N- (6,6-dimethoxy-5-phenylthio-3-oxocyclohex-1-enyl) _4-benzyloxyphenoxyacetamide (compound 97), N- {6,6-Dimethoxy 5- (3-aminophenyl) thio-3-oxocyclohex-1-enyl} -4-benzyloxyphenoxyacetamide (Compound 100), N- {6,6 -Dimethoxy 5- (4-fluorophenyl) thio-3-oxocyclohex-1-enyl} -4-benzyloxyphenoxyacetamide (Compound 108), N- {6,6-dimethoxy 5- ( 3-bromophenyl) thio-3-oxocyclohex-1-enyl} -4-benzyloxyphenoxyacetamide (compound 110), N- {6,6-dimethoxy 5- (2-bromophenyl) ) Thio-3-oxocyclohex-1-enyl} -4-benzyloxyphenoxyacetamide (compound 111), N- {6,6-dimethoxy 5- (3-chlorophenyl) thio-3- O Socyclohex-1-enyl} -4-benzyloxyphenoxyacetamide (compound 113), N- {6,6-dimethoxy 5- (2-chlorophenyl) thio-3-oxo Xy-1-enyl} -4-benzyloxyfoxyacetoamide (compound 114), N- (6,6-dimethoxy-5-carboxymethylthio-3-oxocyclohexyl-1-enyl) -4- Benzyloxyphenoxyacetamide (Compound 1 16), N- (6,6-dimethoxy-5-methoxycarbonylmethylthio-3-oxocyclohexyl-1-enyl) -4-benzyl Oxyphenoxyacetamide (Compound 1 17), N- {6,6-dimethoxy 5- (2-hydroxyethyl) thio-3-oxocyclohexyl} -4-benzyloxy Phenoxyacetamide (compound 12 21), N- {6,6-dimethoxy 5- (2-mercaptoethyl) thio-3-oxocyclohex-1-enyl} -4-benzyloxy Phenoxyacetamide (compound 123), N- {6,6-dimethoxy 5- (2,3-dihydroxypropyl) thio-3-oxocyclohex-1-enyl} -4-benzyloxyphenoxy Ciacetoamide (Compound 124), N- (6,6-dimethoxy-5-carboxyshethylthio-3-oxocyclohex-1-enyl) -4-benzyloxyphenoxyacetamide (Compound 125 ) And N- (6,6-dimethoxy-5-ethoxycarbonylethylthio-3-oxocyclohexenyl-1-enyl) -4-benzyloxyphenoxyacetamide (Compound 126)
実施例 2で得られる化合物 2の 50.7mg(0.124 mmol)をクロ口ホルム / メタ ノール = 2 / 1の混合溶液 25.5mlに溶解し、 トリエチルァミン 18.7 1(0.134 mmol)を加え、 16等分した。 それぞれにチオフエノ一ル 1.3 1(0.013 mmol), 3-アミノチォフエノール 1.2 1(0.011 mmol), 4-フルォロチオフエノ一ル 1.2 1(0.011 mmol)、 3-ブロモチォフエノール 1.2 1(0.012 mmol), 2-ブロモチォ フエノール 1.4 H 1(0.012 mmol)、 3-クロロチオフエノ一ル 1.3 1(0.011 mmo 、 2-クロロチォフエノール 1.3 1(0.011 mmol)、 チォグリコール酸 0.8 H 1C0.012 mmol), チォグリコール酸メチル 1.0 X 1(0.011 mmol), メルカプトエタノー ル 0.8 1(0.011 mmol), 1,2-エタンジチオール 1.0 1(0.012 mmol), 3-メルカ ブト- 1，2-プロパンジオール 1.0 II 1(0.012 mmol)、 3-メルカプトプロピオン酸 1. 0 1(0.011 mmol), 3-メルカプトプロピオン酸ェチル 1.0 1(0.007 mmol)をカロ え、 次いで室温で 1時間 30分超音波にかけた後、 遠心濃縮機で濃縮し、 化合 物 9 7、 化合物 1 0 0、 化合物 1 0 8、 化合物 1 1 0、 化合物 1 1 1、 化合物 1 1 3、 化合物 1 1 4、 化合物 1 1 6、 化合物 1 1 7、 化合物 1 2 1、 化合物 1 2 3、 化合物 1 2 4、 化合物 1 2 5および化合物 1 2 6を得た。 50.7 mg (0.124 mmol) of compound 2 obtained in Example 2 The mixture was dissolved in 25.5 ml of a mixed solution of knol = 2/1, triethylamine 18.71 (0.134 mmol) was added, and the mixture was divided into 16 equal parts. Thiofenol 1.31 (0.013 mmol), 3-aminothiophenol 1.21 (0.011 mmol), 4-fluorothiophenol 1.21 (0.011 mmol), 3-bromothiophenol 1.21 (0.012 mmol) ), 2-bromothiophenol 1.4 H 1 (0.012 mmol), 3-chlorothiophenol 1.31 (0.011 mmol, 2-chlorothiophenol 1.31 (0.011 mmol), thioglycolic acid 0.8 H 1C 0.012 mmol), thioglycol Methyl acid 1.0 X 1 (0.011 mmol), mercaptoethanol 0.8 1 (0.011 mmol), 1,2-ethanedithiol 1.01 (0.012 mmol), 3-mercapto-1,2-propanediol 1.0 II 1 (0.012 mmol) ), 3-mercaptopropionic acid 1.01 (0.011 mmol), 3-ethylethyl mercaptopropionate 1.01 (0.007 mmol), and then sonicated at room temperature for 1 hour 30 minutes, then concentrated by centrifugal concentrator Compound 97, Compound 100, Compound 108, Compound 110, Compound 111, Compound 113, Compound 113 Objects 1 1 4, Compound 1 1 6, Compound 1 1 7, Compound 1 2 1 Compound 1 2 3 Compound 1 2 4 to give Compound 1 2 5 and Compound 1 2 6.
化合物 9 7 Compound 9 7
FABMS m/z ； 520 (M+H)+ FABMS m / z; 520 (M + H) +
化合物 1 0 0 Compound 1 0 0
FABMS m/z ； 535 (M+H)+ FABMS m / z; 535 (M + H) +
化合物 1 0 8 Compound 1 0 8
FABMS m/z ； 538 ( +H)+ FABMS m / z; 538 (+ H) +
化合物 1 1 0 Compound 1 1 0
FABMS m/z ； 598 (M+H)+ FABMS m / z; 598 (M + H) +
化合物 1 1 1 Compound 1 1 1
FABMS m/z ； 598 (M+H)+ FABMS m / z; 598 (M + H) +
化合物 1 1 3 Compound 1 1 3
FABMS m/z ； 554 (M+H)+ FABMS m / z; 554 (M + H) +
化合物 1 1 4 FABMS m/z ； 554 (M+H)+ Compound 1 1 4 FABMS m / z; 554 (M + H) +
化合物 1 1 6 Compound 1 1 6
FABMS m/z ； 502 (M+H)+ FABMS m / z; 502 (M + H) +
化合物 1 1 7 Compound 1 1 7
FABMS m/z ； 516 (M+H)+ FABMS m / z; 516 (M + H) +
化合物 1 2 1 Compound 1 2 1
FABMS m/z ； 487 (M)+ FABMS m / z; 487 (M) +
化合物 1 2 3 Compound 1 2 3
FABMS m/z ； 504 (M+H)+ FABMS m / z; 504 (M + H) +
化合物 1 2 4 Compound 1 2 4
FABMS m/z ； 518 (M+H)+ FABMS m / z; 518 (M + H) +
化合物 1 2 5 Compound 1 2 5
FABMS m/z ； 516 (M+H)+ FABMS m / z; 516 (M + H) +
化合物 1 2 6 Compound 1 2 6
FABMS m/z ； 544 (M+H)+ FABMS m / z; 544 (M + H) +
実施例 9 5 ： N-(6，6-ジメトキシ 5-ベンジルチオ- 3-ォキソシクロへキシ -1-ェ ニル) -4-ベンジルォキシフエノキシァセトアミド (化合物 9 8 )、 N-{6,6-ジメト キシ 5-(4-ァセトアミドフエ二ル)チォ -3-ォキソシクロへキシ -1-ェニル }-4-ベン ジルォキシフエノキシァセトアミド (化合物 1 0 1 )、 N-(6，6-ジメトキシ -5-カル ポキシフエ二ルチオ- 3-ォキソシクロへキシ -1-ェニル )-4-ベンジルォキシフエノ キシァセトアミド (化合物 1 0 4 )、 N-{6,6-ジメトキシ 5-(4-ピリジルチオ) -3-ォ キソシクロへキシ小ェニル }-4-ベンジルォキシフエノキシァセトアミド (化合 物 1 0 5 )、 N-{6,6-ジメトキシ 5-(2-ピリジルチオ) -3-ォキソシクロへキシ小ェ 二ル}_4-ベンジルォキシフエノキシァセトアミド (化合物 1 0 6 )、 N-{6，6-ジメ トキシ 5- (ベンゾチアゾ一ル -2-ィルチオ)- 3-ォキソシク口へキシ -1-ェニル }-4-ベ ンジルォキシフエノキシァセトアミド (化合物 1 0 7 )、 N-{6，6-ジメトキシ 5-(4 -ブロモフエニル)チォ -3-ォキソシクロへキシ -1-ェニル }-4-ベンジルォキシフエ ノキシァセトアミド (化合物 1 0 9 )、 N-{6,6-ジメトキシ— 5-(4-クロ口フエニノ チォ 3-ォキソシクロへキシ -1-ェニル }-4-ベンジルォキシフエノキシァセトアミ ド (化合物 1 1 2 )、 N-{6，6-ジメトキシ 5-(2-アミノエチル)チォ -3-ォキソシクロ へキシ -1-ェニル }-4-ベンジルォキシフエノキシァセトアミド (化合物 1 2 7 )お よび N-[6，6-ジメトキシ 5-{2-(N，N -ジメチルァミノ）ェチル }チォふォキソシク 口へキシ -1-ェニル ]-4-ベンジルォキシフエノキシァセトアミド (化合物 1 2 8 ) 実施例 9 4と同様に、 実施例 2で得られる化合物 2の 42.3mg(0.103 mmol) をクロ口ホルム / メタノール = 2 / 1の混合溶液 21mlに溶解し、 トリエチル ァミン 14.5 1(0.104 mmol) を加え、 14等分した。 それぞれにベンジルメル 力プ夕ン 1.3 1(0.011 mmol), 4-ァセトアミドチオフエノ一ル 1.9mg(0.011 m mol)、 チォサリチル酸 2.0mg(0.013 mmol)、 4-メルカプトピリジン 1.7mg(0.015 mmol), 2-メルカプトピリジン 2.1mg(0.019 mmol), 2-メルカプトべンゾチア ゾール 1.9mg(0.011 mmol)、 4-ブロモチオフエノ一ル 2.8mg(0.015 mmol)> 4-ク ロロチオフエノ一ル 1.8mg(0.012 mmol), 2-アミノエタンチオール 1.4mg(0.018 mmol)、 ジメチルアミノエ夕ンチオール塩酸塩 1.7mg(0.012 mmol)を加え、 次 いで室温で 1時間 30分超音波にかけた後、 遠心濃縮機で濃縮し、 化合物 9 8、 化合物 1 0 1、 化合物 1 0 4、 化合物 1 0 5、 化合物 1 0 6、 化合物 1 0 7、 化合物 1 0 9、 化合物 1 1 2、 化合物 1 2 7および化合物 1 2 8を得た。 Example 95: N- (6,6-dimethoxy 5-benzylthio-3-oxocyclohex-1-enyl) -4-benzyloxyphenoxyacetamide (compound 98), N- {6, 6-Dimethoxy 5- (4-acetamidophenyl) thio-3-oxocyclohex-1-enyl} -4-benzyldioxyphenoxyacetamide (Compound 101), N- (6,6 -Dimethoxy-5-carboxyphenylthio-3-oxocyclohex-1-enyl) -4-benzyloxyphenoxyacetamide (Compound 104), N- {6,6-dimethoxy 5- (4-pyridylthio ) -3-Oxocyclohexoxyenyl} -4-benzyloxyphenoxyacetamide (Compound 105), N- {6,6-dimethoxy 5- (2-pyridylthio) -3-oxocyclo Xyloxy} {4-benzyloxyphenoxyacetamide (compound 106), N- {6,6-dimethoxy 5- (benzothiazolyl-2-ylthio) -3-oxo Cyclic hex-1-enyl} -4-benzyloxyphenoxyacetamide (compound 107), N- {6,6-dimethoxy 5- (4-bromophenyl) thio-3-oxocyclohexyl -1-enyl} -4-benzyloxyfue Nonoxyacetamide (Compound 109), N- {6,6-dimethoxy-5- (4-chloropheninothio-3-oxocyclohex-1-enyl) -4-benzyloxyphenoxyacetamide (Compound 112), N- {6,6-dimethoxy 5- (2-aminoethyl) thio-3-oxocyclohex-1-enyl} -4-benzyloxyphenoxyacetamide (compound 1 27)) and N- [6,6-dimethoxy 5- {2- (N, N-dimethylamino) ethyl] thio-foxy-cyclohexyl-1-enyl] -4-benzyloxyphenoxyacetamide ( Compound 1 2 8) In the same manner as in Example 94, 42.3 mg (0.103 mmol) of compound 2 obtained in Example 2 was dissolved in 21 ml of a mixed solution of chloroform / methanol = 2/1, and triethylamine 14.5 1 (0.104 mmol) was added and the mixture was divided into 14 equal portions: Benzyl mercaptan 1.3 1 (0.011 mmol), 4-acetamidothiophenol 1.9 mg (0.011 mmol) Thiosalicylic acid 2.0 mg (0.013 mmol), 4-mercaptopyridine 1.7 mg (0.015 mmol), 2-mercaptopyridine 2.1 mg (0.019 mmol), 2-mercaptobenzothiazole 1.9 mg (0.011 mmol), 4-bromothiophenol 2.8 mg (0.015 mmol)> 4-chlorothiophenol 1.8 mg (0.012 mmol), 2-aminoethanethiol 1.4 mg (0.018 mmol), dimethylaminoethanethiol hydrochloride 1.7 mg (0.012 mmol), and then After sonication at room temperature for 1 hour and 30 minutes, the mixture was concentrated with a centrifugal concentrator, and compound 98, compound 101, compound 104, compound 105, compound 106, compound 107, compound 1 09, Compound 112, Compound 127 and Compound 128 were obtained.
化合物 9 8 Compound 9 8
FABMS m/z ； 534 (M+H)+ FABMS m / z; 534 (M + H) +
化合物 1 0 1 Compound 1 0 1
FABMS m/z ； 487 (M+H)+ FABMS m / z; 487 (M + H) +
化合物 1 0 4 Compound 1 0 4
FABMS m/z ； 564 (M+H)+ FABMS m / z; 564 (M + H) +
化合物 1 0 5 Compound 1 0 5
FABMS m/z； 521 (M+H)+  FABMS m / z; 521 (M + H) +
化合物 1 0 6 FABMS m/z ； 521 (M+H)+ Compound 1 06 FABMS m / z; 521 (M + H) +
化合物 1 0 7 Compound 1 0 7
FABMS m/z ； 577 (M+H)+ FABMS m / z; 577 (M + H) +
化合物 1 0 9 Compound 1 0 9
FABMS m/z ； 598 (M+H)+ FABMS m / z; 598 (M + H) +
化合物 1 1 2 Compound 1 1 2
FABMS m/z ； 554 (M+H)+ FABMS m / z; 554 (M + H) +
化合物 1 2 7 Compound 1 2 7
FABMS m/z ； 410 (M+H)+ FABMS m / z; 410 (M + H) +
化合物 1 2 8 Compound 1 2 8
FABMS m/z ； 515 (M+H)+ FABMS m / z; 515 (M + H) +
実施例 9 6 ： N-{6，6-ジメトキシ -5-(4-ァミノフエ二ル)チォ -3-ォキソシクロへ キシ -1-ェニル }-4-ベンジルォキシフエノキシァセトアミド（化合物 9 9 ) 実施例 2で得られる化合物 2の 16.3mg(0.040mmol)をク口口ホルム/メ夕ノー ル =1/2の混合溶媒 3mlに溶解しトリェチルァミン 6.0 l(0.040mmol)を加え、 次いで P-アミノチォフエノール 5.6mg(0.045mmol)を加えて、 室温で 4 5分間 攪拌した。 通常の後処理後、 薄層クロマトグラフィー （クロ口ホルムのみ） で 精製し、 化合物 9 9を 7.9mg(36.5 %)得た。 Example 96: N- {6,6-dimethoxy-5- (4-aminophenyl) thio-3-oxocyclohex-1-enyl} -4-benzyloxyphenoxyacetamide (compound 99 ) 16.3 mg (0.040 mmol) of Compound 2 obtained in Example 2 was dissolved in 3 ml of a mixed solvent of stomal form / medium = 1/2, and 6.0 l (0.040 mmol) of triethylamine was added. 5.6 mg (0.045 mmol) of aminothiophenol was added, and the mixture was stirred at room temperature for 45 minutes. After usual post-treatment, the product was purified by thin-layer chromatography (only on black hole form) to obtain 7.9 mg (36.5%) of compound 99.
1H NMR (500 MHz, CDC13) δ ppm ； 9.20 (br s, 1H)， 7.42-7.30 (m， 5H)， 7.2 3-7.20 (m， 2H), 7.14 (s, 1H)， 6.95-6.87 (m, 4H), 6.60-6.57 (m， 2H), 5.03 (s, 2 H), 4.60-4.52 (m, 2H), 3.80 (br s, 2H), 3.72 (dd, J =2.4, 4.5 Hz, IH), 3.40 (s, 1H NMR (500 MHz, CDC1 3 ) δ ppm; 9.20 (br s, 1H), 7.42-7.30 (m, 5H), 7.2 3-7.20 (m, 2H), 7.14 (s, 1H), 6.95-6.87 ( m, 4H), 6.60-6.57 (m, 2H), 5.03 (s, 2H), 4.60-4.52 (m, 2H), 3.80 (br s, 2H), 3.72 (dd, J = 2.4, 4.5 Hz, IH), 3.40 (s,
3H)， 3.03 (s, 3H)， 2.93 (dd, J =4.5, 17.8 Hz, 1H)， 2.60 (dd, J =2.4， 17.8 Hz,3H), 3.03 (s, 3H), 2.93 (dd, J = 4.5, 17.8 Hz, 1H), 2.60 (dd, J = 2.4, 17.8 Hz,
IH) IH)
FABMS m/z ； 534 (M)+ FABMS m / z; 534 (M) +
実施例 9 7 ： N-{6，6-ジメトキシ -5-(4-ヒドロキシフエニル)チォ -3-ォキソシク 口へキシ -1-ェニル }-4-ベンジルォキシフエノキシァセトアミド (化合物 1 0 2 ) 実施例 9 6と同様に、 実施例 2で得られる化合物 2の 410mg(1.00mmol)と 4- ヒドロキシチォフエノ一ル 206mg(1.63mmol)より、 化合物 1 0 2を 452mg(84.2 %)得た。 Example 97: N- {6,6-dimethoxy-5- (4-hydroxyphenyl) thio-3-oxosic-hexoxy-1-enyl} -4-benzyloxyphenoxyacetamide (Compound 1 0 2) Similarly to Example 96, 410 mg (1.00 mmol) of compound 2 obtained in Example 2 and 4- From 206 mg (1.63 mmol) of hydroxythiophenol, 452 mg (84.2%) of compound 102 was obtained.
1H NMR (400 MHz, CDC13) δ ppm ； 9.25 (br s, IH), 7.42-7.26 (m, 7H)， 7.1 8 (s, 1H)， 6.96-6.86 (m， 4H), 6.78-6.45 (m, 2H), 5.03 (s, 2H), 4.61-4.52(m, 2 H), 3.79 (dd, J =2.4, 4.5 Hz, IH), 3.45 (s, 3H), 3.04 (s, 3H)， 2.97 (dd, J =4.5, 1H NMR (400 MHz, CDC1 3 ) δ ppm; 9.25 (br s, IH), 7.42-7.26 (m, 7H), 7.1 8 (s, 1H), 6.96-6.86 (m, 4H), 6.78-6.45 ( m, 2H), 5.03 (s, 2H), 4.61-4.52 (m, 2H), 3.79 (dd, J = 2.4, 4.5 Hz, IH), 3.45 (s, 3H), 3.04 (s, 3H), 2.97 (dd, J = 4.5,
17.8 Hz, 1H)， 2.59 (dd, J =2.4， 17.8 Hz, IH) 17.8 Hz, 1H), 2.59 (dd, J = 2.4, 17.8 Hz, IH)
FABMS m/z ； 536 (M+H)+ FABMS m / z; 536 (M + H) +
実施例 9 8 ： N-{6，6-ジメトキシ -5-(4-メトキシフエ二ル)チォ -3-ォキソシクロ へキシ -1-ェニル }-4-ベンジルォキシフエノキシァセトアミド (化合物 1 0 3 ) 実施例 9 6と同様に、 実施例 2で得られる化合物 2の 14.9mg(0.036mmol)と P-メトキシチオフエノ一ル 4.5 H l(0.037mmol)より、 化合物 1 0 3を 10.1mg(5 0.5 %)得た。 Example 98: N- {6,6-dimethoxy-5- (4-methoxyphenyl) thio-3-oxocyclohex-1-enyl} -4-benzyloxyphenoxyacetamide (Compound 10 3) As in Example 96, 10.1 mg of Compound 103 was obtained from 14.9 mg (0.036 mmol) of Compound 2 obtained in Example 2 and 4.5 Hl (0.037 mmol) of P-methoxythiophenol. (5 0.5%).
1H NMR (500 MHz, CDCI3) δ ppm ； 9.20 (br s, IH), 7.42-7.31 (m, 7H)， 7.1 6 (s, IH), 6.96-6.83 (m, 6H)， 5.04 (s, 2H), 4.61-4.53 (m, 2H), 3.80 (s, 2H), 3. 78 (dd, J =2.4, 4.5 Hz, IH), 3.40 (s, 3H), 3.04 (s, 3H)， 2.95 (dd, J =4.5， 17.8 1H NMR (500 MHz, CDCI3) δ ppm; 9.20 (br s, IH), 7.42-7.31 (m, 7H), 7.16 (s, IH), 6.96-6.83 (m, 6H), 5.04 (s, 2H ), 4.61-4.53 (m, 2H), 3.80 (s, 2H), 3.78 (dd, J = 2.4, 4.5 Hz, IH), 3.40 (s, 3H), 3.04 (s, 3H), 2.95 ( dd, J = 4.5, 17.8
Hz, IH), 2.58 (dd, J =2.4， 17.8 Hz, IH) Hz, IH), 2.58 (dd, J = 2.4, 17.8 Hz, IH)
FABMS m/z ； 550 (M+H)+ FABMS m / z; 550 (M + H) +
実施例 9 9 ： N-{6，6-ジメトキシ -5-(2，5-ジクロロフエニル)チォ -3-ォキソシク 口へキシ -1-ェニル }-4-ベンジルォキシフエノキシァセトアミド (化合物 1 1 5 ) 実施例 9 6と同様に、 実施例 2で得られる化合物 2の 25.9mg(0.063mmol)と 2,5-ジクロロチォフエノール 18.4mg(0.103mmol)より、 化合物 1 1 5を 27.3mg (73.3 %)得た。 Example 99: N- {6,6-dimethoxy-5- (2,5-dichlorophenyl) thio-3-oxosic-hexoxy-1-enyl} -4-benzyloxyphenoxyacetamide ( Compound 1 15) In the same manner as in Example 96, 25.9 mg (0.063 mmol) of compound 2 obtained in Example 2 and 18.4 mg (0.103 mmol) of 2,5-dichlorothiophenol were used to obtain 27.3 of compound 115. mg (73.3%).
1H NMR (500 MHz, CDCI3) δ ppm ； 9.20 (br s, IH), 7.42-7.21 (m, 9H), 6.9 5-6.86 (m， 4H), 5.03 (s, 2H)， 4.61-4.52 (m, 2H)， 3.79 (dd, J =2.3, 4.7 Hz, 1H)， 3.37 (s, 3H), 3.07 (s， 3H), 2.97 (dd, J =4.7, 17.8 Hz, IH), 2.59 (dd, J =2.3， 17.8 Hz, IH)  1H NMR (500 MHz, CDCI3) δ ppm; 9.20 (br s, IH), 7.42-7.21 (m, 9H), 6.9 5-6.86 (m, 4H), 5.03 (s, 2H), 4.61-4.52 (m , 2H), 3.79 (dd, J = 2.3, 4.7 Hz, 1H), 3.37 (s, 3H), 3.07 (s, 3H), 2.97 (dd, J = 4.7, 17.8 Hz, IH), 2.59 (dd, J = 2.3, 17.8 Hz, IH)
FABMS m/z ； 588 (M+H)+ ε 8£卜0/卜 6dr/ld OAV FABMS m / z; 588 (M + H) + ε 8 £ 卜 0 / 卜 6dr / ld OAV
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1H NMR (400 MHz, CDC13) δ ppm ； 9.14 (br s， IH), 7.43-7.27 (m, 5H)， 7.2 1 (s, IH), 6.95-6.83 (m, 4H)， 5.40 (d, J =3.7 Hz, IH), 5.03 (s, 2H)， 4.59-4.50 1H NMR (400 MHz, CDC1 3 ) δ ppm; 9.14 (br s, IH), 7.43-7.27 (m, 5H), 7.2 1 (s, IH), 6.95-6.83 (m, 4H), 5.40 (d, J = 3.7 Hz, IH), 5.03 (s, 2H), 4.59-4.50
(m， 2H), 3.69 (d, J =3.7 Hz, IH), 3.45 (s, 3H), 3.03 (s, 3H)， 2.85 (d, J =7.5(m, 2H), 3.69 (d, J = 3.7 Hz, IH), 3.45 (s, 3H), 3.03 (s, 3H), 2.85 (d, J = 7.5
Hz, 2H), 1.28 (t, J =7.5 Hz, 3H) Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H)
FABMS m/z ； 506 (M+H)+ FABMS m / z; 506 (M + H) +
実施例 1 0 3 : N-{4-クロ口- 6,6-ジメトキシ 5-(2-ヒドロキシェチル)チォ -3- ォキソシク口へキシ -1-ェニル }-4-ベンジルォキシフエノキシァセトアミド (化 合物 1 2 1 ) Example 103: N- {4-chloro-6,6-dimethoxy 5- (2-hydroxyethyl) thio-3-oxocyclohex-1-enyl} -4-benzyloxyphenoxy Cetamide (Compound 1 2 1)
実施例 9 6と同様に、 実施例 6で得られる化合物 6の 21.6mg(0.049mmol)と メルカプトェ夕ノ一ル 3.5 l(0.049mmol)より、 化合物 1 2 2を 22.8mg(90. 0%)得た。  As in Example 96, 22.8 mg (90.0%) of compound 122 was obtained from 21.6 mg (0.049 mmol) of compound 6 obtained in Example 6 and 3.5 l (0.049 mmol) of mercaptophenol. Obtained.
1H NMR (400 MHz, CDCI3) δ ppm ； 9.16 (br s, 1H)， 7.43-7.27 (m, 5H), 7.2 2 (s, 1H)， 6.96-6.83 (m, 4H), 5.40 (s, IH), 5.03 (s, 2H), 4.60-4.50 (m, 2H)， 3. 87-3.69 (m, 1H)， 3.46 (s, 3H), 3.04 (s, 3H), 3.00 (t, J =5.7 Hz, 2H)， 2.12 (t, J =5.7 Hz, 3H)  1H NMR (400 MHz, CDCI3) δ ppm; 9.16 (br s, 1H), 7.43-7.27 (m, 5H), 7.22 (s, 1H), 6.96-6.83 (m, 4H), 5.40 (s, IH ), 5.03 (s, 2H), 4.60-4.50 (m, 2H), 3.87-3.69 (m, 1H), 3.46 (s, 3H), 3.04 (s, 3H), 3.00 (t, J = 5.7 Hz, 2H), 2.12 (t, J = 5.7 Hz, 3H)
FABMS m/z ； 522 (M+H)+ FABMS m / z; 522 (M + H) +
実施例 1 0 4 : N-{4-クロ口- 6,6-ジメトキシ -5-(4-ェチルチオ) -3-ォキソシク 口へキシ -1-ェニル }-4-ベンジルォキシフエノキシァセトアミド （化合物 1 2 9 ) Example 104: N- {4-chloro-6,6-dimethoxy-5- (4-ethylthio) -3-oxocyclohexyl-1-enyl} -4-benzyloxyphenoxyacetamide (Compound 12 9)
実施例 9 6と同様の方法を用いて実施例 2で得られる化合物 2の 13.0mg(0.0 32mmol)とエタンチオール 24.9 l(0.34mmol)より、 通常の後処理後、 薄層ク 口マトグラフィ一 （クロ口ホルムのみ） で精製し、 化合物 1 2 9を 10.5mg(70. 1 %)得た。  Using a method similar to that in Example 6, 13.0 mg (0.032 mmol) of compound 2 obtained in Example 2 and 24.9 l (0.34 mmol) of ethanethiol were subjected to ordinary post-treatment, followed by thin-layer mouth chromatography. Compound 1229 was obtained in an amount of 10.5 mg (70.1%).
1H NMR (400 MHz, CDCI3) δ ppm ； 9.19 (br s， 1H)， 7.43-7.29 (m, 5H)， 7.1 4 (s, 1H)， 6.95-6.83 (m, 4H), 5.03 (s, 2H), 4.54 (s, 2H), 3.58 (dd, J =2.7, 4.3 Hz, 1H)， 3.41 (s, 3H), 3.09 (dd, J =4.3, 7.8 Hz, IH), 3.04 (s, 3H), 2.71 (dd, J =2.7, 7.8 Hz, IH), 2.58 (q， J =7.3 Hz, 2H), 1.25 (t， J =7.3 Hz, 3H) FABMS m/z ； 472 (M+H)+ 1H NMR (400 MHz, CDCI3) δ ppm; 9.19 (br s, 1H), 7.43-7.29 (m, 5H), 7.14 (s, 1H), 6.95-6.83 (m, 4H), 5.03 (s, 2H ), 4.54 (s, 2H), 3.58 (dd, J = 2.7, 4.3 Hz, 1H), 3.41 (s, 3H), 3.09 (dd, J = 4.3, 7.8 Hz, IH), 3.04 (s, 3H) , 2.71 (dd, J = 2.7, 7.8 Hz, IH), 2.58 (q, J = 7.3 Hz, 2H), 1.25 (t, J = 7.3 Hz, 3H) FABMS m / z; 472 (M + H) +
実施例 1 0 5 ： N-(6，6-ジメトキシ -5-アミノフエ二ルチオ- 3-ォキソシクロへ キシ -1-ェニル )-4-ベンジルォキシフエノキシァセトアミド （化合物 1 3 0 ) 実施例 9 6と同様の方法を用いて実施例 6で得られる化合物 6の 18.0mg(0.0 41mmol)と p-ァミノチォフエノ一ル 5.8mg(0.046mmol)より、 化合物 1 3 0を 5. 6mg(24.3 %)得た。 Example 105: N- (6,6-dimethoxy-5-aminophenylthio-3-oxocyclohex-1-enyl) -4-benzyloxyphenoxyacetamide (Compound 130) 9.6 mg (24.3%) of Compound 130 from 18.0 mg (0.041 mmol) of Compound 6 obtained in Example 6 and 5.8 mg (0.046 mmol) of p-aminothiophenol obtained in Example 6 using the same method as 96. Obtained.
1H NMR (400 MHz, CDC13) δ ppm ； 9.23 (br s, 1H)， 7.42-7.27 (m, 5H), 7.1 7 (s, IH), 6.96-6.86 (m, 4H)， 6.61-6.54 (m， 4H)， 5.38 (d, J =3.9 Hz, 1H)， 5.03 (s, 2H), 4.63-4.53 (m, 2H)， 3.80 (d, J =3.9 Hz, IH), 3.12 (s， 3H)， 3.01(s, 3H) FABMS m/z ； 569 (M+H)+ 1H NMR (400 MHz, CDC1 3 ) δ ppm; 9.23 (br s, 1H), 7.42-7.27 (m, 5H), 7.1 7 (s, IH), 6.96-6.86 (m, 4H), 6.61-6.54 ( m, 4H), 5.38 (d, J = 3.9 Hz, 1H), 5.03 (s, 2H), 4.63-4.53 (m, 2H), 3.80 (d, J = 3.9 Hz, IH), 3.12 (s, 3H) ), 3.01 (s, 3H) FABMS m / z; 569 (M + H) +
実施例 1 0 6 N-(4-クロ口- 6，6-ジメトキシ -3-ォキソシクロへキサ -1,4-ジェニ ル)—4-プロピルフエノキシァセトアミド （化合物 1 3 1 ) Example 106 N- (4-chloro-6,6-dimethoxy-3-oxocyclohexa-1,4-genyl) -4-propylphenoxyacetamide (Compound 1331)
実施例 1と同様の方法を用いて、 参考例 1 8で得られる化合物 t 36mg(0.10 imnol)とビス（トリフルォロアセトキシ） ョードベンゼン 140mg(0.33mmol)より、 化合物 1 2 9を 20mg(53%) 得た。  Using the same method as in Example 1, 20 mg (53%) of compound 12 was obtained from 36 mg (0.10 imnol) of compound t obtained in Reference Example 18 and 140 mg (0.33 mmol) of bis (trifluoroacetoxy) benzene. ) Obtained.
1H NMR (400MHz, CDC13) δ ppm ； 8.61 (br s, IH), 7.54 (s， IH), 7.20-6.90 (m， 4H), 6.79 (s， IH), 4.61 (s， 2H), 3.22 (s, 6H)， 2.54 (t, J = 7.3 Hz, 2H), 1. 70-1.52 (m， 2H)， 0.91 (t, J = 7.3 Hz, 3H) 1H NMR (400MHz, CDC1 3) δ ppm; 8.61 (br s, IH), 7.54 (s, IH), 7.20-6.90 (m, 4H), 6.79 (s, IH), 4.61 (s, 2H), 3.22 (s, 6H), 2.54 (t, J = 7.3 Hz, 2H), 1.70-1.52 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H)
FABMS m/z ； 380 (M+H)+ FABMS m / z; 380 (M + H) +
実施例 1 0 7 ： N-(4-クロ口- 3，6-ジォキソシクロへキサ -1,4-ジェニル) -4-プロ ピルフエノキシァセトアミド （化合物 1 3 2 ) Example 107: N- (4-chloro-3,6-dioxocyclohexa-1,4-genyl) -4-propylphenoxyacetamide (Compound 132)
実施例 1 3と同様の方法を用いて、 実施例 1 0 6で得られる化合物 1 3 1の 12mg(0.032mmol)と p-トルエンスルホン酸一水和物 6.0mg(0.032mmol)から、 化 合物 1 3 2を 4.5mg(43%) 得た。  Using a method similar to that of Example 13, the compound was obtained from 12 mg (0.032 mmol) of Compound 1331 obtained in Example 106 and 6.0 mg (0.032 mmol) of p-toluenesulfonic acid monohydrate. 4.5 mg (43%) of product 132 were obtained.
1H NMR (400MHz, CDC13) δ ppm ； 9.32 (br s, IH), 7.83 (s, IH), 7.20-6.85 (m, 4H)， 7.04 (s, IH), 4.62 (s, 2H)， 2.55 (t, J = 7.9 Hz, 2H), 1.70-1.52 (m, 2 H), 0.93 (t， J = 7.3 Hz, 3H) FABMS m/z ； 336(M+3H)+ 1H NMR (400MHz, CDC1 3) δ ppm; 9.32 (br s, IH), 7.83 (s, IH), 7.20-6.85 (m, 4H), 7.04 (s, IH), 4.62 (s, 2H), 2.55 (t, J = 7.9 Hz, 2H), 1.70-1.52 (m, 2 H), 0.93 (t, J = 7.3 Hz, 3H) FABMS m / z; 336 (M + 3H) +
実施例 1 0 8 ： N-(3，6-ジォキソ -4-トリメチルシリルェチルチオシクロへキ サ—1,4-ジェニル) -4-ベンジルォキシフエノキシァセトアミド （化合物 1 3 3 ) および N-[3，6-ジォキソ -4,5-ビス（トリメチルシリルェチルチオ）シクロへキサ -1， 4-ジェニル] -4-ベンジルォキシフエノキシァセ卜アミド （化合物 1 3 4 ) 実施例 6 4と同様の方法を用いて実施例 1 4で得られる化合物 1 4の 18.0m g(0.045mmol)と 2-トリメチルシリルエタンチオール 7.3 l(0.046mmol)より、 通常の後処理後、 薄層クロマトグラフィー （クロ口ホルムのみ） で精製し、 化 合物 1 3 3を 19.8mg(88.3 %)および化合物 1 3 4を 1.8mg(6.3 %)得た。 Example 108: N- (3,6-dioxo-4-trimethylsilylethylthiocyclohexa-1,4-genyl) -4-benzyloxyphenoxyacetamide (Compound 133) and N- [3,6-Dioxo-4,5-bis (trimethylsilylethylthio) cyclohexa-1,4-genenyl] -4-benzyloxyphenoxyacetamide (Compound 134) From 18.0 mg (0.045 mmol) of compound 14 obtained in Example 14 and 7.3 l (0.046 mmol) of 2-trimethylsilylethanethiol obtained in Example 14 using the same method as in 64, thin layer chromatography after usual post-treatment (Only in the form of black mouth) to obtain 19.8 mg (88.3%) of compound 133 and 1.8 mg (6.3%) of compound 134.
化合物 1 3 3 Compound 1 3 3
1H NMR (400 MHz, CDC13) δ ppm ； 9.40 (br s, 1H)， 7.64 (s， IH), 7.43-7.29 (m, 5H)， 6.94 (s, 4H), 6.32 (s, IH), 5.03 (s， 2H), 4.57 (s, 2H), 2.81-2.77 (m, 2H), 1.02-0.97 (m， 2H), 0.09 (s, 9H) 1H NMR (400 MHz, CDC1 3 ) δ ppm; 9.40 (br s, 1H), 7.64 (s, IH), 7.43-7.29 (m, 5H), 6.94 (s, 4H), 6.32 (s, IH), 5.03 (s, 2H), 4.57 (s, 2H), 2.81-2.77 (m, 2H), 1.02-0.97 (m, 2H), 0.09 (s, 9H)
FABMS m/z ； 496 (M+H)+ FABMS m / z; 496 (M + H) +
化合物 1 3 4 Compound 1 3 4
1H NMR (400 MHz, CDC13) δ ppm ； 8.51 (br s, IH), 7.64 (s, IH), 7.43-7.29 (m, 5H)， 6.94 (m, 4H), 5.03 (s, 2H), 4.57 (s, 2H), 3.39-2.84 (m, 4H), 0.93-0. 81(m, 4H), 0.05 (s, 9H)， 0.03 (s, 9H) 1H NMR (400 MHz, CDC1 3 ) δ ppm; 8.51 (br s, IH), 7.64 (s, IH), 7.43-7.29 (m, 5H), 6.94 (m, 4H), 5.03 (s, 2H), 4.57 (s, 2H), 3.39-2.84 (m, 4H), 0.93-0.81 (m, 4H), 0.05 (s, 9H), 0.03 (s, 9H)
FABMS m/z ； 629 (M+2H)+ FABMS m / z; 629 (M + 2H) +
実施例 1 0 9 ： N-(3,6-ジォキソ -4-メトキシカルポ二ルメチルチオシクロへ キサ -1，4-ジェニル) -4-ベンジルォキシフエノキシァセトアミド （化合物 1 3 5 ) Example 109: N- (3,6-dioxo-4-methoxycarbonylmethylthiocyclohexa-1,4-genyl) -4-benzyloxyphenoxyacetamide (Compound 135)
実施例 6 4と同様の方法を用いて実施例 1 4で得られる化合物 1 4の 23.5m g(0.059mmol)、 チォグリコール酸メチル 5.3 H l(0.059mmol)およびトリェチル ァミン 9.8 l(0.059mmol)より、 化合物 1 3 5を 13.5mg(48.9%)得た。  From the compound 14 obtained in Example 14 23.5 mg (0.059 mmol), methyl thioglycolate 5.3 Hl (0.059 mmol) and triethylamine 9.8 l (0.059 mmol) using the same method as in Example 64. 13.5 mg (48.9%) of compound 135 was obtained.
1H NMR (400 MHz, CDC13) δ ppm ； 9.37 (br s, IH), 7.66 (s, IH), 7.43-7.30 (m, 5H), 6.97-6.91 (m, 4H)， 6.48 (s, IH), 5.03 (s， 2H), 4.54 (s， 2H)， 3.79 (s, 3H), 3.62 (s, 2H) 1H NMR (400 MHz, CDC1 3 ) δ ppm; 9.37 (br s, IH), 7.66 (s, IH), 7.43-7.30 (m, 5H), 6.97-6.91 (m, 4H), 6.48 (s, IH ), 5.03 (s, 2H), 4.54 (s, 2H), 3.79 (s, 3H), 3.62 (s, 2H)
FABMS M/Z； 469 (M+2H)+ FABMS M / Z; 469 (M + 2H) +
実施例 1 1 0 ： N-(3,6-ジォキソ -4-フエニルアミノシクロへキサ -1,4-ジェニ ル )_4-ベンジルォキシフエノキシァセトアミド （化合物 1 3 6 ) Example 110: N- (3,6-dioxo-4-phenylaminocyclohexa-1,4-genyl) _4-benzyloxyphenoxyacetamide (Compound 13 36)
実施例 6 4と同様の方法を用いて実施例 1 4で得られる化合物 1 4の ll.Om g(0.028 mmol)とァニリン 2.5 fi 1(0.027 mmol)より、 化合物 1 3 6を 6.0mg(47. 8 %)得た。  Using ll.Omg (0.028 mmol) of compound 14 obtained in Example 14 and aniline 2.5 fi 1 (0.027 mmol) using the same method as in Example 64, 6.0 mg (47 8%).
1H NMR (400 MHz, CDC13) δ ppm ； 9.71 (br s, 1H)， 7.70 (br s, 1H)， 7.56 (s, IH), 7.45-7.22 (m, lOH), 6.94 (s, 4H)， 6.11 (s, 1H)， 5.03 (s, 2H)， 4.59 (s, 2H) 1H NMR (400 MHz, CDC1 3 ) δ ppm; 9.71 (br s, 1H), 7.70 (br s, 1H), 7.56 (s, IH), 7.45-7.22 (m, lOH), 6.94 (s, 4H) , 6.11 (s, 1H), 5.03 (s, 2H), 4.59 (s, 2H)
FABMS m/z ； 455 (M+H)+ FABMS m / z; 455 (M + H) +
実施例 1 1 1 ： N-(3,6-ジォキソ -4-ベンジルチオシクロへキサ -1,4-ジェニル) - 4-ベンジルォキシフエノキシァセトアミド （化合物 1 3 7 ) Example 11: N- (3,6-dioxo-4-benzylthiocyclohexa-1,4-genyl) -4-benzyloxyphenoxyacetamide (Compound 13 7)
実施例 6 4と同様の方法を用いて実施例 1 4で得られる化合物 1 4の 19.1m g(0.048mmol)とべンジルメル力プ夕ン 5.7 l(0.048mmol)より、 化合物 1 3 7 を 13.7mg(58.8%)得た。  From 19.1 mg (0.048 mmol) of compound 14 obtained in Example 14 and 5.7 l (0.048 mmol) of benzylmercaptan obtained in Example 14 using the same method as in Example 64, 13.7 mg of compound 1337 ( 58.8%).
1H NMR (400 MHz, CDC13) δ ppm ； 9.38 (br s, IH), 7.64 (s, 1H)， 7,43-7.27 (m， lOH), 6.99-6.90 (m, 4H), 6.43 (s, 1H)， 5.03 (s, 2H)， 4.57 (s, 2H), 4.02 (s, 2H) 1H NMR (400 MHz, CDC1 3 ) δ ppm; 9.38 (br s, IH), 7.64 (s, 1H), 7,43-7.27 (m, lOH), 6.99-6.90 (m, 4H), 6.43 (s , 1H), 5.03 (s, 2H), 4.57 (s, 2H), 4.02 (s, 2H)
FABMS m/z ； 487 (M+2H)+ FABMS m / z; 487 (M + 2H) +
実施例 1 1 2 ： N-[3，6-ジォキソ -4-(4-クロ口べンジルチオ）シクロへキサ -1，4- ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 1 3 8 ) Example 11: N- [3,6-dioxo-4- (4-chlorobenzylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 13 8)
実施例 6 4と同様の方法を用いて実施例 1 4で得られる化合物 1 4の 20.0m g(0.050mmol)と 4-クロロべンジルメルカプ夕ン 6.7 H l(0.051mmol)より、 化合 物 1 3 8を 15.3mg(58.5%)得た。  Using a method similar to that of Example 64, 20.0 mg (0.050 mmol) of compound 14 obtained in Example 14 and 6.7 Hl (0.051 mmol) of 4-chlorobenzyl mercaptan were used to obtain compound 1 38 Was obtained in 15.3 mg (58.5%).
1H NMR (500 MHz, CDCI3) δ ppm ； 9.37 (br s, 1H)， 7.65 (s， IH), 7.43-7.30 (m, 9H), 6.95-6.91 (m, 4H), 6.39 (s， IH), 5.03 (s, 2H), 4.57 (s, 2H)， 3.99 (s, 2H) 1H NMR (500 MHz, CDCI3) δ ppm; 9.37 (br s, 1H), 7.65 (s, IH), 7.43-7.30 (m, 9H), 6.95-6.91 (m, 4H), 6.39 (s, IH) , 5.03 (s, 2H), 4.57 (s, 2H), 3.99 (s, 2H)
FABMS m/z ； 552 (M+3H)+ FABMS m / z; 552 (M + 3H) +
実施例 1 1 3 ： N-[3，6-ジォキソ -4-(4-メチルフエ二ルチオ）シクロへキサ -1,4- ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 1 3 9 ) Example 11: N- [3,6-dioxo-4- (4-methylphenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 13 9 )
実施例 6 4と同様の方法を用いて実施例 1 4で得られる化合物 1 4の 17.5m g(0.044mmol)と p-チォクレゾ一ル 6.0mg(0.048mmol)より、 化合物 1 3 9を 14.6 mg(68.4 %)得た。  From 17.5 mg (0.044 mmol) of compound 14 obtained in Example 14 and 6.0 mg (0.048 mmol) of p-thiocresol, 14.6 mg of compound 139 was obtained using the same method as in Example 64. 68.4%).
1H NMR (400 MHz, CDC13) δ ppm ； 9.32 (br s， 1H), 7.66 (s, 1H), 7.42-7.28 (m, 9H), 6.94-6.89 (m, 4H)， 5.85 (s， 1H), 5.02 (s, 2H), 4.56 (s, 2H), 2.42 (s, 3H) 1H NMR (400 MHz, CDC1 3 ) δ ppm; 9.32 (br s, 1H), 7.66 (s, 1H), 7.42-7.28 (m, 9H), 6.94-6.89 (m, 4H), 5.85 (s, 1H ), 5.02 (s, 2H), 4.56 (s, 2H), 2.42 (s, 3H)
FABMS m/z ； 486 (M+H)+ FABMS m / z; 486 (M + H) +
実施例 1 1 4 : N-[3，6-ジォキソ -4-(4-メトキシフエ二ルチオ）シクロへキサ -1, 4-ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 1 4 0 ) 実施例 6 4と同様の方法を用いて実施例 1 4で得られる化合物 1 4の 16.8m g(0.042mmol)と p-メトキシベンゼンチオール 5.2 H l(0.042mmol)より、 化合物 1 4 0を 14.5mg(68.5%)得た。 Example 114: N- [3,6-dioxo-4- (4-methoxyphenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 144) ) 16.4 mg (0.042 mmol) of compound 14 obtained in Example 14 and 5.2-H p-methoxybenzenethiol (0.042 mmol) obtained in Example 14 using the same method as in Example 6 mg (68.5%).
1H NMR (400 MHz, CDCI3) δ ppm ； 9.32 (br s, 1H), 7.66 (s, 1H), 7.42-7.29 (m, 7H), 7.07-7.99 (m, 2H), 6.94-6.89 (m, 4H)， 5.85 (s, 1H), 5.02 (s, 2H)， 4. 56 (s, 2H), 3.86 (s, 3H)  1H NMR (400 MHz, CDCI3) δ ppm; 9.32 (br s, 1H), 7.66 (s, 1H), 7.42-7.29 (m, 7H), 7.07-7.99 (m, 2H), 6.94-6.89 (m, 4H), 5.85 (s, 1H), 5.02 (s, 2H), 4.56 (s, 2H), 3.86 (s, 3H)
FABMS m/z ； 502 (M+H)+ FABMS m / z; 502 (M + H) +
実施例 1 1 5 ： N-[3,6-ジォキソ- 5-(4-メトキシフエ二ルチオ）シクロへキサ -1， 4-ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 1 4 1 ) 実施例 6 4と同様の方法を用いて実施例 1 4で得られる化合物 1 4の 23.4m g(0.043mmol)をテトラヒドロフラン 3mlに溶解し、 p-トルエンスルホン酸一水 和物 17mg(0.090mmol)を加え、 次いで 1N-塩酸 3.0ml(3.0mmol)を加え、 室温で 7日間撹拌した。 通常の後処理後、 薄層クロマトグラフィー （クロ口ホルム / メタノール = 98 / 2) で精製し、 合成中間体 9.8mg得た。 これを再びテトラ ヒドロフラン 3mlに溶解し、 塩化第二鉄 3.8mg(0.023mmol)を加え、 室温で 2 日間撹拌した。 通常の後処理後、 薄層クロマトグラフィー （クロ口ホルム / メタノール = 98 / 2) で精製し、 化合物 1 4 1を 6.3mg(2.9 %)得た。 Example 115: N- [3,6-dioxo-5- (4-methoxyphenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 14 1 ) 23.4 mg (0.043 mmol) of compound 14 obtained in Example 14 was dissolved in 3 ml of tetrahydrofuran using a method similar to that of Example 64, and 17 mg (0.090 mmol) of p-toluenesulfonic acid monohydrate was dissolved. Was added, and then 3.0 ml (3.0 mmol) of 1N hydrochloric acid was added, followed by stirring at room temperature for 7 days. After ordinary post-treatment, purification was performed by thin-layer chromatography (form: methanol / methanol = 98/2) to obtain 9.8 mg of a synthetic intermediate. This again It was dissolved in 3 ml of hydrofuran, 3.8 mg (0.023 mmol) of ferric chloride was added, and the mixture was stirred at room temperature for 2 days. After usual post-treatment, the product was purified by thin-layer chromatography (form: methanol / methanol = 98/2) to obtain 6.3 mg (2.9%) of compound 141.
1H NMR (400 MHz, CDC13) δ ppm ； 9.31 (br s, 1H)， 7.54 (s, 1H), 7.44-7.30 1H NMR (400 MHz, CDC1 3 ) δ ppm; 9.31 (br s, 1H), 7.54 (s, 1H), 7.44-7.30
(m, 7H)， 7.00-6.97 (m, 6H)， 6.95 (s, 1H)， 5.04 (s， 2H)， 4.58 (s， 2H)， 3.86 (s,(m, 7H), 7.00-6.97 (m, 6H), 6.95 (s, 1H), 5.04 (s, 2H), 4.58 (s, 2H), 3.86 (s,
3H) 3H)
FABMS m/z ； 503 (M)+ FABMS m / z; 503 (M) +
実施例 1 1 6 ： N-[3,6-ジォキソ -4-(2-メトキシフエ二ルチオ）シクロへキサ -1， 4-ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 1 4 2 ) 実施例 6 4と同様の方法を用いて実施例 1 4で得られる化合物 1 4の 21.6m g(0.054mmol)と o-メトキシベンゼンチオール 6.6 l(0.054mmol)より、 化合物 1 4 2を 25.0mg(91.8%)得た。 Example 1 16: N- [3,6-dioxo-4- (2-methoxyphenylthio) cyclohexa-1,4-genenyl] -4-benzyloxyphenoxyacetamide (Compound 144) ) From 21.6 mg (0.054 mmol) of compound 14 obtained in Example 14 and 6.6 l (0.054 mmol) of o-methoxybenzenethiol obtained in Example 14 using the same method as in Example 6, 25.0 mg of compound 14 2 (91.8%).
1H NMR (400 MHz, CDCI3) δ ppm ； 9.33 (br s， 1H)， 7.66 (s， 1H), 7.53-7.46 (m， 2H), 7.42-7.30 (m, 5H)， 7.08-7.00 (m, 2H), 6.94-6.89 (m, 4H)， 5.79 (s, 1 H), 5.02 (s, 2H)， 4.56 (s， 2H), 3.85 (s, 3H)  1H NMR (400 MHz, CDCI3) δ ppm; 9.33 (br s, 1H), 7.66 (s, 1H), 7.53-7.46 (m, 2H), 7.42-7.30 (m, 5H), 7.08-7.00 (m, 2H), 6.94-6.89 (m, 4H), 5.79 (s, 1H), 5.02 (s, 2H), 4.56 (s, 2H), 3.85 (s, 3H)
FABMS m/z ； 502 (M+H)+ FABMS m / z; 502 (M + H) +
実施例 1 1 7 ： N- (3,6-ジォキソ -4-(2-メトキシカルポニルフエ二ルチオ）シク 口へキサ -1,4-ジェニル) -4-ベンジルォキシフエノキシァセトアミド （化合物 1 4 3 ) Example 11: N- (3,6-dioxo-4- (2-methoxycarbonylphenylthio) cyclohexahexa-1,4-genyl) -4-benzyloxyphenoxyacetamide (compound 1 4 3)
実施例 9 3で得られる化合物 9 6の 18.3mg(0.046mmol)をァセトン 5mlに溶 解し、 炭酸カリウム 19.0mg(0.14mmol)を加え、 次いでヨウ化メチル 8.6 1(0.1 4mmol)を加え、 室温で 3時間 30分攪拌した。 通常の後処理後、 薄層クロマト グラフィー （クロ口ホルム / メタノール = 99 / 1) で精製し、 化合物 1 4 3 を 2.4mg(12.8%)得た。  18.3 mg (0.046 mmol) of the compound 96 obtained in Example 93 was dissolved in 5 ml of acetone, 19.0 mg (0.14 mmol) of potassium carbonate was added, and then 8.61 (0.14 mmol) of methyl iodide was added. For 3 hours and 30 minutes. After usual post-treatment, the product was purified by thin-layer chromatography (form: methanol / methanol = 99/1) to obtain 2.4 mg (12.8%) of compound 144.
1H NMR (400 MHz, CDC13) δ ppm ； 9.31 (br s， 1H)， 7.98-7.94 (m， 1H), 7.6 7 (s, 1H)， 7.62-7.57 (m, 3H), 7.42-7.30 (m， 5H), 6.94-6.89 (m, 4H), 5.80 (s, 1 H)， 5.02 (s, 2H), 4.56 (s, 2H), 3.87 (s, 3H)
Figure imgf000077_0001
 1H NMR (400 MHz, CDC1 3 ) δ ppm; 9.31 (br s, 1H), 7.98-7.94 (m, 1H), 7.6 7 (s, 1H), 7.62-7.57 (m, 3H), 7.42-7.30 ( m, 5H), 6.94-6.89 (m, 4H), 5.80 (s, 1H), 5.02 (s, 2H), 4.56 (s, 2H), 3.87 (s, 3H)
Figure imgf000077_0001
89 H 2Γ6 οε 6寸 sA卜寸 ffi一-.· ())寸z) ( 9H &寸 ssHz HI H寸 £) 6S9S696 H-... 実施例 1 2 1 ： N-[3，6-ジォキソ -4-(3-クロ口フエニルヂォ）シクロへキサ -1,4- ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 1 4 7 ) 89 H 2Γ6 οε 6 s s A Dimension ffi ichi-. ()) Dimension z) (9H & Dimension ssHz HI H Dimension £) 6S9S696 H -... Example 121: N- [3,6-dioxo-4- (3-chlorophenyl) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 144) )
実施例 6 4と同様の方法を用いて実施例 1 4で得られる化合物 1 4の 15.6m g(0.039mmol)と 3-クロロチオフエノ一ル 4.6 H l(0.040mmol)より、 化合物 1 4 7を 13.7mg(69.1%)得た。  From 15.6 mg (0.039 mmol) of the compound 14 obtained in Example 14 and 4.6 Hl of 3-chlorothiophenol (0.040 mmol) obtained in Example 14 using the same method as in Example 64, 13.7 mg of the compound 144 was obtained. (69.1%).
1H NMR (400 MHz, CDC13) δ ppm ； 9.32 (br s, IH), 7.69 (s, IH), 7.53-7.30 1H NMR (400 MHz, CDC1 3 ) δ ppm; 9.32 (br s, IH), 7.69 (s, IH), 7.53-7.30
(m, 9H), 6.94-6.90 (m, 4H)， 5.87 (s, IH), 5.02 (s, 2H)， 4.58 (s， 2H) (m, 9H), 6.94-6.90 (m, 4H), 5.87 (s, IH), 5.02 (s, 2H), 4.58 (s, 2H)
FABMS m/z ； 507 (M+2H)+ FABMS m / z; 507 (M + 2H) +
実施例 1 2 2 ： N-[3，6-ジォキソ -4-(2-クロ口フエ二ルチオ）シクロへキサ -1，4- ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 1 4 8 ) Example 1 222: N- [3,6-dioxo-4- (2-chlorophenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 1 4 8)
実施例 6 4と同様の方法を用いて実施例 1 4で得られる化合物 1 4の 17.8m g(0.045mmol)と 2-クロロチオフエノ一ル 5.1 (i l(0.045mmol)より、 化合物 1 4 8を 14.1mg(62.3%)得た。  From 17.8 mg (0.045 mmol) of compound 14 obtained in Example 14 and 2-chlorothiophenol 5.1 (il (0.045 mmol) using the same method as in Example 64, 14.1 mg of compound 148 was obtained. (62.3%).
1H NMR (400 MHz, CDCI3) δ ppm ； 9.32 (br s, IH), 7.69 (s, 1H)， 7.63-7.59 (m, 2H)， 7.52-7.46 (m, IH), 7.41-7.30 (m， 6H), 6.99-6.89 (m, 4H), 5.74 (s， 1 H)， 5.02 (s, 2H), 4.56 (s, 2H)  1H NMR (400 MHz, CDCI3) δ ppm; 9.32 (br s, IH), 7.69 (s, 1H), 7.63-7.59 (m, 2H), 7.52-7.46 (m, IH), 7.41-7.30 (m, 6H), 6.99-6.89 (m, 4H), 5.74 (s, 1H), 5.02 (s, 2H), 4.56 (s, 2H)
FABMS m/z ； 507 (M+2H)+ FABMS m / z; 507 (M + 2H) +
実施例 1 2 3 ： N-[3，6-ジォキソ -4-(4-ブロモフエ二ルチオ）シクロへキサ -1,4- ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 1 4 9 ) Example 12 3: N- [3,6-dioxo-4- (4-bromophenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 14 9 )
実施例 6 4と同様の方法を用いて実施例 1 4で得られる化合物 1 4の 19.5m g(0.049mmol)と p-ブロモベンゼンチオール 9.7mg(0.051mmol)より、 化合物 1 4 9を 20.0mg(74.1%)得た。  From 19.5 mg (0.049 mmol) of compound 14 obtained in Example 14 and 9.7 mg (0.051 mmol) of p-bromobenzenethiol obtained in Example 14 using the same method as in Example 64, 20.0 mg of Compound 14 9 ( 74.1%).
1H NMR (400 MHz, CDCI3) δ ppm ； 9.32 (br s， IH), 7.68-7.62 (m， 3H), 7.4 2-7.29 (m， 6H)， 6.95-6.89 (m, 4H)， 5.84 (s, 1H)， 5.02 (s， 2H)， 4.56 (s, 2H) FABMS m/z ； 551 (M+H)+ 1H NMR (400 MHz, CDCI3) δ ppm; 9.32 (br s, IH), 7.68-7.62 (m, 3H), 7.4 2-7.29 (m, 6H), 6.95-6.89 (m, 4H), 5.84 (s , 1H), 5.02 (s, 2H), 4.56 (s, 2H) FABMS m / z; 551 (M + H) +
実施例 1 2 4 ： N-[3，6-ジォキソ -4-(3-ブロモフエ二ルチオ)シクロへキサ -1，4- ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 1 5 0 ) 実施例 6 4と同様の方法を用いて実施例 1 4で得られる化合物 1 4の 15.8m g(0.040mmol)と 3-ブロモチォフエノール 4.1 H l(0.040mmol)より、 化合物 1 5 0を 17.8mg(81.4 %)得た。 Example 124: N- [3,6-dioxo-4- (3-bromophenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 150 ) From 15.8 mg (0.040 mmol) of the compound 14 obtained in Example 14 and 4.1 Hl (0.040 mmol) of 3-bromothiophenol obtained in Example 14 using the same method as in Example 64, 17.8 mg of Compound 150 was obtained. (81.4%).
1H NMR (500 MHz, CDC13) δ ppm ； 9.33 (br s, IH), 7.69-7.65 (m, 3H), 7.4 7-7.30 (m, 7H), 6.94-6.90 (m， 4H), 5.87 (s, IH), 5.02 (s, 2H), 4.57 (s, 2H) FABMS m/z ； 551 (M+H)+ 1H NMR (500 MHz, CDC1 3 ) δ ppm; 9.33 (br s, IH), 7.69-7.65 (m, 3H), 7.4 7-7.30 (m, 7H), 6.94-6.90 (m, 4H), 5.87 ( s, IH), 5.02 (s, 2H), 4.57 (s, 2H) FABMS m / z; 551 (M + H) +
実施例 1 2 5 ： N-[3，6-ジォキソ -4-(2-ブロモフエ二ルチオ）シクロへキサ -1,4- ジェニル] -4-ベンジルォキシフエノキシァセトアミド （化合物 1 5 1 ) Example 1 25: N- [3,6-dioxo-4- (2-bromophenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 15 1 )
実施例 6 4と同様の方法を用いて実施例 1 4で得られる化合物 1 4の 17.6m g(0.044mmol)と 2-ブロモチォフエノ—ル 5.3 fi l(0.044mmol)より、 化合物 1 5 1を 17.4mg(74.9%)得た。  From 17.6 mg (0.044 mmol) of compound 14 obtained in Example 14 and 5.3 fil (0.044 mmol) of 2-bromothiophenol obtained in the same manner as in Example 64, 17.4 mg of Compound 151 was obtained. (74.9%).
1H NMR (500 MHz, CDCI3) δ ppm ； 9.33 (br s, IH), 7.79-7.78 (m, IH), 7.6 9 (s, IH), 7.64-7.62 (m, IH), 7.45-7.30 (m, 7H)， 6.95-6.90 (m, 4H), 5.74 (s, 1 H)， 5.02 (s, 2H), 4.57 (s, 2H)  1H NMR (500 MHz, CDCI3) δ ppm; 9.33 (br s, IH), 7.79-7.78 (m, IH), 7.69 (s, IH), 7.64-7.62 (m, IH), 7.45-7.30 (m , 7H), 6.95-6.90 (m, 4H), 5.74 (s, 1H), 5.02 (s, 2H), 4.57 (s, 2H)
FABMS m/z ； 551 (M+H)+ FABMS m / z; 551 (M + H) +
参考例 1 ： 化合物 a Reference Example 1: Compound a
4-ベンジルォキシフエノキシ酢酸 295mg(l.lmmol)を塩化チォニル 3mlに溶 解し、 アルゴン気流下 1時間加熱還流した。 減圧下に溶媒を留去し、 4-ベンジ ルォキシフエノキシ酢酸クロリドの粗生成物を得た。  295 mg (l.lmmol) of 4-benzyloxyphenoxyacetic acid was dissolved in 3 ml of thionyl chloride, and the mixture was heated and refluxed for 1 hour under a stream of argon. The solvent was distilled off under reduced pressure to obtain a crude product of 4-benzyloxyphenoxyacetic acid chloride.
4-メトキシ -2-二トロフエノール 195mg(l.lmmol)を酢酸ェチル 10mlに溶解し、 酸化白金 lmgを添加し、 水素気流下で 2時間攪拌した。 この反応溶液に Ν,Ν- ジメチルァニリン 0.5ml(3.9mmol)と、 上記で得られる 4-ベンジルォキシフエノ キシ酢酸クロリドを塩化メチレン 5mlに溶解したものを加え、 室温で 20分間 攪拌した。 通常の後処理の後、 酢酸ェチル -へキサンより再結晶し、 化合物 a を 384mg(89%)得た。  195 mg (l.lmmol) of 4-methoxy-2-ditrophenol was dissolved in 10 ml of ethyl acetate, lmg of platinum oxide was added, and the mixture was stirred under a hydrogen stream for 2 hours. 0.5 ml (3.9 mmol) of Ν, Ν-dimethylaniline and 4-benzyloxyphenoxyacetic acid chloride obtained above dissolved in 5 ml of methylene chloride were added to the reaction solution, and the mixture was stirred at room temperature for 20 minutes. . After usual work-up, recrystallization from ethyl acetate-hexane gave 384 mg (89%) of compound a.
1H NMR (400MHz, CDCI3) δ ppm ； 8.52 (br s, 1H)， 7.67 (br s， IH), 7.44-7.29 (m， 5H)， 6.97-6.92 (m, 5H)， 6.74-6.72 (m, 2H), 5.04 (s, 2H), 4.62 (s, 2H), 3. 76 (s, 3H) 1H NMR (400 MHz, CDCI3) δ ppm; 8.52 (br s, 1H), 7.67 (br s, IH), 7.44-7.29 (m, 5H), 6.97-6.92 (m, 5H), 6.74-6.72 (m, 2H), 5.04 (s, 2H), 4.62 (s, 2H), 3. 76 (s, 3H)
FABMS m/z ； 380 (M+H)+ FABMS m / z; 380 (M + H) +
参考例 2 ： 化合物 b Reference Example 2: Compound b
3,7,11-トリメチル -2,6,10-ドデカトリェン酸 584mg(2.5mmol)をトルエン 5ml に溶解し、 これに塩化ォキサリル 0.50ml(5.7mmol)を滴下し、 室温で 2時間攪 拌した。 溶媒を留去し、 3 1-トリメチル -2，6，10-ドデカトリェン酸クロリドを 粗生成物として得た。  584 mg (2.5 mmol) of 3,7,11-trimethyl-2,6,10-dodecatrienic acid was dissolved in 5 ml of toluene, and 0.50 ml (5.7 mmol) of oxalyl chloride was added dropwise thereto, followed by stirring at room temperature for 2 hours. The solvent was distilled off to obtain 31-trimethyl-2,6,10-dodecatrienic chloride as a crude product.
2,5-ジメトキシァニリン 541mg(3.5mmol)をピリジン 5mlに溶解し、 これに 上記で得られる 3,7,11-トリメチル -2,6,10-ドデカトリェン酸クロリドを滴下し、 室温で 60分攪拌した。 通常の後処理後、 残渣をシリカゲルカラムクロマトグ ラフィ一 [へキサン 酢酸ェチル = 85 I 15 (v/v)] で精製し、 化合物 bを 76 6mg(83%)得た。  541 mg (3.5 mmol) of 2,5-dimethoxyaniline was dissolved in 5 ml of pyridine, and 3,7,11-trimethyl-2,6,10-dodecatrienic acid chloride obtained above was added dropwise thereto. Stirred. After ordinary post-treatment, the residue was purified by silica gel column chromatography [ethyl hexane acetate = 85 I 15 (v / v)] to obtain 766 mg (83%) of compound b.
1H NMR (500MHz, CDC13) δ ppm ； 8.23 (br s, 1H)， 7.72 (br s, IH), 6.77 (d, J=8.9Hz, 1H)， 6.54 (dd, J=8.9, 3.1Hz, IH), 5.73 (br s, IH), 5.13-5.07 (m， 2H), 3.82 (s, 3H), 3.79 (s, 3H)， 2.22 (d， J=1.3Hz, 3H)， 2.22-2.16 (m， 4H), 2.11-1.9 5 (m， 4H)， 1.68 (d, J=l.lHz, 3H), 1.63 (d, J=1.0Hz， 3H), 1.59 (d, J=0.7Hz, 3 H) 1H NMR (500MHz, CDC1 3) δ ppm; 8.23 (br s, 1H), 7.72 (br s, IH), 6.77 (d, J = 8.9Hz, 1H), 6.54 (dd, J = 8.9, 3.1Hz, IH), 5.73 (br s, IH), 5.13-5.07 (m, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 2.22 (d, J = 1.3 Hz, 3H), 2.22-2.16 ( m, 4H), 2.11-1.95 (m, 4H), 1.68 (d, J = l.lHz, 3H), 1.63 (d, J = 1.0Hz, 3H), 1.59 (d, J = 0.7Hz, 3 H)
FABMS m/z ； 372 (M+H)+ FABMS m / z; 372 (M + H) +
参考例 3 ： 化合物 c Reference Example 3: Compound c
参考例 1と同様の方法を用いて、 2,5-ジメトキシァニリン 1.0g(6.58mmol)と 4-ベンジルォキシフエノキシ酢酸 1.2g(4.65mmol)より、 化合物 Cを 1.58g(91. 4%)得た。  Using the same method as in Reference Example 1, 1.5 g of Compound C (91.91 g) was obtained from 1.0 g (6.58 mmol) of 2,5-dimethoxyaniline and 1.2 g (4.65 mmol) of 4-benzyloxyphenoxyacetic acid. 4%).
1H NMR (400MHz, CDCI3) δ ppm ； 9.00 (br s， IH), 8.13 (d, J=3.2Hz, IH), 7. 46-7.30 (m, 5H)， 6.95 (m， 4H), 6.80 (d, J=9.0Hz, IH), 6.60 (dd, J=9.0, 3.0Hz, 1H NMR (400 MHz, CDCI3) δ ppm; 9.00 (br s, IH), 8.13 (d, J = 3.2 Hz, IH), 7.46-7.30 (m, 5H), 6.95 (m, 4H), 6.80 ( d, J = 9.0Hz, IH), 6.60 (dd, J = 9.0, 3.0Hz,
IH), 5.03 (s, 2H)， 4.57 (s, 2H), 3.82 (s, 3H)， 3.79 (s, 3H) IH), 5.03 (s, 2H), 4.57 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H)
FABMS m/z ； 394 (M+H)+ FABMS m / z; 394 (M + H) +
参考例 4 ： 化合物 d 3,7,11-トリメチル -2，6，10-ドデカトリエン酸 495mg(2.1mmol) をトルエン 5ml に溶解し、 塩化ォキサリル 0.5mlを加え、 室温で 3時間攪拌した。 溶媒を減圧 下に留去し、 3，7，11-トリメチル -2，6,10-ドデカトリェン酸クロリドの粗生成物 を得た。 Reference Example 4: Compound d 495 mg (2.1 mmol) of 3,7,11-trimethyl-2,6,10-dodecatrienoic acid was dissolved in 5 ml of toluene, 0.5 ml of oxalyl chloride was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure to obtain a crude product of 3,7,11-trimethyl-2,6,10-dodecatrienic chloride.
6-クロ口- 4-メトキシ -2-ニトロフエノール 801mg(4.2mmol)を酢酸ェチル 10 mlとエタノール 5mlの混合溶媒に溶解し、 水素気流下で 2時間攪拌した。 反 応溶液をろ過助剤を用いてろ過した後、 ピリジン 10mlと、 上記で得られる 3, 7,11-トリメチル -2,6,10-ドデカトリェン酸クロリドを塩化メチレン 5mlに溶解 したものを加え、 室温で 15分間攪拌した。 通常の後処理の後、 シリカゲル力 ラムクロマトグラフィー [へキサン/酢酸ェチル = 88 / 12(v/v)] で精製し、 化合物 dを 485mg(59%)得た。  801 mg (4.2 mmol) of 6-chloro-4-methoxy-2-nitrophenol was dissolved in a mixed solvent of 10 ml of ethyl acetate and 5 ml of ethanol, and the mixture was stirred under a hydrogen stream for 2 hours. After filtering the reaction solution using a filter aid, 10 ml of pyridine and a solution of 3,7,11-trimethyl-2,6,10-dodecatrienoic acid chloride obtained above in 5 ml of methylene chloride were added. Stirred at room temperature for 15 minutes. After usual post-treatment, purification was performed by silica gel column chromatography [hexane / ethyl acetate = 88/12 (v / v)] to obtain 485 mg (59%) of compound d.
1H NMR (400MHz, CDC13) δ ppm ； 7.60 (br s， IH), 7.32 (br s, IH), 7.27 (d, J=2.7Hz, 1H)， 6.71 (d, J=2.7Hz, 1H)， 5.76 (br s, 1H)， 5.12-5.08 (m, 2H)， 3.74 (s, 3H)， 2.23 (d, J=1.0Hz, 3H), 2.20-2.18 (m, 4H)， 2.11-1.98 (m, 4H)， 1.68 (br s, 3H), 1.63 (br s， 3H), 1.61 (br s, 3H) 1H NMR (400MHz, CDC1 3) δ ppm; 7.60 (br s, IH), 7.32 (br s, IH), 7.27 (d, J = 2.7Hz, 1H), 6.71 (d, J = 2.7Hz, 1H) , 5.76 (br s, 1H), 5.12-5.08 (m, 2H), 3.74 (s, 3H), 2.23 (d, J = 1.0 Hz, 3H), 2.20-2.18 (m, 4H), 2.11-1.98 ( m, 4H), 1.68 (br s, 3H), 1.63 (br s, 3H), 1.61 (br s, 3H)
FABMS m/z ； 392 (M+H)+ FABMS m / z; 392 (M + H) +
参考例 5 ： 化合物 e Reference Example 5: Compound e
参考例 1と同様の方法を用いて、 6-クロ口- 4-メトキシ- 2-ニトロフエノール 283mg(1.4mmol)と 4-ベンジルォキシフエノキシ酢酸 356mg(l.lmmol)より、 化 合物 eを 441mg(77%)得た。  Using the same method as in Reference Example 1, the compound was obtained from 283 mg (1.4 mmol) of 6-chloro-4-methoxy-2-nitrophenol and 356 mg (l.lmmol) of 4-benzyloxyphenoxyacetic acid. e was obtained as 441 mg (77%).
1H NMR (500MHz, CDCI3) (5 ppm ； 8.81 (br s, IH), 7.59 (d, J=2.9Hz, 1H)， 7. 46-7.29 (m, 5H)， 6.97-6.90 (m， 4H)， 6.72 (d, J=2.9Hz, IH), 6.30 (br s, IH), 5. 03 (s, 2H), 4.59 (s, 2H), 3.78 (s, 3H)  1H NMR (500 MHz, CDCI3) (5 ppm; 8.81 (br s, IH), 7.59 (d, J = 2.9 Hz, 1H), 7.46-7.29 (m, 5H), 6.97-6.90 (m, 4H) , 6.72 (d, J = 2.9Hz, IH), 6.30 (br s, IH), 5.03 (s, 2H), 4.59 (s, 2H), 3.78 (s, 3H)
FABMS m/z ； 414 (M+H)+ FABMS m / z; 414 (M + H) +
参考例 6 ： 化合物 f Reference Example 6: Compound f
参考例 2と同様の方法を用いて、 3-クロ口- 2，5-ジメトキシニトロベンゼン 1 62mg(0.74mmol)と 3,7,11-トリメチル -2，6，10-ドデカトリエン酸 110mg(0.46mmo 1)より、 化合物 f を 143mg(76 %)得た。 Using the same method as in Reference Example 2, 3-cloto-2,5-dimethoxynitrobenzene (162 mg, 0.74 mmol) and 3,7,11-trimethyl-2,6,10-dodecatrienoic acid 110 mg (0.46 mmol) From 1), 143 mg (76%) of compound f was obtained.
1H NMR (lOOMHz, CDC13) δ ppm ； 8.05 (d, J=3.2Hz, IH), 7.66 (br s, 1H)， 6. 62 (d, J=3.0Hz, 1H)， 5.72 (br s, 1H)， 5.05 (br s, 2H), 3.83 (s, 3H), 3.78 (s, 3 H), 2.25-1.94 (m, 11H), 1.67 (br s, 3H), 1.63 (br d， J=1.2Hz, 3H), 1.60 (s, 3 H) 1H NMR (lOOMHz, CDC1 3) δ ppm; 8.05 (d, J = 3.2Hz, IH), 7.66 (br s, 1H), 6. 62 (d, J = 3.0Hz, 1H), 5.72 (br s, 1H), 5.05 (br s, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 2.25-1.94 (m, 11H), 1.67 (br s, 3H), 1.63 (br d, J = 1.2Hz, 3H), 1.60 (s, 3H)
FABMS m/z ； 406 (M+H)+ FABMS m / z; 406 (M + H) +
参考例 7 ： 化合物 g Reference Example 7: Compound g
参考例 2と同様の方法を用いて、 4-ベンジルォキシフエノキシ酢酸 433mg(l. 7mmol)と 3-ク口口- 2,5-ジメトキシニトロベンゼン 300mg(1.4mmol)より、 化合 物 gを 523mg(89%)得た。  Using the same method as in Reference Example 2, the compound g was obtained from 433 mg (l.7 mmol) of 4-benzyloxyphenoxyacetic acid and 300 mg (1.4 mmol) of 3,2-dimethoxy-2,5-dimethoxynitrobenzene. 523 mg (89%) were obtained.
1H NMR (100MHz, CDCI3) <5 ppm ； 8.94 (br s， IH), 7.99 (d, J=3.2Hz, 1H)， 7. 5-7.2 (m, 5H), 6.95 (m, 4H)， 6.64 (d, J=3.2Hz, 1H)， 3.76 (s, 3H), 3.64 (s， 3H) FABMS m/z ； 427 (M+H)+ 1H NMR (100 MHz, CDCI3) <5 ppm; 8.94 (br s, IH), 7.99 (d, J = 3.2 Hz, 1H), 7.5-7.2 (m, 5H), 6.95 (m, 4H), 6.64 (d, J = 3.2Hz, 1H), 3.76 (s, 3H), 3.64 (s, 3H) FABMS m / z; 427 (M + H) +
参考例 8 ： 化合物 h Reference Example 8: Compound h
参考例 1と同様の方法を用いて 3,7,11-トリメチル -2,6,10-ドデカトリェン酸 346mg(1.46mmol)と 4-クロ口- 2,5-ジメトキシァニリン塩酸塩 432mg(1.93mmol) より化合物 hを 357mg(60%)得た。  Using the same method as in Reference Example 1, 346 mg (1.46 mmol) of 3,7,11-trimethyl-2,6,10-dodecatrienoic acid and 432 mg (1.93 mmol) of 4-chloro-2,5-dimethoxyaniline hydrochloride were used. ) To give 357 mg (60%) of compound h.
1H NMR (100MHz, CDC13) δ ppm ； 8.35 (s, IH), 7.71 (br s 1H)， 6.87 (s, 1H)， 1H NMR (100MHz, CDC1 3) δ ppm; 8.35 (s, IH), 7.71 (br s 1H), 6.87 (s, 1H),
5.72 (br s， 1H)， 5.10 (br s, 2H), 3.90 (s， 3H)， 3.78 (s, 3H)， 2.3-1.94 (m, 11 H), 1.67 (br s, 3H), 1.62 (br s, 3H)， 1.59 (s, 3H) 5.72 (br s, 1H), 5.10 (br s, 2H), 3.90 (s, 3H), 3.78 (s, 3H), 2.3-1.94 (m, 11H), 1.67 (br s, 3H), 1.62 ( br s, 3H), 1.59 (s, 3H)
FABMS m/z ； 406 (M+H)+ FABMS m / z; 406 (M + H) +
参考例 9 ： 化合物 i Reference Example 9: Compound i
参考例 2と同様の方法を用いて、 4-クロ口- 2,5-ジメトキシァニリン 6.52g(0.0 29mol)と 4-ベンジルォキシフエノキシ酢酸 8.06g(0.031mol)より、 化合物 iを 1 2.3g(98.8%)得た。  Using the same method as in Reference Example 2, compound i was obtained from 6.52 g (0.029 mol) of 4-chloro-2,5-dimethoxyaniline and 8.06 g (0.031 mol) of 4-benzyloxyphenoxyacetic acid. 1 2.3 g (98.8%) was obtained.
1H NMR (400MHz, CDC13) δ ppm ； 8.26 (s, IH), 7.43-7.30 (m, 5H), 6.95-6.93 (m, 4H), 6.92-6.91 (m, 1H)， 5.03 (s, 2H)， 4.56 (s， 2H)， 3.90 (s, 3H)， 3.82 (s, 3H) 1H NMR (400MHz, CDC1 3) δ ppm; 8.26 (s, IH), 7.43-7.30 (m, 5H), 6.95-6.93 (m, 4H), 6.92-6.91 (m, 1H), 5.03 (s, 2H ), 4.56 (s, 2H), 3.90 (s, 3H), 3.82 (s, 3H)
FABMS m/z ； 428 (M+H)+ FABMS m / z; 428 (M + H) +
参考例 1 0 ： 化合物 j Reference Example 10: Compound j
実施例 1と同様の方法を用いて、 3,4-ジクロロ- 2,5-ジメトキシニトロベンゼ ン 99mg(0.39mmol)と 4-ベンジルォキシフエノキシ酢酸 131mg(0.50mmol)より、 化合物 jを 103mg(56%)得た。  Using the same method as in Example 1, compound j was obtained from 3,4-dichloro-2,5-dimethoxynitrobenzene 99 mg (0.39 mmol) and 4-benzyloxyphenoxyacetic acid 131 mg (0.50 mmol). 103 mg (56%) were obtained.
1H NMR (500MHz, CDC13) δ ppm ； 8.97 (br s, 1H), 8.17 (s, 1H)， 7.44-7.30 (m， 5H)， 6.96-6.90 (m, 4H), 5.03 (s, 2H)， 4.60 (s， 2H), 3.92 (s, 3H), 3.68 (s, 3H) 1H NMR (500MHz, CDC1 3) δ ppm; 8.97 (br s, 1H), 8.17 (s, 1H), 7.44-7.30 (m, 5H), 6.96-6.90 (m, 4H), 5.03 (s, 2H) , 4.60 (s, 2H), 3.92 (s, 3H), 3.68 (s, 3H)
FABMS m/z ； 462(M+H)+ FABMS m / z; 462 (M + H) +
参考例 1 1 ： 化合物 k Reference Example 11 1: Compound k
6-ブロモ -4-メトキシ -2-ニトロフエノ一ル 602mg(2.4mmol)をテトラヒドロフ ラン 20mlに溶解し、 スズ 1.71g(14.4mmol)および 1規定塩酸 5ml(5.0mmol) を 加え、 室温で 30分間攪拌した。 過剰のスズを濾別し、 酢酸ェチルで洗浄した。 通常の後処理を行い、 2-ァミノ- 6-ブロモ -4-メトキシフエノールの粗生成物を 得た。  Dissolve 602 mg (2.4 mmol) of 6-bromo-4-methoxy-2-nitrophenol in 20 ml of tetrahydrofuran, add 1.71 g (14.4 mmol) of tin and 5 ml (5.0 mmol) of 1N hydrochloric acid, and then at room temperature for 30 minutes Stirred. Excess tin was filtered off and washed with ethyl acetate. After ordinary post-treatment, a crude product of 2-amino-6-bromo-4-methoxyphenol was obtained.
参考例 2と同様の方法を用いて、 上記の 2-ァミノ- 6-ブロモ -4-メトキシフエ ノール粗生成物および 3,7,11-トリメチル -2,6,10-ドデカトリエン酸 896mg(3.8m mol)より、 化合物 kを 156mg(9%)得た。  Using the same method as in Reference Example 2, the above crude 2-amino-6-bromo-4-methoxyphenol and 3,7,11-trimethyl-2,6,10-dodecatrienoic acid 896 mg (3.8 m mol), 156 mg (9%) of compound k was obtained.
1H NMR (100MHz, CDC13) δ ppm ； 7.63 (br s, 1H), 7.40 (br s, 1H), 7.28 (d, J=3Hz, 1H)， 6.83 (d, J=3Hz, 1H), 5.75 (br s, 1H)， 5.10 (br s, 2H)， 3.72 (s, 3 H), 2.3-1.94 (m, 11H), 1.67 (br s， 3H)， 1.60 (s, 6H) 1H NMR (100MHz, CDC1 3) δ ppm; 7.63 (br s, 1H), 7.40 (br s, 1H), 7.28 (d, J = 3Hz, 1H), 6.83 (d, J = 3Hz, 1H), 5.75 (br s, 1H), 5.10 (br s, 2H), 3.72 (s, 3H), 2.3-1.94 (m, 11H), 1.67 (br s, 3H), 1.60 (s, 6H)
参考例 1 2 ： 化合物 m Reference Example 12 2: Compound m
参考例 1 1と同様の方法を用いて、 6-ブロモ -4-メトキシ -2-ニトロフエノー ル 181mg(0.73mmol)、 スズ 560mg(4.7mmol)、 1規定塩酸 2ml(2.0mmol)、 およ び 4-ベンジルォキシフエノキシ酢酸 196mg(0.76mmol)より、 化合物 mを 126mg (37%)得た。 38 Reference Example 11 Using the same method as in Example 1, 6-bromo-4-methoxy-2-nitrophenol 181 mg (0.73 mmol), tin 560 mg (4.7 mmol), 1N hydrochloric acid 2 ml (2.0 mmol), and 4 From 196 mg (0.76 mmol) of -benzyloxyphenoxyacetic acid, 126 mg (37%) of compound m was obtained. 38
+ (H+W) PIP - z/ i SP SVJ (He 's q) 09Ί '(H£
Figure imgf000084_0001
'Ρ) £9·ΐ '(Η£
Figure imgf000084_0002
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Figure imgf000084_0001
'Ρ) £ 9 · ΐ' (Η £
Figure imgf000084_0002
'Ρ) te' (Η £ 's) Ι9' (Η £
's) ςί '(Ηε 's) 'p) es's) ςί' (Ηε 's)' p) es
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Figure imgf000084_0003
ΜΝ Ht douim ·0)¾ι9ん f, 4 £^ ΐ -0Ι'9'乙-^ ft 4 -Π'ん 'ε ? (lomm ·ο)3ι¾• 9 '(HI' S Jq) 69
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^く,ェ 4 4 ^-^ ^ -ε 、Ο ¾¾^Q)對 feiマ ^ く, ェ 4 4 ^-^ ^ -ε, Ο ¾¾ ^ Q)
d i ^ > ： T P ^ +(H+PM) ;0 · z/ui swavj (H£ £zH9*9=f 'P) '(H£ 'S 09'X '(He 'zHO'X=f 'P) £9'l '(H£ 'ΖΗΔΌ=Γ 'Ρ) 89·ΐ '(Ht 'm) '(H '冚） 9Γ - 02di ^>: TP ^ + (H + PM); 0 · z / ui swavj (H £ £ zH9 * 9 = f 'P)' (H £ 'S 09'X' (He 'zHO'X = f' P) £ 9'l '(H £' ΖΗΔΌ = Γ 'Ρ) 89 · ΐ' (Ht 'm)' (H '冚) 9Γ-02
'(Η£ 'zHO-I=f 'Ρ) £Ζ'Ζ '(HI 'S Jq) ΙΖΎ '(Η£ ' L'Z '(HI 'zW9=f 'b) '(ΗΖ '∞) ιο·ς-ζνς '(HI 'ΖΗΟ·Τ=Γ 'Ρ) 9 '(HI 6 =r 'Ρ) W9 '(HI 'ZH6 =f 'Ρ) Z£'L '(HI 'S Jq) 19· L '(HX 'S Jq) 99*8 ί 冚 dd Q (HO D ' OO ) Ή匪 Ht 6乙翊くェ Π
Figure imgf000084_0004
'(Η £' zHO-I = f 'Ρ) £ Ζ'Ζ' (HI 'S Jq) ΙΖΎ' (Η £ 'L'Z' (HI 'zW9 = f' b) '(ΗΖ' ∞) ιο Σ-ζνς '(HI' ΖΗΟ · Τ = Τ 'Ρ) 9' (HI 6 = r 'Ρ) W9' (HI 'ZH6 = f' Ρ) Z £ 'L' (HI 'S Jq) 19 L '(HX' S Jq) 99 * 8 ί冚dd Q (HO D 'OO) Ή negation H t 6 Otsu翊Kue Π
Figure imgf000084_0004
Figure imgf000084_0005
Z¼
Figure imgf000084_0005
Z¼
。^ §m89l7呦^ ^¾G i— /ェ乙 ^ ! ^ェく、 Ψα ^-ι)-9ゾ 班 - つ Φί«^ ® ^軍土 ¾g ^峯氺 ^ ^^ i^mm ^ -i ^moi Λ(~
Figure imgf000084_0006
a . ^ §M 89l7 呦 ^ ^ ¾G i— / ェ ^^! ^ ェ, Ψα ^ -ι) -9 squad-Tsu Φί «^ ® ^ military soil ¾g ^ mine 氺 ^ ^^ i ^ mm ^ -i ^ m oi Λ (~
Figure imgf000084_0006
a
u呦 i ： ε τ u^ u 呦 i: ε τ u ^
+(H+W) 8 - z/m SWHVd + (H + W) 8-z / m SWHVd
(He 's) L (He 's) L
\m 's)6£*i7 '(Hz 's) εο·ς· '(HI zHs*e=r 'ρ) ς^9 '(m '« S6"9 '(HS '« rt-9\ m 's) 6 £ * i7' (Hz 's) εο · ς ·' (HI zHs * e = r 'ρ) ς ^ 9' (m '«S6" 9' (HS '«rt-9
'L '(HI 'zHg-£=f 'P) 9'L '(HI 'S Jq) 08'8 · ^dd ρ (¾X 'zHWOOX) ¾WN Ht £LS£0/L6d£/lDd 6Z9,I/86 OAV 参考例 1 5 ： 化合物 Q 'L' (HI 'zHg- £ = f' P) 9'L '(HI' S Jq) 08'8 ^ dd ρ (¾X 'zHWOOX) ¾WN H t £ LS £ 0 / L6d £ / lDd 6Z9, I / 86 OAV Reference Example 15: Compound Q
参考例 2と同様の方法を用いて、 2-ァミノ- 6-ヒドロキシメチル -4-メトキシ フエノール 431mg(2.5mmol)と 3,7,11-トリメチル -2,6,10-ドデカトリエン酸 520 mg(2,2mmol)より、 化合物 Qを 730mg(85%)得た。  Using the same method as in Reference Example 2, 431 mg (2.5 mmol) of 2-amino-6-hydroxymethyl-4-methoxyphenol and 520 mg of 3,7,11-trimethyl-2,6,10-dodecatrienoic acid ( 2,2 mmol) to give 730 mg (85%) of compound Q.
1H NMR (100MHz, CDC13) δ ppm ； 8.77 (br s, 1H), 7.63 (br s, 1U\ 7.03 (d, J=3.0Hz, 1H)， 6.55, (d, J=3.0Hz, 1H), 5.78 (br s, 1H)， 5.10 (br s, 2H), 4.73 (b r s, 2H), 3.72 (s, 3H), 2.3-1.94 (m， 11H), 1.67 (br s, 3H), 1.60 (s, 6H) 参考例 1 6 ： 化合物 r 1H NMR (100MHz, CDC1 3) δ ppm; 8.77 (br s, 1H), 7.63 (br s, 1U \ 7.03 (d, J = 3.0Hz, 1H), 6.55, (d, J = 3.0Hz, 1H) , 5.78 (br s, 1H), 5.10 (br s, 2H), 4.73 (brs, 2H), 3.72 (s, 3H), 2.3-1.94 (m, 11H), 1.67 (br s, 3H), 1.60 ( s, 6H) Reference Example 16: Compound r
参考例 1と同様の方法を用いて、 2，3，5-トリメトキシニトロベンゼン 21mg(0. lOmmol)と 4-ベンジルォキシフエノキシ酢酸 43mg(0.17mmol)より、 化合物 rを 30mg(71%)得た。  Using the same method as in Reference Example 1, 30 mg (71%) of compound r was obtained from 2,3,5-trimethoxynitrobenzene 21 mg (0.1 mmol) and 4-benzyloxyphenoxyacetic acid 43 mg (0.17 mmol). )Obtained.
1H NMR (500MHz, CDC13) δ ppm ； 9.02 (br s, 1H), 7.69 (d, J=2.9Hz, 1H)， 7. 1H NMR (500MHz, CDC1 3) δ ppm; 9.02 (br s, 1H), 7.69 (d, J = 2.9Hz, 1H), 7.
42- 7.26 (m, 5H), 6.95-6.91 (m, 4H), 6.28 (d, J=2.9Hz, 1H), 5.02 (s, 2H), 4.58 (s, 2H), 3.83 (s, 3H)， 3.81 (s, 3H), 3.67 (s, 3H) 42- 7.26 (m, 5H), 6.95-6.91 (m, 4H), 6.28 (d, J = 2.9Hz, 1H), 5.02 (s, 2H), 4.58 (s, 2H), 3.83 (s, 3H) , 3.81 (s, 3H), 3.67 (s, 3H)
FABMS m/z ； 424 (M+H)+ FABMS m / z; 424 (M + H) +
参考例 1 7 ： 化合物 s Reference Example 17: Compound s
考例 1と同様の方法を用いて、 2,3-ビス（メトキシメトキシ) -5-メトキシニ トロベンゼン 488mg(1.8mmol)と 4-ベンジルォキシフエノキシ酢酸 557mg(2.0m mol)より、 化合物 Sを 567mg(66%)得た。  Using the same method as in Example 1, the compound was prepared from 488 mg (1.8 mmol) of 2,3-bis (methoxymethoxy) -5-methoxynitrobenzene and 557 mg (2.0 mmol) of 4-benzyloxyphenoxyacetic acid. 567 mg (66%) of S was obtained.
1H匪 R (400MHz, CDC13) δ ppm ； 9.24 (br s， 1H)， 7.79 (d, J=2.9Hz, 1H)， 7.1H negation R (400MHz, CDC1 3) δ ppm; 9.24 (br s, 1H), 7.79 (d, J = 2.9Hz, 1H), 7.
43- 7.29 (m, 5H), 6.93 (s, 4H), 6.52 (d, J=2.9Hz, 1H), 5.17 (s, 2H), 5.06 (s, 2 H), 5.03 (s, 2H), 4.57 (s, 2H), 3.80 (s, 3H)， 3.49 (s, 3H), 3.48 (s, 3H) 43- 7.29 (m, 5H), 6.93 (s, 4H), 6.52 (d, J = 2.9Hz, 1H), 5.17 (s, 2H), 5.06 (s, 2H), 5.03 (s, 2H), 4.57 (s, 2H), 3.80 (s, 3H), 3.49 (s, 3H), 3.48 (s, 3H)
FABMS m/z ； 484 (M+H)+ FABMS m / z; 484 (M + H) +
参考例 1 8 ： 化合物 t Reference Example 18: Compound t
4-クロ口 -2,5-ジメトキシァニリン塩酸塩 448mg(2.0mmol)をジクロロメタン (3 Oml)に溶解し、 4-プロピルフエノキシ酢酸 388mg(2.0mmol)、 塩酸 · 1-ェチル -3- (3-ジメチルァミノプロピル） カルボジィミド (384mg，2.0mmol)およびトリェチ ルァミン (0.28ml， 2.0mmol)を加え室温で 2 5分攪拌した。 通常の後処理により 化合物 tを 670mg(92%)得た。 Dissolve 448 mg (2.0 mmol) of 4-chloro-2,5-dimethoxyaniline hydrochloride in dichloromethane (3 Oml), 388 mg (2.0 mmol) of 4-propylphenoxyacetic acid, hydrochloric acid 1-ethyl-3- (3-Dimethylaminopropyl) carbodiimide (384mg, 2.0mmol) and triethi Lamine (0.28 ml, 2.0 mmol) was added, and the mixture was stirred at room temperature for 25 minutes. The usual work-up gave 670 mg (92%) of compound t.
1H NMR (300MHz, CDCl 3 ) δ ppm ； 8.99 (br s, IH), 8.27 (s, IH), 7.20-6.85 (m, 5H), 4.60 (s, 2H)， 3.90 (s, 3H)， 3.83 (s， 3H), 2.55 (t， J = 7.3 Hz, 2H)， 1. 70-1.50 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H)  1H NMR (300 MHz, CDCl 3) δ ppm; 8.99 (br s, IH), 8.27 (s, IH), 7.20-6.85 (m, 5H), 4.60 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 2.55 (t, J = 7.3 Hz, 2H), 1.70-1.50 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H)
FABMS m/z ； 363 (M)+ FABMS m / z; 363 (M) +
産業上の利用可能性 Industrial applicability
本発明により、 フアルネシルトランスフェラ一ゼ阻害活性を有し、 抗腫瘍剤 として有用な 1, 4—ベンゾキノン誘導体またはその薬理的に許容される塩が提 供される。  The present invention provides a 1,4-benzoquinone derivative or a pharmacologically acceptable salt thereof, which has a pharmacotransferase inhibitory activity and is useful as an antitumor agent.

Claims

請求の範囲 - The scope of the claims -
1. 式 （ I ) 1. Formula (I)
は単結合ま
Figure imgf000087_0001
Is a single bond
Figure imgf000087_0001
たは二重結合を表し、 Xおよび Yは同一または異なって、 水素原子、 ハロゲン、 ヒドロキシ、 置換もしくは非置換の低級アルキル、 置換もしくは非置換の低級 アルコキシ、 低級アルカノィル、 ァミノ、 置換もしくは非置換のモノまたはジ 低級アルキルァミノ、 ァリールァミノ、 ァラルキルァミノ、 低級アルケニルァ ミノ、 置換もしくは非置換の複素環ァミノ、 置換もしくは非置換のアルキルチ ォ、 置換もしくは非置換の複素環チォ、 置換もしくは非置換のァリ一ルチオ、 置換もしくは非置換のァラルキルチオ、 低級アルケニルチオ、 低級アルケニル ォキシ、 置換もしくは非置換のァリ一ルォキシ、 ァラルキルォキシ、 Z (CH 2CH20) nR 4 (式中、 nは 2〜5の整数を表し、 Zは酸素原子、 NHまた は NCH3を表し、 R 4は水素原子または低級アルキルを表す。 ) または置換 もしくは非置換の脂環式複素環基を表し、 R 1および R 2は同一または異なつ て低級アルコキシを表すか、 一緒になつて酸素原子を表し、 尺 3は式(八） X and Y are the same or different and each represents a hydrogen atom, halogen, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, lower alkanoyl, amino, substituted or unsubstituted Mono- or di-lower alkylamino, arylamino, aralkylamino, lower alkenylamino, substituted or unsubstituted heterocyclic amino, substituted or unsubstituted alkylthio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted arylthio, Substituted or unsubstituted aralkylthio, lower alkenylthio, lower alkenyloxy, substituted or unsubstituted aryloxy, aralkyloxy, Z (CH 2 CH 20 ) n R 4 (where n is an integer of 2 to 5) represents, Z is an oxygen atom, NH or NCH 3, R 4 is a hydrogen atom or It represents the grade alkyl.) Or a substituted or unsubstituted alicyclic heterocyclic group, or R 1 and R 2 represent the same or different dates Te lower alkoxy, represent together a connexion oxygen atom, length 3 Equation (8)
Figure imgf000087_0002
Figure imgf000087_0002
で表される 2,6,10-トリメチル -1,5,9-ゥンデ力トリエニルまたは式（B) へ " 2,6,10-trimethyl-1,5,9-ndene trienyl represented by or to formula (B)
(B o) ' (式中、 Wは水素原子、 ハロゲン、 カルボキシ、 低 級アルキル、 低級アルカノィル、 低級アルカノィルォキシ、 低級アルカノィル ォキシアルキル、 ヒドロキシ、 低級アルコキシ、 低級アルコキシアルコキシ、 低級アルケニルォキシ、 置換もしくは非置換のァリールォキシ、 ァラルキルォ キシ、 ニトロ、 ァミノ、 モノまたはジ低級アルキルァミノ、 ァラルキルアミノ、 低級アルケニルァミノ、 置換もしくは非置換のァリール: Γミノ、 置換もしくは 非置換の複素環ァミノ、 アルキルチオ、 低級アルケニルチオ、 置換もしくは非 置換のァリ一ルチオ、 ァラルキルチオまたは置換もしくは非置換の複素環チォ を表す。 ） で表されるァリールォキシメチル基を表す。 ただし、 Xおよび Yが いずれも水素原子であり、 R 1および R 2が一緒になつて酸素原子の場合、 R 3は式 （B ) を表す。 ] で表される 1,4-ベンゾキノン誘導体またはその薬理的 に許容される塩。 (B o ) ′ (wherein, W is a hydrogen atom, halogen, carboxy, lower alkyl, lower alkanol, lower alkanoyloxy, lower alkanoyloxyalkyl, hydroxy, lower alkoxy, lower alkoxyalkoxy, lower alkenyloxy, substitution Or unsubstituted aryloxy, aralkyloxy, nitro, amino, mono- or di-lower alkylamino, aralkylamino, Lower alkenylamino, substituted or unsubstituted aryl: amino, substituted or unsubstituted heterocyclic amino, alkylthio, lower alkenylthio, substituted or unsubstituted arylthio, aralkylthio or substituted or unsubstituted heterocyclicthio Represents ) Represents an aryloxymethyl group. However, when X and Y are both hydrogen atoms and R 1 and R 2 are together and are an oxygen atom, R 3 represents the formula (B). ] Or a pharmacologically acceptable salt thereof.
PCT/JP1997/003873 1996-10-24 1997-10-24 1,4-benzoquinone derivatives WO1998017629A1 (en)

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Publication number Priority date Publication date Assignee Title
JP2014528453A (en) * 2011-10-07 2014-10-27 パイシーズ セラピューティックス エルエルシーＰｉｓｃｅｓ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｌｃ Treatment of malignant and non-malignant diseases with RAS antagonists
CN106146367A (en) * 2015-04-24 2016-11-23 北京大学 Allyl sulfenyl amino 1,4-benzoquinone compounds, its preparation and application
US9738614B2 (en) 2011-10-07 2017-08-22 Pisces Therapeutics, Llc Malignant and non-malignant disease treatment with Ras antagonists

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014528453A (en) * 2011-10-07 2014-10-27 パイシーズ セラピューティックス エルエルシーＰｉｓｃｅｓ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｌｃ Treatment of malignant and non-malignant diseases with RAS antagonists
US9738614B2 (en) 2011-10-07 2017-08-22 Pisces Therapeutics, Llc Malignant and non-malignant disease treatment with Ras antagonists
CN106146367A (en) * 2015-04-24 2016-11-23 北京大学 Allyl sulfenyl amino 1,4-benzoquinone compounds, its preparation and application
CN106146367B (en) * 2015-04-24 2017-12-26 北京大学 Allyl sulfenyl amino 1,4-benzoquinone class compound, it is prepared and application

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