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WO1998057924A1 - Derives d'indene - Google Patents

Derives d'indene Download PDF

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Publication number
WO1998057924A1
WO1998057924A1 PCT/JP1998/002611 JP9802611W WO9857924A1 WO 1998057924 A1 WO1998057924 A1 WO 1998057924A1 JP 9802611 W JP9802611 W JP 9802611W WO 9857924 A1 WO9857924 A1 WO 9857924A1
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WIPO (PCT)
Prior art keywords
group
indene
methanesulfonyl
propyl
carbon atoms
Prior art date
Application number
PCT/JP1998/002611
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English (en)
Japanese (ja)
Inventor
Hiroharu Matsuoka
Noriaki Maruyama
Yasuharu Kato
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
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Filing date
Publication date
Application filed by Chugai Seiyaku Kabushiki Kaisha filed Critical Chugai Seiyaku Kabushiki Kaisha
Priority to AU76749/98A priority Critical patent/AU7674998A/en
Publication of WO1998057924A1 publication Critical patent/WO1998057924A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/14—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—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
    • C07D307/56—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 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/28—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to a novel indene derivative having an anti-inflammatory action and the like, which is useful as a medicine.
  • PGE 2 prostaglandin E 2
  • COX cyclooxygenase
  • NSA ID anti-inflammatory drug
  • the synthetic activity of PGE2 is present in all tissues of the living body and governs the homeostasis of the living body, and when NSAID is administered there, various side effects are caused.
  • PGE 2 has the effect of maintaining blood flow in those organs, but administration of NS AID makes it difficult to maintain local blood flow, resulting in gastric and renal disorders. Is caused.
  • COX-2 the conventional type was called COX-1 and the newly discovered isozyme was called COX-2.
  • COX-2 the newly discovered isozyme was called COX-2.
  • this COX-2 is induced during inflammation and is rarely expressed normally, and the conventional NSA ID non-specifically inhibits both C ⁇ X-1 and COX-2 enzymes This was also clarified. This has raised the possibility that compounds having a COX-2 inhibitory effect may be useful as anti-inflammatory agents.
  • An object of the present invention is to have an inhibitory activity against COX-2,
  • An object of the present invention is to provide an indene derivative useful as a medicine.
  • the present inventors have conducted intensive studies with the aim of developing a compound that inhibits COX-2 and has an anti-inflammatory effect equal to or higher than that of existing NSAIDs such as indomethacin.
  • the indene derivative represented by (I) was found to have excellent anti-inflammatory activity and to be useful as a medicament, and based on this finding, completed the present invention. Disclosure of the invention
  • the present invention provides a compound represented by the general formula (I):
  • 1 ⁇ represents a hydrogen atom, a linear or branched alkyl group having 1 to 7 carbon atoms which may have a halogen atom as a substituent, a linear or branched alkyl group having 2 to 7 carbon atoms
  • a chain alkenyl group, — (CH 2 ) m —R5 (where m represents an integer of 0 to 3, and R 5 is a linear or branched alkyl group having 1 to 3 carbon atoms) Represents an optionally substituted cycloalkyl group having 3 to 6 carbon atoms) or an aryl group;
  • R 2 is a hydrogen atom, 1 (CH 2 ) n —COOR x ,-(CH 2 ) n '- oR y, or a straight-chain or branched alkoxy group having 1 to 3 carbon atoms, n and n in here' each represents an integer of 0 to 3,
  • R x is a hydrogen atom , or a
  • a linear or branched alkyl group having 1 to 7 carbon atoms which may have a halogen atom as a substituent has 1 to 7 carbon atoms.
  • the linear or branched alkyl group of 7 include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, an s-butyl group, and a t-butyl group.
  • n-pentyl, n-hexyl, and n-heptyl are examples of the linear or branched alkyl group of 7 that include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, an s-butyl group, and a t-butyl group.
  • a linear or branched alkyl group having 1 to 6 carbon atoms is preferable.
  • An ethyl group, an n-propyl group, an i-propyl group, and an n-butyl group are more particularly preferred.
  • halogen atom of a linear or branched alkyl group having 1 to 7 carbon atoms which may have a halogen atom as a substituent
  • a fluorine atom is preferable.
  • Particularly preferred specific examples of the linear or branched alkyl group having 1 to 7 carbon atoms which may have a halogen atom as a substituent include an ethyl group, an n-propyl group and an i-propyl group. Groups, n-butyl group, i-butyl group, 3,3,3-trifluoropropyl group, and 4,4,4-trifluorobutyl group.
  • R] is a straight-chain or branched alkenyl group having 2 to 7 carbon atoms, for example, a vinyl group, an aryl group, an i-propenyl group, a 3-butenyl group, a 4-pentenyl group And a 5-hexenyl group and a 6-heptenyl group, among which an aryl group having 3 to 4 carbon atoms and an i-propenyl group are preferred.
  • R l is also (CH 2 ) m —R 5 (where m represents an integer of 0 to 3, and R 5 is substituted with a linear or branched alkyl group having 1 to 3 carbon atoms) Represents a cycloalkyl group having 3 to 6 carbon atoms which may be substituted), and the linear or branched alkyl group having 1 to 3 carbon atoms as a substituent is a methyl group. , An ethyl group, an n-propyl group, and an i-propyl group.
  • Examples of the optionally substituted alkyl group having 3 to 6 carbon atoms include cyclopropyl Examples include a pill group, a methylcyclopropyl group, an ethylcyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.
  • Examples of the group represented by 1 (CH 2) m —R 5 include a cyclopropyl group, a methylcyclopropyl group, an ethylcyclopropyl group, a cyclopropylmethyl group, a cyclopropylethyl group, a methylcyclopropylmethyl group, 2-methylcyclopropylethyl, ethylcyclopropylmethyl, 2-ethylcyclopropylethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, and cyclohexylmethyl And the like, and among them, a cyclopropylmethyl group is preferable.
  • Examples of the aryl group in R 1 include an aromatic hydrocarbon group having 6 to 14 carbon atoms, and examples thereof include a phenyl group, a tolyl group, a xylyl group, a naphthyl group, a biphenyl group, an anthryl group, Phananthryl groups and the like can be mentioned. Among them, a phenyl group, a tolyl group and a naphthyl group are preferred, and a phenyl group is particularly preferred.
  • R i is a hydrogen atom; a linear or branched alkyl group having 1 to 7 carbon atoms, preferably 1 to 6 carbon atoms, which may have a halogen atom as a substituent.
  • 1 ⁇ is a linear or branched alkyl group having 1 to 7 carbon atoms or an aryl group which may have a halogen atom as a substituent, and further has 1 to 6 carbon atoms, particularly 1 to 6 carbon atoms.
  • 2-4 straight-chain or branched-chain alkyl groups which may have a halogen atom as a substituent including ethyl, n-propyl, i-propyl, n-butyl, i-butyl) Groups, 3,3,3-trifluoropropyl, and 4,4,4-trifluorobutyl); and aryl (especially phenyl) are particularly preferred.
  • R 2 is a hydrogen atom, — (CH 2 ) n —COOR x , one (CH 2 ) n ′ —OR y , or a linear or branched C 1 to C 3 Represents an alkoxy group.
  • R v is a hydrogen atom, or a linear or branched C 1 -C 3 Represents an alkyl group, specifically, a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, and an i-propyl group, and preferably a hydrogen atom.
  • R y represents a hydrogen atom or a protecting group for a hydroxyl group, and is preferably a hydrogen atom.
  • hydroxyl-protecting groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, and phenoxycarbonyl groups.
  • Xycarbonyl group trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, dimethylisopropylsilyl group, dimethylisopropylsilyl group, dimethyltexylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, Substituted silyl groups such as ribenzylsilyl group, tri-p-xylylsilyl group, triphenylsilyl group, diphenylmethylsilyl group, and t-butylmethoxyphenylsilyl group; methoxymethyl group, methoxetoxymethyl group , Methylthio Methyl group, t-butylthiomethyl group, / trichloroethyloxymethyl group, trimethylsilylethoxymethyl group, p-methoxybenzyloxymethyl group, p-methylbenzyl
  • 2-hydroxyoxacycloalkyl groups such as tetrahydrofuryl and tetrahydroviranyl groups.
  • silyl groups such as tri-p-xylylsilyl group, triphenylsilyl group, diphenylmethylsilyl group, and t-butylmethoxyphenylsilyl group; methoxymethyl group, methoxyethoxymethyl group, methylthiomethyl group, t-butylthio
  • methyl groups such as methyl group, /?-Trichloroethy
  • R 2 (C H2) n — COOR x (where n is an integer from 0 to 3, R x represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms), for example, a carboxyl group, a carboxymethyl group, a carboxyethyl group, a carboxypropyl group, a methoxycarbonyl group Group, ethoxycarbonyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, 2-methoxycarbonylethyl group, 2-ethoxycarbonylethyl group, 3-methoxycarbonylpropyl group, and 3-ethoxycarbonylpropyl group.
  • a carboxylic acid group and a carboxylic acid methyl group are preferred.
  • R 2 (CH 2 ) n ′-0 R y (where n ′ represents an integer of 0 to 3, and R y represents a hydrogen atom or a protecting group for a hydroxyl group) Hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, ethoxycarbonyloxy, t-butyldimethylsilyloxy, tetrahydropyran-1-yloxy, ethoxycarbonyloxymethyl, t-butyl Dimethylsilyloxymethyl group, tetrahydropyran-1-yloxymethyl group, 2- (ethoxycarbonyloxy) ethyl group, 2- (t-butyldimethylsilyloxy) ethyl group, 2- (tetrahydropyran-12-yloxy) ) Ethyl, 3- (ethoxycarbonyloxy) propyl, 3- (t-butyldimethylsilyloxy) propyl, and 3- (te Rahidoropiran one
  • Examples of the linear or branched alkoxy group having 1 to 3 carbon atoms in R 2 include a methoxy group, an ethoxy group, an i-propyloxy group, and an n-propyloxy group. Of these, a methoxy group and an ethoxy group are preferred.
  • R 2 has the definition as described above, and is particularly preferably a hydrogen atom, a hydroxyl group, or a methoxy group.
  • Examples of the linear or branched alkyl group having 1 to 3 carbon atoms for R 3 include a methyl group, an ethyl group, an n-propyl group, and an i-propyl group, and among them, a methyl group and an ethyl group Ca? preferably, a methyl group is particularly preferred.
  • substituted optionally may be Ariru group, as a substituent of substituted heterocyclic group optionally or optionally substituted cycloalkyl group having a carbon number of 3-6, for example a halogen atom, a carbon A straight-chain or branched-chain alkyl group or alkoxy group of the formulas 1 to 4 (these alkyl groups or alkoxy groups are , A hydroxyl group, or COOR 7 (where R7 represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms), — S (0 ) q-R6 (where q represents an integer of 0 to 2, R6 represents a linear or branched alkyl group having 1 to 3 carbon atoms), an amino group, a nitro group, a carboxy group , A hydroxyl group, COOR 8 (where R 8 represents a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms), and a carbamoyl group.
  • R8 Is a linear or branched C1-C3 And a rubumoyl group
  • a fluorine atom a chlorine atom, a hydroxyl group, a methyl group, an ethyl group, a trifluoromethyl group,
  • the optionally substituted aryl group for R 4 is the same or different and is the above substituent, and is a mono-, di- or tri-substituted aryl group having 6 to 12 carbon atoms. And, for example, a phenyl group and a naphthyl group.
  • phenyl groups which may be the same or different and are mono-, di- or tri-substituted by the above-mentioned substituents are preferable, and among them, 4-methoxyphenyl group, 4-fluorophenyl group and 3- Methoxycarbonylphenyl, 3-carboxyphenyl, 3-carboxymethylphenyl, 4-ethyl-3-carboxyphenyl, 4-hydroxy-3-carboxyphenyl, 3-hydroxymethyl Phenyl group, 2- (2-hydroxyxethyl) phenyl group, 2-carboxymethylphenyl group, 3-carboxy- 1-trifluoromethylphenyl group and 3-methoxycarboxy4-trifluorotrifluoromethyl An enyl group is particularly preferred.
  • the heterocyclic group in the optionally substituted heterocyclic group represented by R 4 is the same or different, and contains 1, 2 or 3 heteroatoms such as an oxygen atom, a nitrogen atom and a sulfur atom.
  • 0-membered monocyclic or bicyclic heterocyclic group such as pyridyl, piperazinyl, piperidinyl, pyrimidinyl, pyrrolyl, viranyl, furyl Group, oxazolyl group, triazolyl group, thioxazolyl group, chenyl group, indolyl group, quinolyl group, benzopyranyl group, benzofuranyl group, and benzozenyl group.
  • a 5- or 6-membered monocyclic heteroaromatic group containing one or two heteroatoms such as an oxygen atom, a nitrogen atom and a sulfur atom is preferred.
  • the optionally substituted heterocyclic group for R 4 include a carboxy group, COOR 8 (where R 8 represents a linear or branched alkyl group having 1 to 3 carbon atoms), or A pyridyl group optionally substituted with a halogen atom; a carboxyl group, CO ⁇ R 8 (where R 8 represents a linear or branched alkyl group having 1 to 3 carbon atoms), or a halogen atom And a carboxyl group, COOR 8 (where Rg represents a linear or branched alkyl group having 1 to 3 carbon atoms), or a halogen atom.
  • An optionally present furyl group is particularly preferred, and 2-carboxypyridine-1-yl group, 2-chlorothiophen-5-yl group, 6-carboxypyridine-12-yl group, 6-methoxycarboxypyridine-12 —Yl group, 5-ethoxycarbonyl Rfuran-12-yl and 5-carboxyfuran-12-yl are more particularly preferred.
  • Examples of the cycloalkyl group having 3 to 6 carbon atoms in the optionally substituted cycloalkyl group having 3 to 6 carbon atoms for R 4 include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Of these, a cyclohexyl group is preferred.
  • R 4 is an optionally substituted aryl group, especially a mono- or di-substituted phenyl group, and an optionally substituted heterocyclic group, particularly a substituted or unsubstituted heterocyclic group.
  • a 5- or 6-membered monocyclic heteroaromatic group containing one oxygen atom, nitrogen atom and one sulfur atom is preferable, and among them, a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms is preferable.
  • an alkoxy group (these groups may be further substituted with a halogen atom, a hydroxyl group, or a carboxyl group), a hydroxyl group, a hydroxyl group, COOR 8 (where R 8 is a group having 1 to 3 carbon atoms) Represents a linear or branched alkyl group), a phenyl group which may be mono- or di-substituted by a halogen atom or a rubamoyl group, and a halogen atom, a carboxy group or COOR 8 (Where R 8 is a straight or branched chain having 1 to 3 carbon atoms) A pyridyl group which may be mono-substituted with a halogen atom, a carboxyl group, or COOR 8 (where R 8 is a linear or branched alkyl group having 1 to 3 carbon atoms) A phenyl group which may be mono-substituted; and a halogen atom,
  • a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted by a halogen atom, or an aryl group;
  • R 2 is a hydrogen atom, a hydroxyl group, or a methoxy group;
  • R 3 is a methyl group; and
  • R 4 is an optionally substituted aryl group or a heterocyclic group. Particularly preferred.
  • the compounds of the general formula (I) include E-form and Z-form compounds, both of which are included in the present invention.
  • R 3 is A compound which is a methyl group, in particular, may have a fluorine atom as a substituent, and may be a linear or branched alkyl having 1 to 6 carbon atoms, particularly 2 to 4 carbon atoms.
  • R 3 is a methyl group
  • R 4 is also good Ariru group or a substituted substituted Compounds which are hetero it3 ⁇ 4 which may be substituted are particularly preferred.
  • the compound of the general formula (I) includes E-form and Z-form compounds, both of which are included in the present invention.
  • Examples of the compound represented by the general formula (I) include (Z) —1- (4-methoxybenzylidene) 1-2-n-propyl-15-methanesulfonyl 1H-indene; (E) —1— (4 -Methoxy benzylidene) 1 2-n-Propyl-5-methanesulfonyl 1 H-Indene; (Z) — 1— (4-Fluorobenzylidene) 1-2-n-Pupylpill-5-Methanesulfonium Lu 1 H—Indene; (E) — 1— (4-Fluorobenzylidene) 1 2 _n—Propyl 5-Methanesulfonyl 1 H—Indene 1—1 (2-Chlorothiophen-5-yl) Methylene 1-2-n-propyl-1-methanesulfonyl 1 H-indene; (Z)-1-1-(3-methoxy
  • the compound of the present invention can also be obtained as a pharmaceutically acceptable salt of the compound of the above formula (I), or a hydrate thereof.
  • Pharmaceutically acceptable salts include salts with alkali metal and alkaline earth metals, and salts with inorganic and organic acids.
  • salts with alkali metals and alkaline earth metals mention may in particular be made of sodium salts, potassium salts and calcium salts.
  • Salts with inorganic acids include salts with hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid
  • salts with organic acids include acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, and malon. Salts with acids, trifluoroacetic acid and the like can be mentioned.
  • the present invention also provides intermediates useful for preparing compounds of formula (I), which are represented by general formula (II):
  • 1 ⁇ represents a hydrogen atom, a linear or branched alkyl group having 1 to 7 carbon atoms which may have a halogen atom as a substituent, a linear or branched alkyl group having 2 to 7 carbon atoms.
  • a branched alkenyl group, — (C H2) m —R5 (where m represents an integer of 0 to 3, and R 5 is a linear or branched alkyl group having 1 to 3 carbon atoms)
  • R 2 represents a hydrogen atom, a (CH 2 ) n —COOR x , a (CH 2 ) n ′ ⁇ Ry, or a linear or branched alkoxy group having 1 to 3 carbon atoms;
  • n and n ′ each represent an integer of 0 to 3
  • R x represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms
  • R y represents R 3 represents a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms;
  • Ri and R 3 have the same definition as in the formula (I).
  • R2 represents a hydrogen atom, - (CH2) n -COOR x , represents an (CH 2) n -ORy, or straight-chain or branched alkoxy group having 1 to 3 carbon atoms .
  • R x represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, specifically, a methyl group, an ethyl group, an n-propyl group, and an i-propyl group. And preferably a methyl group and an ethyl group.
  • R y represents a hydrogen atom or a protecting group for a hydroxyl group, and is preferably a protecting group for a hydroxyl group.
  • hydroxyl-protecting group examples include alkoxycarbonyl groups such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, an aryloxycarbonyl group, a benzyloxycarbonyl group, and a phenoxycarbonyl group.
  • Trimethylsilyl group triethylsilyl group, triisopropylsilyl group, dimethylisopropylsilyl group, dimethylethylsilyl group, dimethyltextilsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, tribenzylsilyl group, tribenzylsilyl group —Substituted silyl groups such as xylylsilyl group, triphenylsilyl group, diphenylmethylsilyl group, and t-butylmethoxyphenylsilyl group; methoxymethyl group, methoxetoxymethyl group, methylthiome , T-butylthiomethyl, /?-Trichloroethyloxymethyl, trimethylsilylethoxymethyl, p-methoxybenzyloxymethyl, p-chlorobenzyloxymethyl, etc.
  • 2-hydroxycycloalkyl groups such as tetrahydrofuryl and tetrahydrobilanyl groups.
  • silyl groups such as tri-p-xylylsilyl group, triphenylsilyl group, diphenylmethylsilyl group, and t-butylmethoxyphenylsilyl group; methoxymethyl group, methoxetoxymethyl group, methylthiomethyl group , T-butylthiomethyl, /?-Trichloroethyloxymethyl, trimethylsilylethoxymethyl, p-methoxybenzyloxymethyl, and substitute
  • Examples of the straight-chain or branched-chain alkoxy group having 1 to 3 carbon atoms in the definition of R 2 of the compound of the formula (II) include, for example, methoxy group, ethoxy group, i-propyloxy group and n-propyloxy group. And so on. Of these, a methoxy group and an ethoxy group are preferred.
  • the alkyl group in this alkoxy group can also function as a protecting group for a hydroxyl group.
  • R 2 is a hydrogen atom and a linear or branched alkoxy group having 1 to 3 carbon atoms (such as a methoxy group, an ethoxy group, an n-propyloxy group, and an i-propyloxy group). Preferred are a hydrogen atom and a methoxy group.
  • the compound of the formula (II) of the present invention can also be obtained as a pharmaceutically acceptable salt of the compound of the above formula (II), or a hydrate thereof.
  • Pharmaceutically acceptable salts include alkali metal salts and alkaline earth metal salts, among which sodium salts, potassium salts, and calcium salts.
  • the compound of the present invention can be prepared by using a reagent having a desired group based on the following reaction formula 11-11.
  • Or OXONE in the formula, is a hydrogen atom, a linear or branched alkyl group having 1 to 7 carbon atoms which may have a halogen atom as a substituent, a linear or branched chain having 3 to 7 carbon atoms Jo alkenyl group, - (CH2) m - R5 ( wherein, m represents an integer of 0 to 3, R 5 is substituted with a linear or branched alkyl group having 1-3 carbon atoms may represent a cycloalkyl group having 3 to 6 carbon atoms), or an ⁇ aryl group; R2 is a hydrogen atom, - (CH2) n - COOR x, - (CH 2) ⁇ ' one ORy, or Represents a linear or branched alkoxy group having 1 to 3 carbon atoms, wherein n and n 'each represent an integer of 0 to 3, and Rx is a hydrogen atom or a carbon atom having 1 to 3 carbon atoms.
  • R 3 is straight Kusariwaka properly of 1 to carbon atoms 3 branched
  • R 4 represents an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted cycloalkyl group having 3 to 6 carbon atoms
  • X represents a halogen atom.
  • Compound 1 is converted to compound 2 by subjecting compound 1 having the desired group R 2 at the 4-position (where X represents a halogen atom) to a base, and then, depending on the group R 3 to be introduced, This is achieved by adding di- (3-alkyl) disulfide and adding a nucleophilic base.
  • di- (3-alkyl) disulfide For example, to introduce a methyl group as group R 3 as di (C i_ 3 alkyl) disulfinate de, using dimethyl disulfinate de.
  • the base lithium hydride, sodium hydride, potassium pistrimethylsilylamide, sodium bistrimethylsilylamide, lithium pistrimethylsilylamide, lithium disopropylamide, and the like are used, but potassium hydride is preferably used.
  • nucleophilic base a force using n-butyllithium, s-butyllithium, t-butyllithium, metallic sodium or the like, preferably t-butyllithium is used.
  • a reaction solvent tetrahydrofuran, ether, dioxane, dimethoxetane or the like is used, and tetrahydrofuran is preferably used.
  • the reaction is carried out at a temperature of 110 to 30 ° C., preferably at a temperature of 110 to 10 for base treatment, and at a temperature of 170 to ⁇ 40 ° C. for nucleophilic base treatment. Do each.
  • Compound 2 is converted into compound 3 by treating compound 2 with a base followed by compound R IX (where R i is a linear or linear carbon atom having 1 to 7 carbon atoms which may have a halogen atom as a substituent.
  • R IX a linear or linear carbon atom having 1 to 7 carbon atoms which may have a halogen atom as a substituent.
  • X represents a halogen atom
  • n-propyl halide when introducing an n-propyl group, use n-propyl halide.
  • n-propyl hydrogenated n-propyl chloride, n-propyl bromide, n-propyl iodide and the like can be used, and n-propyl iodide is preferably used.
  • tetrahydrofuran As the solvent, tetrahydrofuran, ether, dioxane, dimethoxetane, dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like are used, and preferably, tetrahydrofuran is used. You.
  • the reaction is carried out at a temperature of from 100 to 30 ° C, preferably at from 110 to 10 ° C. Conversion of compound 2 or 3 to compound 4 is carried out by a halogenation reaction performed by adding a halogenating agent and a radical initiator to compound 3, and a subsequent elimination reaction by base treatment.
  • halogenating agent examples include N-promosuccinimide (NBS), N-chlorosuccinimide, N-odosuccinimide, N-bromoacetamide, and the like.
  • N-promosquenimide is used.
  • radical initiator azobisisobutyronitrile (AIBN) and benzoyl peroxide are used.
  • AIBN azobisisobutyronitrile
  • benzoyl peroxide are used as a solvent in the halogenation reaction.
  • dichloromethane, chloroform, tetrachloromethane and the like can be used, and tetrachloroethane is preferably used.
  • the halogenation reaction is carried out at a force s carried out at 20 to 100 ° C, preferably at 30 to 80 ° C.
  • potassium hydride sodium hydride, potassium bistrimethylsilylamide (KHMDS), sodium bistrimethylsilylamide, lithium bistrimethylsilylamide, lithium diisopropylamide, n-butyllithium and the like
  • KHMDS potassium bistrimethylsilylamide
  • n-butyllithium potassium bistrimethylsilyl amide
  • reaction solvent tetrahydrofuran, ether, dioxane, dimethoxetane, benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide, or the like is used, and preferably, tetrahydrofuran or toluene is used.
  • the reaction is carried out at a temperature of 110 to 30 ° C, preferably at a temperature of 110 to 10 ° C.
  • Conversion of compound 5 to compound 6 is performed by oxidizing compound 5.
  • Oxidation As the agent, 3-chloroperoxybenzoic acid (mCPBA), OXONE (registered trademark) and the like are preferably used.
  • the reaction solvent dichloromethane, black hole Holm, Te tiger chloromethane, methanol, ethanol, as tetrahydrofuran, water, or these mixed solvent force the like s, preferably, as an oxidizing agent 3- black port perbenzoic
  • an acid use chloroform for the form, and when using OXONE as the oxidizing agent, use a mixed solvent of tetrahydrofuran and water.
  • the reaction is carried out at -10 to 30 ° C, preferably at 0 to 30 ° C.
  • compound 4 which is an intermediate compound in the above reaction formula 11-1, can be also prepared by starting from compound 2 and using a reagent having a desired group based on the following reaction formula 112. it can.
  • Ri is a hydrogen atom, a linear or branched alkyl group having 1 to 7 carbon atoms which may have a halogen atom as a substituent, a linear or branched chain having 3 to 7 carbon atoms Jo alkenyl group, - (CH2) m - R5 (where, m represents the integer of 0 to 3, R 5 is substituted with a linear or branched alkyl group having 1-3 carbon atoms Represents a cycloalkyl group having 3 to 6 carbon atoms), or represents an aryl group; and R2 represents a hydrogen atom or a linear or branched alkoxy group having 1 to 3 carbon atoms.
  • R 3 represents a linear or branched alkyl group having 1 to 3 carbon atoms; X represents a halogen atom.
  • Conversion of compound 2 to compound 7 is performed by reacting compound 2 with hydrazine. In this reaction, an acid and / or a dehydrating agent may coexist.
  • the hydrazine 11-dialkylhydrazine is used, and preferably, 1,1-dimethylhydrazine is used.
  • an inorganic acid such as sulfuric acid or an organic acid such as p-toluenesulfonic acid or camphor sulfonic acid is used, and preferably p-toluenesulfonic acid is used.
  • anhydrous sodium sulfate As the dehydrating agent, anhydrous sodium sulfate, anhydrous magnesium sulfate, molecular sieves, or the like is used, and anhydrous sodium sulfate is preferably used.
  • a reaction solvent ether, tetrahydrofuran, dimethoxetane, dioxane, benzene, toluene, xylene, tetrachloromethane, chloroform, and dichloromethane are used, and preferably toluene is used.
  • the reaction is carried out at 210 ° C., preferably at 800 ° C.
  • Compound 7 is converted to compound 3 by treating compound 7 with a base and then treating compound R 1 X (where 1 ⁇ is a linear or branched C 17 carbon atom which may have a halogen atom as a substituent.
  • the reaction is carried out by acid hydrolysis after introducing the group.
  • Bases include n-butyllithium, lithium diisopropylamide, lithium (pis-trimethylsilyl) amide, sodium (pis-trimethylsilyl) amide, lithium (pis-trimethylsilyl) amide, potassium hydride, sodium hydride and the like.
  • n-butyllithium or lithium diisopropylamide is used.
  • ether, tetrahydrofuran, dimethoxetane, dioxane, benzene, toluene or the like is used, and preferably, tetrahydrofuran is used.
  • the reaction is carried out at 1000 ° C, preferably at 784 ° C.
  • the acid used for the acid hydrolysis hydrochloric acid, sulfuric acid, nitric acid or the like is used, and preferably, sulfuric acid is used.
  • a solvent in the acid hydrolysis reaction a solvent using methanol, ethanol, water, tetrahydrofuran, dioxane or the like, preferably water is used.
  • the reaction is performed at 210 ° C., preferably at 600 ° C. Do with.
  • Conversion of compound 3 to compound 4 is performed by reacting compound 3 with a halogen and then treating with a base.
  • halogen chlorine, bromine, iodine, or the like is used, and preferably bromine is used.
  • a reaction solvent in the halogenation reaction ether, tetrahydrofuran, dimethoxetane, dioxane, benzene, toluene, xylene, tetrachloromethane, chloroform, and dichloromethane are used, and preferably tetrahydrofuran is used.
  • the reaction is carried out at -40 to 20 ° C, preferably at 110 to 10 ° C.
  • DBU 1,8-diazabicyclo [5.4.0] -17-didecene
  • DBU 1,5-diazabicyclo [4.3.0] -15-nonene
  • 1,4-diazabicyclo [2 2.2.2] Use octane, triethylamine, diisopropylethylamine, and the like, and preferably use 1,8-diazabicyclo [5.4.0] -7-indene (DBU).
  • reaction solvent in the base treatment ether, tetrahydrofuran, dimethoxetane, dioxane, benzene, toluene, xylene, tetrachloromethane, chloroform, and dichloromethane are preferably used, and tetrahydrofuran is preferably used.
  • the reaction is carried out at 0 to 60 ° C, preferably at 0 to 30 ° C.
  • compound 4 which is an intermediate compound in the above-mentioned reaction formula 11 can be prepared based on the following reaction formula 13 by starting from compound 2 and using a reagent having a desired group. it can.
  • Ri is a straight-chain or branched alkyl group having a carbon number of 2-7 that may have a halogen atom as a substituent, one (CH2) m _R5 (where, m is 0-3 R 5 represents a cycloalkyl group having 3 to 6 carbon atoms which may be substituted by a linear or branched alkyl group having 1 to 3 carbon atoms) or an aryl group R2 represents a hydrogen atom, — (CH 2 ) n —COOH,-(CH 2 ) n
  • R y represents a linear or branched alkoxy group having 1 to 3 carbon atoms, wherein n and n ′ each represent an integer of 0 to 3, and R y is a hydrogen atom or a hydroxyl group.
  • R 3 represents a linear or branched alkyl group having 1 to 3 carbon atoms; and R represents Ri by adding a methylene group between R and the indanone ring. Represents a group represented by
  • the conversion of compound 2 to compound 8 is performed by treating compound 2 and an aldehyde with a base.
  • aldehyde aldehyde: RCHO (where R has the same definition as above) is used, and preferably, n-butyl aldehyde or isobutyl aldehyde is used.
  • RCHO n-butyraldehyde (that is, R is an n-butyl group) is used as RCHO, becomes an n-pentyl group.
  • sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, or the like is used, and preferably, sodium hydroxide is used.
  • reaction solvent water, methanol, ethanol, propanol, ethers, as tetrahydrofuran, dimethyl Tokishe Tan, Jiokisan, dimethylformamidine de, dimethyl sulfoxide or these mixed forces 5 and the like solvent, preferably water Used.
  • the reaction is carried out at 0 to 100 ° C, preferably at 20 to 80 ° C.
  • the conversion of compound 8 to compound 3 is performed by catalytically reducing compound 8 in a hydrogen atmosphere.
  • the catalyst used for the catalytic reduction include palladium carbon, platinum carbon, palladium black, palladium hydroxide, platinum oxide, hexacloplatinic (IV) acid, Raney nickel, and tris (triphenylphosphine) chlororhodium.
  • palladium carbon is used.
  • Reaction solvents include water, methanol, ethanol, and prono.
  • the reaction is carried out at 1 to 5 atm, preferably at 1 atm.
  • Conversion of compound 3 to compound 4 is performed by reacting compound 3 with a halogen and then treating with a base.
  • a halogen chlorine, bromine, iodine, or the like is used, and preferably bromine is used.
  • a reaction solvent for the reaction with halogen ether, tetrahydrofuran, dimethoxetane, dioxane, benzene, toluene, xylene, tetrachloromethane, chloroform, and dichloromethane are used, and preferably tetrahydrofuran is used.
  • the reaction is carried out at a temperature of from 40 to 20 ° C, preferably from 10 to 10 ° C. Perform in C.
  • Examples of the base include 1,8-diazabicyclo [5.4.0] -17- ⁇ decene (DBU), 1,5-diazabicyclo [4.3.0] -15-nonene, and 1,4-diazabicyclo [2. 2. 2] Use octane, triethylamine, diisopyrupyrethylamine, etc., and preferably use 1,8-diazabicyclo [5.4.0] -17-indene (DBU).
  • DBU 1,8-diazabicyclo [5.4.0] -17- ⁇ decene
  • DBU 1,8-diazabicyclo [5.4.0] -17- ⁇ decene
  • the reaction solvent used in the base treatment is ether, tetrahydrofuran, dimethoxetane, dioxane, benzene, toluene, xylene, tetrachloromethane, chloroform, or dichloromethane, preferably tetrahydrofuran.
  • the reaction is carried out at 0 to 60 ° C, preferably at 0 to 30 ° C.
  • Compound 3 which is an intermediate compound in the above-mentioned Reaction Formula 11-1, wherein Ri is a phenyl group and R 2 is a hydrogen atom, is a compound represented by the following formula 1-4, Can also be prepared by using a reagent having the formula:
  • R i represents a phenylene Le group
  • R 3 represents a linear or branched alkyl group having 1 to 3 carbon atoms
  • R a is a straight-chain or branched having 1 to 3 carbon atoms
  • X and Y each independently represent a halogen atom
  • Bases include lithium disopropylamide, potassium (pis-trimethylsilyl) amide, sodium (bis-trimethylsilyl) amide, lithium (bis-trimethylsilyl) amide (LHMDS), potassium hydride, sodium hydride And preferably lithium (bistrimethylsilyl) amide (LHMDS).
  • alkyl halide an arylalkyl halide substituted with a halogen is used, and preferably, a halogen-substituted benzyl bromide such as 3-bromobenzyl bromide is used.
  • reaction solvent ether, tetrahydrofuran, dimethoxetane, dioxane, benzene, toluene, or the like is used, and preferably, tetrahydrofuran is used.
  • the reaction is carried out at 110 to 0 ° C, preferably at 178 to 140 ° C.
  • the conversion of compound 10 into compound 11 is performed by hydrolyzing compound 10 by treatment with a base.
  • a base sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, or the like is used, and preferably, sodium hydroxide is used.
  • the reaction solvent water, methanol, ethanol, propanol, ether, tetrahydrofuran, dimethoxetane, dioxane, or a mixed solvent thereof is used, and a mixed solvent of water and ethanol is preferably used.
  • the reaction is carried out at 0 to: I 0 0 C, preferably at 20 to 80 0 C.
  • Conversion of compound 11 to compound 12 is performed by converting the compound into an acid halide with a halogenating agent and then cyclizing with a Lewis acid.
  • a halogenating agent thionyl chloride, pentachloride, oxychloride or the like is used, and preferably, thionyl chloride is used.
  • the reaction solvent when the acid halide, ether, Tetorahido port furan, dimethyl Tokishetan, Jiokisan, benzene, toluene, Te Torakuro port methane, black hole Holm, dichloromethane, force 5 and the like dimethylformamidine de ', preferably Uses a black-mouthed form.
  • the reaction is carried out at 30 to 120 ° C, preferably at 50 to 100 ° C.
  • Aluminum chloride, tetrachloride used as Lewis acid for cyclization Tin, titanium tetrachloride or the like is used, preferably aluminum chloride.
  • ether, tetrahydrofuran, dimethoxetane, dioxane, benzene, toluene, tetrachloromethane, chloroform, dichloromethane and the like are used, and preferably chloroform is used.
  • the reaction is carried out at 130 to 40 ° C, preferably at 110 to 20 ° C.
  • the conversion of the compound 12 to the compound 3 is performed by reacting the compound 12 with a metal thioalkoxide having a desired group R 3 .
  • a metal thioalkoxide having a desired group R 3 With sodium Chio alkoxide metal Chio alkoxide, in the case of introducing a methyl group as group R 3 is used Natoriumuchiome Tokishido.
  • As a reaction solvent water, ether, tetrahydrofuran, dimethoxetane, dioxane, benzene, toluene, tetrachloromethane, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide or a mixed solvent thereof is preferably used. Use dimethylformamide.
  • the reaction is carried out at 110 to 100 ° C, preferably at 0 to 50 ° C.
  • reaction formula 1 which is an intermediate compound in the above-mentioned reaction formula 11-11, can also be prepared by using a reagent having a desired group based on the following reaction formula 115.
  • Is a branched alkenyl group, 1 (C H2) m —R5 (where m represents an integer of 0 to 3, and R 5 is a linear or branched alkyl having 1 to 3 carbon atoms) Represents a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with a group) or an aryl group;
  • R 2 represents a hydrogen atom, or a straight or branched chain having 1 to 3 carbon atoms;
  • R 3 represents a linear or branched alkyl group having 1 to 3 carbon atoms;
  • Rb represents a linear or branched alkyl group having 1 to 3 carbon atoms;
  • X represents a halogen atom.
  • the conversion of compound 13 to compound 14 is carried out in the presence of a base in the presence of a desired group (here, a linear or branched alkyl having 1 to 7 carbon atoms which may have a halogen atom as a substituent.
  • a desired group here, a linear or branched alkyl having 1 to 7 carbon atoms which may have a halogen atom as a substituent.
  • the reaction is carried out by reacting the alkyl phosphate with a substituted benzaldehyde having desired groups R 2 and R 3, followed by reduction.
  • a substituted benzaldehyde having desired groups R 2 and R 3, followed by reduction.
  • the base lithium diisopropyl pyramide, potassium (bistrimethylsilyl) amide, sodium (pistrimethylsilyl) amide, lithium (pistrimethylsilyl) amide, lithium hydride, sodium hydride and the like are preferably used.
  • X in the compound R i X is preferably an iodine atom, and when a propyl group is introduced as the group R i, propyl iodide is preferably used.
  • reaction solvent for the preparation of the alkyl phosphate ester having a group and the reaction with a substituted benzaldehyde examples include ether, tetrahydrofuran, dimethyloxetane, dioxane, benzene, toluene, dimethylformamide, dimethylsulfoxide, and the like.
  • tetrahydrofuran is used.
  • the reaction is carried out at 0 to 80 ° C, preferably at 10 to 50 ° C.
  • a 1- or 2-substituted benzaldehyde having a desired group and R 2 is used, preferably a 2-substituted benzaldehyde such as 2-methoxy-3-methylthiobenzaldehyde.
  • the reaction at this time is carried out at 110 to 50 ° C, preferably at 0 to 40 ° C.
  • the reduction is performed by the action of a metal in the alcohol.
  • a reaction solvent in the reduction Use ethanol, propanol, etc., preferably methanol.
  • magnesium is preferably used.
  • the reaction is carried out at 0 to 80 ° C, preferably at 10 to 50 ° C.
  • the compound 14 in which R i is a hydrogen atom can be obtained by not allowing the compound R i X having the group R i to coexist in the reaction system. .
  • the conversion of compound 14 to compound 15 is performed by hydrolyzing compound 14 by treatment with a base.
  • a base sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, or the like is used, and preferably, sodium hydroxide is used.
  • the reaction solvent water, methanol, ethanol, propanol, ether, tetrahydrofuran, dimethyl Tokishetan, Jiokisan or force s' using and mixtures of these solvents, preferably a mixed solvent of water and ethanol.
  • the reaction is carried out at 0 to 100 ° C, preferably at 20 to 80 ° C.
  • the conversion of compound 15 to compound 3 is carried out by converting compound 15 into an acid halide with a halogenating agent and then subjecting the compound to a Lewis acid.
  • a halogenating agent thionyl chloride, phosphorus pentachloride, oxychloride phosphorus and the like are used, and preferably, thionyl chloride is used.
  • the reaction solvent when the acid halide ether, as tetrahydrofuran, dimethyl Tokishetan, Jiokisan, benzene, toluene, Te Torakuro Rometan, black hole Holm, dichloromethane, force the like dimethylformamidine de s, preferably black port Use Holm.
  • the reaction is carried out at 30 to 120 ° C, preferably at 50 to 100 ° C.
  • the Lewis acid used for the cyclization aluminum chloride, tin tetrachloride, titanium tetrachloride or the like is used, and aluminum chloride is preferably used.
  • a reaction solvent in the cyclization a force using ether, tetrahydrofuran, dimethoxetane, dioxane, benzene, toluene, tetrachloromethane, chloroform, dichloromethane, or the like, preferably chloroform.
  • the reaction is carried out at 130 to 40 ° C, preferably at 110 to 20 ° C.
  • the compound wherein R4 is an aryl group substituted with a carboxyl group or a heterocyclic group substituted with a carboxyl group is based on the following reaction scheme 2. It can be prepared by using a desired reagent. Reaction formula
  • Compound 2-1 is a hydrogen atom, a linear or branched alkyl group having 1 to 7 carbon atoms which may have a halogen atom as a substituent, Linear or branched alkenyl group, one (CH 2 ) m —R5 (where m represents an integer of 0 to 3, and R 5 is a linear or branched chain having 1 to 3 carbon atoms)
  • R 3 represents a hydrogen atom, — (CH 2 ) n —COOR x ,-, which represents a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with an alkyl group having a carbon atom.
  • R y represents a hydrogen atom, or a hydroxyl protecting group
  • R 3 is from 1 to the number of carbon atoms
  • R 8 represents a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms
  • Z represents an optionally substituted phenyl group and naphthyl group
  • Xi represents a hydrogen atom, such as an aryl group such as a group, or an optionally substituted pyridyl group, pyrimidinyl group, pyrrolyl group, furyl group, oxazolyl group, thioxazolyl group, and phenyl group
  • a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; a hydroxyl group; — OCORf (where Rf is a carbon atom number such as a methyl group, an ethyl group, an
  • Conversion of compound 2-1 to compound 2-2 is carried out by treating compound 2-1 with a base and hydrolyzing.
  • a base use is made of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like, and preferably, sodium hydroxide or lithium hydroxide.
  • Reaction solvents include water, methanol, ethanol, A solvent such as propanol, ether, tetrahydrofuran, dimethoxetane, dioxane or a mixed solvent thereof is used, and a mixed solvent of water and tetrahydrofuran or a mixed solvent of water and dioxane is preferably used.
  • the reaction is carried out at 0 to 40 ° C, preferably at 0 to 10 ° C.
  • R in R 2 is an alkoxycarbonyl group such as an ethoxycarbonyl group, or an aralkyloxycarbonyl group such as a benzyloxycarbonyl group, or R x in R 2 is a methyl group, an ethyl group
  • R in R 2 is an alkoxycarbonyl group such as an ethoxycarbonyl group, or an aralkyloxycarbonyl group such as a benzyloxycarbonyl group
  • R x in R 2 is a methyl group, an ethyl group
  • elimination (deprotection) of these groups occurs simultaneously with the conversion reaction from compound 2-1 to compound 2-2 It is possible.
  • Compound 3-4 is a hydrogen atom, a linear or branched alkyl group having 1 to 7 carbon atoms which may have a halogen atom as a substituent, Linear or branched alkenyl group, mono (CH 2 ) m —R5 (where m represents an integer of 0 to 3, and R 5 is a straight or branched chain having 1 to 3 carbon atoms) Represents a cycloalkyl group having 3 to 6 carbon atoms, which may be substituted with a chain alkyl group) or an aryl group;
  • R2 is a hydrogen atom, — (CH 2 ) n —CO ⁇ R x , One (CH 2 ) n ′ -OR y , or a linear or branched alkoxy group having 1 to 3 carbon atoms, wherein n and n ′ each represent an integer of 0 to 3, and R x represents a linear or branched alkyl group of a
  • Conversion of compound 3-1 to compound 2-2 is carried out by reacting compound 3-1 with a silyl halide in the presence of a base.
  • Bases are imidazole, pyridine, tri Ethylamine, diisopropylethylamine, 4-dimethylaminopyridine, sodium hydrogen chloride, potassium hydride and the like are used, and preferably, imidazole is used.
  • silyl halide tert-butyldimethylsilyl chloride, trimethylsilyl chloride, triethylsilyl chloride, tert-butyldiphenylsilyl chloride and the like are used, and preferably tert-butyldimethylsilyl chloride is used.
  • reaction solvent ether, tetrahydrofuran, dimethoxetane, dioxane, benzene, toluene, tetrachloromethane, chloroform, dichloromethane, dimethylformamide, dimethylsulfoxide, etc. are used, and preferably, dimethylformamide is used.
  • Use Reaction is 0-100. C, preferably at 0 to 20 ° C.
  • the conversion of compound 3-2 to compound 3-3 is carried out by reacting compound 3-2 with triphenylphosphine.
  • triphenylphosphine As a reaction solvent, use ether, Tetorahido port furan, dimethyl Tokishetan, Jiokisan, benzene, toluene, tetrachloroethene port methane, black hole Holm, dichloromethane, dimethylformamidine de, dimethylsulfoxide, force the like Asetonitoriru s, preferably toluene .
  • the reaction is carried out at 20 to L20 ° C, preferably at 80 to 120 ° C.
  • Bases include lithium diisopropylamide, potassium (pistrimethylsilyl) amide (KHMDS), sodium (bistrimethylsilyl) amide, lithium (bistrimethylsilyl) amide, lithium hydride, sodium hydride and the like.
  • KHMDS potassium (pis-trimethylsilyl) amide
  • Reaction solvents for base treatment and reaction with substituted indenones include ether, tetrahydrofuran, dimethyloxetane, dioxane, benzene, and toluene. And preferably toluene.
  • the reaction is carried out with a base at 0 to 20 ° C, and the reaction with the substituted indenone is carried out at 0 to 120 ° C, preferably at 80 to 120 ° C.
  • a base at 0 to 20 ° C
  • the reaction with the substituted indenone is carried out at 0 to 120 ° C, preferably at 80 to 120 ° C.
  • 3-chloroperoxybenzoic acid, OXONE, magnesium monoperoxide magnesium (MMPP) or the like is used as an oxidizing agent, and preferably OXONE is used.
  • MMPP magnesium monoperoxide magnesium
  • a reaction solvent in the oxidation of sulfide water, methanol, ethanol, propanol, ether, tetrahydrofuran, dimethoxyethane, dioxane, dichloromethane, dichloromethane, or a mixed solvent thereof is preferably used.
  • a mixed solvent of water and tetrahydrofuran is used.
  • the reaction is carried out at -10 to 50 ° C, preferably at 0 to 30 ° C.
  • Oxidation of the hydroxyl group is carried out by using oxidizing agents such as 1,1,1-tris (acetyloxy) 1-1,1-dihydro-1,2-benzo-doxo-l-3 (1H) -one (0633 3 ⁇ 41 ⁇ 11 reagent),
  • Doxo-l-3 (1 H) one 653-1 ⁇ 111 reagent
  • ether, tetrahydrofuran, dimethoxetane, dioxane, dichloromethane, chloroform, or the like is preferably used, and dichloromethane is preferably used.
  • the reaction is carried out at 110 to 50 ° C, preferably at 0 to 30 ° C.
  • oxidizing compound 3-4 Conversion of compound 3-4 to compound 3-5 is performed by oxidizing compound 3-4.
  • oxidizing agent use is made of sodium chlorite, a combination of 2-methyl-2-butene and sodium dihydrogen phosphate, a combination of pyridinium dichromate, chromic acid and sulfuric acid, and preferably sodium chlorite.
  • reaction solvent water, methanol, ethanol, propanol, ether, Te kanni Dorofuran, dimethyl Tokishetan, Jiokisan, dichloromethane, black hole Holm, dimethylformamide ⁇ Mi de force the like acetone or a mixed solvent thereof s, preferably Use a mixed solvent of water and tert-butanol.
  • the reaction is carried out at 0-50 ° C, preferably at 0-30 ° C.
  • Compound 5-1 Compound 5-2 In the formula, is a hydrogen atom, a linear or branched alkyl group having 1 to 7 carbon atoms which may have a halogen atom as a substituent, a compound having 3 to 7 carbon atoms, Linear or branched alkenyl group, one (CH 2 ) m —R 5 (where m represents an integer of 0 to 3, and R 5 is a linear or branched C 1 to C 3 Represents a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with a branched alkyl group) or an aryl group;
  • R 2 is a hydrogen atom; — (CH 2) n ′ — ⁇ R y represents a linear or branched alkoxy group having 1 to 3 carbon atoms, wherein n ′ represents an integer of 0 to 3, Ry represents a hydrogen atom or a protecting group for a hydroxyl group;
  • R 3 represents a linear or branched
  • Compound 5-1 can be converted to compound 5-2 by converting compound 5-1 to a carbonic ester (where R juryis a straight chain having 1 to 3 carbon atoms such as a methyl group, an ethyl group, or an isopropyl group).
  • a carbonic ester where R cautionis a straight chain having 1 to 3 carbon atoms such as a methyl group, an ethyl group, or an isopropyl group.
  • the reaction is carried out by adding ammonia gas or aqueous ammonia
  • the carbonic acid ester preferably carbonic acid ethyl ester
  • the bases are triethylamine and diisopropyl Ethylamine, pyridine, etc., preferably triethylamine, etc.
  • Reaction solvents dichloromethane, chloroform, tetrachloromethane Rometan, benzene, toluene, tetrahydrofuran, ether, a force used etc. Shiokisan s, preferably with dichloromethane.
  • the reaction is one 1 0 to 5 0 ° force 5 carried out at C ', preferably one 1 0-3 0. (:
  • the compound in which is a vinyl group is a 2-octane ethyl group such as a 2-bromoethyl group or a 2-odoethyl group.
  • a compound 4 or a compound 5 in which Ri is a vinyl group obtained by subjecting a compound 5 that is a 2-haloethyl group such as a 2-bromoethyl group or a 2-hydroxyethyl group to a Ri group is a vinyl group. You can get it.
  • a compound 6 in which is a 2-haloethyl group such as a 2-bromoethyl group or a 2-odoethyl group with a base.
  • Bases include sodium hydride, lithium hydride, sodium pistrimethylsilylamide, potassium pistrimethylsilylamide, lithium bistrimethylsilylamide, lithium diisopropylamide, n-butyllithium, s-butyllithium, t-butyllithium, 1,8-diazabicyclo [5.4.0] 17-decene or triethylamine can be used.
  • reaction solvent tetrahydrofuran, ether, dioxane, dimethoxyethane, dimethylformamide, dimethylsulfoxide, toluene, benzene, xylene, tetrachloromethane, a mixture thereof and the like can be used.
  • the reaction is carried out at a temperature of 100 to 5 ° C when an alkyl lithium such as n-butyl lithium is used as a base, and at a temperature of 110 to 10 when a metal hydride such as sodium hydride is used as a base.
  • a metal hydride such as sodium hydride
  • R x force in R 2 ⁇ carbon number 1-3 straight or branched chain
  • the protecting group is an alkyl group of the following
  • a conversion reaction from compound 2-1 to compound 2-2, a conversion reaction from compound 10 to compound 11, a conversion reaction from compound 14 to compound 15, and Reactions having the same effect as these can be mentioned.
  • elimination (deprotection) of R x can be performed simultaneously.
  • R y in R 2 is a hydroxyl-protecting group which is a substituted methyl group such as a methoxymethyl group or a methoxyethoxymethyl group, or a 2-year-old oxacycloalkyl group such as a tetrahydrofuryl group or a tetrahydroviranyl group.
  • acetic acid, hydrochloric acid, sulfuric acid, phenol, toluenesulfonic acid, pyridinum paratoluenesulfonate ( ⁇ ⁇ ⁇ S), or an acidic resin (for example, Ambrist H-15) can be used.
  • the reaction is carried out at a temperature of 10 to 100 ° C, preferably 15 to 60 ° C, using dichloromethane, methanol, ethanol, tetrahydrofuran, dioxane, water or a mixture of two or more thereof as a solvent.
  • the deprotection method can be cited as the deprotection method.
  • R y in R 2 is a protecting group for a hydroxyl group which is a substituted silyl group such as a triethylsilyl group or a t-butyldimethylsilyl group, a fluorine compound (for example, tetrabutylammonium fluoride and the like)
  • a fluorine compound for example, tetrabutylammonium fluoride and the like
  • the reaction is carried out at a temperature of 0 to 80 ° C, preferably 20 to 70 ° C, using, as a solvent, tetrahydrofuran or acetonitrile (preferably tetrahydrofuran) as a solvent.
  • the method can be cited as a method of S Convertibility protection.
  • R 2 is a straight-chain or branched-chain alkoxy group having 1 to 3 carbon atoms, that is, a hydroxyl group protected by an alkyl group
  • deprotection can be carried out by treating with a dealkylating agent.
  • a dealkylating agent the ability to use boron tribromide or trimethylsilane iodide is preferred, and boron tribromide is preferably used.
  • boron tribromide is preferably used as a reaction solvent, dichloromethane, chloroform, tetrachloromethane, benzene, toluene and the like can be used, but dichloromethane is preferably used.
  • the reaction is carried out at a temperature of 110 to 60 ° C, preferably at a temperature of -10 to 30 ° C.
  • the compounds of the present invention other than the compounds described above can be produced by the same method as the above-mentioned method or by a method partially modified appropriately according to the target compound to be produced. Further, the compound of the present invention can also be produced by applying the specific production methods described in Examples.
  • the compound of the present invention has a cyclooxygenase-2 (COX-2) inhibitory action and is useful as an anti-inflammatory agent.
  • COX-2 cyclooxygenase-2
  • the compound of the present invention can be administered orally or parenterally by oral, intravenous injection, mucosal application, transdermal application and the like. The dose in such cases is 3 to 150 mg / kg orally and l to 50 mg / kg parenterally per day.o
  • these compounds When these compounds are administered as a medicine, they can be formulated using conventional formulation techniques, and include tablets, capsules, powders, granules, suppositories, creams, ointments, aqueous solutions, It can be used as a solid or liquid dosage form such as an emulsion, an oily agent or a suspension.
  • excipients disintegrants, lubricants, binders, preservatives, stabilizers, osmotic pressure adjusting agents, or bases, which are commonly used in the formulation, are used.
  • Examples of these additional components include glucose, lactose, starch, carboxymethylcellulose, magnesium stearate, talc, liquid paraffin, polyvinyl alcohol, vegetable oil, polyalkylene glycol, and the like. In addition, it may contain a pharmaceutical ingredient.
  • Table 1 shows the chemical structural formulas of the example compounds.
  • Step 11 II Preparation of 2-n-propyl-1-5-methylthio-11-indanone
  • a solution of the compound obtained in the previous step 250 mg
  • potassium hydride 0.18 g
  • tetrahydrofuran 5 ml
  • iodo-n-propyl 238 mg
  • the mixture was further stirred for 90 minutes, poured into a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate.
  • the ethyl acetate layer was dried over magnesium sulfate, filtered, and concentrated.
  • Step 1-III Preparation of 2-n-propyl-15-methylthio-1-indenone
  • N-promosuccinimid (252 mg)
  • azobisisobutyronitrile A solution of (2.3 mg) in tetrachloromethane (18 ml) was refluxed for 3 hours, filtered after cooling, and the filtrate was concentrated. The resulting residue is (5 ml), add 1,8-diazabicyclo [5.4.0] -17-decene (204 mg) to the solution, stir at 90 ° C for 1 hour, pour into water, and add ethyl acetate. Extracted.
  • Step 11 IV Preparation of 1- (4-Methoxybenzylidene) 1-2_n-propyl-15-methylthio-1H-indene
  • Step 1 1 V Preparation of 1- (4-methoxybenzylidene) 1-2-n-propyl-15-methansulfonyl-1H-indene
  • Step 2-1 Preparation of 1- (4-fluorobenzylidene) 1-2-n-propyl-15-methylthio-1H-indene
  • Step 3-1 Preparation of 1- (2-chlorothiophene-5-yl) methylene-1 2-n-propyl pill-5-methylthio-1H-indene
  • Step 6—II: Preparation of 5-methylthio-11-indanone-1-N, N-dimethylhydrazone-Toluene solution of the compound (10 g) obtained in Step 11-I of Example 1 under nitrogen atmosphere (8 Oml), dimethylhydrazine (12.8 ml), p-toluenesulfonic acid monohydrate (1.07 g) and anhydrous sodium sulfate (23.9 g) were added, and the mixture was heated at 95 ° C. Stir for 1 hour. Then the reaction was filtered and concentrated. The obtained residue was separated by silica gel column chromatography (n-hexane: ethyl acetate 2: 1) to obtain 10.5 g (85%) of a brown powder of the desired product.
  • reaction solution was poured into a saturated aqueous solution of ammonium chloride, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated.
  • a 10% sulfuric acid aqueous solution (10 ml) was added to the obtained residue, and the mixture was heated at 80 ° C.
  • Example 5 In the same manner as in Example 5, the starting material was changed to 1- (3-methoxycarbonylbenzylidene) -1-5-methanesulfonyl 2- (4,4,4-1trifluorobutyl) -1H-indene As a result, the target substance was obtained as a yellow powder.
  • reaction solution was poured into a saturated aqueous solution of ammonium chloride, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated.
  • a 10% aqueous sulfuric acid solution (10 ml) was added to the obtained residue, and the mixture was stirred at 80 ° C for 30 minutes.
  • the reaction solution was poured into water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated.
  • Step 8 III: Preparation of (Z) -1- (3-methoxycarbonylbenzylidene) -1-5-methanesulfonyl-2- (3,3,3-trifluoropropyl) 1-1H-indene
  • Step 10 Preparation of 111—2— (2-methylpropyl) -1-methylthio-1-indenone
  • Example 4 In the same manner as in Example 4, the intended product was obtained by replacing 2-n-propyl-15-methylthio-11-indenone with 2- (2-methylpropyl) -15-methylthio-11-indenone.
  • the target compound was obtained by replacing n-butyl aldehyde with isobutyl aldehyde.
  • the desired product was obtained in the same manner as in Step 10-II of Example 10 except that the starting material was changed to (E) -2-butylidene-15-methylthio-11-indanone.
  • Step 12 -III Preparation of 21-n-butyl-5-methylthio-1-indenone
  • the desired product was obtained in the same manner as in Step 8-II of Example 8 except that the starting material was changed to 2-n-butyl-5-methylthio-11-indanone.
  • Step 1 2 IV: Preparation of (Z) -1- (3-methoxycarbonylbenzylidene) -1-5-methanesulfonyl-2-n-butyl-1H-indene
  • Example 11 In the same manner as in Example 11, the starting material was replaced with (Z) -1- (3-methoxycarbonyldibenzylidene) -15-methanesulfonyl-2-n-butyl-1H-indene, and yellow crystals were obtained. (Z) —1- (3-Carboxybenzylidene) -1-5-methansulfonyl-1-n-butyl-1-H-indene was obtained.
  • Step 1 4 I: Preparation of (E) —2-ethyl-1-5-methylthio-11-indanone In the same manner as in Step 6—III of Example 6, 4,4,4-trifluoro-1-iodobutane was replaced with odoethane to obtain the desired product.
  • the desired product was obtained in the same manner as in Step 6-IV of Example 6 except that the starting material was changed to 2-ethyl-5-methylthio-1-indanone.
  • Step 14 41 III Preparation of (Z) 1-11 (3-Methoxycarbonyl benzylidene) 1-5-Methanesulfonyl-12-ethyl-1H-indene
  • Example 11 In the same manner as in Example 11, the starting material was replaced with (Z) -11- (3-methoxycarbonyldibenzylidene) -15-methanesulfonyl-12-ethyl-1H-indene, and yellow crystals were obtained. (Z) —1- (3-Carboxybenzylidene) -1-5-methanesulfonyl-2-ethyl-1H-indene was obtained.
  • Step 16-II (3- (2- (tert-butyldimethyloxy) ethyl) Preparation of trifenylphosphonium bromide
  • Step 17-1 3- (3-bromophenyl) -1-ethyl phenylpropionate Preparation of steal
  • Step 1 7 11: Preparation of 3- (3-bromophenyl) -12-phenylpropionic acid 3- (3-bromophenyl) -12-phenylpropionic acid ethyl ester (1.79 g), IN aqueous sodium hydroxide ( A mixture of (10 ml) and ethanol (40 ml) was stirred at room temperature for 15 hours. After acidification with hydrochloric acid, the solvent was distilled off, followed by extraction with chloroform. The organic layer was dried and then concentrated to obtain the target product (1.62 g) as white crystals.
  • Example 5 In the same manner as in Example 5, the starting material was replaced with (Z) —1- (3-methoxycarbonylbenzylidene) -1-5-methanesulfonyl-12-phenyl-1-H-indene, and yellow crystals of (Z) were obtained. — 1— (3-Carboxybenzylidene) -1-5-methanesulfonyl-12-phenyl-1-H-indene was obtained.
  • Step 1 9 1: Preparation of (6- (methoxycarbonyl) pyridin-2-yl) methyl-trifluoroene phosphonium bromide
  • Step 1 9-1 II (Z) — 1— ((6- (Methoxycarbonyl) pyridine-12-yl) methylene) -1-5-Methylthio-12-n-propyl-1-H-indene and (E) — 1— ((6- (Methoxycarbonyl) pyridin-2-yl) methylene) -1-5-Methylthio-1-n-propyl-1-H-indene
  • Step 1 9 III: (Z) -1 — ((6— (methoxycarbonyl) pyridine-12-yl) methylene) -1-5-methanesulfonyl-1-2-n-propyl-1H-indene
  • reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated.
  • a mixture of 80 Omg and magnesium (66 lmg) was stirred in methanol (27 ml) for 1 hour.
  • reaction solution was poured into 3N hydrochloric acid, extracted with dichloromethane, washed with saturated saline, dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure.
  • the obtained residue is subjected to silica gel column chromatography.
  • Step 2 1-11 Preparation of 2- (2-Methoxy-3-methylthiophenyl) methyl-1-n-valeric acid
  • Step 21 1-III Preparation of 4-methoxy-1-5-methylthio-2-n-propyl-11-ingnone
  • a catalytic amount of dimethylformamide was added to a thionyl chloride solution (10 ml) of the compound (50 Omg) obtained in the previous step, and the mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure.
  • the obtained residue was dissolved in toluene, washed successively with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • aluminum chloride (496 mg) was added to a dichloromethane (90 ml) solution of the obtained residue, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was poured into ice water, the dichloromethane layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated.
  • Step 2 1 VI: (Z)-1-(4-Fluoro benzylidene) 1-5-Methanesulfo 2-ru 4-Methoxy 2- 2-n-propyl-1 1H-indene
  • a solution of the compound obtained in the previous step (260 mg) in a mixture of tetrahydrofuran-methanol (1: 1, 3.8 ml) was added a suspension of OXONE (1.17 g) in water (3.8 ml) at 0 ° C. ) And stirred at room temperature for 1 hour.
  • the extract was washed successively with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the mixture was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated.
  • Step 24-1 Preparation of 3-chloromethyl-6-ethylmethyl benzoate
  • Triethylamine (1.21 g) was added to a mixture of ethyl 5-methylsalicylate (1.8 g), pivaloyl chloride (1.33 g) and dichloromethane (20 ml) under ice-cooling, and the mixture was cooled to room temperature. And stirred overnight. The reaction mixture was washed sequentially with 2N hydrochloric acid, 2N aqueous sodium hydroxide solution and saturated saline, dried and concentrated to obtain the desired product (2.72 g).
  • Step 2 6 II: (Z) —1— (3-ethoxycarbonyl-2-4-bivaloyloxybenzylidene) -1-5-methanesulfonyl-1-2-n—propyl-1-H-indene and (E) -1-(3 Preparation of 1-ethoxycarbonyl-1-4-bivaloyloxybenzylidene-1-5-methanesulfonyl-2-n-propyl-1-H-indene
  • the ethyl ester was used in the next step without purification: ethyl 5-ethyl bromo-2-benzoyloxybenzoate (2.12 g), triphenylphosphine (2.6 g) and benzene (15 ml) was heated to reflux for 2 hours. The resulting crystals were collected by filtration to obtain 3-ethoxycarbonyl-14-bivaloyloxybenzyltriphenylphosphonium bromide (2.1). The obtained 3-ethoxycarbonyl 4-bivaloyloxybenzyltriphenylphosphonium bromide was used in the next step without purification.
  • Step 2 6 III: Preparation of (Z) -1— (3-carboxyl-1-hydroxybenzylidene) -1-5-methanesulfonyl-1-n-propyl-1-H-indene
  • Step 28—1 Preparation of 2- (2- (tert-butyldimethylsiloxy) ethyl) benzyl Promide
  • Step 2 8 II: (Z) — 1— (2— (2-hydroxyshethyl) benzylidene) —
  • Step 16-II of Example 16 the starting material was replaced with 2- (2- (tert-butyldimethylcyclohexyl) ethyl) benzylbutyramide, and (2— (2— (tert— Butyldimethylcyclohexyl) ethyl) benzyl) triphenylphosphonium bromide was obtained.
  • the obtained (2- (2- (tert-butyldimethylsiloxy) ethyl) benzyl) triphenylphosphonium bromide was used in the next step without purification.
  • reaction solution was diluted with ethyl acetate, and the organic layer was washed with water, dried and concentrated, and the resulting residue was collected.
  • Step 2 9 1: Preparation of (Z) —1— (2— (formylmethyl) benzylidene) -1-5-methanesulfonyl-1- n — n -propyl-1-H-indene
  • Step 2 9 II: Preparation of (Z) —1— (2- (carboxylmethyl) benzylidene) -1-5-methanesulfonyl-2-n-propyl-1-H-indene
  • Step 30—1 Preparation of (5- (ethoxycarbonyl) furan-2-yl) methyltriphenylphosphonium chloride
  • Step 3 0—II: (Z) 1-1 _ ((5- (ethoxycarbonyl) furan-2-yl) methylene) -1-5-Methanesulfonyl 2-n-propyl-1H-indene and Preparation of (E) — 11-((5- (ethoxycarbonyl) furan-1-yl) methylene) -1-5-methanesulfonyl-1-n-propyl-1-H-indene
  • Example 5 In the same manner as in Example 5, the starting material was converted to (Z) -11-((5- (ethoxycarbonyl) furan-1-yl) methylene) -1-5-methanesulfonyl-1-2-n-propyl-1H In place of —indene, orange crystalline (Z) —1-((5-carboxylfuran—2-yl) methylene) -1-5-methanesulfonyl 2-n-propyl-1-H-indene was obtained.
  • Step 3 3-III Preparation of (3- (methoxycarbonyl) -14-trifluoromethylbenzyl) -1-triphenylphosphonium bromide
  • 3-methoxycarbonylbenzyltriphenylphosphonium bromide with (3- (methoxycarbonyl) -14-trifluoromethylbenzyl) -1-trifluorophosphonium bromide, and replace the target compound with a yellow oil. I got it.
  • LPS lipopolysaccharide
  • the amount of thromboxane B2 contained in the supernatant was measured using a thromboxane B2 EIA kit (Cayman), and the solvent was controlled (the same operation as above). at the value set to 1 100% of those prepared without the addition of compound), displaying the concentration giving 50% inhibition activity as IC 5 o values.
  • Table 2 shows the inhibitory activities (IC 50 values) of COX-1 and COX-2 of the compounds of the present invention obtained as a result.
  • the compound of the present invention has an inhibitory effect on COX-2 and is useful as a drug such as an anti-inflammatory drug.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés représentés par la formule (I) (dans laquelle R1 représente hydrogène etc.; R2 représente hydrogène etc.; R3 représente un alkyle C1-C3 linéaire ou ramifié; R4 représente un aryle éventuellement substitué etc.), leurs hydrates, ainsi que des sels de ces deux derniers qui sont acceptables sur le plan pharmaceutique. Ces composés présentent une activité d'inhibition de COX-2 et sont utiles en tant que médicaments, tels que des antiphlogistiques.
PCT/JP1998/002611 1997-06-17 1998-06-15 Derives d'indene WO1998057924A1 (fr)

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AU76749/98A AU7674998A (en) 1997-06-17 1998-06-15 Indene derivatives

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JP15959897 1997-06-17

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022195579A1 (fr) 2021-03-15 2022-09-22 Saul Yedgar Dipalmitoyl-phosphatidyl-éthanol-amine conjuguée à l'acide hyaluronique en combinaison avec des médicaments anti-inflammatoires non stéroïdiens (ains) pour traiter ou soulager des maladies inflammatoires

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022195579A1 (fr) 2021-03-15 2022-09-22 Saul Yedgar Dipalmitoyl-phosphatidyl-éthanol-amine conjuguée à l'acide hyaluronique en combinaison avec des médicaments anti-inflammatoires non stéroïdiens (ains) pour traiter ou soulager des maladies inflammatoires

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