WO1997030030A1 - Derives d'indole - Google Patents

Derives d'indole Download PDF

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Publication number
WO1997030030A1
WO1997030030A1 PCT/JP1997/000366 JP9700366W WO9730030A1 WO 1997030030 A1 WO1997030030 A1 WO 1997030030A1 JP 9700366 W JP9700366 W JP 9700366W WO 9730030 A1 WO9730030 A1 WO 9730030A1
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WIPO (PCT)
Prior art keywords
group
methanesulfonyl
propylindole
compound
carbon atoms
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PCT/JP1997/000366
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English (en)
Japanese (ja)
Inventor
Hiroharu Matsuoka
Noriaki Maruyama
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
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Publication date
Application filed by Chugai Seiyaku Kabushiki Kaisha filed Critical Chugai Seiyaku Kabushiki Kaisha
Priority to AU16715/97A priority Critical patent/AU1671597A/en
Publication of WO1997030030A1 publication Critical patent/WO1997030030A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

Definitions

  • the present invention relates to a novel indole derivative which exhibits an anti-inflammatory effect and the like and is useful as a medicine.
  • 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.
  • COX-2 it was revealed that COX-2 is induced during inflammation and is rarely expressed normally, and it also becomes clear that the conventional NSAID nonspecifically inhibited both enzymes.
  • An object of the present invention is to provide an indole derivative having COX-2 inhibitory activity and the like, which is useful as a drug such as an anti-inflammatory agent.
  • the present inventors have conducted intensive studies with the aim of developing compounds that selectively or non-selectively inhibit COX-2 and have anti-inflammatory effects equal to or higher than existing NSAIDs such as indomethacin. As a result, they have found that the indole derivative represented by the general formula (1) has excellent anti-inflammatory activity and is 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 (1):
  • R 1 is a hydrogen atom, a linear or branched alkyl group having ⁇ 7 carbon atoms, a linear or branched alkenyl group having 2 to 7 carbon atoms, A straight-chain or branched alkynyl group, a cycloalkenyl group having 4 to 6 carbon atoms, an aryl group, a heteroaryl group, or a linear or branched alkyl group having an alkyl moiety of 7 to 7 carbon atoms
  • n represents an integer of 0 to 3
  • R 4 is a cycloalkyl having 3 to 6 carbon atoms which may be substituted with a linear or branched alkyl group having 1 to 3 carbon atoms.
  • R 2 represents one S ⁇ 2 —R s .
  • R 5 represents a linear or branched alkyl group having 1 to 3 carbon atoms.
  • R 3 is an aryl group which may have a substituent, a cycloalkyl group having 3 to 6 carbon atoms which may have a substituent, or a monocyclic hetero group which may have a substituent 3 ⁇ 4 represents a group,
  • examples of the linear or branched alkyl group having 1 to 7 carbon atoms in R 1 include a methyl group, an ethyl group, an n-propyl group, Propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, ⁇ -hexyl group, n- ⁇ butyl group and the like.
  • a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentisole group, and an n-hexizole group are more preferred.
  • Examples of the linear or branched alkenyl group having 2 to 7 carbon atoms for R ′ include, for example, a vinyl group, an aryl group, and an i-propenyl group. Alternatively, a branched alkenyl group is preferable, and an aryl group and an i-propenyl group are more preferable.
  • Examples of the linear or branched alkynyl group having 2 to 7 carbon atoms in R 1 include an ethynyl group and the like, and a straight-chain or branched alkynyl group having 2 to 4 carbon atoms is preferred. preferable.
  • Examples of the cycloalkenyl group having 4 to 6 carbon atoms in R 1 include a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group and the like, and a cyclohexenyl group is preferable.
  • the aryl group in R 1 is a monocyclic, polycyclic, or fused polycyclic having 6 to 12 carbon atoms. And a phenyl group, a biphenyl group and the like, and a phenyl group is preferable.
  • the heteroaryl group for R ′ is a 5- or 6-membered ring containing one or two hetero atoms such as nitrogen IS atoms as ring-constituting atoms, and examples thereof include a pyridyl group.
  • the alkylcarbonyl group in which the alkyl moiety in R 1 is a linear or branched alkyl group having 1 to 7 carbon atoms refers to the above-described starved or branched alkyl group having 1 to 7 carbon atoms
  • All alkyl carbonyl groups include, for example, acetyl group, propionyl group, butyryl group, 2-methylpropionyl group, etc., wherein the alkyl moiety is an aba-chain or branched-chain alkyl group having 1 to 4 carbon atoms.
  • An alkylcarbonyl group is preferred.
  • alkenylcarbonyl group in which the alkenyl moiety in R 1 is a chain chain or branched alkenyl group having 2 to 7 carbon atoms refers to the above-mentioned straight or branched alkenyl group having 2 to 7 carbon atoms.
  • Alkenylcarbonyl groups, which are branched alkenyl groups, are preferred.
  • the alkynylcarbonyl group in which the alkynyl moiety in R ′ is a straight-chain or branched alkynyl group having 2 to 7 carbon atoms refers to the above-mentioned straight-chain or branched alkynyl group having 2 to 7 carbon atoms. And all alkynylcarbonyl groups such as a propioyl group.
  • An alkynylcarbonyl group in which the alkynyl moiety is a straight-chain or branched alkynyl group having 2 to 4 carbon atoms is preferable.
  • the chain- or branched-chain alkyl group having 1 to 3 carbon atoms as a substituent in R 4 represents a methyl group, an ethyl group, a ⁇ -propyl group, or an i-propyl group.
  • Examples of the cycloalkyl group having 3 to 6 carbon atoms which may be substituted with a straight or branched alkyl group having 1 to 3 carbon atoms for R 4 include, for example, a cyclopropyl group, a methylcyclopropyl group , Ethylcyclopropyl, cyclobutyl, cyclo Examples thereof include a pentyl group and a cyclohexyl group, and a cyclopropyl group is preferable.
  • Examples of the group represented by 1 (CH 2 ) m —R 4 in R ′ include a cyclopropyl group, a methylcyclopropyl group, an ethylcyclopropyl group, a cyclopropylmethyl group, a cyclobutylpyruethyl group, and a 2-methyl group Cyclopropylmethyl, 2-methylcyclopropylethyl, 2-ethylcyclopropylmethyl, 2-ethylcyclopropylethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclo Examples include a hexyl group and a cyclohexylmethyl group, and a cyclopropylmethyl group is preferable.
  • R ′ represents a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an aryl group, a propenyl group, and a cyclohexene 1
  • Preferred are a methyl group, a cyclomethyl pyrmethyl group and a phenyl group.
  • R 2 - groups represented by R 5 are methanesulfonyl group, Etansuru Honiru group, n- propanesulfonyl group, i indicates an propanesulfonyl two group, meta Nsuruhoniru group, ethanesulfonyl group, n- A propanesulfonyl group is preferred, and a methanesulfonyl group and an ethanesulfonyl group are more preferred.
  • the substituent of the ring group include a halogen atom, a linear or branched alkyl group or alkoxy group having 4 to 4 carbon atoms which may be substituted with a halogen atom, or one S (0) n.
  • -R 6 (where n represents an integer of 0 to 2, R 6 represents a linear or branched alkyl group having 1 to 3 carbon atoms), an amino group, a divalent group, etc.
  • Fluorine atom chlorine atom, iodine atom, iodine atom, methyl group, ethyl group, n-propyl group, i-propyl group, t-butyl group, trifluoromethyl group, methoxy group, ethoxy group, methylthio group , Methanesulfonyl group, ethanesulfonyl group, amino group, Nitro groups are preferred.
  • the aryl group which may have a substituent in R 3 is the same or different,
  • mono, di, tri may be an aryl group having 6 to 12 carbon atoms which may be substituted, and may be the same or different, and in the above B substituent, mono, di, tri
  • An optionally substituted phenyl group is preferable, and a phenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, a 4-iodophenyl group, a 2,3-difluorophenyl group, a 2,3-difluorophenyl group, 4-dichlorophenyl group, 2,6-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 3,5-dibromophenyl group, 5-bromo-2-chlorophenyl group, 2,3, 5-Trichloro mouth pheny
  • the cycloalkyl group having 3 to 6 carbon atoms in R 3 represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, and a cyclohexyl group is preferable.
  • the monocyclic heterocyclic group represented by R 3 is the same or different and is a 5- to 8-cyclic aliphatic or aromatic containing 2 or 3 hetero atoms such as an oxygen atom, a nitrogen atom, and a sulfur atom.
  • a mono-Hunch type heterocyclic group of an aromatic hydrocarbon for example, a pyridyl group, a piperazinyl group, a piperidinyl group, a pyrimidinyl group, a pyrrolyl group, a vilanyl group, a furyl group, an oxazolyl group, a triazolyl group, a thixoxolyl group, A phenyl group, etc., which may be the same or different and include a 5- or 6-membered aliphatic or aromatic hydrocarbon containing one or two heteroatoms such as an oxygen atom, a nitrogen atom and a sulfur atom;
  • a cyclic heterocyclic group is preferable, and a pyri
  • R 3 is phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-phenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,4-dichlorophenyl, , 6-Dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dibromophenyl, 5-bromo-2-chlorophenyl, 2,3,5-trichlorophenyl Group, 2,4,6-trichlorophenyl group, 2-chloro-4,5-difluorophenyl group, 4-methylphenyl group, 4-ethylphenyl group, 4-n-propylphenyl group, 4-isopropylphenyl
  • R ′, R 2 and R 3 have the same meanings as described above,
  • Examples of the compound represented by are 2-ethyl-1- (4-one-year-old benzoyl) -1-5-methanesulfonylindole, and 1-1 (4-one-year-old benzoyl) -15-methane-sulfonyl 2-n- Propylindole, ⁇ -1 (4-promobenzoyl) —5 -Methanesulfonyl 2- ⁇ -propylindole, 1-1 (4-chlorobenzene) 1 -5-Methanesulfonyl 2-n-propylindole, 5-methanesulfonyl 1- (4-methylbenzoyl) 2- ( ⁇ -propylindole), 5- (methanesulfonyl) -2-propyl-1-1-4-trifluoromethylbenzoyl) indole, 1-1 (4-methylbenzoyl) N-zyl) 1-5-Methanesulfonyl 2-methylindole, 5-methanesul
  • (4-chlorobenzene) 2-5-isoprobenylindole is preferred, and 1-1 (4-fluorobenzoyl) -15-methanesulfonyl 2- ⁇ -propylindole, 1 1- (4-promobenzoyl) -1-5-methanesulfonyl 2- 2- ⁇ -propylindole, 1- (4-chlorobenzoyl) -15-methanesulfonyl-2-n-provindindole are more preferred.
  • the compounds of the present invention can also be obtained as hydrates.
  • R ′, R 2 and R 3 each have the same meaning as described above, and the compound represented by the general formula (2)
  • RR 2 and R 3 each have the same meaning as described above.
  • R 3 has the same meaning as described above,
  • the reactive derivative includes the acid anhydride and the acid chloride.
  • This reaction is carried out using a polar aprotic (aprotic) solvent in the presence of a base.
  • the base at that time is an inorganic metal base, preferably sodium hydride, potassium hydride, more preferably hydrogen: sodium, or an organic base, preferably triethylamine, diisopropylethylamine, pyridine, 2, 6 —Dimethyl-41-aminoviridine is used.
  • the aprotic polar solvent dimethylformamide (DMF), dimethylacetamide, tetrahydrofuran (THF) and the like are used, and dimethylformamide is preferably used.
  • the reaction temperature is preferably between 110 and 100 *, and particularly preferably between 0 and 30.
  • This reaction is carried out by treating the compound of the general formula (2) with a base and then reacting the carboxylic acid chloride or the carboxylic acid anhydride of the general formula (3).
  • the base to be used includes lithium diisoproviramide, lithium pistrimethylsilylamide, potassium pistrimethylsilylamide, sodium bistrimethylsilylamide, sodium hydride, potassium hydride, etc., preferably, sodium hydride is used.
  • the reaction solvent includes tetrahydrofuran, ether, dioxane, dimethyloxetane, dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like, and preferably dimethylformamide is used.
  • the reaction is carried out at a temperature of 0 to 1001, preferably at a temperature of 0 to 30 ° C.
  • the compounds represented by the general formula (2) are each produced by the following production method.
  • the compound is reacted with a reactive derivative of the carboxylic acid of the above general formula (3) to produce a compound represented by the general formula (1).
  • the compound of the present invention can be produced, for example, as follows.
  • R 7 represents a hydrogen atom or a linear or branched alkyl Le group having a carbon number ⁇ 1-6, 8 3 Oyobi 13 ⁇ 4 5, the same meanings as described above.
  • the reaction from compound 1 to compound 2 is performed in the presence of a base using an aprotic polar solvent.
  • a base preferably an inorganic gold base, preferably sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, more preferably sodium hydride, or an organic base, preferably triethylamine, diisopropyl Ethylamine, pyridine, and 2,6-dimethyl-4-aminopyridine are used.
  • the abrotic polar solvent dimethylformamide, dimethylacetamide, tetrahydrofuran and the like are used, and dimethylformamide is preferably used.
  • the reaction temperature is preferably between 110 and 100, and particularly preferably between 0 and 30 ⁇ . preferable.
  • compound 2 is dissolved in an ether solvent such as tetrahydrofuran, dimethoxyethane, and diethyl ether, and the solution is converted into an organic metal base, preferably lithium diisopropylamide (LDA) or lithium. It is added to a solution of xamethyldisilazane, n-butyllithium, more preferably lithium diisopropylamide in tetrahydrofuran or the like, and then trimethylsilyl chloride (TMSCI) is added dropwise.
  • an ether solvent such as tetrahydrofuran, dimethoxyethane, and diethyl ether
  • LDA lithium diisopropylamide
  • TMSCI trimethylsilyl chloride
  • the reaction from compound 3 to compound 4 is carried out by reacting an alkyl carboxylic acid anhydride or an alkyl carboxylate, wherein the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, with dichloromethane, tetra
  • dichloromethane tetra
  • a Lewis acid is added to a solution of an organic solvent such as chloromethane or tetrachloroethane, and the mixture is stirred for a while and then a methane solution of compound 3 in dichloromethane is added dropwise.
  • Lewis acid an acid generally used for a Friedel-Crafts reaction is used, and preferably, aluminum chloride, polyphosphoric acid, boron trifluoride ether, sulfuric acid, antimony pentachloride, iron trichloride, and tin tetrachloride are used.
  • Gallium trichloride is used, and more preferably, aluminum chloride is used.
  • the reaction temperature is preferably 0 to 80 * C, more preferably 0 to 40 * C.
  • the reaction from compound 4 to compound 5 can be performed by a solution of t-butylamine borane complex and aluminum chloride in dichloromethane or the like, or a mixture of sodium borohydride and dichloromethane by trifluoric acid.
  • a solution of compound 4, such as dichloromethane, is added dropwise to the solution.
  • the reaction temperature at this time is from 120 to 40, and preferably from 20 to 30.
  • the reaction from compound 5 to compound 6 is carried out by adding an organic gold base, preferably n-butyllithium or s-butyllithium, and more preferably n-butyllithium, to a solution of compound 5 in tetrahydrofuran or ether. Is added dropwise at 100 to 150 ⁇ , preferably at 180 to 170, and after stirring for a while, dialkyl disulphide R 5 SSR 5 (R 5 is Represents the same meaning as), for example, Dimethydis This is done by dropping sulfide.
  • an organic gold base preferably n-butyllithium or s-butyllithium, and more preferably n-butyllithium
  • the reaction from the compound 6 to the compound 7 is carried out by adding a compound 6 in a solution of an organic solvent such as dichloromethane, chloroform, tetrachloromethane, or the like, preferably in a solution of chloroform in metaclo-perbenzoic acid ( m CPBA).
  • an organic solvent such as dichloromethane, chloroform, tetrachloromethane, or the like
  • m CPBA metaclo-perbenzoic acid
  • water may be added to a solution of the compound 6 in an alcohol, preferably a mixed solvent of methanol and tetrahydrofuran, with water of OXONE® (registered trademark).
  • the reaction from the compound 7 to the compound 8 is carried out by adding an alcohol, preferably methanol, ethanol, or an abrotic polar solvent, preferably dimethylformamide or a mixed solvent of tetrahydrofuran and a polar solvent to water. Is dissolved or suspended, and an inorganic metal base such as sodium hydroxide, potassium hydroxide and lithium hydroxide is added to the reaction mixture. At this time, the reaction is carried out at 0 to 150 ° C, preferably at 80 to 100 ° C.
  • the reaction from compound 8 to compound 9 is carried out in the presence of a base using an aprotic polar solvent.
  • the base at that time is an inorganic gold base, preferably sodium hydride, potassium hydride, more preferably sodium hydride, or an organic base, preferably triethylamine, diisopropylethylamine, pyridine, 2,6-dimethyl-4.
  • One aminoviridine is used.
  • the abrotic polar solvent dimethylformamide, dimethylacetamide, tetrahydrofuran and the like are used, and dimethylformamide is preferably used.
  • the reaction temperature is preferably between 110 and 100, particularly preferably between 0 and 30.
  • R ′ is an alkylcarbonyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 7 carbon atoms, or a linear alkyl group having 2 to 7 carbon atoms in the alkenyl portion.
  • a metal preferably sodium borohydride or lithium aluminum hydride
  • a protecting group is introduced into a hydroxyl group using t-butyldimethylsilyl chloride, methoxymethyl chloride, and the like.
  • hydrochloric acid, dilute sulfuric acid, sulfuric acid, tetrabutylammonium chloride are used.
  • the compound can be produced by treating with a compound such as sodium fluoride or hydrogen fluoride-pyridine derivative to remove the protecting group and then oxidizing.
  • oxidizing agent at this time, manganese dioxide, dimethyl sulfoxide, quinoxalyl chloride, pyridinium chloride and the like are used.
  • the compound of the present invention can be produced, for example, as follows.
  • R 8 represents a linear or branched alkyl group having 1 to 7 carbon atoms
  • A represents a halogen such as a fluorine atom, a chlorine atom, or a bromine atom
  • R a represents a hydrogen atom, a linear or branched alkyl group having 1 to 7 carbon atoms
  • R 3 and R 5 have the same meanings as described above.
  • the reaction from Compound 10 to Compound I1 is carried out in the presence of a base using an aprotic polar solvent.
  • a base preferably an inorganic metal base, preferably sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, more preferably water Sodium iodide or an organic base, preferably triethylamine, diisopropylethylamine, pyridine, 2,6-dimethyl-41-aminopyridine is used.
  • the aprotic polar solvent dimethylformamide, dimethylacetamide, tetrahydrofuran and the like are used, and dimethylformamide is preferably used.
  • the reaction temperature is preferably between 110 and 100, and particularly preferably between 0 and 30.
  • the reaction from compound 11 to compound 12 is carried out by dissolving compound 11 in an organic solvent such as tetrahydrofuran, dimethyloxyethane, and getyl ether, and dissolving the solution in an organic metal base, preferably lithium diisopropylamide, lithium hexamethyldisilazane.
  • organic solvent such as tetrahydrofuran, dimethyloxyethane, and getyl ether
  • organic metal base preferably lithium diisopropylamide, lithium hexamethyldisilazane.
  • R 8 — A (wherein , R 8 and a are each as ⁇ taste as above), preferably carried out dropwise straight ⁇ or branched Arukiruhara I de carbon number ⁇ 1-4.
  • the reaction from the compound 12 to the compound 13 or the reaction from the compound 11 to the compound 13 is carried out by adding a solution of the compound 12 or the compound 11 in tetrahydrofuran or ether or the like to an organometallic base, preferably ⁇ - Butyllithium, s-butyllithium, more preferably n-butyllithium, is preferably from 100 to -500C, preferably from 180 to 170.
  • dialkyl disulfide R 5 SSR 5 (R 5 has the same meaning as described above), for example, dimethyl disulfide is dropped.
  • the reaction from compound 13 to compound 14 is performed by adding perfluorobenzoic acid to a solution of compound 13 in an organic solvent such as dichloromethane, chloroform and tetrachloromethane, and preferably to a solution of chloroform.
  • the reaction may be carried out by adding suspended water of quinone to a solution of a mixed solvent of an alcohol of compound 13, preferably methanol, and tetrahydrofuran.
  • the reaction from compound 14 to compound 15 is carried out using an alcohol, preferably methanol, Compound ⁇ 4 is dissolved or suspended in a solvent mixture of ethanol or an aprotic polar solvent, preferably a polar solvent of dimethylformamide or tetrahydrofuran, and water, and the reaction mixture is mixed with sodium hydroxide and water. This is performed by adding an inorganic gold-base such as potassium oxide or lithium hydroxide.
  • the reaction temperature at this time is 0 to 150 ° C, preferably 80 to 100 ° C.
  • the reaction from the compound 15 to the compound 16 is performed in the presence of a base using an aprotic polar solvent.
  • the base at that time is an inorganic metal base, preferably sodium hydride, potassium hydride, more preferably sodium hydride, or an organic base, preferably triethylamine, diisopropylethylamine, pyridine, 2,6-dimethylene. 4-Aminoviridine is used.
  • dimethylformamide, dimethylacetamide, tetrahydrofuran and the like are used as the aprotic polar solvent, and dimethylformamide is preferably used.
  • the reaction temperature is preferably between 110 and 100 ° C., particularly preferably between 0 and 30 ⁇ .
  • the compound of the present invention can also be produced, for example, as follows.
  • R 3 , R 5 and A have the same meaning as before, and R 1 Q has 1 to 7 carbon atoms.
  • the reaction from the compound 17 to the compound 18 is carried out by dissolving the compound 17 in an ether-based solvent such as tetrahydrofuran, dimethyloxetane, and diethyl ether, and adding an inorganic base, preferably potassium hydride or hydrogen, to the solution.
  • an ether-based solvent such as tetrahydrofuran, dimethyloxetane, and diethyl ether
  • an inorganic base preferably potassium hydride or hydrogen
  • an organic gold base preferably t-butyllithium, s-butyllithium , N-butyllithium, lithium diisopropylamide, more preferably t-butyllithium, preferably at 100-150 ⁇ :, more preferably 180-170 ⁇ , and then dialkyldisulfate.
  • Id R 5 SSR 5 (wherein R 5 has the same meaning as described above), for example, by dropping dimethyl disulfide.
  • the reaction from compound 18 to compound 19 is carried out in the presence of a base using an aprotic polar solvent.
  • a base preferably an inorganic metal base, preferably sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, more preferably sodium hydride, or an organic base, preferably triethylamine, diisopropylamine Luethylamine, pyridine and 2,6-dimethyl-41-aminoviridine are used.
  • the aprotic polar solvent dimethylformamide, dimethylacetamide, tetrahydrofuran and the like are used, and dimethylformamide is preferably used.
  • the reaction temperature is preferably from 110 to 100, particularly preferably from 0 to 30 ° C.
  • the reaction from compound 19 to compound 20 is carried out by dissolving compound 19 in an organic solvent such as tetrahydrofuran, dimethyloxyethane, and getyl ether, and preparing the solution in the solution.
  • Metal base preferably n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamide, lithium hexamethyldisilazane, more preferably n-butyllithium, and then hexamethylphosphate Triamide (HMPA), N, N, N, N-tetramethylethylenediamine (TMEDA) or hexamethylphosphorustriamide (HMPT), preferably HMPA, and the alkyl moiety has 1 carbon atom.
  • HMPA hexamethylphosphate Triamide
  • TEDA N, N, N-tetramethylethylenediamine
  • HMPT hexamethylphosphorustriamide
  • Alkyl halide which is a ⁇ -chain or branched alkyl group having up to 7 carbon atoms, alkyl halide wherein the alkyl portion is a cycloalkyl group having 3 to 6 carbon atoms, cycloalkyl wherein the cycloalkyl portion is a cycloalkyl group having 3 to 6 carbon atoms
  • Halide is such straight town or branched alkenyl halide of 2-7 carbon atoms: R '° - A (wherein, R' ° and A are as defined above) conducted dropwise.
  • the reaction from compound 20 to compound 21 or the reaction from compound 19 to compound 21 is a solution of compound 20 or compound 19 in an organic solvent of dichloromethane, chloroform and tetrachloromethane.
  • an organic solvent of dichloromethane, chloroform and tetrachloromethane Preferably, metachloroperbenzoic acid is added to the solution of black form.
  • the reaction may be carried out by adding a suspension of xyxone to a solution of a compound 20 alcohol, preferably a mixed solvent of methanol and tetrahydrofuran.
  • the reaction from compound 21 to compound 22 is carried out by reacting an alcohol, preferably methanol, ethanol, or an aprotic polar solvent, preferably a mixed solvent of a polar solvent such as dimethylformamide and tetrahydrofuran, with water, 21 is dissolved or suspended, and an inorganic metal base such as sodium hydroxide, potassium hydroxide or lithium hydroxide is added to the reaction mixture.
  • an alcohol preferably methanol, ethanol, or an aprotic polar solvent, preferably a mixed solvent of a polar solvent such as dimethylformamide and tetrahydrofuran
  • an inorganic metal base such as sodium hydroxide, potassium hydroxide or lithium hydroxide
  • the reaction from compound 22 to compound 23 is performed in the presence of a base using an aprotic polar solvent.
  • the base at that time is an inorganic metal base, preferably sodium hydride, potassium hydride, more preferably sodium hydride, or an organic base, preferably Triethylamine, diisopropylethylamine, pyridine, and 2,6-dimethyl 4-aminobiidine are used.
  • dimethylformamide, dimethylacetamide, tetrahydrofuran and the like are used as the aprotic polar solvent, and dimethylformamide is preferably used.
  • the reaction temperature is preferably between 110 and 100 ⁇ , particularly preferably between 0 and 30.
  • the compound of the present invention can also be produced, for example, as follows.
  • R 3 , R 5 and A have the same meaning as described above, R 11 represents an aryl group or a heteroaryl group, R 12 represents a methyl group, an ethyl group or an n-propyl group; 13 represents a hydrogen atom, a methyl group or an ethyl group, or R 12 and R 13 together represent a (CH 2 ) ⁇ — group
  • n represents an integer of 2 to 4, and represents a branched alkenyl group having 3 to 7 carbon atoms, a cycloalkenyl group having 4 to 6 carbon atoms, an aryl group or a heteroaryl group.
  • Examples of the indole derivative compound produced by this production method include compounds 27, 28 and 29 in which R 12 is a methyl group and R 13 is a hydrogen atom, and R ′ 2 and R 13, together with one (CH 2) 4 - compound 27, 28 and 29, R is compound 26 and 30 is a phenyl group and intermediates that are, but each Isopurobe group, hexene one 1 Iru group cycloheteroalkyl is the phenyl group Compound 32 and the like.
  • the reaction from the compound 24 to the compound 25 is carried out by treating the compound 24 with a base and then reacting with tin chloride.
  • Tin chloride, trimethyltin chloride, Toripuchi Ruchinkurorido uses a Bok riff enyl Chin chloride, preferably, Toripuchi Ruchinkurorido (n- B u 3 S n CI ) is used.
  • the base used here includes lithium diisopropylamide, lithium bistrimethylsilylamide, potassium bistrimethylsilylamide, sodium pistrimethylsilylamide, sodium hydrogen hydride, potassium hydride, and the like. Use lithium diisopropylamide.
  • Hexamethylphosphoric acid triamide, tetramethylethylenediamine and the like can be added to the reaction solution in order to improve the nucleophilicity of the generated carbanion.
  • the reaction solvent includes tetrahydrofuran, ether, dioxane, dimethyloxetane, dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like, but preferably tetrahydrofuran is used.
  • the reaction is carried out at a temperature of 110 to 100 ° C, preferably at a temperature of 78 to 0 ° C.
  • R 1 2 and R 1 3 represents the same ⁇ said
  • the reaction is carried out by reacting the ketone represented by Examples of this ketone include acetone and cyclohexanone.
  • the base used herein includes lithium diisopropylamide, lithium bistrimethylsilylamide, potassium bistrimethylsilylamide, sodium pistrimethylsilylamide, sodium hydride, potassium hydrate, and the like. I have.
  • the reaction solvent include tetrahydrofuran, ether, dioxane, dimethyloxetane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and the like.
  • tetrahydrofuran is used.
  • the reaction is carried out at a reaction intensity of 0 to 100, preferably 0 to 30 *.
  • the reaction from the compound 27 to the compound 28 is carried out by treating the compound 27 with an acid.
  • the acid to be used includes a catalytic amount or a small amount of toluenesulfonic acid, sulfuric acid, trifluorosulfonic acid, trifluoromethanesulfonic acid, boron fluoride ether loach, and the like, preferably toluene sulfonic acid.
  • As the reaction solvent benzene, toluene, and xylene are used, and toluene is preferably used.
  • the reaction is carried out at a temperature of from 0 to 200, preferably at a temperature higher than the boiling point of the solvent used.
  • the reaction from compound 28 to compound 29 or the reaction from compound 26 to compound 30 is carried out by oxidizing compound 28 or compound 26, respectively.
  • oxidizing agent there may be mentioned peroxybenzoic acid and sodium periodate.
  • peroxybenzoic acid is used.
  • the reaction is carried out at a temperature of 110 to 30 ° C, preferably at 0 ° C.
  • chloroform, dichloromethane, tetrachloromethane, tetrahydrofuran, water and the like are used, and preferably, chloroform is used.
  • it may be carried out by adding the suspension water of Xixon to a solution of an alcohol of compound 28 or compound 26, preferably a mixed solvent of methanol and tetrahydrofuran.
  • the reaction from compound 29 or compound 30 to compound 31 is performed by hydrolyzing compound 29 or compound 30 with a base, respectively.
  • the base to be used includes sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, magnesium hydroxide and the like, but preferably potassium hydroxide is used.
  • the reaction is carried out at a temperature of from 0 to 100 ° C., preferably from 80 to 100 ° C.
  • As the reaction solvent water, methanol, ethanol, propanol, tetrahydrofuran or a mixed solvent thereof is used, and preferably, methanol is used.
  • reaction from the compound 31 to the compound 32 is carried out by treating the compound 31 with a base, followed by the general formula (3):
  • R 3 has the same meaning as described above.
  • the reaction is carried out by reacting a reactive derivative of a carboxylic acid represented by, for example, carboxylic acid chloride or carboxylic anhydride.
  • the base to be used includes lithium diisopropidoviramide, lithium bistrimethylsilylamide, potassium bistrimethylsilylamide, sodium pistrimethylsilylamide, sodium hydride, potassium hydride, and the like, and preferably, sodium hydride is used.
  • the reaction solvent includes tetrahydrofuran, ether, dioxane, dimethyloxetane, dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like, and preferably dimethylformamide is used.
  • the reaction is carried out at a temperature of 0 to 100 ⁇ , preferably at 0 to 3 ⁇ C.
  • the compounds of the present invention other than the above-mentioned compounds can be produced by the same method as in the above-mentioned production method or by a production method in which a part is appropriately changed depending on the target compound to be produced.
  • the compounds of the present invention can also be produced by applying the specific production methods described in the examples.
  • the compound of the present invention has an inhibitory activity on xygenase-12, and is useful as an anti-inflammatory agent.
  • the compound of the present invention can be administered orally or parenterally, such as oral, intravenous injection, mucosal application, and transdermal application.
  • the dosage in that case is 3 to 15 Omg Zkg for oral and 1 to 5 OmgZkg for parenteral per day.
  • these compounds can be formulated using conventional formulation techniques, such as tablets, capsules, powders, granules, suppositories, creams, soft S agents, and aqueous solutions It can be used as a solid or liquid 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. it can.
  • Examples of these additional ingredients include glucose, lac!
  • Examples include starch, starch, carboxymethylcellulose, magnesium stearate, talc, liquid paraffin, polyvinyl alcohol, vegetable oil, polyalkylene glycol, and the like.
  • the ethyl persulfate layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and boxed.
  • the obtained residue was subjected to silica gel column chromatography, and the desired product (256 mg) was obtained using ethyl persulfate: ⁇ -hexane (1: 8) as an elution solvent.
  • the obtained residual brew is subjected to thin-layer silica gel column chromatography, and the target substance is separated using chloroform: methanol (100: 1) as an elution solvent, and acetone-hexane is further added.
  • the crystals were recrystallized from sun to give the desired crystals (18.1 mg).
  • the methylene chloride layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, concentrated and concentrated.
  • the obtained residue was subjected to silica gel column chromatography, and the desired product (78 Omg) was obtained using n-hexane (1: 4) as an elution solvent.
  • the target product (392 mg) was obtained in the same manner as in Reference Example 2 by using the compound of Reference Example 6 (528 mg) and 70% metaclotobenzoic acid (754 mg).
  • Example 2 A method similar to that of Example 1 using the compound of Reference Example 8 (1 4. Omg), 4 1-year-old benzoyl chloride (1 4. Omg) and 60% sodium hydride (3.5 mg). Thus, the desired product (19.2 mg) was obtained.
  • Example 7 ⁇ -(4-chlorobenzene) 1-5-Methanesulfonyl 2-methylindole
  • the compound of Reference Example 9 72. Omg
  • 4-cyclobenzoyl chloride 90.3 mg
  • hydrogenated sodium the desired product (116 mg) was obtained in the same manner as in Example 1 using the compound (20.6 mg).
  • Example 2 The same procedure as in Example 1 was carried out using the compound of Reference Example 8 (200.Omg), 412 benzoyl chloride (312 mg) and 60% sodium hydride (50.Omg), and the target compound was obtained. (206 mg) was obtained.
  • Example 2 The same operation as in Example 1 was performed using the compound of Reference Example 8 (100.Omg), 2,4-diclo-benzobenzoyl chloride (176 mg) and 60% sodium hydride (25.Omg). (133 mg).
  • Example 2 The same operation as in Example 1 was carried out by using the compound of Reference Example 8 (100. Omg), 4-methoxybenzoyl chloride (13 mg) and 60% sodium hydride (25. Omg). (70. Omg).
  • Example 8 Using the compound of Reference Example 8 (100. Omg), 4-ethylbenzoyl chloride (142 mg) and 60% sodium hydride (25. Omg), the same operation as in Example 1 was carried out to obtain the desired compound (1 32 mg).
  • Example 2 The same procedure as in Example 1 was carried out using the compound of Reference Example 8 (100.Omg), 5-promo-2-benzobenzoyl chloride (533mg) and 60% sodium hydride (25.Omg) to obtain the target compound. (18 Omg).
  • Example 8 Performed using the compound of Reference Example 8 (80.Omg), 4-methylthiobenzoyl chloride (127 mg) obtained from 4-methylthiobenzoic acid and thionyl chloride and 60% sodium hydride (20.Omg). The same operation as in Example 1 was performed to obtain the desired product (129 mg).
  • Example 2 The same operation as in Example 1 was carried out using the compound of Reference Example 8 (100. Omg), 2,4,6-triclomethylbenzoyl chloride (205 mg) and 60% sodium hydride (25.Omg). The desired product (101 mg) was obtained.
  • Example 2 The same operation as in Example 1 was performed using 60% sodium hydride (20. Omg) to obtain the desired product (52 mg).
  • Example 1 was repeated using the compound of Reference Example 8 ( ⁇ 20.Omg), cyclohexylcarbonyl chloride (148 mg) and 60% sodium hydride (30.Omg). The same operation was performed to obtain the desired product (109 mg).
  • Example 2 The same operation as in Example 1 was carried out using the compound of Reference Example 8 (100.Omg), 3,5-dicyclopentabenzoyl chloride (176 mg) and 60% sodium hydrogen hydride (25.Omg). The desired product (118 mg) was obtained.
  • Example 2 The same operation as in Example 1 was performed using the compound of Reference Example 8 (100 ⁇ Omg), 3,4-diclo-benzobenzoyl chloride (176 mg), and 60% sodium hydride (25.Omg). (161 mg).
  • Example 2 The same operation as in Example 1 was carried out using the compound of Reference Example 8 (100. Omg), 2,6-dichlorobenzobenzoyl chloride (176 mg), and 60% sodium hydride (25. Omg). (172 mg).
  • Reference Example 11 The same operation as in Reference Example 3 was carried out using the compound of Example 11 (14 Omg) and a 1N aqueous solution of potassium hydroxide (828 I) to obtain the desired product (72. Omg).
  • Example 2 The same operation as in Example 1 was carried out using 6 mg) and 60% sodium hydride (71.4 mg) to obtain the desired product (71.4 mg).
  • n-butyl iodide (36.4 mg) was added, and the mixture was stirred at 178 ° C for 2 hours.
  • the reaction solution was poured into a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate.
  • the ethyl persulfate layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, passed through, and crimped.
  • the obtained residual brew was subjected to preparative thin-layer silica gel chromatography, and the desired product (40.5 mg) was obtained using ethyl eluate-n-hexane (1: 4) as a developing solvent.
  • Reference example 1 5 2-n-butyl-5-methanesulfonylindole
  • Example 2 The same operation as in Example 1 was performed using 6.7 mg) and 60% sodium hydride (3.8 mg) to obtain the desired product (18.8 mg).
  • Example 18 The same operation as in Example 1 was carried out using the compound of Example 8 (10 Omg), benzoyl chloride (99.1 mg) and 60% sodium hydride (22.6 mg). (126 mg) was obtained.
  • Example 21 The same procedure as in Example 1 was carried out using the compound O 0 Omg of 1), benzoyl chloride (94.Omg) and 60% sodium hydride (21.5 mg). (11 Omg) was obtained.
  • Example 2 The same procedure as in Example 1 was carried out using the compound of Reference Example 24 (33.Omg), 4-benzobenzoyl chloride (34.7 mg) and 60% sodium hydride (7.9 mg), and the target compound was obtained. (42.2 mg) was obtained.
  • Reference Example 10 Compound (30 Omg), Aryl Oxide (183 mg), n-Butyl Lithium (1.56 M, n-Hexane Solution, 949 ⁇ I), Hexamethyldiacid The same operation as in Reference Example 13 was carried out using liamide (355 mg) to obtain the desired product (2 17 mg).
  • Example 2 The same operation as in Example 1 was carried out using the compound of Reference Example 32 (108 mg), 4-chlorobenzoyl chloride (82 tI), and 60% sodium hydride (21 mg) to obtain the target compound ( 1 45 mg).
  • Example 2 The same operation as in Example 1 was carried out using the compound of Reference Example 37 (11 Omg), benzoyl chloride (80 ⁇ I) and 60% sodium hydride (2 Omg), and the target compound (1 17 mg).
  • N-Butyllithium (1.56 M, hexane solution, 76 1 ⁇ I) was added dropwise to a solution of diisopropylamine (132 mg) in tetrahydrofuran (0.75 mI) at 0, and the solution was distorted.
  • a tetrahydrofuran solution (1.25 ml) of 1-benzenesulfonylmethylthioindole (30 Omg) was added dropwise, and the reaction solution was stirred for 30 minutes. Further, the reaction solution was cooled to 178, cyclohexanone (117 mg) was added, the temperature was gradually raised to room temperature while stirring, and the mixture was further stirred for 3 hours.
  • the reaction solution was poured into a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, concentrated and concentrated.
  • the obtained residue was recrystallized from chloroform-hexane to give the target compound as a colorless needle (268 mg, 68%).
  • the desired product (2.4 g, 50%) as a white powder was obtained in the same manner as in Example 1 using acetone (767 mg).
  • Human COX-2 cDNA was recloned from the LPS-stimulated human monocyte cDNA library (CL ONET ECH) by plaque hybridization (p I aquehybridization), and pCOS-1 Into pCOS—hCOX-2.
  • pCOs—hCOX-2 was transfected into CHO cells by electroporation to obtain a COX-2 expression clone 2A12.
  • COX-2 expression clone 2 A12 was plated on a 96-well plate with 300 OZwe II, and after culturing for 48 hours, weII was washed with Hanks solution, and each compound dissolved in Hanks solution was added. And incubated at 37 eC for 30 minutes. The arachidonic acid solution was added to a final concentration of 10 M, and the mixture was further cultured for 30 minutes, and the amount of PGE 2 in the culture supernatant was measured using a PGE 2 ElA kit (CAYMAN). COX-2 activity (%) is measured by measuring the amount of PGE 2 in each we II, with the amount of PGE 2 produced in we II to which Hanks solution was added as 100%, and the IC50 value of each compound. Was calculated. Table 4 shows the results. Table 4 Compound No. C 50 value (M) Example 2 4.0X 10 "7
  • the compound of the present invention has a CO X-2 inhibitory activity and the like, and is useful as a drug such as an anti-inflammatory drug.

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Abstract

Composés représentés par la formule générale (1) ou leurs hydrates, présentant un effet inhibiteur de COX-2 et utiles en tant que médicaments tel qu'un agent antiinflammatoire, formule dans laquelle R1 représente alkyle C¿1-7? linéaire ou ramifié, etc., R?2¿ représente méthanesulfonyle, etc.; R3 représente phényle facultivement substitué, etc.
PCT/JP1997/000366 1996-02-13 1997-02-13 Derives d'indole WO1997030030A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1086950A4 (fr) * 1998-05-26 2002-11-06 Chugai Pharmaceutical Co Ltd Derives d'indole heterocycliques et derives de mono ou de di-azaindole
EP1442016A1 (fr) * 2001-10-10 2004-08-04 Cheil Jedang Corporation Derives 1h-indole servant d'inhibiteur hautement selectif de la cyclooxygenase-2
US6960611B2 (en) 2002-09-16 2005-11-01 Institute Of Materia Medica Sulfonyl-containing 2,3-diarylindole compounds, methods for making same, and methods of use thereof
WO2022120353A1 (fr) * 2020-12-02 2022-06-09 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
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
US11760728B2 (en) 2019-05-31 2023-09-19 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US11925651B2 (en) 2019-05-31 2024-03-12 Ikena Oncology, Inc. TEAD inhibitors and uses thereof

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JPS60209564A (ja) * 1984-03-19 1985-10-22 フアイザー・インコーポレーテツド 鎮痛性抗炎症剤として有効な、２‐オキシインドール‐１‐カルボキサミド化合物
JPH072770A (ja) * 1993-05-12 1995-01-06 Adir 新規な置換インドール類、その製造法及びそのインドール類を含有する製剤組成物
JPH07215966A (ja) * 1991-09-30 1995-08-15 Merck Frosst Canada Inc ロイコトリエン生合成の阻害物質としての（ビシクリック−ヘテロ−アリールメトキシ）インドール
JPH07224063A (ja) * 1991-09-30 1995-08-22 Merck Frosst Canada Inc ロイコトリエン生合成の阻害物質としての（ヘテロ−アリールメトキシ）インドール

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JPS60209564A (ja) * 1984-03-19 1985-10-22 フアイザー・インコーポレーテツド 鎮痛性抗炎症剤として有効な、２‐オキシインドール‐１‐カルボキサミド化合物
JPH07215966A (ja) * 1991-09-30 1995-08-15 Merck Frosst Canada Inc ロイコトリエン生合成の阻害物質としての（ビシクリック−ヘテロ−アリールメトキシ）インドール
JPH07224063A (ja) * 1991-09-30 1995-08-22 Merck Frosst Canada Inc ロイコトリエン生合成の阻害物質としての（ヘテロ−アリールメトキシ）インドール
JPH072770A (ja) * 1993-05-12 1995-01-06 Adir 新規な置換インドール類、その製造法及びそのインドール類を含有する製剤組成物

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1086950A4 (fr) * 1998-05-26 2002-11-06 Chugai Pharmaceutical Co Ltd Derives d'indole heterocycliques et derives de mono ou de di-azaindole
US6673797B1 (en) 1998-05-26 2004-01-06 Chugai Seiyaku Kabushiki Kaisha Heterocyclic indole derivatives and mono- or diazaindole derivatives
US6875770B2 (en) 1998-05-26 2005-04-05 Chugai Seiyaku Kabushiki Kaisha Indole derivative having heterocycle and mono- or diazaindole derivative
US7612070B2 (en) 1998-05-26 2009-11-03 Chugai Seiyaku Kabushiki Kaisha Indole derivative having heterocycle and mono- or diazaindole derivative
JP4549534B2 (ja) * 1998-05-26 2010-09-22 中外製薬株式会社 複素環を有するインドール誘導体及びモノ又はジアザインドール誘導体
EP1442016A1 (fr) * 2001-10-10 2004-08-04 Cheil Jedang Corporation Derives 1h-indole servant d'inhibiteur hautement selectif de la cyclooxygenase-2
EP1442016A4 (fr) * 2001-10-10 2005-05-25 Cheil Jedang Corp Derives 1h-indole servant d'inhibiteur hautement selectif de la cyclooxygenase-2
US6960611B2 (en) 2002-09-16 2005-11-01 Institute Of Materia Medica Sulfonyl-containing 2,3-diarylindole compounds, methods for making same, and methods of use thereof
US11760728B2 (en) 2019-05-31 2023-09-19 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US11925651B2 (en) 2019-05-31 2024-03-12 Ikena Oncology, Inc. TEAD inhibitors and uses thereof
WO2022120353A1 (fr) * 2020-12-02 2022-06-09 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
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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