WO2011081173A1 - Composé tétracyclique - Google Patents

Composé tétracyclique Download PDF

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WO2011081173A1
WO2011081173A1 PCT/JP2010/073681 JP2010073681W WO2011081173A1 WO 2011081173 A1 WO2011081173 A1 WO 2011081173A1 JP 2010073681 W JP2010073681 W JP 2010073681W WO 2011081173 A1 WO2011081173 A1 WO 2011081173A1
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compound
mmol
lower alkyl
substituent
esi
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賢司 内田
公宏 江良
宜資 中里
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協和発酵キリン株式会社
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    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom

Definitions

  • the present invention relates to a tetracyclic compound having a regulatory action on a glucocorticoid receptor or a pharmaceutically acceptable salt thereof.
  • the glucocorticoid receptor belonging to the nuclear receptor family is a ligand-dependent transcription factor that is activated or inactivated in response to binding of a ligand such as endogenous cortisol.
  • the glucocorticoid receptor is usually present in the cytoplasm in a form bound to heat shock protein 90 (Hsp90). However, when the ligand is bound, it dissociates from Hsp90 and moves into the nucleus. After translocation into the nucleus, it forms a complex with a coupling factor that mediates gene expression, and regulates gene expression by binding to a glucocorticoid response site (GRE) on the chromosome.
  • GRE glucocorticoid response site
  • Such regulation of gene expression is involved in various physiological functions such as amino acid metabolism, lipid metabolism, bone / calcium metabolism, water / electrolyte metabolism, gluconeogenesis, anti-inflammatory, immunosuppressive, and central nervous system activation.
  • immunosuppressive action / anti-inflammatory action by the glucocorticoid receptor ligand is widely used for the treatment of acute and chronic diseases.
  • the strong anti-inflammatory effect of glucocorticoids has been shown to be useful in the treatment of many inflammatory diseases.
  • glucocorticoids have high blood sugar, hypertension, hyperlipidemia, osteoporosis, adrenal atrophy, glaucoma, cataract, muscle weakness, infectivity, full moon-like facial appearance, skin atrophy, pigmentation, hyperplasia, insomnia, menstrual abnormalities, etc.
  • the amount used may be limited due to side effects, which is a problem in clinical application.
  • glucocorticoid receptors include reversible obstructive airway disease, chronic obstructive pulmonary disease (COPD), chronic bronchial asthma, intrinsic asthma, extrinsic asthma, dusty asthma, delayed asthma and airway hyperresponsiveness , Bronchitis, interstitial pneumonia, idiopathic interstitial pneumonia, pulmonary edema, toxic pulmonary edema, restrictive lung disease, allergic alveolitis, pulmonary fibrosis, emphysema, adult respiratory distress syndrome (ARDS), rheumatism Disease, reactive arthritis, inflammatory soft tissue disease, osteoarthritis, collagen disease, systemic lupus erythematosus, systemic sclerosis, dermatomyositis, polymyositis, nodular polyarteritis, mixed connective tissue disease, Sjogren's syndrome , Microscopic polyangiitis, Wegener granulomatosis, allergic granulomatous vasculitis, hypersensitivity
  • glucocorticoid receptor modulators having a tricyclic structure (Patent Documents 1 to 5) are known.
  • An object of the present invention is to provide a tetracyclic compound having a regulating action on a glucocorticoid receptor or a pharmaceutically acceptable salt thereof.
  • the present invention relates to the following (1) to (11).
  • Q is -O- or -NR 6- (wherein R 6 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkoxycarbonyl Or a lower alkanoyl optionally having a substituent)
  • X is CR 0 [wherein R 0 may have a hydrogen atom, hydroxy, amino, formyl, cyano, carboxy, halogen, nitro, optionally substituted lower alkyl, optionally substituted] Lower alkoxycarbonyl, optionally substituted lower alkoxy, or —C ( ⁇ O) NR 20 R 21 (wherein R 20 and R 21 are the same or different and represent a hydrogen atom or a substituent.
  • R 2 and R 3 may be the same or different and each may have a hydrogen atom, hydroxy, amino, formyl, cyano, carboxy, halogen, nitro, optionally substituted lower alkyl, or optionally substituted.
  • Lower alkoxycarbonyl, optionally substituted lower alkoxy, or -C ( O) NR 30 R 31 (wherein R 30 and R 31 are the same or different and represent a hydrogen atom or a substituent.
  • R 11 and R 12 are the same or different and each represents a hydrogen atom or optionally substituted lower alkyl, or R 11 and R 12 are Represents a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom)], substituted lower alkyl, optionally substituted aryl, substituent
  • An aromatic heterocyclic group that may have, an aliphatic heterocyclic group that may have a substituent, or a bicyclic group that may have a substituent
  • NR 40 R 41 wherein R 40 and R 41 are the same or different and each represents a hydrogen atom or an optionally substituted aromatic heterocyclic group), (a-2)
  • R 1 is lower alkyl, lower alkyl substituted with —C
  • R 1 is lower alkyl
  • R 4 and R 5 are the same or different and may be substituted lower alkyl
  • R 44 represents lower alkyl, R 45 represents halogen
  • R 44 and R 45 are as defined above, (a-3-3)
  • R 1 is lower alkyl
  • NR 42b R 43b (wherein R 42b and R 43b are the same or different Represents an aromatic heterocyclic group substituted with a hydrogen atom or lower alkoxycarbonyl, or R 42b and R 43b together with the adjacent nitrogen atom may have a substituent.
  • R 1 is 4-fluorophenyl
  • Q is —NR 6 — (wherein R 6 is as defined above).
  • Q is —O—.
  • a therapeutic and / or prophylactic agent for a disease involving a glucocorticoid receptor comprising the tetracyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (6) as an active ingredient .
  • Treatment of a disease involving a glucocorticoid receptor comprising the step of administering an effective amount of the tetracyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (6) and / or Or prevention methods.
  • the tetracyclic compound or the pharmaceutically acceptable salt according to any one of (1) to (6) for use in the treatment and / or prevention of a disease involving a glucocorticoid receptor.
  • Use of the tetracyclic compound or the pharmaceutically acceptable salt according to any one of (1) to (6) for the manufacture of a therapeutic and / or prophylactic agent for a disease involving a glucocorticoid receptor .
  • a disease for example, inflammatory disease, chronic bronchial asthma, rheumatic disease, collagen disease, systemic lupus erythematosus, etc.
  • a disease for example, inflammatory disease, chronic bronchial asthma, rheumatic disease, collagen disease, systemic lupus erythematosus, etc.
  • a regulating action on the glucocorticoid receptor and the like and involving the glucocorticoid receptor And the like are useful tetracyclic compounds or pharmaceutically acceptable salts thereof.
  • each group of formula (I) (i) Examples of the lower alkyl in lower alkyl and lower alkoxy, lower alkanoyl, and lower alkoxycarbonyl include linear or branched alkyl having 1 to 10 carbon atoms.
  • aryl examples include aryl having 6 to 14 carbon atoms. Specific examples include phenyl, naphthyl, azulenyl, anthryl and the like.
  • aliphatic heterocyclic group for example, a 5-membered or 6-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom
  • examples include condensed bicyclic or tricyclic condensed ring aliphatic heterocyclic groups containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically, aziridinyl and azetidinyl.
  • Examples of the aromatic heterocyclic group include a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, Examples thereof include fused or aromatic tricyclic groups containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically furyl and thienyl.
  • the nitrogen-containing heterocyclic group formed together with the adjacent nitrogen atom for example, a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group)
  • the ring group may contain other nitrogen, oxygen or sulfur atoms), a bicyclic or tricyclic condensed 3- to 8-membered ring and containing at least one nitrogen atom.
  • Ring group (the condensed ring heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and more specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, azepanyl, pyrrolyl.
  • Imidazolidinyl imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, homopiperazinyl, oxazolidinyl, 2H-oxazolyl, thioxazolidinyl, 2H-thioxazolyl, morpholino, thiomo Ruphorinyl, dihydroindolyl, dihydroisoindolyl, indolyl, isoindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, benzoimidazolidinyl, benzoimidazolyl, dihydroindazolyl, indazolyl Benzotriazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl,
  • Examples of the bicyclic group include a 3- to 8-membered monocyclic aliphatic heterocyclic ring containing at least one atom selected from a benzene ring, nitrogen atom, oxygen atom and sulfur atom, nitrogen atom, oxygen
  • Examples include groups in which two or more rings selected from a 3 to 8 membered monocyclic aromatic heterocyclic ring containing at least one atom selected from an atom and a sulfur atom, and a cycloalkyl having 3 to 8 carbon atoms are ortho-fused More specifically, naphthyl, azulenyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, benzimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, benzodioxolyl, tetrahydro Quinolyl, tetrahydroisoquinolyl, dihydro-2H-chroman
  • Halogen means each atom of fluorine, chlorine, bromine and iodine.
  • substituents in lower alkyl optionally having substituents, lower alkoxy optionally having substituents, and lower alkoxycarbonyl optionally having substituents may be the same or different.
  • halogen having 1 to 3 substituents, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, C 3-8 cycloalkyl, C 6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group, C 1- 10 alkoxy, C 3-8 cycloalkoxy, C 6-14 aryloxy, C 7-16 aralkyloxy, C 2-11 alkanoyloxy, C 7-15 aroyloxy, C 1-10 alkylsulfanyl, -NR X R Y ( In the formula, R X and R Y are the same or different and are a hydrogen atom, C 1-10 alkyl, C 3-8 cycloalkyl, C 6-14 aryl, an aromatic heterocyclic group, C 7-16 aralkyl, C 2-11 alkanoyl, C 7-15 aroyl, C 1-10 A Job aryloxycarbonyl or an C 7-16 aralkyloxycarbonyl such
  • aryl which may have a substituent, aromatic heterocyclic group which may have a substituent, phenyl which has a substituent at the 3-position, and bicyclic which may have a substituent
  • the substituents in the functional group are the same or different, for example, 1 to 3 substituents having 1 to 3 substituents selected from halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl and substituent A are substituted.
  • the substituent A represents C 1-10 alkoxy, hydroxy and amino
  • the substituent B represents C 1-10 alkyl and oxo
  • the substituent C represents C 1-10 alkyl and hydroxy.
  • Examples of the substituent in the nitrogen-containing heterocyclic group which may be substituted are the same or different, for example, oxo, halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, C 1-10 alkyl, trialkyl having 1 to 3 substituents.
  • C 1-10 alkyl as shown here, C 1-10 alkoxy, C 2-11 alkanoyloxy, C 1-10 alkylsulfanyl, C 2-11 alkanoyl, C 1-10 alkoxycarbonyl, C 1-10 alkylsulfonyl, the C 1-10 alkyl moiety of the C 1-10 alkylcarbamoyl, and di-C 1-10 alkylcarbamoyl, for example, the groups listed illustrative of the lower alkyl are exemplified.
  • the two C 1-10 alkyls in the diC 1-10 alkylcarbamoyl may be the same or different.
  • C 3-8 The cycloalkyl moiety of the cycloalkyl and C 3-8 cycloalkoxy, e.g. cyclic alkyl such as having 3 to 8 carbon atoms can be mentioned. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Examples of the aryl moiety of C 6-14 aryl and C 6-14 aryloxy, C 7-15 aroyl, C 7-15 aroyloxy and C 6-14 aryloxycarbonyl include the groups exemplified in the above aryl examples.
  • the aryl moiety of C 6-14 aryl and C 6-14 aryloxy, C 7-15 aroyl, C 7-15 aroyloxy and C 6-14 aryloxycarbonyl include the groups exemplified in the above aryl examples.
  • Examples of the aryl moiety of C 7-16 aralkyloxy, C 7-16 aralkyl and C 7-16 aralkyloxycarbonyl include the groups exemplified in the above aryl examples.
  • Examples of the alkyl moiety include C 1-10 Examples thereof include alkylene, and more specifically, a group in which one hydrogen atom has been removed from the groups exemplified as the lower alkyl.
  • Examples of the aliphatic heterocyclic group and the aliphatic heterocyclic group portion of the aliphatic heterocyclic carbonyl include the groups exemplified in the above-mentioned aliphatic heterocyclic group.
  • Examples of the aromatic heterocyclic group and the halogen include the groups exemplified in the aromatic heterocyclic group and the halogen, respectively.
  • Examples of the pharmaceutically acceptable salt of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
  • Examples of the pharmaceutically acceptable acid addition salt of compound (I) include inorganic acid salts such as hydrochloride, sulfate, and phosphate, acetate, maleate, fumarate, tartrate, and citrate.
  • organic acid salts such as methanesulfonate, and pharmaceutically acceptable metal salts include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt,
  • pharmaceutically acceptable ammonium salt include salts such as ammonium and tetramethylammonium.
  • examples of the pharmaceutically acceptable organic amine addition salt include morpholine.
  • addition salts such as piperidine, and pharmaceutically acceptable amino acid addition salts include, for example, addition salts such as lysine, glycine, and phenylalanine.
  • Examples of diseases involving glucocorticoid receptors include inflammatory diseases, chronic bronchial asthma, rheumatic diseases, collagen diseases, systemic lupus erythematosus and the like.
  • a method for producing compound (I) will be described.
  • introduction of a protective group commonly used in organic synthetic chemistry and Removal methods e.g., Protective Groups in Organic Synthesis, forth edition, written by TW Greene, John Wiley & Sons Inc. (1999), etc.
  • the method can be used to produce the target compound. Further, the order of reaction steps such as introduction of substituents can be changed as necessary.
  • Production method 1 Among the compounds (I), the compound (IA) in which R 5 is lower alkyl optionally having substituent (s) or aryl optionally having substituent (s) should be produced, for example, according to the following steps. Can do.
  • R 5 ′ is a lower alkyl which may have a substituent in the definition of R 5 , Or aryl optionally having a substituent
  • M represents a tin atom, a boron atom, or a silicon atom
  • Ph represents phenyl
  • R A represents a fluorine atom, a chlorine atom, a bromine atom, an iodine atom
  • p represents an integer of 0 to 3
  • Y 1 represents a chlorine atom, a bromine atom or an iodine atom
  • Y 2 represents Represents a chlorine atom, a bromine atom, or an iodine atom
  • Process 1 Compound (I-A ′′) is obtained by mixing 1 to 30 equivalents of the Wittig reagent represented by formula
  • solvent examples include methanol, ethanol, dichloromethane, acetonitrile, toluene, ethyl acetate, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N -Methylpyrrolidone (NMP), water etc. are mentioned, These can be used individually or in mixture.
  • Examples of the base include n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, sodium hydride, potassium hydride, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, pyridine, triethylamine, Examples thereof include dimethylaminopyridine, N-methylmorpholine, 1,8-diazabicyclo- [5.4.0] -undec-7-ene (DBU), N, N-diisopropylethylamine, and these are used alone or in combination. be able to.
  • DBU 1,8-diazabicyclo- [5.4.0] -undec-7-ene
  • Compound (II ′) is prepared according to the method described in Reference Examples or a known method [for example, Chemical & Pharmaceutical Bulletin, Vol. 39, p. 2429 (1991)]. Obtainable. Compound (III) can be obtained as a commercially available product or according to a known method [for example, Fourth Edition Experimental Chemistry Course 24, p.252, Maruzen (2000)].
  • Process 2 Compound (I-A ′) is obtained by reacting Compound (I-A ′′) with 1 to 5 equivalents of a halogenating reagent in a solvent at a temperature between ⁇ 50 ° C. and 200 ° C. for 5 minutes to 100 hours. Can be manufactured. At this time, 0.01 to 30 equivalents of an additive can be added to promote the reaction.
  • Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, acetic acid, trifluoroacetic acid and the like, and these are used alone or in combination. be able to.
  • Examples of the halogenating reagent include chlorine, hydrogen chloride gas, concentrated hydrochloric acid, hydrobromic acid, tetra-n-butylammonium tribromide, bromine, iodine, N-chlorosuccinimide (NCS), N-bromide.
  • Compound (IA) comprises compound (I-A ′) and 1 to 30 equivalents of compound (VII) in the presence of 0.001 to 1 equivalent of a transition metal catalyst in a solvent at a temperature between ⁇ 50 ° C. and 200 ° C. It can be produced by reacting for 5 minutes to 100 hours. At this time, 0.01 to 30 equivalents of an appropriate additive can be added to promote the reaction.
  • Examples of the solvent include methanol, ethanol, dichloromethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, NMP, water and the like, and these can be used alone or in combination.
  • Examples of the transition metal catalyst include palladium acetate, tetrakis (triphenylphosphine) palladium, palladium chloride, palladium bromide, bis (triphenylphosphine) palladium chloride, dichlorobis (acetonitrile) palladium, and [1,1′-bis (diphenylphosphine).
  • Examples of the additive include triphenylphosphine, tri (o-tolyl) phosphine, 1,1′-bis (diphenylphosphino) ferrocene, 1,2-bis (diphenylphosphino) propane, 2,2′-bis ( Diphenylphosphino) -1,1'-binaphthyl, 1,2-bis (diphenylphosphino) ethane, silver oxide, copper iodide, lithium chloride, cesium fluoride, triethylamine, diethylamine, sodium hydroxide, potassium hydroxide, Examples thereof include sodium carbonate and tripotassium phosphate, and these can be used alone or in combination.
  • Compound (VII) can be obtained as a commercially available product or according to a known method [for example, 5th edition, Experimental Chemistry Course 18, Synthesis of Organic Compounds VI Organic Synthesis Using Metals, p.97, Maruzen (2005)]. Can do. Production method 2 Of compound (I), compound (IA) wherein R 5 is optionally substituted lower alkyl or optionally substituted aryl is produced according to the following steps, for example. You can also.
  • R 1 , R 2 , R 3 , R 4 , R 5 ′ , Q, X, M, R A and p are as defined above, and X 10 is a chlorine atom, a bromine atom, iodine Represents an atom, methanesulfonyloxy, or p-toluenesulfonyloxy, Y A and Y C each represent a chlorine atom, a bromine atom, or an iodine atom, and Y B represents a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, Or represents hydroxy and Y B ′ represents —NHR 6 (wherein R 6 has the same meaning as defined above) Process 1 Compound (II '') can be obtained according to a known method [eg, Org. Synth., Coll. Vol., 5, 450 (1973), or Synth. Commun., 27, 1199 (1997)]. it
  • Compound (IV) is a compound of compound (II '') and compound (III '), which is a Sonogashira reaction (for example, 5th edition, Experimental Chemistry Course 13, Synthesis of Organic Compounds I Hydrocarbons / halides, p.298, Maruzen ( 2005)].
  • Compound (III ′) is obtained as a commercially available product or according to a known method [eg, 5th edition, Experimental Chemistry Lecture 13, Synthesis of Organic Compounds I Hydrocarbons / halides, p.283, Maruzen (2005)]. be able to.
  • Compound (IV) is obtained as a commercially available product or according to a known method [for example, 5th edition, Experimental Chemistry Lecture 13, Synthesis of Organic Compounds I Hydrocarbons / halides, p.341, Maruzen (2005)]. Can do.
  • a compound in which Q is —NR 6 — (wherein R 6 has the same meaning as described above) is obtained by converting compound (IV) into compound (IV-a) once, It can be produced by acting (V ′).
  • Compound (IV-a) is obtained by mixing 1 to 30 equivalents of a halogenating agent, methanesulfonylating agent, or p-toluenesulfonylating agent with Compound (IV) in a solvent at a temperature between 0 ° C. and 200 ° C. It can be produced by reacting for 5 minutes to 100 hours. At this time, 0.01 to 30 equivalents of an appropriate additive can be added to promote the reaction.
  • Examples of the solvent include dichloromethane, dichloroethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, NMP and the like, and these can be used alone or in combination.
  • Examples of the halogenating agent include chlorine, bromine, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, phosphorus oxybromide, methanesulfonyl chloride, p-toluenesulfonyl chloride, thionyl chloride.
  • Examples of the methanesulfonylating agent include methanesulfonyl chloride, methanesulfonic anhydride and the like, and these can be used alone or in combination.
  • Examples of the p-toluenesulfonylating agent include p-toluenesulfonyl chloride, p-toluenesulfonic anhydride and the like, and these can be used alone or in combination.
  • Examples of the additive include lithium chloride, lithium bromide, sodium chloride, sodium bromide, potassium chloride, potassium bromide, sodium iodide, potassium iodide and other metal halides, triethylamine, diisopropylethylamine, DBU, 1, And amines such as 8-diazabicyclo [4.3.0] -5-nonene (DBN).
  • Process 2B Compound (VI) is obtained by adding 1-30 equivalents of Compound (V ′) to Compound (IV-a) in the presence of 1-30 equivalents of a base in a solvent at a temperature between 0 ° C. and 200 ° C. It can be produced by reacting for 5 minutes to 100 hours.
  • Examples of the solvent include dichloromethane, dichloroethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, NMP, water and the like, and these can be used alone or in combination.
  • Examples of the base include metal hydrides such as sodium hydride and potassium hydride, metal alkoxides such as potassium tert-butoxide, amines such as triethylamine, diisopropylethylamine, DBU and DBN.
  • Compound (IA) comprises 1 to 30 equivalents of compound (VI) and 1 to 30 equivalents of compound (VII) in the presence of 0.001 to 1 equivalent of a transition metal catalyst at a temperature between ⁇ 50 ° C. and 200 ° C. for 5 minutes. For 100 hours. At this time, 0.01 to 30 equivalents of an appropriate additive can be added to promote the reaction.
  • Examples of the solvent include methanol, ethanol, dichloromethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, NMP, water and the like, and these can be used alone or in combination.
  • Examples of the transition metal catalyst include palladium acetate, tetrakis (triphenylphosphine) palladium, palladium chloride, palladium bromide, bis (triphenylphosphine) palladium chloride, dichlorobis (acetonitrile) palladium, and [1,1′-bis (diphenylphosphine).
  • Examples of the additive include triphenylphosphine, tri (o-tolyl) phosphine, 1,1′-bis (diphenylphosphino) ferrocene, 1,2-bis (diphenylphosphino) propane, 2,2′-bis ( Diphenylphosphino) -1,1'-binaphthyl, 1,2-bis (diphenylphosphino) ethane, silver oxide, copper iodide, lithium chloride, cesium fluoride, triethylamine, diethylamine, sodium hydroxide, potassium hydroxide, Examples thereof include sodium carbonate and tripotassium phosphate, and these can be used alone or in combination.
  • Compound (VII) is obtained as a commercial product or according to a known method [for example, 5th edition, Experimental Chemistry Course 18, Synthesis of Organic Compounds VI Organic Synthesis Using Metals], p.97, Maruzen (2005)] be able to.
  • Production method 3 Among the compounds (I), a compound (I-Ac) in which R 4 is optionally substituted lower alkyl or optionally substituted aryl is prepared according to the following steps, for example. You can also
  • Compound (XII) can be obtained as a commercial product or according to a known method [for example, 5th edition, Experimental Chemistry Course 13, Synthesis of Organic Compounds I Hydrocarbons / halides, p.341, Maruzen (2005)]. Can do.
  • Compound (XVIII) can be obtained as a commercial product or according to a known method [for example, 5th edition, Experimental Chemistry Course 13, Synthesis of Organic Compounds I Hydrocarbons / halides, p.283, Maruzen (2005)].
  • Process 2 Compound (XX) can be produced from compound (XIX) and compound (IX) in the same manner as in step 2 of production method 2, or step 2A and step 2B.
  • Compound (IX) can be obtained according to a known method [for example, Org. Synth., Coll. Vol., 5, 450 (1973), Synth. Commun., 27, 1199 (1997), etc.].
  • Process 3 Compound (I-Ac) can be produced from compound (XX) and compound (XXI) by the same method as in Step 3 of Production Method 2.
  • Compound (XXI) can be obtained as a commercial product or according to a known method [for example, 5th edition, Experimental Chemistry Course 18, Synthesis of Organic Compounds VI Organic Synthesis Using Metals, p.97, Maruzen (2005)]. Can do. Production method 4 Among the compounds (I), R 5 is an optionally substituted alkyl or an optionally substituted aryl (I-Ae), for example, according to the following steps: It can also be manufactured.
  • Y 10 represents a chlorine atom, a bromine atom or an iodine atom
  • R 5 ′ In the definition of R 5 , ' represents an optionally substituted lower alkyl or an optionally substituted aryl, Me represents methyl
  • Process 1 Compound (XXV) is prepared by mixing 1 to 30 equivalents of bis (pinacolato) diboron with Compound (VI) in the presence of 0.001 to 1 equivalent of a transition metal catalyst at a temperature between ⁇ 50 ° C. and 200 ° C. It can be produced by reacting for from 100 minutes to 100 minutes.
  • Examples of the solvent include methanol, ethanol, dichloromethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, NMP, water and the like, and these can be used alone or in combination.
  • Examples of the transition metal catalyst include platinum catalysts such as tetrakis (triphenylphosphine) platinum, bis (1,5-cyclooctadiene) platinum, and (1,5-cyclooctadiene) platinum.
  • Compound (VI) can be produced by the same method as in step 2, step 2A or step 2B of production method 2.
  • Production method 5 Among the compounds (I), R 5 is -C ( O) NR 40 R 41 (wherein R 40 and R 41 are as defined above), It can also be produced according to the process.
  • Process 1 Compound (IB) is compound (VI) and 1 equivalent to a large excess of compound (VIII) in the presence of 0.001 to 1 equivalent of a transition metal catalyst in a carbon monoxide atmosphere, without solvent, or in a solvent, It can be produced by reacting at a temperature between 50 ° C. and 200 ° C. for 5 minutes to 100 hours. At this time, 0.01 to 30 equivalents of an appropriate additive can be added to promote the reaction.
  • Examples of the solvent include dichloromethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, DMSO, NMP and the like, and these can be used alone or in combination.
  • transition metal catalysts include palladium acetate, tetrakis (triphenylphosphine) palladium, palladium chloride, palladium bromide, bis (triphenylphosphine) palladium, dichlorobis (acetonitrile) palladium, [1,1'-bis (diphenylphosphine).
  • Co-ferrocene] palladium catalysts such as palladium (II) dichloride / dichloromethane complexes (1: 1), nickel catalysts such as nickel chloride, nickel acetylacetonate, bis (1,5-cyclooctadiene) nickel, nickel bromide, etc. Is mentioned.
  • additives include triphenylphosphine, tri (o-tolyl) phosphine, 1,1'-bis (diphenylphosphino) ferrocene, 1,2-bis (diphenylphosphino) propane, 2,2'-bis ( Diphenylphosphino) -1,1'-binaphthyl, 1,2-bis (diphenylphosphino) ethane, silver oxide, copper iodide, lithium chloride, cesium fluoride, triethylamine, diethylamine, sodium hydroxide, potassium hydroxide, Examples thereof include sodium carbonate and tripotassium phosphate, and these can be used alone or in combination.
  • Compound (VI) can also be produced according to the following step A, step B, or step C.
  • R 1a ′ represents lower alkyl in the definition of R 1 or lower alkyl substituted with —C ( ⁇ O) R 7 (wherein R 7 is as defined above).
  • Q, X, R 2 , R 3 , R 4 and Y 4 are as defined above, and Y 5 is a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, or trifluoro.
  • Compound (VI-a) is obtained by mixing compound (VI-c) with 1 to 30 equivalents of compound (IX) without solvent or in a solvent in the presence of 1 to 30 equivalents of a base at ⁇ 50 ° C. and 200 ° C. By reacting at a temperature between 5 minutes and 100 hours.
  • Examples of the solvent include toluene, acetonitrile, THF, 1,4-dioxane, DMF, DMA, NMP, water and the like, and these can be used alone or in combination.
  • Examples of the base include sodium hydride, sodium hydroxide, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like, and these can be used alone or in combination.
  • Compound (VI-c) can be obtained in the same manner as in production method 2, step 2 and steps 2A and 2B.
  • Compound (IX) can be obtained, for example, as a commercial product.
  • the compound (VI-b) bonded to the nitrogen atom at the 1-position of the indazole ring can be produced, for example, according to the following steps.
  • R 1b ′ is phenyl having a substituent at the 3-position, 4-fluorophenyl, or a bicyclic group which may have a substituent, and the sp 2 carbon atom is a bond.
  • Q, X, Y C , R 2 , R 3 and R 4 are as defined above, and Y 6 represents a chlorine atom, a bromine atom, an iodine atom, or trifluoromethanesulfonyloxy
  • Compound (VI-b) comprises compound (VI-c) and 1 to 30 equivalents of compound (X) in the presence of 0.001 to 1 equivalents of copper catalyst in a solvent at a temperature between ⁇ 50 ° C. and 200 ° C. It can be produced by reacting for 5 minutes to 100 hours. At this time, 0.01 to 30 equivalents of an appropriate additive can be added to promote the reaction.
  • Examples of the solvent include methanol, ethanol, dichloromethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, NMP, water and the like, and these can be used alone or in combination.
  • Examples of the copper catalyst include copper (0), copper (I) iodide, copper (II) iodide, copper (II) acetate, copper (II) oxide, and copper (I) chloride.
  • additives include ethylenediamine, trans-1,2-cyclohexanediamine, phenanthroline, potassium carbonate, cesium carbonate, lithium chloride, potassium chloride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, potassium acetate, sodium ethoxide.
  • Compound (X) can be obtained, for example, as a commercial product.
  • Compound (VI-c) can be obtained in the same manner as in step 2 of production method 2, or step 2A and step 2B.
  • Compound (VI-b) can also be produced, for example, according to the following steps.
  • Compound (VI-b) comprises compound (VI-c) and 1 to 30 equivalents of compound (XI) in the presence of 0.001 to 1 equivalents of a copper catalyst in a solvent at a temperature between ⁇ 50 ° C. and 200 ° C. It can be produced by reacting for 5 minutes to 100 hours. At this time, 0.01 to 30 equivalents of an appropriate additive can be added to promote the reaction.
  • Examples of the solvent include methanol, ethanol, dichloromethane, dichloroethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, pyridine, DMF, NMP, water, etc., and these can be used alone or in combination.
  • Examples of the copper catalyst include copper (0), copper iodide (I), copper iodide (II), copper acetate (I), copper acetate (II), copper oxide (I), copper oxide (II), chloride Examples thereof include copper (I).
  • additives include ethylenediamine, trans-1,2-cyclohexanediamine, phenanthroline, potassium carbonate, cesium carbonate, lithium chloride, potassium chloride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, potassium acetate, sodium ethoxide.
  • Compound (XI) can be obtained as a commercial product or according to a known method [for example, 5th edition, Experimental Chemistry Course 18, Synthesis of Organic Compounds VI Organic Synthesis Using Metals, p.97, Maruzen (2005)] be able to.
  • Compound (VI-c) can be obtained in the same manner as in step 2 of production method 2, or step 2A and step 2B.
  • Process 2 Compound (I-B ′) is obtained by converting 0.001 to 1 equivalent of a transition metal catalyst from compound (VI) and 1 equivalent to a large excess of compound (VIII ′) in a carbon monoxide atmosphere without a solvent or in a solvent. It can be produced by reacting in the presence at a temperature between ⁇ 50 ° C. and 200 ° C. for 5 minutes to 100 hours. At this time, 0.01 to 30 equivalents of an appropriate additive can be added to promote the reaction.
  • Examples of the solvent include dichloromethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, DMSO, NMP and the like, and these can be used alone or in combination.
  • transition metal catalysts include palladium acetate, tetrakis (triphenylphosphine) palladium, palladium chloride, palladium bromide, bis (triphenylphosphine) palladium, dichlorobis (acetonitrile) palladium, [1,1'-bis (diphenylphosphine).
  • Co-ferrocene] palladium catalysts such as palladium (II) dichloride / dichloromethane complexes (1: 1), nickel catalysts such as nickel chloride, nickel acetylacetonate, bis (1,5-cyclooctadiene) nickel, nickel bromide, etc. Is mentioned.
  • additives include triphenylphosphine, tri (o-tolyl) phosphine, 1,1'-bis (diphenylphosphino) ferrocene, 1,2-bis (diphenylphosphino) propane, 2,2'-bis ( Diphenylphosphino) -1,1'-binaphthyl, 1,2-bis (diphenylphosphino) ethane, silver oxide, copper iodide, lithium chloride, cesium fluoride, triethylamine, diethylamine, sodium hydroxide, potassium hydroxide, Examples thereof include sodium carbonate and tripotassium phosphate, and these can be used alone or in combination.
  • Compound (IB) can be obtained from Compound (I-B ′) by methods for introducing and removing protecting groups commonly used in organic synthetic chemistry (for example, Protective Groups in Organic Synthesis 4th Edition). Synthesis, forth edition), the method described in TW Greene, John Wiley & Sons Inc. (1999), etc.] can be used.
  • the intermediates and target compounds in each of the above production methods are isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to.
  • the intermediate can be subjected to the next reaction without any particular purification.
  • Some compounds (I) may have stereoisomers such as geometric isomers, optical isomers and tautomers, but the present invention includes all possible isomers and Also included are mixtures thereof.
  • a salt of compound (I) When it is desired to obtain a salt of compound (I), it may be purified as it is when compound (I) is obtained in a salt form, and when it is obtained in a free form, compound (I) is used in an appropriate solvent. It may be dissolved or suspended and isolated and purified by adding an acid or a base.
  • Compound (I) and pharmaceutically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also encompassed in the present invention.
  • Test Example 1 Human Glucocorticoid Receptor Assay A measurement kit (Panvera / Invitrogen, product number: P2893) using polarized fluorescence was used in the above assay. Recombinant human glucocorticoid receptor (part number: P2812), Fluoromone TM labeled dexamethasone (GS Green, part number: P2813), stabilized peptide solution (part number: P2815) and basic buffer (part number: P2814) used in this measurement kit All were stored at ⁇ 80 ° C. until use.
  • the assay buffer is 1/10 times the basic buffer, 1/10 times the stabilized peptide solution, and 1 mol / L DTT (dithiothreitol) at a final concentration of 1 mmol / L. It was prepared by adding 1000 times the amount.
  • the assay method was performed as follows. The test compound was diluted with the assay buffer to the desired double concentration, and 16 ⁇ L was added per well. Next, Fluoromone TM -labeled dexamethasone was diluted with an assay buffer to 4 nmol / L, and 8 ⁇ L was added per well. Further, the recombinant human glucocorticoid receptor was diluted with an assay buffer so as to be 16 nmol / L, and 8 ⁇ L was added per well. After stirring, the mixture was incubated for 2 hours or more in the dark and at room temperature. The fluorescence polarization degree of each well was measured using a plate reader (Perkin Elmer, Fusion or Envision).
  • test compounds and dexamethasone were prepared by diluting dimethyl sulfoxide (DMSO) in F-12 medium without bovine serum, so that the final concentration of DMSO was 0.1% v / v or less. . After incubating at 37 ° C.
  • DMSO dimethyl sulfoxide
  • IL-6 produced in the culture supernatant was quantified by ELISA (R & D System, product number DY206, DouSet ELISA Development System Human IL-6), and the production inhibition rate was calculated from the following formula.
  • Test Example 3 Mouse Breast Cancer Virus (MMTV) Luciferase Assay pGL4.14 plasmid containing a fragment of MMTV-LTR (-200 to +100 relative to the transcription start site) cloned on the 5 ′ end side of the luciferase gene ( Promega Corporation, product number AY864928) was introduced into A549 cells, and a cell line (A549 / MMTV-LTR) showing constitutive resistance to the selected antibiotic hygromycin B was prepared and used for evaluation.
  • MMTV Mouse Breast Cancer Virus
  • A549 / MMTV-LTR cells were transferred to a 96-well plate (25000 cells / well) and cultured overnight under F-12 medium containing 10% bovine serum, and the medium used contained bovine serum per well. Not replaced with 80 ⁇ L of F-12 medium. Next, add 20 ⁇ L of the test compound or 5 ⁇ mol / L dexamethasone diluted with F-12 medium without bovine serum to a concentration 5 times higher than the target concentration, and at 37 ° C., 5% CO 2 for 6 hours. Incubated.
  • Luciferase activity was measured using a plate reader (Perkin Elmer, Topcount) after adding 50 ⁇ L of a luminescent reagent (Promega, product number E2550 or E2650) to each well, lysing the cells by stirring.
  • the MMTV activity indicating the transcription promoting activity via the glucocorticoid receptor was calculated by inserting the amount of luminescence by luciferase into the calculation formula shown below.
  • dexamethasone and prednisolone showed MMTV activity of 100% or more and 80% or more at 300 nmol / L, respectively.
  • compounds 47, 49, 81, 94, 95 and 96 showed MMTV activity of 16%, 17%, 12%, 42%, 51% and 51%, respectively, at a drug concentration of 300 nmol / L. From the above results, it was found that compounds 47, 49, 81, 94, 95 and 96 have weaker transcription promoting activity via glucocorticoid receptor than dexamethasone and prednisolone.
  • Compound (I) or a pharmaceutically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals and humans.
  • the pharmaceutical preparation according to the present invention may contain compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredient for treatment.
  • these pharmaceutical preparations are produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient together with one or more pharmaceutically acceptable carriers.
  • the administration route it is desirable to use one that is most effective in the treatment, and examples thereof include oral administration and parenteral administration such as intravenous administration.
  • examples of the dosage form include tablets and injections.
  • tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.
  • an injection suitable for parenteral administration can be produced using a salt solution, a glucose solution, a mixed solution of a salt solution and a glucose solution, or the like.
  • the dose and frequency of administration of compound (I) or a pharmaceutically acceptable salt thereof vary depending on the administration form, patient age, body weight, nature or severity of symptoms to be treated, etc.
  • 0.01 mg to 1 g, preferably 0.05 to 100 mg per adult is administered once to several times a day.
  • parenteral administration such as intravenous administration
  • 0.001 to 100 mg, preferably 0.01 to 10 mg per adult is administered once to several times a day.
  • the dose and the number of doses vary depending on the various conditions described above.
  • Trimethylsilyl azide (0.038 mL, 0.284 mmol) and boron trifluoride / ethyl ether complex (0.036 mL, 0.284 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature. After completion of the reaction, water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Ammonium chloride (19.5 mg, 0.365 mmol) and reduced iron (40.8 mg, 0.730 mmol) were added to the reaction mixture, and the mixture was further stirred at 90 ° C. for 1 hr. After cooling to room temperature, the reaction mixture was filtered using celite, water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Process 2 5-acetamido-2-iodo-4-methylbenzyl acetate (Compound A2)
  • Compound A1 obtained in step 1 was dissolved in propionitrile (170 mL), acetic anhydride (30 mL) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. Water and diisopropyl ether were added to the reaction solution, and the precipitated crystals were collected by filtration to obtain Compound A2 (14.1 g, yield of two steps: 67%).
  • ESI-MS m / z 348 [M + H] + .
  • Process 6 5- (1-Butynyl) -6- (tert-butyldimethylsilyloxymethyl) -1H-indazole (Compound A6)
  • Compound A5 (1.16 g, 5.79 mmol) obtained in step 5 was dissolved in dichloromethane (30 mL), and imidazole (789 mg, 11.6 mmol) and tert-butylchlorodimethylsilane (1.05 g, 6.95 mmol) were obtained at room temperature. And stirred for 50 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with chloroform.
  • Process 7 1-tert-Butoxycarbonylmethyl-5- (1-butynyl) -6- (tert-butyldimethylsilyloxymethyl) -1H-indazole (Compound A7)
  • Compound A6 (1.35 g, 4.29 mmol) obtained in Step 6 was dissolved in dimethylformamide (20 mL), and 60% sodium hydride (258 mg, 6.44 mmol) and tert-butyl bromoacetate (951 ⁇ L, 6.44 mmol) was added and stirred for 30 minutes.
  • a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate.
  • Process 8 1-tert-Butoxycarbonylmethyl-5- (1-butynyl) -6-hydroxymethyl-1H-indazole (Compound A8)
  • Compound A7 (1.41 g, 3.37 mmol) obtained in step 7 was dissolved in tetrahydrofuran (15 mL), and 1.0 mol / L tetrabutylammonium fluoride / tetrahydrofuran solution (5.05 mg, 5.05 mmol) was added at room temperature. Stir for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate.
  • Step 9 1-tert-Butoxycarbonylmethyl-5- (1-butynyl) -6- (2-iodophenoxy) methyl-1H-indazole (Compound A9)
  • Compound A8 obtained in step 8 (855 mg, 2.72 mmol), 2-iodophenol (778 mg, 3.54 mmol) and triphenylphosphine (1.43 g, 5.44 mmol) were dissolved in toluene (20 mL) and brought to room temperature.
  • 2.2 mol / L diethyl azodicarboxylate / toluene solution (1.85 mL, 4.08 mmol) was added, and the mixture was stirred at 50 ° C. for 20 minutes.
  • a disease for example, inflammatory disease, chronic bronchial asthma, rheumatic disease, collagen disease, systemic lupus erythematosus, etc.
  • a disease for example, inflammatory disease, chronic bronchial asthma, rheumatic disease, collagen disease, systemic lupus erythematosus, etc.
  • a regulating action on the glucocorticoid receptor and the like and involving the glucocorticoid receptor And the like are useful tetracyclic compounds or pharmaceutically acceptable salts thereof.

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Abstract

La présente invention concerne un composé tétracyclique représenté par la formule (I) (dans laquelle Q représente -O- ou équivalent ; X représente CH ou équivalent ; R1 représente un groupe alkyle de faible poids moléculaire ou équivalent ; R2 et R3 représentent indépendamment un atome d'hydrogène ou équivalent ; et R4 et R5 représentent indépendamment un groupe alkyle de faible poids moléculaire qui peut avoir un substituant, ou équivalent) ou un sel pharmaceutiquement acceptable de celui-ci, qui présente une activité de régulation des récepteurs des glucocorticoïdes et équivalent ; et autres.
PCT/JP2010/073681 2009-12-29 2010-12-28 Composé tétracyclique WO2011081173A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014039757A1 (fr) * 2012-09-07 2014-03-13 Abbvie Inc. Modulateurs hétérocycliques de récepteurs hormonaux nucléaires
US9150592B2 (en) 2012-12-21 2015-10-06 Abbvie Inc. Heterocyclic nuclear hormone receptor modulators

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004052847A2 (fr) * 2002-06-26 2004-06-24 Eli Lilly And Company Modulateurs tricycliques du recepteur nucleaire des hormones steroidiennes
WO2005066153A1 (fr) * 2003-12-19 2005-07-21 Eli Lilly And Company Modulateurs du recepteur nucleaire d'hormone steroide tricyclique
WO2005066161A1 (fr) * 2003-12-19 2005-07-21 Eli Lilly And Company Modulateurs tricycliques du recepteur nucleaire de l'hormone steroide
WO2008008882A2 (fr) * 2006-07-14 2008-01-17 Eli Lilly And Company Modulateur du récepteur des glucocorticoïdes et procédés d'utilisation
WO2008021926A2 (fr) * 2006-08-09 2008-02-21 Bristol-Myers Squibb Company Modulateurs du récepteur de glucocorticoïde, de l'activité du ap-1 et/ou du nf-kb et leur utilisation
WO2009089312A1 (fr) * 2008-01-11 2009-07-16 Eli Lilly And Company (e)-n-{3-[1-(8-fluoro-11h-10-oxa-1-aza-dibenzo[a,d]cycloheptèn-5-ylidène)-propyl]-phényl}-méthylsulfonamide en tant que modulateur du récepteur de glucocorticoïde pour le traitement d'une arthrite rhumatoïde
WO2010001990A1 (fr) * 2008-07-03 2010-01-07 協和発酵キリン株式会社 Composé tétracyclique

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004052847A2 (fr) * 2002-06-26 2004-06-24 Eli Lilly And Company Modulateurs tricycliques du recepteur nucleaire des hormones steroidiennes
WO2005066153A1 (fr) * 2003-12-19 2005-07-21 Eli Lilly And Company Modulateurs du recepteur nucleaire d'hormone steroide tricyclique
WO2005066161A1 (fr) * 2003-12-19 2005-07-21 Eli Lilly And Company Modulateurs tricycliques du recepteur nucleaire de l'hormone steroide
WO2008008882A2 (fr) * 2006-07-14 2008-01-17 Eli Lilly And Company Modulateur du récepteur des glucocorticoïdes et procédés d'utilisation
WO2008021926A2 (fr) * 2006-08-09 2008-02-21 Bristol-Myers Squibb Company Modulateurs du récepteur de glucocorticoïde, de l'activité du ap-1 et/ou du nf-kb et leur utilisation
WO2009089312A1 (fr) * 2008-01-11 2009-07-16 Eli Lilly And Company (e)-n-{3-[1-(8-fluoro-11h-10-oxa-1-aza-dibenzo[a,d]cycloheptèn-5-ylidène)-propyl]-phényl}-méthylsulfonamide en tant que modulateur du récepteur de glucocorticoïde pour le traitement d'une arthrite rhumatoïde
WO2010001990A1 (fr) * 2008-07-03 2010-01-07 協和発酵キリン株式会社 Composé tétracyclique

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014039757A1 (fr) * 2012-09-07 2014-03-13 Abbvie Inc. Modulateurs hétérocycliques de récepteurs hormonaux nucléaires
US20140162985A1 (en) * 2012-09-07 2014-06-12 Abbvie Inc. Heterocyclic nuclear hormone receptor modulators
US9193744B2 (en) 2012-09-07 2015-11-24 Abbvie Inc. Heterocyclic nuclear hormone receptor modulators
US9150592B2 (en) 2012-12-21 2015-10-06 Abbvie Inc. Heterocyclic nuclear hormone receptor modulators

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