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WO2009008552A1 - Dérivés de 8-aryl-4-alkylpyrrolo[2,3,4-dé]quinoléine-5(4h)-one et de 8-aryl-4-alkyl-4,5-dihydropyrrolo[2,3,4-dé]quinoléine-5-ol - Google Patents

Dérivés de 8-aryl-4-alkylpyrrolo[2,3,4-dé]quinoléine-5(4h)-one et de 8-aryl-4-alkyl-4,5-dihydropyrrolo[2,3,4-dé]quinoléine-5-ol Download PDF

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Publication number
WO2009008552A1
WO2009008552A1 PCT/JP2008/062877 JP2008062877W WO2009008552A1 WO 2009008552 A1 WO2009008552 A1 WO 2009008552A1 JP 2008062877 W JP2008062877 W JP 2008062877W WO 2009008552 A1 WO2009008552 A1 WO 2009008552A1
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Prior art keywords
quinolin
alkyl
aryl
methyl
methylpyrrolo
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English (en)
Inventor
Atsuro Nakazato
Dai Nozawa
Taketoshi Okubo
Mikako Matsuda
Ludo E.J. Kennis
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to a therapeutic agent for diseases in which corticotropin releasing factor (CRF) is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain, etc.
  • CCF corticotropin releasing factor
  • CRF is a hormone comprising 41 amino acids
  • CRF CRF plays a core role in biological reactions against stresses (Cell. MoI. Neurobiol., 14, 579-588, 1994; Endocrinol., 132, 723-728, 1994; and Neuroendocrine! . 61, 445-452, 1995) .
  • CRF CRF Releasing Factor: Basic and Clinical Studies of a Neuropeptide, pp. 29-52, 1990.
  • Intraventricular administration of CRF to hypophy- sectomized rats and normal rats causes an anxiety-like symptom in both types of rats (Pharmacol. Rev., 43, 425-473, 1991; and Brain Res. Rev., 15, 71-100, 1990).
  • CRF hypothalamus-pituitary-adrenal system
  • the pathway by which CRF functions as a neurotransmitter in central nervous system The review by Owens and Nemeroff in 1991 summarizes diseases in which CRF is involved (Pharmacol. Rev., 43, 425-474, 1991). That is, CRF is involved in depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal diseases, drug dependence, inflammation, immunity-related diseases, etc. It has recently been reported that CRF is involved also in epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, and cephalic external wound (Brain Res. 545, 339-342, 1991; Ann.
  • antagonists against CRF receptors are useful as therapeutic agents for the diseases described above.
  • JP2002-308877 disclose 4-alkylpyrrolo [2, 3, 4- de] quinolin-5 (4H) -one derivatives as phosphodiesterase inhibitors. However none disclose the compounds provided in the present invention.
  • An object of the present invention is to provide an antagonist against CRF receptors which is effective as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain, etc.
  • diseases in which CRF is considered to be involved such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain, etc.
  • the present invention is 8-aryl-4- alkylpyrrolo[2, 3, 4-de] quinolin-5 (4H) -one and 8-aryl-4- alkyl-4, 5-dihydropyrrolo [2, 3, 4-de] quinolin-5-ol derivatives explained below.
  • R 1 and R 2 are the same or different, and independently are hydrogen, Ci- ⁇ alkyl, C 3 _ 7 cycloalkyl, C 3 -. ⁇ 7 cycloalkyl-C 1 - 6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl, hydroxy-Ci- ⁇ alkyl, cyano, cyano-Ci_ 6 alkyl or R 6 (R 7 )N-Ci- 6 alkyl;
  • R 3 is hydrogen or Ci- ⁇ alkyl
  • R 4 is hydroxyl and R 5 is hydrogen; or R 4 and R 5 are taken together to form a carbonyl group; R 6 and R 7 are the same or different, and independently hydrogen or Ci_ 3 alkyl; or R 6 and
  • R 7 are taken together to form - (CH 2 ) S -R 8 - (CH 2 ) t -;
  • R 8 is methylene, oxygen, NR 9 or a single bond;
  • R 9 is hydrogen or Ci- 3 alkyl;
  • s and t are the same or different, and independently an integer selected from 1, 2 or 3;
  • a and B are the same or different, and independently N or CH;
  • X, Y and Z are the same or different, and independently hydrogen, Ci_ 3 alkyl, Ci_ 3 alkoxy, Ci- 3 alkylthio, halogen, trifluoromethyl, trifluoromethoxy or -N(R 10 JR 11 ;
  • R 10 and R 11 are the same or different, and independently hydrogen or Ci- 3 alkyl; or pharmaceutically acceptable salts and hydrates thereof.
  • Ci_ 6 alkyl means a straight chain or branc hed chain alkyl group of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, hexyl, isohexyl or the like.
  • C 3 _ 7 cycloalkyl means a cyclic alkyl group of 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • C 3 - 7 cycloalkyl-Ci_ 6 alkyl means a substituted Ci- 6 alkyl group having the above-mentioned C3_ 7 cycloalkyl as the substituent, such as cyclopropylmethyl, cyclopropylethyl, cyclopentylethyl or the like.
  • Ci- 6 alkoxy means a straight chain or branched chain alkoxy group of 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy, pentyloxy, isopentyloxy or the like.
  • Ci- 6 alkoxy-Ci- 6 alkyl means a substituted Ci- 6 alkyl group having the above-mentioned Ci_ 6 alkoxy group as the substituent, such as methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl or the like.
  • hydroxy-Ci- 6 alkyl means a substituted Ci-galkyl group having hydroxy group, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1- hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4- hydroxybutyl, 5-hydroxypentyl or the like.
  • cyano-Ci-galkyl means a substituted
  • Ci_ 6 alkyl group having cyano group such as cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, 4- cyanobutyl, 5-cyanopentyl or the like.
  • halogen means fluorine, chlorine, bromine or iodine atom.
  • Ci_ 3 alkylthio means a straight chain or branched chain alkylthio group of 1 to 3 carbon atoms, such as methylthio, ethylthio, propylthio or the like.
  • the "pharmaceutically acceptable salts" in the present invention include, for example, salts with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or the like; salts with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, gal
  • isomers such as diastereomers, enantiomers, geometricisomers and tautomeric forms may exist.
  • the compound of the present invention includes the individual isomers and the racemic and non-racemic mixtures of the isomers.
  • R 1 and R 2 are the same or different, and independently are hydrogen, Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, C 3 - 7 cycloalkyl-Ci- 6 alkyl, Ci_ 6 alkoxy-Ci_ 6 alkyl, hydroxy-Ci_ ⁇ alkyl, cyano, cyano-Ci- 6 alkyl or R 6 (R 7 ) N-Ci_ 6 alkyl; R 3 is methyl; R 4 and R 5 are taken together to form a carbonyl group; R 6 and R 7 are the same or different, and independently hydrogen or Ci_ 3 alkyl; A and B are the same or different, and independently N or CH; X, Y and Z are the same or different, and independently hydrogen, Ci_ 3 alkyl, halogen or -N(R 10 JR 11 .
  • R 10 and R 11 are the same or different, and independently hydrogen or Ci_ 3 alkyl; More preferable are compounds of formula [I] , wherein R 1 and R 2 are the same or different, and independently are Ci_ 6 alkyl, C 3 _ 7 cycloalkyl or Ci_ 6 alkoxy-Ci- 6 alkyl.
  • R 3 is methyl;
  • R 4 and R 5 are taken together to form a carbonyl group;
  • a and B are the same or different, and independently N or CH;
  • X, Y and Z are the same or different, and independently hydrogen, methyl, chloro or dimethylamino;
  • Especially preferable compounds of the present invention are:
  • the compounds represented by the formula [I] can be produced, for example, by the process shown in the following reaction scheme 1 or 2 (in the following reaction scheme, R 1 , R 2 , R 3 , X, Y, Z, A and B are as defined above, L 1 , L 2 , W 1 and W 2 are the same or different, and independently chloro, bromo, iodo, methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy or trifluoromethanesulfonyloxy group, Ra, Rb, Rc and Rd are the same or different, and independently Ci_ 3 alkyl, M is an appropriate group such as B(OH) 2 or SnBu 3 for aryl coupling).
  • Reaction Scheme 1 Reaction Scheme 1
  • Stepl Compound (1) can be converted to Compound (3) by reacting Compound (1) with beta-ketoester (2) in the presence or absence of an acid in an inert solvent or without any solvent.
  • the acid includes, for example, organic acids such as formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, trifluoromethanesulfonic acid or the like; inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, nitric acid and the like.
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1, 2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N, N-dimethylformamide, N- methylpyrrolidone, W ⁇ lV-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like
  • ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1, 2-dimethoxyethane and the like
  • hydrocarbons such as
  • Step 2 Compound (3) can be converted to Compound (4) by reacting (3) with a halogenating reagent or a sulfonating reagent in the presence or absence of a base in an inert solvent or without any solvent.
  • the halogenating reagent includes, for example, phosphoryl chloride, phosphoryl bromide, phosphorous pentachloride, phosphorous trichloride, phosphorous pentabromide, phosphorous tribromide, thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl bromide and the like.
  • the sulfonating reagent includes, for example, p-toluenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonic anhydride, methansulfonic anhydride, trifluoromethanesulfonic anhydride, N- phenylbis (trifluoromethanesulfonimide) and the like.
  • the base includes, for example, amines such as triethylamine, diisopropylethylamine, pyridine, N,N- dimethylaniline, N,iV-diethylaniline and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide and the like; and Grignard reagents such as methyl magnesium bromide and the like.
  • amines such as triethylamine, diisopropylethylamine, pyridine, N,N- dimethylaniline, N,iV-diethylaniline and the like
  • inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbon
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1, 2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N, N-dimethylformamide, N- methylpyrrolidone, N,W-dimethylacetamide and the like; dichloromethane; chloroform; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like
  • ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1, 2-dimethoxyethane and
  • L 1 When L 1 is a sulfonyloxy group, L 1 can be converted to a halogen atom by reacting with a halogenating reagent in the presence or absence of a base in an inert solvent or without any solvent.
  • the halogenating reagent includes, for example, potassium iodide, potassium bromide, sodium iodide, sodium bromide, sodium chloride and the like.
  • Step 3 Compound (4) can be converted to Compound (6) by reacting Compound (4) with the corresponding amine (5) in the presence or absence of a base in an inert solvent or without any solvent.
  • the base includes, for example, amines such as triethylamine, -V,W-diisopropylethylamine, pyridine and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; and metal amides such as sodium amide, lithium diisopropylamide and the like.
  • amines such as triethylamine, -V,W-diisopropylethylamine, pyridine and the like
  • inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, barium hydroxide, sodium hydride and the like
  • metal alcoholates such as sodium methoxide
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1, 2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene, xylene and the like; amides such as N, N-dimethylformamide, N- methylpyrrolidone, N, N-dimethylacetamide and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like
  • ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1, 2-dimeth
  • Step 4 Compound (8), a compound of the present invention, can be obtained by reacting Compound (6) with compound (7) in the presence or absence of a catalyst in an inert solvent in the presence or absence of a base.
  • the catalyst includes, for example, tetrakis (triphenylphosphine) palladium (0) , dichlorobis (tri-o-tolylphosphine) palladium (II) , palladium (II) acetate and the like;
  • the base includes, for example, amines such as triethylamine, N, N-diisopropylethylamine, pyridine and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1, 2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene, xylene and the like; esters such as ethyl acetate, ethyl formate and the like; amides such as N r N- dimethylformamide, .W-methylpyrrolidone, N,N- dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like
  • ethers such as diethyl ether,
  • Step 5 Compound (9), a compound of the present invention, can be obtained by reduction of Compound (8) with a conventional reducing agent in an inert solvent.
  • the reducing agent includes, for example, iron, zinc, lithium borohydride, sodium borohydride, calcium borohydride, lithium triethylborohydride, lithium tri- sec-butylborohydride, potassium tri-sec- butylborohydride, zinc borohydride, borane, lithium trimethoxyborohydride, lithium triacetoxyborohydride, tetramethylammonium borohydride, lithium aluminum hydride, sodium aluminum hydride, sodium bis (2- methoxyethoxy) aluminum hydride, diisobutylaluminum hydride, trichlorosilane and the like.
  • the reduction can be also carried out by hydrogenation using a catalyst such as palladium, platinum dioxide, Raney nickel and the like.
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N, N- dimethylformamide, AJ-methylpyrrolidone, N,N- dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents. Reaction Scheme 2 -
  • Step 6 Compound (1) can be converted to Compound (10) by reacting Compound (1) with compound (7) in the same method as described in step 4.
  • Step 7 Compound (10) can be converted to Compound
  • Step 8 Compound (11) can be converted to Compound
  • Step 9 Compound (8), a compound of the present invention, can be obtained by reacting Compound (12) with the corresponding amine (5) in the same method as described in step 3.
  • the compound of the present invention can be converted to a salt with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and the like; with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, naphthalene-2- sulfonic acid and the like; with an inorgan
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane and the like; esters such as ethyl acetate, ethyl formate and the like; ketones such as acetone, methylethylketone and the like; hydrocarbons such as benzene, toluene and the like; amides such as I ⁇ J, N-dimethylformamide, AJ-methylpyrrolidone, N, N- dimethylacetamide and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and
  • the compound of the present invention is useful as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved.
  • the compound of the present invention can be formulated into tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, injections and the like by a conventional preparation technique by adding conventional fillers, binders, disintegrators, pH-adjusting agents, solvents, etc.
  • the compound of the present invention can be administered to an adult patient in a dose of 0.1 to 500 mg per day in one portion or several portions orally or parenterally. The dose can be properly increased or decreased depending on the kind of a disease and the age, body weight and symptom of a patient .
  • Example 1 Example 1
  • the membranes of COS-7 cells expressing monkey CRF x were used as a receptor preparation.
  • 125 I-CRF was used as 125 I-labeled ligand. Binding reaction using the 125 I-labeled ligand was carried out by the following method described in The Journal of Neuroscience, 7, 88 (1987) . Preparation of receptor membranes:
  • COS-7 cells expressing monkey CRFi was homogenized in 50 mM Tris-HCl buffer (pH 7.0) containing 10 mM MgCl 2 , 2 mM EDTA and centrifuged at 48,000 x g for 20 min, and the precipitate was washed once with Tris-HCl buffer. The washed precipitate was suspended in 50 mM Tris-HCl buffer (pH 7.0) containing 10 mM MgCl 2 , 2 mM EDTA, 0.1% bovine serum albumin and 100 kallikrein units/ml aprotinin, to obtain a membrane preparation.
  • CRF receptor binding test :
  • the membrane preparation 150-250 ⁇ g protein/ml
  • 125 I-CRF 0.2 nM
  • a test drug was reacted at 25 0 C or room temperature for 2 hours.
  • the reaction mixture was filtered by suction through a glass filter (GF/C) treated with 0.3% polyethylene imine, and the glass filter was washed three times with phosphate-buffered saline containing 0.01% Triton X-100. After the washing, the radioactivity of the filter paper was measured in a gamma counter.
  • the amount of 125 I-CRF bound when the reaction was carried out in the presence of 1 ⁇ M CRF was taken as the degree of nonspecific binding of 125 I-CRF, and the difference between the total degree of 125 I-CRF binding and the degree of nonspecific 125 I-CRF binding was taken as the degree of specific 125 I-CRF binding.
  • An inhibition curve was obtained by reacting a definite concentration (0.2 nM) of 125 I-CRF with various concentrations of each test drug under the conditions described above. A concentration of the test drug at which binding of 125 I-CRF is inhibited by 50% (IC 50 ) was determined from the inhibition curve.
  • compounds having a high affinity for CRF receptors have been provided. These compounds are effective against diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain, etc.
  • diseases in which CRF is considered to be involved such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain, etc.

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Abstract

La présente invention concerne un antagoniste des récepteurs du CRF qui est efficace en tant qu'agent thérapeutique ou prophylactique pour des maladies dans lesquelles il est considéré que le CRF est impliqué, telles que la dépression, l'anxiété, la maladie d'Alzheimer, la maladie de Parkinson, la chorée de Huntington, un trouble de l'alimentation, l'hypertension, des maladies gastro-intestinales, une dépendance à un médicament, un infarctus cérébral, une ischémie cérébrale, un œdème cérébral, une plaie céphalique externe, une inflammation, des maladies liées à l'immunité, l'alopécie, le syndrome de l'intestin irritable, des troubles du sommeil, l'épilepsie, des dermites, la schizophrénie, des douleurs, etc. Un dérivé de 8-aryl-4-alkylpyrrolo[2,3,4-dé]quinoléine-5(4H)-one ou de 8-aryl-4-alkyl-4,5-dihydropyrrolo[2,3,4-dé]quinoléine-5-ol représenté par la formule [I] suivante, présente une affinité élevée pour les récepteurs du CRF et est efficace contre des maladies dans lesquelles il est considéré que le CRF est impliqué.
PCT/JP2008/062877 2007-07-11 2008-07-10 Dérivés de 8-aryl-4-alkylpyrrolo[2,3,4-dé]quinoléine-5(4h)-one et de 8-aryl-4-alkyl-4,5-dihydropyrrolo[2,3,4-dé]quinoléine-5-ol Ceased WO2009008552A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015112642A1 (fr) 2014-01-21 2015-07-30 Neurocrine Biosciences, Inc. Antagonistes du récepteur crf1 pour le traitement de l'hyperplasie surrénalienne congénitale
US9340509B2 (en) 2013-12-02 2016-05-17 Chemocentryx, Inc. CCR6 compounds
US12128033B2 (en) 2018-12-07 2024-10-29 Neurocrine Biosciences, Inc. Synthetic methods for preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-n-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-n-prop-2-ynyl-1,3-thiazol-2-amine
US12383536B2 (en) 2019-09-27 2025-08-12 Neurocrine Biosciences, Inc. CRF receptor antagonists and methods of use

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