WO2001062718A1 - Dérivé de benzamide et utilisation de celui-ci - Google Patents

Dérivé de benzamide et utilisation de celui-ci Download PDF

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Publication number
WO2001062718A1
WO2001062718A1 PCT/JP2001/001429 JP0101429W WO0162718A1 WO 2001062718 A1 WO2001062718 A1 WO 2001062718A1 JP 0101429 W JP0101429 W JP 0101429W WO 0162718 A1 WO0162718 A1 WO 0162718A1
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group
carbon atoms
ethyl
lower alkyl
alkyl group
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PCT/JP2001/001429
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English (en)
Japanese (ja)
Inventor
Motohide Sato
Kazuhito Harada
Akira Miyazaki
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Japan Tobacco, Inc.
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Priority to AU2001234180A priority Critical patent/AU2001234180A1/en
Publication of WO2001062718A1 publication Critical patent/WO2001062718A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/42—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of mineralocorticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/47—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/40—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
    • C07C323/67—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfonamide groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to a novel benzamide derivative, and more particularly to a benzamide derivative having an antagonistic action on adrenocorticotropic hormone-releasing factor (CRF) receptor, a pharmaceutically acceptable salt thereof or a hydrate thereof. Or a pharmaceutical composition comprising a solvate.
  • CRF adrenocorticotropic hormone-releasing factor
  • CRF is a hormone consisting of 41 amino acids [Science, 2 13, 3, 394 (1 981); J. N eurosci., 7, 88 (1 98 7)], a goat in 1981 [S cience, 2 1 3, 1 394 (1 981)], rat in 1983 [Proc. Natl. Ac ad. S ci. US A, 80, 485 1 (1 983) ] And humans [EMBO J., 2, 775 (1983)], and recently, CRF has been linked to the peripheral immune system and the sympathetic nervous system via the hypothalamus-pituitary-adrenal system.
  • CRF cerebral cortex and subcortex
  • CRF receptors are distributed not only in the pituitary gland but also in the cerebral cortex and subcortex, and there are two subtypes of CRF receptors. It has been shown to be distributed in different areas of the brain, and attention has been focused on the effects of CRF on the central nervous system and its involvement in neuropsychiatric disorders.
  • CRF central nervous system and other peripheral organs, such as the heart, gastrointestinal tract, lungs, spleen, adrenal glands, and gonads
  • CRF is a cause of various diseases in these sites. It is considered a substance, and its research is being actively conducted.
  • CRF CRF-related diseases involving CRF are summarized in the review of Owens and Nemeroff, 1999, [Pharma col. Rev., 43, 425 (1991)]. That is, CRF is involved in depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, hypertension, digestive disorders, drug dependence, inflammation, immune-related diseases, and the like. More recently, CRF has been implicated in these and many other diseases.
  • Inflammatory diseases such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergic disease; generalized anxiety disorder; panic, phobia, obsessive-compulsive disorder; post-traumatic stress disease; Stress-induced sleep disorder; pain perception such as fibromyalgia; severe depression, single episode depression, recurrent depression, pediatric abuse-induced depression, premenstrual discomfort disorder, premenstrual syndrome-related mood disorder, postpartum depression Bipolar disorder; circulatory temperament; fatigue syndrome; stress-induced headache; cancer; human immunodeficiency virus (HIV) infection; Alheimer's disease, Parkinson's disease, Huntington's disease, etc.
  • HIV human immunodeficiency virus
  • Neurodegenerative disease ulcer, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea, mental disorder or strike Les-related postoperative ileus and colon hypersensitivity; eating disorders such as anorexia nervosa and bulimia; hemorrhagic stress; stress-induced psychotic episodes; thyroid dysfunction syndrome; inappropriate antidiarrheal hormone-based symptoms; obesity Infertility; head trauma; spinal trauma; ischemic neuron damage (eg, cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuron damage; epilepsy; cardiovascular and heart such as hypertension, tachycardia and congestive heart failure.
  • eating disorders such as anorexia nervosa and bulimia
  • hemorrhagic stress eg., stress-induced psychotic episodes
  • thyroid dysfunction syndrome inappropriate antidiarrheal hormone-based symptoms
  • obesity Infertility head trauma; spinal trauma; ischemic neuron damage (eg, cerebral ischemia such as cerebral hippocamp
  • immune dysfunction including stress-induced immune dysfunction (eg, stress-induced fever); muscle spasms; urinary incontinence; senile dementia of the Alzheimer type; multiple cerebral infarction dementia; amyotrophic lateral sclerosis Withdrawal symptoms of drugs or alcohol; drug intoxication; osteoporosis; psychosocial dwarfism; hypoglycemia;
  • CRF receptor antagonists are considered to be useful as therapeutic agents for these various diseases. Therefore, CRF receptor antagonists are expected to be a new class of therapeutic agents.
  • Japanese Unexamined Patent Publication No. 9-507805 (WO 95/34563) includes pyrazo- and pyrro-mouth pyridine compounds
  • Japanese Unexamined Patent Application Publication No. 9-507249 (WO 955Z33750).
  • Publications include pyridine, pyrimidine, purinone, pyropyrimidinone and pyropyridinone compounds
  • JP-A-8-259567 (EP 729758) discloses pyrazopyrimidine and pyrropyrimidine compounds.
  • No. 646,152 discloses a pyrazole, pyrazo-opened pyrimidine or pyrimidine pyrimidine compound, and JP-A-9-113228 (EP 772303) discloses a compound such as pyrimidine.
  • Derivatives such as pyrimidine pyrromidine are disclosed in Kaihei 9-188682 (EP 7782777) and in Japanese Patent Application Laid-Open No. 9-504520 (W ⁇ 95 / 150506).
  • 1 N-alkyl-1-N-arylpyrimidineamine derivatives are disclosed in WO 97/35 539 (US Pat. No. 5,912,348), and arylamino condensed pyridine and pyrimidine derivatives are described in WO 97 / No.
  • 3,558,580 discloses pyrimidine and triazine derivatives substituted with aryloxy or arylthio
  • WO97Z35846 discloses aryloxy or arylthio mono-condensed pyridine and pyrimidine derivatives, WO 97Z44038.
  • azolotriazine and pyrimidine compounds are described in WO 98/03510
  • pyrazinone and triazinone derivatives are described in WO98 / 110705
  • arylazine is described in WO 99Z0 1439.
  • WO 99Z0 1454 discloses imidazopyrimidine and imidazo pyridine compounds
  • WO 99Z 103 350 discloses imidazo [4,5-c] pyrazole.
  • the compound is a ring-fused pyridine compound in W099Z11643, an azolotriazine and a pyrimidine compound in W099Z38686, and Japanese Patent Application Laid-Open No. H10-506126 (WO96 / 35689).
  • WO 9 In the publication No. 8/294 13 (US Pat. No.
  • WO 98/42699 discloses a 4-tetrahydropyridylpyrimidine derivative.
  • pyrazoline derivatives in WO 9Z1 2908, quinoline and quinazoline derivatives, in W098Z29 399, condensed pyrimidine compounds, and in WO 98/511, 122, 2, 3 , 5,6-tetrahydro-1,2,6-thiadiazin-3,5-dione 1,1-dioxide derivatives are disclosed in WO 98/080821 (US 586 1398) benzoperimidine-carbon An acid derivative is disclosed, and a benzothiadiazole derivative is disclosed in W099 / 40089.
  • these publications disclose neither the disclosure of the compound of the present invention nor the description suggesting the disclosure.
  • WO 97/36861 discloses a phenylene sulfonamide compound including a benzamide compound having a sulfamoyl group.
  • the publication does not disclose any compound such as the compound of the present invention, nor does it mention any description suggesting this.
  • the compound in the publication is described as an integrin antagonist, and there is no description suggesting a CRF receptor antagonistic action as in the present invention.
  • the present inventors have conducted intensive studies to provide a compound having a CRF receptor antagonistic action as described above, and as a result, have found that a novel benzamide derivative has an excellent CRF receptor antagonistic action, and completed the present invention. Reached.
  • the present invention relates to a novel benzamide derivative shown in the following (1) to (15), a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutical composition containing the same.
  • R t and R 2 may be the same or different;
  • a halogenated lower alkyl group having 1 to 4 carbon atoms having 1 to 4 carbon atoms
  • a cycloalkyl group having 3 to 7 carbon atoms having 3 to 7 carbon atoms
  • R 2 together may optionally have a nitrogen atom, an oxygen atom or a sulfur atom in addition to the nitrogen atom adjacent to R 1 and R 2, and may have 1 to 4 carbon atoms. It may form a 5- or 6-membered saturated heterocyclic ring which may be substituted with an alkyl group,
  • R 3 and R 4 may be the same or different
  • a lower alkoxy group having 1 to 4 carbon atoms having 1 to 4 carbon atoms
  • a lower alkyl group having 1 to 4 carbon atoms which may be replaced by a substituent selected from a hydroxyl group and a lower alkoxy group having 1 to 4 carbon atoms;
  • a halogenated lower alkyl group having 1 to 4 carbon atoms having 1 to 4 carbon atoms
  • a lower alkoxy group having 1 to 4 carbon atoms which may be substituted with a substituent selected from a halogen atom and a C 3 -C 7 alkyl group; a lower alkanoyl group having 2 to 5 carbon atoms;
  • a carbamoyl group which may be substituted by a lower alkyl group having 1 to 4 carbon atoms;
  • a lower alkyl group having 1 to 4 carbon atoms which may be substituted with a substituent selected from a halogen atom and a cycloalkyl group having 3 to 7 carbon atoms, a lower alkanoyl group having 2 to 5 carbon atoms, An amino group which may be substituted with a substituent selected from 2 to 5 lower alkoxyl radicals, a lower alkylsulfonyl group having 1 to 4 carbon atoms, and a cycloalkyl group having 3 to 7 carbon atoms ;
  • a cycloalkyl group having 3 to 7 carbon atoms having 3 to 7 carbon atoms
  • a cycloalkyloxy group having 3 to 7 carbon atoms having 3 to 7 carbon atoms
  • R 6 is A hydrogen atom
  • An amino group optionally substituted with a lower alkyl group having 1 to 4 carbon atoms; a cyano group;
  • a lower alkynyl group having 2 to 4 carbon atoms A carbamoyl group which may be substituted by a lower alkyl group having 1 to 4 carbon atoms;
  • R 5 and R 16 may be linked together to form a 5- to 6-membered saturated heterocyclic ring which may be substituted by a lower alkyl group having 1 to 4 carbon atoms or an oxo group.
  • a lower alkoxy group having 1 to 4 carbon atoms having 1 to 4 carbon atoms
  • R l7 and R 18 may be the same or different
  • a lower alkoxy group having 1 to 4 carbon atoms having 1 to 4 carbon atoms
  • R 8 is
  • aminosulfonyl group optionally substituted with a lower alkyl group having 1 to 4 carbon atoms; or
  • R 2 () and R 21 may be the same or different
  • R 2 () and R 21 together, optionally R 2 . May have a nitrogen atom, an oxygen atom or a sulfur atom in addition to the nitrogen atom adjacent to R 21 and R 21 Which may form a heterocyclic ring).
  • a lower alkyl group having 1 to 4 carbon atoms having 1 to 4 carbon atoms.
  • a lower alkyl group having 1 to 4 carbon atoms which may be substituted with a substituent selected from a carbonyl group and a lower alkoxycarbonyl group having 2 to 5 carbon atoms;
  • a lower alkyl group having 1 to 4 carbon atoms having 1 to 4 carbon atoms
  • R 12 is
  • R 13 A lower alkoxy group having 1 to 4 carbon atoms, R 13 is
  • a lower alkyl group having 1 to 4 carbon atoms which may be substituted with a substituent selected from an aryl group, a carbonyl group and a lower alkoxy carbonyl group having 2 to 5 carbon atoms;
  • a lower alkylsulfonyl group having 1 to 4 carbon atoms having 1 to 4 carbon atoms
  • a lower alkyl group having 1 to 4 carbon atoms A lower alkoxy group having 1 to 4 carbon atoms;
  • a lower alkyl group having 1 to 4 carbon atoms which may be substituted with a halogen atom, a substituent selected from a lower alkylsulfonyl group having 1 to 4 carbon atoms and a lower alkanol group having 2 to 5 carbon atoms
  • a hydroxyl group optionally substituted with a substituent selected from a hydroxyl group and a lower alkyl group having 1 to 4 carbon atoms; or
  • R 12 A halogen atom
  • a lower alkyl group having 1 to 4 carbon atoms which may be substituted with a substituent selected from an aryl group, a carbonyl group and a lower alkoxy carbonyl group having 2 to 5 carbon atoms).
  • the benzamide derivative according to the above (1) which is a hydrogen atom, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • a hydrogen atom or.
  • R P R 2 , R 3 , R 4 , R 5 and R 6 are the same as in the above (1).
  • R 2 may be the same or different
  • a lower alkyl group having 1 to 4 carbon atoms having 1 to 4 carbon atoms
  • a lower alkoxy group having 1 to 4 carbon atoms having 1 to 4 carbon atoms
  • amino group which may be substituted with a lower alkyl group having 1 to 4 carbon atoms; a lower alkoxyl propyl group having 2 to 5 carbon atoms or
  • C 1 which may be substituted with a substituent selected from lower alkoxy groups having 1 to 4 carbon atoms, trifluoromethyl group, cyano group and lower alkoxy groups having 2 to 5 carbon atoms From 6 to 6 alkyl groups; A lower alkenyl group having 2 to 4 carbon atoms; or
  • a benzamide derivative according to the above (4) which is a lower alkynyl group having 2 to 5 carbon atoms), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof (6) and R 2 is an ethyl group.
  • R 5 is an ethyl group, a propyl group, an isopropyl group, a methoxy group or a dimethylamino group,
  • R 6 is an ethoxycarponyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a 2,2,2-trifluoromethylmethoxy group, an aryloxy group or a 2-propynyloxy group;
  • A is 3-ethyl-5-getylsulfamoyl-2-methoxyphenyl, 2-ethoxy-3-ethyl-5 monoethylethylsulfamoylphenyl, 3-ethyl-5-ethylethylsulfamoyl-2-propoxy Phenyl group, 5 — getylsulfamoyl — 3 _ isopropyl _2 — propoxyphenyl group, 5 — getylsulfamoyl-2-propoxy-3- propylphenyl group, 5 getylsulfamoyl 2 — Methoxy-3 monopropylphenyl group, 3 —ethyl-5 _ethylsilsulfamoyl 2 _ (2,2,2 —trifluoroethoxy) phenyl group, 2-aryloxy-3-ethyl-5 -methylethylsulfamoylphenyl The group
  • R 7 , R 8 , R 9 and X are the same as in the above (1), the benzamide derivative according to the above (1) to (3), a pharmaceutically acceptable salt thereof or a hydrate thereof Or solvate.
  • a lower alkoxy group having 1 to 4 carbon atoms having 1 to 4 carbon atoms
  • R 17 and R 18 may be the same or different
  • a lower alkyl group having 1 to 4 carbon atoms which may be substituted with a lower alkoxy group having 1 to 4 carbon atoms,
  • aminosulfonyl group optionally substituted with a lower alkyl group having 1 to 4 carbon atoms; or
  • a cycloalkyl group having 3 to 7 carbon atoms having 3 to 7 carbon atoms
  • R 2 () and R 21 may be the same or different
  • the benzamide derivative according to the above (8) which is S-, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • R 7 is a methoxy group or an ethoxy group
  • R 8 is a methyl group, an ethyl group, a propyl group, a butyl group or a methoxymethyl group
  • R 9 is a getylaminosulfonyl group, a methoxycarbonyl group, an ethoxycarbonyl group or a cyclopropanecarbonyl group, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • A is 3,5-di-ethoxycarbonyl 4-methyl-2-phenyl group, 3,5-di-ethoxycarbonyl 4-propyl-2-pentenyl group, 3,5- Di-ethoxycarbonyl 4- (methoxymethyl) — 2-Chenyl group, 4-Ethyl—3,5-Dimethoxycarbonyl 2-Cenyl group, 3-Ethoxycarbonyl 4-ethyl—5-Methoxycarbo 2-Ru 2-Chenyl, 5-Ethoxycarp 4-L-Ethyl 3-Methoxycarp 2-Ru 2-Chenyl, 5-Cyclopropane Power Rou 3 -1-Ethoxy-CarPoru 4 4-Ethyl 2-Chenyl, 3 A benzamide derivative according to the above (10), which is a 5-, 2-di-ethoxycarbone 4-ethyl 2-ethenyl group or a 3-ethoxycarbonyl 2- 4-ethyl-5-ethylsulfamoyl-2-
  • An adrenal cortex-stimulating hormone-releasing factor (CRF) receptor comprising as an active ingredient the compound according to (1) to (12), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. Antagonists.
  • a therapeutic agent for a disease induced or promoted by CRF comprising a compound according to (1) to (12) above, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.
  • a pharmaceutical composition comprising, as an active ingredient, the compound according to (1) to (12), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • “lower alkyl group having 1 to 4 carbon atoms” means an alkyl group having 1 to 4 carbon atoms which may be linear or branched, and specifically, Methyl, ethyl, propyl, isopropyl, butyl, isopti And sec-butyl, tert-butyl and the like.
  • alkyl group having 1 to 6 carbon atoms means an alkyl group having 1 to 6 carbon atoms which may be linear or branched, and specifically, a methyl group, an ethyl group Groups, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1,1-dimethylpropyl, 1-ethylbutyl, 2-ethylbutyl Examples include tyl, 1,1-dimethylbutyl, and hexyl.
  • “Lower alkenyl group having 2 to 4 carbon atoms” means an alkenyl group having 2 to 4 carbon atoms which may be linear or branched, and specifically, a vinyl group , Aryl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butenyl, 1-methyl-1-propenyl, 1 "Lower alkynyl group having 2 to 4 carbon atoms” such as _methyl-2-propenyl group, 1-ethylvinyl group, 2-methyl-1-propenyl group, 2 _methyl-2-propyl group, etc.
  • alkynyl group having 2 to 4 carbon atoms which may be straight-chain or branched, and specifically, an ethynyl group, 1-propenyl group, 2-propynyl group, 1 —Butynyl group, 2-butenyl group, 3-butynyl group, 1-methyl-2-propynyl group and the like.
  • Halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • Halogenated lower alkyl group having 1 to 4 carbon atoms means the above-mentioned lower alkyl group having 1 to 4 carbon atoms which is substituted by 1 to 3 same or different halogen atoms. Specifically, fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, fluoroethyl, chloroethyl, difluoroethyl, trifluoroethyl, pentachloroethyl Group, bromopro Pill, dichloropropyl, trifluorobutyl and the like.
  • lower alkoxy group having 1 to 4 carbon atoms means the above-mentioned alkoxy group having a lower alkyl group having 1 to 4 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group.
  • lower alkylthio group having 1 to 4 carbon atoms means the above-mentioned alkylthio group having a lower alkyl group having 1 to 4 carbon atoms, specifically, a methylthio group, an ethylthio group, a propylthio group, and an isopropyl group.
  • the “lower alkylsulfur group having 1 to 4 carbon atoms” means the above-mentioned alkylsulfur group having a lower alkyl group having 1 to 4 carbon atoms, and specifically, a methylsulfiel group, Examples include a tylsulfinyl group, a propylsulfinyl group, an isopropylsulfenyl group, a butylsulfinyl group, an isobutylsulfenyl group, a sec-butylsulfinyl group, and a tert-butylsulfinyl group.
  • lower alkylsulfonyl group having 1 to 4 carbon atoms means the above-mentioned alkylsulfonyl group having a lower alkyl group having 1 to 4 carbon atoms, specifically, a methylsulfonyl group, an ethylsulfonyl group.
  • linear or branched lower alkanoyl group having 2 to 5 carbon atoms means the alkanoyl group having a lower alkyl group having 1 to 4 carbon atoms, specifically, an acetyl group, And propionyl group, butyryl group, isoptyryl group, valeryl group, isovaleryl group, and bivaloyl group.
  • C3-C7 cycloalkyl group means a C3-C7 cycloalkyl group, specifically, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and cycloalkyl group. And a heptyl group.
  • cycloalkyloxy group having 3 to 7 carbon atoms means the above-mentioned cycloalkyloxy group having a cycloalkyl group having 3 to 7 carbon atoms, specifically, a cyclopropyloxy group.
  • Aryl group includes phenyl, naphthyl, biphenyl and the like.
  • “5- or 6-membered saturated heterocycle” means a 5- or 6-membered saturated heterocycle having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and specifically, pyrrolidine Ring, tetrahydrofuran ring, imidazolidine ring, morpholine ring, piperidine ring, piperazine ring, tetrahydropyran ring and the like.
  • 5- or 6-membered nitrogen-containing saturated heterocyclic group means a 5- or 6-membered saturated heterocyclic group containing a nitrogen atom and optionally containing an oxygen atom or a sulfur atom, Specific examples include a pyrrolidinyl group, an imidazolidinyl group, a morpholino group, a piperidyl group, and a piperazinyl group.
  • Alkali metal refers to lithium, sodium, potassium, and the like. Hereinafter, this will be described more specifically, but is not necessarily limited to the following.
  • the “lower alkyl group having 1 to 4 carbon atoms” in R 2 is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group, and particularly preferably a methyl group or an ethyl group. is there.
  • the “lower alkoxy group having 1 to 4 carbon atoms” which is a substituent of the lower alkyl group in n R 2 is preferably a methoxy group.
  • cycloalkyl group having 3 to 7 carbon atoms which is a substituent of the lower alkyl group in R 1 and R 2 is preferably a cyclopropyl group.
  • the lower alkyl group may be substituted with 1 to 2 substituents, particularly preferably 1 substituted And it may be substituted with a group.
  • R 1 or R 2 preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a 2-hydroxyethyl group Group, 2-methoxyethyl group, cyclopropylmethyl group, and benzyl group.
  • the “lower alkoxy group having 1 to 4 carbon atoms” in R 1 and R 2 is preferably a methoxy group.
  • halogenated lower alkyl group having 1 to 4 carbon atoms a fluoroethyl group and a trifluoroethyl group are preferable.
  • the “cycloalkyl group having 3 to 7 carbon atoms” in R 1 and R 2 is preferably a cyclopropyl group.
  • the “aryl group” in R p R 2 is preferably a phenyl group
  • R and R 2 in R 2 are taken together to form the “5- or 6-membered saturated heterocyclic ring”, preferably a pyrrolidine ring, a piperidine ring, a piperazine ring, and particularly preferably A pyrrolidine ring and a piperazine ring.
  • R and R 2 in R 2 are preferably taken together to form a “5- or 6-membered lower alkyl group having 1 to 4 carbon atoms” which is a substituent of a 5- or 6-membered saturated complex ring formed. Or a methyl group.
  • R 2 is ⁇ , and the ⁇ optionally substituted '' of the 5- or 6-membered saturated complex ring formed is preferably substituted with 1 or 2 substituents And particularly preferably it may be substituted with one substituent.
  • RR 2 is preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a 2-hydroxyethyl group, a 2-methoxyethyl group, a cyclopropylmethyl group, a benzyl group, a methoxy group, —Fluoroethyl group, 2,2,2-trifluoroethyl group, cyclopropyl group, phenyl group, or and R 2 together form a pyrrolidine ring or a 4-methylpiperazine ring, particularly preferably ethyl. Group.
  • the “halogen atom” in R 3 and R 4 is preferably a fluorine atom.
  • the “lower alkyl group having 1 to 4 carbon atoms” in R 3 and R 4 is a methyl group.
  • the “lower alkoxy group having 1 to 4 carbon atoms” in R 3 and R 4 is preferably a methoxy group or a propoxy group
  • the “lower alkyl group having 1 to 4 carbon atoms” as a substituent of the amino group in R 3 and R 4 is preferably a methyl group or an ethyl group.
  • the “lower alkylsulfonyl group having 1 to 4 carbon atoms” as a substituent of the amino group in R 3 and R 4 is preferably a methylsulfonyl group.
  • the “optionally substituted” of the amino group in R 3 and R 4 means that the amino group may be substituted with one or two substituents.
  • the “optionally substituted amino group” in R 3 and R 4 is preferably a methylamino group, a dimethylamino group, a getylamino group, or a methylsulfonylamino group.
  • R 3 and R 4 are preferably a hydrogen atom, a fluorine atom, a methyl group, a methoxy group, a propoxy group, a methylamino group, a dimethylamino group, a ethylamino group, a methylsulfonylamino group, and particularly preferably a hydrogen atom. .
  • the “halogen atom” for R 5 is preferably a fluorine atom, a chlorine atom, or a bromine atom.
  • the “lower alkyl group having 1 to 4 carbon atoms” for R 5 is a methyl group, an ethyl group, a propyl group or an isopropyl group, and particularly preferably an ethyl group.
  • the “lower alkoxy group having 1 to 4 carbon atoms” as a substituent of the lower alkyl group for R 5 is preferably a methoxy group.
  • the ⁇ optionally substituted '' of the lower alkyl group for R 5 is preferably substituted with 1 to 2 substituents, particularly preferably substituted with 1 substituent That is, it may be done.
  • the “optionally substituted lower alkyl group having 1 to 4 carbon atoms” for R 5 is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a 2-hydroxyethyl group or a 2-methoxyethyl group. And particularly preferably an ethyl group.
  • the “halogenated lower alkyl group having 1 to 4 carbon atoms” for R 5 is preferably a trifluoromethyl group.
  • the “lower alkoxy group having 1 to 4 carbon atoms” for R 5 is preferably a methoxy group, an ethoxy group, or a propoxy group.
  • the “halogen atom” as a substituent of the lower alkoxy group for R 5 is preferably a fluorine atom.
  • the “substituted alkyl group having 3 to 7 carbon atoms” as a substituent of the lower alkoxy group in R 5 is preferably a cyclopropyl group.
  • the “optionally substituted lower alkoxy group having 1 to 4 carbon atoms” for R 5 is preferably a methoxy group, an ethoxy group, a cyclopropylmethoxy group, a trifluoroethoxy group, and particularly preferably a methoxy group. It is.
  • the “lower alkanoyl group having 2 to 5 carbon atoms” for R 5 is preferably an acetyl group.
  • the “lower alkyl group having 1 to 4 carbon atoms” as a substituent of the carpamoyl group in R 5 is preferably a methyl group.
  • the “optionally substituted” of the carbamoyl group for R 5 means that the substituent may be substituted with one or two substituents.
  • the “optionally substituted rubamoyl group” for R 5 is preferably a rubamoyl group, a methylcarbamoyl group, or a dimethylcarbamoyl group.
  • the “lower alkylsulfonyl group having 1 to 4 carbon atoms” for R 5 is preferably a methylsulfonyl group.
  • the “lower alkoxycarbonyl group having 2 to 5 carbon atoms” for R 5 is preferably a methoxycarbonyl group or an ethoxycarbonyl group.
  • halogen atom as the substituent of the lower alkyl group which is the substituent of the amino group in R 5 is preferably a fluorine atom.
  • the “cycloalkyl group having 3 to 7 carbon atoms” as the substituent of the lower alkyl group which is the substituent of the amino group in R 5 is preferably a cyclopropyl group.
  • the “optionally substituted lower alkyl group having 1 to 4 carbon atoms” as the substituent of the amino group in R 5 is preferably a methyl group, an ethyl group, a propyl group, a fluorethyl group, a cyclopropylmethyl group It is.
  • the “lower alkanol group having 2 to 5 carbon atoms” as a substituent of the amino group in R 5 is preferably an acetyl group.
  • the “lower carbonyl group having 2 to 5 carbon atoms” which is a substituent of the amino group in R 5 is preferably methoxycarbonyl or tert-butoxycarbonyl group.
  • the “lower alkylsulfonyl group having 1 to 4 carbon atoms” which is a substituent of the amino group in R 5 is preferably a methylsulfonyl group.
  • the “cycloalkyl group having 3 to 7 carbon atoms” as a substituent of the amino group in R 5 is preferably a cyclopropyl group.
  • the “optionally substituted” amino group in R 5 means that the amino group may be substituted with 1 or 2 substituents.
  • the “optionally substituted amino group” for R 5 is preferably an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a acetylamino group, an N-ethyl-N-methylamino group, an N-methyl-N— Propylamino group, N- (2-fluoroethyl) -N-methylamino group, N- (cyclopropylmethyl) -N-methylamino group, acetylamino group, N-acetyl-N-methylamino group, N-cyclopropyl-1-N-methylamino group, N- (methoxycarbonyl) amino group, N- (tert-butoxycarbonyl) -N-methylamino group, N- (methylsulfonyl) amino group, and particularly preferably dimethylamino group.
  • the “5- or 6-membered nitrogen-containing saturated heterocyclic group” for R 5 is preferably a pyrrolidinyl group or a piperidyl group.
  • the “cycloalkyl group having 3 to 7 carbon atoms” for R 5 is preferably a cyclopropyl group or a cyclopentyl group.
  • the “cycloalkyloxy group having 3 to 7 carbon atoms” for R 5 is preferably a cyclopropyloxy group or a cyclopentyloxy group.
  • R 5 is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 2-hydroxyethyl group , 2-methoxyethyl, trifluoromethyl, methoxy, ethoxy, propoxy, 2,2,2-trifluoroethoxy, cyclopropylmethoxy, acetyl, nitro, cyano, levamoyl Group, methylcarbamoyl group, dimethylcarbamoyl group, methylsulfonyl group, carbonyl group, methoxycarbonyl group, ethoxycarbonyl group, amino group, methylamino group, ethylamino group, dimethylamino group, getylamino group, N-ethyl-N-methylamino group, N —Methyl—N—propyla
  • the “halogen atom” for R 6 is preferably a chlorine atom or a bromine atom.
  • the “lower alkyl group having 1 to 4 carbon atoms” for R 6 is preferably a methyl group or an ethyl group.
  • the “lower alkyl group having 1 to 4 carbon atoms” as a substituent of the amino group in R 6 is preferably a methyl group or an ethyl group.
  • the “optionally substituted” of the amino group in R 6 means that the amino group may be substituted with one or two substituents.
  • the “optionally substituted amino group” for R 6 is preferably a methylamino group, an ethylamino group, a dimethylamino group, or a ethylamino group.
  • the “lower alkoxycarbonyl group having 2 to 5 carbon atoms” for R 6 is preferably a methoxycarbonyl group, an ethoxycarbonyl group, or a propoxycarbonyl group.
  • the “lower alkanoyl group having 2 to 5 carbon atoms” for R 6 is preferably an acetyl group.
  • the “lower alkylthio group having 1 to 4 carbon atoms” for R 6 is preferably a methylthio group or an ethylthio group.
  • the “lower alkylsulfinyl group having 1 to 4 carbon atoms” for R 6 is preferably a methylsulfiel group or an ethylsulfiel group.
  • the “lower alkylsulfonyl group having 1 to 4 carbon atoms” for R 6 is preferably a methylsulfonyl group or an ethylsulfonyl group.
  • the “cycloalkyl group having 3 to 7 carbon atoms” for R 6 is preferably a cyclopropyl group or a cyclopentyl group.
  • the “5- or 6-membered saturated heterocyclic group” for R 6 is preferably a piperazinyl group.
  • the “alkyl group having 1 to 6 carbon atoms” for R 16 is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, or a 1-ethylpropyl group, and particularly preferably a methyl group. It is.
  • the “lower alkoxy group having 1 to 4 carbon atoms” as a substituent of the alkyl group for R 16 is preferably a methoxy group.
  • the “lower alkyl group having 1 to 4 carbon atoms” which is the substituent of the amino group which is the substituent of the alkyl group in R 16 is preferably a methyl group.
  • the “optionally substituted” amino group as a substituent of the alkyl group for R 16 means that the amino group may be substituted with one or two substituents.
  • the “optionally substituted amino group” as the substituent of the alkyl group for R 16 is preferably a dimethylamino group.
  • the “lower alkoxycarbonyl group having 2 to 5 carbon atoms” which is a substituent of the alkyl group in R 16 is preferably a methoxycarbonyl group.
  • cycloalkyl group having 3 to 7 carbon atoms which is a substituent of the alkyl group in R 16 is preferably a cyclopropyl group.
  • the alkyl group may be substituted with 1 to 2 substituents, and it is particularly preferred that the alkyl group is substituted with 1 substituent. Is also a good thing.
  • the “lower alkenyl group having 2 to 4 carbon atoms” for R 16 is preferably an aryl group or a 2-methyl-2-propenyl group.
  • the “lower alkynyl group having 2 to 4 carbon atoms” for R 16 is preferably a 2-propynyl group or a 2-butynyl group.
  • the “lower alkyl group having 1 to 4 carbon atoms”, which is a substituent of the carbamoyl group in R 16 , is preferably a methyl group.
  • the “optionally substituted carbamoyl group” for R 16 is preferably a dimethylcarbamoyl group.
  • the “lower alkylsulfonyl group having 1 to 4 carbon atoms” for R 16 is preferably a methylsulfonyl group or an ethylsulfonyl group.
  • the “cycloalkyl group having 3 to 7 carbon atoms” for R 16 is preferably Or a cyclopropyl group or a cyclopentyl group.
  • the “aryl group” for R 16 is preferably a phenyl group.
  • R 6 is preferably a hydrogen atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a methylamino group, an ethylamino group, a dimethylamino group, a ethylamino group, a cyano group, a carboxy group, a methoxycarbonyl group, an ethoxycarbonyl group.
  • R l6 is formed as a "saturated heterocyclic ring of 5 to 6-membered" is preferably tetrahydrofuran ring, tetrahydropyran Vila down ring, morpholine ring.
  • R 5 and R 16 in R 5 and R 16 are linked together to form a 5- to 6-membered saturated heterocyclic substituent “lower alkyl group having 1 to 4 carbon atoms” which is preferable.
  • it is a methyl group.
  • R 16 gar cord in R 5, R 16, as the "optionally substituted" saturated heterocyclic ring of 5 or 6 membered formed, preferably 1 to 3 substituents And particularly preferably it may be substituted with 1 or 2 substituents.
  • R 5 and R l6 gar cord in R 5, R 16 as the "saturated heterocyclic ring which may be substituted 5 to have 6-membered" formed, preferably tetrahydrofuran ring, morpholine ring, 3, A 3-dimethyltetrahydrofuran ring, a 2,2-dimethyltetrahydrofuran ring, a tetrahydropyran ring, a 2,2-dimethyltetrahydropyran ring, a 4-methylmorpholine ring, and a 4-methyl-3-oxomorpholine ring.
  • the “lower alkoxy group having 1 to 4 carbon atoms” for R 7 is preferably a methoxy group, an ethoxy group, or a tert-butoxy group, and more preferably a methoxy group or an ethoxy group.
  • the “lower alkyl group having 1 to 4 carbon atoms” in R 17 and R 18 is preferably a methyl group, an ethyl group, or a propyl group, and more preferably a methyl group or an ethyl group.
  • the “lower alkoxy group having 1 to 4 carbon atoms” for R 17 and R 18 is preferably a methoxy group.
  • R I8 are formed as the "5 or 6-membered saturated heterocyclic ring" is preferably a pyrrolidine ring.
  • R 7 is preferably a hydroxyl group, a methoxy group, an ethoxy group, a tert-butoxy group, a methylamino group, an ethylamino group, a propylamino group, a dimethylamino group, a acetylamino group, an N-methyl-N-methoxyamino group, a benzylamino group , A 1-pyrrolidinyl group, particularly preferably a methoxy group or an ethoxy group.
  • the “lower alkyl group having 1 to 4 carbon atoms” for R 8 is preferably a methyl group, an ethyl group, a propyl group or a butyl group, and particularly preferably a methyl group, an ethyl group or a propyl group.
  • the “lower alkoxy group having 1 to 4 carbon atoms” as a substituent of the lower alkyl group for R 8 is preferably a methoxy group.
  • the “lower alkyl group having 1 to 4 carbon atoms” as the substituent of the amino group which is the substituent of the lower alkyl group in R 8 is preferably a methyl group or an ethyl group.
  • the “optionally substituted” amino group that is a substituent of the lower alkyl group for R 8 is that the amino group may be substituted with one or two substituents.
  • the “optionally substituted amino group” as the substituent of the lower alkyl group for R 8 is preferably a dimethylamino group or a getylamino group.
  • the lower alkyl group may be substituted with 1 to 2 substituents, and it is particularly preferred that the lower alkyl group is substituted with 1 substituent. That is, it may be done.
  • R 8 is preferably a methyl group, an ethyl group, a propyl group, a butyl group, a methoxymethyl group, a dimethylaminomethyl group, a getylaminomethyl group, particularly preferably a methyl group, an ethyl group, a propyl group, A butyl group and a methoxymethyl group.
  • the “lower alkyl group having 1 to 4 carbon atoms” for R 9 is preferably a methyl group, an ethyl group, and a propyl group, and more preferably a propyl group.
  • the “aryl group” for R g is preferably a phenyl group.
  • the “lower alkyl group having 1 to 4 carbon atoms” as a substituent of the aminosulfonyl group for R 9 is preferably a methyl group or an ethyl group, and particularly preferably an ethyl group.
  • the “optionally substituted” aminosulfonyl group for R 9 includes 1 It may be substituted with 1 to 2 substituents.
  • the “optionally substituted aminosulfonyl group” for R 9 is preferably
  • the “lower alkyl group having 1 to 4 carbon atoms” for R 19 is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group.
  • the “lower alkoxy group having 1 to 4 carbon atoms” for R 19 is preferably a methoxy group, an ethoxy group, a propoxy group, a butoxy group, or a tert-butoxy group, particularly preferably a methoxy group or an ethoxy group. It is.
  • the “cycloalkyl group having 3 to 7 carbon atoms” for R 19 is preferably a cyclopropyl group or a cyclopentyl group, particularly preferably a cyclopropyl group.
  • the “aryl group” for R 19 is preferably a phenyl group.
  • R 2 The “lower alkyl group having 1 to 4 carbon atoms” in R 21 is preferably a methyl group, an ethyl group, or a propyl group, and particularly preferably an ethyl group.
  • R 2 As the “cycloalkyl group having 3 to 7 carbon atoms” for R 21 , a cyclohexyl group is preferable.
  • the “aryl group” in R 20 and R 21 is preferably a phenyl group R 2 .
  • R 2Q and R 21 gar cord in R 21, as the "5- to 6-membered saturated heterocyclic ring" formed is preferably a pyrrolidine ring.
  • R 9 is preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, a phenyl group, a dimethylaminosulfonyl group, a carboxy group, an acetyl group, a propionyl group, a ptyryl group, an isoptyryl group, a pareryl group, or a methoxycarbo group.
  • the “lower alkyl group having 1 to 4 carbon atoms” is preferably a methyl group.
  • a lower alkoxycarbonyl group having 2 to 5 carbon atoms is preferably a methoxycarbonyl group
  • R t The term "optionally substituted" in the lower alkyl group in the above means that the lower alkyl group may be substituted with 1 to 2 substituents, particularly preferably substituted with 1 substituent. It is possible that
  • R 1D is preferably a hydrogen atom, a methyl group, or a methoxycarbonylmethyl group, and particularly preferably a hydrogen atom.
  • the “halogen atom” in R is preferably a fluorine atom.
  • the "lower alkyl group having 1 to 4 carbon atoms" of R u preferably a methyl group.
  • a hydrogen atom preferably a hydrogen atom, a fluorine atom, a nitro group, and a methyl group, and particularly preferably a hydrogen atom.
  • the “halogen atom” for R 12 is preferably a fluorine atom, a chlorine atom, or a bromine atom, and particularly preferably a chlorine atom.
  • the “lower alkyl group having 1 to 4 carbon atoms” for R 12 is preferably Is a methyl group.
  • the “lower alkoxy group having 1 to 4 carbon atoms” for R 12 is preferably a methoxy group.
  • R 12 is preferably a hydrogen atom, a chlorine atom, a fluorine atom, a bromine atom, a nitro group, a methyl group, a trifluoromethyl group, or a methoxy group, and particularly preferably a chlorine atom or a nitro group.
  • the “lower alkoxycarbonyl group having 1 to 4 carbon atoms” for R 13 is preferably a methoxycarbonyl group or a tert-butoxycarbonyl group, particularly preferably a methoxycarbonyl group.
  • the “alkali metal” for R 22 is preferably sodium or potassium.
  • R 22 is preferably a hydrogen atom, sodium or potassium.
  • the “lower alkyl group having 1 to 4 carbon atoms” for R 23 is preferably a methyl group, an ethyl group, a propyl group, or an isobutyl group.
  • the “aryl group” which is a substituent of the lower alkyl group for R 23 is preferably a phenyl group.
  • the “lower alkoxycarbonyl group having 2 to 5 carbon atoms” as a substituent of the lower alkyl group for R 23 is preferably a methoxycarbonyl group or an ethoxycarbonyl group.
  • R 23 preferably a benzyl group, a carboxymethyl group, an ethoxycarbonylmethyl group, a 1-loxyloxyl group, or a 1- (ethoxy) group Carbonyl, ethyl, 2-methoxycarbonylethyl, 1-carboxypropyl, (Methoxycarbonyl) propyl group, 1-Methoxypropyl-2-methylpropyl group, 1- (ethoxycarbonyl) 1-2-Methylpropyl group, (Methoxycarbonyl) (phenyl) methyl group, (methoxycarbonyl) (phenyl) A methyl group, a 1-carboxy-2-phenylethyl group, and a 1-methoxycarbonyl-2-phenylethyl group.
  • the “lower alkylsulfonyl group having 1 to 4 carbon atoms” for R 23 is preferably a methylsulfonyl group.
  • the “aryl group” for R 23 is preferably a phenyl group.
  • the ⁇ optionally substituted '' of the aryl group in R 23 is preferably an aryl group which may be substituted with 1 to 2 substituents, particularly preferably 1 substituent. Is also a good thing.
  • the “optionally substituted aryl group” for R 23 is preferably a 4-hydroxyloxyphenyl group.
  • the “lower alkyl group having 1 to 4 carbon atoms” for R 25 is preferably a methyl group, an ethyl group, or a propyl group.
  • R 25 is preferably a hydrogen atom.
  • R 23 is preferably a methyl group, an ethyl group, a propyl group, a benzyl group, a carboxymethyl group, an ethoxycarbonylmethyl group, a 1-ethoxypropyl group, an 1- (ethoxycarponyl) ethyl group, or a 2-oxopropyloxy group.
  • 1-carboxypropyl group 1-(methoxycarbonyl) propyl group, 1-force ropoxy 2-methylpropyl group, 1-(ethoxycarbonyl) 12-methylpropyl group, (carboxy) (phenyl) methyl group, ( Methoxycarbonyl) (phenyl) methyl group, 1-methoxypropyl-2-phenylethyl group, 1-methoxycarbonyl-2-phenylethyl group, 4-carboxyphenyl group, and methylsulfonyl group.
  • R 13 is preferably a hydroxyl group, a sodium oxy group, a potassium oxy group Group, phosphonoxy group, benzyloxy group, carbonyloxy group, ethoxycarponylmethoxy group, 1-carboxyethoxy group, 1- (ethoxycarponyl) ethoxy group, 2-carboxyethoxy group, 2-carboxylicoxylamino group, 1 _Carpoxypropoxy group, 1- (methoxycarbonyl) propoxy group, 1-methylpropoxy_2-Methylpropoxy group, 1- (ethoxycarbonyl) 1-2-methylpropoxy group, (force-loxy) (phenyl) methoxy group , (Methoxycarbonyl) (Phenyl) Methoxy group, 1-methoxyl-2-phenylethoxy group, 1-methoxycarboxy 2 1-phenylethoxy group, 4-yloxycarbonyl group, carboxy group, amino group, dimethylamino group , N-ethyl
  • the “halogen atom” for R 14 is preferably a fluorine atom, a chlorine atom, or a bromine atom, and particularly preferably a chlorine atom.
  • the “lower alkyl group having 1 to 4 carbon atoms” for R 14 is preferably a methyl group.
  • the “lower alkoxy group having 1 to 4 carbon atoms” for R 14 is preferably a methoxy group.
  • halogen atom as the substituent of the lower alkylsulfonyl group which is the substituent of the amino group in R 14 is preferably a fluorine atom.
  • the “optionally substituted” lower alkylsulfonyl group as a substituent for the amino group for R 14 means that the lower alkylsulfonyl group may be substituted with 1 to 3 substituents.
  • the “sulfonyl group” is preferably a methylsulfonyl group or a trifluoromethylsulfonyl group.
  • the “lower alkanol group having 2 to 5 carbon atoms” which is a substituent of the amino group in R 14 is preferably an acetyl group.
  • the “optionally substituted” of the amino group for R 14 means that the amino group may be substituted with one or two substituents.
  • R u preferably di Mechiruamino group, methylsulfonyl ⁇ amino groups, trifluoperazine Ruo B methyl sulfonyl Ruamino group, Asechiruamino group.
  • the “lower alkylsulfonyl group having 1 to 4 carbon atoms” for R 14 is preferably a methylsulfonyl group.
  • the “lower alkanoyl group having 2 to 5 carbon atoms” for R 14 is preferably an acetyl group.
  • the “lower alkoxycarbonyl group having 2 to 5 carbon atoms” for R 14 is preferably a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, or a tert-butoxycarbonyl group.
  • the “lower alkyl group having 1 to 4 carbon atoms” which is a substituent of the carbamoyl group for R 14 is preferably a methyl group.
  • the “optionally substituted” of the carbamoyl group for R 14 is preferably one or two or more substituents.
  • the “optionally substituted carbamoyl group” for R 14 is preferably a carpamoyl group, a hydroxycarbamoyl group, a methylcarbamoyl group, or a dimethylcarbamoyl group.
  • R 14 is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group, a nitro group, a trifluoromethyl group, an amino group, Tylamino group, methylsulfonylamino group, trifluoromethylsulfonylamino group, acetylamino group, aminosulfonyl group, methylsulfonyl group, acetyl group, methoxycarbonyl group, ethoxycarbonyl group, propoxy group Luponyl group, isopropoxycarbonyl group, tert —Butoxycarbonyl, carboxy, carbamoyl, hydroxycarbamoyl, methylcarbamoyl, dimethylcarbamoyl, cyano, and particularly preferably chlorine and nitro.
  • the “lower alkyl group having 1 to 4 carbon atoms” for R 15 is preferably a methyl group.
  • the “halogen atom” for R 15 is preferably a fluorine atom or a chlorine atom, and particularly preferably a fluorine atom.
  • R 15 is preferably a hydrogen atom, a methyl group, a fluorine atom, a chlorine atom, a nitro group, or a hydroxyl group, and particularly preferably a hydrogen atom.
  • the “lower alkyl group having 1 to 4 carbon atoms” for R 24 is preferably a methyl group.
  • A is a group represented by the aforementioned general formula (II), and R t and R 2 are ethyl groups.
  • R 3 , R 4 , R 10 R n and R 15 are hydrogen atoms
  • R 5 is a methoxy group or a dimethylamino group
  • R 6 is a methoxy group
  • R 12 is a chlorine atom
  • R 13 is A hydroxyl group
  • R 14 is a chlorine atom or a nitro group.
  • “Pharmaceutically acceptable salt” may be any salt that forms a non-toxic salt with the compound represented by the above general formula (I). Examples thereof include hydrochloride and bromide.
  • Inorganic acid salts such as hydrochloride, hydroiodide, sulfate, nitrate, phosphate, carbonate, hydrogencarbonate, perchlorate; formate, acetate, trifluoroacetate, propionate , Oxalate, glycolate, succinate, lactate, maleate, hydroxymaleate, methylmaleate, fumarate Acid salt, adipate, tartrate, malate, citrate, benzoate, citrate, ascorbate, salicylate, 2-acetoxybenzoate, nicotinate, isonicotinate
  • Organic salts such as methanesulfonate, ethanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, naphthalen
  • Acidic amino acid salts Alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; ammonium salts; organic compounds such as trimethylamine salts, triethylamine salts, pyridine salts and picone salts Base salts; and amino acid salts such as lysine salts and arginine salts. In some cases, it may be a hydrate or a solvate with an alcohol or the like.
  • the compound of the present invention has excellent CRF receptor antagonism, and is therefore expected as an agent for preventing or treating diseases in which CRF is induced or promoted.
  • a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is used as a pharmaceutical preparation, it is usually a known pharmacologically acceptable carrier.
  • Excipients, diluents, extenders, disintegrants, stabilizers, preservatives, buffers, emulsifiers, fragrances, colorants, sweeteners, thickeners, corrigents, dissolution aids, and other additives Water, vegetable oils, alcohols such as ethanol or benzyl alcohol, carbohydrates such as polyethylene glycol, glycerol triazetate gelatin, lactose, starch, etc., magnesium stearate, talc, lanolin, petrolatum Tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, troches, aerosols, elixirs It can be administered orally or parenterally in the form of tablets, suspensions,
  • the compounds of the present invention can be used not only as human medicines but also as animal medicines. Can be used.
  • the dose may vary depending on the type and degree of the disease, the compound to be administered and the administration route, the age, sex, weight and the like of the patient.
  • the compound (I) is usually 1 to L per adult per day. It is preferred to administer 000 mg, especially from 5 Omg to 80 Omg.
  • the compound of the present invention can be produced, for example, by the following method.However, the method of producing the compound of the present invention is not limited thereto, and the compound is synthesized by using a known technique. It is possible.
  • the compound when A in the general formula (I) is the general formula (II), the compound can be synthesized by the following method.
  • the following manufacturing method is R t . Is particularly effective when it is a hydrogen atom.
  • Compound (V) (wherein R 1D ′ is a hydrogen atom, and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as described above) are compound (IV) (wherein Ri, R 2 , R 3 , R 4 , R 5, and R 6 are as described above), and an organic solvent such as methanol, ethanol, dimethylformamide, ether, dioxane, tetrahydrofuran, and ethyl acetate, water, or a mixed solvent thereof.
  • an organic solvent such as methanol, ethanol, dimethylformamide, ether, dioxane, tetrahydrofuran, and ethyl acetate, water, or a mixed solvent thereof.
  • the compound (IV) is tin chloride, zinc, iron, nitrous acid Ethyl acetate, acetic acid, methanol, ethanol, ether, tetrahydrofuran, if necessary, in the presence of a reducing agent such as sodium, sodium sulfide, sodium disulfide, etc., with ammonium chloride, hydrochloric acid, etc.
  • a metal catalyst catalytic reduction with hydrogen gas
  • the compound (IV) is tin chloride, zinc, iron, nitrous acid Ethyl acetate, acetic acid, methanol, ethanol, ether, tetrahydrofuran, if necessary, in the presence of a reducing agent such as sodium, sodium sulfide, sodium disulfide, etc., with ammonium chloride, hydrochloric acid, etc.
  • Jiokisan diisopropyl ether, dimethoxyethane E Tan, organic solvent, water or a mixed solvent or without solvent thereof such as toluene, can it to synthesized by reacting under cooling to under heating.
  • R lt , R 12 , R 13 , R 14 and R 15 are as described above) in the presence or absence of a base such as triethylamine, pyridine, N-methylmorpholine, N-methylpiperidine, dichloromethane,
  • a base such as triethylamine, pyridine, N-methylmorpholine, N-methylpiperidine, dichloromethane
  • an organic solvent such as lume, toluene, ether, tetrahydrofuran, dioxane, diisopropylether, dimethoxyethane, ethyl acetate, or a mixed solvent thereof, or without
  • the compound (V) is synthesized from the compound (VII) as shown below. May be.
  • Compound (VIII) (wherein, R 3 is an amino-protecting group such as a tert-butoxycarbonyl group or a benzyloxycarbonyl group; and R 2 , R 3 , R 4 , R 6, and R l ( ) 'Is as described above) is a compound (VII) (wherein RR 2 , R 3 , R 4 , R 5 and R 6 are as defined above), and diphenylphosphoryl azide (DPPA) or the like.
  • DPPA diphenylphosphoryl azide
  • Organic solvent such as dioxane, ether, dichloromethane, tetrahydrofuran, methanol, ethanol, chloroform, benzene, toluene, ethyl acetate, etc., in water or in a mixed solvent or without solvent, under cooling or heating Or reacting compound (VIII) with an organic solvent such as methanol, ethanol, dimethylformamide, ether, dioxane, tetrahydrofuran, ethyl acetate, water or a mixed solvent thereof, palladium carbon, oxidation Gold, Raney nickel, para Jiumu black, the presence of a metal catalyst such as palladium hydroxide can be synthesized by synthesizing the Rukoto to catalytic reduction under a hydrogen gas.
  • the compound when R lfl in the general formula (I) is other than a hydrogen atom, the compound can be also synthesized by treating the compound (I-11) synthesized in the above step 2 in the following step.
  • the compound defined by the general formula (I) can also be synthesized by synthesizing the corresponding compound in the above step 2 or step 5 and then treating in the following step.
  • Compound (I- 14 ) (wherein, Rp R 2 , R 3 , R 4 , R 5 , R 10 , R 1 R 12 , R I 3 , R 14 , R 15 and R 16 are as described above) Is a compound (1-3) wherein R 2 , R 3 , R 4 , R 5 , R 10 , R H , R 12 , R 13 , R 14 and R ! 5 are as defined above.
  • X 2 —R 16 (wherein R 16 and X 2 are as described above) or trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester, etc., in potassium carbonate or sodium carbonate.
  • It can be synthesized by reacting in an organic solvent such as dimethylformamide, acetone, toluene or tetrahydrofuran or a mixed solvent thereof under heating in the presence of a base such as sodium hydrogencarbonate or sodium hydride.
  • organic solvent such as dimethylformamide, acetone, toluene or tetrahydrofuran or a mixed solvent thereof under heating in the presence of a base such as sodium hydrogencarbonate or sodium hydride.
  • R 22 in the general formula (I) is an alkali metal or a phosphono group, or when 3 is —Y_R 23 , the compound (1_5) or the compound (1) in which the corresponding R 13 is a hydroxyl group or an amino group, respectively.
  • it can be synthesized by treating in the following step. That is, it can be synthesized by the following step 7 when R 22 is an alkali metal or a phosphono group, or by the following step 8 when R 13 is —Y_R 23 .
  • Compound (I _ 6) (wherein, R 22 'is an alkali metal, a phosphono radical, R ⁇ , R 2, R 3, R 4, R 5, R 6, R 10, R u, R 12, R 14 and R 15 are as defined above der Ru), the compound (15) (wherein, RR 2, R 3, R 4, R 5, R 6, R 10, R, PR 12, R 14 and R 15 is as described above) in an organic solvent such as tetrahydrofuran, ether, toluene, dimethylformamide, methanol, ethanol or the like, or water or a mixed solvent thereof in the presence of sodium hydrogen carbonate, hydrogen carbonate or the like, and under cooling.
  • an organic solvent such as tetrahydrofuran, ether, toluene, dimethylformamide, methanol, ethanol or the like, or water or a mixed solvent thereof in the presence of sodium hydrogen carbonate, hydrogen carbonate or the like, and under cooling.
  • the reaction is carried out at elevated temperature, or the compound (1-5) and a phosphorylating agent such as tetrabenzylpyrophosphate are reacted with an organic compound such as tetrahydrofuran, ether or toluene in the presence of a base such as sodium hydride.
  • a phosphorylating agent such as tetrabenzylpyrophosphate
  • an organic compound such as tetrahydrofuran, ether or toluene
  • a base such as sodium hydride
  • R 14 in the general formula (I) is a lower alkoxy group having 2 to 5 carbon atoms or a carbamoyl group which may be substituted with a lower alkyl group having 1 to 4 carbon atoms
  • the compound (I-11) in which the corresponding R 14 is a carboxy group can be synthesized by synthesizing the compound in the above step 2 and then treating it in the following step.
  • Compound (I-I2) (wherein, R 14 '' is a lower alkoxycarbonyl group having 2 to 5 carbon atoms or a rubamoyl group which may be substituted with a lower alkyl group having 1 to 4 carbon atoms.
  • R have R 2, R 3, R 4 , R 5, R 6, R 10, R, R l2, R 13 and R 15 are as defined above
  • the compound (1 1 1) (wherein , R t , R 2 , R 3 , R 4 , R 5 , R 6 , R 10 , R 1 R l2 , R 13 and R 15 are as described above) is oxalyl chloride, thionyl chloride, phosphorus trichloride
  • the reaction was carried out under cooling or heating in an organic solvent such as chloroform, dimethylformamide, dichloromethane, toluene, pyridine or a mixed solvent thereof in the presence of an acid halide such as phosphorus pentachloride, phosphorus oxychloride or the like.
  • Amin Moshiku Hydroxide ⁇ Nmoniumu like, black hole Holm, dichloromethane, tetrahydrofuran, in an organic solvent or solvent mixture of these and di Okisan, can be synthesized by reacting under cooling to under heating.
  • R l4 is 2 to 5 of the low-grade alkoxy Cal Poni Le group having a carbon number of the compound (1 1 1) and R 14 '
  • an acid such as sulfuric acid lower alkyl alcohol corresponding to, acetate Echiru
  • R 6 in the general formula (I) is a lower alkylsulfinyl group having 1 to 4 carbon atoms or a lower alkylsulfonyl group having 1 to 4 carbon atoms
  • the corresponding R 6 has 1 to 4 carbon atoms.
  • the compound (I-13) which is a lower alkylthio group, can be synthesized by synthesizing it in the above step 2 and then treating it in the following step.
  • R 5 in the general formula (I) is an amino group
  • the compound (1_15) in which the corresponding R 5 is a nitro group is synthesized in the above step 2, and then treated in the following step. Can be synthesized.
  • Compound (1-1 6) (wherein, R have R 2, R 3, R 4 , R 6, R 10, R u, R 12, R 13, R 14 and R 15 are as defined above) is compound (1-1 5) (wherein, R have R 2, R 3, R 4 , R 6, R 10, R u, R 12, R 13, R 14 and R 15 Ru as described above der )
  • a reducing agent such as tin chloride, zinc, iron, sodium dithionite, sodium sulfide, sodium disulfide, etc., if necessary, with ammonium chloride, hydrochloric acid, etc., with ethyl acetate, acetic acid, methanol, ethanol, ether, It can be synthesized by reacting under cooling or heating in an organic solvent such as tetrahydrofuran, dioxane, diisopropyl ether, dimethoxyethane, toluene or the like, water or a mixed solvent thereof, or without solvent.
  • a in the general formula (I) is the general formula (III), it can be synthesized by the following method.
  • the following manufacturing method is 1 ⁇ . Is particularly effective when it is a hydrogen atom.
  • R, R n , R, R and X are as defined above) in the presence or absence of a base such as triethylamine, pyridine, N-methylmorpholine, N-methylpiperidine, dichloromethane, chloroform , Toluene, ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethoxyethane, ethyl acetate and the like, or a mixed solvent thereof, or a reaction without cooling or heating in a solvent. .
  • a base such as triethylamine, pyridine, N-methylmorpholine, N-methylpiperidine, dichloromethane, chloroform , Toluene, ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethoxyethane, ethyl acetate and the like, or a mixed solvent thereof, or a reaction without cooling or heating in a
  • R 7 of the general formula (III) is - in the case of NR l7 R 18 is that wherein R 7 after the synthesis of the compound Ru hydroxyl der in the above step 1 3 is synthesized even cowpea to performing the following steps Can be.
  • R 7 is _NR 17 R 18 (where R 17 and R 18 are as described above), and R 8 , R 9 , R I0 ′, R 1 R 12, R 13, R l4 , R 15 and X are as defined above], the compound (1 1 8) (wherein, R 8, R 9, R 10 ', R in R 12, R 13 , R 14 , R 15 and X are the same as those described above.
  • a in the general formula (I) is the general formula (III).
  • compounds R 22 is Arukari metal or phosphono group
  • R 13 Gar Y- R 23 is the corresponding compound (I one 1 7) or (1 1 9) the step After the synthesis in 13 or 14, the compound can also be synthesized by treating in the same manner as in the above step 5 or steps 7 to 10, respectively.
  • the compounds (IV), (VI), (VII) and (IX) used in the above steps can be synthesized from commercially available products by using a known method.
  • the compound of the general formula (I) can also be synthesized by performing the above steps 1 to 4 or 13 after treating in the same manner as in step 0.
  • the substituents of the compounds used in the above steps 1 to 14 may be protected with a protecting group by a conventional method or may be subjected to each step after protecting with a protecting group, if necessary. May be desorbed by an ordinary method as needed, or may be desorbed by an ordinary method in the final step.
  • the salt of the general formula (I) or a hydrate or solvate thereof can be synthesized by a conventional method as necessary.
  • the compound (I) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization or chromatography.
  • a known separation and purification means for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization or chromatography.
  • reaction solution was concentrated under reduced pressure, water was added, and the mixture was washed with ether.
  • the aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. Wash the organic layer with saturated saline
  • the dimethylformamidine de (1 0 m l) solution of the above Production Example 1 1 obtained compound (634 mg), under ice-cooling, chloride Anmoniumu (206mg), HOB t ⁇ H 2 0 (445mg), Toriechiruamin (0.54 ml) and WS C ⁇ HC 1 (573 mg) were added, and the mixture was stirred at room temperature overnight. After stirring, a saturated saline solution was added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (1: 1).
  • the filtrate was further concentrated under reduced pressure, hexane (200 ml) was added to the obtained residue, and the mixture was stirred. After the solid was separated by filtration, the filtrate was again concentrated under reduced pressure, hexane (100 ml) was added to the residue, and the slurry was washed.
  • Example 4 To a mixed solvent of the compound obtained in Example 1 (71 mg) in tetrahydrofuran (6 ml) and water (4 ml) was added sodium hydrogen carbonate (12 mg), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried to give the title compound as white amorphous (74 mg, quantitative).
  • Example 4 To a mixed solvent of the compound obtained in Example 1 (71 mg) in tetrahydrofuran (6 ml) and water (4 ml) was added sodium hydrogen carbonate (12 mg), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried to give the title compound as white amorphous (74 mg, quantitative).
  • Example 4 To a mixed solvent of the compound obtained in Example 1 (71 mg) in tetrahydrofuran (6 ml) and water (4 ml) was added sodium hydrogen carbonate (12 mg), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried to give the
  • Triethylamine (2.2 ml) and diphenylphosphoryl azide (3.3 ml) were added to a toluene (30 ml) solution of the crude product (4.44 g) obtained in Production Example 2 described above, and the mixture was heated under reflux for 2 hours. After cooling, benzyl alcohol (1.91 ml) was added at room temperature, and the mixture was heated under reflux overnight. After allowing to cool, water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed successively with 1N sodium hydroxide solution, water, and saturated saline.
  • Example 5 To a solution of the compound (66 1 mg) obtained in the above-mentioned step 4) of Example 5 (66 1 mg) in chloroform (10 ml) was added the crude product (5 lmg) obtained in the above-mentioned Production Example 4; The mixture was refluxed for 2 hours. The reaction solution was diluted with black hole form and washed with water and saturated saline. After drying over sodium sulfate, the mixture was concentrated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-hexane to give the title compound as pale yellow crystals. 97
  • Example 9 To a mixed solution of the compound obtained in Example 7 (151 mg) in tetrahydrofuran (6 ml), methanol (2 ml) and water (4 ml) was added potassium hydrogen carbonate (29 mg), and the mixture was stirred at room temperature for 3 hours. did. After stirring, the reaction mixture was concentrated under reduced pressure and dried to obtain the title compound as orange amorphous (234 mg, yield 99%). 99
  • Example 9 To a mixed solution of the compound obtained in Example 7 (151 mg) in tetrahydrofuran (6 ml), methanol (2 ml) and water (4 ml) was added potassium hydrogen carbonate (29 mg), and the mixture was stirred at room temperature for 3 hours. did. After stirring, the reaction mixture was concentrated under reduced pressure and dried to obtain the title compound as orange amorphous (234 mg, yield 99%). 99
  • Example 9 To a mixed solution of the compound obtained in Example 7 (151 mg) in tetrahydrofuran (6 ml), methanol (2 ml)
  • the colorless oily crude product was obtained by treating the compound obtained in Production Example 8 and benzyl alcohol in the same manner as in Step 3) of Example 5 described above.
  • a colorless oil was obtained by treating the compound obtained in Production Example 10 described above and tert-butyl alcohol in the same manner as in Step 3) of Example 5 above. 106 compounds (64% yield) were obtained (
  • Example 17 The compound obtained in the above-mentioned Production Example 17 was treated in the same manner as in the above-mentioned step 1) of Example 17 to obtain a crude product as a yellow oil.
  • step 1) Using the compound obtained in the step 1) of the above-mentioned Example 9 and 4-benzodioxy-3-tert-butoxycarponylamino-5-chlorobenzoyl chloride, the step 2 of the above-mentioned Example 5 was carried out. The compound was treated in the same manner as in 1) to obtain a pale yellow amorphous compound (yield 65%).
  • Example 30 The compound (87 mg) obtained in Example 28 was dissolved in trifluoroacetic acid (3 ml) and stirred at room temperature for 1.5 hours. After stirring, the mixture was concentrated under reduced pressure and azeotroped with toluene. Thereafter, recrystallization from hexane-tetrahydrofuran gave the title compound (76 mg, yield 98%) as colorless crystals. 119
  • Example 30 The compound (87 mg) obtained in Example 28 was dissolved in trifluoroacetic acid (3 ml) and stirred at room temperature for 1.5 hours. After stirring, the mixture was concentrated under reduced pressure and azeotroped with toluene. Thereafter, recrystallization from hexane-tetrahydrofuran gave the title compound (76 mg, yield 98%) as colorless crystals. 119
  • Example 30 Example 30
  • Example 29 To a solution of the compound obtained in Example 29 (58 mg) in methanol (10 ml) was added concentrated sulfuric acid (0.05 ml), and the mixture was heated under reflux overnight. After heating under reflux, the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The obtained residue was purified by PLTC to give the title compound (5 mg, yield 8%) as an ocher solid.
  • Example 3 1 To a solution of the compound obtained in Example 29 (58 mg) in methanol (10 ml) was added concentrated sulfuric acid (0.05 ml), and the mixture was heated under reflux overnight. After heating under reflux, the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The obtained residue was purified by PLTC to give the title compound (5 mg, yield 8%)
  • Example 5 1) Using previously synthesized 3-amino-4-benzyloxy-5-ethyl-N, N-getylbenzenesulfonamide and 4-acetyloxy-3,5-dichlorobenzoyl chloride, the above-mentioned Example 5 was used. By treating in the same manner as in 1) of step 2), a compound as a milky white solid (yield 59%) was obtained.

Abstract

La présente invention concerne un composé représenté par la formule générale (I), un sel, un hydrate ou un solvate pharmaceutiquement acceptable de celui-ci. Dans cette formule A est éventuellement 3-sulfamoyphényle substitué, éventuellement 2-thienyle substitué, etc.; R10 est hydrogène ou éventuellement alkyle inférieur substitué; R11 est hydrogène, halogène ou hydroxy; R12 est hydrogène, halogène ou nitro; R13 est hydroxy, éventuellement alcoxy inférieur substitué, éventuellement alkylamino inférieur substitué, etc.; R14 est hydrogène, halogène, nitro, etc.; et R15 est hydrogène, halogène ou hydroxy. Ce composé (I) présente un effet antagonistique excellent sur le récepteur CRF. Par conséquent, on s'attend à ce qu'il soit un médicament de prévention ou de traitement pour des maladies, par exemple, causées ou aggravées par un CRF.
PCT/JP2001/001429 2000-02-25 2001-02-26 Dérivé de benzamide et utilisation de celui-ci WO2001062718A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7030145B2 (en) 2003-04-18 2006-04-18 Bristol-Myers Squibb Company Pyridinyl derivatives for the treatment of depression
US7112585B2 (en) 2003-04-18 2006-09-26 Bristol-Myers Squibb Company Pyrimidine derivatives as corticotropin releasing factor inhibitors
WO2010015655A1 (fr) * 2008-08-07 2010-02-11 Novartis Ag Dérivés de cyclohexylamide et leur utilisation en tant qu'antagonistes des récepteurs de crf-1
WO2020202072A1 (fr) * 2019-04-02 2020-10-08 Fondazione Istituto Italiano Di Tecnologia Modulateurs de la concentration de chlorure intracellulaire

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0261503A1 (fr) * 1986-09-23 1988-03-30 VALEAS S.p.A. INDUSTRIA CHIMICA E FARMACEUTICA Dérivés amido-hétérocycliques d'acides benzoiques substitués et compositions thérapeutiques les contenant comme composant actif
WO1994013661A1 (fr) * 1992-12-17 1994-06-23 Pfizer Inc. Pyrazoles substitues utilises comme antagonistes du facteur de liberation de corticotropine (crf)
WO1997000868A1 (fr) * 1995-06-21 1997-01-09 Sanofi Derives de 4-phenylaminothiazole, leur procede de preparation et les compositions pharmaceutiques les contenant
WO1997014684A1 (fr) * 1995-10-17 1997-04-24 Janssen Pharmaceutica N.V. Pyrimidines et triazines substituees par amino
WO1997035580A1 (fr) * 1996-03-27 1997-10-02 Du Pont Pharmaceuticals Company Pyrimidines et triazines a substitution aryloxy et arylthio et derives de celles-ci
WO1998005661A1 (fr) * 1996-08-06 1998-02-12 Pfizer Inc. Derives 6,6- ou 6,7-bicycliques contenant pyrido ou pyrimido substitues
WO1999012908A1 (fr) * 1997-09-09 1999-03-18 Duphar International Research B.V. Derives de quinoleine et de quinazoline possedant une activite antagoniste de facteur de liberation de corticotrophine (crf)

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0261503A1 (fr) * 1986-09-23 1988-03-30 VALEAS S.p.A. INDUSTRIA CHIMICA E FARMACEUTICA Dérivés amido-hétérocycliques d'acides benzoiques substitués et compositions thérapeutiques les contenant comme composant actif
WO1994013661A1 (fr) * 1992-12-17 1994-06-23 Pfizer Inc. Pyrazoles substitues utilises comme antagonistes du facteur de liberation de corticotropine (crf)
WO1997000868A1 (fr) * 1995-06-21 1997-01-09 Sanofi Derives de 4-phenylaminothiazole, leur procede de preparation et les compositions pharmaceutiques les contenant
WO1997014684A1 (fr) * 1995-10-17 1997-04-24 Janssen Pharmaceutica N.V. Pyrimidines et triazines substituees par amino
WO1997035580A1 (fr) * 1996-03-27 1997-10-02 Du Pont Pharmaceuticals Company Pyrimidines et triazines a substitution aryloxy et arylthio et derives de celles-ci
WO1998005661A1 (fr) * 1996-08-06 1998-02-12 Pfizer Inc. Derives 6,6- ou 6,7-bicycliques contenant pyrido ou pyrimido substitues
WO1999012908A1 (fr) * 1997-09-09 1999-03-18 Duphar International Research B.V. Derives de quinoleine et de quinazoline possedant une activite antagoniste de facteur de liberation de corticotrophine (crf)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7030145B2 (en) 2003-04-18 2006-04-18 Bristol-Myers Squibb Company Pyridinyl derivatives for the treatment of depression
US7112585B2 (en) 2003-04-18 2006-09-26 Bristol-Myers Squibb Company Pyrimidine derivatives as corticotropin releasing factor inhibitors
WO2010015655A1 (fr) * 2008-08-07 2010-02-11 Novartis Ag Dérivés de cyclohexylamide et leur utilisation en tant qu'antagonistes des récepteurs de crf-1
US8273900B2 (en) 2008-08-07 2012-09-25 Novartis Ag Organic compounds
EA020921B1 (ru) * 2008-08-07 2015-02-27 Новартис Аг Производные циклогексиламида и их применение в качестве антагонистов рецептора crf-1
WO2020202072A1 (fr) * 2019-04-02 2020-10-08 Fondazione Istituto Italiano Di Tecnologia Modulateurs de la concentration de chlorure intracellulaire

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