WO2011138916A1 - Composé polycyclique - Google Patents

Composé polycyclique Download PDF

Info

Publication number
WO2011138916A1
WO2011138916A1 PCT/JP2011/060242 JP2011060242W WO2011138916A1 WO 2011138916 A1 WO2011138916 A1 WO 2011138916A1 JP 2011060242 W JP2011060242 W JP 2011060242W WO 2011138916 A1 WO2011138916 A1 WO 2011138916A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
methyl
amino
mmol
phenyl
Prior art date
Application number
PCT/JP2011/060242
Other languages
English (en)
Japanese (ja)
Inventor
拓也 池田
高典 山崎
孝明 城島
奈々 高木
Original Assignee
第一三共株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 第一三共株式会社 filed Critical 第一三共株式会社
Publication of WO2011138916A1 publication Critical patent/WO2011138916A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/12—Oxygen atoms acylated by aromatic or heteroaromatic carboxylic acids, e.g. cocaine

Definitions

  • the present invention has an excellent neurokinin NK 1 , neurokinin NK 2 and muscarinic M 3 receptor antagonistic action, or neurokinin NK 1 and muscarinic M 3 receptor antagonistic action, bronchial asthma, chronic obstructive pulmonary disease And the like or a pharmacologically acceptable salt thereof.
  • Non-Patent Document 1 Non-Patent Document 2
  • Non-peptide low molecular compound that antagonize neurokinin NK 1 and neurokinin NK 2 both receptors has been disclosed (Patent Documents 1 and 2), approved as a drug used has not been obtained.
  • Non-Patent Document 3 Compounds that antagonize muscarinic M 3 receptor is a compound having a bronchodilation (Patent Document 3, Patent Document 4, Patent Document 5), it has been used as a bronchodilator agent (Non-Patent Document 4).
  • Patent Document 6 Than by antagonizing both muscarinic M 3 receptors and neurokinin receptors, exerting strong bronchodilation over bronchodilation, each of which is exhibited alone is disclosed (Patent Document 6).
  • a compound that antagonizes both neurokinin NK 1 and neurokinin NK 2 receptors or a compound that antagonizes neurokinin NK 1 receptor is not marketed as a bronchial asthma or COPD therapeutic agent, a single agent is used in combination. There is a problem that it cannot be done.
  • Neurokinin NK 1 , neurokinin NK 2 and muscarinic M 3 receptor are antagonized, or neurokinin NK 1 and muscarinic M 3 receptor are antagonized, resulting in strong bronchodilator action, anti-inflammatory action, antitussive expectorant action
  • the present inventors have completed the present invention by finding a compound that shows antagonistic action on all receptors, or both neurokinin NK 1 and muscarinic M 3 receptors, and shows sustained drug efficacy.
  • the present invention comprises (1) general formula (I)
  • Y represents a partial structure having a neurokinin NK 1 and neurokinin NK 2 receptor antagonistic action or a partial structure having a neurokinin NK 1 receptor antagonistic action;
  • A is represented by a single bond, a triple bond, an oxygen atom, a carbonyl group, a carbonylamino group, an aminocarbonyl group, a group represented by the formula (II), a group represented by the formula (III), or a formula (IV).
  • R 1 represents a hydrogen atom or a C 1 -C 6 alkyl group
  • R 2 represents a hydrogen atom or a C 1 -C 6 alkyl group
  • R 3 represents a hydrogen atom or a C 1 -C 6 alkyl group
  • L 1 represents an oxycarbonyl group, a carbonyloxy group, a (methylamino) carbonyl group or a carbonyl (methylamino) group
  • L 2 represents a single bond or a phenylene group
  • L 3 represents a C 1 -C 6 alkylene group
  • p represents an integer of 1 to 6
  • q represents an integer of 0 to 4
  • r represents an integer of 1 to 8
  • s represents an integer of 1 to 8
  • t represents an integer of 1 to 4
  • CY and CE represent a single bond.
  • C Y is bonded to the group represented by Formula Y
  • C E is bonded to the group represented by Formula E.
  • R 2 is a C 1 -C 6 alkyl group
  • any carbon atom of R 2 may be bonded to any carbon atom of L 3 .
  • E represents a partial structure having a muscarinic M 3 receptor antagonistic action
  • m represents an integer of 0 to 4
  • n represents an integer of 1 to 8.
  • Y is a group represented by formula (V), a group represented by formula (VI) or a group represented by formula (VII)
  • R 4 is independently substituted with 1 to 5 phenyl groups which may be independently substituted with a group selected from substituent group A or with a group selected from substituent group A;
  • a good heterocyclic group R 5 may be independently substituted with 1 to 5 groups independently selected from substituent group A, or may be independently substituted with 1 to 3 groups independently selected from phenyl group or group selected from substituent group A
  • a good heterocyclic group R 6 represents a hydrogen atom or a C 1 -C 6 alkyl group
  • R 7 may be independently substituted with a group selected from Substituent Group A and may be independently substituted with 1 to 5 phenyl groups, or may be independently substituted with 1 to 3 groups selected from Substituent Group A
  • a good heterocyclic group u represents 1 or 2
  • Substituent group A includes a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a hydroxy group,
  • C m represents a single bond and is bonded to a group represented by the formula — (CH 2 ) m —. Or a pharmacologically acceptable salt thereof.
  • E is represented by the group represented by the formula (VIII), the group represented by the formula (IX), the group represented by the formula (X), the group represented by the formula (XI) or the formula (XII).
  • (C n represents a single bond, and is bonded to a group represented by the formula — (CH 2 ) n —) or a pharmacologically acceptable salt thereof.
  • R 1 is a hydrogen atom or a methyl group
  • L 1 is an oxycarbonyl group, a carbonyloxy group, a (methylamino) carbonyl group or a carbonyl (methylamino) group
  • L 2 is a single bond or a phenylene group.
  • a pharmaceutical composition comprising as an active ingredient the compound according to any one of (1) to (15) or a pharmacologically acceptable salt thereof.
  • the pharmaceutical composition is used for treating and / or treating a disease mediated by neurokinin NK 1 , neurokinin NK 2 and / or muscarinic M 3 receptor or a disease mediated by neurokinin NK 1 and / or muscarinic M 3 receptor. Or the pharmaceutical composition as described in (16) for prevention.
  • the pharmaceutical composition is bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, sputum secretion, rhinitis, pain, anxiety, depression, convulsions, parkinson, urinary incontinence, irritable bowel syndrome, prostatic hypertrophy, vomiting (16) for the treatment and / or prevention of peptic ulcer, retinal examination, acute ulceris, keratitis, miosis, excessive salivation by anesthetic, airway secretion and / or ulcer object.
  • the pharmaceutical composition is used for the treatment of bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, sputum hypersecretion, pain, anxiety, depression, convulsions, Parkinson, irritable bowel syndrome and / or prostate hypertrophy and / or The pharmaceutical composition as described in (16) for prevention.
  • the pharmaceutical composition is used to treat a disease mediated by neurokinin NK 1 , neurokinin NK 2 and / or muscarinic M 3 receptor or a disease mediated by neurokinin NK 1 and / or muscarinic M 3 receptor and / or Or use as described in (25) which is a composition for prevention.
  • the pharmaceutical composition is bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, sputum hypersecretion, rhinitis, pain, anxiety, depression, convulsions, parkinson, urinary incontinence, irritable bowel syndrome, prostatic hypertrophy, vomiting
  • a composition for the treatment and / or prevention of peptic ulcer, retinal examination, acute ulceris, keratitis, miosis, excessive salivation by anesthetics, airway secretion and / or ulcers (25) Use of.
  • the pharmaceutical composition is used to treat bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, sputum hypersecretion, pain, anxiety, depression, convulsions, Parkinson, irritable bowel syndrome and / or prostatic hypertrophy and / or The use according to (25), which is a composition for prevention.
  • composition is a composition for treatment and / or prevention of bronchial asthma and / or chronic obstructive pulmonary disease.
  • the disease is a disease mediated by neurokinin NK 1 , neurokinin NK 2 and / or muscarinic M 3 receptor or a disease mediated by neurokinin NK 1 and / or muscarinic M 3 receptor (34) The method described.
  • Diseases include bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, sputum secretion, rhinitis, pain, anxiety, depression, convulsions, parkinson, urinary incontinence, irritable bowel syndrome, prostatic hypertrophy, vomiting, digestion (34)
  • the method according to (34) which is a sex ulcer, retinal examination, acute ulceris, keratitis, miosis, excessive salivation by anesthetic, airway secretion and / or ulcer.
  • the disease is bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, sputum hypersecretion, pain, anxiety, depression, convulsions, Parkinson, irritable bowel syndrome and / or prostate hypertrophy (34) the method of.
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • a fluorine atom or a chlorine atom Preferable is a fluorine atom or a chlorine atom, and more preferable is a fluorine atom.
  • the “C 1 -C 6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms.
  • the “C 1 -C 6 halogenated alkyl group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 6 alkyl group”.
  • halogen atoms 1 to 5 “halogen atoms”
  • trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl or 2,2,2-trifluoroethyl group, and preferably 1 to 5 of the above-mentioned “halogen atoms” are the same or different.
  • Is a group bonded to the “C 1 -C 4 alkyl group” (C 1 -C 4 halogenated alkyl group), and more preferably, the same or different 1 to 5 “halogen atoms” are A group bonded to a “C 1 -C 2 alkyl group” (C 1 -C 2 halogenated alkyl group), and more preferably a trifluoromethyl group.
  • the “C 1 -C 6 alkoxy group” is a group in which the “C 1 -C 6 alkyl group” is bonded to an oxygen atom, and is a linear or branched alkoxy group having 1 to 6 carbon atoms. It is.
  • a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy or pentoxy group preferably a linear or branched alkoxy group having 1 to 4 carbon atoms (C 1 -C 4 alkoxy group), more preferably, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group (C 1 -C 3 alkoxy group), even more preferably at a methoxy group.
  • the “C 1 -C 6 halogenated alkoxy group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 6 alkoxy group”.
  • trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, fluoromethoxy, or 2,2,2-trifluoroethoxy group preferably the same or different 1 to 5 “halogen atoms”.
  • Is a group bonded to the “C 1 -C 4 alkoxy group” (C 1 -C 4 halogenated alkoxy group), and more preferably, the same or different 1 to 5 “halogen atoms” are A group bonded to a “C 1 -C 2 alkoxy group” (C 1 -C 2 halogenated alkoxy group), and more preferably a trifluoromethoxy group.
  • the “C 2 -C 7 alkylcarbonyloxy group” is a group in which one carbonyl group bonded to the “C 1 -C 6 alkyl group” is bonded to an oxygen atom.
  • acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, pivaloyloxy, valeryloxy or isovaleryloxy group and preferably one of the above-mentioned “C 1 -C 4 alkyl groups” is bonded.
  • a group in which a carbonyl group is bonded to an oxygen atom C 2 -C 5 alkylcarbonyloxy group), and more preferably an acetoxy group.
  • the “C 2 -C 7 alkoxycarbonyloxy group” is a group in which one carbonyl group bonded to the “C 1 -C 6 alkoxy group” is bonded to an oxygen atom.
  • methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, s-butoxycarbonyloxy or t-butoxycarbonyloxy group preferably one of the above-mentioned “C 1 —
  • a carbonyl group to which a “C 4 alkoxy group” is bonded is a group (C 2 -C 5 alkoxycarbonyloxy group) bonded to an oxygen atom, and more preferably a methoxycarbonyloxy group.
  • the “heterocyclic group” contains 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, and may further contain 1 or 2 nitrogen atoms, and the sulfur atom contains 2 oxygen atoms.
  • a heterocyclic group such as benzothienyl, benzothiazolyl, benzoxazolyl, isobenzofuranyl, 1,3-dihydroisobenzofuranyl, quinolyl, 1,3-benzodioxolanyl, 1,4-benzodi Oxanyl, indolyl, isoindolyl or indolinyl group.
  • the “phenyl group which may be independently substituted with 1 to 5 groups selected from the substituent group A” is independently 1 to 5 groups with a phenyl group or a group selected from the substituent group A. This is a phenyl group that is substituted.
  • a 4-fluorophenyl group, a 2-methylphenyl group, a 3,5-bis (trifluoromethyl) phenyl group, or a 3,4,5-trimethoxyphenyl group is preferable.
  • the “heterocyclic group optionally substituted by 1 to 3 groups independently selected from the substituent group A” is the above-mentioned “heterocyclic group” or a group selected from the substituent group A.
  • the “heterocyclic group” is independently 1 to 3 substituted.
  • a “C 1 -C 6 alkylene group” is a divalent group formed by removing 2 hydrogen atoms from a straight or branched chain saturated hydrocarbon having 1 to 6 carbon atoms.
  • methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, pentamethylene or hexamethylene group preferably methylene group
  • the “phenylene group” is a divalent group formed by removing two hydrogen atoms from benzene, and is a 1,2-phenylene group, a 1,3-phenylene group, or a 1,4-phenylene group.
  • a 1,3-phenylene group or a 1,4-phenylene group is preferred.
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has all isomers (keto-enol isomer, diastereoisomer, optical isomer, rotational isomer, etc.).
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers because an asymmetric carbon atom is present in the molecule.
  • these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.
  • an optically active raw material compound is used, or a compound according to the present invention is synthesized using an asymmetric synthesis or asymmetric induction method, or a synthesized compound according to the present invention is synthesized. If desired, it can be obtained by isolation using a conventional optical resolution method or separation method.
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may also contain an unnatural proportion of atomic isotopes at one or more of atoms constituting such a compound.
  • atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
  • the compound may also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the pharmacologically acceptable salt refers to a salt that has no significant toxicity and can be used as a medicine.
  • the compound having the general formula (I) of the present invention is reacted with an acid when it has a basic group such as an amino group, and with a base when it has an acidic group such as a carboxyl group. It can be made into a salt by reacting.
  • Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; C 1 -C 6 alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.
  • Organic acid salts such as aryl sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, succinate, maleate; and glycine salt And amino acid salts such as lysine salt, arginine salt, ornithine salt, glutamate and aspartate.
  • examples of the salt based on the acidic group include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt.
  • Inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts , Dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt Amine salts such as organic salt
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may be left in the air or recrystallized to take in water molecules and become a hydrate. Such hydrates are also included in the salts of the present invention.
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also a solvate of the present invention. Included in the salt.
  • a compound having neurokinin NK 1 , neurokinin NK 2 and muscarinic M 3 receptor antagonistic activity refers to a neurokinin NK 1 receptor antagonistic activity, a neurokinin NK 2 receptor antagonistic activity and a muscarinic M 3 receptor antagonistic activity. It is a compound which has all the antagonism of.
  • the “compound having a neurokinin NK 1 and muscarinic M 3 receptor antagonism” is a compound having both a neurokinin NK 1 receptor antagonism and a muscarinic M 3 receptor antagonism.
  • “Has a neurokinin NK 1 receptor antagonistic activity” means that it has a specific binding ability to a neurokinin NK 1 receptor-expressing cell crude membrane specimen and has a neurokinin NK 1 receptor such as substance P-induced airway contraction. It means having a neurokinin NK 1 receptor antagonism evaluated by inhibiting or suppressing the action of a body agonist, and whether or not a specific compound has such an antagonism can be determined by those skilled in the art, For example, it can be easily determined according to the following method.
  • “Has a neurokinin NK 2 receptor antagonistic activity” means that it has a specific binding ability to a neurokinin NK 2 receptor-expressing cell crude membrane specimen, and also neurokinin NK 2 such as neurokinin A-induced airway contraction. It means having a neurokinin NK 2 receptor antagonism evaluated by inhibiting or suppressing the action of a receptor agonist, and whether or not a specific compound has such an antagonism can be determined by those skilled in the art. For example, it can be easily determined according to the following method.
  • the applied method is based on the measurement method (2.3 Receptor binding assay) described in the literature (European Journal of Pharmacology, 2008, vol. 586, pages 306-312), and is determined in advance by setting the neurokinin NK 2 receptor binding ability.
  • the measurement method 2.6 Bronchoconstriction in guinea pigs.
  • “Has muscarinic M 3 receptor antagonism” means that it has a specific binding ability to a cell membrane preparation expressing muscarinic M 3 receptor and an action of a muscarinic M 3 receptor agonist such as acetylcholine-induced airway contraction It has a muscarinic M 3 receptor antagonism evaluated by inhibiting or suppressing the activity, and whether or not a specific compound has such an antagonism can be determined by a person skilled in the art by, for example, the following method Can be easily discriminated according to
  • a method for identifying a “compound having neurokinin NK 1 , neurokinin NK 2 and muscarinic M 3 receptor antagonistic activity” is also encompassed in the present invention.
  • the method comprises the steps of (i) determining whether a test compound has a neurokinin NK 1 receptor antagonism, (ii) whether the test compound has a neurokinin NK 2 receptor antagonism And (iii) determining whether or not the test compound has muscarinic M 3 receptor antagonism.
  • the steps (i) to (iii) can be performed in an arbitrary order or two or more steps simultaneously in parallel.
  • the test compound determined to have each receptor antagonistic activity in any of steps (i) to (iii) is referred to as “a compound having neurokinin NK 1 , neurokinin NK 2 and muscarinic M 3 receptor antagonistic activity”. Identify.
  • a method of identifying a “compound having neurokinin NK 1 and muscarinic M 3 receptor antagonistic activity” is also encompassed in the present invention.
  • the method includes (i) a step of determining whether or not a test compound has a neurokinin NK 1 receptor antagonism; and (iii) whether or not the test compound has a muscarinic M 3 receptor antagonism.
  • the test compound determined to have each receptor antagonism in either step (i) or (iii) is identified as “a compound having neurokinin NK 1 and muscarinic M 3 receptor antagonism”.
  • Step (i) includes (a) measuring the neurokinin NK 1 receptor binding ability of the test compound, and (b) determining whether the compound inhibits or suppresses the action of the neurokinin NK 1 receptor agonist.
  • the neurokinin NK 1 receptor agonist include substance P and the like.
  • the action of the neurokinin NK 1 receptor agonist include substance P-induced airway contraction.
  • Step (ii) includes (c) measuring the neurokinin NK 2 receptor binding ability of the test compound and (d) determining whether the compound inhibits or suppresses the action of the neurokinin NK 2 receptor agonist.
  • the neurokinin NK 2 receptor agonist include neurokinin A.
  • the action of the neurokinin NK 2 receptor agonist include neurokinin A-induced airway contraction.
  • Step (iii) comprises (e) measuring the muscarinic M 3 receptor binding ability of the test compound and (f) determining whether the compound inhibits or suppresses the action of the muscarinic M 3 receptor agonist.
  • the muscarinic M 3 receptor agonist for example, may be mentioned acetylcholine, a methacholine like. Examples of the action of a muscarinic M 3 receptor agonist include acetylcholine-induced airway contraction.
  • the tissue or cell of an animal that endogenously expresses the receptor polypeptide, or a transgenic animal that expresses a recombinant receptor polypeptide or Cell membrane fractions, intact cells, etc., and labeled receptor binding substances can be used.
  • a compound having a neurokinin NK 1 , neurokinin NK 2 and muscarinic M 3 receptor antagonistic activity or “a compound having a neurokinin NK 1 and muscarinic M 3 receptor antagonistic activity” and
  • the identified compound is useful as a medicine, as described later, and in particular, bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, sputum hypersecretion, rhinitis, pain, anxiety, depression, convulsions, parkinson, urine
  • a preventive or therapeutic agent for incontinence, irritable bowel syndrome, prostatic hypertrophy, vomiting, peptic ulcer, retinal examination, acute ulceris, keratitis, miosis, excessive salivation by anesthetic, airway secretion and / or ulcer Useful As a preventive or therapeutic agent for incontinence, irritable bowel syndrome, prostatic hypertrophy, vomiting, peptic ulcer, retinal examination, acute ulceris, kera
  • the method for identifying “a compound having neurokinin NK 1 , neurokinin NK 2 and muscarinic M 3 receptor antagonistic activity” of the present invention is also included in the present invention as a method for identifying a prophylactic or therapeutic agent for such diseases. It is.
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is for neurokinin NK 1 , neurokinin NK 2 and muscarinic M 3 receptor, or neurokinin NK 1 and muscarinic M 3. Since it shows an antagonistic action against the receptor, it is useful as a medicine. Urinary incontinence, irritable bowel syndrome, prostatic hypertrophy, vomiting, peptic ulcer, retinal examination, acute ulceris, keratitis, miosis, excessive salivation by anesthetic, airway secretion and / or ulcer preventive or therapeutic agent As useful.
  • the compound having the general formula (I) of the present invention can be produced according to the literature and examples described below.
  • the partial structure having a neurokinin NK 1 and neurokinin NK 2 receptor antagonistic action or the partial structure having a neurokinin NK 1 receptor antagonistic action is the method described in US7365067, US2003 / 4157 or the like, or similar Manufactured according to the method.
  • Partial structure having a muscarinic M 3 receptor antagonism US2004 / 167167, JP-US2005 / 203,167 discloses, it is prepared according to methods analogous manner or it is described in EP1213281 Patent Publication.
  • the site connecting the two partial structures is Tetrahedron Lett. 1991, 32, 4505, J.M. Org. Chem. 1989, 54, 5522, Organic Letters, Vol. 4, no. 5, 2002; 737-740, etc., or according to the examples described below.
  • the amino group, hydroxy group and / or carboxyl group may be protected using a protecting group as necessary. Processes that require protection / deprotection are described in known methods (eg “Protective Groups Organic Synthesis” (written by Theodora W. Greene, Peter G. M.Wuts, W1999, published by Wiley-Interscience Publication)) Method).
  • the administration form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is, for example, oral administration by tablets, capsules, granules, powders or syrups, or injections or suppositories. Parenteral administration, etc.
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof can be administered pulmonary as a powder, solution or suspension. Formulations for these are produced by well-known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, and diluents.
  • Excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbit, starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin or carboxymethyl starch, crystalline cellulose, low degree of substitution Organic excipients such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internally crosslinked sodium carboxymethylcellulose sodium, gum arabic, dextran, or pullulan; or light anhydrous silicic acid, synthetic silicic acid Silicate derivatives such as aluminum or magnesium aluminate metasilicate, phosphates such as calcium phosphate, carbonates such as calcium carbonate, or It may be inorganic excipients such sulfates such as calcium sulfate.
  • sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbit
  • starch derivatives such as corn starch, potato starch, ⁇ -
  • Lubricants include, for example, stearic acid metal salts such as stearic acid, calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as bee gum or gay wax; boric acid; adipic acid; sulfuric acid such as sodium sulfate Salt; glycol; fumaric acid; sodium benzoate; DL-leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acid such as anhydrous silicic acid or silicic acid hydrate; or the above starch It can be a derivative.
  • stearic acid metal salts such as stearic acid, calcium stearate or magnesium stearate
  • talc colloidal silica
  • waxes such as bee gum or gay wax
  • boric acid adipic acid
  • sulfuric acid such as sodium sulfate Salt
  • glycol fumaric acid
  • the binder may be, for example, polyvinyl pyrrolidone or macrogol, or a compound similar to the excipient.
  • the disintegrant may be, for example, the same compound as the excipient, or a chemically modified starch / cellulose such as croscarmellose sodium, carboxymethyl starch sodium, or cross-linked polyvinyl pyrrolidone.
  • Stabilizers include, for example, paraoxybenzoates such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; Dehydroacetic acid; or sorbic acid.
  • the flavoring agent can be a commonly used sweetener, acidulant, fragrance or the like.
  • the compound of the present invention is combined with water or water. It can be produced by dissolving or suspending it in a mixture of a co-solvent (for example, ethanol, propylene glycol, polyethylene glycol, etc.).
  • a co-solvent for example, ethanol, propylene glycol, polyethylene glycol, etc.
  • Such solutions or suspensions may further comprise preservatives (eg benzalkonium chloride), solubilizers (eg polysorbates such as Tween 80 or Span 80, or surfactants such as benzalkonium chloride). ), Buffering agents, isotonic agents (eg, sodium chloride), absorption enhancers and / or thickeners.
  • the suspension may further contain a suspending agent (for example, microcrystalline cellulose, sodium carboxymethyl cellulose, etc.).
  • composition for pulmonary administration produced as described above is directly administered to the nasal cavity or oral cavity by means common in the field of inhalants (for example, using a dropper, pipette, cannula or nebulizer).
  • a nebulizer the compound of the present invention is combined with a suitable propellant (eg, a chlorofluorocarbon such as dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or a gas such as carbon dioxide) in a pressurized pack. It can be sprayed as a shaped aerosol or administered using a nebulizer.
  • a suitable propellant eg, a chlorofluorocarbon such as dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or a gas such as carbon dioxide
  • the amount of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof varies depending on the symptom, age, etc. of the patient (warm-blooded animal, particularly human).
  • the lower limit is 0.1 mg (preferably 1 mg, more preferably 5 mg) and the upper limit is 1000 mg (preferably 100 mg, more preferably 50 mg) divided into 1 or several times. It is desirable to administer depending on the symptoms.
  • the lower limit is 0.01 mg (preferably 0.1 mg) and the upper limit is 100 mg (preferably 10 mg) per day for adults. Is desirable.
  • the amount used in the case of pulmonary administration of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof varies depending on the symptom, age, etc. of the patient (warm-blooded animal, particularly human).
  • the lower limit is 0.1 ⁇ g / kg (preferably 0.5 ⁇ g / kg) and the upper limit is 10,000 ⁇ g / kg (preferably 1000 ⁇ g / kg) once or several times. It is desirable to administer depending on
  • Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography).
  • TLC Thin Layer Chromatography
  • a silica gel 60F 254 manufactured by Merck or TLC plates NH manufactured by Fuji Silysia is used as a TLC plate, and a solvent used as an elution solvent in column chromatography is used as a developing solvent.
  • a UV detector was adopted.
  • the silica gel for the column is also silica gel SK-85 (230-400 mesh), SK-34 (70-230 mesh) manufactured by Kishida Chemical, silica gel 60N (40-50 ⁇ m) manufactured by Kanto Chemical, Chromatorex manufactured by Fuji Silysia.
  • NH DM1020 100 to 200 mesh
  • DM2035SG 200 to 350 mesh
  • silica gel FL100B manufactured by Fuji Silysia Chemical Ltd.
  • Yamazen's automatic chromatography device Yamazen's automatic chromatography device
  • disposable columns Mertex, Yamazen, Wako Pure Chemical Industries
  • the abbreviations used in the examples have the following significance.
  • HATU O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate
  • WSC ⁇ HCl 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride
  • HOBT ⁇ H 2 O 1-hydroxybenzotriazole monohydrate.
  • 1 H NMR nuclear magnetic resonance
  • MS Mass spectrometry
  • Example 1a 6- [Benzyl (methyl) amino] -4- (2-methylphenyl) pyridine-3-carboxamide N-tert-butyl-6-chloro-4-described in the literature (US 6297375 B1)
  • a mixture of (2-methylphenyl) pyridine-3-carboxamide (32.3 g, 99.7 mmol) and N-benzylmethylamine (64.3 mL, 498.5 mmol) was heated and stirred at 100 ° C. for 20 hours.
  • the reaction mixture was diluted with ethyl acetate, water was added, and the mixture was extracted with ethyl acetate (x2). The organic layer was washed with saturated brine.
  • Example 1b 6- [Benzyl (methyl) amino] -4- (2-methylphenyl) pyridine-3-carboxamide 6- (methylamino) -4- (, a by-product obtained in Example 1a 2-methylphenyl) pyridine-3-carboxamide (15.6 g, 64.7 mmol) in N, N-dimethylformamide solution (130 mL) and potassium carbonate (13.4 g, 97.2 mmol) and benzyl bromide (11 .6 mL, 97.2 mmol) was added, and the mixture was stirred at 80 ° C. for 4 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed successively with water (x3) and saturated brine.
  • the reaction solution was chlorinated with 6- [benzyl (methyl) amino] -4- (2-methylphenyl) pyridine-3-carboxamide (23.7 g, 71.6 mmol) obtained in Examples 1a and 1b.
  • a methylene-methanol mixed solution (4: 1, 477 mL)
  • the mixture was stirred at room temperature for 1 hour.
  • 1N Hydrochloric acid was added to the reaction mixture to adjust the reaction mixture to pH 8-9, and the mixture was extracted with methylene chloride ( ⁇ 3). The organic layer was washed with saturated brine.
  • Example 1e 2- [3,5-bis (trifluoromethyl) phenyl] -N, 2-dimethyl-N- [6- (methylamino) -4- (2-methylphenyl) pyridin-3-yl Propanamide N 2 -benzyl-N 2 , N 5 -dimethyl-4- (2-methylphenyl) pyridine-2,5-diamine (16.2 g, 51.0 mmol) obtained in Example 1d in methylene chloride N, N-diisopropylethylamine (9.4 mL, 54.0 mmol) was added to the solution (140 mL), and 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl chloride ( 15.6 g, 49.1 mmol) was slowly added dropwise and stirred at room temperature for 30 minutes.
  • the reaction solution was filtered using Celite.
  • the residue obtained by distilling off the solvent under reduced pressure was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate ( ⁇ 2), and the organic layer was washed with saturated brine.
  • Example 1g 2- [3,5-bis (trifluoromethyl) phenyl] -N- ⁇ 6-[(7-hydroxyhept-2-in-1-yl) (methyl) amino] -4- (2-Methylphenyl) pyridin-3-yl ⁇ -N, 2-dimethylpropanamide
  • the compound (649 mg, 0.756 mmol) obtained in Example 1f was dissolved in tetrahydrofuran (8 mL), and tetrabutylammonium fluoride ( 1M-tetrahydrofuran solution, 0.908 mL, 0.908 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours.
  • Example 1j (3R) -1- ⁇ 7-[ ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino] -4- (2-Methylphenyl) pyridin-2-yl ⁇ (methyl) amino] hept-5-in-1-yl ⁇ pyrrolidin-3-yl hydroxy (di-2-thienyl) acetate
  • Compound obtained in Example 1g 100 mg, 0.161 mmol
  • ethyl acetate 3 mL
  • triethylamine 54 ⁇ L, 0.194 mmol
  • methanesulfonyl chloride (30 ⁇ L, 0.194 mmol) were added under ice cooling, followed by the same temperature.
  • Example 1i was obtained.
  • yl hydroxy (dithiophen-2-yl) acetate 55 mg, 0.177 mmol
  • potassium carbonate 33 mg, 0.242 mmol
  • potassium iodide 29 mg, 0.177 mmol
  • Example 2a 2- [3,5-bis (trifluoromethyl) phenyl] -N- ⁇ 6-[(5- ⁇ [tert-butyl (diphenyl) silyl] oxy ⁇ pent-2-yne-1- Yl) (methyl) amino] -4- (2-methylphenyl) pyridin-3-yl ⁇ -N, 2-dimethylpropanamide 5 described in the literature (J. Org. Chem. 1989, 54, 5522).
  • Example 2b 2- [3,5-bis (trifluoromethyl) phenyl] -N- ⁇ 6-[(5-bromopent-2-yn-1-yl) (methyl) amino] -4- (2 -Methylphenyl) pyridin-3-yl ⁇ -N, 2-dimethylpropanamide
  • the compound (321 mg, 0.387 mmol) obtained in Example 2a was dissolved in tetrahydrofuran (4 mL), and tetrabutylammonium fluoride (1M- Tetrahydrofuran solution, 0.581 mL, 0.581 mmol) was added, and the mixture was stirred at room temperature for 1 hour.
  • Example 2c (3R) -1- ⁇ 5-[ ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino] -4- (2-Methylphenyl) pyridin-2-yl ⁇ (methyl) amino] pent-3-yn-1-yl ⁇ pyrrolidin-3-yl hydroxy (di-2-thienyl) acetate
  • Compound obtained in Example 2b 75 mg, 0.115 mmol
  • Example 3a 2- [3,5-bis (trifluoromethyl) phenyl] -N- ⁇ 6-[(6-hydroxyhex-2-yn-1-yl) (methyl) amino] -4- (2-Methylphenyl) pyridin-3-yl ⁇ -N, 2-dimethylpropanamide 6- ⁇ [tert-butyl (diphenyl) silyl] oxy ⁇ described in the literature (Tetrahedron Lett.
  • Hex-2-yn-1-ol (277 mg, 0.785 mmol) was dissolved in ethyl acetate (8 mL), and triethylamine (0.131 mL, 0.942 mmol) and methanesulfonyl chloride (73 ⁇ L, 0 mL) were cooled with ice. .942 mmol) was added, followed by stirring at the same temperature for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude mesylate body.
  • the obtained crude mesylate body was dissolved in N, N-dimethylacetamide (4 mL), and the compound obtained in Example 1e (200 mg, 0.393 mmol), potassium carbonate (130 mg, 0.785 mmol), and iodine After adding potassium halide (109 mg, 0.785 mmol), the mixture was stirred at 50 ° C. for 5.5 hours.
  • the reaction solution was diluted with ethyl acetate, and the organic layer was washed successively with water (x3) and saturated brine.
  • Example 3b (3R) -1- ⁇ 6-[ ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino] -4- (2-Methylphenyl) pyridin-2-yl ⁇ (methyl) amino] hex-4-yn-1-yl ⁇ pyrrolidin-3-yl hydroxy (di-2-thienyl) acetate
  • Compound obtained in Example 3a 70 mg, 0.118 mmol
  • ethyl acetate 5 mL
  • triethylamine 40 ⁇ L, 0.284 mmol
  • methanesulfonyl chloride 22 ⁇ L, 0.284 mmol
  • Example 4 4- ⁇ [ ⁇ 4-[(2- ⁇ 4-[(biphenyl-2-ylcarbamoyl) oxy] piperidin-1-yl ⁇ ethyl) (methyl) carbamoyl] benzyl ⁇ (methyl) amino] methyl ⁇ phenyl 4- [(N- ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino] -4- (2-methylphenyl) pyridin-2-yl ⁇ -N-methylglycyl) (methyl) amino] butanoate
  • Example 4a Methyl 4- ⁇ [(4-hydroxybenzyl) amino] methyl ⁇ benzoate Methyl 4- (aminomethyl) benzoate (6.88 g, 34.2 mmol) and 4-hydroxybenzaldehyde (4.60 g, 37.7 mmol) was dissolved in ethanol (300 mL), and the mixture was stirred for 6 hours under heating to reflux. At room temperature, sodium borohydride (1.39 g, 37.3 mmol) was added to the reaction solution, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine.
  • Example 4b 4- ⁇ [(tert-butoxycarbonyl) (4-hydroxybenzyl) amino] methyl ⁇ benzenecarboxylic acid Methyl 4- ⁇ [(4-hydroxybenzyl) amino] methyl ⁇ obtained in Example 4a Benzoate (1.07 g, 3.94 mmol) was dissolved in methylene chloride (39 mL), and a solution of di-tert-butyl dicarbonate (947 mg, 4.34 mmol) in methylene chloride (8 mL) was added. Stir for hours. The solvent was distilled off under reduced pressure to obtain a crude Boc body.
  • the obtained crude Boc body was dissolved in methanol (39 mL), 4N aqueous sodium hydroxide solution (3.94 m, 15.8 mmol) was added, and the mixture was stirred at room temperature for 17 hours and at 50 ° C. for 1.5 hours.
  • Methylene chloride was added to the reaction solution, adjusted to pH 1 with 1N hydrochloric acid, and extracted with methylene chloride ( ⁇ 2). After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was collected by filtration from hexane and a small amount of diethyl ether to give the title object compound (1.23 g, yield 80%). Obtained as a white solid.
  • Example 4c 1- (2- ⁇ [(4- ⁇ [(tert-butoxycarbonyl) (4-hydroxybenzyl) amino] methyl ⁇ phenyl) carbonyl] (methyl) amino ⁇ ethyl) piperidin-4-yl biphenyl -2-ylcarbamate 1- [2- (methylamino) ethyl] piperidin-4-yl biphenyl-2-ylcarbamate (194 mg, 0.550 mmol) and 4- ⁇ [(tert-butoxy) obtained in Example 4b Carbonyl) (4-hydroxybenzyl) amino] methyl ⁇ benzenecarboxylic acid (197 mg, 0.550 mmol) was dissolved in methylene chloride (5.5 mL), and WSC ⁇ HCl (127 mg, 0.660 mmol) was added thereto at room temperature.
  • Example 4d 1- (2- ⁇ [(4- ⁇ [(4-hydroxybenzyl) (methyl) amino] methyl ⁇ phenyl) carbonyl] (methyl) amino ⁇ ethyl) piperidin-4-yl biphenyl-2- Ilcarbamate
  • the compound (100 mg, 0.145 mmol) obtained in Example 4c was dissolved in methanol (3 mL), 4N hydrochloric acid-dioxane (90 ⁇ L, 0.361 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Further, 4N hydrochloric acid-dioxane (363 ⁇ L, 1.44 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours.
  • Example 4f Methyl 4-[(N- ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino] -4- (2- Methylphenyl) pyridin-2-yl ⁇ -N-methylglycyl) (methyl) amino] butanoate
  • the compound obtained in Example 1e (278 mg, 0.546 mmol) was dissolved in toluene (5.5 mL).
  • 0.5M Hexamethyldisilazane potassium in toluene solution (4.37 mL, 2.18 mmol) was added dropwise and stirred at room temperature for 10 minutes.
  • Example 4e A toluene solution (5.5 mL) of methyl 4-[(bromoacetyl) (methyl) amino] butanoic acid ester (688 mg, 2.73 mmol) obtained in Example 4e was added to the reaction solution, and then at 75 ° C. Stir for 41 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate ( ⁇ 3). The organic layer was washed with saturated brine.
  • Example 4g 4-[(N- ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino] -4- (2-methyl Phenyl) pyridin-2-yl ⁇ -N-methylglycyl) (methyl) amino] butanoic acid
  • the compound (129 mg, 0.190 mmol) obtained in Example 4f was dissolved in methanol (2 mL), and 1N aqueous sodium hydroxide solution ( 0.569 mL, 0.569 mmol) was added, followed by stirring at room temperature for 24 hours.
  • Example 4h 4- ⁇ [ ⁇ 4-[(2- ⁇ 4-[(biphenyl-2-ylcarbamoyl) oxy] piperidin-1-yl ⁇ ethyl) (methyl) carbamoyl] benzyl ⁇ (methyl) amino] Methyl ⁇ phenyl 4-[(N- ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino] -4- (2-methylphenyl) Pyridin-2-yl ⁇ -N-methylglycyl) (methyl) amino] butanoate
  • the compound obtained in Example 4d 50 mg, 0.0824 mmol
  • the compound obtained in Example 4g 60 mg, 0.0906 mmol
  • Example 4g 60 mg, 0.0906 mmol
  • Example 5 4-[( ⁇ 4-[(2- ⁇ 4-[(biphenyl-2-ylcarbamoyl) oxy] piperidin-1-yl ⁇ ethyl) (methyl) carbamoyl] benzyl ⁇ amino) methyl] phenyl 4-[(N - ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino] -4- (2-methylphenyl) pyridin-2-yl ⁇ -N -Methylglycyl) (methyl) amino] butanoate
  • Example 5a 4- ⁇ [ ⁇ 4-[(2- ⁇ 4-[(biphenyl-2-ylcarbamoyl) oxy] piperidin-1-yl ⁇ ethyl) (methyl) carbamoyl] benzyl ⁇ (tert-butoxycarbonyl ) Amino] methyl ⁇ phenyl 4-[(N- ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino] -4- (2- Methylphenyl) pyridin-2-yl ⁇ -N-methylglycyl) (methyl) amino] butanoate
  • the compound obtained in Example 4c 125 mg, 0.180 mmol
  • the compound obtained in Example 4g 120 mg, 0 180 mmol
  • WSC ⁇ HCl 42 mg, 0.216 mmol
  • 4-Dimethylaminopyridine (1 mg, 0.009 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2.5 days. Further, 4-dimethylaminopyridine (2 mg, 0.018 mmol) was added and stirred at room temperature for 23 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine.
  • Example 5b 4-[( ⁇ 4-[(2- ⁇ 4-[(biphenyl-2-ylcarbamoyl) oxy] piperidin-1-yl ⁇ ethyl) (methyl) carbamoyl] benzyl ⁇ amino) methyl] phenyl 4-[(N- ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino] -4- (2-methylphenyl) pyridine-2 -Il ⁇ -N-methylglycyl) (methyl) amino] butanoate To a 1,4-dioxane solution (3 mL) of the compound obtained in Example 5a (41 mg, 0.0306 mmol) was added 4N hydrochloric acid-dioxane (3 mL) under ice cooling.
  • Example 6b 2-[(5R) -3- [3,5-Bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3-oxazolidine-5-yl] ethanol
  • Example A tetrahydrofuran solution (1.0 M, 508 mL) of tetrabutylammonium fluoride and acetic acid (70 mL, 1.27 mol) were added to a tetrahydrofuran (500 mL) solution of the compound obtained in 6a (131.76 g, 0.254 mol) at room temperature. For 2 hours.
  • Example 6c 2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3-oxazolidine-5-yl] ethyl methanesulfonate 2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3-oxazolidine-5-yl] ethanol obtained in Example 6b (102.11 g, 0.226 mol), triethylamine (63 mL, 0.452 mol), 4- (dimethylamino) pyridine (2.76 g, 0.0273 mol) in dichloromethane (1000 mL) in methanesulfonyl chloride (1000 mL) under ice cooling.
  • allyl bromide (28.5 mL, 329.6 mmol) was added dropwise and stirred for 1 hour under ice cooling.
  • Water (400 mL) was added dropwise, followed by extraction with ethyl acetate (300 mL, 80 mL ⁇ 2).
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (0% ethyl acetate / n-hexane ⁇ 20%) to obtain 57.15 g of the title object compound as a colorless oil.
  • the obtained crude product was dissolved in a mixed solvent of tetrahydrofuran (400 mL) and water (400 mL), and sodium periodate (52.87 g, 247 mmol) was added little by little while stirring on ice. After the addition, the mixture was stirred at room temperature for 1.5 hours. Water (400 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (300, 150, 100 mL). The organic layers were combined and washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 59.52 g of the crude title object compound as a colorless amorphous.
  • Example 6f ⁇ [(2S) -1 ′-(tert-butoxycarbonyl) -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy ⁇ acetic acid Obtained in Example 6e 59.52 g of crude tert-butyl (2S) -2- (2-oxoethoxy) -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate obtained was dissolved in a mixed solvent of tetrahydrofuran (200 mL) and t-butanol (400 mL), and 2-methyl-2-butene (87.3 mL) was added.
  • Example 6g Ethyl [(2S) -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yloxy] acetate obtained in Example 6f ⁇ [(2S) -1 ′-( tert-butoxycarbonyl) -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy ⁇ acetic acid (28.20 g, 78.0 mmol) in ethanol solution (280 mL) under ice-cooling and stirring. And thionyl chloride (12.3 mL, 156 mmol) was added dropwise and heated to reflux for 2 hours.
  • Example 6i ⁇ [(2S) -1 ′- ⁇ 2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3 -Oxazolidin-5-yl] ethyl ⁇ -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy ⁇ acetic acid
  • Example 6k tert-Butyl 4-[(3-aminopropyl) carbamoyl] piperidine-1-carboxylate 10% Palladium-carbon (dry, 18 mg) was added to the compound obtained in Example 6j (182 mg, 0. (434 mmol) in methanol (4.5 mL) was added, the inside of the system was replaced with a hydrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. After replacing the inside of the system with a nitrogen atmosphere, the reaction solution was filtered using Celite. The residue obtained by distilling off the solvent under reduced pressure was azeotroped with tetrahydrofuran ( ⁇ 2) to give the title object compound (120 mg, 97% yield) as a white solid.
  • Example 6L tert-butyl 4-( ⁇ 3-[( ⁇ [(2S) -1 ′- ⁇ 2-[(5R) -3- ⁇ [3,5-bis (trifluoromethyl) phenyl] carbonyl ⁇ -5- (4-Fluorophenyl) -1,3-oxazolidine-5-yl] ethyl ⁇ -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy ⁇ acetyl) amino ] Propyl ⁇ carbamoyl) piperidine-1-carboxylate
  • the compound obtained in Example 6i (153 mg, 0.221 mmol) was dissolved in methylene chloride (2 mL), and triethylamine (35 ⁇ L, 0.252 mmol) under ice cooling, and , Pivaloyl chloride (27 ⁇ L, 0.219 mmol) was added, and the mixture was stirred at room temperature for
  • Example 6m N- ⁇ 3-[( ⁇ [(2S) -1 ′- ⁇ 2-[(5R) -3- ⁇ [3,5-bis (trifluoromethyl) phenyl] carbonyl ⁇ -5- (4-Fluorophenyl) -1,3-oxazolidine-5-yl] ethyl ⁇ -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy ⁇ acetyl) amino] propyl ⁇ piperidine -4-Carboxamide To the compound obtained in Example 6L (175 mg, 0.182 mmol) was added 2N hydrochloric acid-methanol (1.82 mL, 3.64 mmol), and the mixture was stirred at room temperature for 3 hours.
  • Example 7a 2-[(3S) -1- (2- ⁇ 4- [2- (methylamino) ethyl] phenyl ⁇ ethyl) pyrrolidin-3-yl] -2,2-diphenylacetamide hydrochloride 2- ⁇ (3S) -1- [2- (4- ⁇ 2- [benzyl (methyl) amino] ethyl ⁇ phenyl) ethyl] pyrrolidin-3-yl ⁇ -described in the literature (US2005 / 203167 A1)
  • Example 7b tert-butyl (2- ⁇ [2- (4- ⁇ 2-[(3S) -3- (2-amino-2-oxo-1,1-diphenylethyl) pyrrolidin-1-yl] Ethyl ⁇ phenyl) ethyl] (methyl) amino ⁇ ethyl) methylcarbamate 2-[(3S) -1- (2- ⁇ 4- [2- (methylamino) ethyl] phenyl ⁇ ethyl) obtained in Example 7a Pyrrolidin-3-yl] -2,2-diphenylacetamide hydrochloride (300 mg, 0.680 mmol) was dissolved in 1,2-dichloroethane (7 mL), triethylamine (0.284 mL, 2.04 mmol), tert- Butyl methyl (2-oxoethyl) carbamate (177 mg, 1.02 mmol) and sodium triacetoxyborohydride (
  • Example 7c 2-[(3S) -1- ⁇ 2- [4- (2- ⁇ methyl [2- (methylamino) ethyl] amino ⁇ ethyl) phenyl] ethyl ⁇ pyrrolidin-3-yl] -2 , 2-Diphenylacetamide
  • a methanol solution (2 mL) of the compound obtained in Example 7b (296 mg, 0.494 mmol) was added 4N hydrochloric acid-dioxane (1.24 mL, 4.94 mmol), and 1 at room temperature. The mixture was further stirred at 40 ° C. for 1 hour.
  • Example 7d N- (2- ⁇ [2- (4- ⁇ 2-[(3S) -3- (2-amino-2-oxo-1,1-diphenylethyl) pyrrolidin-1-yl] ethyl ⁇ Phenyl) ethyl] (methyl) amino ⁇ ethyl) -2- ⁇ [(2S) -1 ′- ⁇ 2-[(5R) -3- ⁇ [3,5-bis (trifluoromethyl) phenyl] carbonyl ⁇ -5- (4-Fluorophenyl) -1,3-oxazolidine-5-yl] ethyl ⁇ -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy ⁇ -N-methylacetamide
  • the compound (244 mg, 0.351 mmol) obtained in Example 6i was dissolved in methylene chloride (5 mL), and triethylamine (67 ⁇ L)
  • Example 8a tert-butyl ⁇ 2-[( ⁇ [(2S) -1 ′- ⁇ 2-[(5R) -3- ⁇ [3,5-bis (trifluoromethyl) phenyl] carbonyl ⁇ -5 -(4-Fluorophenyl) -1,3-oxazolidine-5-yl] ethyl ⁇ -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy ⁇ acetyl) (methyl) amino Ethyl ⁇ carbamate
  • the compound (135 mg, 0.194 mmol) obtained in Example 6i was dissolved in methylene chloride (3 mL), and triethylamine (81 ⁇ L, 0.583 mmol) and pivaloyl chloride (25 ⁇ L, 0) were cooled with ice.
  • Example 8b N- (2-aminoethyl) -2- ⁇ [(2S) -1 ′- ⁇ 2-[(5R) -3- ⁇ [3,5-bis (trifluoromethyl) phenyl] carbonyl ⁇ -5- (4-Fluorophenyl) -1,3-oxazolidine-5-yl] ethyl ⁇ -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy ⁇ -N— Methylacetamide
  • the compound (150 mg, 0.176 mmol) obtained in Example 8a was dissolved in methanol (0.9 mL), 4N hydrochloric acid-dioxane (0.883 mL, 3.53 mmol) was added, and then at room temperature for 1 hour.
  • Example 8d 2-[(3S) -1- ⁇ 2- [4- (2-oxoethyl) phenyl] ethyl ⁇ pyrrolidin-3-yl] -2,2-diphenylacetamide obtained in Example 8c 2-[(3S) -1- ⁇ 2- [4- (2-hydroxyethyl) phenyl] ethyl ⁇ pyrrolidin-3-yl] -2,2-diphenylacetamide (150 mg, 0.350 mmol), dimethyl Sulfoxide (0.149 mL, 2.10 mmol) and N, N-diisopropylethylamine (0.183 mL, 1.05 mmol) were dissolved in methylene chloride (4 mL), and sulfur trioxide-pyridine complex (164 mg) was cooled with ice.
  • Example 8e N- (2- ⁇ [2- (4- ⁇ 2-[(3S) -3- (2-amino-2-oxo-1,1-diphenylethyl) pyrrolidin-1-yl] ethyl ⁇ Phenyl) ethyl] amino ⁇ ethyl) -2- ⁇ [(2S) -1 ′- ⁇ 2-[(5R) -3- ⁇ [3,5-bis (trifluoromethyl) phenyl] carbonyl ⁇ -5 (4-Fluorophenyl) -1,3-oxazolidine-5-yl] ethyl ⁇ -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy ⁇ -N-methylacetamide
  • Example 8d The compound obtained in (50 mg, 0.117 mmol) and the compound obtained in Example 8b (88 mg, 0.117 mmol) were dissolved in 1,2-dichloroethane
  • Example 9b N- (3,3,3-triphenylpropanoyl) glycyl-N-[(1- ⁇ 6-[(tert-butoxycarbonyl) amino] hexyl ⁇ piperidin-3-yl) methyl]- ⁇ -alaninamide N- (3,3,3-triphenylpropanoyl) glycyl-N- (piperidin-3-ylmethyl) - ⁇ -alaninamide (203 mg, 0.39 mmol) obtained in Example 9a was acetonitrile.
  • Example 9c N- (3,3,3-triphenylpropanoyl) glycyl-N- ⁇ [1- (6-aminohexyl) piperidin-3-yl] methyl ⁇ - ⁇ -alaninamide dihydrochloride
  • the compound obtained in Example 9b (192 mg, 0.26 mmol) was dissolved in ethanol (2 mL), and 4N hydrochloric acid / 1,4-dioxane solution (2 mL) was added under ice-cooling. Stir for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Ethyl acetate was added under ice-cooling, and further saturated aqueous sodium hydrogen carbonate was added to neutralize and separate the layers. The obtained organic layer was separated to obtain a crude title compound (183 mg) as a pale yellow solid.
  • Example 9e 4-[( ⁇ [(2S) -1 ′- ⁇ 2-[(5R) -3- ⁇ [3,5-bis (trifluoromethyl) phenyl] carbonyl ⁇ -5- (4- Fluorophenyl) -1,3-oxazolidine-5-yl] ethyl ⁇ -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy ⁇ acetyl) (methyl) amino] butanoic acid
  • the compound obtained in Example 9d (133 mg, 0.16 mmol) was dissolved in ethanol (5 mL), and 1N aqueous sodium hydroxide solution (0.33 mL, 0.33 mmol) was added under ice-cooling.
  • Example 9f N- (3,3,3-triphenylpropanoyl) glycyl-N-( ⁇ 1- [6-( ⁇ 4-[( ⁇ [(2S) -1 ′- ⁇ 2-[( 5R) -3- ⁇ [3,5-Bis (trifluoromethyl) phenyl] carbonyl ⁇ -5- (4-fluorophenyl) -1,3-oxazolidine-5-yl] ethyl ⁇ -2,3-dihydrospiro [Inden-1,4′-piperidin] -2-yl] oxy ⁇ acetyl) (methyl) amino] butanoyl ⁇ amino) hexyl] piperidin-3-yl ⁇ methyl) - ⁇ -alaninamide obtained in Example 9e The compound (114 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), triethylamine (100 ⁇ L, 0.72 mmol) and pivaloyl
  • Example 10a 8- ⁇ [tert-butyl (diphenyl) silyl] oxy ⁇ oct-2-yn-1-ol tert-butyl (hept-6-in-1-yloxy) diphenylsilane (12.7 g, 36 .2 mmol) (Tetrahedron, 61, 5, 2005, 1127-1140) was dissolved in tetrahydrofuran (180 mL) and a 2.67 N normal butyl lithium / hexane solution (16.3 mL, 43.5 mmol) at -78 degrees. was added dropwise and stirred at the same temperature for 1 hour under a nitrogen atmosphere.
  • Example 10b 8- ⁇ [tert-Butyl (diphenyl) silyl] oxy ⁇ oct-2-yn-1-yl methanesulfonate 8- ⁇ [tert-butyl (diphenyl) silyl] oxy obtained in Example 10a ⁇ Oct-2-yn-1-ol (700 mg, 1.8 mmol) was dissolved in methylene chloride (10 mL), and cooled with ice, triethylamine (0.39 mL, 2.8 mmol), methanesulfonyl chloride (0.21 mL, 2 mL) .8 mmol) was added, and the mixture was stirred at the same temperature for 1.2 hours under a nitrogen atmosphere.
  • Example 10c 2- [3,5-bis (trifluoromethyl) phenyl] -N- ⁇ 6-[(8- ⁇ [tert-butyl (diphenyl) silyl] oxy ⁇ oct-2-yne-1- Yl) (methyl) amino] -4- (2-methylphenyl) pyridin-3-yl ⁇ -N, 2-dimethylpropanamide
  • the compound synthesized in Example 1e 300 mg, 0.55 mmol) was converted to N, N-dimethyl 8- ⁇ [tert-butyl (diphenyl) silyl] oxy ⁇ oct-2-yn-1-yl methanesulfonate (750 mg, 1.64 mmol) dissolved in acetamide (6 mL) and synthesized in Example 10b at room temperature, Potassium carbonate (226 mg, 1.64 mmol) and potassium iodide (109 mg, 0.67 mmol) were added, and under nitrogen atmosphere at 70
  • Example 10d 2- [3,5-bis (trifluoromethyl) phenyl] -N- ⁇ 6-[(8-hydroxyoct-2-yn-1-yl) (methyl) amino] -4- ( 2-Methylphenyl) pyridin-3-yl ⁇ -N, 2-dimethylpropanamide
  • the compound obtained in Example 10c (320 mg, 0.37 mmol) was dissolved in tetrahydrofuran (5 mL), and 1.0 M was added under ice cooling. Tetrabutylammonium fluoride / tetrahydrofuran solution (0.55 mL, 0.55 mol) was added, and the mixture was stirred at room temperature for 1 hour in a nitrogen atmosphere.
  • Example 10e (3R) -1- ⁇ 8-[ ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino] -4- (2-Methylphenyl) pyridin-2-yl ⁇ (methyl) amino] oct-6-in-1-yl ⁇ pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate
  • Compound obtained in Example 10d 180 mg, 0.28 mmol
  • ethyl acetate 5 mL
  • triethylamine 60 ⁇ L, 0.43 mmol
  • methanesulfonyl chloride 33 ⁇ L, 0.43 mmol
  • Example 11b (3R) -1- [2- (4- ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino]- 4- (2-Methylphenyl) pyridin-2-yl ⁇ piperazin-1-yl) ethyl] pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate
  • Compound obtained in Example 11a (92 mg, 0.151 mmol ) was dissolved in ethyl acetate (2 mL), and triethylamine (25 ⁇ L, 0.181 mmol) and methanesulfonyl chloride (13 ⁇ L, 0.166 mmol) were added under ice cooling, followed by stirring at the same temperature for 2 hours
  • Example 13b 2- [3,5-bis (trifluoromethyl) phenyl] -N- [6- ⁇ [2- (3-hydroxypropoxy) ethyl] (methyl) amino ⁇ -4- (2-methyl (Phenyl) pyridin-3-yl] -N, 2-dimethylpropanamide
  • a tetrahydrofuran solution (4 mL) of the compound obtained in Example 13a (244 mg, 0.336 mmol) in a 0.1 M tetrabutylammonium fluoride / tetrahydrofuran solution ( 403 ⁇ L) was added and stirred at room temperature for 30 minutes.
  • Example 13c (3R) -1- (3- ⁇ 2-[ ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino] -4- (2-Methylphenyl) pyridin-2-yl ⁇ (methyl) amino] ethoxy ⁇ propyl) pyrrolidin-3-yl hydroxy (di-2-thienyl) acetate
  • Compound obtained in Example 13b (142 mg, 0 232 mmol) and (3R) -pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate (55 mg, 0.177 mmol) obtained in Example 1i according to the method described in Example 3b and the title compound (99 mg, 47% yield) was obtained as a white solid.
  • Example 14a Ethyl N- ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino] -4- (2-methylphenyl) pyridine -2-yl ⁇ -N-methylglycinate
  • a toluene solution 49 mL
  • 0.5 M hexamethylene disilazane potassium / toluene The solution (39.3 mL) was added dropwise and stirred at room temperature for 10 minutes.
  • Example 14b N- ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino] -4- (2-methylphenyl) pyridine- 2-yl ⁇ -N-methylglycine
  • 1N aqueous sodium hydroxide solution (6.80 mL)
  • Example 14c N- ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl ⁇ (methyl) amino] -4- (2-methylphenyl) pyridine- 2-yl ⁇ -N-methylglycine monohydrochloride
  • dioxane solution 2 mL
  • 4N hydrochloric acid / dioxane solution 66 ⁇ L
  • the reaction solution was dried under reduced pressure to obtain the crude title compound (46 mg, yield 87%) as a blue solid.
  • Example 14d tert-butyl 4-[(6-ethoxy-6-oxohexyl) amino] benzoate ethyl 6-bromohexanoate (5.55 g, 24.9 mmol) and tert-butyl 4-aminobenzoate (4 .37 g, 22.6 mmol) was dissolved in N, N-dimethylformamide (23 mL), and N, N-diisopropylethylamine (4.72 mL, 27.1 mmol) and potassium iodide (4.13 g, 24.9 mmol) were added. In addition, the mixture was stirred at 65 ° C. for 4 days.
  • the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and the obtained organic layer was dried over anhydrous magnesium sulfate.
  • Example 14e tert-butyl 4-( ⁇ 6-[(2- ⁇ 4-[(biphenyl-2-ylcarbamoyl) oxy] piperidin-1-yl ⁇ ethyl) (methyl) amino] -6-oxohexyl ⁇ Amino) benzoate
  • ethanol 40 mL
  • 1N aqueous sodium hydroxide solution 15.6 mL
  • Example 14f 1- (2- ⁇ [6-( ⁇ 4-[ ⁇ 3-[(tert-butoxycarbonyl) (methyl) amino] propyl ⁇ (methyl) carbamoyl] phenyl ⁇ amino) hexanoyl] (methyl) Amino ⁇ ethyl) piperidin-4-yl biphenyl-2-ylcarbamate 4N hydrochloric acid / dioxane solution (40 mL) was added to the compound obtained in Example 14e (1.08 g, 1.68 mmol), and 13.5 at room temperature. Stir for hours.
  • Example 14g 1- [2- (methyl ⁇ 6-[(4- ⁇ methyl [3- (methylamino) propyl] carbamoyl ⁇ phenyl) amino] hexanoyl ⁇ amino) ethyl] piperidin-4-yl biphenyl-2 -Ilcarbamate
  • 2N hydrochloric acid / methanol solution 4.9 mL
  • the reaction mixture was made alkaline by adding 1N aqueous sodium hydroxide solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate.
  • Example 14h 1- (2- ⁇ [6-( ⁇ 4-[ ⁇ 3-[(N- ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2-methyl Propanoyl ⁇ (methyl) amino] -4- (2-methylphenyl) pyridin-2-yl ⁇ -N-methylglycyl) (methyl) amino] propyl ⁇ (methyl) carbamoyl] phenyl ⁇ amino) hexanoyl] (methyl) amino ⁇ Ethyl) piperidin-4-yl biphenyl-2-ylcarbamate
  • Compound (310 mg, 0.462 mmol) obtained in Example 14g and compound (510 mg, 0.796 mmol) obtained in Example 14c were dissolved in dichloromethane (5 mL).
  • Example 15a (2- ⁇ [(4-Formylphenyl) carbonyl] (methyl) amino ⁇ ethyl) piperidin-4-yl biphenyl-2-ylcarbamate 1- [2- (methylamino) ethyl] piperidine -4-yl biphenyl-2-ylcarbamate (400 mg, 1.13 mmol) and 4-formylbenzoic acid (187 mg, 1.24 mmol) were dissolved in dichloromethane (11 mL), and WSC ⁇ HCl (260 mg, 1.36 mmol) was added. The mixture was added at room temperature and stirred for 14 hours.
  • Example 15b tert-butyl 4-( ⁇ 4-[(2- ⁇ 4-[(biphenyl-2-ylcarbamoyl) oxy] piperidin-1-yl ⁇ ethyl) (methyl) carbamoyl] benzyl ⁇ amino) benzoate
  • the compound obtained in Example 15a (433 mg, 0.892 mmol) and 4-aminobenzoic acid tert-butyl ester (157 mg, 0.811 mmol) were dissolved in dichloromethane (9 mL), acetic acid (42 ⁇ L) and hydrogenated triacetoxy Sodium boron (258 mg, 1.22 mmol) was added at room temperature and stirred overnight.
  • Example 15c 1- ⁇ 2-[( ⁇ 4-[( ⁇ 4-[ ⁇ 3-[(tert-butoxycarbonyl) (methyl) amino] propyl ⁇ (methyl) carbamoyl] phenyl ⁇ amino) methyl] phenyl ⁇ Carbonyl) (methyl) amino] ethyl ⁇ piperidin-4-yl biphenyl-2-ylcarbamate
  • 4N hydrochloric acid-dioxane (12 mL).
  • Triethylamine (418 ⁇ L, 3.01 mmol), tert-butylmethyl [3- (methylamino) propyl] carbamate (122 mg, 0.602 mmol), and WSC ⁇ HCl (138 mg, 6 mL) were added to a crude solution of the obtained crude product in dichloromethane (6 mL). 0.722 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. 4-Dimethylaminopyridine (4 mg) was added and stirred at room temperature for 2.5 days. Ethyl acetate was added to the reaction solution for dilution, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine.
  • Example 15d 1- (2- ⁇ methyl [(4- ⁇ [(4- ⁇ methyl [3- (methylamino) propyl] carbamoyl ⁇ phenyl) amino] methyl ⁇ phenyl) carbonyl] amino ⁇ ethyl) piperidine- 4-yl biphenyl-2-ylcarbamate 2N Hydrochloric acid-methanol solution (4.93 mL) was added to the compound obtained in Example 15c (390 mg, 0.493 mmol) to dissolve and stirred at room temperature. 1N Aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 15e 1- ⁇ 2-[( ⁇ 4-[( ⁇ 4-[ ⁇ 3-[(N- ⁇ 5-[ ⁇ 2- [3,5-bis (trifluoromethyl) phenyl] -2 -Methylpropanoyl ⁇ (methyl) amino] -4- (2-methylphenyl) pyridin-2-yl ⁇ -N-methylglycyl) (methyl) amino] propyl ⁇ (methyl) carbamoyl] phenyl ⁇ amino) methyl] phenyl ⁇ Carbonyl) (methyl) amino] ethyl ⁇ piperidin-4-yl biphenyl-2-ylcarbamate
  • Compound obtained in Example 15d (156 mg, 0.226 mmol) and compound obtained in Example 14c (289 mg, 0.452 mmol)
  • the title compound (101 mg, 36% yield) was obtained as a pale yellow solid according to the method described in Example 14h.
  • Example 16b 4-[( ⁇ [(2S) -1 ′- ⁇ 2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3-oxasolidin-5-yl] ethyl ⁇ -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy ⁇ acetyl) (methyl) amino] butyl methanesulfonate
  • Example 16a The dichloromethane solution (5 mL) of the compound obtained in step (300 mg, 0.385 mmol) was ice-cooled, triethylamine (64 ⁇ L, 0.462 mmol) and methanesulfonyl chloride (36 ⁇ L, 0.462 mmol) were added, and the mixture was stirred as it was for 1 hour.
  • Example 16c (3R) -1- ⁇ 4-[( ⁇ [(2S) -1 '- ⁇ 2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5 -(4-Fluorophenyl) -1,3-oxazolidine-5-yl] ethyl ⁇ -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy ⁇ acetyl) (methyl) amino ] Butyl ⁇ pyrrolidin-3-yl hydroxy (di-2-thienyl) acetate dihydrochloride The compound obtained in Example 16b (150 mg, 0.175 mmol) and the compound obtained in Example 1i (65 mg, 0.21 mmol) ) was dissolved in acetonitrile (5 mL), potassium carbonate (48 mg, 0.35 mmol) was added, and the mixture was stirred at 80 ° C.
  • Sodium hydride 450 mg ( Methyl hydroxy (di-2-thienyl) acetate (2.54 g, 10.0 mmol) and tert-butyl 3-hydroxy were added to a toluene suspension (6.7 mL) of 55% content (mineral oil dispersion), 10.3 mmol).
  • Example 17b 8-Azabicyclo [3.2.1] oct-3-yl hydroxy (di-2-thienyl) acetate
  • a solution of the compound obtained in Example 17a (3.43 g, 7.63 mmol) in dioxane ( (20 mL) was added 4N hydrochloric acid / dioxane solution (20 mL), and the mixture was stirred at room temperature for 5 hours.
  • Example 17c 8- ⁇ 4-[( ⁇ [(2S) -1 ′- ⁇ 2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4- Fluorophenyl) -1,3-oxazolidine-5-yl] ethyl ⁇ -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy ⁇ acetyl) (methyl) amino] butyl ⁇ - 8-Azabicyclo [3.2.1] oct-3-yl hydroxy (di-2-thienyl) acetate dihydrochloride Compound obtained in Example 16b (236 mg, 0.256 mmol) and obtained in Example 17b Compound (107 mg, 0.307 mmol) was dissolved in acetonitrile (5 mL) and potassium carbonate (71 mg, 0.512 mmol) and potassium iodide (85 mg, 0.512 m
  • Test Example 1 [Guinea pig NK 1 receptor binding test] Receptor binding tests can be performed from guinea pig crude film specimens. In other words, after removing lung tissue, which is a highly expressed NK 1 receptor, a crude membrane sample is prepared, [ 3 H] substance P and the test substance are reacted with the crude membrane sample solution, and then the radioactivity is measured after the membrane components are recovered. Thus, the affinity of the test substance for the guinea pig NK 1 receptor can be calculated.
  • Test Example 2 [Guinea pig NK 2 receptor binding test] Receptor binding tests can be performed from guinea pig crude film specimens. In other words, after removing the ileal tissue, which is a highly expressed NK 2 receptor, a crude membrane specimen was prepared, and [ 3 H] SR 48968 or neurokinin A was reacted with the test substance together with the crude membrane specimen solution, and then the radioactivity was recovered after membrane components were recovered. By measuring the affinity of the test substance for the guinea pig NK 2 receptor.
  • a receptor binding test can be performed from a human NK 1 receptor-expressing cell-derived crude membrane specimen.
  • [ 3 H] substance P and the test substance together with the crude membrane sample solution on the crude membrane sample prepared from human-type NK 1 receptor-expressing COS cells measure the radioactivity after collecting membrane components.
  • the affinity of the test substance for the human NK 1 receptor can be calculated.
  • a test substance and 250 ⁇ L of a crude membrane sample solution were added and incubated at room temperature for 35 minutes ([ 3 H] SR 48968 was a final concentration of 1 nM).
  • membrane components were collected on GF / B glass fiber filter paper (Whatman, Biomedical Research and Development Laboratories, Inc.) using an automatic filtration device (Brandel, Biomedical Research and Development Laboratories, Inc.).
  • the glass fiber filter paper was pretreated with a 0.1% polyethyleneimine solution for 4 hours or more in order to keep nonspecific binding low.
  • NK 2 receptor binding activity is 50% bound dose (IC 50) and NK 2 affinity of [3 H] SR 48968 to the receptor than (Kd), affinity for NK 2 receptors of the test substance (Ki ).
  • the membrane components were collected on GF / B glass fiber filter paper (Whatman, Biomedical Research and Development Laboratories, Inc.) using an automatic filtration device (Brandel, Biomedical Research and Development Laboratories, Inc.) [[N -methyl- 3 H]-(-)-Scopolamine methyl chloride has a final concentration of 0.5 nM).
  • the glass fiber filter paper was pretreated with a 0.1% polyethyleneimine solution for 4 hours or more in order to keep nonspecific binding low.
  • the membrane component recovery filter was transferred to a mini plastic vial containing 3 mL of Picoflow, and the radioactivity was measured with a liquid scintillation counter (Perkin Elmer, Tri-Carb 2900TR or 2300TR).
  • the M 3 receptor binding action is determined by the test substance based on the 50% binding dose (IC 50 ) and the affinity (Kd) of [N-methyl- 3 H]-(-)-Scopolamine methyl chloride for the M 3 receptor. It was calculated as the affinity for M 3 receptor (Ki).
  • the compound of the present invention has an excellent muscarinic M 3 receptor binding action.
  • the guinea pig was killed under carbon dioxide, and the amount of pigment leaked to the main trachea was measured according to the Harada method (J. Pharm. Pharmacol. 23, 218 (1971)).
  • the test drug is dissolved in 5% glucose solution, and 0.5 mL / kg solution is administered intratracheally 1 hour before the induction by SP using an intratracheal administration device (Penn-Century. Inc., model 1A-1B) did.
  • the inhibitory action was judged using as an index the amount of dye leaked from the test drug-administered guinea pig.
  • the compound of the present invention has an excellent antagonistic action on the neurokinin NK 1 receptor.
  • the compounds of the present invention are against neurokinin NK 1 , neurokinin NK 2 and muscarinic M 3 receptor, or against neurokinin NK 1 and muscarinic M 3 receptor.
  • Formulation Example Formulation Example 1 Powder A powder is obtained by mixing the compound of Example 1 5g, lactose 895g, and corn starch 100g with a blender.
  • Formulation Example 2 Granules After mixing 5 g of the compound of Example 1, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 300 g of a 10% hydroxypropylcellulose aqueous solution is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules.
  • Formulation Example 3 Tablet Tablet 5 is obtained by mixing 5 g of the compound of Example 4, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate with a blender and then compressing the mixture with a tablet machine.
  • Example 4 Inhalation Solution 1
  • the compound of Example 9 was 10% (W / W), benzalkonium chloride was 0.04% (W / W), phenethyl alcohol was 0.40% (W / W), and purified water was 89.56% ( W / W) is prepared.
  • Example 5 Solution 2 for inhalation
  • the compound of Example 7 is 10% (W / W), benzalkonium chloride is 0.04% (W / W), polyethylene glycol is 10% (W / W), and propylene glycol is 30% (W / W).
  • the solution is prepared so that purified water is 39.96% (W / W).
  • Formulation Example 6 Powder for Inhalation A powder is prepared so that the compound of Example 9 is 40% (W / W) and lactose is 60% (W / W).
  • Example 7 Aerosol Aerosol The compound of Example 7 is 10% (W / W), lecithin is 0.5% (W / W), Freon 11 is 34.5% (W / W), and Freon 12 is 55% ( An aerosol agent is prepared so that it may become (W / W).
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is for neurokinin NK 1 , neurokinin NK 2 and muscarinic M 3 receptor, or neurokinin NK 1 and muscarinic M 3. It is antagonistic to the receptor, has low toxicity and is excellent in pharmacokinetics, so it is useful as a pharmaceutical, especially as a preventive or therapeutic agent for respiratory diseases, allergic diseases and / or nervous system diseases. Useful.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pulmonology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Pain & Pain Management (AREA)
  • Diabetes (AREA)
  • Otolaryngology (AREA)
  • Hematology (AREA)
  • Psychology (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Psychiatry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé présentant une activité antagoniste supérieure des récepteurs de neurokinine NK1, de neurokinine NK2 et de muscarine M3, ou une activité antagoniste supérieure de récepteurs de neurokinine NK1 et de muscarine M3, et qui peut être employé comme agent thérapeutique contre l'asthme, la bronchopneumopathie chronique obstructive, etc., ou l'un de ses sels de qualité pharmaceutique. La présente invention concerne spécifiquement un composé de formule générale (I) ou l'un de ses sels. [Dans la formule, Y représente une structure partielle présentant une activité antagoniste des récepteurs de neurokinine NK1 et de neurokinine NK2 ou une structure partielle présentant une activité antagoniste des récepteurs de neurokinine NK1 ; A représente une liaison simple, une liaison triple, un atome d'oxygène, un groupement carbonyle, etc. ; E représente une structure partielle présentant une activité antagoniste des récepteurs de muscarine M3 ; m représente un entier compris entre 0 et 4 inclus ; et n représente un entier compris entre 1 et 8 inclus.]
PCT/JP2011/060242 2010-05-07 2011-04-27 Composé polycyclique WO2011138916A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2010-107374 2010-05-07
JP2010107374 2010-05-07

Publications (1)

Publication Number Publication Date
WO2011138916A1 true WO2011138916A1 (fr) 2011-11-10

Family

ID=44903768

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2011/060242 WO2011138916A1 (fr) 2010-05-07 2011-04-27 Composé polycyclique

Country Status (2)

Country Link
TW (1) TW201143771A (fr)
WO (1) WO2011138916A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016021562A1 (fr) * 2014-08-06 2016-02-11 キッセイ薬品工業株式会社 Dérivé de cyanothiophène

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000034288A (ja) * 1998-01-23 2000-02-02 Sankyo Co Ltd スピロピペリジン誘導体
JP2005272455A (ja) * 2004-02-25 2005-10-06 Sankyo Co Ltd インダノール誘導体
JP2006160639A (ja) * 2004-12-06 2006-06-22 Sankyo Co Ltd ニューロキニン受容体拮抗剤と抗コリン剤の併用
JP2008546695A (ja) * 2005-06-13 2008-12-25 セラヴァンス， インコーポレーテッド ムスカリン受容体アンタゴニストとして有用なビフェニル化合物
WO2010106988A1 (fr) * 2009-03-17 2010-09-23 第一三共株式会社 Dérivé d'amide

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000034288A (ja) * 1998-01-23 2000-02-02 Sankyo Co Ltd スピロピペリジン誘導体
JP2005272455A (ja) * 2004-02-25 2005-10-06 Sankyo Co Ltd インダノール誘導体
JP2006160639A (ja) * 2004-12-06 2006-06-22 Sankyo Co Ltd ニューロキニン受容体拮抗剤と抗コリン剤の併用
JP2008546695A (ja) * 2005-06-13 2008-12-25 セラヴァンス， インコーポレーテッド ムスカリン受容体アンタゴニストとして有用なビフェニル化合物
WO2010106988A1 (fr) * 2009-03-17 2010-09-23 第一三共株式会社 Dérivé d'amide

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016021562A1 (fr) * 2014-08-06 2016-02-11 キッセイ薬品工業株式会社 Dérivé de cyanothiophène
JPWO2016021562A1 (ja) * 2014-08-06 2017-06-15 キッセイ薬品工業株式会社 シアノチオフェン誘導体

Also Published As

Publication number Publication date
TW201143771A (en) 2011-12-16

Similar Documents

Publication Publication Date Title
US11498900B2 (en) Salts of an LSD1 inhibitor
JP6800969B2 (ja) 呼吸器疾患の処置のためのｊａｋキナーゼ阻害剤化合物
ES2614090T3 (es) Derivados de diamina como inhibidores de leucotrieno A4 hidrolasa
JP5680624B2 (ja) ７−アザ−スピロ［３．５］ノナン−７−カルボン酸エステル誘導体、これらの調製およびこれらの治療用途
US7939527B2 (en) Thiazolopyridin-2-yloxy-phenyl and thiazolopyrazin-2-yloxy-phenyl amines as modulators of leukotriene A4 hydrolase
US9150532B2 (en) Fused cyclopentyl antagonists of CCR2
US7858622B2 (en) Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions
EP3840832B1 (fr) Imidazo[1,2-b]pyridazines utilisées en tant qu&#39;inhibiteurs de trk
JP2001039950A (ja) Ｎ−アシル環状アミン誘導体
JPWO2010106988A1 (ja) アミド誘導体
US20230391739A1 (en) Aryl derivatives for treating trpm3 mediated disorders
KR20150068960A (ko) 치환된 카바메이트 화합물 및 일시적 수용체 전위(trp) 채널 길항제로서의 이의 용도
JP2002316987A (ja) ２−アルコキシベンゼン誘導体を含有する医薬
TW202128640A (zh) Gpr119激動劑
WO2011138916A1 (fr) Composé polycyclique
US9187450B2 (en) Substituted pyridine compound
JP2011116716A (ja) アミン化合物
JP2011116705A (ja) 含窒素環状化合物
KR20060127157A (ko) 인다놀 유도체
EA026088B1 (ru) Азотсодержащее бициклическое ароматическое гетероциклическое соединение
US20230149398A1 (en) Topical pharmaceutical compositions comprising imidazo[1,2-b]pyridazine compounds
US20240059677A1 (en) Substituted pyrimidine derivatives as nicotinic acetylcholinesterase receptor alpha 6 modulator
JP2012126656A (ja) ジヒドロインデン−１，４’−ピペリジン化合物
JP2013124244A (ja) アンモニウム化合物
JP2012126662A (ja) ピペリジン化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11777435

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11777435

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP