WO2011138916A1 - Polycyclic compound - Google Patents

Polycyclic compound Download PDF

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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
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Prior art keywords
group
methyl
amino
mmol
phenyl
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PCT/JP2011/060242
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French (fr)
Japanese (ja)
Inventor
拓也 池田
高典 山崎
孝明 城島
奈々 高木
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第一三共株式会社
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Publication of WO2011138916A1 publication Critical patent/WO2011138916A1/en

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    • 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
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    • 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
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    • 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
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    • A61P11/00—Drugs for disorders of the respiratory system
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    • 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
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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/04—Centrally acting analgesics, e.g. opioids
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    • 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
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    • 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
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P37/08—Antiallergic agents
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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.

Abstract

Disclosed is a compound having superior neurokinin NK1, neurokinin NK2 and muscarine M3 acceptor antagonistic activity, or superior neurokinin NK1 and muscarine M3 acceptor antagonistic activity, and also being useful as a therapeutic agent for bronchial asthma, chronic obstructive pulmonary disease, and the like, or a pharmaceutically acceptable salt thereof. Specifically disclosed is a compound having general formula (I) or a salt thereof. [In the formula, Y is a partial structure having neurokinin NK1 and neurokinin NK2 acceptor antagonistic activity or a partial structure having neurokinin NK1 acceptor antagonistic activity; A is a single bond, triple bond, oxygen atom, carbonyl group, or the like; E is a partial structure having a muscarine M3 acceptor antagonistic action; m is an integer of 0 - 4; and n is an integer of 1 - 8.]

Description

多環式化合物Polycyclic compound
　本発明は、優れたニューロキニンＮＫ１、ニューロキニンＮＫ２及びムスカリンＭ３受容体拮抗作用、又は、ニューロキニンＮＫ１及びムスカリンＭ３受容体拮抗作用を有し、気管支喘息、慢性閉塞性肺疾患等の治療薬として有用な化合物又はその薬理上許容される塩に関する。 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.
　気管支喘息や慢性閉塞性肺疾患（ＣＯＰＤ）では、気管支収縮、気道炎症、粘液分泌、咳嗽などが亢進している。サブスタンスＰあるいはニューロキニンＡが気道収縮作用、炎症作用、咳、粘液分泌に関与しており、サブスタンスＰあるいはニューロキニンＡの両受容体（ニューロキニンＮＫ１及びニューロキニンＮＫ２受容体）に拮抗する化合物は、上記の生理作用を抑制する可能性がある（非特許文献１、非特許文献２）。ニューロキニンＮＫ１及びニューロキニンＮＫ２両受容体に拮抗する非ペプチド性低分子化合物は開示されている（特許文献１、特許文献２）が、薬剤使用としての認可は得られていない。一方、アセチルコリンはムスカリン性Ｍ３受容体に作動することにより、強い気道収縮作用を惹起する（非特許文献３）。ムスカリン性Ｍ３受容体に拮抗する化合物は気管支拡張作用を有する化合物があり（特許文献３、特許文献４、特許文献５）、気管支拡張薬剤として使用されている（非特許文献４）。ムスカリン性Ｍ３受容体およびニューロキニン受容体の両者を拮抗することでより、各々単独で発揮される気管支拡張作用を上回る強い気管支拡張作用を発揮することが開示されている（特許文献６）。しかしながら、ニューロキニンＮＫ１及びニューロキニンＮＫ２両受容体に拮抗する化合物、又は、ニューロキニンＮＫ１受容体に拮抗する化合物が気管支喘息あるいはＣＯＰＤ治療薬として上市されていないことから、単剤を併用することは出来ないという問題点がある。ニューロキニンＮＫ１、ニューロキニンＮＫ２及びムスカリン性Ｍ３受容体を拮抗、又は、ニューロキニンＮＫ１及びムスカリン性Ｍ３受容体を拮抗することで、強い気管支拡張作用、抗炎症作用、鎮咳去痰作用を有する単一の化合物が望まれていた。 In bronchial asthma and chronic obstructive pulmonary disease (COPD), bronchoconstriction, airway inflammation, mucus secretion, cough, etc. are increased. Substance P or Neurokinin A are bronchoconstriction effects, inflammatory effects, coughing, are involved in mucus secretion, antagonizes both receptors of substance P or neurokinin A (neurokinin NK 1 and neurokinin NK 2 receptors) The compound may suppress the physiological action (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. Meanwhile, acetylcholine by actuating the muscarinic M 3 receptors, eliciting a strong bronchoconstriction effect (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). 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). However, since 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 A single compound having
ＵＳ６５１１９７５号公報US65151175 gazette ＵＳ７３６５０６７号公報US7365067 ＵＳ２００４／１６７１６７号公報US2004 / 167167 ＵＳ２００５／２０３１３１号公報US2005 / 203131 Publication ＵＳ２００６／２８１７４０号公報US2006 / 281740 特開２００６－１６０６３９号公報JP 2006-160639 A
　本発明者等は、ニューロキニンＮＫ１、ニューロキニンＮＫ２及びムスカリンＭ３受容体のすべてに拮抗作用を有する単一の化合物の合成とその薬理活性について長年にわたり鋭意研究を行った結果、単一ですべての受容体、又は、ニューロキニンＮＫ１及びムスカリンＭ３両受容体に拮抗作用を示し、持続的に薬効を示す化合物を見出し、本発明を完成した。 As a result of intensive studies over many years on the synthesis and pharmacological activity of a single compound having an antagonistic action on all of neurokinin NK 1 , neurokinin NK 2 and muscarinic M 3 receptor, Thus, 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.
　本発明は、（１）一般式（Ｉ） The present invention comprises (1) general formula (I)
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
［式中、
　Ｙは、ニューロキニンＮＫ１及びニューロキニンＮＫ２受容体拮抗作用を有する部分構造又はニューロキニンＮＫ１受容体拮抗作用を有する部分構造を示し、
　Ａは、単結合、三重結合、酸素原子、カルボニル基、カルボニルアミノ基、アミノカルボニル基、式（ＩＩ）で表される基、式（ＩＩＩ）で表される基又は式（ＩＶ）で表される基 [Where:
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). Base
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
（Ｒ１は、水素原子又はＣ１－Ｃ６アルキル基を示し、
Ｒ２は、水素原子又はＣ１－Ｃ６アルキル基を示し、
Ｒ３は、水素原子又はＣ１－Ｃ６アルキル基を示し、
Ｌ１は、オキシカルボニル基、カルボニルオキシ基、（メチルアミノ）カルボニル基又はカルボニル（メチルアミノ）基を示し、
Ｌ２は、単結合又はフェニレン基を示し、
Ｌ３は、Ｃ１－Ｃ６アルキレン基を示し、
ｐは、１乃至６の整数を示し、
ｑは、０乃至４の整数を示し、
ｒは、１乃至８の整数を示し、
ｓは、１乃至８の整数を示し、
ｔは、１乃至４の整数を示し、
ＣＹ及びＣＥは、単結合を示す。
ＣＹは、式Ｙで表わされる基に結合し、ＣＥは、式Ｅで表わされる基に結合する。
Ｒ２がＣ１－Ｃ６アルキル基の場合、Ｒ２の任意の炭素原子はＬ３の任意の炭素原子と結合してもよい。）を示し、
　Ｅは、ムスカリンＭ３受容体拮抗作用を有する部分構造を示し、
　ｍは、０乃至４の整数を示し、
　ｎは、１乃至８の整数を示す。］を有する化合物又はその薬理上許容される塩に関する。 (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, and C E is bonded to the group represented by Formula E.
When 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. Or a pharmacologically acceptable salt thereof.
　本発明において、好適には、
　（２）　（１）において、
　Ｙが、式（Ｖ）で表される基、式（ＶＩ）で表される基又は式（ＶＩＩ）で表される基 In the present invention, preferably,
(2) In (1),
Y is a group represented by formula (V), a group represented by formula (VI) or a group represented by formula (VII)
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
（Ｒ４は、置換基群Ａから選択される基で独立に１乃至５個置換されていてもよいフェニル基又は置換基群Ａから選択される基で独立に１乃至３個置換されていてもよい複素環基を示し、
Ｒ５は、置換基群Ａから選択される基で独立に１乃至５個置換されていてもよいフェニル基又は置換基群Ａから選択される基で独立に１乃至３個置換されていてもよい複素環基を示し、
Ｒ６は、水素原子又はＣ１－Ｃ６アルキル基を示し、
Ｒ７は、置換基群Ａから選択される基で独立に１乃至５個置換されていてもよいフェニル基又は置換基群Ａから選択される基で独立に１乃至３個置換されていてもよい複素環基を示し、
ｕは、１又は２を示し、
置換基群Ａは、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ハロゲン化アルキル基、ヒドロキシ基、Ｃ１－Ｃ６アルコキシ基、Ｃ１－Ｃ６ハロゲン化アルコキシ基、シアノ基、カルボキシル基、Ｃ２－Ｃ７アルキルカルボニルオキシ基、Ｃ２－Ｃ７アルコキシカルボニルオキシ基、カルバモイル基、ニトロ基及びアミノ基からなる群を示す。
Ｃｍは、単結合を示し、式－（ＣＨ２）ｍ－で表わされる基に結合する。）である化合物又はその薬理上許容される塩。 (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, a C 1 -C 6 alkoxy group, a C 1 -C 6 halogenated alkoxy group, and a cyano group. , A carboxyl group, a C 2 -C 7 alkylcarbonyloxy group, a C 2 -C 7 alkoxycarbonyloxy group, a carbamoyl group, a nitro group and an amino 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.
　（３）　（１）又は（２）において、
　Ｅが、式（ＶＩＩＩ）で表される基、式（ＩＸ）で表される基、式（Ｘ）で表される基、式（ＸＩ）で表される基又は式（ＸＩＩ）で表される基 (3) In (1) or (2),
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). Base
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
（Ｃｎは、単結合を示し、式－（ＣＨ２）ｎ－で表わされる基に結合する。）である化合物又はその薬理上許容される塩。 (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.
　（４）　（１）乃至（３）から選択されるいずれか一項において、
　一般式（Ｉ）が、一般式（Ｉａ） (4) In any one item selected from (1) to (3),
The general formula (I) is represented by the general formula (Ia)
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
である化合物又はその薬理上許容される塩。 Or a pharmacologically acceptable salt thereof.
　（５）　（４）において、
　Ｒ１が、水素原子又はメチル基であり、Ｌ１が、オキシカルボニル基、カルボニルオキシ基、（メチルアミノ）カルボニル基又はカルボニル（メチルアミノ）基であり、Ｌ２が、単結合又はフェニレン基であり、ｐが、２乃至４の整数であり、ｑが、０又は１であり、ｒが、１乃至５の整数である化合物又はその薬理上許容される塩。 (5) In (4),
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, and L 2 is a single bond or a phenylene group. A compound or a pharmacologically acceptable salt thereof, wherein p is an integer of 2 to 4, q is 0 or 1, and r is an integer of 1 to 5.
　（６）　（１）乃至（３）から選択されるいずれか一項において、
　一般式（Ｉ）が、一般式（Ｉｂ） (6) In any one item selected from (1) to (3),
The general formula (I) is represented by the general formula (Ib)
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
である化合物又はその薬理上許容される塩。 Or a pharmacologically acceptable salt thereof.
　（７）　（６）において、
　ｎが、２乃至５の整数である化合物又はその薬理上許容される塩。 (7) In (6),
A compound or a pharmacologically acceptable salt thereof, wherein n is an integer of 2 to 5.
　（８）　（１）乃至（３）から選択されるいずれか一項において、
　一般式（Ｉ）が、一般式（Ｉｃ） (8) In any one item selected from (1) to (3),
General formula (I) is general formula (Ic)
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
である化合物又はその薬理上許容される塩。 Or a pharmacologically acceptable salt thereof.
　（９）　（８）において、
　ｓが、３乃至６の整数であり、ｍが、２乃至４の整数である化合物又はその薬理上許容される塩。 (9) In (8),
A compound or a pharmacologically acceptable salt thereof, wherein s is an integer of 3 to 6, and m is an integer of 2 to 4.
　（１０）　（１）乃至（３）から選択されるいずれか一項において、
　一般式（Ｉ）が、一般式（Ｉｄ） (10) In any one item selected from (1) to (3),
The general formula (I) is represented by the general formula (Id)
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
である化合物又はその薬理上許容される塩。 Or a pharmacologically acceptable salt thereof.
　（１１）　（１０）において、
　Ｒ３が、水素原子又はメチル基であり、ｔが、１乃至４の整数であり、ｍが、１乃至４の整数であり、ｎが、１乃至４の整数である化合物又はその薬理上許容される塩。 (11) In (10),
A compound wherein R 3 is a hydrogen atom or a methyl group, t is an integer of 1 to 4, m is an integer of 1 to 4 and n is an integer of 1 to 4 or a pharmacologically acceptable salt thereof Salt.
　（１２）　（３Ｒ）－１－｛７－［｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝（メチル）アミノ］ヘプト－５－イン－１－イル｝ピロリジン－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート、
（３Ｒ）－１－｛５－［｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝（メチル）アミノ］ペント－３－イン－１－イル｝ピロリジン－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート、
（３Ｒ）－１－｛６－［｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝（メチル）アミノ］ヘキサ－４－イン－１－イル｝ピロリジン－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート、
４－｛［｛４－［（２－｛４－［（ビフェニル－２－イルカルバモイル）オキシ］ピペリジン－１－イル｝エチル）（メチル）カルバモイル］ベンジル｝（メチル）アミノ］メチル｝フェニル　４－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］ブタノエート、
４－［（｛４－［（２－｛４－［（ビフェニル－２－イルカルバモイル）オキシ］ピペリジン－１－イル｝エチル）（メチル）カルバモイル］ベンジル｝アミノ）メチル］フェニル　４－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］ブタノエート、
（３Ｒ）－１－｛２－［｛６－［４－（｛３－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）アミノ］プロピル｝カルバモイル）ピペリジン－１－イル］ヘキサノイル｝（メチル）アミノ］エチル｝ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート、
Ｎ－（２－｛［２－（４－｛２－［（３Ｓ）－３－（２－アミノ－２－オキソ－１，１－ジフェニルエチル）ピロリジン－１－イル］エチル｝フェニル）エチル］（メチル）アミノ｝エチル）－２－｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝－Ｎ－メチルアセタミド、
Ｎ－（２－｛［２－（４－｛２－［（３Ｓ）－３－（２－アミノ－２－オキソ－１，１－ジフェニルエチル）ピロリジン－１－イル］エチル｝フェニル）エチル］アミノ｝エチル）－２－｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝－Ｎ－メチルアセタミド、
Ｎ－（３，３，３－トリフェニルプロパノイル）グリシル－Ｎ－（｛１－［６－（｛４－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）（メチル）アミノ］ブタノイル｝アミノ）ヘキシル］ピペリジン－３－イル｝メチル）－β－アラニンアミド、
（３Ｒ）－１－｛８－［｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝（メチル）アミノ］オクト－６－イン－１－イル｝ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート、
（３Ｒ）－１－［２－（４－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝ピペラジン－１－イル）エチル］ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート、
（３Ｒ）－１－［３－（４－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝ピペラジン－１－イル）－３－オキソプロピル］ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート、
（３Ｒ）－１－（３－｛２－［｛５－［｛２－［３，５－ビス(トリフルオロメチル)フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン-２-イル｝（メチル）アミノ］エトキシ｝プロピル）ピロリジン-３-イル　ヒドロキシ（ジ－２－チエニル）アセテート、
１－（２－｛[６－（｛４－[{３－[（Ｎ－{５－[｛２－[３，５－ビス（トリフルオロメチル）フェニル]－２－メチルプロパノイル｝（メチル）アミノ]－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル)アミノ]プロピル}（メチル）カルバモイル]フェニル}アミノ)ヘキサノイル]（メチル）アミノ｝エチル）ピペリジン－４－イル ビフェニル－２－イルカーバメート、
１－｛２－［（｛４－［（｛４－［｛３－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］プロピル｝（メチル）カルバモイル］フェニル｝アミノ）メチル］フェニル｝カルボニル）（メチル）アミノ］エチル｝ピペリジン－４－イル　ビフェニル－２－イルカーバメート、
（３Ｒ）－１－｛４－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）（メチル）アミノ］ブチル｝ピロリジン－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート、又は、
８－｛４－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）（メチル）アミノ］ブチル｝－８－アザビシクロ［３．２．１］オクト－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート
である化合物又はその薬理上許容される塩。 (12) (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,
(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,
(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,
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,
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,
(3R) -1- {2-[{6- [4-({3-[({[(2S) -1 '-{2-[(5R) -3-{[3,5-bis (tri Fluoromethyl) 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) piperidin-1-yl] hexanoyl} (methyl) amino] ethyl} pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate,
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,
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,
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 [indene-1, 4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butanoyl} amino) hexyl] piperidin-3-yl} methyl) -β-alaninamide,
(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,
(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,
(3R) -1- [3- (4- {5-[{2- [3,5-Bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino] -4- (2- Methylphenyl) pyridin-2-yl} piperazin-1-yl) -3-oxopropyl] pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate,
(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,
1- (2-{[6-({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) hexanoyl] (methyl) amino} ethyl) piperidine- 4-yl biphenyl-2-yl carbamate,
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,
(3R) -1- {4-[({[(2S) -1 ′-{2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluoro Phenyl) -1,3-oxazolidine-5-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl} pyrrolidine- 3-yl hydroxy (di-2-thienyl) acetate, or
8- {4-[({[(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} acetyl) (methyl) amino] butyl} -8-azabicyclo [3 2.1] Oct-3-yl hydroxy (di-2-thienyl) acetate or a pharmacologically acceptable salt thereof.
　（１３）　上記（１２）に記載してある化合物又はその薬理上許容される塩のうちの化合物。 (13) A compound among the compounds described in (12) above or a pharmacologically acceptable salt thereof.
　（１４）　４－［（｛４－［（２－｛４－［（ビフェニル－２－イルカルバモイル）オキシ］ピペリジン－１－イル｝エチル）（メチル）カルバモイル］ベンジル｝アミノ）メチル］フェニル　４－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］ブタノエート、
（３Ｒ）－１－｛２－［｛６－［４－（｛３－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）アミノ］プロピル｝カルバモイル）ピペリジン－１－イル］ヘキサノイル｝（メチル）アミノ］エチル｝ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート、
Ｎ－（２－｛［２－（４－｛２－［（３Ｓ）－３－（２－アミノ－２－オキソ－１，１－ジフェニルエチル）ピロリジン－１－イル］エチル｝フェニル）エチル］アミノ｝エチル）－２－｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝－Ｎ－メチルアセタミド、
１－（２－｛[６－（｛４－[{３－[（Ｎ－{５－[｛２－[３，５－ビス（トリフルオロメチル）フェニル]－２－メチルプロパノイル｝（メチル）アミノ]－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル)アミノ]プロピル}（メチル）カルバモイル]フェニル}アミノ)ヘキサノイル]（メチル）アミノ｝エチル）ピペリジン－４－イル ビフェニル－２－イルカーバメート、
１－｛２－［（｛４－［（｛４－［｛３－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］プロピル｝（メチル）カルバモイル］フェニル｝アミノ）メチル］フェニル｝カルボニル）（メチル）アミノ］エチル｝ピペリジン－４－イル　ビフェニル－２－イルカーバメート、又は、
（３Ｒ）－１－｛４－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）（メチル）アミノ］ブチル｝ピロリジン－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート
である化合物又はその薬理上許容される塩。 (14) 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,
(3R) -1- {2-[{6- [4-({3-[({[(2S) -1 '-{2-[(5R) -3-{[3,5-bis (tri Fluoromethyl) 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) piperidin-1-yl] hexanoyl} (methyl) amino] ethyl} pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate,
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,
1- (2-{[6-({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) hexanoyl] (methyl) amino} ethyl) piperidine- 4-yl biphenyl-2-yl carbamate,
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, or
(3R) -1- {4-[({[(2S) -1 ′-{2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluoro Phenyl) -1,3-oxazolidine-5-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl} pyrrolidine- 3-yl hydroxy (di-2-thienyl) acetate compound or a pharmacologically acceptable salt thereof.
　（１５）　上記（１４）に記載してある化合物又はその薬理上許容される塩のうちの化合物。 (15) A compound among the compounds described in (14) above or a pharmacologically acceptable salt thereof.
　（１６）　（１）乃至（１５）から選択されるいずれか一項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。 (16) A pharmaceutical composition comprising as an active ingredient the compound according to any one of (1) to (15) or a pharmacologically acceptable salt thereof.
　（１７）　医薬組成物が、気管支拡張作用及び抗炎症作用を有する（１６）に記載された医薬組成物。 (17) The pharmaceutical composition according to (16), wherein the pharmaceutical composition has a bronchodilating action and an anti-inflammatory action.
　（１８）　医薬組成物が、ニューロキニンＮＫ１、ニューロキニンＮＫ２及び／又はムスカリンＭ３受容体が介在する疾患又はニューロキニンＮＫ１及び／又はムスカリンＭ３受容体が介在する疾患の治療及び／又は予防のための（１６）に記載された医薬組成物。 (18) 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.
　（１９）　医薬組成物が、呼吸器疾患、アレルギー疾患及び／又は神経系疾患の治療及び／又は予防のための（１６）に記載された医薬組成物。 (19) The pharmaceutical composition according to (16), wherein the pharmaceutical composition is for the treatment and / or prevention of respiratory diseases, allergic diseases and / or nervous system diseases.
　（２０）　医薬組成物が、呼吸器疾患及び／又は神経系疾患の治療及び／又は予防のための（１６）に記載された医薬組成物。 (20) The pharmaceutical composition according to (16), wherein the pharmaceutical composition is for the treatment and / or prevention of respiratory diseases and / or nervous system diseases.
　（２１）　医薬組成物が、気管支喘息、気管支炎、慢性閉塞性肺疾患、咳嗽、喀痰過分泌、鼻炎、痛み、不安、うつ、痙攣、パーキンソン、尿失禁、過敏性腸症候群、前立腺肥大、嘔吐、消化性潰瘍、網膜検査、急性虹彩炎、 角膜炎、縮瞳、麻酔薬による過剰の唾液分泌、気道分泌及び／又は潰瘍の治療及び／又は予防のための（１６）に記載された医薬組成物。 (21) 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 iritis, keratitis, miosis, excessive salivation by anesthetic, airway secretion and / or ulcer object.
　（２２）　医薬組成物が、気管支喘息、気管支炎、慢性閉塞性肺疾患、咳嗽、喀痰過分泌、痛み、不安、うつ、痙攣、パーキンソン、過敏性腸症候群及び／又は前立腺肥大の治療及び／又は予防のための（１６）に記載された医薬組成物。 (22) 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.
　（２３）　医薬組成物が、気管支喘息及び／又は慢性閉塞性肺疾患の治療及び／又は予防のための（１６）に記載された医薬組成物。 (23) The pharmaceutical composition according to (16), wherein the pharmaceutical composition is for the treatment and / or prevention of bronchial asthma and / or chronic obstructive pulmonary disease.
　（２４）　医薬組成物が、経肺投与及び／又は点鼻投与するための、（１９）乃至（２３）から選択されるいずれか一項に記載された医薬組成物。 (24) The pharmaceutical composition according to any one of (19) to (23), wherein the pharmaceutical composition is for pulmonary administration and / or nasal administration.
　（２５）　医薬組成物を製造するための、（１）乃至（１５）から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の使用。 (25) Use of the compound described in any one of (1) to (15) or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.
　（２６）　医薬組成物が、気管支拡張作用及び抗炎症作用を有するための医薬組成物である（２５）に記載の使用。 (26) The use according to (25), wherein the pharmaceutical composition has a bronchodilating action and an anti-inflammatory action.
　（２７）　医薬組成物が、ニューロキニンＮＫ１、ニューロキニンＮＫ２及び／又はムスカリンＭ３受容体が介在する疾患又はニューロキニンＮＫ１及び／又はムスカリンＭ３受容体が介在する疾患の治療及び／又は予防のための組成物である（２５）に記載の使用。 (27) 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.
　（２８）　医薬組成物が、呼吸器疾患、アレルギー疾患及び／又は神経系疾患の治療及び／又は予防のための組成物である（２５）に記載の使用。 (28) The use according to (25), wherein the pharmaceutical composition is a composition for the treatment and / or prevention of respiratory diseases, allergic diseases and / or nervous system diseases.
　（２９）　医薬組成物が、呼吸器疾患及び／又は神経系疾患の治療及び／又は予防のための組成物である（２５）に記載の使用。 (29) The use according to (25), wherein the pharmaceutical composition is a composition for treatment and / or prevention of respiratory diseases and / or nervous system diseases.
　（３０）　医薬組成物が、気管支喘息、気管支炎、慢性閉塞性肺疾患、咳嗽、喀痰過分泌、鼻炎、痛み、不安、うつ、痙攣、パーキンソン、尿失禁、過敏性腸症候群、前立腺肥大、嘔吐、消化性潰瘍、網膜検査、急性虹彩炎、角膜炎、縮瞳、麻酔薬による過剰の唾液分泌、気道分泌及び／又は潰瘍の治療及び／又は予防のための組成物である（２５）に記載の使用。 (30) 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 iritis, keratitis, miosis, excessive salivation by anesthetics, airway secretion and / or ulcers (25) Use of.
　（３１）　医薬組成物が、気管支喘息、気管支炎、慢性閉塞性肺疾患、咳嗽、喀痰過分泌、痛み、不安、うつ、痙攣、パーキンソン、過敏性腸症候群及び／又は前立腺肥大の治療及び／又は予防のための組成物である（２５）に記載の使用。 (31) 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.
　（３２）　医薬組成物が、気管支喘息及び／又は慢性閉塞性肺疾患の治療及び／又は予防のための組成物である（２５）に記載の使用。 (32) The use according to (25), wherein the pharmaceutical composition is a composition for treatment and / or prevention of bronchial asthma and / or chronic obstructive pulmonary disease.
　（３３）　医薬組成物が、経肺投与及び／又は点鼻投与するための医薬組成物である、（２８）乃至（３２）から選択されるいずれか一項に記載された使用。 (33) The use described in any one of (28) to (32), wherein the pharmaceutical composition is a pharmaceutical composition for pulmonary administration and / or nasal administration.
　（３４）　（１）乃至（１５）から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の薬理的な有効量を温血動物に投与する疾病の治療及び／又は予防方法。 (34) Treatment of diseases and / or diseases in which a pharmacologically effective amount of the compound or pharmacologically acceptable salt thereof described in any one of (1) to (15) is administered to a warm-blooded animal Prevention method.
　（３５）　疾病が、ニューロキニンＮＫ１、ニューロキニンＮＫ２及び／又はムスカリンＭ３受容体が介在する疾患又はニューロキニンＮＫ１及び／又はムスカリンＭ３受容体が介在する疾患である（３４）に記載の方法。 (35) 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.
　（３６）　疾病が、呼吸器疾患、アレルギー疾患及び／又は神経系疾患である（３４）に記載の方法。 (36) The method according to (34), wherein the disease is a respiratory disease, allergic disease and / or nervous system disease.
　（３７）　疾病が、呼吸器疾患及び／又は神経系疾患である（３４）に記載の方法。 (37) The method according to (34), wherein the disease is a respiratory disease and / or a nervous system disease.
　（３８）　疾病が、気管支喘息、気管支炎、慢性閉塞性肺疾患、咳嗽、喀痰過分泌、鼻炎、痛み、不安、うつ、痙攣、パーキンソン、尿失禁、過敏性腸症候群、前立腺肥大、嘔吐、消化性潰瘍、網膜検査、急性虹彩炎、角膜炎、縮瞳、麻酔薬による過剰の唾液分泌、気道分泌及び／又は潰瘍である（３４）に記載の方法。 (38) 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 iritis, keratitis, miosis, excessive salivation by anesthetic, airway secretion and / or ulcer.
　（３９）　疾病が、気管支喘息、気管支炎、慢性閉塞性肺疾患、咳嗽、喀痰過分泌、痛み、不安、うつ、痙攣、パーキンソン、過敏性腸症候群及び／又は前立腺肥大である（３４）に記載の方法。 (39) 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.
　（４０）　疾病が、気管支喘息及び／又は慢性閉塞性肺疾患である（３４）に記載の方法。 (40) The method according to (34), wherein the disease is bronchial asthma and / or chronic obstructive pulmonary disease.
　（４１）　一般式（Ｉ）を有する化合物又はその薬理上許容される塩を経肺投与及び／又は点鼻投与することを特徴とする、請求項（３６）乃至（４０）から選択されるいずれか一項に記載された方法、
及び、
　（４２）　温血動物がヒトである請求項（３４）乃至（４１）から選択されるいずれか一項に記載の方法
を挙げることができる。 (41) Any one selected from (36) to (40), characterized in that the compound having the general formula (I) or a pharmacologically acceptable salt thereof is administered pulmonary and / or nasally. Or the method described in
as well as,
(42) The method according to any one of (34) to (41), wherein the warm-blooded animal is a human.
　本発明において、「ハロゲン原子」は、フッ素原子、塩素原子、臭素原子又は沃素原子である。好適には、フッ素原子又は塩素原子であり、より好適には、フッ素原子である。 In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferable is a fluorine atom or a chlorine atom, and more preferable is a fluorine atom.
　本発明において、「Ｃ１－Ｃ６アルキル基」は、炭素数１乃至６個の直鎖又は分枝鎖アルキル基である。例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓ－ブチル、ｔ－ブチル、ペンチル、イソペンチル、２－メチルブチル、ネオペンチル又はヘキシル基であり、好適には、炭素数１乃至４個の直鎖又は分枝鎖アルキル基（Ｃ1－Ｃ４アルキル基）であり、より好適には、メチル基又はエチル基（Ｃ1－Ｃ２アルキル基）であり、更により好適には、メチル基である。 In the present invention, the “C 1 -C 6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl or hexyl group, preferably a straight chain having 1 to 4 carbon atoms Or a branched alkyl group (C 1 -C 4 alkyl group), more preferably a methyl group or an ethyl group (C 1 -C 2 alkyl group), and even more preferably a methyl group. .
　本発明において、「Ｃ１－Ｃ６ハロゲン化アルキル基」は、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ１－Ｃ６アルキル基」に結合した基である。例えば、トリフルオロメチル、トリクロロメチル、ジフルオロメチル、ジクロロメチル、ジブロモメチル、フルオロメチル又は２，２，２－トリフルオロエチル基であり、好適には、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ1－Ｃ４アルキル基」に結合した基（Ｃ１－Ｃ４ハロゲン化アルキル基）であり、より好適には、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ1－Ｃ２アルキル基」に結合した基（Ｃ１－Ｃ２ハロゲン化アルキル基）であり、更により好適には、トリフルオロメチル基である。 In the present invention, 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”. For example, 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.
　本発明において、「Ｃ１－Ｃ６アルコキシ基」は、前記「Ｃ１－Ｃ６アルキル基」が酸素原子に結合した基であり、炭素数１乃至６個の直鎖又は分枝鎖アルコキシ基である。例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓ－ブトキシ、ｔ－ブトキシ又はペントキシ基であり、好適には、炭素数１乃至４個の直鎖又は分枝鎖アルコキシ基（Ｃ１－Ｃ４アルコキシ基）であり、より好適には、メトキシ基、エトキシ基、プロポキシ基又はイソプロポキシ基（Ｃ1－Ｃ３アルコキシ基）であり、更により好適には、メトキシ基である。 In the present invention, 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. For example, 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.
　本発明において、「Ｃ１－Ｃ６ハロゲン化アルコキシ基」は、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ１－Ｃ６アルコキシ基」に結合した基である。例えば、トリフルオロメトキシ、トリクロロメトキシ、ジフルオロメトキシ、ジクロロメトキシ、ジブロモメトキシ、フルオロメトキシ又は２，２，２－トリフルオロエトキシ基であり、好適には、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ１－Ｃ４アルコキシ基」に結合した基（Ｃ１－Ｃ４ハロゲン化アルコキシ基）であり、より好適には、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ1－Ｃ２アルコキシ基」に結合した基（Ｃ１－Ｃ２ハロゲン化アルコキシ基）であり、更により好適には、トリフルオロメトキシ基である。 In the present invention, 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”. For example, 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.
　本発明において、「Ｃ２－Ｃ７アルキルカルボニルオキシ基」は、１個の前記「Ｃ１－Ｃ６アルキル基」が結合したカルボニル基が酸素原子に結合した基である。例えば、アセトキシ、プロピオニルオキシ、ブチリルオキシ、イソブチリルオキシ、ペンタノイルオキシ、ピバロイルオキシ、バレリルオキシ又はイソバレリルオキシ基であり、好適には、１個の前記「Ｃ１－Ｃ４アルキル基」が結合したカルボニル基が酸素原子に結合した基（Ｃ２－Ｃ５アルキルカルボニルオキシ基）であり、より好適には、アセトキシ基である。 In the present invention, 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. For example, 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.
　本発明において、「Ｃ２－Ｃ７アルコキシカルボニルオキシ基」は、１個の前記「Ｃ１－Ｃ６アルコキシ基」が結合したカルボニル基が酸素原子に結合した基である。例えば、メトキシカルボニルオキシ、エトキシカルボニルオキシ、プロポキシカルボニルオキシ、イソプロポキシカルボニルオキシ、ブトキシカルボニルオキシ、ｓ－ブトキシカルボニルオキシ又はｔ－ブトキシカルボニルオキシ基であり、好適には、１個の前記「Ｃ１－Ｃ４アルコキシ基」が結合したカルボニル基が酸素原子に結合した基（Ｃ２－Ｃ５アルコキシカルボニルオキシ基）であり、より好適には、メトキシカルボニルオキシ基である。 In the present invention, 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. For example, 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.
　本発明において、「複素環基」は、硫黄原子、酸素原子又は／及び窒素原子を１乃至３個含み、更に１又は２個の窒素原子を含有してよく、当該硫黄原子は２個の酸素原子が結合してよい４乃至７員複素環基である。例えば、フリル、チエニル、ピロリル、アゼピニル、ピラゾリル、イミダゾリル、オキサゾリル、イソキサゾリル、チアゾリル、イソチアゾリル、１，３，４－オキサジアゾリル、１，３，４－チアジアゾリル、トリアゾリル、テトラゾリル、チアジアゾリル、ピラニル、ピリジル、ピリダジニル、ピリミジニル若しくはピラジニル基のような「芳香族複素環基」、又は、テトラヒドロピラニル、テトラヒドロチエニル、モルホリニル、チオモルホリニル、ピロリジニル、ピロリニル、イミダゾリジニル、ピラゾリジニル、ピペリジニル、ピペラジニル、オキサゾリニル、オキサゾリジニル、イソキサゾリジニル、チアゾリニル、チアゾリジニル、ピラゾリジニル、ジオキソラニル、ジオキサニル若しくは５，６－ジヒドロ－４Ｈ－１，３－オキサジン基のような「部分若しくは完全還元型の飽和複素環基」であり、上記複素環基は、ベンゼン環のような他の環式基と縮環していてもよく（「縮合二環式複素環基」）、例えば、ベンゾチエニル、ベンゾチアゾリル、ベンゾオキサゾリル、イソベンゾフラニル、１,３－ジヒドロイソベンゾフラニル、キノリル、１,３－ベンゾジオキソラニル、１，４－ベンゾジオキサニル、インドリル、イソインドリル若しくはインドリニル基である。 In the present invention, 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 4- to 7-membered heterocyclic group to which atoms may be bonded. For example, furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, An `` aromatic heterocyclic group '' such as a pyrimidinyl or pyrazinyl group, or tetrahydropyranyl, tetrahydrothienyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, Thiazolinyl, thiazolidinyl, pyrazolidinyl, dioxolanyl, dioxanyl or 5,6-dihydro-4H-1,3- A “partially or fully reduced saturated heterocyclic group” such as a xazine group, and the heterocyclic group may be condensed with another cyclic group such as a benzene ring (“fused bicyclic group”). 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.
　本発明において、「置換基群Ａから選択される基で独立に１乃至５個置換されていてもよいフェニル基」は、フェニル基又は置換基群Ａから選択される基で独立に１乃至５個置換されているフェニル基である。好適には、４－フルオロフェニル基、２－メチルフェニル基、３，５－ビス（トリフルオロメチル）フェニル基又は３，４，５－トリメトキシフェニル基である。 In the present invention, 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.
　本発明において、「置換基群Ａから選択される基で独立に１乃至３個置換されていてもよい複素環基」は、前記「複素環基」又は置換基群Ａから選択される基で独立に１乃至３個置換されている前記「複素環基」である。 In the present invention, 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.
　本発明において、「Ｃ１－Ｃ６アルキレン基」は、炭素数１乃至６個の直鎖又は分枝鎖飽和炭化水素から水素２原子を取去ってできる２価の基である。例えば、メチレン、メチルメチレン、エチレン、プロピレン、トリメチレン、テトラメチレン、１－メチルトリメチレン、２－メチルトリメチレン、３－メチルトリメチレン、ペンタメチレン又はヘキサメチレン基であり、好適には、メチレン基、エチレン基、トリメチレン基、テトラメチレン基、ペンタメチレン基又はヘキサメチレン基である。 In the present invention, 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. For example, methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, pentamethylene or hexamethylene group, preferably methylene group, An ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group or a hexamethylene group.
　本発明において、「フェニレン基」は、ベンゼンから水素２原子を取去ってできる２価の基であり、１，２－フェニレン基、１，３－フェニレン基又は１，４－フェニレン基である。好適には、１，３－フェニレン基又は１，４－フェニレン基である。 In the present invention, 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.
　本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、全ての異性体（ケト－エノール異性体、ジアステレオ異性体、光学異性体、回転異性体等）を有する。 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.).
　本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、その分子内に不斉炭素原子が存在するので、種々の異性体を有する。本発明の化合物においては、これらの異性体およびこれらの異性体の混合物がすべて単一の式、即ち一般式（Ｉ）で示されている。従って、本発明はこれらの異性体およびこれらの異性体の任意の割合の混合物をもすべて含むものである。 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. In the compounds of the present invention, 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.
　上記のような立体異性体は、光学活性な原料化合物を用いるか、又は不斉合成若しくは不斉誘導の手法を用いて本発明に係る化合物を合成するか、或いは合成した本発明に係る化合物を所望により通常の光学分割法又は分離法を用いて単離することにより得ることができる。 For the stereoisomer as described above, 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.
　本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、このような化合物を構成する原子の１以上に、原子同位体の非天然割合も含有し得る。原子同位体としては、例えば、重水素（２Ｈ）、トリチウム（３Ｈ）、ヨウ素－１２５（１２５Ｉ）又は炭素－１４（１４Ｃ）などが挙げられる。また、前記化合物は、例えば、トリチウム（３Ｈ）、ヨウ素－１２５（１２５Ｉ）又は炭素－１４（１４Ｃ）などの放射性同位体で放射性標識され得る。放射性標識された化合物は、治療又は予防剤、研究試薬、例えば、アッセイ試薬、及び診断剤、例えば、インビボ画像診断剤として有用である。本発明の化合物の全ての同位体変異種は、放射性であると否とを問わず、本発明の範囲に包含されるものとする。 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. Examples of 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.
　「その薬理上許容される塩」とは、著しい毒性を有さず、医薬として使用され得る塩をいう。本発明の一般式（Ｉ）を有する化合物は、アミノ基のような塩基性の基を有する場合には酸と反応させることにより、又、カルボキシル基のような酸性基を有する場合には塩基と反応させることにより、塩にすることができる。 “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.
　塩基性基に基づく塩としては、例えば、弗化水素酸塩、塩酸塩、臭化水素酸塩、沃化水素酸塩のようなハロゲン化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩、燐酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩のようなＣ１－Ｃ６アルキルスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩のようなアリ－ルスルホン酸塩、酢酸塩、りんご酸塩、フマ－ル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩を挙げることができる。 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.
　一方、酸性基に基づく塩としては、例えば、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩、カルシウム塩、マグネシウム塩のようなアルカリ土類金属塩、アルミニウム塩、鉄塩等の金属塩；アンモニウム塩のような無機塩、ｔ－オクチルアミン塩、ジベンジルアミン塩、モルホリン塩、グルコサミン塩、フェニルグリシンアルキルエステル塩、エチレンジアミン塩、Ｎ－メチルグルカミン塩、グアニジン塩、ジエチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、Ｎ，Ｎ’－ジベンジルエチレンジアミン塩、クロロプロカイン塩、プロカイン塩、ジエタノールアミン塩、Ｎ－ベンジルフェネチルアミン塩、ピペラジン塩、テトラメチルアンモニウム塩、トリス（ヒドロキシメチル）アミノメタン塩のような有機塩等のアミン塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩を挙げることができる。 On the other hand, 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 salts; and include glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, amino acid salts such as aspartate.
　本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、大気中に放置したり、又は、再結晶をすることにより、水分子を取り込んで、水和物となる場合があり、そのような水和物も本発明の塩に包含される。 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.
　本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、他のある種の溶媒を吸収し、溶媒和物となる場合があり、そのような溶媒和物も本発明の塩に包含される。 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.
　「ニューロキニンＮＫ１、ニューロキニンＮＫ２及びムスカリンＭ３受容体拮抗作用を有する化合物」とは、ニューロキニンＮＫ１受容体拮抗作用、ニューロキニンＮＫ２受容体拮抗作用及びムスカリンＭ３受容体拮抗作用の全ての拮抗作用を有する化合物である。 “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.
　「ニューロキニンＮＫ１及びムスカリンＭ３受容体拮抗作用を有する化合物」とは、ニューロキニンＮＫ１受容体拮抗作用及びムスカリンＭ３受容体拮抗作用の両方の拮抗作用をも有する化合物である。 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.
　「ニューロキニンＮＫ１受容体拮抗作用を有する」とは、ニューロキニンＮＫ１受容体発現細胞粗膜標本に対して特異的結合能を持ち、かつ、サブスタンスＰ誘発気道収縮等のニューロキニンＮＫ１受容体アゴニストの作用を阻害又は抑制することによって評価されるニューロキニンＮＫ１受容体拮抗作用を有することをいい、特定の化合物がそのような拮抗作用を持つか否かは、当業者であれば、例えば、以下の方法に従って容易に判別することができる。 “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.
　掛かる方法とは、文献（Ｅｕｒｏｐｅａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈａｒｍａｃｏｌｏｇｙ，２００８，ｖｏｌ．５８６，ｐａｇｅｓ３０６－３１２）記載の測定法（２．３　Ｒｅｃｅｐｔｏｒ　ｂｉｎｄｉｎｇ　ａｓｓａｙ）に従い、ニューロキニンＮＫ１受容体結合能を測定し、予め設定した一定値（Ｋｉ＝１μＭ、好ましくは、Ｋｉ＝１０ｎＭ）以下、及び、文献（Ｂｒｉｔｉｓｈ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈａｒｍａｃｏｌｏｇｙ　ａｎｄ　Ｃｈｅｍｏｔｈｅｒａｐｙ，１９６２，ｖｏｌ．１９，ｐａｇｅｓ１６８－１８２，Ｅｕｒｏｐｅａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈａｒｍａｃｏｌｏｇｙ，１９９２，ｖｏｌ．２３１，ｐａｇｅｓ３１－３８を改変）に従い、気道収縮を測定し、その抑制効果が、気管内に投与したその用量が予め設定した一定値（ＩＤ５０＝１ｍｇ/ｋｇ、好ましくは、ＩＤ５０＝５０μg/ｋｇ）以下であれば、拮抗作用を有すると判定する方法を挙げることができる。 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 1 receptor binding ability. And below (Ki = 1 μM, preferably Ki = 10 nM) and literature (British Journal of Pharmacology and Chemotherapy, 1962, vol. 19, pages 168-182, European Journal Phar. -38), the airway contraction is measured, and the inhibitory effect is determined in advance by the dose administered intratracheally. Constant value (ID 50 = 1mg / kg, preferably, ID 50 = 50μg / kg) equal to or less than, the method determines to have antagonistic action can be exemplified.
　「ニューロキニンＮＫ２受容体拮抗作用を有する」とは、ニューロキニンＮＫ２受容体発現細胞粗膜標本に対して特異的結合能を持ち、かつ、ニューロキニンＡ誘発気道収縮等のニューロキニンＮＫ２受容体アゴニストの作用を阻害又は抑制することによって評価されるニューロキニンＮＫ２受容体拮抗作用を有することをいい、特定の化合物がそのような拮抗作用を持つか否かは、当業者であれば、例えば、以下の方法に従って容易に判別することができる。 “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.
　掛かる方法とは、文献（Ｅｕｒｏｐｅａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈａｒｍａｃｏｌｏｇｙ，２００８，ｖｏｌ．５８６，ｐａｇｅｓ３０６－３１２）記載の測定法（２．３　Ｒｅｃｅｐｔｏｒ　ｂｉｎｄｉｎｇ　ａｓｓａｙ）に従い、ニューロキニンＮＫ２受容体結合能を測定し、予め設定した一定値（Ｋｉ＝１μＭ、好ましくは、Ｋｉ＝１０ｎＭ）以下、及び、測定法（２．６　Ｂｒｏｎｃｈｏｃｏｎｓｔｒｉｃｔｉｏｎ　ｉｎ　ｇｕｉｎｅａ　ｐｉｇｓ）に従い、気道収縮を測定し、その抑制効果が、気管内に投与したその用量が予め設定した一定値（ＩＤ５０＝１ｍｇ/ｋｇ、好ましくは、ＩＤ５０＝５０μg/ｋｇ）以下であれば、拮抗作用を有すると判定する方法を挙げることができる。 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 airway contraction was measured according to the measured constant value (Ki = 1 μM, preferably Ki = 10 nM) or less, and the measurement method (2.6 Bronchoconstriction in guinea pigs). Can be cited as a method of determining that it has an antagonism as long as it is not more than a predetermined value (ID 50 = 1 mg / kg, preferably ID 50 = 50 μg / kg).
　「ムスカリンＭ３受容体拮抗作用を有する」とは、ムスカリンＭ３受容体発現細胞粗膜標本に対して特異的結合能を持ち、かつ、アセチルコリン誘発気道収縮等のムスカリンＭ３受容体アゴニストの作用を阻害又は抑制することによって評価されるムスカリンＭ３受容体拮抗作用を有することをいい、特定の化合物がそのような拮抗作用を持つか否かは、当業者であれば、例えば、以下の方法に従って容易に判別することができる。 “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
　掛かる方法とは、文献（Ｌｉｆｅ　Ｓｃｉｅｎｃｅｓ，１９９３，ｖｏｌ．５２，ｐａｇｅｓ５３７－５４４）記載の測定法（Ｈｕｍａｎ　ｍｕｓｃａｒｉｎｉｃ　ｒｅｃｅｐｔｏｒ　ｓｔｕｄｉｅｓ．）に従い、ムスカリンＭ３受容体結合能を測定し、予め設定した一定値（Ｋｉ＝１μＭ、好ましくは、Ｋｉ＝１０ｎＭ）以下、及び、測定法（Ｂｒｏｎｃｈｏｓｐａｓｍｏｌｙｓｉｓ　ｉｎ　ａｎａｅｓｔｈｅｔｉｚｅｄ　ｄｏｇｓ．を改変）に従い、気道収縮を測定し、その抑制効果が、気管内に投与したその用量が予め設定した一定値（ＩＤ５０＝１ｍｇ/ｋｇ、好ましくは、ＩＤ５０＝５０μg/ｋｇ）以下であれば、拮抗作用を有すると判定する方法を挙げることができる。 According to the method (Human muscarinic receptor studies.) Described in the literature (Life Sciences, 1993, vol. 52, pages 537-544), the muscarinic M 3 receptor binding ability is measured, and a predetermined value ( Ki = 1 μM, preferably Ki = 10 nM) or less, and the measurement of airway contraction was performed according to the measurement method (Bronchospolysis in anesthetized dogs. Modified), and its inhibitory effect was determined by the dose administered into the trachea. If it is below a certain value (ID 50 = 1 mg / kg, preferably ID 50 = 50 μg / kg), a method of determining that it has an antagonistic action can be mentioned.
　掛かる「ニューロキニンＮＫ１、ニューロキニンＮＫ２及びムスカリンＭ３受容体拮抗作用を有する化合物」を同定する方法も本発明に包含される。該方法は、（ｉ）被検化合物がニューロキニンＮＫ１受容体拮抗作用を有するか否かを判定する工程、（ｉｉ）該被検化合物がニューロキニンＮＫ２受容体拮抗作用を有するか否かを判定する工程及び（ｉｉｉ）該被検化合物ムスカリンＭ３受容体拮抗作用を有するか否かを判定する工程を含むことからなる。該方法において工程（ｉ）乃至（ｉｉｉ）は、任意の順序で、あるいは２つ以上の工程を同時に並行して行うことができる。工程（ｉ）乃至（ｉｉｉ）のいずれにおいても各受容体拮抗作用を有すると判定された被検化合物を「ニューロキニンＮＫ１、ニューロキニンＮＫ２及びムスカリンＭ３受容体拮抗作用を有する化合物」として同定する。 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. In the method, 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.
　掛かる「ニューロキニンＮＫ１及びムスカリンＭ３受容体拮抗作用を有する化合物」を同定する方法も本発明に包含される。該方法は、（ｉ）被検化合物がニューロキニンＮＫ１受容体拮抗作用を有するか否かを判定する工程及び（ｉｉｉ）該被検化合物ムスカリンＭ３受容体拮抗作用を有するか否かを判定する工程を含むことからなる。該方法において工程（ｉ）又は（ｉｉｉ）は、任意の順序で、あるいは２つの工程を同時に並行して行うことができる。工程（ｉ）又は（ｉｉｉ）のいずれにおいても各受容体拮抗作用を有すると判定された被検化合物を「ニューロキニンＮＫ１及びムスカリンＭ３受容体拮抗作用を有する化合物」として同定する。 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. Comprising the steps of: In the method, the steps (i) or (iii) can be performed in any order, or two steps can be performed in parallel. 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”.
　工程（ｉ）は（ａ）被検化合物のニューロキニンＮＫ１受容体結合能を測定する工程及び（ｂ）該化合物がニューロキニンＮＫ１受容体アゴニストの作用を阻害又は抑制するか否かを判定する工程を含むことからなる。ニューロキニンＮＫ１受容体アゴニストとしては、例えば、サブスタンスＰ等をあげることができる。ニューロキニンＮＫ１受容体アゴニストの作用としては、例えば、サブスタンスＰ誘発気道収縮等を挙げることができる。 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. Comprising the steps of: Examples of the neurokinin NK 1 receptor agonist include substance P and the like. Examples of the action of the neurokinin NK 1 receptor agonist include substance P-induced airway contraction.
　工程（ｉｉ）は（ｃ）被検化合物のニューロキニンＮＫ２受容体結合能を測定する工程及び（ｄ）該化合物がニューロキニンＮＫ２受容体アゴニストの作用を阻害又は抑制するか否かを判定する工程を含むことからなる。ニューロキニンＮＫ２受容体アゴニストとしては、例えば、ニューロキニンＡ等をあげることができる。ニューロキニンＮＫ２受容体アゴニストの作用としては、例えば、ニューロキニンＡ誘発気道収縮等を挙げることができる。 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. Comprising the steps of: Examples of the neurokinin NK 2 receptor agonist include neurokinin A. Examples of the action of the neurokinin NK 2 receptor agonist include neurokinin A-induced airway contraction.
　工程（ｉｉｉ）は（ｅ）被検化合物のムスカリンＭ３受容体結合能を測定する工程及び（ｆ）該化合物がムスカリンＭ３受容体アゴニストの作用を阻害又は抑制するか否かを判定する工程を含むことからなる。ムスカリンＭ３受容体アゴニストとしては、例えば、アセチルコリン、methacholine等をあげることができる。ムスカリンＭ３受容体アゴニストの作用としては、例えば、アセチルコリン誘発気道収縮等を挙げることができる。 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. Consisting of. 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.
　上記の各受容体結合能を測定する工程には、該受容体ポリペプチドを内在性に発現している動物の組織もしくは細胞、または、組換え受容体ポリペプチドを発現している遺伝子導入動物若しくは細胞の膜画分、無傷な細胞（intact cell）等、および、標識した各受容体結合物質を用いることができる。 In the step of measuring each receptor binding ability, 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.
　また、本発明の方法において「ニューロキニンＮＫ１、ニューロキニンＮＫ２及びムスカリンＭ３受容体拮抗作用を有する化合物」、又は、「ニューロキニンＮＫ１及びムスカリンＭ３受容体拮抗作用を有する化合物」と同定された化合物は、後述するように、医薬として有用であり、特に、気管支喘息、気管支炎、慢性閉塞性肺疾患、咳嗽、喀痰過分泌、鼻炎、痛み、不安、うつ、痙攣、パーキンソン、尿失禁、過敏性腸症候群、前立腺肥大、嘔吐、消化性潰瘍、網膜検査、急性虹彩炎、角膜炎、縮瞳、麻酔薬による過剰の唾液分泌、気道分泌及び／又は潰瘍の予防剤若しくは治療剤として有用である。従って、本発明の「ニューロキニンＮＫ１、ニューロキニンＮＫ２及びムスカリンＭ３受容体拮抗作用を有する化合物」を同定する方法は、かかる疾患の予防若しくは治療剤を同定する方法としても本発明に含まれる。 In the method of the present invention, “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 As a preventive or therapeutic agent for incontinence, irritable bowel syndrome, prostatic hypertrophy, vomiting, peptic ulcer, retinal examination, acute iritis, keratitis, miosis, excessive salivation by anesthetic, airway secretion and / or ulcer Useful. Therefore, 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.
　本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、ニューロキニンＮＫ１、ニューロキニンＮＫ２及びムスカリンＭ３受容体に対して、又は、ニューロキニンＮＫ１及びムスカリンＭ３受容体に対して、拮抗作用を示すので、医薬として有用であり、特に、気管支喘息、気管支炎、慢性閉塞性肺疾患、咳嗽、喀痰過分泌、鼻炎、痛み、不安、うつ、痙攣、パーキンソン、尿失禁、過敏性腸症候群、前立腺肥大、嘔吐、消化性潰瘍、網膜検査、急性虹彩炎、角膜炎、縮瞳、麻酔薬による過剰の唾液分泌、気道分泌及び／又は潰瘍の予防剤若しくは治療剤として有用である。 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 iritis, keratitis, miosis, excessive salivation by anesthetic, airway secretion and / or ulcer preventive or therapeutic agent As useful.
　本発明の一般式（Ｉ）を有する化合物は、以下に記載する文献及び実施例に従って製造することができる。 The compound having the general formula (I) of the present invention can be produced according to the literature and examples described below.
　ニューロキニンＮＫ１及びニューロキニンＮＫ２受容体拮抗作用を有する部分構造又はニューロキニンＮＫ１受容体拮抗作用を有する部分構造は、ＵＳ７３６５０６７号公報、ＵＳ２００３／４１５７号公報等に記載された方法又はそれに類似した方法に従って製造される。 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.
　ムスカリンＭ３受容体拮抗作用を有する部分構造は、ＵＳ２００４／１６７１６７号公報、ＵＳ２００５／２０３１６７号公報、ＥＰ１２１３２８１号公報等に記載された方法又はそれに類似した方法に従って製造される。 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.
　２つの部分構造を結合している部位は、Ｔｅｔｒａｈｅｄｒｏｎ　Ｌｅｔｔ．　１９９１，３２，４５０５、Ｊ．Ｏｒｇ．Ｃｈｅｍ．　１９８９，５４，５５２２、Ｏｒｇａｎｉｃ　Ｌｅｔｔｅｒｓ、Ｖｏｌ．４、Ｎｏ．５、２００２；７３７－７４０等、あるいは下記に記載する実施例に従って製造することができる。また、アミノ基、ヒドロキシ基及び／又はカルボキシル基は、必要に応じて保護基を使用し、保護してもよい。保護・脱保護が必要な工程は、既知の方法（例えば、”Protective Groups in Organic Synthesis” (Theodora W. Greene、Peter G. M.Wuts著、 1999年、Wiley-Interscience Publication発行)等に記載の方法）に準じて行われる。 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. In addition, 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).
　本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩の投与形態は、例えば、錠剤、カプセル剤、顆粒剤、散剤又はシロップ剤等による経口投与、或いは、注射剤又は座剤等による非経口投与であり得る。更に、本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、粉末、溶液又は懸濁液の形態として経肺投与することもできる。これらのための製剤は賦形剤、滑沢剤、結合剤、崩壊剤、安定剤、矯味矯臭剤、希釈剤などの添加剤を用いて周知の方法で製造される。 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. Furthermore, 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.
　賦形剤は、例えば、乳糖、白糖、ぶどう糖、マンニット若しくはソルビットのような糖誘導体、トウモロコシデンプン、バレイショデンプン、α－デンプン、デキストリン若しくはカルボキシメチルデンプンのような澱粉誘導体、結晶セルロース、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム若しくは内部架橋カルボキシメチルセルロースナトリウムのようなセルロース誘導体、アラビアゴム、デキストラン、又は、プルラン等の有機系賦形剤；或いは、軽質無水珪酸、合成珪酸アルミニウム若しくはメタ珪酸アルミン酸マグネシウムのような珪酸塩誘導体、燐酸カルシウムのような燐酸塩、炭酸カルシウムのような炭酸塩、又は、硫酸カルシウムのような硫酸塩等の無機系賦形剤であり得る。 Excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbit, starch derivatives such as corn starch, potato starch, α-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.
　滑沢剤は、例えば、ステアリン酸、ステアリン酸カルシウム若しくはステアリン酸マグネシウムのようなステアリン酸金属塩；タルク；コロイドシリカ；ビーガム若しくはゲイ蝋のようなワックス類；硼酸；アジピン酸；硫酸ナトリウムのような硫酸塩；グリコール；フマル酸；安息香酸ナトリウム；ＤＬ－ロイシン；脂肪酸ナトリウム塩；ラウリル硫酸ナトリウム若しくはラウリル硫酸マグネシウムのようなラウリル硫酸塩；無水珪酸若しくは珪酸水和物のような珪酸類；又は、上記澱粉誘導体であり得る。 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.
　結合剤は、例えば、ポリビニルピロリドン若しくはマクロゴール、或いは、前記賦形剤と同様の化合物であり得る。 The binder may be, for example, polyvinyl pyrrolidone or macrogol, or a compound similar to the excipient.
　崩壊剤は、例えば、前記賦形剤と同様の化合物、又は、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム若しくは架橋ポリビニルピロリドンのような化学修飾されたデンプン・セルロース類であり得る。 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.
　安定剤は、例えば、メチルパラベン若しくはプロピルパラベンのようなパラオキシ安息香酸エステル類；クロロブタノール、ベンジルアルコール若しくはフェニルエチルアルコールのようなアルコール類；塩化ベンザルコニウム；フェノール若しくはクレゾールのようなフェノール類；チメロサール；デヒドロ酢酸；又は、ソルビン酸であり得る。 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.
　矯味矯臭剤は、通常使用される甘味料、酸味料若しくは香料等であり得る。 The flavoring agent can be a commonly used sweetener, acidulant, fragrance or the like.
　本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩を経肺投与するための溶液又は懸濁液を製造する場合には、例えば、本発明の化合物を、水又は水と補助溶媒（例えば、エタノール、プロピレングリコール、ポリエチレングリコール等）の混合物に溶解若しくは懸濁させることにより製造することができる。そのような溶液又は懸濁液は、更に、防腐剤（例えば、塩化ベンザルコニウム）、可溶化剤（例えば、Tween 80若しくはSpan 80のようなポリソルベート、又は塩化ベンザルコニウムのような表面活性剤）、緩衝剤、等張化剤（例えば、塩化ナトリウム）、吸収促進剤及び／又は増粘剤を含有していてもよい。また、懸濁液は、懸濁化剤（例えば、微結晶質セルロース、カルボキシメチルセルロースナトリウム等）を更に含有していてもよい。 When preparing a solution or suspension for pulmonary administration of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof, for example, 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.). 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.).
　上記のように製造した経肺投与するための組成物は、吸入剤の分野で一般的な手段（例えばスポイト、ピペット、カニューレ又は噴霧器を用いて）により鼻腔又は口腔に直接投与される。噴霧器を用いる場合は、本発明の化合物を、適当な噴射剤（例えば、ジクロロフルオロメタン、トリクロロフルオロメタン若しくはジクロロテトラフルオロエタンのようなクロロフルオロカーボン、又は二酸化炭素等のガス等）と共に加圧パックの形にされたエアロゾールとして噴霧するか、ネブライザーを用いて投与することができる。 The 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). When using 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.
　本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩の使用量は患者（温血動物、特に人間）の症状、年齢等により異なるが、例えば経口投与の場合には、成人に対して１日あたり、下限として０．１ｍｇ（好ましくは、１ｍｇ、更に好ましくは、５ｍｇ）、上限として、１０００ｍｇ（好ましくは、１００ｍｇ、更に好ましくは、５０ｍｇ）を１回または数回に分けて、症状に応じて投与することが望ましい。静脈内投与の場合には、成人に対して１日当たり、下限として０．０１ｍｇ（好ましくは０．１ｍｇ）、上限として、１００ｍｇ（好ましくは１０ｍｇ）を１回または数回に分けて、症状に応じて投与することが望ましい。 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). Per day, 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. In the case of intravenous administration, 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.
　また、本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩を経肺投与する場合の使用量は患者（温血動物、特に人間）の症状、年齢等により異なるが、例えば、成人に対して１日あたり、下限として０．１μｇ／ｋｇ（好ましくは０．５μｇ／ｋｇ）、上限として、１００００μｇ／ｋｇ（好ましくは１０００μｇ／ｋｇ）を１回または数回に分けて、症状に応じて投与することが望ましい。 In addition, 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). In an adult, the lower limit is 0.1 μg / kg (preferably 0.5 μg / kg) and the upper limit is 10,000 μg / kg (preferably 1000 μg / kg) once or several times. It is desirable to administer depending on
　以下、実施例および試験例を挙げて、本発明をさらに詳細に説明するが、本発明の範囲はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.
　実施例のカラムクロマトグラフィーにおける溶出はＴＬＣ（Ｔｈｉｎ　Ｌａｙｅｒ　Ｃｈｒｏｍａｔｏｇｒａｐｈｙ，薄層クロマトグラフィー)による観察下に行われた。ＴＬＣ観察においては、ＴＬＣプレートとしてメルク（Ｍｅｒｃｋ)社製のシリカゲル６０Ｆ２５４、もしくは富士シリシア社製のＴＬＣ plates ＮＨを、展開溶媒としてはカラムクロマトグラフィーで溶出溶媒として用いられた溶媒を、検出法としてＵＶ検出器を採用した。カラム用シリカゲルは同じくキシダ化学社製のシリカゲルＳＫ－８５（２３０～４００メッシュ)、ＳＫ－３４（７０～２３０メッシュ）、関東化学社製のシリカゲル６０Ｎ（４０～５０μｍ）、富士シリシア社製のＣｈｒｏｍａｔｏｒｅｘ　ＮＨ　ＤＭ１０２０（１００～２００メッシュ）、ＤＭ２０３５ＳＧ（２００～３５０メッシュ）もしくは富士シリシア化学社製のシリカゲルＦＬ１００Ｂを用いた。通常のカラムクロマトグラフィーの他に、山善社の自動クロマトグラフィー装置（ＹＦＬＣ－ｐｒｅｐ４）とディスポーザブルカラム（モリテックス社、山善社、和光純薬社）を適宜使用した。プレパラティブＴＬＣによる精製にはメルク社製のシリカゲル６０Ｆ２５４、０．５ｍｍ厚、プレート２０×２０ｃｍを用いた。尚、実施例で用いる略号は、次のような意義を有する。
ｍｇ：ミリグラム、ｇ：グラム、ｍＬ：ミリリットル、ＭＨｚ：メガヘルツ、ＨＡＴＵ：Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ´，Ｎ´－テトラメチルウロニウム　ヘキサフルオロホスファート、ＷＳＣ・ＨＣｌ：１－エチル－３－（ジメチルアミノプロピル）カルボジイミド塩酸塩、ＨＯＢＴ・Ｈ２Ｏ：１－ヒドロキシベンゾトリアゾール一水和物。 Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography). In the TLC observation, 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 μm) manufactured by Kanto Chemical, Chromatorex manufactured by Fuji Silysia. NH DM1020 (100 to 200 mesh), DM2035SG (200 to 350 mesh) or silica gel FL100B manufactured by Fuji Silysia Chemical Ltd. was used. In addition to ordinary column chromatography, Yamazen's automatic chromatography device (YFLC-prep4) and disposable columns (Mortex, Yamazen, Wako Pure Chemical Industries) were used as appropriate. The purification by preparative TLC manufactured by Merck silica gel 60F 254, 0.5 mm thick, was used plates 20 × 20 cm. The abbreviations used in the examples have the following significance.
mg: milligram, g: gram, mL: milliliter, MHz: megahertz, 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.
　以下の実施例において、核磁気共鳴（以下、1H NMR)スペクトルは、テトラメチルシランを標準物質として、ケミカルシフト値をδ値(ppm)にて記載した。分裂パターンは一重線をs、二重線をd、三重線をt、四重線をq、ブロードをbrで示した。 In the following examples, nuclear magnetic resonance (hereinafter, 1 H NMR) spectra are described with chemical shift values as δ values (ppm) using tetramethylsilane as a standard substance. The splitting pattern is indicated by s for single lines, d for double lines, t for triple lines, q for quadruple lines, and br for broad lines.
　質量分析（以下、ＭＳ)は、ＦＡＢ(Fast Atom Bombardment) 法、ＥＩ(Electron Ionization)法、ＡＰＣＩ（Atmospheric Pressure Chemical Ionization）もしくはＥＳＩ（Electron Spray Ionization)法で行った。 Mass spectrometry (hereinafter referred to as MS) was performed by FAB (Fast Atom Bombardment) method, EI (Electron Ionization) method, APCI (Atmospheric Pressure Chemical Ionization) or ESI (Electron Spray Ionization) method.
　［実施例１］
（３Ｒ）－１－｛７－［｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝（メチル）アミノ］ヘプト－５－イン－１－イル｝ピロリジン－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート [Example 1]
(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
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
［実施例１ａ］６－［ベンジル（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－３－カルボキサミド
　文献（ＵＳ６２９７３７５　Ｂ１）に記載されているＮ－ｔｅｒｔ－ブチル－６－クロロ－４－（２－メチルフェニル）ピリジン－３－カルボキサミド（３２．３ｇ，９９．７ｍｍｏｌ）とＮ－ベンジルメチルアミン（６４．３ｍＬ，４９８．５ｍｍｏｌ）の混合物を１００℃にて２０時間加熱攪拌した。反応液を酢酸エチルで希釈し、水を加えた後、酢酸エチル（×２）で抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：１－３：２）を用いて精製し、粗製のアミノ化体（４１．５ｇ）を得た。 [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. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1-3: 2) to give a crude amination. A body (41.5 g) was obtained.
　得られた粗製のアミノ化体をメタンスルホン酸（８４ｍＬ，１．３０ｍｍｏｌ）に溶解し、６０℃にて１１時間加熱攪拌した。反応液に氷冷下、水をゆっくり加え、１０Ｎ水酸化ナトリウム水溶液で反応液をｐＨ８－９にした。酢酸エチル（×２）で抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１－酢酸エチル：メタノール＝１０：１）を用いて精製し、標記目的化合物（１２．４ｇ，収率３６％）を黄色固体として得た。副生成物として脱Ｂｎ体である　６－（メチルアミノ）－４－（２－メチルフェニル）ピリジン－３－カルボキサミド（１５．６ｇ，収率６２％）を黄色固体として得た。
標記化合物
1H NMR (CDCl3, 400MHz): δ 2.13 (3H, s), 3.09 (3H, s), 4.80-4.97 (2H, m), 5.08 (2H, brs), 6.19 (1H, s), 7.18-7.36 (9H, m), 8.96 (1H, s).
MS (ESI) m/z: 331 (M+).
脱Ｂｎ体：６－（メチルアミノ）－４－（２－メチルフェニル）ピリジン－３－カルボキサミド
1H NMR (CDCl3, 400MHz): δ 2.16 (3H, s), 2.96 (3H, d, J = 5.1 Hz), 4.98 (1H, brs), 5.09 (2H, brs), 6.09 (1H, s), 7.20-7.22 (1H, m), 7.29-7.38 (3H, m), 8.89 (1H, s).
MS (ESI) m/z: 241 (M+).
［実施例１ｂ］６－［ベンジル（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－３－カルボキサミド
　実施例１ａで得られた副生成物である６－（メチルアミノ）－４－（２－メチルフェニル）ピリジン－３－カルボキサミド（１５．６ｇ，６４．７ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド溶液（１３０ｍＬ）に炭酸カリウム（１３．４ｇ，９７．２ｍｍｏｌ）、及び、臭化ベンジル（１１．６ｍＬ，９７．２ｍｍｏｌ）を加え、８０℃で４時間攪拌した。反応液を酢酸エチルで希釈し、有機層を水（×３）、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１－１：２）を用いて精製し、標記目的化合物（１１．３ｇ，収率５３％）を黄色固体として得た。
1H NMR (CDCl3, 400MHz): δ 2.13 (3H, s), 3.09 (3H, s), 4.80-4.97 (2H, m), 5.08 (2H, brs), 6.19 (1H, s), 7.18-7.36 (9H, m), 8.96 (1H, s).
MS (ESI) m/z: 331 (M+).
［実施例１ｃ］メチル　｛６－［ベンジル（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－３－イル｝カーバメート
　Ｎ－ブロモスクシンイミド（１９．１ｇ，１０７．４ｍｍｏｌ）を塩化メチレン（１０７ｍＬ）に溶解し、氷冷下、ナトリウムメトキシド（６５ｍＬ，２８％メタノール溶液，３３６．５ｍｍｏｌ）を加えた後、同温にて１時間攪拌した。氷冷下、反応液に実施例１ａ及び１ｂで得られた６－［ベンジル（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－３－カルボキサミド（２３．７ｇ，７１．６ｍｍｏｌ）の塩化メチレン－メタノール混合溶液（４：１，４７７ｍＬ）を加えた後、室温にて１時間攪拌した。反応液に１Ｎ　塩酸を加え、反応液をｐＨ８－９にした後、塩化メチレン（×３）で抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：１－１：１）を用いて精製し、標記目的化合物（１９．７ｇ，収率７６％）を黄色油状物として得た。
1H NMR (CDCl3, 400MHz): δ 2.08 (3H, s), 3.05 (3H, s), 3.66 (3H, s), 4.72-4.87 (2H, m), 5.82 (1H, brs), 6.30 (1H, s), 7.10 (1H, d, J = 6.7 Hz), 7.23-7.32 (9H, m)。 The obtained crude aminated product was dissolved in methanesulfonic acid (84 mL, 1.30 mmol), and the mixture was heated and stirred at 60 ° C. for 11 hours. Water was slowly added to the reaction solution under ice cooling, and the reaction solution was adjusted to pH 8-9 with 10N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (x2), and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 1-ethyl acetate: methanol = 10: 1). The title compound (12.4 g, yield 36%) was obtained as a yellow solid. As a by-product, 6- (methylamino) -4- (2-methylphenyl) pyridine-3-carboxamide (15.6 g, yield 62%) as a de-Bn form was obtained as a yellow solid.
Title compound
1 H NMR (CDCl 3 , 400 MHz): δ 2.13 (3H, s), 3.09 (3H, s), 4.80-4.97 (2H, m), 5.08 (2H, brs), 6.19 (1H, s), 7.18- 7.36 (9H, m), 8.96 (1H, s).
MS (ESI) m / z: 331 (M + ).
De-Bn form: 6- (methylamino) -4- (2-methylphenyl) pyridine-3-carboxamide
1 H NMR (CDCl 3 , 400 MHz): δ 2.16 (3H, s), 2.96 (3H, d, J = 5.1 Hz), 4.98 (1H, brs), 5.09 (2H, brs), 6.09 (1H, s) , 7.20-7.22 (1H, m), 7.29-7.38 (3H, m), 8.89 (1H, s).
MS (ESI) m / z: 241 (M + ).
[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. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 1-1: 2) to give the title target compound ( 11.3 g, 53% yield) was obtained as a yellow solid.
1 H NMR (CDCl 3 , 400 MHz): δ 2.13 (3H, s), 3.09 (3H, s), 4.80-4.97 (2H, m), 5.08 (2H, brs), 6.19 (1H, s), 7.18- 7.36 (9H, m), 8.96 (1H, s).
MS (ESI) m / z: 331 (M + ).
[Example 1c] Methyl {6- [Benzyl (methyl) amino] -4- (2-methylphenyl) pyridin-3-yl} carbamate N-bromosuccinimide (19.1 g, 107.4 mmol) was added to methylene chloride (107 mL). ), Sodium methoxide (65 mL, 28% methanol solution, 336.5 mmol) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Under ice-cooling, 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. After adding 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. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1-1: 1) to give the title target compound ( 19.7 g, yield 76%) was obtained as a yellow oil.
1 H NMR (CDCl 3 , 400 MHz): δ 2.08 (3H, s), 3.05 (3H, s), 3.66 (3H, s), 4.72-4.87 (2H, m), 5.82 (1H, brs), 6.30 ( 1H, s), 7.10 (1H, d, J = 6.7 Hz), 7.23-7.32 (9H, m).
　［実施例１ｄ］Ｎ２－ベンジル－Ｎ２，Ｎ５－ジメチル－４－（２－メチルフェニル）ピリジン－２，５－ジアミン
　水素化ビス（エトキシメトキシ）アルミニウム　ナトリウム（７５．８ｍＬ，３．６Ｍトルエン溶液，２７２．８ｍｍｏｌ）に、室温にて、実施例１ｃで得られたメチル　｛６－［ベンジル（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－３－イル｝カーバメート（１９．７ｇ，５４．６ｍｍｏｌ）のトルエン溶液（１８２ｍＬ）をゆっくり加えた後、室温にて１０分間攪拌した。続いて５０℃で２時間攪拌した後、反応液を０℃に冷やし、１Ｎ　水酸化ナトリウム水溶液（１６３．８ｍＬ）をゆっくり加えた。トルエン（×３）で抽出し、有機層を水、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１－３：１）を用いて精製し、標記目的化合物（１６．２ｇ，収率９３％）を黄色油状物として得た。
1H NMR (CDCl3, 400MHz): δ 2.11 (3H, s), 2.77 (3H, s), 2.86 (1H, brs), 3.00 (3H, s), 4.65-4.80 (2H, m), 6.33 (1H, s), 7.13 (1H, d, J = 7.0 Hz), 7.21-7.31 (8H, m), 7.75 (1H, s).
［実施例１ｅ］２－［３，５－ビス（トリフルオロメチル）フェニル］－Ｎ，２－ジメチル－Ｎ－［６－（メチルアミノ）－４－（２－メチルフェニル）ピリジン－３－イル］プロパンアミド
　実施例１ｄで得られたＮ２－ベンジル－Ｎ２，Ｎ５－ジメチル－４－（２－メチルフェニル）ピリジン－２，５－ジアミン（１６．２ｇ，５１．０ｍｍｏｌ）の塩化メチレン溶液（１４０ｍＬ）にＮ，Ｎ－ジイソプロピルエチルアミン（９．４ｍＬ，５４．０ｍｍｏｌ）を加え、氷冷下、２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル　クロリド（１５．６ｇ，４９．１ｍｍｏｌ）をゆっくり滴下し、室温にて３０分間攪拌した。減圧下、溶剤を留去して得られた残渣を酢酸エチルで希釈し、水を加えた後、酢酸エチル（×２）で抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して、粗製のアミド体を得た。 [Example 1d] N 2 -benzyl-N 2 , N 5 -dimethyl-4- (2-methylphenyl) pyridine-2,5-diamine Hydrogenated bis (ethoxymethoxy) aluminum sodium (75.8 mL, 3.6 M) Toluene solution, 272.8 mmol) at room temperature with methyl {6- [benzyl (methyl) amino] -4- (2-methylphenyl) pyridin-3-yl} carbamate (19. 7 g, 54.6 mmol) in toluene (182 mL) was slowly added, and the mixture was stirred at room temperature for 10 minutes. Then, after stirring at 50 degreeC for 2 hours, the reaction liquid was cooled to 0 degreeC and 1N sodium hydroxide aqueous solution (163.8 mL) was added slowly. Extraction was performed with toluene (× 3), and the organic layer was washed successively with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1-3: 1) to give the title target compound ( 16.2 g, 93% yield) was obtained as a yellow oil.
1 H NMR (CDCl 3 , 400 MHz): δ 2.11 (3H, s), 2.77 (3H, s), 2.86 (1H, brs), 3.00 (3H, s), 4.65-4.80 (2H, m), 6.33 ( 1H, s), 7.13 (1H, d, J = 7.0 Hz), 7.21-7.31 (8H, m), 7.75 (1H, s).
[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 residue obtained by distilling off the solvent under reduced pressure was diluted with ethyl acetate, water was added, followed by extraction with ethyl acetate (x2), and 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 amide form.
　１０％パラジウム－炭素（９．３ｇ）に、得られた粗製のアミド体のエタノール溶液（２５５ｍＬ）、及び、４Ｎ　塩酸－ジオキサン（２５．０ｍＬ，１０１．９ｍｍｏｌ）を加え、系内を水素雰囲気に置換した後、６０℃にて３．５時間攪拌した。系内を窒素雰囲気に置換した後、窒素雰囲気下で１０％パラジウム－炭素（４．６ｇ）、及び、４Ｎ　塩酸－ジオキサン（１２．５ｍＬ，５１．０ｍｍｏｌ）を追加し、再び系内を水素雰囲気に置換した後、６０℃にて１．５時間攪拌した。系内を窒素雰囲気に置換した後、セライトを用いて反応液をろ過した。減圧下、溶剤を留去して得られた残渣を酢酸エチルで希釈し、飽和重曹水を加えた後、酢酸エチル（×２）で抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して、ＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）を用いて精製し、標記目的化合物（２２．１ｇ，収率８５％）を黄色固体として得た。
MS (FAB) m/z: 509(M+H)+.  
IR(KBr) νmax 3258, 1659, 1611, 1372, 1281, 1182, 1144, 1082, 898, 683 cm-1.
［実施例１ｆ］２－［３，５－ビス（トリフルオロメチル）フェニル］－Ｎ－｛６－［（７－｛［ｔｅｒｔ－ブチル（ジフェニル）シリル］オキシ｝ヘプト－２－イン－１－イル）（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－３－イル｝－Ｎ，２－ジメチルプロパンアミド
　文献（Ｃｈｅｍｉｓｔｒｙ－Ａ　Ｅｕｒｏｐｅａｎ　Ｊｏｕｒｎａｌ　２００４，１０，２７５９）に記載されている７－｛［ｔｅｒｔ－ブチル（ジフェニル）シリル］オキシ｝ヘプト－２－イン－１－オール（７１９ｍｇ，１．９６ｍｍｏｌ）を酢酸エチル（２０ｍＬ）に溶解し、氷冷下、トリエチルアミン（０．３２８ｍＬ，２．３５ｍｍｏｌ）、及び、塩化メタンスルホニル（０．１８２ｍＬ，２．３５ｍｍｏｌ）を加えた後、同温にて１５分間攪拌した。不溶物をセライトでろ過し、減圧下、溶剤を留去して得られた残渣をＮ，Ｎ－ジメチルアセトアミド（１５ｍＬ）に溶解し、実施例１ｅで得られた２－［３，５－ビス（トリフルオロメチル）フェニル］－Ｎ，２－ジメチル－Ｎ－［６－（メチルアミノ）－４－（２－メチルフェニル）ピリジン－３－イル］プロパンアミド（５００ｍｇ，０．９８１ｍｍｏｌ）、炭酸カリウム（２７１ｍｇ，１．９６ｍｍｏｌ）、及び、ヨウ化カリウム（３２５ｍｇ，１．９６ｍｍｏｌ）を加えた後、８０℃にて４．５時間攪拌した。反応液を酢酸エチルで希釈し、有機層を水（×３）、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８５：１５）を用いて精製し、標記目的化合物（６４９ｍｇ，収率７７％）を褐色油状物として得た。
1H NMR (CDCl3, 400MHz): δ 1.03 (6H, s), 1.05 (9H, s), 1.57-1.66 (4H, m), 2.14-2.18 (2H, m), 2.20-2.24 (2H, m), 2.28-2.32 (1H, m), 3.07 (3H, s), 3.63-3.69 (5H, m), 4.22-4.25 (1H, m), 4.27-4.33 (1H, m), 6.43 (1H, s), 7.34-7.44 (9H, m), 7.64-7.67 (7H, m), 7.75 (1H, s), 8.00 (1H, s)。 To 10% palladium-carbon (9.3 g), an ethanol solution (255 mL) of the obtained crude amide compound and 4N hydrochloric acid-dioxane (25.0 mL, 101.9 mmol) were added, and the inside of the system was put into a hydrogen atmosphere. After the replacement, the mixture was stirred at 60 ° C. for 3.5 hours. After replacing the system with a nitrogen atmosphere, 10% palladium-carbon (4.6 g) and 4N hydrochloric acid-dioxane (12.5 mL, 51.0 mmol) were added under the nitrogen atmosphere, and the system was again filled with a hydrogen atmosphere. Then, the mixture was stirred at 60 ° C. for 1.5 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 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. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified using NH silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title object compound (22.1 g, yield 85). %) As a yellow solid.
MS (FAB) m / z: 509 (M + H) + .
IR (KBr) ν max 3258, 1659, 1611, 1372, 1281, 1182, 1144, 1082, 898, 683 cm -1 .
[Example 1f] 2- [3,5-bis (trifluoromethyl) phenyl] -N- {6-[(7-{[tert-butyl (diphenyl) silyl] oxy} hept-2-yne-1- Yl) (methyl) amino] -4- (2-methylphenyl) pyridin-3-yl} -N, 2-dimethylpropanamide 7- described in the literature (Chemistry-A European Journal 2004, 10, 2759) {[Tert-Butyl (diphenyl) silyl] oxy} hept-2-yn-1-ol (719 mg, 1.96 mmol) was dissolved in ethyl acetate (20 mL), and triethylamine (0.328 mL, 2. 35 mmol) and methanesulfonyl chloride (0.182 mL, 2.35 mmol) were added, followed by stirring at the same temperature for 15 minutes. did. The insoluble material was filtered through celite, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in N, N-dimethylacetamide (15 mL), and the 2- [3,5-bis obtained in Example 1e was dissolved. (Trifluoromethyl) phenyl] -N, 2-dimethyl-N- [6- (methylamino) -4- (2-methylphenyl) pyridin-3-yl] propanamide (500 mg, 0.981 mmol), potassium carbonate (271 mg, 1.96 mmol) and potassium iodide (325 mg, 1.96 mmol) were added, followed by stirring at 80 ° C. for 4.5 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed successively with water (x3) and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 85: 15) to give the title object compound (649 mg, yield). 77%) as a brown oil.
1 H NMR (CDCl 3 , 400 MHz): δ 1.03 (6H, s), 1.05 (9H, s), 1.57-1.66 (4H, m), 2.14-2.18 (2H, m), 2.20-2.24 (2H, m ), 2.28-2.32 (1H, m), 3.07 (3H, s), 3.63-3.69 (5H, m), 4.22-4.25 (1H, m), 4.27-4.33 (1H, m), 6.43 (1H, s ), 7.34-7.44 (9H, m), 7.64-7.67 (7H, m), 7.75 (1H, s), 8.00 (1H, s).
　［実施例１ｇ］２－［３，５－ビス（トリフルオロメチル）フェニル］－Ｎ－｛６－［（７－ヒドロキシヘプト－２－イン－１－イル）（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－３－イル｝－Ｎ，２－ジメチルプロパンアミド
　実施例１ｆで得られた化合物（６４９ｍｇ，０．７５６ｍｍｏｌ）をテトラヒドロフラン（８ｍＬ）に溶解し、テトラブチルアンモニウムフロリド（１Ｍ－テトラヒドロフラン溶液，０．９０８ｍＬ，０．９０８ｍｍｏｌ）を加えた後、室温にて１．５時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲル分取薄層クロマトグラフィー（ヘキサン：酢酸エチル＝１：１）を用いて精製し、標記目的化合物（２５５ｍｇ，収率５４％）を黄色油状物として得た。
MS (FAB) m/z: 620(M+H)+.
IR(liquid film) νmax 2939, 2236, 1746, 1650, 1597, 1501, 1373, 1282, 1184, 1137 cm-1.
［実施例１ｈ］ｔｅｒｔ－ブチル　（３Ｒ）－３－｛［ヒドロキシ（ジチオフェン－２－イル）アセチル］オキシ｝ピロリジン－１－カルボキシレート
　水素化ナトリウム（４．０９ｇ，５５％，９３．８ｍｍｏｌ）のトルエン懸濁液（１８８ｍＬ）に、メチル　ヒドロキシ（ジチオフェン－２－イル）アセテート（３５．８ｇ，１４０．７ｍｍｏｌ）とｔｅｒｔ－ブチル　（３Ｒ）－３－ヒドロキシピロリジン－１－カルボキシレート（１７．６ｇ，９３．８ｍｍｏｌ）の混合物のトルエン溶液（３７６ｍＬ）をなるべく早く加え、系内を２００－３００ｍｍＨｇで減圧しながら８０℃にて２．５時間攪拌した。減圧下、溶剤を留去して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝４：１－１：１）を用いて精製し、標記目的化合物（３３．９ｇ，収率８８％）を褐色油状物として得た。
1H NMR (CDCl3, 400MHz): δ 1.45 (9H, s), 2.04-2.07 (1H, m), 3.24-3.29 (1H, m), 3.34-3.40 (1H, m), 3.44-3.48 (1H, m), 3.53-3.57 (2H, m), 4.64 (1H, s), 5.40-5.43 (1H, m), 6.96-6.98 (2H, m), 7.13-7.15 (2H, m), 7.26-7.29 (2H, m)。 [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. 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, and the resulting residue was purified using silica gel preparative thin layer chromatography (hexane: ethyl acetate = 1: 1) to give the title object compound (255 mg , Yield 54%) as a yellow oil.
MS (FAB) m / z: 620 (M + H) + .
IR (liquid film) ν max 2939, 2236, 1746, 1650, 1597, 1501, 1373, 1282, 1184, 1137 cm -1 .
[Example 1h] tert-Butyl (3R) -3-{[hydroxy (dithiophen-2-yl) acetyl] oxy} pyrrolidine-1-carboxylate sodium hydride (4.09 g, 55%, 93.8 mmol) Toluene suspension (188 mL) was added methyl hydroxy (dithiophen-2-yl) acetate (35.8 g, 140.7 mmol) and tert-butyl (3R) -3-hydroxypyrrolidine-1-carboxylate (17.6 g, A toluene solution (376 mL) of a mixture of 93.8 mmol) was added as soon as possible, and the system was stirred at 80 ° C. for 2.5 hours while reducing the pressure at 200 to 300 mmHg. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1-1: 1) to give the title object compound (33.9 g, yield 88%). Was obtained as a brown oil.
1 H NMR (CDCl 3 , 400 MHz): δ 1.45 (9H, s), 2.04-2.07 (1H, m), 3.24-3.29 (1H, m), 3.34-3.40 (1H, m), 3.44-3.48 (1H , m), 3.53-3.57 (2H, m), 4.64 (1H, s), 5.40-5.43 (1H, m), 6.96-6.98 (2H, m), 7.13-7.15 (2H, m), 7.26-7.29 (2H, m).
　［実施例１ｉ］（３Ｒ）－ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート
　実施例１ｈで得られたｔｅｒｔ－ブチル　（３Ｒ）－３－｛［ヒドロキシ（ジチオフェン－２－イル）アセチル］オキシ｝ピロリジン－１－カルボキシレート（３３．９ｇ，８２．７ｍｍｏｌ）、及び、ｐ－アニシジン（１．０２ｇ，８．２７ｍｍｏｌ）を１，４－ジオキサン（１６６ｍＬ）に溶解し、氷冷下、４Ｎ　塩酸－ジオキサン（２０７ｍＬ，８２７．０ｍｍｏｌ）を加え、室温にて２．５時間撹拌した。反応液に飽和重曹水、及び、炭酸カリウムを加えてアルカリ性にし、酢酸エチル（×３）で抽出した後、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１－酢酸エチル：メタノール＝２０：１）を用いて精製し、標記目的化合物（１７．９ｇ，収率７０％）を紫色固体として得た。
1H NMR (CDCl3, 400MHz): δ 1.85-1.92 (1H, m), 2.00-2.09 (1H, m), 2.87-2.94 (1H, m), 2.99-3.07 (3H, m), 5.36-5.40 (1H, m), 6.96-6.98 (2H, m),7.15-7.17 (2H, m), 7.28 (2H, dd, J = 5.1,1.2 Hz).
［実施例１ｊ］（３Ｒ）－１－｛７－［｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝（メチル）アミノ］ヘプト－５－イン－１－イル｝ピロリジン－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート
　実施例１ｇで得られた化合物（１００ｍｇ，０．１６１ｍｍｏｌ）を酢酸エチル（３ｍＬ）に溶解し、氷冷下、トリエチルアミン（５４μＬ，０．１９４ｍｍｏｌ）、及び、塩化メタンスルホニル（３０μＬ，０．１９４ｍｍｏｌ）を加えた後、同温にて１５分間攪拌した。不溶物をセライトでろ過し、減圧下、溶剤を留去して得られた残渣をＮ，Ｎ－ジメチルホルムアミド（６ｍＬ）に溶解し、実施例１ｉで得られた（３Ｒ）－ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート（５５ｍｇ，０．１７７ｍｍｏｌ）、炭酸カリウム（３３ｍｇ，０．２４２ｍｍｏｌ）、及び、ヨウ化カリウム（２９ｍｇ，０．１７７ｍｍｏｌ）を加えた後、８０℃にて６時間攪拌した。反応液を酢酸エチルで希釈し、有機層を水（×３）、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲル分取薄層クロマトグラフィー（塩化メチレン：メタノール＝２０：１）を用いて精製した。更にシリカゲル分取薄層クロマトグラフィー（塩化メチレン：メタノール＝４０：１、Ｖ／Ｖ、５回展開）を用いて精製し、標記目的化合物（１４ｍｇ，収率１０％）を褐色固体として得た。
MS (FAB) m/z: 911 (M+H)+.
IR(KBr) νmax 2933, 1738, 1651, 1596, 1499, 1373, 1281, 1184, 1137, 708 cm-1。 [Example 1i] (3R) -Pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate tert-Butyl (3R) -3-{[hydroxy (dithiophen-2-yl) acetyl obtained in Example 1h ] Oxy} pyrrolidine-1-carboxylate (33.9 g, 82.7 mmol) and p-anisidine (1.02 g, 8.27 mmol) were dissolved in 1,4-dioxane (166 mL), and the mixture was cooled with ice. 4N Hydrochloric acid-dioxane (207 mL, 827.0 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium hydrogen carbonate and potassium carbonate were added to the reaction solution to make it alkaline, followed by extraction with ethyl acetate (x3), and then the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using NH silica gel column chromatography (hexane: ethyl acetate = 4: 1-ethyl acetate: methanol = 20: 1). The title compound (17.9 g, yield 70%) was obtained as a purple solid.
1 H NMR (CDCl 3 , 400 MHz): δ 1.85-1.92 (1H, m), 2.00-2.09 (1H, m), 2.87-2.94 (1H, m), 2.99-3.07 (3H, m), 5.36-5.40 (1H, m), 6.96-6.98 (2H, m), 7.15-7.17 (2H, m), 7.28 (2H, dd, J = 5.1, 1.2 Hz).
[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) was dissolved in ethyl acetate (3 mL), and triethylamine (54 μL, 0.194 mmol) and methanesulfonyl chloride (30 μL, 0.194 mmol) were added under ice cooling, followed by the same temperature. Stir for 15 minutes. The insoluble material was filtered through celite, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in N, N-dimethylformamide (6 mL), and (3R) -pyrrolidine-3- obtained in Example 1i was obtained. After adding yl hydroxy (dithiophen-2-yl) acetate (55 mg, 0.177 mmol), potassium carbonate (33 mg, 0.242 mmol) and potassium iodide (29 mg, 0.177 mmol), Stir for hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed successively with water (x3) and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel preparative thin layer chromatography (methylene chloride: methanol = 20: 1). Further purification using silica gel preparative thin layer chromatography (methylene chloride: methanol = 40: 1, V / V, 5 developments) gave the title object compound (14 mg, yield 10%) as a brown solid.
MS (FAB) m / z: 911 (M + H) + .
IR (KBr) ν max 2933, 1738, 1651, 1596, 1499, 1373, 1281, 1184, 1137, 708 cm −1 .
　［実施例２］
（３Ｒ）－１－｛５－［｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝（メチル）アミノ］ペント－３－イン－１－イル｝ピロリジン－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート [Example 2]
(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
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
［実施例２ａ］２－［３，５－ビス（トリフルオロメチル）フェニル］－Ｎ－｛６－［（５－｛［ｔｅｒｔ－ブチル（ジフェニル）シリル］オキシ｝ペント－２－イン－１－イル）（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－３－イル｝－Ｎ，２－ジメチルプロパンアミド
　文献（Ｊ．Ｏｒｇ．Ｃｈｅｍ．　１９８９，５４，５５２２）に記載されている５－｛［ｔｅｒｔ－ブチル（ジフェニル）シリル］オキシ｝ペント－２－イン－１－オール（３９９ｍｇ，１．１８ｍｍｏｌ）を酢酸エチル（１２ｍＬ）に溶解し、氷冷下、トリエチルアミン（０．１９７ｍＬ，１．４１ｍｍｏｌ）、及び、塩化メタンスルホニル（０．１１０ｍＬ，１．４１ｍｍｏｌ）を加えた後、同温にて１５分間攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をＮ，Ｎ－ジメチルアセトアミド（６ｍＬ）に溶解し、実施例１ｅで得られた化合物（３００ｍｇ，０．５８９ｍｍｏｌ）、炭酸カリウム（１６３ｍｇ，１．１８ｍｍｏｌ）、及び、ヨウ化カリウム（１４７ｍｇ，０．８８４ｍｍｏｌ）を加えた後、５０℃にて６時間攪拌した。反応液を酢酸エチルで希釈し、有機層を水（×３）、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１－４：１）を用いて精製し、標記目的化合物（３２１ｍｇ，収率６６％）を黄色油状物として得た。
1H NMR (CDCl3, 400MHz): δ 1.03 (9H, s), 1.06 (6H, s), 2.08-2.10 (1H, m), 2.27-2.33 (2H, m), 2.42-2.50 (2H, m), 3.05 (3H, s), 3.66-3.79 (5H, m), 4.20-4.22 (1H, m), 4.24-4.33 (1H, m), 6.41 (1H, s), 7.34-7.43 (8H, m), 7.65-7.68 (7H, m), 7.70-7.73 (1H, m), 7.75 (1H, s), 8.00 (1H, s).
［実施例２ｂ］２－［３，５－ビス（トリフルオロメチル）フェニル］－Ｎ－｛６－［（５－ブロモペント－２－イン－１－イル）（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－３－イル｝－Ｎ，２－ジメチルプロパンアミド
　実施例２ａで得られた化合物（３２１ｍｇ，０．３８７ｍｍｏｌ）をテトラヒドロフラン（４ｍＬ）に溶解し、テトラブチルアンモニウムフロリド（１Ｍ－テトラヒドロフラン溶液，０．５８１ｍＬ，０．５８１ｍｍｏｌ）を加えた後、室温にて１時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲル分取薄層クロマトグラフィー（ヘキサン：酢酸エチル＝２：１）を用いて精製し、アルコール体（１４９ｍｇ，収率６５％）を黄色油状物として得た。 [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). -{[Tert-Butyl (diphenyl) silyl] oxy} pent-2-yn-1-ol (399 mg, 1.18 mmol) was dissolved in ethyl acetate (12 mL) and triethylamine (0.197 mL, 1 .41 mmol) and methanesulfonyl chloride (0.110 mL, 1.41 mmol) were added, followed by stirring at the same temperature for 15 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, and the resulting residue was dissolved in N, N-dimethylacetamide (6 mL) to obtain the compound (300 mg, 0.589 mmol) obtained in Example 1e. , Potassium carbonate (163 mg, 1.18 mmol) and potassium iodide (147 mg, 0.884 mmol) were added, followed by stirring at 50 ° C. for 6 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed successively with water (x3) and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 9: 1-4: 1) to give the title compound ( 321 mg, 66% yield) was obtained as a yellow oil.
1 H NMR (CDCl 3 , 400 MHz): δ 1.03 (9H, s), 1.06 (6H, s), 2.08-2.10 (1H, m), 2.27-2.33 (2H, m), 2.42-2.50 (2H, m ), 3.05 (3H, s), 3.66-3.79 (5H, m), 4.20-4.22 (1H, m), 4.24-4.33 (1H, m), 6.41 (1H, s), 7.34-7.43 (8H, m ), 7.65-7.68 (7H, m), 7.70-7.73 (1H, m), 7.75 (1H, s), 8.00 (1H, s).
[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. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel preparative thin layer chromatography (hexane: ethyl acetate = 2: 1). To obtain an alcohol form (149 mg, yield 65%) as a yellow oily substance.
　得られたアルコール体（６８ｍｇ，０．１１５ｍｍｏｌ）を塩化メチレン（５ｍＬ）に溶解し、トリフェニルホスフィン（３６ｍｇ，０．１３８ｍｍｏｌ）、及び、四臭化炭素（４６ｍｇ，０．１３８ｍｍｏｌ）を加えた後、室温にて３０分間攪拌した。減圧下、溶剤を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）を用いて精製し、標記目的化合物（７５ｍｇ，収率１００％）を褐色油状物として得た。
MS (ESI) m/z: 654 (M+).
［実施例２ｃ］（３Ｒ）－１－｛５－［｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝（メチル）アミノ］ペント－３－イン－１－イル｝ピロリジン－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート
　実施例２ｂで得られた化合物（７５ｍｇ，０．１１５ｍｍｏｌ）をＮ，Ｎ－ジメチルアセトアミド（３ｍＬ）に溶解し、実施例１ｉで得られた（３Ｒ）－ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート（３９ｍｇ，０．１２７ｍｍｏｌ）、及び、炭酸水素ナトリウム（２０ｍｇ，０．２３０ｍｍｏｌ）を加え、５０℃にて４時間攪拌した。反応液にヨウ化カリウム（３８ｍｇ，０．２３０ｍｍｏｌ）を加え、５０℃にて更に９時間攪拌した。反応液を酢酸エチルで希釈し、有機層を水（×３）、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１－１：１）を用いて精製した。さらに逆相分取カラムクロマトグラフィー（Ｗａｔｅｒｓ，ＭＳ　Ｃ１８　ＯＢＤ，５μｍ，３０×１００ｍｍ）（アセトニトリル：０．１％酢酸アンモニウム水溶液＝２０：８０－１００：０）を用いて精製し、標記目的化合物（７ｍｇ，収率７％）を黄色固体として得た。
MS (FAB) m/z: 883(M+H)+.
IR(KBr) νmax 2935, 1738, 1651, 1596, 1499, 1373, 1281, 1184, 1136, 708 cm-1。 After the obtained alcohol (68 mg, 0.115 mmol) was dissolved in methylene chloride (5 mL), triphenylphosphine (36 mg, 0.138 mmol) and carbon tetrabromide (46 mg, 0.138 mmol) were added. And stirred at room temperature for 30 minutes. The residue obtained by evaporating the solvent under reduced pressure was purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title object compound (75 mg, yield 100%) as a brown oil. Obtained.
MS (ESI) m / z: 654 (M + ).
[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) was dissolved in N, N-dimethylacetamide (3 mL) and (3R) -pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate (39 mg, 0. 1) obtained in Example 1i. 127 mmol) and sodium hydrogen carbonate (20 mg, 0.230 mmol) were added, and the mixture was stirred at 50 ° C. for 4 hours. To the reaction solution was added potassium iodide (38 mg, 0.230 mmol), and the mixture was further stirred at 50 ° C. for 9 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed successively with water (x3) and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using NH silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1). Further purification using reverse phase preparative column chromatography (Waters, MS C18 OBD, 5 μm, 30 × 100 mm) (acetonitrile: 0.1% aqueous ammonium acetate solution = 20: 80-100: 0) gave the title compound ( 7 mg, 7% yield) was obtained as a yellow solid.
MS (FAB) m / z: 883 (M + H) + .
IR (KBr) ν max 2935, 1738, 1651, 1596, 1499, 1373, 1281, 1184, 1136, 708 cm −1 .
　［実施例３］
（３Ｒ）－１－｛６－［｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝（メチル）アミノ］ヘキサ－４－イン－１－イル｝ピロリジン－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート [Example 3]
(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
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
［実施例３ａ］２－［３，５－ビス（トリフルオロメチル）フェニル］－Ｎ－｛６－［（６－ヒドロキシへキサ－２－イン－１－イル）（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－３－イル｝－Ｎ，２－ジメチルプロパンアミド
　文献（Ｔｅｔｒａｈｅｄｒｏｎ　Ｌｅｔｔ．　１９９１，３２，４５０５）に記載されている６－｛［ｔｅｒｔ－ブチル（ジフェニル）シリル］オキシ｝ヘキサ－２－イン－１－オール（２７７ｍｇ，０．７８５ｍｍｏｌ）を酢酸エチル（８ｍＬ）に溶解し、氷冷下、トリエチルアミン（０．１３１ｍＬ，０．９４２ｍｍｏｌ）、及び、塩化メタンスルホニル（７３μＬ，０．９４２ｍｍｏｌ）を加えた後、同温にて２０分間攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して粗製のメシレート体を得た。 [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. 1991, 32, 4505) 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 μL, 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.
　得られた粗製のメシレート体をＮ，Ｎ－ジメチルアセトアミド（４ｍＬ）に溶解し、実施例１ｅで得られた化合物（２００ｍｇ，０．３９３ｍｍｏｌ）、炭酸カリウム（１３０ｍｇ，０．７８５ｍｍｏｌ）、及び、ヨウ化カリウム（１０９ｍｇ，０．７８５ｍｍｏｌ）を加えた後、５０℃にて５．５時間攪拌した。反応液を酢酸エチルで希釈し、有機層を水（×３）、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝６：１）を用いて精製し、粗製のアミノ化体を得た。 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. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain a crude aminated product. .
　得られた粗製のアミノ化体をテトラヒドロフラン（５ｍＬ）に溶解し、テトラブチルアンモニウムフロリド（１Ｍ－テトラヒドロフラン溶液，０．９８３ｍＬ，０．９８３ｍｍｏｌ）を加えた後、室温にて１時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣を球状中性シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝６：１－１：１）を用いて精製し、標記目的化合物（９０ｍｇ，収率３０％）を白色固体として得た。
MS (FAB) m/z: 606(M+H)+.
IR(KBr) νmax 2932, 1650, 1597, 1500, 1373, 1282, 1185, 1137, 896, 683 cm-1.
［実施例３ｂ］（３Ｒ）－１－｛６－［｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝（メチル）アミノ］ヘキサ－４－イン－１－イル｝ピロリジン－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート
　実施例３ａで得られた化合物（７０ｍｇ，０．１１８ｍｍｏｌ）を酢酸エチル（５ｍＬ）に溶解し、氷冷下、トリエチルアミン（４０μＬ，０．２８４ｍｍｏｌ）、及び、塩化メタンスルホニル（２２μＬ，０．２８４ｍｍｏｌ）を加えた後、同温にて１５分間攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をＮ，Ｎ－ジメチルアセトアミド（４ｍＬ）に溶解し、実施例１ｉで得られた化合物（３７ｍｇ，０．１１８ｍｍｏｌ）、炭酸水素ナトリウム（２０ｍｇ，０．２３６ｍｍｏｌ）、及び、ヨウ化カリウム（３９ｍｇ，０．２３６ｍｍｏｌ）を加えた後、５０℃にて５時間攪拌した。反応液を酢酸エチルで希釈し、有機層を水（×３）、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１－１：１）を用いて精製した。さらに逆相分取カラムクロマトグラフィー（Ｗａｔｅｒｓ，ＭＳ　Ｃ１８　ＯＢＤ，５μｍ，３０×１００ｍｍ）（アセトニトリル：０．１％酢酸アンモニウム水溶液＝７０：３０－１００：０）を用いて精製し、標記目的化合物（４１ｍｇ，収率３９％）を淡黄色固体として得た。
MS (FAB) m/z: 897(M+H)+.
IR(KBr) νmax 2931, 1732, 1651, 1499, 1373, 1281, 1184, 1137, 1081, 708 cm-1。 The obtained crude aminated product was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (1M-tetrahydrofuran solution, 0.983 mL, 0.983 mmol) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to spherical neutral silica gel column chromatography (hexane: ethyl acetate = 6: 1-1). 1) to give the title object compound (90 mg, yield 30%) as a white solid.
MS (FAB) m / z: 606 (M + H) + .
IR (KBr) ν max 2932, 1650, 1597, 1500, 1373, 1282, 1185, 1137, 896, 683 cm -1 .
[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) was dissolved in ethyl acetate (5 mL), and triethylamine (40 μL, 0.284 mmol) and methanesulfonyl chloride (22 μL, 0.284 mmol) were added under ice cooling, and then at the same temperature. Stir for 15 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, and the resulting residue was dissolved in N, N-dimethylacetamide (4 mL) to obtain the compound obtained in Example 1i (37 mg, 0.118 mmol). , Sodium hydrogen carbonate (20 mg, 0.236 mmol) and potassium iodide (39 mg, 0.236 mmol) were added, and the mixture was stirred at 50 ° C. for 5 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed successively with water (x3) and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using NH silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1). Further purification using reverse phase preparative column chromatography (Waters, MS C18 OBD, 5 μm, 30 × 100 mm) (acetonitrile: 0.1% aqueous ammonium acetate = 70: 30-100: 0) gave the title compound ( 41 mg, 39% yield) was obtained as a pale yellow solid.
MS (FAB) m / z: 897 (M + H) + .
IR (KBr) ν max 2931, 1732, 1651, 1499, 1373, 1281, 1184, 1137, 1081, 708 cm −1 .
　［実施例４］
４－｛［｛４－［（２－｛４－［（ビフェニル－２－イルカルバモイル）オキシ］ピペリジン－１－イル｝エチル）（メチル）カルバモイル］ベンジル｝（メチル）アミノ］メチル｝フェニル　４－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］ブタノエート [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
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
［実施例４ａ］メチル　４－｛［（４－ヒドロキシベンジル）アミノ］メチル｝ベンゾエート
　メチル　４－（アミノメチル）ベンゾエート（６．８８ｇ，３４．２ｍｍｏｌ）、及び、４－ヒドロキシベンズアルデヒド（４．６０ｇ，３７．７ｍｍｏｌ）をエタノール（３００ｍＬ）に溶解し、加熱還流下にて６時間撹拌した。室温にて、反応液に水素化ホウ素ナトリウム（１．３９ｇ，３７．３ｍｍｏｌ）を加え、同温にて１時間撹拌した。反応液に飽和重曹水を加え、塩化メチレンで抽出した後、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をヘキサンと塩化メチレンの混合溶媒から再沈殿し、標記目的化合物（４．９０ｇ，収率５２％）を白色固体として得た。
MS (EI) m/z: 271(M+).
IR(KBr) νmax 2949, 1718, 1612, 1518, 1444, 1282, 1251, 1109, 820, 759 cm-1.
［実施例４ｂ］４－｛［（ｔｅｒｔ－ブトキシカルボニル）（４－ヒドロキシベンジル）アミノ］メチル｝ベンゼンカルボン酸
　実施例４ａで得られたメチル　４－｛［（４－ヒドロキシベンジル）アミノ］メチル｝ベンゾエート（１．０７ｇ，３．９４ｍｍｏｌ）を塩化メチレン（３９ｍＬ）に溶解し、ジ－ｔｅｒｔ－ブチル　ジカーボネート（９４７ｍｇ，４．３４ｍｍｏｌ）の塩化メチレン溶液（８ｍＬ）を加え、室温にて４．５時間攪拌した。減圧下、溶剤を留去して、粗製のＢｏｃ体を得た。 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. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was reprecipitated from a mixed solvent of hexane and methylene chloride to give the title object compound (4.90 g, yield 52%) as a white solid Got as.
MS (EI) m / z: 271 (M + ).
IR (KBr) ν max 2949, 1718, 1612, 1518, 1444, 1282, 1251, 1109, 820, 759 cm -1 .
[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.
　得られた粗製のＢｏｃ体をメタノール（３９ｍＬ）に溶解し、４Ｎ　水酸化ナトリウム水溶液（３．９４ｍ，１５．８ｍｍｏｌ）を加え、室温にて１７時間、５０℃にて１．５時間攪拌した。反応液に塩化メチレンを加え、１Ｎ　塩酸でｐＨ１にした後、塩化メチレン（×２）で抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をヘキサンと少量のジエチルエーテルからろ取し、標記目的化合物（１．２３ｇ，収率８０％）を白色固体として得た。
1H NMR (DMSO-d6, 500MHz): δ 1.35-1.42 (9H, m), 4.21-4.36 (4H, m), 6.72 (2H, d, J = 8.6 Hz), 7.04-7.05 (2H, m), 7.28-7.29 (2H, m), 7.90 (2H, d, J = 8.6 Hz), 9.35 (1H, brs).
MS (FAB) m/z: 358(M+H)+.
［実施例４ｃ］１－（２－｛［（４－｛［（ｔｅｒｔ－ブトキシカルボニル）（４－ヒドロキシベンジル）アミノ］メチル｝フェニル）カルボニル］（メチル）アミノ｝エチル）ピペリジン－４－イル　ビフェニル－２－イルカーバメート
　１－［２－（メチルアミノ）エチル］ピペリジン-４-イル　ビフェニル－２-イルカーバメート（１９４ｍｇ，０．５５０ｍｍｏｌ）及び実施例４ｂで得られた４－｛［（ｔｅｒｔ－ブトキシカルボニル）（４－ヒドロキシベンジル）アミノ］メチル｝ベンゼンカルボン酸（１９７ｍｇ，０．５５０ｍｍｏｌ）を塩化メチレン（５．５ｍＬ）に溶解し、ＷＳＣ・ＨＣｌ（１２７ｍｇ，０．６６０ｍｍｏｌ）を加え、室温にて終夜撹拌した。減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１－酢酸エチル：メタノール＝４０：１）を用いて精製し、標記目的化合物（３７３ｍｇ，収率９８％）を白色固体として得た。
MS (APCI) m/z: 693(M+H)+.
IR(KBr) νmax 2932, 1735, 1691, 1613, 1517, 1450, 1237, 1162, 1045, 751 cm-1。 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.
1 H NMR (DMSO-d6, 500MHz): δ 1.35-1.42 (9H, m), 4.21-4.36 (4H, m), 6.72 (2H, d, J = 8.6 Hz), 7.04-7.05 (2H, m) , 7.28-7.29 (2H, m), 7.90 (2H, d, J = 8.6 Hz), 9.35 (1H, brs).
MS (FAB) m / z: 358 (M + H) + .
[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. Stir overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified using NH silica gel column chromatography (hexane: ethyl acetate = 1: 1-ethyl acetate: methanol = 40: 1) to give the title object compound (373 mg, Yield 98%) was obtained as a white solid.
MS (APCI) m / z: 693 (M + H) + .
IR (KBr) ν max 2932, 1735, 1691, 1613, 1517, 1450, 1237, 1162, 1045, 751 cm −1 .
　［実施例４ｄ］１－（２－｛［（４－｛［（４－ヒドロキシベンジル）（メチル）アミノ］メチル｝フェニル）カルボニル］（メチル）アミノ｝エチル）ピペリジン－４－イル　ビフェニル－２－イルカーバメート
　実施例４ｃで得られた化合物（１００ｍｇ，０．１４５ｍｍｏｌ）をメタノール（３ｍＬ）に溶解し、４Ｎ　塩酸－ジオキサン（９０μＬ，０．３６１ｍｍｏｌ）を加え、室温にて１時間撹拌した。更に反応液に４Ｎ　塩酸－ジオキサン（３６３μＬ，１．４４ｍｍｏｌ）を加え、室温にて１．５時間撹拌した。減圧下、溶剤を留去して得られた残渣をアセトニトリル（３ｍＬ）に溶解し、３７％ホルマリン水溶液（０．２９０ｍＬ）、及び、水素化シアノホウ素ナトリウム（５５ｍｇ，０．８７０ｍｍｏｌ）を加え、室温にて終夜撹拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した後、有機層を水、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：２－酢酸エチル：メタノール＝６０：１）を用いて精製し、標記目的化合物（５０ｍｇ，収率５７％）を黄色油状物として得た。
MS (ESI) m/z: 606 (M+).
［実施例４ｅ］メチル　４－［（ブロモアセチル）（メチル）アミノ］ブタン酸エステル
　メチル　４－（メチルアミノ）ブタン酸エステル　塩酸塩（１．０１ｇ，６．００ｍｍｏｌ）を塩化メチレン（３０ｍＬ）に溶解し、氷冷下、トリエチルアミン（２．０８ｍＬ，１５．０ｍｍｏｌ）、及び、ブロモアセチルクロリド（０．５００ｍＬ，６．００ｍｍｏｌ）を加え、室温にて１時間撹拌した。反応液に１Ｎ　塩酸を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して、標記目的化合物（６８８ｍｇ，収率４５％）を褐色油状物として得た。
1H NMR (CDCl3, 500MHz): δ 1.86-1.98 (2H, m), 2.34-2.39 (2H, m), 2.97 and 3.09 (total 3H, each s), 3.38-3.45 (2H, m), 3.68 and 3.71 (total 3H, s), 4.06 and 4.12 (2H, each s).
［実施例４ｆ］メチル　４－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］ブタノエート
　実施例１ｅで得られた化合物（２７８ｍｇ，０．５４６ｍｍｏｌ）をトルエン（５．５ｍＬ）に溶解し、氷冷下、０．５Ｍ　ヘキサメチルジシラザンカリウムのトルエン溶液（４．３７ｍＬ，２．１８ｍｍｏｌ）を滴下し、室温にて１０分間攪拌した。反応液に実施例４ｅで得られたメチル　４－［（ブロモアセチル）（メチル）アミノ］ブタン酸エステル（６８８ｍｇ，２．７３ｍｍｏｌ）のトルエン溶液（５．５ｍＬ）を加えた後、７５℃にて４１時間攪拌した。反応液に飽和重曹水を加え、酢酸エチル（×３）で抽出した後、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：２－１：２）を用いて精製し、標記目的化合物（１２９ｍｇ，収率３４％）を黄色油状物として得た。
MS (APCI) m/z: 681(M+H)+.
IR(KBr) νmax 1734, 1648, 1502, 1371, 1278, 1170, 1130, 1079, 896, 682 cm-1。 [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 μL, 0.361 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Further, 4N hydrochloric acid-dioxane (363 μL, 1.44 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in acetonitrile (3 mL), 37% formalin aqueous solution (0.290 mL) and sodium cyanoborohydride (55 mg, 0.870 mmol) were added, and room temperature was added. At rt overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using NH silica gel column chromatography (hexane: ethyl acetate = 1: 2-ethyl acetate: methanol = 60: 1). The title compound (50 mg, 57% yield) was obtained as a yellow oil.
MS (ESI) m / z: 606 (M + ).
[Example 4e] Methyl 4-[(bromoacetyl) (methyl) amino] butanoic acid ester Methyl 4- (methylamino) butanoic acid ester hydrochloride (1.01 g, 6.00 mmol) dissolved in methylene chloride (30 mL) Under ice-cooling, triethylamine (2.08 mL, 15.0 mmol) and bromoacetyl chloride (0.500 mL, 6.00 mmol) were added, and the mixture was stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title object compound (688 mg, yield 45%) as a brown oil.
1 H NMR (CDCl 3 , 500MHz): δ 1.86-1.98 (2H, m), 2.34-2.39 (2H, m), 2.97 and 3.09 (total 3H, each s), 3.38-3.45 (2H, m), 3.68 and 3.71 (total 3H, s), 4.06 and 4.12 (2H, each s).
[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. 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. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 2-1: 2) to give the title target compound ( 129 mg, 34% yield) was obtained as a yellow oil.
MS (APCI) m / z: 681 (M + H) + .
IR (KBr) ν max 1734, 1648, 1502, 1371, 1278, 1170, 1130, 1079, 896, 682 cm −1 .
　［実施例４ｇ］４－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］ブタン酸
　実施例４ｆで得られた化合物（１２９ｍｇ，０．１９０ｍｍｏｌ）をメタノール（２ｍＬ）に溶解し、１Ｎ水酸化ナトリウム水溶液（０．５６９ｍＬ，０．５６９ｍｍｏｌ）を加えた後、室温にて２４時間攪拌した。反応液に１Ｎ　塩酸（０．５６９ｍＬ）を加え、塩化メチレン（×３）で抽出した後、無水硫酸ナトリウムで乾燥した。減圧下、溶剤を留去して得られた残渣をテトラヒドロフラン（×２）で共沸し、標記目的化合物（１２０ｍｇ，収率９５％）を淡緑色固体として得た。
MS (APCI) m/z: 667(M+H)+.
［実施例４ｈ］４－｛［｛４－［（２－｛４－［（ビフェニル－２－イルカルバモイル）オキシ］ピペリジン－１－イル｝エチル）（メチル）カルバモイル］ベンジル｝（メチル）アミノ］メチル｝フェニル　４－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］ブタノエート
　実施例４ｄで得られた化合物（５０ｍｇ，０．０８２４ｍｍｏｌ）、及び、実施例４ｇで得られた化合物（６０ｍｇ，０．０９０６ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（３ｍＬ）に溶解し、トリエチルアミン（３４μＬ，０．２４６ｍｍｏｌ）、ＷＳＣ・ＨＣｌ（１８ｍｇ，０．１２４ｍｍｏｌ）、及び、４－ジメチルアミノピリジン（１片）を加え、室温にて１．５時間撹拌した。更に反応液にトリエチルアミン（６８μＬ，０．４９６ｍｍｏｌ）、ＷＳＣ・ＨＣｌ（１８ｍｇ，０．１２４ｍｍｏｌ）、及び、４－ジメチルアミノピリジン（１片）を加え、室温にて終夜撹拌した。反応液に水を加え、酢酸エチルで抽出した後、有機層を水（×２）、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣を逆相分取カラムクロマトグラフィー（Ｗａｔｅｒｓ，ＭＳ　Ｃ１８　ＯＢＤ，５μｍ，３０×１００ｍｍ）（アセトニトリル：０．１％酢酸アンモニウム水溶液＝３０：７０－１００：０）を用いて精製し、標記目的化合物（２２ｍｇ，収率２１％）を黄色固体として得た。
MS (FAB) m/z: 1255(M+H)+.
IR(KBr) νmax 2932, 1734, 1649, 1506, 1398, 1372, 1281, 1184, 1136, 753 cm-1。 [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. 1N Hydrochloric acid (0.569 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (× 3) and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was azeotroped with tetrahydrofuran (× 2) to obtain the title object compound (120 mg, yield 95%) as a pale green solid.
MS (APCI) m / z: 667 (M + H) + .
[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) and the compound obtained in Example 4g (60 mg, 0.0906 mmol) Was dissolved in N, N-dimethylformamide (3 mL), triethylamine (34 μL, 0.246 mmol), WSC · HCl (18 mg, 0.124). mmol) and 4-dimethylaminopyridine (one piece) were added, and the mixture was stirred at room temperature for 1.5 hours. Further, triethylamine (68 μL, 0.496 mmol), WSC · HCl (18 mg, 0.124 mmol) and 4-dimethylaminopyridine (1 piece) were added to the reaction solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water (× 2) and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to reverse phase preparative column chromatography (Waters, MS C18 OBD, 5 μm, 30 × 100 mm) (acetonitrile: 0.1% acetic acid Purification using aqueous ammonium solution = 30: 70-100: 0) gave the title object compound (22 mg, yield 21%) as a yellow solid.
MS (FAB) m / z: 1255 (M + H) + .
IR (KBr) ν max 2932, 1734, 1649, 1506, 1398, 1372, 1281, 1184, 1136, 753 cm −1 .
　［実施例５］
４－［（｛４－［（２－｛４－［（ビフェニル－２－イルカルバモイル）オキシ］ピペリジン－１－イル｝エチル）（メチル）カルバモイル］ベンジル｝アミノ）メチル］フェニル　４－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］ブタノエート [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
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
［実施例５ａ］４－｛［｛４－［（２－｛４－［（ビフェニル－２－イルカルバモイル）オキシ］ピペリジン－１－イル｝エチル）（メチル）カルバモイル］ベンジル｝（ｔｅｒｔ－ブトキシカルボニル）アミノ］メチル｝フェニル　４－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］ブタノエート
　実施例４ｃで得られた化合物（１２５ｍｇ，０．１８０ｍｍｏｌ）、及び、実施例４ｇで得られた化合物（１２０ｍｇ，０．１８０ｍｍｏｌ）を塩化メチレン（２ｍＬ）に溶解し、ＷＳＣ・ＨＣｌ（４２ｍｇ，０．２１６ｍｍｏｌ）を加え、室温にて４時間撹拌した。反応液に４－ジメチルアミノピリジン（１ｍｇ，０．００９ｍｍｏｌ）を加え、室温にて２．５日間撹拌した。更に４－ジメチルアミノピリジン（２ｍｇ，０．０１８ｍｍｏｌ）を加え、室温にて２３時間撹拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン：メタノール＝５０：１－３０：１）を用いて精製し、標記目的化合物（１３５ｍｇ，収率５６％）を黄色固体として得た。
MS (FAB) m/z: 1341(M+H)+.
IR(KBr) νmax 2930, 1694, 1649, 1507, 1403, 1367, 1281, 1183, 1137, 752 cm-1.
［実施例５ｂ］４－［（｛４－［（２－｛４－［（ビフェニル－２－イルカルバモイル）オキシ］ピペリジン－１－イル｝エチル）（メチル）カルバモイル］ベンジル｝アミノ）メチル］フェニル　４－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］ブタノエート
　実施例５ａで得られた化合物（４１ｍｇ，０．０３０６ｍｍｏｌ）の１，４－ジオキサン溶液（３ｍＬ）に、氷冷下、４Ｎ　塩酸－ジオキサン（７７μＬ，０．３０６ｍｍｏｌ）を加え、同温にて１０分間、更に室温にて終夜攪拌した。反応液に飽和重曹水を加えた後、酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下、溶剤を留去して得られた残渣を逆相分取カラムクロマトグラフィー（Ｗａｔｅｒｓ，ＭＳ　Ｃ１８　ＯＢＤ，５μｍ，３０×１００ｍｍ）（アセトニトリル：０．１％酢酸アンモニウム水溶液＝２０：８０－１００：０）を用いて精製し、標記目的化合物（７ｍｇ，収率１８％）を黄色固体として得た。
MS (FAB) m/z: 1241(M+H)+.
IR(KBr) νmax 2929, 1733, 1649, 1506, 1373, 1281, 1184, 1137, 838, 752 cm-1。 [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) and the compound obtained in Example 4g (120 mg, 0 180 mmol) was dissolved in methylene chloride (2 mL), WSC · HCl (42 mg, 0.216 mmol) was added, and the mixture was stirred at room temperature for 4 hours. 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. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (methylene chloride: methanol = 50: 1-30: 1) to give the title compound ( 135 mg, yield 56%) was obtained as a yellow solid.
MS (FAB) m / z: 1341 (M + H) + .
IR (KBr) ν max 2930, 1694, 1649, 1507, 1403, 1367, 1281, 1183, 1137, 752 cm -1 .
[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. 77 μL, 0.306 mmol) was added, and the mixture was stirred at the same temperature for 10 minutes and further at room temperature overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to reverse phase preparative column chromatography (Waters, MS C18 OBD, 5 μm, 30 × 100 mm) (acetonitrile: 0.1% aqueous ammonium acetate solution = 20: 80-100 : 0) to give the title object compound (7 mg, yield 18%) as a yellow solid.
MS (FAB) m / z: 1241 (M + H) + .
IR (KBr) ν max 2929, 1733, 1649, 1506, 1373, 1281, 1184, 1137, 838, 752 cm −1 .
　［実施例６］
（３Ｒ）－１－｛２－［｛６－［４－（｛３－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）アミノ］プロピル｝カルバモイル）ピペリジン－１－イル］ヘキサノイル｝（メチル）アミノ］エチル｝ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート [Example 6]
(3R) -1- {2-[{6- [4-({3-[({[(2S) -1 '-{2-[(5R) -3-{[3,5-bis (tri Fluoromethyl) 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) piperidin-1-yl] hexanoyl} (methyl) amino] ethyl} pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
［実施例６ａ］（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（２－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝エチル）－５－（４－フルオロフェニル）－１，３－オキサゾリジン
　（２Ｒ）－１－アミノ－４－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝－２－（４－フルオロフェニル）ブタン－２－オール（１２８．９２ｇ、０．４１１ｍｏｌ）のベンゼン（１０００ｍＬ）溶液にパラホルムアルデヒド（１８．５０ｇ、０．６１７ｍｏｌ）を加え、水分分離器を取り付けて４時間攪拌還流した。反応混合物を減圧濃縮して（５Ｒ）－５－（２－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝エチル）－５－（４－フルオロフェニル）－１，３－オキサゾリジンの粗製物１３９．４３ｇを褐色油状として得た。 [Example 6a] (5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -5- (4- Fluorophenyl) -1,3-oxazolidine (2R) -1-amino-4-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-fluorophenyl) butan-2-ol (128.92 g, Paraformaldehyde (18.50 g, 0.617 mol) was added to a benzene (1000 mL) solution of 0.411 mol), a water separator was attached, and the mixture was stirred and refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure to give a crude product of (5R) -5- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -5- (4-fluorophenyl) -1,3-oxazolidine 139. 43 g were obtained as a brown oil.
　得られた粗製の（５Ｒ）－５－（２－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝エチル）－５－（４－フルオロフェニル）－１，３－オキサゾリジン（１３９．４３ｇ）、トリエチルアミン（６９ｍＬ，０．４９５ｍｏｌ）、４－（ジメチルアミノ）ピリジン（５．０２ｇ、０．０４１ｍｏｌ）のジクロロメタン（１０００ｍＬ）溶液に、氷冷下、３，５－ビス（トリフルオロメチル）ベンゾイルクロリド（１００ｇ、０．４３４ｍｏｌ）を滴下し、室温で１８時間攪拌した。反応混合物を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（１０％　酢酸エチル／ｎ－ヘキサン）で精製し、標記目的化合物１３１．７６ｇ（収率６２％）を淡黄色油状物として得た。
［実施例６ｂ］２－［（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エタノール
　実施例６ａで得られた化合物（１３１．７６ｇ，０．２５４ｍｏｌ）のテトラヒドロフラン（５００ｍＬ）溶液にテトラブチルアンモニウムフロリドのテトラヒドロフラン溶液（１．０Ｍ，５０８ｍＬ）と酢酸（７０ｍＬ，１．２７ｍｏｌ）を加え、室温で２時間攪拌した。反応混合物に酢酸エチル（１０００ｍＬ）を加え、飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（３０％　酢酸エチル／ｎ－ヘキサン→５０％）で精製して、標記目的化合物１０２．１１ｇ（収率９９％）を無色油状物として得た。
［実施例６ｃ］２－［（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル　メタンスルホネート
　実施例６ｂで得られた２－［（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エタノール（１０２．１１ｇ、０．２２６ｍｏｌ）、トリエチルアミン（６３ｍＬ，０．４５２ｍｏｌ），４－（ジメチルアミノ）ピリジン（２．７６ｇ、０．０２７３ｍｏｌ）のジクロロメタン（１０００ｍＬ）溶液に氷冷下で塩化メタンスルホニル（２６ｍＬ、０．３３６ｍｏｌ）を滴下し、氷冷下で１時間攪拌した。反応混合物を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー（３０％　酢酸エチル／ｎ－ヘキサン→５０％）で精製して、標記目的化合物１０８．２１ｇ（収率９０％）を白色固体として得た。
1H NMR(CDCl3, 400MHz): δ 2.30-2.50(2H, m), 2.91(3H, brs), 3.80-4.21(3H, m), 4.25-4.35(1H, m), 4.90-5.10(1H, m), 5.20-5.40(1H, m), 7.11(2H, brs), 7.20-7.47(2H, m), 7.91(2H, s), 8.00(1H, s);
MS(FAB) m/z: 530(M+H)+;
IR(ATR) νmax  1734, 1646, 1356, 1278, 1171, 1129, 957, 906, 837, 681, 527cm-1。 The resulting crude (5R) -5- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -5- (4-fluorophenyl) -1,3-oxazolidine (139.43 g), triethylamine (69 mL, 0.495 mol), 4- (dimethylamino) pyridine (5.02 g, 0.041 mol) in dichloromethane (1000 mL) under ice-cooling, 3,5-bis (trifluoromethyl) benzoyl chloride (100 g) 0.434 mol) was added dropwise and stirred at room temperature for 18 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10% ethyl acetate / n-hexane) to give 131.76 g (yield 62%) of the title object compound as a pale yellow oil.
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. Ethyl acetate (1000 mL) was added to the reaction mixture, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (30% ethyl acetate / n-hexane → 50%) to give 102.11 g (yield 99%) of the title object compound as a colorless oil.
[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. 26 mL, 0.336 mol) was added dropwise, and the mixture was stirred for 1 hour under ice cooling. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate / n-hexane → 50%) to obtain 108.21 g (yield 90%) of the title object compound as a white solid.
1 H NMR (CDCl 3 , 400 MHz): δ 2.30-2.50 (2H, m), 2.91 (3H, brs), 3.80-4.21 (3H, m), 4.25-4.35 (1H, m), 4.90-5.10 (1H , m), 5.20-5.40 (1H, m), 7.11 (2H, brs), 7.20-7.47 (2H, m), 7.91 (2H, s), 8.00 (1H, s);
MS (FAB) m / z: 530 (M + H) + ;
IR (ATR) ν max   1734, 1646, 1356, 1278, 1171, 1129, 957, 906, 837, 681, 527 cm -1 .
　［実施例６ｄ］ｔｅｒｔ－ブチル　（２Ｓ）－２－（アリルオキシ）－２，３－ジヒドロ－１’Ｈ－スピロ［インデン－１，４’－ピペリジン］－１’－カルボキシレート
　ｔｅｒｔ－ブチル　（２Ｓ）－２－ヒドロキシ－２，３－ジヒドロ－１’Ｈ－スピロ［インデン－１，４’－ピペリジン］－１’－カルボキシレート　（５０．０ｇ，１６４．８ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（１５０ｍＬ）溶液に氷冷攪拌下で水素化ナトリウム（含量５５％、１０．７９ｇ、２４７．２ｍｍｏｌ）を少しずつ添加した。添加後、アリルブロミド（２８．５ｍＬ、３２９．６ｍｍｏｌ）を滴下し、氷冷下で１時間攪拌した。水（４００ｍＬ）を滴下して加えたのち、酢酸エチル（３００ｍＬ、８０ｍＬ×２）で抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（０％　酢酸エチル／ｎ－ヘキサン→２０％）で精製して、標記目的化合物５７．１５ｇを無色油状物として得た。
1H NMR (CDCl3, 400MHz): δ 1.45 (9H, s), 1.65-1.75 (2H, m), 2.05-2.12 (1H, m), 2.95-3.25 (4H, m), 3.80-4.20 (5H, m), 5.13-5.31 (2H, m), 5.86-5.98 (1H, m), 7.11-7.25 (4H, m).
MS (FAB+) m/z: 344 ((M+H)+).
IR (liquid film): 2976,2929,1694,1479,1425,1366,1278,1237,1171,1080,759 cm-1.
［実施例６ｅ］ｔｅｒｔ－ブチル　（２Ｓ）－２－（２－オキソエトキシ）－２，３－ジヒドロ－１’Ｈ－スピロ［インデン－１，４’－ピペリジン］－１’－カルボキシレート
　実施例６ｄで得られたｔｅｒｔ－ブチル　（２Ｓ）－２－（アリルオキシ）－２，３－ジヒドロ－１’Ｈ－スピロ［インデン－１，４’－ピペリジン］－１’－カルボキシレート（５７．１５ｇ）をアセトン（４００ｍＬ）、ｔ－ブタノール（２００ｍＬ）及び水（２００ｍＬ）の混合溶媒に溶解し、氷冷下でＮ－メチルモルホリン　Ｎ－オキシド（２１．２ｇ、１８１ｍｍｏｌ）と四酸化オスミウム（２．５ｗｔ％ｔ－ブタノール溶液、８．３９ｇ、０．８２５ｍｍｏｌ）を加え、室温で４時間攪拌した。反応液にチオ硫酸ナトリウム水溶液（２６ｇ、１００ｍＬ）を加えた後、１０分間攪拌し、有機溶媒を減圧留去した。酢酸エチルを加えて抽出して無水硫酸ナトリウムで乾燥した後、減圧濃縮して粗製のｔｅｒｔ－ブチル　（２Ｓ）－２－（２，３－ジヒドロキシプロポキシ）－２，３－ジヒドロ－１’Ｈ－スピロ［インデン－１，４’－ピペリジン］－１’－カルボキシレート　６９．５８ｇを淡黄色アモルファスとして得た。 [Example 6d] tert-butyl (2S) -2- (allyloxy) -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate tert-butyl (2S ) -2-hydroxy-2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate (50.0 g, 164.8 mmol) N, N-dimethylformamide ( (150 mL) To the solution, sodium hydride (content 55%, 10.79 g, 247.2 mmol) was added little by little under stirring with ice cooling. After the addition, 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.
1 H NMR (CDCl 3 , 400 MHz): δ 1.45 (9H, s), 1.65-1.75 (2H, m), 2.05-2.12 (1H, m), 2.95-3.25 (4H, m), 3.80-4.20 (5H , m), 5.13-5.31 (2H, m), 5.86-5.98 (1H, m), 7.11-7.25 (4H, m).
MS (FAB +) m / z: 344 ((M + H) + ).
IR (liquid film): 2976,2929,1694,1479,1425,1366,1278,1237,1171,1080,759 cm -1 .
Example 6e tert-butyl (2S) -2- (2-oxoethoxy) -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate Tert-Butyl (2S) -2- (allyloxy) -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate (57.15 g) obtained in 6d Was dissolved in a mixed solvent of acetone (400 mL), t-butanol (200 mL) and water (200 mL), and N-methylmorpholine N-oxide (21.2 g, 181 mmol) and osmium tetroxide (2.5 wt. % T-butanol solution, 8.39 g, 0.825 mmol) was added, and the mixture was stirred at room temperature for 4 hours. A sodium thiosulfate aqueous solution (26 g, 100 mL) was added to the reaction solution, followed by stirring for 10 minutes, and the organic solvent was distilled off under reduced pressure. Ethyl acetate was added for extraction, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude tert-butyl (2S) -2- (2,3-dihydroxypropoxy) -2,3-dihydro-1′H— Spiro [indene-1,4′-piperidine] -1′-carboxylate (69.58 g) was obtained as a pale yellow amorphous.
　得られた粗製物をテトラヒドロフラン（４００ｍＬ）と水（４００ｍＬ）の混合溶媒に溶解し、氷冷攪拌下、過ヨウ素酸ナトリウム（５２．８７ｇ、２４７ｍｍｏｌ）を少しずつ加えた。添加後、室温で１．５時間攪拌した。反応溶液に水（４００ｍＬ）を加えて酢酸エチル（３００、１５０、１００ｍＬ）で抽出し、有機層を合わせて飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧濃縮し、粗製の標記目的化合物５９．５２ｇを無色アモルファスとして得た。
1H NMR (CDCl3, 400MHz): δ 1.50 (9H, s), 1.62-1.85 (2H, m), 2.15-2.24 (1H, m), 2.92-4.25 (10H, m), 7.19-7.26 (4H, m), 9.74 (1H, s).
MS (FAB+) m/z: 346 ((M+H)+).
IR (liquid film): 2976,2931,1686,1479,1428,1367,1239, 1010,756 cm-1.
［実施例６ｆ］｛［（２Ｓ）－１’－（ｔｅｒｔ－ブトキシカルボニル）－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝酢酸
　実施例６ｅで得られた粗製のｔｅｒｔ－ブチル　（２Ｓ）－２－（２－オキソエトキシ）－２，３－ジヒドロ－１’Ｈ－スピロ［インデン－１，４’－ピペリジン］－１’－カルボキシレート５９．５２ｇをテトラヒドロフラン（２００ｍＬ）とｔ－ブタノール（４００ｍＬ）の混合溶媒に溶解し、２－メチル－２－ブテン（８７．３ｍＬ）を加えた。氷冷攪拌下、リン酸二水素ナトリウム二水和物（６４．２７ｇ、４１２ｍｍｏｌ）水溶液（１００ｍＬ）及び亜塩素酸ナトリウム（４４．７ｇ、４９４ｍｍｏｌ）を順次添加し、水冷下で２．５時間攪拌した。反応液を氷冷し、４規定水酸化ナトリウム水溶液（２０６ｍＬ）を滴下した。水（２００ｍＬ）及び酢酸エチル（２００ｍＬ）を加えたのち、生じている白色沈殿を濾別し、残渣を水（１００ｍＬ）及び酢酸エチル（１００ｍＬ）で洗浄した。ろ液を氷冷し、４規定塩酸（１６０ｍＬ）を加えて分液抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮し、粗製の標記目的化合物５９．５８ｇを淡黄色アモルファスとして得た。得られた粗製物をジエチルエーテルとｎ－ヘキサンの混合溶媒から再結晶し、標記目的化合物５０．６４ｇを白色固体として得た。
1H NMR (CD3OD, 400MHz): δ 1.48 (9H, s), 1.52-1.64 (2H, m), 1.68-1.75 (1H, m), 2,12-2.20 (1H, m), 3.00 (1H, dd, J=16.5, 3.0 Hz), 3.15 (1H, dd, J=16.5, 5.4 Hz), 3.20-3.40 (1H, m), 3.41-3.60 (1H, m), 3.86-3.99 (2H, m), 4.15-4.17 (2H, m), 4.32-4.37 (1H, m), 7.10-7.20 (4H, m).
MS (FAB+) m/z: 362 ((M+H)+).
IR (KBr): 2976,2932,1756,1690,1643,1479,1430,1366,1279,1169,1119,759 cm-1。 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.
1 H NMR (CDCl 3 , 400 MHz): δ 1.50 (9H, s), 1.62-1.85 (2H, m), 2.15-2.24 (1H, m), 2.92-4.25 (10H, m), 7.19-7.26 (4H , m), 9.74 (1H, s).
MS (FAB +) m / z: 346 ((M + H) + ).
IR (liquid film): 2976,2931,1686,1479,1428,1367,1239, 1010,756 cm -1 .
[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. Under ice-cooling stirring, sodium dihydrogen phosphate dihydrate (64.27 g, 412 mmol) aqueous solution (100 mL) and sodium chlorite (44.7 g, 494 mmol) were sequentially added, followed by stirring under water cooling for 2.5 hours. did. The reaction mixture was ice-cooled, and 4N aqueous sodium hydroxide solution (206 mL) was added dropwise. After adding water (200 mL) and ethyl acetate (200 mL), the resulting white precipitate was filtered off, and the residue was washed with water (100 mL) and ethyl acetate (100 mL). The filtrate was ice-cooled, and 4N hydrochloric acid (160 mL) was added for liquid separation extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 59.58 g of the crude title object compound as a pale yellow amorphous product. The obtained crude product was recrystallized from a mixed solvent of diethyl ether and n-hexane to obtain 50.64 g of the title object compound as a white solid.
1 H NMR (CD 3 OD, 400 MHz): δ 1.48 (9H, s), 1.52-1.64 (2H, m), 1.68-1.75 (1H, m), 2,12-2.20 (1H, m), 3.00 ( 1H, dd, J = 16.5, 3.0 Hz), 3.15 (1H, dd, J = 16.5, 5.4 Hz), 3.20-3.40 (1H, m), 3.41-3.60 (1H, m), 3.86-3.99 (2H, m), 4.15-4.17 (2H, m), 4.32-4.37 (1H, m), 7.10-7.20 (4H, m).
MS (FAB +) m / z: 362 ((M + H) + ).
IR (KBr): 2976,2932,1756,1690,1643,1479,1430,1366,1279,1169,1119,759 cm −1 .
　［実施例６ｇ］エチル　［（２Ｓ）－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イルオキシ］アセテート
　実施例６ｆで得られた｛［（２Ｓ）－１’－（ｔｅｒｔ－ブトキシカルボニル）－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝酢酸（２８．２０ｇ、７８．０ｍｍｏｌ）のエタノール溶液（２８０ｍＬ）に氷冷攪拌下で塩化チオニル（１２．３ｍＬ、１５６ｍｍｏｌ）を滴下し、２時間加熱還流した。放冷後、反応液のエタノールを減圧留去した。得られた黄色油状物に酢酸エチルを加えたのち、炭酸水素ナトリウム水溶液で洗浄した。有機層を分離したのち、水層に酢酸エチルを加えて抽出した。有機層を合わせて無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去した。得られた残留物にトルエンを加えて溶解した後、溶媒を減圧留去し、粗製の標記目的化合物３２．１ｇを淡黄色油状物として得た。
MS (FAB+) m/z: 290 ((M+H)+).
［実施例６ｈ］エチル　｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセテート
　実施例６ｇで得られた粗製のエチル　［（２Ｓ）－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イルオキシ］アセテート（３２．１ｇ）と実施例６ｃで得られた化合物（３７．６ｇ、７０．９ｍｍｏｌ）のアセトニトリル溶液（１６０ｍＬ）に室温攪拌下、炭酸水素ナトリウム（７．１５ｇ、８５．１１ｍｍｏｌ）を加え、窒素雰囲気下、１４時間攪拌還流した。反応液を室温まで放冷したのち、有機溶媒を減圧留去した。得られた残渣に炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層をあわせて無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝２：１―０／１）を用いて精製し、標記目的化合物４７．８ｇ（収率９３％）を白色固体として得た。
MS (APCI) m/z: 723 ((M+H)+).
［実施例６ｉ］｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝酢酸
　実施例６ｈで得られた化合物（３４．１ｇ、４７．１ｍｍｏｌ）のメタノール溶液（３４０ｍＬ）に、氷冷攪拌下、１規定水酸化ナトリウム水溶液（７１ｍＬ、７１ｍｍｏｌ）を滴下し、室温で２時間攪拌した。氷冷攪拌下、１規定塩酸（７１ｍＬ，７１ｍｍｏｌ）を加えて中和した後、メタノールを減圧留去した。残留物に水を加えた後、酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣を酢酸エチルに溶解後、セライトろ過した。ろ液を減圧留去し、標記目的化合物３２．６ｇ（収率９９％）を白色アモルファスとして得た。
1H NMR (CD3OD, 400MHz): δ 1.70-2.08(3H, m), 2.25-2.65(3H, m), 2.82-3.03(2H, m), 3.10-3.62(5H, m), 3.85-4.21(5H, m), 4.25-4.40(1H, m), 5.04-5.50(2H, m), 7.05-7.25(6H, m), 7.40-7.62(2H, m), 7.97-8.20(3H, m),
MS (FAB+) m/z: 695 ((M+H)+).
IR (KBr): 2935,1651,1605,1511,1432,1360,1281,1179,1138,907,682 cm-1。 [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. After allowing to cool, ethanol in the reaction solution was distilled off under reduced pressure. Ethyl acetate was added to the obtained yellow oil, and then washed with an aqueous sodium hydrogen carbonate solution. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Toluene was added to the obtained residue for dissolution, and then the solvent was distilled off under reduced pressure to obtain 32.1 g of the crude title object compound as a pale yellow oil.
MS (FAB +) m / z: 290 ((M + H) + ).
[Example 6h] Ethyl {[(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} acetate Crude ethyl [(2S) — obtained in Example 6g A solution of 2,3-dihydrospiro [indene-1,4′-piperidin] -2-yloxy] acetate (32.1 g) and the compound obtained in Example 6c (37.6 g, 70.9 mmol) in acetonitrile (160 mL) ) Was added with sodium bicarbonate (7.15 g, 85.11 mmol) with stirring at room temperature, and the mixture was stirred and refluxed for 14 hours under a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, the organic solvent was distilled off under reduced pressure. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1-0 / 1) to obtain 47.8 g (yield 93%) of the title object compound as a white solid.
MS (APCI) m / z: 723 ((M + H) + ).
[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 The compound (34.1 g, 47.1 mmol) obtained in Example 6h. ) Was added dropwise to a methanol solution (340 mL) under ice-cooling and 1N aqueous sodium hydroxide solution (71 mL, 71 mmol) was stirred for 2 hours at room temperature. Under ice-cooling and stirring, 1N hydrochloric acid (71 mL, 71 mmol) was added for neutralization, and then methanol was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate and filtered through celite. The filtrate was distilled off under reduced pressure to obtain 32.6 g (yield 99%) of the title object compound as white amorphous.
1 H NMR (CD 3 OD, 400MHz): δ 1.70-2.08 (3H, m), 2.25-2.65 (3H, m), 2.82-3.03 (2H, m), 3.10-3.62 (5H, m), 3.85- 4.21 (5H, m), 4.25-4.40 (1H, m), 5.04-5.50 (2H, m), 7.05-7.25 (6H, m), 7.40-7.62 (2H, m), 7.97-8.20 (3H, m ),
MS (FAB +) m / z: 695 ((M + H) + ).
IR (KBr): 2935,1651,1605,1511,1432,1360,1281,1179,1138,907,682 cm −1 .
　［実施例６ｊ］ｔｅｒｔ－ブチル　４－［（３－｛［（ベンジルオキシ）カルボニル］アミノ｝プロピル）カルバモイル］ピペリジン－１－カルボキシレート
　１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－カルボン酸（２００ｍｇ，０．８７２ｍｍｏｌ）、及び、ベンジル　（３－アミノプロピル）カーバメート　塩酸塩（２１３ｍｇ，０．８７２ｍｍｏｌ）を塩化メチレン（２ｍＬ）に溶解し、トリエチルアミン（０．１４５ｍＬ，１．０５ｍｍｏｌ）、及び、ＷＳＣ・ＨＣｌ（２０１ｍｇ，１．０５ｍｍｏｌ）を加え、室温にて４日間撹拌した。反応液に水を加え、酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：２）を用いて精製し、標記目的化合物（１８２ｍｇ，収率５０％）を無色油状物として得た。
MS (APCI) m/z: 320(M+H)+ : (脱Boc体).
IR(KBr) νmax 2932, 1649, 1531, 1424, 1247, 1162, 1129, 1026, 736, 696 cm-1.
［実施例６ｋ］tert-ブチル4-[(3-アミノプロピル)カルバモイル]ピペリジン-1-カルボキシレート
　１０％パラジウム－炭素（ｄｒｙ，１８ｍｇ）に、実施例６ｊで得られた化合物（１８２ｍｇ，０．４３４ｍｍｏｌ）のメタノール溶液（４．５ｍＬ）を加え、系内を水素雰囲気に置換した後、室温にて２時間攪拌した。系内を窒素雰囲気に置換した後、セライトを用いて反応液をろ過した。減圧下、溶剤を留去して得られた残渣をテトラヒドロフラン（×２）で共沸し、標記目的化合物（１２０ｍｇ，収率９７％）を白色固体として得た。
1H NMR (CDCl3, 500MHz): δ 1.46 (9H, m), 1.59-1.65 (5H, m), 1.80-1.84 (3H, m), 2.17-2.24 (1H, m), 2.71-2.77 (2H, m), 2.81-2.84 (2H, m), 3.37 (2H, q, J = 6.3 Hz), 4.10-4.18 (2H, m), 6.71 (1H, brs).
MS (FAB) m/z: 286(M+H)+.
［実施例６Ｌ］ｔｅｒｔ－ブチル　４－（｛３－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）アミノ］プロピル｝カルバモイル）ピペリジン－１－カルボキシレート
　実施例６ｉで得られた化合物（１５３ｍｇ，０．２２１ｍｍｏｌ）を塩化メチレン（２ｍＬ）に溶解し、氷冷下、トリエチルアミン（３５μＬ，０．２５２ｍｍｏｌ）、及び、塩化ピバロイル（２７μＬ，０．２１９ｍｍｏｌ）を加え、室温にて２５分間撹拌した。反応液に氷冷下、実施例６ｋで得られた化合物（６０ｍｇ，０．２１０ｍｍｏｌ）の塩化メチレン溶液（２ｍＬ）を加え、室温にて１６時間撹拌した。減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝５０：１）を用いて精製し、標記目的化合物（１７５ｍｇ，収率８７％）を白色固体として得た。
MS (APCI) m/z: 962(M+H)+.
IR(KBr) νmax 2931, 1659, 1533, 1430, 1360, 1281, 1174, 1138, 848, 758 cm-1。 [Example 6j] tert-butyl 4-[(3-{[(benzyloxy) carbonyl] amino} propyl) carbamoyl] piperidine-1-carboxylate 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (200 mg , 0.872 mmol) and benzyl (3-aminopropyl) carbamate hydrochloride (213 mg, 0.872 mmol) in methylene chloride (2 mL), triethylamine (0.145 mL, 1.05 mmol), and WSC · HCl (201 mg, 1.05 mmol) was added and stirred at room temperature for 4 days. 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, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give the title object compound (182 mg, yield). 50%) as a colorless oil.
MS (APCI) m / z: 320 (M + H) + : (De-Boc form).
IR (KBr) ν max 2932, 1649, 1531, 1424, 1247, 1162, 1129, 1026, 736, 696 cm -1 .
[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.
1 H NMR (CDCl 3 , 500MHz): δ 1.46 (9H, m), 1.59-1.65 (5H, m), 1.80-1.84 (3H, m), 2.17-2.24 (1H, m), 2.71-2.77 (2H , m), 2.81-2.84 (2H, m), 3.37 (2H, q, J = 6.3 Hz), 4.10-4.18 (2H, m), 6.71 (1H, brs).
MS (FAB) m / z: 286 (M + H) + .
[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 μL, 0.252 mmol) under ice cooling, and , Pivaloyl chloride (27 μL, 0.219 mmol) was added, and the mixture was stirred at room temperature for 25 minutes. A methylene chloride solution (2 mL) of the compound obtained in Example 6k (60 mg, 0.210 mmol) was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 16 hours. The residue obtained by evaporating the solvent under reduced pressure was purified using NH silica gel column chromatography (ethyl acetate: methanol = 50: 1) to give the title object compound (175 mg, yield 87%) as a white solid. Obtained.
MS (APCI) m / z: 962 (M + H) + .
IR (KBr) ν max 2931, 1659, 1533, 1430, 1360, 1281, 1174, 1138, 848, 758 cm −1 .
　［実施例６ｍ］Ｎ－｛３－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）アミノ］プロピル｝ピペリジン－４－カルボキサミド
　実施例６Ｌで得られた化合物（１７５ｍｇ，０．１８２ｍｍｏｌ）に２Ｎ　塩酸－メタノール（１．８２ｍＬ，３．６４ｍｍｏｌ）を加え、室温にて３時間撹拌した。反応液に１Ｎ　水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝２０：１－塩化メチレン：メタノール＝１０：１）を用いて精製し、標記目的化合物（１４７ｍｇ，収率９４％）を白色固体として得た。
MS (APCI) m/z: 842(M+H)+.
IR(KBr) νmax 2931, 1738, 1654, 1534, 1439, 1359, 1281, 1181, 1139, 682 cm-1.
［実施例６ｎ］（３Ｒ）－ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート　４－メチルベンゼンスルホン酸塩
　実施例１ｈで得られたｔｅｒｔ－ブチル　（３Ｒ）－３－｛［ヒドロキシ（ジチオフェン－２－イル）アセチル］オキシ｝ピロリジン－１－カルボキシレート（１５０ｍｇ，０．３６７ｍｍｏｌ）をテトラヒドロフラン（４ｍＬ）に溶解し、ｐ－トルエンスルホン酸・１水和物（１２６ｍｇ，０．７３３ｍｍｏｌ）を加え、５０℃にて１５時間撹拌した。更に反応液にｐ－トルエンスルホン酸・１水和物（６３ｍｇ，０．３６７ｍｍｏｌ）を加え、５０℃にて５時間撹拌した。系中より沈殿した白色固体をろ別し、標記目的化合物（１４９ｍｇ，収率８４％）を白色固体として得た。
1H NMR (CDCl3, 500MHz): δ 2.13-2.21 (2H, m), 2.38 (3H, s), 3.30-3.36 (2H, m), 3.44-3.49 (2H, m), 3.53-3.59 (1H, m), 5.46-5.48 (1H, m), 6.87-6.90 (2H, m), 7.12-7.15 (2H, m), 7.18 (2H, d, J = 8.0 Hz), 7.20-7.22 (2H, m), 7.67 (2H, d, J = 8.0 Hz).
MS (FAB+) m/z: 309(M+H)+ ((3R)-ヒ゜ロリシ゛ン-3-イル ヒト゛ロキシ(シ゛チオフェン-2-イル)アセテート)
MS (FAB-) m/z: 171(M-H)- （４－メチルベンゼンスルホン酸）.
［実施例６ｏ］（３Ｒ）－１－｛２－［（ｔｅｒｔ－ブトキシカルボニル）（メチル）アミノ］エチル｝ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート
　実施例６ｎで得られた（３Ｒ）－ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート　４－メチルベンゼンスルホン酸塩（７２８ｍｇ，１．５１ｍｍｏｌ）を塩化メチレン（１５ｍＬ）に溶解し、トリエチルアミン（０．２３１ｍＬ，１．６６ｍｍｏｌ）、ｔｅｒｔ－ブチル　メチル（２－オキソエチル）カーバメート（２８８ｍｇ，１．６６ｍｍｏｌ）、水素化トリアセトキシホウ素ナトリウム（４８０ｍｇ，２．２７ｍｍｏｌ）、及び、酢酸（０．２６５ｍＬ）を加え、室温にて１７時間撹拌した。反応液に飽和重曹水を加え、酢酸エチル（×３）で抽出した後、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）を用いて精製し、標記目的化合物（７０６ｍｇ，収率１００％）を淡黄色油状物として得た。
1H NMR (CDCl3, 500MHz): δ 1.45 (9H, m), 1.84-1.89 (1H, m), 2.17-2.26 (1H, m), 2.49-2.54 (1H, m), 2.56-2.59 (2H, m), 2.65-2.70 (1H, m), 2.75-2.79 (1H, m), 2.86-2.92 (4H, m), 3.24-3.35 (1H, m), 4.79-4.85 (1H, m), 5.30-5.53 (1H, m), 6.96-6.99 (2H, m), 7.17-7.20 (2H, m), 7.27-7.28 (2H, m).
MS (FAB) m/z: 467(M+H)+。 [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. 1N Aqueous sodium hydroxide solution 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, and the resulting residue was purified using NH silica gel column chromatography (ethyl acetate: methanol = 20: 1-methylene chloride: methanol = 10: 1). The title compound (147 mg, 94% yield) was obtained as a white solid.
MS (APCI) m / z: 842 (M + H) + .
IR (KBr) ν max 2931, 1738, 1654, 1534, 1439, 1359, 1281, 1181, 1139, 682 cm -1 .
[Example 6n] (3R) -pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate 4-methylbenzenesulfonate salt tert-butyl (3R) -3-{[hydroxy ( Dithiophen-2-yl) acetyl] oxy} pyrrolidine-1-carboxylate (150 mg, 0.367 mmol) was dissolved in tetrahydrofuran (4 mL), and p-toluenesulfonic acid monohydrate (126 mg, 0.733 mmol) was added. In addition, the mixture was stirred at 50 ° C. for 15 hours. Further, p-toluenesulfonic acid monohydrate (63 mg, 0.367 mmol) was added to the reaction solution, and the mixture was stirred at 50 ° C. for 5 hours. A white solid precipitated from the system was filtered off to obtain the title object compound (149 mg, yield 84%) as a white solid.
1 H NMR (CDCl 3 , 500MHz): δ 2.13-2.21 (2H, m), 2.38 (3H, s), 3.30-3.36 (2H, m), 3.44-3.49 (2H, m), 3.53-3.59 (1H , m), 5.46-5.48 (1H, m), 6.87-6.90 (2H, m), 7.12-7.15 (2H, m), 7.18 (2H, d, J = 8.0 Hz), 7.20-7.22 (2H, m ), 7.67 (2H, d, J = 8.0 Hz).
MS (FAB +) m / z: 309 (M + H) + ((3R) -hydroxy-3-yl human oxy (dithiophen-2-yl) acetate)
MS (FAB-) m / z: 171 (MH) - (4-methylbenzenesulfonic acid).
[Example 6o] (3R) -1- {2-[(tert-butoxycarbonyl) (methyl) amino] ethyl} pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate obtained in Example 6n ( 3R) -pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate 4-methylbenzenesulfonate (728 mg, 1.51 mmol) was dissolved in methylene chloride (15 mL) and triethylamine (0.231 mL, 1.66 mmol) was dissolved. ), Tert-butyl methyl (2-oxoethyl) carbamate (288 mg, 1.66 mmol), sodium triacetoxyborohydride (480 mg, 2.27 mmol) and acetic acid (0.265 mL) were added, and the mixture was stirred at room temperature for 17 hours Stir. 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. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using NH silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title object compound (706 mg, yield). 100%) as a pale yellow oil.
1 H NMR (CDCl 3 , 500MHz): δ 1.45 (9H, m), 1.84-1.89 (1H, m), 2.17-2.26 (1H, m), 2.49-2.54 (1H, m), 2.56-2.59 (2H , m), 2.65-2.70 (1H, m), 2.75-2.79 (1H, m), 2.86-2.92 (4H, m), 3.24-3.35 (1H, m), 4.79-4.85 (1H, m), 5.30 -5.53 (1H, m), 6.96-6.99 (2H, m), 7.17-7.20 (2H, m), 7.27-7.28 (2H, m).
MS (FAB) m / z: 467 (M + H) <+> .
　［実施例６ｐ］（３Ｒ）－１－［２－（メチルアミノ）エチル］ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート
　実施例６ｏで得られた（３Ｒ）－１－｛２－［（ｔｅｒｔ－ブトキシカルボニル）（メチル）アミノ］エチル｝ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート（７０６ｍｇ，１．５１ｍｍｏｌ）をテトラヒドロフラン（１５ｍＬ）に溶解し、ｐ－トルエンスルホン酸一水和物（８６３ｍｇ，４．５４ｍｍｏｌ）を加え、５０℃にて１５時間撹拌した。反応液に飽和重曹水を加え、塩化メチレン（×３）で抽出した後、有機層を無水硫酸ナトリウムで乾燥した。減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）を用いて精製し、標記目的化合物（４７９ｍｇ，収率８７％）を褐色油状物として得た。
MS (APCI) m/z: 367(M+H)+.
IR(ATR) νmax 2795, 1732, 1435, 1224, 1141, 1089, 1041, 849, 789, 698 cm-1.
［実施例６ｑ］（３Ｒ）－１－｛２－［（６－ブロモヘキサノイル）（メチル）アミノ］エチル｝ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート
　実施例６ｐで得られた（３Ｒ）－１－［２－（メチルアミノ）エチル］ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート（６７ｍｇ，０．１８２ｍｍｏｌ）を酢酸エチル（２ｍＬ）に溶解し、氷冷下、トリエチルアミン（３０μＬ，０．２１８ｍｍｏｌ）、及び６－ブロモヘキサノイル　クロリド（２９μＬ，０．１９１ｍｍｏｌ）を加え、室温にて１時間撹拌した。不溶物をセライトでろ過し、減圧下、溶剤を留去して、標記目的化合物（９９ｍｇ，収率１００％）を淡黄色油状物として得た。
MS (APCI) m/z: 543(M+H)+.
［実施例６ｒ］（３Ｒ）－１－｛２－［｛６－［４－（｛３－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）アミノ］プロピル｝カルバモイル）ピペリジン－１－イル］ヘキサノイル｝（メチル）アミノ］エチル｝ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート
　実施例６ｑで得られた化合物（９９ｍｇ，０．１８２ｍｍｏｌ）をアセトニトリル（２ｍＬ）に溶解し、実施例６ｍで得られた化合物（１４７ｍｇ，０．１７１ｍｍｏｌ）、炭酸水素ナトリウム（２３ｍｇ，０．２６７ｍｍｏｌ）、及び、ヨウ化カリウム（４３ｍｇ，０．２６７ｍｍｏｌ）を加え、５０℃にて４５．５時間攪拌した。反応液を酢酸エチルで希釈し、水を加えた後、酢酸エチル（×３）で抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝５０：１－１５：１）を用いて精製した。さらに逆相分取カラムクロマトグラフィー（Ｗａｔｅｒｓ，ＭＳ　Ｃ１８　ＯＢＤ，５μｍ，３０×１００ｍｍ）（アセトニトリル：０．１％ギ酸アンモニウム水溶液＝６０：４０）を用いて精製し、標記目的化合物（５６ｍｇ，収率２５％）を白色固体として得た。
MS (FAB) m/z: 1324(M+H)+.
IR(KBr) νmax 2932, 1738, 1649, 1533, 1438, 1359, 1281, 1180, 1139, 706 cm-1。 [Example 6p] (3R) -1- [2- (Methylamino) ethyl] pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate (3R) -1- {2- obtained in Example 6o [(Tert-Butoxycarbonyl) (methyl) amino] ethyl} pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate (706 mg, 1.51 mmol) was dissolved in tetrahydrofuran (15 mL), and p-toluenesulfonic acid mono Hydrate (863 mg, 4.54 mmol) was added, and the mixture was stirred at 50 ° C. for 15 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with methylene chloride (× 3). The organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified using NH silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give the title object compound (479 mg, yield 87%) as a brown oil. Got as.
MS (APCI) m / z: 367 (M + H) + .
IR (ATR) ν max 2795, 1732, 1435, 1224, 1141, 1089, 1041, 849, 789, 698 cm -1 .
[Example 6q] (3R) -1- {2-[(6-Bromohexanoyl) (methyl) amino] ethyl} pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate obtained in Example 6p (3R) -1- [2- (methylamino) ethyl] pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate (67 mg, 0.182 mmol) was dissolved in ethyl acetate (2 mL). Triethylamine (30 μL, 0.218 mmol) and 6-bromohexanoyl chloride (29 μL, 0.191 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The insoluble material was filtered through celite, and the solvent was evaporated under reduced pressure to give the title object compound (99 mg, yield 100%) as a pale-yellow oil.
MS (APCI) m / z: 543 (M + H) + .
[Example 6r] (3R) -1- {2-[{6- [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′-piperidine ] -2-yl] oxy} acetyl) amino] propyl} carbamoyl) piperidin-1-yl] hexanoyl} (methyl) amino] ethyl} pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate obtained in Example 6q The obtained compound (99 mg, 0.182 mmol) was dissolved in acetonitrile (2 mL), and the compound (147 mg, 0.171 mmol) obtained in Example 6m, sodium bicarbonate (23 mg) , 0.267 mmol) and potassium iodide (43 mg, 0.267 mmol) were added, and the mixture was stirred at 50 ° C. for 45.5 hours. The reaction mixture was diluted with ethyl acetate, water was added, and the mixture was extracted with ethyl acetate (x3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to NH silica gel column chromatography (ethyl acetate: methanol = 50: 1-15: 1). ). Further purification using reverse phase preparative column chromatography (Waters, MS C18 OBD, 5 μm, 30 × 100 mm) (acetonitrile: 0.1% aqueous ammonium formate = 60: 40) gave the title object compound (56 mg, yield). 25%) as a white solid.
MS (FAB) m / z: 1324 (M + H) + .
IR (KBr) ν max 2932, 1738, 1649, 1533, 1438, 1359, 1281, 1180, 1139, 706 cm −1 .
　［実施例７］
Ｎ－（２－｛［２－（４－｛２－［（３Ｓ）－３－（２－アミノ－２－オキソ－１，１－ジフェニルエチル）ピロリジン－１－イル］エチル｝フェニル）エチル］（メチル）アミノ｝エチル）－２－｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝－Ｎ－メチルアセタミド [Example 7]
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
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
［実施例７ａ］２－［（３Ｓ）－１－（２－｛４－［２－（メチルアミノ）エチル］フェニル｝エチル）ピロリジン－３－イル］－２，２－ジフェニルアセタミド　塩酸塩
　文献（ＵＳ２００５／２０３１６７　Ａ１）に記載されている２－｛（３Ｓ）－１－［２－（４－｛２－［ベンジル（メチル）アミノ］エチル｝フェニル）エチル］ピロリジン－３－イル｝－２，２－ジフェニルアセタミド（１．１１ｇ，２．０９ｍｍｏｌ）と２０％水酸化パラジウム（１００ｍｇ）のエタノール懸濁液（２１ｍＬ）に４Ｎ　塩酸－ジオキサン（１．３０ｍＬ，５．２２ｍｍｏｌ）を加え、系内を水素雰囲気に置換した後、５０℃にて１時間攪拌した。系内を窒素雰囲気に置換した後、セライトを用いて反応液をろ過した。減圧下、溶剤を留去して、標記目的化合物（１．１２ｇ，収率１００％）を白色固体として得た。
MS (FAB) m/z: 599(M+H)+.
IR(KBr) νmax 2930, 2795, 1691, 1446, 1391, 1365, 1155, 1046, 754, 702 cm-1.
［実施例７ｂ］ｔｅｒｔ－ブチル　（２－｛［２－（４－｛２－［（３Ｓ）－３－（２－アミノ－２－オキソ－１，１－ジフェニルエチル）ピロリジン－１－イル］エチル｝フェニル）エチル］（メチル）アミノ｝エチル）メチルカーバメート
　実施例７ａで得られた２－［（３Ｓ）－１－（２－｛４－［２－（メチルアミノ）エチル］フェニル｝エチル）ピロリジン－３－イル］－２，２－ジフェニルアセタミド　塩酸塩（３００ｍｇ，０．６８０ｍｍｏｌ）を１，２－ジクロロエタン（７ｍＬ）に溶解し、トリエチルアミン（０．２８４ｍＬ，２．０４ｍｍｏｌ）、ｔｅｒｔ－ブチル　メチル（２－オキソエチル）カーバメート（１７７ｍｇ，１．０２ｍｍｏｌ）、及び、水素化トリアセトキシホウ素ナトリウム（２１６ｍｇ，１．０２ｍｍｏｌ）を加え、室温にて５．５時間撹拌した。反応液に飽和重曹水を加え、塩化メチレン－メタノール（３：１，×３）で抽出した後、無水硫酸ナトリウムで乾燥した。減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：２－酢酸エチル：メタノール＝２０：１）を用いて精製し、標記目的化合物（３０７ｍｇ，収率７５％）を白色固体として得た。
MS (FAB) m/z: 599(M+H)+.
IR(KBr) νmax 2930, 2795, 1691, 1446, 1391, 1365, 1155, 1046, 754, 702 cm-1。 [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) To an ethanol suspension (21 mL) of 2,2-diphenylacetamide (1.11 g, 2.09 mmol) and 20% palladium hydroxide (100 mg) was added 4N hydrochloric acid-dioxane (1.30 mL, 5.22 mmol). The system was replaced with a hydrogen atmosphere and stirred at 50 ° C. for 1 hour. After replacing the inside of the system with a nitrogen atmosphere, the reaction solution was filtered using Celite. The solvent was distilled off under reduced pressure to obtain the title object compound (1.12 g, yield 100%) as a white solid.
MS (FAB) m / z: 599 (M + H) + .
IR (KBr) ν max 2930, 2795, 1691, 1446, 1391, 1365, 1155, 1046, 754, 702 cm -1 .
[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 (216 mg, 1.02 mmol) l) was added and stirred at room temperature for 5.5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with methylene chloride-methanol (3: 1, x3) and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified using NH silica gel column chromatography (hexane: ethyl acetate = 1: 2-ethyl acetate: methanol = 20: 1) to give the title object compound (307 mg, Yield 75%) was obtained as a white solid.
MS (FAB) m / z: 599 (M + H) + .
IR (KBr) ν max 2930, 2795, 1691, 1446, 1391, 1365, 1155, 1046, 754, 702 cm −1 .
　［実施例７ｃ］２－［（３Ｓ）－１－｛２－［４－（２－｛メチル［２－（メチルアミノ）エチル］アミノ｝エチル）フェニル］エチル｝ピロリジン－３－イル］－２，２－ジフェニルアセタミド
　実施例７ｂで得られた化合物（２９６ｍｇ，０．４９４ｍｍｏｌ）のメタノール溶液（２ｍＬ）に、４Ｎ　塩酸－ジオキサン（１．２４ｍＬ，４．９４ｍｍｏｌ）を加え、室温にて１時間、更に４０℃にて１時間攪拌した。反応液に飽和重曹水を加えた後、塩化メチレン－メタノール（４：１，×３）で抽出し、無水硫酸ナトリウムで乾燥した。減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１００：０－１０：１）を用いて精製し、標記目的化合物（２４０ｍｇ，収率９７％）を黄色固体として得た。
MS (FAB) m/z: 499(M+H)+.
IR(KBr) νmax 2942, 2795, 1681, 1445, 1372, 1152, 1045, 818, 754, 702 cm-1.
［実施例７ｄ］Ｎ－（２－｛［２－（４－｛２－［（３Ｓ）－３－（２－アミノ－２－オキソ－１，１－ジフェニルエチル）ピロリジン－１－イル］エチル｝フェニル）エチル］（メチル）アミノ｝エチル）－２－｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝－Ｎ－メチルアセタミド
　実施例６ｉで得られた化合物（２４４ｍｇ，０．３５１ｍｍｏｌ）を塩化メチレン（５ｍＬ）に溶解し、氷冷下、トリエチルアミン（６７μＬ，０．４７９ｍｍｏｌ）、及び、クロロギ酸イソブチル（５０μＬ，０．３８３ｍｍｏｌ）を加え、室温にて１５分撹拌した。実施例７ｃで得られた２－［（３Ｓ）－１－｛２－［４－（２－｛メチル［２－（メチルアミノ）エチル］アミノ｝エチル）フェニル］エチル｝ピロリジン－３－イル］－２，２－ジフェニルアセタミド（１５９ｍｇ，０．３１９ｍｍｏｌ）の塩化メチレン溶液（５ｍＬ）に氷冷下、反応液を加え、室温にて３．５時間撹拌した。減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：２－酢酸エチル：メタノール＝２０：１）を用いて精製し、標記目的化合物（３１７ｍｇ，収率７７％）を白色固体として得た。
MS (FAB) m/z: 1175(M+H)+.
IR(KBr) νmax 2931, 2800, 1649, 1443, 1358, 1281, 1181, 1139, 757, 702 cm-1。 [Example 7c] 2-[(3S) -1- {2- [4- (2- {methyl [2- (methylamino) ethyl] amino} ethyl) phenyl] ethyl} pyrrolidin-3-yl] -2 , 2-Diphenylacetamide To 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. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with methylene chloride-methanol (4: 1, x3) and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified using NH silica gel column chromatography (ethyl acetate: methanol = 100: 0-10: 1) to give the title object compound (240 mg, yield 97%). Was obtained as a yellow solid.
MS (FAB) m / z: 499 (M + H) + .
IR (KBr) ν max 2942, 2795, 1681, 1445, 1372, 1152, 1045, 818, 754, 702 cm -1 .
[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 μL, 0.479 mmol) and isobutyl chloroformate (50 μL, 0.383 m) were cooled with ice. mol) was added and stirred at room temperature for 15 minutes. 2-[(3S) -1- {2- [4- (2- {Methyl [2- (methylamino) ethyl] amino} ethyl) phenyl] ethyl} pyrrolidin-3-yl] obtained in Example 7c The reaction solution was added to a methylene chloride solution (5 mL) of -2,2-diphenylacetamide (159 mg, 0.319 mmol) under ice cooling, and the mixture was stirred at room temperature for 3.5 hours. The residue obtained by evaporating the solvent under reduced pressure was purified using NH silica gel column chromatography (hexane: ethyl acetate = 1: 2-ethyl acetate: methanol = 20: 1) to give the title object compound (317 mg, Yield 77%) was obtained as a white solid.
MS (FAB) m / z: 1175 (M + H) + .
IR (KBr) ν max 2931, 2800, 1649, 1443, 1358, 1281, 1181, 1139, 757, 702 cm −1 .
　［実施例８］
Ｎ－（２－｛［２－（４－｛２－［（３Ｓ）－３－（２－アミノ－２－オキソ－１，１－ジフェニルエチル）ピロリジン－１－イル］エチル｝フェニル）エチル］アミノ｝エチル）－２－｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝－Ｎ－メチルアセタミド [Example 8]
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
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
［実施例８ａ］ｔｅｒｔ－ブチル　｛２－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）（メチル）アミノ］エチル｝カーバメート
　実施例６ｉで得られた化合物（１３５ｍｇ，０．１９４ｍｍｏｌ）を塩化メチレン（３ｍＬ）に溶解し、氷冷下、トリエチルアミン（８１μＬ，０．５８３ｍｍｏｌ）、及び、塩化ピバロイル（２５μＬ，０．２０４ｍｍｏｌ）を加え、室温にて１５分撹拌した。反応液にｔｅｒｔ－ブチル　［２－（メチルアミノ）エチル］カーバメート　塩酸塩（４５ｍｇ，０．２１４ｍｍｏｌ）を加え、室温にて終夜撹拌した。減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１－１：２）を用いて精製し、標記目的化合物（１５０ｍｇ，収率９１％）を白色固体として得た。
MS (APCI) m/z: 851 (M+H) +.
［実施例８ｂ］Ｎ－（２－アミノエチル）－２－｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝－Ｎ－メチルアセタミド
　実施例８ａで得られた化合物（１５０ｍｇ，０．１７６ｍｍｏｌ）をメタノール（０．９ｍＬ）に溶解し、４Ｎ　塩酸－ジオキサン（０．８８３ｍＬ，３．５３ｍｍｏｌ）を加えた後、室温にて１時間攪拌した。減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）を用いて精製し、標記目的化合物（１２５ｍｇ，収率９５％）を白色固体として得た。
MS (APCI) m/z: 751 (M+H) +.
［実施例８ｃ］２－［（３Ｓ）－１－｛２－［４－（２－ヒドロキシエチル）フェニル］エチル｝ピロリジン－３－イル］－２，２－ジフェニルアセタミド
　文献（ＵＳ２００４／２５４２１９　Ａ１）に記載されている２，２－ジフェニル－２－［（３Ｓ）－ピロリジン－３－イル］アセタミド（１．２２ｇ，４．３４ｍｍｏｌ）のアセトニトリル溶液（４０ｍＬ）に、文献（ＵＳ２００５／２０３１６７　Ａ１）に記載されている２－［４－（２－ヒドロキシエチル）フェニル］エチル　４－メチルベンゼンスルホネート（１．３９ｇ，４．３４ｍｍｏｌ）、及び、Ｎ，Ｎ－ジイソプロピルエチルアミン（２．２７ｍＬ，１３．０ｍｍｏｌ）を加え、６０℃にて１２．５時間加熱攪拌した。反応液に水を加えた後、酢酸エチル（×２）で抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１００：０－２０：１）を用いて精製し、標記目的化合物（１．５３ｇ，収率８２％）を白色固体として得た。
1H NMR (CDCl3, 400MHz): δ 1.76-1.86 (1H, m), 1.88-1.95 (1H, m), 2.15-2.13 (1H, m), 2.26-2.33 (1H, m), 2.62 (1H, t, J = 6.0 Hz), 2.68-2.76 (4H, m), 2.82-2.90 (4H, m), 3.28-3.35 (1H, m), 3.86-3.89 (2H, m), 5.24 (1H, brs), 7.07-7.22 (8H, m), 7.23-7.31 (4H, m), 7.35 (2H, d, J = 7.0 Hz), 8.16 (1H, brs).
MS (APCI) m/z: 429(M+H)+。 [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 μL, 0.583 mmol) and pivaloyl chloride (25 μL, 0) were cooled with ice. .204 mmol) was added and stirred at room temperature for 15 minutes. To the reaction solution was added tert-butyl [2- (methylamino) ethyl] carbamate hydrochloride (45 mg, 0.214 mmol), and the mixture was stirred at room temperature overnight. The residue obtained by distilling off the solvent under reduced pressure was purified using NH silica gel column chromatography (hexane: ethyl acetate = 1: 1-1: 2) to give the title object compound (150 mg, 91% yield). Was obtained as a white solid.
MS (APCI) m / z: 851 (M + H) + .
[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. Stir. The solvent was distilled off under reduced pressure, and the resulting residue was purified using NH silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give the title object compound (125 mg, yield 95%) as a white solid. Obtained.
MS (APCI) m / z: 751 (M + H) + .
[Example 8c] 2-[(3S) -1- {2- [4- (2-hydroxyethyl) phenyl] ethyl} pyrrolidin-3-yl] -2,2-diphenylacetamide Literature (US2004 / 254219) The acetonitrile solution (40 mL) of 2,2-diphenyl-2-[(3S) -pyrrolidin-3-yl] acetamide (1.22 g, 4.34 mmol) described in A1) was added to the literature (US 2005/203167 A1). 2- [4- (2-hydroxyethyl) phenyl] ethyl 4-methylbenzenesulfonate (1.39 g, 4.34 mmol) and N, N-diisopropylethylamine (2.27 mL, 13. 0 mmol) was added and the mixture was heated and stirred at 60 ° C. for 12.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate (× 2), and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using NH silica gel column chromatography (ethyl acetate: methanol = 100: 0-20: 1) to give the title object compound (1.53 g, 82% yield) was obtained as a white solid.
1 H NMR (CDCl 3 , 400 MHz): δ 1.76-1.86 (1H, m), 1.88-1.95 (1H, m), 2.15-2.13 (1H, m), 2.26-2.33 (1H, m), 2.62 (1H , t, J = 6.0 Hz), 2.68-2.76 (4H, m), 2.82-2.90 (4H, m), 3.28-3.35 (1H, m), 3.86-3.89 (2H, m), 5.24 (1H, brs ), 7.07-7.22 (8H, m), 7.23-7.31 (4H, m), 7.35 (2H, d, J = 7.0 Hz), 8.16 (1H, brs).
MS (APCI) m / z: 429 (M + H) + .
　［実施例８ｄ］２－［（３Ｓ）－１－｛２－［４－（２－オキソエチル）フェニル］エチル｝ピロリジン－３－イル］－２，２－ジフェニルアセタミド
　実施例８ｃで得られた２－［（３Ｓ）－１－｛２－［４－（２－ヒドロキシエチル）フェニル］エチル｝ピロリジン－３－イル］－２，２－ジフェニルアセタミド（１５０ｍｇ，０．３５０ｍｍｏｌ）、ジメチルスルホキシド（０．１４９ｍＬ，２．１０ｍｍｏｌ）、及び、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１８３ｍＬ，１．０５ｍｍｏｌ）を塩化メチレン（４ｍＬ）に溶解し、氷冷下、サルファートリオキシド－ピリジンコンプレックス（１６４ｍｇ，１．０５ｍｍｏｌ）を加え、同温にて５．５時間撹拌した。更に反応液にジメチルスルホキシド（７５μＬ，１．０５ｍｍｏｌ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（９２μＬ，０．５２５ｍｍｏｌ）、及び、サルファートリオキシド－ピリジンコンプレックス（８２ｍｇ，０．５２５ｍｍｏｌ）を加え、同温にて１時間、室温にて終夜撹拌した。反応液に水を加え、塩化メチレン（×３）で抽出し、無水硫酸ナトリウムで乾燥した。減圧下、溶剤を留去して、粗製の標記目的化合物（２１８ｍｇ、ジメチルスルホキシド含有）を黄色油状物として得た。
1H NMR (CDCl3, 400MHz): δ 1.40-1.42 (1H, m), 1.47-1.50 (1H, m), 1.99-2.05 (2H, m), 2.74-2.86 (2H, m), 3.04-3.13 (4H, m), 3.62 (2H, s), 3.75-3.84 (2H, m), 7.07 (1H, d, J = 7.8 Hz), 7.17 (1H, d, J = 7.8 Hz), 7.23-7.30 (9H, m), 7.65-7.70 (1H, m), 8.61-8.62 (2H, m), 9.68 (1H, s).
［実施例８ｅ］Ｎ－（２－｛［２－（４－｛２－［（３Ｓ）－３－（２－アミノ－２－オキソ－１，１－ジフェニルエチル）ピロリジン－１－イル］エチル｝フェニル）エチル］アミノ｝エチル）－２－｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝－Ｎ－メチルアセタミド
　実施例８ｄで得られた化合物（５０ｍｇ，０．１１７ｍｍｏｌ）、及び、実施例８ｂで得られた化合物（８８ｍｇ，０．１１７ｍｍｏｌ）を１，２－ジクロロエタン（３ｍＬ）－メタノール（０．５ｍＬ）に溶解し、水素化トリアセトキシホウ素ナトリウム（５０ｍｇ，０．２３４ｍｍｏｌ）を加え、室温にて３時間撹拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：２－０：１００）を用いて精製し、標記目的化合物（２０ｍｇ，収率１５％）を白色固体として得た。
MS (FAB) m/z: 1161(M+H)+.
IR(KBr) νmax 2929, 2802, 1677, 1511, 1444, 1358, 1281, 1139, 757, 702 cm-1。 [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. , 1.05 mmol) and stirred at the same temperature for 5.5 hours. Further, dimethyl sulfoxide (75 μL, 1.05 mmol), N, N-diisopropylethylamine (92 μL, 0.525 mmol), and sulfur trioxide-pyridine complex (82 mg, 0.525 mmol) were added to the reaction solution at the same temperature. Stir for 1 hour at room temperature overnight. Water was added to the reaction solution, extracted with methylene chloride (x3), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the crude title compound (218 mg, containing dimethyl sulfoxide) as a yellow oil.
1 H NMR (CDCl 3 , 400 MHz): δ 1.40-1.42 (1H, m), 1.47-1.50 (1H, m), 1.99-2.05 (2H, m), 2.74-2.86 (2H, m), 3.04-3.13 (4H, m), 3.62 (2H, s), 3.75-3.84 (2H, m), 7.07 (1H, d, J = 7.8 Hz), 7.17 (1H, d, J = 7.8 Hz), 7.23-7.30 ( 9H, m), 7.65-7.70 (1H, m), 8.61-8.62 (2H, m), 9.68 (1H, s).
[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 (3 mL) -methanol (0.5 mL), Hydrogenated triacetate Judicial sodium hydrogen (50 mg, 0.234 mmol) and the mixture was stirred for 3 hours at room temperature. 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. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using NH silica gel column chromatography (hexane: ethyl acetate = 1: 2-0: 100) to give the title object compound (20 mg, 15% yield) was obtained as a white solid.
MS (FAB) m / z: 1161 (M + H) + .
IR (KBr) ν max 2929, 2802, 1677, 1511, 1444, 1358, 1281, 1139, 757, 702 cm −1 .
　［実施例９］
Ｎ－（３，３，３－トリフェニルプロパノイル）グリシル－Ｎ－（｛１－［６－（｛４－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）（メチル）アミノ］ブタノイル｝アミノ）ヘキシル］ピペリジン－３－イル｝メチル）－β－アラニンアミド [Example 9]
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 [indene-1, 4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butanoyl} amino) hexyl] piperidin-3-yl} methyl) -β-alaninamide
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
［実施例９ａ］Ｎ－（３，３，３－トリフェニルプロパノイル）グリシル－Ｎ－（ピペリジン－３－イルメチル）－β－アラニンアミド
　ｔｅｒｔ－ブチル　（３Ｓ）－３－（アミノメチル）ピペリジン－１－カルボン酸エステルに代えて、ｔｅｒｔ－ブチル　３－（アミノメチル）ピペリジン－１－カルボン酸エステル（１．１ｇ、　５．２ｍｍｏｌ）を用いて、ＥＰ１２１３２８１　Ａ１（２００２／０６／１２）に記載した方法に従い、標記目的化合物（２０３ｍｇ、収率４３％）を白色固体として得た。
MS (ESI) : m/z 527 ((M + H )+) ; (フリー体).
［実施例９ｂ］Ｎ－（３，３，３－トリフェニルプロパノイル）グリシル－Ｎ－［（１－｛６－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］ヘキシル｝ピペリジン－３－イル）メチル］－β－アラニンアミド
　実施例９ａで得られたＮ－（３，３，３－トリフェニルプロパノイル）グリシル－Ｎ－（ピペリジン－３－イルメチル）－β－アラニンアミド（２０３ｍｇ、０．３９ｍｍｏｌ）をアセトニトリル（５ｍＬ）に溶解し、室温にて既知化合物６－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］ヘキシル　メタンスルホネート（２８７ｍｇ、０．９６ｍｍｏｌ）（Ｏｒｇａｎｉｃ　Ｌｅｔｔｅｒｓ、Ｖｏｌ．４、Ｎｏ．５、２００２；７３７－７４０）、ヨウ化カリウム（６４ｍｇ、０．３９ｍｍｏｌ）を加え、窒素雰囲気下、５０度で１６時間攪拌した。反応終了後、水を加え、更に酢酸エチルを加えて分液した。得られた有機層を分離し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下、溶剤を留去した。残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル―酢酸エチル：メタノール、１：５）を用いて精製し、標記目的化合物（１９２ｍｇ、収率６９％）を白色固体として得た。
MS (FAB) : m/z 726 ((M + H )+) ;
IR(KBr) νmax  3313, 2932, 1655, 1531, 1446, 1365, 1246, 1171, 753, 702 cm-1.
［実施例９ｃ］Ｎ－（３，３，３－トリフェニルプロパノイル）グリシル－Ｎ－｛［１－（６－アミノヘキシル）ピペリジン－３－イル］メチル｝－β－アラニンアミド　二塩酸塩
　実施例９ｂで得られた化合物（１９２ｍｇ、０．２６ｍｍｏｌ）をエタノール（２ｍＬ）に溶解し氷冷下、４規定塩酸／１，４－ジオキサン溶液（２ｍＬ）を加え、窒素雰囲気下、室温にて４．５時間攪拌した。反応終了後、減圧下、溶剤を留去した。氷冷下にて酢酸エチルを加え、更に飽和重曹水を加え中和し分液した。得られた有機層を分離し、粗製の標記目的化合物（１８３ｍｇ）を薄黄色固体として得た。 [Example 9a] N- (3,3,3-triphenylpropanoyl) glycyl-N- (piperidin-3-ylmethyl) -β-alaninamide tert-butyl (3S) -3- (aminomethyl) piperidine- Described in EP12132281 A1 (2002/06/12) using tert-butyl 3- (aminomethyl) piperidine-1-carboxylic acid ester (1.1 g, 5.2 mmol) instead of 1-carboxylic acid ester According to the method, the title object compound (203 mg, yield 43%) was obtained as a white solid.
MS (ESI): m / z 527 ((M + H) + ); (free).
[Example 9b] N- (3,3,3-triphenylpropanoyl) glycyl-N-[(1- {6-[(tert-butoxycarbonyl) amino] hexyl} piperidin-3-yl) methyl]- β-alaninamide N- (3,3,3-triphenylpropanoyl) glycyl-N- (piperidin-3-ylmethyl) -β-alaninamide (203 mg, 0.39 mmol) obtained in Example 9a was acetonitrile. (5 mL) and dissolved at room temperature with the known compound 6-[(tert-butoxycarbonyl) amino] hexyl methanesulfonate (287 mg, 0.96 mmol) (Organic Letters, Vol. 4, No. 5, 2002; 737-740 ), Potassium iodide (64 mg, 0.39 mmol) was added, and the mixture was added at 50 ° C. under 16 atmospheres. Stir for hours. After completion of the reaction, water was added, and ethyl acetate was further added for liquid separation. The obtained organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-ethyl acetate: methanol, 1: 5) to obtain the title object compound (192 mg, yield 69%) as a white solid.
MS (FAB): m / z 726 ((M + H) + );
IR (KBr) νmax    3313, 2932, 1655, 1531, 1446, 1365, 1246, 1171, 753, 702 cm -1 .
[Example 9c] N- (3,3,3-triphenylpropanoyl) glycyl-N-{[1- (6-aminohexyl) piperidin-3-yl] methyl} -β-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.
　［実施例９ｄ］メチル　４－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）（メチル）アミノ］ブタノエート
　実施例６ｉで得られた化合物（１５０ｍｇ、０．２２ｍｍｏｌ）を、ジクロロメタン（５ｍＬ）に溶解し、氷冷下、トリエチルアミン（７２μＬ、０．５２ｍｍｏｌ）、塩化ピバロイル（２７μＬ、０．２２ｍｍｏｌ）を加え、窒素雰囲気下、同温にて１５分攪拌した。続いて氷冷下、既知化合物メチル　４－（メチルアミノ）ブタン酸エステル　塩酸塩（４４ｍｇ、０．２６ｍｍｏｌ）（ＵＳ５８８６１４３　Ａ１　（１９９９／０３／２３））を加え、窒素雰囲気下、室温で２日間攪拌した。反応終了後、飽和重曹水を加え、更に酢酸エチルを加えて分液した。得られた有機層を分離し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下、溶剤を留去した。残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、１：５）を用いて精製し、標記目的化合物（１３３ｍｇ、収率７６％）を白色固体として得た。
［実施例９ｅ］４－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）（メチル）アミノ］ブタン酸
　実施例９ｄで得られた化合物（１３３ｍｇ、０．１６ｍｍｏｌ）をエタノール（５ｍＬ）に溶解し、氷冷下、１規定水酸化ナトリウム水溶液（０．３３ｍＬ、０．３３ｍｍｏｌ）を加え、室温で３．５時間攪拌した。反応終了後、減圧下、エタノールを留去した後、１規定塩酸水溶液（０．３３ｍＬ、０．３３ｍｍｏｌ）を加え、更に酢酸エチルを加えて分液した。得られた有機層を分離し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下、溶剤を留去し、粗製の標記目的化合物（１１４ｍｇ、収率８７％）を白色固体として得た。
［実施例９ｆ］Ｎ－（３，３，３－トリフェニルプロパノイル）グリシル－Ｎ－（｛１－［６－（｛４－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）（メチル）アミノ］ブタノイル｝アミノ）ヘキシル］ピペリジン－３－イル｝メチル）－β－アラニンアミド
　実施例９ｅで得られた化合物（１１４ｍｇ、０．１４ｍｍｏｌ）を、ジクロロメタン（５ｍＬ）に溶解し、氷冷下、トリエチルアミン（１００μＬ、０．７２ｍｍｏｌ）、塩化ピバロイル（１８μＬ、０．１４ｍｍｏｌ）を加え、窒素雰囲気下、同温にて１５分攪拌した。続いて氷冷下、実施例９ｃで合成したＮ－（３，３，３－トリフェニルプロパノイル）グリシル－Ｎ－｛［１－（６－アミノヘキシル）ピペリジン－３－イル］メチル｝－β－アラニンアミド　二塩酸塩（１８３ｍｇ、０．２７ｍｍｏｌ）を加え、窒素雰囲気下、室温で１８時間攪拌した。反応終了後、飽和重曹水を加え、更に酢酸エチルを加えて分液した。得られた有機層を分離し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下、溶剤を留去した。残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル―酢酸エチル：メタノール、１：５）を用いて精製後、逆相分取カラムクロマトグラフィー（ＸＴｅｒｒａ　Ｐｒｅｐ　ＭＳ　Ｃ１８　ＯＢＤ　５μｍ　３０Φ　ｘ　１００ｍｍ）（アセトニトリル：０．１％酢酸アンモニウム水溶液、５０：５０－アセトニトリル）で精製し、標記目的化合物（５３ｍｇ、収率２６％）を白色固体として得た。
MS (FAB) : m/z 1401 (M+H)+
IR(KBr) νmax  3314, 2931, 1650, 1511, 1359, 1281, 1181, 1139, 757, 702 cm-1。 [Example 9d] Methyl 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] butanoate The compound obtained in Example 6i (150 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (72 μL, 0.52 mmol) and pivaloyl chloride (27 μL, 0.22 mmol) were added under ice-cooling. The mixture was stirred at the same temperature for 15 minutes under the atmosphere. Subsequently, the known compound methyl 4- (methylamino) butanoate hydrochloride (44 mg, 0.26 mmol) (US5886143 A1 (1999/03/23)) was added under ice cooling, and the mixture was stirred at room temperature for 2 days under a nitrogen atmosphere. did. After completion of the reaction, saturated aqueous sodium hydrogen carbonate was added, and ethyl acetate was further added to separate the layers. The obtained organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate, 1: 5) to give the title object compound (133 mg, yield 76%) as a white 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. Stir for hours. After completion of the reaction, ethanol was distilled off under reduced pressure, 1N aqueous hydrochloric acid solution (0.33 mL, 0.33 mmol) was added, and ethyl acetate was further added to separate the layers. The obtained organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the crude title object compound (114 mg, yield 87%) as a white solid. It was.
[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) -β-alaninamide obtained in Example 9e The compound (114 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), triethylamine (100 μL, 0.72 mmol) and pivaloyl chloride (18 μL, 0.14 mmol) were added under ice cooling, and nitrogen was added. Under 囲気, and the mixture was stirred for 15 minutes at the same temperature. Subsequently, N- (3,3,3-triphenylpropanoyl) glycyl-N-{[1- (6-aminohexyl) piperidin-3-yl] methyl} -β synthesized in Example 9c under ice cooling -Alaninamide dihydrochloride (183 mg, 0.27 mmol) was added and stirred at room temperature for 18 hours under a nitrogen atmosphere. After completion of the reaction, saturated aqueous sodium hydrogen carbonate was added, and ethyl acetate was further added to separate the layers. The obtained organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified using NH silica gel column chromatography (ethyl acetate-ethyl acetate: methanol, 1: 5), and then reverse phase preparative column chromatography (XTerra Prep MS C18 OBD 5 μm 30Φ x 100 mm) (acetonitrile: 0.1 % Aqueous ammonium acetate, 50: 50-acetonitrile) to give the title object compound (53 mg, 26% yield) as a white solid.
MS (FAB): m / z 1401 (M + H) +
IR (KBr) νmax    3314, 2931, 1650, 1511, 1359, 1281, 1181, 1139, 757, 702 cm -1 .
　［実施例１０］
（３Ｒ）－１－｛８－［｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝（メチル）アミノ］オクト－６－イン－１－イル｝ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート [Example 10]
(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
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
［実施例１０ａ］８－｛［ｔｅｒｔ－ブチル（ジフェニル）シリル］オキシ｝オクト－２－イン－１－オール
　ｔｅｒｔ－ブチル（ヘプト－６－イン－１－イルオキシ）ジフェニルシラン（１２．７ｇ、３６．２ｍｍｏｌ）（Ｔｅｔｒａｈｅｄｒｏｎ、６１、５、２００５、１１２７－１１４０）をテトラヒドロフラン（１８０ｍＬ）に溶解し、－７８度にて２．６７規定ノルマルブチルリチウム／へキサン溶液（１６．３ｍＬ、４３．５ｍｍｏｌ）を滴下し、窒素雰囲気下、同温にて１時間攪拌した。その後、パラホルムアルデヒド（３．５ｇ、０．１０９ｍｏｌ）を加え１．５時間かけて室温まで昇温した。反応終了後、飽和塩化アンモニウム水を加え、更に酢酸エチルを加えて分液した。得られた有機層を分離し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下、溶剤を留去した。残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、５：１）を用いて精製し、標記化合物（１１．５ｇ、収率８４％）を無色油状物質として得た。
［実施例１０ｂ］８－｛［ｔｅｒｔ－ブチル（ジフェニル）シリル］オキシ｝オクト－２－イン－１－イル　メタンスルホネート
　実施例１０ａで得られた８－｛［ｔｅｒｔ－ブチル（ジフェニル）シリル］オキシ｝オクト－２－イン－１－オール（７００ｍｇ、１．８ｍｍｏｌ）を塩化メチレン（１０ｍＬ）に溶解し氷冷下、トリエチルアミン（０．３９ｍＬ、２．８ｍｍｏｌ）、塩化メタンスルホニル（０．２１ｍＬ、２．８ｍｍｏｌ）を加え、窒素雰囲気下、同温にて１．２時間攪拌した。反応終了後、飽和重曹水を加え、更に酢酸エチルを加えて分液した。得られた有機層を分離し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下、溶剤を留去して、粗製の標記化合物（７５０ｍｇ）を得た。
［実施例１０ｃ］２－［３，５－ビス（トリフルオロメチル）フェニル］－Ｎ－｛６－［（８－｛［ｔｅｒｔ－ブチル（ジフェニル）シリル］オキシ｝オクト－２－イン－１－イル）（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－３－イル｝－Ｎ，２－ジメチルプロパンアミド
　実施例１ｅで合成した化合物（３００ｍｇ、０．５５ｍｍｏｌ）をＮ，Ｎ－ジメチルアセトアミド（６ｍＬ）に溶解し、室温下、実施例１０ｂで合成した８－｛［ｔｅｒｔ－ブチル（ジフェニル）シリル］オキシ｝オクト－２－イン－１－イル　メタンスルホネート（７５０ｍｇ、１．６４ｍｍｏｌ）、炭酸カリウム（２２６ｍｇ、１．６４ｍｍｏｌ）及びヨウ化カリウム（１０９ｍｇ、０．６７ｍｍｏｌ）を加え、窒素雰囲気下、７０度で１７時間攪拌した。反応終了後、飽和重曹水を加え、更に酢酸エチルを加えて分液した。得られた有機層を分離し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下、溶剤を留去した。残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、５：１）を用いて精製し、標記化合物（３２０ｍｇ、収率６７％）を無色油状物質として得た。 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. Thereafter, paraformaldehyde (3.5 g, 0.109 mol) was added and the temperature was raised to room temperature over 1.5 hours. After completion of the reaction, saturated aqueous ammonium chloride was added, and ethyl acetate was further added for liquid separation. The obtained organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate, 5: 1) to obtain the title compound (11.5 g, yield 84%) as a colorless oily substance.
[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. After completion of the reaction, saturated aqueous sodium hydrogen carbonate was added, and ethyl acetate was further added to separate the layers. The obtained organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the crude title compound (750 mg).
[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 degrees for 17 hours. It was 拌. After completion of the reaction, saturated aqueous sodium hydrogen carbonate was added, and ethyl acetate was further added to separate the layers. The obtained organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate, 5: 1) to obtain the title compound (320 mg, yield 67%) as a colorless oily substance.
　［実施例１０ｄ］２－［３，５－ビス（トリフルオロメチル）フェニル］－Ｎ－｛６－［（８－ヒドロキシオクト－２－イン－１－イル）（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－３－イル｝－Ｎ，２－ジメチルプロパンアミド
　実施例１０ｃで得られた化合物（３２０ｍｇ、０．３７ｍｍｏｌ）をテトラヒドロフラン（５ｍＬ）に溶解し、氷冷下、１．０Ｍテトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（０．５５ｍＬ，０．５５ｍｏｌ）を加え、窒素雰囲気下、室温で１時間攪拌した。反応終了後、氷冷下、反応液に飽和塩化アンモニウム水を加え、更に酢酸エチルを加えて分液した。得られた有機層を分離し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下、溶剤を留去した。シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、３：２）を用いて精製し、標記化合物（１９３ｍｇ、収率８３％）を無色油状物質として得た。
MS (FAB) : m/z 634 ((M + H )+) ; (フリー体)
IR (Thin Film) νmax  2936, 1597, 1500, 1398, 1373, 1281, 1185, 1138, 1082, 756 cm-1.
［実施例１０ｅ］（３Ｒ）－１－｛８－［｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝（メチル）アミノ］オクト－６－イン－１－イル｝ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート
　実施例１０ｄで得られた化合物（１８０ｍｇ、０．２８ｍｍｏｌ）を酢酸エチル（５ｍＬ）に溶解し、氷冷下、トリエチルアミン（６０μＬ、０．４３ｍｍｏｌ）、塩化メタンスルホニル（３３μＬ、０．４３ｍｍｏｌ）を加え、窒素雰囲気下、同温にて１．２時間攪拌した。その後、反応液をろ過し、減圧濃縮して得られた残渣をＮ，Ｎ－ジメチルアセトアミド（５ｍＬ）に溶解し、室温下、実施例１ｉで合成した（３Ｒ）－ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート（１７６ｍｇ、０．５９ｍｍｏｌ）、炭酸水素ナトリウム（４８ｍｇ、０．５７ｍｍｏｌ）及びヨウ化カリウム（５７ｍｇ、０．３４１ｍｍｏｌ）を加え、窒素雰囲気下、７０度で２時間攪拌した。反応終了後、飽和重曹水を加え、更に酢酸エチルを加えて分液した。得られた有機層を分離し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下、溶剤を留去した。残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、１：１）を用いて精製後、逆相分取カラムクロマトグラフィー（Ｉｎｅｒｔｓｉｌ　ＯＤＳ－３、３．０ｃｍ×２５ｃｍ）（アセトニトリル：０．１％酢酸アンモニウム水溶液、５０：５０－１００：０）で精製し、標記目的化合物（１１２ｍｇ、収率４３％）を白色固体として得た。
MS (FAB) : m/z 925 ((M + H )+) ; (フリー体)
IR(KCl) νmax  2934, 1737, 1650, 1596, 1499, 1372, 1281, 1184, 1136, 1081 cm-1。 [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. After completion of the reaction, saturated aqueous ammonium chloride was added to the reaction mixture under ice cooling, and ethyl acetate was further added to separate the layers. The obtained organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Purification using silica gel column chromatography (hexane: ethyl acetate, 3: 2) gave the title compound (193 mg, 83% yield) as a colorless oil.
MS (FAB): m / z 634 ((M + H) + ); (free)
IR   (Thin Film) νmax    2936, 1597, 1500, 1398, 1373, 1281, 1185, 1138, 1082, 756 cm -1 .
[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) was dissolved in ethyl acetate (5 mL), and triethylamine (60 μL, 0.43 mmol) and methanesulfonyl chloride (33 μL, 0.43 mmol) were added under ice-cooling. Stir for 1.2 hours. Thereafter, the reaction solution was filtered, and the residue obtained by concentration under reduced pressure was dissolved in N, N-dimethylacetamide (5 mL), and (3R) -pyrrolidin-3-yl hydroxy synthesized in Example 1i at room temperature ( Dithiophen-2-yl) acetate (176 mg, 0.59 mmol), sodium bicarbonate (48 mg, 0.57 mmol) and potassium iodide (57 mg, 0.341 mmol) were added, and the mixture was stirred at 70 ° C. for 2 hours under a nitrogen atmosphere. . After completion of the reaction, saturated aqueous sodium hydrogen carbonate was added, and ethyl acetate was further added to separate the layers. The obtained organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified using NH silica gel column chromatography (hexane: ethyl acetate, 1: 1) and then reverse phase preparative column chromatography (Inertsil ODS-3, 3.0 cm × 25 cm) (acetonitrile: 0.1% acetic acid). Purification with aqueous ammonium solution (50: 50-100: 0) gave the title object compound (112 mg, 43% yield) as a white solid.
MS (FAB): m / z 925 ((M + H) + ); (free body)
IR (KCl) νmax    2934, 1737, 1650, 1596, 1499, 1372, 1281, 1184, 1136, 1081 cm -1 .
　［実施例１１］
（３Ｒ）－１－［２－（４－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝ピペラジン－１－イル）エチル］ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート [Example 11]
(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
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
［実施例１１ａ］２－［３，５－ビス（トリフルオロメチル）フェニル］－Ｎ－｛６－［４－（２－ヒドロキシエチル）ピペラジン－１－イル］－４－（２－メチルフェニル）ピリジン－３－イル｝－Ｎ，２－ジメチルプロパンアミド
　文献（ＵＳ２００３／４１５７　Ａ１）に記載されている２－［３，５－ビス（トリフルオロメチル）フェニル］－Ｎ，２－ジメチル－Ｎ－［４－（２－メチルフェニル）－６－（ピペラジン－１－イル）ピリジン－３－イル］プロパンアミド（１５０ｍｇ，０．２６６ｍｍｏｌ）をアセトニトリル（３ｍＬ）に溶解し、炭酸カリウム（４５ｍｇ，０．３２０ｍｍｏｌ）、及び、２－ブロモエタノール（２４μＬ，０．３２０ｍｍｏｌ）を加えた後、６０℃にて１８時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲル分取薄層クロマトグラフィー（塩化メチレン：メタノール＝２０：１）を用いて精製し、標記目的化合物（１２１ｍｇ，収率７５％）を黄色油状物として得た。
MS (FAB) m/z: 609(M+H)+.
IR(KBr) νmax 1649, 1596, 1487, 1373, 1281, 1185, 1137, 1082, 896, 683 cm-1.
［実施例１１ｂ］（３Ｒ）－１－［２－（４－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝ピペラジン－１－イル）エチル］ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート
　実施例１１ａで得られた化合物（９２ｍｇ，０．１５１ｍｍｏｌ）を酢酸エチル（２ｍＬ）に溶解し、氷冷下、トリエチルアミン（２５μＬ，０．１８１ｍｍｏｌ）、及び、塩化メタンスルホニル（１３μＬ，０．１６６ｍｍｏｌ）を加えた後、同温にて２時間攪拌した。不溶物をセライトでろ過し、減圧下、溶剤を留去して得られた残渣をアセトニトリル（４ｍＬ）に溶解し、実施例１ｉで得られた（３Ｒ）－ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート（４７ｍｇ，０．１５１ｍｍｏｌ）、炭酸カリウム（２５ｍｇ，０．１８１ｍｍｏｌ）、及び、ヨウ化カリウム（２３ｍｇ，０．１５１ｍｍｏｌ）を加えた後、６０℃にて１０時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲル分取薄層クロマトグラフィー（塩化メチレン：メタノール＝２０：１）を用いて精製し、標記目的化合物（６５ｍｇ，収率４８％）を褐色固体として得た。
MS (FAB) m/z: 900(M+H)+.
IR(KBr) νmax  1738, 1651, 1596, 1486, 1372, 1281, 1184, 1137, 896, 708 cm-1。 [Example 11a] 2- [3,5-bis (trifluoromethyl) phenyl] -N- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4- (2-methylphenyl) Pyridin-3-yl} -N, 2-dimethylpropanamide 2- [3,5-bis (trifluoromethyl) phenyl] -N, 2-dimethyl-N— described in the literature (US2003 / 4157 A1) [4- (2-Methylphenyl) -6- (piperazin-1-yl) pyridin-3-yl] propanamide (150 mg, 0.266 mmol) was dissolved in acetonitrile (3 mL) and potassium carbonate (45 mg,. 320 mmol) and 2-bromoethanol (24 μL, 0.320 mmol) were added, followed by stirring at 60 ° C. for 18 hours. 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, and the resulting residue was purified using preparative thin layer chromatography on silica gel (methylene chloride: methanol = 20: 1) to give the title object compound (121 mg , Yield 75%) as a yellow oil.
MS (FAB) m / z: 609 (M + H) + .
IR (KBr) ν max 1649, 1596, 1487, 1373, 1281, 1185, 1137, 1082, 896, 683 cm -1 .
[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 μL, 0.181 mmol) and methanesulfonyl chloride (13 μL, 0.166 mmol) were added under ice cooling, followed by stirring at the same temperature for 2 hours. The insoluble material was filtered through celite, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in acetonitrile (4 mL). The (3R) -pyrrolidin-3-yl hydroxy (dithiophene-) obtained in Example 1i 2-yl) acetate (47 mg, 0.151 mmol), potassium carbonate (25 mg, 0.181 mmol), and potassium iodide (23 mg, 0.151 mmol) were added, and the mixture was stirred at 60 ° C. for 10 hours. 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, and the resulting residue was purified using preparative thin layer chromatography on silica gel (methylene chloride: methanol = 20: 1) to give the title object compound (65 mg , Yield 48%) as a brown solid.
MS (FAB) m / z: 900 (M + H) + .
IR (KBr) ν max 1738, 1651, 1596, 1486, 1372, 1281, 1184, 1137, 896, 708 cm −1 .
　［実施例１２］
（３Ｒ）－１－［３－（４－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝ピペラジン－１－イル）－３－オキソプロピル］ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート [Example 12]
(3R) -1- [3- (4- {5-[{2- [3,5-Bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino] -4- (2- Methylphenyl) pyridin-2-yl} piperazin-1-yl) -3-oxopropyl] pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
［実施例１２ａ］２－［３，５－ビス（トリフルオロメチル）フェニル］－Ｎ－｛６－［４－（３－クロロプロパノイル）ピペラジン－１－イル］－４－（２－メチルフェニル）ピリジン－３－イル｝－Ｎ，２－ジメチルプロパンアミド
　文献（ＵＳ２００３／４１５７　Ａ１）に記載されている２－［３，５－ビス（トリフルオロメチル）フェニル］－Ｎ，２－ジメチル－Ｎ－［４－（２－メチルフェニル）－６－（ピペラジン－１－イル）ピリジン－３－イル］プロパンアミド（２００ｍｇ，０．３５４ｍｍｏｌ）を塩化メチレン（４ｍＬ）に溶解し、トリエチルアミン（５９μＬ，０．４２５ｍｍｏｌ）、及び、３－クロロプロパノイル　クロリド（４１μＬ，０．３９０ｍｍｏｌ）を加えた後、室温にて終夜攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲル分取薄層クロマトグラフィー（塩化メチレン：メタノール＝３０：１）を用いて精製し、標記目的化合物（２０３ｍｇ，収率８８％）を白色固体として得た。
1H NMR (CDCl3, 400MHz): δ 1.34 (6H, brs), 1.48-1.51 (1H, m), 2.11-2.15 (2H, m), 2.31-2.35 (2H, m), 2.53-2.58 (1H, m), 2.86 (2H, t, J = 7.0 Hz), 3.52-3.54 (2H, m), 3.61-3.63 (2H, m), 3.68-3.69 (2H, m), 3.76-3.78 (2H, m), 3.86 (2H, t, J = 7.0 Hz), 6.52 (1H, brs), 7.25-7.29 (4H, m), 7.66 (2H, brs), 7.76 (1H, s), 8.02 (1H, s).
MS (FAB) m/z: 655(M+H)+.
［実施例１２ｂ］（３Ｒ）－１－［３－（４－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝ピペラジン－１－イル）－３－オキソプロピル］ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート
　実施例１２ａで得られた化合物（２０３ｍｇ，０．３１０ｍｍｏｌ）をアセトニトリル（６ｍＬ）に溶解し、実施例１ｉで得られた（３Ｒ）－ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート（９６ｍｇ，０．３１０ｍｍｏｌ）、炭酸カリウム（５２ｍｇ，０．３７２ｍｍｏｌ）、及び、ヨウ化ナトリウム（４７ｍｇ，０．３１０ｍｍｏｌ）を加えた後、６０℃にて１０時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧下、溶剤を留去して得られた残渣をシリカゲル分取薄層クロマトグラフィー（塩化メチレン：メタノール＝２０：１）を用いて精製し、標記目的化合物（１１２ｍｇ，収率３９％）を褐色固体として得た。
MS (FAB) m/z: 928(M+H)+.
IR(KBr) νmax  1740, 1648, 1485, 1439, 1373, 1282, 1229, 1184, 1136, 708 cm-1。 [Example 12a] 2- [3,5-bis (trifluoromethyl) phenyl] -N- {6- [4- (3-chloropropanoyl) piperazin-1-yl] -4- (2-methylphenyl) ) Pyridin-3-yl} -N, 2-dimethylpropanamide 2- [3,5-bis (trifluoromethyl) phenyl] -N, 2-dimethyl-N described in the literature (US2003 / 4157 A1) -[4- (2-Methylphenyl) -6- (piperazin-1-yl) pyridin-3-yl] propanamide (200 mg, 0.354 mmol) was dissolved in methylene chloride (4 mL) and triethylamine (59 μL, 0 .425 mmol) and 3-chloropropanoyl chloride (41 μL, 0.390 mmol) were added, and the mixture was stirred at room temperature overnight. 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, and the resulting residue was purified using preparative thin layer chromatography on silica gel (methylene chloride: methanol = 30: 1) to give the title object compound (203 mg , Yield 88%) as a white solid.
1 H NMR (CDCl 3 , 400 MHz): δ 1.34 (6H, brs), 1.48-1.51 (1H, m), 2.11-2.15 (2H, m), 2.31-2.35 (2H, m), 2.53-2.58 (1H , m), 2.86 (2H, t, J = 7.0 Hz), 3.52-3.54 (2H, m), 3.61-3.63 (2H, m), 3.68-3.69 (2H, m), 3.76-3.78 (2H, m ), 3.86 (2H, t, J = 7.0 Hz), 6.52 (1H, brs), 7.25-7.29 (4H, m), 7.66 (2H, brs), 7.76 (1H, s), 8.02 (1H, s) .
MS (FAB) m / z: 655 (M + H) + .
[Example 12b] (3R) -1- [3- (4- {5-[{2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino]- 4- (2-Methylphenyl) pyridin-2-yl} piperazin-1-yl) -3-oxopropyl] pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate Compound obtained in Example 12a (203 mg , 0.310 mmol) in acetonitrile (6 mL), (3R) -pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate (96 mg, 0.310 mmol), potassium carbonate ( 52 mg, 0.372 mmol) and sodium iodide (47 mg, 0.310 mmol) were added, and the mixture was stirred at 60 ° C. for 10 hours. It was. 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, and the resulting residue was purified using preparative thin layer chromatography on silica gel (methylene chloride: methanol = 20: 1) to give the title object compound (112 mg Yield 39%) as a brown solid.
MS (FAB) m / z: 928 (M + H) + .
IR (KBr) ν max 1740, 1648, 1485, 1439, 1373, 1282, 1229, 1184, 1136, 708 cm −1 .
　［実施例１３］
（３Ｒ）－１－（３－｛２－［｛５－［｛２－［３，５－ビス(トリフルオロメチル)フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン-２-イル｝（メチル）アミノ］エトキシ｝プロピル）ピロリジン-３-イル　ヒドロキシ（ジ－２－チエニル）アセテート [Example 13]
(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
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
［実施例１３ａ］２－［３，５－ビス(トリフルオロメチル)フェニル］－Ｎ－［６－｛［２－（３－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝プロポキシ）エチル］（メチル）アミノ｝－４－（２－メチルフェニル）ピリジン-３-イル］－Ｎ，２－ジメチルプロパンアミド
　２－［３，５－ビス(トリフルオロメチル)フェニル］－Ｎ－｛６－［（２－ヒドロキシエチル）（メチル）アミノ］－４－（２－メチルフェニル）ピリジン-３-イル｝－Ｎ，２－ジメチルプロパンアミド（３００ｍｇ、０．３６１ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド溶液（４ｍＬ）に水素化ナトリウム（３８ｍｇ、55% in oil、０．８６６ｍｍｏｌ）を加え、室温で２０分間撹拌した。（３－ブロモプロポキシ）（ｔｅｒｔ－ブチル）ジメチルシラン（２５０μＬ、１．０８ｍｍｏｌ）を加え、９０℃で４．５時間撹拌した。（３－ブロモプロポキシ）（ｔｅｒｔ－ブチル）ジメチルシラン（１６７μＬ、０．７２１ｍｍｏｌ）を追加し、９０℃で３時間撹拌した。反応液に酢酸エチルを加えて希釈したのち、水及び飽和食塩水で洗浄し、有機層を無水硫酸ナトリウムで乾燥した。溶剤を減圧留去して得られた残渣をシリカゲル分取薄層クロマトグラフィー（ｎ－ヘキサン：酢酸エチル＝４：１）で精製し、標記化合物（２４４ｍｇ、収率９３％）を無色油状物として得た。
1H NMR (CDCl3, 400MHz): δ 0.03 (6H, s), 0.88 (9H, s), 1.30-1.33 (4H, m), 1.48-1.51 (2H, m), 1.73-1.80 (2H, m), 2.13-2.15 (2H, m), 2.29-2.33 (2H, m), 2.55-2.58 (1H, m), 3.09 (3H, s), 3.51 (2H, t, J = 6.3Hz), 3.61-3.64 (2H, m), 3.68 (2H, t, J = 6.3Hz), 3.70-3.78 (2H, m), 3.79-3.86 (1H, m), 6.36 (1H, s), 7.21-7.31 (4H, m), 7.65-7.68 (2H, m), 7.75 (1H, s), 7.96 (1H, s).
［実施例１３ｂ］２－［３，５－ビス(トリフルオロメチル)フェニル］－Ｎ－［６－｛［２－（３－ヒドロキシプロポキシ）エチル］（メチル）アミノ｝－４－（２－メチルフェニル）ピリジン-３-イル］－Ｎ，２－ジメチルプロパンアミド
　実施例１３ａで得られた化合物（２４４ｍｇ、０．３３６ｍｍｏｌ）のテトラヒドロフラン溶液（４ｍＬ）に０．１Ｍ　テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（４０３μＬ）を加え、室温で３０分撹拌した。０．１Ｍ　テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（４０３μＬ）を追加し、室温で２０分撹拌した。反応液に水を加えた後、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶剤を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル＝２：１－１：２）で精製し、標記化合物（１８９ｍｇ、収率９２％）を白色固体として得た。
MS (FAB) m/z: 612(M+H)+.
IR(KBr) νmax 2931, 1651, 1597, 1505, 1373, 1282, 1184, 1136, 896, 683 cm-1.
［実施例１３ｃ］（３Ｒ）－１－（３－｛２－［｛５－［｛２－［３，５－ビス(トリフルオロメチル)フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン-２-イル｝（メチル）アミノ］エトキシ｝プロピル）ピロリジン-３-イル　ヒドロキシ（ジ－２－チエニル）アセテート
　実施例１３ｂで得られた化合物（１４２ｍｇ、０．２３２ｍｍｏｌ）及び実施例１ｉで得られた（３Ｒ）－ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート（５５ｍｇ，０．１７７ｍｍｏｌ）を用いて実施例３ｂに記載した方法に従い、標記化合物（９９ｍｇ，収率４７％）を白色固体として得た。
MS (FAB) m/z: 903(M+H)+.
IR(KBr) νmax 2934, 1738, 1651, 1597, 1505, 1373, 1282, 1136, 896, 708 cm-1。 [Example 13a] 2- [3,5-bis (trifluoromethyl) phenyl] -N- [6-{[2- (3-{[tert-butyl (dimethyl) silyl] oxy} propoxy) ethyl] ( Methyl) amino} -4- (2-methylphenyl) pyridin-3-yl] -N, 2-dimethylpropanamide 2- [3,5-bis (trifluoromethyl) phenyl] -N- {6-[( 2-hydroxyethyl) (methyl) amino] -4- (2-methylphenyl) pyridin-3-yl} -N, 2-dimethylpropanamide (300 mg, 0.361 mmol) in N, N-dimethylformamide (4 mL) ) Was added sodium hydride (38 mg, 55% in oil, 0.866 mmol), and the mixture was stirred at room temperature for 20 minutes. (3-Bromopropoxy) (tert-butyl) dimethylsilane (250 μL, 1.08 mmol) was added, and the mixture was stirred at 90 ° C. for 4.5 hours. (3-Bromopropoxy) (tert-butyl) dimethylsilane (167 μL, 0.721 mmol) was added, and the mixture was stirred at 90 ° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel preparative thin layer chromatography (n-hexane: ethyl acetate = 4: 1) to give the title compound (244 mg, yield 93%) as a colorless oil. Obtained.
1 H NMR (CDCl 3 , 400 MHz): δ 0.03 (6H, s), 0.88 (9H, s), 1.30-1.33 (4H, m), 1.48-1.51 (2H, m), 1.73-1.80 (2H, m ), 2.13-2.15 (2H, m), 2.29-2.33 (2H, m), 2.55-2.58 (1H, m), 3.09 (3H, s), 3.51 (2H, t, J = 6.3Hz), 3.61- 3.64 (2H, m), 3.68 (2H, t, J = 6.3Hz), 3.70-3.78 (2H, m), 3.79-3.86 (1H, m), 6.36 (1H, s), 7.21-7.31 (4H, m), 7.65-7.68 (2H, m), 7.75 (1H, s), 7.96 (1H, s).
[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 To 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 μL) was added and stirred at room temperature for 30 minutes. A 0.1 M tetrabutylammonium fluoride / tetrahydrofuran solution (403 μL) was added, and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1-1: 2) to obtain the title compound (189 mg, yield 92%) as a white solid.
MS (FAB) m / z: 612 (M + H) + .
IR (KBr) ν max 2931, 1651, 1597, 1505, 1373, 1282, 1184, 1136, 896, 683 cm -1 .
[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.
MS (FAB) m / z: 903 (M + H) + .
IR (KBr) ν max 2934, 1738, 1651, 1597, 1505, 1373, 1282, 1136, 896, 708 cm −1 .
　［実施例１４］
１－（２－｛[６－（｛４－[{３－[（Ｎ－{５－[｛２－[３，５－ビス（トリフルオロメチル）フェニル]－２－メチルプロパノイル｝（メチル）アミノ]－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル)アミノ]プロピル}（メチル）カルバモイル]フェニル}アミノ)ヘキサノイル]（メチル）アミノ｝エチル）ピペリジン－４－イル ビフェニル－２－イルカーバメート [Example 14]
1- (2-{[6-({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) hexanoyl] (methyl) amino} ethyl) piperidine- 4-yl biphenyl-2-yl carbamate
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
［実施例１４ａ］エチル Ｎ－{５－[{２－[３，５－ビス(トリフルオロメチル)フェニル]－２－メチルプロパノイル}(メチル)アミノ]－４－(２－メチルフェニル)ピリジン－２－イル}－Ｎ－メチルグリシネート
　実施例１ｅで得られた化合物（２．５０ｇ、４．９１ｍｍｏｌ）のトルエン溶液（４９ｍＬ）に氷冷撹拌下、０．５Ｍヘキサメチレンジシラザンカリウム／トルエン溶液（３９．３ｍＬ）を滴下し、室温で１０分間撹拌した。再氷冷後、ブロモ酢酸エチル（５．４４ｍＬ、４９．１ｍｍｏｌ）を滴下し、７５℃で４日間加熱撹拌した。反応液に水を加えたのち、酢酸エチルで抽出（２回）し、得られた有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥し、溶剤を減圧留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル＝６：１）及びシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル＝９：１－４：１）を用いて精製し、標記化合物（１．３５ｇ、４６％）を黄色油状物として得た。
1H NMR (CDCl3, 500MHz): δ 1.27 (3H, t, J = 7.5 Hz), 1.47-1.56 (6H, m), 2.12-2.16 (2H, m), 2.25-2.33 (3H, m), 2.53-2.57 (1H, m), 3.10 (3H, s), 3.66 (2H, s), 4.18 (2H, q, J = 7.5 Hz), 6.42 (1H, s), 7.23-7.28 (4H, m), 7.64-7.66 (2H, m), 7.75 (1H, s), 7.96 (1H, s).
MS (APCI) m/z: 596 (M+H)+.
［実施例１４ｂ］Ｎ－{５－[{２－[３，５－ビス(トリフルオロメチル)フェニル]－２－メチルプロパノイル}(メチル)アミノ]－４－(２－メチルフェニル)ピリジン－２－イル}－Ｎ－メチルグリシン
　実施例１４ａで得られた化合物（１．３５ｇ、２．２７ｍｍol）のエタノール溶液(２３ｍＬ)に１規定水酸化ナトリウム水溶液（６．８０ｍＬ）を加え、室温で１．５時間撹拌した。反応液に１規定塩酸水溶液（６．８０ｍＬ）を加えたのち、エタノールを減圧留去した。ジクロロメタンを加えて抽出したのち、無水硫酸ナトリウムで乾燥した。溶剤を減圧乾固し、粗製の標記化合物（１．０５ｇ、収率８１％）を黄緑固体として得た。
1H NMR (CDCl3, 500MHz): δ 1.18-1.38 (6H, m), 2.12-2.27 (4H, m), 2.34-2.38 (1H, m), 2.55-2.61 (1H, m), 3.15 (3H, s), 4.19-4.23 (1H, m), 4.38-4.43 (1H, m), 6.54 (1H, s), 7.23-7.27 (3H, m), 7.31-7.34 (1H, m), 7.63 (2H, s), 7.76 (1H, s), 7.95 (1H, s).
MS (APCI) m/z: 568 (M+H)+.
［実施例１４ｃ］Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシン　一塩酸塩
　実施例１４ｂで得られた化合物（５０ｍｇ、０．０８８１ｍｍol）のジオキサン溶液（２ｍＬ）に氷冷下で4規定塩酸／ジオキサン溶液（６６μＬ）を加えた。反応液を減圧乾固し、粗製の標記化合物（４６ｍｇ、収率８７％）を青色固体として得た。
MS (FAB) m/z: 568(M+H)+.(フリー体)
IR(KBr) νmax 2981, 1734, 1648, 1471, 1373, 1282, 1185, 1136, 897, 683 cm-1.
　［実施例１４ｄ］ｔｅｒｔ－ブチル　４－［（６－エトキシ－６－オキソヘキシル）アミノ］ベンゾエート
　６－ブロモヘキサン酸エチル（５．５５ｇ、２４．９ｍｍｏｌ）と４－アミノ安息香酸ｔｅｒｔ－ブチル（４．３７ｇ、２２．６ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（２３ｍＬ）に溶解し、Ｎ，Ｎ－ジイソプロピルエチルアミン（４．７２ｍＬ、２７．１ｍｍｏｌ）及びヨウ化カリウム（４．１３ｇ、２４．９ｍｍｏｌ）を加えて、６５℃で４日間攪拌した。反応液に酢酸エチルを加えて希釈したのち、水及び飽和食塩水で洗浄し、得られた有機層を無水硫酸マグネシウムで乾燥した。溶剤を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル＝９：１－１：１）で精製し、標記化合物（５．６１ｇ、収率７４％）を白色固体として得た。
1H NMR (CDCl3, 500 MHz): δ1.26 (2H, t, J=7.32 Hz), 1.39-1.48 (2H, m), 1.56 (9H, s), 1.59-1.73 (4H, m), 2.32 (2H, t, J=7.32 Hz), 3.17 (2H, t, J=7.08 Hz), 4.04 (1H, s), 4.13 (2H, q, J=7.00 Hz), 6.52 (2H, d, J=8.79 Hz), 7.81 (2H, d, J=8.79 Hz). 
MS (FAB) m/z: 335 (M)+;
IR (KBr) νmax 3385, 1727, 1682, 1602, 1288, 1269, 1158, 1113, 842, 772 cm-1.
［実施例１４ｅ］ｔｅｒｔ－ブチル　４－（｛６－［（２－｛４－［（ビフェニル－２－イルカルバモイル）オキシ］ピペリジン－１－イル｝エチル）（メチル）アミノ］－６－オキソヘキシル｝アミノ）ベンゾエート
　実施例１４ｄで得られた化合物（３．５６ｇ、１０．６ｍｍｏｌ）のエタノール溶液（４０ｍＬ）に、１規定水酸化ナトリウム水溶液（１５．６ｍＬ）を加えて、５０℃で１．５時間攪拌した。酢酸エチル（２．０ｍＬ、１．５ｍｍｏｌ）を加えた後、反応液を減圧濃縮し、氷冷下で１規定塩酸水溶液（１６ｍＬ）を加えた。生じた沈殿をろ取し、水、ｎ－ヘキサン、及びジイソプピルエーテルで洗浄し、６－｛［４－（ｔｅｒｔ－ブトキシカルボニル）フェニル］アミノ｝ヘキサン酸（３．０１ｇ、収率９２％）を白色固体として得た。 [Example 14a] Ethyl N- {5-[{2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino] -4- (2-methylphenyl) pyridine -2-yl} -N-methylglycinate To a toluene solution (49 mL) of the compound obtained in Example 1e (2.50 g, 4.91 mmol) under stirring with ice-cooling, 0.5 M hexamethylene disilazane potassium / toluene The solution (39.3 mL) was added dropwise and stirred at room temperature for 10 minutes. After ice cooling again, ethyl bromoacetate (5.44 mL, 49.1 mmol) was added dropwise, and the mixture was heated with stirring at 75 ° C. for 4 days. Water was added to the reaction solution, followed by extraction with ethyl acetate (twice), and the resulting organic layer was washed with saturated brine. The residue obtained by drying with anhydrous sodium sulfate and evaporating the solvent under reduced pressure was subjected to NH silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) and silica gel column chromatography (n-hexane: ethyl acetate = 9). : 1-4: 1) to give the title compound (1.35 g, 46%) as a yellow oil.
1 H NMR (CDCl 3 , 500MHz): δ 1.27 (3H, t, J = 7.5 Hz), 1.47-1.56 (6H, m), 2.12-2.16 (2H, m), 2.25-2.33 (3H, m), 2.53-2.57 (1H, m), 3.10 (3H, s), 3.66 (2H, s), 4.18 (2H, q, J = 7.5 Hz), 6.42 (1H, s), 7.23-7.28 (4H, m) , 7.64-7.66 (2H, m), 7.75 (1H, s), 7.96 (1H, s).
MS (APCI) m / z: 596 (M + H) + .
[Example 14b] N- {5-[{2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino] -4- (2-methylphenyl) pyridine- 2-yl} -N-methylglycine To a solution of the compound obtained in Example 14a (1.35 g, 2.27 mmol) in ethanol (23 mL) was added 1N aqueous sodium hydroxide solution (6.80 mL), and the mixture was stirred at room temperature. Stir for 5 hours. A 1N aqueous hydrochloric acid solution (6.80 mL) was added to the reaction solution, and ethanol was evaporated under reduced pressure. Extraction was performed by adding dichloromethane, followed by drying over anhydrous sodium sulfate. The solvent was evaporated to dryness to give the crude title compound (1.05 g, 81% yield) as a yellow-green solid.
1 H NMR (CDCl 3 , 500MHz): δ 1.18-1.38 (6H, m), 2.12-2.27 (4H, m), 2.34-2.38 (1H, m), 2.55-2.61 (1H, m), 3.15 (3H , s), 4.19-4.23 (1H, m), 4.38-4.43 (1H, m), 6.54 (1H, s), 7.23-7.27 (3H, m), 7.31-7.34 (1H, m), 7.63 (2H , s), 7.76 (1H, s), 7.95 (1H, s).
MS (APCI) m / z: 568 (M + H) + .
[Example 14c] N- {5-[{2- [3,5-bis (trifluoromethyl) phenyl] -2-methylpropanoyl} (methyl) amino] -4- (2-methylphenyl) pyridine- 2-yl} -N-methylglycine monohydrochloride To the dioxane solution (2 mL) of the compound obtained in Example 14b (50 mg, 0.0881 mmol) was added 4N hydrochloric acid / dioxane solution (66 μL) under ice-cooling. . The reaction solution was dried under reduced pressure to obtain the crude title compound (46 mg, yield 87%) as a blue solid.
MS (FAB) m / z: 568 (M + H) + . (Free body)
IR (KBr) ν max 2981, 1734, 1648, 1471, 1373, 1282, 1185, 1136, 897, 683 cm -1 .
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. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1-1: 1) to give the title compound (5.61 g, yield 74%) as white. Obtained as a solid.
1 H NMR (CDCl 3 , 500 MHz): δ1.26 (2H, t, J = 7.32 Hz), 1.39-1.48 (2H, m), 1.56 (9H, s), 1.59-1.73 (4H, m), 2.32 (2H, t, J = 7.32 Hz), 3.17 (2H, t, J = 7.08 Hz), 4.04 (1H, s), 4.13 (2H, q, J = 7.00 Hz), 6.52 (2H, d, J = 8.79 Hz), 7.81 (2H, d, J = 8.79 Hz).
MS (FAB) m / z: 335 (M) + ;
IR (KBr) ν max 3385, 1727, 1682, 1602, 1288, 1269, 1158, 1113, 842, 772 cm -1 .
Example 14e tert-butyl 4-({6-[(2- {4-[(biphenyl-2-ylcarbamoyl) oxy] piperidin-1-yl} ethyl) (methyl) amino] -6-oxohexyl } Amino) benzoate To a solution of the compound obtained in Example 14d (3.56 g, 10.6 mmol) in ethanol (40 mL) was added 1N aqueous sodium hydroxide solution (15.6 mL), and the mixture was added at 50 ° C. for 1.5. Stir for hours. Ethyl acetate (2.0 mL, 1.5 mmol) was added, the reaction mixture was concentrated under reduced pressure, and 1N aqueous hydrochloric acid solution (16 mL) was added under ice-cooling. The resulting precipitate was collected by filtration, washed with water, n-hexane and diisopropyl ether, and 6-{[4- (tert-butoxycarbonyl) phenyl] amino} hexanoic acid (3.01 g, yield 92%). ) Was obtained as a white solid.
　得られた化合物（３．０１ｇ、９．７９ｍｍoｌ）及び１－［２－（メチルアミノ）エチル］ピペリジン－４－イル　ビフェニル－２－イルカーバメート（３．１４ｇ、８．９０ｍｍｏｌ）をジクロロメタン（８９ｍＬ）に溶解し、ＷＳＣ・ＨＣｌ（２．２５ｍｇ、１１．８ｍｍｏｌ）、及び４－Ｎ，Ｎ－ジメチルアミノピリジン（１２ｍｇ、０．０９８ｍｍｏｌ）を氷冷下で加え、室温で２０分間攪拌した。反応液を減圧濃縮後、酢酸エチルを加えて炭酸水素ナトリウム水溶液で洗浄し、得られた有機層を無水硫酸マグネシウムで乾燥した。溶剤を減圧留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：８－０：１０）を用いて精製し、標記化合物（５．６３ｇ、収率９８％）を白色固体として得た。
MS (FAB) m/z: 643 (M+H)+;
IR (KBr) νmax 2932, 1696, 1605, 1523, 1292, 1160, 1045, 772, 749, 702 cm-1.
［実施例１４ｆ］１－（２－｛［６－（｛４－［｛３－［（ｔｅｒｔ－ブトキシカルボニル）（メチル）アミノ］プロピル｝（メチル）カルバモイル］フェニル｝アミノ）ヘキサノイル］（メチル）アミノ｝エチル）ピペリジン-４-イル　ビフェニル－２-イルカーバメート
　実施例１４ｅで得られた化合物（１．０８ｇ、１．６８ｍｍｏｌ）に４規定塩酸／ジオキサン溶液（４０ｍＬ）を加え、室温で１３．５時間撹拌した。反応液にトルエンを加えた後、溶剤を減圧留去し、粗製の４－（｛６－［（２－｛４－［（ビフェニル－２-イルカルバモイル）オキシ］ピペリジン-１-イル｝エチル）（メチル）アミノ］－６－オキソヘキシル｝アミノ）安息香酸　二塩酸塩を得た。 The resulting compound (3.01 g, 9.79 mmol) and 1- [2- (methylamino) ethyl] piperidin-4-yl biphenyl-2-ylcarbamate (3.14 g, 8.90 mmol) were dissolved in dichloromethane (89 mL). WSC · HCl (2.25 mg, 11.8 mmol) and 4-N, N-dimethylaminopyridine (12 mg, 0.098 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with an aqueous sodium hydrogen carbonate solution. The obtained organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using NH silica gel column chromatography (hexane: ethyl acetate = 2: 8-0: 10) to give the title compound (5.63 g, yield 98%). Obtained as a white solid.
MS (FAB) m / z: 643 (M + H) + ;
IR (KBr) ν max 2932, 1696, 1605, 1523, 1292, 1160, 1045, 772, 749, 702 cm -1 .
[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. Toluene was added to the reaction solution, and the solvent was distilled off under reduced pressure to obtain crude 4-({6-[(2- {4-[(biphenyl-2-ylcarbamoyl) oxy] piperidin-1-yl} ethyl). (Methyl) amino] -6-oxohexyl} amino) benzoic acid dihydrochloride was obtained.
　得られた粗製のカルボン酸体にジクロロメタン（２５ｍＬ）及びトリエチルアミン（９３８μＬ、６．７３mmol）を加えて溶解し、氷冷撹拌下、塩化ピバロイル（２１３ｍｇ、１．７７ｍｍol）のジクロロメタン溶液（４ｍＬ）を滴下した。室温で１５分間撹拌したのち、tert-ブチル メチル[3-(メチルアミノ)プロピル]カーバメート（３５７ｍｇ、１．７７mmol）を滴下し、室温で３０分間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて洗浄した後、さらに分離した水層に酢酸エチルを加えて抽出した(２回)。有機層を合わせて無水硫酸マグネシウムで乾燥し、溶剤を減圧留去した。得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル＝１：１－０：１）を用いて精製し、標記化合物（９４８ｍｇ、収率８９％）を白色固体として得た。
MS (FAB) m/z: 771 (M+H)+.
IR (KBr) νmax 3340, 2932, 1694, 1609, 1523, 1396, 1045, 831,765, 748, 703 cm-1。 Dichloromethane (25 mL) and triethylamine (938 μL, 6.73 mmol) are added to the obtained crude carboxylic acid and dissolved, and a solution of pivaloyl chloride (213 mg, 1.77 mmol) in dichloromethane (4 mL) is added dropwise with stirring under ice cooling. did. After stirring at room temperature for 15 minutes, tert-butylmethyl [3- (methylamino) propyl] carbamate (357 mg, 1.77 mmol) was added dropwise and stirred at room temperature for 30 minutes. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution, and further extracted with ethyl acetate added to the separated aqueous layer (twice). The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-hexane: ethyl acetate = 1: 1-0: 1) to obtain the title compound (948 mg, yield 89%) as a white solid.
MS (FAB) m / z: 771 (M + H) + .
IR (KBr) ν max 3340, 2932, 1694, 1609, 1523, 1396, 1045, 831,765, 748, 703 cm −1 .
　［実施例１４ｇ］１－［２－（メチル｛６－［（４－｛メチル［３－（メチルアミノ）プロピル］カルバモイル｝フェニル）アミノ］ヘキサノイル｝アミノ）エチル］ピペリジン-４-イル　ビフェニル－２-イルカーバメート
　実施例１４ｆで得られた化合物（１０３ｍｇ、０．０７６ｍｍｏｌ）に２規定塩酸／メタノール溶液（４．９ｍＬ）を加え、室温で一晩撹拌した。反応液に１規定水酸化ナトリウム水溶液を加えてアルカリ性にしたのち、酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥した。溶剤を減圧留去し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー(酢酸エチル：メタノール＝２０：１→ジクロロメタン：メタノール＝１０：１)を用いて精製し、標記化合物（３１０ｍｇ、９５％）を白色固体として得た。
MS(FAB) m/z: 671(M+H)+.
［実施例１４ｈ］１－（２－｛［６－（｛４－［｛３－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］プロピル｝（メチル）カルバモイル］フェニル｝アミノ）ヘキサノイル］（メチル）アミノ｝エチル）ピペリジン－４－イル　ビフェニル－２－イルカーバメート
　実施例１４ｇで得られた化合物（３１０ｍｇ、０．４６２ｍｍｏｌ）及び実施例１４ｃで得られた化合物（５１０ｍｇ、０．７９６ｍｍｏｌ）をジクロロメタン（５ｍＬ）に溶解し、トリエチルアミン（１９２μＬ、１．３９ｍｍｏｌ）、ジメチルアミノピリジン（２ｍｇ）及びＷＳＣ・ＨＣｌ（１３３ｍｇ、０．６９４ｍｍｏｌ）を加えて室温で１８時間撹拌した。反応液を減圧濃縮したのち、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶剤を減圧留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝６０：１－５０：１）を用いて精製し、粗製の標記化合物（２７１ｍｇ）を淡褐色固体として得た。得られた粗製物を逆相分取カラムクロマトグラフィー（日本ウォーターズ，ＭＳ　Ｃ１８　ＯＢＤ，５μｍ，３０×１００ｍｍ）（アセトニトリル：０．１％ギ酸アンモニウム水溶液＝６０：４０）を用いて精製し、標記目的化合物（１８０ｍｇ，収率５４％）を淡黄色固体として得た。
MS (FAB) m/z: 1220 (M+H)+.
IR(KBr) νmax 2933, 1731, 1647, 1495, 1398, 1281, 1181, 1136, 1080, 765 cm-1。 Example 14g 1- [2- (methyl {6-[(4- {methyl [3- (methylamino) propyl] carbamoyl} phenyl) amino] hexanoyl} amino) ethyl] piperidin-4-yl biphenyl-2 -Ilcarbamate To the compound obtained in Example 14f (103 mg, 0.076 mmol) was added 2N hydrochloric acid / methanol solution (4.9 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was made alkaline by adding 1N aqueous sodium hydroxide solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using NH silica gel column chromatography (ethyl acetate: methanol = 20: 1 → dichloromethane: methanol = 10: 1) to give the title compound (310 mg, 95%). Obtained as a white solid.
MS (FAB) m / z: 671 (M + H) + .
[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). In triethylamine (192 μL, 1.39 mmol), dimethylaminopyridine (2 mg) and WSC · HCl (133 mg, 0.694 mmol) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified using NH silica gel column chromatography (ethyl acetate: methanol = 60: 1-50: 1) to obtain the crude title compound (271 mg) as a light brown solid. It was. The resulting crude product was purified using reverse phase preparative column chromatography (Nippon Waters, MS C18 OBD, 5 μm, 30 × 100 mm) (acetonitrile: 0.1% aqueous ammonium formate = 60: 40) for the purpose of The compound (180 mg, yield 54%) was obtained as a pale yellow solid.
MS (FAB) m / z: 1220 (M + H) + .
IR (KBr) ν max 2933, 1731, 1647, 1495, 1398, 1281, 1181, 1136, 1080, 765 cm −1 .
　［実施例１５］
１－｛２－［（｛４－［（｛４－［｛３－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］プロピル｝（メチル）カルバモイル］フェニル｝アミノ）メチル］フェニル｝カルボニル）（メチル）アミノ］エチル｝ピペリジン－４－イル　ビフェニル－２－イルカーバメート [Example 15]
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
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
［実施例１５ａ］１－（２－｛［（４－ホルミルフェニル）カルボニル］（メチル）アミノ｝エチル）ピペリジン－４－イル　ビフェニル－２－イルカーバメート
　１－［２－（メチルアミノ）エチル］ピペリジン－４－イル　ビフェニル－２－イルカーバメート（４００ｍｇ、１．１３ｍｍｏｌ）及び４－ホルミル安息香酸（１８７ｍｇ、１．２４ｍｍｏｌ）をジクロロメタン（１１ｍＬ）に溶解し、ＷＳＣ・ＨＣｌ（２６０ｍｇ、１．３６ｍｍｏｌ）を室温で加え、そのまま１４時間撹拌した。反応液の溶剤を減圧留去し、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、溶剤を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン：メタノール＝３０：１）を用いて精製し、標記化合物（４３３ｍｇ、収率７９％）を白色固体として得た。
1H NMR (CDCl3, 500MHz): δ 1.24-1.31 (1H, m), 1.64-1.70 (1H, m), 1.82-1.87 (1H, m), 1.92-1.96 (1H, m), 2.07-2.12 (1H, m), 2.30-2.35 (1H, m), 2.43-2.46 (1H, m), 2.63-2.65 (1H, m), 2.77-2.82 (1H, m), 2.95 (1.5H, m), 3.11 (1.5H, m), 3.29-3.32 (1H, m), 3.65-3.67 (1H, m), 4.64-4.68 (1H, m), 4.74-4.76 (1H, m), 6.59 (2H, s), 7.12-7.15 (1H, m), 7.22 (1H, d, J = 7.5 Hz), 7.34-7.38 (2H, m), 7.41-7.44 (1H, m), 7.47-7.51 (2H, m), 7.54-7.58 (2H, m), 7.92 (2H, d, J = 8.0 Hz), 8.08-8.12 (1H, m), 10.05 (1H, s).
MS (APCI) m/z: 486 (M+H)+.
［実施例１５ｂ］ｔｅｒｔ－ブチル　４－（｛４－［（２－｛４－［（ビフェニル－２－イルカルバモイル）オキシ］ピペリジン－１－イル｝エチル）（メチル）カルバモイル］ベンジル｝アミノ）ベンゾエート
　実施例１５ａで得られた化合物（４３３ｍｇ、０．８９２ｍｍｏｌ）及び４－アミノ安息香酸ｔｅｒｔ－ブチルエステル（１５７ｍｇ、０．８１１ｍｍｏｌ）をジクロロメタン（９ｍＬ）に溶解し、酢酸（４２μＬ）及び水素化トリアセトキシホウ素ナトリウム（２５８ｍｇ、１．２２ｍｍｏｌ）を室温で加え、一晩撹拌した。反応液の溶剤を減圧留去し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル＝１：１－１：２）を用いて精製し、標記化合物（３９９ｍｇ、収率７４％）を白色固体として得た。
1H NMR (CDCl3, 500MHz): δ 1.55 (9H, s), 1.65-1.68 (1H, m), 1.82-1.87 (1H, m), 1.91-1.96 (1H, m), 2.08-2.11 (1H, m), 2.30-2.33 (1H, m), 2.42-2.52 (1H, m), 2.60-2.64 (1H, m), 2.76-2.80 (1H, m), 2.97-3.09 (3H, m), 3.32-3.37 (2H, m), 3.63-3.66 (2H, m), 4.41 (1H, d, J = 5.2 Hz), 4.46-4.48 (1H, m), 4.66-4.76 (2H, m), 6.55-6.59 (3H, m), 7.11-7.15 (2H, m), 7.21 (1H, d, J = 7.5 Hz), 7.35-7.40 (5H, m), 7.42 (1H, d, J = 7.5Hz), 7.49 (2H, t, J = 7.5 Hz), 7.81 (2H, d, J = 8.6 Hz), 8.08-8.12 (2H, m).
MS (APCI) m/z: 663 (M+H)+.
［実施例１５ｃ］１－｛２－［（｛４－［（｛４－［｛３－［（ｔｅｒｔ－ブトキシカルボニル）（メチル）アミノ］プロピル｝（メチル）カルバモイル］フェニル｝アミノ）メチル］フェニル｝カルボニル）（メチル）アミノ］エチル｝ピペリジン－４－イル　ビフェニル－２－イルカーバメート
　実施例１５ｂで得られた化合物（３９９ｍｇ、０．６０２ｍｍｏｌ）のジオキサン溶液（３ｍＬ）に４規定塩酸－ジオキサン（１２ｍＬ）を加え、室温で１４．５時間撹拌した。反応液にトルエンを加えたのち、溶剤を減圧乾固して、粗製の４－（｛４－［（２－｛４－［（ビフェニル－２－イルカルバモイル）オキシ］ピペリジン－１－イル｝エチル）（メチル）カルバモイル］ベンジル｝アミノ）安息香酸　二塩酸塩を白色固体として得た。 [Example 15a] 1- (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. The solvent of the reaction solution was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 30: 1) to obtain the title compound (433 mg, yield 79%) as a white solid.
1 H NMR (CDCl 3 , 500 MHz): δ 1.24-1.31 (1H, m), 1.64-1.70 (1H, m), 1.82-1.87 (1H, m), 1.92-1.96 (1H, m), 2.07-2.12 (1H, m), 2.30-2.35 (1H, m), 2.43-2.46 (1H, m), 2.63-2.65 (1H, m), 2.77-2.82 (1H, m), 2.95 (1.5H, m), 3.11 (1.5H, m), 3.29-3.32 (1H, m), 3.65-3.67 (1H, m), 4.64-4.68 (1H, m), 4.74-4.76 (1H, m), 6.59 (2H, s) , 7.12-7.15 (1H, m), 7.22 (1H, d, J = 7.5 Hz), 7.34-7.38 (2H, m), 7.41-7.44 (1H, m), 7.47-7.51 (2H, m), 7.54 -7.58 (2H, m), 7.92 (2H, d, J = 8.0 Hz), 8.08-8.12 (1H, m), 10.05 (1H, s).
MS (APCI) m / z: 486 (M + H) + .
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 μL) and hydrogenated triacetoxy Sodium boron (258 mg, 1.22 mmol) was added at room temperature and stirred overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was purified using NH silica gel column chromatography (n-hexane: ethyl acetate = 1: 1-1: 2) to give the title compound (399 mg, yield 74). %) As a white solid.
1 H NMR (CDCl 3 , 500MHz): δ 1.55 (9H, s), 1.65-1.68 (1H, m), 1.82-1.87 (1H, m), 1.91-1.96 (1H, m), 2.08-2.11 (1H , m), 2.30-2.33 (1H, m), 2.42-2.52 (1H, m), 2.60-2.64 (1H, m), 2.76-2.80 (1H, m), 2.97-3.09 (3H, m), 3.32 -3.37 (2H, m), 3.63-3.66 (2H, m), 4.41 (1H, d, J = 5.2 Hz), 4.46-4.48 (1H, m), 4.66-4.76 (2H, m), 6.55-6.59 (3H, m), 7.11-7.15 (2H, m), 7.21 (1H, d, J = 7.5 Hz), 7.35-7.40 (5H, m), 7.42 (1H, d, J = 7.5 Hz), 7.49 ( 2H, t, J = 7.5 Hz), 7.81 (2H, d, J = 8.6 Hz), 8.08-8.12 (2H, m).
MS (APCI) m / z: 663 (M + H) + .
[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 To a solution of the compound obtained in Example 15b (399 mg, 0.602 mmol) in dioxane (3 mL) was added 4N hydrochloric acid-dioxane (12 mL). ) And stirred at room temperature for 14.5 hours. After adding toluene to the reaction solution, the solvent was evaporated to dryness to give crude 4-({4-[(2- {4-[(biphenyl-2-ylcarbamoyl) oxy] piperidin-1-yl} ethyl). ) (Methyl) carbamoyl] benzyl} amino) benzoic acid dihydrochloride was obtained as a white solid.
　得られた粗製物のジクロロメタン溶液（６ｍＬ）にトリエチルアミン（４１８μＬ、３．０１ｍｍｏｌ）、ｔｅｒｔ－ブチル　メチル［３－（メチルアミノ）プロピル］カーバメート（１２２ｍｇ、０．６０２ｍｍｏｌ）、及びＷＳＣ・ＨＣｌ（１３８ｍｇ、０．７２２ｍｍｏｌ）を加え、室温で３．５時間撹拌した。４－ジメチルアミノピリジン（４ｍｇ）を加え、室温で２．５日間撹拌した。反応液に酢酸エチルを加えて希釈し、有機層を飽和炭酸水素ナトリウム水溶液、及び飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥したのち、溶剤を減圧留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝６０：１）を用いて精製し、標記化合物（３９２ｍｇ、収率８２％）を白色固体として得た。
MS (APCI) m/z: 791 (M+H)+.
IR(KBr) νmax 2932, 1693, 1609, 1522, 1449, 1398, 1222, 1045, 833, 765 cm-1。 Triethylamine (418 μL, 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. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using NH silica gel column chromatography (ethyl acetate: methanol = 60: 1) to give the title compound (392 mg, yield). 82%) was obtained as a white solid.
MS (APCI) m / z: 791 (M + H) + .
IR (KBr) ν max 2932, 1693, 1609, 1522, 1449, 1398, 1222, 1045, 833, 765 cm −1 .
　［実施例１５ｄ］１－（２－｛メチル［（４－｛［（４－｛メチル［３－（メチルアミノ）プロピル］カルバモイル｝フェニル）アミノ］メチル｝フェニル）カルボニル］アミノ｝エチル）ピペリジン－４－イル　ビフェニル－２－イルカーバメート
　実施例１５ｃで得られた化合物（３９０ｍｇ、０．４９３mmol）に２規定塩酸―メタノール溶液（４．９３ｍＬ）を加えて溶解し、室温撹拌した。反応液に１規定水酸化ナトリウム水溶液を加えたのち、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥したのち、溶剤を減圧留去して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝２０：１→ジクロロメタン：メタノール＝１０：１）を用いて精製し、標記化合物（３０６ｍｇ、収率９０％）を白色固体として得た。
1H NMR (CDCl3, 500MHz): δ 1.54-1.61 (6H, m), 1.64-1.69 (1H,m), 1.77-1.86 (3H, m), 1.91-1.95 (1H, m), 2.07-2.11 (1H, m), 2.31-2.64 (8H, m), 2.76-2.80 (1H, m), 2.97-3.02 (3H, m), 3.07-3.10 (1H, m), 3.33-3.37 (1H, m), 3.47-3.51 (2H, m), 3.63-3.66 (1H, m), 4.30-4.33 (1H, m), 4.39-4.40 (1H, m), 4.69-4.75 (1H, m), 6.56-6.58 (3H, m), 7.11-7.15 (1H, m), 7.21-7.73 (2H, m), 7.26-7.27 (3H, m), 7.35-7.40 (5H, m), 7.43 (1H, d, J = 7.5Hz), 7.49 (2H, t, J = 7.5 Hz), 8.07-8.11 (1H, m).
MS (APCI) m/z: 691 (M+H)+.
［実施例１５ｅ］１－｛２－［（｛４－［（｛４－［｛３－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］プロピル｝（メチル）カルバモイル］フェニル｝アミノ）メチル］フェニル｝カルボニル）（メチル）アミノ］エチル｝ピペリジン－４－イル　ビフェニル－２－イルカーバメート
　実施例１５ｄで得られた化合物（１５６ｍｇ、０．２２６ｍｍｏｌ）及び実施例１４ｃで得られた化合物（２８９ｍｇ、０．４５２ｍｍｏｌ）を用いて実施例１４ｈに記載した方法に従い、標記化合物（１０１ｍｇ、収率３６％）を淡黄色固体として得た。
MS (FAB) m/z: 1240 (M+H)+.
IR(KBr) νmax 2931, 1733, 1609, 1495, 1398, 1281, 1182, 1136, 1079, 752 cm-1。 [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. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using NH silica gel column chromatography (ethyl acetate: methanol = 20: 1 → dichloromethane: methanol = 10: 1). The title compound (306 mg, 90% yield) was obtained as a white solid.
1 H NMR (CDCl 3 , 500MHz): δ 1.54-1.61 (6H, m), 1.64-1.69 (1H, m), 1.77-1.86 (3H, m), 1.91-1.95 (1H, m), 2.07-2.11 (1H, m), 2.31-2.64 (8H, m), 2.76-2.80 (1H, m), 2.97-3.02 (3H, m), 3.07-3.10 (1H, m), 3.33-3.37 (1H, m) , 3.47-3.51 (2H, m), 3.63-3.66 (1H, m), 4.30-4.33 (1H, m), 4.39-4.40 (1H, m), 4.69-4.75 (1H, m), 6.56-6.58 ( 3H, m), 7.11-7.15 (1H, m), 7.21-7.73 (2H, m), 7.26-7.27 (3H, m), 7.35-7.40 (5H, m), 7.43 (1H, d, J = 7.5 Hz), 7.49 (2H, t, J = 7.5 Hz), 8.07-8.11 (1H, m).
MS (APCI) m / z: 691 (M + H) + .
[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.
MS (FAB) m / z: 1240 (M + H) + .
IR (KBr) ν max 2931, 1733, 1609, 1495, 1398, 1281, 1182, 1136, 1079, 752 cm −1 .
　［実施例１６］
（３Ｒ）－１－｛４－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）（メチル）アミノ］ブチル｝ピロリジン－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート　二塩酸塩 [Example 16]
(3R) -1- {4-[({[(2S) -1 ′-{2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluoro Phenyl) -1,3-oxazolidine-5-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl} pyrrolidine- 3-yl hydroxy (di-2-thienyl) acetate dihydrochloride
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
［実施例１６ａ］２－｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（４－フルオロフェニル）－１，３－オキサソリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝－Ｎ－（４－ヒドロキシブチル）－Ｎ－メチルアセタミド
　実施例６ｉで得られた化合物（２５０ｍｇ、０．３６０ｍｍｏｌ）、４－（メチルアミノ）ブタン－１－オール（４４．６ｍｇ、０．４３２ｍｍｏｌ）を用いて実施例６Ｌに記載した方法に従い、標記化合物（２０４ｍｇ、収率７３％）を白色固体として得た。
MS (FAB) m/z: 781 (M+H)+.
IR(KBr) νmax 3426, 2932, 1648, 1359, 1281, 1181, 1139, 907, 758, 682 cm-1.
［実施例１６ｂ］４－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（４－フルオロフェニル）－１，３－オキサソリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）（メチル）アミノ］ブチル　メタンスルホネート
　実施例１６ａで得られた化合物（３００ｍｇ、０．３８５ｍｍｏｌ）のジクロロメタン溶液（５ｍＬ）を氷冷し、トリエチルアミン（６４μＬ、０．４６２ｍｍｏｌ）及び塩化メタンスルホニル（３６μＬ、０．４６２ｍｍｏｌ）を加え、そのまま１時間撹拌した。反応液に水を加え、ジクロロメタンで抽出した。シリカゲルカラムクロマトグラフィー（酢酸エチル：ジクロロメタン：メタノール＝５：５：０－５：５：１）を用いて精製し、標記化合物（３２７ｍｇ、収率９９％）を得た。
MS(FAB) m/z : 858 ((M+H)+, フリー体)
IR(KBr) νmax: 3437, 1651, 1511, 1436, 1359, 1282, 1225, 1174, 1138, 1108, 848, 760, 682, 529 cm-1.
［実施例１６ｃ］（３Ｒ）－１－｛４－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）（メチル）アミノ］ブチル｝ピロリジン－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート　二塩酸塩
　実施例１６ｂで得られた化合物（１５０ｍｇ、０．１７５ｍｍol）及び実施例１ｉで得られた化合物（６５ｍｇ、０．２１ｍｍｏｌ）をアセトニトリル（５ｍＬ）に溶解し、炭酸カリウム（４８ｍｇ、０．３５ｍｍol）を加えて８０℃で２０時間撹拌した。反応液を減圧濃縮したのち、水を加え、ジクロロメタンで抽出した。ＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル：ジクロロメタン＝０：１００－５０：５０）を用いて精製し、標記化合物のフリー体（５１ｍｇ、収率２７％）を得た。得られたフリー体を酢酸エチルに溶解し、１規定塩酸水溶液で洗浄した。有機層を分離して減圧乾固し、標記化合物を白色固体として得た。
IR(KBr) νmax: 3259, 2935, 2565, 1742, 1652, 1510, 1434, 1359, 1282, 1228, 1180, 1139, 848, 760, 707, 682 cm-1.
MS(FAB) m/z : 1071 ((M+H)+, フリー体)。 [Example 16a] 2-{[(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} -N- (4-hydroxybutyl) -N-methylacetamide Examples Using the compound obtained in 6i (250 mg, 0.360 mmol) and 4- (methylamino) butan-1-ol (44.6 mg, 0.432 mmol) according to the method described in Example 6L, the title compound (204 mg Yield 73%) as a white solid.
MS (FAB) m / z: 781 (M + H) + .
IR (KBr) ν max 3426, 2932, 1648, 1359, 1281, 1181, 1139, 907, 758, 682 cm -1 .
[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 μL, 0.462 mmol) and methanesulfonyl chloride (36 μL, 0.462 mmol) were added, and the mixture was stirred as it was for 1 hour. . Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. Purification using silica gel column chromatography (ethyl acetate: dichloromethane: methanol = 5: 5: 0-5: 5: 1) gave the title compound (327 mg, yield 99%).
MS (FAB) m / z: 858 ((M + H) + , free body)
IR (KBr) ν max : 3437, 1651, 1511, 1436, 1359, 1282, 1225, 1174, 1138, 1108, 848, 760, 682, 529 cm -1 .
[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. for 20 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. Purification was carried out using NH silica gel column chromatography (ethyl acetate: dichloromethane = 0: 100-50: 50) to obtain a free form of the title compound (51 mg, yield 27%). The resulting free form was dissolved in ethyl acetate and washed with 1N aqueous hydrochloric acid. The organic layer was separated and evaporated to dryness to give the title compound as a white solid.
IR (KBr) ν max : 3259, 2935, 2565, 1742, 1652, 1510, 1434, 1359, 1282, 1228, 1180, 1139, 848, 760, 707, 682 cm -1 .
MS (FAB) m / z: 1071 ((M + H) + , free form).
　［実施例１７］
８－｛４－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）（メチル）アミノ］ブチル｝－８－アザビシクロ［３．２．１］オクト－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート　二塩酸塩 [Example 17]
8- {4-[({[(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} acetyl) (methyl) amino] butyl} -8-azabicyclo [3 2.1] Oct-3-yl hydroxy (di-2-thienyl) acetate dihydrochloride
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
［実施例１７ａ］ｔｅｒｔ－ブチル　３－［２－ヒドロキシ（ジ－２－チエニル）アセトキシ］－８－アザビシクロ［３．２．１］オクタン－８－カルボキシレート
　窒素雰囲気下、水素化ナトリウム（４５０ｍｇ（含量５５％、鉱油分散物）、１０．３ｍｍｏｌ）のトルエン懸濁溶液（６．７ｍＬ）にメチル　ヒドロキシ（ジ－２－チエニル）アセテート（２．５４ｇ、１０．０ｍｍｏｌ）とｔｅｒｔ－ブチル　３－ヒドロキシ－８－アザビシクロ［３．２．１］オクタン－８－カルボキシレート（２．２７ｇ、１０．０ｍｍｏｌ）をトルエン（２０ｍＬ）ーテトラヒドロフラン（１０ｍＬ）混合溶液を室温撹拌下で滴下した。室温で１０分間撹拌した後、系内を２００－３００ｍｍＨｇで減圧しながら７５℃で１時間撹拌し、さらに３．５時間加熱還流した。放冷後、１０％クエン酸水溶液及び水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、溶剤を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル＝１０：１－５：１）を用いて精製し、標記化合物を白色固体（３．７５ｇ、収率８３％）として得た。
1H NMR (CDCl3, 400MHz): δ 1.20-1.54(2H, m), 1.44(9H,s), 1.66-1.82(4H, m), 2.01-2.25(2H, m), 3.95-4.25(2H, m), 5.24(1H,dd, J=4.7, 5.1 Hz), 7.00(2H, dd, J=3.9, 4.7 Hz), 7.16(2H, d, J=3.9 Hz), 7.31(2H, d, J=4.7 Hz).
MS(FAB) m/z: 450 (M+H)+.
IR(KBr) νmax 3453, 2974, 1717, 1686, 1401, 1274, 1026, 794, 706 cm-1.
［実施例１７ｂ］８－アザビシクロ［３．２．１］オクト－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート
　実施例１７ａで得られた化合物（３．４３ｇ、７．６３ｍｍｏｌ）のジオキサン溶液（２０ｍＬ）に４規定塩酸／ジオキサン溶液（２０ｍＬ）を加えて室温で５時間撹拌した。溶剤を減圧濃縮し、酢酸エチルと１規定水酸化ナトリウム水溶液を加えて抽出した（３回）。有機層を無水硫酸マグネシウムで乾燥し、溶剤を減圧留去した。得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：０－１０：１）を用いて精製し、標記化合物（２．２２ｇ、収率８３％）を淡黄色固体として得た。
MS(FAB) m/z: 350 (M+H)+.
IR(KBr) νmax 2947, 1732, 1494, 1244, 1233, 1080, 1034, 850, 703 cm-1.
［実施例１７ｃ］８－｛４－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）（メチル）アミノ］ブチル｝－８－アザビシクロ［３．２．１］オクト－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート　二塩酸塩
　実施例１６ｂで得られた化合物（２３６ｍｇ、０．２５６ｍｍol）及び実施例１７ｂで得られた化合物（１０７ｍｇ、０．３０７ｍｍｏｌ）をアセトニトリル（５ｍＬ）に溶解し、炭酸カリウム（７１ｍｇ、０．５１２ｍｍｏｌ）及びヨウ化カリウム（８５ｍｇ、０．５１２ｍｍｏｌ）を加えて８０℃で２０時間撹拌した。反応液を減圧濃縮したのち、水を加え、ジクロロメタンで抽出した。ＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル：ジクロロメタン＝０：１００－１００：０）及び逆相カラムを用いて精製し、標記化合物のフリー体（４２ｍｇ、収率１５％）を得た。得られたフリー体を酢酸エチルに溶解し、１規定塩酸水溶液で洗浄した。有機層を分離して減圧乾固し、標記化合物を白色固体として得た。
IR(KBr) νmax: 3416, 2954, 2571, 1737, 1650, 1510, 1434, 1360, 1282, 1225, 1176, 1139, 848, 759, 707, 682 cm-1.
MS(FAB) m/z : 1111 ((M+H)+, フリー体)。 Example 17a tert-butyl 3- [2-hydroxy (di-2-thienyl) acetoxy] -8-azabicyclo [3.2.1] octane-8-carboxylate 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). A mixed solution of -8-azabicyclo [3.2.1] octane-8-carboxylate (2.27 g, 10.0 mmol) in toluene (20 mL) -tetrahydrofuran (10 mL) was added dropwise with stirring at room temperature. After stirring at room temperature for 10 minutes, the system was stirred at 75 ° C. for 1 hour while reducing the pressure at 200 to 300 mmHg, and further heated to reflux for 3.5 hours. After allowing to cool, 10% aqueous citric acid solution and water were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1-5: 1) to obtain the title compound as a white solid (3.75 g, yield 83%).
1 H NMR (CDCl 3 , 400MHz): δ 1.20-1.54 (2H, m), 1.44 (9H, s), 1.66-1.82 (4H, m), 2.01-2.25 (2H, m), 3.95-4.25 (2H , m), 5.24 (1H, dd, J = 4.7, 5.1 Hz), 7.00 (2H, dd, J = 3.9, 4.7 Hz), 7.16 (2H, d, J = 3.9 Hz), 7.31 (2H, d, J = 4.7 Hz).
MS (FAB) m / z: 450 (M + H) + .
IR (KBr) ν max 3453, 2974, 1717, 1686, 1401, 1274, 1026, 794, 706 cm -1 .
[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. The solvent was concentrated under reduced pressure, and extracted by adding ethyl acetate and 1N aqueous sodium hydroxide solution (three times). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate: methanol = 10: 0-10: 1) to obtain the title compound (2.22 g, yield 83%) as a pale yellow solid.
MS (FAB) m / z: 350 (M + H) + .
IR (KBr) ν max 2947, 1732, 1494, 1244, 1233, 1080, 1034, 850, 703 cm -1 .
[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 mmol) were added. Stir at 80 ° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. Purification was performed using NH silica gel column chromatography (ethyl acetate: dichloromethane = 0: 100-100: 0) and a reverse phase column to obtain the free form of the title compound (42 mg, yield 15%). The resulting free form was dissolved in ethyl acetate and washed with 1N aqueous hydrochloric acid. The organic layer was separated and evaporated to dryness to give the title compound as a white solid.
IR (KBr) ν max : 3416, 2954, 2571, 1737, 1650, 1510, 1434, 1360, 1282, 1225, 1176, 1139, 848, 759, 707, 682 cm -1 .
MS (FAB) m / z: 1111 ((M + H) + , free form).
　（試験例１）
［モルモットNK1受容体結合試験］
　モルモット粗膜標本より受容体結合試験を実施できる。すなわちNK1受容体高発現部位である肺組織を摘出後粗膜標本を作製し、[3H]substance Pと被験物質を粗膜標本液とともに反応させた後、膜成分回収後放射活性を測定することにより、被験物質のモルモットNK1受容体への親和性を算出できる。 (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.
　（試験例２）
［モルモットNK2受容体結合試験］
　モルモット粗膜標本より受容体結合試験を実施できる。すなわちNK2受容体高発現部位である回腸組織を摘出後粗膜標本を作製し、[3H]SR 48968またはneurokinin Aと被験物質を粗膜標本液とともに反応させた後、膜成分回収後放射活性を測定することにより、被験物質のモルモットNK2受容体への親和性を算出できる。 (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.
　（試験例３）
［モルモットM3受容体結合試験］
　モルモット粗膜標本より受容体結合試験を実施できる。すなわちM3受容体高発現部位である顎下腺組織を摘出後粗膜標本を作製し、[N-methyl-3H]-(-)-Scopolamine methyl chlorideと被験物質を粗膜標本液とともに反応させた後、膜成分回収後放射活性を測定することにより、被験物質のモルモットM3受容体への親和性を算出できる。 (Test Example 3)
[Guinea M 3 receptor binding test]
Receptor binding tests can be performed from guinea pig crude film specimens. That produced a crude membrane specimen after removal of the submandibular gland tissue is M 3 receptor withers expression site, [N-methyl- 3 H] - (-) - is reacted with Scopolamine methyl chloride and test substance crude membrane specimen solution after, by measuring the film component recovery after radioactivity can calculate the affinity to guinea pig M 3 receptors of the test substances.
　（試験例４）
［ヒトNK1 受容体結合試験］
　ヒト型NK1受容体発現細胞由来粗膜標本より受容体結合試験を実施できる。すなわちヒト型NK1受容体発現COS細胞より調製した粗膜標本に対して、[3H]substance Pと被験物質を粗膜標本液とともに反応させた後、膜成分回収後放射活性を測定することにより、被験物質のヒトNK1受容体への親和性を算出できる。 (Test Example 4)
[Human NK 1 receptor binding test]
A receptor binding test can be performed from a human NK 1 receptor-expressing cell-derived crude membrane specimen. In other words, after reacting [ 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. Thus, the affinity of the test substance for the human NK 1 receptor can be calculated.
　（試験例５）
［ヒトNK2 受容体結合試験］
（a）粗膜標本の作製
　ヒト型NK2受容体発現COS細胞の凍結保存細胞液を緩衝液（0.04% bovine serum albumin (BSA)を含む50 mMトリス－塩酸, pH7.4）で希釈して5.0x105 cells/mLとし、粗膜標本として用いた。
（b）受容体結合試験
　[3H]SR 48968（GEヘルスケア・ジャパン（株））を50 mMトリス－塩酸（pH7.4）、6 mM塩化マンガン４水和物、800 μg/mL　BSA、8 μg/mLキモスタチン、8 μg/mL ロイペプチン、80 μg/mL バシトラシン、20 μg/mL ホスホラミドン混合液で希釈した。この混合液250 μLに、被験物質と粗膜標本液250 μLを加え、室温で、35分インキュベートした（[3H]SR 48968は、最終濃度1 nM）。反応後、自動濾過装置（Brandel , Biomedical Research and Development Laboratories, Inc.）を用いて、GF/Bガラス繊維濾紙（Whatman , Biomedical Research and Development Laboratories, Inc.）上に膜成分を回収した。なお、ガラス繊維濾紙は、非特異結合を低く抑えるため、0.1%ポリエチレンイミン液で、4時間以上前処理して用いた。膜成分回収フィルターを、ピコフロー3 mLを含むミニプラスチックバイアルに移し、液体シンチレーション・カウンター（Perkin Elmer, Tri-Carb 2900TRあるいは2300TR）にて放射活性を測定した。
NK2 受容体結合作用は、50%結合薬用量（IC50）およびNK2受容体に対する[3H]SR 48968の親和性（Kd）より、被験物質のNK2受容体への親和性（Ki）として算出した。 (Test Example 5)
[Human NK 2 receptor binding test]
(A) Preparation of crude membrane specimen Dilute cryopreserved cell solution of human NK 2 receptor-expressing COS cells with buffer (50 mM Tris-HCl, pH 7.4 containing 0.04% bovine serum albumin (BSA)) 5.0 × 10 5 cells / mL were used as a crude membrane sample.
(B) Receptor binding test [ 3 H] SR 48968 (GE Healthcare Japan Co., Ltd.) was mixed with 50 mM Tris-HCl (pH 7.4), 6 mM manganese chloride tetrahydrate, 800 μg / mL BSA, Diluted with a mixture of 8 μg / mL chymostatin, 8 μg / mL leupeptin, 80 μg / mL bacitracin, and 20 μg / mL phosphoramidon. To this mixed solution (250 μL), a test substance and 250 μL 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). After the reaction, 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. 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).
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 ).
　結果を表１に示す。
（表１）
－－－－－－－－－－－－－－
　実施例　　Ｋｉ（ｎＭ）
－－－－－－－－－－－－－－
　　　６　　　１．０
　　　７　　　１．２
　　　８　　　１．２
　　　９　　　２．０
　上記の結果から、本発明の化合物は、優れたニューロキニンＮＫ２受容体結合作用を有する。 The results are shown in Table 1.
(Table 1)
--------------
Example Ki (nM)
--------------
6 1.0
7 1.2
8 1.2
9 2.0
From the above results, the compound of the present invention has an excellent neurokinin NK 2 receptor binding action.
　（試験例６）
［ヒトM3 受容体結合試験］
（a）粗膜標本の作製
　ヒト型M3受容体発現CHO細胞の凍結保存細胞液を緩衝液（0.5 mM EDTAを含む50 mMトリス－塩酸, pH7.4）で希釈して5.0x105 cells/mLとし、粗膜標本として用いた。
（b）受容体結合試験
　[N-methyl-3H]-(-)-Scopolamine methyl chloride（GEヘルスケア・ジャパン（株））を0.5 mM EDTAを含む 50 mMトリス－塩酸（pH7.4）で希釈し、その混合液250 μLに被験物質と粗膜標本液250 μLを加え、室温で、60分インキュベートした。反応後、自動濾過装置（Brandel, Biomedical Research and Development Laboratories, Inc.）を用いて、GF/Bガラス繊維濾紙（Whatman , Biomedical Research and Development Laboratories, Inc.）上に膜成分を回収した（[N-methyl-3H]-(-)-Scopolamine methyl chlorideは、最終濃度0.5 nM）。なお、ガラス繊維濾紙は、非特異結合を低く抑えるため、0.1%ポリエチレンイミン液で、4時間以上前処理して用いた。膜成分回収フィルターを、ピコフロー3 mLを含むミニプラスチックバイアルに移し、液体シンチレーション・カウンター（Perkin Elmer, Tri-Carb 2900TRあるいは2300TR）にて放射活性を測定した。
M3 受容体結合作用は、50%結合薬用量（IC50）およびM3受容体に対する[N-methyl-3H]-(-)-Scopolamine methyl chlorideの親和性（Kd）より、被験物質のM3受容体への親和性（Ki）として算出した。 (Test Example 6)
[Human M 3 receptor binding test]
(A) the crude membrane specimen cryopreserved cell suspension of buffer prepared human M 3 receptor expressing CHO cells (50 mM Tris containing 0.5 mM EDTA - HCl, pH7.4) 5.0x10 5 cells were diluted with / mL was used as a crude membrane sample.
(B) Receptor Binding Test [N-methyl- 3 H] - (-) - Scopolamine methyl chloride (GE Healthcare Japan Corporation) and 50 mM Tris containing 0.5 mM EDTA - with hydrochloric acid (pH 7.4) After dilution, 250 μL of a test substance and a crude membrane sample solution were added to 250 μL of the mixed solution, and incubated at room temperature for 60 minutes. After the reaction, 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).
　結果を表２に示す。
（表２）
－－－－－－－－－－－－－－
　実施例　　Ｋｉ（ｎＭ）
－－－－－－－－－－－－－－
　　　２　　３３．３
　　　４　　２３．４
　　　５　　　３．９
　　　６　　２３．８
　　　７　　３１．１
　　　８　　２９．１
　　　９　　３６．６
　　１１　　１４．６
　　１２　　２３．３
　　１３　　３２．７
　　１４　　　１．１
　　１５　　　６．８
　　１６　　２８．８
－－－－－－－－－－－－－－。 The results are shown in Table 2.
(Table 2)
--------------
Example Ki (nM)
--------------
2 33.3
4 23.4
5 3.9
6 23.8
7 31.1
8 29.1
9 36.6
11 14.6
12 23.3
13 32.7
14 1.1
15 6.8
16 28.8
--------------.
　上記の結果から、本発明の化合物は、優れたムスカリンＭ３受容体結合作用を有する。 From the above results, the compound of the present invention has an excellent muscarinic M 3 receptor binding action.
　（試験例７）
[Methacholine気道収縮の抑制作用（in vivo, 気管内投与）]
　健常モルモットを用い、ムスカリン受容体アゴニストであるmethacholineによる気道収縮に対する抑制作用をKonzett-Roessler（Naunyn-Schmiedebergs Arch. Exp. Pathol. pharmakol. 195, 71(1940)）の変法を用いて、気道内圧を指標として調べることができる。 (Test Example 7)
[Inhibition of methacholine airway contraction (in vivo, intratracheal administration)]
In healthy guinea pigs, the inhibitory effect on airway contraction by the muscarinic receptor agonist methacholine was tested using a modified method of Konzet-Roessler (Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 195, 71 (1940)). Can be examined as an index.
　（試験例８）
[血管透過性亢進の抑制作用（in vivo, 気管内投与）]
　血管透過性亢進の抑制作用は、健常モルモット（体重400g前後、ハートレー系雄性モルモット）を用い、ＮＫ１受容体作動薬であるsubstance P （ＳＰ）による血管透過性亢進に対する抑制作用を、漏出色素量を指標として調べた。
ペントバルビタール（30mg/kg, i.p.）で麻酔したモルモットの大腿静脈内に色素（Evans blue：40mg/kg, i.v.）を投与し、直ちにＳＰ（1μg/kg）を静脈注射することにより、血管透過性の亢進を惹起した。１５分後、モルモットを二酸化炭素下に致死させ、主気管部位に漏出した色素量をHarada法（J. Pharm. Pharmacol. 23, 218(1971)）に従って測定した。
被験薬物は5%グルコース溶液に溶解し、0.5 mL/kgの溶液を気管内投与器具（Penn-Century. Inc., model 1A-1B) を用いて、SPによる惹起の1時間前に気管内投与した。
抑制作用は、被検薬物投与モルモットの漏出色素量を指標にして判断した。 (Test Example 8)
[Inhibition of increased vascular permeability (in vivo, intratracheal administration)]
Inhibition of increased vascular permeability was achieved by using healthy guinea pigs (weight around 400 g, Hartley male guinea pigs), and inhibiting the increase in vascular permeability caused by substance P (SP), an NK1 receptor agonist. Investigated as an indicator.
Vascular permeability is achieved by administering a dye (Evans blue: 40 mg / kg, iv) into the femoral vein of a guinea pig anesthetized with pentobarbital (30 mg / kg, ip) and immediately injecting SP (1 μg / kg) intravenously. Caused an increase in. After 15 minutes, 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.
　結果を表３に示す。
（表３）
－－－－－－－－－－－－－－－－－－
　実施例　　抑制率（１００ｕｇ／ｋｇ）
－－－－－－－－－－－－－－－－－－
　　　３　　　９４．５％
－－－－－－－－－－－－－－－－。 The results are shown in Table 3.
(Table 3)
------------------
Example Suppression rate (100 ug / kg)
------------------
3 94.5%
----------------.
　上記の結果から、本発明の化合物は、ニューロキニンＮＫ１受容体に対して優れた拮抗作用を有する。 From the above results, the compound of the present invention has an excellent antagonistic action on the neurokinin NK 1 receptor.
　（試験例９）
[Substance P誘発気道収縮の抑制作用（in vivo, 気管内投与）]
　健常モルモットを用い、NK1受容体アゴニストであるsubstance P（SP）による気道収縮に対する抑制作用をKonzett-Roessler（Naunyn-Schmiedebergs Arch. Exp. Pathol. pharmakol. 195, 71(1940)）の変法を用いて、気道内圧を指標として調べることができる。 (Test Example 9)
[Inhibition of Substance P-induced airway contraction (in vivo, intratracheal administration)]
In a healthy guinea pig, the inhibitory effect on airway contraction by substance P (SP), an NK 1 receptor agonist, was modified by a modification of Konzet-Roessler (Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 195, 71 (1940)). Using it, airway pressure can be examined as an index.
　（試験例１０）
[Neurokinin A誘発気道収縮の抑制作用（in vivo,気管内投与）]
　健常モルモットを用い、NK２受容体アゴニストであるneurokinin A（NKA）による気道収縮に対する抑制作用をKonzett-Roessler（Naunyn-Schmiedebergs Arch. Exp. Pathol. pharmakol. 195, 71(1940)）の変法を用いて、気道内圧を指標として調べることができる。 (Test Example 10)
[Inhibition of Neurokinin A-induced airway contraction (in vivo, intratracheal administration)]
In healthy guinea pigs, the inhibitory effect on airway contraction by neurokinin A (NKA), an NK 2 receptor agonist, was modified by a modification of Konzet-Roessler (Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 195, 71 (1940)). Using it, airway pressure can be examined as an index.
　表１乃至表３の結果から、本発明の化合物は、ニューロキニンＮＫ１、ニューロキニンＮＫ２及びムスカリンＭ３受容体に対して、又は、ニューロキニンＮＫ１及びムスカリンＭ３受容体に対して、優れた拮抗作用を有し、気管支喘息、気管支炎、慢性閉塞性肺疾患、咳嗽、喀痰過分泌、鼻炎、痛み、不安、うつ、痙攣、パーキンソン、尿失禁、過敏性腸症候群、前立腺肥大、嘔吐、消化性潰瘍、網膜検査、急性虹彩炎、角膜炎、縮瞳、麻酔薬による過剰の唾液分泌、気道分泌及び潰瘍からなる群から選ばれる疾患の治療剤及び／又は予防剤として有用である。 From the results of Tables 1 to 3, 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. Has superior antagonism, bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, sputum secretion, rhinitis, pain, anxiety, depression, convulsions, parkinson, urinary incontinence, irritable bowel syndrome, prostatic hypertrophy, vomiting It is useful as a therapeutic and / or prophylactic agent for diseases selected from the group consisting of peptic ulcer, retinal examination, acute iritis, keratitis, miosis, excessive salivation by anesthetic, airway secretion and ulcer.
　製剤例
　製剤例１　散剤
　実施例１の化合物　５ｇ、乳糖　８９５ｇおよびトウモロコシデンプン　１００ｇをブレンダーで混合することにより、散剤が得られる。 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.
　製剤例２　顆粒剤
　実施例１の化合物　５ｇ、乳糖　８６５ｇおよび低置換度ヒドロキシプロピルセルロース　１００ｇを混合した後、１０％ヒドロキシプロピルセルロース水溶液　３００ｇを加えて練合する。これを押し出し造粒機を用いて造粒し、乾燥すると顆粒剤が得られる。 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.
　製剤例３　錠剤
　実施例４の化合物　５ｇ、乳糖　９０ｇ、トウモロコシデンプン　３４ｇ、結晶セルロース　２０ｇおよびステアリン酸マグネシウム　１ｇをブレンダーで混合した後、錠剤機で打錠することにより、錠剤が得られる。 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.
　製剤例４　吸入用液剤１
　実施例９の化合物が１０％（Ｗ／Ｗ）、塩化ベンザルコニウムが０．０４％（Ｗ／Ｗ）、フェネチルアルコールが０．４０％（Ｗ／Ｗ）、精製水が８９．５６％（Ｗ／Ｗ）となるように液剤を調製する。 Formulation 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.
　製剤例５　吸入用液剤２
　実施例７の化合物が１０％（Ｗ／Ｗ）、塩化ベンザルコニウムが０．０４％（Ｗ／Ｗ）、ポリエチレングリコールが１０％（Ｗ／Ｗ）、プロピレングリコールが３０％（Ｗ／Ｗ）、精製水が３９．９６％（Ｗ／Ｗ）となるように液剤を調製する。 Formulation 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).
　製剤例６　吸入用散剤
　実施例９の化合物が４０％（Ｗ／Ｗ）、ラクトースが６０％（Ｗ／Ｗ）となるように散剤を調製する。 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).
　製剤例７　エアゾール剤
　実施例７の化合物が１０％（Ｗ／Ｗ）、レシチンが０．５％（Ｗ／Ｗ）、フロン１１が３４．５％（Ｗ／Ｗ）、フロン１２が５５％（Ｗ／Ｗ）となるようにエアゾール剤を調製する。 Formulation Example 7 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).
　本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、ニューロキニンＮＫ１、ニューロキニンＮＫ２及びムスカリンＭ３受容体に対して、又は、ニューロキニンＮＫ１及びムスカリンＭ３受容体に対して、拮抗作用を示し、毒性が少なく、体内動態が優れているので、医薬として有用であり、特に、呼吸器疾患、アレルギー疾患及び／又は神経系疾患の予防剤若しくは治療剤として有用である。
  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.

Claims (29)

  1. 　一般式（Ｉ）
    Figure JPOXMLDOC01-appb-C000001
    ［式中、
    　Ｙは、ニューロキニンＮＫ１及びニューロキニンＮＫ２受容体拮抗作用を有する部分構造又はニューロキニンＮＫ１受容体拮抗作用を有する部分構造を示し、
    　Ａは、単結合、三重結合、酸素原子、カルボニル基、カルボニルアミノ基、アミノカルボニル基、式（ＩＩ）で表される基、式（ＩＩＩ）で表される基又は式（ＩＶ）で表される基
    Figure JPOXMLDOC01-appb-C000002
    （Ｒ１は、水素原子又はＣ１－Ｃ６アルキル基を示し、
    Ｒ２は、水素原子又はＣ１－Ｃ６アルキル基を示し、
    Ｒ３は、水素原子又はＣ１－Ｃ６アルキル基を示し、
    Ｌ１は、オキシカルボニル基、カルボニルオキシ基、（メチルアミノ）カルボニル基又はカルボニル（メチルアミノ）基を示し、
    Ｌ２は、単結合又はフェニレン基を示し、
    Ｌ３は、Ｃ１－Ｃ６アルキレン基を示し、
    ｐは、１乃至６の整数を示し、
    ｑは、０乃至４の整数を示し、
    ｒは、１乃至８の整数を示し、
    ｓは、１乃至８の整数を示し、
    ｔは、１乃至４の整数を示し、
    ＣＹ及びＣＥは、単結合を示す。
    ＣＹは、式Ｙで表わされる基に結合し、ＣＥは、式Ｅで表わされる基に結合する。
    Ｒ２がＣ１－Ｃ６アルキル基の場合、Ｒ２の任意の炭素原子はＬ３の任意の炭素原子と結合してもよい。）を示し、
    　Ｅは、ムスカリンＭ３受容体拮抗作用を有する部分構造を示し、
    　ｍは、０乃至４の整数を示し、
    　ｎは、１乃至８の整数を示す。］を有する化合物又はその薬理上許容される塩。     Formula (I)
    Figure JPOXMLDOC01-appb-C000001
    [Where:
    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). Base
    Figure JPOXMLDOC01-appb-C000002
    (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, and C E is bonded to the group represented by Formula E.
    When 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. Or a pharmacologically acceptable salt thereof.
  2. 　請求項１において、Ｙが、式（Ｖ）で表される基、式（ＶＩ）で表される基又は式（ＶＩＩ）で表される基
    Figure JPOXMLDOC01-appb-C000003
    （Ｒ４は、置換基群Ａから選択される基で独立に１乃至５個置換されていてもよいフェニル基又は置換基群Ａから選択される基で独立に１乃至３個置換されていてもよい複素環基を示し、
    Ｒ５は、置換基群Ａから選択される基で独立に１乃至５個置換されていてもよいフェニル基又は置換基群Ａから選択される基で独立に１乃至３個置換されていてもよい複素環基を示し、
    Ｒ６は、水素原子又はＣ１－Ｃ６アルキル基を示し、
    Ｒ７は、置換基群Ａから選択される基で独立に１乃至５個置換されていてもよいフェニル基又は置換基群Ａから選択される基で独立に１乃至３個置換されていてもよい複素環基を示し、
    ｕは、１又は２を示し、
    置換基群Ａは、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ハロゲン化アルキル基、ヒドロキシ基、Ｃ１－Ｃ６アルコキシ基、Ｃ１－Ｃ６ハロゲン化アルコキシ基、シアノ基、カルボキシル基、Ｃ２－Ｃ７アルキルカルボニルオキシ基、Ｃ２－Ｃ７アルコキシカルボニルオキシ基、カルバモイル基、ニトロ基及びアミノ基からなる群を示す。
    Ｃｍは、単結合を示し、式－（ＣＨ２）ｍ－で表わされる基に結合する。）である化合物又はその薬理上許容される塩。     In Claim 1, Y is the group represented by the group represented by the group represented by the formula (V), the formula (VI), or the formula (VII).
    Figure JPOXMLDOC01-appb-C000003
    (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, a C 1 -C 6 alkoxy group, a C 1 -C 6 halogenated alkoxy group, and a cyano group. , A carboxyl group, a C 2 -C 7 alkylcarbonyloxy group, a C 2 -C 7 alkoxycarbonyloxy group, a carbamoyl group, a nitro group and an amino 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.
  3. 　請求項１又は２において、Ｅが、式（ＶＩＩＩ）で表される基、式（ＩＸ）で表される基、式（Ｘ）で表される基、式（ＸＩ）で表される基又は式（ＸＩＩ）で表される基
    Figure JPOXMLDOC01-appb-C000004
    （Ｃｎは、単結合を示し、式－（ＣＨ２）ｎ－で表わされる基に結合する。）である化合物又はその薬理上許容される塩。     In Claim 1 or 2, E is a group represented by formula (VIII), a group represented by formula (IX), a group represented by formula (X), a group represented by formula (XI), or Group represented by formula (XII)
    Figure JPOXMLDOC01-appb-C000004
    (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.
  4. 　請求項１乃至３から選択されるいずれか一項において、一般式（Ｉ）が、一般式（Ｉａ）
    Figure JPOXMLDOC01-appb-C000005
    である化合物又はその薬理上許容される塩。     In any one selected from Claim 1 thru | or 3, General formula (I) is general formula (Ia).
    Figure JPOXMLDOC01-appb-C000005
    Or a pharmacologically acceptable salt thereof.
  5. 　請求項４において、Ｒ１が、水素原子又はメチル基であり、Ｌ１が、オキシカルボニル基、カルボニルオキシ基、（メチルアミノ）カルボニル基又はカルボニル（メチルアミノ）基であり、Ｌ２が、単結合又はフェニレン基であり、ｐが、２乃至４の整数であり、ｑが、０又は１であり、ｒが、１乃至５の整数である化合物又はその薬理上許容される塩。 In Claim 4, 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, and L 2 is a simple group. A compound or a pharmacologically acceptable salt thereof, which is a bond or a phenylene group, p is an integer of 2 to 4, q is 0 or 1, and r is an integer of 1 to 5.
  6. 　請求項１乃至３から選択されるいずれか一項において、一般式（Ｉ）が、一般式（Ｉｂ）
    Figure JPOXMLDOC01-appb-C000006
    である化合物又はその薬理上許容される塩。     In any one selected from Claim 1 thru | or 3, General formula (I) is general formula (Ib).
    Figure JPOXMLDOC01-appb-C000006
    Or a pharmacologically acceptable salt thereof.
  7. 　請求項６において、ｎが、２乃至５の整数である化合物又はその薬理上許容される塩。 The compound or a pharmacologically acceptable salt thereof according to claim 6, wherein n is an integer of 2 to 5.
  8. 　請求項１乃至３から選択されるいずれか一項において、一般式（Ｉ）が、一般式（Ｉｃ）
    Figure JPOXMLDOC01-appb-C000007
    である化合物又はその薬理上許容される塩。     In any one selected from Claims 1 thru | or 3, General formula (I) is general formula (Ic).
    Figure JPOXMLDOC01-appb-C000007
    Or a pharmacologically acceptable salt thereof.
  9. 　請求項８において、ｓが、３乃至６の整数であり、ｍが、２乃至４の整数である化合物又はその薬理上許容される塩。 The compound or a pharmacologically acceptable salt thereof according to claim 8, wherein s is an integer of 3 to 6, and m is an integer of 2 to 4.
  10. 　請求項１乃至３から選択されるいずれか一項において、一般式（Ｉ）が、一般式（Ｉｄ）
    Figure JPOXMLDOC01-appb-C000008
    である化合物又はその薬理上許容される塩。     In any one selected from Claims 1 thru | or 3, General formula (I) is General formula (Id).
    Figure JPOXMLDOC01-appb-C000008
    Or a pharmacologically acceptable salt thereof.
  11. 　請求項１０において、Ｒ３が、水素原子又はメチル基であり、ｔが、１乃至４の整数であり、ｍが、１乃至４の整数であり、ｎが、１乃至４の整数である化合物又はその薬理上許容される塩。 The compound according to claim 10, wherein R 3 is a hydrogen atom or a methyl group, t is an integer of 1 to 4, m is an integer of 1 to 4, and n is an integer of 1 to 4. Or a pharmacologically acceptable salt thereof.
  12. 　４－［（｛４－［（２－｛４－［（ビフェニル－２－イルカルバモイル）オキシ］ピペリジン－１－イル｝エチル）（メチル）カルバモイル］ベンジル｝アミノ）メチル］フェニル　４－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］ブタノエート、
    （３Ｒ）－１－｛２－［｛６－［４－（｛３－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）アミノ］プロピル｝カルバモイル）ピペリジン－１－イル］ヘキサノイル｝（メチル）アミノ］エチル｝ピロリジン－３－イル　ヒドロキシ（ジチオフェン－２－イル）アセテート、
    Ｎ－（２－｛［２－（４－｛２－［（３Ｓ）－３－（２－アミノ－２－オキソ－１，１－ジフェニルエチル）ピロリジン－１－イル］エチル｝フェニル）エチル］アミノ｝エチル）－２－｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－｛［３，５－ビス（トリフルオロメチル）フェニル］カルボニル｝－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝－Ｎ－メチルアセタミド、
    １－（２－｛[６－（｛４－[{３－[（Ｎ－{５－[｛２－[３，５－ビス（トリフルオロメチル）フェニル]－２－メチルプロパノイル｝（メチル）アミノ]－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル)アミノ]プロピル}（メチル）カルバモイル]フェニル}アミノ)ヘキサノイル]（メチル）アミノ｝エチル）ピペリジン－４－イル ビフェニル－２－イルカーバメート、
    １－｛２－［（｛４－［（｛４－［｛３－［（Ｎ－｛５－［｛２－［３，５－ビス（トリフルオロメチル）フェニル］－２－メチルプロパノイル｝（メチル）アミノ］－４－（２－メチルフェニル）ピリジン－２－イル｝－Ｎ－メチルグリシル）（メチル）アミノ］プロピル｝（メチル）カルバモイル］フェニル｝アミノ）メチル］フェニル｝カルボニル）（メチル）アミノ］エチル｝ピペリジン－４－イル　ビフェニル－２－イルカーバメート、又は、
    （３Ｒ）－１－｛４－［（｛［（２Ｓ）－１’－｛２－［（５Ｒ）－３－［３，５－ビス（トリフルオロメチル）ベンゾイル］－５－（４－フルオロフェニル）－１，３－オキサゾリジン－５－イル］エチル｝－２，３－ジヒドロスピロ［インデン－１，４’－ピペリジン］－２－イル］オキシ｝アセチル）（メチル）アミノ］ブチル｝ピロリジン－３－イル　ヒドロキシ（ジ－２－チエニル）アセテート
    である化合物又はその薬理上許容される塩。     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,
    (3R) -1- {2-[{6- [4-({3-[({[(2S) -1 '-{2-[(5R) -3-{[3,5-bis (tri Fluoromethyl) 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) piperidin-1-yl] hexanoyl} (methyl) amino] ethyl} pyrrolidin-3-yl hydroxy (dithiophen-2-yl) acetate,
    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,
    1- (2-{[6-({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) hexanoyl] (methyl) amino} ethyl) piperidine- 4-yl biphenyl-2-yl carbamate,
    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, or
    (3R) -1- {4-[({[(2S) -1 ′-{2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluoro Phenyl) -1,3-oxazolidine-5-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl} pyrrolidine- 3-yl hydroxy (di-2-thienyl) acetate compound or a pharmacologically acceptable salt thereof.
  13. 　請求項１乃至１２から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof as an active ingredient.
  14. 　医薬組成物が、気管支拡張作用及び抗炎症作用を有する請求項１３に記載された医薬組成物。 The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition has a bronchodilating action and an anti-inflammatory action.
  15. 　医薬組成物が、ニューロキニンＮＫ１、ニューロキニンＮＫ２及び／又はムスカリンＭ３受容体が介在する疾患又はニューロキニンＮＫ１及び／又はムスカリンＭ３受容体が介在する疾患の治療及び／又は予防のための請求項１３に記載された医薬組成物。 A pharmaceutical composition for treating and / or preventing a neurokinin NK 1 , a neurokinin NK 2 and / or a disease mediated by a muscarinic M 3 receptor or a disease mediated by a neurokinin NK 1 and / or a muscarinic M 3 receptor A pharmaceutical composition according to claim 13 for.
  16. 　医薬組成物が、呼吸器疾患、アレルギー疾患及び／又は神経系疾患の治療及び／又は予防のための請求項１３に記載された医薬組成物。 14. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition is for the treatment and / or prevention of respiratory diseases, allergic diseases and / or nervous system diseases.
  17. 　医薬組成物が、気管支喘息、気管支炎、慢性閉塞性肺疾患、咳嗽、喀痰過分泌、鼻炎、痛み、不安、うつ、痙攣、パーキンソン、尿失禁、過敏性腸症候群、前立腺肥大、嘔吐、消化性潰瘍、網膜検査、急性虹彩炎、 角膜炎、縮瞳、麻酔薬による過剰の唾液分泌、気道分泌及び／又は潰瘍の治療及び／又は予防のための請求項１３に記載された医薬組成物。 The pharmaceutical composition is bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, vaginal hypersecretion, rhinitis, pain, anxiety, depression, convulsions, parkinson, urinary incontinence, irritable bowel syndrome, prostatic hypertrophy, vomiting, digestibility 14. A pharmaceutical composition according to claim 13 for the treatment and / or prevention of ulcers, retinal examination, acute iritis, keratitis, miosis, excessive salivation by anesthetics, airway secretion and / or ulcers.
  18. 　医薬組成物が、気管支喘息及び／又は慢性閉塞性肺疾患の治療及び／又は予防のための請求項１３に記載された医薬組成物。 14. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition is for the treatment and / or prevention of bronchial asthma and / or chronic obstructive pulmonary disease.
  19. 　医薬組成物が、経肺投与及び／又は点鼻投与するための、請求項１６乃至１８から選択されるいずれか一項に記載された医薬組成物。 The pharmaceutical composition according to any one of claims 16 to 18, wherein the pharmaceutical composition is for pulmonary administration and / or nasal administration.
  20. 　医薬組成物を製造するための、請求項１乃至１２から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の使用。 Use of the compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.
  21. 　医薬組成物が、気管支拡張作用及び抗炎症作用を有するための医薬組成物である請求項２０に記載の使用。 21. The use according to claim 20, wherein the pharmaceutical composition is a pharmaceutical composition for having bronchodilating action and anti-inflammatory action.
  22. 　医薬組成物が、ニューロキニンＮＫ１、ニューロキニンＮＫ２及び／又はムスカリンＭ３受容体が介在する疾患又はニューロキニンＮＫ１及び／又はムスカリンＭ３受容体が介在する疾患の治療及び／又は予防のための組成物である請求項２０に記載の使用。 A pharmaceutical composition for treating and / or preventing a neurokinin NK 1 , a neurokinin NK 2 and / or a disease mediated by a muscarinic M 3 receptor or a disease mediated by a neurokinin NK 1 and / or a muscarinic M 3 receptor 21. Use according to claim 20, which is a composition for.
  23. 　医薬組成物が、気管支喘息、気管支炎、慢性閉塞性肺疾患、咳嗽、喀痰過分泌、鼻炎、痛み、不安、うつ、痙攣、パーキンソン、尿失禁、過敏性腸症候群、前立腺肥大、嘔吐、消化性潰瘍、網膜検査、急性虹彩炎、 角膜炎、縮瞳、麻酔薬による過剰の唾液分泌、気道分泌及び／又は潰瘍の治療及び／又は予防のための組成物である請求項２０に記載の使用。 The pharmaceutical composition is bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, vaginal hypersecretion, rhinitis, pain, anxiety, depression, convulsions, parkinson, urinary incontinence, irritable bowel syndrome, prostatic hypertrophy, vomiting, digestibility Use according to claim 20, which is a composition for the treatment and / or prevention of ulcers, retinal examinations, acute iritis, keratitis, miosis, excessive salivation by anesthetics, airway secretion and / or ulcers.
  24. 　医薬組成物が、経肺投与及び／又は点鼻投与するための医薬組成物である、請求項２３に記載された使用。 The use according to claim 23, wherein the pharmaceutical composition is a pharmaceutical composition for pulmonary administration and / or nasal administration.
  25. 　請求項１乃至１２から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の薬理的な有効量を温血動物に投与する疾病の治療及び／又は予防方法。 A method for treating and / or preventing a disease, comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof.
  26. 　疾病が、ニューロキニンＮＫ１、ニューロキニンＮＫ２及び／又はムスカリンＭ３受容体が介在する疾患又はニューロキニンＮＫ１及び／又はムスカリンＭ３受容体が介在する疾患である請求項２５に記載の方法。 Disease, The method of claim 25 neurokinin NK 1, neurokinin NK 2 and / or muscarinic M 3 diseases receptor-mediated or neurokinin NK 1 and / or muscarinic M 3 receptor is mediated diseases .
  27. 　疾病が、気管支喘息、気管支炎、慢性閉塞性肺疾患、咳嗽、喀痰過分泌、鼻炎、痛み、不安、うつ、痙攣、パーキンソン、尿失禁、過敏性腸症候群、前立腺肥大、嘔吐、消化性潰瘍、網膜検査、急性虹彩炎、角膜炎、縮瞳、麻酔薬による過剰の唾液分泌、気道分泌及び／又は潰瘍である請求項２５に記載の方法。 The disease 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, peptic ulcer, 26. The method of claim 25, wherein the method is retinal examination, acute iritis, keratitis, miosis, excessive salivation by anesthetic, airway secretion and / or ulcer.
  28. 　一般式（Ｉ）を有する化合物又はその薬理上許容される塩を経肺投与及び／又は点鼻投与することを特徴とする、請求項２７に記載された方法。 The method according to claim 27, wherein the compound having the general formula (I) or a pharmacologically acceptable salt thereof is administered by pulmonary administration and / or nasal administration.
  29. 　温血動物がヒトである請求項２５乃至２８から選択されるいずれか一項に記載の方法。 The method according to any one of claims 25 to 28, wherein the warm-blooded animal is a human.
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Cited By (1)

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

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000034288A (en) * 1998-01-23 2000-02-02 Sankyo Co Ltd Spiropiperidine derivative
JP2005272455A (en) * 2004-02-25 2005-10-06 Sankyo Co Ltd Indanol derivative
JP2006160639A (en) * 2004-12-06 2006-06-22 Sankyo Co Ltd Combined use of neurokinin receptor antagonist and anti-cholin agent
JP2008546695A (en) * 2005-06-13 2008-12-25 セラヴァンス， インコーポレーテッド Biphenyl compounds useful as muscarinic receptor antagonists
WO2010106988A1 (en) * 2009-03-17 2010-09-23 第一三共株式会社 Amide derivative

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000034288A (en) * 1998-01-23 2000-02-02 Sankyo Co Ltd Spiropiperidine derivative
JP2005272455A (en) * 2004-02-25 2005-10-06 Sankyo Co Ltd Indanol derivative
JP2006160639A (en) * 2004-12-06 2006-06-22 Sankyo Co Ltd Combined use of neurokinin receptor antagonist and anti-cholin agent
JP2008546695A (en) * 2005-06-13 2008-12-25 セラヴァンス， インコーポレーテッド Biphenyl compounds useful as muscarinic receptor antagonists
WO2010106988A1 (en) * 2009-03-17 2010-09-23 第一三共株式会社 Amide derivative

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016021562A1 (en) * 2014-08-06 2016-02-11 キッセイ薬品工業株式会社 Cyanothiophene derivative
JPWO2016021562A1 (en) * 2014-08-06 2017-06-15 キッセイ薬品工業株式会社 Cyanothiophene derivatives

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