WO2007089031A1 - Dérivés de pipéridine comme antagonistes des récepteurs des tachykinines - Google Patents

Dérivés de pipéridine comme antagonistes des récepteurs des tachykinines Download PDF

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Publication number
WO2007089031A1
WO2007089031A1 PCT/JP2007/052160 JP2007052160W WO2007089031A1 WO 2007089031 A1 WO2007089031 A1 WO 2007089031A1 JP 2007052160 W JP2007052160 W JP 2007052160W WO 2007089031 A1 WO2007089031 A1 WO 2007089031A1
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group
substituent
optionally
group optionally
compound
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PCT/JP2007/052160
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Junya Shirai
Takeshi Yoshikawa
Hideyuki Sugiyama
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Takeda Pharmaceutical Company Limited
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Publication of WO2007089031A1 publication Critical patent/WO2007089031A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel piperidine derivative having excellent antagonistic action for a tachykinin receptor, and use thereof.
  • Tachykinin is a generic term for a group of neuropeptides.
  • Substance P SP
  • neurokinin-A and neurokinin-B are known in mammals, and these peptides are known to bind to the corresponding receptors (neurokinin-1 , neurokinin-2 and neurokinin-3) that exist in a living body and thereby to exhibit various biological activities.
  • SP is a peptide consisting of 11 amino acids.
  • SP is broadly distributed over the central and peripheral nervous systems, and has various physiological activities such as vasodilation, enhancement of vascular extravasation, contraction of smooth muscles, excitation of neurons, salivation, enhancement of diuresis, immunological enhancement and the like, in addition to the function as a transmitter substance for primary sensory neurons.
  • various physiological activities such as vasodilation, enhancement of vascular extravasation, contraction of smooth muscles, excitation of neurons, salivation, enhancement of diuresis, immunological enhancement and the like, in addition to the function as a transmitter substance for primary sensory neurons.
  • SP released from the terminal in the spinal (dorsal) horn due to a pain impulse transmits the information of pain to secondary neurons, and that SP released from the peripheral terminal induces an inflammatory response in the receptor thereof.
  • SP is involved in various disorders (e.g., pain, headache, particularly migraine, Alzheimer's disease, multiple sclerosis, cardiovascular, modulation, chronic inflammatory diseases such as chronic rheumatic arthritis, respiratory diseases including asthma or allergic rhinitis, intestinal inflammatory diseases including ulcerative colitis and Crohn's disease, ocular damage and ocular inflammatory diseases, proliferative vitreous retinopathy, irritable bowel syndrome, urinary frequency, psychosis, vomiting, etc.) [see a review article: Physiological Reviews, VoI 73, pp. 229-308 (1993); Journal of Autonomic Pharmacology, Vol. 13, pp. 23-93 (1993)].
  • disorders e.g., pain, headache, particularly migraine, Alzheimer's disease, multiple sclerosis, cardiovascular, modulation, chronic inflammatory diseases such as chronic rheumatic arthritis, respiratory diseases including asthma or allergic rhinitis, intestinal inflammatory diseases including ulcerative colitis and Crohn's disease, ocular damage and ocular inflammatory diseases,
  • EP-A-436, 334 disclosed are the compound of the formula:
  • R a and R b are bonded to each other to form ring A, or they are the same or different and represent a hydrogen atom or a substituent in Ring M;
  • ring A and B are homocyclic or heterocyclic rings optionally having substituent (s) , respectively and at least one of them is a heterocyclic ring optionally having substituent ( s );
  • Ring C is a homocyclic or heterocyclic ring optionally having substituent (s) ;
  • Ring Z is a nitrogen-containing heterocyclic ring optionally having substituent ( s ) ; and n is an integer of 1 to 6, or salts thereof, and the like.
  • WO03/101964 describes a compound having a tachykinin receptor antagonistic action, which is represented by the formula:
  • Ar is an aryl group, an aralkyl group or an aromatic heterocyclic group, each of which optionally having substituent ( s) , R 1 is a hydrogen atom, a hydrocarbon group optionally having substituent ( s) , an acyl group or a heterocyclic group optionally having substituent (s) , X is an oxygen atom or an imino group optionally having a substituent, Z is a methylene group optionally having substituent ( s) , ring A is a piperidine ring optionally further having substituent ( s ), ring B is an aromatic ring optionally having substituent (s) , provided when Z is a methylene group substituted by an oxo group, then R 1 is not a methyl group and when Z is a methylene group substituted by a methyl group, then B is an aromatic ring having substituent ( s) , or a salt thereof.
  • US 2005/0256164 A describes a compound having a tachykinin receptor antagonistic action, which is represented by the formula: wherein m is 0 or 1 ; n is 0 or 1; s is 0 or 1; L is -0- or -N(R 4 )-; R 1 and R 2 are each independently hydrogen atom, aryl, heteroaryl, Ci- 6 alkyl, heterocyloalkyl, Ci-6 alkylheterocycloalkyl, Ci- 6 alkylheteroaryl, Ci-6 alkyl-0-aryl, Ci_ s alkylaryl, and -CH 2 N(R 4 ) (R 5 ), wherein each of said heterocyloalkyl, Ci_ 6 alkylheterocycloalkyl, Ci-6 alkylheteroaryl, Ci- 6 alkyl-O-aryl, aryl, C ⁇ - ⁇ ' alkylaryl, heteroaryl and -GH 2 N(R 4
  • An object of the present invention is to provide a piperidine derivative having antagonistic action for a tachykinin receptor, etc. with a different chemical structure from the known compounds including the above- mentioned compounds, an agent for the prophylaxis or treatment of lower urinary tract diseases comprising the compound, and the like.
  • the present invention relates to: [1] a compound represented by the formula (I) :
  • Ar is a phenyl group optionally having substituent (s ) ,
  • R 1 is a hydrogen atom, a hydrocarbon group optionally having- substituent (s) ,. an acyl group or a heterocyclic group optionally having substituent ( s ),
  • Z is a methylene group optionally , having Ci- ⁇ alkyl group (s)
  • ring A is a piperidine ring optionally further having substituent (s)
  • B is a monocyclic aromatic heterocyclic group optionally having substituent ( s) ( substituents of monocyclic aromatic heterocycle may be bonded to each other to form a ring) or a salt thereof;
  • Ci_ 6 alkyl-carbonyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci- 6 alkyl-carbonylamino group, (b) a 5- or 6-membered nitrogen-containing heterocyclic group optionally having 1 to 4 substituents selected from the group consisting of a Ci-e alkyl group and an oxo group, (c) a carbamoyl group, (d) a hydroxy group and (e) a Ci_ 6 alkylsulfonyl group,
  • a 5- or 6-membered nitrogen-containing heterocycle- carbonyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci- 6 alkyl group, (b) an oxo group and (c) Ci-6 alkyl-carbonyl group optionally having hydroxy group (s), or
  • a pyrimidyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci-6 alkyl group, (b) a Ci-6 alkoxy group optionally having halogen atom(s) and (c) a C3-6 cycloalkyl group,
  • a pyrazolyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci-s alkoxy group and (b) a C s _ 10 aryl group optionally having halogen atom(s) or
  • thiazolyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci-6 alkoxy group and (b) a C s _ 10 aryl group; [11] the compound of the above-mentioned [I]/ wherein Ar is a phenyl group, R 1 is (1) a hydrogen atom,
  • Ci- 6 alkyl-carbonyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci- 6 alkyl-carbonylamino group, (b) a 5- or 6-membered nitrogen-containing heterocyclic group optionally having 1 to 4 substituents selected from the group consisting of a Ci_ 6 alkyl group and an oxo group, (c) a carbamoyl group, (d) a hydroxy group and (e) a Ci-e alkylsulfonyl group, (3) a Ci_6 alkoxy-carbonyl group,
  • a 5- or 6-membered nitrogen-containing heterocycle- carbonyl group optionally having 1 to 3 substituents ⁇ selected from the group consisting of (a) a Ci- ⁇ alkyl group, (b) an oxo group and '(c) a Ci- 6 alkyl-carbonyl group optionally having hydroxy group (s), or
  • (6) a mono-Ci-6 alkyl-carbamoyl group, Z is a methylene group, ring A is a piperidine ring without further substituent ( s ) , and
  • B is (1) a pyridyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a halogen atom, (b) a Ci- S alkyl group, (c) a hydroxy group, (d) a Ci_6 alkoxy group, (e) a C ⁇ -io aryl group optionally having cyano group (s) and (f) a nitrogen- containing aromatic heterocyclic group optionally substituted by Ci-6 alkyl group (s) optionally having halogen atom(s), (2) a pyrimidyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci_ 6 alkyl group, (b) a C 3. -6 alkoxy group optionally having halogen atom(s) and (c) a C 3 - 6 cycloalkyl group,
  • a pyrazolyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci- 6 alkoxy group and (b) a C ⁇ -IO aryl group optionally having halogen atom(s) or
  • thiazolyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci_6 alkoxy group and (b) a C ⁇ -io aryl group;
  • Ar is a phenyl group optionally having substituent (s ) ,
  • R 1 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) , an acyl group or a heterocyclic group optionally having substituent ( s ), Z is a methylene group optionally having C ⁇ -6 alkyl group (s) , ring A is a piperidine ring optionally further having substituent ( s) , and
  • B is a monocyclic aromatic heterocyclic group optionally having substituent ( s) (substituents of monocyclic aromatic heterocycle may be bonded to each other to form a ring) or a salt thereof;
  • Ar is a phenyl group optionally having substituent (s ),
  • R 1 is a hydrogen atom, a hydrocarbon group optionally having substituent ( s ) , an acyl group or a heterocyclic group optionally having substituent ( s ),
  • Z is a methylene group optionally having Ci-6 alkyl group (s)
  • ring A is a piperidine ring
  • B is a monocyclic aromatic heterocyclic group optionally having substituent ( s) (substituents of monocyclic aromatic heterocycle may be bonded to each other to form a ring) or a salt thereof, or a prodrug thereof and a pharmaceutically acceptable carrier;
  • Ar is a phenyl group optionally having substituent (s )
  • R 1 is a hydrogen atom, a hydrocarbon group optionally having substituent ( s ), an acyl group or a heterocyclic group optionally having substituent ( s ),
  • Z is a methylene group optionally having C ⁇ -6 alkyl group (s)
  • ring A is a piperidine ring optionally further having substituent ( s )
  • B is a monocyclic aromatic heterocyclic group optionally having substituent ( s ) (substituents of monocyclic aromatic heterocycle may be bonded to each other to form a ring) or a salt thereof, or a prodrug thereof;
  • Ar is a phenyl group optionally having substituent (s )
  • R 1 is a hydrogen atom, a hydrocarbon group optionally having substituent ( s) , an acyl group or a heterocyclic group optionally having substituent (s )
  • Z is a methylene group optionally having Ci-6 alkyl group (s)
  • ring A is a piperidine ring optionally further having substituent ( s)
  • B. is a monocyclic aromatic heterocyclic group optionally having substituent ( s) (substituents of monocyclic aromatic heterocycle may be bonded to each other to form a ring) or a salt thereof, or a prodrug thereof for the production of an agent for the prophylaxis or treatment of lower urinary tract disease, gastrointestinal disease or central nervous system disease; and the like.
  • Ar is a phenyl group optionally having substituent ( s ) .
  • the substituent for the "phenyl group” includes, for example, 1 to 3 substituents selected from the group consisting of (1) halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (2) Ci_ 3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, etc.), (3) nitro, (4) cyano, (5) optionally halogenated Ci- 6 alkyl, (6) optionally halogenated C2-6 alkenyl, (7) optionally halogenated C 2 -6 alkynyl, (8) optionally halogenated C3-6 cycloalkyl, (9) C 6 -i4 aryl (e.g., phenyl, 1-naphthyl, 2- naphthyl, biphenylyl, 2-anthryl, etc.) optionally substituted with substituent (s), halogen
  • di-C ⁇ - 14 arylamino e.g., diphenylamino , etc.
  • acyl (19) acylamino, (20) acyloxy, (21) 5- to 7- membered cyclic amino optionally having substituent ( s) , (22) 5- to 10-membered aromatic heterocyclic group optionally substituted with optionally halogenated C ⁇ -6 alkyl (e.g., 1-, 2- or 3- pyrrolyl, 1-, 2-, 4- or 5- imidazolyl, 1- , 3-, 4- or 5- pyrazolyl, 1- or 3- triazolyl, 1-, 2- or 5- tetrazolyl, 2-, 4- or 5- thiazolyl, 3-, 4- or 5- isothiazolyl, 2-, 4- or 5- oxazolyl, 3-, 4- or 5- isoxazolyl, furazanyl, 2- or 3- furyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- pyrazinyl, 2-, 4- or 5-pyrimidinyl, 3- or 4-pyridazinyl, 2-, 3-, 4-, 5-, 5-
  • Ci- 6 alkyl includes, for example, Ci- 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), optionally having 1 to 5, preferably 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine, etc.) and the like, specifically, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2, 2, 2-trifluoroethyl, pentafluoroethyl , propyl, 3,3,3- trifluoropropyl, isopropyl, butyl, 4, 4 , 4-trifluorobutyl , isobutyl, sec-butyl,
  • the "optionally halogenated C 2 -e alkenyl” includes, for example, C 2 -6 alkenyl (e.g., vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine, etc.) ' and the like, specifically, vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, 3,3,3- trifluoro-1-propenyl, 4, 4, 4-trifluoro-1-butenyl, etc.
  • C 2 -6 alkenyl e.g., vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, 3,3,3- trifluoro-1-propenyl, 4, 4, 4-triflu
  • the "optionally halogenated C 2 -6 alkynyl” includes, for example, C 2 -6 alkynyl (e.g., ethynyl, propargyl, butynyl, 1-hexynyl, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.) and the like, specifically, ethynyl, propargyl, butynyl, 1-hexynyl, 3,3, 3-trifluoro-1-propynyl, 4,4, 4-trifluoro-1-butynyl, etc.
  • C 2 -6 alkynyl e.g., ethynyl, propargyl, butynyl, 1-hexynyl, 3,3, 3-trifluoro-1-propynyl, 4,4, 4-trifluoro-1-butynyl, etc.
  • the "optionally halogenated C3-.6 cycloalkyl” includes, for example, C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine, etc.) and the like, specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4- dichlorocyclohexyl, 2, 2 , 3, 3-tetrafluorocyclopentyl, 4- chlorocyclohexyl, etc.
  • C3-6 cycloalkyl e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • 1 to 3 halogen atom(s) e
  • Ci_ 6 alkoxy includes, for example, Ci_ 6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,' se.c-butoxy, pentyloxy, hexyloxy, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine, etc.) and the like, specifically, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2- trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4- trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.
  • Ci_ 6 alkoxy e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,' se.c-butoxy, pentyloxy
  • Ci_ e alkylthio e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec- butylthio, tert-butylthio, etc.
  • halogen atom(s) e.g., fluorine, chlorine, bromine, iodine, etc.
  • hydrocarbon group optionally having substituent ( s )" represented by R 3 , R 4 or R 4 ' includes, for example, the same group as those referred to herein for the "hydrocarbon group optionally having substituent (s) " represented by R 1 which will be described below.
  • the "substituent” for the "amino group optionally having substituent (s) " represented by R 3 includes, for example, a hydrocarbon group optionally having substituent (s) , a heterocyclic group optionally having substituent (s) , a hydroxy group optionally having a substituent, an acyl group and the like.
  • the "hydrocarbon group optionally having substituent ( s) " as the “substituent” for the "amino group optionally having substituent ( s )” represented by R 3 includes, for example, the same group as those referred to herein for the "hydrocarbon group optionally having substituent ( s) " represented by R 1 which will be described below.
  • heterocyclic group optionally having substituent (s) " as the "substituent” in the "amino group optionally having substituent ( s )" represented by R 3 includes, for example, the same group as those referred to herein for the "heterocyclic group optionally having substituent ( s) " represented by R 1 which will be described below.
  • the "hydroxy group optionally having a substituent" as the "substituent” for the "amino group optionally having substituent ( s) " represented by R 3 includes, for example, (i) hydroxy group, (ii) Ci_ 6 alkoxy group (e.g., methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, t-butoxy group, etc.), (iii) C ⁇ -i 4 aryloxy group (e.g., phenyloxy group, naphthyloxy group, etc.), (iv) formyloxy group or Ci-6 alkyl-carbonyloxy group (e.g., acetoxy group, propionyloxy group, etc.) and (v) C 6 -i4 aryl-carbonyloxy group (e.g., benzoyloxy group, naphthyl-carbonyloxy group, etc.) and the like, and preferably, hydroxy group and Ci-6 alkoxy group (
  • the "hydrocarbon group optionally having substituent ( s) " represented by R” includes, for example, the same group as those referred to herein for the "hydrocarbon group optionally having substituent (s )" represented by R 1 which will be described below.
  • the "amino group optionally having substituent ( s) " represented by R 3 may form a cyclic amino group (e.g., 5- to 9-membered cyclic amino group optionally having 1 to 3 hetero atoms such as an oxygen atom, a sulfur atom, etc. in addition to a nitrogen atom (e.g., pyrrolidino group, piperidino group, piperazino group, morpholino group, etc.) and the like.
  • a cyclic amino group e.g., 5- to 9-membered cyclic amino group optionally having 1 to 3 hetero atoms such as an oxygen atom, a sulfur atom, etc. in addition to a nitrogen atom (e.g., pyrrolidino group, piperidino group, piperazino group, morpholino group, etc.) and the like.
  • the "hydroxy group optionally having a substituent” represented by R 3 includes, for example, the same group as those referred to herein for the "hydroxy group optionally having a substituent” as the “substituent” for the above-mentioned “amino group optionally having substituent ( s) " represented by R 3 , and the like .
  • heterocyclic group optionally having substituent (s) " represented by R 3 includes, for example, the same group as those referred to herein for the “heterocyclic group optionally having substituent ( s) " represented by R 1 which will be described below.
  • acylamino includes, for example, formylamino, Ci_ 6 alkyl-carbonylamino (e.g., acetylamino, etc.), heterocycle-Ci- s alkyl-carbonylamino (e.g., piperidino-acetylamino optionally having oxo, etc.), C 3 -7 cycloalkyl-carbonylamino (e.g., cyclopropylcarbonylamino , etc.), C6-14 aryl- carbonylamino (e.g., phenylcarbonylamino, naphthylcarbonylamino, etc.), heterocycle-carbonylamino (e.g., thienylcarbonylamino, furylcarbonylamino, pyrrolylcarbonylamino, etc.), Ci- ⁇ alkoxy-carbonylamino (e.g., methoxycarbonylamino , ethoxycarbon
  • acyloxy includes, for example, formyloxy, C ⁇ -6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy, etc.), heterocycle-Ci-6 alkyl- carbonyloxy, C3-7 cycl ⁇ alkyl-carbonyloxy (e.g., cyclopropylcarbonyloxy, etc.), C 6 -i 4 aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy, etc.), heterocycle-carbonyloxy (e.g., nicotinoyloxy) , C3.-6 alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), C 6 - I4 aryloxy-carbonyloxy, heterocycleoxy-carbonyloxy, mono-Ci-6 alkyl-carbamoyloxy
  • heterocycle-Ci_ 6 alkyl-carbonylamino heterocycle-carbonylamino, heterocycleoxy-carbonylamino, heterocycle-sulfonylamino, heterocycle-Ci-6 alkyl-carbonyloxy, heterocycle- carbonyloxy and heterocycleoxy-carbonyloxy
  • 5- to 14-membered preferably 5- to 9-membered, more preferably 5- or 6-membered
  • non-aromatic heterocycle containing, besides carbon atoms, 1 to 4 of one or two kinds of hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (e.g., pyrrolidinyl, tetrahydrofuryl, - tetrahydrothienyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like), or 5- to 14-membered (preferably
  • the "5- to 7-membered saturated cyclic amino" for the “5- to 7-membered saturated cyclic amino optionally having substituent (s) " includes, for example, morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, etc.
  • the "substituent" in the ⁇ 5- to 7-membered saturated cyclic amino optionally having substituent ( s) " includes, for example, Ci-6 alkyl (e.g., methyl ⁇ ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, hexyl, etc.)/ C ⁇ -n aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2- anthryl, etc.), a 5- to 10-it ⁇ embered aromatic heterocyclic group (e.g., 2- or 3-thienyl, 2-, 3- or 4- pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5- isoquinolyl, 1-, 2- or 3-indolyl, 2-benzothiazolyl, 2- benzo [b ]
  • a phenyl group optionally having halogen atom (e.g., fluorine atom, etc.) or Ci-6 alkyl (e.g., methyl, etc.) is preferable, and a phenyl group optionally substituted at the para-position and the like by fluorine atom or methyl is more preferable.
  • ⁇ R 1 is a hydrogen atom, a hydrocarbon group optionally having substituent ( s) , an acyl group or a heterocyclic group optionally having substituent (s) .
  • the "hydrocarbon group” for the “hydrocarbon group optionally having substituent ( s) " represented by R 1 includes, for example, aliphatic hydrocarbon group, monocyclic saturated hydrocarbon group, aromatic hydrocarbon group, etc., preferably having 1 to 16 carbons, and specifically, for example, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, ⁇ etc .
  • alkyl group is preferably, for example, a lower alkyl group, etc., for example, Ci-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • alkenyl group is preferably, for example, a lower alkenyl group, etc., for example, C2-6 alkenyl group such as vinyl, 1-propenyl, allyl, isopropenyl, butenyl, isobutenyl, etc.
  • alkynyl group is preferably, for example, lower alkynyl group, etc., for example, C2-6 alkynyl group such as ethynyl, propargyl, 1-propynyl, etc.
  • cycloalkyl group is preferably, for example, lower cycloalkyl group, etc., for example, C 3 - 6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • aryl group is preferably, for example, C 6 -i4 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, etc., specifically, a phenyl group, etc.
  • the substituent that the "hydrocarbon group" for the "hydrocarbon group optionally having substituent ( s )" represented by R 1 may have includes, for example, (1) halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), (2) nitro group, (3) cyano group, (4) hydroxy group, (5) optionally halogenated lower alkyl group (e.g., optionally halogenated Ci- 5 alkyl group such as methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2- trifluoroethyl, pentafluoroethyl, propyl, 3,3,3- trifluoropropyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 4 , 4, 4-trifluorobutyl, pen
  • mono-lower alkylamino group e.g., mono-Ci-6 alkylamino group such as methylamino, ethylamino, etc.
  • di-lower alkylamino group e.g., di-Ci- 6 alkylamino group such as dimethylamino, diethylamino, etc.
  • 16) 2160 mono-Ce- 14 arylamino e.g., phenylamino, 1-naphthylamino, 2-naphthylamino, etc.
  • di-C 6 -i4 arylamino group e.g., diphenylamino, etc.
  • acylamino group (19) carboxyl group, (20) aryl group (e.g., C 6 -i4 aryl group such as phenyl, naphthyl, biphenyl, 2-anthryl, etc.), (21) aryloxy group (e.g., C 6 -I 4 aryloxy group such as phenyloxy, naphthyloxy, etc.), (22) optionally halogenated lower alkylcarbonylamin
  • optionally halogenated Ci_ 6 alkyl-carbonylamino group such as acetylamino, trifluoroacetylamino, etc.
  • optionally halogenated lower alkylsulfonyl group e.g., optionally halogenated C ⁇ -6 alkylsulfonyl group such as methylsulfonyl , trifluoromethylsulfonyl, etc.
  • optionally halogenated lower alkylsulfonylamino group e.g., optionally halogenated Ci_ 6 alkylsulfonylamino group such as methylsulfonylamino, trifluoromethylsulfonylamino, etc.
  • optionally halogenated lower alkoxycarbonylamino group e.g., optionally halogenated Ci_6 alkoxy-carbonylamino group such as methoxycarbonylamino, trifluoromethoxycarbonyla
  • hydrocarbon group for the “hydrocarbon group optionally having substituent ( s) " optionally has 1 to 5, preferably 1 to 3 substituents mentioned above at the substitutable position (s) on the hydrocarbon group.
  • the number of the substituents is 2 or more, the substituents may be the same or different.
  • acyl as the "substituent” for the "hydrocarbon group optionally having substituent (s) " represented by R 1 includes, for example, formyl, Ci_ 6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), heterocycle-Ci-6 alkyl-carbonyl, C3-7 cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl, etc.), C 6 _i 4 aryl-carbonyl (e.g., phenylcarbonyl, naphthylcarbonyl, etc.), heterocycle-carbonyl (e.g., nicotinoyl, etc.), Ci-.
  • Ci_ 6 alkyl-carbonyl e.g., acetyl, propionyl, etc.
  • heterocycle-Ci-6 alkyl-carbonyl C3-7 cycloalkyl-carbonyl (e.g., cyclopropyl
  • alkoxy-carbonyl e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • C ⁇ -n aryloxy- carbonyl e.g., phenoxycarbonyl, naphthoxycarbonyl, etc.
  • heterocycleoxy-carbonyl Ci_ 6 ' alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.), C 6 -i4 arylsulfonyl (e.g., phenylsulfonyl , 2-naphthylsulfonyl, 1- naphthylsulfonyl , etc.), heterocycle-sulfonyl, Ci- ⁇ alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl, propylsulfiny
  • the heterocycle of the heterocycle-Ci-6 alkyl-carbonyl, heterocycle-carbonyl, heterocycleoxy-carbonyl and heterocycle-sulfonyl includes, for example, 5- to 14- membered (preferably 5- to 9-membered, more preferably 5- or 6-membered) non-aromatic heterocycle containing, besides carbon atoms, 1 to 4 of one or two kinds of hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (e.g., pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, tetrahydropyra ⁇ yl , morpholinyl, thiomorpholinyl, piperazinyl, etc.) or 5- to 14- membered (preferably 5- to 9-membered, more preferably 5- or 6-membered) aromatic heterocyclic group containing, besides carbon atoms, 1 to 4 of one or two
  • acyloxy and “acylamino” as the "substituent" for the "hydrocarbon group optionally having substituent ( s )" represented by R 1 include the same group as those referred to herein for the aforementioned "acyloxy” and “acylamino” as the substituent of the "phenyl group optionally having substituent ( s )" represented by Ar.
  • the "5- to 7-membered cyclic amino optionally having substituent (s) " as the "substituent” for the "hydrocarbon group optionally having substituent ( s) " represented by R 1 includes the same group as those referred to herein for the aforementioned "5- to 7- membered cyclic amino optionally having substituent ( s )" as the substituent of the "phenyl group optionally having substituent (s) " represented by Ar.
  • heterocyclic group as the "substituent” for the "hydrocarbon group optionally having substituent (s) " represented by R 1 includes, for example, 5- to 14-membered (preferably 5- to 9-membered, more preferably 5- or 6-membered) aromatic heterocyclic group containing, besides carbon atoms, 1 to 4 of one or two kinds of hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1 , 2 , 3-oxadiazolyl / 1, 2 , 4-oxadiazolyl , 1,3,4- oxadiazolyl, furazanyl, 1, 2 , 3-thiadiazolyl , 1,2,4- thiadiazolyl, 1, 3 , 4-
  • heterocyclic group is optionally further condensed with other aromatic or non-aromatic homocyclic ring or heterocycle.
  • the "heterocyclic group” may. also have substituent (s) such as halogen atom, optionally halogenated Ci_ 6 alkyl, Ci- 5 alkoxy, oxo and the like.
  • substituent (s) such as halogen atom, optionally halogenated Ci_ 6 alkyl, Ci- 5 alkoxy, oxo and the like.
  • substituent (s) such as halogen atom, optionally halogenated Ci_ 6 alkyl, Ci- 5 alkoxy, oxo and the like.
  • the “optionally halogenated lower alkyl group” as the "substituent” for the "hydrocarbon group optionally having substituent ( s) " represented by R 1 includes the same group as those referred to herein for the aforementioned "optionally halogenated Ci_6 alkyl group” as the substituent of the
  • acyl group represented by R 1 includes, for example, the same group as those referred to herein above for the foregoing "acyl” as the substituent of the "phenyl group optionally having substituent (s) " represented by Ar.
  • heterocyclic group for the “heterocyclic group optionally having substituent (s )" represented by R 1 includes, for example, 5- to 14-membered (preferably 5- to 10-membered) (monocyclic to tricyclic, preferably, monocyclic or dicyclic) aromatic or non-aromatic heterocyclic group containing 1 to 4 (preferably 1 to 3) hetero atoms of one or two kinds selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms, etc.
  • 5-membered aromatic heterocyclic group containing, besides carbon atoms, 1.to 4 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, such as 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl , 2-, 4- or 5- thiazolyl, 3-, 4- or 5-isothiazolyl, 3-, 4- or 5- pyrazolyl, 2-, 4- or 5-imidazolyl, 1 , 2 , 3-triazolyl, 1, 2, 4-triazolyl, IH- or 2H-tetrazolyl , etc., 6-membered aromatic heterocyclic group containing, besides carbon atoms, 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, such as 2-, 3- or 4-pyridyl, 2-, 3-
  • 5- or 6-membered non-aromatic heterocyclic group containing, besides carbon atoms, 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, such as pyrrolidinyl , tetrahydrofuryl, tetrahydrothienyl, piperidinyl, tetrahydr ' opyranyl, morpholinyl , thiomorpholinyl, piperazinyl, pyrazolidinyl, pyranyl, thiopyranyl, tetrahydrothiopyranyl, dihydropyrimidinyl (e.g.,
  • 5- to 7-membered (preferably 5- or 6-membered) nitrogen-containing heterocyclic group containing 1 to 3 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom in addition to carbon atoms is preferred.
  • the substituent that the "heterocyclic group” for the “heterocyclic group optionally having substituent ( s) " may have includes the same group as those referred to herein for the aforementioned substituent that the "hydrocarbon group” for the “hydrocarbon group optionally having substituent ( s) " may have, for example, (1) halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (2) lower alkyl group (e.g., Ci-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), (3) cycloalkyl group (e.g., C 3 - s cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (4) lower
  • aralkyl group such as benzyl, ⁇ -methylbenzyl, phenethyl, etc.
  • aryl group e.g., C6-10 aryl group such as phenyl, naphthyl, etc., preferably phenyl group, etc.
  • lower alkoxy group e.g., Ci- 6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.
  • aryloxy group e.g., C ⁇ -io aryloxy group such as phenoxy, etc.
  • acyl e.g., formyl group, lower alkyl-carbonyl group (e.g., Ci_ s alkyl-carbonyl group such as acetyl, propionyl, butyryl, isobutyryl, etc.) which is optionally substituted with the substituent (s )
  • aryl-carbonyl group such as benzoyl group, naphthoyl group, etc.
  • carbamoyl group e.g., C 3 - 14 aryl-carbonyl group such ' as benzoyl group, naphthoyl group, etc.
  • carbamoyl group e.g., carbamoyl group, sulfo group, sulfino group, phosphono group, sulfamoyl group, lower alkylsulfinyl group (e.g., Ci- 6 alkylsulfinyl group such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.), arylsulfinyl group (e.g., C ⁇ -i4 arylsulfinyl group such as phenylsulfinyl, naphthylsulfin
  • acyl include .the same group as those referred to herein for the above- mentioned “acyl”, “acyloxy” and “acylamino", which are substituents that the "hydrocarbon group" in the
  • hydrocarbon group optionally having substituent (s) may have .
  • heterocyclic group for the “heterocyclic group optionally having substituent (s )" may have 1 to 5, preferably 1 to 3 of the above-mentioned substituents at the substitutable position(s) of the heterocyclic group. When the number of the substituents is 2 or more, the substituents may be the same or different.
  • R 1 is preferably a hydrogen atom or an acyl group.
  • hydrocarbon group optionally having substituent (s) ", "amino group optionally having substituent ( s )", “hydroxy group optionally having a substituent” or “heterocyclic group optionally having substituent ( s )” represented by R 5 includes the same group as those referred to herein for the aforementioned “hydrocarbon group optionally ⁇ raving substituent (s) ", "amino group optionally having substituent ( s )", “hydroxy group optionally having a substituent” or “heterocyclic group optionally having substituent ( s) " represented by R 3 .
  • Ci_6 alkyl group e.g., methyl group, ethyl group, etc.
  • substituents selected from the group consisting of (i) formylamino, (ii) C ⁇ - ⁇ alkyl-carbonylamino (e.g., acetylamino, etc.), (Ui) 1 Ci- 6 alkoxy-carbonylamino (e.g., methoxycarbonylamino, etc.), (iv) heterocyclic group optionally having substituent (s) selected from the group consisting of Ci- 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), hydroxy, formyl, Ci-6 alkyl-carbonyl (e.g., acetyl, etc.), formylamino, oxo and C ⁇ - 6 alkyl-carbonyla
  • C ⁇ - 1 4 aryl group e.g., phenyl group, etc.
  • substituents selected from the group consisting of (i) formylamino group and (ii) Ci_ 6 alkyl-carbonylamino group (e.g., acetylamino, etc.) and the like, and the like are preferable.
  • Ci-6 alkoxy group e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, etc. is preferable.
  • heterocyclic group optionally having substituent ( s) " for R 5 5- or 6-membered aromatic or nonaromatic heterocyclic group containing, besides carbon atom, 1 or 2 nitrogen atoms (particularly, 1- piperidinyl group, 4-piperidinyl group, 1, 4-piperazinyl group, 5-imidazolyl group, 3-pyridyl group, 1,2,3,6- ⁇ tetrahydropyrimidin-4-yl group), which optionally has 1 to 3 substituents selected from the group consisting of (i) Ci-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), (ii) Ci-6 alkyl group having substituent ( s ) selected from the group consisting of formyl, Ci_ 6 alkyl-carbonyl (e.g., acetyl, etc.), Ci- 6 alkoxy- carbonyl (e.g., methoxycarbonyl, isoprop
  • R 1 (1) a hydrogen atom, (2) a Ci- ⁇ alkyl-carbonyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci-6 alkyl-carbonylamino group, (b) a 5- or 6-membered nitrogen-containing heterocyclic group optionally having 1 to 4 substituents selected from the group consisting of a Ci-6 alkyl group and an oxo group, (c) a carbamoyl group, (d) a hydroxy group and (e) a C ⁇ -6 alkylsulfonyl group, (3) a Ci-6 alkoxy-carbonyl group, (4) a C3-6 cycloalkyl-carbonyl group optionally having carbamoyl group (s), (5) a 5- or 6-membered nitrogen- containing heterocycle-carbonyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci-6 alkyl group, (b) an oxo group
  • Z is a methylene group optionally having Ci_ 6 alkyl group (s) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl and the like.
  • Ci_ 6 alkyl group (s) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl and the like.
  • Z is preferably a methylene group.
  • Ring A is a piperidine ring optionally further having substituent ( s ) . That is, ring A further optionally has 1 to 8 substituents besides R 1 , -NH-Z-B and Ar .
  • substituted of the "piperidine ring optionally having substituent ( s) " includes those referred to herein for the aforementioned substituent of the "phenyl group optionally having substituent (s) " for Ar.
  • Ring A is preferably a piperidine ring having no substituent other than R 1 , -NH-Z-B and Ar.
  • B is a monocyclic aromatic heterocyclic group optionally having substituent ( s) (substituents of monocyclic aromatic heterocycle may be bonded to each other to form a ring) .
  • a 5- or 6-membered monocyclic aromatic heterocyclic group containing, besides carbon atom, 1 to 4 hetero atom selected from the group consisting of nitrogen atom, oxygen atom, sulfur atom and the like e.g., pyrrolyl group (1 ⁇ , 2- or 3- pyrrolyl group), imidazolyl group (1-, 2-, 4- or 5- imidazolyl group), pyrazolyl group (1-, 3-, 4- or 5- pyrazolyl group), triazolyl group (1- or 3-triazolyl group), tetrazolyl group (1-, 2- or 5-tetrazolyl group), thiazolyl group (2-, 4- or 5-thiazolyl group), isothiazolyl group (3-, 4- or 5-isothiazolyl group), oxazolyl group (2-, 4- or 5-oxazolyl group) , isox
  • the monocyclic aromatic heterocyclic group is condensed with a ring (e.g., C3-8 cycloalkane ring (e.g., cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring, etc.), C ⁇ -io aryl ring (e.g., benzene ring, naphthalene ring, etc.), heterocycle (e.g., pyrrole ring, imidazole ring, pyrazole ring, triazole ring, tetrazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, fura
  • a ring e.g., C3-8 cycloalkane ring (e.g., cyclopropane ring, cycl
  • a nitrogen-containing aromatic heterocyclic group optionally having substituent ( s ) e.g., pyrrolyl group (1-, 2- or 3-pyrrolyl group), imidazolyl group (1-, 2-, 4- or 5-imidazolyl group), pyrazolyl group (1-, 3-, 4- or 5-pyrazolyl group), triazolyl group (1- or 3- triazolyl group), tetrazolyl group (1-, 2- or 5- tetrazolyl group) , thiazolyl group (2-, 4- or 5- thiazolyl group), isothiazolyl group (3-, 4- or 5- isothiazolyl group), oxazolyl group (2-, 4- or 5- oxazolyl group), isoxazolyl group (3-, 4- or 5- isoxazolyl group) , furazanyl group, pyridyl group (2-, 3- or 4-pyridyl group) , pyrazinyl group, pyrimidinyl
  • a pyridyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a halogen atom, (b) a Ci- ⁇ alkyl group, (c) a hydroxy group, (d) a Ci-6 alkoxy group, (e) a C 5 -I 0 aryl group optionally having cyano group (s) and (f) a nitrogen- containing aromatic heterocyclic group optionally substituted by Ci-6 alkyl group (s) optionally having halogen atom(s), (2) a pyrimidyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci-6 alkyl group, (b) a Ci-6 alkoxy group optionally having halogen atom(s) and (c) a C 3 _ s cycloalkyl group, (3) a pyrazolyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci_ 6 alk
  • each symbol is> as defined above, is preferable, and particularly, an optically active form represented by the formula (I-b) wherein each symbol is as defined above, is preferable.
  • Ci- 6 alkyl-carbonyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci- 6 alkyl-carbonylamino group, (b) a 5- or 6-membered nitrogen-containing heterocyclic group optionally having 1 to 4 substituents selected from the group consisting of a Ci_ 6 alkyl group and an oxo group, (c) a carbamoyl group, (d) a hydroxy group and (e) a Ci-6 alkylsulfonyl group, (3) a Ci-6 alkoxy-carbonyl group,
  • a 5- or 6-membered nitrogen-containing heterocycle- carbonyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci-6 alkyl group, (b) an oxo group and (c) a Ci-6 alkyl-carbonyl group optionally having hydroxy group (s), or
  • (6) a mono-Ci-6 alkyl-carbamoyl group
  • Z is a methylene group
  • B is (1) a pyridyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a halogen atom, (b) a Ci_ 6 alkyl group, (c) a hydroxy group, (d) a Ci- ⁇ alkoxy group, (e) a C 3 -io aryl group optionally having cyano group (s) and (f) a nitrogen- containing aromatic heterocyclic group optionally substituted by Ci- 6 alkyl group (s) optionally having halogen atom(s), (2) a pyrimidyl group optionally having 1 to 3 substituents selected from the group consisting of (a) a Ci- 6 alkyl group, (b) a Ci-e alkoxy group optionally having halogen atom(s) and (c) a C3-6 cycloalkyl group, (3) a
  • the salt of compound (I) includes, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with basic or acidic amino acid, etc.
  • Suitable examples of the metal salt include an alkali metal salt such as a sodium salt, a potassium salt, etc.; an alkaline earth metal salt such as a calcium salt, a magnesium salt, a barium salt, etc.; an aluminum salt, etc.
  • Suitable examples of the salts with an organic base include salts with trimethylamine, • triethylamine, pyridine, picoline, 2 , 6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'- dibenzylethylenediamine, etc.
  • Suitable examples of the salts with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • Suitable examples of the salts with an organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, etc.
  • Suitable examples of the salts with a basic amino acid include salts with arginine, lysine, ornithine, etc.
  • Suitable examples of the salts with an acidic amino acid include salts with asparaginic acid and glutamic acid, etc.
  • inorganic salts such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, barium salt, etc.), an ammonium salt, etc.
  • alkali metal salt e.g., sodium salt, potassium salt, etc.
  • alkaline earth metal salt e.g., calcium salt, magnesium salt, barium salt, etc.
  • ammonium salt e.g., sodium salt, potassium salt, etc.
  • salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • salts with an organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p- toluene sulfonic acid, etc.
  • the prodrug of the compound (I) or a salt thereof of the present invention means, a compound which is converted to the compound (I) of the present invention under the physiological condition in the living body by a reaction with an enzyme, a gastric acid, or the like, that is, by enzymatic oxidation, reduction, hydrolysis, etc. or by hydrolysis with gastric acid, etc.
  • the prodrug of the compound (I) of the present invention includes a compound wherein the amino group of the compound (I) of the present invention is modified with acyl, alkyl or phosphoryl (e.g., a compound wherein the amino group of the compound (I) of the present invention is modified to eicosanoyl, alanyl, pentylaminocarbonyl, ( 5-methyl-2-oxo-l, 3-dioxolen-4- yl ) methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl , tert-butyl, etc.); a compound wherein the hydroxy group of the compound (I) of the present invention is modified with acyl, alkyl, phosphoryl or boryl (e.g., a compound wherein the hydroxy group of the compound (I) of the present invention is modified with acetyl, palmitoyl, propanoyl, pivalo
  • the prodrug of the compound (I) of the present invention may be a compound, which is converted into the compound (I) of the present invention under the physiological conditions, as described in "Pharmaceutical Research and Development", Vol. 7 (Drug Design), pp. 163-198 (1990), published by Hirokawa Publishing Co.
  • Solvate for example, hydrates of the compound represented by the formula (I) and a salt thereof are all included in the scope of the present invention.
  • the compound represented by the formula (I) may be labeled with an isotope (e.g., 3 H, 14 C, 35 S, 125 I, etc.) and the like . If ' the compound (I) of the present invention according to the present invention has chiral center, isomers such as an enantiomer or a diastereomer may exist. Such isomers and a mixture thereof are all included in the scope of the present invention.
  • Compound (I) or a salt thereof of the present invention can be prepared according to a method described in WO 03/101964, specifically, using Method A or Method B below. [Method A]
  • Compound (I) or a salt thereof of the present invention can be prepared by subjecting a compound represented by the formula (Ib) :
  • each symbol is as defined above or a salt thereof (hereinafter to be referred to as compound (Ib)), to a reaction with a compound represented by the formula (III) : R la -OH (III) wherein R la is a hydrocarbon group optionally having substituent (s) , an acyl group or a heterocyclic group optionally having substituent ( s) , which is an acylating agent or an alkylating agent, a salt thereof or a reactive derivative thereof.
  • the "hydrocarbon group optionally having substituent ( s ), the acyl group or the heterocyclic group optionally having substituent ( s )" represented by R la includes the same group as those referred to herein above for the foregoing group represented by R 1 .
  • the reactive derivative of the compound (III) includes, for example, a compound represented by the formula (Ilia) :
  • the leaving group represented by L includes, for example, halogen atom (e.g., chlorine atom, bromine atom, iodine atom, etc.), substituted sulfonyloxy group (e.g., Ci_6 alkylsulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy, etc.; C 6 -i4 arylsulfonyloxy group such as benzenesulfonyloxy, p- toluenesulfonyloxy, etc.; and C7-16 aralkylsulfonyloxy group such as benzylsulfonyloxy group, etc.), acyloxy (acetoxy, benzoyloxy, etc.), carbonates, trichloroacetoimidates , oxalates, phosphites (e.g., methyl phosphite, etc.), phosphoranes
  • the reaction using the above-mentioned reactive derivative as an alkylating agent can be carried out by subjecting the compound (Ib) to a reaction with the reactive derivative, usually in a solvent in the presence of base.
  • the solvent includes, for example, alcohols such as methanol, ethanol, propanol, etc., ethers such as dimethoxyethane, dioxane, tetrahydrofuran, etc., ketones such as acetone, etc., nitriles such as acetonitrile, etc., amides such as N,N-dimethylformamide, etc., sulfoxides such as dimethyl sulfoxide, etc., water and the like, which may be used in a suitable mixture.
  • the base includes, for example, an organic base such as trimethylamine, triethylamine, N-methylmorpholine, pyridine, picoline, N, N-dimethylaniline, etc., and an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, etc.
  • the amount of the base to be used is, for example, about 1 to about 100 molar equivalents, preferably about 1 to about 10 molar equivalents, per 1 mole of the compound (Ib) .
  • the reactive derivative includes, for example, halides (e.g., chloride, bromide, iodide, etc.), sulfuric acid esters, or sulfonic acid esters (e.g., methanesulfonate, p-toluenesulfonate, benzenesulfonate, etc.) and the like, and particularly halides.
  • the amount of the reactive derivative to be used is, for example, 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mole of the compound (Ib) .
  • the reaction can be promoted by adding an additive.
  • Such an additive includes, for example, iodides such as sodium iodide, potassium iodide, etc. and the amount to be used is about 0.1 to 10 molar equivalents, preferably about 0.1 to 5 molar equivalents, per 1 mole of the substrate. 007/052160
  • the reaction temperature is generally -10 0 C to 200 0 C, preferably about 0 0 C to HO 0 C, and the reaction time is generally 0.5 to 48 hrs, preferably 0.5 to 16 hrs .
  • the reaction using the above-mentioned reactive derivative as an acylating agent depends on the kind of reactive derivative or the compound (Ib), but it is usually carried out in a solvent. If necessary, a suitable base may be added to promote the reaction.
  • the solvent includes, for example, hydrocarbons such as benzene, toluene, etc., ethers such as ethyl ether, dioxane, tetrahydrofuran, etc., halogenated hydrocarbons such as chlor.oform, dichloromethane, etc., esters such as ethyl acetate, etc., amides such as N,N- dimethylformamide , etc., aromatic amines such as pyridine, etc., water and the like, which may be used in a suitable mixture.
  • hydrocarbons such as benzene, toluene, etc.
  • ethers such as ethyl ether, dioxane, tetrahydrofuran, etc.
  • halogenated hydrocarbons such as chlor.oform, dichloromethane, etc.
  • esters such as ethyl acetate, etc.
  • amides such as N,N- dimethylformamide , etc.
  • the base includes, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, etc., carbonate such as sodium carbonate, potassium carbonate, etc., acetate such as sodium acetate, tertiary amines such as trimethylamine, triethylamine, N-methylmorpholine, etc., aromatic amines such as pyridine, picoline, N, N-dimethylaniline, etc. and the like.
  • the amount of the base to be used is, for example, about 1 to about 100 molar equivalents, preferably about 1 to about 10 molar equivalents, per 1 mole of the compound (Ib) .
  • the acylating agent includes, for example, carboxylic acid, sulfonic acid, . phosphoric acid, carbonic acid or a reactive derivative thereof (e.g., acid halide, acid anhydride, mixed acid anhydride, active ester, etc.), isocyanic acid ester, isothiocyanic acid ester and the like.
  • the amount of such an acylating agent to be used is usually 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mole of the compound (Ib) .
  • the reaction temperature is generally -10 0 C to 150°C, preferably about 0 0 C to 100°C, and the reaction time is generally 15 min to 24 hrs, preferably 30 min to 16 hrs .
  • the compound (Ib) used as the starting material in Method A can be prepared by subjecting the compound (Ia) obtained by Method B mentioned below to deacylation.
  • Such deacylation can be carried out according a known method, for example, the method described in Theodora W. Greene, Peter G. M. Wuts, "Protective Groups in Organic Synthesis, 3 rd Ed.,” (1999) Wiley- Interscience, and the like, or an analogous method thereto.
  • the reaction is usually carried out in the presence of an acid or a base, if necessary, in a solvent that does not adversely influence the reaction though it depends on the kinds of the compound (Ia) .
  • the acid is preferably mineral acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), carboxylic acids (e.g., acetic acid, trifluoroacetic acid, trichloroacetic acid, etc.), sulfonic acids (e.g., methanesulfonic acid, toluenesulfonic acid, etc.), Lewis acids (e.g., aluminum chloride, tin chloride, zinc bromide, etc.) and the like. If necessary, it may be used in a mixture of two or more.
  • the amount of the acid to be used varies depending on the kinds of the solvent and other reaction conditions, but it is usually about 0.1 molar equivalents or more, per 1 mole of the compound (Ia), and the acid can be used as a solvent.
  • the base is preferably an inorganic base (alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, etc., alkali metal carbonates such as sodium carbonate, potassium carbonate, etc., alkoxides such as sodium methoxide, sodium ethoxide, etc. and the like), or an organic base (amines such as trimethylamine, triethylamine, diisopropylethylamine, etc., cyclic amines such as pyridine, 4-dimethylaminopyridine, etc.) and the like, and particularly, sodium hydroxide, potassium hydroxide, sodium ethoxide and the like.
  • inorganic base alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, etc., alkali metal carbonates such as sodium carbonate, potassium carbonate, etc.
  • the amount of the base to be used varies depending on the kinds of the solvent and other reaction conditions, but is generally about 0.1 to about 10 molar equivalents, preferably about 0.1 to about 5 molar equivalents, per 1 mole of the compound (Ia) .
  • the solvent that does not adversely influence the reaction includes, for example, alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, tert-butanol, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; ethers such as diethyl ether, diisopropyl ether, tert- butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.; nitriles such as acetonitrile, etc.; esters such as ethyl acetate, etc.; carboxylic acids such as acetic acid, etc.; amides such as N,N- dimethylformamide, N,
  • the reaction temperature is for example, about -
  • reaction time varies depending on the kinds of the compound (Ia), the reaction temperature and the like, and it is for example, about 0.5 to about 100 hrs, 052160 preferably about 0.5 to about 24 hrs .
  • the present process is a process of converting a compound represented by the 'formula (IV) (hereinafter to be referred to as compound (IV) ) to imine or oxime, followed by reducing it to thus prepare a compound represented by the formula (V) (hereinafter to be referred to as the amine compound (V) ) .
  • Conversion of the compound (IV) into the imine or oxime can be carried out by using a known method.
  • the reaction can be carried out by using various amines in a solvent inert to the reaction.
  • the amines include, for example, ammonia such as aqueous ammonia, ammonium chloride, ammonium acetate, etc., hydroxyamines such as hydroxyamine, O- methylhydroxyamine, O-benzylhydroxyamine, etc., organic amines such as- benzylamine, aminodiphenylmethane, 1- phenylethylamine, etc., and may be used as a salt form such as hydrochloride, sulfate, etc. or as an aqueous solution thereof.
  • the amount of the amine to be used is, for example, about 1 to 50 molar equivalents, preferably about 1 to 10 molar equivalents, per 1 mole of the compound (IV) .
  • the solvent which is inert to the reaction includes, for example, aromatic hydrocarbons such as toluene, xylene, etc., aliphatic hydrocarbons such as heptane, hexane, etc., halogenated hydrocarbons such as chloroform, dichloromethane, etc., ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., alcohols such as methanol, ethanol, 2-propanol, butanol, benzyl alcohol, etc., nitriles such as acetonitrile, etc., N, N-dimethylformamide, dimethyl sulfoxide, and the like. These solvents may be used in a mixture at a suitable ratio .
  • aromatic hydrocarbons such as toluene, xylene, etc.
  • aliphatic hydrocarbons such as heptane, hexane, etc.
  • halogenated hydrocarbons such
  • the reaction can advantageously proceed by adding a catalyst.
  • a catalyst is preferably mineral acids (e.g., hydrochloric acid, hydrobromic acid> sulfuric acid, etc.), carboxylic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.), sulfonic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid, etc.), Lewis acids (e.g., aluminum chloride, zinc chloride, zinc bromide, boron trifluoride, titanium chloride, etc.), acetate (e.g., sodium acetate, potassium acetate, etc.), molecular sieves (e.g., molecular sieves 3A, 4A, 5A, etc.), dehydrating agent (e.g., magnesium sulfate, etc) and the like.
  • the amount of the catalyst to be used is, for example, about 0.01 to 50 molar equivalent
  • the reaction temperature is generally about 0°C to 200°C, preferably about 20°C to 150°C, and the reaction time is generally 0.5 to 48 hrs, preferably 0.5 to 24 hrs .
  • the conversion of the imine or oxime into the amine compound (V) can be carried out according to various reduction reactions in a solvent inert to the reaction.
  • the reduction reactions can be carried out by a method known per se, for example, a method using metal hydride or a method by catalytic hydrogenation .
  • the metal hydride includes, for example, sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride, diisobutylaluminum hydride, aluminum hydride, lithium aluminum hydride, a borane complex (a borane-THF complex, catechol borane, etc.) and the like, with preference given to sodium borohydride, sodium cyanoborohydride, sodium
  • the amount of the metal hydride to be used is, for example, about 1 to about 50 molar equivalents, preferably about 1 to about 10 molar equivalents, per 1 mole of the imine or oxime.
  • the reduction reaction using metal hydride is generally carried out in a solvent inert to the reaction.
  • Such solvent includes, for example, aromatic hydrocarbons such as toluene, xylene, etc., aliphatic hydrocarbons such as heptane, hexane, etc., halogenated hydrocarbons such as chloroform, dichloromethane, etc., ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., alcohols such as methanol, ethanol, 2-propanol, butanol, benzyl alcohol, etc., nitriles such as acetonitrile, etc., N, N-dimethylformamide, dimethyl sulfoxide and the like. These solvents may be used in a mixture' at a suitable ratio.
  • aromatic hydrocarbons such as toluene, xylene, etc.
  • aliphatic hydrocarbons such as heptane, hexane, etc.
  • halogenated hydrocarbons such as chloroform, dichloromethan
  • the reaction temperature is generally about
  • reaction time is generally 5 min to 48 hrs, preferably 1 to 24 hrs.
  • the catalytic hydrogenation can be carried out under a hydrogen atmosphere and in the presence of a catalyst.
  • the catalyst is preferably palladium compounds such as palladium carbon, palladium hydroxide, palladium oxide, etc., nickel compounds such as nickel sponge catalyst, etc., platinum compounds such as platinum oxide, platinum carbon, etc., rhodium compounds such as rhodium carbon, etc. and the like, and the amount to be used is about 0.001 to about 1 molar equivalents, preferably about 0.01 to about 0.5 molar equivalents, per 1 mole of the imine or oxime.
  • the catalytic hydrogenation is generally carried out in a solvent inert to the reaction.
  • solvent includes, for example, alcohols such as methanol, ethanol, propanol, butanol, etc.; hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; ethers such as diethyl ether, dioxane, tetrahydrofuran, etc.; esters such as ethyl acetate, etc.; amides such as N,N-dimethylformamide, etc.; carboxylic acids such as acetic acid, etc.; water, - or a mixture thereof.
  • the hydrogen pressure under which the reaction is carried out is generally about 1 to 50 atm, preferably about 1 to 10 atm.
  • the reaction temperature is generally about 0 0 C to 150°C, preferably about 20°C to 100°C, and the reaction time is generally 5 min to 72 hrs, preferably 0.5 to.40 hrs.
  • the amine compound (V) can be also prepared directly from the compound (IV) while carrying out the following reduction reaction without isolating imine or oxime which is an intermediate.
  • pH of the reaction mixture is preferably from about 4 to about 5.
  • the amine compound (V) is converted to the compound (Ia) by subjecting the amine compound (V) to an alkylation reaction or a reductive alkylation reaction .
  • the alkylation reaction can be carried out by a method known per se.
  • the alkylation 007/052160 reaction can be carried out by subjecting the amine compound (V) to a reaction with a compound represented by the formula (VI) :
  • the reactive derivative of the compound (VI) includes, for example, a compound represented by the formula (Via) :
  • the leaving group represented by L 1 includes, for example, halogen atom (e.g. ' , chlorine atom, bromine atom, iodine atom, etc.), substituted sulfonyloxy group (e.g., ⁇ Ci-6 alkylsulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy, etc.; C 6 -I 4 arylsulfonyloxy group such as benzenesulfonyloxy, p- toluenesulfonyloxy, etc.; and C 7 - I6 aralkylsulfonyloxy group such as a benzylsulfonyloxy group, etc.; Ci_ 6 alkoxysulfonyloxy group such as methoxysulfonyloxy, etc.) and the like.
  • halogen atom e.g. '
  • chlorine atom bromine atom,
  • the reaction using the compound (VI) or the above- mentioned reactive derivative (Via) as an alkylating agent can be carried out by subjecting the amine compound (V) to a reaction with the compound (VI) or the reactive derivative (Via) , usually in a solvent in the presence of base though it depends on the kinds of the compound (VI), the reactive derivative (Via) or the amine compound (V) .
  • the solvent includes, for example, alcohols such as methanol, ethanol, propanol, etc., ethers such as dimethoxyethane, dioxane, tetrahydrofuran, etc., ketones such as acetone, etc., nitriles such as acetonitrile, etc., amides such as N, N- dimethylformamide, etc., sulfoxides such as dimethyl sulfoxide, etc., water and the like, which may be used in a suitable mixture.
  • alcohols such as methanol, ethanol, propanol, etc.
  • ethers such as dimethoxyethane, dioxane, tetrahydrofuran, etc.
  • ketones such as acetone, etc.
  • nitriles such as acetonitrile
  • amides such as N, N- dimethylformamide, etc.
  • sulfoxides such as dimethyl sulfoxide, etc., water and
  • the base includes, for example, an organic base such as trimethylamine, triethylamine, N- methylmorpholine, pyridine, picoline, N, N- dimethylaniline, etc., and an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, etc.
  • the amount of the base to be used is, for example, about 1 to about 100 molar equivalents, preferably about 1 to about 10 molar equivalents, per 1 mole of the amine compound (V) .
  • the reactive derivative (Via) includes, for example, halides (e.g., chloride, bromide, iodide, etc.), sulfuric acid esters, or sulfonic acid esters (e.g., ⁇ methanesulfonat.e, p-toluenesulfonate, benzenesulfonate, etc.) and the like, and particularly halides.
  • the amount of the compound (VI) or the reactive derivative (Via) to be used is, for example, about 1 to about 5 molar equivalents, preferably about 1 to about 3 molar equivalents, per 1 mole of the amine compound (V) .
  • the reaction can be promoted by adding an additive.
  • an additive includes, for example, iodides such as sodium iodide, potassium iodide, etc. and the amount to be used is about 0.1 to about 10 molar equivalents, preferably about 0.1 to about 5 molar equivalents, per 1 mole of the amine compound (V) .
  • the reaction temperature is generally about -10 0 C • to about 200 0 C, preferably about 0 0 C to about 110 0 C
  • the reaction time is generally about 0.5 to about 48 hrs, preferably about 0.5 to about 16 hrs .
  • the reductive alkylation reaction can be carried out by a method known per se, for example, by reacting the amine compound (V) with a compound represented by the formula (VII) :
  • R 6 is a hydrogen atom or Ci-e alkyl group, and each of the other symbol is as defined above, or a salt thereof (hereinafter to be referred to as compound (VII)), and reducing the prepared imine or iminium ion.
  • the reaction to prepare imine or iminium ion and to reduce the product can be carried out according to the method described in Process 1.
  • the compound (Ia) can be also prepared directly from the amine compound (V) while carrying out the following reduction reaction without isolating imin.e or iminium ion which is an intermediate.
  • pH of the reaction mixture ⁇ is preferably from about 4 to about 5.
  • the present process is a process for converting the compound (IV) into the compound (Ia) by reductive amination.
  • the present reaction can be carried out by the known method per se, for example, by reacting the compound (IV) with a compound represented by the formula (VIII) :
  • the reaction to prepare imine or iminium ion and to reduce the product can be carried out according to the method described in Process 1.
  • the compound (Ia) can be also prepared directly from the compound (IV) while carrying out the following reduction reaction without isolating imine or iminium ion which is an intermediate.
  • pH of the reaction mixture is preferably from about 4 to about 5.
  • optically active compound (I) can be produced using, as a starting compound, an optically active compound represented by the formula (Va)
  • inorganic acids e.g., hydrochloric acid, sulfuric acid, hydrobromic acid, etc.
  • the starting compound when the starting compound may form a salt in each of the above-mentioned reactions, the compound may be used as a salt.
  • Such salt includes, for example, those exemplified as a salt of compound (D .
  • Compound (I) of the present invention thus prepared by such methods, can be isolated and purified by a typical separation means such as recrystallization, distillation, chromatography, etc.
  • compound (I) contains an optical isomer, a stereoisomer, a regioisomer or a rotamer, these are also included in compound (I), and can be obtained as a single product according to synthesis and separation methods known per se (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.) .
  • the optical isomer resolved from this compound is also included in compound (I) .
  • the optical isomer can be prepared by a method known per se. To be specific, an optically active synthetic intermediate is used, or the final racemate product is subjected to optical resolution according to a conventional method to give an optical isomer.
  • the method of optical resolution may be a method known per se, such as a fractional recrystallization method, a chiral column method, a diastereomer method, etc .
  • 1) Fractional recrystallization method A method wherein a salt of a racemate with an optically active compound (e.g., (+ ) -mandelic acid, (- ) -mandelic acid, (+) -tartaric acid, (-) -tartaric acid, (+) -1-phenethylamine, (- ) -1-phenethylamine, cinchonine, (-) -cinchonidine, brucine, etc.) is formed, which is separated by a fractional recrystallization method, and if desired, a free optical isomer is obtained by a neutralization step.
  • an optically active compound e.g., (+ ) -mandelic acid, (- ) -mandelic acid, (+) -tartaric acid, (-)
  • a method wherein a racemate or a salt thereof is applied to a column for separation of an optical isomer (a chiral column) to allow separation.
  • a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) , CHIRAL series (manufactured by Daicel Chemical Industries, Ltd.) and the like, and developed with water, various buffers (e.g., phosphate buffer) and organic solvents (e.g., ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) solely or in admixture to separate the optical isomer.
  • a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences Inc.) and the like is used to allow separation
  • Diastereomer method A method wherein a racemic mixture is prepared into a diastereomeric mixture by chemical reaction with an optically active reagent, which is made into a single substance by a typical separation means (e.g., a fractional recrystallization method, a chromatography method, etc.) and the like, and is subjected to a chemical treatment such as hydrolysis and the like to separate an optically active reagent moiety, whereby an optical isomer is obtained.
  • a typical separation means e.g., a fractional recrystallization method, a chromatography method, etc.
  • compound (I) when compound (I) contains hydroxy, or primary or secondary amino group within a molecule, the compound and an optically active organic acid (e.g./ MTPA [ ⁇ -methoxy- ⁇ - ( trifluoromethyl) phenylacetic acid], (- ) -menthoxyacetic acid, etc.) and the like are subjected to condensation reaction to give diastereomers of the ester compound or the amide compound, respectively.
  • compound (I) has a carboxylic acid group
  • this compound and an optically active amine or an alcohol reagent are subjected to condensation reaction to give diastereomers of the ester compound or the amide compound, respectively.
  • the separated diastereomer is converted to an optical isomer of the original compound by acid hydrolysis or base hydrolysis.
  • Compound (I) may be in the form of a crystal.
  • the crystal of compound (I) can be prepared by • crystallization of compound (I) by a crystallization method known per se.
  • Examples of the crystallization method include a method of crystallization from a solution, a method of crystallization from vapor, a method of crystallization from the melts and the like.
  • the "crystallization from a solution” is typically a method of shifting a. non-saturated state to supersaturated state by varying factors involved in solubility of compounds (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of solvent.
  • solvent composition a concentration method, a cold removing method, a reaction method (a diffusion method, an electrolysis method) , a hydrothermal growth method, a flux method and the like can be mentioned.
  • solvent to be used examples include aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), haloge-nated hydrocarbons (e.g., dichloromethane, chloroform, etc.), saturated hydrocarbons (e.g., hexane, heptane, cyclohexane, etc.), ethers (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.)/ nitriles (e.g., acetonitrile, etc.), ketones (e.g., acetone, etc.), sulfoxides (e.g., dimethyl sulfoxide, etc.), acid amides (e.g., N, N-dimethylformamide, etc.), esters (e.g., ethyl acetate, etc.), alcohols (e.g., methanol,
  • the "crystallization from vapor” is, for example, a vaporization method (a sealed tube method, a gas stream method) , a gas phase reaction method, a chemical transportation method and the like.
  • the "crystallization from the melts” is, for example, a normal freezing method (a Czockralski method, a temperature gradient method and a Bridgman method) , a zone melting method (a zone leveling method and a floating zone method) , a special growth method (a VLS method and a liquid phase epitaxy method) and the like.
  • the crystallization method include a method of dissolving compound (I) in a suitable solvent (e.g., alcohols such as methanol, ethanol, etc. and the like) at a temperature of 20 to 120°C, and cooling the resulting solution to a temp.erature not higher than the temperature of dissolution (e.g., 0 to 50°C, preferably 0 to 20°C) and the like.
  • a suitable solvent
  • crystals of the present invention can be isolated, for example, by filtration and the like.
  • crystal analysis by powder X-ray diffraction is generally performed.
  • a method for determining the crystal direction a mechanical method, an optical method and the like can also be mentioned.
  • the crystals of compound (I) obtained by the above-mentioned production method (hereinafter to be abbreviated as the "crystal of the present invention") has high purity and high quality, and low hygroscopicity, is not denatured even after a long-term preservation under general conditions, and is extremely superior in the stability. Moreover, the crystal is superior in biological properties (e.g., pharmacokinetics (absorption, distribution, metabolism, excretion), efficacy expression, etc.), and thus it is extremely useful as a pharmaceutical composition.
  • biological properties e.g., pharmacokinetics (absorption, distribution, metabolism, excretion), efficacy expression, etc.
  • the specific rotation ([ ⁇ ] D ) means that measured using, for example, polarimeter (JASCO Corporation (JASCO), P-1030 polarimeter (No.AP-2)) and the like.
  • the melting point means that measured using, for example, 'a micromelting point apparatus (Yanako, MP-500D) or a DSC (differential scanning calorimetry) device (SEIKO, EXSTAR 6000) and the like.
  • the peak by powder X-ray diffraction means that measured using, for • example, RINT Ultima + 2100 (Rigaku Corporation), etc. with a Cu-Ka ray as a ray source.
  • the melting points and the peak by powder X-ray diffraction may vary depending on the measurement apparatuses, the measurement conditions and the like.
  • the crystal in the present specification may show different values from the melting point or the peak by powder X-ray diffraction described in the present specification, as long as it is within each of a general error range.
  • the compound of the present invention has excellent antagonistic action for a tachykinin receptor, particularly substance P receptor antagonistic action including the inhibitory action for the increased permeability of blood vessel of a trachea induced by capsaicin, neurokinin A receptor antagonistic action.
  • the compound of the present invention has low toxicity and thus it is safe.
  • the compounds of the present invention having excellent antagonistic actions for substance P receptors and neurokinin A receptors, etc. can be used as a safe pharmaceutical composition for preventing and treating the following diseases related to sub.stance P in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, bovines, sheep, monkeys, humans, etc . ) .
  • Lower urinary tract diseases for example, • overactive bladder, stress urinary incontinence, mixed urinary incontinence, lower urinary tract symptoms accompanied by prostatic hyperplasia, pelvic visceral pain, lower urinary tract symptoms accompanied by chronic prostatitis, abnormal urination such as lower urinary tract symptoms accompanied by interstitial cystitis , etc .
  • Lower urinary tract diseases for example, • overactive bladder, stress urinary incontinence, mixed urinary incontinence, lower urinary tract symptoms accompanied by prostatic hyperplasia, pelvic visceral pain, lower urinary tract symptoms accompanied by chronic prostatitis, abnormal uri
  • Gastrointestinal diseases for example, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis syndrome, Crohn's disease, diseases caused by a spiral urease-positive gram-negative bacterium (e.g., Helicobacter pylori, etc.) (e.g., gastritis, gastric ulcer, etc.), gastric cancer, postgastrostomy disorder, dyspepsia, esophageal ulcer, pancreatitis, polyp of the colon, cholelithiasis, hemorrhoids, peptic ulcer, situational ileitis, vomiting, nausea, motion sickness, anorexia, bulimia, constipation, diarrhea, borborygmi, etc. ]
  • a spiral urease-positive gram-negative bacterium e.g., Helicobacter pylori, etc.
  • gastritis e.g., gastritis, gastric ulcer, etc.
  • gastric cancer postgastros
  • Inflammatory or allergic diseases for example, allergic rhinitis, conjunctivitis, gastrointestinal allergy, pollinosis, anaphylaxis, dermatitis, herpes, psoriasis, bronchitis, expectoration, retinopathy, postoperative and posttraumatic inflammation, regression of puffiness, pharyngitis, cystitis, meningitidis, inflammatory ophthalmic diseases, etc.
  • Osteoarthropathy diseases for example, rheumatoid arthritis (chronic rheumatoid arthritis), arthritis deformans, rheumatoid myelitis, osteoporosis, abnormal growth of cells, bone fracture, bone refracture, osteomalacia, osteopenia, osseous Behcet's disease, rigid myelitis, articular tissue destruction by .
  • Respiratory diseases for example, cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombi/pulmonary obliteration, pulmonary sarcoidosis, pulmonary tuberculosis, interstitial pneumonia, silicosis, adult tachypnea syndrome, chronic obliterative pulmonary diseases, cough, etc.
  • Respiratory diseases for example, cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombi/pulmonary obliteration, pulmonary sarcoidosis, pulmonary tuberculosis, interstitial pneumonia, silicosis, adult tachypnea syndrome, chronic obliterative pulmonary diseases, cough, etc.
  • Infectious diseases [HIV infectious diseases, virus infectious diseases due to cytomegalo virus, influenza virus, herpes virus and the like, rickettsia infectious diseases, bacterial infectious diseases, sexually- • transmitted diseases, carinii pneumonia, helicobacter pylori infectious disease, systemic fungal infectious diseases , ' tuber
  • Cancers for example, primary, metastatic or recurrent breast cancer, prostatic cancer, pancreatic cancer, gastric cancer, lung cancer, colorectal cancer (colon cancer, rectal cancer, anal cancer) , esophagus cancer, duodenal cancer, head and neck cancer (tongue cancer, pharynx cancer, larynx cancer) , brain tumor, neurinoma, non-small cell lung cancer, small cell lung cancer, hepatic cancer, renal cancer, colic cancer, uterine cancer (cancer of the uterine body, uterine cervical cancer) , ovarian cancer, bladder cancer, skin cancer, hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer, bone tumor, hemangioma, angiofibroma, retinosarcoma, penis cancer, pediatric solid cancer, Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, tumor of the maxillary sinus, fibrous histi
  • Central nerve diseases e.g., neurodegenerative diseases (e.g., Alzheimer's disease, Down's disease, Parkinson's disease, Creutzfeldt- Jakob' s disease, amyotrophic lateral sclerosis (ALS), Huntington chorea, diabetic neuropathy, multiple sclerosis, etc.), mental diseases (e.g., schizophrenia, depression, mania, anx.iety neurosis, obsessive- compulsive neurosis, panic disorder, epilepsy, alcohol dependence, anxiety symptom, anxious mental state, dysthymia, cyclothymia, nervous hypersensitivity, autism, syncope, addiction, decreased libido, etc.), central and peripheral nerve disorders (e.g., head trauma, spinal cord injury, brain edema, disorders of sensory function, abnormality of sensory function, disorders of autonomic nervous function and abnormality of autonomic nervous function, whiplash injury, etc.), memory disorders (e.g., senile dementia, amnesia, cerebrovascular dementia
  • Pains e.g., pelvic visceral pain including headache, migraine, neuralgia, cystodynia, etc.
  • Autoimmune diseases for example, collagen disease, systemic lupus erythematosus, scleroderma, polyarteritis, myasthenia gravis, multiple sclerosis, Sjogren's syndrome, Behcet's disease, etc.
  • Hepatic diseases e.g., hepatitis (including, chronic hepatitis), cirrhosis, interstitial hepatic diseases, etc. ]
  • Pancreatic diseases e.g., pancreatitis (including chronic pancreatitis), etc.
  • Renal diseases e.g., nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, dialysis complications, organ disorders including nephropathia by radiation, diabetic nephropathy, etc.
  • Metabolic diseases e.g., diabetic diseases (insulin-dependent diabetes, diabetic complications, diabetic retinopathy, diabetic microangiopathy, diabetic neuropathy, etc.); impaired glucose tolerance, obesity, benign prostatic hypertrophy, sexual dysfunction, etc.]
  • Endocrine diseases e.g., Addison's disease,
  • Transplant rejection e.g., posttransplantational rejection, posttransplantational polycythemia, hypertension, organ disorder and/or vascular hypertrophy, .graft-versus-host disease, etc.
  • (b) Abnormality in characteristic of blood and/or ⁇ blood components e.g., enhancement in platelet aggregation, abnormality of erythrocyte deformability, enhancement in leukocyte adhesiveness, increase in blood viscosity, polycythemia, vascular peliosis, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome (DIC), multiple myelopathy, etc.
  • (c) Gynecologic diseases e.g., climacteric disorder, gestational toxicosis, endometriosis, hysteromyoma, ovarian disease, mammary disease, premenstrual syndrome, etc.
  • Dermatic diseases e.g., keloid, angioma, psoriasis, pruritus, etc.
  • Ophthalmic diseases e.g., glaucoma, ocular hypertension disease, etc.
  • Otolaryngological diseases e.g., Menuel syndrome, tinnitus, gustation disorder, dizziness, disequilibrium, dysphagia, etc.
  • the 'compound of the present invention is particularly useful as a tachykinin receptor antagonist, as an agent for ameliorating and treating symptoms of lower urinary tract such as urinary frequency, urinary incontinence, etc., as an agent for the prophylaxis or treatment of gastrointestinal disea.se and as an agent for the prophylaxis or treatment of central nervous system disease.
  • it is useful as an agent for the prophylaxis or treatment of overactive bladder, irritable bowel syndrome, inflammatory bowel disease, vomiting, nausea, depression, anxiety neurosis, anxiety symptom, pelvic visceral pain or interstitial cystitis.
  • the pharmaceutical preparations comprising the compound of the present invention may be in any solid forms of powders, granules, tablets, capsules, suppositories, etc., and in any liquid forms of syrups, emulsions, injections, suspensions, etc.
  • the pharmaceutical preparations including the compound of the present invention can be produced by any conventional methods, for example, blending, kneading, granulation, tabletting, coating, sterilization, emulsification, etc., in accordance with the forms of the preparations to be produced.
  • any conventional methods for example, blending, kneading, granulation, tabletting, coating, sterilization, emulsification, etc.
  • each of the items in General Principles for pharmaceutical preparations in the Japanese Pharmacopeia can be made reference to.
  • the pharmaceutical preparations of the present invention may be formulated into a sustained release preparation containing active ingredients and biodegradable polymer compounds.
  • the sustained release preparation can be produced according to the method described in JP-A-9-263545.
  • the content of the compound or a salt thereof in the present invention varies depending on the forms of the preparations, but is generally about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.5 to 20% by weight, relative to the total weight of each preparation.
  • the compound of the present invention when used in the above-mentioned pharmaceutical preparations, it • may be used alone, or in admixture with a suitable, pharmaceutically acceptable carrier, for example, exci.pients (e.g., starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, arabic gum, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, alginic acid, gelatin, polyvinyl pyrrolidone, etc.), lubricants (e.g., stearic acid, magnesium stearate, calcium stearate, ' talc, etc.), disintegrants (e.g., calcium carboxymethylcellulose, talc, etc.), diluents (e.g., water for injection, physiological saline, etc.) and if desired, with the additives (e.g., a stabilizer, a ⁇ preservative, a color
  • the dose varies depending on the kinds of the 'compound of the present invention or a pharmaceutically acceptable salt thereof, the administration route, the condition and the age of patients, etc.
  • the dose for oral administration of the pharmaceutical preparation to an adult patient suffering from abnormal urination is generally from about 0.005 to 50 mg/kg body/day, preferably from about 0.05 to 10 mg/kg body/day, more preferably from about 0.2 to 4 mg/kg body/day, based on the compound of the present invention, which may be administered once a day or in two or three divided portions a day.
  • the dose when the pharmaceutical composition of the present invention is a sustained release preparation varies dep.ending on the kinds and the content of compound (I), the formulation, the duration time of drug release, the animals to be administered (e.g., mammals such as humans, rats, mice, cats, dogs, rabbits, bovines, swines, etc.), and the object of administration.
  • the animals to be administered e.g., mammals such as humans, rats, mice, cats, dogs, rabbits, bovines, swines, etc.
  • the object of administration e.g., when it is parenterally administered, preferably about 0.1 to about 100 mg of compound (I) may be released from the preparation for 1 week.
  • the compound of the present invention can be used in a mixture or combination with other pharmaceutically active ingredients at a suitable ratio.
  • a dose can be reduced as compared with separate administration of the compound of the present invention or other pharmaceutically active ingredients. More specifically, when the compound of the present invention is combined with anticholinergic agents or NK-2 receptor antagonists, the dose can be reduced as compared with separate administration of anticholinergic agents or NK-2 receptor antagonists, and therefore, side effects such as dry mouth can be reduced;
  • a drug to be combined with the compound of the present invention can be selected; (3) by choosing other pharmaceutically active ingredients which have different mechanism of action from that of the compound of the present invention, the therapeutic period can be designed longer;
  • a drug which is mixed or combined with the compound of the present invention includes the following :
  • Insulin preparations e.g., animal insulin preparations extracted from the bovine or swine pancreas; human insulin preparations synthesized by a genetic engineering technique using Escherichia coli or. a yeast; insulin zinc; protamine zinc insulin; a fragment or a derivative of insulin (e.g., INS-I, etc.), agents for potentiating insulin sensitivity (e.g., pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, JTT-501, MCC-555, YM-440, GI-262570,
  • agents for potentiating insulin sensitivity e.g., pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, JTT-501, MCC-555, YM-440, GI-262570,
  • ⁇ -glucosidase inhibitors e.g., voglibose, acarbose, miglitol, emiglitate, etc.
  • biguanides e.g., phenformin, metformin, buformin, etc.
  • sulfonylureas e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, etc.
  • other insulin secretagogues e.g., repaglinide, senaglinide, mitiglinide or its calcium salt hydrate, GLP-I, nateglinide, etc.
  • dipeptidylpeptidase IV inhibitors e.g., vildagliptin, sitagliptin, saxagliptin, aloglip
  • ⁇ 3 agonists e.g., CL-316243, SR- 58611-A, UL-TG-307, AJ-9677, AZ40140, etc.
  • amylin agonists e.g., pramlintide, etc.
  • phosphotyrosine phosphatase inhibitors e.g., vanadic acid, etc.
  • gluconeogenesis inhibitors e.g., glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, etc.
  • SGLT sodium- glucose cotransporter
  • Aldose reductase inhibitors e.g., tolrestat, epalrestat, zenarestat, zopolrestat, fidarestat (SNK- 860), minalrestat (ARI-509) , CT-112, etc.
  • neurotrophic factors e.g., NGF, NT-3, etc.
  • AGE inhibitors e.g., ALT-945, pimagedine, pyratoxathine, N-phenacylthiazolium bromide (ALT-766), EXO-226, etc.
  • active oxygen scavengers e.g., thioctic acid, etc.
  • cerebral vasodilators e.g., tiapuride, etc.
  • Statin compounds inhibiting cholesterol synthesis e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or their salt (e.g., sodium salt, etc.) and the like
  • squalene synthase inhibitors or fibrate compounds having triglyceride lowering action e.g., bezafibrate, clofibrate, simfibrate, clinofibrate, etc.
  • Angiotensin converting enzyme inhibitors e.g., captopril, enalapril, delapril, etc.
  • angiotensin II antagonists e.g., losartan, candesartan cilexetil, etc.
  • calcium antagonists e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, etc.
  • clonidine and the like.
  • Antiobesity drugs acting on the central nervous system e.g. dexfenfluramine, fenfluramine, phentermine, sibutramine, anfepramone, dexamphetamine, mazindol, phenylpropanolamine, c.lobenzorex, etc.
  • pancreatic lipase inhibitors e.g. orlistat, etc.
  • ⁇ 3 agonists e.g. CL-316243, SR-58611-A, UL-TG-307, AJ-9677, AZ40140, etc.
  • anorectic peptides e.g. leptin, CNTF (Cil.iary Neurotrophic Factor), etc.
  • cholecystokinin agonists e.g. lintitript, FPL-15849, etc.
  • Xanthine derivatives e.g., theobromine sodium salicylate, theobromine calcium salicylate, etc.
  • thiazide preparations e.g., ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide, etc.
  • antialdosterone preparations e.g., spironolactone, triamterene, etc.
  • carbonic anhydrase inhibitors e.g., acetazolamide, etc.
  • chlorobenzenesulfonamide preparations e.g., chlorthalidone, mefruside, indapamide, etc.
  • azosemide isosorbide, ethacrynic acid, piretanide, bumet
  • Alkylating agents e.g., cyclophosphamide, ifosfamide, etc.
  • metabolic antagonists e.g., methotrexate, 5-fluorouracil, etc.
  • antitumor antibiotics e.g., mitomycin, adriamycin, etc.
  • plant- derived antitumor agents e.g., vincristine, vindesine, taxol, etc.
  • cisplatin carboplatin, etoposide, etc.
  • 5-fluorouracil derivatives such as Furtulon and Neo-Furtulon are preferred.
  • Microorganism- or bacterium-derived components e.g., muramyl dipeptide derivatives, Picibanil, etc.
  • imr ⁇ unopotent iator polysaccharides e.g./ lentinan, schizophyllan, krestin, etc.
  • genetically engineered cytokines e.g., interferons, interleukins (IL), etc.
  • colony . stimulating factors e.g., granulocyte colony stimulating factor, erythropoietin, etc.
  • interleukins such as IL-I, IL-2, IL-12, etc. are preferred.
  • Progesterone derivatives e.g., megestrol acetate
  • metoclopramide pharmaceuticals e.g., tetrahydrocannabinol pharmaceuticals (the above reference is applied to both)
  • fat metabolism ameliorating agents e.g., eicosapentanoic acid
  • growth hormones IGF-I
  • antibodies to the cachexia- inducing factors such as TNF- ⁇ , LIF, IL- 6 and oncostatin M.
  • Steroids e.g., dexamethasone, etc.
  • sodium hyaluronate e.g., sodium hyaluronate
  • cyclooxygenase inhibitors e.g., indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoxib, etc.
  • Glycosylation inhibitors e.g., ALT-711, etc.
  • nerve regeneration promoting drugs e.g., Y-1,28, VX853, prosaptide, etc.
  • drugs acting on the central nervous system e.g., antidepressants such as desipramine, amitriptyline, imipramine, fluoxetine, paroxetine, doxepin, duloxetine, venlafaxine, etc.
  • anticonvulsants e.g., lamotrigine, carbamazepine, gabapentin
  • antiarrhythmic drugs e.g., mexiletine
  • acetylcholine receptor ligands e.g., ABT-594
  • endothelin receptor antagonists e.g., ABT-627
  • monoamine uptake inhibitors e.g., tramadol
  • indoleamine uptake inhibitors e.g., fluoxetine, paroxetine
  • Ot 2 receptor agonists e.g., clonidine
  • local analgesics e.g., capsaicin
  • protein kinase C inhibitors e.g., LY-333531
  • antianxiety drugs e.g., benzodiazepines
  • phosphodiesterase inhibitors e.g., sildenafil
  • dopamine receptor agonists e.g., apomorphine
  • dopamine receptor antagonists e.g., haloperidol
  • serotonin receptor agonists e.g., tandospirone citrate, sumatryptan, tegaserod
  • serotonin receptor antagonists e.g., cyproheptadine hydrochloride, ondansetron
  • serotonin uptake inhibitors e.g., fluvoxamine maleate, fluoxetine,, paroxetine
  • Anticholinergic agents include, for example, atropine, scopolamine, homatropine, tropicamide, cyclopentolate, butylscopolamine bromide, propantheline bromide, methylbenactyzium bromide, mepenzolate bromide, flavoxate, pirenzepine, ipratropium bromide, trihexyphenidyl, oxybutynin, propiverine, darifenacin, tolterodine, solifenacin, temiverine, trospium chloride or a salt thereof (e.g., atropine sulfate, scopolamine hydrogen bromide, homatropine hydrogen bromide, cyclopentolate hydrochloride, flavoxate hydrochloride, pirenzepine hydrochloride, trihexyphenidyl hydrochloride, oxybutynin chloride, tolterodine tartrate, solifenacin succinate, etc.),
  • NK-2 receptor antagonists include, for example, a piperidine derivative such as GR159897, GR149861, SR48968 (saredutant) , SR144190, YM35375, YM38336, ZD7944, L-743986, MDL105212A, ZD6021, MDL105172A, SCH205528, SCH62373, R-113281, etc., a perhydroisoindole derivative such as RPR-106145, etc., a quinoline derivative such as SB-414240, etc., a pyrrolopyrimidine derivative such as ZM-253270, etc., a pseudopeptide derivative such as MEN11420 (nepadutant ) , SCH217048, L-659877, PD-147714 (CAM-2291), MENl 0376, S16474, etc., and others such as GR100679, DNK333, GR94800, UK-224671, MEN10376, MEN106
  • composition comprising a mixture or combination of the compound of the present invention and the concomitant drugs may be formulated into
  • the combination preparation of the present invention can be formulated by mixing the compound of the present invention and active ingredients of the concomitant drugs separately or at the same time as itself or with pharmaceutically acceptable carriers in the same manner as in the aforementioned method of producing the pharmaceutical preparation comprising the compound of the present invention.
  • a daily dose of the combination preparation of the present invention varies depending on severity of the symptoms, age, sex, weight and sensitivity of the subject to be administered, time and interval of administration, property, formulation and kinds of pharmaceutical preparation, kinds of active ingredients, etc., and is not particularly limited.
  • the dose in terms of the compound of the present invention is not particularly limited if it causes no problems of side effects.
  • a daily dosage is usually in a range of about 0.005 to 100 mg, preferably about 0.05 to 50 mg, and more preferably about 0.2 to 30 mg, per 1 kg body weight of mammals, which may be administered once a day or in two or three divided portions a day.
  • the dose of the compound or the combination preparation of the present invention may be set within the range such that it causes no problems of side effects .
  • the daily do.se as the compound or the combination preparation of the present invention varies depending on severity of symptoms, age, sex, weight and sensitivity of the subject to be administered, time and interval of administration, property, formulation and kinds of pharmaceutical preparation, kinds of active ingredients, etc., and is not particularly limited.
  • a daily dosage in terms of active ingredients is usually in the order of about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, and more preferably about 0.1 to 100 mg, per 1 kg body weight of mammals, which may be administered once a day or in two to four divided portions a day.
  • the compound of the present invention and the combination drugs may be administered at the same time or, the combination drugs may be administered before administering the compound of the present invention, and vice versa.
  • staggered administration .the time interval varies depending on the active ingredients to be administered, a formulation and an administration route.
  • the combination drugs may be administered 1 minute to 3 days, preferably 10 min to 1 day, more preferably 15 min to 1 hr after ' administering the combination drugs.
  • the combination drugs may be administered 1 minute to 1 day, preferably 10 min to 6 hrs, more preferably 15 min to 1 hr after administering the compound of the present invention.
  • the combination preparation of the present invention the content of the compound of the present invention varies depending on the forms of the preparation, but usually in the order of 0.01 to 100 wt%, preferably 0.1 to 50 wt%, and further preferably 0.5 to 20 wt%, relative to the total preparation. Examples
  • Silica Gel 60 (70 to 230 mesh) produced by Merck & Co., Inc. was used.
  • the "room temperature” referred herein means temperature generally from about 10°C to 35°C.
  • sodium sulfate or magnesium sulfate was used for drying extract.
  • Boc tert-butyloxycarbonyl group
  • Ph phenyl group N: normal concentration
  • Solvents Solution A; water . containing 0.05% trifluoroacetic acid, Solution B; acetonitrile containing 0.05% trifluoroacetic acid
  • step 1 To a solution of 6-methoxypyridine-3-amine (24.8 g) and Et 3 N (26.3 g) in methylene chloride (250 mL) was added trifluoroacetic anhydride (48.3 g) at O 0 C, and the mixture was stirred at room temperature for 2 hrs . To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated.
  • step 2 To a solution of the compound obtained in step 1 (22.0 g) in carbon tetrachloride (300 itiL) was added triphenyl phosphine (39.3 g) , and the mixture was stirred at 95°C for 20 hrs. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DMF (250 mL) , and sodium azide (10.4 g) was added at 0°C.
  • step 2 To a solution of the compound obtained in step 2 (4.9 g) in acetic acid (15 mL) was added sodium acetate (1.65 g) , the mixture was stirred for 10 min and bromine (4.8 g) was added at room temperature. The reaction mixture was stirred at 80°C for 14 hrs, water (40 mL) was added, and the mixture was extracted with methylene chloride. The organic layer was washed with IN aqueous sodium hydroxide solution and IN aqueous sodium thiosulfate solution, dried over anhydrous magnesium sulfate and concentrated.
  • step 4 A solution of the compound obtained in step 3 (2.32 g) and zinc cyanide (0.84 g) in DMF (15 ⁇ iL) was added Pd(PPh 3 ) 4 (0.41 g) , and the mixture was stirred at
  • step 2 The residue was purified by silica gel column chromatography (solvent gradient; 0—»50% ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give methyl 3-hydroxypyridine-2- carboxylate (35.5 g, 64%) as white crystals. (step 2)
  • step 2 A solution of the compound obtained in step 2 (9.42 g) , methyl iodide (2.78 mL) and potassium carbonate (7.29 g) in DMF (80 mL) was stirred at room temperature for 4 hrs, and poured into cold water. The mixture was extracted twice with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated.
  • step .4 To a solution of the compound obtained in step 3 (7.56 g) in THF (110 mL) was added diisobutylaluminum hydride (DIBAL-H) ( 1.5M toluene solution, 24.6 mL) at -
  • N' -phenylacetphydrazide (17.0 g) in phosphorus oxychloride (104 g) was added diethyl ethoxymethylenemalonate (24.5 g) at room temperature, and the mixture was stirred at 70°C for 3 hrs.
  • the reaction mixture was cooled by pouring into water and the precipitate was collected by filtration.
  • the precipitate was washed with water, dissolved in ethyl acetate, and the mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated.
  • step 2 To a solution of the compound obtained in step 1 (0.70 g) and K 2 CO 3 (0.58 g) in DMF (12 itiL) was added methyl iodide (0.224 mL) , and the mixture was stirred ⁇ at room temperature for 4 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with IN KHSO4 and brine, dried over anhydrous magnesium - sulfate and concentrated. The residue was purified by silica gel column chromatography (solvent gradient;
  • step 3 ethyl 3-methoxy-l-phenyl- lH-pyrazole-4-carboxylate (0.48 g, 65%) as white crystals .
  • step 4 The residue was purified by silica gel column chromatography (solvent gradient; 0—»33% ethyl acetate/hexane) to give (3-methoxy-l-phenyl-lH-pyrazol-4-yl)methanol (0.32 g, 88%) as colorless oil. (step 4)
  • step 1 Using the compound obtained in step 1 and in the same manner as in the method described in Reference Example 4, step 1 - 4, the title compound was obtained.
  • step 3 To a solution of the compound obtained in step 3 (1.11 g) in toluene (50 mL) was added manganese dioxide (5.23g), and the mixture was stirred at room temperature for 3 days. The insoluble material was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 0—»20% ethyl acetate/hexane) to give the title compound (0.72 g, 66%) as pale-yellow crystals.
  • step 2 The residue was purified by silica gel column chromatography (solvent; 10% ethyl acetate/hexane) to give 4-chloro-2-isopropyl-6- methoxypyrimidine (0.80 g, 86%) as colorless oil. (step 2)
  • step 4 The residue was purified by silica gel column chromatography (solvent; 10% ethyl acetate/hexane) to give a mixture of 5-bromo-4 , 6-diisopropoxy-2- isopropylpyrimidine and 5-bromo-4-isopropoxy-2- isopropyl- 6-it ⁇ ethoxypyrimidine (molar ratio, about 85:15) (1.02 g, 76%) as colorless oil/ This was directly used for the next step without further purification, (step 4) s To a solution of the compound obtained in step 3 (1.02 g) in THF (20 mL ) was added dropwise a 1.6M n- butyllithium-hexane solution (2.4 mL) at -78°C, and the mixture was stirred at -78°C for l v hr.
  • step 2 To a 2N aqueous sodium hydroxide solution (17 itiL) of the compound obtained in step 1 (5.Og) was added methyl sulfate (3.07 mL) at room temperature. The reaction mixture was heated to 50 - 55°C, and a 2N aqueous sodium hydroxide solution was appropriately added to maintain the reaction mixture at pH 7 - 8.5.
  • step 3 To a solution of the compound obtained in step 3 (6.0 g) in acetic acid (40 iuL) was added N- brofflosuccinimide (6.1 g) at room temperature, and the mixture was stirred at 65°C for 2 hrs. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The resultant product was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried, and the solvent was evaporated under reduced pressure.
  • step 2 To a solution of the compound obtained in step 1 (3.19 g) in ethyl acetate (10 mL) was added 4N hydrogen chloride/ethyl acetate (10 mL) , and the mixture was stirred at 50 0 C for 1 hr . The reaction mixture was concentrated under reduced pressure, and the precipitate was filtrated with IPE to give benzyl piperidine-4-carboxylate monohydrochloride (2.53 g, 99%) as a white powder.
  • step 2 To a solution of the compound obtained in step 2 (2.5Og), Et 3 N (1.36 mL) and glycol acid (0.82 g) in acetonitrile (25ml) were added WSC-HCl (2.24 g) and HOBt-H 2 O (1.80 g) , and the mixture was stirred at room temperature for 12 hrs . The reaction mixture was poured into water and the resultant product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried, and the solvent was evaporated under reduced' pressure .
  • the obtained residue was purified by silica gel column chromatography (solvent gradient; 10 ⁇ 50% ethyl acetate/hexane) to give benzyl l-glycoloylpiperidine-4- carboxylate (2.71 g, 100%) as colorless oil.
  • step 3 • A solution of the compound obtained in step 3 (6.25 g) and 10% palladium carbon (2.5 g) in ethanol (200 mL) was stirred at room temperature under 1 atm hydrogen atmosphere for 14 hrs. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (3.90 g, 93%) as a white powder.
  • the obtained residue was purified by silica gel column chromatography (solvent gradient; 50—»67% ethyl acetate/hexane) and crystallized from ethyl acetate-IPE to give 2-cyclopropyl-6-isobutylpyrimidine- 4-ol (1.31 g, 7.5%) as. a white powder.
  • step 1 A solution of the compound obtained in step 1 (1.30 g) in phosphorus oxychloride (1.26 mL) was stirred at 110 0 C for 4 hrs.
  • the reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate.
  • the organic layer was washed with water and a saturated aqueous sodium hydrogen carbonate solution, dried, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (solvent gradient; 1—»10% ethyl acetate/hexane) to give 4-chloro-2-cyclopropyl- 6- isobutylpyrimidine (1.21 g, 85%) as colorless oil.
  • step 2 To a solution of the compound obtained in step 2 (1.20 g) in methanol (14 mL) was added a 28% sodium methoxide/methanol (2 mL) solution at room temperature, and the mixture was heated under reflux for 14 hrs. The reaction mixture was concentrated under reduced pressure, and ice-cold water was poured onto the residue. The resultant product was extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried, and the solvent was evaporated under reduced pressure.
  • step 5 A solution of the compound obtained in step 4
  • N-acetylglycine (6.44 g) was suspended in acetonitrile (120 itiL) .
  • 3-Phenylpiperidin-4-one monohydrochloride (10.58 g)
  • Et 3 N (5.06 g)
  • WSC-HCl 11.50 g
  • a reduction reaction was carried out at 50°C, hydrogen pressure of 0.5-1 MPa until the hydrogen absorption ceased.
  • the reaction mixture was filtered under pressurization under a nitrogen stream, and the sponge nickel catalyst was washed twice with ethanol (10 mL) .
  • the filtrate was concentrated under reduced pressure.
  • Water (100 mL) was added to the residue and the mixture was refluxed for 30 min. After cooling to room temperature, a seed crystal was added and the mixture was stirred for 2 hrs . The precipitated crystals were collected by filtration, and washed twice with water (50 mL) .
  • Example 4 To a mixture of the compound obtained in Example 2 (0.13 g) in methanol (1 mL) -ethyl acetate (2 mL) was added a 4N hydrogen chloride/ethyl acetate (1 mL) solution and the mixture was stirred at 80 0 C for 10 hrs . The reaction mixture was concentrated to dryness, and crystallized from methanol/IPE to give the title compound (0.080 g, 65%) as white crystals. MS(ESI+): 385 (M-3HC1+H) Example 4
  • Example 12 Using the compound obtained in Example 12 and hydroxyacetic acid, and in the same manner as in the method described in Example 5, the title compound was obtained.
  • Example 12 Using the compound obtained in Example 12 and 1- methyl-lH-imidazole-5-carboxylic acid, and in the same manner as in the method described in Example 5, the title compound was obtained.
  • Example 12 Using the compound obtained in Example 12 and the compound obtained in Reference Example 9, and in the 2160 same manner as in the method described in Example 5, the title compound was obtained.
  • Example 12 Using the compound obtained in Example 12 and 2,4- dihydroxypyrimidine-5-carboxylic acid monohydrate, and in the same manner as in the method described in Example 5, the title compound was obtained.
  • Example 38 4- ⁇ 5-[ ( ⁇ (3R,4S) -l-[ (5, 5-dimethyl-2,4-dioxo-1,3- oxazolidin-3- ⁇ l) acetyl] -3-phen ⁇ lpiperidin-4- yl ⁇ amiiio) methyl ] -6-methoxypyridin-3-yl ⁇ benzonitrile
  • Example 1 60 mg of lactose and 35 mg of corn starch is granulated using 0.03 mL of an aqueous solution of 10 wt% hydroxypropylmethylcellulose (3 mg as hydroxypropylmethylcellulose) , and then dried at 40°C 5 and sieved. The obtained granules are mixed with 2 mg of magnesium stearate and compressed. The obtained uncoated tablets are sugar-coated with an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The thus-coated tablets are glazed with bees wax to obtain finally-coated tablets.
  • Preparative Example 2 Preparative Example 2
  • the ampoule is sterilized, and then sealed to obtain a solution for injection.
  • Radioligand receptor binding inhibitory activity (Binding inhibitory activity using receptor from human lymphoblast cells (IM-9))
  • the receptor was prepared from human lymphoblast cells (IM-9) .
  • IM-9 cells (2 x 10 5 cells/ mL) were incubated for 3 days, which was then subjected to centrifuge for 10 min at 500 x G to obtain cell pellets.
  • the obtained pellets were washed with PBS' (GIBCO), which were then homogenized using Polytron homogenizer ("Kinematika” , Germany) in Buffer A (50 itiM Tris-HCl buffer (pH 7.4) containing 120 mM sodium chloride, 5 mM potassium chloride, 2 ⁇ g/mL chymostatin, 40 ⁇ g/mL bacitracin, 40 ⁇ g/mL APMSF and 1 mM ethylenediamine tetraacetate), which was subjected to ' centrifugation at 100,000 x G for 40 min.
  • Buffer A 50 itiM Tris-HCl buffer (pH 7.4) containing 120 mM sodium chloride, 5 mM potassium chloride, 2 ⁇ g/mL chymostatin, 40 ⁇
  • the sediment fraction was suspended in Buffer B (50 mM Tris-HCl (pH 7.4), 0.02% bovine serum albumin, 2 ⁇ g/mL chymostatin, 40 ⁇ g/mL bacitracin, 40 ⁇ g/m ' L (p-amidinophenyl) methanesulfonyl fluoride (APMSF), 3 mM MgCl 2 ), which was then preserved frozen (-80 0 C) as a specimen of the receptor.
  • Buffer B 50 mM Tris-HCl (pH 7.4), 0.02% bovine serum albumin, 2 ⁇ g/mL chymostatin, 40 ⁇ g/mL bacitracin, 40 ⁇ g/m ' L (p-amidinophenyl) methanesulfonyl fluoride (APMSF), 3 mM MgCl 2 ), which was then preserved frozen (-80 0 C) as a specimen of the receptor.
  • Buffer B
  • Buffer B (50 ⁇ L) was added to a 96 well microassay plate (Corning) . Thereto was added the membrane standard (50 ⁇ L) suspended in buffer B at 250 ⁇ g/mL. A measurement buffer (50 ⁇ L) containing 2% dimethyl sulfoxide was added to examine the total binding, 50 ⁇ L of 4 ⁇ M non-labeled SP diluted with a measurement buffer containing 2% dimethyl sulfoxide was added to examine the nonspecific binding, and 50 ⁇ L of a test compound (containing 2% dimethyl sulfoxide) diluted with a measurement buffer was added to examine the binding inhibitory activity of the test compound.
  • a 125 I-Bolton Hunter substance P ( 125 I-BHSP) solution 50 ⁇ L was added to each well.
  • a cell harvester Perkin-Elmer
  • rapid filtration was carried out through GF/C filter plate (Perkin-Elmer) to stop the reaction and then GF/C filter plate was washed ten times with 250 ⁇ l of 50 mM Tris-HCl buffer (pH 7.4) containing 0.02% bovine serum albumin.
  • the GF/C filter plate was dried, microscinti-0 (20 ⁇ L) was added and the radioactivity was measured by TopCount (Perkin- Elmer) .
  • the GF/C filter plate had been immersed in
  • the specific binding is a value obtained by subtracting nonspecific binding from the total binding.
  • the binding inhibitory activity of the test compound is shown by a ratio of a value obtained by subtracting the measurement value when the test compound was added from the total binding, to the specific binding.
  • the radio ligand means substance P labeled with [ 1 2 5 I ] .
  • Compound (I), a salt thereof and a prodrug of the present invention have a high tachykinin receptor antagonistic action, particularly a substance P receptor antagonistic action, are rich in sustainability, show small toxicity, are safe as pharmaceutical agents, and show a small influence on other agents. Therefore, the compound (I) a salt thereof and a prodrug thereof of the present invention are useful as pharmaceutical agents, such as tachykinin receptor antagonists, agents 'for the prophylaxis or treatment of lower urinary tract diseases and the like.

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Abstract

L'invention concerne un nouveau dérivé de pipéridine représenté par la formule (I) (I) dans laquelle Ar est un groupe phényle ayant le cas échéant un ou plusieurs substituants, R1 est un atome d'hydrogène, un groupe hydrocarbure ayant le cas échéant un ou plusieurs substituants, un groupe acyle ou un groupe hétérocyclique ayant le cas échéant un ou plusieurs substituants, Z est un groupe méthylène ayant le cas échéant un ou plusieurs groupes alkyles en C1 à C6, le noyau A est un noyau pipéridine ayant le cas échéant un ou plusieurs autres substituants, et B est un groupe hétérocyclique aromatique monocyclique ayant le cas échéant un ou plusieurs substituants (les substituants de l'hétérocycle aromatique monocyclique peuvent être liés les uns aux autres pour former un noyau cyclique), ou un de ses sels, ayant une action d'antagoniste des récepteurs des tachykinines supérieure et autres, et étant utile comme agent de prévention ou de traitement d'une maladie du système urinaire inférieur et similaire.
PCT/JP2007/052160 2006-02-01 2007-02-01 Dérivés de pipéridine comme antagonistes des récepteurs des tachykinines WO2007089031A1 (fr)

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US76389406P 2006-02-01 2006-02-01
US60/763,894 2006-02-01

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* Cited by examiner, † Cited by third party
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WO2009110520A1 (fr) 2008-03-05 2009-09-11 武田薬品工業株式会社 Composé hétérocyclique
WO2010007800A1 (fr) * 2008-07-18 2010-01-21 大鵬薬品工業株式会社 Nouveau composé uracile ayant une structure amide et son sel
WO2010032856A1 (fr) 2008-09-19 2010-03-25 武田薬品工業株式会社 Composé hétérocyclique contenant de l'azote et son utilisation
JP2012505173A (ja) * 2008-10-09 2012-03-01 エフ．ホフマン−ラ ロシュ アーゲー ピロリジンｎ−ベンジル誘導体
EP2921481A1 (fr) * 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Dérivés d'acide de 4-piperidine
US9585875B2 (en) 2011-12-19 2017-03-07 Dompé Farmaceutici S.P.A. TRPM8 antagonists
CN113912622A (zh) * 2020-07-10 2022-01-11 上海纽思克生物科技有限公司 三环嘧啶酮类化合物、其制备方法、其组合物和用途

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US6297259B1 (en) * 1996-02-21 2001-10-02 Aventis Pharmaceuticals Inc. Substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl) benzamides useful for the treatment of allergic diseases
US20020002164A1 (en) * 1992-06-29 2002-01-03 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists
WO2003101964A1 (fr) * 2002-05-31 2003-12-11 Takeda Pharmaceutical Company Limited Derive piperidine, procede de production, et utilisation

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US20020002164A1 (en) * 1992-06-29 2002-01-03 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists
US6297259B1 (en) * 1996-02-21 2001-10-02 Aventis Pharmaceuticals Inc. Substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl) benzamides useful for the treatment of allergic diseases
WO2003101964A1 (fr) * 2002-05-31 2003-12-11 Takeda Pharmaceutical Company Limited Derive piperidine, procede de production, et utilisation

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009110520A1 (fr) 2008-03-05 2009-09-11 武田薬品工業株式会社 Composé hétérocyclique
WO2010007800A1 (fr) * 2008-07-18 2010-01-21 大鵬薬品工業株式会社 Nouveau composé uracile ayant une structure amide et son sel
WO2010032856A1 (fr) 2008-09-19 2010-03-25 武田薬品工業株式会社 Composé hétérocyclique contenant de l'azote et son utilisation
JP2012505173A (ja) * 2008-10-09 2012-03-01 エフ．ホフマン−ラ ロシュ アーゲー ピロリジンｎ−ベンジル誘導体
US9585875B2 (en) 2011-12-19 2017-03-07 Dompé Farmaceutici S.P.A. TRPM8 antagonists
AU2012357747B2 (en) * 2011-12-19 2017-09-07 Dompe' Farmaceutici S.P.A. TRPM8 antagonists
US9856246B2 (en) 2011-12-19 2018-01-02 Dompé Farmaceutici S.P.A. TRPM8 antagonists
EP2921481A1 (fr) * 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Dérivés d'acide de 4-piperidine
CN113912622A (zh) * 2020-07-10 2022-01-11 上海纽思克生物科技有限公司 三环嘧啶酮类化合物、其制备方法、其组合物和用途
CN113912622B (zh) * 2020-07-10 2023-12-01 上海纽思克生物科技有限公司 三环嘧啶酮类化合物、其制备方法、其组合物和用途

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