USRE49686E1 - Nitrogen-containing heterocyclic compound and use of same - Google Patents

Nitrogen-containing heterocyclic compound and use of same Download PDF

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USRE49686E1
USRE49686E1 US17/076,227 US200917076227A USRE49686E US RE49686 E1 USRE49686 E1 US RE49686E1 US 200917076227 A US200917076227 A US 200917076227A US RE49686 E USRE49686 E US RE49686E
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Junya Shirai
Hideyuki Sugiyama
Taku Kamei
Hironobu Maezaki
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Takeda Pharmaceutical Co Ltd
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Definitions

  • the present invention relates to a novel nitrogen-containing heterocyclic compound 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 NK-A
  • NK-B neurokinin B
  • these peptides are known to bind to the corresponding receptors (neurokinin-1 (NK-1), neurokinin-2 (NK-2) and neurokinin-3 (NK-3)) that exist in a living body and thereby to exhibit various biological activities.
  • NK-1 neurokinin-1
  • NK-2 neurokinin-2
  • NK-3 neurokinin-3
  • SP has the longest history and has been studied in detail. In 1931, the existence of SP in the extract from equine intestines was confirmed, and in 1971, its structure was determined. 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 permeability, 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 of 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 vitreoretinopathy, an irritable bowel syndrome, urinary frequency, psychosis, vomiting, etc.) [see, for example, Physiological Reviews, Vol. 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, prolifer
  • WO03/057668 describes a compound represented by the formula
  • each of rings A and B is an optionally substituted aromatic ring, or rings A and B may be bonded to each other to form a ring by linking bonds or substituents thereof;
  • ring C is a nitrogenous saturated heterocyclic ring optionally having substituents besides oxo (excluding 2,3-dioxopyrrolidine ring);
  • R 1 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; and is a single bond or a double bond, or a salt thereof.
  • Ar is an aryl group, an aralkyl group or an aromatic heterocyclic group, each of which may be substituted
  • R 1 is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group
  • X is an oxygen atom or an optionally substituted imino group
  • Z is an optionally substituted methylene group
  • Ring A is a further optionally substituted piperidine ring
  • Ring B is an optionally substituted aromatic ring, provided that when Z is a methylene group substituted with an oxo group, R 1 is not a methyl group, and when Z is a methylene group substituted with a methyl group, Ring B is a substituted aromatic ring, or a salt thereof.
  • WO2005/068427 describes a compound represented by the formula
  • ring A is a nitrogen-containing heterocycle optionally further having substituent(s)
  • ring B and ring C are each an aromatic ring 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 an optionally halogenated C 1-6 alkyl group
  • Y is a methylene group optionally having substituent(s)
  • m and n are each an integer of 0 to 5
  • m+n is an integer of 2 to 5, and is a single bond or a double bond, or a salt thereof.
  • WO2006/030975 describes a compound represented by the formula
  • Ar is an aryl group optionally having substituent(s), R is a C 1-6 alkyl group, 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, ring A is a piperidine ring optionally further having substituent(s), and ring B is a benzene ring having substituent(s), or a salt thereof.
  • WO2006/115286 describes an optically active compound represented by the formula
  • R1 is a hydrogen atom or a group represented by R1′—C( ⁇ O)— wherein R1′ s (i) an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group, (ii) an optionally substituted C 1-6 alkyl group, or (iii) an optionally substituted C 1-6 alkoxy group, and R2 is a hydrogen atom, an optionally substituted C 1-3 alkyl group, or a C 3-6 cycloalkyl group, excluding cis-1-(methoxyacetyl)-N-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]-3-phenyl-4-piperidinamine and cis-1-[(1-acetyl-4-piperidinyl)carbonyl]-N-[2-methoxy-5-[5-(trifluoromethyl)-H
  • WO2007/015588 describes a compound represented by the formula
  • 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)
  • R 2 is a hydrogen atom, a C 1-6 alkyl group optionally having substituent(s) or a C 3-6 cycloalkyl group optionally having substituent(s)
  • Z is a methylene group optionally having a C 1-6 alkyl group
  • ring A is a piperidine ring optionally further having substituent(s)
  • ring B and ring C are benzene rings optionally further having substituent(s)
  • R 2 optionally forms a ring together with the adjacent substituent on the ring B, excluding the compounds represented by the formula:
  • WO2007/089031 describes a compound represented by the formula
  • 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 1-6 alkyl group(s)
  • ring A is a piperidine ring optionally further having sub stituent(s)
  • B is a monocyclic aromatic heterocyclic group optionally having substituent(s) (substituents of the monocyclic aromatic heterocycle may be bonded to each other to form a ring), or a salt thereof.
  • WO2008/133344 describes a compound represented by the formula
  • R 1 is carbamoylemthyl, methylsulfonylethylcarbonyl and the like;
  • R 2 is methyl or cyclopropyl;
  • R 3 is hydrogen atom or methyl;
  • R 4 is a chlorine atom or trifluoromethyl;
  • R 5 is a chlorine atom or trifluoromethyl; and a group represented by the formula
  • R 6 is a hydrogen atom, methyl, ethyl or isopropyl
  • R 7 is a hydrogen atom, methyl or a chlorine atom
  • R 8 is a hydrogen atom, a fluorine atom, a chlorine atom or methyl, or 3-methylthiophen-2-yl, or a salt thereof.
  • WO2009/072643 describes a compound represented by the formula
  • ring A is a nitrogen-containing heterocycle optionally further having substituent(s)
  • ring B is an aromatic ring optionally having substituent(s)
  • ring C is a cyclic group optionally having substituent(s)
  • R 1 is a hydrogen atom, a hydrocarbon group optionally having substituent(s), an acyl group, a heterocyclic group optionally having substituent(s) or an amino group optionally having substituent(s)
  • R 2 is an optionally halogenated C 1-6 alkyl group
  • m and n are each an integer of 0 to 5, m+n is an integer of 2 to 5, and is a single bond or a double bond, excluding N-[(rac.)-(3R,4R)-1-benzyl-4-phenylpiperidin-3-yl]-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide, N-isopropyl-4-methoxy-3-(3-methoxy
  • m, n and s are each independently 0 or 1
  • L is —O— or —NR 4 —
  • R 1 and R 2 are each independently hydrogen, aryl, heteroaryl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-heteroaryl and the like
  • R 3 is hydrogen and the like
  • X and Y are each independently hydrogen, (C 1 -C 6 )alkyl and the like, as a NK-1 and NK-3 receptor antagonist.
  • tachykinin as a receptor antagonist for tachykinin, SP, NK-A or NK-B.
  • R 3 , R 4 and R 5 are independently hydrogen, lower alkyl, mono (or di or tri)halo(lower)alkyl and the like; and R 6 and R 7 are each independently hydrogen or lower alkoxy, and the like, 7 —Z— is a bond or —CH(R 11 )— wherein R 11 is hydrogen or lower alkyl, R 1 and R 2 are independently hydrogen or lower alkyl, or in combination form oxo, R 8 is hydrogen, (5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl) methyl or an amino protecting group, R 9 and R 10 are hydrogen, halogen and the like, or a salt thereof, as a compound having a tachykinin receptor antagonistic action.
  • NK-2 receptor a selective peptidic antagonist of NK-2 receptor is known (Br. J. Pharmacol., 1990, vol. 100, pages 588-592 and WO97/31941).
  • these known peptidic NK-2 antagonists have low activity and are metabolically unstable. Therefore, it is difficult to provide them as practical prophylactic drugs or therapeutic drugs.
  • SR 48968 (Brit. J. Pharmacol. 1992, vol. 105, page 77), GR-159897 (Bioorg. Med. Chem. Lett. 1994, vol. 4, page 1951), CP 96345 (Science, 1991, vol. 251, page 435), RP 67580 (Proc. Nat. Acad. Sci. 1991, vol. 88, page 10208), ZD 7944 (Abstracts of Papers, Part 1, 214th NATIONAL Meeting of the American Chemical Society, Las Vegas, Nev., Sep. 7-11, 1997, MEDI 264), WO02/38547, WO02/38548, WO02/083663, WO02/083664 and the like are known.
  • JP-A-2007-277231 and WO 2006/030984 describe, as synthesis intermediates for tachykinin receptor antagonist, the following compounds.
  • WO2004/111000 discloses, as synthesis intermediates for tachykinin receptor antagonist, the following compounds.
  • WO2000/018403 discloses, as synthesis intermediates for NK1 receptor antagonist, the following compounds.
  • US 2007/0167433 describes, as synthesis intermediates for ⁇ -secretase, cathepsin D, plasmepsin II and/or HIV protease inhibitor
  • WO2006/005741 describes, as synthesis intermediates for rennin inhibitory substance, the following compounds.
  • WO2003/045920 discloses, as melanin coagulation hormone receptor (MHC-1R) antagonists, the following compounds.
  • WO2002/088101 discloses, as a BACE ( ⁇ amyloid precursor protease) inhibitor, the following compound.
  • NK-3 receptor a compound showing an NK-3 receptor binding action is considered to be promising as a therapeutic drug for the central nervous system diseases.
  • An object of the present invention is to provide a nitrogen-containing heterocyclic compound having an antagonistic action for a tachykinin receptor, etc. and having a chemical structure different from that of known compounds including the above-mentioned compounds, a medicament comprising the compound, and the like.
  • a nitrogen-containing heterocyclic compound represented by the following formula (I) (hereinafter sometimes to be simply referred to as compound (I)) or a salt thereof has, based on its specific chemical structure, a strong tachykinin receptor antagonistic action, particularly, an NK-1 receptor antagonistic action, an NK-2 receptor antagonistic action, an NK-3 receptor antagonistic action and the like, and is sufficiently satisfactory as a medicament.
  • a strong tachykinin receptor antagonistic action particularly, an NK-1 receptor antagonistic action, an NK-2 receptor antagonistic action, an NK-3 receptor antagonistic action and the like, and is sufficiently satisfactory as a medicament.
  • the present invention relates to [1] a compound represented by the formula
  • ring A is a niotrogen-containing heterocycle
  • ring B is an aromatic ring optionally having substituent(s)
  • ring D is an aromatic ring optionally having substituent(s)
  • L is a group represented by the formula
  • R 2 , R 3 , R 4a and R 4b are each independently a hydrogen atom, an optionally halogenated C 1-6 alkyl group or an optionally halogenated C 3-6 cycloalkyl group, or R 2 and R 3 are optionally bonded via an alkylene chain or an alkenylene chain, or R 4a and R 4b are optionally bonded via an alkylene chain or an alkenylene chain;
  • R 1 is a hydrogen atom or a substituent;
  • m and n are each independently an integer of 0 to 5; m+n is an integer of 2 to 5; and is a single bond or double bond, provided when L is a group represented by the formula
  • ring D is an aromatic ring having substituent(s) (excluding N-(4-amino-2-isopropylquinolin-6-yl)-N′-[2-phenylpiperidin-3-yl]urea, N-(4-amino-2-isopropylquinolin-6-yl)-N′-[1-(tert-butoxycarbonyl)-2-phenylpiperidin-3-yl]urea and N-[4-(biphenyl-4-yl)piperidin-3-yl]-N′-(naphthalen-2-yl)urea) or a salt thereof; [2] the compound of the above-mentioned [1], wherein ring A is a piperidine ring or a pyrrolidine ring; [3] the compound of the above-mentioned [1], wherein ring B is a phenyl group optionally having substituent(s) or a pyrid
  • R 3′ is a hydrogen atom or a C 1-6 alkyl group; [9] the compound of the above-mentioned [1], wherein ring D is a 3,5-bis(trifluoromethyl)phenyl group or a 3,5-dichlorophenyl group; [10] methyl 4- ⁇ [(3S,4R)-3-[ ⁇ [3,5-bis(trifluoromethyl)phenyl](methyl)carbamoyl ⁇ (methyl)amino]-4-(4-fluorophenyl)pyrrolidin-1-yl]carbonyl ⁇ piperidine-1-carboxylate of the above-mentioned [1], or a salt thereof; [11] 1-[(3S,4R)-4-(4-chlorophenyl)-1- ⁇ [4-(methylsulfonyl)piperazin-1-yl]carbonyl ⁇ pyrrolidin-3-yl]-3-(3,5-dichlorophenyl)-1,3-
  • Compound (I) or a salt thereof of the present invention is superior in the tachykinin receptor antagonistic action, particularly, an NK-1 receptor antagonistic action, an NK-2 receptor antagonistic action, an NK-3 receptor antagonistic action and the like, and safe as a medicament due to low toxicity thereof. Accordingly, compound (I) or a salt thereof of the present invention is useful as a medicament, for example, an agent for the prophylaxis or treatment of various diseases such as a lower urinary tract disease, a digestive tract disease or a central nervous system disease and the like.
  • ring A is a nitrogen-containing heterocycle
  • m and n are each an integer of 0 to 5
  • m+n is an integer of 2 to 5
  • ring A is a 5- to 8-membered saturated or unsaturated nitrogen-containing heterocycle containing, as a ring-constituting atom, one nitrogen atom and 4 to 7 carbon atoms, and having, as substituents, R 1 , ring B and a partial structure:
  • ring A for example, a ring having the following structure is preferable.
  • ring A a piperidine ring or a pyrrolidine ring is more preferable.
  • ring B and ring D are each an aromatic ring optionally having substituent(s).
  • aromatic ring examples include an aryl group and an aromatic heterocyclic group.
  • aryl group a C 6-14 aryl group such as phenyl, naphthyl, anthryl, phenanthryl etc. and the like is used, with preference given to phenyl.
  • aromatic heterocyclic group a 5- or 6-membered aromatic heterocyclic group containing, besides carbon atoms, 1 to 4 hetero atoms of one or two kinds selected from a nitrogen atom, an oxygen atom and a sulfur atom (e.g., furyl, thienyl, pyridyl, pyrrolyl, imidazolyl, pyrazolyl, indolyl, thiazolyl, oxazolyl, thiadiazolyl, triazolyl, tetrazolyl etc.), a bicyclic or tricyclic fused ring group containing, besides carbon atoms, 1 to 4 hetero atoms of one or two kinds selected from a nitrogen atom, an oxygen atom and a sulfur atom (preferably, a group formed by condensation of the above-mentioned 5- to 6-membered aromatic heterocycle and one or two 5- or 6-membered heterocycles optionally containing, besides carbon atoms, 1 to 4 heterocycle
  • substituents of ring B and ring D include 1 to 3 substituents selected from
  • a halogen atom e.g., fluorine, chlorine, bromine, iodine, etc.
  • a C 1-6 alkyl group optionally having 1 to 5 (preferably 1 to 3) substituents selected from a carbamoyl group, a C 1-3 alkoxy group, a C 1-3 alkyl-carbonyl amino group, a C 1-6 alkoxy-carbonyl amino group, a C 6-14 aryl-carbonyl amino group and a halogen atom (e.g., 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, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropent
  • Ring B is preferably a phenyl group optionally having substituent(s), a thienyl group or a pyridyl group each of which optionally has substituent(s), (1) a phenyl group optionally having 1 to 3 substituents selected from (i) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms and (ii) a halogen atom, (2) a thienyl group optionally having 1 to 3 C 1-6 alkyl groups optionally having 1 to 3 halogen atoms or (3) a pyridyl group optionally having 1 to 3 substituents selected from (i) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms and (ii) a halogen atom is more preferable, and (1) a phenyl group optionally having 1 or 2 substituents selected from (i) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms (e.g., fluor
  • a phenyl group optionally having 1 or 2 substituents selected from (i) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms (e.g., fluorine atom) (e.g., methyl, trifluoromethyl) and (ii) a halogen atom (e.g., fluorine atom, chlorine atom) or (2) a pyridyl group optionally having one halogen atom (e.g., fluorine atom, chlorine atom) is particularly preferable.
  • halogen atom e.g., fluorine atom
  • a pyridyl group optionally having one halogen atom (e.g., fluorine atom, chlorine atom) is particularly preferable.
  • Ring D is preferably a phenyl group, a pyrrolyl group, a thienyl group, a furyl group, a pyrazolyl group, an indolyl group, a benzimidazolyl group or a pyridyl group, each of which optionally has substituent(s).
  • ring D is not 6-quinolyl and naphthyl. Ring D is preferably monocyclic.
  • a 5- to 10-membered aromatic heterocyclic group containing, besides carbon atoms, 1 to 4 hetero atoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom, and optionally substituted by 1 to 3 alkyl groups optionally having 1 to 3 halogen atoms and the like are preferable.
  • ring D More preferable examples of the ring D include
  • a C 1-6 alkyl group optionally having 1 to 3 halogen atoms (e.g., fluorine atom)(e.g., methyl, isopropyl, tert-butyl, trifluoromethyl),
  • halogen atoms e.g., fluorine atom
  • halogen atom e.g., fluorine atom, chlorine atom, bromine atom
  • a C 1-6 alkoxy group optionally having 1 to 3 halogen atoms (e.g., fluorine atom)(e.g., methoxy, trifluoromethoxy),
  • a di-C 1-6 alkylamino group e.g., dimethylamino
  • a C 3-8 cycloalkyl group e.g., cyclopentyl, cyclohexyl
  • a C 6-14 aryl group optionally having 1 to 3 halogen atoms (e.g., chlorine atom)(e.g., phenyl, chlorophenyl), and
  • a 5- to 10-membered aromatic heterocyclic group containing, besides carbon atoms, 1 to 4 hetero atoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom, and optionally substituted by 1 to 3 C 1-6 alkyl groups optionally having 1 to 3 halogen atoms (e.g., methyl, trifluoromethyl) (e.g., pyrazolyl, tetrazolyl, trifluoromethyltetrazolyl), or [2] a pyrrolyl group, a thienyl group, a furyl group, a pyrazolyl group, or a pyridyl group each of which optionally is substituted by 1 to 3, preferably 1, C 6-14 aryl (e.g., phenyl) optionally substituted by 1 to 3 C 1-6 alkoxy groups (e.g., methoxy).
  • 1 to 3 C 1-6 alkyl groups optionally having 1 to 3 halogen
  • ring D is preferably a phenyl group optionally having substituent(s),
  • a phenyl group optionally having 1 or 2 substituents selected from (1) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms (e.g., fluorine atom) (e.g., methyl, trifluoromethyl), (2) a halogen atom (e.g., chlorine atom, bromine atom), (3) a C 1-6 alkoxy group optionally having 1 to 3 halogen atoms (e.g., fluorine atom) (e.g., methoxy, trifluoromethoxy) and (4) a 5- to 10-membered aromatic heterocyclic group containing, besides carbon atoms, 1 to 4 hetero atoms of one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom, and optionally substituted by 1 to 3 C 1-6 alkyl groups optionally having 1 to 3 halogen atoms (e.g., methyl, trifluoromethyl) (e.g., tetra) selected from
  • ring D is a 3,5-bis(trifluoromethyl)phenyl group, it is preferable for expression of NK1 receptor antagaonistic activity, and when ring D is a 3,5-dichlorophenyl group, it is preferable for expression of NK3 receptor antagaonistic activity.
  • R 1 is a hydrogen atom or a substituent.
  • R 1 examples include a hydrocarbon group optionally having substituent(s), an acyl group, a heterocyclic group optionally having substituent(s), and a group represented by —NR 5 R 6 wherein R 5 and R 6 are each independently a hydrogen atom, a hydrocarbon group optionally having substituent(s), or an acyl group, or in combination show an oxygen atom.
  • an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group and an aralkyl group are used.
  • alkyl group for example, a C 1-6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the like are preferable, and C 1-4 alkyl is more preferable.
  • a C 1-6 alkyl group e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • alkenyl group for example, a C 2-6 alkenyl group (e.g., vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, etc.) and the like are preferable.
  • a C 2-6 alkenyl group e.g., vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, etc.
  • alkynyl group for example, a C 2-6 alkynyl group (e.g., ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl, etc.) and the like are preferable.
  • a C 2-6 alkynyl group e.g., ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl, etc.
  • cycloalkyl group for example, a C 3-8 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) and the like are preferable, and a C 3-6 cycloalkyl group is more preferable.
  • cycloalkenyl group for example, a C 3-8 cycloalkenyl group (e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.) and the like are preferable, and a C 3-6 cycloalkenyl group is more preferable.
  • aryl group for example, a C 6-14 aryl group (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, etc.) and the like are preferable.
  • aralkyl group for example, a C 7-16 aralkyl group (e.g., benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.) and the like are preferable.
  • a C 7-16 aralkyl group e.g., benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.
  • substituent of the “hydrocarbon group” examples include 1 to 3 substituents selected from
  • a halogen atom e.g., fluorine, chlorine, bromine, iodine etc.
  • a C 3-8 cycloalkyl group optionally having 1 to 5 (preferably 1 to 3) halogen atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl etc.),
  • halogen atoms e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl etc.
  • a C 6-14 aryl group e.g., phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl etc.
  • a C 1-6 alkyl group optionally having 1 to 5, preferably 1 to 3, substituents selected from a halogen atom, an amino group, a C 1-6 alkoxy-carbonylamino group and a C 1-3 alkyl-carbonylamino group,
  • a C 1-6 alkoxy group optionally having 1 to 3 halogen atoms (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.),
  • halogen atoms e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.
  • a alkylthio group optionally having 1 to 3 halogen atoms (e.g., methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio etc.),
  • halogen atoms e.g., methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio etc.
  • a C 6-14 arylthio group e.g., phenylthio, naphthylthio etc.
  • a mono-C 1-6 alkylamino group e.g., methylamino, ethylamino etc.
  • a mono-C 6-14 arylamino group e.g., phenylamino, 1-naphthylamino, 2-naphthylamino etc.
  • a di-C 1-6 alkylamino group e.g., dimethylamino, diethylamino etc.
  • a C 1-6 alkyl-carbonyl group e.g., acetyl, propionyl etc.
  • a C 1-6 alkyl-carbonyl group optionally having 1 to 3 substituents selected from a hydroxyl group
  • (21) a C 6-14 aryl-carbonyl group (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl etc.),
  • a C 1-6 alkoxy-carbonyl group e.g., methoxycarbonyl, ethoycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.
  • (25) a 3- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclyl-carbonyl group (e.g., piperidinocarbonyl, morpholinocarbonyl) containing, besides carbon atoms, 1 to 5 hetero atoms of one to three kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom, and optionally having 1 to 3 halogen atoms (e.g., fluorine atom), (26) a C 3-8 cycloalkylcarbamoyl group, (27) a carbamoyl group,
  • a mono-C 1-6 alkyl-carbamoyl group e.g., methylcarbamoyl, ethylcarbamoyl etc.
  • a di-C 1-6 alkyl-carbamoyl group e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.
  • a C 6-14 aryl-carbamoyl group e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.
  • a C 1-6 alkylsulfonyl group e.g., methylsulfonyl, ethylsulfonyl etc.
  • a C 6-14 arylsulfonyl group e.g., phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl etc.
  • a C 1-6 alkylsulfinyl group e.g., methylsulfinyl, ethylsulfinyl etc.
  • a C 6-14 arylsulfinyl group e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl etc.
  • a C 6-14 arylsulfinyl group e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl etc.
  • a C 1-6 alkyl-carbonylamino group e.g., acetylamino, propionylamino, isobutyrylamino, pivaloylamino etc.
  • substituents selected from a hydroxyl group and a C 1-3 alkoxy group e.g., acetylamino, propionylamino, isobutyrylamino, pivaloylamino etc.
  • a C 6-14 aryl-carbonylamino group e.g., benzoylamino, naphthoylamino etc.
  • a 3- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclyl-carbonylamino group e.g., pyridylcarbonylamino
  • a 3- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclyl-oxycarbonylamino group e.g., tetrahydropyranyloxycarbonylamino
  • a C 6-14 aryloxycarbonylamino group optionally having a nitro group
  • a 3- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic group containing, besides carbon atoms, 1 to 5 hetero atoms of one to three kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom, and optionally having 1 to 4 substituents selected from a C 1-6 alkyl group optionally having 1 to 3 halogen atoms (e.g., 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, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-
  • a 4-membered ring group containing, besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom such as 2- or 3-azetidinyl, 2- or 3-oxetanyl and the like;
  • a 5-membered ring group containing, besides carbon atoms, 1 to 4 hetero atoms selected from 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, 1-, 2- or 3-pyrrolidinyl, 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-, 3- or 4-pyrazolidinyl, 2-, 4- or 5-imidazolyl, 1-, 2- or 4-imidazolidinyl, 1,2,3-triazolyl
  • a 5- to 7-membered (preferably 5- or 6-membered) aromatic or non-aromatic heterocyclic group containing, besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom is preferable.
  • acyl group examples include an acyl group represented by the formula: —(C ⁇ O)—R 7 , —(C ⁇ O)—OR 7 , —(C ⁇ O)—NR 7 R 8 , —(C ⁇ S)—R 7 , —(C ⁇ S)—NHR 7 , —(C ⁇ O)—NR 8 —NR 8′ —(C ⁇ O)—R 9 or —SO 2 —R 9 wherein R 7 is a hydrogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s) or a carbamoyl group, R 8 and R 8′ are each a hydrogen atom or a C 1-6 alkyl group, and R 9 is a hydrocarbon group optionally having substituent(s) or a heterocyclic group optionally having substituent(s).
  • hydrocarbon group optionally having substituent(s) and “heterocyclic group optionally having substituent(s)” for R 7 or R 9 those similar to the “hydrocarbon group optionally having substituent(s)” or “heterocyclic group optionally having substituent(s)” for R 1 are used.
  • C 1-6 alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
  • R 1 is a nitroso group (—NO).
  • R 1 is preferably
  • a C 1-6 alkyl group e.g., methyl, ethyl
  • substituents selected from (a) a carbamoyl group, (b) a hydroxy group, (c) a C 1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.) and (d) a 5- to 7-membered aromatic or non-aromatic heterocyclic group (e.g., piperidyl) containing, besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and optionally substituted by 1 to 3 substituents selected from a C 1-6 alkyl-carbonyl group (e.g., acetyl etc.) and a C 1-6 alkoxycarbonyl group (e.g., tert-butoxycarbonyl etc.),
  • a 4- to 7-membered aromatic or nonaromatic heterocyclic group containing, besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom (e.g., piperidyl, azetinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyridyl, pyrimidinyl, thiazolyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, thiomorpholinyl), and optionally having 1 to 3 substituents selected from
  • a C 3-8 cycloalkyl group e.g., cyclohexyl, cyclobutyl
  • substituents selected from
  • a 5- to 7-membered aromatic or nonaromatic heterocyclic group containing, besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom (e.g., tetrahydropyranyl), or
  • R 5′ and R 6′ are independently
  • R 7′′′ and R 8′′ are independently
  • R 1 is
  • a C 1-6 alkyl group e.g., methyl, ethyl
  • substituents selected from (a) a carbamoyl group, (b) a hydroxy group, (c) a C 1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.) and (d) a 5- to 7-membered aromatic or non-aromatic heterocyclic group containing, besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom (e.g., piperidyl), and optionally substituted by a C 1-6 alkyl-carbonyl group (e.g., acetyl etc.), (3) a C 3-6 cycloalkenyl group (e.g., cyclopentenyl, cyclohexenyl etc.) optionally
  • a C 1-6 alkyl group e.g., methyl, tert-butyl
  • a 5- to 7-membered aromatic or nonaromatic heterocyclic group containing, besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom (e.g., tetrahydropyranyl)
  • R 5′ and R 6′ are independently
  • R 7′′′ and R 8′′ are independently
  • L is a group represented by the formula
  • R 2 , R 3 , R 4a and R 4b are each independently a hydrogen atom, an optionally halogenated C 1-6 alkyl group or an optionally halogenated C 3-6 cycloalkyl group, or R 2 and R 3 may be bonded via an alkylene chain or an alkenylene chain or R 4a and R 4b may be bonded via an alkylene chain or an alkenylene chain.
  • Examples of the “optionally halogenated C 1-6 alkyl group” for R 2 , R 3 , R 4a or R 4b include a C 1-6 alkyl group optionally having 1 to 5 (preferably 1 to 3) halogen atoms (e.g., fluorine, chlorine, bromine, iodine etc.) (e.g., 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, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-
  • Examples of the “optionally halogenated C 3-6 cycloalkyl group” for R 2 , R 3 , R 4a or R 4b include a C 3-6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine etc.), and the like.
  • a C 3-6 cycloalkyl group e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine etc.
  • Examples of the alkylene chain mediating the bond of R 2 and R 3 , and R 4a and R 4b include a C 2-6 alkylene group such as ethylene, trimethylene, propylene and the like.
  • Examples of the alkenylene chain mediating the bond of R 2 and R 3 , and R 4a and R 4b include a C 2-6 alkenylene group such as —CH ⁇ CH—, —CH 2 —CH ⁇ CH—, —CH ⁇ CH—CH 2 and the like.
  • R 2 is preferably a hydrogen atom or a C 1-6 alkyl group, more preferably a C 1-4 alkyl group (e.g., methyl, ethyl), and particularly preferably a methyl group.
  • R 3 is preferably a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group (e.g., cyclopropyl), more preferably a alkyl group (e.g., methyl), and particularly preferably a hydrogen atom or a methyl group.
  • R 2 and R 3 are bonded via an ethylene, a trimethylene or —CH ⁇ CH— is also preferable.
  • R 4a and R 4b are preferably both hydrogen atoms, or an embodiment wherein they are bonded via an alkylene chain (e.g., ethylene) is preferable.
  • L is preferably a group represented by the formula
  • R 3′ is a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group (e.g., cyclopropyl).
  • R 3′ is preferably a hydrogen atom or a C 1-6 alkyl group, more preferably a hydrogen atom or a C 1-4 alkyl group (e.g., methyl), and particularly preferably a hydrogen atom or a methyl group.
  • ring D is an aromatic ring having substituent(s), preferably a phenyl group having substituent(s).
  • Compound (I) does not include N-(4-amino-2-isopropylquinolin-6-yl)-N′-[2-phenylpiperidin-3-yl]urea, N-(4-amino-2-isopropylquinolin-6-yl)-N′-[1-(tert-butoxycarbonyl)-2-phenylpiperidin-3-yl]urea and N-[4-(biphenyl-4-yl) piperidin-3-yl]-N′-(naphthalen-2-yl)urea.
  • ring A is a piperidine ring or a pyrrolidine ring
  • ring B is a phenyl group optionally having substituent(s) or a
  • ring D is a phenyl group optionally having substituent(s),
  • L is a group represented by the formula
  • R 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group, or bonded via an alkylene chain or an alkenylene chain
  • R 4a and R 4b are each independently a hydrogen atom, or bonded via an alkylene chain or an alkenylene chain
  • R 1 is a hydrogen atom, a hydrocarbon group optionally having substituent(s), an acyl group, a heterocyclic group optionally having substituent(s), or a group represented by —NR 5 R 6 (R 5 and R 6 are each independently a hydrogen atom, a hydrocarbon group optionally having substituent(s), or an acyl group)
  • m and n are each independently an integer of 1 or 2
  • m+n is an integer of 2 or 3
  • ring A is a piperidine ring or a pyrrolidine ring
  • ring B is (1) a phenyl group optionally having 1 to 3 substituents selected from a C 1-6 alkyl group optionally having 1 to 3 halogen atoms and a halogen atom or (2) a thienyl group optionally having 1 to 3 C 1-6 alkyl groups optionally having 1 to 3 halogen atoms
  • ring D is a phenyl group optionally having 1 or 2 substituents selected from (1) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms (e.g., fluorine atom) (e.g., methyl, trifluoromethyl), (2) a halogen atom (e.g., chlorine atom, bromine atom), (3) a C 1-6 alkoxy group optionally having 1 to 3 halogen atoms (e.g., fluorine atom) (e.g., methoxy, trifluoromethoxy) and (4) a 5- to 10-membered aromatic heterocyclic group containing,
  • R 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group (e.g., methyl), or bonded via an alkylene chain
  • R 4a and R 4b are each independently a hydrogen atom, or bonded via an alkylene chain
  • R 1 is (1) a hydrogen atom, (2) a C 1-6 alkyl group optionally having 1 to 3 substituents selected from (a) a carbamoyl group, (b) a hydroxy group, (c) a C 1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.) and (d) a 5- to 7-membered aromatic or nonaromatic heterocyclic group containing, besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom (e.g., piperidyl), and optionally substituted by 1 to
  • R 7′′ is a C 1-6 alkyl group (e.g., methyl, tert-butyl),
  • R 5′ and R 6′ are independently
  • ring A is a ring represented by
  • ring B is (1) a phenyl group optionally having 1 or 2 substituents selected from a C 1-6 alkyl group (e.g., methyl) and a halogen atom (e.g., fluorine atom, chlorine atom) or (2) a thienyl group optionally having one C 1-6 alkyl group (e.g., methyl),
  • ring D is a phenyl group optionally having 1 or 2 substituents selected from a C 1-6 alkyl group (e.g., methyl) optionally having 1 to 3 halogen atoms (e.g., fluorine atom) (particularly preferably a 3,5-bis(trifluoromethyl)phenyl group),
  • L is a group represented by the formula
  • R 2 and R 3 are each independently a C 1-6 alkyl group (e.g., methyl),
  • R 1 is (1) a C 1-6 alkyl group optionally having 1 to 3 substituents selected from (a) a carbamoyl group, (b) a hydroxy group and (c) a 5- to 7-membered aromatic or nonaromatic heterocyclic group containing, besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom (e.g., piperidyl), and optionally having 1 to 3 C 1-6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.) (e.g., methyl, ethyl, carbamoylmethyl), or (2) a group represented by the formula: —(C ⁇ O)—R 7′′′ wherein R 7′′′ is a 4- to 7
  • ring A is a ring represented by
  • ring B is (1) a phenyl group optionally having 1 to 3 substituents selected from a C 1-6 alkyl group optionally having 1 to 3 halogen atoms and a halogen atom or (2) a pyridyl group optionally having one halogen atom (e.g., fluorine atom) (particularly preferably 5-fluoropyridin-2-yl group), ring D is a phenyl group optionally having 1 to 3 substituents selected from (1) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms (e.g., fluorine atom) (e.g., methyl, trifluoromethyl), (2) a halogen atom (e.g., chlorine atom, bromine atom), (3) a C 1-6 alkoxy group optionally having 1 to 3 halogen atoms (e.g., fluorine atom) (e.g., methoxy, trifluoromethoxy) and (4) a pheny
  • R 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group (e.g., methyl), or bonded via an alkylene chain
  • R 4a and R 4b are each independently a hydrogen atom, or bonded via an alkylene chain
  • R 1 is (1) a hydrogen atom
  • a C 1-6 alkyl group e.g., methyl, tert-butyl
  • a 5- to 7-membered aromatic or nonaromatic heterocyclic group containing, besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom (e.g., tetrahydropyranyl)
  • R 5′ and R 6′ are independently
  • R 7′′′ and R 8 ′′ are independently
  • Compound (I)-4 shows a good NK1 receptor antagaonistic activity.
  • ring A is a ring represented by
  • ring B is (1) a phenyl group optionally having 1 to 3 substituents selected from a C 1-6 alkyl group optionally having 1 to 3 halogen atoms and a halogen atom or (2) a pyridyl group optionally having 1 to 3 substituents selected from a C 1-6 alkyl group optionally having 1 to 3 halogen atoms and a halogen atom
  • ring D is a phenyl group optionally having 1 to 3 substituents selected from (1) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms (e.g., fluorine atom) (e.g., methyl, trifluoromethyl), and (2) a halogen atom (e.g., chlorine atom, bromine atom)
  • L is a group represented by the formula
  • R 2 and R 3 are each independently a C 1-6 alkyl group (e.g., methyl), R 1 is (1) a group represented by the formula: —(C ⁇ O)—R 7′
  • R 7′′′ and R 8′′ are independently
  • Compound (I)-5 shows a good NK2 receptor antagaonistic activity.
  • ring A is a ring represented by
  • ring B is a phenyl group optionally having 1 to 3 substituents selected from a C 1-6 alkyl group optionally having 1 to 3 halogen atoms and a halogen atom
  • ring D is a phenyl group optionally having 1 to 3 substituents selected from (1) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms (e.g., fluorine atom) (e.g., methyl, trifluoromethyl), and (2) a halogen atom (e.g., chlorine atom, bromine atom) (particularly preferably 3,5-bis(trifluoromethyl)phenyl group, 3,5-dichlorophenyl group or 4-chlorophenyl group), L is a group represented by the formula
  • R 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group (e.g., methyl), or bonded via an alkylene chain,
  • R 1 is (1) a group represented by the formula: —(C ⁇ O)—R 7′
  • R 7′′′ and R 8′′ are independently
  • Compound (I)-6 shows a good NK3 receptor antagaonistic activity.
  • a 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 basic amino acid include salts with arginine, lysine, ornithine, etc.
  • Suitable examples of the salts with acidic amino acid include salts with aspartic acid and glutamic acid, etc.
  • salts are preferred.
  • preferred salts are 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.
  • preferred salts are salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., or 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-toluenesulfonic acid, etc.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.
  • the prodrug of compound (I) or a salt thereof of the present invention means a compound which is converted to 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.; by hydrolysis with gastric acid, etc.
  • the prodrug of compound (I) of the present invention includes a compound wherein an amino group of compound (I) is modified with acyl, alkyl or phosphoryl (e.g., a compound wherein an amino group of compound (I) of the present invention is modified with eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl or t-butyl, etc.); a compound wherein a hydroxyl group of compound (I) of the present invention is modified with acyl, alkyl, phosphoric acid or boric acid (e.g., a compound wherein a hydroxyl group of compound (I) is modified with acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl
  • the prodrug of compound (I) of the present invention may be a compound, which is converted into 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.
  • the present invention encompasses a solvate (e.g., hydrate) of compound (I) or a salt thereof.
  • Compound (I) may be labeled with an isotope (e.g., 3 H, 14 C, 35 S, 125 I, etc.) and the like.
  • Compound (I) may also be a deuterated compound.
  • 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. In addition, there can be instances where the isomers by conformation are generated in cases, but such isomers or a mixture thereof are also included in compound (I) or a salt thereof.
  • the intermediates produced in the following production methods may be isolated and purified by column chromatography, recrystallization, distillation and the like, or may be used as they are for the next step without isolation.
  • the compound (I) of the present invention or a salt thereof can be produced by the following method A to method F.
  • compound (I) when compound (I) is a compound represented by the formula (VII) or a salt thereof (hereinafter to be referred to as compound (VII)), and R 2a ⁇ R 3a , it can be produced by the following method A.
  • R 1a is a hydrocarbon group optionally having substituent(s), an acyl group, an amino group or a heterocyclic group
  • R 2a and R 3a are each an optionally halogenated C 1-6 alkyl group or an optionally halogenated C 3-6 cycloalkyl group
  • Boc is a tert-butoxycarbonyl group, and other symbols are as defined above.
  • hydrocarbon group optionally having sub stituent(s)”, “acyl group” and “heterocyclic group” for R 1a are as defined for the “hydrocarbon group optionally having sub stituent(s)”, “acyl group” and “heterocyclic group” for R 1 .
  • a compound represented by the formula (II) or a salt thereof (hereinafter to be referred to as compound (II)) is subjected to a rearrangement reaction step (step 1-1), then subsequently to a hydrolysis step (step 1-2) to convert to a compound represented by the formula (III) or a salt thereof (hereinafter to be referred to as compound (III)).
  • This step can be performed according to a method known per se (e.g., the methods described in “4th Ed. Jikken Kagaku Koza (Courses in Experimental Chemistry) 20, Organic Synthesis II”, The Chemical Society of Japan Ed., 1991 and the like), or a method analogous thereto.
  • rearrangement reaction examples include Hofmann rearrangement reaction, Schmidt rearrangement reaction, Curtius rearrangement reaction and the like. While the rearrangement reaction varies depending on compound (II), generally, it is preferably the Curtius rearrangement reaction.
  • the Curtius rearrangement reaction is generally carried out by reacting compound (II) with an azidating agent in a solvent that does not adversely influence the reaction in the presence of a base, and heating.
  • the base examples include inorganic bases (alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkoxides such as sodium methoxide, sodium ethoxide and the like, and the like), organic bases (amines such as trimethylamine, triethylamine, diisopropylethylamine and the like; aromatic amines such as pyridine, 4-dimethylaminopyridine and the like; and the like) and the like.
  • inorganic bases alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like
  • alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like
  • alkali metal carbonates such as sodium carbonate, potassium carbonate and the like
  • alkoxides such as sodium meth
  • organic bases triethylamine, diisopropylethylamine and the like
  • the amount of the base to be used varies depending on the kind of the solvent and the other reaction conditions, it is generally about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents, per 1 mol of compound (II).
  • azidating agent examples include diphenylphosphoryl azide (DPPA).
  • Examples of the solvent that does not adversely influence the reaction include hydrocarbons (benzene, toluene, xylene, hexane, heptane and the like), halogenated hydrocarbons (dichloromethane, chloroform and the like), ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like), nitriles (acetonitrile and the like), amides (N,N-dimethylformamide, N,N-dimethylacetamide and the like), sulfoxides (dimethyl sulfoxide and the like) and the like.
  • Such solvent may be used in a mixture of two or more at a suitable ratio.
  • the reaction temperature is, for example, within the range of about ⁇ 50° C. to 200° C., preferably about 0° C. to 100° C. While the reaction time varies depending on the kind of compound (II), the reaction temperature and the like, it is, for example, about 0.5 to 24 hr, preferably about 0.5 to 2 hr.
  • the hydrolysis can be carried out according to a method known per se, for example, in the presence of a base, as necessary in a solvent that does not adversely influence the reaction.
  • the base examples include inorganic bases (alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkoxides such as sodium methoxide, sodium ethoxide and the like, and the like), organic bases (amines such as trimethylamine, triethylamine, diisopropylethylamine and the like; aromatic amines such as pyridine, 4-dimethylaminopyridine and the like; and the like) and the like.
  • lithium hydroxide, sodium hydroxide, potassium hydroxide and the like are preferable.
  • the amount of the base to be used varies depending on the kind of the solvent and the other reaction conditions, it is generally about 1 to 100 molar equivalents, preferably about 1 to 20 molar equivalents, per 1 mol of compound (II).
  • Examples of the solvent that does not adversely influence the reaction include hydrocarbons (benzene, toluene, xylene, hexane, heptane and the like), halogenated hydrocarbons (dichloromethane, chloroform and the like), ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like), nitriles (acetonitrile and the like), amides (N,N-dimethylformamide, N,N-dimethylacetamide and the like), sulfoxides (dimethyl sulfoxide and the like), water and the like.
  • Such solvent may be used in a mixture of two or more at a suitable ratio.
  • the reaction temperature is, for example, within the range of about ⁇ 50° C. to 200° C., preferably about 0° C. to 100° C. While the reaction time varies depending on the kind of compound (II), the reaction temperature and the like, it is, for example, about 0.5 to 24 hr, preferably about 0.5 to 2 hr.
  • compound (X) wherein each symbol is as defined above, or a salt thereof (hereinafter to be referred to as compound (X)) to give a compound represented by the formula (IV) or a salt thereof (hereinafter to be referred to as compound (IV)).
  • Compound (X) is commercially available or can be produced by a known method. The amount thereof to be used is about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, of compound (X) per 1 mol of compound (III).
  • the above-mentioned reaction is generally performed in a solvent that does not adversely influence the reaction, and a convenient base may be added for the progress of the reaction.
  • the solvent include hydrocarbons (benzene, toluene and the like), ethers (diethyl ether, dioxane, tetrahydrofuran and the like), esters (ethyl acetate and the like), halogenated hydrocarbons (chloroform, dichloromethane and the like), amides (N,N-dimethylformamide and the like), aromatic amines (pyridine and the like), water and the like, which may be appropriately mixed.
  • Examples of the base include metal hydrides (lithium hydride, sodium hydride, potassium hydride, calcium hydride and the like), alkali metal hydroxides (sodium hydroxide, potassium hydroxide and the like), hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate and the like), carbonates (sodium carbonate, potassium carbonate and the like), acetates (sodium acetate and the like), tertiary amines (trimethylamine, triethylamine, N-methylmorpholine and the like), aromatic amines (pyridine, picoline, N,N-dimethylaniline and the like) and the like.
  • metal hydrides lithium hydride, sodium hydride, potassium hydride, calcium hydride and the like
  • alkali metal hydroxides sodium hydroxide, potassium hydroxide and the like
  • hydrogen carbonates sodium hydrogen carbonate, potassium hydrogen carbonate and the like
  • carbonates sodium carbonate, potassium carbonate and the like
  • acetates sodium
  • the amount of the base to be used is generally about 1 to 100 molar equivalents, preferably about 1 to 5 molar equivalents, per 1 mol of compound (III).
  • the reaction temperature is generally about ⁇ 80 to 150° C., preferably about 0 to 50° C.
  • the reaction time is generally about 0.5 to 48 hr, preferably about 0.5 to 16 hr.
  • compound (1V) is reacted with a compound represented by the formula R 2a —X (XI) or R 3a —X (XI′) wherein X is a leaving group, or a salt thereof (hereinafter to be referred to as compound (XI)) to give a compound represented by the formula (V) or a salt thereof (hereinafter to be referred to as compound (V)).
  • Examples of the leaving group for X include a halogen atom (chlorine atom, bromine atom, iodine atom and the like), a substituted sulfonyloxy group (a C 1-6 alkylsulfonyloxy group such as methylsulfonyloxy, ethylsulfonyloxy and the like; a C 6-14 arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy and the like; a C 7-16 aralkylsulfonyloxy group such as benzylsulfonyloxy and the like, and the like), an acyloxy group (acetoxy group, benzoyloxy group and the like), an oxy group substituted by a hetero ring or an aryl group (succinimideoxy, benzotriazolyloxy, quinolyloxy, 4-nitrophenoxy and the like),
  • This reaction can be generally performed by reacting compound (XI) in a solvent in the presence of a base.
  • the solvent include alcohols (methanol, ethanol, propanol and the like), ethers (dimethoxyethane, dioxane, tetrahydrofuran and the like), ketones (acetone and the like), nitriles (acetonitrile and the like), amides (N,N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like), water and the like, which may be appropriately mixed and used.
  • the base includes, for example, organic bases (trimethylamine, triethylamine, N-methylmorpholine, pyridine, picoline, N,N-dimethylaniline and the like), inorganic bases (potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and the like), metal amides (lithium hexamethyl disilazide, sodium hexamethyl disilazide, potassium hexamethyl disilazide, lithium diisopropylamide and the like), metal hydrides (lithium hydride, sodium hydride, calcium hydride) and the like.
  • the amount of the base to be used is, for example, about 1 to 100 molar equivalents, preferably about 1 to 10 molar equivalents, per 1 mol of compound (IV).
  • an additive can also be used to promote the reaction.
  • the additive include an iodide (sodium iodide, potassium iodide and the like) and the like.
  • the amount thereof to be used is about 0.1 to 10 molar equivalents, preferably about 0.1 to 5 molar equivalents, per 1 mol of compound (XI).
  • the reaction temperature is generally ⁇ 10 to 200° C., preferably about 0 to 110° C.
  • the reaction time is generally 0.5 to 48 hr, preferably about 0.5 to 16 hr.
  • compound (VI) is subjected to deprotection to produce compound represented by the formula (VI) or a salt thereof (hereinafter to be referred to as compound (VI)).
  • the deprotection can be carried out according to a known method (e.g., “Protective Groups in Organic Synthesis, 3 rd Ed.” by Theodora W. Greene, Peter G. M. Wuts, published by Wiley-Interscience, 1999). While the deprotection varies depending on, for example, the kind of compound (IV), it is generally in the presence of an acid, as necessary in a solvent that does not adversely influence the reaction.
  • the acid examples include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid etc.), carboxylic acids (acetic acid, trifluoroacetic acid, trichloroacetic acid, etc.), sulfonic acids (methanesulfonic acid, toluenesulfonic acid, etc.), Lewis acids (aluminum chloride, tin chloride, zinc bromide, etc.) and the like. If necessary, it may be used in a mixture of two or more. While the amount of the acid to be used varies depending on the kinds of the solvent and other reaction conditions, it is usually about 0.1 molar equivalents or more, per 1 mol of compound (V), and it can be used as a solvent.
  • the solvent that does not adversely influence the reaction includes alcohols (methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, t-butanol, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), nitriles (acetonitrile, etc.), esters (ethyl acetate, etc.), carboxylic acids (acetic acid, etc.), amides (N,N-dimethylformamide, etc.), sulfoxides (dimethyl sulfoxide, etc.),
  • the reaction temperature is, for example, about ⁇ 50° C. to 200° C., preferably about 0° C. to 100° C. While the reaction time varies depending on the kinds of compound (V), the reaction temperature and the like, it is, for example, about 0.5 to 100 hr, preferably about 0.5 to 24 hr.
  • compound (VI) is subjected to an alkylation reaction, acylation reaction, enamine formation reaction, reductive condensation reaction or amination reaction to give compound (VII).
  • compound (VI) is reacted with a compound represented by the formula R 1b —OH (XII) or R 1b —X (XIIa) wherein R 1b is a hydrocarbon group optionally having substituent(s), an acyl group or a heterocyclic group, and other symbols are as defined above, or a salt thereof (hereinafter to be referred to as compound (XII) and compound (XIIa), respectively) to give compound (VII).
  • hydrocarbon group optionally having substituent(s)”, “acyl group” and “heterocyclic group” for R 1b are as defined for “hydrocarbon group optionally having substituent(s)”, “acyl group” and “heterocyclic group” for R 1 .
  • Compound (XII) and compound (XIIa) are commercially available or can be produced by a known method. The amount thereof to be used is about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, of compound (XII) or compound (XIIa) per 1 mol of compound (VI).
  • alkylation reaction can be performed by a method known per se, it can be generally performed by reacting compound (XIIa) in a solvent in the presence of a base, and can be performed by a method similar to the method described in Method A, step 3.
  • the acylation reaction can be performed by a method known per se, for example, the method described in “4th Ed. Jikken Kagaku Koza (Courses in Experimental Chemistry) 22, Organic Synthesis IV”, The Chemical Society of Japan Ed., 1991 and the like, or a method analogous thereto. Examples of such method include a method using a condensing agent, a method via a reactive derivative and the like.
  • condensing agent examples include dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide and hydrochloride thereof, benzotriazol-1-yl-tris(dimethylamino)pho sphonium hexafluorophosphate, diphenylphosphoryl azide and the like.
  • the amount of the condensing agent to be used is about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, per 1 mol of compound (VI).
  • the amount of the additive to be used is about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, per 1 mol of compound (VI).
  • the above-mentioned reaction is generally performed in a solvent that does not adversely influence the reaction, and a convenient base may be added for the progress of the reaction.
  • the solvent include hydrocarbons (benzene, toluene and the like), ethers (diethyl ether, dioxane, tetrahydrofuran and the like), esters (ethyl acetate and the like), halogenated hydrocarbons (chloroform, dichloromethane and the like), amides (N,N-dimethylformamide and the like), aromatic amines (pyridine and the like), water and the like, which may be appropriately mixed.
  • Examples of the base include alkali metal hydroxides (sodium hydroxide, potassium hydroxide and the like), hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate and the like), carbonates (sodium carbonate, potassium carbonate and the like), acetates (sodium acetate and the like), tertiary amines (trimethylamine, triethylamine, N-methylmorpholine and the like), aromatic amines (pyridine, picoline, N,N-dimethylaniline and the like) and the like.
  • the amount of the base to be used is generally about 1 to 100 molar equivalents, preferably about 1 to 5 molar equivalents, per 1 mol of compound (VI).
  • the reaction temperature is generally about ⁇ 80 to 150° C., preferably about 0 to 50° C.
  • the reaction time is generally about 0.5 to 48 hr, preferably about 0.5 to 16 hr.
  • a compound represented by the formula (XIIa) e.g., an acid halide, an acid anhydride, a mixed acid anhydride, an activity ester and the like
  • an isocyanic acid ester e.g., an isothiocyanic acid ester and the like
  • the conversion of compound (XII) to a reactive derivative (compound (XIIa)) can be performed according to a method known per se.
  • a method using an acid halide e.g., thionyl chloride, oxalyl chloride and the like
  • a method using a halide of phosphorus or phosphoric acid e.g., phosphorus trichloride, phosphorus pentachloride and the like
  • the reaction is generally performed in a solvent that does not adversely influence the reaction, and a convenient base may be added for the progress of the reaction.
  • the kind of the solvent and base to be used for the reaction, amount of use, reaction temperature and reaction time are similar to those described for the above-mentioned “method using a condensing agent”.
  • compound (VI) is condensed with aldehyde or ketone to give an enamine.
  • the enamine formation reaction is carried out generally in a solvent that does not adversely influence the reaction.
  • the solvent include aromatic hydrocarbons (toluene, xylene and the like), aliphatic hydrocarbons (heptane, hexane and the like), halogenated hydrocarbons (chloroform, dichloromethane and the like), ethers (diethyl ether, tetrahydrofuran, dioxane and the like), alcohols (methanol, ethanol, 2-propanol, butanol, benzyl alcohol and the like), nitriles (acetonitrile and the like), amides (N,N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like) and the like.
  • Such solvent may be used in a mixture at a suitable ratio.
  • the aldehyde include formalin, aliphatic aldehydes (acetaldehyde and the like) optionally having substituent(s), aromatic aldehydes (benzaldehyde and the like) optionally having substituent(s) and the like.
  • the ketone include aliphatic ketones (acetone, cyclohexanone, piperidone and the like) optionally having substituent(s), aromatic ketones (acetophenone, benzophenone and the like) optionally having substituent(s) and the like.
  • the amount thereof to be used is, for example, about 1 to 100 molar equivalents, preferably about 1 to 5 molar equivalents, per 1 mol of compound (VI).
  • the reaction may be advantageously promoted using a catalyst.
  • the catalyst include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like), carboxylic acids (formic acid, acetic acid, propionic acid, trifluoroacetic acid and the like), sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid and the like), Lewis acids (aluminum chloride, zinc chloride, zinc bromide, boron trifluoride, titanium chloride and the like), acetates (sodium acetate, potassium acetate and the like), molecular sieves (molecular sieves 3A, 4A, 5A and the like) and the like.
  • the amount of the catalyst to be used is, for example, about 0.01 to 50 molar equivalents, preferably about 0.1 to 10 molar equivalents, per 1 mol of compound (VI).
  • the reaction temperature is generally about 0° C. to 200° C., preferably about 20° C. to 150° C.
  • the reaction time is generally 0.5 to 48 hr, preferably 0.5 to 24 hr.
  • the above-mentioned enamine or iminium ion is subjected to a reduction reaction to give compound (VII).
  • the iminium on can be obtained by a method similar to the above-mentioned enamine formation reaction.
  • the reduction reaction of enamine or iminium ion can be carried out according to a method known per se, for example, a method using a metal hydride and a method by catalytic hydrogenation reaction.
  • metal hydride as a reducing agent examples include metal hydrides (sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride, diisobutylaluminum hydride, aluminum hydride, lithium aluminum hydride and the like), borane complexes (borane-tetrahydrofuran complex, catecholborane and the like) and the like.
  • metal hydrides sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride, diisobutylaluminum hydride, aluminum hydride, lithium aluminum hydride and the like
  • borane complexes borane complexes (borane-tetrahydrofuran complex, catecholborane and the like) and the like.
  • the amount of the reducing agent to be used is, for example, about 1 to 50 molar equivalents, preferably about 1 to 10 molar equivalents, per 1 mol of compound (VI).
  • the solvent include aromatic hydrocarbons (toluene, xylene and the like), aliphatic hydrocarbons (heptane, hexane and the like), halogenated hydrocarbons (chloroform, dichloromethane and the like), ethers (diethyl ether, tetrahydrofuran, dioxane and the like), alcohols (methanol, ethanol, 2-propanol, butanol, benzyl alcohol and the like), nitriles (acetonitrile and the like), amides (N,N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like) and the like.
  • Such solvent may be used in a mixture at a suitable ratio.
  • the reaction temperature is generally about ⁇ 80° C. to 80° C., preferably about ⁇ 40° C. to 40° C.
  • the reaction time is generally 5 min to 48 hr, preferably 1 to 24 hr.
  • the catalytic hydrogenation reaction can be carried out in the presence of a catalyst under a hydrogen atmosphere.
  • a catalyst include palladium compounds (palladium carbon, palladium hydroxide, palladium oxide, etc.), nickel compounds (Raney-nickel, etc.), platinum compounds (platinum oxide, platinum carbon, etc.), rhodium compounds (rhodium acetate, etc.) and the like.
  • the amount thereof to be used is about 0.001 to 1 equivalent, preferably about 0.01 to 0.5 equivalent, per 1 mol of compound (VI).
  • the catalytic hydrogenation reaction can be generally carried out in a solvent inert to the reaction.
  • the solvent include alcohols (methanol, ethanol, propanol, butanol, etc.), hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether, dioxane, tetrahydrofuran, etc.), esters (ethyl acetate, etc.), amides (N,N-dimethylformamide, etc.), carboxylic acids (acetic acid, etc.), water and a mixture thereof.
  • the hydrogen pressure at 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° C. to 150° C., preferably about 20° C. to 100° C.
  • the reaction time is generally about 5 min to 72 hr, preferably about 0.5 to 40 hr.
  • the above-mentioned formation reaction and reduction reaction of the enamine or iminium ion are simultaneously carried our without isolation of the intermediate enamine or iminium ion.
  • the pH of the reaction mixture is preferably about 4 to 5.
  • N-nitroso compound obtained by subjecting compound (VI) to N-nitrosation is reduced and, for example, the above-mentioned alkylation reaction or acylation reaction and the like are performed by a method known per se to give compound (VII).
  • the N-nitrosation reaction can be carried out according to a method known per se, for example, the methods described in “4th Ed. Jikken Kagaku Koza (Courses in Experimental Chemistry) 20, Organic Synthesis II”, The Chemical Society of Japan Ed. 1991 and the like, or a method analogous thereto.
  • Examples of the method include a method using tert-butyl nitrite or sodium nitrite.
  • the amount thereof to be used is about 1 equivalent to 20 equivalents, preferably about 1 equivalent to 5 equivalents.
  • the reaction is generally carried out in a solvent that does not adversely influence the reaction.
  • the reaction may be promoted using an acid.
  • the solvent examples include hydrocarbons (benzene, toluene, xylene and the like), halogenated hydrocarbons (dichloromethane, chloroform and the like), ethers (diethyl ether, dioxane, tetrahydrofuran and the like), carboxylic acids (acetic acid and the like), water and a mixture thereof.
  • the acid examples include hydrochloric acid, nitric acid and the like.
  • the reaction temperature is generally about 0° C. to 150° C., preferably about 0° C. to 100° C.
  • the reaction time is generally 5 min to 72 hr, preferably 0.5 to 40 hr.
  • the reduction reaction of N-nitroso compound can be generally carried out by using a metal or a metal salt or a metal hydride.
  • the metal or metal salt to be used include alkali metals (lithium, sodium, potassium and the like), alkaline earth metals (magnesium, calcium and the like), other metals (zinc, chrome, titanium, iron, samarium, selenium and the like), metal salts (zinc-amalgam, zinc-copper alloy, aluminum-amalgam, sodium hydrosulfite and the like) and the like.
  • the metal hydride include lithium aluminum hydride.
  • the amount of the reducing agent to be used is 1 to 50 molar equivalents, preferably about 1 to 5 molar equivalents, per 1 mol of the substrate.
  • Examples of the solvent to be used for the reaction include alcohols (methanol, ethanol, 2-propanol, t-butanol, benzyl alcohol and the like), amines (liquid ammonia, methylamine, ethylamine, ethylenediamine and the like), ethers (diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like), mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like), carboxylic acids (acetic acid and the like), amides (hexamethylphosphoramide), water and the like.
  • Such solvent may be used alone or in a mixture.
  • the reaction temperature is generally about ⁇ 80° C. to 150° C., preferably about ⁇ 80° C. to 100° C.
  • the reaction time is generally 5 min to 48 hr, preferably 1 to 24 hr.
  • compound (IV) is deprotected to give a compound represented by the formula (VIII) or a salt thereof (hereinafter to be referred to as compound (VIII)).
  • This step can be performed by a method similar to the method described in Method A, step 4.
  • compound (VIII) is subjected to an alkylation reaction, acylation reaction, enamine formation reaction, reductive condensation reaction, or amination reaction to give a compound represented by the formula (IX) or a salt thereof (hereinafter to be referred to as compound (IX)).
  • This step can be performed by a method similar to the method described in Method A, step 5.
  • compound (IX) is reacted with a compound represented by the formula R 2a —X (XI) or R 3a —X (XI′) wherein each symbol is as defined above, or a salt thereof to give compound (VII).
  • This step can be performed by a method similar to the method described in Method A, step 3.
  • compound (II) is subjected to a rearrangement reaction to convert to a compound represented by the formula (XIII) or a salt thereof (hereinafter to be referred to as compound (XIII)).
  • This step can be performed by a method similar to the rearrangement reaction described in Method A, step 1-1.
  • compound (XLVII) wherein each symbol is as defined above, or a salt thereof (hereinafter to be referred to as compound (XLVII)) to give compound (IV).
  • Compound (XLVII) is commercially available or can be produced by a known method. The amount thereof to be used is about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, of compound (XIX) per 1 mol of compound (XIII). This step can be performed by a method similar to the method described in Method A, step 2.
  • compound (I) when compound (I) is a compound represented by the formula (VIIa) or a salt thereof (hereinafter to be referred to as compound (VIIa)), it can be produced by the following Method B.
  • each symbol is as defined above, or a salt thereof (hereinafter to be referred to as compound (XIX)) to give a compound represented by the formula (XIV) or a salt thereof (hereinafter to be referred to as compound (XIV)).
  • Compound (XIX) is commercially available or can be produced by a known method. The amount thereof to be used is about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, of compound (XIX) per 1 mol of compound (XIII). This step can be performed by a method similar to the method described in Method A, step 2. (Step 2)
  • compound (XIV) is reacted with a compound represented by the formula R 2a —X (XI) wherein each symbol is as defined above, or a salt thereof to give a compound represented by the formula (XV) or a salt thereof (hereinafter to be referred to as compound (XV)).
  • This step can be performed by a method similar to the method described in Method A, step 3.
  • compound (XV) is deprotected to give a compound represented by the formula (XVI) or a salt thereof (hereinafter to be referred to as compound (XVI)).
  • This step can be performed by a method similar to the method described in Method A, step 4.
  • compound (XVI) is subjected to an alkylation reaction, acylation reaction, enamine formation reaction, reductive condensation reaction, or amination reaction to give compound (VIIa).
  • This step can be performed by a method similar to the method described in Method A, step 5.
  • compound (XIV) is deprotected to give a compound represented by the formula (XVII) or a salt thereof (hereinafter to be referred to as compound (XVII)).
  • This step can be performed by a method similar to the method described in Method A, step 4.
  • compound (XVII) is subjected to an alkylation reaction, acylation reaction, enamine formation reaction, reductive condenation reaction, or amination reaction to give a compound represented by the formula (XVIII) or a salt thereof (hereinafter to be referred to as compound (XVIII)).
  • This step can be performed by a method similar to the method described in Method A, step 5.
  • step 3 compound (XVIII) is reacted with a compound represented by the formula R 2a —X (XI) wherein each symbol is as defined above, or a salt thereof to give compound (VIIa).
  • This step can be performed by a method similar to the method described in Method A, step 3.
  • Compound (VIIa) can be produced by the following Method C.
  • compound (III) is subjected to trifluoroacetylation reaction to give the compound represented by the formula (XX) or a salt thereof (hereinafter to be referred to as compound (XX)).
  • This reaction can be carried out according to a known method (e.g., “Protective Groups in Organic Synthesis, 3 rd Ed.” by Theodara W. Greene, Peter G. M. Wuts, published by Wiley-Interscience, 1999).
  • This reaction can be generally carried out by reacting compound (III) with a trifluoroacetylating agent in a solvent that does not adversely influence the reaction in the presence of a base.
  • trifluoroacetylating agent examples include trifluoroacetates (ethyl trifluoroacetate and the like), trifluoroacetic anhydride, succinimide trifluoroacetate and the like.
  • the amount of the trifluoroacetylating agent to be used is generally about 1 to 100 molar equivalents, preferably about 1 to 10 molar equivalents, per 1 mol of compound (III).
  • Examples of the base include alkali metal hydroxides (sodium hydroxide, potassium hydroxide and the like), hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate and the like), carbonates (sodium carbonate, potassium carbonate and the like), acetates (sodium acetate and the like), tertiary amines (trimethylamine, triethylamine, N-methylmorpholine) aromatic amines (pyridine, picoline, N,N-dimethylaniline and the like) and the like.
  • the amount of the base to be used is generally about 1 to 100 molar equivalents, preferably about 1 to 10 molar equivalents, per 1 mol of compound (III).
  • Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, t-butanol and the like), aromatic hydrocarbons (benzene, toluene, xylene and the like), aliphatic hydrocarbons (hexane, heptane and the like), halogenated hydrocarbons (dichloromethane, chloroform and the like), ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like), nitriles (acetonitrile and the like), esters (ethyl acetate and the like), carboxylic acids (acetic acid and the like), amides (N,N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the
  • the reaction temperature is, for example, within the range of about ⁇ 50° C. to 200° C., preferably about 0° C. to 100° C. While the reaction time varies depending on the kind of compound (III) or a salt thereof, the reaction temperature and the like, it is, for example, about 0.5 to 100 hr, preferably about 0.5 to 24 hr.
  • compound (XX) is reacted with a compound represented by the formula R 2a —X (XI) wherein each symbol is as defined above, or a salt thereof to give a compound represented by the formula (XXI) or a salt thereof (hereinafter to be referred to as compound (XXI)).
  • This step can be performed by a method similar to the method described in Method A, step 3. (Step 3)
  • compound (XXI) is deprotected to give a compound represented by the formula (XXII) or a salt thereof (hereinafter to be referred to as compound (XXII)).
  • This step can be performed by a method similar to the method described in Method A, step 4.
  • compound (XXII) is subjected to an alkylation reaction, acylation reaction, enamine formation reaction, reductive condensation reaction, or amination reaction to give a compound represented by the formula (XXIII) or a salt thereof (hereinafter to be referred to as compound (XXIII)).
  • This step can be performed by a method similar to the method described in Method A, step 5.
  • This reaction can be carried out according to a known method (e.g., “Protective Groups in Organic Synthesis, 3rd Ed.,” by Theodara W. Greene, Peter G. M. Wuts, published by Wiley-Interscience, 1999).
  • a known method e.g., “Protective Groups in Organic Synthesis, 3rd Ed.,” by Theodara W. Greene, Peter G. M. Wuts, published by Wiley-Interscience, 1999.
  • Examples of the base include alkali metal hydroxides (sodium hydroxide, potassium hydroxide and the like), hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate and the like), carbonates (sodium carbonate, potassium carbonate and the like), acetates (sodium acetate), ammonium salts (benzyltriethylammonium hydroxide and the like) and the like.
  • the amount of the base to be used is generally about 1 to 100 molar equivalents, preferably about 1 to 10 molar equivalents, per 1 mol of compound (XXIII).
  • Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, t-butanol and the like), aromatic hydrocarbons (benzene, toluene, xylene and the like), aliphatic hydrocarbons (hexane, heptane and the like), halogenated hydrocarbons (dichloromethane, chloroform and the like), ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like), nitriles (acetonitrile and the like), esters (ethyl acetate and the like), carboxylic acids (acetic acid and the like), amides (N,N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the
  • the reaction temperature is, for example, within the range of about ⁇ 50° C. to 200° C., preferably about 0° C. to 100° C. While the reaction time varies depending on the kind of compound (XXIII), the reaction temperature and the like, it is, for example, about 0.5 to 400 hr, preferably about 0.5 to 120 hr.
  • compound (XXV) is reacted with a compound represented by the formula R 3a —X (XI′) [wherein each symbol is as defined above, or a salt thereof (hereinafter to be referred to as compound (XI′)) to give compound (VIIa).
  • Compound (XI′) is commercially available or can be produced by a known method. The amount thereof to be used is about 1 to 10 molar equivalents, preferably about 1 to 4 molar equivalents, of compound (XI′) per 1 mol of compound (XXV).
  • This step can be performed by a method similar to the method described in Method A, step 3.
  • compound (I) is a compound represented by the formula (XXX) or a salt thereof (hereinafter to be referred to as compound (XXX)), and R 2a ⁇ R 3a , can be produced by the following Method D.
  • each symbol is as defined above, or a salt thereof (hereinafter to be referred to as compound (XXXI)) to give a compound represented by the formula (XXVII) or a salt thereof (hereinafter to be referred to as compound (XXVII)).
  • Compound (XXXI) is commercially available or can be produced by a known method. The amount thereof to be used is about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, of compound (XXXI) per 1 mol of compound (III). This step can be performed by a method similar to the method described in Method A, step 2. (Step 2)
  • each symbol is as defined above, or a salt thereof (hereinafter to be referred to as compound (XXXII)) to give compound (XXVII).
  • Compound (XXXII) is commercially available or can be produced by a known method. The amount thereof to be used is about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, of compound (XXXII) per 1 mol of compound (XIII). This step can be performed by a method similar to the method described in MethodA, step 2. (Step 3)
  • compound (XXVII) is reacted with a compound represented by the formula R 2a —X (XI) or R 3a —X (XI′) wherein each symbol is as defined above, or a salt thereof to give a compound represented by the formula (XXVIII) or a salt thereof (hereinafter to be referred to as compound (XXVIII)).
  • This step can be performed by a method similar to the method described in Method A, step 3. (Step 4)
  • compound (XXVIII) is deprotected to give a compound represented by the formula (XXIX) or a salt thereof (hereinafter to be referred to as compound (XXIX)).
  • This step can be performed by a method similar to the method described in Method A, step 4.
  • compound (XXIX) is subjected to an alkylation reaction, acylation reaction, enamine formation reaction, reductive condensation reaction, or amination reaction to give compound (XXX).
  • This step can be performed by a method similar to the method described in Method A, step 5.
  • compound (I) when compound (I) is a compound represented by the formula (XXXVII) or a salt thereof (hereinafter to be referred to as compound (XXXVII)), it can be produced by the following Method E.
  • each symbol is as defined above, or a salt thereof (hereinafter to be referred to as compound (XXXVIII)) to give a compound represented by the formula (XXXIII) or a salt thereof (hereinafter to be referred to as compound (XXXIII)).
  • Compound (XXXVIII) is commercially available or can be produced by a known method. The amount thereof to be used is about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, of compound (XXXVIII) per 1 mol of compound (III). This step can be performed by a method similar to the method described in Method A, step 2. (Step 2)
  • compound (XXXIII) is treated with a base to give a compound represented by the formula (XXXIV) or a salt thereof (hereinafter to be referred to as compound (XXXIV)).
  • the reaction is performed in a solvent that does not adversely influence the reaction.
  • the base examples include organic bases (trimethylamine, triethylamine, N-methylmorpholine, pyridine, picoline, N,N-dimethylaniline and the like), inorganic bases (potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and the like), alkali metal alkoxide (sodium methoxide, sodium ethoxide, sodium-t-butoxide, potassium-t-butoxide and the like), metal amides (lithium disilazide, sodium disilazide, potassium disilazide, lithium diisopropylamide and the like), metal hydrides (lithium hydride, sodium hydride, potassium hydride, calcium hydride) and the like.
  • organic bases trimethylamine, triethylamine, N-methylmorpholine, pyridine, picoline, N,N-dimethylaniline and the like
  • inorganic bases potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and
  • the amount of the base to be used is, for example, about 1 to 100 molar equivalents, preferably about 1 to 10 molar equivalents, per 1 mol of compound (XXXIII).
  • the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol and the like), ethers (dimethoxyethane, dioxane, tetrahydrofuran and the like), ketones (acetone and the like), nitriles (acetonitrile and the like), amides (N,N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like), water and the like, which may be appropriately mixed and used.
  • an additive can also be used to promote the reaction.
  • the additive include iodides (sodium iodide, potassium iodide, tetrabutylammonium iodide and the like) and the like.
  • the amount thereof to be used is about 0.1 to 10 molar equivalents, preferably about 0.1 to 5 molar equivalents, per 1 mol of compound (XXXIII).
  • the reaction temperature is generally ⁇ 10 to 200° C., preferably about 0 to 120° C.
  • the reaction time is generally 0.5 to 48 hr, preferably about 0.5 to 16 hr.
  • each symbol is as defined above, or a salt thereof (hereinafter to be referred to as compound (XXXIX)) to give a compound represented by the formula (XXXV) or a salt thereof (hereinafter to be referred to as compound (XXXV)).
  • Compound (XXXIX) is commercially available or can be produced by a known method. The amount thereof to be used is about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, of compound (XXXIX) per 1 mol of compound (XXIV). This step can be performed by a method similar to the method described in Method A, step 3. (Step 4)
  • compound (XXXV) is deprotected to give a compound represented by the formula (XXXVI) or a salt thereof (hereinafter to be referred to as compound (XXXVI)).
  • This step can be performed by a method similar to the method described in Method A, step 4.
  • compound (XXXVI) is subjected to an alkylation reaction, acylation reaction, enamine formation reaction, reductive condensation reaction, or amination reaction to give compound (XXXVII).
  • This step can be performed by a method similar to the method described in MethodA, step 5.
  • compound (I) is a compound represented by the formula (XLV) or a salt thereof (hereinafter to be referred to as compound (XLV)), it can be produced by the following method F.
  • each symbol is as defined above, or a salt thereof (hereinafter to be referred to as compound (XLVI)) to give imine, which is then subjected to a reduction reaction to give a compound represented by the formula (XL) or a salt thereof (hereinafter to be referred to as compound (XL)).
  • Compound (XLVI) is commercially available or can be produced by a known method. The amount thereof to be used is about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, of compound (XLVI) per 1 mol of compound (III). This step can be performed by a method similar to the reductive condensation reaction described in Method A, step 5. (Step 2)
  • compound (XL) is deprotected to give a compound represented by the formula (XLI) or a salt thereof (hereinafter to be referred to as compound (XLI)).
  • This step can be performed by a method similar to the method described in Method A, step 4.
  • compound (XLI) is subjected to tert-butoxycarbonylation reaction to give the compound represented by the formula (XLII) or a salt thereof (hereinafter to be referred to as compound (XLII)).
  • This reaction can be carried out according to a known method (e.g., “Protective Groups in Organic Synthesis, 3 rd Ed.” by Theodara W. Greene, Peter G. M. Wuts, published by Wiley-Interscience, 1999).
  • a known method e.g., “Protective Groups in Organic Synthesis, 3 rd Ed.” by Theodara W. Greene, Peter G. M. Wuts, published by Wiley-Interscience, 1999.
  • the reaction varies depending on the kind of compound (XLI)
  • it is generally carried out by reacting compound (XLI) or a salt thereof with a tert-butoxycarbonylating agent in the presence of a base, as necessary in a solvent that does not adversely influence the reaction.
  • Examples of the base include alkali metal hydroxides (sodium hydroxide, potassium hydroxide and the like), hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate and the like), carbonates (sodium carbonate, potassium carbonate and the like), acetates (sodium acetate and the like), tertiary amines (trimethylamine, triethylamine, N-methylmorpholine and the like), aromatic amines (pyridine, picoline, N,N-dimethylaniline and the like) and the like.
  • the amount of the base to be used is generally about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, per 1 mol of compound (XLI).
  • tert-butoxycarbonylating agent examples include di-tert-butyl bicarbonate and the like.
  • the amount thereof to be used is about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, per 1 mol of compound (XLI).
  • Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, t-butanol and the like), aromatic hydrocarbons (benzene, toluene, xylene and the like), aliphatic hydrocarbons (hexane, heptane and the like), halogenated hydrocarbons (dichloromethane, chloroform and the like), ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like), nitriles (acetonitrile and the like), esters (ethyl acetate and the like), carboxylic acids (acetic acid and the like), amides (N,N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the
  • the reaction temperature is, for example, within the range of about ⁇ 50° C. to 200° C., preferably about 0° C. to 100° C. While the reaction time varies depending on the kind of compound (XLI), the reaction temperature and the like, it is, for example, about 0.5 to 100 hr, preferably about 0.5 to 24 hr.
  • compound (XLII) is subjected to a carbonylation reaction to give a compound represented by the formula (XLIII) or a salt thereof (hereinafter to be referred to as compound (XLIII)).
  • carbonates such as N,N′-carbonyldiimidazole, phosgene, bis (trichloromethyl) carbonate or diethyl carbonate and the like are used.
  • the reaction is generally performed in a solvent that does not adversely influence the reaction, and a convenient base may be added for the progress of the reaction.
  • the solvent examples include alcohols (methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, t-butanol and the like), hydrocarbons (benzene, toluene and the like), ethers (ethylether, dioxane, tetrahydrofuran and the like), amides (N,N-dimethylformamide and the like), aromatic amines (pyridine and the like), water and the like, which may be appropriately mixed.
  • alcohols methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, t-butanol and the like
  • hydrocarbons benzene, toluene and the like
  • ethers ethylether, dioxane, tetrahydrofuran and the like
  • amides N,N-dimethylformamide and the like
  • aromatic amines pyridine and the like
  • Examples of the base include metal hydrides (lithium hydride, sodium hydride, potassium hydride, calcium hydride and the like), alkali metal hydroxides (sodium hydroxide, potassium hydroxide and the like), hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate and the like), carbonates (sodium carbonate, potassium carbonate and the like), acetates (sodium acetate and the like), tertiary amines (trimethylamine, triethylamine, N-methylmorpholine and the like), aromatic amines (pyridine, picoline, N,N-dimethylaniline and the like) and the like.
  • the amount of the base to be used is generally about 1 to 100 molar equivalents, preferably about 1 to 5 molar equivalents, per 1 mol of compound (XLII).
  • the reaction temperature is, for example, about ⁇ 50 to 200° C., preferably about 0 to 100° C., and the reaction time varies depending on the kind of compound (XLII), reaction temperature and the like. It is, for example, about 0.5 to 100 hr, preferably about 0.5 to 24 hr.
  • compound (XLIII) is deprotected to give a compound represented by the formula (XLIV) or a salt thereof (hereinafter to be referred to as compound (XLIV)).
  • This step can be performed by a method similar to the method described in Method A, step 4.
  • compound (XLIV) is subjected to an alkylation reaction, acylation reaction, enamine formation reaction, reductive condensation reaction, or amination reaction to give compound (XLV).
  • This step can be performed by a method similar to the method described in Method A, step 5.
  • Compound (II) produced in the above-mentioned Method A and Method B can also be produced according to a known method (e.g., WO2005/068427, WO2006/004195, Bioorganic & Medicinal Chemistry Letters 13 (2003) 4431-4435, Bioorganic & Medicinal Chemistry Letters 15 (2005) 4023-4028, Bioorganic & Medicinal Chemistry Letters 17 (2007) 5310-5315 and the like).
  • a known method e.g., WO2005/068427, WO2006/004195, Bioorganic & Medicinal Chemistry Letters 13 (2003) 4431-4435, Bioorganic & Medicinal Chemistry Letters 15 (2005) 4023-4028, Bioorganic & Medicinal Chemistry Letters 17 (2007) 5310-5315 and the like.
  • Such protecting group includes, for example, protecting groups described in “Protective Groups in Organic Synthesis, 3 rd Ed.” by Theodora W. Greene, Peter G. M. Wuts, published by Wiley-Interscience, 1999.
  • the protecting group for the amino group includes, for example, a formyl group, a C 1-6 alkyl-carbonyl group (an acetyl group, a propionyl group, etc.), a phenylcarbonyl group, a C 1-6 alkyl oxycarbonyl group (a methoxycarbonyl group, an ethoxycarbonyl group, etc.), a aryloxycarbonyl group (a phenyloxycarbonyl group, etc.), a C 7-10 aralkylcarbonyl group (a benzyloxycarbonyl group, etc.), a benzyl group, a benzhydryl group, a trityl group, a phthaloyl, etc., each of which may be substituted.
  • Such substituent includes, for example, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), a C 1-6 alkylcarbonyl group (an acetyl group, a propionyl group, a butylcarbonyl group, etc.), a nitro group and the like.
  • the number of substituent is in the order of 1 to 3.
  • a protecting group for the carboxyl group includes, for example, a C 1-6 alkyl group (a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, etc.), a phenyl group, a trityl group, a silyl group and the like, each of which may be substituted.
  • Such substituent includes, for example, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), a formyl group, a C 1-6 alkyl-carbonyl group (an acetyl group, a propionyl group, a butylcarbonyl group, etc.), a nitro group and the like.
  • a halogen atom a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.
  • a formyl group a C 1-6 alkyl-carbonyl group (an acetyl group, a propionyl group, a butylcarbonyl group, etc.)
  • the number of substituent is in the order of 1 to 3.
  • the protecting group for the hydroxyl group includes, for example, a C 1-6 alkyl group (a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, etc.), a phenyl group, a C 7-10 aralkyl group (a benzyl group, etc.), a formyl group, a C 1-6 alkyl-carbonyl group (an acetyl group, a propionyl group, etc.), a aryloxycarbonyl group (a phenyloxycarbonyl group, etc.), a C 7-10 aralkyl-carbonyl group (a benzyloxycarbonyl group, etc.), a pyranyl group, a furanyl group, a silyl group and the like, each of which may be substituted.
  • a C 1-6 alkyl group a methyl group, an
  • Such substituent includes, for example, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), a C 1-6 alkyl group, a phenyl group, a C 7-10 aralkyl group, a nitro group and the like.
  • the number of substituent is in the order of 1 to 4.
  • Such protecting groups can be removed by a known deprotection method or the method described in “Protective Groups in Organic Synthesis, 3 rd Ed.” by Theodora W. Greene, Peter G. M. Wuts, published by Wiley-Interscience, 1999, or an analogous method thereto.
  • treatment with an acid, a base, reduction, ultraviolet radiation, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like can be used.
  • a salt with for example, inorganic acids (hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), organic acids (methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.), inorganic bases (alkali metals such as sodium, potassium, etc., alkaline earth metals such as calcium, magnesium, etc., aluminum, ammonium, etc.), or organic bases (trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, etc.) and the like can be produced in a routine manner.
  • inorganic acids hydroochloric acid, sulfuric acid, hydrobromic acid, etc.
  • organic acids methanesulfonic acid, benzenesulfonic acid,
  • the compound when the starting compound forms 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 (I).
  • Compound (I) of the present invention thus produced by such method, 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 encompassed in compound (I), and can be obtained as a single product according to synthesis and separation methods known per se (concentration, solvent extraction, column chromatography, recrystallization, etc.). For example, when compound (I) has an optical isomer, an optical isomer resolved from this compound is also encompassed in compound (I).
  • the optical isomer can be produced 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.
  • 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.
  • an optically active compound e.g., (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, ( ⁇ )-1-phenethylamine, cinchonine, ( ⁇ )-cinchonidine, brucine, etc.
  • 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 and the like, and developed with water, various buffers (phosphate buffer, etc.) and organic solvents (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.
  • an optically active reagent which is made into a single substance by a typical separation means (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.
  • compound (I) when compound (I) contains hydroxy, or primary or secondary amino in a molecule, the compound and an optically active organic acid (MTPA [ ⁇ -methoxy- ⁇ -(trifluoromethyl)phenylacetic acid], ( ⁇ )-menthoxyacetic acid, etc.) and the like are subjected to condensation reaction to give diastereomers in the ester form or in the amide form, respectively.
  • MTPA optically active organic acid
  • 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 in the amide form or in the ester form, respectively.
  • the separated diastereomer is converted to an optical isomer of the original compound by acid hydrolysis or base hydrolysis.
  • Compound (I) or a salt thereof may be in the form of a crystal.
  • crystal of compound (I) or a salt thereof (hereinafter, it may be referred to as crystal of the present invention) can be produced by crystallization of compound (I) or a salt thereof 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 cooling 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 (benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, etc.), saturated hydrocarbons (hexane, heptane, cyclohexane, etc.), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (acetonitrile, etc.), ketones (acetone, etc.), sulfoxides (dimethyl sulfoxide, etc.), amides (N,N-dimethylformamide, etc.), esters (ethyl acetate, etc.), alcohols (methanol, ethanol, isopropyl alcohol, etc.), water and the like. These solvents are used alone or in a combination of two or more at a suitable ratio (e.g., 1:1 to 1:100 (a volume ratio)).
  • 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, etc.), a zone melting method (a zone leveling method and a floating zone method, etc.), a special growth method (a VLS method and a liquid phase epitaxy method, etc.) and the like.
  • Preferable examples of the crystallization method include a method of dissolving compound (I) or a salt thereof in a suitable solvent (e.g., alcohols such as methanol, ethanol, etc., etc.) at a temperature of 20 to 120° C., and cooling the resulting solution to a temperature not higher than the temperature of dissolution (e.g., 0 to 50° C., preferably 0 to 20° C.) and the like.
  • a suitable solvent e.g., alcohols such as methanol, ethanol, etc., etc.
  • crystals of the present invention can be isolated, for example, by filtration and the like.
  • the melting point means that measured using, for example, a micro melting point apparatus (Yanako, MP-500D) or a DSC (differential scanning calorimetry) device (SEIKO, EXSTAR6000) and the like.
  • the peak by a powder X-ray diffraction means that measured using, for example, RINT2100 (Rigaku Corporation), etc. with a Cu—K ⁇ 1 ray (tube voltage: 40 KV; tube current: 50 mA) as a ray source.
  • the specific rotation ([ ⁇ ] D ) means, for example, a specific rotation measured using a polarimeter (JASCO, P-1030 polarimeter (No. AP-2)) and the like.
  • the melting points and the peak by a powder X-ray diffraction 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 described in the present specification or the peak by a powder X-ray diffraction vary depending on the measurement apparatuses, as long as they are within each of a general error range.
  • the crystal of the present invention is superior in physicochemical properties (melting point, solubility, stability, etc.) and biological properties (pharmacokinetics (absorption, distribution, metabolism, excretion), efficacy expression, etc.), and thus it is extremely useful as a medicament.
  • Compound (I) or a salt thereof or a prodrug thereof of the present invention (hereinafter sometimes to be abbreviated as the compound of the present invention) has a suppressive action on the promotion of tracheal vascular permeability induced by capsaicin, as well as a superior tachykinin receptor antagonistic action, for example, an SP receptor antagonistic action (an NK-1 receptor antagonistic action), NK-2 and NK-3 receptor antagonistic action and the like. It may concurrently have an NK-1 receptor antagonistic action and an NK-3 receptor antagonistic action, or an NK-2 receptor antagonistic action and an NK-3 receptor antagonistic action.
  • the compound of the present invention is superior in an NK-1 and NK-2 receptors antagonistic action, particularly an NK-1 receptor antagonistic action. Moreover, the compound of the present invention is superior in an NK-1 and NK-2 dual receptor antagonistic action, and an NK-1, NK-2 and NK-3 triple receptor antagonistic action. Such compound of the present invention has low toxicity and is safe.
  • the compound of the present invention having the above-mentioned superior action can be used for mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) as a safe prophylactic or therapeutic drug for the SP-associated diseases indicated below.
  • mammals e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.
  • Lower urinary tract diseases including lower urinary tract dysfunction, lower urinary tract symptom and the like
  • overactive bladder prostatic hyperplasia, interstitial cystitis, chronic prostatitis
  • urine collection symptom diurnal urinary frequency, nocturnal urinary frequency, urinary urgency, urinary incontinence, stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturnal enuresis, continuous urinary incontinence, other urinary incontinence, enhanced, decreased or missing bladder sensation etc.
  • voiding symptom weak urinary stream (or slow stream), split urinary stream (or splitting stream), spraying stream, intermittent urinary stream (or intermittent stream), voiding postponement (or hesitancy), straining at urination (or straining), terminal dribbling (or terminal dribble) etc.
  • post-micturition symptom sense of residual urine, post-micturition dribble etc.
  • Inflammatory or allergic diseases for example, inflammatory bowel disease, allergic rhinitis, conjunctivitis, gastrointestinal allergy, pollinosis, anaphylaxis, dermatitis, herpes, psoriasis, bronchitis, expectoration, retinopathy, postoperative and posttraumatic inflammation, regression of puffiness, pharyngitis, cystitis, meningitidis, inflammatory ocular disease, etc.
  • Osteoarthropathy diseases for example, rheumatoid arthritis (rheumatoid arthritis), arthritis deformans, rheumatoid myelitis, osteoporosis, abnormal growth of cells, bone fracture, bone refracture, osteomalacia, osteopenia, Peget's disease
  • Cancers for example, primary, metastatic or recurrent breast cancer, prostatic cancer, pancreatic cancer, gastric cancer, lung cancer, colorectal cancer (colorectal cancer, rectal cancer, anal cancer), esophagus cancer, duodenal cancer, head and neck cancer (cancer of the tongue, pharynx cancer, laryngeal cancer), brain tumor, schwannoma, non-small cell lung cancer, small cell lung cancer, liver cancer, kidney cancer, biliary tract cancer, uterine cancer (uterine body cancer, cervical cancer), ovarian cancer, urinary bladder cancer, skin cancer, Hemangioma, malignant lymph
  • the compound of the present invention is useful as a tachykinin receptor antagonist, particularly, as an agent for the prophylaxis or treatment of the above-mentioned lower urinary tract diseases, digestive tract diseases, central nervous system diseases and the like.
  • the compound of the present invention is useful as a tachykinin receptor antagonist, particularly, as an agent for the prophylaxis or treatment of the above-mentioned lower urinary tract diseases, digestive tract diseases, central nervous system diseases and the like.
  • a pharmaceutical preparation containing the compound of the present invention may be in the form of a solid preparation such as powder, granule, tablet, capsule, suppository, orally disintegrable film and the like or a liquid such as syrup, emulsion, injection, suspension and the like.
  • the pharmaceutical preparations 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 Rules for Preparations in the Japanese Pharmacopoeia 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 of the present invention or a salt thereof varies depending on the forms of the preparations, but is generally in the order of about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably 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, excipients (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, polyvinylpyrrolidone, 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 colorant, a fragrance, a
  • It can be formulated into the solid preparations such as powders, fine granules, granules, tablets, capsules, orally disintegrable films, etc., or into the liquid preparations such as injections, etc., and can be administered non-parenterally or parenterally.
  • the dose of the pharmaceutical preparation of the present invention 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 micturition 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, in terms of the compound of the present invention, which may be administered once a day or in two or three divided portions a day.
  • the dose of the pharmaceutical composition of the present invention in the form of a sustained release preparation varies depending on the kinds and the content of compound (I) or a salt thereof, 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, pigs, etc.), and the purpose of administration.
  • the animals to be administered e.g., mammals such as humans, rats, mice, cats, dogs, rabbits, bovines, pigs, etc.
  • the purpose of administration e.g., when it is applied by parenteral administration, preferably about 0.1 to about 100 mg of compound (I) or a salt thereof is 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; (2) according to symptoms of patient (mild symptoms, severe symptoms, etc.), 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; (4) by choosing other pharmaceutically active ingredients which have different mechanism of action from that of the compound of the present invention, continuation of therapeutic effects can be obtained; and (5) by combining the compound of the present invention and other pharmaceutically active ingredients, excellent effects such as synergic effects can be obtained.
  • 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-1, etc.), insulin sensitizers (e.g., pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, JTT-501, MCC-555, YM-440, GI-262570, KRP-297, FK-614, CS-011, etc.), ⁇ -glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (e.g., phenformin, metformin, buformin, etc.), sulfonylureas (e.g.,
  • 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., tiapride, etc.
  • Statin compounds inhibiting cholesterol synthesis e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or their salt (e.g., sodium salt, etc.), etc.
  • 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, clobenzorex, 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 (Ciliary 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, ifosamide, 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.
  • immunopotentiator 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.
  • IL-1, IL-2, IL-12, etc. are preferred.
  • Progesterone derivatives e.g., megestrol acetate
  • metoclopramide pharmaceuticals e.g., tetrahydrocannabinol pharmaceuticals (the above references are applied to both)
  • fat metabolism ameliorating agents e.g., eicosapentanoic acid
  • growth hormones IGF-1
  • 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-128, VX853, prosaptide, etc.
  • drugs acting on the central nervous system e.g., antidepressants such as desipramine, amitriptyline, imipramine, fluoxetine, paroxetine, doxepin, etc.
  • anticonvulsants e.g., lamotrigine, carbamazepine
  • 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
  • narcotic analgesics e.g., morphine
  • 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, 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, etc.), preferably, oxybutynin, propive
  • 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), MEN10376, S16474, etc., and others such as GR100679, DNK333, GR94800, UK-224671, MEN10376, MEN10627, or a salt
  • composition comprising a mixture or combination of the compound of the present invention and the combination 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 combination drugs separately or at the same time as itself or with pharmaceutically acceptable carriers in the same manner as in the 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 dose 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.
  • 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 minutes to 1 day, more preferably 15 minutes to 1 hour after administering the combination drugs.
  • the combination drugs may be administered 1 minute to 1 day, preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 hour after administering the compound of the present invention.
  • 0.001 to 200 mg/kg of the combination drugs formulated as an oral preparation is administered orally and then after about 15 minutes, about 0.005 to 100 mg/kg of the compound of the present invention formulated as an oral preparation is administered orally as a daily dose.
  • 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.
  • Measurement instrument LC-MS system, Waters Corporation
  • the molecular weight of the corresponding compound is indicated as M.
  • Measurement instrument CLASS-VP system, Shimadzu Corporation
  • Solvent Solution A; 0.1% trifluoroacetic acid-containing water,
  • Solvent Solution A; 0.1% trifluoroacetic acid-containing water,
  • step 1 To the reaction mixture was added copper iodide(I) (12.6 g), and the compound (56.2 g) obtained in step 1 was slowly added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, and further at room temperature for 1 hr. The reaction mixture was poured into water (40 mL), diethyl ether (500 mL) was added, and the precipitate was removed by decantation. The reaction solution was washed with aqueous ammonium chloride solution and saturated brine and dried, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (solvent gradient; 20% ethyl acetate/hexane ⁇ >2.5% aqueous ammonia/17.5% methanol/ethyl acetate) to give crude ethyl 3-(3,4-dichlorophenyl)-1-methylpiperidine-4-carboxylate (cis/trans mixture) (75.5 g) as a brown oil.
  • the organic layer was washed with water and dried, and the solvent was under reduced pressure to give a pale-yellow powder.
  • the obtained pale-yellow powder was recrystallized from THF-IPE to give (3R*,4R*)-1-(tert-butoxycarbonyl)-3-(3,4-dichlorophenyl)piperidine-4-carboxylic acid (58.6 g, 47%) as a white powder.
  • the obtained white powder (39.1 g (98.8% de) was dissolved in a solution of citric acid (16.7 g) in water (250 mL) and ethyl acetate (250 mL) and the mixture was stirred at room temperature for 1 hr. The organic layer was separated, washed with water and saturated brine, and dried. The solvent was evaporated under reduced pressure to give (3R,4R)-1-(tert-butoxycarbonyl)-3-(3,4-dichlorophenyl)piperidine-4-carboxylic acid (28.7 g, 97%) as a white powder.
  • step 4 By reaction in the same manner as in the method described in Reference Example 1, step 4 and using the compound (9.1 g) obtained in step 1, DPPA (10.0 g), and triethylamine (5.0 mL), and purification by silica gel column chromatography (NH Chromatorex) (30% ethyl acetate/hexane) to give the title compound (4.78 g, 57%) as a white powder.
  • step 1 To the compound (11.1 g) obtained in step 1 were added acetic acid (25 mL) and hydrochloric acid (25 mL), and the mixture was heated at 100° C. for 2 hr. The reaction mixture was cooled and concentrated to give 1-benzyl-5-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid monohydrochloride (8.82 g, 78%).
  • the obtained residue was purified by silica gel column chromatography (solvent gradient; 10 ⁇ 40% ethyl acetate/hexane) to give tert-butyl (3R*,4R*)-3-(3,4-dichlorophenyl)-4-[(trifluoroacetyl)amino]piperidine-1-carboxylate (0.84 g, 95%) as a white amorphous solid.
  • the obtained residue was purified by silica gel column chromatography (solvent gradient; 5 ⁇ 40% ethyl acetate/hexane) to give tert-butyl (3R*,4R*)-3-(3,4-dichlorophenyl)-4-[methyl(trifluoroacetyl)amino]piperidine-1-carboxylate (0.72 g, 89%) as a pale-yellow amorphous solid.
  • step 3 To a solution of the compound (0.49 g) obtained in step 3,1-acetylpiperidine-4-carboxylic acid (0.33 g) and triethylamine (0.53 mL) in DMF (5 mL) was added DEPC (0.29 mL), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (solvent gradient; 0 ⁇ 9% methanol/ethyl acetate) to give N-[(3R*,4R*)-1-[(1-acetylpiperidin-4-yl)carbonyl]-3-(3,4-dichlorophenyl)piperidin-4-yl]-2,2,2-trifluoro-N-methylacetamide (0.66 g, 100%) as a white amorphous solid.
  • Step 4 To a solution of the compound (26.4 g) obtained in step 3 and triethylamine (13.0 mL) in acetonitrile (260 mL) was added Boc 2 O (20.4 g) at 0° C., and the mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine and dried, and the solvent was evaporated under reduced pressure.
  • Step 2 p To a solution of the compound (12.1 g) obtained in step 1 in DMF (55 mL) was added sodium hydride (1.82 g) at 0° C. The reaction mixture was stirred at 0° C. for 5 min, methyl iodide (11.4 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The extract was washed with saturated brine, dried and concentrated under reduced pressure.
  • step 2 To the compound (12.4 g) obtained in step 2 was added 2N hydrogen chloride/2-propanol (100 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (9.36 g, 93%) as a white powder.
  • step 1 The compound (1.76 g) obtained in step 1 was dissolved in DMSO (30 mL), sodium hydride (0.59 g) was added at 0° C., and the mixture was stirred for 5 min. To the reaction mixture was added 2-bromo-1-chloroethane (0.77 mL), and the mixture was stirred at room temperature for 45 min. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution, dried and concentrated under reduced pressure.
  • the absolute configuration was determined by single crystal X-ray crystal structure analysis of tert-butyl (3R,4S)-3- ⁇ [(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl ⁇ -4-(4-fluorophenyl)pyrrolidine-1-carboxylate.
  • the reaction mixture was diluted with aqueous sodium thio sulfate solution, and extracted with ethyl acetate.
  • the extract was washed with water and extracted with 0.5N aqueous sodium hydroxide solution.
  • the extract was washed with ethyl acetate, acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate.
  • the extract was washed with water and saturated brine, dried and concentrated under reduced pressure to give (3R,4S)-1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)pyrrolidine-3-carboxylic acid (0.185 g, 88%) as a white powder.
  • step 2 By reaction and purification in the same manner as in the method described in Reference Example 13, step 2 and using the compound obtained in step 1, methyl (3R*,4R*)-1-benzyl-4-(4-fluorophenyl)pyrrolidine-3-carboxylate was obtained.
  • step 3 By reaction and purification in the same manner as in the method described in Reference Example 20, step 3 and using tert-butyl (3S,4R)-3- ⁇ [(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl ⁇ -4-(3,4-dichlorophenyl)pyrrolidine-1-carboxylate obtained in step 1, (3S,4R)-1-(tert-butoxycarbonyl)-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylic acid was obtained.
  • reaction solution was cooled, 8N aqueous sodium hydroxide solution (15 mL) was added, and the mixture was stirred at room temperature for 2 hr.
  • the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure to give the title compound (0.76 g, 26%) as a colorless oil.
  • step 7 To a methanol solution of the compound (2.8 g) obtained in step 7 was added a solution of sodium hydroxide (0.7 g) in water (30 mL), and the mixture was stirred at room temperature for 3 hr. The mixture was concentrated under reduced pressure, diluted with water, and washed with ethyl acetate. The aqueous layer was acidified (pH 5) with acetic acid, extracted with dichloromethane, dried and concentrated under reduced pressure to give (3S,4S)-1-(tert-butoxycarbonyl)-4-(5-fluoropyridin-2-yl)pyrrolidine-3-carboxylic acid (2.3 g, 85%) as a white oil.
  • step 2 A solution of the compound (0.48 g) obtained in step 2, Boc 2 O (0.41 g), triethylamine (0.17 mL) and dimethylaminopyridine (0.15 g) in DMAc (5 mL) was stirred at room temperature for 1.5 hr, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, dried and concentrated under reduced pressure.
  • step 3 By reaction and purification in the same manner as in the method described in Reference Example 35, step 3 and using the compound obtained in step 2, the title compound was obtained.
  • step 1 to step 3 and using ethyl glycolate the title compound was obtained.
  • step 3 By reaction and purification in the same manner as in the method described in Reference Example 35, step 3 and using the compound obtained in step 1, the title compound was obtained.

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