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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P25/00—Drugs for disorders of the nervous system
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

• the present invention has an arginine-vasopressin 1b (hereinafter also referred to as V1b) receptor antagonistic action, and has a central psychiatric disorder (mood disorder, anxiety disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder) And a compound useful as a prophylactic or therapeutic agent in diseases such as epilepsy.
• V1b arginine-vasopressin 1b
• V1b receptors are involved in ACTH secretion from the posterior lobe of the pituitary gland, and are thought to be responsible for various psychoregulatory functions throughout the brain.
• the V1b receptor has been suggested to be associated with mood disorders and anxiety disorders, and the usefulness of V1b receptor antagonists has been studied.
• Arginine-vasopressin is a 9-amino acid peptide that is biosynthesized mainly in the hypothalamus and is involved in the regulation of plasma osmotic pressure, blood pressure, and body fluid volume as a pituitary posterior lobe hormone. In addition, its presence has been confirmed in a wide area in the brain, suggesting that it is involved in the mechanism of mental function regulation.
• the AVP receptor has three subtypes of V1a, V1b and V2 receptors, all of which are 7-transmembrane receptors.
• the V1b receptor like the V1a receptor, is coupled to Gq / 11 and promotes the PI response.
• V1b receptors are most abundant in the pituitary gland and are involved in ATH secretion from the posterior pituitary gland by AVP. In addition to the pituitary gland, it is distributed over a wide area of the brain, and is also present in the limbic system such as the hippocampus, amygdala, and olfactory cortex, the cerebral cortex, the olfactory bulb, and the raphe nucleus, which is the origin of the serotonin nervous system. In recent years, it has been suggested that the V1b receptor is associated with mood disorders and anxiety disorders, and the usefulness of V1b receptor antagonists has been studied. In addition, it has been reported that an anxiolytic-like action of a V1b receptor antagonist and an antidepressant and anxiolytic action in various animal models.
• Patent Documents 1 to 11 and Non-Patent Documents 1 to 5 are known as compounds having a V1b receptor antagonistic activity, but the structure is completely different from that of the present compound.
• An object of the present invention is to provide a compound having a V1b receptor antagonistic action.
• Ring A represents an optionally substituted 5- to 7-membered nitrogen-containing saturated heterocyclic ring
• R 1 is (1) —CH ⁇ CH—R x (wherein R x represents an optionally substituted C 6-14 aryl group or an optionally substituted aromatic heterocyclic group).
• R y represents an optionally substituted C 6-14 aryl group.
• R 2 , R 3 , R 4 and R 5 each independently represent a hydrogen atom or a substituent;
• R 6 is optionally substituted C 6-14 aryl group, an optionally substituted C 7-16 aralkyl group optionally or optionally substituted C 6-10 aryl -C 2-6 alkenyl group, Show.
• An arginine-vasopressin 1b receptor antagonist comprising a compound represented by formula (hereinafter also referred to as compound (I)) or a salt thereof.
• Ring A represents an optionally substituted 5- to 7-membered nitrogen-containing saturated heterocyclic ring
• R 2 , R 3 , R 4 and R 5 each independently represent a hydrogen atom or a substituent;
• R 6 is optionally substituted C 6-14 aryl group, an optionally substituted C 7-16 aralkyl group optionally or optionally substituted C 6-10 aryl -C 2-6 alkenyl group, Show.
• An arginine-vasopressin 1b receptor antagonist comprising a compound represented by the formula:
• Ring Aa represents an optionally substituted 5- to 7-membered nitrogen-containing saturated heterocyclic ring
• R 1a represents an optionally substituted C 6-14 aryl group, or an optionally substituted aromatic heterocyclic group
• At least one of R 2a , R 3a , R 4a and R 5a represents a substituent, and the rest each independently represents a hydrogen atom or a substituent
• R 6a represents an optionally substituted C 6-14 aryl group or an optionally substituted C 7-16 aralkyl group.
• a salt thereof hereinafter also referred to as compound (Ia)
• [2a] General formula (Ia):
• Ring Aa represents an optionally substituted 5- to 7-membered nitrogen-containing saturated heterocyclic ring
• R 1a represents an optionally substituted C 6-14 aryl group
• At least one of R 2a , R 3a , R 4a and R 5a represents a substituent, and the rest each independently represents a hydrogen atom or a substituent
• R 6a represents an optionally substituted C 6-14 aryl group or an optionally substituted C 7-16 aralkyl group.
• Ring Ab represents an optionally substituted 5- to 7-membered nitrogen-containing saturated heterocyclic ring
• R 1b is (1) a C 6-14 aryl group substituted with a nitro group and a C 1-6 alkoxy group, (2) optionally substituted benzofuryl, or (3) represents an optionally substituted indanyl
• R 2b , R 3b , R 4b and R 5b each independently represent a hydrogen atom or a substituent
• R 6b represents an optionally substituted C 6-14 aryl group.
• a salt thereof hereinafter also referred to as compound (Ib)
• Ring Ab represents an optionally substituted 5- to 7-membered nitrogen-containing saturated heterocyclic ring
• R 1b represents a C 6-14 aryl group substituted with a nitro group and a C 1-6 alkoxy group
• R 2b , R 3b , R 4b and R 5b each independently represent a hydrogen atom or a substituent
• R 6b represents an optionally substituted C 6-14 aryl group.
• R 1b is (1) a C 6-10 aryl group substituted with one nitro group and one or two C 1-6 alkoxy groups, (2) benzofuryl, or (3) The compound or a salt thereof according to the above [7], which is indanyl.
• Ring Ac represents a 5- to 7-membered nitrogen-containing saturated heterocyclic ring
• R 1c represents an optionally substituted C 6-14 aryl group
• R 2c , R 3c , R 4c and R 5c each independently represent a hydrogen atom or a substituent
• R 6c is an optionally substituted C 6-14 aryl group, an optionally substituted C 7-16 aralkyl group optionally or optionally substituted C 6-10 aryl -C 2-6 alkenyl group, Show.
• a salt thereof hereinafter also referred to as compound (Ic)
• R 6c is, C 1-6 alkyl group optionally substituted C 6-10 aryl group, C 1-6 alkyl optionally substituted C 7-16 aralkyl group, or a group C 6,
• Ring Ad represents an optionally substituted 5- to 7-membered nitrogen-containing saturated heterocyclic ring
• R 1d represents an optionally substituted C 6-14 aryl group
• At least one of R 2d , R 3d , R 4d and R 5d represents a substituent, and the rest each independently represents a hydrogen atom or a substituent
• R 6d represents an optionally substituted C 6-14 aryl group
• n d represents an integer of 1 to 5.
• a salt thereof hereinafter also referred to as compound (Id)).
• a pharmaceutical composition comprising the compound according to any one of [2] to [21] above or a salt thereof, and a pharmaceutically acceptable carrier.
• Mood disorder, anxiety disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder or epilepsy containing the compound or salt thereof according to any one of [1] to [21] above Preventive or therapeutic agent.
• Compound (I) has a V1b receptor antagonism, and thus has a central psychiatric disorder (mood disorder, anxiety disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, epilepsy, etc.) It is useful as a preventive or therapeutic agent.
• a central psychiatric disorder mood disorder, anxiety disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, epilepsy, etc.
• halogen atom in the present specification include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
• substituted includes “optionally substituted hydrocarbon group”, “optionally substituted heterocyclic group”, “optionally substituted hydroxy group”, “substituted” And optionally substituted amino group, “optionally substituted sulfanyl group”, “acyl group”, “halogen atom”, “cyano group”, “nitro group” and the like.
• Examples of the “optionally substituted hydrocarbon group” in the present specification include “an optionally substituted C 1-10 alkyl group” and “an optionally substituted C 2-10 alkenyl group”.
• An optionally substituted C 6-10 aryl-C 2-6 alkenyl group ”.
• C 1-10 alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl and hexyl. , Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like. Of these, a C 1-6 alkyl group is preferable.
• C 1-6 alkyl (group) examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl. Hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
• C 2-10 alkenyl group examples include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- Methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, etc. Is mentioned. Of these, a C 2-6 alkenyl group is preferable.
• C 2-6 alkenyl (group) examples include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, Examples include 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl and the like.
• C 2-10 alkynyl group examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Examples include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like. Of these, a C 2-6 alkynyl group is preferable.
• C 2-6 alkynyl (group) examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, Examples include 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.
• Examples of the “C 3-10 cycloalkyl group” in the present specification include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. Of these, a C 3-6 cycloalkyl group is preferable.
• Examples of the “C 3-8 cycloalkyl (group)” in the present specification include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Of these, a C 3-6 cycloalkyl group is preferable.
• C 3-10 cycloalkenyl group examples include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl and 3-cyclohexen-1-yl. Etc. Of these, a C 3-6 cycloalkenyl group is preferable.
• C 3-8 cycloalkenyl (group) includes, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexene-1 -Yl and the like. Of these, a C 3-6 cycloalkenyl group is preferable.
• C 4-10 cycloalkadienyl group examples include 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadiene- 1-yl and the like can be mentioned. Of these, a C 4-6 cycloalkadienyl group is preferable.
• C 4-8 cycloalkadienyl (group)” includes, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclo And hexadien-1-yl. Of these, a C 4-6 cycloalkadienyl group is preferable.
• C 3-10 cycloalkyl group “C 3-10 cycloalkenyl group” and “C 4-10 cycloalkadienyl group” are each condensed with a benzene ring to form a condensed ring group.
• Examples of such a condensed ring group include indanyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl and the like.
• C 6-14 aryl (group) examples include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like.
• the “C 6-14 aryl (group)” may be condensed with another ring, and examples thereof include fluorenyl, dihydronaphthyl, tetrahydronaphthyl and the like. Of these, a C 6-10 aryl group is preferable.
• C 7-16 aralkyl (group) examples include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like. Of these, a C 7-13 aralkyl group is preferable.
• Examples of the “C 6-10 aryl-C 2-6 alkenyl group” in the present specification include styryl, 3-phenyl-2-propenyl and the like. Of these, a C 6-10 aryl-C 2-4 alkenyl group is preferable.
• C 1-6 alkoxy (group) examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
• heterocycle (group) examples include an aromatic heterocyclic group and a non-aromatic heterocyclic group.
• aromatic heterocyclic group in the present specification include 4 to 7-membered (containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring-constituting atom ( And preferably monocyclic aromatic heterocyclic groups and condensed aromatic heterocyclic groups (preferably those having 8 to 12 members).
• Examples of the condensed aromatic heterocyclic group include a ring corresponding to the 4- to 7-membered monocyclic aromatic heterocyclic group and a 5- or 6-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms.
• a ring corresponding to the 4- to 7-membered monocyclic aromatic heterocyclic group and a 5- or 6-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms.
• Examples include groups to be derived.
• Monocyclic aromatic heterocyclic groups such as furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl; Quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, benzotriazolyl, indolyl, indazolyl, carbazolyl, pyrrolopyrazinyl, imidazopyridyl, thienopyr
• non-aromatic heterocyclic group examples include 4 to 7 members containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom. (Preferably 5 or 6 membered) monocyclic non-aromatic heterocyclic group and condensed non-aromatic heterocyclic group (preferably having 8 to 12 members).
• monocyclic non-aromatic heterocyclic group and condensed non-aromatic heterocyclic group (preferably having 8 to 12 members).
• condensed non-aromatic heterocyclic group examples include a ring corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group, and a 5- or 6-membered aromatic containing 1 or 2 nitrogen atoms.
• 1 or 2 rings selected from a heterocycle (eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocycle containing one sulfur atom (eg, thiophene) and a benzene ring
• a heterocycle eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
• a 5-membered aromatic heterocycle containing one sulfur atom eg, thiophene
• benzene ring examples thereof include a group derived from a condensed ring and a group obtained by partial saturation of the group.
• non-aromatic heterocyclic group Azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxazolinyl, thiazolinyl, imidazolinyl, dioxolyl, dioxolanyl, dihydrooxadiazolyl, thiol, pyranyl Monocyclic non-aromatic heterocyclic groups such as tetrahydrofuryl, pyrazolidinyl, pyrazolinyl, tetrahydropyrimidinyl, dihydrotriazolyl, tetrahydrotriazolyl; Dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, dihydro
• fused ring group for example, a condensed aromatic heterocyclic group (preferably 8 to 12-membered), a condensed non-aromatic heterocyclic group (preferably 8 to 12-membered), Examples thereof include a condensed C 10-14 aryl group and a condensed non-aromatic hydrocarbon group (preferably having 8 to 12 members).
• the “fused aromatic heterocyclic group” and “fused non-aromatic heterocyclic group” include the above-mentioned “fused aromatic heterocyclic group” and “fused non-aromatic heterocyclic group”.
• Examples of the “fused C 10-14 aryl group” include a group derived from a condensed ring having 10 to 14 carbon atoms in the above “C 6-14 aryl group”.
• Examples of the “condensed non-aromatic hydrocarbon group” include the above-mentioned “C 3-10 cycloalkyl group”, “C 3-10 cycloalkenyl group” and “C 4-10 cycloalkadienyl group”. Examples thereof include those condensed with a benzene ring.
• the “5- to 7-membered nitrogen-containing saturated heterocyclic ring” in the present specification includes, for example, at least one nitrogen atom in addition to a carbon atom as a ring constituent atom, and is further selected from an oxygen atom, a sulfur atom and a nitrogen atom. Examples thereof include a 5- to 7-membered nitrogen-containing saturated heterocyclic ring which may contain 1 to 2 heteroatoms.
• nitrogen-containing saturated heterocyclic ring examples include pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, thiazolidine, piperidine, piperazine, azepane, morpholine, thiomorpholine, and among them, pyrrolidine, piperidine and azepane are preferable.
• the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different. The substituent may be further substituted with the substituent A.
• Examples of the “optionally substituted hydroxy group” in the present specification include “an optionally substituted C 1-10 alkyl group”, “an optionally substituted C 2-10 alkenyl group”, “Optionally substituted C 3-10 cycloalkyl group”, “optionally substituted C 3-10 cycloalkenyl group”, “ optionally substituted C 6-14 aryl group”, “substituted Substituents selected from “ optionally substituted C 7-16 aralkyl group”, “ optionally substituted C 6-10 aryl-C 2-6 alkenyl group”, “optionally substituted heterocyclic group”, etc. And a hydroxy group which may be substituted with.
• Examples of the “optionally substituted sulfanyl group” in the present specification include “an optionally substituted C 1-10 alkyl group”, “an optionally substituted C 2-10 alkenyl group”, “Optionally substituted C 3-10 cycloalkyl group”, “optionally substituted C 3-10 cycloalkenyl group”, “ optionally substituted C 6-14 aryl group”, “substituted Substituents selected from “ optionally substituted C 7-16 aralkyl group”, “ optionally substituted C 6-10 aryl-C 2-6 alkenyl group”, “optionally substituted heterocyclic group”, etc. And a sulfanyl group which may be substituted with.
• Examples of the “optionally substituted amino group” in the present specification include “an optionally substituted C 1-10 alkyl group”, “an optionally substituted C 2-10 alkenyl group”, “Optionally substituted C 3-10 cycloalkyl group”, “optionally substituted C 3-10 cycloalkenyl group”, “ optionally substituted C 6-14 aryl group”, “substituted Optionally substituted C 7-16 aralkyl group ”,“ optionally substituted C 6-10 aryl-C 2-6 alkenyl group ”,“ optionally substituted heterocyclic group ”,“ acyl group ”, etc. And an amino group which may be mono- or di-substituted with a substituent selected from:
• acyl group in the present specification, for example, the formula: -COR A, -CO-OR A , -S (O) 2 R A, -SOR A, -CO-NR A 'R B', - CS-NR A 'R B ', -S (O) 2 NR A 'R B ' [wherein, R A represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted complex. A ring group is shown.
• R A ′ and R B ′ are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or R A ′ and R B ′ are A nitrogen-containing heterocyclic ring which may be substituted with an adjacent nitrogen atom may be formed], and the like.
• the “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” formed by R A ′ and R B ′ together with the adjacent nitrogen atom includes, for example, at least one ring-constituting atom other than a carbon atom And a 5- to 7-membered nitrogen-containing heterocyclic ring which may contain 1 to 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms.
• the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, azepane, morpholine, thiomorpholine and the like.
• the nitrogen-containing heterocycle may have 1 to 5 (preferably 1 or 2) substituents at substitutable positions.
• substituents include the above-described substituent A.
• each substituent may be the same or different.
• Ring A represents a 5- to 7-membered nitrogen-containing saturated heterocyclic ring which may be substituted.
• the “5- to 7-membered nitrogen-containing saturated heterocycle” of the “optionally substituted 5- to 7-membered nitrogen-containing saturated heterocycle” represented by ring A is preferably a pyrrolidine ring, a piperidine ring or an azepane ring, Particularly preferred is a piperidine ring.
• Ring A is Preferably, each is a pyrrolidine ring, piperidine ring or azepane ring, each of which may be substituted, More preferably, a pyrrolidine ring, a piperidine ring or an azepane ring each optionally substituted with a C 1-6 alkyl group (preferably methyl), More preferably, it is a piperidine ring optionally substituted with a C 1-6 alkyl group (preferably methyl), Particularly preferred is a piperidine ring.
• R 1 is (1) —CH ⁇ CH—R x (wherein R x represents an optionally substituted C 6-14 aryl group or an optionally substituted aromatic heterocyclic group).
• R 1 is preferably (1) —CH ⁇ CH—R x (wherein R x is an optionally substituted C 6-10 aryl group (preferably phenyl), or an optionally substituted 5- or 6-membered monocycle) A group represented by the formula aromatic heterocyclic group (preferably pyridyl); (2) a group represented by —CH 2 —O—R y (wherein R y is an optionally substituted C 6-10 aryl group (preferably phenyl)); (3) — (CH 2 ) n —R z (wherein R z is an optionally substituted C 6-10 aryl group (preferably phenyl), and n is an integer of 1 to 5) A group represented by: (4) an optionally substituted C 6-10 aryl group (preferably phenyl, naphthyl); (5) an optionally substituted 8- to 12-membered fused aromatic heterocyclic group (preferably benzofuryl); or (6) An optionally substituted 8- to 12-membered condensed non-ar
• R 2 , R 3 , R 4 and R 5 each independently represent a hydrogen atom or a substituent.
• R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom or an optionally substituted C 1-6 alkyl group (preferably methyl).
• at least one of R 2 , R 3 , R 4 and R 5 is a substituent, and the rest are each independently a hydrogen atom or a substituent.
• at least one of R 2 , R 3 , R 4 and R 5 is an optionally substituted C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom.
• it is an optionally substituted C 1-6 alkyl group (preferably methyl).
• R 2 , R 3 , R 4 and R 5 is a C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or C 1-6 alkyl A group (preferably methyl). Even more preferably, one of R 2 , R 3 , R 4 and R 5 is a C 1-6 alkyl group (preferably methyl) and the remaining three are hydrogen atoms. Particularly preferably, among R 2 , R 3 , R 4 and R 5 , R 3 or R 4 is a C 1-6 alkyl group (preferably methyl), and the remaining three are hydrogen atoms.
• R 6 is optionally substituted C 6-14 aryl group, an optionally substituted C 7-16 aralkyl group optionally or optionally substituted C 6-10 aryl -C 2-6 alkenyl group, Show.
• R 6 is Preferably, a C 6-14 aryl group (preferably phenyl), a C 7-16 aralkyl group (preferably benzyl) or C 6-, each optionally substituted with a C 1-6 alkyl group (preferably methyl).
• C 1-6 alkyl group (preferably methyl) optionally C 6-10 aryl group optionally substituted by (preferably phenyl), C 1-6 alkyl group (preferably methyl) substituted with Or a C 7-16 aralkyl group (preferably benzyl) or a C 6-10 aryl-C 2-6 alkenyl group (preferably 3-phenyl-2-propenyl); More preferably, it is a C 6-10 aryl group (preferably phenyl) substituted with a C 1-6 alkyl group (preferably methyl), Particularly preferred is phenyl substituted at the meta position with one C 1-6 alkyl group (preferably methyl).
• Ring Aa represents an optionally substituted 5- to 7-membered nitrogen-containing saturated heterocyclic ring.
• the “5- to 7-membered nitrogen-containing saturated heterocycle” of the “optionally substituted 5- to 7-membered nitrogen-containing saturated heterocycle” represented by ring Aa is preferably a pyrrolidine ring, a piperidine ring or an azepane ring, Particularly preferred is a piperidine ring.
• Ring Aa is Preferably, each is a pyrrolidine ring, piperidine ring or azepane ring, each of which may be substituted, More preferably, a pyrrolidine ring, a piperidine ring or an azepane ring each optionally substituted with a C 1-6 alkyl group (preferably methyl), More preferably, it is a piperidine ring optionally substituted with a C 1-6 alkyl group (preferably methyl), Particularly preferred is a piperidine ring.
• R 1a represents an optionally substituted C 6-14 aryl group or an optionally substituted aromatic heterocyclic group.
• R 1a is Preferably, it is an optionally substituted C 6-10 aryl group (preferably phenyl), or an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group (preferably pyridyl).
• a C 6-10 aryl group preferably phenyl or a 5- or 6-membered monocyclic aromatic heterocyclic group (preferably pyridyl), each of which may be substituted with a nitro group
• it is a C 6-10 aryl group (preferably phenyl) optionally substituted with a nitro group, or a 5- or 6-membered monocyclic aromatic heterocyclic group (preferably pyridyl)
• Particularly preferred is a C 6-10 aryl group (preferably phenyl) optionally substituted with a nitro group.
• At least one of R 2a , R 3a , R 4a and R 5a represents a substituent, and the rest each independently represents a hydrogen atom or a substituent.
• at least one of R 2a , R 3a , R 4a and R 5a is an optionally substituted C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or An optionally substituted C 1-6 alkyl group (preferably methyl).
• at least one of R 2a , R 3a , R 4a and R 5a is a C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or C 1-6 alkyl A group (preferably methyl).
• R 2a , R 3a , R 4a and R 5a is a C 1-6 alkyl group (preferably methyl), and the remaining three are hydrogen atoms.
• R 2a , R 3a , R 4a and R 5a , R 3a or R 4a is a C 1-6 alkyl group (preferably methyl), and the remaining three are hydrogen atoms.
• R 6a represents an optionally substituted C 6-14 aryl group or an optionally substituted C 7-16 aralkyl group.
• R 6a is Preferably, it is a C 6-14 aryl group (preferably phenyl) or a C 7-16 aralkyl group (preferably benzyl), each optionally substituted with a C 1-6 alkyl group (preferably methyl). More preferably, it is a C 6-10 aryl group (preferably phenyl) optionally substituted with a C 1-6 alkyl group (preferably methyl), or a C 7-13 aralkyl group (preferably benzyl).
• it is a C 6-10 aryl group (preferably phenyl) substituted with a C 1-6 alkyl group (preferably methyl), Particularly preferred is phenyl substituted at the meta position with one C 1-6 alkyl group (preferably methyl).
• the bond of R 1a may be any of (E) and (Z) with respect to carbonyl, but is preferably (E).
• Ring Ab represents a 5- to 7-membered nitrogen-containing saturated heterocyclic ring which may be substituted.
• the “5- to 7-membered nitrogen-containing saturated heterocycle” of the “optionally substituted 5- to 7-membered nitrogen-containing saturated heterocycle” represented by ring Ab is preferably a pyrrolidine ring, a piperidine ring or an azepane ring, Particularly preferred is a piperidine ring.
• Ring Ab is Preferably, each is a pyrrolidine ring, piperidine ring or azepane ring, each of which may be substituted, More preferably, a pyrrolidine ring, a piperidine ring or an azepane ring each optionally substituted with a C 1-6 alkyl group (preferably methyl), More preferably, it is a piperidine ring optionally substituted with a C 1-6 alkyl group (preferably methyl), Particularly preferred is a piperidine ring.
• R 1b is (1) a C 6-14 aryl group substituted with a nitro group and a C 1-6 alkoxy group, (2) optionally substituted benzofuryl, or (3) Indanyl which may be substituted.
• R 1b is Preferably, (1) a C 6-10 aryl group (preferably phenyl) substituted with a nitro group and a C 1-6 alkoxy group (preferably methoxy, ethoxy), (2) optionally substituted benzofuryl, or (3) optionally substituted indanyl, More preferably, (1) a C 6-10 aryl group (preferably phenyl) substituted with a nitro group and a C 1-6 alkoxy group (preferably methoxy, ethoxy), (2) benzofuryl, or (3) Indanyl, More preferably, (1) a C 6-10 aryl group (preferably phenyl) substituted with one nitro group and one or two (preferably one) C 1-6 alkoxy groups (preferably methoxy, ethoxy), (2)
• R 2b , R 3b , R 4b and R 5b each independently represent a hydrogen atom or a substituent.
• R 2b , R 3b , R 4b and R 5b are each independently a hydrogen atom or an optionally substituted C 1-6 alkyl group (preferably methyl).
• at least one of R 2b , R 3b , R 4b and R 5b is a substituent, and the rest are each independently a hydrogen atom or a substituent.
• at least one of R 2b , R 3b , R 4b and R 5b is an optionally substituted C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom.
• R 2b , R 3b , R 4b and R 5b is a C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or C 1-6 alkyl A group (preferably methyl).
• one of R 2b , R 3b , R 4b and R 5b is a C 1-6 alkyl group (preferably methyl) and the remaining three are hydrogen atoms.
• R 2b , R 3b , R 4b and R 5b is a C 1-6 alkyl group (preferably methyl), and the remaining three are hydrogen atoms.
• R 6b represents an optionally substituted C 6-14 aryl group.
• R 6b is Preferably, it is a C 6-14 aryl group (preferably phenyl) optionally substituted with a C 1-6 alkyl group (preferably methyl). More preferably, it is a C 6-10 aryl group (preferably phenyl) optionally substituted with a C 1-6 alkyl group (preferably methyl). More preferably, it is a C 6-10 aryl group (preferably phenyl) substituted with a C 1-6 alkyl group (preferably methyl), Particularly preferred is phenyl substituted at the meta position with one C 1-6 alkyl group (preferably methyl).
• Ring Ac represents a 5- to 7-membered nitrogen-containing saturated heterocyclic ring.
• Ring Ac is preferably a pyrrolidine ring, piperidine ring or azepane ring, more preferably a piperidine ring.
• R 1c represents an optionally substituted C 6-14 aryl group.
• R 1c is Preferably, it is an optionally substituted C 6-10 aryl group (preferably phenyl), More preferably, it is a C 6-10 aryl group (preferably phenyl) optionally substituted with a nitro group.
• R 2c , R 3c , R 4c and R 5c each independently represent a hydrogen atom or a substituent.
• R 2c , R 3c , R 4c and R 5c are each independently a hydrogen atom or an optionally substituted C 1-6 alkyl group (preferably methyl).
• at least one of R 2c , R 3c , R 4c and R 5c is a substituent, and the rest are each independently a hydrogen atom or a substituent.
• R 2c , R 3c , R 4c and R 5c is an optionally substituted C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom Alternatively, it is an optionally substituted C 1-6 alkyl group (preferably methyl). More preferably, at least one of R 2c , R 3c , R 4c and R 5c is a C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or C 1-6 alkyl A group (preferably methyl). Even more preferably, one of R 2c , R 3c , R 4c and R 5c is a C 1-6 alkyl group (preferably methyl) and the remaining three are hydrogen atoms. Particularly preferably, among R 2c , R 3c , R 4c and R 5c , R 3c or R 4c is a C 1-6 alkyl group (preferably methyl), and the remaining three are hydrogen atoms.
• R 6c is an optionally substituted C 6-14 aryl group, an optionally substituted C 7-16 aralkyl group optionally or optionally substituted C 6-10 aryl -C 2-6 alkenyl group, Show.
• R 6c is Preferably, a C 6-14 aryl group (preferably phenyl), a C 7-16 aralkyl group (preferably benzyl) or C 6-, each optionally substituted with a C 1-6 alkyl group (preferably methyl).
• C 1-6 alkyl group (preferably methyl) optionally C 6-10 aryl group optionally substituted by (preferably phenyl), C 1-6 alkyl group (preferably methyl) substituted with Or a C 7-16 aralkyl group (preferably benzyl) or a C 6-10 aryl-C 2-6 alkenyl group (preferably 3-phenyl-2-propenyl); More preferably, it is a C 6-10 aryl group (preferably phenyl) substituted with a C 1-6 alkyl group (preferably methyl), Particularly preferred is phenyl substituted at the meta position with one C 1-6 alkyl group (preferably methyl).
• Ring Ad represents an optionally substituted 5- to 7-membered nitrogen-containing saturated heterocyclic ring.
• the “5- to 7-membered nitrogen-containing saturated heterocycle” of the “optionally substituted 5- to 7-membered nitrogen-containing saturated heterocycle” represented by ring Ad is preferably a pyrrolidine ring, a piperidine ring or an azepane ring, Particularly preferred is a piperidine ring.
• each is a pyrrolidine ring, piperidine ring or azepane ring, each of which may be substituted, More preferably, a pyrrolidine ring, a piperidine ring or an azepane ring each optionally substituted with a C 1-6 alkyl group (preferably methyl), More preferably, it is a piperidine ring optionally substituted with a C 1-6 alkyl group (preferably methyl), Particularly preferred is a piperidine ring.
• R 1d represents an optionally substituted C 6-14 aryl group.
• R 1d is Preferably, it is an optionally substituted C 6-10 aryl group (preferably phenyl), More preferably, it is a C 6-10 aryl group (preferably phenyl) optionally substituted with a nitro group, Particularly preferred is a C 6-10 aryl group (preferably phenyl).
• At least one of R 2d , R 3d , R 4d and R 5d represents a substituent, and the rest each independently represents a hydrogen atom or a substituent.
• at least one of R 2d , R 3d , R 4d and R 5d is an optionally substituted C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or An optionally substituted C 1-6 alkyl group (preferably methyl).
• at least one of R 2d , R 3d , R 4d and R 5d is a C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or C 1-6 alkyl A group (preferably methyl).
• one of R 2d , R 3d , R 4d and R 5d is a C 1-6 alkyl group (preferably methyl), and the remaining three are hydrogen atoms.
• R 2d , R 3d , R 4d and R 5d is a C 1-6 alkyl group (preferably methyl), and the remaining three are hydrogen atoms.
• R 6d represents an optionally substituted C 6-14 aryl group.
• R 6d is Preferably, it is a C 6-14 aryl group (preferably phenyl) optionally substituted with a C 1-6 alkyl group (preferably methyl). More preferably, it is a C 6-10 aryl group (preferably phenyl) optionally substituted with a C 1-6 alkyl group (preferably methyl). More preferably, it is a C 6-10 aryl group (preferably phenyl) substituted with a C 1-6 alkyl group (preferably methyl), Particularly preferred is phenyl substituted at the meta position with one C 1-6 alkyl group (preferably methyl).
• n d represents an integer of 1 to 5.
• n d is preferably an integer of 1 to 3, and more preferably 3.
• compound (I), compound (Ia), compound (Ib), compound (Ic) and compound (Id) are novel compounds.
• preferred compounds, compound (Ia), compound (Ib), compound (Ic) and compound (Id) are shown.
• Ring Aa is a pyrrolidine ring, piperidine ring or azepane ring each optionally substituted;
• R 1a is an optionally substituted C 6-10 aryl group (preferably phenyl);
• At least one of R 2a , R 3a , R 4a and R 5a is an optionally substituted C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or a substituted
• R 6a is an optionally substituted C 6-14 aryl group or an optionally substituted C 7-16 aralkyl group.
• Ring Aa is a pyrrolidine ring, piperidine ring or azepane ring each optionally substituted;
• R 1a is an optionally substituted C 6-10 aryl group (preferably phenyl), or an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group (preferably pyridyl);
• At least one of R 2a , R 3a , R 4a and R 5a is an optionally substituted C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or a substituted
• R 6a is an optionally substituted C 6-14 aryl group or an optionally substituted C 7-16 aralkyl group.
• Ring Aa is a pyrrolidine ring, piperidine ring or azepane ring each optionally substituted with a C 1-6 alkyl group (preferably methyl);
• R 1a is a C 6-10 aryl group (preferably phenyl) optionally substituted with a nitro group;
• At least one of R 2a , R 3a , R 4a and R 5a is a C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or a C 1-6 alkyl group (preferably And a C 6-14 aryl group (preferably phenyl) or a C 7-16 aralkyl group (preferably R 6a ), each optionally substituted with a C 1-6 alkyl group (preferably methyl).
• Ring Aa is a pyrrolidine ring, piperidine ring or azepane ring each optionally substituted with a C 1-6 alkyl group (preferably methyl);
• R 1a is a C 6-10 aryl group (preferably phenyl) or a 5- or 6-membered monocyclic aromatic heterocyclic group (preferably pyridyl), each optionally substituted with a nitro group;
• At least one of R 2a , R 3a , R 4a and R 5a is a C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or a C 1-6 alkyl group (preferably And a C 6-14 aryl group (preferably phenyl) or a C 7-16 aralkyl group (preferably R 6a ), each optionally substituted with a C 1-6 alkyl group (preferably methyl).
• Ring Aa is a piperidine ring optionally substituted with a C 1-6 alkyl group (preferably methyl);
• R 1a is a C 6-10 aryl group (preferably phenyl) optionally substituted with a nitro group;
• One of R 2a , R 3a , R 4a and R 5a is a C 1-6 alkyl group (preferably methyl) and the remaining three are hydrogen atoms; and
• R 6a is a C 1-6 alkyl group (preferably Is a C 6-10 aryl group (preferably phenyl) optionally substituted with methyl), or a C 7-13 aralkyl group (preferably benzyl).
• Compound (Ia) is a piperidine ring optionally substituted with a C 1-6 alkyl group (preferably methyl);
• R 1a is a C 6-10 aryl group (preferably phenyl) optionally substituted with a nitro group;
• Ring Aa is a piperidine ring optionally substituted with a C 1-6 alkyl group (preferably methyl);
• R 1a is a C 6-10 aryl group (preferably phenyl) optionally substituted with a nitro group, or a 5- or 6-membered monocyclic aromatic heterocyclic group (preferably pyridyl);
• One of R 2a , R 3a , R 4a and R 5a is a C 1-6 alkyl group (preferably methyl) and the remaining three are hydrogen atoms; and
• R 6a is a C 1-6 alkyl group (preferably Is a C 6-10 aryl group (preferably phenyl) optionally substituted with methyl), or a C 7-13 aralkyl group (preferably benzyl).
• Compound (Ia) is a piperidine ring optionally substituted with a C 1-6 alkyl group (preferably methyl);
• R 1a is a C 6-10 aryl group (preferably phenyl
• Ring Aa is a piperidine ring;
• R 1a is a C 6-10 aryl group (preferably phenyl) optionally substituted with a nitro group;
• R 2a , R 3a , R 4a and R 5a , R 3a or R 4a is a C 1-6 alkyl group (preferably methyl), and the remaining three are hydrogen atoms; and
• R 6a is C 1 A C 6-10 aryl group (preferably phenyl) substituted with a -6 alkyl group (preferably methyl), Compound (Ia).
• Ring Ab is a pyrrolidine ring, piperidine ring or azepane ring each optionally substituted;
• R 1b is a C 6-14 aryl group (preferably phenyl) substituted with a nitro group and a C 1-6 alkoxy group (preferably methoxy, ethoxy);
• At least one of R 2b , R 3b , R 4b and R 5b is an optionally substituted C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or a substituted
• R 6b is an optionally substituted C 6-14 aryl group, Compound (Ib).
• Ring Ab is a pyrrolidine ring, piperidine ring or azepane ring each optionally substituted;
• R 1b is (1) a C 6-10 aryl group (preferably phenyl) substituted with a nitro group and a C 1-6 alkoxy group (preferably methoxy, ethoxy), (2) optionally substituted benzofuryl, or (3) optionally substituted indanyl;
• At least one of R 2b , R 3b , R 4b and R 5b is an optionally substituted C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or a substituted
• R 6b is an optionally substituted C 6-14 aryl group, Compound (Ib).
• Ring Ab is a pyrrolidine ring, piperidine ring or azepane ring each optionally substituted with a C 1-6 alkyl group (preferably methyl);
• R 1b is a C 6-10 aryl group (preferably phenyl) substituted with a nitro group and a C 1-6 alkoxy group (preferably methoxy, ethoxy);
• At least one of R 2b , R 3b , R 4b and R 5b is a C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or a C 1-6 alkyl group (preferably
• R 6b is a C 6-14 aryl group (preferably phenyl) optionally substituted with a C 1-6 alkyl group (preferably methyl).
• Ring Ab is a pyrrolidine ring, piperidine ring or azepane ring each optionally substituted with a C 1-6 alkyl group (preferably methyl);
• R 1b is (1) a C 6-10 aryl group (preferably phenyl) substituted with a nitro group and a C 1-6 alkoxy group (preferably methoxy, ethoxy), (2) optionally substituted benzofuryl, or (3) optionally substituted indanyl;
• At least one of R 2b , R 3b , R 4b and R 5b is a C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or a C 1-6 alkyl group (preferably
• R 6b is a C 6-14 aryl group (preferably phenyl) optionally substituted with a C 1-6 alkyl group (preferably methyl).
• Ring Ab is a piperidine ring optionally substituted with a C 1-6 alkyl group (preferably methyl);
• R 1b is a C 6-10 aryl group (preferably phenyl) substituted with a nitro group and a C 1-6 alkoxy group (preferably methoxy, ethoxy);
• One of R 2b , R 3b , R 4b and R 5b is a C 1-6 alkyl group (preferably methyl) and the remaining three are hydrogen atoms; and
• R 6b is a C 1-6 alkyl group (preferably Is a C 6-10 aryl group (preferably phenyl) optionally substituted with methyl), Compound (Ib).
• Ring Ab is a piperidine ring optionally substituted with a C 1-6 alkyl group (preferably methyl);
• R 1b is (1) substituted with a nitro group and a C 1-6 alkoxy group (preferably methoxy, ethoxy) (preferably one nitro group and one or two (preferably one) C 1-6 alkoxy groups)
• a C 6-10 aryl group preferably phenyl
• R 4b and R 5b is a C 1-6 alkyl group (preferably methyl) and the remaining three are hydrogen atoms; and
• R 6b is a C 1-6 alkyl group (preferably Is a C 6-10 aryl group (preferably phenyl) optionally substituted with methyl), Compound (Ib).
• Ring Ab is a piperidine ring
• R 1b is a C 6-10 aryl group (preferably phenyl) substituted with one nitro group and one or two (preferably one) C 1-6 alkoxy groups (preferably methoxy, ethoxy). Yes; Of R 2b , R 3b , R 4b and R 5b , R 3b or R 4b is a C 1-6 alkyl group (preferably methyl), and the remaining three are hydrogen atoms; and R 6b is C 1 A C 6-10 aryl group (preferably phenyl) substituted with a -6 alkyl group (preferably methyl), Compound (Ib).
• Ring Ab is a piperidine ring
• R 1b is (1) a C 6-10 aryl group (preferably phenyl) substituted with one nitro group and one or two (preferably one) C 1-6 alkoxy groups (preferably methoxy, ethoxy), or (2) indanyl
• R 2b , R 3b , R 4b and R 5b , R 3b or R 4b is a C 1-6 alkyl group (preferably methyl), and the remaining three are hydrogen atoms
• R 6b is C 1 A C 6-10 aryl group (preferably phenyl) substituted with a -6 alkyl group (preferably methyl), Compound (Ib).
• Ring Ac is a pyrrolidine ring, piperidine ring or azepane ring;
• R 1c is an optionally substituted C 6-10 aryl group (preferably phenyl);
• At least one of R 2c , R 3c , R 4c and R 5c is an optionally substituted C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or a substituted be a C 1-6 alkyl group be a (preferably methyl);
• R 6c is an optionally substituted C 6-14 aryl group, an optionally substituted C 7-16 aralkyl group or a substituted, An optionally substituted C 6-10 aryl-C 2-6 alkenyl group, Compound (Ic).
• Ring Ac is a pyrrolidine ring, piperidine ring or azepane ring;
• R 1c is a C 6-10 aryl group (preferably phenyl) optionally substituted with a nitro group;
• At least one of R 2c , R 3c , R 4c and R 5c is a C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or a C 1-6 alkyl group (preferably And a C 6-14 aryl group (preferably phenyl), a C 7-16 aralkyl group (preferably phenyl), and R 6c each optionally substituted with a C 1-6 alkyl group (preferably methyl).
• Ring Ac is a piperidine ring;
• R 1c is a C 6-10 aryl group (preferably phenyl) optionally substituted with a nitro group;
• One of R 2c , R 3c , R 4c and R 5c is a C 1-6 alkyl group (preferably methyl) and the remaining three are hydrogen atoms; and
• R 6c is a C 1-6 alkyl group (preferably Is a C 6-10 aryl group (preferably phenyl) optionally substituted with methyl), a C 7-16 aralkyl group (preferably benzyl) optionally substituted with a C 1-6 alkyl group (preferably methyl) Or a C 6-10 aryl-C 2-6 alkenyl group (preferably 3-phenyl-2-propenyl), Compound (Ic).
• Ring Ac is a piperidine ring;
• R 1c is a C 6-10 aryl group (preferably phenyl) optionally substituted with a nitro group;
• R 2c , R 3c , R 4c and R 5c , R 3c or R 4c is a C 1-6 alkyl group (preferably methyl), and the remaining three are hydrogen atoms; and
• R 6c is C 1 A C 6-10 aryl group (preferably phenyl) substituted with a -6 alkyl group (preferably methyl), Compound (Ic).
• Ring Ad is a pyrrolidine ring, piperidine ring or azepane ring each optionally substituted;
• R 1d is an optionally substituted C 6-10 aryl group (preferably phenyl);
• At least one of R 2d , R 3d , R 4d and R 5d is an optionally substituted C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or a substituted
• R 6d is an optionally substituted C 6-14 aryl group; and
• nd is an integer of 1 to 5, Compound (Id).
• Ring Ad is a pyrrolidine ring, piperidine ring or azepane ring, each optionally substituted with a C 1-6 alkyl group (preferably methyl);
• R 1d is a C 6-10 aryl group (preferably phenyl) optionally substituted with a nitro group;
• At least one of R 2d , R 3d , R 4d and R 5d is a C 1-6 alkyl group (preferably methyl), and the rest are each independently a hydrogen atom or a C 1-6 alkyl group (preferably Methyl);
• R 6d is a C 6-14 aryl group (preferably phenyl) optionally substituted with a C 1-6 alkyl group (preferably methyl); and
• nd is an integer of 1 to 5, Compound (Id).
• Ring Ad is a piperidine ring optionally substituted with a C 1-6 alkyl group (preferably methyl);
• R 1d is a C 6-10 aryl group (preferably phenyl);
• One of R 2d , R 3d , R 4d and R 5d is a C 1-6 alkyl group (preferably methyl) and the remaining three are hydrogen atoms;
• R 6d is a C 6-10 aryl group (preferably phenyl) optionally substituted with a C 1-6 alkyl group (preferably methyl); and
• n d is an integer of 1 to 3 (preferably 3 ) Compound (Id).
• Ring Ad is a piperidine ring;
• R 1d is a C 6-10 aryl group (preferably phenyl);
• R 2d , R 3d , R 4d and R 5d R 3d or R 4d is a C 1-6 alkyl group (preferably methyl), and the remaining three are hydrogen atoms;
• R 6d is a C 6-10 aryl group (preferably phenyl) substituted with a C 1-6 alkyl group (preferably methyl); and
• nd is an integer of 1 to 3 (preferably 3) , Compound (Id).
• compound (I) When compound (Ia), compound (Ib), compound (Ic), compound (Id) or compound (I) (hereinafter collectively referred to as compound (I)) is a salt, examples thereof include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
• metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
• the salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
• Examples include salts with ethylenediamine and the like.
• Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
• salt with organic acid examples include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include salts with sulfonic acid, p-toluenesulfonic acid and the like.
• salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
• inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts
• a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
• organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
• Each raw material compound may form a salt as long as it does not inhibit the reaction.
• Examples of such a salt include the same salts as the salt of compound (I).
• a raw material compound can be easily obtained and used commercially, or can be produced according to a method known per se or a method analogous thereto.
• Compound (I) can be produced according to Reaction Schemes 1-2.
• P 1 represents a protecting group for a carboxy group, and other symbols are as defined above.
• Examples of the “carboxy-protecting group” represented by P 1 include a C 1-6 alkyl group (methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.), phenyl group, trityl group, silyl group
• These protecting groups may have a substituent.
• substituents examples include halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.), formyl groups, C 1-6 alkyl-carbonyl groups (acetyl, propionyl, butylcarbonyl, etc.), nitro groups, etc.
• the number of substituents is about 1 to 3.
• a C 1-6 alkyl group is preferred, and methyl and ethyl are particularly preferred.
• This step is a step of obtaining compound (3) by reacting compound (1) with compound (2) in a solvent in the presence of a condensing agent.
• the amount of compound (2) to be used is generally 1-2 equivalents, preferably 1-1.2 equivalents, relative to compound (1).
• the condensing agent include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC ⁇ HCl), and the like.
• the amount of the condensing agent to be used is generally 1-2 equivalents, preferably 1-1.2 equivalents, relative to compound (1). If necessary, the reaction may be carried out in the presence of a condensation accelerator or the like or a base.
• condensation accelerator examples include 1-hydroxybenzotriazole (HOBt) monohydrate.
• the amount of the condensation accelerator used is usually 1 to 2 equivalents, preferably 1 to 1.2 equivalents, relative to compound (1).
• the base examples include organic bases such as triethylamine, N, N-diisopropylethylamine, 4- (dimethylamino) pyridine (DMAP), and pyridine.
• the amount of the base to be used is generally 0.1-2 equivalents, preferably 0.1-1.2 equivalents, relative to compound (1).
• the solvent include methylene chloride, N, N-dimethylformamide, chloroform and the like.
• the reaction temperature is usually 0 to 35 ° C., preferably 15 to 25 ° C., and the reaction time is usually 1 to 24 hours.
• compound (3) can be produced by converting compound (1) to an acid halide using a halogenating agent and then reacting with compound (2) in a solvent in the presence of a base.
• the amount of compound (2) to be used is generally 1-2 equivalents, preferably 1-1.2 equivalents, relative to compound (1).
• the halogenating agent include thionyl chloride, oxalyl chloride, phosphorus trichloride, sulfuryl chloride and the like.
• the amount of the halogenating agent to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound (1).
• the base include organic bases such as triethylamine, N, N-diisopropylethylamine, and pyridine.
• the amount of the base to be used is generally 1 to 2 equivalents, preferably 1 to 1.2 equivalents, relative to compound (1).
• the solvent include methylene chloride, chloroform, toluene, tetrahydrofuran and the like.
• the reaction temperature is usually 0 to 45 ° C., preferably 0 to 25 ° C., and the reaction time is usually 1 to 24 hours.
• This step is a step of obtaining compound (4) by deprotecting compound (3).
• Deprotection is performed, for example, by reacting compound (3) with a base in a solvent.
• the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
• the amount of the base to be used is generally 1-2 equivalents, preferably 1-1.2 equivalents, relative to compound (3).
• the solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane and the like. These are preferably used by mixing with water at an appropriate ratio.
• the reaction temperature is usually 0 to 80 ° C., preferably 15 to 25 ° C., and the reaction time is usually 1 to 24 hours.
• Process 3 This step is a step in which compound (I) is obtained by reacting compound (4) with compound (5). This step is performed by the same method as in step 1 of the manufacturing route (1).
• P 2 represents an amino-protecting group, and other symbols are as defined above.
• amino-protecting group represented by P 2 include a formyl group, a C 1-6 alkyl-carbonyl group (acetyl, propionyl, etc.), a phenylcarbonyl group, a C 1-6 alkyl-oxycarbonyl group (methoxycarbonyl, Ethoxycarbonyl, tert-butoxycarbonyl etc.), aryloxycarbonyl group (phenyloxycarbonyl etc.), C 7-10 aralkyl-carbonyl group (benzyloxycarbonyl etc.), benzyl group, benzhydryl group, trityl group, phthaloyl group etc.
• These protecting groups may have a substituent.
• substituents include halogen atoms (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), C 1-6 alkyl-carbonyl groups (acetyl, propionyl, butylcarbonyl, etc.), nitro groups and the like.
• the number of substituents is about 1 to 3. Preferred are tert-butoxycarbonyl and benzyloxycarbonyl.
• This step is a step of obtaining the compound (7) by reacting the compound (6) with the compound (5). This step is performed by the same method as in step 1 of the manufacturing route (1).
• This step is a step of obtaining compound (8) by deprotecting compound (7).
• Deprotection is performed, for example, by reacting compound (7) with an acid in a solvent when P 2 is tert-butoxycarbonyl or the like.
• the acid include hydrochloric acid, trifluoroacetic acid (TFA), formic acid and the like.
• the amount of the acid to be used is generally 2-100 equivalents, preferably 5-10 equivalents, relative to compound (7).
• the solvent include 1,4-dioxane, tetrahydrofuran, ethyl acetate and the like.
• the reaction temperature is usually 0 to 35 ° C., preferably 15 to 25 ° C., and the reaction time is usually 1 to 24 hours.
• Process 3 In this step, compound (8) and compound (2) are reacted to obtain compound (I). This step is performed by the same method as in step 1 of the manufacturing route (1).
• Compounds (1), (2), (5) and (6) which are raw material compounds can be commercially available or can be produced by a method known per se.
• the target compound In each reaction of the target compound and raw material synthesis, when the raw material compound has an amino group, a carboxy group, or a hydroxy group as a substituent, these groups are protected with a protecting group that is generally used in peptide chemistry and the like. It may be. In this case, the target compound can be obtained by removing the protecting group as necessary after the reaction.
• Examples of the protecting group for amino group include formyl group, C 1-6 alkyl-carbonyl group (acetyl, propionyl, etc.), phenylcarbonyl group, C 1-6 alkyl-oxycarbonyl group (methoxycarbonyl, ethoxycarbonyl, tert- Butoxycarbonyl group, etc.), aryloxycarbonyl group (phenyloxycarbonyl etc.), C 7-10 aralkyl-carbonyl group (benzyloxycarbonyl etc.), benzyl group, benzhydryl group, trityl group, phthaloyl group, etc.
• the group may have a substituent.
• substituents include halogen atoms (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), C 1-6 alkyl-carbonyl groups (acetyl, propionyl, butylcarbonyl, etc.), nitro groups and the like.
• the number of substituents is about 1 to 3.
• Examples of the protecting group for the carboxy group include a C 1-6 alkyl group (methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.), a phenyl group, a trityl group, a silyl group, and the like. These protecting groups may have a substituent. Examples of these substituents include halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.), formyl groups, C 1-6 alkyl-carbonyl groups (acetyl, propionyl, butylcarbonyl, etc.), nitro groups, etc. The number of substituents is about 1 to 3.
• Examples of the protecting group for the hydroxy group include C 1-6 alkyl groups (methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.), phenyl groups, C 7-10 aralkyl groups (benzyl, etc.) , Formyl group, C 1-6 alkyl-carbonyl group (acetyl, propionyl etc.), aryloxycarbonyl group (phenyloxycarbonyl etc.), C 7-10 aralkyl-carbonyl group (benzyloxycarbonyl etc.), pyranyl group, furanyl group , A silyl group, and the like, and these protective groups may have a substituent.
• C 1-6 alkyl groups methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.
• phenyl groups C 7-10 aralkyl groups (benz
• substituents examples include halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.), C 1-6 alkyl groups, phenyl groups, C 7-10 aralkyl groups, nitro groups, and the like.
• the number of substituents is about 1 to 4.
• inorganic acid hydrogen chloric acid, sulfuric acid, hydrobromic acid, etc.
• organic acid methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid
• Oxalic acid fumaric acid, maleic acid, tartaric acid, etc.
• inorganic bases alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum or ammonium
• organic bases trimethylamine, triethylamine, pyridine, A salt with picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N′-dibenzylethylenediamine, etc.
• the compound when the raw material compound can form a salt, the compound may be used as a salt.
• a salt for example, those exemplified as the salt of compound (I) are used.
• the compound (I) of the present invention produced by such a method can be isolated and purified by usual separation means such as recrystallization, distillation, chromatography and the like.
• compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), as well as synthetic methods and separation methods known per se (concentration). , Solvent extraction, column chromatography, recrystallization, etc.), each can be obtained as a single product.
• compound (I) has an optical isomer
• the optical isomer resolved from the compound is also encompassed in compound (I).
• the optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.
• Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a mixture of crystal forms.
• the crystal can be produced by crystallization by applying a crystallization method known per se.
• Compound (I) may be a hydrate, a non-hydrate, a solvate, or a non-solvate.
• the compound of the present invention has low toxicity and is used as it is or mixed with a pharmacologically acceptable carrier to make a pharmaceutical composition, so that a mammal (eg, human, mouse, rat, rabbit, dog, cat, Cattle, horses, pigs, monkeys) can be used as preventive or therapeutic agents for various diseases described below.
• a mammal eg, human, mouse, rat, rabbit, dog, cat, Cattle, horses, pigs, monkeys
• the pharmacologically acceptable carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
• excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light
• excipients include anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate.
• lubricant examples include magnesium stearate, calcium stearate, talc and colloidal silica.
• Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples include propylmethylcellulose and polyvinylpyrrolidone.
• disintegrant examples include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.
• Suitable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.
• solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Is mentioned.
• suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone , Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.
• surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate
• polyvinyl alcohol, polyvinylpyrrolidone Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
• Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.
• buffer solutions such as phosphate, acetate, carbonate, citrate.
• a preferred example of the soothing agent is benzyl alcohol.
• Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
• Preferable examples of the antioxidant include sulfite and ascorbate.
• the colorant examples include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye) and natural dyes (eg, ⁇ -carotene, chlorophyll, bengara).
• water-soluble edible tar dyes eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.
• water-insoluble lake dyes Eg, the aluminum salt of the water-soluble edible tar dye
• natural dyes eg, ⁇ -carotene, chlorophyll, bengara
• Suitable examples of sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
• Examples of the dosage form of the pharmaceutical composition include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, and lozenges.
• Oral preparations such as syrup, emulsion, suspension, film (eg, orally disintegrating film); and injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, Intravenous preparations, external preparations (eg, transdermal preparations, ointments), suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc. Oral preparations are mentioned. These can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration).
• compositions may be controlled-release preparations (eg, sustained-release microcapsules) such as immediate-release preparations or sustained-release preparations.
• the pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
• the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight.
• an oral preparation When manufacturing an oral preparation, it may be coated for the purpose of taste masking, enteric solubility or sustainability, if necessary.
• coating base used for coating examples include sugar coating base, water-soluble film coating base, enteric film coating base and sustained-release film coating base.
• sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
• water-soluble film coating base examples include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) ], Synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan.
• enteric film coating bases include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) ] Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)]; natural products such as shellac.
• cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate
• methacrylic acid copolymer L (Eudragit L (trade name) ]
• Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer
• sustained-release film coating base examples include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit Acrylic polymer such as NE (trade name)].
• cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit Acrylic polymer such as NE (trade name)].
• the above-mentioned coating bases may be used by mixing two or more of them in an appropriate ratio. Moreover, you may use light-shielding agents, such as a titanium oxide, ferric oxide, etc. in the case of coating.
• the compound of the present invention has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity), few side effects, and mammals (eg, humans, cows, horses, dogs, cats, Monkeys, mice, rats) can be used as preventive or therapeutic agents for various diseases or as diagnostic agents.
• toxicity eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity
• mammals eg, humans, cows, horses, dogs, cats, Monkeys, mice, rats
• the compound of the present invention has excellent V1b receptor antagonism, and central psychiatric disorders (mood disorders, anxiety disorders, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, epilepsy, etc.) It is useful as a preventive or therapeutic agent.
• the dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, etc. For example, when administered orally to an adult bone disease patient, it is usually about 0.01 to 100 mg / kg as a single dose.
• the body weight is preferably 0.05 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight, and it is desirable to administer this amount once to three times a day.
• Example 2 (1) Synthesis of ethyl 1-[(2-nitrophenoxy) acetyl] -3-piperidinecarboxylate
• Ethyl 3-piperidinecarboxylate (0.753 g) was dissolved in dichloromethane (25 mL), and o-nitrophenoxyacetic acid (1 .13 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.11 g) and 4- (dimethylamino) pyridine (60 mg) were added and stirred at room temperature overnight.
• the reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and concentrated under reduced pressure.
• Example 34 (1) Synthesis of [1- (t-butoxycarbonyl) piperidin-3 (S) -yl]-[4- (3-methylphenyl) -3-methylpiperazin-1-yl] methanone (S) —N— t-Butoxycarbonylnipecotic acid (159 mg) was dissolved in dichloromethane (3 mL) to give 1-hydroxybenzotriazole monohydrate (97 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (145 mg) and 2-methyl-1- (m-tolyl) piperazine (120 mg) were added and stirred at 25 ° C. overnight.
• the following compounds were produced using the corresponding raw materials.
• the corresponding raw material used a commercial item, or manufactured according to a method known per se.
• the structural formulas and physicochemical data of the compounds are shown in Table 1.
• Formulation Example 1 (Manufacture of capsules) 1) Compound of Example 2 30 mg 2) Fine powder cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg 60 mg total 1), 2), 3) and 4) are mixed and filled into gelatin capsules.
• Formulation Example 2 Manufacture of tablets
• Test Example 1 Method for Measuring V1b Receptor Antagonism HEK293 cells stably expressing human V1b receptor were cultured in Dulbecco's modified Eagle medium (4500 mg / L glucose, 10% FBS, containing penicillin / streptomycin) and the day before the test. 30000 cells were seeded per well of a 96 well plate (black transparent bottom, half area). One hour before the measurement, the culture solution was removed and replaced with a buffer solution (1 ⁇ HBSS, 20 mM HEPES pH 7.4), a loading dye solution (FLIPR Calcium 5 assay kit) was added, and the mixture was allowed to stand in a 37 ° C. CO 2 incubator.
• Dulbecco's modified Eagle medium 4500 mg / L glucose, 10% FBS, containing penicillin / streptomycin
• the compound of the present invention has an arginine-vasopressin 1b receptor antagonistic action, it has central psychiatric disorders (mood disorders, anxiety disorders, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, epilepsy, etc.) It is useful as a preventive or therapeutic agent for various diseases.

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