WO2013129622A1 - 複素環化合物およびその用途 - Google Patents
複素環化合物およびその用途 Download PDFInfo
- Publication number
- WO2013129622A1 WO2013129622A1 PCT/JP2013/055566 JP2013055566W WO2013129622A1 WO 2013129622 A1 WO2013129622 A1 WO 2013129622A1 JP 2013055566 W JP2013055566 W JP 2013055566W WO 2013129622 A1 WO2013129622 A1 WO 2013129622A1
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- WIPO (PCT)
- Prior art keywords
- group
- substituted
- phenyl
- salt
- optionally substituted
- Prior art date
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Classifications
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- 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
- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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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
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/28—Cinnolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—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
- C07D401/02—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
- C07D401/10—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 aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- C07D403/10—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 aromatic rings
Definitions
- the present invention relates to a heterocyclic compound having cholinergic muscarinic M1 receptor positive allosteric modulator activity and useful as a medicament for preventing or treating Alzheimer's disease, schizophrenia, pain (pain), sleep disorder and the like.
- positive allosteric modulator activity refers to the action of binding to a site different from the endogenous activator (acetylcholine in the receptor) to enhance the receptor function.
- Acetylcholine is a neurotransmitter that transmits stimuli through parasympathetic and motor nerves.
- Acetylcholine receptors are classified into ligand-gated ion channels (cholinergic nicotinic receptors) and G protein-coupled receptors (cholinergic muscarinic receptors).
- the cholinergic muscarinic receptor is one of the receptors for the excitatory neurotransmitter acetylcholine and was named based on the selective activation of the receptor by muscarinic. Muscarinic receptors are further classified into subtypes M1 to M5.
- Non-Patent Document 1 Non-Patent Document 1
- Patent Document 1 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 2 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 3 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 4 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 5 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 6 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 7 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 8 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 9 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 10 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 11 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 12 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 13 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 14 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 15 discloses the following compounds as intermediates of cannabinoid receptor ligands.
- Patent Document 16 discloses the following compounds as intermediates of chemokine receptor CCXCKR2 antagonists.
- EP 0560604 discloses the following compounds as 5-HT 3 receptor antagonists.
- Patent Document 18 discloses the following compounds as 5-HT 3 antagonists.
- Patent Document 19 discloses the following compounds as compounds having an antiallergic action based on a 5-lipoxygenase inhibitory action and the like.
- Patent Document 20 discloses the following compounds as compounds having a myocardial contraction enhancing action, a coronary blood flow increasing action, a hypotensive action and the like.
- Patent Document 21 discloses the following compounds as compounds that suppress the release of convulsions inducing substances produced as a result of antigen-antibody reaction.
- Patent Document 22 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 23 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 24 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 25 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 26 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 27 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 28 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 29 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 30 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 31 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 32 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 33 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 34 discloses the following compounds as M1 receptor positive allosteric modulators.
- Patent Document 35 discloses the following compounds as M1 receptor positive allosteric modulators.
- Non-Patent Document 2 discloses the following compounds as HIV-1 ⁇ Tat-TAR interaction inhibitors.
- Non-patent Document 3 The following compounds are disclosed in Oriental Journal of Chemistry (2007), 23 (3), and 935-942 (Non-patent Document 3).
- Non-patent Document 4 disclose the following compounds as CB2-selective cannabinoid receptor ligands.
- Non-Patent Document 5 discloses the following compounds as CB2 receptor ligands.
- Non-patent Document 6 discloses the following compounds as CB2 cannabinoid receptor agonists.
- Non-patent Document 7 discloses the following compounds as 5-HT 3 antagonists.
- Non-Patent Document 8 discloses the following compounds.
- Non-Patent Document 9 discloses the following compounds.
- Non-patent Document 10 The following compounds are disclosed in Journal of Heterocyclic Chemistry (1984), 21 (1), 107-112 (Non-patent Document 10).
- M1 receptor cholinergic muscarinic M1 receptor
- the present inventors have found that the compound represented by the following formula (I) has cholinergic muscarinic M1 receptor (M1 receptor) positive allosteric modulator activity.
- M1 receptor cholinergic muscarinic M1 receptor
- R 1 is an optionally substituted amino group, or an optionally substituted cyclic amino group
- R 2 and R 3 are each independently a hydrogen atom or a substituent
- Ring A represents an optionally substituted 5- to 10-membered ring.
- R 1 is not a methoxy (methyl) amino group
- R 1 is not an amino group substituted with a substituent selected from a saturated azabicyclo ring group and a tetrazolyl group which may be substituted
- R 1 is a formula
- R a may have 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group and a nitro group as a substituent on the phenyl ring, and a hydroxyl group as a substituent on the lower alkyl group.
- D is an alkylene group or an alkylene group interrupted by at least one double bond
- R c is a hydrogen atom or a lower alkyl group
- R f is a phenyl group, a nitrogen atom-containing heteroaryl group or a diphenylmethyl group
- R g is a hydrogen atom or a lower alkyl group
- n is 2 or 3
- R h and R i are phenyl groups;
- the phenyl group or phenyl moiety in the definition of R f , R h and R i may be substituted with 1 to 3 halogen atoms, lower alkyl group, trifluoromethyl group, lower alkoxy group or hydroxyl group
- Ring A is not an unsubstituted phenyl group; and (6)
- R 2 and R 3 are both hydrogen atoms
- Ring A is an unsubstituted C 3-6 cycloalkyl group, or a halogen atom at the 4-position Or it is not a phenyl group having a methyl group.
- compound (I) may be abbrevi
- R 1 is an optionally substituted amino group, or an optionally substituted cyclic amino group
- R 2 and R 3 are each independently a hydrogen atom or a substituent
- Ring A represents an optionally substituted 5- to 10-membered ring.
- R 1 is not a methoxy (methyl) amino group
- R 1 is not an amino group substituted with a substituent selected from a saturated azabicyclo ring group and a tetrazolyl group which may be substituted
- R 1 is a formula
- R a may have 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group and a nitro group as a substituent on the phenyl ring, and a hydroxyl group as a substituent on the lower alkyl group.
- D is an alkylene group or an alkylene group interrupted by at least one double bond
- R C is a hydrogen atom or a lower alkyl group
- R f is a phenyl group, a nitrogen atom-containing heteroaryl group or a diphenylmethyl group
- R g is a hydrogen atom or a lower alkyl group
- n is 2 or 3
- R h and R i are phenyl groups
- the phenyl group or phenyl moiety in the definition of R f , R h and R i may be substituted with 1 to 3 halogen atoms, lower alkyl group, trifluoromethyl group, lower alkoxy group or hydroxyl group
- Ring A is not an unsubstituted phenyl group; (6) when R 2 and R 3 are both hydrogen atoms, ring A is not an unsubstituted C 3-6 cycloalkyl group or a phenyl group having a halogen atom or a methyl group at the 4-position; (7) R 2 is not an amino group; and (8) Excluding
- R 1 is (a) (1) amino group, (2) (i) hydroxyl group, (ii) C 1-3 alkoxy group, (iii) C 3-6 cycloalkyl group substituted with 1 to 3 hydroxyl groups, (iv) phenyl group, (v) furyl group (Vi) a tetrahydrofuranyl group, (vii) a piperidino group and (viii) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a morpholino group, (3) a C 3-6 cycloalkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group and a hydroxymethyl group, (4) a 4- to 10-membered cyclic amino group, (5) a halogen atom, a phenyl group optionally substituted with 1 to 3 substituents selected from a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atom
- [3A] The compound according to [3] or a salt thereof (excluding the following compounds) (i) N-cyclohexyl-1,4-dihydro-1-[(4-methoxyphenyl) methyl] -4-oxo-3-quinolinecarboxamide, and (ii) 1,4-dihydro-1-[(4-methoxyphenyl) methyl] -N- (2-methylphenyl) -4-oxo-3-quinolinecarboxamide).
- [3C] The compound according to [3B] or a salt thereof (excluding the following compounds) (i) N-cyclohexyl-1,4-dihydro-1-[(4-methoxyphenyl) methyl] -4-oxo-3-quinolinecarboxamide, and (ii) 1,4-dihydro-1-[(4-methoxyphenyl) methyl] -N- (2-methylphenyl) -4-oxo-3-quinolinecarboxamide).
- R 1 is (a) (1) amino group, (2) (i) hydroxyl group, (ii) C 1-3 alkoxy group, (iii) C 3-6 cycloalkyl group substituted with 1 to 3 hydroxyl groups, (iv) phenyl group, (v) furyl group (Vi) a tetrahydrofuranyl group, (vii) a piperidino group and (viii) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a morpholino group, (3) a C 3-6 cycloalkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group and a hydroxymethyl group, (4) piperidino group, (5) a halogen atom, a phenyl group optionally substituted with 1 to 3 substituents selected from a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms and a hydroxymethyl group,
- [3E] The compound described in [3D] or a salt thereof (excluding the following compounds) (i) N-cyclohexyl-1,4-dihydro-1-[(4-methoxyphenyl) methyl] -4-oxo-3-quinolinecarboxamide, and (ii) 1,4-dihydro-1-[(4-methoxyphenyl) methyl] -N- (2-methylphenyl) -4-oxo-3-quinolinecarboxamide).
- R 1 is (a) (1) amino group, (2) (i) hydroxyl group, (ii) C 1-3 alkoxy group, (iii) C 3-6 cycloalkyl group substituted with 1 to 3 hydroxyl groups, (iv) phenyl group, (v) furyl group , (Vi) a piperidino group and (vii) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from a morpholino group, (3) a C 3-6 cycloalkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group and a hydroxymethyl group, (4) a 4- to 10-membered cyclic amino group, (5) a halogen atom, a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and a phenyl group optionally substituted with 1 to 3 substituents selected from hydroxymethyl group , (6) a di
- [3G] The compound according to [3F] or a salt thereof (excluding the following compounds) (i) N-cyclohexyl-1,4-dihydro-1-[(4-methoxyphenyl) methyl] -4-oxo-3-quinolinecarboxamide, and (ii) 1,4-dihydro-1-[(4-methoxyphenyl) methyl] -N- (2-methylphenyl) -4-oxo-3-quinolinecarboxamide).
- R 1 In the definition of R 1 , (a) (4) the 4- to 10-membered cyclic amino group is a piperidino group, (b) a 4- to 10-membered cyclic amino group which may be substituted with 1 to 3 substituents selected from a hydroxyl group and a hydroxymethyl group, (1) an azetidin-1-yl group substituted with 1 to 3 hydroxyl groups, (2) a pyrrolidin-1-yl group substituted with 1 to 3 hydroxymethyl groups, (3) a piperidino group optionally substituted by 1 to 3 hydroxyl groups, or (4) a 1,3-dihydro-2H-isoindol-2-yl group, The compound according to [3F] or a salt thereof.
- [3K] The compound according to [3J] or a salt thereof (excluding the following compounds) (i) N-cyclohexyl-1,4-dihydro-1-[(4-methoxyphenyl) methyl] -4-oxo-3-quinolinecarboxamide, and (ii) 1,4-dihydro-1-[(4-methoxyphenyl) methyl] -N- (2-methylphenyl) -4-oxo-3-quinolinecarboxamide).
- R 1 is (a) (1) amino group, (2) (i) hydroxyl group, (ii) C 1-3 alkoxy group, (iii) C 3-6 cycloalkyl group substituted with 1 to 3 hydroxyl groups, (iv) phenyl group, and (v) tetrahydrofuranyl
- R 1 In the definition of R 1 , (a) (4) the 4- to 7-membered cyclic amino group is a piperidino group, (b) a 4- to 7-membered cyclic amino group which may be substituted with 1 to 3 substituents selected from a hydroxyl group and a hydroxymethyl group, (1) an azetidin-1-yl group substituted with 1 to 3 hydroxyl groups, (2) a pyrrolidin-1-yl group substituted with 1 to 3 hydroxymethyl groups, or (3) a piperidino group, The compound according to [3M] or a salt thereof.
- R 1 is (1) an amino group, (2) Substituted with 1 to 3 substituents selected from (i) hydroxyl group, (ii) C 1-3 alkoxy group and (iii) C 3-6 cycloalkyl group substituted with 1 to 3 hydroxyl groups An optionally substituted C 1-6 alkyl group, (3) a C 3-6 cycloalkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group and a hydroxymethyl group, (4) piperidino group, (5) a phenyl group which may be substituted with 1 to 3 substituents selected from C 1-6 alkyl groups which may be substituted with 1 to 3 halogen atoms, and (6) an amino group optionally substituted with one substituent selected from tetrahydropyranyl groups substituted with 1 to 3 hydroxyl groups, R 2 and R 3 are the same and are a hydrogen atom or a halogen atom, or R 2 is a hydrogen
- [4B] The compound according to [4A] or a salt thereof (excluding the following compounds) (i) N-cyclohexyl-1,4-dihydro-1-[(4-methoxyphenyl) methyl] -4-oxo-3-quinolinecarboxamide, and (ii) 1,4-dihydro-1-[(4-methoxyphenyl) methyl] -N- (2-methylphenyl) -4-oxo-3-quinolinecarboxamide).
- R 1 is (1) an amino group, (2) a C 3-6 cycloalkyl group substituted with 1 to 3 substituents selected from a halogen atom and a hydroxyl group, and (3) an amino group substituted with one substituent selected from tetrahydropyranyl groups substituted with 1 to 3 hydroxyl groups
- R 2 and R 3 are the same and are a hydrogen atom or a halogen atom, or R 2 is a hydrogen atom, R 3 is a halogen atom
- X is —CH ⁇ or —N ⁇
- Ring A has 4-position (i) a C 1-3 alkoxy group, (ii) a carbamoyl group, (iii) a pyrazolyl group optionally substituted with 1 to 3 C 1-3 alkyl groups, and (vi) 1 Or a phenyl group substituted with a substituent selected from a pyridyl group substituted with three C 1-3 alkyl groups,
- R 1 is substituted with one substituent selected from a C 3-6 cycloalkyl group substituted with 1 to 3 hydroxyl groups and a tetrahydropyranyl group substituted with 1 to 3 hydroxyl groups
- R 1 is substituted with one substituent selected from a C 3-6 cycloalkyl group substituted with 1 to 3 hydroxyl groups and a tetrahydropyranyl group substituted with 1 to 3 hydroxyl groups.
- An amino group, R 2 and R 3 are the same and are a hydrogen atom or a halogen atom, or R 2 is a hydrogen atom, R 3 is a halogen atom, X is —CH ⁇ or —N ⁇ , Ring A is a substituent selected from 4-position (i) a C 1-3 alkoxy group, (ii) a carbamoyl group and (ii) a pyrazolyl group optionally substituted with 1 to 3 C 1-3 alkyl groups A phenyl group substituted with The compound according to [1] or [2], or a salt thereof.
- R 1 is substituted with one substituent selected from a C 3-6 cycloalkyl group substituted with 1 to 3 hydroxyl groups and a tetrahydropyranyl group substituted with 1 to 3 hydroxyl groups.
- a medicament comprising the compound according to any one of [1] to [9] or a salt thereof.
- Alzheimer's disease schizophrenia, pain or sleep, characterized by administering an effective amount of the compound according to any one of [1] to [9] or a salt thereof to a mammal. How to prevent or treat a disorder.
- [15A] Use of the compound according to any one of [1] to [9] or a salt thereof for the manufacture of a preventive or therapeutic agent for Alzheimer's disease, schizophrenia, pain or sleep disorder.
- [16A] The compound according to any one of [1] to [9] or a salt thereof for use in cholinergic muscarinic M1 receptor positive allosteric modulation.
- [17A] The compound according to any one of [1] to [9] or a salt thereof for use in the prevention or treatment of Alzheimer's disease, schizophrenia, pain or sleep disorder.
- a cholinergic muscarinic M1 receptor positive allosteric modulator comprising administering an effective amount of the compound according to any one of [1] to [9] or a salt thereof to a mammal. Rate method.
- [18A] A method for enhancing the function of M1 receptor, comprising administering an effective amount of the compound according to any one of [1] to [9] or a salt thereof to a mammal.
- the compound of the present invention has cholinergic muscarinic M1 receptor positive allosteric modulator activity, it is useful as a preventive or therapeutic agent for Alzheimer's disease, schizophrenia, pain (pain), sleep disorder and the like.
- lower means 1 to 6 carbon atoms.
- Halogen atom includes fluorine atom, chlorine atom, bromine atom and iodine atom.
- C 1-3 alkyl group means a linear or branched C 1-3 alkyl group, and examples thereof include methyl, ethyl, propyl and isopropyl.
- C 1-6 alkyl group means a linear or branched C 1-6 alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl , Isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 1,2-dimethylbutyl, 1,2,2-trimethylpropyl and the like.
- C 1-10 alkyl group means a linear or branched C 1-10 alkyl group, for example, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl. , Neopentyl, tert-pentyl, 1,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 1,2-dimethylbutyl, 1,2,2-trimethylpropyl, heptyl, octyl, nonyl, decyl, etc. Is mentioned.
- C 2-10 alkyl group means a linear or branched C 2-10 alkyl group such as ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl. , Neopentyl, tert-pentyl, 1,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 1,2-dimethylbutyl, 1,2,2-trimethylpropyl, heptyl, octyl, nonyl, decyl, etc. Is mentioned.
- C 1-3 alkyl group substituted with 1 to 3 halogen atoms means a straight chain substituted with 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) or Means a branched C 1-3 alkyl group, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, chloromethyl, 2-chloroethyl, bromomethyl, 2 -Bromoethyl and the like.
- C 2-6 alkenyl group means a linear or branched C 2-6 alkenyl group such as vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3 -Butenyl and the like.
- C 1-6 alkoxy group means a linear or branched C 1-6 alkoxy group, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, Pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1,2-dimethylpropyloxy, hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 1,2-dimethylbutyloxy, 1,2 , 2-trimethylpropyloxy and the like.
- C 1-3 alkoxy group means a linear or branched C 1-3 alkoxy group, and examples thereof include methoxy, ethoxy, propoxy, and isopropoxy.
- C 1-3 alkoxy group substituted with 1 to 3 halogen atoms means a straight chain substituted with 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) or Means a branched C 1-3 alkoxy group, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, chloromethoxy, 2-chloroethoxy, bromomethoxy , 2-bromoethoxy and the like.
- C 3-10 cycloalkyl group examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
- C 3-6 cycloalkyl group examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
- C 3-6 cycloalkenyl group examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
- C 6-14 aryl group examples include phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), anthryl, phenanthryl and the like. C 6-10 aryl groups such as phenyl and naphthyl are preferred.
- Aromaatic group means an aromatic hydrocarbon group or an aromatic heterocyclic group.
- aromatic hydrocarbon group examples include C 6-14 aromatic hydrocarbon groups such as phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), anthryl, phenanthryl and the like.
- aromatic heterocyclic group is a 5- to 14-membered member containing 1 to 4 (preferably 1 to 3, more preferably 1 or 2) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
- aromatic heterocyclic group for example Thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, Monocyclic aromatic heterocyclic groups such as 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, furazanyl, pyranyl; Benzothienyl, benzofuranyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl, benzoisothiazolyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazoly
- heterocyclic group is a 5- to 14-membered (preferably 1 to 4 (preferably 1 to 3, more preferably 1 or 2) heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom) Is a 5- to 10-membered) (monocyclic, bicyclic or tricyclic, preferably monocyclic or bicyclic) heterocyclic group.
- the “cyclic amino group” includes a 4- to 10-membered cyclic amino group, preferably a 4- to 7-membered cyclic amino group.
- the “4- to 10-membered cyclic amino group” may contain 1 to 3 (preferably 1) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom. Or a 10-membered cyclic amino group. Specifically, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl, 1,3-dihydro-2H-isoindole-2 -Yl and the like.
- the “4- to 7-membered cyclic amino group” may contain 1 to 3 (preferably 1) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom. Or a 7-membered cyclic amino group. Specific examples include azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl and the like.
- non-aromatic heterocyclic group includes 1 to 4 (preferably 1 to 3, more preferably 1 or 2) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
- 7-membered saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group eg, azetidinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl (eg, 1,4-diazepanyl), oxazepanyl (eg, 1,4-oxazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, pyrazolidinyl, ox
- R 1 represents an amino group which may be substituted or a cyclic amino group which may be substituted.
- the “optionally substituted amino group” represented by R 1 has the formula —N (R 4 ) (R 5 ) (wherein R 4 and R 5 each independently represents a hydrogen atom or a substituent Represents a group represented by:
- R 4 or R 5 (1) an amino group, (2) an optionally substituted C 1-10 alkyl group, (3) an optionally substituted C 2-6 alkenyl group, (4) an optionally substituted C 1-6 alkoxy group, (5) an optionally substituted C 3-10 cycloalkyl group, (6) an optionally substituted C 3-6 cycloalkenyl group, (7) an optionally substituted cyclic amino group (eg, piperidino group), (8) an optionally substituted aromatic group (eg, phenyl group, pyrazolyl group), (9) an optionally substituted dihydroindenyl group, (10) Non-aromatic heterocyclic group which may be substituted (eg, tetrahydrofuryl group, tetrahydropyranyl group) Etc.
- a substituent represented by R 4 or R 5 (1) an amino group, (2) an optionally substituted C 1-10 alkyl group, (3) an optionally substituted C 2-6 alkenyl group, (4) an optionally substituted C
- C 1-10 alkyl group C 2-6 alkenyl group” and “C 1-6 alkoxy group” are substituted with, for example, 1 to 3 substituents selected from the following substituent group A. May be.
- substituent group A (A) a halogen atom, (B) a cyano group, (C) a hydroxyl group, (D) a nitro group, (E) a formyl group, (F) a C 1-6 alkoxy group (preferably a C 1-3 alkoxy group), (G) a C 3-6 cycloalkyl group optionally substituted with 1 to 3 hydroxyl groups, (H) a C 6-14 aryl group, (I) a cyclic amino group (eg, piperidino group, morpholino group), (J) a heterocyclic group (eg, furyl group, tetrahydrofuranyl group), (K) a C 1-6 alkyl-carbonyl group, (L)
- C 3-10 cycloalkyl group “C 3-6 cycloalkenyl group”, “cyclic amino group”, “aromatic group”, “dihydroindenyl group” and “non-aromatic heterocyclic group” are For example, it may be substituted with 1 to 3 substituents selected from the following substituent group B.
- [Substituent group B] (A) a halogen atom, (B) a cyano group, (C) a hydroxyl group, (D) a nitro group, (E) a formyl group, (F) a C 1-6 alkoxy group (preferably a C 1-3 alkoxy group), (G) a C 3-6 cycloalkyl group optionally substituted with 1 to 3 hydroxyl groups, (H) a C 6-14 aryl group, (I) a cyclic amino group (eg, piperidino group, morpholino group), (J) a heterocyclic group (eg, furyl group, tetrahydrofuranyl group), (K) a C 1-6 alkyl-carbonyl group, (L) an amino group, (M) a mono- or di-C 1-6 alkylamino group (preferably a mono- or di-C 1-3 alkylamino group), and (n) 1 to 3 substituents selected from a
- R 4 and R 5 are the same or different, Hydrogen atom, A C 1-6 alkyl group, C 1-3 alkyl group with a hydroxyl group may be substituted or a C 1-3 alkyl group substituted by optionally substituted at an amino group optionally C 2-10 alkyl group, A C 3-10 cycloalkyl group, or Examples thereof include an aromatic group (eg, phenyl group, pyridyl group) which may be substituted with a substituent selected from a halogen atom, a C 1-6 alkyl group, a C 1-3 alkoxy group, a hydroxyl group and an amino group.
- an aromatic group eg, phenyl group, pyridyl group
- R 4 and R 5 are as follows: R 4 is a hydrogen atom, and R 5 is a 2-hydroxyethyl group, a 2-methoxyethyl group, a 2-hydroxycyclohexyl group, a 2-hydroxycyclopentyl group, 2- (hydroxy A methyl) cyclohexyl group, or a 3-hydroxytetrahydropyran-4-yl group.
- R 4 is a hydrogen atom and R 5 is a 2-hydroxycyclohexyl group, 2-hydroxycyclopentyl group, 2- (hydroxymethyl) cyclohexyl group or 3-hydroxytetrahydropyran-4-yl group, the nitrogen of the amino group
- R 5 is a 2-hydroxycyclohexyl group, 2-hydroxycyclopentyl group, 2- (hydroxymethyl) cyclohexyl group or 3-hydroxytetrahydropyran-4-yl group
- the nitrogen of the amino group The relative arrangement of the bond between the atom and the carbon atom on the ring, and the bond between the hydroxyl group or hydroxymethyl group and the carbon atom on the ring is preferably trans.
- R 1 has an absolute configuration represented by the following formula is preferable.
- one of R 4 or R 5 is a hydrogen atom.
- the “cyclic amino group” in the “optionally substituted cyclic amino group” represented by R 1 may have, for example, (1) a halogen atom, (2) hydroxyl group, (3) an optionally substituted C 1-6 alkyl group, (4) an optionally substituted C 2-6 alkenyl group, (5) an optionally substituted C 1-6 alkoxy group, (6) an optionally substituted C 3-6 cycloalkyl group, (7) an optionally substituted C 3-6 cycloalkenyl group, (8) an optionally substituted C 6-14 aryl group, (9) an optionally substituted heterocyclic group, (10) a C 1-6 alkyl-carbonyl group, (11) Substituents selected from C 1-6 alkoxy-carbonyl groups and the like can be mentioned.
- the number of substituents is 1 to 4, preferably 1 to 3.
- the “C 1-6 alkyl group”, “C 2-6 alkenyl group” and “C 1-6 alkoxy group” are substituted with 1 to 3 substituents selected from the above-mentioned substituent group A. Also good.
- the “C 3-6 cycloalkyl group”, “C 3-6 cycloalkenyl group”, “C 6-14 aryl group” and “heterocyclic group” are 1 to 3 selected from the substituent group B described above It may be substituted with a substituent.
- R 1 is preferably (a) (1) amino group, (2) (i) hydroxyl group, (ii) C 1-3 alkoxy group, (iii) C 3-6 cycloalkyl group substituted with 1 to 3 hydroxyl groups, (iv) phenyl group, (v) furyl group (Vi) a tetrahydrofuranyl group, (vii) a piperidino group and (viii) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a morpholino group, (3) a C 3-6 cycloalkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group and a hydroxymethyl group, (4) a 4- to 10-membered cyclic amino group (eg, piperidino), (5) a halogen atom, a phenyl group optionally substituted with 1 to 3 substituents selected from a C 1-6 alkyl group optionally substituted with
- R 1 is (a) (1) amino group, (2) C which may be substituted with one or two substituents selected from a hydroxyl group, a C 1-3 alkoxy group, a C 3-6 cycloalkyl group, a phenyl group, a furyl group, a tetrahydrofuranyl group and a morpholino group 1-6 alkyl groups, (3) a C 3-6 cycloalkyl group optionally substituted with a hydroxyl group or a hydroxymethyl group, (4) a 4- to 7-membered cyclic amino group (eg, piperidino), (5) a phenyl group which may be substituted with a substituent selected from a halogen atom, a C 1-6 alkyl group and a hydroxymethyl group, (6) a dihydroindenyl group substituted with a hydroxyl group, (7) pyrazolyl group, (8) a tetrahydrofuranyl group, and (9) an amino group, (2)
- R 2 and R 3 each independently represent a hydrogen atom or a substituent.
- substituent represented by R 2 or R 3 (1) a halogen atom, (2) a cyano group, (3) Nitro group, (4) hydroxyl group, (5) a C 1-6 alkyl group (preferably a C 1-3 alkyl group) optionally substituted with 1 to 3 halogen atoms, (6) a C 1-6 alkoxy group (preferably a C 1-3 alkoxy group) optionally substituted by 1 to 3 halogen atoms, (7) a carboxy group, (8) a C 1-6 alkyl-carbonyl group, (9) a C 1-6 alkoxy-carbonyl group, (10) a carbamoyl group, (11) mono- or di-C 1-6 alkylcarbamoyl group, (12) an amino group, (13) Mono- or di-C 1-6 alkylamino group and the like.
- R 2 and R 3 are preferably the same as a hydrogen atom or a halogen atom, and more preferably the same as a hydrogen atom or a fluorine atom.
- R 2 is a hydrogen atom and R 3 is a halogen atom or a C 1-3 alkoxy group substituted with 1 to 3 halogen atoms is also preferred.
- Ring A represents an optionally substituted 5- to 10-membered ring. Provided that ring A is not an unsubstituted phenyl group; and when R 2 and R 3 are both hydrogen atoms, ring A is an unsubstituted C 3-6 cycloalkyl group, or a halogen atom or methyl group at the 4-position. It is not a phenyl group.
- Examples of the “5- to 10-membered ring” of the “optionally substituted 5- to 10-membered ring” represented by ring A include 5- to 10-membered saturated rings, aromatic rings and condensed rings. The saturated ring, aromatic ring and condensed ring contain 1 to 4 (preferably 1 to 3, more preferably 1 or 2) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Also good.
- Preferred structures for the saturated ring are each optionally substituted azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 1,4-diazepanyl, cycloheptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (excluding unsubstituted cyclohexyl) Yes
- a preferable structure as the aromatic ring is a 6-membered ring, each of which may be substituted, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, phenyl (provided that unsubstituted and 4-substituted halogen atoms are substituted)
- Preferred structures for the fused ring are each optionally substituted naphthyl, quinolyl, isoquinolyl, cinnolinyl, quinolidiny
- the “5- to 10-membered ring” of the “optionally substituted 5- to 10-membered ring” represented by ring A may have, for example, (1) a halogen atom, (2) a cyano group, (3) Nitro group, (4) hydroxyl group, (5) a C 1-6 alkyl group (preferably a C 1-3 alkyl group) optionally substituted with 1 to 3 halogen atoms, (6) a C 1-6 alkoxy group (preferably a C 1-3 alkoxy group) optionally substituted by 1 to 3 halogen atoms, (7) a carboxy group, (8) a C 1-6 alkyl-carbonyl group, (9) a C 1-6 alkoxy-carbonyl group, (10) a carbamoyl group, (11) mono- or di-C 1-6 alkylcarbamoyl group, (12) an amino group, (13) mono- or di-C 1-6 alkylamino group, (14) A heterocyclic group optionally substituted with
- Ring A is preferably (i) a C 1-3 alkyl group substituted with 1 to 3 halogen atoms at the 4-position, (ii) a C 1-3 alkoxy group, (iii) a carbamoyl group, (iv) Substituted with a substituent selected from a pyrazolyl group optionally substituted with 1 to 3 C 1-6 alkyl groups and (v) a pyridyl group substituted with 1 to 3 C 1-6 alkyl groups It is a phenyl group.
- Ring A is more preferably (i) a C 1-3 alkyl group substituted with 1 to 3 halogen atoms at the 4-position, (ii) a C 1-3 alkoxy group, (iii) a carbamoyl group and (iv ) A phenyl group substituted with a substituent selected from a pyrazolyl group.
- Ring A is more preferably a phenyl group substituted at the 4-position with a substituent selected from a C 1-3 alkoxy group, a carbamoyl group and a pyrazolyl group.
- R 1 is (a) (1) amino group, (2) (i) hydroxyl group, (ii) C 1-3 alkoxy group, (iii) C 3-6 cycloalkyl group optionally substituted with hydroxyl group, (iv) phenyl group, (v) furyl group, ( vi) a C 1-6 alkyl group optionally substituted with one or two substituents selected from a tetrahydrofuranyl group, (vii) a piperidino group and (viii) a morpholino group, (3) a C 3-6 cycloalkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group and a hydroxymethyl group, (4) a 4- to 10-membered cyclic amino group (eg, piperidino), (5) a phenyl group which may be substituted with a substituent selected
- R 1 is (a) (1) amino group, (2) C which may be substituted with one or two substituents selected from a hydroxyl group, a C 1-3 alkoxy group, a C 3-6 cycloalkyl group, a phenyl group, a furyl group, a tetrahydrofuranyl group and a morpholino group 1-6 alkyl groups, (3) a C 3-6 cycloalkyl group optionally substituted with a hydroxyl group or a hydroxymethyl group, (4) a 4- to 7-membered cyclic amino group (eg, piperidino), (5) a phenyl group which may be substituted with a substituent selected from a halogen atom, a C 1-6 alkyl group and a hydroxymethyl group, (6) a dihydroindenyl group substituted with a hydroxyl group, (7) pyrazolyl group, (8) a tetrahydr
- examples of such a salt include a salt with an inorganic base, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, basic or acidic Examples include salts with amino acids.
- the salt with an inorganic base 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.
- salt with an organic base examples include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like.
- salt with inorganic acid examples include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- And salts with toluenesulfonic acid.
- salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
- salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
- pharmaceutically acceptable salts include, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, phthalic acid, etc., when the compound has a basic functional group.
- salts with organic acids such as acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
- inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.) And ammonium salts.
- 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.
- Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
- co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
- the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
- Compound (I) includes within its scope solvates (eg, hydrates) and non-solvates.
- Compound (I) may be a compound labeled or substituted with an isotope (eg, 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I, etc.), and isotope
- an isotope eg, 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I, etc.
- the compound labeled or substituted with an element can be used, for example, as a tracer (PET tracer) used in Positron Emission Tomography (PET), and is useful in fields such as medical diagnosis.
- PET tracer used in Positron Emission Tomography (PET)
- isomers such as enantiomers or diastereomers may exist. All such isomers and mixtures thereof are included within the scope of the present invention. In addition, isomers due to conformation or tautomerism may be produced, and such isomers or mixtures thereof are also included in the compound (I) of the present invention.
- R 1 , R 2 , R 3 , X and ring A are as defined above.
- the compound represented by the general formula (I) can be produced, for example, by the method shown below or a method analogous thereto. In the following synthesis method, the starting compound may be used as a salt, and as such a salt, those exemplified as the salt of compound (I) are used.
- Examples of the inert solvent used in the method for producing the compound of the present invention include the following solvents.
- Ether solvents Aromatic hydrocarbon solvents such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane: Aliphatic hydrocarbon solvents such as benzene, toluene, xylene, trifluoromethylbenzene
- Solvent Amide solvents such as cyclohexane and hexane: Halogenated hydrocarbon solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide: Dichloromethane, chloroform, carbon tetrachloride, 1,2- Nitrile solvents such as dichloroethane: Sulfoxide solvents such as acetonitrile and propionitrile Ketone solvents such as dimethyl sulfox
- Examples of the base used in the production method of the compound of the present invention include the following bases.
- Inorganic bases Basic salts such as sodium hydroxide, potassium hydroxide, magnesium hydroxide: Metal alkoxides such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate: Sodium methoxide, sodium ethoxide, potassium tert -Alkali metal hydrides such as butoxide: Metal amides such as sodium hydride and potassium hydride: Aromatic amines such as sodium amide, lithium diisopropylamide and lithium hexamethyldisilazide: Tertiary amines such as pyridine and lutidine: Triethylamine, diisopropylethylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpho
- Compound (I) can be produced by an amidation reaction of compound (II).
- Compounds (II) and (III) are commercially available reagents, methods shown in Reference Examples or methods analogous thereto, or known methods (Journal of Heterocyclic Chemistry, 1998, 35, 955 or Chemical and Pharmaceutical Bulletin, 1988, 36, 1321).
- the above “amidation reaction” includes the following “method using a dehydration condensing agent”, “method using a reactive derivative of carboxylic acid” and the like.
- reaction is performed by reacting compound (II) and compound (III) in an inert solvent in the presence of the dehydrating condensing agent. If necessary, in the presence of a catalytic amount to 5 molar equivalents of 1-hydroxybenzotriazole (HOBt) relative to compound (II) and a catalytic amount to 5 molar equivalents of base relative to compound (II). A reaction may be performed.
- Compound (III) is easily commercially available, and can also be produced according to a method known per se or a method analogous thereto.
- the amount of compound (III) to be used is generally 0.5 to 5 molar equivalents, preferably 0.8 to 1.5 molar equivalents, relative to compound (II).
- the “dehydration condensing agent” include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC ⁇ HCl or WSC), O- (7-azabenzotriazole- 1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU) and the like.
- the amount of the “dehydration condensing agent” to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (II).
- the “inert solvent” include nitrile solvents, amide solvents, halogenated hydrocarbon solvents, ether solvents and the like. These may be used as a mixture of two or more at an appropriate ratio. Of these, amide solvents are preferred.
- Examples of the “base” include “aromatic amines”, “tertiary amines” and the like. Of these, triethylamine and diisopropylethylamine are preferable.
- the reaction temperature is generally ⁇ 70 to 150 ° C., preferably ⁇ 20 to 100 ° C.
- the reaction time is usually 0.1 to 100 hours, preferably 1 to 48 hours.
- Acid acid anhydrides with C 1-6 alkyl carbonate, etc.
- active esters eg, esters with optionally substituted phenol, HOBt, N-hydroxysuccinimide, etc.
- substituents examples include 1 to 5 substituents selected from the aforementioned substituent group B.
- optionally substituted phenol include, for example, phenol, pentachlorophenol, pentafluorophenol, p-nitrophenol and the like.
- the reactive derivative is preferably an acid halide.
- inert solvent examples include ether solvents, halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, aliphatic hydrocarbon solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents.
- a solvent, water, etc. are mentioned. These may be used as a mixture of two or more at an appropriate ratio. Of these, acetonitrile, tetrahydrofuran (THF), dichloromethane, chloroform and the like are preferable.
- base examples include “aromatic amines”, “tertiary amines” and the like. Of these, triethylamine and diisopropylethylamine are preferable.
- the reaction temperature is usually ⁇ 20 ° C. to 100 ° C., preferably ⁇ 20 ° C. to 50 ° C.
- the reaction time is usually 5 minutes to 40 hours, preferably 30 minutes to 18 hours.
- L 1 and L 2 represent a leaving group
- R 6 represents a substituent on ring A
- R 1 , R 2 , R 3 , X and ring A are as defined above.
- the above formula shows a method for producing the target compound (Ib) by introducing the substituent R 6 onto the ring A of the compound (compound (Ia) using (IV).
- the leaving groups L 1 and L 2 include alkali metals (eg, lithium, sodium, etc.), halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C 1-6 alkoxy groups (eg, methoxy group).
- C 6-14 aryloxy group eg, phenoxy group, etc.
- optionally substituted acyloxy group eg, acetyloxy group, benzoyloxy group, etc.
- optionally halogenated C 1-6 Alkylsulfonyloxy group eg, methanesulfonyloxy group, ethanesulfonyloxy group, trichloromethanesulfonyloxy group, trifluoromethanesulfonyloxy (triflate) group, etc.
- optionally substituted C 6-14 arylsulfonyloxy group [example] as, C 1-6 alkyl group (e.g., methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec- butyl group, tert- butyl group, Bae Butyl group, a hexyl group, etc.), C 1-6 al
- an optionally substituted C 1-6 alkylsilyl group eg, trimethylsilyl group
- an optionally substituted C 1-6 alkylstannyl group eg, tributylstannyl group
- Examples thereof include C 2-6 alkenylstannyl group which may be substituted, C 6-14 arylstannyl group which may be substituted, metal-containing substituent such as magnesium halide, zinc halide and the like.
- L 1 and L 2 also contain a substituent that can be converted to a leaving group, and can be converted to the leaving group by a reaction known per se in a desired step.
- a reaction known per se for example, when L 1 and L 2 are methylthio groups, there are cases where they are converted to methanesulfonyl groups by an oxidation reaction.
- the starting compounds (Ia) and (IV) shown in the above reaction can be produced by a commercially available reagent, a method known per se, a method shown in Reference Examples or a method analogous thereto.
- This reaction is carried out in the presence of a base, an additive and a metal catalyst in a solvent that does not adversely influence the reaction, if necessary.
- the amount of compound (IV) to be used is generally about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, relative to compound (Ia).
- bases examples include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undeca Amines such as -7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide.
- the amount of these bases to be used is preferably about 1 to about 5 molar equivalents relative to compound (Ia).
- additives examples include inorganic salts such as sodium iodide and potassium iodide, ammonium salts such as tetrabutylammonium iodide, and molecular sieves such as molecular sieve 3A and molecular sieve 4A.
- the amount of such “additive” to be used is about 0.1 to 500 times, preferably 0.1 to 30 times, by weight with respect to compound (Ia).
- metal catalyst examples include metals such as nickel, palladium, copper, metal salts, and metal complexes composed of these and ligands. Examples of these reagents include tetrakis (triphenylphosphine) palladium.
- a ligand may be added to the reaction system.
- these ligands include phosphine ligands (eg, triphenylphosphine, 2,2′-bis (diphenylphosphino) -1, 1'-binaphthyl, 2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl, 2- (dicyclohexylphosphino) -3,6-dimethoxy-2', 4 ', 6'-Triisopropyl-1,1'-biphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2 ', 4', 6'-triisopropyl-1,1'-biphenyl 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 2-dicyclohex
- the amount of the “metal catalyst” to be used is generally about 0.0001 to 1000% by weight, preferably about 0.01 to 200% by weight, relative to compound (Ia).
- the amount of the “ligand” to be used is generally about 0.0001 to about 1000% by weight, preferably about 0.01 to about 200% by weight, relative to compound (Ia).
- This reaction is advantageously carried out without solvent or using a solvent inert to the reaction.
- a solvent is not particularly limited as long as the reaction proceeds, but for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-2-propanol, 2-methyl-2-butanol and the like.
- the raw material compound when the raw material compound has a hydroxy group, an amino group, a carboxy group or a carbonyl group as a substituent, a protective group generally used in peptide chemistry or the like may be introduced into these groups.
- the target compound can be obtained by removing the protecting group as necessary after the reaction.
- Examples of the protecting group for hydroxy group include C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl group, trityl group, C 7-10 aralkyl group (eg, benzyl).
- Formyl group C 1-6 alkyl-carbonyl group (eg, acetyl, propionyl), benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl Group, silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl group (eg, 1-allyl) and the like.
- C 1-6 alkyl-carbonyl group eg, acetyl, propionyl
- benzoyl group C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl)
- 2-tetrahydropyranyl group 2-tetrahydrofuranyl Group
- silyl group eg
- halogen atoms eg, fluorine, chlorine, bromine, iodine
- C 1-6 alkyl groups eg, methyl, ethyl, propyl
- C 1-6 alkoxy groups eg, methoxy, ethoxy, propoxy
- protecting groups for amino groups include formyl group, C 1-6 alkyl-carbonyl group (eg, acetyl, propionyl), C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl) Benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl group (eg, 1-allyl),
- Examples of the protecting group for the carboxy group include a C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), a C 7-11 aralkyl group (eg, benzyl), a phenyl group, and trityl.
- Groups, silyl groups eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, tert-butyldiphenylsilyl
- C 2-6 alkenyl groups eg, 1-allyl
- halogen atoms eg, fluorine, chlorine, bromine, iodine
- C 1-6 alkoxy groups eg, methoxy, ethoxy, propoxy
- nitro groups etc. May be.
- Examples of the protecting group for the carbonyl group include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di-C 1-6 alkylacetal) and the like.
- the method for removing these protecting groups can be carried out according to a method known per se, for example, the method described in Protective Group in Organic Synthesis, published by John Wiley and Sons (1980). Good. For example, a method using acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide, etc.) A reduction method or the like is used.
- a method using acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide, etc.) A
- compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and are synthesized by a known synthesis method and separation method, respectively. 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.
- optical resolution method a method known per se, for example, fractional recrystallization method, chiral column method, diastereomer method and the like are used.
- 1) Fractional recrystallization method Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, ( ⁇ )-1-phenethylamine, cinchonine, ( ⁇ )-cinchonidine, brucine, etc.
- Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, ( ⁇ )-1-phenethylamine, cinchonine, ( ⁇ )-cinchonidine, brucine, etc.
- Chiral column method A method in which a racemate or a salt thereof is separated by applying to an optical isomer separation column (chiral column).
- an optical isomer separation column chiral column
- a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Corporation), water, various buffers (eg, phosphate buffer),
- Optical isomers are separated by developing an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) as a single or mixed solution.
- an organic solvent eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.
- Diastereomer method A mixture of racemates is made into a mixture of diastereomers by chemical reaction with an optically active reagent, and this is converted into a single substance through ordinary separation means (for example, fractional recrystallization, chromatography method, etc.). Then, the optical isomer is obtained by separating the optically active reagent site by chemical treatment such as hydrolysis reaction.
- the compound (I) when the compound (I) has a hydroxyl group or a primary or secondary amino group in the molecule, the compound and an optically active organic acid (for example, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid], ( ⁇ )-Menthoxyacetic acid and the like) are subjected to a condensation reaction to give ester or amide diastereomers, respectively.
- an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
- compound (I) When compound (I) is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, it is known per se. It can be converted into a free form or other desired salt by the method or a method analogous thereto.
- Compound (I) may be used as a prodrug.
- the prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
- a compound in which the amino group of the compound (I) is acylated, alkylated or phosphorylated eg, the amino group of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, t-butylated compounds, etc.
- Compounds in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated, borated eg, hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated , Alanylated, dimethylaminomethylcarbonylated compounds,
- the compound (I) may be a crystal, and it is included in the compound (I) of the present invention regardless of whether the crystal form is single or a crystal form mixture.
- the crystal can be produced by crystallization by applying a crystallization method known per se.
- Compound (I) is used for mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.)
- Psychiatric disorders eg, depression, major depression, bipolar depression, mood disorders, emotional disorders (seasonal emotional disorders, etc.), recurrent depression, postpartum depression, stress disorder, depressive symptoms, Mania, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, phobia, social phobia, social anxiety disorder, obsessive compulsive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, Tourette syndrome, autism , Fragile X syndrome, Rett syndrome, adaptation disorder, bipolar disorder, neurosis, schizophrenia (eg, positive symptoms, negative symptoms, cognitive symptoms), chronic fatigue syndrome, anxiety, obsessive-compulsive disorder, epilepsy, anxiety symptoms , Unpleasant mental state, emotional abnormalities, emotional temperament, nervousness, fainting, sputum, decreased libido, attention deficit hyperactivity disorder (
- compound (I) Since compound (I) has excellent cholinergic muscarinic M1 receptor positive allosteric modulator activity, it can be expected to have excellent preventive and therapeutic effects on the above diseases.
- “Positive allosteric modulator” means an endogenous activator that binds to a site different from that of the endogenous activator (acetylcholine in the receptor) and increases the affinity of the endogenous activator.
- the compound which has the effect action which enhances the receptor activation function which has.
- a “cholinergic muscarinic M1 receptor positive allosteric modulator” is a class of receptors for the excitatory endogenous neurotransmitter acetylcholine, named after muscarin selectively activates the receptor. Enhances the receptor activating function of acetylcholine through actions such as binding to a site different from acetylcholine and increasing the affinity of acetylcholine for M1 receptor, one of the muscarinic receptor subtypes It refers to a compound having the action of
- Cholinergic muscarinic M1 receptor positive allosteric modulation (cholinergic muscarinic M1 receptor positive allosteric modulation) is an excitability named based on the selective activation of the receptor by muscarinic. Affinity of acetylcholine by binding a positive allosteric modulator to a site different from acetylcholine for M1 receptor, one of the subtypes of muscarinic receptor, one of the receptors for acetylcholine It refers to the action of enhancing the receptor activation function of acetylcholine through effects such as enhancing sex.
- the “cholinergic muscarinic M1 receptor positive allosteric modulation method” refers to the receptor for the excitatory endogenous neurotransmitter acetylcholine, named after muscarin selectively activates the receptor.
- a positive allosteric modulator By binding a positive allosteric modulator to a site different from acetylcholine to M1 receptor, which is one of the subtypes of muscarinic receptors, acetylcholine This is a method for enhancing the receptor activation function of.
- Compound (I) has excellent pharmacokinetics (eg, blood drug half-life, intracerebral transferability, metabolic stability) and low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug Mammals (eg, mice, rats, hamsters, rabbits, cats, dogs) because they have excellent properties as pharmaceuticals such as better interaction and carcinogenicity, and less side effects. , Cattle, sheep, monkeys, humans, etc.) and can be safely administered orally or parenterally.
- pharmacokinetics eg, blood drug half-life, intracerebral transferability, metabolic stability
- low toxicity eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity
- drug Mammals eg, mice, rats, hamsters, rabbits, cats, dogs
- Cattle, sheep, monkeys, humans, etc. can be safely administered orally or parenterally.
- Parenter includes intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, intracerebral, intrarectal, intravaginal, intraperitoneal, intratumoral, proximal to tumor, etc. Includes direct lesion administration.
- the preparation containing Compound (I) may be any of solid preparations such as powders, granules, tablets, capsules, orally disintegrating films, and liquid preparations such as syrups, emulsions and injections.
- the medicament of the present invention can be produced by a conventional method such as mixing, kneading, granulation, tableting, coating, sterilization, emulsification, etc., depending on the form of the preparation. Regarding the production of the preparation, for example, each item of the Japanese Pharmacopoeia General Rules for Preparations can be referred to.
- the medicament of the present invention may be formed into a sustained release agent containing an active ingredient and a biodegradable polymer compound.
- the sustained-release agent can be prepared according to the method described in JP-A-9-263545.
- the content of the compound (I) varies depending on the form of the preparation, but is usually 0.01 to 100% by weight, preferably 0.1 to 50% as the amount of the compound (I) relative to the whole preparation. % By weight, more preferably about 0.5 to 20% by weight.
- an appropriate pharmacologically acceptable carrier for example, an excipient (for example, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), a binder ( For example, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone, etc.), lubricant (eg, stearic acid, magnesium stearate, calcium stearate, talc, etc.), disintegrant (eg, , Carboxymethylcellulose calcium, talc, etc.), diluents (eg, water for injection, physiological saline, etc.), additives (eg, stabilizers, preservatives, colorants, fragrances, solubilizers, emulsifiers, buffers) as necessary Agents, tonicity agents, etc.) Combined
- Compound (I) can also be administered directly to the affected area of a joint disease when it is formed into a topical preparation and administered.
- an injection is preferable.
- a parenteral agent for local administration eg, injection into intramuscular, subcutaneous, organ, joint sites, solid preparations such as implants, granules, powders, liquids such as suspensions, ointments, etc.
- It can also be administered.
- compound (I) is used as a dispersant (eg, surfactants such as Tween 80, HCO-60, polysaccharides such as carboxymethylcellulose, sodium alginate, hyaluronic acid, polysorbate, etc.), preservatives. (Eg, methylparaben, propylparaben, etc.), isotonic agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.), buffers (eg, calcium carbonate, etc.), pH adjusters (eg, sodium phosphate, phosphate)
- a dispersant eg, surfactants such as Tween 80, HCO-60, polysaccharides such as carboxymethylcellulose, sodium alginate, hyaluronic acid, polysorbate, etc.
- preservatives eg, methylparaben, propylparaben, etc.
- isotonic agents eg, sodium chloride, mannitol, sorbitol,
- Injectables that can be used as oily suspensions by dispersing with vegetable oils such as sesame oil and corn oil or phospholipids such as lecithin mixed with them, or medium chain fatty acid triglycerides (eg, miglycol 812). To do.
- vegetable oils such as sesame oil and corn oil or phospholipids such as lecithin mixed with them, or medium chain fatty acid triglycerides (eg, miglycol 812).
- the dose of compound (I) varies depending on the administration subject, administration route, and symptoms, and is not particularly limited.
- (I) when administered orally to an adult patient with schizophrenia (adult, body weight 40 to 80 kg, eg 60 kg) (I) is, for example, 0.001 to 1000 mg / kg body weight per day, preferably 0.01 to 100 mg / kg body weight per day, more preferably 0.1 to 10 mg / kg body weight per day. This amount can be administered once to three times daily.
- the medicament containing the compound of the present invention can be prepared by singly using the compound of the present invention alone or pharmaceutically with the compound of the present invention according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia). It can be used as a pharmaceutical composition mixed with an acceptable carrier.
- a method for producing a pharmaceutical preparation eg, a method described in the Japanese Pharmacopoeia
- It can be used as a pharmaceutical composition mixed with an acceptable carrier.
- examples of the medicament containing the compound of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules).
- controlled release formulations eg, immediate release formulations, sustained release formulations, sustained
- various organic or inorganic carriers commonly used as a starting material are used.
- excipients, lubricants, binders and disintegrants are used, and in liquid preparations, solvents, solubilizers, suspending agents, isotonic agents, buffering agents, and the like Soothing agents and the like are used.
- preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
- excipients examples include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid.
- lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
- binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like.
- disintegrant examples include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
- solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
- solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
- suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like.
- surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
- polyvinyl alcohol polyvinylpyrrolidone
- hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose
- isotonic agent examples include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
- buffer solutions such as phosphate, acetate, carbonate, citrate, and the like.
- Examples of soothing agents include benzyl alcohol.
- preservative examples include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid and the like.
- antioxidant examples include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
- the pharmaceutical composition varies depending on the dosage form, administration method, carrier, etc., but the compound of the present invention is usually 0.01 to 100% (w / w), preferably 0.1 to 95% (w / W), it can be produced according to a conventional method.
- the compound of the present invention may be used in combination with other active ingredients (hereinafter abbreviated as concomitant drugs).
- concomitant drug examples include the following. Benzodiazepines (chlordiazepoxide, diazepam, potassium chlorazebuate, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel inhibitors (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, Clomipramine hydrochloride, etc.), selective serotonin reuptake inhibitors (fluvoxamine maleate, floxetine hydrochloride, citalopram hydrochloride, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-noradrenaline reuptake inhibitors (venlafaxine hydrochloride, hydrochloric acid) Duloxetine, desvenlafaxine hydrochloride, etc.
- Dyslipidemia drugs (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthesis inhibitors), abnormal behavioral drugs, or drugs to prevent wandering due to dementia (sedatives, Anti-anxiety drugs, etc.), apoptosis inhibitors, anti-obesity drugs, anti-diabetes drugs, anti-hypertensive drugs, hypotension drugs, rheumatic drugs (DMARD), anti-cancer drugs, hypoparathyroidism drugs (PTH), calcium receptors Antagonists, sex hormones or their derivatives (progesterone Estradiol, estradiol benzoate, etc.), nerve differentiation-promoting drugs, nerve regeneration-promoting drugs, non-steroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.
- the dosage can be reduced.
- the drug used in combination with the compound of the present invention can be selected according to the patient's symptoms (mild, severe, etc.), (3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be set longer. (4) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the therapeutic effect can be sustained. (5) By using the compound of the present invention in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.
- the concomitant drug of the present invention is referred to as “the concomitant drug of the present invention”.
- the timing of administration of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention or the pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are administered to the subject of administration. They may be administered at the same time or may be administered with a time difference.
- the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
- the administration mode of the concomitant drug of the present invention is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
- Examples of such dosage forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) separate preparation of the compound of the present invention and the concomitant drug.
- different time intervals in different administration routes for example, the compound of the present invention; administration in the order of the concomitant drugs, or administration in the reverse order
- the concomitant drug of the present invention has low toxicity.
- the compound of the present invention or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a known method, for example, a pharmaceutical composition such as a tablet (sugar-coated tablet). , Including film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, etc., orally or parenterally (eg, topical, rectal, intravenous administration) Etc.) can be safely administered.
- An injection can be administered intravenously, intramuscularly, subcutaneously, or into an organ, or directly to a lesion.
- Examples of the pharmacologically acceptable carrier that may be used for producing the concomitant drug of the present invention include various organic or inorganic carrier substances commonly used as a preparation material.
- excipients lubricants, binders and disintegrants can be used.
- solvents, solubilizers, suspending agents, tonicity agents, buffers, soothing agents, and the like can be used.
- additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
- excipients examples include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid.
- lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
- binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like.
- disintegrant examples include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
- solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
- solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
- suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like.
- surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
- polyvinyl alcohol polyvinylpyrrolidone
- hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose
- isotonic agent examples include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
- buffer solutions such as phosphate, acetate, carbonate, citrate, and the like.
- Examples of soothing agents include benzyl alcohol.
- preservative examples include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid and the like.
- antioxidant examples include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
- the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
- the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is about 0.5 to 20% by weight.
- the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably based on the whole preparation. About 0.5 to 20% by weight.
- the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. .
- the same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
- the reaction mixture was diluted with water and ethyl acetate, the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate) to give the title compound (0.048 g).
- reaction solution was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was solidified with diisopropyl ether-ethyl acetate to give the title compound (0.09 g) as a white solid.
- reaction solution was diluted with ethyl acetate, and the insoluble material was removed by filtration.
- the filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated.
- the residue was purified by silica gel chromatography (hexane-ethyl acetate-methanol) to give the title compound (0.035 g) as a pale yellow solid.
- Formulation Example 1 (1) 10.0 g of the compound obtained in Example 1 (2) Lactose 60.0g (3) Cornstarch 35.0g (4) Gelatin 3.0g (5) Magnesium stearate 2.0g After a mixture of 10.0 g of the compound obtained in Example 1, 60.0 g of lactose and 35.0 g of corn starch was granulated through a 1 mm mesh sieve using 30 mL of 10 wt% aqueous gelatin solution (3.0 g as gelatin). , Dried at 40 ° C. and sieved again. The obtained granules are mixed with 2.0 g of magnesium stearate and compressed. The obtained core tablet is coated with a sugar coating with an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are polished with beeswax to obtain 1000 coated tablets.
- Formulation Example 2 (1) 10.0 g of the compound obtained in Example 1 (2) Lactose 70.0g (3) Cornstarch 50.0g (4) 7.0g soluble starch (5) Magnesium stearate 3.0 g After 10.0 g of the compound obtained in Example 1 and 3.0 g of magnesium stearate are granulated with 70 mL of an aqueous solution of soluble starch (7.0 g as soluble starch), it is dried, 70.0 g of lactose and 50.0 g of corn starch Mix with. Compress the mixture to obtain 1000 tablets.
- Test example 1 Measurement of cholinergic muscarinic M1 receptor positive allosteric modulator (M1PAM) activity
- M1PAM activity The activity of a test compound in the presence of acetylcholine at an EC20 concentration (final concentration of 0.6 nM) giving 20% of the maximum activity was measured as M1PAM activity.
- the method is as follows. CHO-K1 cells in which human M1 receptor (hCHRM1) was forcibly expressed were seeded at 5,000 cells / well on a 384-well black transparent bottom plate (BD Falcon), and cultured for one day at 37 ° C in a 5% CO 2 incubator .
- hCHRM1 human M1 receptor
- assay buffer A containing calcium indicator (Recording medium (Dojindo), 0.1% bovine serum albumin (BSA) (Wako Pure Chemical Industries), 2.5 ⁇ g / mL Fluo-4 AM (Dojindo)) 0.08% Pluronic F127 (Dojindo), 1.25 mM probenecid (Dojindo)) was added at 30 ⁇ L / well. The mixture was allowed to stand in a 37 ° C., 5% CO 2 incubator for 30 minutes, and then allowed to stand at room temperature for another 30 minutes.
- calcium indicator Recording medium (Dojindo), 0.1% bovine serum albumin (BSA) (Wako Pure Chemical Industries)
- BSA bovine serum albumin
- Pluronic F127 Dojindo
- 1.25 mM probenecid Dojindo
- test compound diluted with assay buffer B (HBSS (Invitrogen), 20 mM HEPES (Invitrogen), 0.1% BSA) containing nM acetylcholine, and then fluoresced with FLIPRtetra (molecular device) Values were measured for 1 minute every second.
- the amount of change in fluorescence when acetylcholine with a final concentration of 1 ⁇ M was added was defined as 100%, and the amount of change in fluorescence when DMSO was added instead of the test compound was defined as 0%. ),
- the inflection point of the concentration dependence curve of the test compound was calculated as an IP value. The results are shown in Table 2.
- Test example 2 Central migration (Kp value) measurement test A. About the compounds of Examples 6 and 10 (intravenous administration: iv) A-1.
- Example 6 Animal: Jcl ICR mouse male 7 weeks old n 3 Feeding: Non-fasting administration conditions: Intravenous administration 0.20 mg / 1 mL / kg (4 compounds / cassette administration) Administration medium: N, N-dimethylacetamide (DMA) / 1,3-Butanediol (1: 1) Collected samples: plasma, brain (prepared with 4 volumes of physiological saline to prepare homogenate) Plasma collection time: 0.25 hours Brain collection time: 0.25 hours A-2.
- Example 10 Animal: Jcl ICR mouse male 8 weeks old n 3 Feeding: Non-fasting administration conditions: Intravenous administration 0.20 mg / 1 mL / kg (4 compounds / cassette administration) Administration medium: DMA / 1,3-Butanediol (1: 1) Collected samples: plasma, brain (prepared with 4 volumes of physiological sa
- DMSO standard solution dissolving solvent
- the compound of the present invention is useful as a pharmaceutical agent such as a cholinergic muscarinic M1 receptor function-enhancing drug, Alzheimer's disease, schizophrenia, pain (pain), sleep disorder and the like.
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Abstract
Description
アセチルコリンは、副交感神経や運動神経で刺激を伝達する神経伝達物質である。アセチルコリン受容体はリガンド依存性イオンチャンネル(コリン作動性ニコチン受容体)とGタンパク質共役型受容体(コリン作動性ムスカリン受容体)に分類される。コリン作動性ムスカリン受容体は、興奮性の神経伝達物質アセチルコリンに対する受容体の1種であり、ムスカリンが当該受容体を選択的に活性化することに基づいて命名された。ムスカリン受容体はさらに細かくM1ないしM5のサブタイプで分類され、M1受容体は脳に広く分布し、特に学習、記憶、睡眠、神経因性の痛みなどに深くかかわっていることが知られている。脳生理学におけるコリン作動性ムスカリンM1受容体の重要性は周知であり、M1受容体機能増強作用を有する化合物は、精神疾患、神経変性疾患、記憶障害、痛み及び睡眠障害等の予防又は治療薬として有用であると期待されている(非特許文献1)
[1] 式(I)
R1は置換されていてもよいアミノ基、または置換されていてもよい環状アミノ基、
R2およびR3はそれぞれ独立して水素原子、または置換基、
Xは-CH=、または-N=、
環Aは置換されていてもよい5ないし10員環を表す。]
で表される化合物、またはその塩
(ただし、
(1)R1はメトキシ(メチル)アミノ基ではない;
(2)R1は置換されていてもよい飽和アザビシクロ環基およびテトラゾリル基から選ばれる置換基で置換されたアミノ基ではない;
(3)R1は式
Rbは水素原子またはフェニル低級アルキル基である)
で表される基ではない;
(4)R1は式
Rcは水素原子または低級アルキル基であり、
Rgは水素原子または低級アルキル基であり、
nは2または3であり、
RhおよびRiはフェニル基であり、
Rf、RhおよびRiの定義におけるフェニル基またはフェニル部分は1ないし3個のハロゲン原子、低級アルキル基、トリフルオロメチル基、低級アルコキシ基または水酸基で置換されていてもよい)
で表される基ではない;
(5)環Aが無置換のフェニル基ではない;且つ
(6)R2およびR3がともに水素原子のとき、環Aが無置換のC3-6シクロアルキル基、または4位にハロゲン原子またはメチル基を有するフェニル基ではない。)(本明細書中、「化合物(I)」と略記する場合がある)。
R1は置換されていてもよいアミノ基、または置換されていてもよい環状アミノ基、
R2およびR3はそれぞれ独立して水素原子、または置換基、
Xは-CH=、または-N=、
環Aは置換されていてもよい5ないし10員環を表す。]
で表される化合物、またはその塩
(ただし、
(1)R1はメトキシ(メチル)アミノ基ではない;
(2)R1は置換されていてもよい飽和アザビシクロ環基およびテトラゾリル基から選ばれる置換基で置換されたアミノ基ではない;
(3)R1は式
Rbは水素原子またはフェニル低級アルキル基である)
で表される基ではない;
(4)R1は式
RC は水素原子または低級アルキル基であり、
Rgは水素原子または低級アルキル基であり、
nは2または3であり、
RhおよびRiはフェニル基であり、
Rf、RhおよびRiの定義におけるフェニル基またはフェニル部分は1ないし3個のハロゲン原子、低級アルキル基、トリフルオロメチル基、低級アルコキシ基または水酸基で置換されていてもよい)
で表される基ではない;
(5)環Aが無置換のフェニル基ではない;
(6)R2およびR3がともに水素原子のとき、環Aが無置換のC3-6シクロアルキル基、または4位にハロゲン原子またはメチル基を有するフェニル基ではない;
(7)R2がアミノ基ではない;且つ、
(8)以下の化合物を除く
(i) N-シクロヘキシル-1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-4-オキソ-3-キノリンカルボキサミド、および
(ii) 1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-N-(2-メチルフェニル)-4-オキソ-3-キノリンカルボキサミド。)。
(a)(1)アミノ基、
(2)(i)水酸基、(ii)C1-3アルコキシ基、(iii)1ないし3個の水酸基で置換されたC3-6シクロアルキル基、(iv)フェニル基、(v)フリル基、(vi)テトラヒドロフラニル基、(vii)ピペリジノ基および(viii)モルホリノ基から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基、
(3)ハロゲン原子、水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよいC3-6シクロアルキル基、
(4)4ないし10員環状アミノ基、
(5)ハロゲン原子、1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよいフェニル基、
(6)1ないし3個の水酸基で置換されたジヒドロインデニル基、
(7)ピラゾリル基、
(8)テトラヒドロフラニル基、および
(9)1ないし3個の水酸基で置換されたテトラヒドロピラニル基
から選ばれる1または2個の置換基で置換されていてもよいアミノ基、または
(b)水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよい4ないし10員環状アミノ基であり、
R2およびR3は同一で水素原子、またはハロゲン原子であるか、あるいは
R2は水素原子であり、R3はハロゲン原子、または1ないし3個のハロゲン原子で置換されたC1-3アルコキシ基であり、
Xは-CH=、または-N=であり、
環Aは
4位が(i)1ないし3個のハロゲン原子で置換されたC1-3アルキル基、(ii)C1-3アルコキシ基、(iii)カルバモイル基、(iv)1ないし3個のC1-3アルキル基で置換されていてもよいピラゾリル基および(v)1ないし3個のC1-3アルキル基で置換されたピリジル基から選ばれる置換基で置換されたフェニル基である、
[1]または[2]記載の化合物、またはその塩。
(ただし、以下の化合物を除く
(i) N-シクロヘキシル-1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-4-オキソ-3-キノリンカルボキサミド、および
(ii) 1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-N-(2-メチルフェニル)-4-オキソ-3-キノリンカルボキサミド)。
(ただし、以下の化合物を除く
(i) N-シクロヘキシル-1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-4-オキソ-3-キノリンカルボキサミド、および
(ii) 1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-N-(2-メチルフェニル)-4-オキソ-3-キノリンカルボキサミド)。
(a)(1)アミノ基、
(2)(i)水酸基、(ii)C1-3アルコキシ基、(iii)1ないし3個の水酸基で置換されたC3-6シクロアルキル基、(iv)フェニル基、(v)フリル基、(vi)テトラヒドロフラニル基、(vii)ピペリジノ基および(viii)モルホリノ基から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基、
(3)ハロゲン原子、水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよいC3-6シクロアルキル基、
(4)ピペリジノ基、
(5)ハロゲン原子、1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよいフェニル基、
(6)1ないし3個の水酸基で置換されたジヒドロインデニル基、
(7)ピラゾリル基、
(8)テトラヒドロフラニル基、および
(9)1ないし3個の水酸基で置換されたテトラヒドロピラニル基
から選ばれる1または2個の置換基で置換されていてもよいアミノ基、または
(b)(1)1ないし3個の水酸基で置換されたアゼチジン-1-イル基、
(2)1ないし3個のヒドロキシメチル基で置換されたピロリジン-1-イル基、
(3)1ないし3個の水酸基で置換されていてもよいピペリジノ基、または
(4)1,3-ジヒドロ-2H-イソインドール-2-イル基であり、
R2およびR3は同一で水素原子、またはハロゲン原子であるか、あるいは
R2は水素原子であり、R3はハロゲン原子、または1ないし3個のハロゲン原子で置換されたC1-3アルコキシ基であり、
Xは-CH=、または-N=であり、
環Aは
4位が(i)1ないし3個のハロゲン原子で置換されたC1-3アルキル基、(ii)C1-3アルコキシ基、(iii)カルバモイル基、(iv)1ないし3個のC1-3アルキル基で置換されていてもよいピラゾリル基および(v)1ないし3個のC1-3アルキル基で置換されたピリジル基から選ばれる置換基で置換されたフェニル基である、
[1]または[2]記載の化合物、またはその塩。
(ただし、以下の化合物を除く
(i) N-シクロヘキシル-1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-4-オキソ-3-キノリンカルボキサミド、および
(ii) 1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-N-(2-メチルフェニル)-4-オキソ-3-キノリンカルボキサミド)。
(a)(1)アミノ基、
(2)(i)水酸基、(ii)C1-3アルコキシ基、(iii)1ないし3個の水酸基で置換されたC3-6シクロアルキル基、(iv)フェニル基、(v)フリル基、(vi)ピペリジノ基および(vii)モルホリノ基から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基、
(3)ハロゲン原子、水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよいC3-6シクロアルキル基、
(4)4ないし10員環状アミノ基、
(5)ハロゲン原子、1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよいフェニル基、
(6)1ないし3個の水酸基で置換されたジヒドロインデニル基、
(7)テトラヒドロフラニル基、および
(8)1ないし3個の水酸基で置換されたテトラヒドロピラニル基
から選ばれる1または2個の置換基で置換されていてもよいアミノ基、または
(b)水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよい4ないし10員環状アミノ基であり、
R2およびR3は同一で水素原子、またはハロゲン原子であるか、あるいは
R2は水素原子であり、R3はハロゲン原子、または1ないし3個のハロゲン原子で置換されたC1-3アルコキシ基であり、
Xは-CH=であり、
環Aは
4位が(i)1ないし3個のハロゲン原子で置換されたC1-3アルキル基、(ii)C1-3アルコキシ基、(iii)カルバモイル基、(iv)1ないし3個のC1-3アルキル基で置換されていてもよいピラゾリル基および(v)1ないし3個のC1-3アルキル基で置換されたピリジル基から選ばれる置換基で置換されたフェニル基である、
[1]または[2]記載の化合物、またはその塩。
(ただし、以下の化合物を除く
(i) N-シクロヘキシル-1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-4-オキソ-3-キノリンカルボキサミド、および
(ii) 1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-N-(2-メチルフェニル)-4-オキソ-3-キノリンカルボキサミド)。
(ただし、以下の化合物を除く
(i) N-シクロヘキシル-1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-4-オキソ-3-キノリンカルボキサミド、および
(ii) 1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-N-(2-メチルフェニル)-4-オキソ-3-キノリンカルボキサミド)。
(a)(4)4ないし10員環状アミノ基が、ピペリジノ基であり、
(b)水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよい4ないし10員環状アミノ基が、
(1)1ないし3個の水酸基で置換されたアゼチジン-1-イル基、
(2)1ないし3個のヒドロキシメチル基で置換されたピロリジン-1-イル基、
(3)1ないし3個の水酸基で置換されていてもよいピペリジノ基、または
(4)1,3-ジヒドロ-2H-イソインドール-2-イル基である、
[3F]記載の化合物、またはその塩。
(ただし、以下の化合物を除く
(i) N-シクロヘキシル-1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-4-オキソ-3-キノリンカルボキサミド、および
(ii) 1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-N-(2-メチルフェニル)-4-オキソ-3-キノリンカルボキサミド)。
(a)(1)アミノ基、
(2)(i)水酸基、(ii)C1-3アルコキシ基、(iii)1ないし3個の水酸基で置換されたC3-6シクロアルキル基、(iv)フェニル基および(v)テトラヒドロフラニル基から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基、
(3)水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよいC3-6シクロアルキル基、
(4)4ないし10員環状アミノ基、
(5)C1-6アルキル基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよいフェニル基、
(6)1ないし3個の水酸基で置換されたジヒドロインデニル基、
(7)ピラゾリル基、および
(8)1ないし3個の水酸基で置換されたテトラヒドロピラニル基
から選ばれる1または2個の置換基で置換されていてもよいアミノ基、または
(b)水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよい4ないし10員環状アミノ基であり、
R2およびR3は同一で水素原子であり、
Xは-N=であり、
環Aは
4位が(i)C1-3アルコキシ基および(ii)カルバモイル基から選ばれる置換基で置換されたフェニル基である、
[1]または[2]記載の化合物、またはその塩。
(a)(4)4ないし7員環状アミノ基が、ピペリジノ基であり、
(b)水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよい4ないし7員環状アミノ基が、
(1)1ないし3個の水酸基で置換されたアゼチジン-1-イル基、
(2)1ないし3個のヒドロキシメチル基で置換されたピロリジン-1-イル基、または
(3)ピペリジノ基である、
[3M]記載の化合物、またはその塩。
(1)アミノ基、
(2)(i)水酸基、(ii)C1-3アルコキシ基および(iii)1ないし3個の水酸基で置換されたC3-6シクロアルキル基から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基、
(3)ハロゲン原子、水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよいC3-6シクロアルキル基、
(4)ピペリジノ基、
(5)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基から選ばれる1ないし3個の置換基で置換されていてもよいフェニル基、および
(6)1ないし3個の水酸基で置換されたテトラヒドロピラニル基
から選ばれる1個の置換基で置換されていてもよいアミノ基であり、
R2およびR3は同一で水素原子、またはハロゲン原子であるか、あるいは
R2は水素原子であり、R3はハロゲン原子であり、
Xは-CH=、または-N=であり、
環Aは
4位が(i)1ないし3個のハロゲン原子で置換されたC1-3アルキル基、(ii)C1-3アルコキシ基、(iii)カルバモイル基、(iv)1ないし3個のC1-3アルキル基で置換されていてもよいピラゾリル基および(v)1ないし3個のC1-3アルキル基で置換されたピリジル基から選ばれる置換基で置換されたフェニル基である、
[1]または[2]記載の化合物、またはその塩。
(ただし、以下の化合物を除く
(i) N-シクロヘキシル-1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-4-オキソ-3-キノリンカルボキサミド、および
(ii) 1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-N-(2-メチルフェニル)-4-オキソ-3-キノリンカルボキサミド)。
(1)アミノ基、
(2)ハロゲン原子および水酸基から選ばれる1ないし3個の置換基で置換されたC3-6シクロアルキル基、および
(3)1ないし3個の水酸基で置換されたテトラヒドロピラニル基
から選ばれる1個の置換基で置換されたアミノ基であり、
R2およびR3は同一で水素原子、またはハロゲン原子であるか、あるいは
R2は水素原子であり、R3はハロゲン原子であり、
Xは-CH=、または-N=であり、
環Aは
4位が(i)C1-3アルコキシ基、(ii)カルバモイル基、(iii)1ないし3個のC1-3アルキル基で置換されていてもよいピラゾリル基および(vi)1ないし3個のC1-3アルキル基で置換されたピリジル基から選ばれる置換基で置換されたフェニル基である、
[1]または[2]記載の化合物、またはその塩。
1ないし3個の水酸基で置換されたC3-6シクロアルキル基、および1ないし3個の水酸基で置換されたテトラヒドロピラニル基から選ばれる1個の置換基で置換されたアミノ基であり、
R2およびR3は同一で水素原子、またはハロゲン原子であるか、あるいは
R2は水素原子であり、R3はハロゲン原子であり、
Xは-CH=、または-N=であり、
環Aは
4位が(i)C1-3アルコキシ基、(ii)カルバモイル基および(ii)1ないし3個のC1-3アルキル基で置換されていてもよいピラゾリル基から選ばれる置換基で置換されたフェニル基である、
[1]または[2]記載の化合物、またはその塩。
1ないし3個の水酸基で置換されたC3-6シクロアルキル基、および1ないし3個の水酸基で置換されたテトラヒドロピラニル基から選ばれる1個の置換基で置換されたアミノ基であり、
R2およびR3は同一で水素原子、またはハロゲン原子であるか、あるいは
R2は水素原子であり、R3はハロゲン原子であり、
Xは-CH=であり、
環Aは
4位が(i)C1-3アルコキシ基および(ii)1ないし3個のC1-3アルキル基で置換されていてもよいピラゾリル基から選ばれる置換基で置換されたフェニル基である、
[1]または[2]記載の化合物、またはその塩。
N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-4-オキソ-1-[4-(1H-ピラゾール-1-イル)ベンジル]-1,4-ジヒドロシンノリン-3-カルボキサミド、
1-(4-カルバモイルベンジル)-N-((1S,2S)-2-ヒドロキシシクロヘキシル)-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド、
1,5-アンヒドロ-2,3-ジデオキシ-3-({[5,8-ジフルオロ-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-イル]カルボニル}アミノ)-DL-threo-ペンチトール、
5,8-ジフルオロ-N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド、
5,8-ジフルオロ-N-[(1S,2S)-2-ヒドロキシシクロヘキシル]-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド、
1,5-アンヒドロ-2,3-ジデオキシ-3-({[1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロシンノリン-3-イル]カルボニル}アミノ)-DL-threo-ペンチトール、
1-(4-カルバモイルベンジル)-N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド、
1-(4-カルバモイルベンジル)-N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-4-オキソ-1,4-ジヒドロシンノリン-3-カルボキサミド、
1-(4-カルバモイルベンジル)-N-[(1S,2S)-2-ヒドロキシシクロヘキシル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド、
8-フルオロ-N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-4-オキソ-1-[4-(1H-ピラゾール-1-イル)ベンジル]-1,4-ジヒドロキノリン-3-カルボキサミド、
N-[(1,2-trans)-5,5-ジフルオロ-2-ヒドロキシシクロヘキシル]-5,8-ジフルオロ-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド、
N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-4-オキソ-1-[4-(1H-ピラゾール-5-イル)ベンジル]-1,4-ジヒドロキノリン-3-カルボキサミド、
1-(4-カルバモイルベンジル)-N-[(1,2-trans)-2-フルオロシクロヘキシル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド、
8-フルオロ-N-[(1,2-trans)-2-ヒドロキシシクロペンチル]-4-オキソ-1-[4-(1H-ピラゾール-1-イル)ベンジル]-1,4-ジヒドロキノリン-3-カルボキサミド、
N-[(1,2-trans)-2-ヒドロキシシクロペンチル]-1-[4-(2-メチルピリジン-4-イル)ベンジル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド、および
1-[4-(1,3-ジメチル-1H-ピラゾール-4-イル)ベンジル]-N-[(1,2-trans)-2-ヒドロキシシクロペンチル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド
から選ばれる化合物、またはその塩。
1,5-アンヒドロ-2,3-ジデオキシ-3-({[5,8-ジフルオロ-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-イル]カルボニル}アミノ)-DL-threo-ペンチトール、
5,8-ジフルオロ-N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド、
1-(4-カルバモイルベンジル)-N-[(1S,2S)-2-ヒドロキシシクロヘキシル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド、
8-フルオロ-N-[(1,2-trans)-2-ヒドロキシシクロペンチル]-4-オキソ-1-[4-(1H-ピラゾール-1-イル)ベンジル]-1,4-ジヒドロキノリン-3-カルボキサミド、および
1-[4-(1,3-ジメチル-1H-ピラゾール-4-イル)ベンジル]-N-[(1,2-trans)-2-ヒドロキシシクロペンチル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド
から選ばれる化合物、またはその塩。
5,8-ジフルオロ-N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド、
8-フルオロ-N-[(1,2-trans)-2-ヒドロキシシクロペンチル]-4-オキソ-1-[4-(1H-ピラゾール-1-イル)ベンジル]-1,4-ジヒドロキノリン-3-カルボキサミド、および
1-[4-(1,3-ジメチル-1H-ピラゾール-4-イル)ベンジル]-N-[(1,2-trans)-2-ヒドロキシシクロペンチル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド
から選ばれる化合物、またはその塩。
以下に本発明について詳細に説明する。
「芳香族炭化水素基」としては、C6-14芳香族炭化水素基、例えば、フェニル、ナフチル(例、1-ナフチル、2-ナフチル)、アントリル、フェナントリル等が挙げられる。
「芳香族複素環基」としては、窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を1ないし4個(好ましくは1ないし3個、より好ましくは1または2個)含有する5ないし14員(好ましくは5ないし10員)の芳香族複素環基、例えば、
チエニル、フリル、ピロリル、イミダゾリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル、1,2,4-オキサジアゾリル、1,3,4-オキサジアゾリル、1,2,4-チアジアゾリル、1,3,4-チアジアゾリル、トリアゾリル、テトラゾリル、フラザニル、ピラニルなどの単環式芳香族複素環基;
ベンゾチエニル、ベンゾフラニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、フェノキサチイニル、インドリル、イソインドリル、1H-インダゾリル、プリニル、4H-キノリジニル、イソキノリル、キノリル、フタラジニル、ナフチリジニル、キノキサリニル、キナゾリニル、シンノリニル、カルバゾリル、β-カルボリニル、フェナントリジニル、アクリジニル、フェナジニル、フェノチアジニル、フェノキサジニルなどの縮合多環式(好ましくは2または3環式)芳香族複素環基等が挙げられる。
「芳香族基」としては、好ましくは、フェニル基、ピリジル基(例、2-ピリジル、3-ピリジル、4-ピリジル)が挙げられる。
チエニル、フリル、ピロリル、イミダゾリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル、1,2,4-オキサジアゾリル、1,3,4-オキサジアゾリル、1,2,4-チアジアゾリル、1,3,4-チアジアゾリル、トリアゾリル、テトラゾリル、フラザニル、ピラニルなどの単環式芳香族複素環基;
ベンゾチエニル、ベンゾフラニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、フェノキサチイニル、インドリル、イソインドリル、1H-インダゾリル、プリニル、4H-キノリジニル、イソキノリル、キノリル、フタラジニル、ナフチリジニル、キノキサリニル、キナゾリニル、シンノリニル、カルバゾリル、β-カルボリニル、フェナントリジニル、アクリジニル、フェナジニル、フェノチアジニル、フェノキサジニルなどの縮合多環式(好ましくは2または3環式)芳香族複素環基;
アゼチジニル、ピロリジニル、テトラヒドロフリル、テトラヒドロチエニル、ピペリジニル、テトラヒドロピラニル、モルホリニル、チオモルホリニル、ピペラジニル、アゼパニル、ジアゼパニル(例、1,4-ジアゼパニル)、オキサゼパニル(例、1,4-オキサゼパニル)、オキサゾリジニル、イソオキサゾリジニル、チアゾリジニル、イソチアゾリジニル、イミダゾリジニル、ピラゾリジニル、オキサジアゾリジニル(例、1,2,4-オキサジアゾリジニル、1,3,4-オキサジアゾリジニル)、チアジアゾリジニル(例、1,2,4-チアジアゾリジニル、1,3,4-チアジアゾリジニル)、ピロリニル、オキサゾリニル、イソオキサゾリニル、チアゾリニル、イソチアゾリニル、イミダゾリニル、ピラゾリニル、オキサジアゾリニル(例、1,2,4-オキサジアゾリニル、1,3,4-オキサジアゾリニル)、チアジアゾリニル(例、1,2,4-チアジアゾリニル、1,3,4-チアジアゾリニル)等の非芳香族複素環基等が挙げられる。
R1で表される「置換されていてもよいアミノ基」は、式-N(R4)(R5)(式中、R4およびR5は、それぞれ独立して、水素原子または置換基を表す)で表される基である。
(1)アミノ基、
(2)置換されていてもよいC1-10アルキル基、
(3)置換されていてもよいC2-6アルケニル基、
(4)置換されていてもよいC1-6アルコキシ基、
(5)置換されていてもよいC3-10シクロアルキル基、
(6)置換されていてもよいC3-6シクロアルケニル基、
(7)置換されていてもよい環状アミノ基(例、ピペリジノ基)、
(8)置換されていてもよい芳香族基(例、フェニル基、ピラゾリル基)、
(9)置換されていてもよいジヒドロインデニル基、
(10)置換されていてもよい非芳香族複素環基(例、テトラヒドロフリル基、テトラヒドロピラニル基)
等が挙げられる。
[置換基群A]
(a)ハロゲン原子、
(b)シアノ基、
(c)水酸基、
(d)ニトロ基、
(e)ホルミル基、
(f)C1-6アルコキシ基(好ましくは、C1-3アルコキシ基)、
(g)1ないし3個の水酸基で置換されていてもよいC3-6シクロアルキル基、
(h)C6-14アリール基、
(i)環状アミノ基(例、ピペリジノ基、モルホリノ基)、
(j)複素環基(例、フリル基、テトラヒドロフラニル基)、
(k)C1-6アルキル-カルボニル基、
(l)アミノ基、および
(m)モノ-またはジ-C1-6アルキルアミノ基(好ましくは、モノ-またはジ-C1-3アルキルアミノ基)。
[置換基群B]
(a)ハロゲン原子、
(b)シアノ基、
(c)水酸基、
(d)ニトロ基、
(e)ホルミル基、
(f)C1-6アルコキシ基(好ましくは、C1-3アルコキシ基)、
(g)1ないし3個の水酸基で置換されていてもよいC3-6シクロアルキル基、
(h)C6-14アリール基、
(i)環状アミノ基(例、ピペリジノ基、モルホリノ基)、
(j)複素環基(例、フリル基、テトラヒドロフラニル基)、
(k)C1-6アルキル-カルボニル基、
(l)アミノ基、
(m)モノ-またはジ-C1-6アルキルアミノ基(好ましくは、モノ-またはジ-C1-3アルキルアミノ基)、および
(n)ハロゲン原子および水酸基から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基(好ましくは、C1-3アルキル基)。
水素原子、
C1-6アルキル基、
C1-3アルキル基で置換されていてもよい水酸基またはC1-3アルキル基で置換されていてもよいアミノ基で置換されていてもよいC2-10アルキル基、
C3-10シクロアルキル基、または、
ハロゲン原子、C1-6アルキル基、C1-3アルコキシ基、水酸基およびアミノ基から選ばれる置換基で置換されていてもよい芳香族基(例、フェニル基、ピリジル基)が挙げられる。
R4が水素原子であり、R5が2-ヒドロキシシクロヘキシル基、2-ヒドロキシシクロペンチル基、2-(ヒドロキシメチル)シクロヘキシル基または3-ヒドロキシテトラヒドロピラン-4-イル基であるとき、アミノ基の窒素原子と環上の炭素原子との結合、および水酸基またはヒドロキシメチル基と環上の炭素原子との結合の相対配置はtransであることが好ましい。
特に、R1が以下の式で表される絶対配置を有する態様が好ましい。
(1)ハロゲン原子、
(2)水酸基、
(3)置換されていてもよいC1-6アルキル基、
(4)置換されていてもよいC2-6アルケニル基、
(5)置換されていてもよいC1-6アルコキシ基、
(6)置換されていてもよいC3-6シクロアルキル基、
(7)置換されていてもよいC3-6シクロアルケニル基、
(8)置換されていてもよいC6-14アリール基、
(9)置換されていてもよい複素環基、
(10)C1-6アルキル-カルボニル基、
(11)C1-6アルコキシ-カルボニル基
等から選ばれる置換基が挙げられる。置換基の数は1ないし4個、好ましくは1ないし3個である。
前記「C3-6シクロアルキル基」、「C3-6シクロアルケニル基」、「C6-14アリール基」および「複素環基」は、前記の置換基群Bから選ばれる1ないし3個の置換基で置換されていてもよい。
(a)(1)アミノ基、
(2)(i)水酸基、(ii)C1-3アルコキシ基、(iii)1ないし3個の水酸基で置換されたC3-6シクロアルキル基、(iv)フェニル基、(v)フリル基、(vi)テトラヒドロフラニル基、(vii)ピペリジノ基および(viii)モルホリノ基から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基、
(3)ハロゲン原子、水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよいC3-6シクロアルキル基、
(4)4ないし10員環状アミノ基(例、ピペリジノ)、
(5)ハロゲン原子、1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよいフェニル基、
(6)1ないし3個の水酸基で置換されたジヒドロインデニル基、
(7)ピラゾリル基、
(8)テトラヒドロフラニル基、および
(9)1ないし3個の水酸基で置換されたテトラヒドロピラニル基
から選ばれる1または2個の置換基で置換されていてもよいアミノ基、または
(b)水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよい4ないし10員環状アミノ基(例、アゼチジン-1-イル、ピロリジン-1-イル、ピペリジノ、1,3-ジヒドロ-2H-イソインドール-2-イル)である。
(a)(1)アミノ基、
(2)水酸基、C1-3アルコキシ基、C3-6シクロアルキル基、フェニル基、フリル基、テトラヒドロフラニル基およびモルホリノ基から選ばれる1または2個の置換基で置換されていてもよいC1-6アルキル基、
(3)水酸基またはヒドロキシメチル基で置換されていてもよいC3-6シクロアルキル基、
(4)4ないし7員環状アミノ基(例、ピペリジノ)、
(5)ハロゲン原子、C1-6アルキル基およびヒドロキシメチル基から選ばれる置換基で置換されていてもよいフェニル基、
(6)水酸基で置換されたジヒドロインデニル基、
(7)ピラゾリル基、
(8)テトラヒドロフラニル基、および
(9)水酸基で置換されたテトラヒドロピラニル基
から選ばれる1または2個の置換基で置換されていてもよいアミノ基、または
(b)水酸基およびヒドロキシメチル基から選ばれる置換基で置換されていてもよい4ないし7員環状アミノ基(例、アゼチジン-1-イル、ピロリジン-1-イル、ピペリジノ)である。
R2またはR3で表される置換基としては、
(1)ハロゲン原子、
(2)シアノ基、
(3)ニトロ基、
(4)水酸基、
(5)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基(好ましくは、C1-3アルキル基)、
(6)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基(好ましくは、C1-3アルコキシ基)、
(7)カルボキシ基、
(8)C1-6アルキル-カルボニル基、
(9)C1-6アルコキシ-カルボニル基、
(10)カルバモイル基、
(11)モノ-またはジ-C1-6アルキルカルバモイル基、
(12)アミノ基、
(13)モノ-またはジ-C1-6アルキルアミノ基
等が挙げられる。
あるいは、R2が水素原子であり、R3がハロゲン原子、または1ないし3個のハロゲン原子で置換されたC1-3アルコキシ基である態様も好ましい。
環Aで表される「置換されていてもよい5ないし10員環」の「5ないし10員環」としては、5ないし10員の飽和環、芳香環および縮合環が挙げられる。前記の飽和環、芳香環および縮合環は、窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を1ないし4個(好ましくは1ないし3個、より好ましくは1または2個)含有していてもよい。
飽和環として好ましい構造は、それぞれ置換されていてもよい、アゼチジニル、ピロリジニル、ピペリジニル、アゼパニル、1,4-ジアゼパニル、シクロヘプチル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル(ただし、無置換シクロヘキシルを除く)であり、
芳香環として好ましい構造は、6員環であって、それぞれ置換されていてもよい、ピリジル、ピリミジニル、ピリダジニル、ピラジニル、トリアジニル、フェニル(ただし、無置換および4位にハロゲン原子が置換されたフェニルを除く)であり、
縮合環として好ましい構造は、それぞれ置換されていてもよい、ナフチル、キノリル、イソキノリル、シンノリニル、キノリジニル、キノキサリニル、キナゾリニル、フタラジニル、ナフチリジニル、ベンゾピラニル、ベンゾフラニル、インデニル、ベンゾチエニル、インドリル、ベンズイミダゾリル、ベンゾトリアゾリル、イミダゾピリジル、ベンズオキサジニル、デカリニルである。
(1)ハロゲン原子、
(2)シアノ基、
(3)ニトロ基、
(4)水酸基、
(5)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基(好ましくは、C1-3アルキル基)、
(6)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基(好ましくは、C1-3アルコキシ基)、
(7)カルボキシ基、
(8)C1-6アルキル-カルボニル基、
(9)C1-6アルコキシ-カルボニル基、
(10)カルバモイル基、
(11)モノ-またはジ-C1-6アルキルカルバモイル基、
(12)アミノ基、
(13)モノ-またはジ-C1-6アルキルアミノ基、
(14)1ないし3個のC1-6アルキル基で置換されていてもよい複素環基(例えば、ピラゾリル基、ピリジル基等の窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を1ないし4個(好ましくは1ないし3個、より好ましくは1または2個)含有する5ないし10員の芳香族複素環基)
等が挙げられる。置換基の数は1ないし4個、好ましくは1ないし3個、より好ましくは1または2個、特に好ましくは1個である。
環Aは、より好ましくは、4位が(i)1ないし3個のハロゲン原子で置換されたC1-3アルキル基、(ii)C1-3アルコキシ基、(iii)カルバモイル基および(iv)ピラゾリル基から選ばれる置換基で置換されたフェニル基である。
環Aは、さらに好ましくは、4位がC1-3アルコキシ基、カルバモイル基およびピラゾリル基から選ばれる置換基で置換されたフェニル基である。
[化合物(I)-A]
式(I)中、
R1は
(a)(1)アミノ基、
(2)(i)水酸基、(ii)C1-3アルコキシ基、(iii)水酸基で置換されていてもよいC3-6シクロアルキル基、(iv)フェニル基、(v)フリル基、(vi)テトラヒドロフラニル基、(vii)ピペリジノ基および(viii)モルホリノ基から選ばれる1または2個の置換基で置換されていてもよいC1-6アルキル基、
(3)ハロゲン原子、水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよいC3-6シクロアルキル基、
(4)4ないし10員環状アミノ基(例、ピペリジノ)、
(5)ハロゲン原子、C1-6アルキル基およびヒドロキシメチル基から選ばれる置換基で置換されていてもよいフェニル基、
(6)水酸基で置換されたジヒドロインデニル基、
(7)ピラゾリル基、
(8)テトラヒドロフラニル基、および
(9)水酸基で置換されたテトラヒドロピラニル基
から選ばれる1または2個の置換基で置換されていてもよいアミノ基、または
(b)水酸基およびヒドロキシメチル基から選ばれる置換基で置換されていてもよい4ないし10員環状アミノ基(例、アゼチジン-1-イル、ピロリジン-1-イル、ピペリジノ、1,3-ジヒドロ-2H-イソインドール-2-イル)であり、
R2およびR3は同一で水素原子、またはハロゲン原子であるか、あるいは
R2は水素原子であり、R3はハロゲン原子、または1ないし3個のハロゲン原子で置換されたC1-3アルコキシ基であり、
Xは-CH=、または-N=であり、
環Aは、
4位が(i)1ないし3個のハロゲン原子で置換されたC1-3アルキル基、(ii)C1-3アルコキシ基、(iii)カルバモイル基および(iv)ピラゾリル基から選ばれる置換基で置換されたフェニル基である化合物、またはその塩。
式(I)中、
R1は
(a)(1)アミノ基、
(2)水酸基、C1-3アルコキシ基、C3-6シクロアルキル基、フェニル基、フリル基、テトラヒドロフラニル基およびモルホリノ基から選ばれる1または2個の置換基で置換されていてもよいC1-6アルキル基、
(3)水酸基またはヒドロキシメチル基で置換されていてもよいC3-6シクロアルキル基、
(4)4ないし7員環状アミノ基(例、ピペリジノ)、
(5)ハロゲン原子、C1-6アルキル基およびヒドロキシメチル基から選ばれる置換基で置換されていてもよいフェニル基、
(6)水酸基で置換されたジヒドロインデニル基、
(7)ピラゾリル基、
(8)テトラヒドロフラニル基、および
(9)水酸基で置換されたテトラヒドロピラニル基
から選ばれる1または2個の置換基で置換されていてもよいアミノ基、または
(b)水酸基およびヒドロキシメチル基から選ばれる置換基で置換されていてもよい4ないし7員環状アミノ基(例、アゼチジン-1-イル、ピロリジン-1-イル、ピペリジノ)であり、
R2およびR3は同一で水素原子、またはハロゲン原子であり、
Xは-CH=、または-N=であり、
環Aは、
4位がC1-3アルコキシ基、カルバモイル基およびピラゾリル基から選ばれる置換基で置換されたフェニル基である化合物、またはその塩。
化合物(I)は、薬学的に許容され得る共結晶または共結晶塩であってもよい。ここで、共結晶または共結晶塩とは、各々が異なる物理的特性(例えば、構造、融点、融解熱、吸湿性、溶解性および安定性等)を持つ、室温で二種またはそれ以上の独特な固体から構成される結晶性物質を意味する。共結晶または共結晶塩は、自体公知の共結晶化法に従い製造することができる。
化合物(I)は溶媒和物(例えば、水和物)および無溶媒和物をその範囲内に包含する。また、化合物(I)は、同位元素(例、2H、3H、11C、14C、18F、35S、125Iなど)などで標識または置換された化合物であってもよく、同位元素で標識または置換された化合物は、例えば、陽電子断層法(Positron Emission Tomography,PET)において使用するトレーサー(PETトレーサー)として用いることができ、医療診断などの分野において有用である。
上記一般式(I)で示される化合物は、例えば、以下に示す方法またはこれに準ずる方法などによって製造することができる。なお、以下の合成法において、原料化合物は塩として用いてもよく、このような塩としては、化合物(I)の塩として例示したものが用いられる。
エーテル系溶媒:ジエチルエーテル、ジイソプロピルエーテル、ジフェニルエーテル、テトラヒドロフラン、1,4-ジオキサン、1,2-ジメトキシエタン等
芳香族炭化水素系溶媒:ベンゼン、トルエン、キシレン、トリフルオロメチルベンゼン等
脂肪族炭化水素系溶媒:シクロヘキサン、ヘキサン等
アミド系溶媒:N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、ヘキサメチルホスホリックトリアミド等
ハロゲン化炭化水素系溶媒:ジクロロメタン、クロロホルム、四塩化炭素、1,2-ジクロロエタン等
ニトリル系溶媒:アセトニトリル、プロピオニトリル等
スルホキシド系溶媒:ジメチルスルホキシド等
ケトン系溶媒:アセトン、メチルエチルケトン等
無機塩基類:水酸化ナトリウム、水酸化カリウム、水酸化マグネシウム等
塩基性塩類:炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸カルシウム、炭酸水素ナトリウム等
金属アルコキシド類:ナトリウムメトキシド、ナトリウムエトキシド、カリウムtert-ブトキシド等
アルカリ金属水素化物類:水素化ナトリウム、水素化カリウム等
金属アミド類:ナトリウムアミド、リチウムジイソプロピルアミド、リチウムヘキサメチルジシラジド等
芳香族アミン類:ピリジン、ルチジン等
第3級アミン類:トリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン、シクロヘキシルジメチルアミン、4-ジメチルアミノピリジン、N,N-ジメチルアニリン、N-メチルピペリジン、N-メチルピロリジン、N-メチルモルホリン等
化合物(I)は、化合物(II)のアミド化反応によって製造することができる。化合物(II)および(III)は市販の試薬、参考例に示した方法またはそれに準じた方法、あるいは公知の方法(Journal of Heterocyclic Chemistry, 1998, 35, 955もしくはChemical and Pharmaceutical Bulletin, 1988, 36, 1321)を参考に調製することができる。
化合物(II)と化合物(III)を脱水縮合剤の存在下、不活性溶媒中で反応させることによって行われる。必要に応じ、化合物(II)に対して、触媒量ないし5モル当量の1-ヒドロキシベンゾトリアゾール(HOBt)、および化合物(II)に対して、触媒量ないし5モル当量の塩基等の存在下に反応を行ってもよい。
化合物(III)は市販されているものを容易に入手でき、また、自体公知の方法またはこれらに準じた方法に従って製造することもできる。
化合物(III)の使用量は化合物(II)に対して、通常0.5ないし5モル当量、好ましくは0.8ないし1.5モル当量である。
上記「脱水縮合剤」としては、例えば、ジシクロヘキシルカルボジイミド(DCC)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(EDC・HClまたはWSC)、O-(7-アザベンゾトリアゾール-1-イル)-N,N,N',N'-テトラメチルウロニウム ヘキサフルオロリン酸塩(HATU)等が挙げられる。「脱水縮合剤」の使用量は化合物(II)に対して、通常1ないし10モル当量、好ましくは1ないし5モル当量である。
上記「不活性溶媒」としては、例えば、ニトリル系溶媒、アミド系溶媒、ハロゲン化炭化水素系溶媒、エーテル系溶媒等が挙げられる。これらは、二種以上を適宜の割合で混合して用いてもよい。なかでもアミド系溶媒が好ましい。
上記「塩基」としては、例えば、「芳香族アミン類」、「第3級アミン類」等が挙げられる。なかでもトリエチルアミン、ジイソプロピルエチルアミンが好ましい。
反応温度は、通常-70ないし150℃、好ましくは-20ないし100℃である。
反応時間は、通常0.1ないし100時間、好ましくは1ないし48時間である。
化合物(II)の反応性誘導体と、化合物(II)に対して、0.5ないし5モル当量(好ましくは0.8ないし3モル当量)の化合物(III)とを不活性溶媒中で反応させる。必要に応じ、化合物(II)に対して、1ないし10モル当量、好ましくは1ないし3モル当量の塩基の存在下に反応を行ってもよい。
化合物(II)の「反応性誘導体」としては、例えば、酸ハライド(例、酸クロリド、酸ブロミド)、混合酸無水物(例、C1-6アルキル-カルボン酸、C6-10アリール-カルボン酸、C1-6アルキル炭酸等との酸無水物)、活性エステル(例、置換基を有していてもよいフェノール、HOBt、N-ヒドロキシスクシンイミド等とのエステル)等が挙げられる。
上記「置換基を有していてもよいフェノール」における「置換基」としては、例えば、前記の置換基群Bから選ばれる1ないし5個の置換基が挙げられる。
また、「置換基を有していてもよいフェノール」の具体例としては、例えば、フェノール、ペンタクロロフェノール、ペンタフルオロフェノール、p-ニトロフェノール等が挙げられる。
反応性誘導体は、好ましくは酸ハライドである。
上記「不活性溶媒」としては、例えば、エーテル系溶媒、ハロゲン化炭化水素系溶媒、芳香族炭化水素系溶媒、脂肪族炭化水素系溶媒、ニトリル系溶媒、アミド系溶媒、ケトン系溶媒、スルホキシド系溶媒、水等が挙げられる。これらは、二種以上を適宜の割合で混合して用いてもよい。なかでもアセトニトリル、テトラヒドロフラン(THF)、ジクロロメタン、クロロホルム等が好ましい。
上記「塩基」としては、例えば、「芳香族アミン類」、「第3級アミン類」等が挙げられる。なかでもトリエチルアミン、ジイソプロピルエチルアミンが好ましい。
反応温度は、通常-20℃ないし100℃、好ましくは-20℃ないし50℃である。
反応時間は、通常5分間ないし40時間、好ましくは30分間ないし18時間である。
上記式は化合物(化合物(Ia)の環A上に(IV)を用いて置換基R6を導入して目的化合物(Ib)を製造する方法を示したものである。
脱離基L1およびL2としては、例えば、アルカリ金属 (例、リチウム、ナトリウム等)、ハロゲン原子 (例、フッ素、塩素、臭素、ヨウ素等)、C1-6アルコキシ基 (例、メトキシ基等)、C6-14アリールオキシ基 (例、フェノキシ基等)、置換されていてもよいアシルオキシ基 (例、アセチルオキシ基、ベンゾイルオキシ基等)、ハロゲン化されていてもよいC1-6アルキルスルホニルオキシ基 [例、メタンスルホニルオキシ基、エタンスルホニルオキシ基、トリクロロメタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ (トリフラート) 基等]、置換されていてもよいC6-14アリールスルホニルオキシ基 [例として、C1-6アルキル基 (例、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、sec-ブチル基、tert-ブチル基、ペンチル基、ヘキシル基等)、C1-6アルコキシ基 (例、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、sec-ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基等) およびニトロ基から選ばれる置換基を1ないし3個有していてもよいC6-14アリールスルホニルオキシ基等が挙げられ、具体例としては、ベンゼンスルホニルオキシ基、m-ニトロベンゼンスルホニルオキシ基、p-トルエンスルホニルオキシ基、ナフチルスルホニルオキシ基等]、C1-6アルキルオキソニオ基 (例、ジメチルオキソニオ基、ジエチルオキソニオ基等)、ジアゾ基、ジアゾニオ基、置換されていてもよいC6-14アリールヨードニオ基 (例、フェニルヨードニオ基)、ホウ素官能基 (例
上記反応で示される原料化合物(Ia)および(IV)は市販の試薬あるいは自体公知の方法、参考例に示した方法またはそれに準じた方法によって製造することができる。
かかる「塩基」としては、例えば水酸化カリウム、水酸化ナトリウム、炭酸水素ナトリウム、炭酸カリウムなどのアルカリ金属塩;ピリジン、トリエチルアミン、N,N-ジメチルアニリン、1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エンなどのアミン類;水素化カリウム、水素化ナトリウムなどの金属水素化物;ナトリウムメトキシド、ナトリウムエトキシド、カリウム tert-ブトキシドなどのアルカリ金属アルコキシドが挙げられる。
これら塩基の使用量は、化合物(Ia)に対し、好ましくは約1ないし約5モル当量である。
かかる「添加剤」としては、ヨウ化ナトリウム、ヨウ化カリウムなどの無機塩、ヨウ化テトラブチルアンモニウムなどのアンモニウム塩、モレキュラーシーブ3A、モレキュラーシーブ4A等のモレキュラーシーブ類が挙げられる。
かかる「添加剤」の使用量は、化合物(Ia)に対し重量比で、約0.1ないし500倍、好ましくは0.1ないし30倍である。
かかる「金属触媒」としては、ニッケル、パラジウム、銅等の金属、金属塩、またはこれらと配位子からなる金属錯体等が挙げられ、それらの試薬としては、例えば、テトラキス(トリフェニルホスフィン)パラジウム(0)、ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド-ジクロロメタン付加体、トリス(ジベンジリデンアセトン)ジパラジウム(0)、ビス(ジ-tert-ブチル(4-ジメチルアミノフェニル)ホスフィン)ジクロロパラジウム(II)、クロロ(2-ジシクロヘキシルホスフィノ-2',4',6'-トリイソプロピル-1,1'-ビフェニル)[2-(2-アミノエチル)フェニル)]パラジウム(II)、クロロ-(2-ジシクロヘキシルホスフィノ-2',6'-ジイソプロポキシ-1,1'-ビフェニル)[2-(2-アミノエチル)フェニル]パラジウム(II)-メチル-tert-ブチルエーテル付加物、クロロ[2-(ジシクロヘキシルホスフィノ)-3,6-ジメトキシ-2',4',6'-トリイソプロピル-1,1'-ビフェニル][2-(2-アミノエチル)フェニル]パラジウム(II)-メチル-tert-ブチルエーテル付加物、クロロ[2-(ジ-tert-ブチルホスフィノ)-2',4',6'-トリイソプロピル-1,1'-ビフェニル][2-(2-アミノエチル)フェニル)]パラジウム(II)、trans-ジクロロビス(トリ-o-トリルホスフィン)パラジウム(II)、トリフルオロ酢酸パラジウム(II)、酢酸パラジウム(II)、ニッケル(II)アセチルアセトナート、塩化ニッケル1,2-ビス(ジフェニルホスフィノ)エタン錯体、ヨウ化銅、臭化銅、塩化銅、酢酸銅、酸化銅等が挙げられる。さらに、配位子を反応系中に加えてもよく、これらの配位子としては、例えば、ホスフィン配位子 [例、トリフェニルホスフィン、2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル、2-ジシクロへキシルホスフィノ-2',6'-ジイソプロポキシ-1,1'-ビフェニル、2-(ジシクロヘキシルホスフィノ)-3,6-ジメトキシ-2',4',6'-トリイソプロピル-1,1'-ビフェニル、2-ジ-tert-ブチルホスフィノ-3,4,5,6-テトラメチル-2',4',6'-トリイソプロピル-1,1'-ビフェニル、2-(ジ-tert-ブチルホスフィノ)ビフェニル、2-(ジシクロヘキシルホスフィノ)ビフェニル、2-ジシクロヘキシルホスフィノ-2',6'-ジメトキシ-1,1'-ビフェニル、2-ジシクロヘキシルホスフィノ-2',4',6'-トリイソプロピル-1,1'-ビフェニル、2-(ジシクロヘキシルホスフィノ)-2'-(N,N-ジメチルアミノ)ビフェニル、1,1'-ビス(ジフェニルホスフィノ)フェロセン、トリ-tert-ブチルホスフィン、トリシクロヘキシルホスフィン、4,5-ビス(ジフェニルホスフィノ)-9,9-ジメチルキサンテン等]、アミン配位子 (N,N'-ジメチルエチレンジアミン、trans-1,2-ジアミノシクロヘキサン、trans-N,N'-ジメチル-1,2-シクロヘキサンジアミン、1,10-フェナントロリン、4,7-ジメトキシ-1,10-フェナントロリン、3,4,7,8-テトラメチル-1,10-フェナントロリン等)、ジケトン配位子 (2-アセチルシクロヘキサノン、2-イソブチリルヘキサノン、2,2,6,6-テトラメチル-3,5-ヘプタンジオン等)、サリチルアルドキシム、プロリン等が挙げられる。
該「金属触媒」の使用量は、化合物(Ia)に対して、通常約0.0001ないし1000重量%、好ましくは約0.01ないし200重量%である。
該「配位子」の使用量は、化合物(Ia)に対して、通常約0.0001ないし約1000重量%、好ましくは約0.01ないし約200重量%である。
本反応は無溶媒または反応に不活性な溶媒を用いて行うのが有利である。このような溶媒としては反応が進行する限り特に限定されないが、例えばメタノール、エタノール、1-プロパノール、2-プロパノール、1-ブタノール、2-メチル-2-プロパノール、2-メチル-2-ブタノール等のアルコール類、ジエチルエーテル、ジイソプロピルエーテル、シクロペンチルメチルエーテル、テトラヒドロフラン、2-メチルテトラヒドロフラン、1,4-ジオキサン、1,2-ジメトキシエタン等のエーテル類、シクロヘキサン、ヘキサン等の炭化水素類、ベンゼン、クロロベンゼン、トルエン、キシレン、(トリフルオロメチル)ベンゼンなどの芳香族炭化水素類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、1-メチル-2-ピロリドン等のアミド類、ジクロロメタン、クロロホルム、四塩化炭素、1,2-ジクロロエタン等のハロゲン化炭化水素類、アセトニトリル、プロピオニトリル等のニトリル類、ジメチルスルホキシド等のスルホキシド類、ピリジン、ルチジン、キノリン等の含窒素芳香族炭化水素類および水等の溶媒またはこれらの混合溶媒等が好ましい。
反応温度は、通常、約-50ないし約150℃、好ましくは約-10ないし約100℃である。
反応時間は、通常、約0.5ないし約20時間である。
1)分別再結晶法
ラセミ体と光学活性な化合物(例えば、(+)-マンデル酸、(-)-マンデル酸、(+)-酒石酸、(-)-酒石酸、(+)-1-フェネチルアミン、(-)-1-フェネチルアミン、シンコニン、(-)-シンコニジン、ブルシンなど)と塩を形成させ、これを分別再結晶法によって分離し、所望により、中和工程を経てフリーの光学異性体を得る方法。
ラセミ体またはその塩を光学異性体分離用カラム(キラルカラム)にかけて分離する方法。例えば液体クロマトグラフィーの場合、ENANTIO-OVM(トーソー社製)あるいは、ダイセル社製 CHIRALシリーズなどのキラルカラムに光学異性体の混合物を添加し、水、種々の緩衝液(例、リン酸緩衝液)、有機溶媒(例、エタノール、メタノール、イソプロパノール、アセトニトリル、トリフルオロ酢酸、ジエチルアミンなど)を単独あるいは混合した溶液として展開させることにより、光学異性体を分離する。
ラセミ体の混合物を光学活性な試薬と化学反応によってジアステレオマーの混合物とし、これを通常の分離手段(例えば、分別再結晶、クロマトグラフィー法等)などを経て単一物質とした後、加水分解反応などの化学的な処理により光学活性な試薬部位を切り離すことにより光学異性体を得る方法。例えば、化合物(I)が分子内に水酸基または1,2級アミノ基を有する場合、該化合物と光学活性な有機酸(例えば、MTPA〔α-メトキシ-α-(トリフルオロメチル)フェニル酢酸〕、(-)-メントキシ酢酸等)などとを縮合反応に付すことにより、それぞれエステル体またはアミド体のジアステレオマーが得られる。一方、化合物(I)がカルボン酸基を有する場合、該化合物と光学活性アミンまたはアルコール試薬とを縮合反応に付すことにより、それぞれアミド体またはエステル体のジアステレオマーが得られる。分離されたジアステレオマーは、酸加水分解あるいは塩基性加水分解反応に付すことにより、元の化合物の光学異性体に変換される。
また、化合物(I)のプロドラッグは、医薬品の開発,第7巻(分子設計),163-198頁(廣川書店)に記載されているような生理的条件で化合物(I)に変化するものであってもよい。
(1)精神疾患[例、うつ病、大うつ病、双極性うつ病、気分変調障害、情動障害(季節性情動障害など)、再発性うつ病、産後うつ病、ストレス性障害、うつ症状、躁病、不安、全般性不安障害、不安症候群、パニック障害、恐怖症、社会性恐怖症、社会性不安障害、強迫性障害、心的外傷後ストレス症候群、外傷後ストレス障害、トゥレット症候群、自閉症、脆弱X症候群、レット症候群、適応障害、双極性障害、神経症、統合失調症(例、陽性症状、陰性症状、認知症状)、慢性疲労症候群、不安神経症、強迫神経症、てんかん、不安症状、不快精神状態、情緒異常、感情循環気質、神経過敏症、失神、耽溺、性欲低下、注意欠陥多動性障害(ADHD)、精神病性大うつ病、難治性大うつ病、治療抵抗性うつ病]、
(2)神経変性疾患[例、アルツハイマー病、アルツハイマー型老人性認知症、パーキンソン病、ハンチントン舞踏病、多発脳梗塞性認知症、前頭側頭認知症、パーキンソン型前頭側頭認知症、進行性核上麻痺、ピック症候群、ニーマン-ピック症候群、大脳皮質基底核変成症、ダウン症、血管性認知症、脳炎後のパーキンソン病、レヴィー小体認知症、HIV性認知症、筋萎縮性脊髄側索硬化症(ALS)、運動神経原性疾患(MND)、クロイツフェルト・ヤコブ病又はプリオン病、脳性麻痺、多発性硬化症]、
(3)加齢に伴う認知・記憶障害[例、加齢性記憶障害、老人性認知症]、
(4)睡眠障害[例、内在因性睡眠障害(例、精神生理性不眠など)、外在因性睡眠障害、概日リズム障害(例、時間帯域変化症候群(時差ボケ)、交代勤務睡眠障害、不規則型睡眠覚醒パターン、睡眠相後退症候群、睡眠相前進症候群、非24時間睡眠覚醒など)、睡眠時随伴症、内科又は精神科障害(例、慢性閉塞性肺疾患、アルツハイマー病、パーキンソン病、脳血管性認知症、統合失調症、うつ病、不安神経症)に伴う睡眠障害、ストレス性不眠症、不眠症、不眠性神経症、睡眠時無呼吸症候群]、
(5)麻酔薬、外傷性疾患又は神経変性疾患などに起因する呼吸抑制、
(6)外傷性脳損傷、脳卒中、神経性食欲不振、摂食障害、神経性無食欲症、過食症、その他の摂食障害、アルコール依存症、アルコール乱用、アルコール性健忘症、アルコール妄想症、アルコール嗜好性、アルコール離脱、アルコール性精神病、アルコール中毒、アルコール性嫉妬、アルコール性躁病、アルコール依存性精神障害、アルコール精神病、薬物嗜好、薬物恐怖症、薬物狂、薬物離脱、偏頭痛、ストレス性頭痛、緊張性頭痛、糖尿病性ニューロパシー、肥満、糖尿病、筋肉痙攣、メニエール病、自律神経失調症、脱毛症、緑内障、高血圧、心臓病、頻脈、うっ血性心不全、過呼吸、気管支喘息、無呼吸、乳幼児突然死症候群、炎症性疾患、アレルギー疾患、インポテンス、更年期障害、不妊症、癌、HIV感染による免疫不全症候群、ストレスによる免疫不全症候群、脳脊髄膜炎、末端肥大症、失禁、メタボリック・シンドローム、骨粗しょう症、消化性潰瘍、過敏性腸症候群、炎症性腸疾患、潰瘍性大腸炎、クローン病、ストレス性胃腸障害、神経性嘔吐、消化性潰瘍、下痢、便秘、術後イレウス、ストレス性胃腸障害、
(7)痛み(疼痛)
等の疾患の予防または治療薬、
特に好ましくは、コリン作動性ムスカリンM1受容体機能増強薬、アルツハイマー病、統合失調症、痛み(疼痛)、睡眠障害等の予防または治療薬として有効である。
ベンゾジアゼピン(クロルジアゼポキシド、ジアゼパム、クロラゼブ酸カリウム、ロラゼパム、クロナゼパム、アルプラゾラム等)、L-型カルシウムチャネル阻害薬(プレガバリン等)、三環性又は四環性抗うつ薬(塩酸イミプラミン、塩酸アミトリプチリン、塩酸デシプラミン、塩酸クロミプラミン等)、選択的セロトニン再取り込み阻害薬(マレイン酸フルボキサミン、塩酸フロキセチン、臭酸シタロプラム、塩酸セルトラリン、塩酸パロキセチン、シュウ酸エスシタロプラム等)、セロトニン-ノルアドレナリン再取り込み阻害薬(塩酸ベンラファキシン、塩酸デュロキセチン、塩酸デスベンラファキシン等)、ノルアドレナリン再取り込み阻害薬(メシル酸レボキセチン等)、ノルアドレナリン-ドパミン再取り込み阻害薬(塩酸ブプロピオン等)、ミルタザピン、塩酸トラゾドン、塩酸ネファゾドン、塩酸ブプロピオン、マレイン酸セチプチリン、5-HT1A作動薬(塩酸ブスピロン、クエン酸タンドスピロン、塩酸オセモゾタン等)、5-HT3拮抗薬(シアメマジン等)、心臓選択的ではないβ阻害薬(塩酸プロプラノロール、塩酸オキシプレノロール等)、ヒスタミンH1拮抗薬(塩酸ヒドロキシジン等)、統合失調症治療薬(クロルプロマジン、ハロペリドール、スルピリド、クロザピン、塩酸トリフルオペラジン、塩酸フルフェナジン、オランザピン、フマル酸クエチアピン、リスペリドン、アリピプラゾール等)、CRF拮抗薬、その他の抗不安薬(メプロバメート等)、タキキニン拮抗薬(MK-869、サレデュタント等)、代謝型グルタミン酸受容体に作用する薬剤、CCK拮抗薬、β3アドレナリン拮抗薬(塩酸アミベグロン等)、GAT-1阻害薬(塩酸チアガビン等)、N-型カルシウムチャネル阻害薬、2型炭酸脱水素酵素阻害薬、NMDAグリシン部位作動薬、NMDA拮抗薬(メマンチン等)、末梢性ベンゾジアゼピン受容体作動薬、バソプレッシン拮抗薬、バソプレッシンV1b拮抗薬、バソプレッシンV1a拮抗薬、ホスホジエステラーゼ阻害薬、オピオイド拮抗薬、オピオイド作動薬、ウリジン、ニコチン酸受容体作動薬、チロイドホルモン(T3、T4)、TSH、TRH、MAO阻害薬(硫酸フェネルジン、硫酸トラニルシプロミン、モクロベミド等)、5-HT2A拮抗薬、5-HT2A逆作動薬、COMT阻害薬(エンタカポン等)、双極性障害治療薬(炭酸リチウム、バルプロ酸ナトリウム、ラモトリジン、リルゾール、フェルバメート等)、カンナビノイドCB1拮抗薬(リモナバント等)、FAAH阻害薬、ナトリウムチャネル阻害薬、抗ADHD薬(塩酸メチルフェニデート、塩酸メタンフェタミン等)、アルコール依存症治療薬、自閉症治療薬、慢性疲労症候群治療薬、痙攣治療薬、線維筋痛症治療薬、頭痛治療薬、不眠症治療薬(エチゾラム、ゾピクロン、トリアゾラム、ゾルピデム、ラメルテオン、インジプロン等)、禁煙のための治療薬、重症筋無力症治療薬、脳梗塞治療薬、躁病治療薬、過眠症治療薬、疼痛治療薬、気分変調症治療薬、自律神経失調症治療薬、男性及び女性の性機能障害治療薬、偏頭痛治療薬、病的賭博治療薬、下肢静止不能症候群治療薬、物質依存症治療薬、アルコール関連症の治療薬、過敏性腸症候群治療薬、アルツハイマー病治療薬(ドネペジル、ガランタミン、メマンチン等)、パーキンソン病治療薬、ALS治療薬(リルゾール、神経栄養因子等)、コレステロール低下薬のような脂質異常症治療薬(スタチンシリーズ(プラバスタチンナトリウム、アトルバスタチン、シンバスタチン、ロスバスタチン等)、フィブレート(クロフィブレート等)、スクワレン合成阻害薬)、異常行動治療薬又は認知症による放浪癖の抑制薬(鎮静薬、抗不安薬等)、アポトーシス阻害薬、抗肥満薬、糖尿病治療薬、高血圧治療薬、低血圧治療薬、リューマチ治療薬(DMARD)、抗癌剤、副甲状腺機能低下症治療薬(PTH)、カルシウム受容体拮抗薬、性ホルモン又はその誘導体(プロゲステロン、エストラジオール、安息香酸エストラジオール等)、神経分化促進薬、神経再生促進薬、非ステロイド系抗炎症薬(メロキシカム、テノキシカム、インドメタシン、イブプロフェン、セレコキシブ、ロフェコキシブ、アスピリン等)、ステロイド(デキサメタゾン、酢酸コルチゾン等)、抗サイトカイン薬(TNF阻害薬、MAPカイネース阻害薬等)、抗体医薬、核酸又は核酸誘導体、アプタマー薬など。
(1)本発明の化合物又は併用薬物を単独で投与する場合に比べて、その投与量を軽減することができる、
(2)患者の症状(軽症、重症など)に応じて、本発明の化合物と併用する薬物を選択することができる、
(3)本発明の化合物と作用機序が異なる併用薬物を選択することにより、治療期間を長く設定することができる、
(4)本発明の化合物と作用機序が異なる併用薬物を選択することにより、治療効果の持続を図ることができる、
(5)本発明の化合物と併用薬物とを併用することにより、相乗効果が得られる、等の優れた効果を得ることができる。
以下の実施例中の「室温」は通常約10℃ないし約35℃を示す。混合溶媒において示した比は、特に断らない限り容量比を示す。%は、特に断らない限り重量%を示す。
以下の参考例および実施例においては下記の略号を使用する。
THF: テトラヒドロフラン
DMF: N,N-ジメチルホルムアミド
DMSO: ジメチルスルホキシド
DME: 1,2-ジメトキシエタン
MS (マススペクトル) は、LC/MS (液体クロマトグラフ質量分析計) により測定した。イオン化法としては、ESI (Electrospray Ionization、エレクトロスプレーイオン化) 法、または、APCI (Atmospheric Pressure Chemical Ionization、大気圧化学イオン化) 法を用いた。データは実測値 (found) を記載した。
5,8-ジフルオロ-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸
1H NMR (400 MHz, DMSO-d6) δ 3.34 (3H, s), 5.79 (2H, d, J = 3.7 Hz), 6.90 (2H, d, J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.36-7.45 (1H, m), 7.73-7.84 (1H, m), 9.13 (1H, s), 14.79 (1H, s).
1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロシンノリン-3-カルボン酸
1H NMR (400 MHz, DMSO-d6) δ 3.71 (3H, s), 5.88 (2H, s), 6.91 (2H, d, J = 8.6 Hz), 7.31 (2H, d, J = 8.6 Hz), 7.69 (1H, t, J = 7.6 Hz), 7.97 (1H, t, J = 7.5 Hz), 8.03-8.11 (1H, m), 8.31 (1H, d, J = 7.8 Hz), 14.35 (1H, brs).
1-(4-カルバモイルベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸
1H NMR (300 MHz, DMSO-d6) δ 5.94 (2H, s), 7.24-7.43 (3H, m), 7.55-7.68 (1H, m), 7.74-8.00 (5H, m), 8.41 (1H, d, J = 8.3 Hz), 9.32 (1H, s), 15.15 (1H, s).
1-(4-カルバモイルベンジル)-4-オキソ-1,4-ジヒドロシンノリン-3-カルボン酸
1H NMR (300 MHz, DMSO-d6) δ 6.01 (2H, s), 7.38 (3H, d, J = 8.3 Hz), 7.69 (1H, dt, J = 7.8, 4.1 Hz), 7.83 (2H, d, J = 8.3 Hz), 7.95 (3H, d, J = 3.4 Hz), 8.32 (1H, d, J = 8.0 Hz), 14.29 (1H, brs).
1-(4-カルバモイルベンジル)-4-オキソ-8-(トリフルオロメトキシ)-1,4-ジヒドロキノリン-3-カルボン酸
1H NMR (400 MHz, DMSO-d6) δ 5.97 (2H, s), 7.12 (2H, d, J = 7.8 Hz), 7.37 (1H, brs), 7.67-7.75 (1H, m), 7.79 (2H, d, J = 7.6 Hz), 7.88 (1H, d, J = 7.8 Hz), 7.95 (1H, brs), 8.47 (1H, d, J = 7.8 Hz), 9.20 (1H, s), 14.64 (1H, s).
1-(クロロメチル)-4-(1,1-ジフルオロエチル)ベンゼン
1H NMR (400 MHz, DMSO-d6) δ 1.96 (3H, t, J = 18.8 Hz), 4.81 (2H, s), 7.41-7.73 (4H, m).
1-[4-(1,1-ジフルオロエチル)ベンジル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸
1H NMR (400 MHz, DMSO-d6) δ 1.92 (3H, t, J = 19.0 Hz), 5.94 (2H, s), 7.38 (2H, d, J = 8.1 Hz), 7.54 (2H, d, J = 8.1 Hz), 7.63 (1H, t, J = 7.1 Hz), 7.77-7.94 (2H, m), 8.40 (1H, d, J = 6.8 Hz), 9.33 (1H, s), 15.15 (1H, brs).
1-[4-(1H-ピラゾール-1-イル)ベンジル]-4-オキソ-1,4-ジヒドロシンノリン-3-カルボン酸
1H NMR (400 MHz, DMSO-d6) δ 6.00 (2H, s), 6.53 (1H, s), 7.47 (2H, d, J = 8.6 Hz), 7.66-7.75 (2H, m), 7.82 (2H, d, J = 8.3 Hz), 7.93-8.00 (1H, m), 8.01-8.08 (1H, m), 8.33 (1H, d, J = 8.1 Hz), 8.47 (1H, d, J = 2.2 Hz), 14.33 (1H, brs).
8-クロロ-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸
1H NMR (400 MHz, DMSO-d6) δ3.70 (3H, s), 6.15 (2H, s), 6.88 (2H, d, J = 8.8 Hz), 7.05 (2H, d, J = 8.8 Hz), 7.61 (1H, t, J = 7.9 Hz), 7.99 (1H, dd, J = 7.8, 1.5 Hz), 8.43 (1H, dd, J = 8.1, 1.5 Hz), 9.10 (1H, s), 14.64 (1H, s).
3-ベンジルテトラヒドロベンゾ[d]オキサゾール-2,5(3H,6H)-ジオン
1H NMR (400 MHz, CDCl3) δ 1.93-2.02 (1H, m), 2.33-2.49 (3H, m), 2.63-2.71 (2H, m), 3.31-3.38 (1H, m), 4.27-4.34 (2H, m), 4.56 (1H, d, J = 14.8 Hz), 7.31-7.40 (5H, m).
3-ベンジル-5,5-ジフルオロヘキサヒドロベンゾ[d]オキサゾール-2(3H)-オン
1H NMR (400 MHz, CDCl3): δ 1.65-1.93 (3H, m), 2.22-2.34 (3H, m), 3.23-3.29 (1H, m), 3.89-3.95 (1H, m), 4.36-4.46 (2H, m), 7.27-7.38 (5H, m).
2-(ベンジルアミノ)-4,4-ジフルオロシクロヘキサノール
1H NMR (400 MHz, CDCl3): δ 1.47-1.64 (6H, m), 1.72-1.88 (1H, m), 2.04-2.19 (2H, m), 3.30-3.36 (1H, m), 3.73 (1H, d, J = 12.8 Hz), 3.94 (1H, d, J = 12.8 Hz), 7.28-7.39 (5H, m).
(1,2-trans)-2-アミノ-4,4-ジフルオロシクロヘキサノール塩酸塩
1H NMR (400 MHz, CDCl3): δ 1.39-1.48 (1H, m), 1.86-2.11 (4H, m), 2.38-2.45 (1H, m), 2.90-2.96 (1H, m), 3.55-3.62 (1H, m), 5.66 (1H, d, J = 5.6 Hz), 8.20 (3H, brs).
4-オキソ-1-{4-[1-(テトラヒドロ-2H-ピラン-2-イル)-1H-ピラゾール-5-イル]ベンジル}-1,4-ジヒドロキノリン-3-カルボン酸エチル
1H NMR (400 MHz, DMSO-d6) δ 1.31 (3H, t, J = 7.0 Hz), 1.43-1.63 (3H, m), 1.76 (1H, d, J = 12.7 Hz), 1.90 (1H, brs), 2.36 (1H, d, J = 10.5 Hz), 3.50 (1H, t, J = 9.5 Hz), 3.94 (1H, d, J = 11.2 Hz), 4.26 (2H, q, J = 6.6 Hz), 5.16 (1H, d, J = 9.8 Hz), 5.76 (2H, s), 6.43 (1H, s), 7.39 (2H, d, J = 7.8 Hz), 7.42-7.57 (4H, m), 7.62-7.76 (2H, m), 8.27 (1H, d, J = 8.1 Hz), 8.97 (1H, s).
4-オキソ-1-{4-[1-(テトラヒドロ-2H-ピラン-2-イル)-1H-ピラゾール-5-イル]ベンジル}-1,4-ジヒドロキノリン-3-カルボン酸
1H NMR (400 MHz, DMSO-d6) δ 1.39-1.62 (3H, m), 1.76 (1H, d, J = 12.5 Hz), 1.91 (1H, brs), 2.36 (1H, d, J = 10.8 Hz), 3.49 (1H, d, J = 9.0 Hz), 3.94 (1H, d, J = 10.5 Hz), 5.16 (1H, d, J = 9.3 Hz), 5.96 (2H, s), 6.44 (1H, s), 7.42 (2H, d, J = 8.1), 7.47-7.58 (3H, m), 7.65 (1H, d, J = 3.9 Hz), 7.91 (2H, brs), 8.42 (1H, d, J = 8.1 Hz), 9.35 (1H, s), 15.18 (1H, s).
1-(4-ブロモベンジル)-N-[(1,2-trans)-2-ヒドロキシシクロペンチル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド
1H NMR (300MHz, DMSO-d6) δ 1.37-1.94 (5H, m), 2.00-2.17 (1H, m), 3.88-4.10 (2H, m), 5.77 (2H, s), 5.86 (1H, s), 7.13-7.30 (2H, m), 7.44-7.97 (5H, m), 8.29-8.44 (1H, m), 9.08 (1H, s), 10.03 (1H, d, J = 7.4 Hz).
5,8-ジフルオロ-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 345.2
1H NMR (400 MHz, DMSO-d6) δ 3.71 (3H, s), 5.68 (2H, d, J = 3.2 Hz), 6.90 (2H, d, J = 8.6 Hz), 7.08 (2H, d, J = 8.6 Hz), 7.17-7.32 (1H, m), 7.55-7.70 (2H, m), 8.89 (1H, s), 9.01 (1H, d, J = 4.2 Hz).
5,8-ジフルオロ-1-(4-メトキシベンジル)-4-オキソ-N-フェニル-1,4-ジヒドロキノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 421.1
1H NMR (400 MHz, DMSO-d6) δ 3.71 (3H, s), 5.76 (2H, d, J = 2.7 Hz), 6.91 (2H, d, J = 8.6 Hz), 7.12 (3H, d, J = 8.1 Hz), 7.27-7.41 (3H, m), 7.65-7.78 (3H, m), 9.05 (1H, s), 12.06 (1H, s).
5,8-ジフルオロ-N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-4-オキソ-1-[4-(1H-ピラゾール-1-イル)ベンジル]-1,4-ジヒドロキノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 479.3
1H NMR (400 MHz, DMSO-d6) δ 1.16-1.38 (4H, m), 1.54-1.70 (2H, m), 1.80-1.91 (1H, m), 1.97-2.07 (1H, m), 3.36-3.44 (1H, m), 3.61-3.71 (1H, m), 4.83 (1H, d, J = 4.9 Hz), 5.82 (2H, d, J = 2.4 Hz), 6.53 (1H, s), 7.20-7.33 (3H, m), 7.59-7.69 (1H, m), 7.72 (1H, s), 7.80 (2H, d, J = 8.3 Hz), 8.45 (1H, d, J = 2.4 Hz), 8.93 (1H, s), 9.81 (1H, d, J = 7.3 Hz).
N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-4-オキソ-1-[4-(1H-ピラゾール-1-イル)ベンジル]-1,4-ジヒドロシンノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 444.2
1H NMR (400 MHz, DMSO-d6) δ 1.20-1.39 (4H, m), 1.57-1.71 (2H, m), 1.87 (1H, brs), 2.06 (1H, brs), 3.37-3.46 (1H, m), 3.65-3.77 (1H, m), 4.84 (1H, d, J = 4.9 Hz), 5.95 (2H, s), 6.53 (1H, s), 7.44 (2H, d, J = 8.6 Hz), 7.62 (1H, t, J = 7.5 Hz), 7.72 (1H, s), 7.81 (2H, d, J = 8.6 Hz), 7.85-7.99 (2H, m), 8.30 (1H, d, J = 8.1 Hz), 8.46 (1H, d, J = 2.2 Hz), 9.78 (1H, d, J = 7.6 Hz).
1-(4-カルバモイルベンジル)-N-[(1S,2S)-2-ヒドロキシシクロヘキシル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 420.3
1H NMR (300 MHz, DMSO-d6) δ 1.30 (4H, d, J = 8.3 Hz), 1.55-1.71 (2H, m), 1.87 (1H, d, J = 8.3 Hz), 2.03 (1H, d, J = 10.6 Hz), 3.34-3.46 (1H, m), 3.71 (1H, d, J = 8.7 Hz), 4.81 (1H, d, J = 4.9 Hz), 5.85 (2H, s), 7.28 (2H, d, J = 8.3 Hz), 7.34 (1H, brs), 7.50 (1H, t, J = 7.2 Hz), 7.65-7.77 (2H, m), 7.82 (2H, d, J = 8.3 Hz), 7.92 (1H, brs), 8.36 (1H, d, J = 7.6 Hz), 9.09 (1H, s), 10.08 (1H, d, J = 7.6 Hz).
1,5-アンヒドロ-2,3-ジデオキシ-3-({[5,8-ジフルオロ-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-イル]カルボニル}アミノ)-DL-threo-ペンチトール
MS (ESI+): [M+H]+ 445.1
1H NMR (400 MHz, DMSO-d6) δ 1.38-1.58 (1H, m), 1.95-2.12 (1H, m), 3.04-3.16 (2H, m), 3.41-3.49 (1H, m), 3.71 (3H, s), 3.74-3.87 (3H, m), 5.17 (1H, d, J = 5.6 Hz), 5.71 (2H, brs), 6.90 (2H, d, J = 8.6 Hz), 7.08 (2H, d, J = 8.6 Hz), 7.16-7.37 (1H, m), 7.56-7.75 (1H, m), 8.90 (1H, s), 9.85 (1H, d, J = 7.1 Hz).
5,8-ジフルオロ-N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 443.2
1H NMR (400 MHz, DMSO-d6) δ 1.14-1.37 (4H, m), 1.66 (2H, brs), 1.85 (1H, d, J = 2.9 Hz), 2.01 (1H, brs), 3.35-3.44 (1H, m), 3.58-3.68 (1H, m), 3.71 (3H, s), 4.82 (1H, d, J = 4.9 Hz), 5.70 (2H, d, J = 2.4 Hz), 6.90 (2H, d, J = 8.6 Hz), 7.07 (2H, d, J = 8.6 Hz), 7.20-7.29 (1H, m), 7.59-7.70 (1H, m), 8.88 (1H, s), 9.79 (1H, d, J = 7.6 Hz).
5,8-ジフルオロ-N-[(1S,2S)-2-ヒドロキシシクロヘキシル]-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 443.1
1H NMR (400 MHz, DMSO-d6) δ 1.14-1.37 (4H, m), 1.54-1.69 (2H, m), 1.80-1.91 (1H, m), 1.96-2.07 (1H, m), 3.36-3.43 (1H, m), 3.58-3.74 (4H, m), 4.82 (1H, d, J = 5.1 Hz), 5.70 (2H, d, J = 2.4 Hz), 6.90 (2H, d, J = 8.8 Hz), 7.07 (2H, d, J = 8.6 Hz), 7.19-7.30 (1H, m), 7.65 (1H, ddd, J = 13.9, 9.2, 4.3 Hz), 8.88 (1H, s), 9.79 (1H, d, J = 7.3 Hz).
1,5-アンヒドロ-2,3-ジデオキシ-3-({[1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロシンノリン-3-イル]カルボニル}アミノ)-DL-threo-ペンチトール
MS (ESI+): [M+H]+ 410.1
1H NMR (400 MHz, DMSO-d6) δ 1.52 (1H, brs), 2.09 (1H, brs), 3.12 (1H, t, J = 10.1 Hz), 3.36-3.55 (2H, m), 3.70 (3H, s), 3.74-3.95 (3H, m), 5.16 (1H, d, J = 5.6 Hz), 5.83 (2H, s), 6.90 (2H, d, J = 8.8 Hz), 7.28 (2H, d, J = 8.8 Hz), 7.54-7.67 (1H, m), 7.82-7.93 (1H, m), 7.93-8.02 (1H, m), 8.28 (1H, d, J = 8.1 Hz), 9.82 (1H, d, J = 7.3 Hz).
1-(4-カルバモイルベンジル)-4-オキソ-1,4-ジヒドロシンノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 323.1
1H NMR (300 MHz, DMSO-d6) δ 5.92 (2H, s), 7.36 (3H, d, J = 8.0 Hz), 7.53-7.65 (1H, m), 7.77-7.99 (6H, m), 8.28 (1H, d, J = 8.0 Hz), 8.87 (1H, d, J = 2.3 Hz).
1-(4-カルバモイルベンジル)-N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 420.2
1H NMR (300 MHz, DMSO-d6) δ 1.30 (4H, d, J = 8.3 Hz), 1.55-1.71 (2H, m), 1.87 (1H, d, J = 8.3 Hz), 2.03 (1H, d, J = 10.6 Hz), 3.34-3.46 (1H, m), 3.71 (1H, d, J = 8.7 Hz), 4.81 (1H, d, J = 4.9 Hz), 5.85 (2H, s), 7.28 (2H, d, J = 8.3 Hz), 7.34 (1H, brs), 7.50 (1H, t, J = 7.2 Hz), 7.65-7.77 (2H, m), 7.82 (2H, d, J = 8.3 Hz), 7.92 (1H, brs), 8.36 (1H, d, J = 7.6 Hz), 9.09 (1H, s), 10.08 (1H, d, J = 7.6 Hz).
1-(4-カルバモイルベンジル)-N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-4-オキソ-1,4-ジヒドロシンノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 421.2
1H NMR (300 MHz, DMSO-d6) δ 1.16-1.41 (4H, m), 1.55-1.71 (2H, m), 1.82-1.93 (1H, m), 1.98-2.09 (1H, m), 3.35-3.47 (1H, m), 3.63-3.76 (1H, m), 4.79 (1H, d, J = 5.3 Hz), 5.96 (2H, s), 7.35 (3H, d, J = 8.0 Hz), 7.57-7.64 (1H, m), 7.78-7.89 (4H, m), 7.93 (1H, brs), 8.29 (1H, d, J = 8.0 Hz), 9.74 (1H, d, J = 7.6 Hz).
1-(4-カルバモイルベンジル)-N-[(1S,2S)-2-ヒドロキシシクロヘキシル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 420.3
1H NMR (400 MHz, DMSO-d6) δ 1.15-1.39 (4H, m), 1.55-1.71 (2H, m), 1.81-1.92 (1H, m), 2.05 (1H, brs), 3.40 (1H, brs), 3.69 (1H, brs), 4.83 (1H, d, J = 4.6 Hz), 5.85 (2H, s), 7.28 (2H, d, J = 7.6 Hz), 7.37 (1H, brs), 7.50 (1H, t, J = 7.3 Hz), 7.66-7.76 (2H, m), 7.82 (2H, d, J = 7.6 Hz), 7.94 (1H, brs), 8.36 (1H, d, J = 7.8 Hz), 9.09 (1H, s), 10.09 (1H, d, J = 7.3 Hz).
8-フルオロ-N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-4-オキソ-1-[4-(1H-ピラゾール-1-イル)ベンジル]-1,4-ジヒドロキノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 461.3
1H NMR (400 MHz, DMSO-d6) δ 1.15-1.39 (4H, m), 1.55-1.70 (2H, m), 1.87 (1H, d, J = 9.5 Hz), 2.03 (1H, d, J = 11.2 Hz), 3.37-3.45 (1H, m), 3.69 (1H, d, J = 8.3 Hz), 4.83 (1H, d, J = 5.1 Hz), 5.86 (2H, brs), 6.52 (1H, s), 7.24 (2H, d, J = 8.3 Hz), 7.51 (1H, td, J = 7.9, 4.4 Hz), 7.64 (1H, dd, J = 14.5, 7.9 Hz), 7.72 (1H, s), 7.80 (2H, d, J = 8.3 Hz), 8.22 (1H, d, J = 8.1 Hz), 8.44 (1H, d, J = 2.2 Hz), 9.01 (1H, s), 9.93 (1H, d, J = 7.6 Hz).
N-[(1,2-trans)-5,5-ジフルオロ-2-ヒドロキシシクロヘキシル]-5,8-ジフルオロ-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 479.3
1H NMR (400 MHz, DMSO-d6) δ 1.58 (1H, brs), 1.77-2.20 (4H, m), 2.30-2.41 (1H, m), 3.54-3.81 (4H, m), 4.02 (1H, brs), 5.15 (1H, brs), 5.70 (2H, brs), 6.90 (2H, d, J = 7.8 Hz), 7.08 (2H, d, J = 7.8 Hz), 7.25 (1H, t, J = 9.8 Hz), 7.66 (1H, brs), 8.88 (1H, s), 9.93 (1H, d, J = 7.1 Hz).
N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-4-オキソ-1-[4-(1H-ピラゾール-5-イル)ベンジル]-1,4-ジヒドロキノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 443.3
1H NMR (400 MHz, DMSO-d6) δ 1.17-1.38 (4H, m), 1.56-1.70 (2H, m), 1.87 (1H, d, J = 10.0 Hz), 2.03 (1H, d, J = 12.5 Hz), 3.37-3.47 (1H, m), 3.66-3.74 (1H, m), 4.83 (1H, d, J = 4.9 Hz), 5.80 (2H, s), 6.66 (1H, d, J = 2.0 Hz), 7.27 (2H, d, J = 8.1 Hz), 7.51 (1H, t, J = 7.8 Hz), 7.69-7.81 (5H, m), 8.36 (1H, d, J = 7.8 Hz), 9.10 (1H, s), 10.10 (1H, d, J = 7.6 Hz), 12.88 (1H, brs).
1-(4-カルバモイルベンジル)-N-[(1,2-trans)-2-フルオロシクロヘキシル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 422.1
1H NMR (400 MHz, DMSO-d6) δ 1.30-1.46 (3H, m), 1.49-1.77 (3H, m), 1.91-2.12 (2H, m), 3.99-4.12 (1H, m), 4.45-4.66 (1H, m), 5.85 (2H, s), 7.29 (2H, d, J = 8.1 Hz), 7.36 (1H, brs), 7.51 (1H, t, J = 7.3 Hz), 7.66-7.77 (2H, m), 7.82 (2H, d, J = 8.3 Hz), 7.94 (1H, brs), 8.36 (1H, d, J = 7.1 Hz), 9.11 (1H, s), 10.20 (1H, d, J = 8.3 Hz).
8-フルオロ-N-[(1,2-trans)-2-ヒドロキシシクロペンチル]-4-オキソ-1-[4-(1H-ピラゾール-1-イル)ベンジル]-1,4-ジヒドロキノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 447.2
1H NMR (300MHz, DMSO-d6) δ 1.38-1.95 (5H, m), 2.02-2.18 (1H, m), 3.88-4.10 (2H, m), 5.86 (2H, d, J = 2.8 Hz), 6.47-6.56 (1H, m), 7.25 (2H, d, J = 8.5 Hz), 7.51 (1H, td, J = 8.0, 4.4 Hz), 7.59-7.69 (1H, m), 7.72 (1H, d, J = 1.7 Hz), 7.79 (2H, d, J = 8.5 Hz), 8.21 (1H, d, J = 7.9 Hz), 8.44 (1H, d, J = 2.5 Hz), 9.02 (1H, s), 9.89 (1H, d, J = 7.2 Hz).
N-[(1,2-trans)-2-ヒドロキシシクロペンチル]-1-[4-(2-メチルピリジン-4-イル)ベンジル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 454.4
1H NMR (300MHz, DMSO-d6) δ 1.37-1.95 (5H, m), 2.02-2.18 (1H, m), 2.45 (3H, s), 3.89-4.11 (2H, m), 4.94 (1H, d, J = 3.4 Hz), 5.86 (2H, s), 7.36 (2H, d, J = 8.1 Hz), 7.41-7.57 (3H, m), 7.70-7.82 (4H, m), 8.36 (1H, d, J = 7.7 Hz), 8.47 (1H, d, J = 5.1 Hz), 9.13 (1H, s), 10.05 (1H, d, J = 7.2 Hz).
1-[4-(1,3-ジメチル-1H-ピラゾール-4-イル)ベンジル]-N-[(1,2-trans)-2-ヒドロキシシクロペンチル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド
MS (ESI+): [M+H]+ 457.4
1H NMR (300MHz, DMSO-d6) δ 1.37-1.96 (5H, m), 2.02-2.17 (1H, m), 2.24 (3H, s), 3.75 (3H, s), 3.89-4.10 (2H, m), 5.78 (2H, s), 7.24 (2H, d, J = 8.3 Hz), 7.39 (2H, d, J = 8.3 Hz), 7.47-7.56 (1H, m), 7.71-7.86 (3H, m), 8.35 (1H, dd, J = 8.0, 1.2 Hz), 9.09 (1H, s), 10.05 (1H, d, J = 7.4 Hz).
実施例7ないし9、11ないし26、28ないし70、72、76、77、79、81、82、83、86、87、および89ないし91の化合物は、市販の試薬、あるいは参考例で得た化合物を用いて、上記の方法、またはそれらに準じた方法に従って製造した。表中のMSは実測値を示す。
(1)実施例1で得られた化合物 10.0g
(2)乳糖 60.0g
(3)コーンスターチ 35.0g
(4)ゼラチン 3.0g
(5)ステアリン酸マグネシウム 2.0g
実施例1で得られた化合物10.0gと乳糖60.0gおよびコーンスターチ35.0gの混合物を、10重量%ゼラチン水溶液30mL(ゼラチンとして3.0g)を用い、1mmメッシュの篩を通して顆粒化した後、40℃で乾燥し再び篩過する。得られた顆粒をステアリン酸マグネシウム2.0gと混合し、圧縮する。得られた中心錠を、蔗糖、二酸化チタン、タルクおよびアラビアゴムの水懸濁液による糖衣でコーティングする。コーティングが施された錠剤をミツロウで艶出して1000錠のコート錠を得る。
(1)実施例1で得られた化合物 10.0g
(2)乳糖 70.0g
(3)コーンスターチ 50.0g
(4)可溶性デンプン 7.0g
(5)ステアリン酸マグネシウム 3.0g
実施例1で得られた化合物10.0gとステアリン酸マグネシウム3.0gを可溶性デンプンの水溶液70mL(可溶性デンプンとして7.0g)で顆粒化した後、乾燥し、乳糖70.0gおよびコーンスターチ50.0gと混合する。混合物を圧縮して1000錠の錠剤を得る。
コリン作動性ムスカリンM1受容体ポジティブアロステリックモジュレーター(M1PAM)活性の測定
最大活性の20%の作用を与えるEC20濃度 (最終濃度0.6 nM)のアセチルコリン存在下での被検化合物の活性をM1PAM活性として測定した。その方法は以下のとおりである。384ウェル黒色透明底プレート (BDファルコン)にヒトM1受容体 (hCHRM1)を強制発現させたCHO-K1細胞を5,000個/ウェルで播種し、37℃、5% CO2インキュベーター内で一日培養した。細胞プレートの培地を除去後、カルシウム指示薬を含むアッセイ緩衝液A (Recording medium (同仁化学)、0.1% ウシ血清アルブミン(BSA) (和光純薬)、2.5 μg/mL Fluo-4 AM (同仁化学)、0.08% Pluronic F127 (同仁化学)、1.25 mM probenecid (同仁化学))を30 μL/ウェル添加した。37℃、5% CO2インキュベーター内に30分間静置した後、室温でさらに30分間静置した。2.4 nMのアセチルコリンを含むアッセイ緩衝液B (HBSS (Invitrogen)、20 mM HEPES (Invitrogen)、0.1% BSA)で希釈調製した被検化合物を、10 μL/ウェル添加し、FLIPRtetra (モレキュラーデバイス)で蛍光値を1秒毎に1分間測定した。最終濃度が1 μM のアセチルコリンを添加した際の蛍光値変化量を100%、被検化合物の代わりにDMSOを添加した場合の蛍光値変化量を0%と定義して被検化合物の活性(%)、被検化合物の濃度依存曲線の変曲点をIP値として算出した。結果を表2に示す。
中枢移行性(Kp値)の測定試験
A. 実施例6および10の化合物について(静脈内投与:i.v.)
A-1.実施例6
動物:Jcl ICR マウス雄性 7週齢 n=3
摂餌:非絶食
投与条件:静脈内投与 0.20 mg/1 mL/kg (4化合物/カセット投与)
投与媒体:N,N-ジメチルアセトアミド(DMA)/1,3-Butanediol (1:1)
採取試料:血漿、脳(4倍量の生理食塩水を加えてホモジネートを調製)
血漿採取時間:0.25時間
脳採取時間:0.25時間
A-2.実施例10
動物:Jcl ICRマウス雄性 8週齢 n=3
摂餌:非絶食
投与条件:静脈内投与 0.20 mg/1 mL/kg (4化合物/カセット投与)
投与媒体:DMA/1,3-Butanediol (1:1)
採取試料:血漿、脳(4倍量の生理食塩水を加えてホモジネートを調製)
血漿採取時間:0.5時間
脳採取時間:0.5時間
カラム:Shimadzu Shim-pack XR-ODS (2.2 μm, 2.0 x 30 mm)
移動相A:10 mmol/L ギ酸アンモニウム/ギ酸 (100:0.2, v/v)
移動相B:アセトニトリル/ギ酸(100:0.2, v/v)
流速:0.7 mL/min.
カラム温度:50℃
サンプル注入量:1 μL(実施例6),2 μL(実施例10)
脳前処理条件:試料50 μLに標準溶液溶解溶媒(DMSO)または標準溶液5 μLを添加した。内部標準物質を含んだアセトニトリル150 μLを加えて激しく攪拌した。5250 rpmで遠心分離を行った。遠心分離上清60 μLに希釈溶媒160 μLを添加した。この溶液40 μLをとり、希釈溶媒160 μLを添加し、化合物脳内濃度測定用試料溶液とした(希釈溶媒として移動相A:移動相B=7:3 (v/v)を用いた)。
動物:Jcl ICR マウス雄性 10週齢 n=3
摂餌:非絶食
投与条件:経口投与 1 mg/10 mL/kg (5化合物/カセット投与)
投与媒体:0.5% メチルセルロース溶液
採取試料:血漿、脳(4倍量の生理食塩水を加えてホモジネートを調製)
血漿採取時間:1時間
脳採取時間:1時間
カラム:Shimadzu Shim-pack XR-ODS (2.2 μm, 2.0 x 30 mm)
移動相A:10 mmol/L ギ酸アンモニウム/ギ酸 (100:0.2, v/v)
移動相B:アセトニトリル/ギ酸(100:0.2, v/v)
流速:0.7 mL/min.
カラム温度:50℃
サンプル注入量:1 μL
脳前処理条件:試料50 μLに標準溶液溶解溶媒(DMSO/アセトニトリル (2:8))または標準溶液5 μLを添加した。内部標準物質を含んだアセトニトリル150 μLを加えて激しく攪拌した。5250 rpmで遠心分離を行った。遠心分離上清12 μLに希釈溶媒208 μLを添加した。この溶液50 μLをとり、希釈溶媒150 μLを添加し、化合物脳内濃度測定用試料溶液とした(希釈溶媒として移動相A:移動相B=7:3 (v/v)を用いた)。
Claims (18)
- 式(I)
R1は置換されていてもよいアミノ基、または置換されていてもよい環状アミノ基、
R2およびR3はそれぞれ独立して水素原子、または置換基、
Xは-CH=、または-N=、
環Aは置換されていてもよい5ないし10員環を表す。]
で表される化合物、またはその塩
(ただし、
(1)R1はメトキシ(メチル)アミノ基ではない;
(2)R1は置換されていてもよい飽和アザビシクロ環基およびテトラゾリル基から選ばれる置換基で置換されたアミノ基ではない;
(3)R1は式
Rbは水素原子またはフェニル低級アルキル基である)
で表される基ではない;
(4)R1は式
Rcは水素原子または低級アルキル基であり、
Rgは水素原子または低級アルキル基であり、
nは2または3であり、
RhおよびRiはフェニル基であり、
Rf、RhおよびRiの定義におけるフェニル基またはフェニル部分は1ないし3個のハロゲン原子、低級アルキル基、トリフルオロメチル基、低級アルコキシ基または水酸基で置換されていてもよい)
で表される基ではない;
(5)環Aが無置換のフェニル基ではない;且つ
(6)R2およびR3がともに水素原子のとき、環Aが無置換のC3-6シクロアルキル基、または4位にハロゲン原子またはメチル基を有するフェニル基ではない。)。 - 式(I)
R1は置換されていてもよいアミノ基、または置換されていてもよい環状アミノ基、
R2およびR3はそれぞれ独立して水素原子、または置換基、
Xは-CH=、または-N=、
環Aは置換されていてもよい5ないし10員環を表す。]
で表される化合物、またはその塩
(ただし、
(1)R1はメトキシ(メチル)アミノ基ではない;
(2)R1は置換されていてもよい飽和アザビシクロ環基およびテトラゾリル基から選ばれる置換基で置換されたアミノ基ではない;
(3)R1は式
Rbは水素原子またはフェニル低級アルキル基である)
で表される基ではない;
(4)R1は式
RC は水素原子または低級アルキル基であり、
Rgは水素原子または低級アルキル基であり、
nは2または3であり、
RhおよびRiはフェニル基であり、
Rf、RhおよびRiの定義におけるフェニル基またはフェニル部分は1ないし3個のハロゲン原子、低級アルキル基、トリフルオロメチル基、低級アルコキシ基または水酸基で置換されていてもよい)
で表される基ではない;
(5)環Aが無置換のフェニル基ではない;
(6)R2およびR3がともに水素原子のとき、環Aが無置換のC3-6シクロアルキル基、または4位にハロゲン原子またはメチル基を有するフェニル基ではない;
(7)R2がアミノ基ではない;且つ、
(8)以下の化合物を除く
(i) N-シクロヘキシル-1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-4-オキソ-3-キノリンカルボキサミド、および
(ii) 1,4-ジヒドロ-1-[(4-メトキシフェニル)メチル]-N-(2-メチルフェニル)-4-オキソ-3-キノリンカルボキサミド。)。 - R1は
(a)(1)アミノ基、
(2)(i)水酸基、(ii)C1-3アルコキシ基、(iii)1ないし3個の水酸基で置換されたC3-6シクロアルキル基、(iv)フェニル基、(v)フリル基、(vi)テトラヒドロフラニル基、(vii)ピペリジノ基および(viii)モルホリノ基から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基、
(3)ハロゲン原子、水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよいC3-6シクロアルキル基、
(4)4ないし10員環状アミノ基、
(5)ハロゲン原子、1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよいフェニル基、
(6)1ないし3個の水酸基で置換されたジヒドロインデニル基、
(7)ピラゾリル基、
(8)テトラヒドロフラニル基、および
(9)1ないし3個の水酸基で置換されたテトラヒドロピラニル基
から選ばれる1または2個の置換基で置換されていてもよいアミノ基、または
(b)水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよい4ないし10員環状アミノ基であり、
R2およびR3は同一で水素原子、またはハロゲン原子であるか、あるいは
R2は水素原子であり、R3はハロゲン原子、または1ないし3個のハロゲン原子で置換されたC1-3アルコキシ基であり、
Xは-CH=、または-N=であり、
環Aは
4位が(i)1ないし3個のハロゲン原子で置換されたC1-3アルキル基、(ii)C1-3アルコキシ基、(iii)カルバモイル基、(iv)1ないし3個のC1-3アルキル基で置換されていてもよいピラゾリル基および(v)1ないし3個のC1-3アルキル基で置換されたピリジル基から選ばれる置換基で置換されたフェニル基である、
請求項1または2記載の化合物、またはその塩。 - R1は
(1)アミノ基、
(2)(i)水酸基、(ii)C1-3アルコキシ基および(iii)1ないし3個の水酸基で置換されたC3-6シクロアルキル基から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基、
(3)ハロゲン原子、水酸基およびヒドロキシメチル基から選ばれる1ないし3個の置換基で置換されていてもよいC3-6シクロアルキル基、
(4)ピペリジノ基、
(5)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基から選ばれる1ないし3個の置換基で置換されていてもよいフェニル基、および
(6)1ないし3個の水酸基で置換されたテトラヒドロピラニル基
から選ばれる1個の置換基で置換されていてもよいアミノ基であり、
R2およびR3は同一で水素原子、またはハロゲン原子であるか、あるいは
R2は水素原子であり、R3はハロゲン原子であり、
Xは-CH=、または-N=であり、
環Aは
4位が(i)1ないし3個のハロゲン原子で置換されたC1-3アルキル基、(ii)C1-3アルコキシ基、(iii)カルバモイル基、(iv)1ないし3個のC1-3アルキル基で置換されていてもよいピラゾリル基および(v)1ないし3個のC1-3アルキル基で置換されたピリジル基から選ばれる置換基で置換されたフェニル基である、
請求項1または2記載の化合物、またはその塩。 - R1は
(1)アミノ基、
(2)ハロゲン原子および水酸基から選ばれる1ないし3個の置換基で置換されたC3-6シクロアルキル基、および
(3)1ないし3個の水酸基で置換されたテトラヒドロピラニル基
から選ばれる1個の置換基で置換されたアミノ基であり、
R2およびR3は同一で水素原子、またはハロゲン原子であるか、あるいは
R2は水素原子であり、R3はハロゲン原子であり、
Xは-CH=、または-N=であり、
環Aは
4位が(i)C1-3アルコキシ基、(ii)カルバモイル基、(iii)1ないし3個のC1-3アルキル基で置換されていてもよいピラゾリル基および(vi)1ないし3個のC1-3アルキル基で置換されたピリジル基から選ばれる置換基で置換されたフェニル基である、
請求項1または2記載の化合物、またはその塩。 - 1,5-アンヒドロ-2,3-ジデオキシ-3-({[5,8-ジフルオロ-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-イル]カルボニル}アミノ)-DL-threo-ペンチトール、またはその塩。
- 5,8-ジフルオロ-N-[(1,2-trans)-2-ヒドロキシシクロヘキシル]-1-(4-メトキシベンジル)-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド、またはその塩。
- 8-フルオロ-N-[(1,2-trans)-2-ヒドロキシシクロペンチル]-4-オキソ-1-[4-(1H-ピラゾール-1-イル)ベンジル]-1,4-ジヒドロキノリン-3-カルボキサミド、またはその塩。
- 1-[4-(1,3-ジメチル-1H-ピラゾール-4-イル)ベンジル]-N-[(1,2-trans)-2-ヒドロキシシクロペンチル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボキサミド、またはその塩。
- 請求項1または2に記載の化合物、またはその塩を含有する医薬。
- コリン作動性ムスカリンM1受容体ポジティブアロステリックモジュレーターである請求項10記載の医薬。
- アルツハイマー病、統合失調症、痛みまたは睡眠障害の予防または治療薬である請求項10記載の医薬。
- 哺乳動物に対して、請求項1または2記載の化合物、またはその塩を有効量投与することを特徴とする、アルツハイマー病、統合失調症、痛みまたは睡眠障害の予防または治療方法。
- コリン作動性ムスカリンM1受容体ポジティブアロステリックモジュレーターを製造するための、請求項1または2記載の化合物、またはその塩の使用。
- アルツハイマー病、統合失調症、痛みまたは睡眠障害の予防または治療薬を製造するための、請求項1または2記載の化合物、またはその塩の使用。
- コリン作動性ムスカリンM1受容体ポジティブアロステリックモジュレーションに使用するための、請求項1または2記載の化合物、またはその塩。
- アルツハイマー病、統合失調症、痛みまたは睡眠障害の予防または治療に使用するための、請求項1または2記載の化合物、またはその塩。
- 哺乳動物に対して、請求項1または2記載の化合物、またはその塩を有効量投与することを特徴とする、コリン作動性ムスカリンM1受容体ポジティブアロステリックモジュレート方法。
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US9403802B2 (en) | 2016-08-02 |
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