WO2000031021A1 - β-AMYLOID PROTEIN PRODUCTION/SECRETION INHIBITORS - Google Patents
β-AMYLOID PROTEIN PRODUCTION/SECRETION INHIBITORS Download PDFInfo
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- WO2000031021A1 WO2000031021A1 PCT/JP1999/006450 JP9906450W WO0031021A1 WO 2000031021 A1 WO2000031021 A1 WO 2000031021A1 JP 9906450 W JP9906450 W JP 9906450W WO 0031021 A1 WO0031021 A1 WO 0031021A1
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- alkyl
- alkoxy
- halogenated
- mono
- optionally halogenated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- 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
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- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/50—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Definitions
- the present invention relates to an excellent / 3 amyloid protein production / secretion inhibitor, a novel amine derivative having the action, and a method for producing the same.
- Alzheimer's disease is a neurodegenerative disease characterized by the formation of senile plaques and neurofibrillary tangles with neuronal degeneration.
- the senile plaque most characteristic of Alzheimer's disease is composed mainly of / 3 amyloid protein (hereinafter sometimes abbreviated as Ai3).
- A) 3 consisting of 40 or 42 amino acids (hereinafter abbreviated as A / 3 1-40 and A31-42, respectively) is toxic to nerve cells and induces neurofibrillary tangles It is known to
- a drug that inhibits the production and secretion of A3 is particularly useful as a prophylactic for the disease in patients who are genetically likely to suffer from the disease, such as familial Alzheimer's disease.
- drugs that promote secretion of secreted-type APP include (1) neurodegenerative diseases (eg, Alzheimer's disease, Down's syndrome, senile dementia, Parkinson's disease, Creutzfeldt-Jakob disease, Amyotrophic lateral sclerosis, diabetic neuropathy, Huntington's chorea, multiple sclerosis, etc.), (2) cerebrovascular disorders (eg, cerebral infarction, cerebral hemorrhage, etc.), neuropathy due to head injury or spinal cord injury, etc. It is useful for prevention and treatment.
- neurodegenerative diseases eg, Alzheimer's disease, Down's syndrome, senile dementia, Parkinson's disease, Creutzfeldt-Jakob disease, Amyotrophic lateral sclerosis, diabetic neuropathy, Huntington's chorea, multiple sclerosis, etc.
- cerebrovascular disorders eg, cerebral infarction, cerebral hemorrhage, etc.
- neuropathy due to head injury or spinal cord injury etc. It is useful for prevention and treatment.
- EP-A-652009 discloses a peptide derivative having a protease inhibitory action and an A3 production inhibitory action at a cellular level.
- JP-A-2-91052 discloses that
- JP-A-2-73069 discloses a thiazole derivative having a monoamine oxidase inhibiting activity.
- W098 / 38156 discloses a compound having a condensed ring skeleton of a benzene ring and a 4- to 8-membered ring, and having a / 3 amyloid production / secretion inhibitory action.
- Japanese Patent Application Laid-Open No. 5-239005 discloses N- (2-aminominethyl) benzamides useful for treating senile dementia. No effect is described.
- the 5/1 7 1 8 3 has a Hosuhoripa Ichize A 2 inhibitory action, although compounds useful in the treatment of such senile dementia are disclosed,] for a 3-amyloid production-secretion inhibitory effect is Not listed.
- WO98-066691 discloses an amine derivative having an inhibitory effect on aggregation and accumulation of 3 amyloid proteins and useful for the prevention and treatment of Alzheimer's disease, but inhibits i3 amyloid production and secretion. No effect is described.
- WO 91/196697 discloses a pyridine derivative having angiotensin 11 antagonistic activity.
- JP-A-3-142277 discloses an amine compound used for a recording material.
- WO 93/23 040 discloses 17-ethers and thioethers of 4-azasteroids having 5 ⁇ -reductase inhibitory activity.
- the present inventors have conducted intensive studies on A) 3 compounds having a production / secretion inhibitory action, and as a result,
- Ar represents an aromatic group which may have a substituent
- X and Y may be the same or different, and represent one O—, —S—, —CO—, —SO—, — S ⁇ 2 —, — NR 8 —, — CONR 8 —, —S ⁇ 2 NR 8 — and —COO— divalent group
- R 8 is a hydrogen atom, a carbon atom which may have a substituent.
- Or a salt thereof has an unexpectedly excellent inhibitory action on [3] amyloid protein production and secretion. Furthermore, the present inventors have conducted studies based on these findings, and as a result, completed the present invention.
- Ar represents an aromatic group which may have a substituent
- X and Y are the same or different and are —O—, —S—, —CO—, —SO—, — S ⁇ 2 —, — NR 8 —, — CONR 8 —, — S0 2 NR s —, and —CO—a divalent group selected from the group (R 8 is a hydrogen atom, a carbon atom which may have a substituent.
- a monocyclic aromatic ring which may be substituted; / 3 amyloid protein production / secretion inhibitor comprising a compound represented by
- Ar is (i) a halogen atom, (ii) ⁇ —3 alkylenedioxy, UH) nitro, (iv) cyano, (V) optionally halogenated — 6 alkyl, (vi) C 6 — Ariruokishi one ⁇ - 6 alkyl, (vii) C ⁇ - 6 alkyl one C 6 - 1 () ⁇ Li one Roux C 2 _ 6 alkenyl, (viii) optionally C 3 which may be halogenated - 6 cycloalkyl le, ( ix) (a) octogen, (W ⁇ -3 alkylenedioxy, (c) nitro, (d) cyano, (e) optionally halogenated Ci-ealkyl, (f) halogen Optionally substituted C 3 _ 6 cycloalkyl, (g) optionally halogenated alkoxy, (h) optionally halogenated — 6-alkylthio, (i
- Alkylamino (m) formyl, (n) carboxy, (0) rubamoyl, (p) optionally halogenated alkyl- Luponyl, (qllC ⁇ 6- alkoxy-Ruponyl, (r) mono- ⁇ - 6 al Kill - Power Rubamoiru, (S) di - alkyl Ichiriki Rubamoiru, (t) optionally halogenated alkylsulfonyl, (U) Horumiruamino, optionally (V) halide ( ⁇ _ 6 alkyl one carboxamide, Ji bets 6 alkoxy - Cal Bokisamido, (chi).
- (xviii) 1 (a) optionally halogenated and C ⁇ - 6 alkyl, (b) halogen atom, (dCi- 3 alkylenedioxy O carboxymethyl, (d) nitro, (e) Shiano, (f) halogenated It is optionally C 3 - 6 cycloalkyl, (g) optionally halogenated good an alkoxy, (h) alkylthio which may be halogenated, (i) hydroxy, (j) ⁇ Mino, (k) mono- (to 6 alkylamino, (0 g (: ⁇ 6 alkylamino, (m) formyl, (n) carboxy, (0) rubamoyl, (p) optionally halogenated alkyl Carbonyl, (q) C i- 6 alkoxy mono-rubonyl, (r) mono-alkyl-mono-rubamoyl, (s) di-C ⁇ 6 alkyl mono-rubumboyl, (t
- R 3 is a hydrogen atom, or (i) a halogen atom, (iDC ⁇ 3 alkylenedioxy, (iii) nitro, (iv) cyano, (V) optionally halogenated — 6 alkyl, (vi ) Optionally halogenated C 3 _ 6 cycloalkyl, (vii) optionally halogenated C 6 alkoxy, (viii) optionally halogenated C 6 alkylthio, (ix) hydroxy, (X) amino, (xi) 6- alkylamino, (xii) di
- (xiii) 1 (a) optionally halogenated and C ⁇ - 6 alkyl, (b) halogen atom, (c) flicking 3 alkylene O carboxymethyl, (d) nitro, (e) Shiano, (f) halogen Optionally substituted C 3 _ 6 cycloalkyl, (g) optionally halogenated alkoxy, (h) optionally halogenated — 6 alkylthio, (i) hydroxy, (j) amino, ( k) mono - Arukiruamino, (1) di - C ⁇ - 6 Arukiruamino, (m) formyl, (n) force Rupokishi, (0) force Rubamoiru may be (p) halogenated - 6 alkylene Lou force Ruponiru , (q) C 1 _ 6 alkoxy - power Ruponiru, (r) mono- alkyl - power Rubamoiru, (s) Gee alkyl Ichiriki
- halogenated which may be C 3 _ 6 cycloalkyl, may be (g) halogenated - 6 alkoxy, (h) halo ( 6 ) alkylthio, (i) hydroxy, (j) amino, (k) mono-alkylamino, (1) di-6-alkylamino, (m) formyl, (n) lipoxy, ( 0) dirubamoyl, (p) optionally halogenated — 6 alkyl-diphenyl, (q) C ⁇ e; alkoxy monodipropyl, (r) mono- 6 alkyl monocarbamoyl; —Halvamoyl, (t) optionally halogenated alkylsulfonyl, (u) formylamino, (V) optionally halogenated C i-ealkyl mono-l-lupoxamide, (w)
- ⁇ ⁇ may be halogenated — 6-alkyl monopropionyl
- alkylsulfonyl which may be halogenated, (xiv) formyl, (XV) lipoxy, (xvi) force Rubamoiru, (xvii) an optionally halogenated ( ⁇ -6 alkyl - power Ruponiru, (xvi ii) ⁇ - 6 alkoxy Ichiriki Ruponiru, (xix) C 6 - 1 () Ariru one carbonyl, (XX) C 6 - 1 ( ) Ariruokishi - carbonyl, (xxi) C 7 _ 16 Ararukiruokishi Ichiriki Ruponiru, (xxi i) mono - C i _ 6 alkyl - power Rubamoiru, (xxiii) G C ⁇ - 6 alkyl - power Rubamoiru, (xxiv) C 6 -. ⁇ Li
- R 3a is (i) a halogen atom, (iDCi 3 alkylenedioxy, (iii) nitro, (iv) cyano, (V) optionally halogenated, alkyl, (vi) halogenated good C 3 6 cycloalkyl, (vii) optionally halogenated good alkoxy, (viii) optionally halogenated optionally C ⁇ 6 alkylthio, (ix) hydroxy, (X) Amino, (xi) Monoalkylamino, (xii) di (: ⁇ 6 alkylamino, (xiii) ⁇ (a) optionally halogenated ⁇ 6 alkyl, (b) halogen atom, (c) ⁇ alkylenedioxy, (d) Nitro, (e) cyano, (f) optionally halogenated C 3 _ 6 cycloalkyl, (g) optionally halogenated — 6 alkoxy, (h) optionally halogenated
- - 6 alkyl one carbonylation Ruoki sheet, (2) 1 ⁇ 6 alkoxy Ichiriki Ruponiruokishi, (aa) mono- 6 alkyl - 1 to 5 atoms selected from the group consisting of alkyl Ichiriki Rubamoiruokishi - Cal Bamoiruokishi and (bb) di substituents 4 may have a Ariru, optionally 2 (a) halogenated (: Bok 6 alkyl, (b) halogen atom, (C ⁇ s alkylenediamine O carboxymethyl, (d) nitro, (e) Shiano, (f) optionally halogenated and C 3 _ 6 cycloalkyl, (g) halogenated may Ji 6 alkoxy, (h) halogenation which may be C i - 6 alkylthio, (0 hydroxy, (j) amino, (k) mono (: 6 alkylamino, (1) dialkylamino, (m) formyl, (n
- an optionally halogenated C ⁇ - 6 alkoxy may be (h) halogenation - 6 alkylthio, (i) hydroxy, (j) Amino, (k) mono - Arukiruamino, (1) Gee C ⁇ - 6 Arukiruamino, (m) formyl, (n) force Rupokishi, (0) force Rubamoiru, alkyl which may be (P) halogenated - power Ruponiru, (0) 0 ⁇ - 6 alkoxy - power Ruponiru, (r) mono- 6 alkyl one local Bamoiru, (S) Gee alkyl Ichiriki Rubamoiru, (t) substituted alkylsulfonyl which may be halogenated, (U) Horumiruamino, (V) a halogen 6-alkyl-potassium lipoxamide, (v C i- 6 alkoxy), (v C i- 6 alkoxy,
- halogenation is may CI- e alkylthio, (i) hydroxy, (j) Amino, (k) mode no one 6- alkylamino, (1) di-alkylamino, (m) formyl, (n) lupoxy, (0) rubamoyl, (p) optionally halogenated 6- alkyl-carbonyl, (q) -6-alkoxy-lponyl (R) mono- 6- alkyl-carbamoyl, (s) di-alkyl-carbamoyl, (t) optionally halogenated alkylsulfonyl, (u) formylamino, (V)
- a 7- to 7-membered saturated cyclic amino which may have 1 to 3 substituents selected from the group consisting of d- 6 alkylsulfonyl which may be octogenated, (xiv) formyl, (XV ) Carboxy, (xvi) rubamoyl, (xvii) optionally halogenated alkyl-propylonyl, (xviii) alkoxy-propylonyl, (xixiCe ⁇ .
- nicotinate noisy Ruo alkoxy and (xxxix) C 6 - i 0 to 1 Ru selected from Ariruokishi may have 5 substituents, Ji alkyl, C 2 _ 6 alkenyl, C 2 - 6 alkynyl, C 3 - 6 cycloalkyl, C 3 - 6 cycloalkyl and fused ring group of benzene ring, c 6 _ 14 Ariru, c 7 - 19 Ararukiru or nitrogen atom besides carbon atom, a sulfur atom and an oxygen atom It 1 selected et indicates 5 of stone 14-membered heterocyclic group containing heteroatoms four of the,
- R 4 represents a hydrogen atom or C alkyl, or R 3 and R 4 together with an adjacent nitrogen atom contain at least one nitrogen atom other than a carbon atom, and are selected from a nitrogen atom, a sulfur atom and an oxygen atom. It may contain three heteroatoms and may form a 5- to 7-membered nitrogen-containing heterocycle.
- R 5 is a hydrogen atom or C ⁇ alkyl
- R 6 is the R 3 and as defined
- R 6a is the R 3 a as defined above
- R 6b R 4 and Ashiruamino and represented by as defined shows a] (xxi) formula: a O- COR 7, - O- COOR 7 or a O-CONHR 7 wherein, R 7 is shows the same meaning as the R 3 Which may have 1 to 5 substituents selected from the group consisting of acyloxy represented by
- a ring formed by condensing with one or two benzene rings is directly connected by a single bond, and the number of bonds directly connecting the rings is any number from an aromatic ring aggregate that is one less than the number of ring systems.
- C2 to C3 containing a C2 to C4 bicyclic or tricyclic aromatic hydrocarbon or (2) a carbon atom other than a nitrogen atom, a sulfur atom and an oxygen atom, which contain 1 to 4 heteroatoms.
- a monovalent fused aromatic group formed by removing any one hydrogen atom from a 14-membered fused polycyclic aromatic heterocycle,
- X and Y are the same or different, one O—, one S—, one CO—, one SO—, — S0 2 —, — NR 8 —, one CONR 8 —, — S0 2 NR 8 — and one COO— color selection
- R 8 is (1) hydrogen atom, (2) (i) a halogen atom, (IDCi- 3 ⁇ Rukirenjiokishi, (iii) nitro, (iv) Shiano, is (V) halide (Vi) optionally halogenated C 3 _ 6 cycloalkyl, (vii) optionally halogenated — 6 alkoxy, (viii) optionally halogenated 6 alkylthio (Ix) hydroxy, (X) amino, (xi) monoalkyl 6 alkylamino, (xii) di-alkylamino,
- (xiii) 1 (a) optionally halogenated alkyl, (b) halogen atom, (c) Ci one 3 alkylenedioxy O carboxymethyl, (d) nitro, (e) Shiano, are (f) halogenated C 3 _ 6 cycloalkyl, (g) optionally halogenated alkoxy, (h) optionally halogenated C ⁇ 6 alkylthio, (i) hydroxy, (j) amino, (k) Mono- 6- alkylamino, (1) G-6-alkylamino, (m) formyl, (n) carboxy, (0) rubamoyl, (p) optionally halogenated alkyl-carbonyl, (.) ⁇ -6 alkoxy one carbonyl, (r) mono- Ci-e alkyl Ichiriki Rubamoiru, (s) G CI- 6 alkyl Ichiriki Rubamoiru, (t) optionally halogenated C ⁇ - 6 alkylsulf
- C 6 — aryl which may have 1 to 5 substituents selected from the group consisting of ⁇ 6 alkoxy mono-rubonyloxy, (aa) mono-alkyl mono-carbamoyloxy and (bb) di-6-alkyl mono-rubamoyloxy , (2) (a) optionally halogenated alkyl, (b) halogen atom, (C n alkylenedioxy, (d) nitro, (e) cyano, (D optionally halogenated C 3 _ 6 Cycloalkyl, (g) optionally halogenated Ci- 6 alkoxy, (h) optionally halogenated 6 alkylthio, (i) hydroxy, (j) amino, (k) monoalkylamino , (1) di- 6- alkylamino, (m) formyl, (n) ruboxy, (0) rubamoyl, (P) optionally halogenated alkyl-one lpionyl, (q) alkoxy-
- a 7- to 7-membered saturated cyclic amino which may have 1 to 3 substituents selected from the group consisting of d-6 alkylsulfonyl which may be octogenated, (xiv) formyl, (XV (Xvi) lubamoyl, (xvii) optionally halogenated 6- alkyl-l-ponyl, (xviiDCi-e alkoxyl-l-pulponyl, (xix) C 6 -i.
- one Roux force Rubamoiruokishi, (xxxviii) nicotinoyl noisy Ruo alkoxy and (xxxix) C 6 - 10 to 1 Ru selected from Ariruokishi may have 5 substituents, alkyl, C 2 _ e alkenyl, C 2 - 6 alkynyl, C 3 - 6 cycloalkyl, C 3 _ 6 cycloalkyl and fused ring group of benzene ring, ⁇ 6 _ 14 Ariru or c 7 _ 19 Ararukiru or,
- R 3 is a hydrogen atom or (i) a halogen atom, (ii) one 3 alkylene O carboxymethyl, (iii) nitro, (iv) Shiano, (v) optionally halogenated alkyl, may be (vi) halogenated C 3 - 6 consequent opening alkyl, (vii) optionally halogenated C [I 6 alkoxy, (viii) halogen of which may be alkylthio, (ix) hydroxy, (X) Amino, (xi) mode No-C 6 alkylamino, (xii) C-ealkylamino,
- (xiii) 1 (a) optionally halogenated — 6 alkyl, (b) halogen atom, (c) 3 alkylenedioxy, (d) nitro, (e) cyano, (f) halogenated which may be C 3 - 6 cycloalkyl, (g) halogenated or may be one 6 alkoxy, (h) optionally halogenated alkylthio, (i) hydroxy, (j) Amino, (k) mono - (- Bok 6 Arukiruamino, (1) di - 6 Arukiruamino, (m) formyl, (n) carboxy, (0) force Rubamoiru may be (p) halogenated CI- e alkyl Le - carbonyl, (q) C 1 _ 6 alkoxy - power Ruponiru, (r) a mono - 6 alkyl Ichiriki Rubamoiru, (s) di - alkyl Ichiriki Rubamoiru
- ⁇ ⁇ may be halogenated — may have 1 to 3 substituents selected from the group consisting of 6 alkylsulfonyl, and may have 5 to 7 membered saturated cyclic amino, (xiv) formyl, (XV) carboxy (Xvi) rubamoyl, (xvi i) optionally halogenated — 6-alkyl- propylonyl, (xviii) alkoxycarbonyl, (xix). Ariel Ippiki Luponir, (XX).
- Ariruokishi - carbonyl (xxi) C 7 16 Ararukiruokishi carbonyl, (xxii) mono- alkyl - Karubamo I le, (xxiii) Gee Ji 6 alkyl - Power Rubamoiru, (xxiv) C 6.
- Ariru - Power Rubamoiru, (XXV) good C ⁇ 6 alkylsulfonyl which may be halogenated, (xxvi) C 6.
- (xxxviii) nicotinoyl noisy Ruo alkoxy and (xxxix) to 1 Ru is selected from C 6 _ 10 Ariruokishi may have 5 substituents, alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 6 cycloalkyl, C 3 _ 6 cycloalkyl and fused ring group of benzene ring, C 14 Ariru, C 7 - 19 Ararukiru or nitrogen atom in addition to carbon atoms, to 1 selected from sulfur atom and oxygen atom 4 A 5- or 14-membered heterocyclic group containing 5 heteroatoms,
- R 3a is (i) a halogen atom, (iDC ⁇ salkylenedioxy, (Hi) nitro, (iv) cyano, (V) optionally halogenated alkyl, (vi) halogenated which may C 3 _ 6 cycloalkyl, may be (vii) halogenated - 6 alkoxy, (viii) optionally halogenated or 6 alkylthio, (ix) hydroxy, (X) Amino, (xi) Mono--6 alkylamino, (xii) dialkylamino, (xiii) 1 (a) optionally halogenated C- 6 alkyl, (b) halogen atom, (c) 3-alkylenedioxy, (d) nitro , (e) Shiano, (f) an optionally halogenated C 3 - 6 cycloalkyl, (g) optionally halogenated alkoxy, (h) halogenated may Ji 6 alkylthio, (
- ⁇ ⁇ Alkoxy mono-lponyl (r) mono-alkyl-carbamoyl, (s) di-C ⁇ 6 alkyl-l-bamoyl, (t) optionally halogenated alkylsulfonyl, (U) formylamino, (V ) may be halogenated ⁇ - 6 alkyl one carboxamido, ⁇ ) ( ⁇ - 6 alkoxy Ichiriki Rupokisamido,
- 6- alkylamino (m ) Formyl, (n) lupoxy, (0) rubamoyl, (P) optionally halogenated alkyl monoluponyl, (q) 6 alkoxy-luponyl, (r) mono- 6 alkyl-cal Bamoyl, (s) di-alkyl monoalkyl rubamoyl, (t) optionally halogenated 6 alkylsulfonyl, (u) formylamino, (V) optionally halogenated alkyl-carboxamide, ⁇ ) ( ⁇ 6 Alkoxy-carboxa De, (s) C ⁇ 6 alkylsulfonyl ⁇ amino, (y) C ⁇ 6 alkyl one carbonyl O carboxymethyl, (z) alkoxy Ichiriki Ruponiruokishi, (aa) mono - C - 6 alkyl Ichiriki Rubamoiru Okishi and (bb) di one C i _ 6 1
- 6 halogenated 5 may have 3 substituents to 1 Ru is selected from the group consisting also be 6 alkylsulfonyl which is to 7-membered saturated cyclic Amino, (xiv) formyl, (XV) force Rupokishi (Xvi) carbamoyl, (xvii) optionally halogenated C 6 alkyl monocarbonyl, (xvi ii) 6 alkoxy mono propylonyl, (Xix). ⁇ Li one Roux carbonyl, (XX) C 6 _ 10 Ariruokishi - carbonyl,
- Li one Roux force Rubamoiruokishi, (xxxviii) nicotinoyl noisy Ruo alkoxy and (xxxix) C 6 - may have 10 1 Ru is selected from Ariruokishi to 5 substituents, C i-6 alkyl, C 2 — 6 alkenyl, c 2 - 6 alkynyl, c 3 _ 6 cycloalkyl, c 3 _ 6 cycloalkyl and fused ring group of benzene ring, c 6 - 14 Ariru, c 7 _ 19 Ararukiru or nitrogen atom besides carbon atom, a sulfur atom And a 5- or 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from and an oxygen atom,
- R 4 together with hydrogen atom or ( ⁇ _ 6 force or R 3 represents an alkyl and R 4 are the adjacent nitrogen atom, a nitrogen atom containing at least one nitrogen atom in addition to carbon atoms, selected from sulfur atom and oxygen atom Or a 5- or 7-membered nitrogen-containing heterocyclic ring which may contain 1 to 3 heteroatoms.
- a divalent group represented by the formula 1 or 2 contain an optionally alkylene, C 2 one 6 Aruke shows a two alkylene or C 2 _ 6 alkynylene,
- R 1 and R 2 are (1) hydrogen atom or (2) (i) halogen atom, (iDCi- 3 alkylenedioxy, (iii) nitro, (iv) cyano, (V) optionally halogenated C alkyl , (vi) optionally halogenated optionally C 3 _ 6 cycloalkyl, (vii) halogenation which may be alkoxy, (viii) optionally halogenated have good 6 alkylthio, (ix) hydroxy, (X) amino, (xi) mono-alkyl 6- amino, (xii) di- 6- alkylamino, (xiii) formyl, (xiv) lipoxy, (XV) rubamoyl, (xvi) may be halogenated 6- alkyl monopropyl, (xviDC ⁇ 6 alkoxy-carbonyl, (xviii) mono--6-alkyl-carbamoyl, (xix) di--6-alkyl-potam
- R 1 and R 2 together with the adjacent nitrogen atom (i) (a) optionally halogenated or ⁇ Bok 6 alkyl, (b) halogen atom, (Ci-g alkylene O carboxymethyl, (d) nitro, ( e) Shi ⁇ Bruno, (f) an optionally halogenated C 3 - 6 cycloalkyl, (g) halogenated (H) optionally halogenated C i-e alkylthio, (i) hydroxy, (j) amino, (k) mono ( ⁇ -6 alkylamino, (1) ( 6 ) alkylamino, (m) formyl, (n) lipoxy, (0) rubamoyl, (p) alkyl-carbonyl optionally halogenated, (q) alkenyl-carbonyl, (q) mono - - 6 alkyl - power Rubamoiru, (S) G ⁇ - 6 alkyl - power Rubamoiru, (t) substituted alkyls
- Alkoxy-capillon (r) mono-C ⁇ 6 alkyl Moil, (s) G C ⁇ 6 alkyl - Power Rubamoiru, (t) optionally halogenated C i-e alkylsulfonyl, (U) Horumiruamino, optionally (V) halide C ⁇ - 6 Alkyl monopropoxamide, (w) 6 alkoxy-carpoxamide, (S) Alkylcarbonylcarbonyl,).
- Aryl to carbonyl (V) optionally halogenated C 6 alkyl-carbonyl and (vi) optionally halogenated C 6 .alkylsulfonyl.
- a ring is indicated by the A r- X- above, a halogen atom, an optionally halogenated ( ⁇ alkyl, optionally halogenated ( ⁇ _ 6 an alkoxy, hydroxy and Amino A benzene ring or a carbon atom which may have 1 to 3 substituents selected from the group consisting of: a nitrogen atom, a sulfur atom and an oxygen atom; Inhibitor according to claim 1, which represents a 6-membered aromatic heterocyclic ring,
- X is a group represented by the formula: — (CH 2 ) p x O— (where p 1 represents an integer of 1 to 3), and 2 Formula— (CH 2 ) p 2 — (wherein, p 2 represents an integer of 1 to 3); 3 a group represented by the formula — (CH 2 ) p 3 OC ⁇ NH— (where p 3 represents an integer of 1 to 3) 8.
- X is represented by the formula — (CH 2 ) pi ⁇ (where p 1 represents an integer of 1 to 3).
- Y is a formula — (CH 2 ) q ⁇ ONR 9 (CH 2 ) r 1 — (wherein q 1 and r 1 are each an integer of 0 to 3 and the sum is an integer of 3 or less, R 9 is a group or 2 Shiki represented by a hydrogen atom or a halogenated may CI_ 6 alkyl or optionally halogenated alkyl Ichiriki Ruponiru) (CH 2) q 2 COO (CH 2 the inhibitor according to claim 1, which is a group represented by r 2- (wherein, Q 2 and r 2 are each 0 to 3 and a total thereof is an integer of 3 or less), 1 1.
- Y is the formula — (CH 2 ) q ⁇ ONR 9 (CH 2 ) r 1 — (wherein, Q 1 and r 1 are each an integer of 0 to 3 and their sum is 3 or less; 9 is a hydrogen atom or an optionally halogenated alkyl or an optionally halogenated C ⁇ 6 alkyl monovalent rubonyl), an inhibitor according to item 1,
- R 1 and R 2 may each be substituted with a 1hydrogen atom or 2carpoxyl or alkoxymonocarbonyl — represent a 6-alkyl group, or R 1 and R 2 together with an adjacent nitrogen atom 2.
- a ring is a benzene ring or a 6-membered nitrogen-containing aromatic heterocyclic ring which may be substituted with a halogen atom or an alkoxy,
- a r C 6 _ 14 is optionally substituted with a halogen atom Ariru group or Biff Eniriru group,
- X is 1 Shiki (CH 2) ⁇ ' ⁇ - (wherein, [rho 1 is from 1 represents an integer of 3) you express a group, 2 formula - (CH 2) p 2 - ( wherein, p 2 ⁇ represents an integer of 1 to 3), 3 a group represented by the formula — (CH 2 ) p 3 OCONH— (where p 3 represents an integer of 1 to 3), 4 CONH or 5 S ⁇ 2 NH, Y is a formula — (CH 2 ) q ⁇ ON R 9 (CH 2 ) r 1 — (wherein Q 1 and r 1 are each 0 to 3 and the total is 3
- R 9 may be a hydrogen atom or halogenated — 6 alkyl or halogenated — 6 alkyl-carbonyl) or a group represented by the formula — (CH 2 ) a group represented by q 2 COO (CH 2 ) r 2- (wherein q 2 and r 2 are each 0 to 3
- R 1 and R 2 are each 1 a hydrogen atom or 2 Karupokishiru, ( ⁇ _ 6 alkoxy - carbonyl or di _ C - 6 alkyl two Tororiru in or represents an C i _ 6 alkyl which may be substituted, or an R 1 R 2 together with the adjacent nitrogen atom 5 or 6 Form a membered nitrogen-containing heterocycle,
- a ring is a halogen atom or ⁇ - 6 inhibitor as set forth in claim 1, wherein a nitrogen-containing aromatic heterocycle benzene ring or 6-membered optionally substituted with alkoxy,
- Ar is 4- aryl or biphenyl, optionally substituted with a halogen atom, and X is-(CH 2 ) ⁇ - (p is an integer of 1 to 3), —CON
- the ring A is a benzene ring or a 6-membered nitrogen-containing aromatic heterocyclic ring which may be substituted with a halogen atom or de-e alkoxy
- the compound is 5-chloro-N- [2- ( ⁇ , ⁇ -getylamino) ethyl] -2-methoxy-4- (1-naphthoylamino) benzamide,
- Ar ′ represents a ring-assembled aromatic group which may have a substituent
- X ′ is a group represented by the following formula: — (CH 2 ) p iO— (where p 1 represents an integer of 1 to 3), and 2 formula — (CH 2 ) p 2 — (where p 2 Represents an integer of 1 to 3), or 3 CONH,
- Y is a formula (CH 2 ) q ⁇ ONR 9 (CH 2 ) r 1 (where ( ⁇ ⁇ !! is an integer of 0 to 3 and a total of 3 or less, respectively) the, R 9 is a hydrogen atom or a halogenated may have 6 alkyl or optionally halogenated alkyl -. group represented by showing a carbonyl), or 2 Shiki (CH 2) q 2 C OO (CH 2 ) r 2- (wherein, Q 2 and r 2 are each 0 to 3 and the sum thereof is an integer of 3 or less),
- R 1 and R 2 may each have a hydrogen atom or a substituent.
- Bok 6 shows an alkyl le
- R 1 and R 2 may form a nitrogen-containing heterocyclic ring which may have a substituent together with the adjacent nitrogen atom, may have an A ring substituent Shows a good monocyclic aromatic ring.
- Ar ′ is (i) a halogen atom, (ii) C ⁇ 3 alkylenedioxy, (iii) dinitro, (iv) cyano, (V) optionally halogenated alkyl, (vi) C 6 10 ⁇ Li one Ruokishi - - 6 alkyl, (vii) C Medicine 6 alkyl C 6 10 ⁇ Li - Lou C 2 _ 6 alkenyl, (viii) optionally C 3 6 a cycloalkyl which may be halogenated, (ix) (a) a halogen atom, (WC ⁇ 3 alkylene O carboxymethyl, (c) nitro, (d) Shiano, (e) optionally halogenated alkyl, (f) an optionally halogenated C 3 6 Cycloalkyl, (g) optionally halogenated C 6 alkoxy, (h) optionally halogenated (: ⁇ 6 alkylthio, (i) hydroxy, (j) amino, (
- ⁇ Alkylsulfonylamino,). ⁇ Alkyl-carbonyloxy,). C may have 1 to 5 substituents selected from the group consisting of ⁇ 6 alkoxycarbonyloxy, (aa) mono- 6 alkyl monocyclic rubamoyloxy and (bb) di-C i 6 alkyl monocyclic rubamoyloxy.
- (xviii) (a) optionally halogenated alkyl, (b) halogen atom, (dialkylenedioxy, (d) nitro, (e) cyano, (f) optionally halogenated C 3 6 cycloalkyl, (g) may be halogenated - 6 an alkoxy, (h) optionally C ⁇ 6 alkylthio which may be halogenated, (i) hydroxy, (j) ⁇ amino, (k) Mono- ⁇ -alkylamino, (1) di-C ⁇ -e-alkylamino, (m) formyl, (n) ruboxy, (0) rubamoyl, (p) optionally halogenated d- Alkyl-carbonyl,).
- IC ⁇ e alkylsulfonylamino 1 to 5 substitutions selected from the group consisting of: alkyl monophenyloxy, (z) alkoxy monopolyoxy, (aa) mono (: ⁇ 6 alkyl monopolyrubamoyloxy and (bb) di-6-alkyl monopolyrubamoyloxy. which may have a group C 6 _ 14 7 reel,
- halogenated alkyl may be (g) halogenated - 6 alkoxy, may be (h) halogenation - 6 alkylthio, (i) hydroxy, (j) Amino, (k) model no — 6-alkylamino, (1) di-Ci- 6- alkylamino, (in) formyl, (n) ruboxy, (0) rubamoyl, (p) 6- alkyl-halponyl optionally halogenated, ((3 ) ⁇ 6 alkoxy mono-rubonyl, (r) mono-alkyl monocarbamoyl, (s) di-alkyl mono-rubamoyl, (t) 6- alkylsulfonyl optionally halogenated, (u) halogenated alkyl, (b) halogen atom, (c Ci-s alkylenedioxy, (d) nitro, (e) cyano, (f) optionally halogenated C 3 _ 6 cycloal
- halogenated which may be C 3_ 6 cycloalkyl
- halogenated may be Ci- e alkoxy, which may be (h) halogenation ( ⁇ alkylthio, (i) hydroxy, (j) Amino, (k) model no ( ⁇ _ 6 Arukiruamino , (1) di - Arukiruamino, (m) formyl, (n) force Rupokishi, (0) force Rubamoiru, (p) may be halogenated CI- e alkyl - carbonyl, (q) ⁇ - 6 alkoxy - power Ruponiru, (r) mono - C, _ 6 alkyl one local Bamoiru, (S) Gee alkyl - Power Rubamoiru, (t) optional
- halogenated which may be C 3 _ 6 cycloalkyl, (g) may be halogenated ⁇ - 6 alkoxy, (h) May be halogenated — 6-alkylthio, (i) hydroxy, (j) amino, (k) mono-alkylamino, (1) Gee-6-alkylamino, (m) formyl, (n) power lipoxy, (0 ) force Rubamoiru, (which may be p) halogenated - 6 alkyl one carbonyl, (q) (: I 6 alkoxy - carbonyl, (r) mono- 6 alkyl - Cal Bamoiru, (s) G ( ⁇ _ 6 alkyl - power Rubamoiru, (t) eight halogenated which may be alkylsulfonyl, (u) Horumiruamino, (V) halogenated or may be 6 alkyl
- R 3 is a hydrogen atom, or (i) a halogen atom, (iD C ⁇ -3 alkylenedioxy (Iii) nitro, (iv) cyano, and (v) halogenated.
- Et alkyl (vi) an optionally halogenated C 3 "6 cycloalkyl, ⁇ may be (vii) halogenated - 6 alkoxy, may be (viii) halogenated - 6 alkyl Chio, (ix) hydroxy, (X) Amino, (xi) mono- ⁇ - 6 Arukiruamino, (xii) di-one - 6 Arukiruamino,
- (xiii) 1 (a) may be halogenated ⁇ - 6 alkyl, (b) halogen atom, (c) C ⁇ - 3 alkylenedioxy O carboxymethyl, (d) nitro, (e) Shiano, (f) halogenated which may be C 3 - 6 cycloalkyl, may be (g) halogenated - 6 alkoxy, (h) alkylthio which may be halogenated, (0-hydroxy, (j) Amino, ( k) mono - Arukiruamino, (1) di one 6 Arukiruamino, (m) formyl, (n) carboxy, (0) force Rubamoiru, (p) halogenated may ⁇ DOO 6 alkyl Le - carbonyl, (q !
- halogenation which may be optionally CI- e alkyl, (b) halogen atom, ((C ⁇ s alkylenediamine O carboxymethyl, (d) nitro, (e) Shiano, (optionally D halogenated C 3 _ 6 cycloalkyl Alkyl, (g) optionally halogenated C ⁇ 6 alkoxy, (h) optionally halogenated alkylthio, (i) hydroxy, (j) amino, (k) monoalkylamino, (1) G (: $ 6 alkylamino , (M) formyl, (n) force Rupokishi, (0) force Rubamoiru, (P) halogenated alkyl one optionally force Ruponiru, (q ⁇ - 6 alkoxy - Power Ruponiru, (r) mono- CI- 6 alkyl one local Bamoiru, (s) G C ⁇ - 6 alkyl, (b) halogen atom, ((
- Ci-e alkyl which may be halogenated
- halogen atom (d C ⁇ -3 alkylenedioxy, (d) nitro, (e) cyano, (D halogenated also a C 3 _ 6 cycloalkyl, (g) optionally halogenated C [i 6 alkoxy, (h) halogenation which may be optionally 6 alkylthio, (i) hydroxy, (j) Amino, (k ) Mono--6-alkylamino, (1) di- 6- alkylamino, (m) formyl, (n) -lupoxy, (0) r-rubamoyl, (P) optionally halogenated —6-alkyl-carbonyl, ( q) Ci- 6 alkoxy-carbonyl, (r) mono- ⁇ - 6 alkyl-carbamoyl, (s) di- 6 alkyl-carbamoyl, (t) optionally halogen
- halogenated ⁇ - 6 alkyl may be halogenated ⁇ - 6 alkyl, (b) halogen atom, ((C ⁇ - 3 alkylenedioxy O carboxymethyl, (d) nitro, (e) Shiano, have been (0 halide which may C 3 -6 cycloalkyl, (g) optionally halogenated alkoxy may be (h) halogenation ⁇ - 6 alkylthio, (i) hydroxy, (j) Amino, (k) Mono-C-e-alkylamino, (1) di- 6- alkylamino, (m) formyl, (n) rupoxy, (0) rubamoyl, (P) optionally halogenated alkylamine, (q) C - 6 alkoxy - power Ruponiru, (r) mono- C ⁇ - 6 alkyl - Cal Bamoiru, (S) Gee alkyl Ichiriki Rubamoiru, (t) optional
- halogenated C ⁇ - 6 1 no Ru is selected from the group consisting of alkylsulfonyl to three 5 which may have a substituent to 7-membered saturated cyclic Amino,
- R 3a is (i) a halogen atom, (ii) C ⁇ - 3 alkylenedioxy O carboxymethyl, (iii) nitro, (iv) shea ⁇ Bruno, (V) eight halogenated by optionally ( ⁇ _ 6 alkyl, (Vi) halogenated Good C 3 _ 6 cycloalkyl, (vii) optionally halogenated C 6 optionally alkoxy, (viii) alkylthio which may be halogenated, (ix) hydroxy, (X) Amino, (xi) Mono--6 alkylamino, (xii) di-6-alkylamino, (xiii) 1 (a) optionally halogenated (: ⁇ 6 alkyl, (b) halogen atom, (c) 3-alkylenedioxy, (d ) nitro, (e) Shiano, (f) an optionally halogenated C 3 - 6 cycloalkyl, may be (g)
- ⁇ may be (g) halogenated - 6 alkoxy, (h) halogenation which may be alkylthio, (i) hydroxy, (j) Amino, (k) mono - - 6 Arukiruamino, (1) di one ( ⁇ -6 Arukiruamino, (m) formyl, (n) force Rupokishi, (0) force Rubamoiru, optionally (p) halogenated ( ⁇ - 6 alkyl Ichiriki Ruponiru , (q) alkoxy Ichiriki Ruponiru, (r) mono- C _ 6 alkyl one local Bamoiru, (s) di - C ⁇ - 6 alkyl Ichiriki Rubamoiru, (t) optionally halogenated or 6 alkylsulfonyl, ( u) formylamino, (V) optionally halogenated C i- 6 alkyl monopropanol, ( ⁇
- ⁇ ⁇ may be halogenated—optionally having 5 to 7 membered saturated cyclic amino, which may have 1 to 3 substituents selected from the group consisting of 6 alkylsulfonyl,
- one Roux force Rubamoiruokishi may have a (xxxviii) nicotinoyl noisy Ruo alkoxy and (xxxix) C 1 no Ru is selected from 6 _ 10 Ariruokishi to 5 substituents, alkyl, C 2 _ 6 alkenyl, C 2 6 alkynyl, C 3 _ 6 cycloalkyl, C 3 _ 6 cycloalkyl and fused ring group of benzene ring, C 6 _ 14 Ariru, nitrogen source in addition to C 7 19 Ararukiru or carbon atoms A 5- or 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and oxygen,
- R 4 represents a hydrogen atom or an alkyl, or R 3 and R 4 together with an adjacent nitrogen atom contain at least one nitrogen atom other than a carbon atom, and are selected from a nitrogen atom, a sulfur atom and an oxygen atom. It may form a 5- to 7-membered nitrogen-containing heterocyclic ring which may contain one heteroatom.
- R 1 and R 2 are (1) hydrogen atom or (2) (i) halogen atom, (iDCi- 3 alkylenedioxy, (iii) nitro, (iv) cyano, (V) optionally halogenated d— 6 alkyl, (vi) optionally halogenated C 3 _ 6 cycloalkyl, (vii) optionally halogenated alkoxy, (viii) optionally halogenated (: tri 6 alkylthio, ( (ix) hydroxy, (X) amino, (xi) mono-alkylamino, (xii) dialkylamino, (xiii) formyl, (xiv) carboxy, (xv) rubamoyl, (xvi) optionally halogenated Alkyl - carbonyl, (xvii) Ci-e alkoxy Ichiriki Ruponiru, ⁇ 0 mono - (- 1 _ 6 Arukiru - Karubamo I le, (xix) di
- a halogen atom In addition to the substituent represented by Ar′—X′— in the ring A, a halogen atom, an optionally halogenated Ci-e alkyl, or an optionally halogenated ( ⁇ alkoxy, hydroxy, and amino A benzene ring or a carbon atom optionally having 1 to 3 substituents selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, and containing 1 to 3 heteroatoms 5 or 22.
- Y is a formula — (CH 2 ) q ⁇ ONR 9 (CH 2 ) r 1 (wherein Q 1 and are each an integer of 0 to 3 and the total is 3 or less, and R 9 is A hydrogen atom or an optionally halogenated Ci- 6 alkyl or an optionally halogenated alkyl-carbonyl group).
- R 1 and R 2 each represent a d-6 alkyl group optionally substituted with a 1hydrogen atom or a 2carboxyl or C ⁇ —e alkoxy monocarbonyl, or R 1 and R 2 represent 22.
- R 1 and R 2 are each 1 a hydrogen atom or 2 Karupokishiru, ( ⁇ _ 6 alkoxy one carbonyl or di-C ⁇ 6 alkyl two preparative port drill with an optionally substituted C j _
- Ring A is a benzene ring or a 6-membered nitrogen-containing aromatic heterocycle, 31.
- Ar ′ is biphenylyl, and X ′ is — (CH 2 ) ⁇ ⁇ ⁇ - ( ⁇ 1 And Y ′ is —C ⁇ NH (CH 2 ) s— (s is an integer of 1 to 3), and R 1 and R 2 are each an integer of 1 to 3.
- a ring may be substituted with a halogen atom or a C i-6 alkoxy 22.
- X a represents an oxygen atom, a sulfur atom which may be oxidized, or an imino which may have a substituent, and other symbols have the same meanings as those described in the item 21.
- X a represents an oxygen atom, a sulfur atom which may be oxidized, or an imino which may have a substituent, and other symbols have the same meanings as those described in the item 21.
- Xb represents a group obtained by removing Xa from X ′
- L represents a leaving group or hydroxy
- X ′ and Ar ′ have the same meaning as described in Section 21. Or a salt thereof, or
- a r ′ represents an optionally substituted ring-assembling aromatic group
- X ′ represents a formula _ (CH 2 ) ⁇ -(wherein p 1 represents an integer of 1 to 3.
- A) a group represented by the formula ( 2 ), a group represented by the formula — (CH 2 ) p 2 — (where p 2 represents an integer of 1 to 3) or 3 CO NH
- Y ′ represents a formula ( 2 ) — (CH 2 ) qiCONR 9 (CH 2 ) r 1 — (wherein and r 1 are each an integer of 0 to 3 and the total is 3 or less
- R 9 is a hydrogen atom or a halogenated Or a halogenated C alkyl—indicating carbonyl) or a group represented by the formula — (CH 2 ) Q 2 COO (CH 2 ) r 2- (wherein q 2 and r 2 is each 0 to 3 and the sum thereof is an integer of 3 or less), and
- R 1 and R 2 May form a nitrogen-containing heterocyclic ring which may have a substituent together with an adjacent nitrogen atom, and ring A represents a monocyclic aromatic ring which may further have a substituent. Or a salt thereof, or a pharmaceutical composition comprising the prodrug thereof;
- a r represents an aromatic group which may have a substituent, X and Y are different were identical or, - O-, one S CO -SO one S_ ⁇ 9 one, -NR 8
- R 8 represents a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group
- R 1 and R 2 represent a hydrogen atom or an optionally substituted C alkyl
- R 1 and R 2 represent a nitrogen-containing group which may have a substituent together with an adjacent nitrogen atom.
- a ring represents a monocyclic aromatic ring which may further have a substituent.
- Ar represents an aromatic group which may have a substituent
- X and Y are the same or different and are 110, 1 S-, 1 CO-, 1 SO-,- Divalent group selected from S ⁇ 2 —, one NR 8 —, — CONR 8 —, — S ⁇ 2 NR 8 — and one COO—
- R 8 is a hydrogen atom, a carbon atom which may have a substituent.
- Ar represents an aromatic group which may have a substituent
- X and Y are the same or different and each represents —0—, one S—, one CO—, one SO—, —S ⁇ 2 —, — NR 8—, —CONR 8 —, one S 0 2 NR 8 — and one COO— divalent group
- R 8 is a hydrogen atom, a hydrocarbon group which may have a substituent Or represents an acyl
- a divalent Ci—e aliphatic hydrocarbon group which may contain one or two of these divalent groups
- R 1 and R 2 represent a hydrogen atom or a substituent.
- R 1 and R 2 may form a nitrogen-containing heterocycle optionally have a substituent together with the adjacent nitrogen atom, a ring A substituent It represents a monocyclic aromatic ring which may be present. Or a salt thereof, or a prodrug thereof, and
- Ar represents an aromatic group which may have a substituent
- X and Y are the same or different and are —O—, —S—, one CO—, one SO—, — S0 2 —, — NR 8 —, — CONR 8 —, one S ⁇ 2 NR 8 — and one COO— divalent group
- R 8 is a hydrogen atom, an optionally substituted hydrocarbon Or a divalent aliphatic hydrocarbon group which may contain one or two of these divalent groups, wherein R 1 and R 2 have a hydrogen atom or a substituent.
- R 1 and R 2 may form a nitrogen-containing heterocyclic ring which may have a substituent together with an adjacent nitrogen atom, and ring A further has a substituent. And a monocyclic aromatic ring. ] Or a salt thereof, or a prodrug thereof.
- halogenated ( ⁇ _ 6 alkyl) For example, 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, or iodine ( ⁇ -6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) may be used.
- halogen atoms e.g., fluorine, chlorine, bromine, or iodine
- ⁇ -6 alkyl e.g, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
- Is for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pennofluorethyl, propyl, 3, 3, 3- Trifluoropropyl, isopropyl, butyl, 4,4,4-Trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trihexylhexyl Are used.
- the "optionally halogenated C 3 _ 6 cycloalkyl” includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, or iodine ) which may have a C 3 - 6 cycloalkyl (e.g., consequent opening, cyclobutyl, cyclopentyl, cyclohexylene hexyl etc.) and the like.
- halogen atoms e.g., fluorine, chlorine, bromine, or iodine
- C 3 - 6 cycloalkyl e.g., consequent opening, cyclobutyl, cyclopentyl, cyclohexylene hexyl etc.
- halogenated-6 alkoxy includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) Alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, pentyloxy, etc.) and the like may be used.
- halogenated alkylthio includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). 6-alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) and the like are used.
- Specific examples include, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluoroethylthio, pentylthio, hexylthio and the like.
- halogenated — 6 alkyl-carbonyl includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine which may have, etc.) C ⁇ - 6 alkyl - power Lupo Nyl (eg, acetyl, propanoyl, butanol, pentanoyl, hexanoyl, etc.) is used.
- Specific examples include, for example, acetyl, monochloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, hexanoyl and the like.
- the “optionally halogenated alkylsulfonyl” includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (Eg, 6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, etc.) and the like.
- halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
- 6 alkylsulfonyl eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butyl
- Specific examples include, for example, methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, to For xyls rufonyl etc. It is.
- halogenated alkyl-carboxamide includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
- 6- alkyl monocyclic lipoxamide eg, acetoamide, etc.
- Specific examples include, for example, acetoamide, trifluoroacetamide, propanamide, butanamide and the like.
- aromatic group represented by Ar for example, a monocyclic aromatic group, a ring aggregated aromatic group, a condensed aromatic group and the like are used.
- the “monocyclic aromatic group” for example, a monovalent group formed by removing any one hydrogen atom from a benzene ring or a 5- or 6-membered aromatic heterocyclic ring is used.
- the “5- or 6-membered aromatic heterocycle” for example, one or more hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom (for example, 1 to 3, preferably 1 to 2 And 5- or 6-membered aromatic heterocycles.
- thiophene, furan, pyrrole, imidazole, pyrazol, thiazol, oxazol, pyridine, pyrazine, pyrimidine, pyridazine ring and the like are used. You.
- monocyclic aromatic group examples include phenyl, 2- or 3-phenyl, 2- or 3-furyl, 1, 2- or 3-pyrrolyl, 2- or 4-imidazolyl, 3- Or 4-pyrazolyl, 2-, 4-mono or 5-thiazolyl, 2-, 4-mono or 5-oxazolyl, 2-, 3- or 4-pyridyl, 2-pyrazinyl, 2-, 4-mono or 5-pyrimidinyl, 3- or 4-pyridazinyl and the like are used, and phenyl and the like are preferable.
- ring-assembled aromatic group for example, two or more (preferably two or three) aromatic rings are directly connected by a single bond, and the number of bonds directly connecting the rings is the number of ring systems.
- a group obtained by removing one arbitrary hydrogen atom from one less aromatic ring assembly is used.
- aromatic ring an aromatic hydrocarbon, an aromatic heterocycle, or the like is used.
- aromatic hydrocarbon includes, for example, a monocyclic or condensed polycyclic (for example, bicyclic or tricyclic) aromatic hydrocarbon having 6 to 14 carbon atoms (eg, benzene, naphthylene) , Inden, anthracene, etc.).
- the “aromatic heterocyclic ring” includes, for example, one or more hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (for example, 1 to 4, preferably 1 to 2) in addition to carbon atoms.
- a to 14-membered, preferably 5- to 10-membered, aromatic heterocycle is used.
- Examples of the aromatic ring assembly in which these aromatic rings are directly connected by a single bond include, for example, a benzene ring, a naphthylene ring and a 5- to 10-membered (preferably 5- or 6-membered) aromatic heterocyclic ring.
- an aromatic ring aggregate formed of two (preferably two) is used.
- Preferred examples of the aromatic ring assembly include benzene, naphthalene, pyridine, pyrimidine, thiophene, furan, thiazol, isothiazole, oxazole, 1,2,4-oxazidazole, 1,3,4-oxazidazole.
- More specific examples include, for example, 2-, 3- or 4-biphenyl, 3- (1-naphthyl) _1,2,4-oxoxadiazol-5-yl, 3- (2-naphthyl) 1-1 , 2,4-oxaziazol-5-yl, 3- (2-benzofuranyl) — 1,2,4-oxaziazol-5-yl, 3-phenyl—1,2,4-oxaziazol— 5-yl, 3- (2-benzoxazolyl) 1-1,2,4-oxaziazol-l 2-yl, 3- (3-pindolyl)-1,2,4-oxaxazol_2-yl , 3 _ (2-indolyl) — 1,2,4-oxadiazo —lu 2-yl, 4-phenylthiazolu-2-yl, 41- (2-benzofuranyl) thiazoyl —2— 4-phenyl-1,3-oxazole-5-yl
- condensed aromatic group examples include condensed polycyclic (preferably di- to tetra-cyclic, preferably di- or tri-cyclic) monovalent groups formed by removing any one hydrogen atom from an aromatic ring. Is used.
- condensed polycyclic aromatic ring a condensed polycyclic aromatic hydrocarbon And condensed polycyclic aromatic heterocycles.
- Examples of the “condensed polycyclic aromatic hydrocarbon” include a condensed polycyclic (bi- or tri-cyclic) aromatic hydrocarbon having 9 to 14 carbon atoms (eg, naphthylene, indene, anthracene) Etc.) are used.
- fused polycyclic aromatic heterocycle examples include 9 to 14 including one or more (for example, 1 to 4) heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms.
- a member, preferably a 9- or 10-membered fused polycyclic aromatic heterocycle is used.
- benzofuran, benzimidazole, benzoxosazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene isoquinoline, quinoline, indole, quinoxaline, phenanthridine, phenothiazine, phenoxazine, phthalimide And aromatic heterocycles.
- condensed aromatic groups include, for example, 1-naphthyl, 2-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-benzofuranyl, 2-benzothiazolyl, 2-benzimidazolyl, Examples include 1-indolyl, 2—indolyl, and 3—indolyl, among which 1-naphthyl and 2-naphthyl are preferred.
- Examples of the substituent of the aromatic group represented by Ar include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), 3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano May be halogenated
- a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
- 3 alkylenedioxy eg, methylenedioxy, ethylenedioxy, etc.
- nitro, cyano May be halogenated
- the ⁇ aromatic group '' may have, for example, 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions of the aromatic group, and when the number of the substituents is 2 or more, Each substituent may be the same or different.
- the "optionally substituted C 7 _ 1 6 Ararukiru" - as the "C 7 1 6 Ararukiru” for example, benzyl, off Enechiru And naphthylmethyl.
- Echirenjiokishi nitro, Shiano
- ⁇ - 6 alkylsulfonyl ⁇ amino e.g., methyl Suruhoniruamino, E chill sulfonyl ⁇ amino etc.
- C ⁇ - 6 alkyl - force Lupo two Ruokishi e.g, Asetokishi, prop noisy Ruo carboxymethyl, etc.
- C ⁇ - 6 alkoxy - power Ruponiruokishi e.g., methoxycarbonyl O carboxy, ethoxycarbonyl O carboxymethyl, propoxycarbonyl O alkoxy, butoxycarbonyl O carboxymethyl, etc.
- mono- ( ⁇ _ 6 alkyl Ichiriki Rubamoiruokishi e.g., methylcarbamoyl O alkoxy, 1 to 5 dialkyl 6- alkyl-rubumoyloxy (eg, dimethyl-l-rubamoyloxy, getylcarbamoyloxy, etc.
- the ⁇ 5- to 7-membered saturated cyclic amino '' of the ⁇ optionally substituted 5- or 7-membered saturated cyclic amino '' includes, for example, morpholino, Thiomorpholino, piperazine-11-yl, piperidino, pyrrolidine-11-yl, hexamethylene-11-yl and the like are used.
- substituted 5- to 7-membered saturated cyclic amino examples include, for example, an optionally halogenated — 6 alkyl, an optionally substituted C 6 - 14 Ariru, substituents may c 7 _ 19 have a Ararukiru, 5 which may have a substituent group to 10-membered aromatic heterocyclic group may have a substituent.
- Aryl-carbonyl, optionally halogenated Bok 6 alkyl - carbonyl, Ru used three has from 1 to such good C ⁇ 6 alkylsulfonyl be halogenation.
- c 6 _ 14 Ariru of the “optionally c 6 _ 14 Ariru have a substituent", for example, phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, etc. Is used. Preferred is phenyl and the like.
- C 7 _ 19 Ararukiru of the “optionally optionally C 7 _ 19 Ararukiru may have a substituent"
- substituent For example, benzyl, phenethyl, Jifuenirumechiru, triphenylmethyl, 1 one naphthoquinone Chirumechiru, 2-naphthylmethyl, 2,2-diphenylethyl, '3-phenylpentyl pill, 4-phenylbutyl, 5-phenylpentyl and the like are used, and preferably benzyl.
- Examples of the “5- to 10-membered aromatic heterocyclic group” in the “optionally substituted 5- to 10-membered aromatic heterocyclic group” include, for example, 2-, 3- and 1 21
- 59 is, for example, 4-pyridyl, 11-, 2- or 3-indolyl, 2- or 3- phenyl, and preferably 2-, 3- or 4-pyridyl.
- substituted aryl In the “optionally substituted aryl.” Include, for example, benzoyl, 1.1-naphthoyl, 2-naphthoyl and the like.
- halogenated which may be C doctor 6 alkyl, optionally halogenated C 3 _ 6 cycloalkyl, optionally halogenated C [physicians 6 alkoxy, it may be halogenated
- _ 6 alkylthio hydroxy, amino, mono-alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-alkylamino (eg, dimethylamino, getylamino, dipropylamino, dibutylamino, ethylmethylamino) Mino), formyl, carboxy, carbamoyl, optionally halogenated C i -ealkyl-caprolponyl, Ci- 6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, such as tert- butoxycarbonyl), mono- C ⁇ 6 alkyl Ichiriki Rubamoiru (e.g., methylcarbamoyl, etc.
- mono-alkylamino eg, methylamino, ethylamino, prop
- acyl as “substituent” of “aromatic group which may have a substituent” represented by Ar, “acylamino” and “acyloxy” in “acyloxy” include, for example,
- R 3 is (i) a hydrogen atom
- a hydrocarbon group which may have a substituent, specifically, as a substituent, an octane gen atom, 3 alkylenedioxy, nitro, cyano, or halogenated (: 6 Alkyl, optionally halogenated C 3 _ 6 cycloalkyl, optionally halogenated — 6 alkoxy, optionally halogenated — 6 alkylthio, hydroxy, amino, monono 6 alkylamino, di- 6 Alkylamino, optionally substituted 5- to 7-membered cyclic amino, formyl, carboxy, carbamoyl, optionally halogenated — 6-alkyl-carbonyl, alkoxy-carbonyl, arylcarbonyl, .
- Ariruokishi one carbonyl, C 7 - 16 Ararukiruokishi Ichiriki Ruponiru, mono- Ji Bok 6 alkyl Ichiriki Rubamoiru, di - ⁇ - 6 Alkyl Ichiriki Rubamoiru, ⁇ 6 _ 10 ⁇ reel - Power Rubamoiru may be halogenated - 6 alkylsulfonyl, C 6 - 10 ⁇ Li one Rusuruhoniru, Horumiruamino may be halogenated - 6 alkyl one power Rupokisamido, C 6 _ 1 () ⁇ Li one Roux carboxamide, alkoxy - Karupokisamido, - 6 alkylsulfonyl ⁇ amino, 6 alkyl - Cal Boniruokishi, Ariru -.
- a heterocyclic group which may have a substituent, specifically, as a substituent, a halogen atom, (: ⁇ 3 alkylenedioxy, nitro, cyano, optionally halogenated alkyl , optionally halogenated C 3 _ 6 cycloalkyl optionally, halogen of which may be alkoxy, optionally halogenated ( ⁇ - 6 Al Kiruchio, hydroxy, Amino, mono - 6 Arukiruamino, di - ( ⁇ -6 alkylamino, optionally substituted 5- to 7-membered cyclic amino, formyl, carboxy, renzamoyl, optionally halogenated ⁇ - ⁇ - alkyl monoalkyl, Ci- 6- alkoxy-carbonyl, .aryl-carbonyl, .aryl-carbonyl, 6- aralkyloxy-l-ponyl, mono 6- alkyl-l-rubamoyl, g-6
- I Ariru Ichiriki Rubamoiru may be halogenated - 6 alkylsulfonyl, C 6 _ 10 ⁇ Li one Rusuruhoniru, Horumiruamino, halogenated Ji may ⁇ alkyl - Carboxamide, C 6 _ 1 () aryl-carboxamide, alkoxy monocarboxamide, —6 alkylsulfonylamino, alkyl monopropyloxy, .aryl-carbonyloxy, Ci- 6 alkoxy-carponyloxy, mono——6 alkyl —Chemical alkyl carbamoyloxy, C 6 — 1 () aryl—Chemical carbamoyloxy, C 6 —1 () aryl—Chemical group optionally having 1 to 5 substituents selected from carbamoyloxy, nicotinyloxy, and aryloxy. Show,
- R 3a is (i) a hydrocarbon group which may have a substituent, specifically, a halogen atom, C ⁇ -3 alkylenedioxy, nitro, cyano, halogenated it may also be - 6 alkyl, optionally halogenated C 3 _ 6 cycloalkyl, may be halogenated ⁇ - 6 alkoxy, or halogenated - 6 alkylthio, hydroxy, Amino, mono - Ci -e alkylamino, di- (:
- an optionally substituted heterocyclic group specifically, as a substituent, a halogen atom, alkylenedioxy, nitro, cyano, optionally halogenated alkyl, halogenated which may be C 3 - 6 cycloalkyl, halogen of which may be alkoxy, it may be halogenated.
- Et al Kiruchio, hydroxy, Amino, mono - Arukiruamino, di - 6 alkyl Ruamino, 5 which may have a substituent to 7-membered cyclic Amino, formyl, Cal Bokishi force Rubamoiru may be halogenated - 6 alkyl one carbonylation Le, (:..
- R 4 represents a hydrogen atom or alkyl, or R 3 and R 4 may form a nitrogen-containing heterocyclic ring with an adjacent nitrogen atom. Is used.
- the hydrocarbon group represented by R 3 and R 3 a, 1 or a group obtained by removing a hydrogen atom from a hydrocarbon compound are used, for example, chain or cyclic hydrocarbon group (e.g., alkyl Le, alkenyl, alkynyl, Cycloalkyl, aryl, aralkyl, etc.). Among them, the following chain or cyclic hydrocarbon groups having 1 to 19 carbon atoms are preferred.
- alkyl e.g., methyl, Echiru, propyl, isopropyl, butyl Le, isobutyl, sec one heptyl, tert- butyl, pentyl, hexyl, etc.
- C 2 _ 6 alkenyl e.g., vinyl, Ariru, Isopurope Nil, 2-butenyl, etc.
- C 3 _ 6 cycloalkyl e.g., cyclopropyl, cyclobutyl, Shikurobe pentyl, cyclohexylene hexyl, etc.
- the C 3 _ 6 cycloalkyl may be fused to one benzene ring
- Ariru e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-I Ndeniru, 2-anthryl
- phenyl preferably phenyl
- the heterocyclic group represented by R 3 and R 3 a for example, nitrogen atom in addition to carbon atoms, 1 or 2 species selected from nitrogen and oxygen atoms, 1 to 4 (rather preferably has 1 to 3 5 to 14 membered (monocyclic, bicyclic or tricyclic) heterocyclic ring containing heteroatoms, preferably (i) 5 to 14 membered (preferably 5 to 10 membered)
- An aromatic heterocyclic ring, (ii) a 5- to 10-membered non-aromatic heterocyclic ring, or (iii) a monovalent group formed by removing any one hydrogen atom from a 7- to 10-membered bridged heterocyclic ring is used.
- Examples of the above “5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle” include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazol, benzisothiazole, and naphtho.
- 5- to 10-membered non-aromatic heterocycle for example, pyrrolidine, imidazoline, virazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine and the like are used.
- heterocyclic group is preferably a 5- to 10-membered (1- or 2-membered (including 1 or 2 and preferably 1 to 4 heteroatoms) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. (Monocyclic or bicyclic) It is a heterocyclic group.
- Non-aromatic heterocycles such as 1- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl, morpholino And the like.
- a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom is preferable.
- R 4 for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like are used.
- nitrogen-containing heterocycle formed by R 3 and R 4 together with an adjacent nitrogen atom
- examples of the “nitrogen-containing heterocycle” formed by R 3 and R 4 together with an adjacent nitrogen atom include, for example, 1 to 1 selected from a nitrogen atom, a sulfur atom and an oxygen atom containing at least one nitrogen atom other than a carbon atom.
- a 5- to 7-membered nitrogen-containing heterocyclic ring which may contain three hetero atoms is used, and examples thereof include piperidine, morpholine, thiomorpholine, piperazine, and pyrrolidine.
- acyl as the “substituent” of the “aromatic group” represented by Ar include formyl, carboxy, carbamoyl, optionally halogenated C ⁇ ⁇ ⁇ ⁇ -6 alkyl monopropylonyl , Alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), and may have a substituent.
- Aryl carbonyl optionally having C 6.
- Ariruokishi - carbonyl but it may also have a substituent group C 7 - 1 6
- Ararukiruokishi one carbonyl, double heterocyclic carbonyl may also be 5-6 membered substituted, mono - ⁇ - 6 alkyl - Power Rubamoiru And dialkyl rubamoyl (eg, dimethylcarbamoyl, getylcarbamoyl, ethylmethyl rubamoyl, etc.), and may have a substituent.
- Ariel—Lubamoyl An optionally substituted 5- to 6-membered heterocyclic compound rubamoyl, optionally halogenated—6 alkylsulfonyl, optionally substituted C 6.
- arylsulfonyl arylsulfonyl.
- the "optionally substituted C 6 _ 10 ⁇ Li one Roux carbonyl” - as the “C 6 10 ⁇ Li one Lou carbonyl", for example, Benzoiru, 1 one Nafutoi methylphenol, 2 Naphthoyl or the like is used.
- the “C 60 aryloxy-carbonyl” of the “optionally substituted aryloxycarbonyl”, for example, phenoxycarbonyl and the like are used.
- C 7 _ 16 Ararukiruokishi one carbonitrile nil in “an optionally substituted C 7 _ 16 Ararukiruokishi one carbonyl also", for example, benzyl O alkoxycarbonyl, such as Hue phenethyl Ruo propoxycarbonyl sulfonyl is used.
- “5- to 6-membered heterocyclic carbonyl” of the “optionally substituted 5- to 6-membered heterocyclic carbonyl” for example, nicotinyl, isonicotinyl, 2-tenol, 3-tenol, 2-furoyl, 3-furoyl, morpholinocarbonyl, piperidinocarbonyl, 1-pyrrolidinylcarbonyl and the like are used.
- ". Ji may have a substituent ⁇ Li one Lou force Rubamoiru" as "C 6 - - 10 Ariru force Rubamoiru", for example, phenylene carbamoyl, 1 one naphthylcarbamoyl, 2-naphthylcarbamoyl is Used.
- Examples of the “5- to 6-membered heterocyclic carbamoyl” of the “optionally substituted 5- to 6-membered heterocyclic carbamoyl” include 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, Pyridylcarbamoyl, 2-Chenylcarbamoyl, 3-Chenylcarbamoyl and the like are used.
- Aryl-force rubamoyl as “substituent” of the - "10 ⁇ Li one Rusuruhoniru which may have a substituent C 6" "may have a substituent 5-6 membered heterocyclic force Rubamoiru” and Is a halogen atom, alkylene O carboxymethyl, nitro, Shiano, optionally halogenated alkyl optionally, optionally halogenated alkoxy optionally, alkylthio which may be halogenated, hydroxy, Amino, mono- ⁇ - 6 Arukiruamino, di - Arukiruamino, formyl, carboxy, Cal Bamoiru may be halogenated CI- 6 alkyl - power Ruponiru, - 6 alkoxy one carbonyl, mono - C ⁇ - 6 alkyl Ichiriki Rubamoiru, di - C i - 6 alkyl Ichiriki Rubamoiru, optionally halogenated al
- R 5 is a hydrogen atom or 6 alkyl
- R 6 has the same meaning as R 3
- R 6a has the same meaning as R 3a
- R 6b has the same meaning as R 4. Is used.
- R 5 and R 6b '( ⁇ 6 alkyl ", those similar to represented by R 4' ( ⁇ 6 Al kill" is used.
- acylamino as the "substituent" of the "aromatic group optionally having substituent (s)" represented by Ar, preferably, formylamino, an optionally halogenated alkyl monofunctional lipoxamide, a substituent May be included.
- Ali-carboxamide eg, phenylcarboxamide, naphthylcarboxamide, etc.
- alkoxy-carboxamide eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide
- alkylsulfonylamino eg, methylsulfonylamino, ethylsulfonylamino, etc.
- acyloxy as the “substituent” of the “optionally substituted aromatic group” represented by Ar, for example, the aforementioned “optionally substituted”
- oxy substituted with one “acyl” as described in the “substituent” of the “aromatic group” may be used, and preferably has the formula: —O—COR 7 , —O—COOR 7 or 1 O—CONHR 7
- R 7 has the same meaning as R 3 ], and the like.
- alkyl-carbonyloxy eg, acetoxy, propanoyloxy, etc.
- a substituent may be used.
- Ali-carbonyloxy eg, benzoyloxy, 11-naphthoyloxy, 2-naphthoyloxy, etc.
- alkoxy-carbonyloxy eg, methoxycarbonyl, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarponyloxy, etc.
- Mono- 6 alkyl monorubumoxy eg, methyl carbamoyloxy, ethylcarbamoyloxy, etc.
- dialkyl 6 alkyl monorubumoxy eg, dimethylcarbamoyloxy, getyl carbamoyloxy, etc.
- Alba-rubyoloxy eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.
- nicotinyloxy etc.
- Ar is preferably an optionally substituted ring-assembling aromatic group (particularly, 2-, 3- or 4-biphenylyl).
- X and Y are _ ⁇ ichi, —S—, one CO—, —SO—, one SO 2 —, — NR 8 —, one CONR 8 — (including — C ⁇ NR S — and — NR 8 CO—), — S0 2 NR 8 — (— S ⁇ 2 NR 8 — and — NR 8 S0 2 — ) And a divalent group selected from one COO (R 8 represents a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group which may have a substituent) or these shows a 6 aliphatic hydrocarbon group - 2 valent group may have one or two comprise divalent ⁇ .
- optionally substituted hydrocarbon group represented by R 8 the same as the aforementioned “optionally substituted hydrocarbon group” represented by R 3 can be used. Of these, halogenated — 6-alkyl and the like are preferable.
- acyl represented by R 8 those similar to the “acyl” as the substituent of the aromatic group represented by Ar described above are used. Among them, formyl, carbamoyl, optionally halogenated C- 6 alkyl-carbonyl, alkoxy carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxy propyl, tert-butoxycarbonyl, etc.), the optionally substituted C 6 - 10 ⁇ reel over carbonyl, which may have the substituent.
- Aryloxy-carbonyl the above-mentioned optionally substituted C 7 — 16 7 ralkyoxy-carbonyl, 5- or 6-membered heterocyclic carbonyl optionally substituted, mononoalkyl monolrubamoyl, G Alkyl rubamoyl (eg, dimethylcarbamoyl, getylcarbamoyl, ethylmethylcarbamoyl, etc.), and may have the above substituent.
- the may have a substituent 5 or 6-membered heterocyclic ring force Rubamoiru, C alkylsulfonyl which may be halogenated, the may have a substituent group C 6 _ 1 ( ) Arylsulfonyl and the like are preferable, and 6- alkyl-carbonyl which may be halogenated is particularly preferable.
- ( ⁇ _ 6 alkylene, C 2 _ 6 alkenylene, C 2 - such as 6 alkynylene are used.
- the ⁇ 3 ⁇ 6 alkylene includes, for example, _CH 2 —, one (CH 2 ) 2 —, one (CH 2 ) 3 —, one (CH 2 ) 4 —, one (CH 2 ) 5 —,-(CH 2) 6 - Ji linear such ⁇ - 6 alkylene addition, one to three (: I 3 alkyl which may have a d-3 ⁇ alkylene (e.g., - CH 2 _, - (CH 2 ) 2 —,-(CH 2 ) 3 — etc.) Used.
- a d-3 ⁇ alkylene e.g., - CH 2 _, - (CH 2 ) 2 —,-(CH 2 ) 3 — etc.
- the 6 alkynylene for example, one C three C foremost, one CH 2 - - the C 2 C three C-, one C ⁇ C- CH 2 -, _C ⁇ C one CH 2 CH 2 one, - CH 2 CH 2 one C ⁇ C one, one CH 2 - C ⁇ C- CH 2 - one (CH 2) 2 - C ⁇ C one CH 2 one, - (CH 2) 2 - C three C- (CH 2) 2 - ,-(CH 2 ) 3 _C 3 C—CH 2 — and other linear C 2 — 6 alkynylene, as well as C 2 _ 3 alkynylene optionally having 1 to 3 alkyls (eg, — C ⁇ C-, - CH 2 - C three C one one C ⁇ C- CH 2 -, - C ⁇ C- CH 2 CH 2 -, one CH 2 CH 2 -, etc. C ⁇ C it) is used.
- C 2 _ 3 alkynylene optionally having 1 to 3 alkyls (eg
- the ⁇ Jii 6 aliphatic hydrocarbon group in particular, C ⁇ - 3 alkylene, C 2 _ 3 alkenylene alkylene, such as C i-3 aliphatic hydrocarbon group such as C 2 _ 6 alkynylene are preferred.
- One hundred and one represented by X, - S-, - CO-, -SO-, one S0 2 -, - NR 8 - , - CONR 8 -, -S0 2 NR 8 - , and divalent selected from a COO- the a group was 1 or Examples 2 comprises a divalent C i _ 6 aliphatic hydrocarbon group, for example,
- a group was 1 or Examples 2 comprises a divalent C _ 6 aliphatic hydrocarbon group, for example,
- w represents an integer of 1 to 6, particularly preferably 1 to 4, particularly preferably 1 or 2.
- 1 ⁇ 2 represents an integer of 1 to 3, respectively, and 1 or 2 preferable.
- Z is - S- - CO- - SO- - S_ ⁇ 2 - one NR 8 -, one CONR 8 - - S0 2 NR 8 - and - COO- indicates, Z is the same When there are two in the formula, they may be the same or different. ] Are also preferably used.
- R 9 represents a hydrogen atom, an optionally halogenated alkyl or an optionally halogenated C 6 alkyl monovalent ponyl) or a group represented by the formula: — (CH 2 ) Q 2 COO (CH 2 ) a group represented by r 2- (wherein, Q 2 and r 2 are each 0 to 3 and the total thereof is an integer of 3 or less) and the like, and particularly, a group represented by the formula — (CH 2 ) ⁇ CONR 9 (CH 2 ) r 1 — (wherein q 1 and r 1 are each an integer of 0 to 3 and the total is 3 or less, and R 9 is a hydrogen atom or halogenated Which represents an optionally substituted 6 alkyl or an optionally halogenated alkyl monocarbon
- alkyl represented by R 1 and R 2 for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like are used, and among them, methyl, ethyl, propyl Are preferred.
- Examples of the substituent of the —6 alkyl represented by R 1 and R 2 include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), ( ⁇ _ 3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.) , nitro, Shiano, optionally halogenated be also alkyl halogenated by C 3 - 6 cycloalkyl, optionally halogenated alkoxy optionally, halogenated or may be one 6 Arukiruchio, hydroxy, Amino , Mono--6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-alkylamino (example, dimethylamino, cetamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), formyl
- alkyl monocarboxamides 6 alkoxy monocarboxamides (eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc.), alkylsulfonylaminos (eg, methylsulfonylamino, ethylsulfonylamino, etc.), ( ⁇ 6 alkyl one Karuboniruo alkoxy (eg, Asetokishi, such as prop-Noi Ruo carboxymethyl), C ⁇ - 6 alkoxy Ichiriki Lupo Niruokishi (e.g., methoxycarbonyl O alkoxy, E WINCH carboxymethyl Cal Poni Ruo carboxymethyl, Propo alkoxycarbonyl O alkoxy, butoxy Carbonyloxy, etc.) Mono-C alkyl rubamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.),
- aziridine, azetidine, morpholine, thiomorpholine, piperidine, piperazine, pyrrolidine, hexamethyleneimine, heptamethyleneimine, hexahydropyrimidine, 1,4-diazepane, and their unsaturated cyclic Amines eg, 1,2,5,6-tetrahydropyridine etc.
- morpholine, piperidine, piperazine, pyrrolidine and the like are preferable.
- Examples of the ⁇ substituent '' of the ⁇ nitrogen-containing heterocyclic ring which may have a substituent '' formed together with the nitrogen atom to which R 1 and R 2 are attached include, for example, the above-mentioned ⁇ may have a substituent One to three substituents the same as the substituents that the “5- to 7-membered saturated cyclic amino” may have are used.
- R 1 and R 2 are, for example, (1) a hydrogen atom or (2) alkyl which may be substituted by carboxyl, alkoxy-carbonyl or di-C i-ealkylnitrolyl, or R 1 and R 2 represent It is preferable to form a 5- or 6-membered nitrogen-containing heterocycle (eg, piperidino, pyrrolidine-1-yl, etc.) together with an adjacent nitrogen atom.
- a 5- or 6-membered nitrogen-containing heterocycle eg, piperidino, pyrrolidine-1-yl, etc.
- R 1 and R 2 for example, 6 alkyl (eg, methyl, ethyl, propyl, etc.) is preferable, and R 1 and R 2 are piperidino, pyrrolidine-1-yl together with the adjacent nitrogen atom. It is preferable to form such as.
- R 1 and R 2 represents a C ⁇ -alkyl which may have a substituent, and particularly, even if both R 1 and R 2 have a substituent. when showing a good C i _ 6 alkyl is preferred.
- a monocyclic aromatic ring represented by ring A for example, a benzene ring or a 5- or 6-membered aromatic heterocycle is used.
- the “5- or 6-membered aromatic heterocycle” includes, for example, one or more hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms (for example, one to three, preferably one to two) And 5- or 6-membered aromatic heterocycles.
- thiophene, furan, pyrrole, imidazole, pyrazol, thiazol, oxazole, pyridine, 2-pyridone, pyrazine, pyrimidine, pyridazine and the like are used.
- the ring A is preferably a halogen atom or a benzene ring which may be substituted with ( ⁇ 6 alkoxy) or a 6-membered nitrogen-containing aromatic heterocyclic ring, particularly preferably a benzene ring, a pyridine ring or a 2-pyridone ring.
- a benzene ring or a pyridine ring is preferred.
- Ring A is substituted at a substitutable position with a group represented by the formula Ar—X—.
- Ring A may further have a substituent in addition to the group represented by the formula Ar-X-.
- substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an optionally halogenated — 6 alkyl, an optionally halogenated C i- ⁇ alkoxy, Hydroxy, amino and the like are used.
- halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
- an optionally halogenated — 6 alkyl an optionally halogenated C i- ⁇ alkoxy, Hydroxy, amino and the like are used.
- a halogen atom eg, chlorine and the like
- an alkoxy eg, methoxy and the like
- substituents may be substituted at substitutable positions of the ring A, and when the number of substituents is two or more, each substituent may be the same or different.
- Ring A is preferably a benzene ring substituted only with a group represented by the formula Ar—X—.
- Ar is a biphenyl group (eg, 2-, 3- or 4-biphenyl) which may be substituted with a halogen atom (in particular, chlorine), and X is a formula (CH 2 ) pi A group represented by ⁇ 1 (wherein p 1 represents an integer of 1 to 3, and preferably p 1 represents 1); ( 2 ) a formula — (CH 2 ) p 2 — (where p 2 is 1 Or a group represented by the formula (CH 2 ) p 3 OCONH- (where p 3 represents an integer of 1 to 3, preferably P 3 represents 1).
- Y is formula 1 - (CH 2) q J CON 9 (CH 2) r 1 i (wherein, Q 1 and r 1 are 3 from 0 respectively and A total of which is an integer of 3 or less, and R 9 represents a hydrogen atom or an alkyl which may be halogenated or d- 6 which may be halogenated.
- a r is a halogen atom (especially chlorine) may be substituted with C 6 - 14 ⁇ Li one Le group (especially, phenyl, 1, 2-naphthyl, etc.) or Bifue two drill group (e.g., 2 Table in (wherein, [rho 1 is an integer of 1 to 3, preferably a [rho 1 1) - a, 3- or 4 Bifue two Lil), X is formula 1 one (CH 2) tau> iota Base, 2 formula
- R 1 and R 2 are preferably integers of 1 to 3.
- Ar is a halogen atom (particularly, chlorine, etc.) optionally substituted C 6 _ 14 Ariru (particularly, phenyl, 1, 2-naphthyl etc.) or Bifue two drill, X gar (CH 2) ⁇ - (p is an integer of 1 to 3), — CONH—, one S0 2 NH— or alkylene, Y is 3 alkylene, and one CONH (CH 2 ) s-(s is an integer of 1 to 3 ) or - COO (CH 2) t - in is an integer of 1 a stone 3), R 1 and R 2 are each a hydrogen atom or Bok 6 alkyl Le (especially, methyl, Echiru, alkyl, etc.), such as propyl Or R 1 and R 2 together with the adjacent nitrogen atom form a 5- or 6-membered nitrogen-containing heterocycle (especially piperidino, pyrrolidine-1-yl, etc.), and the A ring is a halogen atom ( Especially substituted
- N- [4- ⁇ [2- (1-pyrrolidinyl) ethyl] amino ⁇ carbonyl ⁇ phenyl] (4-biphenylyl) carboxamide and the like are preferable.
- the compound represented by the formula (Ia) is a novel compound It is.
- the ring-assembled aromatic group optionally having a substituent represented by A r ′ includes the ring-assembled aromatic group optionally having a substituent represented by A r ′ described above. Similar ones are used, and among them, biphenyl (eg, 2-, 3- or 4-biphenyl) is preferable.
- X ' is 1 formula - (CH 2) p ⁇ - (wherein, P 1 denotes an integer of 1 to 3) groups represented by, 2 Shiki (CH 2) p 2 - (wherein, p 2 Represents a group represented by 1 to 3) or 3 CONH, and in particular, represented by the formula — (CH 2 ) p x O- (wherein p 1 has the same meaning as described above) And the like. 1 or 2 is preferable as p 1, particularly 1 is preferred. p 2 is preferably 1 or 2, and particularly preferably 1.
- Y ' is a formula — (CH 2 ) q ⁇ ONR 9 (CH 2 ) r 1 (where (1 1 and 1 are each 0 to 3 and the total is 3 or less)
- R 9 represents a hydrogen atom or an optionally halogenated alkyl or an optionally halogenated alkyl monophenylene) or a group represented by the formula (CH 2 ) q 2 COO (CH 2 ) r 2 — (wherein, Q 2 and r 2 are each 0 to 3 and the total is an integer of 3 or less).
- (CH 2) c ⁇ CONR 9 (CH 2) r 1 i (wherein each symbol is as defined above) and a group you express in are preferred.
- q 1 and Q 2 0 or 1 is preferable, and 0 is particularly preferable.
- r 1 and r 2 are preferably an integer of 1 to 3, particularly preferably 1 or 2, and particularly preferably 1.
- R 9 is preferably a hydrogen atom, an optionally halogenated Ci_ 3 alkyl (especially, methyl, ethyl, etc.) or an optionally halogenated alkyl-carbonyl (especially, acetyl, etc.), and particularly preferably hydrogen Atoms are preferred.
- R 1 and R 2 are each a hydrogen atom or a carboxyl, alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl) or di- 6- alkylnitrolyl (eg, dimethylnitrolyl, getylnitrolyl) Alkyl which may be substituted with (particularly, methyl, ethyl, propyl And R 1 and R 2 together with an adjacent nitrogen atom form a 5- or 6-membered nitrogen-containing heterocyclic ring.
- alkoxy-carbonyl eg, methoxycarbonyl, ethoxycarbonyl
- di- 6- alkylnitrolyl eg, dimethylnitrolyl, getylnitrolyl
- the ring A is preferably a benzene ring which may be substituted by a halogen atom (eg, chlorine) or alkoxy (eg, methoxy, ethoxy) or a 6-membered nitrogen-containing aromatic heterocyclic ring.
- a halogen atom eg, chlorine
- alkoxy eg, methoxy, ethoxy
- a 6-membered nitrogen-containing aromatic heterocyclic ring e.g, a benzene ring or a 2-pyridone ring is preferred, and a benzene ring or a pyridine ring is particularly preferred.
- Ar ′ is biphenylyl (eg, 2-, 3- or 4-biphenylyl), and X is a 1- (CH 2 ) p : 0- (wherein, p 1 represents an integer of 1 to 3); 2 a group represented by the formula — (CH 2 ) p 2- (where p 2 represents an integer of 1 to 3); or 3 C ⁇ NH, Y 'is the formula — (CH 2 ) q ⁇ CON R 9 (CH 2 ) r 1 (where Q 1 and r 1 are each 0 to 3 and the total is 3 or less integer, R 9 is a hydrogen atom or halogenated optionally may _ 6 alkyl (in particular alkyl) or optionally halogenated alkyl one carbonyl (especially Asechiru, alkyl Lou force Ruponiru such E chill carbonyl) group or the formula represented by the illustrated) - (CH 2) q 2 COO (CH 2) r 2 - ( wherein,
- N- [4- ⁇ [2- (1-pyrrolidinyl) ethyl] amino ⁇ aminopropyl ⁇ phenyl] (4-biphenylyl) carpoxamide and the like are preferable.
- Examples of the compound (I) and the salt of the compound (Ia) 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, and a basic or acidic amino acid. And the like.
- the salt with an inorganic base include an alkali metal salt such as a sodium salt and a potassium salt; an alkaline earth metal salt such as a calcium salt, a magnesium salt and a barium salt; and an aluminum salt.
- Suitable examples of salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzyl A salt with ethylenediamine or the like is used.
- Preferable examples of the salt with an inorganic acid include a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, A salt with p-toluenesulfonic acid or the like is used.
- Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like.
- Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, glutamic acid, and the like. And salt is used.
- salts pharmaceutically acceptable salts are preferred.
- an alkali metal salt eg, sodium salt, potassium salt, etc.
- an alkaline earth metal salt eg, calcium salt, magnesium salt
- Barium salts, etc. ammonium salts, etc.
- compound (I) or (Ia) has a basic functional group, hydrochloride, sulfate, phosphoric acid Salts, inorganic salts such as hydrobromide, or organic salts such as acetate, maleate, fumarate, succinate, methanesulfonate, P-toluenesulfonate, citrate, tartrate Is used.
- Compound (I) of the present invention compound (Ia) or a salt thereof (hereinafter, compound of the present invention)
- Prodrugs are compounds that are converted into the compounds of the present invention by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, that is, enzymatically oxidize, reduce, hydrolyze, etc. And a compound which undergoes hydrolysis or the like by gastric acid or the like to change to the compound of the present invention.
- Examples of the prodrug of the compound of the present invention include compounds in which the amino group of the compound of the present invention is acylated, alkylated, and phosphorylated (eg, the amino group of the compound of the present invention is eicosanoylated, alanylated, pentylyl).
- Minocarbonylation (5-methyl-1-oxo-1,3-dioxolen-1-41) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, bivaloyloxymethylation, tert-butyl
- the hydroxyl group of the compound of the present invention is acylated, alkylated, phosphorylated, and borated (eg, the hydroxyl group of the compound of the present invention is acetylated, palmitoylated, propanoylated, vivaloylated, etc.) Succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylylated compounds, etc.); the compounds of the present invention.
- the ethoxyl group is converted to ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarponyloxyshethyl ester, phthalidyl ester, 5-methyl-2-oxo-1,3-dioxolen-41-yl) methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compounds, etc.).
- These compounds can be produced from the compound of the present invention by a method known per se.
- the prodrug of the compound of the present invention can be prepared under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs,” Volume 7, Molecular Design, pp. 163 to 198. It may be changed to the compound of the invention.
- the compound (I) or (Ia) may be either an anhydride or a hydrate. If a hydrate, may have one to three H 2 0 molecules.
- the production method of compound (Ia) is described below.
- the compound (Ia) may be prepared by a method known per se, for example, in the compound (Ia), wherein X is an oxygen atom, an optionally oxidized sulfur atom or a substituent. When it contains mino, compound (Ia) is produced according to the following production method. “Room temperature” usually indicates 0 to 30 ° C.
- X a represents an oxygen atom, a sulfur atom which may be oxidized, or an imino which may have a substituent.
- X a represents an oxygen atom, a sulfur atom which may be oxidized, or an imino which may have a substituent.
- Compound (I) can be subjected to an alkylation reaction or an acylation reaction to obtain compound (Ia).
- Alkylation reaction and “acylation reaction” are carried out by methods known per se, for example, ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, ACADEMIC PRESS, INC., 1 It can be carried out according to the method described in 989, etc.
- Examples of the leaving group represented by L include a halogen atom (for example, chlorine, bromine, iodine, etc.), an alkylsulfonyloxy which may be halogenated (for example, methanesulfonyloxy, ethanesulfonyloxy, triflate such Ruo b methane Suruhoniruokishi), etc. good C 6 ⁇ 0 ⁇ Li one Rusuruhoniru Okishi have a substituent is used.
- Examples of the “substituent” of the “C. optionally substituted C. arylsulfonyloxy” include 1 to 3 halogen atoms, optionally halogenated alkyl or.
- C 61 () arylsulfonyloxy examples include, for example, benzenesulfonyloxy, P-toluenesulfonyloxy, and toluenesulfonyloxy. And 2-naphthalenesulfonyloxy.
- the compound (II) and an equivalent to excess amount of the compound (III) are reacted in an inert solvent. If necessary, the reaction can be carried out by adding a base.
- Xa is an imino which may have a substituent, the base is not always essential.
- the reaction temperature is usually about ⁇ 20 ° C. (: up to 100 ° C., preferably room temperature to 80 ° C.)
- the reaction time is usually 0.5 hour to 1 day.
- inert solvent examples include alcohol solvents, ether solvents, halogen solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, and water alone or in combination. Two or more kinds can be used as a mixture. Of these, preferred are acetonitrile, N, N-dimethylformamide (DMF), acetone, ethanol, pyridine and the like.
- alkali metal or alkaline earth metal hydrides eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.
- alkali metal or alkaline earth metal amides eg, lithium Amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, Strong bases such as lower alkoxides of alkali metals or alkaline earth metals (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.);
- alkali metal, alkaline earth metal or silver hydroxide eg, silver hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.
- alkali metal, alkaline earth Metal or silver carbonate e.g., sodium carbonate Inorganic bases such as potassium carbonate, cesium carbonate, silver carbonate
- alkali metal or alkaline earth metal bicarbonates eg, sodium bicarbonate, potassium bicarbonate, etc.
- Preferred reaction conditions are, for example, in the case of an alkylation reaction, compound (11), 1 to 2 equivalents of compound (III) and 1 to 5 equivalents of a base (eg, potassium carbonate, sodium hydride, sodium hydroxide, carbonate) Silver, etc.) in acetonitrile or DMF for about 1 hour to 2 days.
- a base eg, potassium carbonate, sodium hydride, sodium hydroxide, carbonate
- Silver e.g, potassium carbonate, sodium hydride, sodium hydroxide, carbonate
- the preferred reaction temperature depends on the base used, for example, room temperature when using sodium hydride, room temperature to 80 when using potassium carbonate. ° C is preferred.
- Preferred reaction conditions are, for example, in the case of an acylation reaction, compound (11), 1 equivalent to 1.5 equivalents of compound (III) and 1 equivalent to 5 equivalents of a base (eg, sodium hydride, sodium hydroxide, carbonate) Potassium, sodium bicarbonate, triethylamine, etc.) are stirred in an inert solvent (eg, water, ethyl acetate, DMF, acetonitrile, pyridine alone or a mixed solvent of two or more thereof) at room temperature for usually 1 hour to 6 hours. I do.
- a base eg, sodium hydride, sodium hydroxide, carbonate
- Potassium sodium bicarbonate
- triethylamine Triethylamine, etc.
- an inert solvent eg, water, ethyl acetate, DMF, acetonitrile, pyridine alone or a mixed solvent of two or more thereof
- a compound in which Y ′ is — (CH 2 ) qCONR 9 (CH 2 ) r is obtained by, for example, reacting a carboxylic acid derivative (IV) with an amine (V) by an amidation reaction shown in the following production method 2.
- the above-mentioned “amidation reaction” may be performed according to a method known per se, for example, (1) a method of reacting a compound (IV) with an amine (V) in the presence of a dehydrating condensing agent, or (2) a compound A method of reacting a reactive derivative of (IV) with an amine (V) is used.
- compound (IV) 1 to 5 equivalents of amine (V) and 1 to 2 equivalents of a dehydrating condensing agent are reacted in an inert solvent at room temperature, usually for 10 to 24 hours. .
- 1 to 1.5 equivalents of trihydroxy-1H-benzotriazole (HOBt) and / or 1 to 5 equivalents of a base for example, triethylamine
- dehydration condensing agent for example, dicyclohexylcarboimide (DCC), tolethyl-3- (3-dimethylaminopropyl) carboimide hydrochloride (WSC) and the like are used. Among them, WSC is preferred.
- DCC dicyclohexylcarboimide
- WSC tolethyl-3- (3-dimethylaminopropyl) carboimide hydrochloride
- inert solvent examples include single solvents such as nitrile solvents (preferably acetonitrile), amide solvents (preferably DMF), halogen solvents (preferably dichloromethane), and ether solvents (preferably THF). Alternatively, a mixture of two or more of these can be used.
- reaction (2) a reactive derivative of the compound (IV) and 1 to 5 equivalents (preferably 1 to 3 equivalents) of the amine (V) are added in an inert solvent, usually at about 20 ° C.
- the reaction is carried out at 50 ° C (preferably room temperature) for 5 minutes to 40 hours (preferably 1 hour to 18 hours). If necessary, 1 to 10 equivalents, preferably 1 to 3 equivalents of W 1
- Examples of the “reactive derivative” of the compound (IV) include acid halides (eg, acid chloride, acid bromide, etc.), mixed acid anhydrides (eg, alkyl-carboxylic acid,
- the “substituent” of the “phenol which may have a substituent” for example, a halogen atom, nitro, or halogenated — 6 alkyl or halogenated — 6 alkoxy 1 to 5 are used.
- a substituent for example, phenol, pentachlorophenol, penfluorophenol, p-nitrophenol and the like are used.
- the reactive derivative is preferably an acid halide ⁇ active ester.
- potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, sodium hydrogencarbonate examples include sodium alkoxides (eg, sodium methoxide, sodium ethoxide, sodium butoxide), and organic amines (eg, triethylamine, pyridine, triazole, imidazole, hydroxypyridine, etc.).
- the inert solvent include alcohol solvents, ether solvents, halogen solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, and water alone or in combination. Two or more of these can be used in combination. Among them, methanol, ethanol, acetonitrile, dichloromethane, chloroform and the like are preferable.
- an active ester preferably a methyl ester or ethyl ester
- 1 to 5 equivalents of an amine (V) are catalytically or 2 equivalents of an organic amine (eg, triethylamine, pyridine, triazole, imidazo, etc.).
- an organic amine eg, triethylamine, pyridine, triazole, imidazo, etc.
- hydroxypyridine in an inert solvent.
- the reaction temperature is from room temperature to reflux conditions (preferably 50 to 120 ° C), and the reaction time is preferably 1 to 60 hours.
- an alcohol solvent eg, methanol, ethanol, etc.
- the carboxylic acid (IV) and amine (V) used for the reaction are commercially available or easily available.
- a benzoic acid derivative can be obtained by the production method described in WO93 / 24442.
- the compound ( ⁇ ) thus obtained is further subjected to a reaction known per se, for example, a hydrolysis reaction, an esterification reaction, an amidation reaction, an oxidation reaction, a reduction reaction, or a deprotection reaction described below, by combining one or two, It can be led to the compound (I).
- a reaction known per se for example, a hydrolysis reaction, an esterification reaction, an amidation reaction, an oxidation reaction, a reduction reaction, or a deprotection reaction described below, by combining one or two, It can be led to the compound (I).
- ether solvent for example, methanol, ethanol, isopropanol, tert-butanol and the like are used.
- ether solvent include getyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane and the like.
- halogen solvent for example, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride and the like are used.
- aromatic solvent for example, benzene, toluene, xylene, pyridine and the like are used.
- hydrocarbon solvent for example, hexane, pentane, cyclohexane and the like are used.
- amide solvent for example, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpiperidone and the like are used.
- ketone-based solvent for example, acetone, methylethyl ketone and the like are used.
- sulfoxide solvent for example, dimethyl sulfoxide (DMSO) or the like is used.
- nitrile solvent for example, acetonitrile, propionitrile and the like are used.
- a protecting group generally used in peptide chemistry or the like may be introduced into these groups. After the reaction, the desired compound can be obtained by removing the protecting group as necessary.
- protecting groups for amino include, for example, formyl, alkyl-propionyl (eg, acetyl, propionyl, etc.), and alkoxy-carbonyl (eg, methoxycal Boniru, ethoxycarbonyl, tert- butoxycarbonyl) Benzoiru, C 7 _i.
- Ararukiru - carbonyl e.g., benzylcarbonyl and the like
- C 7 14 Ararukiru Okishi - carbonyl e.g., benzyl O alkoxycarbonyl, such as 9-O-les methoxy mosquito Ruponiru
- trityl e.g., benzyl O alkoxycarbonyl, such as 9-O-les methoxy mosquito Ruponiru
- trityl e.g., benzyl O alkoxycarbonyl, such as 9-O-les methoxy mosquito Ruponiru
- trityl e.g., benzyl O alkoxycarbonyl, such as 9-O-les methoxy mosquito Ruponiru
- trityl e.g., benzyl O alkoxycarbonyl, such as 9-O-les methoxy mosquito Ruponiru
- trityl e.g.
- These groups may be substituted with one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), alkoxy (eg, methoxy, ethoxy, propoxy, etc.) or nitro.
- halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
- alkoxy eg, methoxy, ethoxy, propoxy, etc.
- Carboxy protecting groups include, for example, alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), C 7 aralkyl (eg, benzyl, etc.), phenyl, trityl, silyl (eg, trimethylsilyl, Toryechi Rushiriru, dimethyl Hue El silyl, tert- butyldimethylsilyl, etc. tert- butyl Jechirushiriru), C 2 _ 6 alkenyl (eg, Bok Ariru) and the like.
- alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.
- C 7 aralkyl eg, benzyl, etc.
- phenyl, trityl eg, silyl (eg, tri
- These groups may be substituted with one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), ⁇ 6 alkoxy (eg, methoxy, ethoxy, propoxy, etc.) or nitro.
- halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
- ⁇ 6 alkoxy eg, methoxy, ethoxy, propoxy, etc.
- Hydroxy protecting groups include, for example, alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, C 7 .
- Ararukiru e.g., benzyl etc.
- formyl e.g., Asechiru, propionyl, etc.
- Benzoiru .7 ⁇ Ararukiru -.
- Carbonyl e.g., benzyl Cal Poni Le
- 2-tetrahydropyran Vila sulfonyl 2 -Tetrahydrofuranyl
- silyl eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butylethylsilyl, etc.
- C 26 alkenyl eg, triaryl, etc.
- the group can be one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), —6 alkyl (eg, methyl, ethyl, n-propyl, etc.), 6 alkoxy (eg, methoxy, ethoxy, Or nitro or the like.
- halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
- —6 alkyl eg, methyl, ethyl, n-propyl, etc.
- 6 alkoxy eg, methoxy, ethoxy, Or nitro or the like.
- Examples of the protecting group for carbonyl are, for example, cyclic acetal (e.g., 1,3-dioxane Acyclic acetal (eg, di-C ⁇ 6 alkyl acetal, etc.).
- cyclic acetal e.g., 1,3-dioxane Acyclic acetal (eg, di-C ⁇ 6 alkyl acetal, etc.).
- the method for removing these protecting groups may be a method known per se, for example, a method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980). Can be done. For example, acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiolrubamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halides (eg, trimethylsilyl halide, trimethylsilyl bromide, etc.) The method used and the reduction method are used.
- Compound (Ia) can be isolated and purified by known means, for example, solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like.
- the starting compound of the compound (Ia) or a salt thereof can be isolated and purified by the same known means as described above, but can be directly used as a reaction mixture in the next step without isolation. May be provided as a raw material.
- the compound (la) contains an optical isomer, a stereoisomer, a positional isomer, and a rotamer
- these are also contained as the compound (la) and are synthesized by a synthesis method and a separation method known per se. Can be obtained as a single item.
- the compound (Ia) has an optical isomer
- the optical isomer separated from the compound is also included in the compound (Ia).
- 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 racemic mixture of the final product according to a conventional method.
- optical resolution method a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method and the like are used.
- Racemic and optically active compounds eg, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-triphenethylamine, (-)-triphenethylamine, (Cinconin, (-)-cinchonidine, brucine, etc.
- Racemic and optically active compounds eg, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-triphenethylamine, (-)-triphenethylamine, (Cinconin, (-)-cinchonidine, brucine, etc.
- a free optical isomer via a neutralization step.
- a method in which a racemate or a salt thereof is applied to an optical isomer separation column (chiral column) for separation For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANT IO-0VM (manufactured by Toso One) or CHIRAL series manufactured by Daicel, and water, various buffer solutions (for example, phosphate buffer) are added. Solution) and an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) alone or as a mixed solution to separate optical isomers.
- a chiral column such as CP-Chirasil-DeXCB (manufactured by GL Sciences).
- a racemic mixture is formed into a mixture of diastereomers by a chemical reaction with an optically active reagent, which is converted into a single substance through ordinary separation means (eg, fractional recrystallization, chromatography, etc.), and then subjected to a hydrolysis reaction.
- optically active reagent e.g, fractional recrystallization, chromatography, etc.
- a method for obtaining optical isomers by separating optically active reagent sites by chemical treatment such as For example, when the compound (I) has hydroxy or primary or secondary amino in the molecule, the compound and an optically active organic acid (for example, MPTA [-methoxy- ⁇ - (trifluoromethyl) phenylacetic acid]), (-)-Menthoxyacetic acid or the like) to give a diastereomer of an ester form or an amide form, respectively.
- an optically active organic acid for example, MPTA [-methoxy- ⁇ - (trifluoromethyl) phenylacetic acid]
- (-)-Menthoxyacetic acid or the like to give a diastereomer of an ester form or an amide form, respectively.
- compound (I) has a carboxylic acid group
- the compound is subjected to a condensation reaction with an optically active amine or an alcohol reagent to obtain an amide or ester diastereomer, respectively.
- Compound (I) or a salt thereof can be produced according to the method for producing compound (Ia) or a salt thereof described above, or can be produced by a method known per se or a method analogous thereto.
- Compound (I) is an excellent; 3 amyloid protein (Ai31-40, A141-A1, A ⁇ 1-42 or (and) A] 31_43, especially Ai31_4 0 or (and) ⁇ ⁇ 1 2) 2 2 2 2 2 2 2 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ .
- Compound (Ia) also has a / 3 amyloid protein production 'secretion inhibitory action.
- Compound (I) also has low toxicity, and the compound obtained in Example 8 described later has particularly excellent translocation into the brain.
- compound (I) can safely be used for the production of i3 amyloid protein, particularly i3 amyloid protein, from mammals (eg, rat, mouse, guinea pig, rabbit, egret, hidge, poma, bush, pear, monkey, human, etc.). It is useful as a preventive / therapeutic agent for diseases caused by production and secretion.
- mammals eg, rat, mouse, guinea pig, rabbit, egret, hidge, poma, bush, pear, monkey, human, etc.
- Examples of the disease include diseases such as senile dementia, Alzheimer's disease, Down's syndrome, Parkinson's disease, amyloid angiopathy, and cerebrovascular disorders; 3 disorders due to amyloid protein. ) Is particularly suitable for Alzheimer's disease.
- the compound (I) can be formulated according to a means known per se.
- a pharmaceutical composition such as a compound (I) can be prepared by mixing an appropriate amount of the compound (I) as it is or a pharmacologically acceptable carrier in the formulation step.
- Tablets including sugar-coated tablets, film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release tablets, etc., orally or parenterally (eg, topical, It can be safely administered rectally or intravenously.
- the content of compound (I) is usually about 0.1 to 100% by weight of the whole preparation.
- the dosage varies depending on the administration subject, administration route, disease, etc.
- an active ingredient (compound (I)) as an oral agent for an adult (about 60 kg) as an oral drug for Alzheimer's disease
- the dose is about 0.1 to 500 mg, preferably about 1 to 100 mg, more preferably 5 to 100 mg, which can be administered once or several times a day.
- Examples of the pharmacologically acceptable carrier used in the production of the composition of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, lubricants, and binders in solid preparations. Agents, disintegrants; solvents in liquid preparations, dissolution aids, suspending agents, tonicity agents, buffers, soothing agents and the like. Also, if necessary, Additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used.
- excipient for example, lactose, sucrose, D-mannitol, starch, corn corn, crystalline cellulose, light caffeic anhydride and the like are used.
- lubricant for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like are used.
- binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and carboxymethylcellulose sodium.
- disintegrant for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl cellulose, L-hydroxypropylcellulose and the like are used.
- solvent for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like are used.
- solubilizer for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like are used.
- suspending agent examples include surfactants such as stearyl toluene luminamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; for example, polyvinyl alcohol, Hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose are used.
- tonicity agent for example, glucose, D-sorbyl, sodium chloride, glycerin, D-mannitol and the like are used.
- buffers for example, buffers such as phosphate, acetate, carbonate, and citrate are used.
- the soothing agent for example, benzyl alcohol and the like are used.
- preservative for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like are used.
- antioxidant for example, sulfite, ascorbic acid and the like are used.
- the present invention will be further described in detail with reference to the following reference examples, examples, and experimental examples. However, these examples are merely examples and do not limit the present invention, and do not depart from the scope of the present invention. May be changed.
- the infrared absorption spectrum was measured by a diffuse reflection method using a Fourier transform infrared spectrophotometer.
- Recrystallization solvent ethyl acetate / disopropyl ether.
- Recrystallization solvent ethyl acetate / disopropyl ether.
- Potassium carbonate (0.131 g) was added to a DMF solution (10 ml) of 4- [3- (N, N-dipropylamino) propyl] phenol hydrochloride (0.152 g) and 1-bromomethylnaphthylene (0.165 g). . Under ice-cooling, add 60% oily sodium hydride (0.044 g) to the reaction mixture, Was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated.
- Recrystallization solvent methanol / getyl ether.
- Recrystallization solvent ethanol / getyl ether.
- Recrystallization solvent ethanol / getyl ether.
- Recrystallization solvent ethanol / getyl ether.
- Recrystallization solvent ethyl / getyl ether.
- Recrystallization solvent ethanol / getyl ether.
- Recrystallization solvent Ethyl acetate / Jetyl ether.
- N-methylethylenediamine (7.4 ml) was added dropwise to a solution of ethyl trifluoroacetate (10 ml) in geethyl ether (20 ml) under ice cooling over 1 hour. After the dropwise addition, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. The ether was removed from the reaction solution to give the title compound (14 g).
- Methyl 4- (4-biphenylylmethoxy) phenylacetate (60.0 g), N, N-dimethylethylenediamine (47.7 g), 1H-1,2,4-triazole (12.6 g) in toluene (120 ml
- the solution was stirred at 100 ° C for 8 hours under a nitrogen stream, cooled to an internal temperature of 60 ⁇ 2 ° C, and ethyl acetate (240 ml) was added over 20 minutes.
- the mixture was heated under reflux for another 30 minutes and left at room temperature overnight.
- the mixture was stirred for 2 hours under ice-water cooling, and the precipitated crystals were collected by filtration and washed with ethyl acetate (120 ml) to obtain the title compound (71.7 g).
- 6- (4-Bifenylylmethoxy) nicotinic acid (500 mg) and WSC (380 mg) were added to a mixture of acetonitrile (5 ml) and THF (10 ml) of tri (2-aminoethyl) piperidine (260 mg). mg), 11081 (26011 ⁇ )-triethylamine (0.71111) were added at room temperature. After stirring at room temperature for 36 hours, a 5% aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and concentrated. The residue was purified by alumina column chromatography (THF) and recrystallized from ethyl acetate to obtain the title compound (450 mg). Melting point: 160-163 ° C
- Example compounds 13 and 14 were synthesized according to Example 12.
- Recrystallization solvent ethanol.
- Recrystallization solvent ethanol.
- Example 16- [4-[(4-biphenylmethoxy) phenyl] -N- [2- (N-methylamino) ethyl] acetoamide Dissolve 4- [4- (biphenylylmethoxy) phenyl] -N- [2- (N-methylamino) ethyl] acetamide hydrochloride (46 mg) in saturated aqueous sodium bicarbonate and extract with THF-ethyl acetate (1). did. The organic layer was washed with water and saturated saline, dried over sodium sulfate and concentrated. The residue was dissolved in THF and purified by alumina column chromatography (developing solvent: THF, methanol) to give the title compound. (7 mg) was obtained.
- Human 'Neuroblastoma I MR-32 cells American type culture'-purchased from American Type Culture Center.
- DMEM Dulbecco's modified Eagle's medium
- FCS fetal calf serum
- penicillin 5000 U / ml
- Z streptomycin 5 mg / ml
- PBS Phosphate / saline buffer
- Block Ace (brand name): Purchased from Dainippon Pharmaceutical.
- Bovine serum albumin (abbreviated as BSA): Purchased from Sigma. Culture flask: Use Falcon.
- 48-well multiwell plate Made by Coaster.
- A311-40 standard product and A / 31-42 standard product purchased from Bachem.
- IMR-32 cells were cultured in a flask containing 10% FC SZDMEM culture medium (Falcon, 750 ml) in 10% carbon dioxide / 90% air at 37 ° C until confluent (full) . After culturing, IMR-32 cells were seeded in a 48-well multiwell plate at 2.5 ⁇ 10 5 cells in a Z-well, and after culturing under the same conditions for 3 days, the culture solution was removed by suction.
- FC SZDMEM culture medium Falcon, 750 ml
- the DMF solution containing the test substance was dissolved in 0.5 ml of 0.5% BSA / DMEM, added to the plate, and cultured for 24 hours.
- a DMF solution containing no test substance dissolved in 0.5 ml of 0.5% BSA / DMEM was used.
- the supernatant was collected and stored at below 120 ° C until A / 3 measurement.
- BAN-50 antibody or BNT-77 antibody was used as a primary antibody.
- B A-27 antibody was used as a secondary antibody.
- BC-55 antibody was used as a secondary antibody.
- BAN-50 antibody or BNT-77 antibody dissolved in 0.1 M carbonate buffer ( ⁇ 9.6) at a concentration of 15 g / ml, was added to the polyethylene microplate one by one at a time. Left overnight at 4 ° C. After the plate surface was washed three times with PBS, a blocking solution (25% Block Ace Z0.1% sodium azide ZPBS) 200 ⁇ 1 was added. In this state, it was stored at 4 ° C. until the supernatant was added in the above (1).
- the plate surface was washed three times with PBS, and then the primary reaction buffer (20 mM phosphate buffer, pH 7.0; 400 mM NaCl; 2 mM EDTA; 10% Block Ace; 0% (2% BSA; 0.05% sodium azide) 501 was added.
- the primary reaction buffer (20 mM phosphate buffer, pH 7.0; 400 mM NaCl; 2 mM EDTA; 10% Block Ace; 0% (2% BSA; 0.05% sodium azide) 501 was added.
- 100 A supernatants and A 3 (1-40 or A / 31-42 standard) diluted in primary reaction buffer 1000, 200, 40 and 8 pg / ml, respectively) (Dilution) 100 was added, and the mixture was allowed to stand at 4 ° C.
- the plate was washed three times with PBS, and dissolved in a secondary reaction buffer (20 mM phosphate buffer, pH 7.0; 400 mM NaCl: 2 mM EDTA; 1% BSA). 1
- compound (I) Since compound (I) has an excellent inhibitory action on amyloid protein production and secretion, diseases caused by ⁇ -amyloid protein (for example, diseases such as senile dementia, Alzheimer's disease, Down's disease, Parkinson's disease, and amyloid angiopathy) , 3) amyloid protein disorders during cerebrovascular disorders, etc.) is effective in preventing 'treatment'.
- Compound (Ia) also has excellent 0-amyloid protein production 'secretion inhibitory action.
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Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/856,317 US6586475B1 (en) | 1998-11-20 | 1999-11-16 | β-amyloid protein production/secretion inhibitors |
EP99972620A EP1132376A4 (en) | 1998-11-20 | 1999-11-18 | BETA-AMYLOID PROTEIN PRODUCTION / SECRETION INHIBITORS |
CA002351692A CA2351692A1 (en) | 1998-11-20 | 1999-11-18 | Inhibitors of production and/or secretion of amyloid-.beta. protein |
AU11833/00A AU1183300A (en) | 1998-11-20 | 1999-11-18 | Beta-amyloid protein production/secretion inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP33101898 | 1998-11-20 | ||
JP10/331018 | 1998-11-20 |
Publications (1)
Publication Number | Publication Date |
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WO2000031021A1 true WO2000031021A1 (en) | 2000-06-02 |
Family
ID=18238918
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1999/006450 WO2000031021A1 (en) | 1998-11-20 | 1999-11-18 | β-AMYLOID PROTEIN PRODUCTION/SECRETION INHIBITORS |
Country Status (5)
Country | Link |
---|---|
US (1) | US6586475B1 (ja) |
EP (1) | EP1132376A4 (ja) |
AU (1) | AU1183300A (ja) |
CA (1) | CA2351692A1 (ja) |
WO (1) | WO2000031021A1 (ja) |
Cited By (9)
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WO2001082925A1 (fr) * | 2000-04-28 | 2001-11-08 | Takeda Chemical Industries, Ltd. | Antagonistes de l'hormone concentrant la melanine |
US6436972B1 (en) * | 2000-04-10 | 2002-08-20 | Dalhousie University | Pyridones and their use as modulators of serine hydrolase enzymes |
WO2001078709A3 (en) * | 2000-04-12 | 2003-04-17 | Minerva Biotechnologies Corp | Treatment of neurodegenerative disease |
US6670399B2 (en) | 1999-12-23 | 2003-12-30 | Neurochem (International) Limited | Compounds and methods for modulating cerebral amyloid angiopathy |
JPWO2003055850A1 (ja) * | 2001-12-27 | 2005-05-12 | 第一製薬株式会社 | βアミロイド蛋白産生・分泌阻害剤 |
US7601868B2 (en) | 2003-02-12 | 2009-10-13 | Takeda Pharmaceutical Company Limited | Amine derivative |
US7939551B2 (en) | 2000-05-03 | 2011-05-10 | Amgen Inc. | Combination therapeutic compositions |
US8357711B2 (en) | 2007-03-23 | 2013-01-22 | Pfizer Limited | Heterocyclic sulfonamides as inhibitors of ion channels |
US9145354B2 (en) | 2011-11-01 | 2015-09-29 | Astex Therapeutics Limited | Pharmaceutical compounds |
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DE69939864D1 (de) * | 1998-01-29 | 2008-12-18 | Amgen Inc | Ppar-gamma modulatoren |
US7041691B1 (en) * | 1999-06-30 | 2006-05-09 | Amgen Inc. | Compounds for the modulation of PPARγ activity |
US20030171399A1 (en) * | 2000-06-28 | 2003-09-11 | Tularik Inc. | Quinolinyl and benzothiazolyl modulators |
GB0214149D0 (en) * | 2002-06-19 | 2002-07-31 | Glaxo Group Ltd | Chemical compounds |
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AU2006310612A1 (en) * | 2005-11-03 | 2007-05-10 | F. Hoffmann-La Roche Ag | Arylsulfonylchromans as 5-HT6 inhibitors indolylmaleimide derivatives as protein kinase inhibitors |
WO2007147762A1 (en) * | 2006-06-20 | 2007-12-27 | F. Hoffmann-La Roche Ag | Arylsulfonamidyl tetralin derivatives and uses thereof |
EP2041079A1 (en) * | 2006-06-20 | 2009-04-01 | F. Hoffmann-Roche AG | Arylsulfonyl naphthalene derivatives and uses thereof |
AU2007263084A1 (en) * | 2006-06-20 | 2007-12-27 | F. Hoffmann-La Roche Ag | Tetralin and indane derivatives and uses thereof |
JP4891111B2 (ja) * | 2007-02-16 | 2012-03-07 | 富士フイルム株式会社 | ズームレンズ |
JP2013505297A (ja) * | 2009-09-21 | 2013-02-14 | ヴァンダービルト ユニバーシティー | mGluR5の正のアロステリック調節因子としてのO−ベンジルニコチンアミド類似体 |
WO2013106328A1 (en) * | 2012-01-09 | 2013-07-18 | Envivo Pharmaceuticals, Inc. | Tetrasubstituted benzenes for treatment of early onset alzheimer's disease |
DK3054936T5 (da) | 2013-10-10 | 2024-03-18 | Eastern Virginia Medical School | 4-((2-hydroxy-3-methoxybenzyl)amino) benzensulfonamid derivater som 12-lipoxygenase inhibitorer |
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WO1994001408A1 (en) | 1992-07-10 | 1994-01-20 | Laboratoires Glaxo S.A. | Anilide derivatives |
US5451677A (en) | 1993-02-09 | 1995-09-19 | Merck & Co., Inc. | Substituted phenyl sulfonamides as selective β 3 agonists for the treatment of diabetes and obesity |
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JP3775780B2 (ja) | 1997-09-18 | 2006-05-17 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 薬剤の経口的バイオアベイラビリテイを向上させるための縮合イミダゾール誘導体 |
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1999
- 1999-11-16 US US09/856,317 patent/US6586475B1/en not_active Expired - Fee Related
- 1999-11-18 AU AU11833/00A patent/AU1183300A/en not_active Abandoned
- 1999-11-18 EP EP99972620A patent/EP1132376A4/en not_active Withdrawn
- 1999-11-18 CA CA002351692A patent/CA2351692A1/en not_active Abandoned
- 1999-11-18 WO PCT/JP1999/006450 patent/WO2000031021A1/ja not_active Application Discontinuation
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EP0487745A1 (en) * | 1990-06-19 | 1992-06-03 | Meiji Seika Kabushiki Kaisha | Pyridine derivative with angiotensin ii antagonism |
JPH05239005A (ja) * | 1992-02-28 | 1993-09-17 | Kitsuen Kagaku Kenkyu Zaidan | N−(2−アミノエチル)ベンズアミド類およびその新規中間体 |
WO1998017648A1 (en) * | 1996-10-18 | 1998-04-30 | Xenova Limited | Anthranilic acid derivatives as multi drug resistance modulators |
WO1998038156A1 (en) * | 1997-02-27 | 1998-09-03 | Takeda Chemical Industries, Ltd. | Amine compounds, their production and use as amyloid-beta production inhibitors |
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Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6670399B2 (en) | 1999-12-23 | 2003-12-30 | Neurochem (International) Limited | Compounds and methods for modulating cerebral amyloid angiopathy |
US6436972B1 (en) * | 2000-04-10 | 2002-08-20 | Dalhousie University | Pyridones and their use as modulators of serine hydrolase enzymes |
WO2001078709A3 (en) * | 2000-04-12 | 2003-04-17 | Minerva Biotechnologies Corp | Treatment of neurodegenerative disease |
WO2001082925A1 (fr) * | 2000-04-28 | 2001-11-08 | Takeda Chemical Industries, Ltd. | Antagonistes de l'hormone concentrant la melanine |
US6930185B2 (en) * | 2000-04-28 | 2005-08-16 | Takeda Chemical Industries, Ltd. | Melanin-concentrating hormone antagonist |
US7939551B2 (en) | 2000-05-03 | 2011-05-10 | Amgen Inc. | Combination therapeutic compositions |
JPWO2003055850A1 (ja) * | 2001-12-27 | 2005-05-12 | 第一製薬株式会社 | βアミロイド蛋白産生・分泌阻害剤 |
US7601868B2 (en) | 2003-02-12 | 2009-10-13 | Takeda Pharmaceutical Company Limited | Amine derivative |
US8357711B2 (en) | 2007-03-23 | 2013-01-22 | Pfizer Limited | Heterocyclic sulfonamides as inhibitors of ion channels |
US8741934B2 (en) | 2007-03-23 | 2014-06-03 | Pfizer Limited | Inhibitors of ion channels |
US9145354B2 (en) | 2011-11-01 | 2015-09-29 | Astex Therapeutics Limited | Pharmaceutical compounds |
Also Published As
Publication number | Publication date |
---|---|
CA2351692A1 (en) | 2000-06-02 |
US6586475B1 (en) | 2003-07-01 |
EP1132376A1 (en) | 2001-09-12 |
AU1183300A (en) | 2000-06-13 |
EP1132376A4 (en) | 2002-09-18 |
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