NZ623185B2 - 1-arylcarbonyl-4-oxy-piperidine compounds useful for the treatment of neurodegenerative diseases - Google Patents

1-arylcarbonyl-4-oxy-piperidine compounds useful for the treatment of neurodegenerative diseases Download PDF

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NZ623185B2
NZ623185B2 NZ623185A NZ62318512A NZ623185B2 NZ 623185 B2 NZ623185 B2 NZ 623185B2 NZ 623185 A NZ623185 A NZ 623185A NZ 62318512 A NZ62318512 A NZ 62318512A NZ 623185 B2 NZ623185 B2 NZ 623185B2
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optionally substituted
ring
compound
atom
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Haruhi Ando
William John Farnaby
Tatsuki Koike
Masato Yoshikawa
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Takeda Pharmaceutical Company Limited
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Priority claimed from PCT/JP2012/076257 external-priority patent/WO2013054822A1/en
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Publication of NZ623185B2 publication Critical patent/NZ623185B2/en

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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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Abstract

Disclosed are 1-(het)arylcarbonyl-4-oxypiperidine compounds of formula (I) active as cholesterol 24-hydroxylase (CH24H) inhibitors, wherein the substituents are as defined in the specification. Also disclosed is the use of a compound of formula (I) for the prophylaxis or treatment of neurodegenerative disease such as Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, glaucoma, multiple sclerosis, epilepsy, and schizophrenia. Examples of compounds of formula (I) are: (4-benzyl-4-hydroxypiperidin-1-yl) (2,4'-bipyridin-3-yl)methanone 2,4'-bipyridin-3-yl(4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)methanone (4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl) (2-(pyrimidin-4-yl)pyridin-3-yl)methanone ve disease such as Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, glaucoma, multiple sclerosis, epilepsy, and schizophrenia. Examples of compounds of formula (I) are: (4-benzyl-4-hydroxypiperidin-1-yl) (2,4'-bipyridin-3-yl)methanone 2,4'-bipyridin-3-yl(4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)methanone (4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl) (2-(pyrimidin-4-yl)pyridin-3-yl)methanone

Description

DESCRIPTION l-ARYLCARBONYLOXY-PIPERIDINE COMPOUNDS USEFUL FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES Technical Field The present invention relates to a heterocyclic compound having a cholesterol 24—hydroxylase (in the present specification, sometimes to be abbreviated as “CH24H”) inhibitory action, pharmaceutical composition comprising same, and the like.
[0002] (Background of the Invention) Alzheimer’s disease is a progressive neurodegenerative disease characterized by the deposition of amyloid B protein (AB), accumulation of phosphorylated tau in a nerve cell (neurofibrillary tangle), and nerve cell death. In recent years, the number of patients with Alzheimer is increasing because of aging, but an effective treatment method has not been developed as yet. The eutic drugs for Alzheimer’s disease which are tly used in the medical front are mainly cholinesterase (AchE) inhibitors. While AchE inhibitors provide a certain, confirmed level of usefulness, since they aim to ment depressed acetylcholine, the treatment with AchE inhibitor is merely a symptomatic therapy.
Thus, the prompt development of a basic remedy and lactic drug has been strongly desired.
It has been clarified that the presence of allele 84 of apolipoprotein E (ApoE) controlling the cholesterol metabolism is a strong risk factor of Alzheimer's e [non—patent nt 1: Science, vol.26l, 921—923, 1993]. After this finding, the correlation between plural gene polymorphisms bearing the expression of protein controlling the cholesterol metabolism and the onset ncy of mer's disease has been shown, suggesting the correlation between the cholesterol metabolism and Alzheimer’s e [non—patent document 2: Neurobiol. Aging, , 421—426, 2003, non-patent document 3: Mol. Psychiatry, vol.8, 635—638, 2003]. Moreover, it has been reported that Cyp46 (same as sterol 24-hydroxylase (CH24H)”), which is terol oxidase specifically expressed in-the brain, is a risk factor of Alzheimer’s disease [non~ patent document 4: Neurosci. Lett., vol.328, pages 9—12, 2002].
Furthermore, it has also been reported that Cyp46(CH24H) is expressed in periphery of deposited amyloid in Alzheimer patients [non-patent document 5: J. Biol. Chem., vol.279, pages 34674-34681, 2004], 24S—hydroxycholesterol (24—HC), which is a metabolite f, increases in the brain spinal cord fluid (CSF) of Alzheimer patients [non—patent document 6: Neurosci. Lett., vol.324, pages 83—85, 2002, non-patent document 7: Neurosci. Lett., 7, pages 83—87, 2006] and that 24—HC induces cell death of SH—SYSY cell, which is a human neuroblast line [non—patent document 8: Brain Res., 8, pages 171—175, 1999], and rats treated with 24—HC into the cerebral ventricle showed impaired short—term memory, which is commonly observed in Alzheimer's disease, suggesting that hippocampal neurons were damaged by 24—HC [non—patent nt 9: cience, vol.l64, pages 398—403, 2009]. These findings suggest that Cyp46(CH24H) is deeply involved in the ogy of Alzheimer’s disease. Therefore, a compound that inhibits the activity of Cyp46 (CH24H) (i.e., Cyp46(CH24H) inhibitor) suppresses nerve cell death, AB increase,‘ intracerebral inflammation and the like ed in Alzheimer’s disease, by decreasing intracerebral 24—HC, and is promising as a therapeutic or prophylactic drug showing not only an improvement of symptom but also a suppression of progression. Moreover, it has been reported that AchE inhibitor clinically used as a therapeutic drug for Alzheimer’s disease shows an improving effect on memory disorders induced by AB in mouse [non—patent document 10: h Journal of Pharmacology, vol.l49, pages 998—1012, 2006], and Cyp46(CH24H) inhibitor showing an improvement effect for memory disorders in AB overexpression animal model (APP enic mouse, APP/P31 double transgenic mouse etc.) is promising as a therapeutic drug for Alzheimer’s disease.
As a concept of the prestage of Alzheimer’s disease, a mild cognitive impairment has been proposed, and about half of those having this disorder is said to progress into the Alzheimer’s disease in the future. In recent years, it has been reported that 24—HC increases not-only in ts with Alzheimer’s disease but also in CSF of patients with mild cognitive impairment [non—patent document 7: Neurosci. Lett., vol.397, pages 83—87, 2006]. This finding suggests that Cyp46(CH24H) is involved in the ogy of mild ive ment, and therefore, a Cyp46(CH24H) inhibitor is promising as a new therapeutic drug for Alzheimer’s disease or a prophylactic drug for the progression into the Alzheimer’s disease.
In recent years, moreover, it has been reported that 24— HC in the blood increases before expression of the symptom in an autoimmune encephalomyelitis model, which is an animal model of multiple sis which is one of the demyelination diseases in the central nervous system [non-patent document 11: J. Neurosci. Res., , pages 1499—1505, 2007].' Multiple sclerosis is often ped in younger people of about 30 years old, and scarcely developed in the elderly of 60 years or older. It has also been reported that 24—HC increases in multiple sclerosis patients aging from 21 to 50 [non—patent document 12: Neurosci. Lett., vol.33l, pages 163— 166, 2002]. These findings suggest that Cyp46(CH24H) is involved in the pathology of multiple sclerosis, and therefore, Cyp46(CH24H) inhibitor is promising as a new therapeutic or prophylactic drug for multiple sis.
Traumatic brain injury (also referred to as TBI in the present specification) is a condition exerting an extremely harmful influence on the health of individual, for which no effective cure has been established. In the repair process following tissue damage in TBI, reconstruction of nerve cell membrane and distribution of intracerebral terol activated along with the growth of glial cell are suggested [non-patent document 13: Proc. Natl. Acad. Sci. USA, vol.lOZ, pages 8333—8338, 2005]. In a rat TBI model, an enhanced expression of Cyp46(CH24H) after trauma has been reported [non—patent document 14: J. Neurotrauma, vol.25, pages 1087- 1098, 2008]. er, it has also been reported that 24eHC s nerve cells [non—patent document 8: Brain Res., vol.818, pages 171—175, 1999], and therefore, Cyp46(CH24H) inhibitor is promising as a new therapeutic or prophylactic drug for TBI.
As a pathological significance of 24—HC in neurodegenerative diseases, an inflammatory gene expression— enhancing action in nerve cells has been reported [non—patent document 15: NeuroReport, vol.l6, pages 909-913, 2005]. In addition, it is suggested that an intracerebral inflammation reaction accompanied by activation of glial cell is a pathological change characteristic of neurodegenerative diseases [non—patent document 16: Glia, vol.50, pages 427—434, 2005]. In recent years, a therapeutic effect by suppression of intracerebral mation has also been reported for neurodegenerative diseases such as gton’s e, Parkinson’s e and amyotrophic lateral sclerosis and the like [non—patent document 17: M01. Neurodegeneration, vol.4, pages 47—59, 2009]. Therefore, suppression of intracerebral inflammation by decreasing 24—HC by the inhibition of Cyp46(CH24H) is ing as a new therapeutic or prophylactic drug for neurodegenerative es such as Huntington’s ,disease, Parkinson’s disease, cerebral infarction, glaucoma, amyotrophic l sclerosis and the like.
Glaucoma is the main cause of blindness, and is considered a serious social problem. However, normal intraocular pressure type field stenosis, which is the major symptom of the disease, has no effective cure. In recent years, it has also been reported that gene polymorphism of Cyp46(CH24H) associated with high blood 24—HC is related to the risk of the onset of glaucoma atent document 18: Invest. Ophthalmol. Vis. Sci., vol.50, pages 5712—5717, 2009], and Cyp46(CH24H) inhibitor is promising as a therapeutic or lactic drug for glaucoma.‘ Spasm is a disease that occurs in fits along with abnormal electric excitement of intracerebral nerve cells.
Spasm is also one of the characteristic clinical findings in Alzheimer’s disease [non—patent document 19: Epilepsia, vol.47, pages 2, 2006], and it has been reported that spasm is highly frequently developed in APP/P81 double transgenic mouse which is one kind of Alzheimer’s disease models due to AB overexpression atent document 20: J. Neurosci., vol.29, pages 3453-3462, 2012]. It has been reported that carbamazepine, which is a therapeutic drug for spasm, shows a short term memory improving effect in a Y—maze test using mouse spasm model [non—patent document 21: J. Neurol.
Neurosurg. Psychiatry, vol.48, pages 459—468, 1985]. Thus, in animal model with spasm symptoms, CH24H) inhibitor showing a short term memory improving effect is promising as a therapeutic or prophylactic drug for spasm.
Since phrenia shows a variety of logical symptoms such as hallucination, delusion, excitation, manic— sive state and the like, therapeutic drugs therefor have been developed from various angles. In recent years, it has been pointed out that changes in the cholesterol metabolism are involved in the abnormality of neural activity seen in schizophrenia [non—patent document 22: J. Psychiatry Neurosci., vol.36, pages 47-55, 2011]. Since cytotoxic s such as oxidative stress also contribute to the pathology of schizophrenia, nerve cell toxicity due to 24—HC may aggravate the symptoms [non—patent nt 23: Psychoneuroendocrinology, vol.28, pages 83-96, 2003]. Therefore, Cyp46(CH24H) inhibitor that inhibits metabolism of cholesterol into 24—HC in the brain is promising as a new therapeutic or prophylactic drug for schizophrenia.
[0011] Examples of the compound having a structure similar to the present compound include the following compounds.
Patent document 1 discloses the following compound: | R5R5 N G / / 2 XQ“ Y<G1 \Rz Xf‘xa wherein X1, X2 and X3 are independently N, O, S, C or the like; G1 is CRfig, NR7, or ally substituted nitrogen—containing heterocycloalkyl; G2 is a single bond, optionally substituted alkyl or the like; R1 is aryl, nitrogen—containing aryl or the like; R2 is ally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl or the like; R3 and R4 are independently H, halogen, ally substituted alkyl or the like; R5, R6, R7 and Re are independently H, halogen, optionally tuted alkyl or the like; R5 and R6 in combination optionally form oxo; and Ra and Rb are independently H, halogen, optionally substituted alkyl or the like, as an agent for the treatment of inflammation disease, Alzheimer’s disease and the like.
Patent nt 2 discloses the following compound: wherein V is carbonyl or the like; A is N or C(H); R1 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or the like; R2, R”, R3, R“, R5, R“, R5 and R5a are independently H, halogen, optionally substituted alkyl or the like; R6 is N, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl or the like; R8 is a single bond, alkynylene or alkenylene; and R9 and R10 are independently H, n, optionally substituted alkyl or the like, as an agent for the treatment of autoimmune diseases, Alzheimer’s e, age—related dementia and the like.
Patent document 3 discloses the following compound:
[0018] wherein A-B is N—O, O—N or N(H)—N; R1 is H, Cpfi alkyl, Cyg alkoxy, hydroxy, halogen or the like; R2 is H, aryl, heteroaryl, Cyfi alkyl or the like; Q is a nitrogen—containing ring (the following formula (IIb) etc.) ,X“Y\ _§—%K_L/Zlm (R6)n ; R6 is H, hydroxy, aryl or the like; X, Y and Z are independently 0, NR7 or CR2; R7 is, H, Cyfi alkyl, ng alkenyl, CL4 alkoxy, heteroaryl—Cye alkyl, yfi alkyl or the like; and n is 0-3, as an agent for the treatment of diseases ated with immune e, dementia, hypertension, diabetes and the like (e.g., Alzheimer’s disease etc.)
[0022] Patent document 4 discloses the following compound: R2”Tm / \ N\ ,N wherein Ht is a heterocyclic group (pyrrol—3—yl, [1,2,4]triazol—3—yl, [1,2,3]triazol—4-yl or tetrazol—S-yl, the pyrrol—3—yl has R3 and Qn-R“, and the [1,2,4]triazol—3-yl or [1,2,3]triazol—4—yl has R3 or Qn-R4); T and Q are independently —C(O)— or the like;2 m and n are independently O-l; R2 is R or the like; R3 is R7, halogen, cyano or the like; R is a CL6 hydrocarbon group, C640 aryl, Caflo heteroaryl, C343 cycloalkyl or the like; and R7 is H, an optionally substituted Cpfi hydrocarbon group or the like, as an agent for the treatment of autoimmune es, Alzheimer’s disease and the like.
Document List Patent Document Patent Document 1: Patent Document 2: Patent Document 3: Patent nt 4: WO 02/088097 Non-Patent Document Non—Patent Document ’4 Science, vol.26l, 921—923, 1993 Non—Patent Document N Neurobiol. Aging, vol.24, 421—426, 2003 Non-Patent Document m Mol. Psychiatry, vol.8, 635—638, 2003 Non-Patent Document e Neurosci. Lett., vol.328, pages 9—12, 2002 Non—Patent Document 5: J. Biol. Chem., 9, pages 34674— 34681, 2004 Non—Patent nt 6: Neurosci. Lett., 4, pages 83-85, 2002 Non—Patent Document 7: Neurosci. Lett., vol.397, pages 83—87, 2006 Non—Patent Document 8: Brain Res., 8, pages 5, 1999 Non—Patent Document 9: Neuroscience, vol.164, pages 398—403, 2009 Non—Patent Document 10: British Journal of Pharmacology, vol.l49, pages 998—1012, 2006 Non—Patent Document 11: J. ci. Res., vol.85, pages 1499- 1505, 2007 Non—Patent Document 12: Neurosci. Lett., vol.331, pages 163— 166, 2002 Non—Patent Document 13: Proc. Natl. Acad. Sci. USA, vol.102, pages 8333—8338, 2005 Non—Patent Document 14: J. Neurotrauma, vol.25, pages 1087— 1098, 2008 Non—Patent Document 15: NeuroReport, vol.16, pages 909—913, 2005 Non—Patent Document 16: Glia, vol.50, pages 427—434, 2005 Non-Patent Document 17: M01. Neurodegeneration, vol.4, pages 47459, 2009 Non~Patent Document 18: Invest. Opthalmol. Vis. Sci., , pages 5712-5717, 2009 Non-Patent Document 19: Epilepsia, vol.47, pages 867-872, 2006 Non—Patent nt 20: J. Neurosci., , pages 3453—3462, 2012 tent Document 21: J. Neurol. Neurosurg. Psychiatry, vol.48, pages 459—468, 1985 Non—Patent Document 22: J. Psychiatry Neurosci., vol.36, pages 47—55, 2011 Non—Patent Document 23: Psychoneuroendocrinology, vol.28, pages 83—96, 2003 Summary of the Invention Problems to be Solved by the Invention An object of the t invention is to provide a compound having a superior CH24H inhibitory action, which is useful as an agent for the prophylaxis or treatment of neurodegenerative disease (e.g., Alzheimer’s disease, mild cognitive impairment, Huntington’s disease, son’s disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, glaucoma, multiple sis and the like), epilepsy, schizophrenia and the like, or to at least provide the public with a useful ative.
Means of Solving the Problems The present inventors have conducted intensive studies in an attempt to solve the mentioned problem and found that a compound represented by the following formula (I) has a superior CH24H inhibitory action, which resulted in the tion of the present invention.
Accordingly, the present invention provides the following.
A compound represented by the formula (I): n R1 is an optionally substituted C1-6 alkyl group; R2 is a hydrogen atom or an optionally tuted C1-6 alkyl group; R3 is an optionally substituted 5- or 6-membered aromatic heterocyclic group; ring A is a further optionally substituted piperidine ring (the piperidine ring is optionally bridged); and ring B is a further optionally substituted 5- or 6-membered aromatic ring (X and Y are independently a carbon atom or a nitrogen atom), or a salt thereof.
The compound or salt of the above-mentioned [1], wherein R3 is an optionally substituted 5— or 6—membered en- containing aromatic heterocyclic group.
The compound or salt of the above—mentioned [1], wherein R3 is a 5— or 6-membered en—containing aromatic heterocyclic group optionally substituted by 1 to 3 halogen atoms.
The compound or salt of the above—mentioned [1], wherein R3 is a group represented by n «isN I wherein ring Cl is an optionally substituted 6-membered nitrogen— containing aromatic cycle containing at least one nitrogen atom; and ring C2 is an optionally substituted 5—membered nitrogen— containing aromatic heterocycle containing at least one en atom, each of which is optionally substituted by 1 to 3 halogen atoms.
The nd or salt of the above—mentioned [1], wherein ring B is benzene, thiazole, isoxazole, pyrazole, pyridine or pyrazine (X and Y are independently a carbon atom or a nitrogen atom), each of which is, in addition to R3 and -C(=O)- ring A, optionally substituted by 1 to 3 tuents selected from (1) a halogen atom, (2) a Cyfi alkyl group optionally substituted by 1 to 3 halogen atoms, (3) a Che alkoxy group, and (4) a Che alkylenedioxy group.
The nd or salt of the above—mentioned [1], wherein ring B is nnnn z©©w©© each of which is, in addition to R3 and -ring A, optionally substituted by l to 3 substituents selected from (1) a halogen atom, (2) a Cyfi alkyl group optionally substituted by l to 3 halogen atoms, (3) a Chg alkoxy group, and (4) a Cyfi alkylenedioxy group.
The compound or salt of the above—mentioned [l], wherein R2 is a hydrogen atom.
The compound or salt of the above—mentioned [1], wherein R1 is a C35 alkyl group optionally substituted by l to 3 substituents selected from (1) a C644 aryl group optionally substituted by l to 3 substituents ed from (a) a halogen atom, (b) a cyano group, and (c) a Cbs alkoxy group optionally substituted by l to 3 halogen atoms (2) a 5— or 6—membered monocyclic aromatic heterocyclic group optionally tuted by l to 3 substituents selected from (a) a halogen atom, (b) a cyano group, and (c) a Cyfi alkoxy group optionally substituted by l to 3 halogen atoms, and (3) a 3— to 8~membered monocyclic non-aromatic heterocyclic group optionally substituted by l to 3 substituents selected from (a) a n atom, (b) a cyano group, and (c) a CL4 alkoxy group optionally substituted by l to 3 halogen atoms; R2 is a hydrogen atom or a Cyfi alkyl group; R3 is a 5- or 6—membered nitrogen-containing aromatic heterocyclic group optionally substituted by l to 3 n atoms; ring A is a piperidine ring having no substituent other than R% Rz—O— and —C(=O)—ring B, or an oxa—9—azabicyclo[3.3.l]nonane ring having no substituent other than R1, RZ—O— and —C(=O)—ring B; and ring B is a 5— or 6—membered ic ring which is, in addition to R3 and -C(=O)—ring A, optionally substituted by l to 3 substituents selected from (1) a halogen atom, (2) a Cyfi alkyl group optionally substituted by l to 3 halogen atoms, (3) a Cyfi alkoxy group and (4) a Cyfi alkylenedioxy group. (4~benzyl—4—hydroxypiperidin—l—yl)(2,4'—bipyridin—3— yl)methanone or a salt thereof. 2,4‘-bipyridin—3—yl(4—(4—fluorobenzyl)—4— hydroxypiperidin—l—yl)methanone or a salt thereof. [ll] 2,4‘-bipyridin—3—yl(4-(2,4—difluorobenzyl) hydroxypiperidin—l—yl)methanone or a salt thereof.
[12] fluorobenzyl)—4—hydroxypiperidin-l—yl)(2- (pyrimidin—4-yl)pyridin—3-yl)methanone or a salt f.
A medicament comprising the compound or salt of the above—mentioned [1].
The medicament of the above—mentioned [13], which is a cholesterol 24—hydroxylase inhibitor. 2012/076257 The medicament of the above—mentioned [13], which is an agent for the prophylaxis or treatment of neurodegenerative disease.
The medicament of the above—mentioned [15], wherein the neurodegenerative disease is Alzheimer’s disease, mild cognitive impairment, Huntington’s e, Parkinson's disease or multiple sclerosis.
The compound or salt of the above—mentioned [l] for use in the prophylaxis or treatment of neurodegenerative disease.
[18] The nd or salt of the above—mentioned [17], wherein the egenerative disease is Alzheimer’s disease, mild ive impairment, gton’s disease, Parkinson’s disease or multiple sis.
A method of inhibiting a cholesterol 24—hydroxylase in a mammal, which comprises stering an effective amount of the compound or salt of the above—mentioned [l] to a mammal.
A method for the prophylaxis or treatment of neurodegenerative disease in a mammal, which comprises administering an effective amount of the compound or salt of the above-mentioned [1] to a mammal.
The method of the above—mentioned [20], wherein the neurodegenerative disease is Alzheimer’s disease, mild cognitive impairment, Huntington’s disease, son's disease or multiple sclerosis.
[22] Use of the compound or salt of the above-mentioned [1] for the production of an agent for the prophylaxis or treatment of neurodegenerative disease.
Use of the above—mentioned [22], wherein the neurodegenerative disease is Alzheimer's disease, mild ive impairment, Huntington’s disease, Parkinson’s disease or multiple sclerosis.
Effect of the Invention Compound (I) has a superior CH24H inhibitory action, which is useful as an agent for the prophylaxis or treatment of neurodegenerative disease (e.g., mer’s disease, mild cognitive impairment, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain , cerebral infarction, glaucoma, multiple sclerosis and the like), epilepsy, schizophrenia and the like.
(Detailed Description of the Invention) In the present ication, the “halogen atom” means a fluorine atom, a chlorine atom, a e atom or an iodine atom.
In the present specification, the “Cbfi alkyl (group)” means, for example, methyl, ethyl, propyl, isopropyl, butyl, yl, sec—butyl, tert—butyl, pentyl, isopentyl, neopentyl, l—ethylpropyl, hexyl, isohexyl, methylbutyl, 2,2— dimethylbutyl, 3,3-dimethylbutyl, lbutyl or the like.
In the present specification, the “Cfifi alkenyl (group)” means, for example, vinyl, l—propenyl, 2—propenyl, 2—methyl—l— propenyl, l—butenyl, nyl, 3—butenyl, yl—2—butenyl, l—pentenyl, 2—pentenyl, 3—pentenyl, 4—pentenyl, 4—methyl—3— pentenyl, l—hexenyl, 3—hexenyl, 5—hexenyl or the like.
In the present specification, the “Czfi alkynyl (group)” means, for example, ethynyl, l—propynyl, ynyl, l-butynyl, 2—butynyl, 3—butynyl, l-pentynyl, ynyl, 3—pentynyl, 4— pentynyl, l,l—dimethylprop—Z—yn—l—yl, l—hexynyl, 2-hexynyl, 3— hexynyl, 4—hexynyl, 5—hexynyl or the like.
In the present specification, the “Cyfi alkoxy (group)” means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec—butoxy, tert—butoxy, pentyloxy, isopentyloxy, hexyloxy or the like.
In the present specification, the “C26 alkenyloxy (group)” means, for example, vinyloxy, l—propenyloxy, 2— propenyloxy, 2—methyl—l—propenyloxy, l—butenyloxy, 2- butenyloxy, 3-butenyloxy, 3—methyl-2—butenyloxy, l—pentenyloxy, 2—pentenyloxy, 3—pentenyloxy, 4—pentenyloxy, 4-methyl—3— WO 54822 pentenyloxy, l-hexenyloxy, nyloxy, 5—hexenyloxy or the like.
In the t specification, the “CZfi loxy (group)” means, for example, ethynyloxy, l—propynyloxy, 2— propynyloxy, l—butynyloxy, 2—butynyloxy, 3-butynyloxy, l- pentynyloxy, 2—pentynyloxy, 3-pentynyloxy, 4—pentynyloxy, 1,1- dimethylprop—Z—yn—l—yloxy, l—hexynyloxy, 2—hexynyloxy, 3— hexynyloxy, 4—hexynyloxy, 5—hexynyloxy or the like.
In the present specification, the “Cbfi alkylenedioxy (group)” means, for example, methylenedioxy, ethylenedioxy or the like.
In the present specification, the “CL6 alkoxy—carbonyl (group)” means, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, oxycarbonyl, tert-butoxycarbonyl or the like.
In the present specification, the “Cyfi alkyl—carbonyl (group)” means, for example, acetyl, propanoyl, yl, 2— methylpropanoyl or the like.
In the present specification, the “mono-Cyfi alkylamino (group)” means, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, ylamino, tert— butylamino or the like.
In the present specification, the “di-Cpfi alkylamino (group) II means, for e, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobfitylamino, di—tert—butylamino or the like.
[0041] In the present specification, the “C}€ cycloalkyl (group)” means, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or the like.
In the present specification, the “C34 cycloalkyl (group) means, for example, cycloalkyl having 3 to 6 carbon WO 54822 2012/076257 atoms, from among the above—mentioned C}3 cycloalkyl (group).
In the present specification, the “C3fi cycloalkyloxy ) II means, for example, cyclopropyloxy, cyclobutyloxy, entyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy or the like.
In the present specification, the “Cyfi cycloalkyloxy (group) II means, for e, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or the like.
In the present specification, the “C3a cycloalkenyl )” means, for example, cyclopropenyl (e.g., 2— cyclopropen-l—yl), cyclobutenyl (e.g., 2—cyclobuten—l—yl), cyclopentenyl (e.g., 2—cyclopenten-l-yl, 3—cyclopenten—l—yl), cyclohexenyl (e.g., 2-cyclohexen—l—yl, 3—cyclohexen—l—yl) or the like.
In the present specification, the “C33 cycloalkenyloxy (group)” means, for example, cyclopropenyloxy (e.g., 2— cyclopropen—l—yloxy), cyclobutenyloxy (e.g., 2-cyclobuten-1— yloxy), cyclopentenyloxy (e.g., 2—cyclopenten-l—yloxy, 3— cyclopenten—l—yloxy), cyclohexenyloxy (e.g., 2—cyclohexen-l— yloxy, 3—cyclohexen—l—yloxy) or the like.
In the present specification, the “C6fl4 aryl (group)” means, for e, phenyl, l-naphthyl, 2—naphthyl or the like.
In the present specification, the “C644 aryloxy (group)” means, for example, phenoxy, thyloxy, 2-naphthyloxy or the like.
In the present specification, the “C744 aralkyl )” means, for example, benzyl, phenethyl or the like. 3O In the present specification, the “C744 aralkyloxy (group)” means, for example, benzyloxy, phenethyloxy or the like.
In the present specification, the “heterocyclic group” means an aromatic heterocyclic group or a non—aromatic 2012/076257 heterocyclic group.
In the present specification, the “aromatic cyclic group” means a monocyclic aromatic heterocyclic group or a fused aromatic heterocyclic group.
In the present specification, examples of the “monocyclic aromatic heterocyclic group” include a 5— to 7—membered (preferably 5— or 6—membered) monocyclic aromatic heterocyclic group containing, as a ring—constituting atom besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom (optionally ed) and a nitrogen atom (optionally oxidized). Examples f include furyl (e.g., 2—furyl, 3-furyl), thienyl (e.g., 2—thienyl, 3—thienyl), pyridyl (e.g., 2-pyridyl, dyl, 4—pyridyl), pyrimidinyl (e.g., midinyl, 4—pyrimidinyl, 5—pyrimidinyl), pyridazinyl (e.g., 3—pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), pyrrolyl (e.g., l—pyrrolyl, 2—pyrrolyl, 3—pyrrolyl), imidazolyl (e.g., l—imidazolyl, 2-imidazolyl, 4— imidazolyl, 5—imidazolyl), pyrazolyl (e.g., l—pyrazolyl, 3— pyrazolyl, 4—pyrazolyl), lyl (e.g., 2—thiazolyl, 4— thiazolyl, 5—thiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4—isothiazolyl, S—isothiazolyl), oxazolyl (e.g., 2—oxazolyl, 4—oxazolyl, 5—oxazolyl), isoxazolyl (e.g., 3—isoxazolyl, 4— isoxazolyl, 5—isoxazolyl), oxadiazolyl (e.g., 1,2,4-oxadiazol— -yl, oxadiazol—2—yl), thiadiazolyl (e.g., 1,3,4— thiadiazol-Z-yl), triazolyl (e.g., 1,2,4-triazol—l—yl, 1,2,4— triazol—3—yl, 1,2,3-triazol-l—yl, l,2,3—triazol~2—yl, 1,2,3— triazol—4—yl), tetrazolyl (e.g., tetrazol—l~yl, tetrazol—S-yl), triazinyl (e.g., 1,2,4—triazin—l-yl, 1,2,4—triazinyl) and the like.
[0045] In the present specification, examples of the “fused aromatic heterocyclic group” include a 8— to lZ—membered fused aromatic heterocyclic group, specifically, a group d from a fused ring wherein a ring corresponding to the 5— to 7— membered clic ic heterocyclic group is fused with a C644 aromatic hydrocarbon; and a group d from a fused ring wherein rings corresponding to the 5— to 7—membered clic aromatic heterocyclic groups are fused. es thereof include quinolyl (e.g., 2—quinolyl, 3—quinolyl, 4— quinolyl, 6-quinolyl), isoquinolyl (e.g., 3—isoquinolyl), quinazolyl (e.g., 2—quinazolyl, 4—quinazolyl), quinoxalyl (e.g., Z—quinoxalyl, 6-quinoxalyl), benzofuranyl (e.g., 2— benzofuranyl, 3—benzofuranyl), benzothienyl (e.g., 2— benzothienyl, 3—benzothienyl), benzoxazolyl (e.g., 2— benzoxazolyl), benzisoxazolyl (e.g., 7—benzisoxazolyl), benzothiazolyl (e.g., 2—benzothiazolyl), benzimidazolyl (e.g., benzimidazol—l—yl, benzimidazol—Z—yl, benzimidazol—S—yl), benzotriazolyl (e.g., 1H—l,2,3—benzotriazol—5-yl), indolyl (e.g., indol-l—yl, indol—2—yl, indol—3—yl, indol-S-yl), indazolyl (e.g., lH-indazol—3—yl), pyrrolopyrazinyl (e.g., 1H— pyrrolo[2,3—b]pyrazin—2—yl, lH-pyrrolo[2,3-b]pyrazin—6—yl), imidazopyridyl (e.g., lH—imidazo[4,5—bjpyridin—2—yl, 1H— imidazo[4,S—c]pyridin—2—yl, dazo[l,2-a]pyridin—3—yl), thienopyridyl (e.g., thieno[2,3—b]pyridin-3—yl), opyrazinyl (e.g., lH-imidazo[4,5—b]pyrazin—2—yl), lopyridyl (e.g., lH—pyrazolo[4,3—c]pyridin-3—yl), pyrazolothienyl (e.g., azolo[3,4—b]thiophen—2—yl), pyrazolotriazinyl (e.g., pyrazolo[5,l—c][1,2,4]triazin—3-yl) and the like.
[0046] In the present specification, the “non—aromatic heterocyclic group” means a monocyclic non—aromatic heterocyclic group or a fused omatic heterocyclic group.
In the present specification, examples of the “monocyclic non—aromatic heterocyclic group” include a 3— to 8—membered (preferably 5— or 6—membered) clic non—aromatic heterocyclic group containing, as a ring—constituting atom besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom (optionally oxidized) and a nitrogen atom (optionally oxidized). Examples f include azetidinyl (e.g., l—azetidinyl, 2~azetidinyl), pyrrolidinyl (e.g., l-pyrrolidinyl, 2—pyrrolidinyl), piperidyl (e.g., dino, 2—piperidyl, 3—piperidyl, ridyl), morpholinyl (e.g., morpholino), thiomorpholinyl (e.g., thiomorpholino), piperazinyl (e. g., l—piperazinyl, 2— piperazinyl, 3—piperazinyl), oxazolidinyl (e.g., oxazolidin—Z— yl), lidinyl.(e.g., thiazolidin—Z—yl), dihydrothiopyranyl (e.g. , dihydrothiopyran—3-yl, dihydrothiopyran—4—yl), imidazolidinyl (e.g., imidazolidin—Z— yl, olidin—3—yl), oxazolinyl (e.g., oxazolin-Z-yl), thiazolinyl (e.g., thiazolin—2-yl), imidazolinyl (e.g., imidazolin—2—yl, imidazolin—3—yl), dioxolyl (e.g., 1,3—dioxol- 4-yl), dioxolanyl (e.g., 1,3—dioxolan—4—yl), dihydrooxadiazolyl (e.g. , 4,5—dihydro—l,2,4—oxadiazol—3—yl), pyranyl (e.g., 2~pyranyl , 4—pyranyl), tetrahydropyranyl (e.g., 2-tetrahydropyranyl, 3—tetrahydropyranyl, 4—tetrahydropyranyl) \ thiopyranyl (e.g., 4—thiopyranyl), tetrahydrothiopyranyl (e.g., 2—tetrahydrothiopyranyl, 3—tetrahydrothiopyranyl, 4— tetrahydrothiopyranyl), 1—oxidotetrahydrothiopyranyl (e.g., l— oxidotetrahydrothiopyran—4—yl), 1,1— dioxidotetrahydrothiopyranyl (e.g., 1,1— dioxidotetrahydrothiopyran—4—yl), tetrahydrofuryl (e.g., tetrahydrofuran—B—yl, tetrahydrofuran—Z-yl), yl (e.g., oxetan—2—yl, oxetan—B—yl), pyrazolidinyl (e.g., pyrazolidin—l— yl, lidin—B-yl), pyrazolinyl (e.g., pyrazolin-l—yl), tetrahydropyrimidinyl (e .g., tetrahydropyrimidin—l—yl), dihydrotriazolyl (e.g., 2,3—dihydro—1H—l,2,3—triazol—1—yl), tetrahydrotriazolyl (e.g ., 2,3,4 ,5—tetrahydro—lH—l,2,3— triazol—l-yl), azepanyl (e.g., l—azepanyl, 2-azepanyl, 3— azepanyl, 4—azepanyl), opyridyl (e.g., opyridin-l- yl, dihydropyridin—Z—yl, dihydropyridin~3—yl, dihydropyridin— 4-yl), tetrahydropyridyl (e.g., l,2,3,4—tetrahydropyridin—l-yl, 1,2,3,4-tetrahydropyridin—2—yl, 1,2,3,4—tetrahydropyridin—3—yl, 1,2,3,4—tetrahydropyridin-4—yl) and the like.
[0047] In the present specification, examples of the “fused non— aromatic heterocyclic group” include a 8— to lZ—membered fused non—aromatic cyclic group, specifically, a group derived from a fused ring wherein a ring corresponding to the 3— to 8- membered monocyclic non—aromatic heterocyclic group is fused with a C6fl4 aromatic hydrocarbon; a group derived from a fused ring n rings corresponding to the 3* to 8-membered monocyclic non—aromatic heterocyclic groups are fused; a group derived from a fused ring wherein a ring corresponding to the 3— to 8—membered monocyclic non-aromatic cyclic group is fused with a ring corresponding to the 5— to 7—membered monocyclic aromatic heterocyclic group; and a group wherein the above—mentioned group is partially saturated. Examples thereof include dihydroindolyl (e.g., 2,3—dihydro—1H—indol—l-yl), dihydroisoindolyl (e.g., l,3-dihydro—2H-isoindol—2—yl), dihydrobenzofuranyl (e.g., 2,3-dihydro—l—benzofuran-S—yl), tetrahydrobenzofuranyl (e.g., 4,5,6,7—tetrahydro—l—benzofuran— 3-yl), dihydrobenzodioxinyl (e.g., 2,3—dihydro—l,4— benzodioxin—Z—yl), dihydrobenzodioxepinyl (e.g., 3,4—dihydro— 2H-l,5-benzodioxepin—2—yl), chromenyl (e.g., omen-2—yl, 2H-chromen—3—yl), dihydrochromenyl (e.g., 3,4—dihydro—2H— chromen—Z—yl), dihydroquinolyl (e.g., 1,2—dihydroquinolin—4— yl), tetrahydroquinolyl (e.g., 1,2,3,4—tetrahydroquinolin—4- yl), oisoquinolyl (e.g., l,2—dihydroisoquinolin—4—yl), tetrahydroisoquinolyl (e.g., 1,2,3,4—tetrahydroisoquinolin—4— yl), dihydrophthalazinyl (e.g., l,4—dihydrophthalazin—4—yl) and the like.
In the present specification, examples of the “5— or 6— 3o membered aromatic heterocyclic group” include furyl (e.g., 2— furyl, 3—furyl), thienyl (e.g., 2—thienyl, 3—thienyl), pyridyl (e.g., 2—pyridyl, 3—pyridyl, 4—pyridyl), dinyl (e.g., 2— dinyl, 4—pyrimidinyl, midinyl), pyridazinyl (e.g., 3—pyridazinyl, 4—pyridazinyl), nyl (e.g., 2—pyrazinyl), pyrrolyl (e.g., l-pyrrolyl, 2-pyrrolyl, 3—pyrrolyl), imidazolyl (e.g., azolyl, 2—imidazolyl, 4—imidazolyl, 5— imidazolyl), pyrazolyl (e.g., l-pyrazolyl, 3—pyrazolyl, 4— pyrazolyl), thiazolyl (e.g., 2—thiazolyl, 4—thiazolyl, 5— lyl), isothiazolyl (e.g., 3eisothiazolyl, 4—isothiazolyl, -isothiazolyl), oxazolyl (e.g., 2—oxazolyl, 4-oxazolyl, 5— oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5— isoxazolyl), oxadiazolyl (e.g., l,2,4—oxadiazol—5~yl, 1,3,4— oxadiazol—Z-yl), thiadiazolyl (e.g., 1,3,4—thiadiazol—2—yl), triazolyl (e.g., 1,2,4—triazol-l—yl, 1,2,4—triazol—3—yl, 1,2,3—triazol—1—yl, 1,2,3—triazol—2—yl, 1,2,3—triazol—4—yl), tetrazolyl (e.g., tetrazol—l—yl, tetrazol—S—yl), triazinyl (e.g., 1,2,4—triazin—1—yl,'l,2,4—triazin—3—yl) and the like.
In the present specification, examples of the “5— or 6— membered nitrogen—containing aromatic heterocyclic group” include a 5— or 6—membered en-containing aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, at least one nitrogen atom, and ally ning 1 or 2 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Examples thereof include pyridyl (e.g., 2—pyridyl, 3—pyridyl, 4— pyridyl), pyrimidinyl (e.g., 2—pyrimidinyl, 4—pyrimidinyl, 5— pyrimidinyl), pyridazinyl (e.g., 3—pyridazinyl, 4—pyridazinyl), pyrazinyl (e.g., 2—pyrazinyl), pyrrolyl (e.g., l—pyrrolyl, 2— pyrrolyl, olyl), imidazolyl (e.g., l—imidazolyl, 2— imidazolyl, 4—imidazolyl, S—imidazolyl), pyrazolyl (e.g., l- pyrazolyl, 3—pyrazolyl, 4—pyrazolyl), lyl (e.gl, 2— thiazolyl, 4—thiazolyl, 5—thiazolyl), isothiazolyl (e.g., 3— isothiazolyl, 4-isothiazolyl, S—isothiazolyl), oxazolyl (e.g., 2—oxazolyl, 4—oxazolyl, olyl), isoxazolyl (e.g., 3— isoxazolyl, 4—isoxazolyl, 5—isoxazolyl), oxadiazolyl (e.g., oxadiazol—5—yl, oxadiazol-2—yl), thiadiazolyl (e.g., 1,3,4—thiadiazol—2—yl), triazolyl (e.g., 1,2,4—triazol— l—yl, triazol-3—yl, l,2,3~triazol—l—yl, l,2,3-triazol~2— yl, 1,2,3—triazol—4—yl), tetrazolyl (e.g., tetrazol-l—yl, tetrazol—S—yl), nyl (e.g., triazin-l—yl, 1,2,4— triazin—B—yl) and the like.
In the present specification, the “C644 aromatic arbon” means, for example, benzene, naphthalene or the like.
In the present specification, the “5~ or 6—membered aromatic ring” means, for example, benzene, a 5— or 6—membered aromatic heterocycle or the like.
In the present specification, examples of the “5— or 6— membered aromatic heterocycle” include a 5— or 6—membered clic aromatic heterocycle containing, as a ring— constituting atom besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom (optionally oxidized) and a nitrogen atom (optionally oxidized). Examples thereof include furan, ene, pyridine, pyrimidine, 'pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole, triazine and the like.
In the present specification, examples of the “5— or 6— membered nitrogen—containing aromatic cycle” include a 5— or 6—membered nitrogen—containing aromatic cycle ning, as a ring—constituting atom besides carbon atoms, at least one nitrogen atom, and optionally containing 1 or 2 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Examples thereof include pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, ole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole, triazine and the like.
Each symbol of the formula (I) is explained below.
[0055] In the formula (I), R1 is an optionally substituted Chg alkyl group.
In the formula (I), R2 is a hydrogen atom or an optionally substituted Chg alkyl group.
[0056] The “Cbfi alkyl group" of “optionally substituted Chg alkyl group” for R1 or R2 optionally has 1 to 5 (preferably 1 to 3) tuents at tutable positions. Examples of the substituent include substituents selected from the following Substituent Group A. When the number of substituents is two or more, the substituents may be the same or different. tuent Group A: (l) a halogen atom; (2) a cyano group; (3) a nitro group; (4) a hydroxy group; (5) a C}g cycloalkyl group optionally substituted by l to 3 substituents selected from (a) a halogen atom, (b) a cyano group (c) a Cbfi alkyl group optionally substituted by l to 3 halogen atoms, and (d) a Cke alkoxy group optionally substituted by l to 3 . halogen atoms; (6) a C644 aryl group ally substituted by l to 3 substituents selected from (a) a n atom, (b) a cyano group, (c) a Cyfi alkyl group optionally substituted by l to 3 halogen atoms, and (d) a Cpfi alkoxy group optionally substituted by l to 3 halogen atoms; (7) a Cyfi alkoxy group optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, (b) a cyano group, (c) a C&g cycloalkyl group optionally having 1 to 3 halogen atoms, (d) a C;B lkenyl group optionally having 1 to 3 halogen atoms, (e) a C644 aryl group optionally having 1 to 3 halogen atoms, (f) a 5— or 6—membered monocyclic aromatic heterocyclic group; (8) a Cyfi alkenyloxy group (e.g., vinyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy) optionally having 1 to 3 halogen atoms; (9) a C26 alkynyloxy group (e.g., ethynyloxy, propynyloxy, butynyloxy, yloxy, hexynyloxy) optionally having 1 to 3 halogen atoms; (10) a Cyg cycloalkyloxy group (e.g., cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, exyloxy) optionally having 1 to 3 halogen atoms; (ll) a C38 cycloalkenyloxy group (e.g., cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy) optionally having 1 to 3 halogen atoms; (12) a C644 aryloxy group ally having 1 to 3 halogen atoms; (13) a C744 aralkyloxy group ally having 1 to 3 halogen atoms; (14) a carbamoyl group ally mono- or di-substituted by substituent(s) selected from (a) a Cyfi alkyl group, (b) a Cyfi cycloalkyl group, (C) a C6u4 aryl group, (d) a Cbfi alkoxy group, (e) a 5— or 6—membered monocyclic aromatic heterocyclic group, (f) a 8- to lZ—membered fused aromatic heterocyclic group, (g) a 3— to 8—membered clic non-aromatic heterocyclic group, and (h) a 8— to 12—membered fused non—aromatic heterocyclic group; (15) a sulfamoyl group optionally mono— or di—substituted by tuent(s) selected from a ) a CLfi alkyl group, b) a C}5 cycloalkyl group, c) a C644 aryl group, ( d ) a Cyfi alkoxy group, (e) a 5— or 6—membered monocyclic aromatic heterocyclic group, (f) a 8— to 12—membered fused aromatic heterocyclic group, (g) a 3— to 8—membered monocyclic non—aromatic heterocyclic group, and (h) a 8— to 12—membered fused non—aromatic heterocyclic group; (16) a formyl group; (17) a Cyfi alkyl—carbonyl group; (18) a CZfi alkenyl—carbonyl group (e.g., acryloyl, butenoyl, pentenoyl, hexenoyl, heptenoyl); (19) a Cfifi alkynyl—carbonyl group (e.g., propioloyl, propynylcarbonyl, butynylcarbonyl, pentynylcarbonyl, lcarbonyl); (20) a C}3 cycloalkyl~carbony1 group (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, entylcarbonyl, cyclohexylcarbonyl); (21) a Cyfi cycloalkenyl—carbonyl group (e.g., ropenylcarbonyl, cyclobutenylcarbonyl, cyclopentenylcarbonyl, cyclohexenylcarbonyl); 3o (22) a C644 aryl—carbonyl group (e.g., benzoyl, 1— naphthylcarbonyl, 2—naphthylcarbonyl); (23) a C34 cycloalkyl—Cyfi alkyl—carbonyl group (e.g., cyclopropylacetyl, 3—cyclopropylpropiony1, cyclobutylacetyl, cyclopentylacetyl, cyclohexylacetyl, cyclohexylpropionyl); (24) a C}e cycloalkenyl—Cyg alkyl-carbonyl group (e.g., cyclopentenylacetyl, cyclohexenylacetyl, 3— cyclohexenylpropionyl, 3—cyclohexenylpropionyl); (25) a C744 aralkyl—carbonyl group (e.g., phenylacetyl, 3— phenylpropionyl); (26) a 5— or 6—membered monocyclic aromatic heterocyclylcarbonyl group (e.g., furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, oxazolylcarbonyl, isooxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, imidazolylcarbonyl, lcarbonyl, pyrazolylcarbonyl); (27) a 8— to lZ—membered fused aromatic cyclylcarbonyl group (e.g., benzofuranylcarbonyl, isobenzofuranylcarbonyl, benzothienylcarbonyl, isobenzothienylcarbonyl, indolylcarbonyl, isoindolylcarbonyl, indazolylcarbonyl, benzimidazolylcarbonyl, benzoxazolylcarbonyl); (28) a 3— to ered monocyclic non—aromatic heterocyclylcarbonyl group (e.g., oxiranylcarbonyl, azetidinylcarbonyl, oxetanylcarbonyl, thietanylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofurylcarbonyl, thioranylcarbonyl, piperidylcarbonyl); (29) a 8— to lZ—membered fused non—aromatic cyclylcarbonyl group (e.g., dihydrobenzofuranyl); (30) an amino group optionally mono— or di—substituted by substituent(s) selected from (a) a CLfi alkyl group optionally having 1 to 3 halogen atoms, (b) a Cbfi alkyl—carbonyl group optionally having 1 to 3 halogen atoms, (c) a C}$ cycloalkyl—carbonyl group, (d) a C644 arbonyl group optionally having 1 to 3 halogen atoms, (e) a 5— or 6—membered monocyclic aromatic cyclylcarbonyl group, (f) a 8— to lZ—membered fused ic heterocyclylcarbonyl group, (g) a 3— to 8—membered monocyclic non—aromatic heterocyclylcarbonyl group, and (h) a 8— to lZ—membered fused non—aromatic heterocyclylcarbonyl group; (31) a sulfanyl group; (32) a Cyfi alkylsulfanyl group (e.g., methylsulfanyl, ethylsulfanyl); (33) a C}6 alkenylsulfanyl group (e.g., vinylsulfanyl, ylsulfanyl); (34) a Czfi alkynylsulfanyl group (e.g., ethynylsulfanyl, propynylsulfanyl); (35) a Cye cycloalkylsulfanyl group (e.g., ropylsulfanyl, cyclobutylsulfanyl); (36) a C}@ cycloalkenylsulfanyl group (e.g., cyclopropenylsulfanyl, cyclobutenylsulfanyl); (37) a C644 arylsulfanyl group (e.g., phenylsulfanyl); (38) a C3¢ cycloalkyl—Cyfi alkylsulfanyl group (e.g., cyclopropylmethylsulfanyl); (39) a C34 cycloalkenyl—Cyfi alkylsulfanyl group (e.g., cyclopentenylmethylsulfanyl); (40) a Cyfi alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl); (41) a C}6 alkenylsulfinyl group (e.g., vinylsulfinyl, propenylsulfinyl); (42) a Czfi alkynylsulfinyl group (e.g., lsulfinyl, propynylsulfinyl); (43) a C3fi cycloalkylsulfinyl group (e.g., cyclopropylsulfinyl, cyclobutylsulfinyl); (44) a Cyg cycloalkenylsulfinyl group (e.g., ropenylsulfinyl, cyclobutenylsulfinyl); (45) a C644 arylsulfinyl group (e.g., phenylsulfinyl); (46) a C3% cycloalkyl—Cyfi ulfinyl group (e.g., cyclopropylmethylsulfinyl); (47) a ng cycloalkenyl—Cyfi alkylsulfinyl group (e.g., cyclopentenylmethylsulfinyl); (48) a Cyfi alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl); (49) a Cgfi lsulfonyl group (e.g., vinylsulfonyl, propenylsulfonyl); (50) a CZ£ lsulfonyl group (e.g., ethynylsulfonyl, propynylsulfonyl); (51) a C3€ cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl, cyclobutylsulfonyl); (52) a C3fi lkenylsulfonyl group (e.g., cyclopropenylsulfonyl, cyclobutenylsulfonyl); (53) a C644 arylsulfonyl group (e.g., phenylsulfonyl); (54) a C}fl cycloalkyl—Cyg alkylsulfonyl group (e.g., cyclopropylmethylsulfonyl); (55) a C33 cycloalkenyl—Cbfi alkylsulfonyl group (e.g., entenylmethylsulfonyl); (56) a C6¢4 aryl-Cpg alkylsulfonyl group (e.g., benzylsulfonyl); (57) a 5— or 6-membered monocyclic aromatic heterocyclylsulfonyl group (e.g., furylsulfonyl, thienylsulfonyl, pyridylsulfonyl); (58) a 8— to lZ—membered fused aromatic heterocyclylsulfonyl group (e.g., benzofuranylsulfonyl, isobenzofuranylsulfonyl); (59) a 3- to 8—membered monocyclic non-aromatic heterocyclylsulfonyl group (e.g., oxiranylsulfonyl, inylsulfonyl); (60) a 8- to 12—membered fused non—aromatic heterocyclylsulfonyl group (e.g., dihydrobenzofuranylsulfonyl); (61) a 5- or 6—membered monocyclic aromatic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl, pyrazolyl, linyl) optionally substituted by l to 3 substituents selected from (a) a halogen atom, (b) a C36 alkyl group optionally substituted by l to 3 halogen atoms, and (c) a CLe alkoxy group ally substituted by l to 3 halogen atoms; (62) a 8— to lZ—membered fused aromatic heterocyclic group (e.g., benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indolyl, isoindolyl, lyl, idazolyl, benzoxazolyl) optionally substituted by l to 3 substituents selected from (a) a halogen atom, (b) a Cbfi alkyl group optionally substituted by l to 3 halogen atoms, and (c) a Cyfi alkoxy group optionally substituted by l to 3 halogen atoms; (63) a 3— to 8—membered monocyclic non—aromatic heterocyclic group (e.gl, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, piperazinyl, dihydrooxadiazolyl, thiazolinyl) optionally substituted by l to.3 tuents selected from (a) a halogen atom, (b) a Cyfi alkyl group optionally substituted by l to 3 halogen atoms, (c) a Cyfi alkoxy group optionally substituted by l to 3 halogen atoms, and (d) an oxo group; (64) a 8- to lZ—membered fused non-aromatic cyclic group (e.g., dihydrobenzofuranyl) optionally substituted by l to 3 substituents selected from (a) a halogen atom, (b) a Cyfi alkyl group optionally substituted by l to 3 halogen atoms, (c) a Cyfi alkoxy group ally substituted by l to 3 en atoms, and (d) an oxo group; (65) a 5— or ered monocyclic aromatic heterocyclyloxy group (e.g., furyloxy, thienyloxy, pyrrolyloxy, oxazolyloxy, isooxazolyloxy, thiazolyloxy, isothiazolyloxy, imidazolyloxy, loxy, pyrazolyloxy); (66) a 8— to lZ—membered fused aromatic heterocyclyloxy group (e.g., benzofuranyloxy, isobenzofuranyloxy, benzothienyloxy, isobenzothienyloxy, indolyloxy, isoindolyloxy, indazolyloxy, benzimidazolyloxy, benzoxazolyloxy); (67) a 3— to ered monocyclic non—aromatic heterocyclyloxy group (e.g., yloxy, azetidinyloxy, oxetanyloxy, thietanyloxy, pyrrolidinyloxy, tetrahydrofuryloxy, thioranyloxy, dyloxy); (68) a 8— to lZ-membered fused non—aromatic heterocyclyloxy group (e.g., dihydrobenzofuranyloxy); (69) a carboxy group; (70) a Cyfi alkoxy—carbonyl group; (71) a C25 alkenyloxy-carbdnyl group (e.g., vinyloxycarbonyl, propenyloxycarbonyl, butenyloxycarbonyl, yloxycarbonyl, hexenYloxycarbonyl); (72) a Czfi alkynyloxy—carbonyl group (e.g., ethynyloxycarbonyl, propynyloxycarbonyl, butynyloxycarbonyl, pentynyloxycarbonyl, loxycarbonyl); (73) a C3fi cycloalkyloxy-carbonyl group (e.g., cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl); (74) a C3g cycloalkenyloxy-carbonyl group (e.g., ropenyloxycarbonyl, cyclobutenyloxycarbonyl, cyclopentenyloxycarbonyl, cyclohexenyloxycarbonyl); (75) a C644 aryloxy—carbonyl group (e.g., phenoxycarbonyl, l- naphthyloxycarbonyl, thyloxycarbonyl); (76) a C3$ cycloalkyl—Cyg alkoxy—carbonyl group (e.g., cyclopropylmethyloxycarbonyl, cyclopropylethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, cyclohexylethyloxycarbonyl); (77) a C}g cycloalkenyl—Cys alkoxy—carbonyl group (e.g., cyclopentenylmethyloxycarbonyl, cyclohexenylmethyloxycarbonyl, cyclohexenylethyloxycarbonyl, cyclohexenylpropyloxycarbonyl); (78) a C74A aralkyloxy—carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl); (79) a mono—Cyfi alkylthiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, propylthiocarbamoyl); (80) a di’CLfi alkylthiocarbamoyl group (e.g., dimethylthiocarbamoyl, diethylthiocarbamoyl, dipropylthiocarbamoyl); (81) a Cyfi alkyl—carbonyloxy group (e.g., acetyloxy, propanoyloxy, butanoyloxy, ylpropanoyloxy); (82) an imino group optionally substituted by a hydroxy group; (83) a CLfi alkylenedioxy group (e.g., methylenedioxy, ethylenedioxy).
In one preferable embodiment, R1 is ably a Che alkyl group (preferably a Cyg alkyl group (e.g., methyl, ethyl, propyl, pyl)) optionally substituted by 1 to 3 tuents selected from (1) a C6fl4 aryl group (e.g., phenyl) optionally substituted by l to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a Cyfi alkoxy group (e.g., methoxy) optionally substituted by l to 3 halogen atoms (e.g., a ne atom), (2) a 5— or 6—membered monocyclic aromatic heterocyclic group (e.g., pyridyl), and (3) a 3— to 8-membered clic non—aromatic heterocyclic group (e.g., thiazolinyl).
In another preferable embodiment, R1 is preferably a Cye alkyl group (preferably a Cpg alkyl group (e.g., methyl, ethyl, propyl, isopropyl)) optionally substituted by l to 3 substituents selected from (1) a C644 aryl group (e.g., phenyl) optionally substituted by l to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a CL6 alkoxy group (e.g., methoxy) optionally tuted by l to 3 halogen atoms (e.g., a fluorine atom), (2) a 5— or 6—membered monocyclic aromatic heterocyclic group (e.g., pyridyl) optionally tuted by l to 3 substituents ed from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a Cyfi alkoxy group (e.g., methoxy) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and (3) a 3- to 8—membered monocyclic non—aromatic heterocyclic group (e.g., thiazolinyl) optionally substituted by l to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a Cbfi alkoxy group (e.g., y) optionally substituted by l to 3 n atoms (e.g., a fluorine atom).
R1 is more preferably a Cbg alkyl group (preferably a Cy3 alkyl group (e.g., methyl, ethyl, propyl, isopropyl)) optionally substituted by l to 3 substituents selected from (l) a C644 aryl group (e.g., ) optionally substituted by l to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a ctr alkoxy group (e.g., methoxy) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (2) a 5— or 6—membered monocyclic aromatic heterocyclic group (e.g., pyridyl), and (3) a 3— to 8—membered clic non—aromatic heterocyclic group (e.g., thiazolinyl).
R2 is preferably a hydrogen atom or a C36 alkyl group (preferably a Cyg alkyl group (e.g., )), particularly preferably a hydrogen atom.
[0062] In the formula (I), R3 is an optionally substituted 5— or ered aromatic heterocyclic group.
The “5— or 6—membered aromatic heterocyclic group” of the “optionally substituted 5- or 6—membered aromatic heterocyclic group for R3 is preferably a 5— or 6—membered nitrogen— containing ic heterocyclic group rably l, pyrimidinyl, pyridazinyl or oxazolyl), more preferably a group represented by 01 C32 N or I wherein ring C1 is an optionally substituted 6—membered nitrogen— containing aromatic heterocycle containing at least one nitrogen atom; and ring C2 is an optionally tuted 5-membered nitrogen— containing ic heterocycle containing at least one nitrogen atom, (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl).
[0065] The “5— or 6—membered aromatic heterocyclic group” of the “optionally substituted 5— or 6-membered aromatic heterocyclic group” for R3 optionally has 1 to 5 (preferably 1 to 3) substituents at substitutable positions. Examples of the substituent include substituents selected from the ing Substituent Group B.. When the number of substituents is two or more, the substituents may be the same or different.
Substituent Group B: (l) the above—mentioned Substituent Group A; (2) a Cpfi alkyl group optionally substituted by l to 3 substituents selected from (a) a halogen atom, (b) a cyano group, (c) a hydroxy group, (d) a Cyg cycloalkyl group optionally substituted by l to 3 substituents selected from (i) a halogen atom, (ii) a cyano group, and (iii) a Cyfi alkyl group optionally tuted by l to 3 halogen atoms; (e) a C644 aryl group optionally substituted by l to 3 substituents ed from (i) a halogen atom, (ii) a cyano group, and (iii) a Cyfi alkyl group optionally substituted by l to 3 halogen atoms, (f) a Cyfi alkoxy group optionally substituted by l to 3 halogen atoms, (g) an amino group optionally mono— or di—substituted by Cys alkyl group(s), (h) a 5— or 6—membered monocyclic aromatic cyclic group, (i) a 8— to lZ—membered fused aromatic heterocyclic group, (j) a 3— to 8—membered monocyclic non—aromatic heterocyclic group, (k) a 8— to lZ—membered fused non—aromatic heterocyclic group, (l) a carboxy group, and (m) a Cyfi —carbonyl group optionally substituted by l to 3 halogen atoms; (3) a C26 l group optionally substituted by l to 3 substituents selected from (a) a halogen atom, (b) a hydroxy group, (c) a Cyfi alkoxy group, (d) an amino group optionally mono— or di—substituted by Chg alkyl group(s), (e) a carboxy group, and (f) a Cyfi alkoxy—carbonyl group; (4) a CT¢4 aralkyl group optionally substituted by 1 to 3 substituents selected from (a) a n atom, (b) a hydroxy group, (c) a Cyfi alkoxy group, and (d) a Cyfi alkyl group optionally substituted by l to 3 n atoms; and (5) an oxo group.
In one preferable embodiment, R3 is preferably a 5— or 6— membered aromatic heterocyclic group (preferably l, pyrimidinyl, pyridazinyl or yl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom).
In another preferable ment, R3 is preferably an optionally substituted 5- or 6—membered nitrogen—containing aromatic heterocyclic group (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl).
R3 is more preferably a 5- or 6—membered nitrogen— containing aromatic heterocyclic group (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl) optionally substituted by l to 3 n atoms (e.g., a fluorine atom).
R3 is particularly preferably a group represented by C1 02 N or wherein ring Cl is an optionally substituted 6—membered nitrogen— containing aromatic heterocycle containing at least one nitrogen atom; and ring C2 is an optionally substituted 5—membered nitrogen— containing ic heterocycle ning at least one en atom, (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl), each of which is optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom).
In the formula (I), ring A is a further optionally substituted piperidine ring (the piperidine ring is optionally bridged).
The “piperidine ring” of the “further optionally substituted piperidine ring” for ring A is optionally bridged.
Examples of the bridged piperidine ring include oxa-9— azabicyclo[3.3.l]nonane and the like.
[0071] The “piperidine ring” of the “further optionally tuted piperidine ring” for ring A optionally has, besides R1, RZ—O— and —C(=O)—ring B, l to 4 (preferably 1 to 3) tuents at substitutable positions. Examples.of the substituent include substituents selected from the above- ned Substituent Group B. When the number of substituents is two or more, the tuents may be the same or different.
Ring A is ably a piperidine ring having no substituent other than R1, Rz—O- and —C(=O)—ring B, or an oxa— 9—azabicyclo[3.3.l]nonane ring having no substituent other than R1, Rg—O— and —C(=O)—ring B.
Ring A is more preferably a piperidine ring having no substituent other than R1, Rg-O— and —C(=O)-ring B .
[0073] In the formula (I), ring B is a further optionally substituted 5— or 6—membered aromatic ring (X and Y are independently a carbon atom or a en atom).
In one preferable embodiment, the “5— or 6—membered aromatic ring” of the “further optionally substituted 5— or 6— membered aromatic ring” for ring B is preferably benzene, thiazole, isoxazole, pyrazole, pyridine or pyrazine (X and Y are independently a carbon atom or a nitrogen atom), more preferably
[0074] In another preferable embodiment, the “5— or 6—membered aromatic ring” of the “further ally tuted 5— or 6— membered aromatic ring” for ring B is preferably a 6—membered aromatic ring (X and Y are ndently a carbon atom or a nitrogen atom), more preferably e, pyridine or pyrazine.
The “5— or 6—membered aromatic ring” of the “further optionally substituted 5— or 6—membered aromatic ring” for ring B optionally has, besides R3 and —C(=O)—ring A, 1 to 4 (preferably 1 to 3) tuents at substitutable ons.
Examples of the substituent include substituents selected from the above—mentioned Substituent Group B. When the number of substituents is two or more, the substituents may be the same or different.
In one preferable embodiment, ring B is preferably a 5— or 6-membered aromatic ring (preferably benzene, le, isoxazole, pyrazole, pyridine or pyrazine) (X and Y are independently a carbon atom or a nitrogen atom), which is, in addition to R3 and —C(=O)—ring A, optionally substituted by l to 3 substituents selected from (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a Cyfi alkyl group (e.g., methyl, tert—butyl) optionally tuted by l to 3 halogen atoms (e.g., a ne atom), (3) a Cyfi alkoxy group (e.g., methoxy), and (4) a C36 alkylenedioxy group (e.g., methylenedioxy), more preferably benzene, thiazole, isoxazole, pyrazole, pyridine or pyrazine (X and Y are independently a carbon atom or a en atom), each of which is, in addition to R3 and — C(=O)—ring A, optionally substituted by l to 3 substituents selected from (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a Cbfi alkyl group (e.g., methyl, tert—butyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (3) a Cbfi alkoxy group (e.g., methoxy), and (4) a Cyfi alkylenedioxy group (e.g., methylenedioxy), particularly preferably DQJQQN\ \ N\ / / / NF ___N HN——T __R N::\ 8-ik /N \ NH/V \ o/g/s or /%/N each of which is, in addition to R3 and -C(=0)—ring A, optionally substituted by l to 3 substituents selected from (1) a n atom (e.g., a fluorine atom, a chlorine atom), (2) a Cyfi alkyl group (e.g., , tert-butyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (3) a Chg alkoxy group (e.g., methoxy), and (4) a Cyfi alkylenedioxy group (e.g., methylenedioxy).
In another preferable embodiment, ring B is preferably a 6-membered aromatic ring (X and Y are independently a carbon atom or a nitrogen atom, preferably benzene, pyridine or pyrazine), which is, in addition to R3 and —C(=O)-ring A, ally substituted by l to 3 substituents selected from (1) a halogen atom (e.g., a ne atom, a chlorine atom), (2) a Cyfi alkyl group (e.g., methyl, tert—butyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (3) a Cyfi alkoxy group (e.g., methoxy), and (4) a Cbfi nedioxy group (e.g., methylenediOXy). able examples of compound (I) include the following compounds.
[Compound A] Compound (I) wherein R1 is a Cbfi alkyl group (preferably a C33 alkyl group (e.g., methyl, ethyl, propyl, isopropyl)) optionally tuted by l to 3 substituents ed from (1) a C644 aryl group (e.g., phenyl) optionally tuted by l to 3 substituents selected from (a) a halogen atom (e.g., a ne atom), (b) a cyano group, and (c) a Cyfi alkoxy group (e.g., methoxy) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (2) a 5— or 6—membered monocyclic aromatic heterocyclic group (e.g., pyridyl), and (3) a 3— to 8—membered monocyclic non—aromatic heterocyclic group (e.g., thiazolinyl); R? is a hydrogen atom or a Cyfi alkyl group (preferably a Cb3 alkyl group (e.g., methyl)); R3 is a 5— or 6—membered aromatic heterocyclic group (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl) optionally substituted by l to 3 n atoms (e.g., a fluorine atom); ring A is a piperidine ring having no tuent other than RR Rz—O— and —C(=O)—ring B; and ring B is a 5- or 6—membered aromatic ring (preferably benzene, thiazole, isoxazole, pyrazole, pyridine or pyrazine) (X and Y are ndently a carbon atom or a en atom), which is, in addition to R3 and —C(=O)-ring A, optionally substituted by l to 3 substituents selected from (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a Cyfi alkyl group (e.g., methyl, tert—butyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (3) a Cyfi alkoxy group (e.g., methoxy), and (4) a Cyfi alkylenedioxy group (e.g., methylenedioxy), or a salt thereof.
[Compound Bl] Compound (I) wherein R} is a Cyfi alkyl group (preferably a Cy3 alkyl group (e.g., , ethyl, propyl, isopropyl)) optionally substituted by l to 3 substituents selected from (1) a C6¢4 aryl group (e.g., ) optionally substituted by l to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a Cyfi alkoxy group (e.g., methoxy) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (2) a 5— or 6—membered monocyclic aromatic heterocyclic group (e.g., pyridyl), and (3) a 3- to 8—membered monocyclic non—aromatic heterocyclic group (e.g., thiazolinyl); R2 is a hydrogen atom or a Chg alkyl group rably a Ck3 alkyl group (e.g., methyl)) (preferably a hydrogen atom); R3 is a 5— or 6-membered nitrogen—containing aromatic heterocyclic group (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom); ring A is a piperidine ring having no substituent other than RH RZ-O— and —C(=O)-ring B; and ring B is benzene, thiazole, isoxazole, pyrazole, pyridine or pyrazine (X and Y are independently a carbon atom or a nitrogen atom), each of which is, in addition to R3 and —C(=O)— ring A, optionally substituted by l to 3 substituents selected from (1) a halogen atom (e.g., a ne atom, a chlorine atom), (2) a Cyfi alkyl group (e.g., methyl, tert—butyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (3) a Cbfi alkoxy group (e.g., methoxy), and (4) a Cyfi alkylenedioxy group (e.g., methylenedioxy), or a salt thereof.
[Compound B2] Compound (I) wherein R1 is a Cyfi alkyl group (preferably a C33 alkyl group (e.g., methyl, ethyl, , isopropyl)) optionally substituted by l to 3 substituents selected from (1) a C644 aryl group (e.g., ) optionally tuted by l to 3 tuents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a CLfi alkoxy group (e.g., methoxy) optionally tuted by l to 3 halogen atoms (e.g., a fluorine atom), (2) a 5— or 6—membered clic aromatic heterocyclic group (e.g., pyridyl), and (3) a 3— to 8—membered monocyclic non—aromatic heterocyclic group (e.g., thiazolinyl); R2 is a hydrogen atom or a Cyfi alkyl group (preferably a Ck3 alkyl group (e.g., methyl)) rably a hydrogen atom); R3 is_a 5— or ered nitrogen—containing aromatic heterocyclic group (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom); ring A is a piperidine ring having no substituent other than R% RZ—O— and —C(=O)—ring B; and ring B is a 6—membered aromatic ring (X and Y are independently a carbon atom or a nitrogen atom, preferably benzene, pyridine or pyrazine), which is, in on to R3 and —C(=O)—ring A, optionally substituted by l to 3 substituents selected from (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a Cyfi alkyl group (e.g., methyl, tert—butyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (3) a Cbfi alkoxy group (e.g., methoxy), and (4) a Cy5 alkylenedioxy group (e.g., enedioxy), or a salt thereof.
[Compound C] Compound (I) n R1 is a Cbfi alkyl group (preferably a Cyg alkyl group (e.g., , ethyl, propyl, isopropyl)) optionally substituted by l to 3 substituents selected from (l) a C644 aryl group (e.g., ) optionally substituted by l to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a Cyfi alkoxy group (e.g., methoxy) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (2) a 5— or 6—membered monocyclic aromatic heterocyclic group (e.g., pyridyl), and (3) a 3— to ered monocyclic non—aromatic heterocyclic group (e.g., thiazolinyl); R2 is a hydrogen atom or a Cpe alkyl group (preferably a C14 alkyl group (e.g., methyl)) rably a hydrogen atom); R3 is a group represented by c1 CZ N or wherein ring Cl is an optionally tuted 6—membered nitrogen— containing aromatic heterocycle containing at least one nitrogen atom; and ring C2 is an optionally substituted 5—membered en— containing aromatic heterocycle containing at least one nitrogen atom, (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl), each of which is optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom); ring A is a piperidine ring having no substituent other than R% Rz—O— and —C(=O)—ring B; and ring B is
[0088] QQQQ OW\CC<8 or C each of which is, in on to R3 and -C(=O)—ring A, optionally substituted by l to 3 substituents ed from (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a Cyfi alkyl group (e.g., methyl, tert—butyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (3) a Cyfi alkoxy group (e.g., methoxy), and (4) a Cbfi nedioxy group (e.g., methylenedioxy), or a salt thereof.
[0090] [Compound D1] Compound (I) wherein R1 is a Cba alkyl group rably a Crs alkyl group (e.g., methyl, ethyl, propyl, isopropyl)) optionally substituted by l to 3 substituents selected from '(1) a C644 aryl group (e.g., phenyl) ally substituted by 1 to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a CLfi alkoxy group (e.g., methoxy) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (2) a 5— or 6—membered monocyclic aromatic heterocyclic group (e.g., pyridyl) optionally substituted by l to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a Cyfi alkoxy group (e.g., methoxy) ally substituted by l to 3 halogen atoms (e.g., a fluorine atom), and (3) a 3— to 8—membered monocyclic non—aromatic heterocyclic group (e.g., linyl) optionally substituted by l to 3 substituents selected from (a) a n atom (e.g., a fluorine atom), (b) a cyano group, and (c) a Cyfi alkoxy group (e.g., methoxy) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom); R2 is a hydrogen atom or a Cbfi alkyl group (preferably a Clg alkyl group (e.g., methyl)) (preferably a hydrogen atom); 2012/076257 R3 is a 5— or 6—membered nitrogen—containing aromatic heterocyclic group (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl) optionally substituted by l to 3 n atoms (e.g., a ne atom); ring A is a piperidine ring having no substituent other than R% R?~O— and —C(=O)—ring B, or an oxa-9—azabicyclo[3.3.l]nonane ring having no substituent other than R1, Rg-O— and ~C(=O)—ring B; and ring B is a 5— or 6—membered aromatic ring (preferably benzene, thiazole, isoxazole, pyrazole, pyridine or pyrazine) (X and Y are independently a carbon atom or a nitrogen atom), which is, in addition to R3 and -C(=O)—ring A, optionally substituted by l to 3 substituents ed from (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a Cpfi alkyl group (e.g., methyl, tert—butyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (3) a Cbfi alkoxy group (e.g., methoxy), and (4) a Chg alkylenedioxy group (e.g., methylenedioxy), or a salt thereof.
[0091] [Compound D2] Compound (I) wherein R1 is a Cyfi alkyl group (preferably a Cyg alkyl group (e.g., methyl, ethyl, propyl, pyl)) optionally substituted by l to 3 substituents selected from (1) a C644 aryl group (e.g., phenyl) optionally substituted by l to 3 tuents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a Cyfi alkoxy group (e.g., methoxy) optionally tuted by l to 3 halogen atoms (e.g., a fluorine atom), (2) a 5- or 6—membered monocyclic aromatic heterocyclic group (e.g., pyridyl), and (3) a 3- to 8—membered monocyclic non—aromatic heterocyclic group (e.g., thiazolinyl); R2 is a en atom or a Cyfi alkyl group (preferably a Cb3 alkyl group (e.g., methyl)) (preferably a hydrogen atom); R3 is a 5— or ered nitrogen—containing aromatic heterocyclic group (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl) optionally substituted by l to 3' halogen atoms (e.g., a fluorine atom); ring A is a dine ring having no substituent other than RR RZ—O— and —C(=O)—ring B; and ring B is a 5— or 6—membered aromatic ring (preferably benzene, thiazole, ole, pyrazole, pyridine or pyrazine) (X and Y are independently a carbon atom or a nitrogen atom), which is, in addition to R3 and -C(=O)—ring A, optionally substituted by l to 3 tuents selected from (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a Cyfi alkyl group (e.g., methyl, tert-butyl) ally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (3) a Cbfi alkoxy group (e.g., methoxy) and (4) a Cbfi alkylenedioxy group (e.g., methylenedioxy), or a salt thereof.
[Compound El] Compound (I) wherein R1 is a Cbfi alkyl group (preferably a Cb3 alkyl group (e.g., methyl, ethyl, propyl, isopropyl)) optionally substituted by l to 3 substituents selected from (1) a Cfiqq aryl group (e.g., phenyl) optionally substituted by l to 3 tuents selected from (a) a n atom (e.g., a fluorine atom), (b) a cyano group, and (c) a Cyfi alkoxy group (e.g., methoxy) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (2) a 5- or 6—membered monocyclic aromatic heterocyclic group (e.g., pyridyl) optionally substituted by l to 3 substituents selected from (a) a halogen atom (e.g., a ne atom), (b) a cyano group, and (c) a CLfi alkoxy group (e.g., methoxy) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), and (3) a 3— to 8—membered monocyclic non—aromatic heterocyclic group (e.g., thiazolinyl) optionally tuted by l to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a Cyfi alkoxy group (e.g., methoxy) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom); R2 is a hydrogen atom or a Cyfi alkyl group (preferably a Cy3 alkyl group (e.g., methyl)) (preferably a hydrogen atom); R3 is a 5— or 6—membered en-containing ic heterocyclic group (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom); ring A is a piperidine ring having no substituent other than R% RZ—O— and —C(=O)—ring B, or an oxa—9—azabicyclo[3.3.l]nonane ring having no substituent other than R1, RZ-O— and —ring B; and ring B is benzene, thiazole, ole, pyrazole, pyridine or pyrazine (X and Y are independently a carbon atom or a en atom), each of which is, in addition to R3 and —C(=O)— ring A, optionally substituted by 1 to 3 substituents selected from (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a Cbfi alkyl group (e.g., methyl, tert—butyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (3) a Cyfi alkoxy group (e.g., methoxy), and (4) a Cyfi alkylenedioxy group (e.g., methylenedioxy), or a salt thereof.
WO 54822 [Compound E2] Compound (I) wherein R1 is a CL6 alkyl group (preferably a Cyg alkyl group (e.g., methyl, ethyl, propyl, isopropyl)) optionally substituted by l to 3 substituents selected from (1) a C64A aryl group (e.g., phenyl) optionally substituted by l to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a Cyfi alkoxy group (e.g., methoxy) optionally substituted by l to 3 halogen atoms (e.g., a ne atom), (2) a 5— or 6—membered monocyclic aromatic heterocyclic group (e.g., pyridyl), and (3) a 3— to 8—membered monocyclic non—aromatic cyclic group (e.g., thiazolinyl); R2 is a hydrogen atom or a Cbfi alkyl group (preferably a Cy3 alkyl group (e.g., )) (preferably a hydrogen atom); R3 is a 5— or 6—membered nitrogen-containing aromatic heterocyclic group (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom); ring A is a piperidine ring having no substituent other than RH Rg-O— and -C(=O)—ring B; and ring B is benzene, thiazole, isoxazole, pyrazole, pyridine or pyrazine (X and Y are independently a carbon atom or a nitrogen atom), each of which is, in addition to R3 and —C(=O)— ring A, optionally substituted by l to 3 substituents selected from (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a Cyfi alkyl group (e.g., , utyl) ally substituted by l to 3 halogen atoms (e.g., a ne atom), (3) a Chg alkoxy group (e.g., methoxy), and (4) a Cyfi alkylenedioxy group (e.g., methylenedioxy), or a salt thereof.
[Compound E3] Compound (I) wherein R1 is a CLfi alkyl group (preferably a Cyg alkyl group (e.g., methyl, ethyl, propyl, isopropyl)) optionally substituted by l to 3 substituents selected from (1) a C644 aryl group (e.g., phenyl) optionally substituted by l to 3 tuents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a Chg alkoxy group (e.g., methoxy) optionally substituted by l to 3 n atoms (e.g., a fluorine atom), (2) a 5- or 6—membered monocyclic aromatic heterocyclic group (e.g., pyridyl), and (3) a 3? to 8—membered monocyclic omatic heterocyclic group (e.g., thiazolinyl); R2 is a hydrogen atom or a Cyfi alkyl group (preferably a Ck3 alkyl group (e.g., methyl)) (preferably a hydrogen atom); R3 is a 5— or 6—membered nitrogen—containing aromatic heterocyclic group rably l, pyrimidinyl, pyridazinyl or oxazolyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom); ring A is a piperidine ring having no substituent other than R1 Rg—O— and -C(=O)~ring B; and ring B is bbnn z@©@©©m© each of which is, in on to R3 and —C(=O)—ring A, optionally substituted by l to 3 tuents selected from (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a Cyfi alkyl group (e.g., methyl, tert—butyl) optionally tuted by l to 3 halogen atoms (e.g., a fluorine atom), (3) a Cyfi alkoxy group (e.g., methoxy), and (4) a Cyfi alkylenedioxy group (e.g., methylenedioxy), or a salt thereof.
[0097] [Compound Fl] Compound (I) wherein R1 is a cps alkyl group (preferably a Cra alkyl group (e.g., methyl, ethyl, propyl, isopropyl)) optionally substituted by l to 3 substituents selected from (1) a C6¢4 aryl group (e.g., phenyl) optionally substituted by l to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (C) a Cyfi alkoxy group (e.g., methoxy) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (2) a 5— or 6—membered monocyclic aromatic heterocyclic group (e.g., pyridyl) ally substituted by l to 3 substituents ed from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (C) a Cbfi alkoxy group (e.g., methoxy) optionally substituted by l to 3 n atoms (e.g., a fluorine atom), and (3) a 3— to 8—membered monocyclic non—aromatic heterocyclic group (e.g., thiazolinyl) optionally substituted by l to 3 tuents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a Cyfi alkoxy group (e.g., methoxy) optionally tuted by l to 3 halogen atoms (e.g., a fluorine atom); R2 is a hydrogen atom or a C33 alkyl group (preferably a Cp3 alkyl group (e.g., methyl)) (preferably a hydrogen atom); R3 is a group ented by c1 CZ N or wherein ring Cl is an optionally substituted 6-membered en— containing aromatic heterocycle containing at least one nitrogen atom; and ring C2 is an ally substituted S—membered nitrogen— containing aromatic heterocycle containing at least one nitrogen atom, (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl), each of which is optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom); ring A is a piperidine ring having no substituent other than R1, RZ—O— and —C(=O)—ring B, or an oxa—9—azabicyclo[3.3.1]nonane ring having no substituent other than R1, RZ—O— and —C(=O)—ring B; and ring B is a 5- or 6-membered ic ring (preferably e, thiazole, isoxazole, pyrazole, ne or pyrazine) (X and Y are independently a carbon atom or a nitrogen atom), which is, in addition to R3 and —C(=O)—ring A, optionally substituted by l to 3 substituents selected from (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a Cyfi alkyl group (e.g., methyl, tert—butyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (3) a Cpfi alkoxy group (e.g., methoxy), and (4) a Cbfi alkylenedioxy group (e.g., enedioxy), or a salt thereof.
[Compound F2] Compound (I) n R1 is a CL6 alkyl group (preferably a Crs alkyl group (e.g., methyl, ethyl, propyl, pyl)) optionally substituted by l to 3 substituents selected from (1) a C644 aryl group (e.g., phenyl) optionally substituted by l to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and‘ (c) a Cyfi alkoxy group (e.g., methoxy) optionally substituted by l to 3 n atoms (e.g., a fluorine atom), (2) a 5— or 6—membered monocyclic aromatic heterocyclic group (e.g., pyridyl), and (3) a 3- to 8—membered monocyclic non—aromatic heterocyclic group (e.g., thiazolinyl); R2 is a hydrogen atom or a Cyfi alkyl group (preferably a Cb3 alkyl group (e.g., methyl)) rably a hydrogen atom); R3 is a group represented by c1 02 N or
[0102] wherein ring Cl is an optionally substituted 6—membered nitrogen— containing aromatic heterocycle ning at least one nitrogen atom; and ring C2 is an optionally substituted 5—membered nitrogen— containing aromatic heterocycle containing at least one nitrogen atom, WO 54822 (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl), each of which is optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom); ring A is a dine ring having no substituent other than R1, RZ—O— and —C(=O)-ring B; and ring B is a 5— or 6—membered aromatic ring (preferably benzene, thiazole, isoxazole, pyrazole, pyridine or ne) (X and Y are independently a carbon atom or a nitrogen atom), which is, in addition to R3 and -C(=O)—ring A, optionally substituted by l to 3 substituents selected from (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a Ckfi alkyl group (e.g., methyl, tert—butyl) ally substituted by l to 3 halogen atoms (e.g., a ne atom), (3) a Cbfi alkoxy group (e.g., methoxy), and (4) a Cyfi nedioxy group (e.g., methylenedioxy), or a salt thereof.
[Compound G1] Compound (I) wherein R1 is a Cyfi alkyl group (preferably a Cyg alkyl group (e.g., methyl, ethyl, propyl, isopropyl)) optionally substituted by l to 3 tuents selected from (1) a C644 aryl group (e-g-, phenyl) optionally substituted by l to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (C) a Cy5 alkoxy group (e.g., methoxy) optionally substituted by l to 3 n atoms (e.g., a fluorine atom), (2) a 5— or 6—membered monocyclic aromatic heterocyclic group (e.g., pyridyl) optionally substituted by‘l to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (C) a Cyfi alkoxy group (e.g., methoxy) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), and (3) a 3— to 8-membered monocyclic non—aromatic heterocyclic group (e.g., linyl) optionally substituted by l to 3 substituents selected from (a) a n atom (e.g., a fluorine atom), (b) a cyano group, and (c) a C}; alkoxy group (e.g., methoxy) optionally substituted by l to 3 halogen atoms (e.g., a ne atom); R2 is a hydrogen atom or a Chg alkyl group (preferably a Cy3 alkyl group (e.g., methyl)) (preferably a hydrogen atom); R3 is a group represented by C1 CZ N or wherein ring C1 is an optionally substituted 6—membered nitrogen— ning aromatic heterocycle ning at least one nitrogen atom; and ring C2 is an optionally substituted 5—membered nitrogen- containing aromatic heterocycle containing at least one en atom, (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl), each of which is optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom); ring A is a piperidine ring having no substituent other than R3 Rf—O— and -C(=O)—ring B, or an oxa—9—azabicyclo[3.3.l]nonane ring having no substituent other than R}, RZ—O— and —C(=O)—ring B; and ring B is benzene, thiazole, isoxazole, pyrazole, pyridine or pyrazine (X and Y are independently a carbon atom or a nitrogen atom), each of which is, in addition to R3 and —C(=O)— ring A, optionally substituted by l to 3 substituents ed from (l) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a Cyfi alkyl group (e.g., methyl, tert—butyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (3) a Cyfi alkoxy group (e.g., methoxy), and (4) a Cyfi alkylenedioxy group (e.g., methylenedioxy), or a salt thereof.
[0106] [Compound GZ] Compound (I) wherein R1 is a Chg alkyl group (preferably a CP3 alkyl group (e.g., methyl, ethyl, , isopropyl)) optionally substituted by l to 3 substituents selected from (1) a C644 aryl group (e.g., phenyl) ally substituted by l to 3 substituents selected from (a) a halogen atom (e.g., a ne atom), (b) a cyano group, and (c) a C}@ alkoxy group (e.g., methoxy) optionally tuted by l to 3 halogen atoms (e.g., a fluorine atom), (2) a 5— or 6—membered monocyclic aromatic heterocyclic group (e.g., l), and (3) a 3— to 8—membered monocyclic non—aromatic heterocyclic group (e.g., thiazolinyl); R2 is a hydrogen atom or a Chg alkyl group (preferably a C14 alkyl group (e.g., methyl)) (preferably a hydrogen atom); R3 is a group represented by
[0107] N or ring Cl is an optionally substituted ered nitrogen— containing aromatic heterocycle containing at least one nitrogen atom; and ring C2 is an optionally substituted 5—membered nitrogen— containing aromatic heterocycle containing at least one nitrogen atom, (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl), each of which is optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom); ring A is a piperidine ring having no substituent other than R% RZ—O- and ~C(=O)—ring B; and ring B is QDQJNQN \ \ / / / NE \__NNH HN——§\ \__Nb szqg\ S——QN / \ each of which is, in addition to R3 and —ring A, optionally substituted by l to 3 substituents selected from (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a Cyfi alkyl group (e.g., methyl, tert-butyl) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom),' (3) a Cyfi alkoxy group (e.g., y), and (4) a Cbfi alkylenedioxy group (e.g., methylenedioxy), or a salt thereof.
[0111] und G3] nd (I) wherein R1 is a Cyfi alkyl group (preferably a CLa alkyl group (e.g., methyl, ethyl, propyl, isopropyl)) optionally substituted by l 2012/076257 to 3 substituents selected from (1) a C6fl4 aryl group (e.g., phenyl) optionally substituted by l to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, and (c) a Cyfi alkoxy group (e.g., methoxy) optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom), (2) a 5— or 6—membered monocyclic ic heterocyclic group (e.g., pyridyl), and (3) a 3— to 8—membered monocyclic omatic heterocyclic group (e.g., thiazolinyl); R2 is a hydrogen atom; R3 is a group represented by
[0112] C1 02 wherein ring Cl is an optionally substituted 6—membered nitrogen— containing ic heterocycle ning at least one nitrogen atom; and ring C2 is an optionally substituted 5—membered nitrogen— containing aromatic heterocycle containing at least one nitrogen atom, (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl), each of which is optionally substituted by l to 3 halogen atoms (e.g., a fluorine atom); ring A is a piperidine ring having no substituent other than RR R2—O— and -C(=O)—ring B; and ring B is onnn /@©©©©m© each of which is, in addition to R3 and —C(=O)—ring A, optionally substituted by 1 to 3 substituents selected from (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a Cyfi alkyl group (e.g., , utyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), (3) a Cyfi alkoxy group (e.g., methoxy), and (4) a Cbfi alkylenedioxy group (e.g., methylenedioxy), or a salt thereof.
[Compound G4] Compound (I) selected from (4-benzylhydroxypiperidin—l—yl)(2,4'-bipyridin—3— yl)methanone, 2,4'—bipyridin—3—yl(4—(4—fluorobenzyl)—4—hydroxypiperidin—1— yl)methanone, 2,4'—bipyridinyl(4-(2,4—difluorobenzyl)—4—hydroxypiperidin— 1-yl)methanone, and (4—(4—fluorobenzyl)-4—hydroxypiperidin—1—yl)(2—(pyrimidin—4— yl)pyridin—3—yl)methanone or a salt thereof.
When compound (I) is in a form of a salt, es thereof include metal salts, an um salt, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acid, and the like.
Preferable examples of the metal salt include alkali metal salts such as sodium salt, potassium salt and the like; ne earth metal salts such as m salt, magnesium salt, barium salt and the like; an aluminum salt, and the like.
Preferable examples of the salt with organic base e salts with trimethylamine, triethylamine, pyridine, picoline, 2,6—lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'— dibenzylethylenediamine and the like. Preferable examples of the salt with nic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid e salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid,. tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p— esulfonic acid and the like. Preferable examples of the salt with basic amino acid e salts with arginine, lysine, ornithine and the like. Preferable examples of the salt with acidic amino acid include salts with ic acid, glutamic acid and the like.
Of these, a pharmaceutically acceptable salt is preferable. For example, when a compound has an acidic functional group, examples thereof include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt etc.) and the like, ammonium salt etc., and when a compound has a basic functional group, examples thereof include salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acid such as acetic acid, phthalic acid, c acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p—toluenesulfonic acid and the like.
[Production Method] The compound of the present invention and the starting compounds can be produced by a method known per se, for example, by method shown in the following scheme and the like.
In the following, the “room ature” generally means 0 — 40°C and, unless otherwise specified, each symbol in the chemical formulas described in the schemes is as defined above.
In the formulas, each compound includes salts, and examples of such salt include those similar to the salts of the compound of the present invention and the like. The compound obtained in each step can be used directly as the reaction mixture or as a crude product for the next reaction. It can also be isolated from a reaction mixture by a conventional method, and can be easily purified by a separation means such as tallization, distillation, tography and the like.
When the compound in the formula is commercially ble, a commercially available t can also be used directly. When each ring in the a (1) has a substituent, the corresponding precursor also has a similar substituent.
When the starting compound has an amino group, a carboxyl group, a y group or a heterocyclic group, these groups may be protected by a protecting group generally used in peptide chemistry and the like. By removing the protecting group as necessary after the reaction, the objective compound can be obtained. The protection and deprotection can be performed according to a method known per se, for example, the method described in “Protective Groups in Organic Synthesis, 3rd Ed”, John Wiley and Sons, Inc. (1999) (Theodora W. Greene, Peter G. M. Wuts). In the following schemes, P1 is a carboxy— protecting group, and P2 is a protecting group for the nitrogen atom of amine or amide, and the protecting group known per se can be used. For e, P1 is preferably a benzyl group, a methyl group, an ethyl group, a tert—butyl group or the like, and P2 is preferably a tert—butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group or the like.
[0120] Examples of the “leaving group” for LG1 - LG4 include a n atom (e.g., a ne atom, a bromine atom, an iodine atom etc.), Cyfi alkylsulfonyloxy optionally substituted by halogen atom(s) (e.g., a chlorine atom, a bromine atom, an iodine atom etc.) (e.g., esulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy etc.), C640 arylsulfonyloxy optionally substituted by CLfi alkyl group(s) (e.g., methyl, ethyl, propyl, pyl, butyl, isobutyl, sec-butyl, tert— butyl, pentyl, isopentyl, neopentyl, l—ethylpropyl, hexyl, isohexyl, 1,1—dimethylbutyl, methylbutyl, 3,3— dimethylbutyl, Z—ethylbutyl etc.) (e.g., benzenesulfonyloxy, p—toluenesulfonyloxy etc.), Cyfi alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl etc.) and the like. In addition, a substituent capable of ting to a leaving group is encompassed in LG1 — LG4, and it can be converted to a leaving group by a reaction known per se in a desired step.
For example, when LGl — L64 is a methylthio group, it is converted to a methanesulfonyl group by oxidation reaction.
The following each step can be performed t solvent, or by dissolving or suspending starting material compound in a suitable solvent prior to the reaction. In this case, solvent may be used alone, or two or more kinds of these solvents may be mixed in an appropriate ratio and used. Specific examples of the t used for the production method of the compound of the present invention include the followings. alcohols: methanol, l, l—propanol, 2—propanol, tert— butyl alcohol, 2—methoxyethanol etc. ethers: diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, l,4~dioxane, 1,2—dimethoxyethane etc. aromatic hydrocarbons: benzene, chlorobenzene, toluene, xylene etc. saturated arbons: cyclohexane, hexane etc. amides: N,N—dimethylformamide, N,N—dimethylacetamide, hexamethylphosphoric triamide etc. halogenated hydrocarbons: dichloromethane, chloroform, carbon tetrachloride, l,2~dichloroethane.etc. es: acetonitrile, propionitrile etc. sulfoxides: dimethylsulfoxide etc. aromatic organic bases: pyridine, lutidine etc. acid ides: acetic anhydride etc. organic acids: formic acid, acetic acid, propionic acid, trifluoroacetic acid, esulfonic acid etc. inorganic acids: hydrochloric acid, sulfuric acid etc. esters: methyl acetate, ethyl acetate, butyl e etc. ketones: acetone, methylethylketone etc.
Specific examples of the base or acid scavenger used for the production method of the compound of the present invention e the followings. inorganic bases: sodium hydroxide, potassium hydroxide, magnesium hydroxide etc. basic salts: sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate etc. organic bases: triethylamine, diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4— ylaminopyridine, N,N—dimethylaniline, N—methylpiperidine, N—methylpyrrolidine, N—methylmorpholine, 1,5— diazabicyclo[4.3.0]—5—nonene, l,4-diazabicyclo[2.2.2]octane, l,8—diazabicyclo[5.4.0]-7—undecene, imidazole etc. metal des: sodium methoxide, sodium ethoxide, potassium tert—butoxide etc. alkali metal hydrides: sodium hydride, potassium hydride etc. metal amides: sodium amide, lithiumdiisopropylamide, lithiumhexamethyldisilazide etc. organic m reagents: methyllithium, n—butyllithium, sec— ithium, tert—butyllithium etc.
Specific examples of the acid or acid catalyst used for the production method of the compound of the present invention include the followings. inorganic acids: hydrochloric acid, ic acid, nitric acid, hydrobromic acid, phosphoric acid etc. organic acids: acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p— toluenesulfonic acid, lO—camphorsulfonic acid etc.
Lewis acid: boron trifluoride ether complex, zinc iodide, anhydrous um chloride, anhydrous zinc chloride, ous iron chloride etc.
Compound (I) can be synthesized, for example, according to Production Method A, Production Method B or the like explained below.
The s in each scheme in the production method are as defined above, unless otherwise specified. In each reaction in Production Method A and B, Ra is a en atom or an optionally substituted Cyfi alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec—butyl, tert—butyl, pentyl, isopentyl, neopentyl, l—ethylpropyl, hexyl, isohexyl, 1,1—dimethylbutyl, 2,2—dimethylbutyl, 3,3-dimethylbutyl, 2— ethylbutyl etc.), or two Ra in combination ally form a ring such as 4,4,5,5—tetramethyl—l,3,2—dioxaborolane and the like.
[0125] [Production Method A] e 1) \ ND“ I + R3—B(0Ra)2 /) or N Rz—O (E) m ——‘_—’—’—’ (E) L_f:lH(9) YX‘Y PO1 (E) StepA1— X‘Y StepA—3 HOW-r WJKEW I T Step A— 4 I NYX‘Yl 0 LG‘ 0 R3 (8)R O R3 (2) (5) (I) Ra-LG2 (7) P1OY® Slap A " 2 0 BwWh wherein each symbo1 is as defined above.
The compound of the present invention can be ed by a sequence of reaction steps of Step A—l to Step A-4.
(Step A—l) Compound (5) can be produced by reacting compound (2) with compound (3) or compound (4) (R? = 4—pyrimidinyl). The reaction is carried out in the presence of a metal catalyst.
The metal catalyst is preferably a palladium compound [e.g., palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), a complex of palladium(II) acetate and 1,1’—bis(diphenylphosphino)ferrocene, etc.]. The amount of the metal catalyst to be used is about 0.000001 — 1.0 mol per 1 mol of compound (2). The metal catalyst can be used together with a phosphine ligand. The amount of the phosphine ligand to be used is about 0.01 — 5 mol per 1 mol of nd (2). Examples of the phosphine ligand include triphenylphosphine, 4,5—bis(diphenylphosphino)- 9,9—dimethylxanthene, tri-tert—butylphosphine and the like. In addition, a salt such as tri—tert—butylphosphine tetrafluoroborate can be used. The on is generally carried out in the ce of a base. Examples of the base include inorganic bases, basic salts and the like. When desired, the on may be carried out by adding an additive such as copper(I) cyanide, (I) bromide and the like. The amount of nd (3) or compound (4) to be used is about 0.8 — 10 mol per 1 mol of nd (2). The amount of the base to be used is about 1 — 20 mol per 1 mol of compound (2). The amount of the additive to be used is about 0.000001 — 5.0 mol per 1 mol of compound (2). When a metal catalyst unstable to oxygen is used for the reaction, the reaction is preferably carried out in a stream of an inactive gas such as argon gas, nitrogen gas and the like. This reaction is advantageously carried out in a solvent inert to the reaction. While the solvent is not particularly limited as long as the reaction proceeds, preferable es thereof include ls, ethers, aromatic arbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, esters, water, mixed solvents thereof and the like. While the on time varies depending on the reagent or solvent to be used, it is generally 1 min — 200 hr. The reaction temperature is preferably 0 - 150°C. In addition, the reaction can be carried out with irradiation of microwave in order to promote the reaction., (Step A-Z) Compound (5) can also be produced by reacting compound (6) with compound (7). The reaction is carried out in the same manner as in Step A—l, When desired, compound (5) produced in Step A—l or Step A—2 can be subjected to a ion step. For example, when nd (5) contains N—oxido or a halogen atom, it is removed by a reduction reaction known per se using palladium carbon and the like.
(Step A—3) Compound (8) can be produced by removing the protecting group P1 of compound (5). The removal of the protecting group can be carried out ing to a method known per se, for example, the method described in “Protective Groups in Organic Synthesis, 3rd Ed”, John Wiley and Sons, Inc. (1999) (Theodora W. , Peter G. M. Wuts), or the like.
Compound (8) can also be produced according to a method known per se, or a method analogous thereto.
(Step A—4) nd (I) can be produced by reacting carboxylic acid (8) or a reactive derivative thereof with compound (9).
Examples of the ve derivative of the carboxylic acid include acid halides such as acid chlorides, acid bromides and the like; acid amides with pyrazole, imidazole, benzotriazole and the like; mixed acid anhydrides with as acetic acid, propionic acid, butyric acid and the like; acid azides; activated esters such as diethoxyphosphate ester, diphenoxyphosphate ester, p—nitrophenyl ester, 2,4— dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, ester with N—hydroxysuccinimide, ester with N— hydroxyphthalimide, ester with l-hydroxybenzotriazole, ester with ro-l—hydroxybenzotriazole, ester with l—hydroxy—lH- done, and the like; activated thioesters such as 2— pyridyl thioester, 2—benzothiazolyl thioester and the like, and the like. Compound (I) can also be produced by directly reacting carboxylic acid (8) with compound (9) in the ce of a suitable condensing agent, instead of using the reactive derivative. Examples of the condensing agent e N,N'— disubstituted carbodiimides such as N,N'— dicyclohexylcarbodiimide, l—ethyl—B-(3— dimethylaminopropyl)carbodiimide (WSC) hydrochloride and the like; azolides such as N,N'—carbonyldiimidazole and the like; dehydrating agents such as N—ethoxycarbonyl—2—ethoxy~l,2- dihydroquinoline, phosphorus oride, alkoxyacetylene and the like; 2—halogenopyridiniums such as 2- chloromethylpyridinium iodide, ro—l—methylpyridinium iodide and the like; phosphorylcyanides such as lphosphorylcyanide and the like; 2—(7—azabenzotriazol—l— yl)—l,1,3,3—tetramethyluronium hexafluorophosphate (HATU), O- (7—azabenzotriazol—l—yl)-N,N,N',N'—tetramethyluronium tetrafluoroborate (TATU) and the like. When a condensing agent is used, the reaction is considered to progress via a reactive derivative of carboxylic acid (8). The amount of carboxylic acid (8) or a reactive derivative thereof to be used is WO 54822 generally about 0.8 — 5 mol per 1 mol of compound (9). This reaction is advantageously carried out in a solvent inert to the on. While the solvent is not particularly d as long as the reaction proceeds, preferable examples thereof e ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases, mixed solvents f. The reaction can be carried out in the presence of a basic salt, an organic bases or the like in order to promote the reaction. In addition, when an acidic substance is released due the reaction, a basic salt, an c base and the like can be used in order to remove it from the reaction system. While the reaction time varies depending on the t or solvent to be used, it is generally 10 min - 72 hr. The reaction temperature is preferably 0 — 100°C.
[Production Method B] (Scheme 2) Fifi“ RLNOWh \Nb- + 2_ TC? R333:9 °r O X 1'30A HO F)B StepB-1 S‘epB-Z NTX‘Y (10)LG (11)L O R3
[0133] wherein each symbol is as d above.
Compound (I) can also be produced by a sequence of reaction steps of Step B-1 to Step B—2.
(Step B—l) Compound (11) can be produced by reacting carboxylic acid (10) or a reactive derivative thereof with compound (9). The reaction can be carried out in the same manner as in Step A—4.
(Step B—2) Compound (I) can be produced by reacting compound (11) with compound (3) or compound (4) (R3 = 4—pyrimidinyl). The reaction can be d out in the same manner as in Step A—l.
[Production Method C] e 3) RLM 1 RL—O R1~O O (13) U132A Step C-1 RLAOA N‘PZ Step 0.2 [vbA NH (12) (14) (9) wherein M1 is a magnesium atom and halogen atom moiety derived from the Grignard reagent, or a m atom moiety derived from the organic lithium reagent; and the other each symbols are as defined above.
Compound (9) may be a commercially available product, or can be produced by a sequence of reaction steps of Step C—l to Step C—2. Alternatively, compound (9) can also be produced according to a method known per se or a method ous thereto.
(Step C—l) Compound (14) wherein R2 is a hydrogen atom can be produced by ng compound (12) with an organic metal reagent (13). Examples of the organic metal reagent include the Grignard reagents, organic lithium reagents and the like.
The amount of the organic metal reagent to be used is about 1 — 10 mol per 1 mol of compound (12). This reaction is ageously carried out in a solvent inert to the reaction.
While the solvent is not particularly limited as long as the reaction proceeds, preferable examples thereof include ethers, aromatic arbons, saturated arbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, mixed solvents thereof and the like. While the reaction time varies depending on the reagent or solvent to be used, it is generally 10 min - 100 hr. The reaction temperature is preferably —78 — 50°C.
When desired, the obtained nd can be subjected to 2012/076257 an alkylation step. For example, the obtained compound can be reacted with a compound ented by Rgfilf wherein R‘2a is an ally substituted CLfi alkyl group, in the presence of a base.
(Step C—2) Compound (9) can be produced by removing the protecting group P2 of compound (14). The removal of the protecting group can be carried out ing to a method known per se, for example, the method described in “Protective Groups in Organic sis, 3rd Ed”, John Wiley and Sons, Inc. (1999) (Theodora W. Greene, Peter G. M. Wuts), or the like.
The starting compound and/or the production intermediate for the aforementioned nd (I) may form a salt, which is not particularly limited as long as the reaction can be performed and, for example, those similar to the salts optionally formed by the entioned compound (I) and the like, and the like are used.
As for the configuration isomers (E, Z forms) of compound (I), they can be isolated and purified when isomerization occurs by, for example, a general separation means such as extraction, recrystallization, distillation, chromatography and the like, and a pure compound can be produced. In addition, it is also possible to isomerize a double bond by the methods described in Jikken Kagaku Kouza (Courses in Experimental Chemistry) 14 (The Chemical Society of Japan ed.), pages 251 to 253, 4th Edition Jikken Kagaku Kouza 19 (The Chemical Society of Japan ed.), pages 273 to 274 or a method according thereto, using heating, an acid catalyst, a transition metal complex, a metal catalyst, a radical catalyst, light irradiation or a strong base catalyst and the like, and obtain the corresponding pure isomer.
When desired, nd (I) can be synthesized by 2012/076257 performing deprotection, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension on, and substituent exchange reaction singly or two or more thereof in combination.
In each of the above—mentioned reactions, when the nd has a functional group such as an amino group, a carboxyl group or a hydroxy group, the reaction can be carried out after a protecting group generally used in peptide chemistry and the like is introduced into these groups. By removing the protecting group as necessary after the reaction, the objective compound can be obtained.
Examples of the ting group e formyl; Cb6 alkyl—carbonyl (e.g., acetyl, propionyl etc.), phenylcarbonyl, Chg alkoxy—carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl etc.), phenyloxycarbonyl, Cmflo aralkyloxy—carbonyl (e.g., benzyloxycarbonyl etc.), , phthaloyl and the like, each of which is optionally substituted. Examples of the substituent include a halogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), Cpfi alkyl—carbonyl (e.g., acetyl, propionyl, valeryl etc.), nitro and the like. The number of substituents is, for example, 1 to 3.
The removal method of the protecting group can be carried out according to a method known per se, and for example, a method using acid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N—methyldithiocarbamate, tetrabutylammonium de, palladium acetate and the like, a reduction method, and the like can be employed.
[0143] The thus—obtained compound (I), other on intermediate therefor and starting compounds thereof can be isolated and purified from a reaction mixture according to a method known per se, for e, extraction, concentration, neutralization, tion, distillation, recrystallization, column chromatography, thin layer chromatography, preparative high mance liquid chromatography (preparative HPLC), moderate—pressure preparative liquid chromatography ate— pressure preparative LC) and the like.
A salt of compound (I) can be produced by a method known per se. For example, when compound (I) is a basic compound, it can be produced by adding an nic acid or organic acid, or when compound (I) is an acidic compound, by adding an organic base or inorganic base.
Compound (I) may be a prodrug, and the prodrug of compound (I) refers to a compound which is converted to compound (I) as a result of a reaction with an enzyme, c acid, etc. under physiological conditions in vivo, thus a compound that undergoes enzymatic ion, reduction, hydrolysis etc. to convert to compound (I) and a compound that undergoes hydrolysis and the like by gastric acid, etc. to convert to compound (I).
[0146] Examples of the prodrug for compound (I) include (1) a compound obtained by ting an amino group in compound (I) to acylation, alkylation or phosphorylation (e.g., a compound obtained by subjecting an amino group in nd (I) to eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2—oxo—l,3—dioxolen—4—yl)methoxycarbonylation, tetrahydrofurylation, pyrrolidylmethylation, pivaloyloxymethylation, tert—butylation, ethoxycarbonylation, tert—butoxycarbonylation, acetylation, cyclopropylcarbonylation); (2) a compound obtained by subjecting a hydroxy group in compound (I) to acylation, alkylation, phosphorylation or boration (e.g., a compound obtained by ting a hydroxy group in compound (I) to acetylation, oylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation or dimethylaminomethylcarbonylation); (3) a compound obtained by subjecting a carboxyl group in compound (I) to esterification or amidation (e.g., a compound ed by subjecting a carboxyl group in nd (I) to ethylesterification, phenylesterification, carboxymethylesterification, dimethylaminomethylesterification, pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification, phthalidylesterification, (5—methyloxo—l,3—dioxolen—4—yl)methylesterification, cyclohexyloxycarbonylethylesterification or methylamidation) and the like. Any of these compounds can be produced from compound (I) according to a method known per se.
A prodrug of compound (I) may also be one which is converted to compound (I) under physiological ions as described in HIN no KAIHATSU (Development of Pharmaceuticals)”, Vol. 7, Design of Molecules, p. 163—198, Published by HIROKAWA SHOTEN (1990).
In the present specification, compound (I), and a prodrug thereof are sometimes collectively abbreviated as “the compound of the present ion”.
When compound (I) has isomers such as optical isomer, stereoisomer, positional isomer, rotamer and the like, such isomers and a mixture thereof are also encompassed in nd (I). For e, when compound (I) has optical isomers, an optical isomer resolved from this compound is also encompassed in compound (I). These isomers can be obtained as a single product according to synthesis methods or separation methods known per se (e.g., concentration, solvent extraction, column tography, recrystallization, etc.).
Compound (I) may be a crystal, and a single crystal form and a mixture of crystal forms are both encompassed in compound (I). The crystal can be produced by crystallizing according to a crystallization method known per se.
Compound (I) may be a hydrate, a non—hydrate, a e or a non—solvate.
Compound (I) may be labeled with an isotope (e.g., 3H, 11c, 14c, 18F, 358, 1251 etc.) and the like.
Compound (I) also encompasses a deuterium conversion form wherein 1H is converted to 2H(D).
Compound (I) may be a pharmaceutically acceptable cocrystal or a salt thereof. The cocrystal or a salt thereof means a crystalline substance constituted with two or more special solids at room temperature, each having ent physical properties (e.g., structure, melting point, melting heat, hygroscopicity, solubility and stability etc.). The cocrystal or a salt thereof can be produced according to a cocrystallization a method known per se.
Compound (I) may also be used as a PET tracer.
The compound of the present invention has low toxicity, and can be used as it is or in the form of a pharmaceutical composition by mixing with a pharmacologically acceptable carrier etc. to mammals (e.g., human, mouse, rat, rabbit, dog, cat, , horse, swine, monkey) as an agent for the prophylaxis or treatment of s diseases ned below.
[0152] As pharmacologically acceptable carriers, various organic or inorganic carrier substances conventionally used as preparation als can be used. These are incorporated as excipient, lubricant, binder and disintegrant for solid preparations, or solvent, solubilizing agent, suspending agent, isotonicity agent, buffer and soothing agent for liquid preparations, and the like, and preparation ves such as vative, antioxidant, colorant, sweetening agent and the like can be added as necessary.
[0153] able examples of the excipient include lactose, sucrose, D—mannitol, D—sorbitol, , gelatinated starch, dextrin, crystalline cellulose, low~substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum , pullulan, light anhydrous silicic acid, synthesis um silicate and magnesium alumino metasilicate. able examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silica.
[0155] Preferable examples of the binder include nated , sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone.
Preferable es of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid and low— substituted hydroxypropylcellulose.
Preferable examples of the solvent include water for injection, physiological brine, Ringer’s on, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.
Preferable es of the solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, l, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate and sodium acetate.
Preferable examples of the suspending agent include 2012/076257 surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; polysorbates; and polyoxyethylene hydrogenated castor oil.
Preferable examples of the isotonicity agent include sodium de, ol, itol, D—sorbitol and e. able examples of the buffer include buffers such as phosphate, acetate, ate, citrate and the like.
Preferable examples of the soothing agent include benzyl alcohol.
Preferable examples of the preservative include p— oxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
Preferable examples of the antioxidant include sulfite [and ascorbate.
Preferable es of the colorant include aqueous water—soluble food tar colors (e.g., food colors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like food colors), water insoluble lake dyes (e.g., aluminum salt of the aforementioned water—soluble food tar color) and natural dyes (e.g., B— carotene, chlorophyll, ferric oxide red).
Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame and stevia.
[0165] Examples of the dosage form of the pharmaceutical composition include oral preparations such as tablet (including sugar—coated tablet, film—coated tablet, sublingual tablet, orally disintegrating tablet), capsules ding soft capsule, microcapsule), granule, powder, troche, syrup, emulsion, suspension, films (e.g., orally disintegrable films) and the like; and parenteral agents such as injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), external preparations (e.g., dermal preparation, ointment), suppository (e.g., rectal itory, vaginal suppository), pellet, nasal preparation, pulmonary ation (inhalant), eye drop and the like.
These can be respectively safely administered orally or parenterally (e.g., topically, rectally, intravenously administered).
These preparations may be a release control ation (e.g., sustained—release microcapsule) such as an immediate— release ation, a sustained—release preparation and the like.
The pharmaceutical ition can be produced according to a method conventionally used in the field of pharmaceutical formulation, for example, the method bed in the Japanese Pharmacopoeia, and the like.
While the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, dose of the compound of the present invention and the like, it is, for example, about 0.1 to 100 wt%.
During production of an oral ation, g may be applied as necessary for the purpose of masking of taste, WO 54822 enteric property or durability.
Examples of the coating base to be used for coating include sugar coating base, water-soluble film coating base, enteric film coating base and sustained—release film coating base.
As the sugar coating base, sucrose is used. Moreover, one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
Examples of the soluble film coating base include cellulose polymers such as hydroxypropyl ose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methylhydroxyethyl cellulose etc.; synthetic polymers such as polyvinylacetal diethylaminoacetate, lkyl methacrylate copolymer E [Eudragit E (trade name)], nylpyrrolidone etc.; and polysaccharides such as pullulan etc.
[0173] Examples of the enteric film coating base include cellulose polymers such as hydroxypropylmethyl ose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethylethyl Cellulose, cellulose acetate phthalate etc.; acrylic polymers such as methacrylic acid copolymer L git L (trade name)], methacrylic acid copolymer LD [Eudragit L—3OD55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)] etc.; and lly occurring substances such as shellac etc.
[0174] es of the sustained—release film coating base include cellulose polymers such as ethyl cellulose etc.; and acrylic polymers such as aminoalkyl methacrylate copolymer RS git RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)] etc.
The mentioned coating bases may be used after mixing with two or more kinds thereof at riate ratios.
For coating, for example, a light shielding agent such as titanium oxide, red ferric oxide and the like can be used.
The compound of the present invention shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and a few side effects. Therefore, it can be used as an agent for the prophylaxis or treatment or a diagnostic of s diseases in a mammal (e.g., human, bovine, horse, dog, cat, monkey, mouse, rat).
The compound of the present invention has a superior CH24H inhibitory action and can suppress nerve cell death, AB increase, intracerebral inflammation and the like.
Accordingly, the compound of the present invention is useful for the prophylaxis, improvement of symptoms, ssion of ssion or treatment of es involving enhanced function of CH24H, for example, neurodegenerative disease.
In the present specification, the “neurodegenerative disease” means a disease associated with ration of neural tissues.
Specific examples of the neurodegenerative disease include Alzheimer’s disease, mild cognitive impairment, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, glaucoma, multiple sclerosis and the like.
In addition, the nd of the present invention is useful for the prophylaxis, improvement of symptoms, suppression of progression or treatment of diseases involving ed function of CH24H, for example, epilepsy, schizophrenia and the like.
Moreover, the compound of the present invention is useful for the prophylaxis, improvement of symptoms, suppression of progression or ent of diseases involving enhanced function of CH24H, for example, spasm and the like.
The dose of the compound of the present invention varies depending on the administration subject, route of stration, target disease, symptoms, etc. For example, when it is administered orally to an adult patient (body weight 60 kg), its dose is about 0.01 to 100 mg/kg body weight per dose, preferably 0.05 to 30 mg/kg body weight per dose, more preferably 0.1 to 10 mg/kg body weight per dose and this amount is desirably administered in l to 3 portions daily.
When the compound of the present invention is applied to each of the above—mentioned es, it can be used in an appropriate combination with a medicament or a treatment method generally employed for the disease.
Examples of the medicament (hereinafter to be abbreviated as “concomitant drug”) to be used in combination with the nd of the present invention include acetylcholine esterase inhibitors (e.g., donepezil, rivastigmine, hamine, zanapezil etc.), antidementian agents (e.g., memantine), inhibitors of B amyloid protein production, secretion, lation, coagulation and/or deposition, 0 ase inhibitors (e.g., 6—(4—biphenylyl)methoxy-2—[2-(N,N- dimethylamino)ethyl]tetralin, 6-(4—biphenylyl)methoxy—2-(N,N— dimethylamino)methyltetralin, 6—(4—biphenylyl)methoxy-2—(N,N— dipropylamino)methyltetralin, 2—(N,N-dimethylamino)methyl(4’— Vmethoxybiphenyl-4—yl)methoxytetralin, 6—(4—bipheny1yl)methoxy—2— [2—(N,N—diethylamino)ethyl]tetralin, 2-[2—(N,N— ylamino)ethyl]—6—(4’—methylbiphenyl—4~yl)methoxytetralin, 2—[2—(N,N—dimethylamino)ethyl]—6—(4’-methoxybiphenyl—4— yl)methoxytetra1in, 4’-dimethoxybiphenyl—4—yl)methoxy—Z— [2—(N,N—dimethy1amino)ethyl]tetralin, 6—[4—(1,3—benzodioxol—5— WO 54822 yl)phenyl]methoxy-2—[2-(N,N-dimethylamino)ethyl]tetralin, 6— (3’,4’—dimethoxybiphenyl—4—yl)methoxy—Z-[2—(N,N— dimethylamino)ethletetralin, an optically active form thereof, a salt thereof and a hydrate thereof, OM99—2 (WOOl/OO663)), y secretase inhibitory agent, B amyloid protein coagulation inhibitory agent (e.g., PTI—OO703, ALZHEMED (NC—531), PPI—368 (JP—A—ll—514333), PPI—558 (JP—A—ZOOl—SOOBSZ), 652 (Biochem.
J. (1999), 340(1), 283—289)), B amyloid vaccine, B amyloid degrading enzyme and the like, cerebral function activators (e.g., aniracetam, nicergoline), other therapeutic drug for Parkinson’s disease [(e.g., ne receptor agonists (e.g., L— DOPA, bromocriptine, pergolide, talipexole, pramipexole, Cabergoline, adamantadine), a ine oxidase (MAO) inhibitors (e.g., deprenyl, ine (selegiline), remacemide, riluzole), anticholinergic agents (e.g., trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone)], therapeutic drug for amyotropic lateral sclerosis (e.g., riluzole etc., neurotrophic ), therapeutic drug for abnormal behavior, wandering and the like due to the progress of dementia (e.g., sedative drug, xiety drug), apoptosis inhibitors (e.g., CPI—1189, IDN— 6556, CEP—l347), neuronal differentiation or regeneration promoters (e.g., leteprinim, xaliproden (SR—57746eA), SB—216763, Y—128, VX—853, prosaptide, 5,6-dimethoxy—2—[2,2,4,6,7— pentamethyl—3—(4-methylphenyl)—2,3—dihydro—l—benzofuran—S— yl]isoindoline, 5,6—dimethoxy[3-(4—isopropylphenyl)— 6,7—pentamethyl—2,3—dihydro—l—benzofuran—S—yl]isoindoline, 6—[3-(4—isopropylphenyl)—2,2,4,6,7—pentamethyl—2,3~dihydro—l— benzofuran-S—yl]—6,7—dihydro—5H-[l,3]dioxolo[4,5—f]isoindole and optically active forms, salts and hydrates thereof), antidepressants (e.g., desipramine, amitriptyline, imipramine, tramadol), antiepilepsy drug (e.g., lamotrigine), antianxiety drugs (e.g., benzodiazepine), non—steroidal nflammatory drugs (e.g., meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin), disease—modifying heumatic drugs s), anti—cytokine drugs (e.g., TNF inhibitor, MAP kinase inhibitor), steroidal drugs (e.g., dexamethasone, hexestrol, one acetate), eutic agents for incontinence or frequent urination (e.g., flavoxate hloride, ynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitors (e.g., sildenafil te)), dopamine agonists (e.g., apomorphine etc.), antiarrhythmics (e.g., mexiletine), sex hormones or tives thereof (e.g., progesterone, estradiol, estradiol benzoate), therapeutic agents for osteoporosis (e.g., alfacalcidol, calcitriol, elcatonin, onin salmon, estriol, ipriflavone, disodium pamidronate, sodium alendronate hydrate, disodium incadronate), parathyroid hormone (PTH), calcium receptor antagonists, eutic drugs for insomnia (e.g., benzodiazepine medicament, non—benzodiazepine medicament, melatonin agonist), therapeutic drugs for schizophrenia (e.g., typical ychotic agents such as haloperidol and the like; atypical antipsychotic agents such as clozapine, olanzapine, risperidone, aripiprazole and the like; medicament acted on metabotropic glutamate receptor or ionic channel—conjugated glutamate receptor;phosphodiesterase tor) and the like.
In addition, a combined use with a transplantation method of neural stem cell or neural precursor cell prepared from embryonic stem cell or nervous tissue, or fetal neural tissue, and a combined use with a pharmaceutical agent such as an immunosuppressant after the transplantation and the like.
Furthermore, the compound of the present invention may be used in combination with the following concomitant drugs. (1) therapeutic agent for diabetes For example, insulin preparations (e.g., animal insulin preparation extracted from the pancreas of bovine, swine; human insulin preparation genetically synthesized using Escherichia coli, yeast; zinc insulin; protamine zinc insulin; n fragment or derivatives (e.g., INS—1), oral insulin preparation), insulin sensitizer (e.g., pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate), Tesaglitazar, Ragaglitazar, Muraglitazar, Edaglitazone, Metaglidasen, Naveglitazar, AMG— l3l, THR—O921), d—glucosidase inhibitor (e.g., ose, acarbose, miglitol, emiglitate), biguanide (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate)), insulin secretagogue nylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, ide, glybuzole), repaglinide, nateglinide, mitiglinide or calcium salt hydrate thereof, glucose—dependent insulin secretagogue (e.g., [(3S)—6—({2',6'—dimethyl—4‘—[3— (methylsulfonyl)propoxy]biphenyl-3—yl}methoxy)—2,3—dihydro—l— uran—3—yl]acetic acid or a salt thereof)], dipeptidyl ase IV inhibitor (e.g., Alogliptin, Vildagliptin, Sitagliptin, Saxagliptin, , TS—OZl), B3 agonist (e.g., AJ—9677), GPR4O agonist, GLP—1 receptor agonist [e.g., GLP—l, GLP—lMR agent, NN-2211, AC-2993 (exendin—4), BIM—51077, Aib(8,35)hGLP-l(7,37)NH2, CJC—ll3l], amylin agonist (e.g., pramlintide), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate), gluconeogenesis inhibitor (e.g., glycogen phosphorylase tor, glucose—6-phosphatase inhibitors, glucagon antagonists), SGLUT m—glucose cotransporter) inhibitor (e.g., T—1095), droxysteroid dehydrogenase inhibitor (e.g., BVT-3498), adiponectin or an agonist f, IKK inhibitor (e.g., AS—2868), leptin resistance improving drugs, somatostatin receptor ts, glucokinase activators (e.g., Ro—28—l675), GIP se—dependent insulinotropic e) and the like. (2) therapeutic agents for diabetic complications For example, aldose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT—llZ), rophic factor and an increasing agent thereof (e.g., NGF, NT-3, BDNF, neurotrophic factors and increasing drugs described in WOOl/l4372 (e.g., hlorophenyl)—2—(2— methyl—l—imidazolyl)—5—[3—(2—methylphenoxy)propyl]oxazole)), nerve regeneration ing agent (e.g., , PKC inhibitor (e.g., ruboxistaurin mesylate), AGE inhibitor (e.g., , pimagedine, pyratoxanthine, N—phenacylthiazolium bromide (ALT766), ALT—711, EXO—226, Pyridorin, pyridoxamine), active oxygen scavengers (e.g., thioctic acid), cerebral lator (e.g., tiapuride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), apoptosis signal regulating kinase—l(ASK—l) inhibitor and the like can be mentioned. (3) therapeutic agent for hyperlipidemia For example, statin compound (e.g., pravastatin, tatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or a salt thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., lapaquistat acetate or a salt f), fibrate compound (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), ACAT inhibitor (e.g., Avasimibe, Eflucimibe), anion exchange resin (e.g., colestyramine), probucol, nicotinic acid drug (e.g., nicomol, niceritrol), ethyl icosapentate, phytosterol (e.g., soysterol, gamma oryzanol) and the like. (4) pertensive agent For example, angiotensin converting enzyme inhibitor (e.g., captopril, enalapril, delapril), angiotensin II antagonist (e.g., candesartan cilexetil, an, eprosartan, valsartan, telmisartan, irbesartan, rtan, l—[[2’—(2,5— dihydro—S—oxo—4H—1,2,4-oxadiazol—3—yl)biphenyl—4—yl]methyl]—2— ethoxy—lH—benzimidazole—7—carboxylic acid, Azilsartan, Azilsartan medoxomil), calcium antagonist (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassium channel opener (e.g., levcromakalim, L-27152, AL 0671, NIP— 121), clonidine and the like. (5) antiobesity agent For example, central—acting antiobesity agent (e.g., dexfenfluramine, fenfluramine, phentermine, sibutramine, amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists (e.g., SB—568849; SNAP- 7941; compounds bed in WOOl/82925 and W001/87834); neuropeptide Y antagonist (e.g., CP—422935); cannabinoid receptor antagonists (e.g., SR-l41716, SR—147778); ghrelin antagonist; llfi-hydroxysteroid dehydrogenase tor (e.g., 98)), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), B3 agonist (e.g., AJ—9677, AZ40140), anorectic peptides (e.g., leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonist (e.g., lintitript, EFL—15849), anorexigenic agent (e.g., P—57) and the like. (6) ic For e, xanthine derivative (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparation (e.g., ethiazide, cyclopenthiazide, trichloromethyazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide), antialdosterone preparation (e.g., olactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), chlorobenzenesulfonamide agent (e.g., chlortalidone, mefruside, indapamide), azosemide, isosorbide, ethacrynic acid, nide, bumetanide, furosemide and the like. (7) chemotherapeutic agent For example, alkylating agents (e.g., cyclophosphamide, ifosfamide), metabolic antagonists (e.g., methotrexate, 5— uracil or derivative f), antitumor antibiotics (e.g., mitomycin, adriamycin), derived antitumor agents (e.g., stine, ine, Taxol), cisplatin, carboplatin, etoposide and the like. Of these, Furtulon and NeoFurtulon, which are 5—fluorouracil derivatives, and the like are preferable. (8) immunotherapeutic agent For example, microorganism or bacterial components (e.g., muramyl dipeptide tive, Picibanil), polysaccharides having immunity potentiating activity (e.g., lentinan, schizophyllan, krestin), cytokines obtained by genetic engineering techniques (e.g., interferon, interleukin (IL)), colony stimulating factors (e.g., ocyte colony stimulating factor, erythropoietin) and the like, with preference given to interleukins such as IL—1, IL—2, IL—12 and the like. (9) antithrombotic agent For example, heparin (e.g., heparin sodium, heparin calcium, dalteparin sodium), warfarin (e.g., warfarin potassium), anti—thrombin drug (e.g., argatroban), thrombolytic agent (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase), platelet aggregation inhibitor (e.g., ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like. (10) cachexia improving medicament For example, xygenase inhibitors (e.g., indomethacin etc.) [Cancer Research, Vol. 49, pages 5935—5939, 1989], progesterone derivatives (e.g., rol acetate) [Journal of Clinical Oncology, Vol. 12, pages 213—225, 1994], glucosteroids (e.g., dexamethasone etc.), opramide agents, ydrocannabinol agents (publications are all as mentioned above), fat metabolism improving agents (e.g., eicosapentanoic acid etc.) [British Journal of Cancer, Vol. 68, WO 54822 pages 314—318, 1993], growth hormones, IGF—l, or antibodies to a cachexia-inducing factor such as TNF—d, LIF, IL—6, oncostatin M and the like.
Two or more kinds of the above—mentioned concomitant drugs may be used in combination at an appropriate ratio.
It is also possible to apply compound of the present invention to each of the above—mentioned diseases in combination with a biologic (e.g., antibody, vaccine preparation and the like), or as a combination therapy in combination with gene therapy method and the like.
Examples of the antibody and vaccine preparation e vaccine preparation to angiotensin II, vaccine preparation to CETP, CETP antibody, TNFa antibody and antibody to other cytokine, amyloid B vaccine preparation, type 1 diabetes vaccine (e.g., DIAPEP-277 manufactured by Peptor Ltd.), anti—HIV antibody, HIV vaccine preparation and the like, antibody or vaccine preparation to cytokine, renin-angiotensin enzyme and a product thereof, antibody or vaccine ation to enzyme or protein ed in blood lipid metabolism, antibody or vaccine to enzyme or protein involved in blood ation or fibrinolytic system, antibody or e preparation to protein involved in saccharometabolism or insulin resistance and the like.
In addition, a combined use with a biological preparation ed in a growth factor such as GH, IGF and the like is possible.
Examples of the gene therapy method include a treatment method using a gene relating to cytokine, renin—angiotensin enzyme and a t thereof, G n, G protein conjugated receptor and its phosphorylation enzyme, a treatment method using a DNA decoy such as NFKB decoy and the like, a treatment method using an antisense, a treatment method using a gene ng to an enzyme or protein involved in blood lipid metabolism (e.g., gene relating to metabolism, excretion or absorption of cholesterol or triglyceride or HDL—cholesterol or blood phospholipid), a treatment method using a gene relating to an enzyme or protein involved in angiogenesis therapy targeting obstruction of peripheral vessel and the like (e.g., growth factors such as HGF, VEGF etc.), a treatment method using a gene relating to a protein involved in saccharometabolism or insulin resistance, an nse to cytokine such as TNF and the like, and the like.
In addition, it is possible to use in combination with s organ regeneration s such as heart regeneration, kidney regeneration, pancreas regeneration, blood vessel regeneration and the like or cell transplantation therapy utilizing bone marrow cell (myelomonocytic cell, myeloid stem cell) or an cial organ utilizing tissue engineering (e.g., artificial blood vessel and cardiac muscle cell sheet).
The time of administration of the compound of the present invention and that of the concomitant drug are not limited, and they may be administered simultaneously or in a staggered_ manner to the administration subject. Furthermore, the compound of the present invention and the concomitant drug may be stered as two kinds of ations containing each' active ingredient, or a single ation containing both active ingredients.
[0198] The dose of the concomitant drug can be appropriately determined based on the dose employed in al situations.
The mixing ratio of the compound of the present invention and a concomitant drug can be appropriately determined depending on the administration subject, administration route, target 2012/076257 disease, symptom, combination and the like. When the subject of administration is human, for example, a concomitant drug can be used in 0.01 - 100 parts by weight relative to 1 part by weight of the compound of the present invention.
Examples The present ion is explained in detail in the following by referring to Examples, Experimental Examples and Formulation Examples, which are not to be construed as limitative, and the invention may be changed within the scope of the present invention.
In the following Examples, the “room temperature” lly means about 10°C to about 35°C. The ratios indicated for mixed solvents are volume mixing ratios, unless otherwise specified. % means wt%, unless otherwise specified.
In silica gel column chromatography, NH means use of aminopropylsilane—bound silica gel. In HPLC (high performance liquid chromatography), C18 means use of octadecyl—bound silica gel. The ratios of elution solvents are volume mixing ratios, unless ise specified.
The iations used in the specification mean the following.
THE: tetrahydrofuran DME: 1,2—dimethoxyethane DMF: N,N—dimethylformamide DMA: N,N-dimethylacetamide DMSO: dimethyl sulfoxide ESI: electrospray method APCI: atmospheric chemical ionization [M+H]+: molecular ion peak M: mol concentration N: N concentration' IPE: diisopropyl ether HATU: 7—azabenzotriazol—l-yl)-l,l,3,3—tetramethyl uronium hexafluorophosphate DMTMM: dimethoxy[l.3.5]triazin—2-yl)—4—methylmorpholinium HPLC: high performance liquid chromatography TFA: trifluoroacetic acid mp: melting point 1H NMR (protone nuclear magnetic resonance spectrum) was measured by Fourier—transform type NMR. For the analysis, ACD/SpecManager (trade name) and the like were used. Peaks with very mild protons such as a hydroxy group, an amino group and the like are note described.
[0204] MS (mass spectrum) was measured by LC/MS (liquid chromatography mass spectrometer). As the tion method, ESI (ElectroSpray Ionization) method, or APCI (Atomospheric Pressure Chemical Ionization) method was used. The data tes those found. Generally, a molecular ion peak is observed. In the case of a compound having a tert— butoxycarbonyl group (—Boc), a peak after ation of a tert—butoxycarbonyl group or tert—butyl group may be observed as a fragment ion. In the case of a compound having a hydroxy group (—OH), a peak after elimination of H20 may be observed as a fragment ion. In the case of a salt, a molecular ion peak or fragment ion peak of free form is generally observed.
The elemental analysis value (Anal.) shows Calculated value (Calcd) and Found value (Found).
Example 1 zyl~4-hydroxypiperidin—l-yl)(5-methyl(pyridin-4— yl)phenyl)methanone
[0207] A) methyl 5—methyl-2—(pyridin—4—yl)benzoate A mixture of methyl o—5—methylbenzoate (5.2 g), pyridine—4—boronic acid (4.2 g), sodium carbonate (4.8 g), tetrakis(triphenylphosphine)palladium(O) (1.3 g), water (10 mL) and DME (50 mL) was heated under reflux overnight under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, and filtered through silica gel. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.5 g). 1H NMR (300 MHz, CDClg) 5 2.45 (3H, s), 3.65 (3H, s), 7.18—7.25 (3H, m), 7.39 (1H, d, J = 7.9 Hz), 7.73 (1H, s), 8.59—8.64 (2H, B) 5—methyl—2-(pyridin~4—yl)benzoic acid thride A mixture of methyl 5—methyl—2-(pyridin—4-yl)benzoate (8.8 g), 6 N hydrochloric acid (65 mL) and acetic acid (100 mL) was heated under reflux overnight. The solvent was evaporated under reduced pressure, and the obtained solid was washed with ethyl acetate to give the title compound (6.6 g).
MS (APCI+): [M+H]+ 214.3.
C) (4—benzyl—4—hydroxypiperidin—l—yl)(5—methyl—2—(pyridin—4- yl)phenyl)methanone A suspension of 5—methyl—2-(pyridin—4-yl)benzoic acid hydrochloride (0.33 g), yl—4—hydroxypiperidine (0.38 g), HATU (0.75 g) and triethylamine (0.92 mL) in DMF (5.0 mL) was stirred ght at room temperature. The reaction mixture was diluted with water, and the e was extracted with 3O ethyl acetate. The extract was washed with ted brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and then purified by preparative HPLC (C18, mobile phase: water /acetonitrile ining 0.1% TFA)), the obtained fraction was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate.
The extract was dried over anhydrous sodium sulfate. The solvent was evaporated_under reduced pressure. The obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (0.33 g). 1H NMR (400 MHz, DMSO—ds) 5 0.01-1.13 (2H, m), 1.22—1.49 (2H, m), 2.20—2.47 (4H, m), 2.56—2.78 (2H, m), 2.82—3.09 (2H, m), 4.09—4.29 (1H, m), 4.31—4.39 (1H, m), 6.99—7.28 (6H, m), 7.29— 7.49 (4H, m), 8.52—8.66 (2H, m).
Example 2 (4-benzyl—4—hydroxypiperidin—l—yl)(3—methyl—5—(pyridin—4-yl)- 1,2—oxazol—4—yl)methanone A) ethyl yl—5—(pyridin—4—yl)-1,2—oxazole—4—carboxylate To a mixture of ethyl acetoacetate (7.1 mL) and 2 M methylamine THF solution (28 mL) was added iodine (2.2 g) under water bath, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with saturated brine, and ted with ethyl acetate/THE. The extract was dried over anhydrous sodium sulfate, and the solvent was ated under reduced pressure.
To a solution of the obtained residue in toluene (60 mL) were added triethylamine (12 mL) and isonicotinoyl chloride (5.2 g), and the mixture was stirred overnight at room temperature. The insoluble material was filtered off, and the filtrate was concentrated under d pressure. The residue was diluted with saturated brine, and the mixture was extracted with ethyl acetate. The t was dried over ous sodium sulfate, and the solvent was evaporated under reduced pressure.
A sion of the ed residue and hydroxylamine hydrochloride (2.6 g) in acetic acid (50 mL) was heated under WO 54822 reflux for 3 hr, and the solvent was evaporated under reduced re. To the e was added saturated aqueous sodium hydrogen carbonate on, and the e was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.95 g).
MS (APCI+): [M+H]+ 233.2.
[0212] B) 3-methyl(pyridinyl)—l,2—oxazole—4—carboxylic acid To a solution of ethyl 3-methyl(pyridin—4—yl)—l,2— oxazole—4—carboxylate (0.95 g) in a mixed solvent of THF (20 mL)/methanol (10 mL) was added 1N aqueous sodium hydroxide solution (5.0 mL), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added water, and the mixture was washed with ethyl acetate. The obtained aqueous layer was acidified with lN hydrochloric acid, sodium chloride was added o until the mixture became saturated, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.48 g).
MS (ESI+): [M+H]+ 204.9.
[0213] C) (4—benzyl—4—hydroxypiperidin—l-yl)(3—methyl—5—(pyridin—4— yl)—l,2-oxazol—4-yl)methanone A suspension of 3—methyl—5-(pYridin—4—yl)—l,2—oxazole—4— carboxylic acid (0.25 g), 4-benzyl—4—hydroxypiperidine (0.35 g), HATU (0.70 g) and triethylamine (0.85 mL) in DMF (5.0 mL) was stirred at room temperature for 3 hr. The on mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. ‘The t was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and then purified by preparative HPLC (C18, mobile phase: water/acetonitrile ining 0.1% TFA)), and the ed fraction was trated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate.
The extract was dried over anhydrous sodium sulfate, and the solvent was ated under reduced pressure to give the title compound (0.29 g). 1H NMR (400 MHz, DMSO—de) 5 1.12-1.37 (2H, m), 1.41—1.60 (2H, m), 2.23 (3H, s), 2.65 (2H, brs), 3.05—3.31 (3H, m), 4.21—4.37 (1H, m), 4.54 (1H, s), 7.03-7.34 (5H, m), 7.50—7.60 (2H, m), 8.73 (2H, d, J = 5.3 Hz).
Example 4 4—((4—hydroxy—1—(5—methyl—2—(pyridin—4—yl)benzoyl)piperidin—4- yl)methyl)benzonitrile A) tert-butyl 4—(4—bromobenzyl)—4—hydroxypiperidine-1— carboxylate To a suspension of magnesium (2.9 g) in diethyl ether (50 mL) was added dropwise 1,2—dibromoethane (0.90 mL) at room temperature, and the reaction mixture was vigorously stirred at room temperature for 20 min. To the reaction mixture was added dropwise a solution of 4—bromobenzyl e (25 g) in diethyl ether (150 mL) over 30 min or more at 0°C, and then added dropwise a solution of tert—butyl 4—oxopiperidine-1— carboxylate (16 g) in diethyl ether (200 mL) over 30 min or more 0°C. The reaction mixture was allowed to warm to room ature, and stirred at room temperature for 3 hr. To the reaction mixture was added saturated s ammonium chloride solution (200 mL), and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under d pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12 g). 1H NMR (400 MHz, CDCl3) 5 1.45 (9H, s), 1.47 (2H, brs), 1.55 (2H, dd, J = 12.0, 3.6 Hz), 2.71 (2H, s), 3.08 (2H, t, J = 11.6 Hz), 3.85 (2H, brs), 7.07 (2H, d, J = 8.4 Hz), 7.44 (2H, d, J = 8.4 Hz).
B) tert—butyl 4—(4-cyanobenzyl)~4—hydroxypiperidine—1— carboxylate A mixture of tert-butyl 4—(4-bromobenzyl)—4- hydroxypiperidine—l—carboxylate (35 g), K4Fe(CN)6 (12 g), palladium(II) acetate (1.1 g), sodium ate (11 g), 2- propanol (7.5 mL) and DMA (150 mL) was stirred at 120°C for 12 hr. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane, and filtered h celite. The filtrate was washed with water and saturated brine, dried over ous magnesium sulfate, and the solvent was evaporated under reduced re. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (17 g). 1H NMR (400 MHz, CDCl3) 5 1.46 (9H, s), 1.47 (2H, brs), 1.55— 1.56 (2H, m), 2.82 (2H, s), 3.09 (2H, t, J = 11.6 Hz), 3.87 (2H, brs), 7.33 (2H, d, J = 8.4 Hz), 7.62 (2H, d, J = 8.4 Hz).
C) 4-(4—cyanobenzyl)-4—hydroxypiperidine hydrochloride To a solution of utyl 4-(4—cyanobenzyl)—4— hydroxypiperidine—1-carboxylate (19 g) in 1,4—dioxane (50 mL) was added 4.0 M HCl/1,4—dioxane solution (76 mL) at 0°C, and the mixture was stirred at room temperature for 10 hr. The resulting solid was collected by tion, washed with ethyl acetate (100 mL) and diethyl ether (200 mL), and dried under reduced pressure to give the title compound (9.3 g). 1H NMR (400 MHz, DMSO—de) 5 1.52 (2H, d, J = 13.2 Hz), 1.72 (2H, td, J = 13.2, 4.8 Hz), 2.83 (2H, s), 2.93—3.07 (4H, m), 5.00 (1H, s), 7.45 (2H, d, J = 8.0 Hz), 7.76 (2H, d, J = 8.0 Hz), 8.86 (1H, brs), 9.15 (1H, hrs).
D) 4—((4—hydroxy—1-(5—methy1-2—(pyridin—4— yl)benzoyl)piperidin—4—y1)methyl)benzonitrile By a method similar to that in Example 1, the title compound was obtained. 1H NMR (400 MHz, DMSO-dg) 5 —0.07—0.93 (1H, m), 0.96-1.14 (1H, m), 1.21—1.54 (2H, m), 2.28-2.48 (4H, m), 2.55—3.08 (4H, m), 4.08-4.30 (1H, m), 4.49 (1H, d, J = 10.6 Hz), .50 (7H, m), .76 (2H, m), 8.60 (2H, dd, J = 16.2, 5.3 Hz).
[0219] Example 8 (4—hydroxy—4~methy1piperidin—1—yl)(5—methyl(pyridin—4— yl)phenyl)methanone A) 1—(S—methyl—Z—(pyridin—4—y1)benzoyl)piperidin-4—one A suspension of 5—methyl-2—(pyridin—4—yl)benzoic acid hydrochloride (2.0 g), piperidin—4—one hydrochloride (1.2 g), DMTMM (3.3 g) and N—methylmorpholine (2.6 mL) in DMF (30 mL) was d at room temperature for 5 hr, and then overnight at 100°C. The reaction e was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced re.
The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.73 g).
MS (APCI+): [M+H]+ 295.1.
B) (4—hydroxy—4—methylpiperidin—1—yl)(5—methyl—2-(Pyridin—4— yl)phenyl)methanone 3 M magnesium bromide-diethyl ether solution (0.84 mL) was added to a solution of l—(5—methyl—2—(pyridin—4- yl)benzoyl)piperidin—4—one (0.37 g) in THF (10 mL) at 0°C, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water at 0°C, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried oVer anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.19 g). 1H NMR (300 MHz, CDC13) 5 0.09—1.64 (8H, m), 2.42 (3H, s), 2.58—3.27 (3H, m), 4.18-4.39 (1H, m), 7.09—7.56 (5H, m), 8.61 (2H, d, J = 4.5 Hz).
Example 9 (4—benzyl—4—hydroxypiperidin—l-yl)(5—(pyridin—4—yl)-1,3- benzodioxol—4—yl)methanone A) (4~benzy1-4—hydroxypiperidin—1—yl)(5—bromo—l,3—benzodioxol— 4-yl)methanone A suspension of o—1,3—benzodioxole—4—carboxylic acid (0.50 g), 4-benzyl—4—hydroxypiperidine (0.59 g), HATU (1.2 g) and triethylamine (1.4 mL) in DMF (5.0 mL) was stirred overnight at room temperature. The on mixture was d with water, and the e was ted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.85 g).
MS (APCI+): [M+H]+ 418.1.
B) (4—benzylhydroxypiperidin—l—yl)(5—(pyridin—4-yl)—1,3— benzodioxol—4-yl)methanone A mixture of (4-benzy1—4—hydroxypiperidin—1—yl)(5-bromo— 1,3—benzodioxol—4—y1)methanone (0.50 g), ne-4—boronic acid (0.22 g), sodium carbonate (0.38 g), tetrakis(triphenylphosphine)palladium(0) (0.069 g), water (0.50 mL) and DME (2.5 mL) was stirred at 150°C for 1 hr under microwave irradiation. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with ted brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.85 g). 1H NMR (300 MHz, CDC13) 5 0.18—0.32 (1H x 1/2, m), 1.03—1.12 (1H x 1/2, m), 1.15—1.36 (2H, m), 1.42—1.74 (2H, m), 2.38—2.52 (1H, m), 2.72 (1H, s), 2.75—2.88 (1H, m), 2.97—3.25 (2H, m), 4.40—4.54 (1H, m), 6.10 (2H, s), 6.87—6.98 (2H, m), 7.02—7.16 (2H, m), 7.22—7.34 (4H, m), .47 (1H, m), .67 (2H, Example 14 (4-benzyl—4—hydroxypiperidin—1-yl)(2—(pyrimidin—4— y1)phenyl)methanone A) methyl 2—(6—chloropyrimidin—4-yl)benzoate A mixture of methyl 2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan—Z—yl)benzoate (2.0 g), 2,6-dichloropyrimidine (1.4 g), sodium carbonate (2.4 g), tetrakis(triphenylphosphine)palladium(0) (0.44 g), water (2.0 mL) and DME (10 mL) was stirred at 150°C for 1 hr under microwave irradiation. The reaction mixture was d with water, and the mixture was ted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was ed by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.60 g). 1H NMR (300 MHz, CDC13) a 3.75 (3H, s), 7.49—7.67 (4H, m), 7.90 (1H, dd, J = 7.3, 1.3 Hz), 9.01 (1H, d, J = 1.3 Hz).
B) methyl 2-(pyrimidin—4—yl)benzoate A suspension of methyl 2—(6—chloropyrimidin—4—yl)benzoate (0.60 g), triethylamine (1.7 mL) and 10% palladium carbon WO 54822 (containing water (50%), 0.26 g) in methanol (20 mL) was stirred at room temperature for 1 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with saturated brine. The t was dried over anhydrous sodium sulfate, and the solvent was ated under reduced pressure to give the title compound (0.49 g).
MS (APCI+): [M+H]+ 215.2.
[0228] C) 2-(pyrimidin—4—yl)benzoic acid hydrochloride A mixture of methyl 2—(pyrimidin—4—yl)benzoate (0.49 g), acetic acid (2.0 mL) and 6 N hydrochloric acid (10 mL) was heated under reflux for 5 hr. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate to give the title compound (0.45 g).
MS (APCI+): [M+H]+ 201.2.
D) (4—benzyl-4—hydroxypiperidin—l—yl)(2—(pyrimidin-4— yl)phenyl)methanone A sion of imidin—4—yl)benzoic acid hydrochloride (0.20 g), 4—benzyl—4—hydroxypiperidine (0.24 g), HATU (0.48 g) and ylamine (0.59 mL) in DMF (3.0 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.11 g). 1H NMR (300 MHz, CDCl3) 5 1.29—1.42 (2H, m), l.50~l.78 (3H, m), 2.61—2.82 (2H, m), 2.86—3.40 (3H, m), 4.37—4.60 (1H, m), 7.06— 7.46 (6H, m), 7.47—7.84 (4H, m), .81 (1H, m), 8.85—9.27 (1H, m).
[0230] 2012/076257 Example 16 (4-benzyl—4—hydroxypiperidin—1—yl)(5—methyl(pyridin-4—yl)— 1H-pyrazol—4—yl)methanone A) ethyl 2—isonicotinoyl—3—oxobutanoate A mixture of isonicotinic acid (10 g) and thionyl chloride (18 mL) was stirred at 70°C for 2 hr. The reaction mixture was concentrated under reduced re, to the residue was added dichloromethane (280 mL), and the ium chloride (11) (5.1 g), ne (8.5 g) and ethyl 3— oxobutanoate (14 g) were added thereto at 0°C. The reaction mixture was stirred at room temperature for 3 hr, and poured into water, and the mixture was extracted with dichloromethane.
The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced re to give the title compound (11 g). 1H NMR (400 MHz, CDCl3) 5 0.88 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 3.96 (2H, q, J 6.8 Hz), 7.36 (2H, m), 8.75 (2H, brs).
B) ethyl 5—methyl—3-(pyridin—4—yl)~1H—pyrazole—4—carboxylate To a solution of ethyl 2—isonicotinoyl—3—oxobutanoate (8.0 g) in ethanol (80 mL) was added hydrazine (1.7 g), and the mixture was stirred at room temperature for 1 hr, and poured into saturated aqueous sodium en carbonate solution. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.4 g). 1H NMR (400 MHz, CDCla) 5 1.26 (3H, t, J = 7.2 Hz), 2.51 (3H, s), 4.25 (2H, q, J = 6.8 Hz), 7.63 (2H, dd, J = 1.6, 4.8 Hz), 8.66 (2H, dd, J = 1.6, 4.8 Hz), 11.84 (1H, brs).
C) 5—methyl—3—(pyridin—4—yl)—1H—pyrazole—4—carboxylic acid To a solution of ethyl 5-methyl—3—(pyridin—4—yl)—1H— pyrazole—4—carboxylate (3.1 g) in ethanol (20 mL) were added sodium hydroxide (8.0 g) and water (10 mL), and the mixture was heated under reflux ght. The solvent was evaporated under reduced pressUre, the pH of the mixture was adjusted to with 2 N hydrochloric acid, and mixture was concentrated under reduced pressure. The obtained solid was collected by filtration and washed with water to give the title nd (2.4 g)- 1H NMR (400 MHz, DMSO-de) 5 2.49 (3H, s), 7.68 (2H, d, J = 6.0 Hz), 8.61 (2H, d, J = 6.0 Hz), 12.5 (1H, brs), 13.5 (1H, brs).
D) (4—benzyl—4—hydroxypiperidin—1-y1)(5—methyl—3—(pyridin—4— yl)—1H—pyrazol-4—yl)methanone A mixture of 5—methyl-3—(pyridin—4-yl)—1H—pyrazole—4— carboxylic acid (0.47 g) and thionyl chloride (5 mL) was stirred at 70°C for 2 hr. The reaction mixture was concentrated under reduced re, and to the residue were added dichloromethane (5.0 mL) and triethylamine (0.29 g). The mixture was added to a solution of 4—benzyl—4— hydroxypiperidine (0.36 g) in dichloromethane (5 mL), and the mixture heated under reflux for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with ted brine, and dried over anhydrous sodium sulfate. The solvent was ated under reduced pressure. The residue was ed by silica gel column chromatography (ethyl acetate/hexane), and then purified again by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title nd (0.070 g). 1H NMR (300 MHz, CDC13) 5 1.25 (2H, s), 1.63 (2H, s), 2.31 (3H, s), 2.67 (2H, s), 3.07—3.16 (1H, m), 3.30—3.34 (1H, m), 3.49 (2H, s), 4.59 (1H, d, J = 12.4 Hz), 7.11 (2H, s), 7.28—7.33 (3H, m), 7.56 (2H, s), 8.61 (2H, d, J = 4.8 Hz).
Example 30 (4-fluoro—2—(pyridin—4—yl)phenyl)(4—hydroxy—4-(pyridin—2— ylmethyl)piperidin—l—yl)methanone A) methyl 4—fluoro—2—(pyridin-4—yl)benzoate A mixture of methyl 2—bromo—4—fluorobenzoate (1.5 g), pyridine—4—boronic acid (0.95 g), sodium carbonate (1.0 g), tetrakis(triphenylphosphine)palladium(0) (0.22 g), water (1.5 mL) and DME (9.0 mL) was stirred at 120°C for 1 hr under microwave ation. The reaction mixture was diluted with water, and the e was extracted with ethyl acetate. The ' extract was washed with water and saturated brine, and dried over ous magnesium sulfate, and the t was evaporated under d pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.89 g).
MS (APCI+): [M+H]+ 232.1.
B) 4—fluoro—2—(pyridin-4—yl)benzoic acid hydrochloride A mixture of methyl 4—fluoro—2—(pyridin—4—yl)benzoate (0.88 g) and 6 N hydrochloric acid (13 mL) was stirred at 90°C for 18 hr. The solvent was evaporated under reduced pressure to give the title compound (0.96 g). 1H NMR (300 MHz, DMSO—de) 5 7.27—7.65 (2H, m), 7.82—8.26 (3H, m), 8.95 (2H, d, J = 6.4 Hz), 13.25 (1H, brs).
[0238] C) (4-fluoro(pyridin—4—yl)phenyl)(4—hydroxy—4~(pyridin—2— ylmethyl)piperidin—l—yl)methanone A suspension of 4—fluoro—2~(pYridin—4—yl)benzoic acid hydrochloride (0.15 g), 4—(pyridin-2—ylmethyl)piperidin—4—ol (0.17 g), HATU (0.34 g) and triethylamine(0.41 mL) in DMF (2.0 mL) was stirred at room temperature for 2 hr. The on mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the t was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.16 g). 1H NMR (300 MHz, CDC13) 5 0.97—1.12 (1H, m), 1.20—1.34 (1H, m), 1.39—1.60 (2H, m), 2.55 (1H, s), 2.74—3.29 (4H, m), 4.40 (1H, d, J = 13.2 Hz), 7.01—7.23 (4H, m), 7.31—7.54 (3H, m), 7.63 (1H, t, J = 7.6 Hz), 8.44 (1H, brs), 8.58-8.76 (2H, m).
Example 37 (4-(4—fluorobenzyl)—4—hydroxypiperidin-l-yl)(5-methyl—2- (pyridin—4—yl)phenyl)methanone A) tert—butyl 4—(4-fluorobenzyl)—4—hydroxypiperidine—1— carboxylate To a suspension of ium (1.2 g) and 1,2— dibromoethane (0.11 mL) in THF (30 mL) was added a solution of 4—fluorobenzyl chloride (6.3 mL) in THF (10 mL) at room temperature under a nitrogen atmosphere, and the e was stirred for 1 hr at the same temperature. The reaction mixture was cooled to —78°C, a solution of utyl iperidine— l—carboxylate (5.0 g) in THF (10 mL) was added thereto, and the mixture was allowed to warm to room temperature, and stirred for 2 days. To the reaction mixture was added water at 0°C, and then saturated s potassium sodium te solution, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The e was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (4.8 g)- 1H NMR (300 MHz, CDClg) 5 1 34—1 72 (13H, m), 2.73 (2H, s), 3.09 (2H, t, J = 11.3 Hz), 3.85 (2H, d, J = 9.8 Hz), 6.95—7.06 (2H, m), 7.10—7.20 (2H, m).
B) 4—(4—fluorobenzyl)—4—hydroxypiperidine hydrochloride To a solution of tert—butyl 4—(4—fluorobenzyl)—4- hydroxypiperidine-1—carboxylate (2.0 g) in ethanol (10 mL) was added 2.0 M HCl/ethanol solution (20 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was ated under reduced pressure, and the obtained solid was recrystallized from ethanol/hexane to give the title compound (1.4 g). 1H NMR (400 MHZ, DMSO—dg) 5 1.40—1.77 (4H, m), 2.71 (2H, s), 2.86-3.16 (4H, m), 4.79 (1H, s), .33 (4H, m), 8.83 (2H, brs).
C) (4—(4—fluorobenzyl)—4—hydroxypiperidin—l—yl)(5—methyl—2— (pyridin—4—yl)phenyl)methanone By a method similar to that in Example 1, the title nd was obtained. 1H NMR (300 MHz, CDCl3) 5 0.08—1.56 (5H, m), 2.28—2.47 (4H, m), 2.51—2.82 (2H, m), 2.87—3.15 (2H, m), 4.33—4.59 (1H, m), 6.88— 7.57 (9H, m), .75 (2H, m).
Example 44 (4—benzyl—4-hydroxypiperidin—l~yl)(2,4'—bipyridin—3— yl)methanone A) ethyl 2,4'—bipyridine-3~carboxylate A mixture of ethyl 2—chloronicotinate (16.2 g), pyridine— 4—boronic acid (12.9 g), sodium carbonate (27.8 g), tetrakis(triphenylphosphine)palladium(0) (5.04 g), water (50.0 mL) and DME (250 mL) was stirred overnight at 100°C under a nitrogen atmosphere. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over ous sodium e. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (14.1 g). 1H NMR (300 MHZ, c0c13) 5 1.09 (3H, t, J = 7.0 Hz), 4.19 (2H, q, J = 7.0 Hz), 7.39—7.48 (3H, m), 8.21 (1H, dd, J = 7.8, 1.7 Hz), 8.66—8.74 (2H, m), 8.81 (1H, dd, J = 4.7, 1.7 Hz).
B) 2,4'—bipyridine-3—carboxylic acid dihydrochloride A solution of ethyl 2,4'—bipyridine—3—carboxy1ate (14.1 g) in 6 N hloric acid (200 mL) was heated under reflux ght. The solvent was evaporated under reduced pressure, to the obtained residue was added toluene, and the solvent was again evaporated under reduced pressure to give the title compound (16.4 g).
MS (APCI+): [M+H]+ 201.1.
C) (4~benzyl—4—hydroxypiperidin—l—yl)(2,4'—bipyridin—3— y1)methanone A suspension of 2,4'—bipyridine—3—carboxylic acid dihydrochloride (5.0 g), y1-4—hydroxypiperidine (3.9 g), HATU (10 g) and triethylamine(13 mL) in DMF (50 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (3.2 g). 1H NMR (300 MHz, 00013) 5 0.06—1.74 (5H, m), 2.34—3.18 (5H, m), .60 (1H, m), 6.98—7.15 (2H, m), .34 (3H, m), 7.41 (1H, dd, J = 7.6, 4.9 Hz), 7.61 (1H, d, J = 5.3 Hz), 7.70-7.83 (2H, m), .81 (3H, m). mp 150—152°C Example 54 (4—benzyl—4—hydroxypiperidin—l—y1)(2—(pyrimidin—4—yl)pyridin— 3—yl)methanone A) methyl 2-(3—oxidepyrimidin—4—yl)nicotinate A mixture of methyl 2—chloronicotinate (2.0 g), pyrimidine 1—oxide (0.95 g), potassium carbonate (3.2 g), palladium(II) acetate (0.13 g), tri-tert—butylphosphine tetrafluoroborate (0.51 g), copper(I) cyanide (0.10 g) and 1,4-dioxane (20 mL) was stirred at 150°C for 2 hr under microwave irradiation. The reaction mixture was diluted with ethyl acetate, and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.48 g).
MS (APCI+): [M+H]+ 232.1.
B) methyl 2-(pyrimidin—4—yl)nicotinate A suspension of methyl 2—(3—oxidepyrimidin—4— yl)nicotinate (0.28 g), triethylamine (0.84 mL) and 10% ium carbon (containing water (50%), 0.20 g) in methanol (10 mL) was d at room temperature for 5 hr under a hydrogen atmosphere. The reaction mixture was ed, and the te was concentrated under reduced pressure. The e was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title nd (0.20 g).
MS (APCI+): [M+H]+ 216.0.
[0250] C) 2-(pYrimidin-4—yl)nicotinic acid dihydrochloride A mixture of methyl 2—(pyrimidin—4—y1)nicotinate (0.19 g), acetic acid (1.0 mL) and 6 N hydrochloric acid (5 mL) was heated under reflux for 5 hr. The solvent was evaporated under d pressure to give the title compound (0.26 g).
MS (APCI+): [M+H]+ 202.1.
D) (4—benzyl~4—hydroxypiperidin—1-yl)(2-(pyrimidin—4— yl)pyridin—3-yl)methanone A suspension of 2—(pyrimidin—4—yl)nicotinic acid dihydrochloride (0.24 g), 4—benzyl—4—hydroxypiperidine (0.20 g), HATU (0.50 g) and triethylamine (0.74 mL) in DMF (6 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium e. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (0.085 g). 1H NMR (300 MHz, CDCl3) 5 1.27—2.00 (5H, m), 2.80 (2H, s), 3.09—3.52 (3H, m), 4.43—4.67 (1H, m), 7.12—7.22 (2H, m), 7.28— 7.50 (4H, m), 7.61—7.75 (1H, m), 8.16—8.27 (1H, m), 8.73—9.23 (3H, m).
[0252] e 67 2,4'—bipyridin—3—yl(4—(4—fluorobenzyl)—4—hydroxypiperidin—l- hanone A suspension of 2-chloronicotinic acid (0.15 g), 4—(4— fluorobenzyl)-4—hydroxypiperidine hydrochloride (0.26 g), HATU (0.43 g) and triethylamine (0.66 mL) in DMF (5 mL) was stirred at room ature for 4 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, and dried over- anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in DME (5.0 mL), and ne-4—boronic acid (0.13 g), sodium ate (0.20 g), tetrakis(triphenylphosphine)palladium(0) (0.055 g) and water (1.0 mL) were added thereto, and the mixture was d 3O at 140°C for l hr under microwave irradiation. The reaction mixture was diluted with water, and the e was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and then purified by preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), and the obtained fraction was concentrated under reduced pressure.
To the residue was added saturated s sodium en carbonate solution, and the mixture was extracted with ethyl e. The extract was dried over anhydrous sodium sulfate, and the solvent was ated under reduced pressure to give the title compound (0.21 g). 1H NMR (300 MHz, CDClg) 5 0.83—1.58 (5H, m), 2.31—2.50 (1H, m), 2.56—3.18 (4H, m), 4.39—4.62 (1H, m), 6.89—7.18 (4H, m), 7.42 (1H, dd, J = 7.5, 4.9 Hz), 7.61 (1H, d, J = 4.9 Hz), 7.69—7.86 (2H, m), 8.67 (1H, d, J = 4.5 Hz), 8.71—8.83 (2H, m).
Example 70 4—((1-(2,4'—bipyridinylcarbonyl)—4—hydroxypiperidin-4— yl)methyl)benzonitrile A) 4—(1—((2—chlor0pyridin—3-yl)carbonyl)~4-hydroxypiperidin—4— yl)benzonitrile A suspension of ronicotinic acid (0.20 g), 4—(4— cyanobenzyl)-4—hydroxypiperidine hydrochloride (0.32 g), HATU (0.72 g) and triethylamine (0.89 mL) in DMF (4.0 mL) was stirred overnight at room ature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and filtered through basic silica gel. The filtrate was concentrated under reduced pressure to give the title compound (0.45 g).
MS (APCI+): [M+H]+ 356.0.
[0255] B) 4—((1—(2,4‘-bipyridin—3-ylcarbonyl)-4—hydroxypiperidin—4— yl)methyl)benzonitrile A mixture of 4—(1—((2—chloropyridin—3—yl)carbonyl)—4— hydroxypiperidin-4—yl)benzonitrile (0.45 g), pyridine—4— boronic acid (0.19 g), sodium carbonate (0.40 g), tetrakis(triphenylphosphine)palladium(O) (0.073 g), water (0.60 mL) and DME (3.0 mL) was stirred at 150°C for 1 hr under microwave irradiation. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was ated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.27 g). 1H NMR (300 MHz, CDCl3) 5 0.00—1.62 (5H, m), 2.35—3.17 (5H, m), 4.41—4.63 (1H, m), 7.16—7.45 (3H, m), 7.50—7.85 (5H, m), 8.65 (1H, d, J = 4.9 Hz), 8.71—8.84 (2H, m).
Example 82 (4—benzyl—4-hydroxypiperidin—l—yl)(2—(l,3—oxazol—5— yl)phenyl)methanone A) methyl 2—(l,3-oxazol—5-yl)benzoate To a solution of methyl 2—formylbenzoate (15 g) and tosylmethyl isocyanide (18 g) in methanol (250 mL) was added potassium ate (15 g), and the mixture was heated under reflux for 16 hr. The reaction mixture was concentrated under reduced pressure, the residue was d with ethyl acetate, and the mixture was washed with water and saturated brine. The extract was dried over anhydrous sodium e, and the solvent was evaporated under reduced pressure. The e was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (4.0 g). 1H NMR (300 MHz, CDClg) 5 3.85 (3H, s), 7.30 (1H, s), 7.40—7.50 (1H, m), 7.50—7.65 (2H, m), 7.75-7.85 (1H, m), 7.94 (1H, s).
B) 2—(l,3—oxazol~5—yl)benzoic acid To a solution of methyl 2—(1,3—oxazol-5—yl)benzoate (4.0 g) in THF (40 mL) was added 2 N aqueous sodium hydroxide on (20 mL), and the e was stirred at room temperature stirred for 2 days. To the reaction e was added water, and the mixture was washed with tert-butyl methyl ether. The pH of the obtained aqueous layer was adjusted to 2 with 2N hloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with ted brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The e was washed with ethyl acetate/petroleum ether to give the title compound (3.3 1H NMR (400 MHz, DMSO—ds) 5 7.45 (1H, s), 7.50—7.60 (1H, m), 7.60—7.70 (2H, m), 7.70—7.80 (1H, m), 8.46 (1H, 5), 13.19 (1H, brs).
C) (4—benzyl-4—hydroxypiperidin—l-yl)(2—(l,3—oxazol—5— yl)phenyl)methanone A suspension of —oxazol—5—yl)benzoic acid (0.30 g), 4—benzyl—4—hydroxypiperidine (0.36 g), l—(3— dimethylaminopropyl)—3-ethylcarbodiimide hydrochloride (0.46 g), l—hydroxybenzotriazole (0.40 g) and triethylamine (0.40 g) in DMF (3 mL) was stirred at room temperature for 16 hr. The on mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (0.28 g).
MS (APCI+): [M+H]+ 363.2. 1H NMR (400 MHz, CDCl3) 5 0.90—1.05 (0.5H, m), 1.20—1.40 (2H, m), .55 (0.5H, m), 1.55-1.65 (1.5H, m), 1.70—1.80 (0.5H, m), 2.60—2.83 (2H, m), 3.00—3.30 (3H, m), 4.50—4.70 (1H, m), 7.10—7.20 (2H, m), 7.20—7.25 (0.5H, m), 7.30—7.40 (4H, m), 7.40—7.50 (2.5H, m), 7.65—7.75 (1H, m), 7.79 (0.5H, s), 7.89 (0.5H, s).
[0260] Example 86 2,4‘—bipyridin—3—yl(4—(3,4—difluorobenzyl)—4~hydroxypiperidin— 1—yl)methanone A) tert—butyl —dif1uorobenzyl)—4—hydroxypiperidine—1- carboxylate To a suspension of magnesium (1.2 g) and 1,2— dibromoethane (0.11 mL) in diethyl ether (30 mL) was added a solution of 3,4—difluorobenzy1 bromide (10 g) in diethyl ether (10 mL) at room_temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with THF (30 mL), and cooled to — 78°C. .A solution of tert—butyl 4—oxopiperidine-1—carboxylate (5.0 g) in THF (10 mL) was added thereto, and the e was allowed to warm to room temperature, and was stirred overnight.
To the reaction mixture was added a small amount of 1N hydrochloric acid at 0°C to quench the reaction. Saturated aqueous potassium sodium tartrate solution was added thereto, and the mixture was ted with ethyl e. The extract was washed with ted brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (4.9 g). 1H NMR (300 MHz, CDC13) 5 1.37—1.68 (14H, m), 2.71 (2H, s), 3.09 (2H, t, J = 11.5 Hz), 3.86 (2H, d, J = 9.8 Hz), 6.90 (1H, ddd, J = 6.1, 4.1, 2.3 Hz), .18 (2H, m).
B) 4—(3,4—difluorobenzyl)—4—hydroxypiperidine hydrochloride To a solution of utyl 4-(3,4—difluorobenzyl)—4- hydroxypiperidine-1—carboxylate (4.7 g) in ethanol (30 mL) was added 2.0 M HCl/ethanol solution (36 mL), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the obtained solid was. tallized from ethyl acetate/diisopropyl ether to give WO 54822 the title compound (3.5 g). 1H NMR (400 MHz, DMSO—d6) 6 1.38—1.81 (4H, m), 2.72 (2H, s), 2.88—3.14 (4H, m), 4.91 (1H, s), 6.97-7.16 (1H, m), 7.23—7.43 (2H, m), 8.98 (2H, brs).
[0263] C) 2,4'-bipyridin—3-yl(4—(3,4—difluorobenzyl)—4— hydroxypiperidin-l—yl)methanone A suspension of 2,4'-bipyridine—3—carboxylic acid dihydrochloride (0.30 g), 4—(3,4—difluorobenzyl)~4— hydroxypiperidine hydrochloride (0.38 g), HATU (0.63 g) and triethylamine (0.77 mL) in DMF (4.0 mL) was stirred at room temperature for 18 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over ous magnesium sulfate, and the solvent was evaporated under d pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.32 g). 1H NMR (300 MHz, CDCl3) 5 0.84—1.00 (1H, m), .38 (2H, m), 1.43—1.60 (1H, m), 2.28—2.49 (1H, m), 2.55—2.75 (1H, m), 2.78- 3.17 (3H, m), 4.41—4.62 (1H, m), 6.67—7.01 (2H, m), .17 (1H, m), 7.43 (1H, dd, J = 7.5, 4.9 Hz), 7.62 (1H, d, J = 4.5 Hz), 7.71—7.86 (2H, m), 8.67 (1H, d, J = 4.9 Hz), 8.72—8.84 (2H, m).
[0264] Example 87 2,4'—bipyridin—3—yl(4—(2,4-difluorobenzyl)—4-hydroxypiperidin— 1—yl)methanone A) tert—butyl 4—(2,4-difluorobenzyl)—4—hydroxypiperidine—1— carboxylate To a sion of magnesium (1.2 g) and 1,2— dibromoethane (0.11 mL) in diethyl ether (30 mL) was added a solution of 2,4—difluorobenzy1 bromide (10 g) in diethyl ether (10 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with THE (30 mL), and cooled to — 78°C, and a solution of tert-butyl 4—oxopiperidine—l- ylate (5.0 g) in THF (10 mL) was added o. The mixture was allowed to warm to room temperature, and stirred overnight. To the on mixture was added a small amount of 1N hydrochloric acid at 0°C to quench the reaction. Saturated aqueous potassium sodium tartrate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with ted brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and tallized from ethyl acetate/hexane to give the title compound (3.9 g). 1H NMR (300 MHz, CDC13) 5 1.38—1.52 (11H, m), 1.56—1.73 (2H, m), 2.78 (2H, d, J = 1.1 Hz), 3.10 (2H, t, J = 11.5 Hz), 3.86 (2H, d, J = 10.2 Hz), 6.76—6.90 (2H, m), 7.19 (1H, td, J = 8.6, 6.6 Hz).
B) 4—(2,4—difluorobenzyl)—4—hydroxypiperidine hydrochloride To a solution of tert—butyl 4—(2,4—difluorobenzyl)—4— ypiperidine—l—carboxylate (3.7 g) in ethanol (30 mL) was added 2.0 M HCl/ethanol solution (28 mL), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the obtained solid was recrystallized from ethyl acetate/diisopropyl ether to give the title nd (2.9 g). 1H NMR (400 MHz, DMSO—de) 5 1.39-1.87 (4H, m), 2.73 (2H, s), 2.87—3.16 (4H, m), 4.92 (1H, s), 7.04 (1H, td, J = 8.5, 2.6 Hz), 7.18 (1H, td, J = 9.9, 2.4 Hz), 7.30—7.50 (1H, m), 8.76 (1H, brs), 9.10 (1H, brs).
C) 2,4'—bipyridin—3-yl(4—(2,4—dif1uorobenzyl)—4— hydroxypiperidin—l—yl)methanone A suspension of 2,4'—bipyridine-3—carboxylic acid dihydrochloride (0.30 g), 4—(2,4—difluorobenzyl)—4— hydroxypiperidine hydrochloride (0.38 g), HATU (0.63 g) and triethylamine (0.77 mL) in DMF (4.0 mL) was stirred at room temperature for 18 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and ted brine, and dried over anhydrous ium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to .20 give the title compound (0.30 g). 1H NMR (300 MHz, CDCl3) 5 0.81—1.62 (4H, m), 2.36—2.57 (1H, m), .20 (4H, m), 4.39—4.62 (1H, m), 6.71—6.90 (2H, m), 6.95— 7.20 (lH, m), 7.36—7.49 (1H, m), 7.63 (1H, brs), 7.74 (2H, brs), 8.53—8.88 (3H, m).
[0268] Example 92 (4-(4—fluorobenzyl)—4—hydroxypiperidin-l—yl)(2—(pyrimidin—4- idin—3—yl)methanone A suspension of 2-(pyrimidin—4—yl)nicotinic acid dihydrochloride (0.25 g), 4—(4—fluorobenzyl)—4— hydroxypiperidine hloride (0.22 g), HATU (0.52 g) and triethylamine (0.76 mL) in DMF (3 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl e. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (0.050 g). 1H NMR (300 MHz, CDCl3) 5 .98 (5H, m), 2.76 (2H, s), 3.10—3.50 (3H, m), 4.44—4.67 (1H, m), 6.96—7.07 (2H, m), 7.09— 7.20 (2H, m), 7.40—7.50 (1H, m), 7.62—7.76 (1H, m), 8.23 (1H, d, J = 4.9 Hz), 8.74 (1H, dd, J = 4.5, 1.5 Hz), 8.81—9.23 (2H, mp 171-173°c e 44 (4—benzyl—4—hydroxypiperidin-1—yl)(2,4'-bipyridin—3- y1)methanone A) (4-benzyl-4—hydroxypiperidin—1~y1)(2—chloropyridin-3— y1)methanone To a mixture of 2—chloronicotinic acid (1.0 g), toluene (15 mL) and DME (5 mL) was added thionyl chloride (0.51 mL), and the mixture was stirred at 90°C for 4 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in THF (15 mL), and triethylamine (0.97 mL) and 4—benzyl-4—hydroxypiperidine (1.1 g) were added thereto. The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere, ted aqueous sodium en carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over ous sodium e. The t was evaporated under reduced pressure.- The residue was ed by silica gel column chromatography (ethyl acetate/hexane) to give the title compound.(1.9 g).
MS (APCI+): [M+H]+ 331.1.
B) (4—benzyl—4—hydroxypiperidin—1—yl)(2,4'—bipyridin—3- yl)methanone A mixture of (4—benzy1—4—hydroxypiperidin—1—yl)(2— chloropyridin-3—y1)methanone (5.0 g), tetrakis(triphenylphosphine)palladium(O) (0.87 g), pyridine-4— boronic acid (2.2 g), sodium carbonate (4.8 g), DMF (50 mL) and water (10 mL) was stirred overnight at 100°C under a nitrogen atmosphere. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over ous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was ed by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (3.4 g). The compound was crystallized from ethyl acetate/heptane to give the title compound as crystals. 1H NMR (300 MHz, CDCl3) 5 0.05—1.73 (5H, m), 2.34—2.53 (1H, m), 2.61—3.25 (4H, m), 4.37—4.64 (1H, m), 6.96—7.16 (2H, m), 7.19— 7.34 (3H, m), 7.42 (1H, dd, J = 7.6, 4.9 Hz), 7.54-7.85 (3H, m), 8.60—8.83 (3H, m). mp 150°C Example 92 (4—(4—fluorobenzyl)hydroxypiperidin—l—yl)(2—(pyrimidin-4— yl)pyridin—3—yl)methanone
[0273] A) ethyl 2—(l—ethoxyvinyl)nicotinate To a mixture of ethyl ronicotinate (23 g), tributyl(l—ethoxyvinyl)tin (64 mL) and toluene (400 mL) was added tetrakis(triphenylphosphine)palladium(0) (7.3 g), and the mixture was stirred overnight at 80°C under an argon here. The solvent was evaporated under reduced pressure, and the e was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and then purified ' by silica gel column tography (ethyl acetate/hexane) to give the title compound (27 g). 1H NMR (300 MHz, CDCl3) 5 1.31—1 42 (6H, m), 3.91 (2H, q, J = 7.2 Hz), 4.34 (2H, q, J = 7.2 Hz), 4.43 (1H, d, J = 2.3 Hz), 4.95 (1H, d, J = 2.3 Hz), 7.29 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, dd, J = 7.7, 1.7 Hz), 8.64 (1H, dd, J = 4.9, 1.9 Hz).
[0274] B) ethyl 2—acetylnicotinate To a mixture of ethyl 2—(l—ethoxyvinyl)nicotinate (27 g) and acetone (300 mL) was added 2M hloric acid (370 mL), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, to the residue were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium e. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column tography (ethyl acetate/hexane) to give the title nd (15 g). 1H NMR (300 MHz, CDCl3) a 1.37 (3H, t, J = 7.2 Hz), 2.69 (3H, s), 4.39 (2H, q, J = 7.2 Hz), 7.47 (1H, dd, J = 7.7, 4.7 Hz), 8.02 (1H, dd, J = 7.9, 1.5 Hz), 8.71 (1H, dd, J = 4.9, 1.5 Hz).
C) (4-(4—fluorobenzyl)—4—hydroxypiperidin—1-yl)(2—(pyrimidin— 4—yl)pyridin—3—yl)methanone A mixture of ethyl 2—acetylnicotinate (15 g), N,N— dimethylformamide yl acetal (150 mL) and acetonitrile (150 mL) was heated under reflux overnight. The reaction mixture was concentrated under reduced re. The obtained solid was washed with a mixed solvent of ethyl acetate and hexane, and dissolved in n—butanol (150 mL) and N,N— diisopropylethylamine (150 mL). Formamidine acetate (48 g) was added thereto, and the mixture was heated under reflux for 3 days, and concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with water and saturated brine. To the aqueous layer was added potassium carbonate, and the mixture was eXtracted with ethyl acetate.
The combined organic layers were dried over anhydrous sodium sulfate, and the t was evaporated under reduced pressure.
The residue was ed by silica gel column chromatography (ethyl acetate/hexane) to give ethyl imidin—4— yl)nicotinate (5.8 g) and butyl 2-(pyrimidin—4—yl)nicotinate (1.8 g), respectively. A mixture thereof was dissolved in a mixed solvent of ethanol (100 mL) and water (20 mL), 4M aqueous lithium hydroxide solution (13 mL) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was trated under reduced pressure, and the obtained residue was dissolved in water. The pH of the solution was adjusted to 4 with 1M hloric acid, and reaction mixture was concentrated under reduced pressure. To the ed residue were added DMF (100 mL), triethylamine (15 mL), 4—(4—fluorobenzyl)—4—hydroxypiperidine hydrochloride (6.5 g) and HATU (13 g), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, the insoluble al was removed by filtration, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure.
The e was purified by silica gel column tography (NH, ethyl acetate/hexane), and then purified by silica gel column chromatography (methanol/ethyl acetate), and crystallized from ethyl acetate/hexane to give the title compound (2.5 g) as crystals. 1H NMR (300 MHz, CDC13) 5 1.18—2.09 (5H, m), 2.77 (2H, brs), 3.08—3.63 (3H, m), 4.61 (1H, d, J = 12.1 Hz), 6.91-7.86 (6H, m), 8.25 (1H, brs), 8.68—9.36 (3H, m). mp 174°C e 102 (4-(2,4~difluorobenzyl)—4—hydroxypiperidin—1—yl)(2—(1,3— oxazol-S-yl)phenyl)methanone
[0277]‘ A sion of 2—(1,3—oxazol—5—y1)benzoic acid (0.15 g), 4—(2,4—difluorobenzyl)-4—hydroxypiperidine hydrochloride (0.16 g), HATU (0.36 g) and triethylamine (1.1 mL) in DMF (5.0 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced re. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.26 g). 1H NMR (300 MHz, CDCl3) 5 .86 (5H, m), 2.67 (1H, s), 2.79 (1H, s), 2.99—3.36 (3H, m), 4.60 (1H, m), 6.74-6.90 (2H, m), 7.04—7.23 (1H, m), 7.27—7.52 (4H, m), 7.71 (1H, m), 7.90 (1H, Example 105 (4-(2,4—difluorobenzyl)—4—hydroxypiperidin—1—yl)(2—(pyrimidin— 4—yl)pyridin—3—yl)methanone A suspension of 2—(pyrimidin-4—yl)nicotinic acid dihydrochloride (0.36 g), 4—(2,4—dif1uorobenzyl)—4— hydroxypiperidine hydrochloride (0.42 g), HATU (0.75 g) and triethylamine (1.1 mL) in DMF (5 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the e was ted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The e was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (0.18 g). 1H NMR (300 MHz, CDCl3) 5 1.29—2.01 (5H, m), 2.80 (2H, s), 3.09—3.49 (3H, m), 4.40-4.66 (1H, m), 6.76-6.91 (2H, m), 7.10— 7.24 (1H, m), 7.38—7.51 (1H, m), 7.60—7.76 (1H, m), 8.17—8.29 (1H, m), 8.70—8.78 (1H, m), 8.79—8.90 (1H, m), 8.91—9.23 (1H, m).
The compounds of the examples ed according to the above—mentioned method or a method analogous thereto are shown in the following tables. MS in the tables means those found.
Table l zy1hydroxypiperidin—1— yl)(5-methyl(pyridin—4- y1)pheny1)methanone (4—benzy1*4~hydroxypiperidin-l- y1)(3—methy1~5—(pyridin—4—y1)—1,2— oxazol—4—y1)methanone (4-hydroxy(pyridin~2- ylmethy1)piperidin-l-y1)(5-methyl— 2—(pyridin—4-yl)pheny1)methanone 4—((4-hydroxy(5-methyl (pyridinyl)benzoyl)piperidin y1)methyl)benzonitrile (4-hydroxyisopropylpiperidin methy1—2—(pyridin—4— y1)pheny1)methanone (4*benzyl—4—hydroxypiperidin-1' yl)(5-fluoro(pyridin-4— y1)pheny1)methanone (4-benzyl-4—hydroxypiperidin yl)(5-chloro-2~(Pyridin y1)pheny1)methanone (4-hydroxy-4—methy1piperidin-l- yl)(5-methy1-2—(Dyridin y1)pheny1)methanone 1.2 1 2012/076257 Table 2 EN 1 IUPAC Name Chemical Structure — (4—benzy1*4‘hydroxypiperidin y1)(5—(pyridin—4—y1)—1,3— 417.1 benzodioxol—4‘y1)methanone (4-benzy1hydroxypiperidin-l— methoxy(pyridin 403.2 yl)pheny1)methanone (4“benzylhydroxypiperidin*1~ // y1)(2—(pyridin—4— 373.2 y1)pheny1)methanone (4-benzy1—4-hydroxypiperidin yl)(4—methy1-2—(pYridin 387. 2 y1)pheny1)methanone (4-benzy1hydroxypiperidin—l- yl)(4*f1uoro—2—(pYridin 391. 3 yl)pheny1)methanone (4-benzy1hydroxypiperidin y1)(2-(pyrimidin—4— 374.2 y1)phenyl)methanone (4-benzylhydroxypiperidin—l- y1)(5—methy1—2—(pyrimidin—4— 388.2 yl)pheny1)methanone (4-benzy1—4~hydroxypiperidin yl)(5—methy1(DYIidin-4—yl)-1H— 377. 2 pyrazol—4—yl)methanone 1232 2012/076257 Table 3 (4—benzy1-4‘hydroxypiperidin-l— yl)(1,5—dimethy1—3—(pYridin‘4-y1)— lH-pyrazoly1)methanone (4-benzylhydroxypiperidin yl)(3-f1uoro-2—(pYridin—4- y1)phenyl)methanone (4-benzy1-4*hydroxypiperidin yl)(2-f1uoro-6—(pyridin-4— y1)phenyl)methanone (5-f1uoro-2—(pyridin—4— y1)pheny1)(4-hydroxy—4'(pyridin~2- ylmethyl)piperidin-l-y1)methanone (4—ethy1hydroxypiperidin-l- yl)(S'methyl-Z—(DYridin yl)pheny1)methanone roxypropylpiperidin-l- yl)(5-methy1—2”(pYridin-4— y1)phenyl)methanone (4-hydroxy-4—(pyridin-2— ylmethy1)piperidin—1*y1)(2- (pyridiny1)pheny1)methanone (4—hydroxy—4—(pyridin—2— ylmethyl)piperidin-l~y1)(5- (pyridiny1)-1,3-thiazol—4- y1)methanone 1213 Table 4 Example IUPAC Name No. _hem1calStructure (4*benzy1hydroxypiperidin—1- y1)(5—(pyridin—4—y1)—1,3—thiazol—4— hanone (4-benzylhydroxypiperidin—ly1 )(4—(pyridin—4—y1)—1,s—thiazol—s— y1)methanone zy1-4—hydroxypiperidin yl)(3-methy1-2—(DYridin-4— y1)phenyl)methanone (4—benzyl—4—hydroxypiperidin—1- yl)(2-(3-f1uoropyridin—4— y1)pheny1)methanone (2—(3-fluoropyridin-4—yl)phenyl)(4— hydroxy-4—(pyridin—2- ylmethyl)piperidin—l-y1)methanone (4—f1uoro—2—(pyridin—4— yl)phenyl)(4-hydroxy-4—(pYridin—2— ylmethyl)piperidin-l—yl)methanone (4-benzy1—4—hydroxypiperidin-l— y1)(2—methy1—5—(pyridin—4—y1)—1,3— thiazol~4~y1)methanone (4-benzy1hydroxypiperidin—1- yl)(lfimethy1~4‘(Pyridinyl)-1H— pyrazol-S-yl)methanone IL24 Table 5 IUPAC Name Chemical Structure ‘/ OH (4-hydroxy(DYridin-2— \ \N’N ylmethy1)piperidinyl)(1-methy1— N \\ 378.2 4"(pyridin~4—yl)~1H~pyrazol y1)methanone (4-hydroxy-4‘(pyridin ylmethyl)piperidin-1—yl)(2— (pyrimidin-4—yl)phenyl)methanone (4-hydroxy—4-(pYridin-2— ylmethy1)piperidin-1‘yl)(2—methy1- —(pyridin—4—y1)-1,3-thiazol y1)methanone (4*benzy1hydroxypiperidin—1- yl)(2—methyl-6‘(DYridin-4‘ ny1)methanone f1uorobenzy1)—4- hydroxypiperidin~1-y1)(5—methy1—2~ (pyridin—4—yl)pheny1)methanone (4-(4-f1uorobenzyl)-4— hydroxypiperidin-l-yl)(2-(pyridin- 4-yl)phenyl)methanone (4-(4,5-dihydro-1,3-thiazol-2— ylmethyl)hydroxypiperidin—1— yl)(5-methy1-2’(pyridin—4— y1)phenyl)methanone S'dihydr0‘1,3-thiazol ylmethyl)-4—hydroxypiperidin yl) (2~(pyridin—4— yl)phenyl)methanone 1253 Table 6 (4—benzy1hydroxypiperidin-1— y1)(5-(pYridinyl) (trifluoromethyl)—1H-pyrazol-4— y1)methanone (4—benzylhydroxypiperidin-l— yl)(1-tert-buty1-5—(DYridin-4—yl)- 3*(trifluoromethyl)—1H*pyrazol hanone (4-benzylhydroxypiperidin*1— yl)(2-methy1(pyridiny1)-1,3- thiazol~5-y1)methanone (4-benzy1hydroxypiperidin-l- yl)(2,4’-bipyridiny1)methanone ((7-endo)benzy1hydroxyoxa- 9*azabicyclo[3.3.1]non~9-y1)(2- (pyridin—4-y1)pheny1)methanone (4-benzy1-4—hydroxypiperidin—1— f1uoro—2—(pyrimidin—4— yl)pheny1)methanone (4-(4-fluorobenzy1)—4- hydroxypiperidin-l—yl)(4-fluoro~2- (pyrimidin—4—y1)phenyl)methanone (4‘(4-f1uorobenzy1)-4— hydroxypiperidin-l-yl)(2- (pyrimidiny1)phenyl)methanone 1.2 6 Table 7 E 1 IUPAC Name Chemical Structure (4—(2-f1uorobenzy1)—4— hydroxypiperidin‘l-yl)(2—(Dyridin- 4-y1)pheny1)methanone (4“(3-f1uorobenzy1)-4— hydroxypiperidin—l—yl)(2—(pYridin— 4-yl)pheny1)methanone (4—(3—f1uorobenzyl)—4— hydroxypiperidin-l-yl)(2- (pyrimidin-4—y1)phenyl)methanone (4-(2—f1uorobenzyl)—4— hydroxypiperidin—l-yl)(2— (pyrimidin-4—yl)pheny1)methanone (4—benzy1hydroxypiperidin-l- yl)(4,5-dif1uoro~2“(p¥ridin‘4- y1)phenyl)methanone (4-benzy1-4—hydroxypiperidin-l- (pyrimidin-4—y1)pYridin-B— y1)methanone (4—benzy1—4—hydroxypiperidin-lyl )(4,5-dif1uoro-2—(pYrimidin—4— ny1)methan0ne (4,5—dif1uoro-2—(Pyrimidin*4— yl)pheny1)(4-hydroxy(pyridin ylmethyl)piperidin-l-y1)methanone 12'7 Table 8 E 1 IUPAC Name Chemi cal Structure — (4-benzyl—4—hydroxypiperidin-l- yl)(5-f1uoro—2—(pyrimidin*4- y1)pheny1)methanone (5—fluor0'2—(pyrimidin~4- yl)phenyl)(4-hydroxy—4’(Dyridin—2— ylmethyl)piperidin-l—y1)methanone (4-benzy1—4-methoxypiperidin-l- yl)(5-methy1*2—(pYridin y1)phenyl)methanone .(4-benzyl-4—hydroxypiperidiny1)(2—methy1—4—(pYIimidin—4—y1)—1,3-thiazolyl)methanone (4-hydroxy-4—(pyridin ylmethyl)piperidin—1-y1)(2-methy1- 4—(pyrimidin—4—y1)-1,3—thiazol y1)methanone (4-(4-fluorobenzy1) hydroxypiperidin-l-yl)(2-methy1 (pyrimidiny1)*1,3-thiazol—5- hanone (4-f1uoro(pyrimidin—4— y1)pheny1)(4-hydroxy—4—(pyridin yl)piperidin—l-yl)methanone 2,4’~bipyridinyl(4*(2- fluorobenzyl)~4-hydroxypiperidin y1)methanone 1.2 8 Table 9 Example IUPAC Name Chemical Structure lllllHHlllll 2,4’~bipyridiny1(4-(3-fluorobenzyl)-4—hydroxypiperidinyl)methanone 2,4’—bipyridin—3'yl(4-hydroxy-4~ (pyridin-Z-ylmethyl)piperidin-l- yl)methanone 2,4’-bipyridiny1(4—(4— fluorobenzyl)~4—hydroxypiperidin—l- y1)methanone 4-((4—hydroxy-1—(2—(pyrimidin-4— y1)benzoy1)piperidin-4~ yl)methy1)benzonitrile 4-((1—(4—f1uoro-2—(pyrimidin-4— yl)benzoyl)~4-hydroxypiperidin-4— y1)methyl)benzonitrile 4‘((1-(2,4"bipyridin onyl)”4-hydroxypiperidin-4— yl)methy1)benzonitrile 2-((1-(2,4’-bipyridin ylcarbonyl)—4—hydroxypiperidin hy1)benzonitrile 3-((1-(2,4’-bipyridin-3— ylcarbonyl)hydroxypiperidin y1)methy1)benzonitrile 3.2 9 Table 10 Exam 1e IUPAC Name Chem cal, Structure 4-((4-hydroxy—1—((2-methyl-4— \I:::L\/+:::j S’§( (pyrimidin—4—y1)—1,3—thiaz01~5— N " 420.1 y1)carbony1)piperidin—4— y1)methy1)benzonitrile 2-((1-(4-f1uoro-2~(pyrimidin—4- yl)benzoyl)-4—hydroxypiperidin-4— 417.2 yl)methy1)benzonitrile 3~((1-(4-f1uoro-2—(pyrimidin—4— yl)benzoyl)-4*hydroxypiperidin“4— 417.1 y1)methy1)benzonitrile (4-benzy1‘4—hydroxypiperidin-l- Y1)(3-(pyridin—4-y1)pyrazin 375.2 yl)methanone 2*((1—(5-f1uor0‘2-(pyrimidin yl)benzoyl)-4—hydroxypiperidin‘4— yl)methy1)benzonitrile (5-f1uoro-2—(pYrimidin-4— yl)benzoyl)~4—hydroxypiperidin-4— yl)methy1)benzonitrile (5-f1uoro—2—(DYrimidin yl)benzoyl)—4-hydroxypiperidin—4— y1)methy1)benzonitrile (4-(4-fluorobenzyl)~4- hydroxypiperidin-l-yl)(5-f1uoro—2- (pyrimidin-4—y1)pheny1)methanone 1.30 Table 11 Example IUPAC Name Chemlcal. Structure (4-(4-f1uorobenzyl)-4* hydroxypiperidinvl-yl)(3-(pyridin- 4-y1)pyrazin—Z—y1)methanone (4-benzyl-4—hydroxypiperidin—l- y1)(2-(1,3-oxazol y1)pheny1)methanone (4-benzyl-4—hydroxypiperidin yl)(4-(1-methyl-1H-pyrazol—4— yl)PYridin-S-y1)methanone (4-benzy1“4‘hydroxypiperidin yl)(3,4’—bipyridin-3’-yl)methanone (4-benzy1hydroxypiperidin‘l- y1)(2—(DYridazin—4- y1)pheny1)methanone ipyridinyl(4—(3,4- difluorobenzyl)-4*hydroxypiperidin- 1-y1)methanone 2,4’-bipyridin—3-y1(4-(2,4- difluorobenzyl)—4~hydroxypiperidin- 1-y1)methanone (4-(3,4—dif1uorobenzy1) hydroxypiperidin-l-yl)(2-methy1 idin—4—y1)-1,3-thiaz01"5— y1)methanone 1.31 WO 54822 Table 12 E 1 IUPAC Name Chemical Structure (4-(2,4-dif1uorobenzy1)-4— hydroxypiperidin-l-yl)(2-methy1 (pyrimidin~4—y1)~1,3-thiazol-5~ y1)methanone (4—(2,3—difluorobenzy1) hydroxypiperidin-l-yl)(2-methyl (pyrimidinyl)-1,3-thiazol—5— y1)methanone 4—((4—hydroxy—1—((2—(pyrimidin—4— y1)pyridinyl)carbonyl)piperidin* 4~yl)methyl)benzonitrile f1uorobenzy1) hydroxypiperidin—l—yl)(2- (pyrimidin—4-yl)pYridin y1)methanone 2,4’-bipyridin-3—y1(4—(2,3- difluorobenzyl)hydroxypiperidin- 1—y1)methanone 4-((4—hydroxy-1—(2—(pyridin-4— zoy1)piperidin*4— y1)methyl)benzonitrile 4—((1-(5-f1uoro(pyridin—4- y1)benzoy1)hydroxypiperidin—4- y1)methyl)benzonitrile 4-((1—(4—f1uoro-27(pyridin-4— yl)benzoyl)~4‘hydroxypiperidin yl)methy1)benzonitri1e 1.32 Table 13 EN01 IUPAC Name Chemical Structure — 2,4’—bipyridin-3‘y1(4-hydroxy-4—(4* methoxybenzyl)piperidin-1~ y1)methanone 2,4’—bipyridiny1(4-hydroxy(4— (trifluoromethoxy)benzy1)piperidin— 1-y1)methanone (4-(4-fluorobenzy1)-4~ hydroxypiperidin*1—yl)(1-methy1—4— iny1)"IH-pyrazol—S- y1)methanone Table 14 IUPAC Name Chemical Structure (4-(4-f1uorobenzy1) hydroxypiperidin-l—yl)(2-(1,3— oxazol-S-yl)pheny1)methanone 4-dif1uorobenzyl) hydroxypiperidin—l—yl)(2-(1,3— oxazol-S-y1)pheny1)methanone (4-(2,4-dif1uorobenzy1)-4— hydroxypiperidin-l—yl)(2~(1,3— oxazol—S-yl)pheny1)methanone 4-((4-hydroxy(2—(1,3-oxazol yl)benzoy1)piperidin—4- yl)methy1)benzonitrile (4—hydroxy-4—(pyridin ylmethy1)piperidin—1~y1)(2—(1,3— oxazol-5~y1)pheny1)methanone (4-(2,4-difluorobenzyl)—4— hydroxypiperidin-l-yl)(2- (pyrimidin~4—yl)pYridin-S- yl)methanone (4-(3,4-dif1uorobenzy1) hydroxypiperidin-l-yl)(2- idin—4—y1)pyridin—B- y1)methanone 1.34 WO 54822 Formulation Example 1 (production of capsule) 1) compound of Example 1 30 mg 2) finely divided powder cellulose 10 mg 3) lactose 19 mg 4) magnesium stearate 1 mg Total 60 mg 1), 2), 3) and 4) are mixed and filled in a gelatin
[0296] Formulation Example 2 (production of tablet) 1) compound of Example 1 30 g 2) lactose 50 g 3) cornstarch 15 g 4) calcium carboxymethylcellulose 44 g ) magnesium stearate 1 g 1000 tablets total 140 g The total amount of 1), 2) and 3) and 4) (30 g) is d with water, vacuum dried, and sieved. The sieved powder is mixed with 4) (14 g) and 5) (1 g), and the mixture is punched by a tableting machine, whereby 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.
Experimental Example 1: Construction of human CH24H (CYP46) expression vector A plasmid DNA for expressing human CH24H in FreeStyle 293 cell was produced as follows. Using Full—Length Mammalian Gene Collection No.4819975 (Invitrogen) as a te, and the following two kinds of synthesis DNAs: ’—GCCCCGGAGCCATGAGCCCCGGGCTG-3’ (SEQ ID NO: 1) and CTGCCTGGAGGCCCCCTCAGCAG-3’ (SEQ ID NO: 2), PCR was performed to amplify 91—1625 bp region of human CH24H (BC022539). The obtained fragment was cloned using TOPO TA g Kit (Invitrogen). The obtained fragment was subcloned to pcDNA3.1(+) digested with BamHI and XhoI to give a d DNA (pcDNA3.l(+)/hCH24H) for human CH24H expression.
Experimental Example 2: Expression of human CH24H and preparation of human CH24H lysate The expression of human CH24H was performed using FreeStyle 293 Expression System (Invitrogen). According to the manual attached to FreeStyle 293 Expression System and using the plasmid DNA (pcDNA3.l(+)/hCH24H) for human CH24H expression constructed in mental e 1, a transient expression using FreeStyle 293—F cell was performed. After transfection, the cells were cultured with shaking at 37°C, 8% C02, 125 rpm for 2 days. The cells were collected by centrifugation, and suspended in a buffer for suspension (100 mM potassium phosphate (pH 7.4), 0.1 mM EDTA, 1 mM DTT, 20% Glycerol). The suspended product was disrupted by a on homogenizer (manufactured by Kinematica), and centrifuged at 9OOOXg for 10 min, and the supernatant was collected. The collected supernatant was eserved (—80°C) as a human CH24H lysate standard product.
Experimental Example 3: Measurement of CH24H inhibitory activity For the ement of CH24H inhibitory activity, using the human CH24H lysate prepared in Experimental Example 2, the amount of 24—HC produced from cholesterol by catalysis of CH24H was measured in the presence of a test compound, and the amount was compared with that in the absence of the test compound. That is, a test compound solution at various concentrations were mixed with a reaction buffer (50 mM potassium phosphate containing 0.1% BSA and te, EDTA— free protease inhibitor cocktail, pH 7.4) and human CH24H lysate. Then, [MC] cholesterol (53 mCi/mmol specific ty, uM) was added, and CH24H reaction was performed at 37°C for 5 hr. After completion of the reaction, a quenching solution consisting of chloroform/methanol/distillation water (2:2:1 v/V) was added, and the resulting 24-HC was extracted by shaking. The extract was applied to silica gel thin layer chromatography (ethyl acetate:toluene=4:6), and the obtained l4C-24HC fraction was measured with BASZSOO (Fujifilm Corporation).
The inhibitory rate (%) was ated from the ratio of radioactivity in the presence of a test compound relative to the radioactivity in the absence of the test compound. The s are shown in the following Tables 15 and 16.
Table 15 Test compound Inhibitory rate (%) at 1 uM Example 1 92 Example 2 90 Example 5 70 Example 30 Example 32 Example 34 Example 39 Example 41 Example 44 Example Example Example 58 Example Example 60 e 63 Example 67 Example 70 Example 82 Example 86 e 87 e 92 Example 97 Table 16 Test compound Inhibitory rate Example 102 89 Example 105 95 Experimental Example 4: Quantification test of 24—HC Animals used were 6—week—old female 6N mice (3 mice/group). A test nd was suspended in a 0.5% aqueous methylcellulose [133—14255 WAKO] solution (1 mg/mL). The body weight of the mice was measured, and the solution was forcibly administered orally and repeatedly once a day for 3 days. At 16 hours after the third stration, half of the brain was recovered, and the amount of 24—HC was measured.
The wet weight of the brain was measured, and the brain was homogenized with about 4-fold amount (0.5 mL) of saline.
This solution was used as a brain extract. 24—HC in the brain extract was extracted with an acetonitrile solution (98% acetonitrile, 1.98% methanol, 0.02% formic acid), and quantified by HPLC. The average value of 24—HC amount was calculated and the results are shown in relative values with the l group as 100%. The results are shown in the following Table 17.
Table 17 Test compound decrease rate (%) at 10 mg/kg e 14 67 Example 30 87 Example 44 55 Example 54 64 Example 92 Example 105 mental Example 5: Y—maze test using APP/P81 double transgenic mouse Animals used were 3—month—old female APP/P81 double transgenic mice (10—15 mice/group). A test compound was suspended in a 0.5% s methylcellulose [133—14255 WAKO] solution (1 mg/mL). The body weight of the mice was measured, and the solution was forcibly administered orally and repeatedly once a day for 14 days. At 16 hours after the 13th administration, spontaneous ation behavior in Y—maze test was evaluated. Using a particular arm of a Y—shaped test apparatus as the starting point, the frequency of moving to a different arm was counted for 5 min. The first two times of entry were excluded from the total number of entry. In addition, the mice that entered less than 10 times in total were excluded. Movement to an arm different from the arm into which the mouse entered last but one was considered an alternation or, and the ratio to the total number of moving was calculated as a spontaneous alternation behavior rate. As comparison subjects, a control group (test compound- non treatment group) and a control group in wild—type mice were used. The s are shown in the following Table 18.
Table 18 Spontaneous alternation behavior rate (%) Test wild—type mice APP/P81 double enic mouse compound control group control group 10 mg/kg Example 44 68 e 92 Industrial Applicability The nd of the present invention has a superior CH24H inhibitory action, which is useful as an agent for the prophylaxis or treatment of neurodegenerative disease (e.g., Alzheimer's disease, mild cognitive impairment, Huntington’s disease, Parkinson’s disease, amyotrophic l sclerosis, traumatic brain injury, cerebral infarction, glaucoma, le sclerosis and the like), epilepsy, schizophrenia and the like.
[0307] This application is based on patent application No. 2011— 22274l,filed in Japan, the contents of which are encompassed in full herein.

Claims (24)

1. A compound represented by the formula (I): 5 R1 is a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from (1) a C6-14 aryl group ally substituted by 1 to 3 substituents selected from (a) a halogen atom, 10 (b) a cyano group, and (c) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms (2) a 5- or 6-membered monocyclic aromatic cyclic group ally substituted by 1 to 3 substituents 15 selected from (a) a halogen atom, (b) a cyano group, and (c) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, and 20 (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, (b) a cyano group, and 25 (c) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms; R2 is a hydrogen atom or a C1-6 alkyl group; R3 is a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 halogen 30 atoms; ring A is a piperidine ring having no substituent other than R1, R2-O- and -C(=O)-ring B, or an oxaazabicyclo[3.3.1]nonane ring having no tuent other than R1, R2-O- and -C(=O)-ring B; and 5 ring B is a 5- or 6-membered aromatic ring wherein X and Y are ndently a carbon atom or a nitrogen atom, which is, in on to R3 and -C(=O)-ring A, optionally substituted by 1 to 3 substituents selected from (1) a halogen atom, 10 (2) a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (3) a C1-6 alkoxy group and (4) a C1-6 alkylenedioxy group, or a salt thereof.
2. The compound or salt of claim 1, wherein R3 is a group represented by C1 C2 N or wherein 20 ring C1 is an optionally substituted 6-membered nitrogencontaining ic heterocycle containing at least one nitrogen atom; and ring C2 is an optionally substituted 5-membered nitrogencontaining aromatic heterocycle containing at least one 25 nitrogen atom, each of which is optionally substituted by 1 to 3 halogen atoms.
3. The compound or salt of claim 1, wherein ring B is benzene, 30 thiazole, isoxazole, pyrazole, pyridine or pyrazine wherein X and Y are independently a carbon atom or a en atom,and n each ring B is, in addition to R3 and -C(=O)-ring A, optionally substituted by 1 to 3 substituents ed from (1) a halogen atom, (2) a C1-6 alkyl group optionally substituted by 1 to 3 5 halogen atoms, (3) a C1-6 alkoxy group, and (4) a C1-6 alkylenedioxy group.
4. The compound or salt of claim 1, wherein ring B is N N NH N HN N N N S N NH O S N 10 , each of which is, in addition to R3 and -C(=O)-ring A, optionally substituted by 1 to 3 tuents selected from (1) a halogen atom, (2) a C1-6 alkyl group optionally substituted by 1 to 3 15 halogen atoms, (3) a C1-6 alkoxy group, and (4) a C1-6 alkylenedioxy group.
5. The compound or salt of claim 1, wherein R2 is a hydrogen 20 atom.
6. (4-benzylhydroxypiperidinyl)(2,4'-bipyridin yl)methanone or a salt thereof. 25
7. 2,4'-bipyridinyl(4-(4-fluorobenzyl)hydroxypiperidin- 1-yl)methanone or a salt thereof.
8. 2,4'-bipyridinyl(4-(2,4-difluorobenzyl) hydroxypiperidinyl)methanone or a salt thereof.
9. (4-(4-fluorobenzyl)hydroxypiperidinyl)(2-(pyrimidin- 4-yl)pyridinyl)methanone or a salt f.
10. A ment comprising the compound or salt of claim 1.
11. The medicament of claim 10, which is a cholesterol 24- hydroxylase inhibitor.
12. The medicament of claim 10, which is an agent for the prophylaxis or treatment of neurodegenerative disease.
13. The medicament of claim 12, wherein the neurodegenerative 15 disease is Alzheimer’s disease, mild cognitive impairment, Huntington’s disease, Parkinson’s disease or multiple sclerosis.
14. The nd or salt of claim 1 for use in the prophylaxis 20 or treatment of egenerative disease.
15. The compound or salt of claim 14, wherein the neurodegenerative disease is Alzheimer’s e, mild cognitive impairment, Huntington’s disease, Parkinson’s 25 disease or multiple sclerosis.
16. Use of the compound or salt of claim 1 for the production of an agent for the prophylaxis or treatment of neurodegenerative disease.
17. Use of claim 16, n the neurodegenerative disease is selected from Alzheimer’s disease, mild cognitive ment, Huntington’s disease, Parkinson’s disease or multiple sclerosis.
18. A compound according to claim 1, substantially as herein bed with nce to any one of the examples. 5
19. The medicament according to claim 10, substantially as herein described with reference to any one of the examples.
20.(4-benzylhydroxypiperidinyl)(2,4'-bipyridin yl)methanone or a salt thereof according to claim 6, 10 substantially as herein described with reference to any one of the examples.
21. 2,4'-bipyridinyl(4-(4-fluorobenzyl)hydroxypiperidin- 1-yl)methanone or a salt thereof according to claim 7, 15 substantially as herein described with reference to any one of the examples.
22. 2,4'-bipyridinyl(4-(2,4-difluorobenzyl) hydroxypiperidinyl)methanone or a salt thereof according to 20 claim 8, substantially as herein described with reference to any one of the examples.
23. fluorobenzyl)hydroxypiperidinyl)(2-(pyrimidin- 4-yl)pyridinyl)methanone or a salt thereof according to 25 claim 9, substantially as herein described with reference to any one of the examples.
24. The use according to claim 16, substantially as herein described with reference to any one of the examples. PCT/JPZ'UIZ 076257
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