Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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
  • A61P25/28—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

Definitions

• the present invention relates to a pharmaceutical, more particularly, to a polycyclic imidazolylpyrazine derivative effective for the treatment of a neurodegenerative disease caused by amyloid- ⁇ (hereinafter referred to as A ⁇ ) such as Alzheimer's disease or Down's syndrome and a medicine, in particular, a medicine for the treatment of a disease caused by A ⁇ comprising the compound as an active ingredient.
• a ⁇ amyloid- ⁇
• Alzheimer's disease is a disease characterized by degeneration and loss of neurons as well as formation of senile plaques and neurofibrillary degeneration.
• a symptom improving agent typified by an acetylcholinesterase inhibitor
• a fundamental remedy to inhibit progression of the disease has not yet been developed. It is necessary to develop a method for controlling the cause of the onset of pathology in order to create a fundamental remedy for Alzheimer's disease.
• a ⁇ -proteins as metabolites of amyloid precursor proteins are highly involved in degeneration and loss of neurons and onset of symptoms of dementia (see NON-PATENT DOCUMENTS 1 and 2, for example).
• Main molecular species of A ⁇ -protein are A ⁇ 40 consisting of 40 amino acids and A ⁇ 42 with two amino acids added at the C-terminal.
• the A ⁇ 40 and A ⁇ 42 are known to have high aggregability (see NON-PATENT DOCUMENT 3, for example) and to be main components of senile plaques (see NON-PATENT DOCUMENTS 3, 4 and 5, for example).
• a ⁇ 40 and A ⁇ 42 are increased by mutation in APP and presenilin genes which is observed in familial Alzheimer's disease (see NON-PATENT DOCUMENTS 6, 7 and 8, for example). Accordingly, a compound that reduces the production of A ⁇ 40 and A ⁇ 42 is expected as a progression inhibitor or prophylactic agent for Alzheimer's disease.
• a ⁇ is produced by cleaving APP by ⁇ -secretase and subsequently by ⁇ -secretase.
• Nonpeptidic compounds are, for example, MRK-560 (see NON-PATENT DOCUMENTS 16 and 17) and compounds having a plurality of aromatic rings as disclosed in PATENT DOCUMENTS 1 and 2.
• the compound represented by the formula (VI) as disclosed in page 17 of the specification differs from the compound of the present invention in that the compound is limited to a compound having a 2-aminothiazolyl group as a main structure.
• the compound represented by the formula (I) as disclosed in page 6 of the specification of PATENT DOCUMENT 2 differs from the compound of the present invention in that the former compound does not have pyrazine ring in the partial structure defined as A ⁇ 2.
• PATENT DOCUMENT 1 WO 2004/110350
• PATENT DOCUMENT 2 WO 2007/102580
• NON-PATENT DOCUMENT 1 Klein WL, and seven others, Alzheimer's disease-affected brain:
• ADDLs oligomeric A ⁇ ligands
• NON-PATENT DOCUMENT 2 Nitsch RM, and sixteen others, Antibodies against ⁇ -amyloid slow cognitive decline in Alzheimer's disease, Neuron, 2003, May 22; 38, p. 547-554.
• NON-PATENT DOCUMENT 3 Jarrett JT, and two others, The carboxy terminus of the ⁇ amyloid PROTEIN is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimers 1 disease, Biochemistry, 1993, 32 (18), p. 4693-4697.
• NON-PATENT DOCUMENT 4 Glenner GG 1 and one other, Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochemical and Biophysical Research Communications, 1984, May 16, 120 (3), p. 885-890.
• NON-PATENT DOCUMENT 5 Masters CL, and five others, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proceeding of the National Academy of Science USA, 1985, Jun, 82 (12), p. 4245-4249.
• NON-PATENT DOCUMENT 6 Gouras GK, and eleven others, Intraneural A ⁇ 42 accumulation in human brain, American Journal of Pathology, 2000, Jan, 156 (1), p. 15-20.
• NON-PATENT DOCUMENT 7 Scheuner D, and twenty others, Secreted amyloid ⁇ -protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nature Medicine, 1996, Aug, 2 (8), p. 864-870.
• NON-PATENT DOCUMENT 8 Forman MS, and four others, Differential effects of the Swedish mutant amyloid precursor protein on ⁇ -amyloid accumulation and secretion in neurons and nonneuronal cells, The Journal of Biological Chemistry, 1997, Dec, 19, 272 (51), p. 32247- 32253.
• NON-PATENT DOCUMENT 9 Shearman MS, and nine others, L-685, 458, an Aspartyl Protease Transition State Mimic, Is a Potent Inhibitor of Amyloid ⁇ -Protein Precursor ⁇ - Secretase Activity, Biochemistry, 2000, Aug, 1 , 39 (30), p. 8698-8704.
• NON-PATENT DOCUMENT 10 Shearman MS, and six others, Catalytic Site-Directed ⁇ - Secretase Complex Inhibitors Do Not Discriminate Pharmacologically between Notch S3 and ⁇ - APP Clevages, Biochemistry, 2003, Jun, 24, 42 (24), p. 7580-7586.
• NON-PATENT DOCUMENT 11 Lanz TA, and three others, Studies of A ⁇ pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the ⁇ - secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-Nl-[(7S)-5-methyl-6- oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575), The Journal of Pharmacology and Experimental Therapeutics, 2004, Apr, 309 (1), p. 49-55.
• NON-PATENT DOCUMENT 12 Wong GT, and twelve others, Chronic treatment with the ⁇ - secretase inhibitor LY-411, 575 inhibits ⁇ -amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation, The Journal of Biological Chemistry, 2004, Mar, 26, 279 (13), p. 12876-12882.
• NON-PATENT DOCUMENT 13 Gitter BD, and ten others, Stereoselective inhibition of amyloid beta peptide secretion by LY450139, a novel functional gamma secretase inhibitor, Neurology of Aging 2004, 25, sup2, p. 571.
• NON-PATENT DOCUMENT 14 Lanz TA, and eighteen others, Concentration-dependent modulation of amyloid- ⁇ in vivo and in vitro using the ⁇ -secretase inhibitor, LY-450139, The Journal of Pharmacology and Experimantal Therapeutics, 2006, Nov, 319 (2) p. 924-933.
• NON-PATENT DOCUMENT 15 Siemers ER, and thirteen others, Effects of a ⁇ -secretase inhibitor in a randamized study of patients with Alzheimer disease, Neurology, 2006, 66, p. 602- 604.
• NON-PATENT DOCUMENT 16 Best JD, and nine others, In vivo characterization of A ⁇ (40) changes in brain and cerebrospinal fluid using the novel ⁇ -secretase inhibitor N-[cis-4-[(4- chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]- 1 ,1,1 -trifiuoromethanesulphonlamide (MK-560) in the rat, The Journal of Pharmacology and Experimental Therapeutics, 2006, May 317 (2) p. 786-790.
• NON-PATENT DOCUMENT 17 Best JD, and thirteen others
• the novel ⁇ -secretase inhibitor N- [cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]- 1 ,1,1- trifluoromethanesulphonlamide (MK-560) reduces amylid plaque deposition without evidence notch-related pathology in the Tg2576 mouse, The Journal of Pharmacology and Experimental Therapeutics, 2007, Feb, 320 (2) p. 552-558.
• a compound that inhibits the production of A ⁇ 40 and A ⁇ 42 from APP has been expected as a therapeutic or prophylactic agent for a disease caused by A ⁇ which is typified by Alzheimer's disease.
• a nonpeptidic compound having high efficacy which inhibits the production of A ⁇ 40 and A ⁇ 42 has not yet been known.
• the present invention relates to the following 1) to 20):
• Rj and R 2 are the same or different and each represent a substituent selected from the following Substituent Group al ; m represents an integer of 0 to 3; n represents an integer of 0 to 2; X 1 represents i) a single bond, ii) [0010]
• X 2 represents i) a single bond, ii) a Cl -6 alkylene group or iii) -X 3 - (wherein X 3 represents -NR 5 - , -O-, -C(O)-, -S-, -S(O)- or -S(O) 2 - and R 5 represents a hydrogen atom, a C 1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkanoyl group or a C 1-6 alkylsulfonyl group);
• Ring A represents i) a f ⁇ ve-membered aromatic heterocyclic group or ii) a five-membered aromatic heterocyclic group fused with a 5- to 14-membered non-aromatic ring group, which contains two or more nitrogen atoms and may have 1 to 3 substituents selected from the following Substituent Group bl (wherein the non-aromatic ring group may have a crosslinked structure or a spiro ring system); and
• Ring B represents a monocyclic or fused cyclic aromatic ring group selected from the group consisting of the formulas [2] to [19]: [0012]
• each of which may have 1 to 3 substituents selected from the following Substituent Group cl, Substituent Group al: a Cl-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a Cl-6 alkoxy group, a C2-6 alkenyloxy group, a C3-8 cycloalkyloxy group, an amino group (wherein the amino group may have one C2-6 alkanoyl group or Cl-6 alkylsulfonyl group or 1 to 2 Cl-6 alkyl groups or C3-8 cycloalkyl groups), a cyano group, a formyl group, a halogen atom, a hydroxyl group and a nitro group;
• Substituent Group bl a Cl-6 alkyl group (wherein the alkyl group may be substituted with 1 to 3 halogen atoms), a C2-6 alkenyl group, a C3-8
• Substituent Group cl i) an amino group (wherein the amino group may have one C2-6 alkanoyl group, Cl-6 alkylsulfonyl group or C3-8 cycloalkylsulfonyl group or 1 to 2 Cl-6 alkyl groups or C3-8 cycloalkyl groups), ii) a cyano group, iii) a halogen atom, iv) a hydroxyl group and v) v)-i) a Cl-6 alkyl group, v)-ii) a C2-6 alkenyl group, v)-iii) a C2-6 alkynyl group, v)-iv) a Cl-6 alkoxy group, v)-v) a Cl-6 alkylthio group, v)-vi) a Cl-6 alkylaminocarbonyl group, v)-vii) a C 1-6 alkylsulfonyl group, v)
• Ring A is a rive-membered aromatic heterocyclic group selected from the group consisting of the formulas [20] to [26]: [0014]
• A* represents a bonding site to X 2 , or any one ring selected from the group consisting of the formulas [28] to [39]: [0018]
• [0021] represents a single bond or a double bond, each of which may have 1 to 3 substituents selected from Substituent Group bl; 3) The compound or pharmacologically acceptable salt or ester thereof according to
• Ring A is any one ring selected from the group consisting of the formulas [21], [28], [29], [31], [32] and [34] to [37]: [0022]
• Ring A is any one ring selected from the group consisting of the formulas [21],
• Ring A is a ring of the formula [28-1]: [0029]
• Ring B is a phenyl group, a pyridyl group, an oxazolyl group, an imidazolyl group, a thiazolyl group, a dihydrobenzofuranyl group or a thienyl group; 7) The compound or pharmacologically acceptable salt or ester thereof according to
• R 2 is a Cl-6 alkoxy group and n is 1;
• R 3 and R 4 are the same or different and are each (1) a hydrogen atom or (2) a halogen atom; 15)
• R 3 and R 4 are each a hydrogen atom
• the substituent for Ring A is a substituent selected from the group consisting of: a Cl-6 alkyl group (wherein the alkyl group may be substituted with 1 to 3 halogen atoms), a C3-8 cycloalkyl group, a C6-14 aryl group, a C6-14 aryl-Cl-6 alkyl group, a Cl-6 alkoxy group, a C3- 8 cycloalkyloxy group, a C2-6 alkanoyl group, a C7-15 aroyl group, a Cl-6 alkylsulfonyl group, a C3-8 cycloalkylsulfonyl group, a C6-14 arylsulfonyl group, a cyano group, a formyl group, a halogen atom, a hydroxyl group and an oxo group; 17) The compound or pharmacologically acceptable salt or ester thereof according to 1), wherein the substituent for Ring B
• a medicine comprising the compound or pharmacologically acceptable salt or ester thereof according to any one of 1) to 18) above as an active ingredient; and 20) The medicine according to 19) above for the treatment of a disease selected from
• Alzheimer's disease dementia, Down's syndrome and amyloidosis.
• a ⁇ according to the present invention are novel inventions that have not yet been described in any documents.
• the compound of the present invention can be converted to a chemical probe for capturing a target protein in a bioactive low-molecular compound.
• the compound of the present invention can be converted to an affinity chromatography probe, a photoaffinity probe or the like by introducing a labeling group, a linker or the like into a moiety differing from a structural moiety essential for expression of activity of the compound by a technique described in J. Mass Spectrum. Soc. Jpn. Vol. 51, No. 5, 2003, p. 492-498 or WO 2007/139149, for example.
• Examples of the labeling group, the linker or the like used for the chemical probe include groups shown in the following group consisting of (1) to (5):
• protein labeling groups such as photoaffinity labeling groups (such as a benzoyl group, a benzophenone group, an azido group, a carbonylazido group, a diaziridine group, an enone group, a diazo group and a nitro group) and chemical affinity groups (such as a ketone group substituted at the ⁇ -carbon atom with a halogen atom, a carbamoyl group, an ester group, an alkylthio group, Michael acceptors such as ⁇ , ⁇ -unsaturated ketones and esters, and an oxirane group),
• photoaffinity labeling groups such as a benzoyl group, a benzophenone group, an azido group, a carbonylazido group, a diaziridine group, an enone group, a diazo group and a nitro group
• chemical affinity groups such as a ketone group substituted at the ⁇ -carbon atom with a halogen
• cleavable linkers such as -S-S-, -0-Si-O-, monosaccharides (such as a glucose group and a galactose group) and disaccharides (such as lactose), and enzymatically cleavable oligopeptide linkers,
• fishing tag groups such as biotin and 3-(4,4-difluoro-5,7-dimethyl-4H-3a,4a- diaza-4-bora-s-indacen-3-yl)propionyl,
• detectable markers such as radioactive labeling groups such as 125 1, 32 P, 3 H and 14 C; fluorescence labeling groups such as fluorescein, rhodamine, dansyl, umbelliferone, 7- mtrofurazanyl and 3-(4,4-difluoro-5,7-dimethyl-4H-3a,4a-diaza-4-bora-s-indacen-3- yl)propionyl; chemiluminescent groups such as luciferin and luminol; and heavy metal ions such as lanthanoid metal ions and radium ions, and (5) groups bound to solid-phase carriers such as glass beads, glass beds, microtiter plates, agarose beads, agarose beds, polystyrene beads, polystyrene beds, nylon beads and nylon beds.
• radioactive labeling groups such as 125 1, 32 P, 3 H and 14 C
• fluorescence labeling groups such as fluorescein, rhodamine
• the probe When a probe is prepared by introducing a labeling group or the like selected from the group consisting of (1) to (5) above into the compound of the present invention in accordance with a method described in the above documents or the like, the probe can be used as a chemical probe for identification of labeled proteins useful for searching for novel drug targets, for example.
• a structural formula of a compound may represent a certain isomer for convenience.
• the present invention includes all isomers and isomer mixtures such as geometric isomers which can be generated from the structure of a compound, optical isomers based on asymmetric carbon, stereoisomers and tautomers.
• the present invention is not limited to the description of a chemical formula for convenience and may include any one of the isomers or mixtures thereof.
• the compound of the present invention may have an asymmetric carbon atom in the molecule and exist as an optically active compound or racemate, and the present invention includes each of the optically active compound and the racemate without limitations.
• crystal polymorphs of the compound may be present, the compound is not limited thereto as well and may be present as a single crystal form or a mixture of single crystal forms.
• the compound may be an anhydride or hydrate.
• the present invention also includes isotopically-labelled compounds, which are identical to the compounds of formula (I), except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number uusually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 123 I and 125 I.
• Compounds of the present invention and pharmaceutically acceptable derivatives e.g.
• Isotopically— labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and/or 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. 3 H and 14 C are considered useful due to their ease of preparation and detectability. 11 C and 18 F isotopes are considered useful in PET (positron emission tomography), and 125 I isotopes are considered useful in SPECT (single photon emission computerized tomography), all useful in brain imaging.
• Isotopically labelled compounds of formula (I) of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
• Alzheimer's disease includes a wide variety of conditions such as Alzheimer's disease (for example, refer to, Klein WL, and 7 others, Alzheimer's disease- affected brain: Presence of oligomeric A ⁇ ligands (ADDLs) suggests a molecular basis for reversible memory loss, Proceeding National Academy of Science USA, 2003, Sep 2, 100 (18), p. 10417-10422; Nitsch RM, and 16 others, Antibodies against ⁇ -amyloid slow cognitive decline in Alzheimer's disease, Neuron, 2003, May 22, 38 (4), p.
• ADDLs oligomeric A ⁇ ligands
• senile dementia for example, refer to, Blass JP, Brain metabolism and brain disease: Is metabolic deficiency the proximate cause of Alzheimer dementia? Journal of Neuroscience Research, 2001, Dec 1, 66 (5), p. 851-856
• frontotemporal dementia for example, refer to, Evin G, and 11 others, Alternative transcripts of presenilin-1 associated with frontotemporal dementia, Neuroreport, 2002, Apr 16, 13 (5), p. 719- 723
• Pick disease for example, refer to, Yasuhara O, and 3 others, Accumulation of amyloid precursor protein in brain lesions of patients with Pick disease, Neuroscience Letters, 1994, Apr 25, 171 (1-2), p.
• Down's syndrome for example, refer to, Teller JK, and 10 others, Presence of soluble amyloid ⁇ -peptide precedes amyloid plaque formation in Down's syndrome, Nature Medicine, 1996, Jan, 2 (1), p. 93-95; Tokuda T, and 6 others, Plasma levels of amyloid ⁇ proteins A ⁇ 1-40 and A ⁇ 1-42 (43) are elevated in Down's syndrome, Annals of Neurology, 1997, Feb, 41 (2), p. 271-273), cerebrovascular angiopathy (for example, refer to, Hayashi Y, and 9 others, Evidence for presenilin-1 involvement in amyloid angiopathy in the Alzheimer's disease- affected brain, Brain Research, 1998, Apr 13, 789 (2), p. 307-314; Barelli H, and 15 others,
• Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's Disease due to a novel presenilin-1 mutation, Brain, 2001, Dec, 124 (12), p. 2383-2392), hereditary cerebral hemorrhage with amyloidosis (Dutch type) (for example, refer to, Cras P, and 9 others, Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692AIa --> GIy mutation, Acta Neuropathology (Berl), 1998, Sep, 96 (3), p.
• Dutch type hereditary cerebral hemorrhage with amyloidosis
• cognitive impairment for example, refer to, Laws SM, and 7 others, Association between the presenilin-1 mutation Glu318Gly and complaints of memory impairment, Neurobiology of Aging, 2002, Jan-Feb, 23 (1), p. 55-58
• memory disturbance/learning disturbance for example, refer to, Vaucher E, and 5 others, Object recognition memory and cholinergic parameters in mice expressing human presenilin 1 transgenes, Experimental Neurology, 2002 Jun, 175 (2), p. 398-406; Morgan D, and 14 others, A ⁇ peptide vaccination prevents memory loss in an animal model of Alzheimer's disease, Nature, 2000 Dec 21-28, 408 (6815), p.
• cerebrovascular dementia for example, refer to, Sadowski M, and 6 others, Links between the pathology of Alzheimer's disease and vascular dementia, Neurochemical Research, 2004, Jun, 29 (6), p. 1257-1266
• ophthalmoplegia for example, refer to, O'Riordan S, and 7 others
• Presenilin- 1 mutation E280G
• spastic paraparesis and cranial MRI white-matter abnormalities
• multiple sclerosis for example, refer to, Gehrmann J, and 4 others, Amyloid precursor protein (APP) expression in multiple sclerosis lesions, GHa, 1995, Oct, 15 (2), p. 141-51; Reynolds WF, and 6 others, Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer's disease, Experimental Neurology, 1999, Jan, 155 (1), p. 31-41), head injury, skull damage (for example, refer to, Smith DH, and 4 others, Protein accumulation in traumatic brain injury,
• APP Amyloid precursor protein
• apraxia for example, refer to, Matsubara- Tsutsui M, and 7 others, Molecular evidence of presenilin 1 mutation in familial early onset dementia, American journal of Medical Genetics, 2002, Apr 8, 114 (3), p. 292-298
• prion disease familial amyloid neuropathy, triplet repeat disease (for example, refer to, Kirkitadze MD, and 2 others, Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies, Journal of Neuroscience Research, 2002, Sep 1, 69 (5), p.
• Amyloid- ⁇ deposition in the cerebral cortex in Dementia with Lewy bodies is accompanied by a relative increase in A ⁇ PP mRNA isoforms containing the Kunitz protease inhibitor, Neurochemistry International, 2005, Feb, 46 (3), p. 253-260; Primavera J, and 4 others, Brain accumulation of amyloid- ⁇ in Non- Alzheimer Neurodegeneration, Journal of Alzheimer's Disease, 1999, Oct, 1 (3), p.
• Parkinsonism-dementia complex for example, refer to, Schmidt ML, and 6 others, Amyloid plaques in Guam amyotrophic lateral sclerosis/ parkinsonism-dementia complex contain species of A ⁇ similar to those found in the amyloid plaques of Alzheimer's disease and pathological aging, Acta Neuropathologica (Berl), 1998, Feb, 95 (2), p. 117-122; Ito H, and 3 others, Demonstration of ⁇ amyloid protein- containing neurofibrillary tangles in parkinsonism-dementia complex on Guam, Neuropathology and applied neurobiology, 1991, Oct, 17 (5), p.
• frontotemporal dementia and Parkinsonism linked to chromosome 17 for example, refer to, Rosso SM, and 3 others, Coexistent tau andamyloid pathology in hereditary frontotemporal dementia with tau mutations, Annals of the New York academy of sciences, 2000, 920, p. 115-119
• Dementia with argyrophilic grains for example, refer to, Tolnay M, and 4 others, Low amyloid (A ⁇ ) plaque load and relative predominance of diffuse plaques distinguish argyrophilic grain disease from Alzheimer's disease, Neuropathology and applied neurobiology, 1999, Aug, 25 (4), p.
• Niemann-Pick disease for example, refer to, Jin LW, and 3 others, Intracellular accumulation of amyloidogenic fragments of amyloid- ⁇ precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities, American Journal of Pathology, 2004, Mar, 164 (3), p. 975-985
• amyotrophic lateral sclerosis for example, refer to, Sasaki S, and another, Immunoreactivity of ⁇ -amyloid precursor protein in amyotrophic lateral sclerosis, Acta Neuropathologica (Berl), 1999, May, 97 (5), p.
• hydrocephalus for example, refer to, Weller RO, Pathology of cerebrospinal fluid and interstitial fluid of the CNS: Significance for Alzheimer's disease, prion disorders and multiple sclerosis, Journal of Neuropathology and Experimental Neurology, 1998, Oct, 57 (10), p. 885-894; Silverberg GD, and 4 others, Alzheimer's disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis, Lancet neurology, 2003, Aug, 2 (8), p.
• Cerebral amyloid angiopathy Accumulation of A ⁇ in interstitial fluid drainage pathways in Alzheimer's disease, Annals of the New York academy of sciences, 2000, Apr, 903, p. 110-117; Yow HY, and another, A role for cerebrovascular disease in determining the pattern of ⁇ -amyloid deposition in Alzheimer's disease, Neurology and applied neurobiology, 2002, 28, p. 149; Weller RO, and 4 others, Cerebrovascular disease is a major factor in the failure of elimination of A ⁇ from the aging human brain, Annals of the New York academy of sciences, 2002, Nov, 977, p.
• paraparesis for example, refer to, O'Riordan S, and 7 others, Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities, Neurology, 2002, Oct 8, 59 (7), p. 1108-1110; Matsubara-Tsutsui M, and 7 others, Molecular evidence of presenilin 1 mutation in familial early onset dementia, American journal of Medical Genetics, 2002, Apr 8, 114 (3), p. 292-298; Smith MJ, and 11 others, Variable phenotype of Alzheimer's disease with spastic paraparesis, Annals of Neurology, 2001, 49 (1), p.
• spasm for example, refer to, Singleton AB, and 13 others, Pathology of early-onset Alzheimer's disease cases bearing the Thrll3-114ins presenilin-1 mutation, Brain, 2000, Dec, 123 (Ptl2), p. 2467-2474
• mild cognitive impairment for example, refer to, Gattaz WF, and 4 others, Platelet phospholipase A2 activity in Alzheimer's disease and mild cognitive impairment, Journal of Neural Transmission, 2004, May, 111 (5), p. 591-601; Assini A, and M others, Plasma levels of amyloid ⁇ -protein 42 are increased in women with mild cognitive impariment, Neurology, 2004, Sep 14, 63 (5), p.
• arteriosclerosis for example, refer to, De Meyer GR, and 8 others, Platelet phagocytosis and processing of ⁇ -amyloid precursor protein as a mechanism of macrophage activation in atherosclerosis, Circulation Reserach, 2002, Jun 14, 90 (11), p. 1197-1204).
• Ri and R 2 are the same or different and each represent a substituent selected from the following Substituent Group al . [0041]
• the "Substituent Group al” refers to a group consisting of a C 1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C 1-6 alkoxy group, a C2-6 alkenyloxy group, a C3-8 cycloalkyloxy group, an amino group (wherein the amino group may have one C2-6 acyl group or C 1-6 alkylsulfonyl group or 1 to 2 C 1-6 alkyl groups or C3-8 cycloalkyl groups), a cyano group, a formyl group, a halogen atom, a hydroxyl group and a nitro group.
• a Cl-6 alkyl group, a C3-8 cycloalkyl group, a halogen atom, a Cl-6 alkoxy group and a C3-8 cycloalkyloxy group are preferable, and a Cl-6 alkyl group, a halogen atom and a Cl-6 alkoxy group are particularly preferable.
• m represents an integer of 0 to 3 and is preferably 0 to 2, and particularly preferably 1 to 2.
• n represents an integer of 0 to 2 and is preferably 0 to 1, and particularly preferably 1.
• Xi represents i) a single bond, ii) [0045]
• X 2 represents i) a single bond, ii) a Cl-6 alkylene group or iii) -X 3 - (wherein X 3 represents -NR5-
• R 5 represents a hydrogen atom, a Cl-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkanoyl group or a Cl-6 alkylsulfonyl group), and is preferably i) a single bond or ii)
• Ring A represents i) a five-membered aromatic heterocyclic group or ii) a five- membered aromatic heterocyclic group fused with a 5- to 14-membered non-aromatic ring group, which contains two or more nitrogen atoms and may have 1 to 3 substituents selected from the following Substituent Group bl (wherein the non-aromatic ring group may have a crosslinked structure or a spiro ring system).
• the "five-membered aromatic heterocyclic group” is not particularly limited insofar as it is a five-membered aromatic heterocyclic group containing two or more nitrogen atoms.
• the group preferably refers to a five-membered aromatic heterocyclic group selected from the group consisting of the formulas [20] to [26]:
• A* represents a bonding site to X 2 , and more preferably refers to a ring of the formula [21]: [0053]
• the group may have 1 to 3 substituents selected from the following Substituent Group bl. [0055]
• the "f ⁇ ve-membered aromatic heterocyclic group fused with a 5- to 14-membered non-aromatic ring group (wherein the non-aromatic ring group may have a crosslinked structure or a spiro ring system)" is not particularly limited insofar as it is a five-membered aromatic heterocyclic group fused with a 5- to 14-membered non-aromatic ring group which contains two or more nitrogen atoms (wherein non-aromatic ring group may have a crosslinked structure or a spiro ring system).
• the group is preferably any one ring selected from the group consisting of the formulas [28] to [39]: [0056]
• [0063] are as defined above, and particularly preferably a ring selected from the group consisting of the formula [28-1]: [0064]
• the group may have 1 to 3 substituents selected from the following Substituent Group bl.
• the phrase "may have a crosslinked structure or a spiro ring system” refers to the fact that two carbon atoms on the non-aromatic ring group together may form a crosslinked structure, or the fact that a carbon atom on the non-aromatic ring group may form a spiro ring system.
• the "Substituent Group bl” refers to a group consisting of a Cl -6 alkyl group
• alkyl group may be substituted with 1 to 3 halogen atoms
• a C2-6 alkenyl group a C3-8 cycloalkyl group, a C6-14 aryl group, a C6-14 aryl-Cl-6 alkyl group, a Cl -6 alkoxy group, a C2-6 alkenyloxy group, a C3-8 cycloalkyloxy group, a C2-6 alkanoyl group, a C4-9 cycloalkylcarbonyl group, a C7-15 aroyl group, a C 1-6 alkylsulfonyl group, a C2-6 alkenylsulfonyl group, a C3-8 cycloalkylsulfonyl group, a C6-14 arylsulfonyl group, a C 1-6 alkylthio group, a C2-6 alkenylthio group, a C3-8 cycloalkylthio group,
• a substituent selected from the group consisting of a C 1-6 alkyl group (wherein the alkyl group may be substituted with 1 to 3 halogen atoms), a C3-8 cycloalkyl group, a C6-14 aryl group, a C6-14 aryl-Cl-6 alkyl group, a C 1-6 alkoxy group, a C3-8 cycloalkyloxy group, a C2-6 alkanoyl group, a C7-15 aroyl group, a C 1-6 alkylsulfonyl group, a C3-8 cycloalkylsulfonyl group, a C6-14 arylsulfonyl group, a cyano group, a formyl group, a halogen atom, a hydroxyl group and an oxo group.
• Ring B represents, for example, a monocyclic or fused cyclic aromatic ring group selected from the group consisting of the formulas [2] to [19]: [0070]
• Ring B is preferably a phenyl group, a pyridyl group, an oxazolyl group, an imidazolyl group, a thiazolyl group, a dihydrobenzofuranyl group or a thienyl group, and particularly preferably a phenyl group or a pyridyl group.
• Ring B may have 1 to 3 substituents selected from the following Substituent Group cl.
• Substituent Group cl refers to a group consisting of i) an amino group (wherein the amino group may have one C2-6 alkanoyl group, C 1-6 alkylsulfonyl group or C3-8 cycloalkylsulfonyl group or 1 to 2 C 1-6 alkyl groups or C3-8 cycloalkyl groups), ii) a cyano group, iii) a halogen atom, iv) a hydroxyl group and v) v)-i) a C 1-6 alkyl group, v)-ii) a C2-6 alkenyl group, v)-iii) a C2-6 alkynyl group, v)-iv) a Cl -6 alkoxy group, v)-v) a C 1-6 alkylthio group, v)-vi) a C 1-6 alkylaminocarbonyl group, v)-vii) a
• Particularly preferable is a substituent selected from the group consisting of i) a halogen atom and ii) ii)-i) a Cl -6 alkyl group and Ii)-Il) a C 1-6 alkoxy group, each of which may have 1 to 3 substituents selected from the group consisting of a Cl -6 alkyl group and a halogen atom.
• C 1-6 alkyl group refers to an alkyl group having 1 to 6 carbon atoms.
• Preferable examples of the group include linear or branched alkyl groups such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tertiary butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, an n-hexyl group, a 1-methylpropyl group, an 1,2-dimethylpropyl group, a 1-ethylpropyl group, a l-methyl-2- ethylpropyl group, a l-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group, a 1- methylbutyl group, a 2-methylbutyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 2-ethylbutyl group,
• halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like and is preferably a fluorine atom, a chlorine atom or a bromine atom.
• C 1-6 alkylene group refers to an alkylene group having 1 to 6 carbon atoms.
• the group include linear or branched alkyl groups such as a methylene group, an ethylene group, a methylmethylene group, a propylene group, a methylethylene group, an ethylmethylene group, a dimethylmethylene group, a butylene group, a methylpropylene group, an ethylethylene group, a dimethylethylene group, a propylmethylene group, a pentylene group and a hexylene group.
• a methylene group, an ethylene group, a methylmethylene group, a propylene group, a methylethylene group, an ethylmethylene group and a dimethylmethylene group are preferable, for example.
• C3-8 cycloalkyl group refers to a cyclic alkyl group having 3 to 8 carbon atoms.
• Preferable examples of the group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.
• C2-6 alkanoyl group refers to an alkyl group having 1 to 6 carbon atoms in which one hydrogen atom is substituted with a carbonyl group.
• Preferable examples of the group include an acetyl group, a propionyl group and a butyryl group.
• C 1-6 alkylsulfonyl group refers to an alkyl group having 1 to 6 carbon atoms in which one hydrogen atom is replaced by a sulfonyl group.
• Preferable examples of the group include a methanesulfonyl group and an ethanesulfonyl group.
• C2-6 alkenyl group refers to an alkenyl group having 2 to 6 carbon atoms.
• Preferable examples of the group include linear or branched alkenyl groups such as a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 1-buten-l-yl group, a 1-buten-
• C 1-6 alkoxy group refers to an alkyl group having 1 to 6 carbon atoms in which a hydrogen atom is replaced by an oxygen atom.
• the group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n- butoxy group, an isobutoxy group, a sec-butoxy group, a tertiary butoxy group, an n-pentoxy group, an isopentoxy group, a sec-pentoxy group, a tertiary pentoxy group, an n-hexoxy group, an isohexoxy group, a 1,2-dimethylpropoxy group, a 2-ethylpropoxy group, a l-methyl-2- ethylpropoxy group, a l-ethyl-2-methylpropoxy group, a 1,1,2-trimethylpropoxy group, a 1,1,2- trimethylpropoxy group, a 1,1-dimethylbutoxy group,
• C2-6 alkenyloxy group refers to an alkenyl group having 2 to 6 carbon atoms in which one hydrogen atom is replaced by an oxygen atom.
• the group include linear or branched alkenyloxy groups such as a vinyloxy group, an allyloxy group, a 1-propenyloxy group, an isopropenyloxy group, a 1-buten-l-yloxy group, a l-buten-2-yloxy group, a l-buten-3-yloxy group, a 2-buten-l-yloxy group and a 2-buten-2-yloxy group.
• C3-8 cycloalkyloxy group refers to a cyclic alkyl group having 3 to 8 carbon atoms in which one hydrogen atom is replaced by an oxygen atom.
• the group include a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, a cyclohexoxy group and a cycloheptyloxy group.
• C6-14 aryl group refers to an aromatic hydrocarbon group having 6 to 14 carbon atoms.
• Preferable examples of the group include a phenyl group, a naphthyl group, an anthryl group and a phenanthryl group.
• C6-14 aryl-Cl-6 alkyl group refers to an alkyl group having 1 to 6 carbon atoms in which one hydrogen atom is replaced by the aforementioned "C6-14 aryl group”.
• Preferable examples of the group include a benzyl group, a phenethyl group, a phenylpropyl group, a naphthylmethyl group, a naphthylethyl group and a naphthylpropyl group.
• the "C4-9 cycloalkylcarbonyl group” refers to a cyclic alkyl group having 3 to 8 carbon atoms substituted with a carbonyl group.
• Preferable examples of the group include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group and a cycloheptylcarbonyl group.
• the "C7-15 aroyl group” refers to the aforementioned "C6-14 aryl group” substituted with a carbonyl group.
• Preferable examples of the group include a benzoyl group, a naphthylcarbonyl group and an anthrylcarbonyl group.
• C2-6 alkenylsulfonyl group refers to an alkenyl group having 2 to 6 carbon atoms in which one hydrogen atom is replaced by a sulfonyl group.
• the group include linear or branched alkenylsulfonyl groups such as a vinylsulfonyl group, an allylsulfonyl group, a 1-propenylsulfonyl group, an isopropenylsulfonyl group, a 1-buten-l- ylsulfonyl group, a l-buten-2-ylsulfonyl group, a l-buten-3-ylsulfonyl group, a 2-buten-l- ylsulfonyl group and a 2-buten-2-ylsulfonyl group.
• C3-8 cycloalkylsulfonyl group refers to a cyclic alkyl group having 3 to 8 carbon atoms in which one hydrogen atom is replaced by a sulfonyl group.
• the group include a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, a cyclohexylsulfonyl group and a cycloheptylsulfonyl group.
• C6-14 arylsulfonyl group refers to an aromatic hydrocarbon group having 6 to 14 carbon atoms in which one hydrogen atom is replaced by a sulfonyl group.
• Preferable examples of the group include a phenylsulfonyl group, a naphthylsulfonyl group and an anthrylsulfonyl group.
• C 1-6 alkylthio group refers to an alkyl group having 1 to 6 carbon atoms in which one hydrogen atom is replaced by a sulfur atom.
• the group include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, a tert-butylthio group, an n-pentylthio group, an isopentylthio group, a neopentylthio group, an n-hexylthio group and a 1-methylpropylthio group.
• C2-6 alkenylthio group refers to an alkenylthio group having 2 to 6 carbon atoms.
• Preferable examples of the group include linear or branched alkenylthio groups such as a vinylthio group, an allylthio group, a 1-propenylthio group, an isopropenylthio group, a 1- buten-1-ylthio group, a l-buten-2-ylthio group, a l-buten-3-ylthio group, a 2-buten-l-ylthio group and a 2-buten-2-ylthio group.
• C3-8 cycloalkylthio group refers to a cyclic alkyl group having 3 to 8 carbon atoms in which one hydrogen atom is replaced by a sulfur atom.
• the group include a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group and a cycloheptylthio group.
• Examples of the "aminosulfonyl group which may have 1 to 2 C 1-6 alkyl groups,
• C2-6 alkenyl groups or C3-8 cycloalkyl groups include an aminosulfonyl group as well as a methylaminosulfonyl group, an ethylaminosulfonyl group, a dimethylaminosulfonyl group, a diethylaminosulfonyl group, a vinylaminosulfonyl group, an allylaminosulfonyl group, a cyclopropylaminosulfonyl group, a cyclobutylaminosulfonyl group and a cyclohexylaminosulfonyl group.
• amino group which may have one C2-6 alkanoyl group, C 1-6 alkylsulfonyl group or C3-8 cycloalkylsulfonyl group or 1 to 2 Cl -6 alkyl groups or C3-8 cycloalkyl groups
• amino group as well as an acetylamino group, an propionylamino group, a methanesulfonylamino group, an ethanesulfonylamino group, a pentanesulfonylamino group, a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a cyclopropylamino group, a cyclobutylamino group and a cyclohexylamino group.
• C 1-6 alkylaminocarbonyl group refers to an alkyl group having 1 to 6 carbon atoms in which one hydrogen atom is replaced by an aminocarbonyl group.
• Preferable examples of the group include a methylaminocarbonyl group, an ethylaminocarbonyl group, a propylaminocarbonyl group, a butylaminocarbonyl group and a hexylaminocarbonyl group.
• Cl -6 alkylaminosulfonyl group refers to an alkyl group having 1 to 6 carbon atoms in which one hydrogen atom is replaced by an aminosulfonyl group.
• the group include a methylaminosulfonyl group, an ethylaminosulfonyl group, a propylaminosulfonyl group, a butylaminosulfonyl group and a hexylaminosulfonyl group.
• the "pharmacologically acceptable salt” is not particularly limited insofar as it is a pharmacologically acceptable salt formed with the compound of the general formula (I) which is a therapeutic agent for a disease caused by A ⁇ .
• the salt include hydrohalides (such as hydrofluorides, hydrochlorides, hydrobromides and hydroiodides), inorganic acid salts (such as sulfates, nitrates, perchlorates, phosphates, carbonates and bicarbonates), organic carboxylates (such as acetates, oxalates, maleates, tartrates, fumarates and citrates), organic sulfonates (such as methanesulfonates, trifiuoromethanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates and camphorsulfonates), amino acid salts (such as aspartates and glutamates), quaternary amine salts, alkali metal salts (such as sodium salts and potassium salts) and alkali earth metal salts (such as magnesium salts and calcium salts).
• hydrohalides such as hydrofluorides, hydrochlorides, hydrobro
• Ring A is preferably a five-membered aromatic heterocyclic group selected from the group consisting of the formulas [20] to [26]: [0099]
• a « represents a bonding site to X 2 , or any one ring selected from the group consisting of the formulas [28] to [39]: [0103]
• [0106] represents a single bond or a double bond, each of which may have 1 to 3 substituents selected from Substituent Group bl .
• Ring A is more preferably any one ring selected from the group consisting of the formulas [21], [28], [29], [31], [32] and [34] to [37]: [0107]
• Ring A is particularly preferably any one ring selected from the group consisting of the formulas [21], [28-1], [29-1], [31-1], [32-1] and [34-1] to [37-1]:
• Ring A is most preferably a ring of the formula [28- 1 ] : [0115]
• Ring B is preferably a phenyl group, a pyridyl group, an oxazolyl group, an imidazolyl group, a thiazolyl group, a dihydrobenzofuranyl group or a thienyl group, and more preferably a phenyl group.
• X 2 is preferably i) a single bond or ii) a C 1-6 alkylene group, and X 2 is more preferably a single bond.
• Ri is a Cl -6 alkyl group or a halogen atom and m is 1 to 2.
• R 2 is a C 1-6 alkoxy group and n is 1.
• R 3 and R4 are the same or different and are each (1) a hydrogen atom or (2) a halogen atom. More preferably, R 3 and R 4 are both hydrogen atoms.
• the substituent for Ring A is preferably a substituent selected from the group consisting of a C 1-6 alkyl group (wherein the alkyl group may be substituted with 1 to 3 halogen atoms), a C3-8 cycloalkyl group, a C6-14 aryl group, a C6-14 aryl-Cl-6 alkyl group, a Cl -6 alkoxy group, a C3-8 cycloalkyloxy group, a C2-6 alkanoyl group, a C7-15 aroyl group, a C 1-6 alkylsulfonyl group, a C3-8 cycloalkylsulfonyl group, a C6-14 arylsulfonyl group, a cyano group, a formyl group, a halogen atom, a hydroxyl group and an oxo group.
• a C 1-6 alkyl group wherein the alkyl group may be substituted with 1 to 3 hal
• the substituent for Ring B is preferably a substituent selected from the group consisting of i) an amino group (wherein the amino group may have one C2-6 alkanoyl group, C 1-6 alkylsulfonyl group or C3-8 cycloalkylsulfonyl group or 1 to 2 C 1-6 alkyl groups or C3-8 cycloalkyl groups), ii) a cyano group, iii) a halogen atom, iv) a hydroxyl group and v) v)-i) a Cl- 6 alkyl group, v)-ii) a Cl -6 alkoxy group, v)-iii) a C 1-6 alkylthio group and v)-iv) a phenyl group, each of which may have 1 to 3 substituents selected from the group consisting of a C 1-6 alky
• amyloid- ⁇ such as Alzheimer's disease, senile dementia, Down's syndrome or amyloidosis.
• R 1 , R 2 , Xi, X 2 , m, n, Ring A and Ring B are as defined above, is synthesized according to a method such as the following General Preparation Method 1 and General Preparation Method 2, for example.
• the method comprises a protection reaction step and a deprotection reaction step appropriately, using a protecting group known to a person skilled in the art which is suitably selected for each step (see T. Greene et al., "Protective Groups in Organic Synthesis", John Wiley & Sons, Inc., New York, 1981).
• the method comprises substituent conversion, substituent introduction and the like suitable for each step and known to a person skilled in the art. It is also obvious that, in order to prepare the compound of the present invention conveniently, all isomers and isomer mixtures such as geometric isomers which can be generated from the structure of the compound, optical isomers based on asymmetric carbon, stereoisomers, and tautomers can be prepared as a single compound by a technique known to a person skilled in the art which is suitable for each step such as fractional crystallization or column chromatography. [0132] General Preparation Method 1
• Ri, R 2 , X 1 , X 2 , m, n, Ring A and Ring B are as defined above;
• XA represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom or a sulfonate group such as a methanesulfonate group, a p-toluenesulfonate group or a trifluoromethanesulfonate group;
• X B represents a trialkylstannyl group, a boronic acid group, a boronate group such as a pinacol boronate group, alkylboronalkenyl group, a C2-6 alkenyl group or a C2-6 alkynyl group.
• the above General Preparation Method 1 is a method for preparing the compound of the general formula [I] by subjecting to coupling reaction in Step 1-1 a compound of the general formula (a-1) and a compound of the general formula (b-2) or a method for preparing the compound of the general formula [I] by subjecting to coupling reaction in Step 1-1 a compound of the general formula (a-2) and a compound of the general formula (b-1) in which the substituents X A and X B are replaced by each other.
• the coupling reaction in Step 1-1 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
• a method known to a person skilled in the art may be used for the reaction.
• Preferable examples of the method include Mizoroki-Heck reaction (see R.F. Heck, “Org. Reactions.”, 1982, vol. 27, p. 345, for example), Suzuki-Miyaura reaction (see A. Suzuki, “Chem. Rev.”, 1995, vol. 95, p. 2457, for example), Sonogashira reaction (see K. Sonogashira, "Comprehensive Organic Synthesis", 1991, vol. 3, p. 521, for example) and Stille coupling reaction (see J.K.
• a halogen compound or trifluoromethanesulfonate group compound of the general formula (a-1) is preferably coupled with 1.0 to 5.0 equivalents of a compound of the general formula (b-2) (wherein X B is preferably a C2-6 alkenyl group) with respect to the compound of the general formula (a-1) in the presence of 0.01 to 0.2 equivalent of a transition metal catalyst with respect to the compound of the general formula (a-1), for example.
• This reaction is preferably performed in the presence of a solvent from the viewpoint of handleability and stirring efficiency.
• the solvent used varies according to the starting material and the transition metal catalyst used, and is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
• the solvent include acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, xylene, l-methyl-2-pyrrolidone and N,N- dimethylformamide.
• the reaction temperature must be a temperature that can complete the coupling reaction, and is preferably room temperature to 150 0 C. This reaction is performed preferably in an inert gas atmosphere, and more preferably in a nitrogen or argon atmosphere.
• the transition metal catalyst is preferably a palladium complex, for example, and more preferably a known palladium complex such as palladium (II) acetate, dichlorobis(triphenylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium (0). It is also preferable to appropriately add a phosphine ligand (preferably triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine or 2-(di-tert-butylphosphino)biphenyl, for example) in order to make the reaction efficiently proceed.
• a phosphine ligand preferably triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine or 2-(di-tert-butylphosphin
• a preferable result may be achieved in the presence of a base.
• the base used is not particularly limited insofar as it is used in a coupling reaction similar to this reaction.
• Preferable examples of the base include triethylamine, N,N-diisopropylethylamine, N 5 N- dicyclohexylmethylamine and tetrabutylammonium chloride.
• the reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored by a known chromatography technique.
• a halogen compound or trifluoromethanesulfonate compound of the general formula (a-1) is preferably coupled with 1.0 to 5.0 equivalents of a compound of the general formula (b-2) (wherein X B is preferably a boronic acid group, a boronate group such as a pinacol boronate group, an alkylboronalkenyl group or the like) with respect to the compound of the general formula (a-1) in the presence of 0.01 to 0.5 equivalent of a transition metal catalyst with respect to the compound of the general formula (a-1), for example.
• This reaction is preferably performed in the presence of a solvent from the viewpoint of handleability and stirring efficiency.
• the solvent used varies according to the starting material and the transition metal catalyst used, and is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
• the solvent include acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, xylene, l-methyl-2-pyrrolidone, N,N-dimethylformamide, water and a mixed solvent thereof.
• the reaction temperature must be a temperature that can complete the coupling reaction, and is preferably room temperature to 200 0 C.
• the transition metal catalyst is preferably a known palladium complex, and more preferably a known palladium complex such as palladium (II) acetate, dichlorobis(triphenylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium (0).
• a phosphorus ligand (preferably triphenylphosphine, tri-o-tolylphosphine, tricyclohexylphosphine or tri-tert-butylphosphine, for example) may be appropriately added in order to make the reaction efficiently proceed.
• a quaternary ammonium salt preferably tetrabutylammonium chloride or tetrabutylammonium bromide, for example, may also be appropriately added in order to make the reaction efficiently proceed.
• a preferable result may be achieved in the presence of a base.
• the base used at this time varies according to the starting material, the solvent used and the like, and is not particularly limited.
• the base include sodium hydroxide, barium hydroxide, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, cesium carbonate and potassium phosphate.
• the reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored by a known chromatography technique.
• the Sonogashira reaction vary according to the starting material, the solvent and the transition metal catalyst, and are not particularly limited insofar as the conditions are similar to those in this reaction. A method known to a person skilled in the art may be used for the reaction.
• a compound of the general formula (a-1) is coupled with 1.0 to 5.0 equivalents of a compound of the general formula (b-2) (wherein XB is preferably a C2-6 alkynyl group) with respect to the compound of the general formula (a-1) in the presence of 0.01 to 0.2 equivalent of a transition metal catalyst with respect to the compound of the general formula (a- 1), for example.
• a compound of the general formula (b-2) wherein XB is preferably a C2-6 alkynyl group
• the solvent used include acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, l-methyl-2-pyrrolidone, N,N- dimethylformamide and dimethyl sulfoxide. More preferable examples of the solvent include tetrahydrofuran, 1,4-dioxane, l-methyl-2-pyrrolidone and N,N-dimethylformamide.
• the reaction temperature must be a temperature that can complete the coupling reaction, and is preferably room temperature to 150 0 C.
• the transition metal catalyst is, for example, a known palladium complex, and more preferably a known palladium complex such as palladium (II) acetate, dichlorobis(triphenylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium (0).
• a phosphorus ligand (preferably triphenylphosphine, tri-o-tolylphosphine or tri-tert- butylphosphine, for example) may be appropriately added, for example, in order to make the reaction efficiently proceed.
• a metal halide or a quaternary ammonium salt preferably copper (I) iodide, lithium chloride, tetrabutylammonium fluoride or silver (I) oxide, for example.
• a preferable result may be achieved in the presence of a base.
• the base used here is not particularly limited insofar as it is used in a coupling reaction similar to this reaction.
• Preferable examples of the base include basic solvents such as diethylamine, triethylamine, N,N-diisopropylethylamine, piperidine and pyridine.
• a halogen compound or trifluoromethanesulfonate group compound of the general formula (a-1) is preferably coupled with 1.0 to 5.0 equivalents of a compound of the general formula (b-2) (wherein X B is preferably a trialkylstannyl group) with respect to the compound of the general formula (a-1) in the presence of 0.01 to 0.2 equivalent of a transition metal catalyst with respect to the compound of the general formula (a-1), for example. It is preferable to appropriately use in this reaction 0.1 to 5.0 equivalents of copper (I) halide or/and lithium chloride in order to make the reaction efficiently proceed.
• the solvent used in this reaction include toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, l-methyl-2-pyrrolidone and dimethyl sulfoxide.
• the reaction temperature must be a temperature that can complete the coupling reaction, and is preferably room temperature to 150 0 C.
• the preferable transition metal catalyst is a palladium complex, preferably a known palladium complex such as palladium (II) acetate, dichlorobis(triphenylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium (0), for example, and more preferably palladium (II) acetate, tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium (0), for example.
• a known palladium complex such as palladium (II) acetate, dichlorobis(triphenylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium (0), for example, and more preferably
• a phosphorus ligand (preferably triphenylphosphine, tri-o-tolylphosphine, 1 ,3- bis(diphenylphosphino)propane or tri-tert-butylphosphine, for example) may be appropriately added, for example, in order to make the reaction efficiently proceed.
• This reaction is performed preferably in an inert gas atmosphere, and more preferably in a nitrogen or argon atmosphere. Under preferable reaction conditions, the reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored by a known chromatography technique.
• Step 1-2 is an example of a method for preparing a compound of the general formula (a-2) and a compound of the general formula (b-2) in which the substituents X A and XB are replaced by each other.
• This step varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
• the same method as in Step 1-1 may be preferably used such as Mizoroki-Heck reaction (see R.F. Heck, "Org. Reactions.”, 1982, vol. 27, p. 345, for example), Suzuki-Miyaura reaction (see A. Suzuki, “Chem. Rev.”, 1995, vol. 95, p. 2457, for example), Sonogashira reaction (see K.
• the compound of the formula (a-1), the compound of the formula (a-2), the compound of the formula (b-1) and the compound of the formula (b-2) are known or commercially available compounds or are compounds that can be prepared from these compounds by a conventional method. [0141]
• Ri, R 2 , m, n and X A are as defined above; R A and RB are as defined for Ri above;
• Li represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom or a sulfonate group such as a methanesulfonate group, a p-toluenesulfonate group or a trifluoromethanesulfonate group; and
• L 2 represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, a sulfonate group such as a methanesulfonate group, a p-toluenesulfonate group or a trifluoromethanesulfonate group or a boronic acid group.
• the compound of the general formula (a-1) can be prepared from an amine compound (a-3) as a starting material through formylation in Step 2-1, coupling reaction in Step 2-2 and formation of an imidazole ring in Step 2-3, or can be prepared from a compound of the general formula (a-4) as a starting material by coupling reaction in Step 2-4.
• Step 2-1 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
• a method known to a person skilled in the art may be used for the reaction.
• a method reported in many documents or the like T. Greene et al., "Protective Groups in Organic Synthesis", John Wiley & Sons, Inc., New York, 1981, for example
• Step 2-2 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
• a method known to a person skilled in the art may be used for the reaction.
• Preferable examples of the method include a method of stirring a compound of the general formula (a-5) and 1.0 to 10.0 equivalents of a compound of the general formula (c-1) with respect to the compound of the general formula (a- 5) in a solvent in the presence of 1.0 to 10.0 equivalents of a base with respect to the compound of the general formula (a-5).
• the base used varies according to the starting material and is not particularly limited.
• Preferable examples of the base include alkali metal hydrides (such as sodium hydride and lithium hydride), alkali metal salts (such as potassium carbonate, sodium carbonate and cesium carbonate) and metal alkoxides (such as sodium methoxide and potassium tert-butoxide).
• the solvent used varies according to the starting material, and is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
• the solvent include ether solvents such as tetrahydrofuran, 1 ,4-dioxane and diethyl ether; halogenated solvents such as methylene chloride, 1,2-dichloroethane and chloroform; polar solvents such as N,N-dirnethylformamide and N- methylpyrrolidone; non-polar solvents such as toluene and benzene; and mixtures thereof.
• ether solvents such as tetrahydrofuran, 1 ,4-dioxane and diethyl ether
• halogenated solvents such as methylene chloride, 1,2-dichloroethane and chloroform
• polar solvents such as N,N-dirnethylformamide and N- methylpyrrolidon
• the reaction temperature must be a temperature that can complete the reaction without promoting formation of an undesirable by-product, and is preferably 0 0 C to 200 0 C, for example. Under preferable reaction conditions, the reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored by a known chromatography technique. An undesirable by-product can be removed by a technique known to a person skilled in the art such as a conventional chromatography technique, extraction or/and crystallization. [0147]
• Step 2-3 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
• a method known to a person skilled in the art may be used for the reaction.
• a method reported in many documents or the like such as described in The Chemistry of Heterocyclic Compounds. Imidazole and Derivatives, Part I, p. 33, Inters. Publish. 1953) may be used.
• Preferable examples of the method include a method for preparing the compound of the general formula (a-1) by forming an imidazole ring from a compound of the general formula (a-6) and ammonia, ammonium salt, formamide or the like as a nitrogen source.
• the solvent used is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
• the solvent include non-polar solvents such as toluene and benzene; alcohol solvents such as methanol and ethanol; organic acids such as acetic acid or trifluoroacetic acid, sulfonic acids such as p-toluenesulfonic acid and trifluoromethanesulfonic acid; water; and mixtures thereof.
• Formamide may optionally be used as a nitrogen atom source and as a solvent.
• the reaction temperature must be a temperature that can complete the reaction without promoting formation of an undesirable by-product, and is preferably room temperature to 250 0 C, for example.
• the yield may be improved when the reaction is performed using a tight container. Under preferable reaction conditions, the reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored by a known chromatography technique. An undesirable by-product can be removed by a technique known to a person skilled in the art such as a conventional chromatography technique, extraction or/and crystallization. [0148]
• the coupling reaction in Step 2-4 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
• a method known to a person skilled in the art may be used for the reaction.
• a method reported in many documents or the like (such as described in D.D. Davey et al., "J. Med. Chem.”, 1991, vol. 34, p. 2671 -2677) may be used.
• Examples of the method include a method of stirring a compound of the general formula (a-4) and 1.0 to 5.0 equivalents of an imidazole compound (c-2) with respect to the compound of the general formula (a-4) in a solvent in the presence or absence of 1.0 to 5.0 equivalents of a base with respect to the compound of the general formula (a-4).
• Preferable examples of the base used include sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, barium carbonate, pyridine, lutidine and triethylamine.
• the solvent used varies according to the starting material, and is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
• the solvent include acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide and N-methylpyrrolidine.
• the base may optionally be used as a solvent.
• the reaction temperature must be a temperature that can complete the reaction without promoting formation of an undesirable by-product, and is preferably room temperature to 150 0 C, for example. Under preferable reaction conditions, the reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored by a known chromatography technique. An undesirable by-product can be removed by a technique known to a person skilled in the art such as a conventional chromatography technique or/and crystallization.
• Examples of the coupling reaction in Step 2-4 include a method of stirring a compound of the general formula (a-4) (wherein L 2 is preferably a boronic acid group or the like) in a solvent in the presence of a copper catalyst (such as described in J.P. Collman et al., "Org. Letters.”, 2000, vol. 2, p. 1233-1236).
• Preferable examples of the method include a method of stirring a compound of the general formula (a-4) and 0.1 to 10.0 equivalents of an imidazole compound (c-2) with respect to the compound of the general formula (a-4) in a solvent in the presence of 0.01 to 1.0 equivalent of a copper reagent such as copper, copper bromide or copper iodide with respect to the compound of the general formula (a-4).
• a copper reagent such as copper, copper bromide or copper iodide with respect to the compound of the general formula (a-4).
• the copper reagent used varies according to the starting material and is not particularly limited.
• the copper reagent include copper (I) halide, copper (II) acetate, copper (II) nitrate and di- ⁇ -hydroxo-bis[(N,N,N',N'-tetramethylethylenediamine)copper (II)] chloride.
• the solvent used varies according to the starting material, the reagent and the like, and is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
• the solvent include ether solvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether; halogenated solvents such as methylene chloride, 1,2-dichloroethane and chloroform; polar solvents such as ethyl acetate, N,N-dimethylformamide and N-methylpyrrolidone; non-polar solvents such as toluene, benzene and dichlorobenzene; and mixtures thereof.
• a base may be used depending on the starting material, the reagent and the like.
• the base include organic bases such as triethylamine, pyridine and tetramethylethylenediamine; alkali metal salts such as potassium carbonate, sodium carbonate, potassium acetate, sodium acetate and cesium carbonate; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.
• the reaction temperature must be a temperature that can complete the reaction without promoting formation of an undesirable by-product, and is preferably room temperature to 200 0 C, for example. Good results such as reduction in the reaction time and improvement of the yield can be achieved when the reaction is performed in an oxygen atmosphere or air stream. Under preferable reaction conditions, the reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored by a known chromatography technique. An undesirable by-product can be removed by a technique known to a person skilled in the art such as a conventional chromatography technique, extraction or/and crystallization.
• X 2 , X A , Ring A and Ring B are as defined above; L3 and L4 are as defined for L 1 above; Xc represents a C2-4 alkylene group, or a C2-3 alkylene group in which one methylene group is replaced by an oxygen atom or a nitrogen atom (wherein the nitrogen atom may have a substituent such as a C 1-6 alkyl group or a benzyl group); Pi represents a carboxyl-protecting group such as a methyl group, an ethyl group, a benzyl group, an allyl group, a triphenylmethyl group, a tert-butyl group or a tert-butyldimethylsilyl group, or a hydrogen atom; and P 2 represents a nitrogen-protecting group such as a tert-butoxycarbonyl group or a benzyloxycarbonyl group.
• the compound of the general formula (b-1) can be prepared from a compound of the general formula (d-1) as a starting material through alkylation in Step 3-1, hydrazidation and deprotection reaction in Step 3-2, formation of Ring A in Step 3-3 and Sandmeyer reaction in Step 3-4.
• Step 3-1 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction. A method known to a person skilled in the art may be used for the reaction.
• Preferable examples of the method include a method of stirring a compound of the general formula (d-1) and 1.0 to 10.0 equivalents of a compound of the general formula (e-1) with respect to the compound of the general formula (d- 1) in a solvent in the presence of 1.0 to 10.0 equivalents of a base with respect to the compound of the general formula (d-1).
• the base used varies according to the starting material and is not particularly limited.
• the base include alkali metal hydrides (such as sodium hydride and lithium hydride), alkali metal salts (such as potassium carbonate, sodium carbonate and cesium carbonate), metal alkoxides (such as sodium methoxide and potassium tert-butoxide) and organometallic bases (such as butyllithium, lithium diisopropylamide and lithium bistrimethylsilylamide).
• alkali metal hydrides such as sodium hydride and lithium hydride
• alkali metal salts such as potassium carbonate, sodium carbonate and cesium carbonate
• metal alkoxides such as sodium methoxide and potassium tert-butoxide
• organometallic bases such as butyllithium, lithium diisopropylamide and lithium bistrimethylsilylamide.
• the solvent include ether solvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether; halogenated solvents such as methylene chloride, 1,2-dichloroethane and chloroform; polar solvents such as N,N- dimethylformamide and N-methylpyrrolidone; non-polar solvents such as toluene and benzene; and mixtures thereof.
• the reaction temperature must be a temperature that can complete the reaction without promoting formation of an undesirable by-product, and is preferably -100 0 C to 100 0 C, for example. Under preferable reaction conditions, the reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored by a known chromatography technique. An undesirable by-product can be removed by a technique known to a person skilled in the art such as a conventional chromatography technique, extraction or/and crystallization. [0154]
• the hydrazidation reaction as the first stage of Step 3-2 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
• An amidation reaction known to a person skilled in the art may be used for the reaction.
• a method reported in many documents or the like such as described in The Chemical Society of Japan (ed.), Jikken Kagaku Koza (Courses in Experimental Chemistry), 4th edition (vol. 22) Yuki Gosei (Organic Synthesis) [IV], Maruzen Co., Ltd., November 1992, p. 137-144) may be used.
• the deprotection reaction as the second stage varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
• the Ring A formation reaction in Step 3-3 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
• a method known to a person skilled in the art may be used for the reaction.
• Preferable examples of the method include a method of heating a compound of the general formula (d-3) and 1.0 to 10.0 equivalents of aminoguanidine, isothiourea, cyanamide or the like with respect to the compound of the general formula (d-3) in a solvent under basic or acidic conditions.
• the base or acid used varies according to the starting material and is not particularly limited.
• Examples of the base or acid include bases such as alkali metal hydrides (such as sodium hydride and lithium hydride), alkali metal salts (such as potassium carbonate, sodium carbonate and cesium carbonate), metal alkoxides (such as sodium methoxide and potassium tert-butoxide) and organic bases (such as triethylamine, pyridine and 1,8- diazabicyclo[5.4.0]undec-7-ene); and acids such as hydrochloric acid, sulfuric acid, p- toluenesulfonic acid and camphorsulfonic acid.
• bases such as alkali metal hydrides (such as sodium hydride and lithium hydride), alkali metal salts (such as potassium carbonate, sodium carbonate and cesium carbonate), metal alkoxides (such as sodium methoxide and potassium tert-butoxide) and organic bases (such as triethylamine, pyridine and 1,8- diazabicyclo[5.4.0]undec-7-
• the solvent used varies according to the starting material, and is not particularly limited insofar as the solvent does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
• the solvent include alcohol solvents such as methanol, ethanol and tert-butanol; ether solvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether; halogenated solvents such as methylene chloride, 1,2-dichloroethane and chloroform; polar solvents such as acetonitrile, N,N-dimethylformamide and N-methylpyrrolidone; non-polar solvents such as xylene, toluene and benzene; and mixtures thereof.
• the reaction temperature must be a temperature that can complete the reaction without promoting formation of an undesirable by-product, and is preferably -100 0 C to 100 0 C, for example. Under preferable reaction conditions, the reaction is completed in 1 to 48 hours, and the progress of the reaction can be monitored by a known chromatography technique. An undesirable by-product can be removed by a technique known to a person skilled in the art such as a conventional chromatography technique, extraction or/and crystallization. [0156]
• the Sandmeyer reaction in Step 3-4 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction. A method known to a person skilled in the art may be used for the reaction.
• X 2 , XA, X C5 P I , L 3 , Ring A and Ring B are as defined above, wherein X B represents a C2-6 alkenyl group and L 5 represents a leaving group such as a phenylthio group or a p-tolylsulfanyl group.
• the compound of the general formula (b-2) can be prepared from a compound of the general formula (b-1) as a starting material in Step 1-2 as described above.
• the compound can be prepared from a compound of the general formula (d-2) as a starting material through hydrazidation in Step 4- 1 , acy lation in Step 4-2, formation of Ring A in Step 4-
• Step 4-1 may employ the same amidation reaction as in the aforementioned Step
• Preferable examples of the method include a method of stirring a compound of the general formula (d-2) and 1.0 to 10.0 equivalents of hydrazine with respect to the compound of the general formula (d-1) in a solvent. Neutral reaction conditions are preferred in order to make the reaction conveniently proceed.
• the solvent used varies according to the starting material, and is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
• the solvent include ether solvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether; halogenated solvents such as methylene chloride, 1,2-dichloroethane and chloroform; polar solvents such as N 5 N- dimethylformamide and N-methylpyrrolidone; non-polar solvents such as toluene and benzene; and mixtures thereof.
• the reaction temperature must be a temperature that can complete the reaction without promoting formation of an undesirable by-product, and is preferably room temperature to 100 0 C, for example. Under preferable reaction conditions, the reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored by a known chromatography technique. An undesirable by-product can be removed by a technique known to a person skilled in the art such as a conventional chromatography technique, extraction or/and crystallization.
• Step 4-2 may employ the same amidation reaction as in the aforementioned Step
• Step 4-3 may employ the same cyclization conditions as in the aforementioned Step 2-3.
• a compound of the general formula (b-4) can be conveniently prepared by heating with stirring a compound of the general formula (d-5) and 1.0 to 10 equivalents of phosphorus oxychloride with respect to the compound of the general formula (d- 5) and then heating the resulting compound and 1.0 to 10 equivalents of ammonium acetate with respect to the compound of the general formula (d-5) in an acetic acid solvent, for example.
• the thermal decomposition reaction in Step 4-4 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
• a method known to a person skilled in the art may be used for the reaction.
• a method reported in many documents or the like such as described in W. Carrutthers, "Some modern methods of organic synthesis, Third Edition” (Cambridge University Press, 1986, p. 120- 121)) may be used.
• the compound of the general formula (b-2) can be conveniently prepared by subjecting the compound of the general formula (b-4) to an oxidation reaction known to a person skilled in the art and heating the compound, for example.
• Ri, R 2 , X 1 , X 2 , Xc, Pi, L 3 , m, n, Ring A and Ring B are as defined above.
• the above General Preparation Method 2 shows an example describing preparation of the compound of the general formula [I] by subjecting a compound of the general formula (a-7) and a compound of the general formula (d-6) to cyclization reaction in Step 5-1.
• the Ring A formation reaction in Step 5-1 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
• a method known to a person skilled in the art may be used for the reaction.
• Preferable examples of the method include a method of stirring a compound of the general formula (a-7) and 1.0 to 5.0 equivalents of a compound of the general formula (d-6) with respect to the compound of the general formula (a-7) in a solvent in the presence of 1.0 to 10.0 equivalents of a base with respect to the compound of the general formula (a-7).
• This reaction is preferably performed in the presence of a solvent from the viewpoint of handleability and stirring efficiency.
• the solvent used varies according to the starting material, and is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
• the solvent include alcohol solvents such as methanol, ethanol and tert-butanol; ether solvents such as tetrahydrofuran, 1,4- dioxane and diethyl ether; halogenated solvents such as methylene chloride, 1,2-dichloroethane and chloroform; polar solvents such as acetonitrile, propionitrile, N,N-dimethylformamide and N-methylpyrrolidone; non-polar solvents such as toluene and benzene; and mixtures thereof.
• the base used varies according to the starting material and is not particularly limited.
• the base include alkali metal hydrides (such as sodium hydride and lithium hydride), alkali metal salts (such as potassium carbonate, sodium carbonate and cesium carbonate), metal alkoxides (such as sodium methoxide and potassium tert-butoxide) and organic bases (such as triethylamine, N,N-diisopropylethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene and imidazole).
• the reaction temperature must be a temperature that can complete the reaction without promoting formation of an undesirable by-product, and is preferably room temperature to 200 0 C, for example.
• the reaction is completed in 1 to 7 days, and the progress of the reaction can be monitored by a known chromatography technique.
• An undesirable by-product can be removed by a technique known to a person skilled in the art such as a conventional chromatography technique, extraction or/and crystallization.
• the compound of the formula (d-6) is a known or commercially available compound or is a compound that can be prepared from such a compound by a conventional method.
• Preparation of compound of general formula (a-7) The following formula shows an example of preparation of the compound of the general formula (a-7).
• Ri, R 2 , m, n, X A and P 2 are as defined above; and M A represents a metal such as zinc or copper.
• the compound of the general formula (a-7) can be prepared from a compound of the general formula (a-1) as a starting material through coupling reaction in Step 6-1, hydrolysis reaction and hydrazidation in Step 6-2 and deprotection reaction in Step 6-3.
• the compound can be prepared from a compound of the general formula (a-1) as a starting material through coupling reaction in Step 6-4 and deprotection reaction in Step 6-3.
• Step 6-1 and Step 6-4 vary according to the starting material and are not particularly limited insofar as the conditions are similar to those in these reactions.
• a method known to a person skilled in the art may be used for the reactions. Mizoroki-Heck reaction (see R.F. Heck, “Org. Reactions.”, 1982, vol. 27, p. 345, for example), Sonogashira reaction (see K. Sonogashira, "Comprehensive Organic Synthesis", 1991, vol. 3, p. 521, for example) or the like is preferable.
• This reaction is preferably performed in the presence of a solvent from the viewpoint of handleability and stirring efficiency.
• the solvent used varies according to the starting material and the transition metal catalyst used, and is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
• the solvent include acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, l-methyl-2- pyrrolidone and N,N-dimethylformamide.
• the reaction temperature must be a temperature that can complete the coupling reaction, and is preferably room temperature to 150 0 C. This reaction is performed preferably in an inert gas atmosphere, and more preferably in a nitrogen or argon atmosphere.
• the transition metal catalyst is preferably a palladium complex, for example, and more preferably a known palladium complex such as palladium (II) acetate, dichlorobis(triphenylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium (0). It is also preferable to appropriately add a phosphorus ligand (preferably triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine or 2-(di-tert-butylphosphino)biphenyl, for example) in order to make the reaction efficiently proceed.
• a phosphorus ligand preferably triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine or 2-(di-tert-butylphosphino)bi
• a preferable result may be achieved in the presence of a base.
• the base used is not particularly limited insofar as it is used in a coupling reaction similar to this reaction.
• Preferable examples of the base include triethylamine, N,N-diisopropylethylamine, N 5 N- dicyclohexylmethylamine and tetrabutylammonium chloride.
• the reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored by a known chromatography technique.
• the Sonogashira reaction vary according to the starting material, the solvent and the transition metal catalyst, and are not particularly limited insofar as the conditions are similar to those in this reaction.
• a method known to a person skilled in the art may be used for the reaction.
• a compound of the general formula (a-1) is coupled with 1.0 to 5.0 equivalents of a compound of the general formula (f-2) or a compound of the general formula (f- 3), wherein Xi is preferably [0174]
• the solvent used include acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, l-methyl-2-pyrrolidone, N,N- dimethylformamide and dimethyl sulfoxide. More preferable examples of the solvent include tetrahydrofuran, 1,4-dioxane, l-methyl-2-pyrrolidone and N,N-dimethylformamide.
• the reaction temperature must be a temperature that can complete the coupling reaction, and is preferably room temperature to 150 0 C.
• This reaction is performed preferably in an inert gas atmosphere, and more preferably in a nitrogen or argon atmosphere. Under preferable reaction conditions, the reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored by a known chromatography technique.
• the transition metal catalyst is, for example, a known palladium complex, and more preferably a known palladium complex such as palladium (II) acetate, dichlorobis(triphenylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0) or tris(diben2ylideneacetone)dipalladium (0).
• a phosphorus ligand preferably triphenylphosphine, tri-o-tolylphosphine or tritert-butylphosphine, for example
• a metal halide or a quaternary ammonium salt preferably copper (I) iodide, lithium chloride, tetrabutylammonium fluoride or silver (I) oxide, for example.
• a preferable result may be achieved in the presence of a base.
• the base used here is not particularly limited insofar as it is used in a coupling reaction similar to this reaction.
• Preferable examples of the base include organic bases such as diethylamine, triethylamine, N 5 N- diisopropylethylamine, piperidine and pyridine.
• the coupling reaction in Step 6-1 may also employ a compound of the general formula (f-4) (wherein Xi is preferably a single bond).
• a halogen compound or trifiuorornethanesulfonate group compound of the general formula (a-1) is preferably coupled with 1.0 to 5.0 equivalents of a compound of the general formula (f-4) (wherein X 1 is preferably a single bond) with respect to the compound of the general formula (a-1) in the presence of 0.01 to 0.2 equivalent of a transition metal catalyst with respect to the compound of the general formula (a-1), for example.
• This reaction is preferably performed in the presence of a solvent from the viewpoint of handleability and stirring efficiency.
• the solvent used varies according to the starting material and the transition metal catalyst used, and is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
• the solvent include acetonitrile, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, l-methyl-2-pyrrolidone and N 5 N- dimethylformamide.
• the reaction temperature must be a temperature that can complete the coupling reaction, and is preferably room temperature to 150 0 C. This reaction is performed preferably in an inert gas atmosphere, and more preferably in a nitrogen or argon atmosphere.
• the transition metal catalyst is preferably a palladium complex, for example, and more preferably a known palladium complex such as palladium (II) acetate, dichlorobis(triphenylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium (0). It is also preferable to appropriately add a phosphorus ligand (preferably triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine or 2-(di-tert-butylphosphino)biphenyl, for example) in order to make the reaction efficiently proceed.
• a phosphorus ligand preferably triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine or 2-(di-tert-butylphosphino)bi
• a preferable result may be achieved in the presence of a base.
• the base used is not particularly limited insofar as it is used in a coupling reaction similar to this reaction.
• Preferable examples of the base include triethylamine, N 5 N-diisopropylethylamine, N 5 N- dicyclohexylmethylamine and tetrabutylammonium chloride.
• the reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored by a known chromatography technique.
• the hydrolysis reaction as the first stage of Step 6-2 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
• a method known to a person skilled in the art may be used for the reaction.
• a method reported in many documents such as described in The Chemical Society of Japan (ed.), Jikken Kagaku Koza (Courses in Experimental Chemistry), 4th edition (vol. 22) Yuki Gosei (Organic Synthesis) [IV], Maruzen Co., Ltd., November 1992, p. 12-13) may be used.
• the hydrazidation reaction as the second stage varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
• An amidation reaction known to a person skilled in the art may be used for the reaction.
• the deprotection reaction in Step 6-3 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
• a deprotection reaction known to a person skilled in the art may be used for the reaction.
• a method reported in many documents or the like see T. Greene et al., "Protective Groups in Organic Synthesis", John Wiley & Sons, Inc., New York, 1981, for example) may be used.
• X 2 , Xc, Ring B, Pi, L 3 and L 4 are as defined above.
• the compound of the general formula (d-6) can be prepared from a compound of the general formula (d-7) as a starting material through alkylation reaction in Step 3-1 and imidation in Step 7-1.
• Step 3-1 is performed by the same method as described above and can prepare a compound of the general formula (d-8) from a compound of the general formula (d-7).
• Step 7-1 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
• a method known to a person skilled in the art may be used for the reaction.
• Preferable examples of the method include a method of stirring the compound of the general formula (d-8) in an alcohol solvent in the presence of 5.0 to 100.0 equivalents of an acid with respect to the compound of the general formula (d-8).
• the acid used varies according to the starting material and is not particularly limited.
• Preferable examples of the acid include hydrogen chloride gas and acetyl chloride.
• the solvent used varies according to the starting material, and is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
• the solvent include alcoholic solvents such as methanol, ethanol and tert-butanol.
• Preferable examples of the solvent also include halogenated solvents such as a methylene chloride, 1,2-dichloroethane and chloroform; polar solvents such as N 5 N- dimethylformamide and N-methylpyrrolidone; non-polar solvents such as toluene and benzene; and mixed solvents thereof.
• the reaction temperature must be a temperature that can complete the reaction without promoting formation of an undesirable by-product, and is preferably 0 0 C to 100 0 C, for example.
• the reaction is completed in 1 to 7 days, and the progress of the reaction can be monitored by a known chromatography technique.
• An undesirable by-product can be removed by a technique known to a person skilled in the art such as a conventional chromatography technique, extraction or/and crystallization.
• the compound of the formula (d-7) and the compound of the formula (e-1) are known or commercially available compounds or are compounds that can be prepared from these compounds by a conventional method.
• the compound of the general formula (I) or pharmacologically acceptable salt thereof according to the present invention is effective for the treatment of a disease caused by A ⁇ and is excellent in terms of pharmacokinetics, toxicity, stability, absorption and the like.
• a therapeutic agent for a disease caused by A ⁇ comprising the compound of the formula (I) or pharmacologically acceptable salt thereof according to the present invention as an active ingredient can be prepared by a conventional method.
• the dosage form include tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, inhalants, suppositories, injections, ointments, ophthalmic solutions, ophthalmic ointments, nasal drops, ear drops, cataplasms and lotions.
• the agent can be prepared by using ingredients typically used such as an excipient, a binder, a lubricant, a colorant and a corrective, and ingredients used where necessary such as a stabilizer, an emulsif ⁇ er, an absorbefacient, a surfactant, a pH adjuster, a preservative and an antioxidant, and can be prepared by blending ingredients generally used as materials for a pharmaceutical preparation.
• ingredients typically used such as an excipient, a binder, a lubricant, a colorant and a corrective
• ingredients used where necessary such as a stabilizer, an emulsif ⁇ er, an absorbefacient, a surfactant, a pH adjuster, a preservative and an antioxidant, and can be prepared by blending ingredients generally used as materials for a pharmaceutical preparation.
• ingredients include animal and vegetable oils such as soybean oil, beef tallow and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; a silicone resin; silicone oil; surfactants such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil and a polyoxyethylene-polyoxypropylene block copolymer; water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, a carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene
• excipient used examples include lactose, corn starch, saccharose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide.
• binder used include polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, a polypropylene glycol-polyoxyethylene block copolymer and meglumine.
• disintegrant used include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin and carboxymethylcellulose calcium.
• Examples of the lubricant used include magnesium stearate, talc, polyethylene glycol, silica and hydrogenated vegetable oil.
• Examples of the colorant used include those permitted to be added to pharmaceuticals.
• Examples of the corrective used include cocoa powder, menthol, empasm, mentha oil, borneol and cinnamon powder.
• an oral preparation is prepared by adding an active ingredient compound or a salt thereof or a hydrate of the compound or salt, an excipient, and, where necessary, a binder, a disintegrant, a lubricant, a colorant and a corrective, for example, and then forming the mixture into powder, fine granules, granules, tablets, coated tablets or capsules, for example, by a conventional method. It is obvious that tablets or granules may be appropriately coated, for example, sugar coated, where necessary.
• a syrup or an injection preparation is prepared by adding a pH adjuster, a solubilizer and an isotonizing agent, for example, and a solubilizing agent, a stabilizer and the like where necessary by a conventional method.
• An external preparation may be prepared by any conventional method without specific limitations.
• a base material any of various materials usually used for a pharmaceutical, a quasi drug, a cosmetic or the like can be used. Examples of the base material include materials such as animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals and purified water.
• a pH adjuster, an antioxidant, a chelator, a preservative and fungicide, a colorant, a flavor or the like may be added where necessary. Further, an ingredient having a differentiation inducing effect such as a blood flow enhancer, a bactericide, an antiphlogistic, a cell activator, vitamin, amino acid, a humectant or a keratolytic agent may be blended where necessary.
• the dose of the therapeutic agent according to the present invention varies according to the degree of symptoms, age, sex, body weight, mode of administration, type of salt and specific type of disease, for example.
• the compound of the formula (I) or pharmacologically acceptable salt thereof is orally administered to an adult at about 30 ⁇ g to 10 g, preferably 100 ⁇ g to 5 g, and more preferably 100 ⁇ g to 100 mg per day, or is administered to an adult by injection at about 30 ⁇ g to 1 g, preferably 100 ⁇ g to 500 mg, and more preferably 100 ⁇ g to 30 mg per day, in a single dose or several divided doses, respectively.
• the compound of the formula (I) or pharmacologically acceptable salt thereof according to the present invention may be used in combination with compounds having the following mechanisms.
• the compounds usable in combination include cholinesterase inhibitors (e.g., donepezil, huperzine A, tacrine, rivastigmine, galantamine); AMPA receptor antagonists (e.g., 1,2-dihydropyridine compounds such as 3-(2-cyanophenyl)-5-(2-pyridyl)-l- phenyl-l,2-dihydropyridin-2-one); NMDA receptor antagonists (e.g., memantine); acetylcholine releasing stimulants (e.g., pramiracetam; aniracetam); calcium channel agonists (e.g., nef ⁇ racetam); free radical scavengers (e.g., EGb 761); platelet activating factor antagonists (e.g., EGb 761); platelet aggregation antagonists (e.g., EGb 761, triflusal); insulin sensitizers (e.g., rosi
• angiogenesis inhibitors e.g., paclitaxel
• immunosuppressants e.g., paclitaxel
• tubulin antagonists e.g., paclitaxel
• thromboxane A synthase inhibitors e.g., triflusal
• antioxidants e.g., idebenone
• alpha adrenoreceptor antagonists e.g., nicergoline
• estrogen antagonists e.g., conjugated estrogens, trilostane
• 3-beta hydroxysteroid dehydrogenase inhibitors e.g., trilostane
• signal transduction pathway inhibitors e.g., trilostane
• melatonin receptor agonists e.g., ramelteon
• immunostimulants e.g., immune globulin, icosapentethyl ester, procaine
• HIV entry inhibitors e.g., procaine
• butylcholine esterase inhibitor e.g., bisnorcymserine
• alpha adrenergic receptor antagonists e.g., nicergoline
• NO synthase type II inhibitors e.g., arundic acid
• chelating agents e.g., PBT 2
• amyloid fibrillogenesis inhibitors e.g., TTP488, PF 4494700
• serotonin 4 receptor agonists e.g., PRX 03140
• serotonin 6 receptor antagonists e.g., SB 742457
• benzodiazepine receptor inverse agonists e.g., radequinil
• Ca channel antagonists e.g., safinamide
• nicotinic receptor agonists e.g., ispronicline
• BACE inhibitor e.g., CTS 21166
• the above compounds include, for example, donepezil, huperzine A, tacrine, rivastigmine, galantamine, pramiracetam, aniracetam, nefiracetam, EGb 761, rosiglitazone, rasagiline, levacecarnine, celecoxib, 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl- l,2-dihydropyridin-2-one, talampanel, becampanel, memantine, xaliproden, tarenflurbil, tramiprosate, leuprorelin-D, taltirelin, risperidone, cevimeline, modafinil, alosetron, aripiprazole, mifepristone, atorvastatin, propentofylline, choline alfoscerate, FPF 1070 (CAS Number 143637- 01-8), rimonabant,
• ABT 107 ABT 560, TC 5619, TAK 070, N- [(lS,2R)-3-(3,5-Difluorophenyl)-l-hydroxy-l-[(5S,6R)-5-methyl-6-(neopentyloxy)morpholin-3- yl]propan-2-yl]acetamide hydrochloride, 6-Fluoro-5-(2-fluoro-5-methylphenyl)-3,4- dihydropyridine, 2- Amino-6- [2-(3 '-methoxybiphenyl-3 -yl)ethyl] -3 ,6-dimethyl-5 ,6- hydroxypyrimidin-4(3H)-one, AZD 1080, ARA 014418, XD 4241, Z 321 (CAS No.
• Monoclonal antibody 266 duloxetine, escitalopram oxalate, fluoxetine, fluvoxamine maleate, paroxetine, sertraline, dapoxetine, desvenlafaxine, sibutramine, nefazodone, milnacipran, desipramine, duloxetine, and bicifadine.
• (+)-8-(4-Fluoro-2-trifluoromethylphenvn-2- ( f EV2-r6-methoxy-5-(4-methyl- 1 H-imidazol- 1 - yl)pyrazin-2-yl]vinvU-5,6,7 ⁇ 8-tetrahydro-[l .2.41triazolo[l ,5-a]pyridine and (-)-8-(4-fluoro-2- trifluoromethylphenylV2- ((E)-2-[6-methoxy-5-(4-methyl- 1 H-imidazol- 1 -yl)pyrazin-2-yl1 vinyl ) - 5,6.7.8-tetrahvdro-ri.2.41triazolo ⁇ .5-alpyridine [0191]
• Tris(dibenzylieneacetone)dipalladium (140 mg), tri(o-tolyl)phosphine (93.1 mg) and TEA (358 uL) were added to a suspension of 8-(2,4-difiuoro-phenyl)-2-vinyl-5,6,7,8- tetrahydro[l,2,4]triazolo[l,5-a]pyridine obtained in Reference Example 5 (200 mg) and 5- bromo-3-methoxy-2-(4-methyl-lH-imidazol-l-yl)pyrazine obtained in Reference Example 1 (226 mg) in toluene (13.3 mL), followed by stirring at 110 0 C for 18 hours.
• the solid in the reaction solution was removed by filtration through celite, and the filtrate was concentrated under reduced pressure.
• the resulting residue was purified by silica gel column chromatography (carrier: ChromatorexTM NH manufactured by Fuji Silysia Chemical Ltd.(hereinafter abbreviated as "NH silica gel”)) to obtain 124 mg of a racemate of the title compound.
• the resulting racemate was separated by CHIRALPAKTM IC manufactured by Daicel Chemical Industries, Ltd.
• the reaction mixture was brought back to room temperature, diluted with ethyl acetate and then filtered through celite. Water and brine were added to the filtrate, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: ChromatorexTM NH) to obtain the racemic title compound.
• the racemic title compound was separated by CHIRALPAKTM IC manufactured by Daicel Chemical Industries, Ltd.
• Acetic anhydride 150 ml was added dropwise to formic acid (150 ml) under ice- cooling, followed by stirring at the same temperature for 25 minutes.
• the property values of the compound are as follows.
• the residue was purified by silica gel column chromatography, and the eluted fraction was concentrated under reduced pressure.
• the resulting residue was solidified with tert-butyl methyl ether, and the solid was collected by filtration.
• the solid was washed with ether tert- butyl methyl ether-heptane (2: 1) and air-dried to obtain 20.4 g of the title compound.
• the property values of the compound are as follows.
• Phosphorus oxychloride (75.6 mL) was added to N-[3-(2,4-difluorophenyl)-2- oxopiperidin-l-yl]-3-p-tolylsulfanylpropionamide (3.66 g), followed by stirring at 120 0 C for one hour. Then, the reaction solution was concentrated under reduced pressure. Ammonium acetate (6.66 g) and acetic acid (90 mL) were sequentially added to the resulting residue, and the reaction mixture was stirred at 15O 0 C for 2.5 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and aqueous ammonia were added to the resulting residue, and the organic layer was separated.
• BOPCl (7.9 g) was added to a solution of 5-chloro-2-(5-isopropyl-4-methoxy-2- methylphenyl)pentanoic acid (6.2 g), tert-butyl carbazate (4.1 g) and IPEA (10.8 ml) in dichloromethane (120 ml) under ice-cooling. Then, the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. A sodium bicarbonate solution and tert-butyl methyl ether were added to the residue, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate.
• the neuronal cell suspension was diluted with the medium and then plated in a volume of 100 ⁇ l/well at an initial cell density of 5 x 10 5 cells/cm 2 in a 96- well polystyrene culture plate pre- coated with poly-L or D-lysine (Falcon Cat #35-3075, Becton Dickinson Labware, Franklin Lakes, NJ, USA coated with poly-L-lysine using the method shown below, or BIOCO ATTM cell environments Poly-D-lysine cell ware 96- well plate, Cat #35-6461, Becton Dickinson Labware, Franklin Lakes, NJ, USA). Poly-L-lysine coating was carried out as follows.
• a poly-L-lysine (SIGMA P2636, St. Louis, MO, USA) solution was aseptically prepared with a 0.15 M borate buffer (pH 8.5).
• 100 ⁇ g/well of the solution was added to the 96-well polystyrene culture plate and incubated at room temperature for one or more hours or at 4 0 C overnight or longer. Thereafter, the coated 96-well polystyrene culture plate was washed with sterile water four or more times, and then dried or rinsed with sterile PBS or medium, and used for cell plating.
• the plated cells were cultured in the culture plate at 37°C in 5% CO 2 -95% air for one day.
• DMSO dimethyl sulfoxide
• the cells were cultured for three days after addition of the compound, and the total amount of the medium was collected. The resulting medium was used as an ELISA sample. [0267] Evaluation of cell survival
• MTT MTT assay
• 100 ⁇ l/well of a pre- warmed medium was added to the wells.
• 8 ⁇ l/well of a solution of 8 mg/ml of MTT (SIGMA M2128, St. Louis, MO, USA) in D-PBS(-) (Dulbecco's phosphate buffered Saline, SIGMA D8537, St. Louis, MO, USA) was added to the wells.
• the 96-well polystyrene culture plate was incubated in an incubator at 37 0 C in 5% CO 2 -95% air for 20 minutes.
• the MTT lysis buffer was prepared as follows. 100 g of SDS (sodium dodecyl sulfate (sodium lauryl sulfate), WAKO 191-07145, Osaka, Japan) was dissolved in a mixed solution of 250 mL of N,N-dimethylformamide (WAKO 045-02916, Osaka, Japan) with 250 mL of distilled water. 350 ⁇ l each of concentrated hydrochloric acid and acetic acid were further added to the solution to allow the solution to have a final pH of about 4.7.
• % of CTRL ((A55O_sample - A550_bkg)/(A550_CTRL - bkg)) x 100 (A550_sample: absorbance at 550 nm of sample well, A550_bkg: absorbance at 550 nm of background well, A550 CTRL: absorbance at 550 nm of control group well) [0268] A ⁇ ELISA
• a ⁇ ELISA Human/Rat ⁇ Amyloid (42) ELISA Kit Wako (#290-62601) from Wako Pure Chemical Industries, Ltd. or Human Amyloid beta ( 1 -42) Assay Kit (#27711 ) from IBL Co., Ltd. was used.
• a ⁇ ELISA was carried out according to the protocols recommended by the manufacturers (methods described in the attached documents). However, the A ⁇ calibration curve was created using beta-amyloid peptide 1-42, rat (Calbiochem, #171596 [A ⁇ 42 ]). The results are shown in Table 1 as percentage to the A ⁇ concentration in the medium of the control group (% of CTRL). [0269]
• the compound of the general formula (I) or pharmacologically acceptable salt thereof according to the present invention have an A ⁇ 42 production reducing effect.
• the present invention can particularly provide a therapeutic agent for a neurodegenerative disease caused by A ⁇ such as Alzheimer's disease or Down's syndrome.
• the compound of the general formula (I) according to the present invention has an A ⁇ production reducing effect, and thus is particularly useful as a therapeutic agent for a neurodegenerative disease caused by A ⁇ such as Alzheimer's disease or Down's syndrome.

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