WO2012046771A1 - Composé de cycloalcane - Google Patents

Composé de cycloalcane Download PDF

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Publication number
WO2012046771A1
WO2012046771A1 PCT/JP2011/072989 JP2011072989W WO2012046771A1 WO 2012046771 A1 WO2012046771 A1 WO 2012046771A1 JP 2011072989 W JP2011072989 W JP 2011072989W WO 2012046771 A1 WO2012046771 A1 WO 2012046771A1
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WIPO (PCT)
Prior art keywords
lower alkyl
optionally substituted
compound
halogen
cyclohexyl
Prior art date
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PCT/JP2011/072989
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English (en)
Japanese (ja)
Inventor
真五 山崎
絵理子 本庄
清寛 三水
昭雄 黒田
公一 米沢
敏 林辺
鈴木　貴之
博昭 星井
泰之 三谷
洋紀 赤芝
Original Assignee
アステラス製薬株式会社
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Publication of WO2012046771A1 publication Critical patent/WO2012046771A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
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    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
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    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D311/78—Ring systems having three or more relevant rings
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    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to a novel cycloalkane compound or a pharmaceutically acceptable salt thereof useful as a pharmaceutical, particularly an agent for preventing or treating Alzheimer's disease.
  • AD Alzheimer's disease
  • QOL quality of life
  • Senile plaques are amyloid ⁇ peptides (A ⁇ 40 or A ⁇ 42) consisting of 40 or 42 residues that form aggregates extracellularly and are considered to be pathological changes that occur in the early stages of AD.
  • a ⁇ 40 produced in vivo is higher than A ⁇ 42, but A ⁇ 42 is more aggregated than A ⁇ 40, and the genes for amyloid ⁇ precursor protein (APP) and presenilin protein that cause early-onset familial AD Since many of the mutations increase the production of A ⁇ 42, not A ⁇ 40, A ⁇ 42 has come to be considered as a causative agent for the onset of AD (Non-patent Document 1).
  • amyloid ⁇ precursor protein APP
  • BACE1 ⁇ -site APP cleaving enzyme 1
  • a ⁇ 42 amyloid ⁇ precursor protein
  • BACE1 ⁇ -site APP cleaving enzyme 1
  • the production of A ⁇ 42 can be suppressed by regulating the function of ⁇ -secretase.
  • the effect has been confirmed with a plurality of compounds. For example, ⁇ -411575, a ⁇ -secretase inhibitor, decreased A ⁇ 40 and A ⁇ 42 in the brain of APP transgenic mice, which are AD model animals, and suppressed senile plaque formation (Non-patent Document 2).
  • Non-patent Document 3 Some non-steroidal anti-inflammatory drugs have been reported to regulate only the amount of A ⁇ 42 without changing the amount of A ⁇ 40 produced by regulating the function of ⁇ -secretase.
  • Non-patent Documents 4 and 5 it is known that the ⁇ -secretase function regulators described in Patent Documents 1 to 6 reduce A ⁇ 42 without affecting the amount of A ⁇ 40 (Non-patent Documents 4 and 5). Since A ⁇ 42 is considered to be a causative agent of the onset of AD, a compound that lowers A ⁇ 42 is expected to be a therapeutic drug that suppresses the progression of AD pathology.
  • Patent Document 1 it is reported that the compound of the formula (A) which is piperidine and related compounds selectively inhibits the production of A ⁇ (1-42) and is useful for treatment of Alzheimer's disease and the like. . (See the official gazette for symbols in the formula.)
  • Patent Document 2 it is reported that the compound of the formula (B) has a ⁇ -secretase function regulating action and is useful for treatment of Alzheimer's disease and the like. (See the official gazette for symbols in the formula.)
  • Patent Document 3 it is reported that the compound of the formula (C) has a ⁇ -secretase function regulating action and is useful for treatment of Alzheimer's disease and the like. (See the official gazette for symbols in the formula.)
  • Patent Document 4 it is reported that the compound of formula (D) has a ⁇ -secretase function regulating action and is useful for treatment of Alzheimer's disease and the like. (See the official gazette for symbols in the formula.)
  • Patent Document 5 reports that the compound of formula (E) selectively inhibits the production of A ⁇ (1-42) and is useful for treatment of Alzheimer's disease and the like. (See the official gazette for symbols in the formula.)
  • Patent Document 6 reports that the compound of the formula (F) selectively inhibits the production of A ⁇ (1-42) and is useful for treatment of Alzheimer's disease and the like. (See the official gazette for symbols in the formula.)
  • Patent Document 7 discloses a compound of formula (G) which is a tachykinin receptor antagonist. Further, in the background art of the patent document, it is reported that tachykinin receptor antagonists are useful for prevention and / or treatment of Alzheimer's disease together with a number of disease names. The compound group is characterized in that ring A is essential. (See the official gazette for symbols in the formula.)
  • Patent Document 8 reports that the compound of formula (H) has a ⁇ -secretase function-modulating action and is useful for the treatment of Alzheimer's disease and the like.
  • X and Y are C (R 9 ) 2 , NR 10 , or O, and the other symbols are referred to in the publication.
  • An object of the present invention is to provide a pharmaceutical composition, particularly a compound having a gamma secretase function-modulating action useful as a preventive and / or therapeutic agent for a disease associated with amyloid ⁇ peptide deposition in the brain.
  • the present invention contains a cycloalkane compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof and a cycloalkane compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. It relates to a composition.
  • R 1 and R 2 are the same or different from each other, and may be substituted lower alkyl, O- (optionally substituted lower alkyl), optionally substituted lower alkenyl, optionally substituted.
  • R 3 and R 5 are the same or different from each other, and H, OH, halogen, optionally substituted lower alkyl, O- (optionally substituted lower alkyl), or lower alkyl (this lower alkyl is Amino optionally substituted with halogen), R 4 is an optionally substituted lower alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, or an optionally substituted heterocyclic group; W is a single bond or -CR W1 R W2- R W1 and R W2 are the same or different from each other, and H, OH, halogen, optionally substituted lower alkyl, O- (optionally substituted lower alkyl), or lower alkyl
  • the present invention relates to a pharmaceutical composition for preventing and / or treating a disease associated with amyloid ⁇ peptide deposition in the brain, comprising a compound of formula (I) or a salt thereof, ie a compound of formula (I) or a salt thereof
  • the present invention relates to a preventive and / or therapeutic agent for a disease associated with amyloid ⁇ peptide deposition in a brain containing a salt.
  • the invention also relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of diseases associated with amyloid ⁇ peptide deposition in the brain, amyloid ⁇ peptide deposition in the brain.
  • a compound of formula (I) or a salt thereof for the prevention and / or treatment of a disease associated with the disease, a compound of formula (I) for the prevention and / or treatment of a disease associated with amyloid ⁇ peptide deposition in the brain, or a method thereof
  • a method for the prevention and / or treatment of diseases associated with amyloid ⁇ peptide deposition in the brain comprising administering to a patient an effective amount of a salt and a compound of formula (I) or a salt thereof.
  • the compound of the present invention strongly suppresses the production of A ⁇ 42 and has an excellent ⁇ -secretase function regulating action, Alzheimer's disease (AD), mild cognitive impairment (MCI), cerebral amyloid angiopathy, Dutch hereditary cerebral hemorrhage It is useful as a preventive and / or therapeutic agent for diseases related to amyloid ⁇ peptide deposition in the brain such as (HCHWA-D), multiple infarct dementia, fighting dementia, or Down's syndrome.
  • AD Alzheimer's disease
  • MCI mild cognitive impairment
  • cerebral amyloid angiopathy Dutch hereditary cerebral hemorrhage
  • the compound of formula (I) or a salt thereof may be referred to as “the compound (I) of the present invention” or “compound (I)”.
  • lower alkyl means linear or branched alkyl having 1 to 6 carbon atoms (hereinafter abbreviated as C 1-6 ), such as methyl, ethyl, n-propyl, isopropyl, n- Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
  • C 1-6 linear or branched alkyl having 1 to 6 carbon atoms
  • C 1-6 such as methyl, ethyl, n-propyl, isopropyl, n- Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
  • C 1-6 linear or branched alkyl having 1 to 6 carbon atoms
  • Linear lower alkyl means linear C 1-6 alkyl among the above “lower alkyl”, and includes methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl. It is. In another embodiment, linear C 1-4 alkyl is used, and in another embodiment, linear C 1-3 alkyl is used.
  • Branched lower alkyl means a branched C 3-6 alkyl among the above “lower alkyl”, for example, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, Isohexyl and the like. In another embodiment, it is branched C 3-5 alkyl, and in another embodiment, it is branched C 3-4 alkyl.
  • lower alkyl having a quaternary carbon means a C 4-6 alkyl having a quaternary carbon among the above “branched lower alkyl”, and examples thereof include tert-butyl, neopentyl, tert-pentyl and the like. In another embodiment, tert-butyl.
  • “Lower alkenyl” refers to linear or branched C 2-6 alkenyl such as vinyl, propenyl, butenyl, pentenyl, 1-methylvinyl, 1-methyl-2-propenyl, 1,3-butadienyl, 1, Such as 3-pentadienyl.
  • Another embodiment is C 2-4 alkenyl, and yet another embodiment is C 2-3 alkenyl.
  • “Lower alkynyl” means linear or branched C 2-6 alkynyl such as ethynyl, propynyl, butynyl, pentynyl, 1-methyl-2-propynyl, 1,3-butadiynyl, 1,3-pentadiynyl and the like. It is. In another embodiment, C 2-4 alkynyl. It is.
  • “Lower alkylene” means linear or branched C 1-6 alkylene such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene. 1,1,2,2-tetramethylethylene and the like. Another embodiment is C 1-4 alkylene, and yet another embodiment is C 1-3 alkylene.
  • Cycloalkyl is a C 3-10 saturated hydrocarbon ring group, which may have a bridge. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like. Another embodiment is C 3-8 cycloalkyl, and yet another embodiment is C 5-7 cycloalkyl.
  • the “aryl” is a C 6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and includes a cyclic group condensed with a C 5-8 cycloalkene at its double bond site.
  • aryl is a C 6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and includes a cyclic group condensed with a C 5-8 cycloalkene at its double bond site.
  • a “heterocyclic” group is i) a 3-8 membered, alternatively 5-7 membered monocyclic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, and Ii)
  • the monocyclic heterocycle is condensed with one or two rings selected from the group consisting of a monocyclic heterocycle, a benzene ring, a C 5-8 cycloalkane and a C 5-8 cycloalkene.
  • Monocyclic saturated heterocyclic groups (a) those containing 1 to 4 nitrogen atoms, such as azepanyl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, azocanyl, hexamethyleneimino , Homopiperazinyl, etc .; (B) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, such as thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl and the like; (C) those containing 1 to 2 sulfur atoms, such as tetrahydrothiopyranyl; (D) those containing 1 to 2 sulfur atoms, such as t
  • (1) monocyclic unsaturated heterocyclic group (a) containing 1 to 4 nitrogen atoms, such as pyrrolyl, 2-pyrrolinyl, imidazolyl, 2-imidazolinyl, pyrazolyl, 2-pyrazolinyl, pyridyl, dihydropyridyl , Tetrahydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, triazinyl, dihydrotriazinyl, azepinyl and the like; (B) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, for example thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl, Oxazinyl and the like; (C
  • a condensed polycyclic saturated heterocyclic group (a) one containing 1 to 5 nitrogen atoms, such as quinuclidinyl, 7-azabicyclo [2.2.1] heptyl, 3-azabicyclo [3.2.2] nonanyl, 2,8-diazaspiro [4.5] dec-8-yl, 2,3,6,8-tetraazaspiro [4.5] decan-8-yl, etc .; (B) those containing 1 to 4 nitrogen atoms, and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, such as trithiadiazaindenyl, dioxoleumidazolidinyl, 6- Oxa-2,8-diazaspiro [4.5] decan-8-yl, 6-thia-2,8-diazaspiro [4.5] decan-8-yl and the like; (C) those containing 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, such as 2,6-dioxabicycl
  • condensed polycyclic unsaturated heterocyclic group (a) containing 1 to 5 nitrogen atoms for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, dihydrobenzimidazolyl, tetrahyzolobenzimidazolyl, quinolyl, tetrahydro Quinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, imidazopyridyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, acridinyl, quinoxalinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl, phthalazinyl, dihydroindazo Ryl, benzopyrimidinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pyri
  • the “nitrogen-containing heterocycle” group is one of the above “heterocycle” groups (1) (a), (1) (b), (2) (a), (2) (b), (3) A material containing 1 to 5 nitrogen atoms, such as (a), (3) (b), (4) (a) and (4) (b).
  • the “nitrogen-containing unsaturated heterocycle” group is a group (2) (a), (2) (b), (4) (a) and (4) among the above “nitrogen-containing heterocycle” groups. (B) and the like having an unsaturated bond.
  • the “nitrogen-containing monocyclic saturated heterocycle” group is a group selected from the above-mentioned “monocyclic saturated heterocycle” groups such as (1) (a), (1) (b), etc. It contains 5 nitrogen atoms.
  • the “nitrogen-containing monocyclic unsaturated heterocycle” group includes the above “monocyclic unsaturated heterocycle” groups such as (2) (a), (2) (b), etc. One containing 1 to 5 nitrogen atoms.
  • the “nitrogen-containing fused polycyclic saturated heterocycle” group is the above-mentioned “fused polycyclic saturated heterocycle” group such as (3) (a), (3) (b), etc. One containing 1 to 5 nitrogen atoms.
  • the “nitrogen-containing fused polycyclic unsaturated heterocycle” group is a group such as (4) (a) and (4) (b) among the above “fused polycyclic unsaturated heterocycle” groups. And those containing 1 to 5 nitrogen atoms.
  • Halogen means F, Cl, Br, I, preferably F, Cl.
  • Disease related to amyloid ⁇ peptide deposition in the brain is a concept including a disease related to production and / or deposition of A ⁇ 42, and is not particularly limited.
  • AD Alzheimer's disease
  • MCI mild cognitive impairment
  • HHWA-D Dutch hereditary cerebral hemorrhage
  • multiple infarct dementia fighting dementia, or Down syndrome.
  • AD Alzheimer's disease
  • a ⁇ 1-42 is an abbreviation of amyloid ⁇ protein that is excised as a molecular species of amino acid 42 residues, and is an insoluble cell composed of proteins, lipids, carbohydrates and salts in the brains of Alzheimer and Down syndrome patients It is the central component of external deposits (senile or neuritic plaques) (CLMasters et al. PNAS 82, 4245-4249, 1985).
  • a ⁇ x-42 means a molecular species in which the N-terminal side is deleted from “A ⁇ 1-42”.
  • a ⁇ 42 means a generic name including the above A ⁇ 1-42 and A ⁇ x-42.
  • “optionally substituted” means unsubstituted or having 1 to 5 substituents.
  • those substituents may be the same, or may mutually differ.
  • —N (lower alkyl) 2 includes an ethylmethylamino group.
  • substituents allowed in the “optionally substituted aryl”, “optionally substituted cycloalkyl” and “optionally substituted heterocycle” groups in R 4 include the following (a ) To (l), SF 5 and oxo ( ⁇ O). As another embodiment, the groups shown in the following (a) to (j) and oxo ( ⁇ O) can be mentioned.
  • the following (a) to (c), (e), and (h) to (l) are further exemplified as the substituents allowed in the “optionally substituted aryl” for R 4 . .
  • the aryl may be substituted with halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens).
  • the heterocyclic group may be substituted with halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens).
  • the cycloalkyl may be substituted with halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens).
  • (K) amino, nitro optionally substituted with 1 or 2 lower alkyls, which may be substituted with oxo ( O) or cycloalkyl.
  • Examples of the substituents allowed in the “optionally substituted lower alkyl” in R 4 include the groups shown in the above (a) to (i) and oxo ( ⁇ O). .
  • Another embodiment includes the groups shown in the above (a) and (g).
  • Yet another embodiment includes the group shown in (a) above.
  • Yet another embodiment includes the group shown in the above (g).
  • substituents allowed in the “optionally substituted aryl”, “optionally substituted cycloalkyl” and “optionally substituted heterocycle” groups in R 1 and R 2 For example, the groups shown in the above (a) to (j) and oxo ( ⁇ O) can be mentioned. Another embodiment includes the groups shown in the above (a), (b), (f), (i) and (j). Yet another embodiment includes the groups shown in the above (a), (b), (f) and (j). Still another embodiment of the substituent allowed in “optionally substituted aryl” in R 1 and R 2 includes the groups shown in the above (b), (f) and (j). Still another embodiment of the substituents allowed in the “optionally substituted cycloalkyl” in R 1 and R 2 is shown in (a), (b), (i) and (j) above. Groups.
  • substituents allowed in “optionally substituted lower alkyl”, “optionally substituted lower alkenyl” and “optionally substituted lower alkynyl” in R 1 and R 2 examples thereof include the groups shown in the above (a) to (i) and oxo ( ⁇ O).
  • Another embodiment includes the groups shown in the above (a) to (b) and (g) to (i).
  • Still another embodiment includes the groups shown in the above (a) and (g).
  • Yet another embodiment includes the group shown in (a) above.
  • Examples of the substituents allowed in the “optionally substituted lower alkyl” in R 5 include the groups shown in the above (a) to (i). Another embodiment includes the group shown in (a) above.
  • Examples of the substituents allowed in the “optionally substituted lower alkylene” in L include the groups shown in the above (a) to (h). Another embodiment includes the group shown in the above (b).
  • Examples of the substituents allowed in the “optionally substituted lower alkyl” in L include the groups shown in the above (a) to (h). Another embodiment includes the group shown in the above (a).
  • Examples of the substituents allowed in the “optionally substituted tetrazole group” in Z include the groups shown in the above (g) to (j).
  • the “optionally substituted heterocycle” group in R 1 and R 2 is preferably an “optionally substituted nitrogen-containing monocyclic unsaturated heterocycle” group, and more preferably “substituted” An optionally substituted pyridine ", more preferably” an optionally substituted pyridin-3-yl ".
  • substituents allowed in the “optionally substituted nitrogen-containing monocyclic unsaturated heterocycle” group “optionally substituted pyridine” and “optionally substituted pyridin-3-yl”
  • the same group as the “optionally substituted heterocycle” group in the above R 1 and R 2 can be mentioned.
  • the “optionally substituted aryl” in R 1 and R 2 is preferably “optionally substituted phenyl”.
  • a substituent allowed in the “optionally substituted phenyl” for example, the same group as the “optionally substituted aryl” in the above R 1 and R 2 can be mentioned.
  • the “optionally substituted cycloalkyl” in R 1 and R 2 is preferably “optionally substituted C 3-7 cycloalkyl”, more preferably “optionally substituted C 3 5-7 cycloalkyl ”, more preferably“ optionally substituted cyclohexyl ”.
  • An embodiment of an acceptable substituent in the “ optionally substituted C 3-7 cycloalkyl”, “ optionally substituted C 5-7 cycloalkyl” and “optionally substituted cyclohexyl” As, for example, the same group as the “optionally substituted cycloalkyl” in the above R 1 and R 2 can be mentioned.
  • the “optionally substituted heterocycle” group in R 4 is preferably an “optionally substituted nitrogen-containing unsaturated heterocycle” group, more preferably “optionally substituted pyridine, An optionally substituted quinoline or 1,2,3,6-tetrahydropiperazine ”, more preferably“ an optionally substituted pyridine-3-yl, an optionally substituted quinoline-3 ”. -Yl or optionally substituted 1,2,3,6-tetrahydropiperazin-4-yl ”.
  • optionally substituted nitrogen-containing unsaturated heterocycle “optionally substituted pyridine, optionally substituted quinoline, or 1,2,3,6-tetrahydropiperazine” and “substituted Permissible in “optionally substituted pyridin-3-yl, optionally substituted quinolin-3-yl, or optionally substituted 1,2,3,6-tetrahydropiperazin-4-yl”
  • a substituent for example, the same group as the “optionally substituted heterocycle” group in the above R 4 can be mentioned.
  • the “optionally substituted aryl” for R 4 is preferably “optionally substituted phenyl”. As an aspect with the substituent permitted in the “optionally substituted phenyl”, for example, the same group as the “optionally substituted aryl” in the above R 4 can be mentioned.
  • the “optionally substituted cycloalkyl” in R 4 is preferably “optionally substituted C 5-6 cycloalkyl”.
  • the substituent allowed in the “ optionally substituted C 5-6 cycloalkyl” for example, the same group as the “ optionally substituted cycloalkyl” in the above R 4 can be exemplified. Can be mentioned.
  • heterocyclic group of “aryl optionally substituted with a heterocyclic group” in R 4 is preferably a “monocyclic saturated heterocyclic” group, more preferably “pyrrolidine or tetrahydropyran”. More preferably, it is “pyrrolidin-1-yl or tetrahydropyran-4-yl”.
  • R 3 and R 5 are the same or different from each other, and H, OH, halogen, optionally substituted lower alkyl, O- (optionally substituted lower alkyl), or lower alkyl (this lower alkyl is Amino optionally substituted with halogen), R 4 is an optionally substituted lower alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, or an optionally substituted heterocyclic group; W is a single bond or -CR W1 R W2- R W1 and R W2 are the same or different from each other, and H, OH, halogen, optionally substituted lower alkyl, O- (optionally substituted lower alkyl), or lower alkyl
  • Y is a single bond, or -CH 2- , However, when W is a single bond and one of R 1 and R 2 is optionally substituted lower alkyl, the other is optionally substituted aryl or optionally substituted heterocycle Not a group. )
  • R 11 , R 12 , R 13 And R 14 Wherein H is H.
  • R 1 And R 2 Are the same or different from each other, optionally substituted lower alkyl, O- (optionally substituted lower alkyl), optionally substituted lower alkenyl, optionally substituted cycloalkyl, O- A compound which is (optionally substituted cycloalkyl), aryl which may be substituted, or heterocyclic group which may be substituted.
  • R 1 And R 2 are the same or different from each other, branched lower alkyl optionally substituted by halogen, linear lower alkyl substituted by halogen, halogen or lower alkyl (this lower alkyl is 1 to 3 Optionally substituted with cycloalkyl, optionally substituted with cycloalkyl, halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens) Good O- (cycloalkyl), halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens) aryl, or halogen or lower alkyl (this The lower alkyl is a heterocyclic group which may be substituted with 1 to 3 halogen atoms.
  • R 1 And R 2 are the same or different from each other, branched lower alkyl optionally substituted by halogen, linear lower alkyl substituted by halogen, halogen or lower alkyl (this lower alkyl is 1 to 3 C optionally substituted with halogen) 5-7 Cycloalkyl, O- (C optionally substituted with halogen 5-7 Cycloalkyl), halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens), phenyl or tetrahydropyran optionally substituted with halogen
  • R 1 Is lower alkyl having a quaternary carbon and R 2 Is a lower alkyl having a quaternary carbon, or C 5-7 A compound that is a cycloalkyl.
  • R 1 And R 2 Are the same or different from each other and optionally substituted cycloalkyl.
  • R 1 And R 2 Are the same or different from each other, and are compounds which are cycloalkyl optionally substituted with halogen or lower alkyl, which lower alkyl may be substituted with 1 to 3 halogens.
  • R 1 And R 2 Are the same or different from each other and may be substituted with halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens). 5-7 A compound that is a cycloalkyl. (10) R 1 And R 2 Are the same or different from each other, and cyclopentyl, halogen or lower alkyl (this lower alkyl) which may be substituted with halogen or lower alkyl (which may be substituted with 1 to 3 halogens).
  • R 1 And R 2 Are the same or different from each other and are cyclohexyl which may be substituted with halogen or lower alkyl (which may be substituted with 1 to 3 halogens).
  • R 1 And R 2 Are the same or different from each other and are cyclopentyl, cyclohexyl, or cycloheptyl.
  • R 1 And R 2 Are the same or different from each other and optionally substituted aryl.
  • R 1 And R 2 Are the same or different from each other and are aryls optionally substituted by halogen, cyano or lower alkyl, which may be substituted with 1 to 3 halogens.
  • R 1 And R 2 Are the same or different from each other and are phenyl optionally substituted by halogen, cyano or lower alkyl, which lower alkyl may be substituted with 1 to 3 halogens.
  • R 1 And R 2 Are the same or different from each other and are phenyl optionally substituted by F or trifluoromethyl.
  • R 1 And R 2 are the same or different from each other and are phenyl or 4-trifluorophenyl. (19) R 1 And R 2 Are the same or different from each other and optionally substituted lower alkyl. (20) R 1 And R 2 Are the same or different from each other, and are a branched lower alkyl which may be substituted with halogen, or a linear lower alkyl substituted with halogen. (21) R 1 And R 2 Are the same or different from each other and are trifluoromethyl, isopropyl, or tert-butyl. (22) R 1 And R 2 In which is isopropyl. (23) R 1 Is isopropyl and R 2 In which is trifluoromethyl.
  • R 1 Is a lower alkyl having a quaternary carbon optionally substituted with halogen
  • R 2 Is a lower alkyl having a quaternary carbon which may be substituted with a halogen, or a linear lower alkyl substituted with a halogen.
  • R 1 And R 2 Are lower alkyl having the same or different from each other and having a quaternary carbon which may be substituted with halogen.
  • R 1 And R 2 In which is tert-butyl.
  • R 1 Is a branched lower alkyl optionally substituted with halogen, or a linear lower alkyl substituted with halogen
  • R 2 Is a cycloalkyl optionally substituted with halogen or lower alkyl, which lower alkyl may be substituted with 1 to 3 halogens.
  • R 1 Is a branched lower alkyl optionally substituted with halogen, or a linear lower alkyl substituted with halogen
  • R 2 Is optionally substituted by halogen or lower alkyl (which may be substituted with 1 to 3 halogens) 5-7
  • R 1 Is branched lower alkyl optionally substituted with halogen, R 2 In which is cyclopentyl, cyclohexyl, or cycloheptyl.
  • R 1 Is isopropyl or tert-butyl and R 2 In which is cyclopentyl, cyclohexyl or cycloheptyl.
  • R 1 Is isopropyl and R 2 Is a cyclohexyl compound.
  • R 1 Is a lower alkyl having a quaternary carbon optionally substituted with halogen, and R 2 In which is cyclopentyl, cyclohexyl or cycloheptyl.
  • R 1 Is tert-butyl and R 2 In which is cyclopentyl, cyclohexyl or cycloheptyl.
  • R 1 Is tert-butyl and R 2 Is a cyclohexyl compound.
  • a compound wherein q and p are the same or different from each other and are 1 or 2.
  • a compound wherein q and p are the same or different from each other and are 2 or 3.
  • the compound wherein q is 2 and p is 1 or 2.
  • the compound wherein q and p are 1.
  • the compound wherein q and p are 1.
  • the compound wherein q and p are 2.
  • Still another embodiment of the compounds (I) and (I ′) of the present invention is a compound comprising a combination of two or more of the groups described in the above (1) to (56). Specifically, The following compounds are mentioned. (57) R 11 , R 12 , R 13 And R 14 The compound according to (2) to (35), wherein is H.
  • R Five (1) to (47) or (57) to (69) is a compound wherein is H, halogen, or lower alkyl optionally substituted with halogen.
  • (71) R Five (1) to (47), or (57) to (69).
  • (72) R X1 And R X2 (1) to (49), or (57) to (71).
  • (73) The compound described in (1) to (50) or (57) to (72), wherein n is 2.
  • n is 2, 3, or 4.
  • L is lower alkylene.
  • R 1 And R 2 Are the same or different from each other, optionally substituted cycloalkyl, optionally substituted lower alkyl, O- (optionally substituted lower alkyl), or optionally substituted aryl.
  • R 1 And R 2 Are the same or different from each other, cycloalkyl, lower alkyl optionally substituted with halogen, O- (lower alkyl optionally substituted with aryl), or lower alkyl (this lower alkyl is substituted with halogen) A compound which is aryl optionally substituted with (optionally).
  • R 1 And R 2 Are the same as or different from each other, cycloalkyl, linear lower alkyl optionally substituted with F, branched lower alkyl, O- (lower alkyl optionally substituted with phenyl), or tri A compound which is aryl optionally substituted with fluoromethyl.
  • R 1 And R 2 are the same or different from each other, C 3-6 Cycloalkyl, linear lower alkyl optionally substituted with F, branched lower alkyl, O- (lower alkyl optionally substituted with phenyl), or substituted with trifluoromethyl A compound that is a good phenyl.
  • R 1 And R 2 Are the same or different from each other, C 3-6 Cycloalkyl, methyl optionally substituted with F, branched C 3-5 A compound that is alkyl, O- (methyl optionally substituted with phenyl), or phenyl optionally substituted with trifluoromethyl.
  • R 1 And R 2 are the same or different from each other, and cyclohexyl, methyl, trifluoromethyl, isopropyl, tert-butyl, O- (methyl optionally substituted with phenyl), or phenyl optionally substituted with trifluoromethyl A compound.
  • R 1 And R 2 Are the same or different from each other and are cycloalkyl or lower alkyl
  • R 1 And R 2 Are the same or different from each other and are cycloalkyl, linear lower alkyl, or branched lower alkyl.
  • R 1 And R 2 Are the same or different from each other, C 3-6 A compound which is cycloalkyl, linear lower alkyl, or branched lower alkyl.
  • R 1 And R 2 Are the same or different from each other, C 3-6 Cycloalkyl, methyl, or branched C 3-5 A compound that is alkyl.
  • R 1 And R 2 Are the same or different from each other and are cyclohexyl, methyl, isopropyl, or tert-butyl.
  • R 1 And R 2 are the same or different from each other, and may be a branched lower alkyl optionally substituted with a halogen, a linear lower alkyl substituted with a halogen, a cycloalkyl, or a halogen or a lower alkyl (the lower alkyl is 1 A compound which is aryl optionally substituted with 1 to 3 halogens.
  • R 1 And R 2 are the same or different from each other and may be substituted with a halogenated branched lower alkyl, a halogen-substituted linear lower alkyl, C 5-7 A compound that is cycloalkyl, or phenyl optionally substituted with halogen or lower alkyl, which lower alkyl may be substituted with 1 to 3 halogens.
  • R Five (83) to (95) or (110) to (122) is a compound wherein is H, halogen, or lower alkyl optionally substituted with halogen.
  • (124) R Five (83) to (95), or (110) to (122).
  • (125) R X1 And R X2 (83) to (95), or (110) to (124).
  • (126) The compounds described in (83) to (95) or (110) to (125), wherein n is 2.
  • n is 2, 3, or 4 (1) to (50), (53) to (56), (79), (81) to (95), (110) to (125) Or a compound described in (128) to (132).
  • L is lower alkylene (1) to (53), (55) to (56), (79) to (80), (82) to (95), (110) to (128), Or compounds according to (131) to (133).
  • R Four Are an optionally substituted aryl or an optionally substituted heterocyclic group (1) to (45), (48) to (56), (79) to (95), (110) The compound according to (120) or (123) to (135).
  • R Four Is halogen, cyano, lower alkyl (this lower alkyl may be substituted with halogen or OH), O- (lower alkyl optionally substituted with halogen), cycloalkyl, SF Five Or -SO 2 -Aryl which may be substituted with lower alkyl, or heterocyclic groups which may be substituted with lower alkyl (which may be substituted with halogen or aryl) (1) to ( 45), (48) to (56), (79) to (95), (110) to (120), or (123) to (135).
  • (140) R Four Is halogen, cyano, lower alkyl (this lower alkyl may be substituted with F or OH), O— (lower alkyl optionally substituted with F), cycloalkyl, SF Five Or -SO 2 -Phenyl optionally substituted with lower alkyl, lower alkyl (this lower alkyl may be substituted with F), pyridyl, quinolyl, or lower alkyl (this lower alkyl is (1) to (45), (48) to (56), (79) to (95) which are 1,2,3,6-tetrahydropiperazine optionally substituted with (optionally substituted with phenyl) ), (110) to (120), or (123) to (135).
  • Examples of specific compounds included in the present invention include the following compounds or salts thereof.
  • “Rac-” means a racemate of the described compound and its enantiomer. ⁇ (1R * , 3S * , 4R * )-4- [bis (cyclohexylmethyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl ⁇ acetic acid, ⁇ (1R * , 3S * , 4R * )- ⁇ 4-[(cyclohexylmethyl) (3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl ⁇ acetic acid, ⁇ (1R * , 3S * , 4R * )-4- [bis (3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl ⁇ acetic acid, ⁇ (1R * , 3S * ,
  • tautomers and geometric isomers may exist depending on the type of substituent.
  • the compound of the formula (I) may be described in only one form of an isomer, but the present invention includes other isomers, separated isomers, or those isomers. And mixtures thereof.
  • the compound of formula (I) may have an asymmetric carbon atom or axial asymmetry, and optical isomers based on these may exist.
  • the present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.
  • the present invention includes a pharmaceutically acceptable prodrug of the compound represented by the formula (I).
  • a pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions.
  • groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Is mentioned.
  • the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and may form an acid addition salt or a salt with a base depending on the type of substituent. is there.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium and
  • the present invention also includes various hydrates and solvates of the compound of formula (I) and salts thereof, and crystalline polymorphic substances.
  • the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
  • Rf Production example number (when a or b is written after the number, it means that two products were obtained in one reaction)
  • Ex Example number (when a or b is written after the number, it means that two products were obtained in one reaction)
  • FAB + Shows m / z value in FAB-MS (positive ion), and shows [M + H] + peak unless otherwise specified.
  • FAB- FAB-MS showed the m / z value in (anion) Unless otherwise specified [MH] - a peak
  • ESI + Shows m / z value in ESI-MS (positive ion), and shows [M + H] + peak unless otherwise specified.
  • ESI- ESI-MS showed the m / z value in (anion) Unless otherwise specified [MH] - a peak
  • EI Shows m / z value in EI-MS (positive ion), and shows M + peak unless otherwise specified.
  • CI + Shows m / z value in CI-MS (positive ion), and shows [M + H] + peak unless otherwise specified.
  • APCI / ESI + Shows the m / z value in APCI / ESI (positive ion), showing [M + H] + peak unless otherwise specified
  • NMR1 ⁇ (ppm) of a typical peak in 1 H NMR in CDCl 3
  • NMR2 ⁇ (ppm) of a typical peak in 1 H NMR in pyridine-d 5
  • NMR3 ⁇ (ppm) of a typical peak in 1 H NMR in CD 3 OD
  • free Compound instead of 1 H NMR data of the salts of the compounds means that described 1 H NMR data of the free form
  • RT column using CHIRALPAK AD-H, hexane / EtOH / Et 2 NH
  • ABS-SINGLE-3 A compound produced from ABS-SINGLE-5 as a raw material, and the substituent on the cyclohexane ring has one of the following three-dimensional structures
  • ABS-SINGLE-4 A compound produced from ABS-SINGLE-6 as a raw material, the substituent on the cyclohexane ring has any of the following three-dimensional structures
  • ABS-SINGLE-5 a compound in which a substituent on the cyclohexane ring has any one of the following three-dimensional structures, and a compound obtained preferentially among these in a reaction to obtain the compound
  • ABS-SINGLE-6 a compound in which the substituent on the cyclohexane ring has one of the following steric structures, and a compound obtained preferentially among these in a reaction to obtain the compound
  • ABS-SINGLE-7 Among the compounds synthesized by the method of Production Example 674, the conditions described in the Production Example (col
  • ABS-SINGLE-11 Among the compounds synthesized by the method of Production Example 677, the compound that exhibits the 1 H-NMR peak described in the Production Example, or the compound produced using the compound as a raw material, cyclohexane
  • the compound in which the substituent on the ring has any of the following three-dimensional structures is meant.
  • ABS-SINGLE-12 A compound manufactured from ABS-SINGLE-11 as a raw material, the substituent on the cyclohexane ring has one of the following three-dimensional structures, and the solid at the position of the arrow is S A mixture of compounds which is R.
  • ABS-SINGLE-13 Compound synthesized by the method of Example 371 using the ABS-SINGLE-11 compound as a raw material, and showing a 1 H-NMR peak described in the production examples, or a salt of the compound, cyclohexane A compound in which a substituent on the ring has any of the following three-dimensional structures, and a compound having a relative configuration different from that of ABS-SINGLE-14.
  • ABS-SINGLE-14 Compound synthesized by the method of Example 371 using the ABS-SINGLE-11 compound as a raw material, and showing a 1 H-NMR peak described in the production examples, or a salt of the compound, and cyclohexane A compound in which a substituent on the ring has any of the following three-dimensional structures, and a compound having a relative configuration different from that of ABS-SINGLE-13.
  • the compound of the formula (I) and a salt thereof can be produced by applying various known synthesis methods using characteristics based on the basic structure or the type of substituent. At that time, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protective group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. There is a case. In particular, among the following production examples and example compounds, when a compound having OH is used, it may be desirable to introduce a suitable protecting group so that the OH group does not cause a side reaction, so that the reaction proceeds. .
  • protecting groups include protecting groups described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” by PGM Wuts and TW Greene. These may be appropriately selected according to the reaction conditions.
  • the desired compound after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group as necessary.
  • the prodrug of the compound of formula (I) introduces a specific group at the stage from the raw material to the intermediate, or reacts further using the obtained compound of formula (I), as in the case of the protecting group.
  • the reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
  • typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description.
  • the manufacturing method of this invention is not limited to the example shown below.
  • the compound (I) of the present invention can be obtained by reacting the compound (27) with aldehydes or ketones. In this reaction, an equal amount or an excess amount of compound (27) and aldehydes or ketones are used, and a mixture thereof is heated to reflux from ⁇ 45 ° C. in a solvent inert to the reaction in the presence of a reducing agent. Under stirring, preferably at 0 ° C. to room temperature, usually for 0.1 hour to 5 days.
  • Examples of the solvent used here are not particularly limited, but halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, alcohols such as methanol and ethanol, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like. And ethers thereof, and mixtures thereof.
  • Examples of the reducing agent include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride and the like. It may be preferable to carry out the reaction in the presence of a dehydrating agent such as molecular sieves, or an acid such as acetic acid or hydrochloric acid, or an additive such as a titanium (IV) isopropoxide complex.
  • a reduction catalyst for example, palladium carbon, Raney nickel, etc.
  • a solvent such as methanol, ethanol, ethyl acetate
  • an acid such as acetic acid or hydrochloric acid.
  • This reaction can also be obtained by reacting compound (27) with R 2- (CR 13 R 14 ) p -Lv.
  • Lv represents a leaving group and includes, for example, halogen, methanesulfonyloxy, p-toluenesulfonyloxy group and the like.
  • the compound (27) and R 2- (CR 13 R 14 ) p -Lv are used in an equal amount or in an excess amount, and a mixture of these in a solvent inert to the reaction in the presence of a base, The reaction is carried out at 45 ° C. under heating and reflux, preferably at 0 ° C. to 80 ° C., usually for 0.1 hour to 5 days.
  • Examples of the solvent used here are not particularly limited, but halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, N, N- Examples include dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof.
  • the base used here is an inorganic base such as cesium carbonate, potassium phosphate, potassium carbonate, sodium carbonate or potassium hydroxide, or an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine. Is mentioned.
  • compound (Ia) can be obtained by reacting compound (26) with amines. This reaction can be carried out using the same reaction conditions as in the aforementioned (first production method).
  • R Pr represents a substituent that becomes a protective group for carboxylic acid after the reaction of lower alkyl, aryl, etc.
  • TMS represents a trimethylsilyl group.
  • Compound (2) can be obtained by reacting compound (1) with alcohols or phenols (28). In this reaction, the compound (2) is used in an equal or excessive amount of an alcohol or phenol (28), and the mixture is heated to reflux in a solvent inert to the reaction or in the absence of solvent and from under cooling. Under stirring, preferably at 0 ° C. to 80 ° C., usually for 0.1 hour to 5 days.
  • solvent used here examples include, but are not limited to, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dichloromethane and 1,2-dichloroethane.
  • Halogenated hydrocarbons such as chloroform, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof. It may be advantageous to carry out the reaction in the presence of an acid such as sulfuric acid, hydrochloric acid, thionyl chloride, etc., to facilitate the reaction.
  • the above reaction can also be carried out in the presence of a condensing agent.
  • a condensing agent examples include dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC ⁇ HCl) and the like can be used.
  • WSC ⁇ HCl 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • the compound (3) can be synthesized by a Diels-Alder reaction between the compound (2) and the compound (29).
  • a mixture of the compound (2) and an equal amount or an excess amount of the compound (29) is heated in a solvent inert to the reaction or in the absence of a solvent from cooling to heating, preferably from -50 ° C to 150 ° C.
  • the reaction is carried out at 0 ° C., more preferably from 0 to 130 ° C., usually for 1 hour to 10 days, preferably 1 to 3 days.
  • solvent used in these steps include, but are not limited to, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, and diethyl ether. , Ethers such as tetrahydrofuran, dioxane, dimethoxyethane and the like.
  • R X1a and R X2a represent R X1 and R X2 groups other than H
  • Lv represents a leaving group
  • Q represents-(CR X1 R X2 ) n-1- .
  • Compound (5) can be obtained by addition reaction of compound (4) and R X1a -Lv.
  • the leaving group include halogen, methanesulfonyloxy, p-toluenesulfonyloxy group and the like.
  • compound (4) and an equal amount or excess amount of R X1a -Lv are used in the presence of a base, and a mixture thereof is cooled in a solvent inert to the reaction or in the absence of solvent.
  • the mixture is stirred for 0.1 hour to 5 days under heating and reflux, preferably at 0 to 80 ° C.
  • solvent used here include, but are not limited to, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dichloromethane and 1,2-dichloroethane.
  • Halogenated hydrocarbons such as chloroform, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof.
  • the base used here is a metal amide such as lithium diisopropylamide (LDA) or lithium tetramethyldisilazide (LHMDS), or an inorganic substance such as cesium carbonate, potassium phosphate, potassium carbonate, sodium carbonate or potassium hydroxide.
  • LDA lithium diisopropylamide
  • LHMDS lithium tetramethyldisilazide
  • an inorganic substance such as cesium carbonate, potassium phosphate, potassium carbonate, sodium carbonate or potassium hydroxide.
  • compound (6) can be obtained by addition reaction of compound (5) and R X2a -Lv. This reaction can be carried out using the same reaction conditions as for compound (3) and R X1a -Lv.
  • R Cr represents a substituent that becomes a protecting group for carboxylic acid after the reaction of lower alkyl, aryl, etc.
  • R P represents lower alkyl.
  • Compound (8) can be obtained by hydrolysis reaction of compound (7). This reaction can be carried out with reference to the aforementioned Green et al.
  • the compound (9) can be obtained by converting the compound (8) into an acyl azide and then converting it into an isocyanate by a Curtius rearrangement reaction, followed by an addition reaction with the compound (30).
  • the azidation step is carried out in an inert solvent in the reaction under cooling to heating, preferably at 0 ° C.
  • the reaction is carried out by reacting with an azide reagent such as azide usually for 0.1 to 10 hours, preferably 3 to 6 hours. Or it can also manufacture by making (8) into reactive derivatives, such as an acid chloride, and making it react with azide salts, such as sodium azide.
  • an azide reagent such as azide usually for 0.1 to 10 hours, preferably 3 to 6 hours.
  • it can also manufacture by making (8) into reactive derivatives, such as an acid chloride, and making it react with azide salts, such as sodium azide.
  • the acyl azide is cooled to heated in a solvent inert to the reaction, preferably 0 to 100 ° C., more preferably 70 to 90 ° C., usually 0.1 to 10 hours, preferably 1 to 4 It is carried out by reacting for about an hour.
  • the reaction mixture is added to an equal or excess amount of compound (30) under heating, preferably at 0 ° C. to 100 ° C., more preferably at 70 to 90 ° C., and usually for 0.1 to 10 hours, preferably React for about 1 to 3 hours.
  • the intermediate acyl azide or isocyanate is stable, it may be isolated and then subjected to the next reaction.
  • the solvent used in these steps include, but are not limited to, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, and diethyl ether.
  • the compound (10) can be obtained by reacting the compound (9) with a phosphonic acid ester compound (31) or a phosphonium salt.
  • this reaction is not specifically limited, For example, it can carry out by Horner-Emmons (Horner-Emmons) reaction or Wittig (Wittig) reaction.
  • the compound (9) is added in the presence of an equivalent amount or an excess amount of the phosphonic acid ester compound (31).
  • ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, N, N-dimethylformamide and dimethyl
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • N, N-dimethylformamide and dimethyl examples thereof include sulfoxide or a mixture thereof.
  • a base such as sodium bis (trimethylsilyl) amide, n-butyllithium, tert-butoxypotassium, sodium ethoxide, sodium methoxide, sodium hydride, etc., in order to facilitate the reaction. There are cases.
  • Examples of the phosphonate compound (31) include triethyl phosphonoacetate.
  • Compound (11) can be obtained by hydrogenation reaction and deprotection reaction of compound (10). In this reaction, the compound (10) is usually stirred for 1 hour to 5 days in a solvent inert to the reaction in the presence of a metal catalyst in a hydrogen atmosphere. This reaction is usually carried out under cooling to heating, preferably at room temperature.
  • Examples of the solvent used here are not particularly limited, but alcohols such as methanol, ethanol and 2-propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, water, ethyl acetate, N, N- Examples include dimethylformamide, dimethyl sulfoxide, and mixtures thereof.
  • metal catalysts palladium catalysts such as palladium carbon, palladium black and palladium hydroxide, platinum catalysts such as platinum plate and platinum oxide, nickel catalysts such as reduced nickel and Raney nickel, rhodium catalysts such as tetrakistriphenylphosphine chlororhodium, reduction
  • An iron catalyst such as iron is preferably used.
  • an equivalent to excess amount of cyclohexene, formic acid, ammonium formate or the like relative to compound (10) can be used as a hydrogen source.
  • This reaction may also be performed by bringing compound (10) into contact with magnesium in the presence of methanol. This reaction is usually carried out under cooling to heating, preferably at room temperature.
  • the solvent used here are not particularly limited, but alcohols such as methanol, ethanol and 2-propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, water, ethyl acetate, N, N- Examples include dimethylformamide, dimethyl sulfoxide, and mixtures thereof.
  • compound (38) can be obtained by an amidation reaction of NH 3 with a carboxylic acid form obtained by hydrolysis of compound (7) or a reactive derivative thereof.
  • carboxylic acid form of compound (7) is used, NH 3 is used in the same amount or in excess of the carboxylic acid form, and the mixture is heated in the presence of a condensing agent in a solvent inert to the reaction from under cooling. Under stirring, preferably at -20 ° C to 60 ° C, usually for 0.1 hour to 5 days.
  • solvent used here are not particularly limited, but aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, diethyl ether, tetrahydrofuran , Ethers such as dioxane and dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile or water, and mixtures thereof.
  • aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform
  • diethyl ether diethyl ether
  • tetrahydrofuran Ethers such as dioxane and dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, eth
  • condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole, diphenyl phosphate azide, and phosphorus oxychloride. Is not to be done. It may be preferred for the reaction to use an additive (eg 1-hydroxybenzotriazole). Performing the reaction in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide can facilitate the reaction. May be advantageous.
  • an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine
  • an inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide can facilitate the reaction. May be advantageous.
  • reaction is with a reactive derivative of the carboxylic acid form
  • a method of reacting with NH 3 can also be used.
  • reactive derivatives of carboxylic acids include acid halides obtained by reacting with halogenating agents such as phosphorus oxychloride and thionyl chloride, mixed acid anhydrides obtained by reacting with isobutyl chloroformate, 1-hydroxy Examples include active esters obtained by condensation with benzotriazole and the like.
  • the reaction of these reactive derivatives with NH 3 is carried out in a solvent inert to the reaction of halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc., under cooling to heating, preferably from ⁇ 20 ° C. Can be performed at 60 ° C.
  • compound (12) can be obtained by the reduction reaction of compound (38).
  • compound (38) is usually treated for 0.1 hour to 3 days with an equal or excess reducing agent in a solvent inert to the reaction, under cooling to heating, preferably at -20 ° C to 80 ° C. To do.
  • ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane
  • alcohols such as methanol, ethanol and 2-propanol
  • aromatics such as benzene, toluene and xylene.
  • hydrocarbons N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, and mixtures thereof.
  • a hydride reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride, a metal reducing agent such as sodium, zinc, or iron, and the reducing agents described in the following documents are preferably used.
  • the compound (14) can be obtained by referring to the aforementioned Greene et al. Document, introducing a protecting group into the compound (12) and converting it into the compound (13), followed by an oxidation reaction. .
  • This reaction can be obtained by oxidizing the hydroxyl group with reference to the aforementioned Larock et al.
  • this reaction is not particularly limited, for example, compound (13) and an equivalent amount or an excess amount of dimethyl sulfoxide in the presence of a suitable activator and base, in a solvent inert to the reaction, from cooling to heating.
  • the treatment is preferably performed at -20 ° C to 80 ° C, usually for 0.1 hour to 3 days.
  • the solvent used here include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, N, N-dimethyl
  • halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • N, N-dimethyl examples include formamide, dimethyl sulfoxide, ethyl acetate, water, or a mixture thereof.
  • oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, sulfur trisulfide-pyridine complex and the like are used, and as the base, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine or An organic base such as pyridine is used.
  • tetrapropylammonium pearlate is used as a catalyst, N-methylmorpholine-N-oxide is used as a reoxidant, and in a solvent inert to the reaction, from cooling to heating, preferably- Treat at 20 to 80 ° C, usually for 0.1 hour to 3 days.
  • solvent used here examples include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, or a mixture thereof. Can be mentioned. As another example, it can be carried out using a pervalent iodine reagent such as Dess-Martin reagent or a chromic acid reagent such as pyridinium chlorochromate or pyridinium dichromate. Compound (15) can be obtained by reacting compound (14) with compound (33).
  • halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform
  • aromatic hydrocarbons such as benzene, toluene, and xylene, or a mixture thereof.
  • a pervalent iodine reagent such as Dess-Martin reagent or a chromic acid reagent such as pyr
  • This reaction can be performed, for example, under the same conditions as the Horner-Emmons reaction and the Wittig reaction described in (Raw Material Synthesis 3) above.
  • Compound (16) can be obtained by hydrogenation reaction of compound (15). This reaction can be performed using the same conditions as the hydrogenation reaction described in (Raw Material Synthesis 3).
  • Compound (18) can be obtained by subjecting compound (17) to compound (34) to a coupling reaction.
  • a mixture of the compound (17) and an equal amount or an excess amount of the compound (34) is heated in a solvent inert to the reaction or without solvent, from cooling to heating under reflux, preferably from 0 ° C to 80 ° C. In general, the mixture is stirred for 0.1 hour to 5 days.
  • solvent used here examples include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dichloromethane, 1,2 -Halogenated hydrocarbons such as dichloroethane and chloroform, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile and mixtures thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane
  • dichloromethane 1,2 -Halogenated hydrocarbons such as dichloroethane and chloroform, N, N-dimethylformamide, dimethyl sulfoxide, ethyl
  • an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine
  • an inorganic base such as cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium hydroxide, cesium fluoride or potassium fluoride. It may be advantageous to carry out the reaction in order to make the reaction proceed smoothly.
  • the above reaction is not particularly limited, but it can also be performed using a catalyst such as that used in the Suzuki-Miyaura cross-coupling reaction.
  • the catalyst used here is not particularly limited, but tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate, dichloro [1,1′-bis (diphenylphosphenylphosphino) ferrocene] palladium (II ), Bistriphenylphosphine palladium (II) chloride, bis (tricyclohexylphosphine) palladium (II) dichloride, and the like.
  • a coupling reaction can be performed using metal palladium (0).
  • compound (19) can be obtained by addition reaction of compound (18) and compound (35) and subsequent desilylation reaction.
  • a mixture of the compound (18) and an equal amount or an excess amount of the compound (35) is cooled to heated under reflux in a solvent inert to the reaction or in the absence of a solvent, preferably from 0 ° C to 80 ° C. In general, the mixture is stirred for 0.1 hour to 5 days.
  • solvent used here examples include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dichloromethane, 1,2 -Halogenated hydrocarbons such as dichloroethane and chloroform, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile and mixtures thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane
  • dichloromethane 1,2 -Halogenated hydrocarbons such as dichloroethane and chloroform, N, N-dimethylformamide, dimethyl sulfoxide, ethyl
  • the desilylation reaction can be carried out with reference to the aforementioned Green et al.
  • Compound (20) can be obtained by addition reaction of compound (19) and R 4 -Lv. This reaction can be carried out using the same reaction conditions as in the above (Raw material synthesis 2).
  • Compound (21) can be obtained by a condensation reaction of compound (20) and nitromethane.
  • a mixture of the compound (20) and an equal amount or an excess amount of nitromethane is heated in a solvent inert to the reaction or in the absence of a solvent from cooling to heating under reflux, preferably at 0 ° C. to 80 ° C.
  • the mixture is usually stirred for 0.1 hour to 5 days.
  • solvent used here examples include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dichloromethane, 1,2 -Halogenated hydrocarbons such as dichloroethane and chloroform, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile and mixtures thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane
  • dichloromethane 1,2 -Halogenated hydrocarbons such as dichloroethane and chloroform, N, N-dimethylformamide, dimethyl sulfoxide, ethyl
  • reaction is carried out in the presence of a base such as sodium bis (trimethylsilyl) amide, n-butyllithium, tert-butoxypotassium, sodium ethoxide, sodium methoxide, sodium hydride, etc. in order to facilitate the reaction. May be advantageous.
  • a base such as sodium bis (trimethylsilyl) amide, n-butyllithium, tert-butoxypotassium, sodium ethoxide, sodium methoxide, sodium hydride, etc.
  • base such as sodium bis (trimethylsilyl) amide, n-butyllithium, tert-butoxypotassium, sodium ethoxide, sodium methoxide, sodium hydride, etc.
  • Compound (19) can be produced by this method in addition to the method of (Raw material synthesis 5).
  • Compound (23) can be obtained by reacting compound (18) with compound (36). In this reaction, a mixture of the compound (18) and an equal amount or an excess amount of the compound (36) is heated to reflux in a solvent inert to the reaction or without solvent, preferably from 0 ° C. to 80 ° C. In general, the mixture is stirred for 0.1 hour to 5 days.
  • solvent used here are not particularly limited, but ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, methanol And alcohols such as ethanol, 2-propanol and tert-butanol, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile and mixtures thereof.
  • ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane
  • halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform
  • methanol And alcohols such as ethanol, 2-propanol and tert-butanol, N, N-dimethylformamide, dimethyl
  • the reaction is carried out in the presence of a base such as tert-butoxy potassium, sodium ethoxide, sodium methoxide, sodium hydride, or a Lewis acid such as titanium (IV) chloride, iron (III) chloride, aluminum chloride, boron trifluoride.
  • a base such as tert-butoxy potassium, sodium ethoxide, sodium methoxide, sodium hydride, or a Lewis acid such as titanium (IV) chloride, iron (III) chloride, aluminum chloride, boron trifluoride.
  • a base such as tert-butoxy potassium, sodium ethoxide, sodium methoxide, sodium hydride, or a Lewis acid such as titanium (IV) chloride, iron (III) chloride, aluminum chloride, boron trifluoride.
  • Compound (24) can be produced by subjecting compound (23) to a hydrolysis reaction or a dealkylation reaction with reference to the aforementioned Green et al.
  • Compound (25) can be
  • halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • N, N-dimethyl examples include formamide, dimethyl sulfoxide, ethyl acetate, water, acetonitrile, or a mixture thereof.
  • a copper catalyst such as copper (I) oxide in order to facilitate the reaction.
  • Compound (19) can be produced by subjecting compound (25) to a protection reaction with reference to the aforementioned Green et al.
  • the compounds of formula (I) are isolated and purified as free compounds, their salts, hydrates, solvates or polymorphic substances.
  • the salt of the compound of formula (I) can also be produced by subjecting it to a conventional salt formation reaction. Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
  • Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers.
  • optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.
  • Test Example 1 Evaluation of inhibitory action of compounds on A ⁇ 1-42 production ability of SK-N-BE (2) cells (1) Seeding of SK-N-BE (2) cells SK-N-, a human neuroblastoma BE (2) cells were seeded in a 96-well plate (Biocoat REF356640) coated with poly-D-lysine at a density of 3 ⁇ 10 5 cells / cm 2 . After sowing, the cells were cultured for 24 hours in RPMI1640 medium (containing Penicillin / Streptomycin and 10% fetal bovine serum).
  • RPMI1640 medium containing Penicillin / Streptomycin and 10% fetal bovine serum
  • a dimethyl sulfoxide solution in which a prescribed concentration of the test compound was dissolved was diluted 200-fold with RPMI1640 medium (containing Penicillin / Streptomycin and 10% fetal bovine serum).
  • the medium was extracted from the 96-well plate after culturing in (1), a medium containing the test compound was added by 50 ⁇ l / well and incubated at 37 ° C. for 6 hours. The medium was collected in an amount of 35 ⁇ l / well and applied to the ELISA plate prepared in (2) and reacted at 4 ° C. overnight.
  • the ELISA plate was washed with 50 mM sodium phosphate buffer (pH 7.4) and then diluted 1000-fold with Phosphate buffered saline (Invitrogen 12720-017) containing 1% Bovine serum albumin and 0.05% Tween-20. (Recognize N-terminal of A ⁇ 1-42; IBL # 10326) The solution was treated with 35 ⁇ l / well and reacted at 4 ° C. for 1 hour.
  • Streptavidin-HRP conjugate (Invitrogen SA100-01) solution diluted 5000 times with Phosphate buffered saline containing 1% Bovine serum albumin and 0.05% Tween-20 was treated with 35 ⁇ l / well and reacted at room temperature for 15 minutes. . After washing again, Tetra methyl benzidine solution (attached to Wako Pure Chemicals # 292-64501) was treated at 35 ⁇ l / well and allowed to react at room temperature for 30 minutes.
  • the inhibition rate of A ⁇ 1-42 production by the compounds in each experiment was defined as 0% inhibition when the dimethyl sulfoxide alone was added to the medium, and 100% inhibition when the value was measured only in the unused medium.
  • the index IC 50 was calculated.
  • Table 1 shows IC 50 values of typical compounds of the present invention. Ex represents an Example compound number described later.
  • Test Example 2 Evaluation of inhibitory effect of compounds on A ⁇ x-42 production ability of SK-N-BE (2) cells (1) Seeding of SK-N-BE (2) cells SK-N-, a human neuroblastoma BE (2) cells were seeded at a density of 3 ⁇ 10 5 cells / cm 2 in a 96-well plate (Biocoat REF356640) coated with poly-D-lysine. After sowing, the cells were cultured for 24 hours in RPMI medium (containing Penicillin / Streptomycin and 10% FCS).
  • RPMI medium containing Penicillin / Streptomycin and 10% FCS.
  • a ⁇ x-42 amount in medium A dimethyl sulfoxide solution in which a test compound having a specified concentration was dissolved was diluted 200-fold with RPMI1640 medium (containing Penicillin / Streptomycin and 10% fetal bovine serum). The medium was extracted from the 96-well plate after the culture, a medium containing the test compound was added by 50 ⁇ l / well, and incubated at 37 ° C. for 6 hours. The medium was collected, and the amount of A ⁇ x-42 was measured using Human / Rat ⁇ Amyloid (42) ELISA Kit, High-Sensitive (Wako Pure Chemicals # 292-64501). The measurement followed the instructions attached to the kit.
  • the medium was added to an antibody-immobilized microplate and allowed to react overnight at 4 ° C. After washing the plate, a labeled antibody solution was added and reacted at 4 ° C. for 1 hour. After washing the plate, Tetra methyl benzidine solution was added and reacted at room temperature for 30 minutes. After adding the reaction stop solution, the absorbance at an absorption wavelength of 450 nm was measured, and the amount of A ⁇ x-42 was calculated based on a calibration curve prepared from the absorbance of the A ⁇ 1-42 standard solution measured at the same time.
  • cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Assay kit (Promega G7571) on the plate after collecting the medium, and the amount of A ⁇ x-42 in the same well measured by the above method was measured as cell viability Standardized.
  • the inhibition rate of A ⁇ x-42 production by the compound in each experiment was defined as 0% inhibition when the dimethyl sulfoxide alone was added to the medium, and 100% inhibition with the value measured only in the unused medium.
  • the index IC 50 was calculated. As a result, the compound of the present invention showed A ⁇ x-42 production inhibitory activity.
  • Table 1 shows IC 50 values of typical compounds of the present invention. Ex represents an Example compound number described later.
  • Test Example 1 and Test Example 2 are tests related to inhibition of A ⁇ 42 production, and even if only the test example 1 or the test example 2 is a compound, the other test shows the same inhibitory action. it is conceivable that.
  • Test Example 3 Evaluation of the effect of reducing the amount of A ⁇ x-42 in the mouse brain by a compound (1) Animal administration and tissue collection 5-week-old male ddY mice (Japan SLC) were used in groups of 4 to 5 cases. The test compound was suspended in a 0.5% aqueous methylcellulose solution, and this solution was orally administered to mice so as to be 10 mL per 1 kg body weight. Three hours after administration, cervical dislocation was performed, and the brain was quickly removed, and then the hippocampus was separated and collected on ice.
  • the collected hippocampus was immediately frozen in liquid nitrogen and stored at ⁇ 80 ° C. until measurement.
  • (2) Measurement of the amount of A ⁇ x-42 in the hippocampus The hippocampus was weighed, 10 times the amount of Tris buffered saline (Wako Pure Chemicals # 317-90175) was added, and the mixture was homogenized on ice. Transfer the homogenate to a centrifuge tube and centrifuge at 100,000 g for 1 hour to measure the amount of A ⁇ x-42 in the supernatant using Human / Rat ⁇ Amyloid (42) ELISA Kit, High-Sensitive (Wako Pure Chemicals # 292-64501) did. The measurement followed the instructions attached to the kit.
  • the supernatant was added to an antibody-immobilized microplate and allowed to react overnight at 4 ° C. After washing the plate, a labeled antibody solution was added and reacted at 4 ° C. for 1 hour. After washing the plate, Tetra methyl benzidine solution was added and reacted at room temperature for 30 minutes. After adding the reaction stop solution, the absorbance at an absorption wavelength of 450 nm was measured, and the amount of A ⁇ x-42 was calculated based on a calibration curve prepared from the absorbance of the A ⁇ 1-42 standard solution measured at the same time.
  • Test Example 4 Evaluation of reducing effect of A ⁇ x-42 amount in rat brain by compound (1) Animal administration and tissue collection Four to five male SD rats (Nippon Charles River) aged 6 weeks were used. The test compound was suspended in 0.5% aqueous methylcellulose solution and orally administered to rats at a rate of 5 mL / kg. After decapitation 4 to 6 hours after administration, the brain was quickly removed, and the hippocampus was isolated and collected on ice. The collected hippocampus was immediately frozen in liquid nitrogen and stored at ⁇ 80 ° C. until measurement.
  • the compound of Example 46 showed a decrease of 13% (1 mg / kg), 28% (3 mg / kg), and 45% (10 mg / kg), respectively, with respect to the vehicle group.
  • Test Example 5 Rat 4-day repeated dose toxicity test (1) General toxicity test Four to six female SD rats (Nippon Charles River) aged 8 weeks were used. The test compound was suspended in 0.5% aqueous methylcellulose solution and orally administered to the rats once a day for 4 days at a rate of 5 mL / kg. The day after the final administration, blood was collected from the femoral vein under isoflurane anesthesia and transferred to a tube containing EDTA.
  • liver and thyroid gland were removed and infiltrated and fixed with 10% formalin solution.
  • Hematology tests hematocrit, hemoglobin, erythrocytes, reticulocytes, leukocytes, eosinophils, neutrophils, basophils, monocytes, lymphocytes, platelets
  • Serum biochemical tests bilirubin, cholesterol, AST, ALT, urea nitrogen
  • a pathological specimen was prepared from the formalin-fixed organ and histopathological examination was performed.
  • the general toxicity test is not limited to this test method, and may be performed using a method well-known to those skilled in the art and arbitrary modified methods.
  • Thyroid hormone (T4 and T3) concentrations in plasma were measured using Total Thyroxine (T4) ELISA Kit (Alpha Diagnostic International # 1100) and Total Triiodothyronine (T3) ELISA Kit (Alpha Diagnostic International # 1700). The measurement followed the instructions attached to the kit. Specifically, plasma and HRP-labeled T4 or T3 were added to an anti-T4 or T3 antibody-immobilized microplate and reacted at 37 ° C. for 1 hour. After washing the plate, HRP substrate solution was added and allowed to react for 30 minutes at room temperature.
  • Thyroid-stimulating hormone (TSH) concentration in plasma was measured using the Rodent TSH ELISA Kit (Endocrine Technologies, ERKR7015). The measurement followed the instructions attached to the kit. Specifically, plasma and HRP-labeled anti-TSH antibody were added to an anti-TSH antibody-immobilized microplate and reacted at 37 ° C. for 3 hours. After washing the plate, HRP substrate solution was added and allowed to react for 20 minutes at room temperature.
  • this hormone concentration test method is not limited to the said test method, You may implement using the method well-known to those skilled in the art, and arbitrary modified methods.
  • the compound of Example 46 and the compound of Example 47 of the compound of the present invention did not have liver or thyroid pathological changes. Alternatively, some of the various hematological parameters or serum biochemical parameters did not change significantly in the measured values. Alternatively, there was no significant change in the concentration of thyroid hormone or thyroid stimulating hormone.
  • HepG2 cells were obtained from ATCC.
  • HepG2 cell culture medium (DMEM) is purchased from Wako Pure Chemical Industries, Ltd., assay medium (DMEM phenol red free), cell culture additive (Fetal bovine serum (FBS), MEM nonessential amino acid, L-glutamete, penicillin and amphotericin B)
  • FBS Fetal bovine serum
  • MEM nonessential amino acid L-glutamete
  • Opti-MEM and pCNDA3.1 were purchased from Invitrogen, and charcoal / dextran-treated serum was purchased from Hyclone.
  • FugeneHD transfection reagent, luciferase expression plasmids (pGL4.10, pGL4.17, pGL4.75) and dual chloriferase assay system were purchased from Promega.
  • the firefly reporter plasmid was created by inserting the human CYP3A4 or CYP1A1 promoter region into pGL4.10 (pGL4-CYP3A4 or pGL4-CYP1A1), and the nuclear receptor Pregnane X receptor (PXR) expression plasmid was prepared by inserting the human PXR gene into pCDNA3.1 (pCNDA3.1-hPXR).
  • Renilla luciferase reporter plasmid pGL4.75 purchased from Promega was used. HepG2 cells are cultured in DMEM (containing 10% FBS, 1 mM MEM non-essential amino acids solution, 2 mM L-glutamate, 100 U / ml penicillin and 0.25 ⁇ g / ml Amphotericin B), and human CYP3A4 and CYP1A1 In the reporter assay, DMEM phenol red free (5% charcoal / dextran-treated FBS, including cell culture additive) was seeded in a 10 cm dish at 3 ⁇ 10 6 cells / dish 6 hours before transfection.
  • DMEM containing 10% FBS, 1 mM MEM non-essential amino acids solution, 2 mM L-glutamate, 100 U / ml penicillin and 0.25 ⁇ g / ml Amphotericin B
  • human CYP3A4 and CYP1A1 In the reporter assay, DMEM
  • the transfection mix is 300 ⁇ l Opti-MEM solution, 0.5 ⁇ g pGL4-CYP3A4, 1 ⁇ g pCNDA3.1-hPXR and 1.25 ⁇ g Renilla luciferase reporter plasmid for CYP3A4 reporter assay, 0.5 ⁇ g for CYP1A1 reporter assay.
  • PGL4-CYP1A1 and 1.25 ⁇ g of Renilla luciferase reporter plasmid were added, 24 ⁇ l of FugeneHD reagent was added, and the mixture was allowed to stand for 15 minutes.
  • Example 46 of the compound of the present invention After correcting the firefly luciferase activity with the renilla luciferase activity, the induction ratio with respect to DMSO control was calculated, and the drug concentration when doubling was defined as EC2fold and expressed as induction activity data.
  • EC2fold was 10 ⁇ M or more for human CYP3A4 and human CYP1A1.
  • Test Example 7 Other Tests The compound of Example 46 of the compound of the present invention is good in all non-pharmacological pharmacological tests (metabolic enzyme inhibition test, hERG channel inhibition test, solubility test, membrane permeability test, liver microsome metabolism test). Results are shown.
  • a ⁇ 40 production inhibitory action was measured for some of the compounds of the present invention, and it was confirmed that they had selective A ⁇ 42 production inhibitory action.
  • the compound of the formula (I) strongly suppresses the production of A ⁇ 42 and has an excellent ⁇ -secretase function regulating action.
  • some of the compounds of the present invention showed good results in single or multiple toxicity evaluation tests, and their safety could be confirmed.
  • some of the compounds of the present invention did not show significant activity with respect to the human CYP3A4 and / or human CYP1A1 enzyme inducing action. Therefore, it can be used as a preventive or therapeutic agent for diseases related to amyloid ⁇ peptide deposition in the brain.
  • a pharmaceutical composition containing one or more compounds of the compound of formula (I) or a salt thereof as an active ingredient is an excipient usually used in the art, that is, a pharmaceutical excipient or a pharmaceutical carrier.
  • Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
  • a solid composition for oral administration tablets, powders, granules and the like are used.
  • one or more active ingredients are mixed with at least one inert excipient.
  • the composition may contain an inert additive such as a lubricant, a disintegrant, a stabilizer and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol.
  • the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.
  • Injections for parenteral administration include sterile aqueous or non-aqueous liquid preparations, suspensions or emulsions.
  • aqueous solvent include distilled water for injection or physiological saline.
  • Non-aqueous solvents include alcohols such as ethanol.
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. They also be manufactured in the form of sterile solid compositions, it may be dissolved in sterile water or a sterile solvent for injection or suspended prior to use.
  • External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like.
  • ointment bases Generally used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
  • Transmucosal agents such as inhalants or transnasal agents solids, is used as a liquid or semi-solid form, it can be prepared according to conventional known methods. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added.
  • an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to.
  • Dry powder inhaler or the like may be for single or multiple administration can utilize a dry powder or a powder-containing capsule. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane or carbon dioxide.
  • a suitable propellant for example, a suitable gas such as chlorofluoroalkane or carbon dioxide.
  • the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses.
  • the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day.
  • a transmucosal agent about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
  • the compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective.
  • the combination may be administered simultaneously, separately separately, or at desired time intervals.
  • the simultaneous administration preparation may be a compounding agent or may be separately formulated.
  • Production Example 1 Using the compound of Production Example 606b as a raw material, the compound was produced in the same manner as in Production Example 141 described later.
  • Production Example 6 Using the compound of Production Example 3 as a raw material, the compound was produced in the same manner as in Production Example 188 described later.
  • Production Example 11 Using the compound of Production Example 606b as a raw material, the compound was produced in the same manner as in Production Example 536 described later.
  • Production Example 12 Using the compound of Production Example 606b as a raw material, the compound was produced in the same manner as in Production Example 532 described later.
  • Production Example 13 Using the compound of Production Example 3 as a raw material, the compound was produced in the same manner as in Production Example 547 described later.
  • Production Example 18 Using the compound of Production Example 606a as a raw material, the compound was produced in the same manner as in Production Example 141 described later.
  • Production Example 22 Using the compound of Production Example 20a as a raw material, the compound was produced in the same manner as in Production Example 188 described later.
  • Production Example 24 Using the compound of Production Example 20a as a raw material, the compound was produced in the same manner as in Production Example 547 described later.
  • Triethyl phosphonoacetate (8.9 g) was added to a suspension of 55% sodium hydride (1.6 g) in tetrahydrofuran (196 mL) under ice cooling. The reaction mixture was stirred for 15 minutes under ice-cooling, and then benzyl rac- ⁇ (1R, 2S) -4-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexyl ⁇ carbamate (13 g) was added.
  • reaction mixture was further stirred for 1 hour under ice-cooling, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with a 2: 1 mixed solvent of hexane and ethyl acetate.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was recrystallized from 2-propanol (80 mL), the mother liquor was concentrated, and the residue was further recrystallized from 2-propanol (40 mL).
  • the filtrate and washings were concentrated under reduced pressure, basified with saturated aqueous sodium hydrogen carbonate solution and 1M aqueous sodium hydroxide solution (0.2 mL), and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Production Example 115 The compound of Production Example 317 was used as a raw material, and the same process as in Production Example 105 and Production Example 25 was continuously carried out.
  • Production Example 258 The compound of Production Example 303 was used as a raw material and produced in the same manner as in Production Example 188.
  • Production Example 313 Using the compound of Production Example 348 as a raw material, the compound was produced in the same manner as in Production Example 354 described later.
  • Production Example 343 Using the compound of Production Example 314 as a raw material, the compound was produced in the same manner as in Production Example 397 described later.
  • Production Example 345 The compound of Production Example 26 was used as a starting material, and in the same manner as in Production Example 412 described later, (R) -1-phenylethylamine was used instead of (S) -1-phenylethylamine.
  • Production Example 346 The compound of Production Example 25 was used as a starting material, and in the same manner as in Production Example 49 described later, (R) -1-phenylethylamine was used instead of (S) -1-phenylethylamine.
  • Production Example 348 Using the compound of Production Example 345 as a raw material, the compound was produced in the same manner as in Production Example 470 described later.
  • Production Example 354 The compound of Production Example 468 was used as a raw material and produced in the same manner as in Production Example 141.
  • Production Example 397 Using the compound of Production Example 381b as a raw material, the compound was produced in the same manner as in Production Example 188.
  • the filtrate was extracted with chloroform, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was dissolved in methanol (45 ml), 28% sodium methoxide in methanol (1.28 g) was added, and the mixture was stirred at 60 ° C. for 4 hr. After cooling to 0 ° C., saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Production Example 419 The compound of Production Example 31 was used as a starting material, and in the same manner as in Production Example 415, (S) -1- (4-methoxyphenyl) ethylamine was used instead of (S) -1-phenylethylamine.
  • Production Example 433 The compound of Production Example 117 was used as a starting material, and in the same manner as in Production Example 422, (S) -1- (4-methoxyphenyl) ethylamine was used instead of (S) -1-phenylethylamine.
  • Production Example 461 The compound of Production Example 140 was used as a raw material and synthesized by adding hydrochloric acid in the same manner as in Production Example 460.
  • Production Example 470 Using the compound of Production Example 435 as a raw material, the compound was produced in the same manner as in Production Example 442.
  • the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.
  • the solvent was evaporated under reduced pressure, 1M hydrochloric acid (10 mL) was added to the residue, and the mixture was stirred at room temperature for 15 hr. Ethyl acetate was added to the reaction mixture and stirred, and the organic layer was removed. A saturated aqueous sodium hydrogen carbonate solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate.
  • Production Example 483 Using the compound of Production Example 484 as a raw material, the compound was produced in the same manner as in Production Example 80.
  • the reaction mixture was stirred at room temperature for 5 days and extracted with chloroform.
  • the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the carbamate was obtained as colorless amorphous (660 mg).
  • Production Example 489 The compound of Production Example 490 was used as a raw material and produced in the same manner as in Production Example 188.
  • Production Example 490 Using the compound of Production Example 491 as a raw material, the compound was produced in the same manner as in Production Example 141.
  • Production Example 491 Using the compound of Production Example 492 as a raw material, the compound was produced in the same manner as in Production Example 631 described later.
  • Production Example 492 The compound of Production Example 35 was used as a starting material, and in the same manner as in Production Example 80, diethyl (cyanomethyl) phosphonate was used instead of triethyl phosphonoacetate.
  • Production Example 493 Using the compound of Production Example 631 as a raw material, this was produced by successively carrying out the same methods as in Production Example 141 and Example 84 described later.
  • Production Example 494 Using the compound of Production Example 495a as a raw material, the compound was produced in the same manner as in Production Example 188.
  • Production Example 495 Using the compound of Production Example 497 as a raw material, the compound was produced in the same manner as in Production Example 141.
  • Production Example 497 Using the compound of Production Example 483 as a raw material, the compound was produced in the same manner as in Production Example 631 described later.
  • Production Example 498 Using the compound of Production Example 514 as a raw material, the same method as Production Example 141 was performed, and triethylamine was added to the reaction mixture.
  • Production Example 511 Using the compound of Production Example 521 as a raw material, the salt of the raw material was desalted and then produced in the same manner as in Production Example 141 described later.
  • Production Example 513 The compound of Production Example 94 was used as a raw material, and the mixture was desalted after completion of the reaction in the same manner as in Production Example 603 described later.
  • Production Example 514 Using the compound of Production Example 93 as a raw material, the compound was produced in the same manner as in Production Example 631 described later.
  • Production Example 519 Using the compound of Production Example 101 as a raw material, the same process as in Production Example 631 was carried out for production. The product was isolated without desalting after the reaction.
  • Production Example 532 Using the compound of Production Example 520 as a raw material, sodium iodide was added to the reaction mixture in the same manner as in Production Example 536 described later.
  • Production Example 555 Using the compound of Production Example 183 as a raw material, sodium iodide was added to the reaction mixture in the same manner as in Production Example 547.
  • Production Example 602 Using the compound of Production Example 488 as a raw material, the compound was produced in the same manner as in Production Example 585.
  • the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and ethyl (+)- ⁇ (1R * , 3S * , 4R * )-4-amino-3- [4- (trifluoromethyl) phenyl] Cyclohexyl ⁇ acetate was obtained as a colorless oil (165 mg). Further, the solvent was distilled off from the recrystallized mother liquor under reduced pressure, and the resulting residue was treated with a saturated aqueous sodium hydrogen carbonate solution and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Production Example 615 The compound of Production Example 622 was used as a raw material and was produced in the same manner as in Production Example 608 using benzenesulfonic acid instead of hydrogen chloride.
  • Production Example 625 Using the compound of Production Example 83 as a raw material, the same method as in Production Example 618 was performed, and halogen was also reduced at the same time.
  • Production Example 626 Using the compound of Production Example 481 as a raw material, the same method as in Production Example 618 was performed, and the double bond part was also reduced at the same time.
  • Production Example 631 Using the compound of Production Example 80 as a raw material, the same process as in Production Example 618 and Production Example 608 was continuously performed.
  • Production Example 633 Using the compound of Production Example 477 as a raw material and using the same method as in Production Example 631, the double bond part was also reduced at the same time.
  • Production Example 641 Using the compound of Production Example 640 as a raw material, the compound was produced in the same manner as in Production Example 584.
  • Production Example 650 Using the compound of Production Example 644 as a raw material, using the same method as in Production Example 308, using titanium tetraethoxide instead of titanium tetraisopropoxide
  • Production Example 660 Using the compound of Production Example 701 as a raw material, the compound was produced in the same manner as in Production Example 115.
  • Production Example 661 Using the compound of Production Example 660 as a raw material, using the same method as in Production Example 308, using titanium tetraethoxide instead of titanium tetraisopropoxide
  • Production Example 667 The compound of Production Example 663 was used as a raw material and produced in the same manner as in Production Example 536.
  • the reaction mixture was concentrated under reduced pressure, basified with 1M aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel chromatography (hexane / ethyl acetate), and (7R * , 8S * )-N-[(1S) -1-phenylethyl] -7- [4- (trifluoro) Methyl) benzyl] -1,4-dioxaspiro [4.5] decan-8-amine (883 mg) was obtained.
  • Production Example 679 The compound of Production Example 678 was used as a raw material and produced in the same manner as in Production Example 80.
  • Production Example 680 Using the compound of Production Example 679 as a raw material, a double bond was reduced and a phenylethyl group was removed simultaneously in the same manner as in Production Example 618.
  • Production Example 681 The compound of Production Example 680 was used as a raw material and produced in the same manner as in Production Example 141.
  • Production Example 682 The compound of Production Example 681 was used as a raw material and produced in the same manner as in Production Example 188.
  • Production Example 684 Using the compound of Production Example 674a as a raw material, the compound was produced in the same manner as in Production Example 141.
  • Production Example 685 The compound of Production Example 674b was used as a raw material and produced in the same manner as in Production Example 141.
  • Production Example 688 Using the compound of Production Example 686a as a raw material, the compound was produced in the same manner as in Production Example 141.
  • Production Example 690 The compound of Production Example 686b was used as a raw material and produced in the same manner as in Production Example 141.
  • Example 1 Ethyl ⁇ (1R * , 3S * , 4R * )-4- [bis (cyclohexylmethyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl ⁇ acetate (395 mg) in 1: 1 methanol- To a tetrahydrofuran (6 mL) solution was added 1 M aqueous sodium hydroxide solution (2 mL). The reaction mixture was stirred at room temperature overnight, 1M hydrochloric acid (2 mL) was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 9 Using the compound of Production Example 13 as a raw material, the compound was produced in the same manner as in Example 84 described later.
  • Example 12 Using the compound of Example 3 as a raw material, the compound was produced in the same manner as in Example 236 described later.
  • Example 19 Using the compound of Production Example 24 as a raw material, the compound was produced in the same manner as in Example 84 described later.
  • Example 21 Using the compound of Example 306 as a raw material, the compound was produced in the same manner as in Example 236 described later.
  • Example 24 rac- ⁇ (1R, 3S, 4R) -4- [Bis (2-phenylethyl) amino] -3-cyclopentylcyclohexyl ⁇ acetic acid (131 mg) in ethanol (15 mL) in platinum dioxide (55 mg) and acetic acid (4 mL) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere of 3 atm.
  • the reaction mixture was filtered through celite and washed with ethanol, and the filtrate was concentrated under reduced pressure.
  • Example 26 Using the compound of Production Example 344 as a raw material, the compound was produced in the same manner as in Example 29 described later.
  • Example 27 Using the compound of Example 309 as a raw material, the compound was produced in the same manner as in Example 236 described later.
  • Example 29 Using the compound of Production Example 355b as a raw material, the compound was produced in the same manner as in Example 84 described later.
  • Example 49 Using the compound of Example 313 as a raw material, the compound was produced in the same manner as in Example 236 described later.
  • Example 78 rac- ⁇ (1R, 3S, 4R) -4-[(cyclohexylmethyl) (3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl ⁇ acetonitrile (100 mg) in toluene (2 mL ) Sodium azide (72 mg) and triethylamine hydrochloride (153 mg) were added to the solution, and the mixture was stirred at 100 ° C. overnight.
  • Example 79 Methyl rac- ⁇ (1R, 2S) -3-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexyl ⁇ acetate (250 mg) and 3-methylbutylamine (139 mg) and titanium tetraisopropoxide (226 mg) was added. The reaction mixture was stirred at 60 ° C. for 3 hr, diluted with 1,2-dichloromethane (3 mL), and sodium triacetoxyborohydride (337 mg) was added. The reaction mixture was stirred at room temperature for 6 hr, celite and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was filtered through celite.
  • the filtrate was extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was dissolved in acetonitrile (3 mL) and sodium carbonate (169 mg) and 4- (trifluoromethyl) benzyl bromide (190 mg) were added.
  • the reaction mixture was stirred at 60 ° C. for 2 days, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
  • Formic acid (7 mg) and 37% aqueous formaldehyde solution (0.05 mL) were added to a THF (2 mL) solution.
  • the reaction mixture was stirred at 60 ° C. for 6 hours and concentrated under reduced pressure.
  • Example 82 Using the compound of Production Example 494 as a raw material, the compound was produced in the same manner as in Example 84 described later.
  • Example 84 The compound of Production Example 543b was used as a raw material, and was produced by successively carrying out the same methods as in Example 85 and Example 236 described later.
  • Example 85 Ethyl rac- ⁇ (1R, 3S, 4R) -4-[(2-cyclohexylethyl) (3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl ⁇ acetate (62 mg)
  • a 1M aqueous solution of sodium hydroxide (500 ⁇ L) was added to a methanol-tetrahydrofuran (3 mL) solution.
  • the reaction mixture was stirred at room temperature overnight, 1M hydrochloric acid (500 ⁇ L) was added, and the solvent was evaporated under reduced pressure.
  • Example 202 The compound of Production Example 277 was used as a raw material and was produced in the same manner as in Example 84.
  • Example 236 To a solution of rac-[(1R, 3S, 4R) -4-[(cyclohexylmethyl) (3-methylbutyl) amino] -3- (4-fluorophenyl) cyclohexyl] acetic acid (42 mg) in ethyl acetate (2 mL) Add 4M hydrogen chloride in ethyl acetate (30 ⁇ L) and concentrate to rac-[(1R, 3S, 4R) -4-[(cyclohexylmethyl) (3-methylbutyl) amino] -3- (4-fluorophenyl) [Cyclohexyl] acetic acid hydrochloride was obtained as a colorless amorphous substance (45 mg).
  • Example 306 The compound of Production Example 22 was used as a raw material, and the production was carried out in the same manner as in Example 85.
  • Example 309 The compound of Production Example 313 was used as a raw material and was produced in the same manner as in Example 85.
  • Example 311 Using the compound of Production Example 403 as a raw material, the compound was produced in the same manner as in Example 85.
  • Example 355 The compound of Production Example 649 was used as a raw material and was produced in the same manner as in Example 85.
  • Example 368 Using the compound of Example 355 as a raw material, the compound was produced in the same manner as in Example 236.
  • Example 369 The compound of Production Example 691 was used as a raw material and produced in the same manner as in Example 84.
  • Example 371 The compound of Production Example 682 was used as a raw material and was produced in the same manner as in Example 85, and the two diastereomers were separated by silica gel chromatography (chloroform / ethyl acetate).
  • Example 373 The compound of Example 371a was used as a starting material, and the compound was prepared in the same manner as in Example 236.
  • Example 375 The compound of Production Example 683 was used as a raw material and produced in the same manner as in Example 84.
  • Example 376 The compound of Production Example 684 was used as a raw material and was produced in the same manner as in Example 84.
  • Example 377 The compound of Production Example 685 was used as a raw material and produced in the same manner as in Example 84.
  • Example 378 The compound of Production Example 689 was used as a raw material and produced in the same manner as in Example 84.
  • Example compounds shown in the following table were produced using the corresponding raw materials.
  • the following table shows the structures, production methods and physicochemical data of the example compounds.
  • the compound of the present invention strongly suppresses the production of A ⁇ 42 and has an excellent ⁇ -secretase function regulating action, Alzheimer's disease (AD), cerebral amyloid angiopathy, Dutch hereditary cerebral hemorrhage (HCHWA-D), multiple infarctions It is useful as a prophylactic / therapeutic agent for diseases related to amyloid ⁇ peptide deposition in the brain such as sexual dementia, fist dementia, or Down syndrome.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Neurology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Les inventeurs ont étudié intensément des composés qui possèdent une activité inhibitrice de la production de Aβ42 et ils ont découvert qu'un composé (I) de la présente invention, dans lequel un acide carboxylique ou un groupe tétrazole est lié au radical cycloalcane directement ou par l'intermédiaire d'un lieur et une amine est liée au radical cycloalcane directement ou par l'intermédiaire d'un lieur, ou l'un des sels pharmaceutiquement acceptables du composé inhibe fortement la production de Aβ42. En outre, les inventeurs ont découvert que ces composés exercent une excellente action sur la fonction de la γ‑sécrétase et ils ont ainsi complété la présente invention.
PCT/JP2011/072989 2010-10-05 2011-10-05 Composé de cycloalcane WO2012046771A1 (fr)

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JP2010-226100 2010-10-05
JP2010226100A JP2014001142A (ja) 2010-10-05 2010-10-05 シクロアルカン化合物

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KR102568997B1 (ko) * 2019-06-20 2023-08-22 프레시젼 나노시스템스 유엘씨 핵산 전달을 위한 이온화 가능한 지질

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JP2006503862A (ja) * 2002-10-03 2006-02-02 アストラゼネカ・アクチエボラーグ 新規なラクタムおよびその使用
JP2007501261A (ja) * 2003-05-19 2007-01-25 エフ．ホフマン−ラ　ロシュ　アーゲー アルツハイマー病治療のためのγ−セクレターゼインヒビターとしての２，３，４，５−テトラヒドロベンゾ〔Ｆ〕〔１，４〕オキサゼピン−５−カルボン酸アミド誘導体
JP2010526808A (ja) * 2007-05-07 2010-08-05 シェーリング コーポレイション ガンマセクレターゼ調節剤
JP2010529015A (ja) * 2007-06-01 2010-08-26 シェーリング コーポレイション γセクレターゼ修飾因子
WO2011092611A1 (fr) * 2010-01-29 2011-08-04 Pfizer Inc. Aminocyclohexanes et aminotétrahydropyranes et composés associés comme modulateurs de gamma-sécrétase

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Publication number Priority date Publication date Assignee Title
JP2006503862A (ja) * 2002-10-03 2006-02-02 アストラゼネカ・アクチエボラーグ 新規なラクタムおよびその使用
JP2007501261A (ja) * 2003-05-19 2007-01-25 エフ．ホフマン−ラ　ロシュ　アーゲー アルツハイマー病治療のためのγ−セクレターゼインヒビターとしての２，３，４，５−テトラヒドロベンゾ〔Ｆ〕〔１，４〕オキサゼピン−５−カルボン酸アミド誘導体
JP2010526808A (ja) * 2007-05-07 2010-08-05 シェーリング コーポレイション ガンマセクレターゼ調節剤
JP2010529015A (ja) * 2007-06-01 2010-08-26 シェーリング コーポレイション γセクレターゼ修飾因子
WO2011092611A1 (fr) * 2010-01-29 2011-08-04 Pfizer Inc. Aminocyclohexanes et aminotétrahydropyranes et composés associés comme modulateurs de gamma-sécrétase

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104496854A (zh) * 2015-01-06 2015-04-08 上海医药工业研究院 3-环己基-1,1-二甲基脲类化合物及其制备方法和应用
CN104496854B (zh) * 2015-01-06 2017-09-22 上海医药工业研究院 3‑环己基‑1,1‑二甲基脲类化合物及其制备方法和应用

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