WO2010123017A1 - Tetrazole compound - Google Patents

Tetrazole compound Download PDF

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Publication number
WO2010123017A1
WO2010123017A1 PCT/JP2010/057035 JP2010057035W WO2010123017A1 WO 2010123017 A1 WO2010123017 A1 WO 2010123017A1 JP 2010057035 W JP2010057035 W JP 2010057035W WO 2010123017 A1 WO2010123017 A1 WO 2010123017A1
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WIPO (PCT)
Prior art keywords
compound
methyl
mixture
added
stirred
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PCT/JP2010/057035
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French (fr)
Japanese (ja)
Inventor
賢二 根来
圭 大貫
康博 米徳
和幸 倉本
泰治 浦野
史良 岩崎
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アステラス製薬株式会社
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Publication of WO2010123017A1 publication Critical patent/WO2010123017A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to a novel tetrazole compound or a pharmaceutically acceptable salt thereof useful as a pharmaceutical, particularly an insulin secretagogue, a prophylactic / therapeutic agent for diabetes.
  • Diabetes is a disease whose main feature is chronic hyperglycemia, and develops due to an absolute or relative lack of insulin action. In clinical practice, it is roughly divided into insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). In non-insulin dependent diabetes mellitus (NIDDM), a decrease in insulin secretion from pancreatic ⁇ -cells is one of the main causes of onset, and particularly postprandial hyperglycemia due to early insulin secretion disorder is observed.
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • sulfonylurea (SU) agents are the mainstream as insulin secretagogues, but they are prone to hypoglycemia and are known to cause secondary ineffectiveness due to pancreatic exhaustion in long-term administration. Moreover, although the SU agent is effective for blood glucose control between meals, it is difficult to suppress hyperglycemia after meals.
  • GPR40 is a G protein-coupled receptor highly expressed in pancreatic ⁇ cells identified as a fatty acid receptor and has been reported to be involved in the insulin secretory action of fatty acids (Non-patent literature). 1). Therefore, GPR40 receptor agonists are expected to correct postprandial hyperglycemia based on insulin secretion-promoting action, so insulin-dependent diabetes (IDDM), non-insulin-dependent diabetes (NIDDM) ⁇ Abnormal fasting blood glucose level) It is useful as a preventive or therapeutic agent for mild diabetes.
  • IDDM insulin-dependent diabetes
  • NIDDM non-insulin-dependent diabetes
  • Patent Document 2 it is reported that the compound of the formula (B) has a GPR40 receptor modulating action and is useful as an insulin secretagogue and a preventive and / or therapeutic agent for diabetes. (See the official gazette for symbols in the formula.)
  • Patent Document 3 reports that the oxazolidinedione compound of the formula (C) has a blood glucose lowering action and a blood lipid lowering action and is useful for the treatment of diabetes. (See the official gazette for symbols in the formula.)
  • the oxadiazolidinedione compound of formula (D) has a plasminogen activation inhibitor (PAI) -1 inhibitory action and is useful for the treatment of thrombus, atrial fibrillation, myocardial ischemia, diabetes, etc. It has been reported that. (Where X is Indicates. For other symbols, see the publication. )
  • PAI plasminogen activation inhibitor
  • Patent Document 5 it is reported that the compound of the formula (E) has a GPR40 receptor modulating action and is useful as an insulin secretagogue and a preventive and / or therapeutic agent for diabetes. (See the official gazette for symbols in the formula.)
  • Patent Document 6 reports that the compound of formula (F) has a GPR40 receptor-modulating action and is useful as an insulin secretion-promoting agent or a prophylactic and / or therapeutic agent for diabetes. (Where Is For other symbols. )
  • Patent Document 7 it is reported that the compound of the formula (G) has a GPR40 receptor modulating action and is useful as an insulin secretagogue and a preventive and / or therapeutic agent for diabetes. (See the official gazette for symbols in the formula.)
  • Non-patent document 2 Patent document 8, Patent document 9, Patent document 10 and Patent document 11 have a blood glucose lowering action and are useful for the treatment of diabetes.
  • Patent Literature 12 Patent Literature 13, Patent Literature 14, Patent Literature 15 and Patent Literature 16 have been reported as compounds useful for the treatment of these.
  • the compound of the present invention is not specifically disclosed, and there is no suggestion of the compound of the present invention.
  • An object of the present invention is to provide a compound having a GPR40 agonistic activity that is useful as an active ingredient of a pharmaceutical composition, for example, an insulin secretagogue and a preventive / therapeutic agent for diabetes.
  • the present inventors bonded a tetrazole group to the 2 or 3 ring moiety via methylene, and -O-methylene or -NH- to the 2 or 3 ring moiety. It has been found that the compound (I) of the present invention or a pharmaceutically acceptable salt thereof, to which benzene substituted with a 6-membered monocyclic aromatic ring is bonded via methylene has excellent GPR40 agonist activity. Furthermore, the present inventors have found that these compounds have an excellent insulin secretion promoting action and strongly suppress an increase in blood glucose after glucose loading, thereby completing the present invention.
  • the present invention relates to a tetrazole compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical comprising the tetrazole compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. Relates to the composition.
  • R A1 is H or halogen; m is 1 or 2, R A2 and R A3 are H or R A2 and R A3 are combined to form -CH 2 -C (R X1 ) (R X2 )- R X1 and R X2 are H or R X1 and R X2 are C 2-7 alkylene which may be substituted together, Z is N or CR Z , R Z is H or halogen; L is O or NH; R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be the same or different from each other, H, halogen, optionally substituted lower alkyl, or —O— (substituted Optionally lower alkyl) R 7 is H, halogen, —O— (optionally substituted heterocyclic group), or —O— (CR 71 R 72 ) p —R 73 ; R 71 and R 72 are the same or different from each other, H, OH, or optionally substituted
  • the present invention relates to a pharmaceutical composition for preventing or treating a disease involving GPR40 containing a compound of formula (I) or a salt thereof, that is, GPR40 containing a compound of formula (I) or a salt thereof.
  • the present invention relates to a preventive or therapeutic agent for diseases.
  • the present 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 a disease involving GPR40, a formula for the prevention or treatment of a disease involving GPR40.
  • the present invention relates to a method for preventing or treating a disease involving GPR40, which comprises administering to a patient an effective amount of a compound of formula (I) or a salt thereof, and a compound of formula (I) or a salt thereof.
  • the compound of the present invention has an excellent GPR40 agonistic action, it can be used as an insulin secretagogue, diabetes (insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), or borderline (glucose tolerance / fasting blood glucose It is useful as a prophylactic / therapeutic agent for diseases involving GPR40, such as abnormal values) and mild diabetes.
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • borderline borderline
  • 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
  • Alkylene means linear or branched 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 1-6 alkylene, yet another embodiment is C 1-4 alkylene, and yet another embodiment is C 1-3 alkylene, and yet another embodiment.
  • 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 a double bond site thereof.
  • 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 a double bond site thereof.
  • Heterocycle means i) a 3 to 8 membered, alternatively 5 to 7 membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and ii)
  • the monocyclic heterocycle is formed by condensing 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.
  • heterocycle examples include the following embodiments.
  • 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 and 1 to
  • (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 and the like; (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-dioxabicyclo
  • 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 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 refers to 1 to 5 of the above “heterocycle” groups, as in (2) (a), (2) (b), etc.
  • the thing containing a nitrogen atom refers to 1 to 5 of the above “heterocycle” groups, as in (2) (a), (2) (b), etc. The thing containing a nitrogen atom.
  • the “nitrogen-containing polycyclic saturated heterocycle” group is a group of 1 to 5 of the above “heterocycle” groups, such as (3) (a), (3) (b), etc.
  • the thing containing a nitrogen atom is a group of 1 to 5 of the above “heterocycle” groups, such as (3) (a), (3) (b), etc. The thing containing a nitrogen atom.
  • the “nitrogen-containing fused polycyclic unsaturated heterocycle” group includes 1 to 5 of the above “heterocycle” groups as in (4) (a) and (4) (b) Containing nitrogen atoms.
  • the “6-membered monocyclic aromatic ring” refers to a monocyclic ring group of aromatic 6-membered ring structure among the above “aryl” and “heterocycle”. For example, phenyl, pyridyl, pyrimidyl and the like.
  • aryl and heterocyclic groups are described as monovalent groups, they may represent divalent or higher groups depending on circumstances.
  • Halogen means F, Cl, Br, I, preferably F, Br, Cl.
  • R X1 and R X2 are combined to form C 2-7 alkylene
  • R X1 and R X2 are combined with the carbon atom to which they are bonded to form a C 3-8 saturated hydrocarbon ring. It shows that.
  • saturated hydrocarbon ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like.
  • Another embodiment is C 2-6 alkylene, and yet another embodiment is C 2-4 alkylene.
  • optionally substituted means unsubstituted or having 1 to 5 substituents.
  • those substituents may be the same, or may mutually differ.
  • Examples of the substituents allowed in the “optionally substituted heterocycle” group for R 7 include the groups shown in the following (a) to (i) and oxo ( ⁇ O): .
  • Still another embodiment includes, for example, a group shown in the following (i) and oxo ( ⁇ O).
  • C amino or nitro optionally substituted with 1 or 2 lower alkyls.
  • (F) -CHO, -CO-lower alkyl, -CO-cycloalkyl, -CO-monocyclic saturated heterocyclic group (this heterocyclic group is halogen, lower alkyl, -O-lower alkyl or oxo ( O ), Cyano.
  • (G) Aryl or cycloalkyl. These groups may each be substituted with halogen, lower alkyl or —O-lower alkyl.
  • (H) a heterocyclic group. The heterocyclic group may be substituted with halogen, lower alkyl, —O-lower alkyl or oxo ( ⁇ O).
  • (I) Lower alkyl optionally substituted with one or more groups selected from the substituents shown in the above (a) to (h).
  • substituents allowed in the “optionally substituted lower alkyl” in R 1 , R 2 , R 3 , R 4 , R 5 and R 6 include, for example, the above (a) to (h ).
  • substituents allowed in the “optionally substituted lower alkyl” in R 1 , R 2 , R 3 , R 4 , R 5 and R 6 include, for example, the above (a) to (h ).
  • Still another embodiment includes, for example, the group shown in the above (a) and oxo ( ⁇ O).
  • Examples of the substituents allowed in the “optionally substituted lower alkyl” in R 71 and R 72 include the groups shown in the above (a) to (h). As another embodiment, for example, the groups shown in the above (a) to (e) and oxo ( ⁇ O) can be mentioned. Still another embodiment includes, for example, the group shown in the above (b) and oxo ( ⁇ O).
  • a compound of the formula (I ′) or a salt thereof is shown.
  • R A1 is H or halogen; m is 1 or 2, R A2 and R A3 are H, or R A2 and R A3 are combined to form —CH 2 —C (R X1 ) (R X2 ) — R X1 and R X2 are H, or R X1 and R X2 together are C 2-7 alkylene, Z is N or CR Z , R Z is H or halogen; L is O or NH; R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different from each other, and are H, halogen, lower alkyl, or —O-lower alkyl, R 7 is H, halogen, -O-heterocyclic group, or -O- (CR 71 R 72 ) p -R 73 , R 71 and R 72 may
  • R A2 and R A3 are integrally —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 are all ethylene.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be the same or different from each other and are H or lower alkyl.
  • R 1 , R 2 and R 3 are H, and R 4 , R 5 and R 6 are methyl.
  • R 7 is —O— (CR 71 R 72 ) p —R 73 , p is 3, and — (CR 71 R 72 ) 3 — is —CH 2 —CH (OH) —CH 2-The compound in which R 73 is OH.
  • R 7 is —O-heterocyclic group.
  • R 7 is —O-heterocyclic group, and the heterocyclic group is (tetrahydro-2H-pyran-4-yl).
  • Y a and Y b may be the same or different from each other, N or CR Y , and R Y is H.
  • R A1 is H or F
  • m is 1
  • R A2 and R A3 are H
  • Z is N or CR Z
  • R Z is H
  • L is NH
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be the same or different from each other, H or lower alkyl
  • R 7 is- O- (CR 71 R 72 ) p -R 73
  • p is 3,-(CR 71 R 72 ) 3 -is -CH 2 -CH (OH) -CH 2-
  • R 73 is , OH, Y a and Y b may be the same or different from each other, N or CR Y , and R Y is H.
  • R A1 is H or F
  • m is 1, R A2 and R A3 are H
  • Z is N or CR Z
  • R Z is H
  • L is NH
  • R 1 , R 2 and R 3 are H
  • R 4 , R 5 and R 6 are methyl
  • R 7 is —O— (CR 71 R 72 ) p -R 73
  • p is 3,-(CR 71 R 72 ) 3 -is -CH 2 -CH (OH) -CH 2-
  • R 73 is OH
  • a compound in which b is the same as or different from each other, N or CR Y , and R Y is H.
  • R A1 is H
  • m is 1
  • R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —
  • R X1 and R X2 Is H
  • Z is N or CR Z
  • R Z is H
  • L is NH
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Is H or lower alkyl
  • R 7 is an —O-heterocyclic group
  • Y a and Y b may be the same or different from each other, N or CR Y
  • R A1 is H, m is 1, and R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 Is H, Z is N or CR Z , R Z is H, L is NH, R 1 , R 2 and R 3 are H, R 4 , R 5 and R 6 are methyl, R 7 is —O— (CR 71 R 72 ) p —R 73 , p is 3, and — (CR 71 R 72 ) 3 — is —CH 2 -CH (OH) -CH 2- , R 73 is OH, Y a and Y b may be the same or different from each other, N or CR Y , and R Y is A compound that is H.
  • R A1 is H
  • m is 1
  • R A2 and R A3 are —CH 2 —C (R X1 ) (R X2 ) —
  • R X1 and R X2 Is H
  • Z is N or CR Z
  • R Z is H
  • L is NH
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Is H or lower alkyl
  • R 7 is —O— (CR 71 R 72 ) p —R 73
  • p is 3
  • — (CR 71 R 72 ) 3 — is —CH
  • R A1 is H
  • m is 1
  • R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —
  • R X1 and R X2 Is H
  • Z is N or CR Z
  • R Z is H
  • L is NH
  • R 1 , R 2 and R 3 are H
  • R 4 , R 5 and R 6 are methyl
  • R 7 is an —O-heterocyclic group
  • the heterocyclic group is (tetrahydro-2H-pyran-4-yl)
  • Y a and Y b are And N or CR Y which may be the same as or different from each other, and R Y is H.
  • R A1 is H
  • m is 1
  • R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —
  • R X1 and R X2 R X1 and R X2 together are C 2-7 alkylene
  • Z is N or CR Z
  • R Z is H
  • L is NH
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are H or lower alkyl
  • R 7 is an —O-heterocyclic group
  • Y a and Y b are the same or different from each other.
  • a compound wherein N or CR Y and R Y is H.
  • R A1 is H
  • m is 1
  • R A2 and R A3 are —CH 2 —C (R X1 ) (R X2 ) —
  • R X1 and R X2 R X1 and R X2 are ethylene together
  • Z is N or CR Z
  • R Z is H
  • L is NH
  • R 1 , R 2 and R 3 is H
  • R 4 , R 5 and R 6 are methyl
  • R 7 is —O— (CR 71 R 72 ) p —R 73
  • p is 3
  • — (CR 71 R 72 ) 3 — is —CH 2 —CH (OH) —CH 2 —
  • R 73 is OH
  • Y a and Y b may be the same or different from each other, N, or , CR Y and R Y is H.
  • R A1 is H, m is 1, and R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 R X1 and R X2 together are C 2-7 alkylene, Z is N or CR Z , R Z is H, L is NH, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are H or lower alkyl, R 7 is —O— (CR 71 R 72 ) p —R 73 , and p is 3.
  • R A1 is H, m is 1, and R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 R X1 and R X2 are ethylene together, Z is N or CR Z , R Z is H, L is NH, R 1 , R 2 and R 3 is H, R 4 , R 5 and R 6 are methyl, R 7 is an —O-heterocyclic group, and the heterocyclic group is (tetrahydro-2H-pyran-4-yl And Y a and Y b may be the same or different from each other, N or CR Y , and R Y is H.
  • Still another embodiment of the compounds (I) and (I ′) of the present invention is shown below.
  • (24) The compound wherein R A1 is H and m is 1.
  • (30) The compound wherein R 1 , R 2 and R 3 are H, and R 4 , R 5 and R 6 are lower alkyl.
  • R 7 is —O— (CR 71 R 72 ) p —R 73
  • — (CR 71 R 72 ) p — is —CH 2 —CH 2 —, —CH 2 —CH (OH) -CH 2 -, - CH 2 -CH (CH 2 OH) -CH 2 -, - CH 2 -CH 2 -CH (CH 3) -, or, -CH 2 -CH 2 -C (CH 3) 2 -
  • R 73 is OH.
  • R 7 is —O— (CR 71 R 72 ) p —R 73 , — (CR 71 R 72 ) p — is —CH 2 —CH 2 —, and R 73 is OH.
  • a compound. (33) R 7 is —O— (CR 71 R 72 ) p —R 73 , and — (CR 71 R 72 ) p — is —CH 2 —CH 2 —CH (CH 3 ) —, or A compound wherein —CH 2 —CH 2 —C (CH 3 ) 2 — and R 73 is OH.
  • R 7 is —O— (CR 71 R 72 ) p —R 73 , — (CR 71 R 72 ) p — is — (CH 2 ) p —, and R 73 is lower alkyl.
  • R 7 is —O— (CR 71 R 72 ) p —R 73 , — (CR 71 R 72 ) p — is — (CH 2 ) p —, and R 73 is (tetrahydro -2H-pyran-4-yl).
  • R 7 is -O- (CR 71 R 72 ) p -R 73 ,-(CR 71 R 72 ) p- is-(CH 2 ) p- , and R 73 is (2 , 2-dimethyl-1,3-dioxolan-4-yl).
  • compounds comprising a combination of two or more of the groups described in the above (1) to (13) and (24) to (38) Specific examples include the following compounds.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be the same or different from each other, H or lower alkyl (10) to (12), (31) (36) or (39) to (47) (49) (10) to (12), (31) to (36), wherein R 1 , R 2 and R 3 are H, and R 4 , R 5 and R 6 are lower alkyl, or ( 39) to (47).
  • R 1 , R 2 and R 3 are H, and R 4 , R 5 and R 6 are methyl (10) to (12), (31) to (36), or (39 ) To (47).
  • Y a and Y b may be the same or different from each other, N or CR Y , and R Y is H (10) to (12), (31) to (36) Or a compound according to (39) to (50).
  • Examples of specific compounds included in the present invention include the following compounds. (2R) -3-( ⁇ 2,2 ', 6-Trimethyl-3'-[( ⁇ 4- [2- (1H-tetrazol-5-yl) ethyl] phenyl ⁇ amino) methyl] biphenyl-4-yl ⁇ Oxy) propane-1,2-diol, 2-Methyl-4- ⁇ [2,2 ', 6-trimethyl-3'-( ⁇ [1- (1H-tetrazol-5-ylmethyl) -2,3-dihydro-1H-inden-5-yl] oxy ⁇ Methyl) biphenyl-4-yl] oxy ⁇ butan-2-ol, (2R) -3- ⁇ [2,2 ', 6-Trimethyl-3'-( ⁇ [1 '-(1H-tetrazol-5-ylmethyl) -1', 3'-dihydrospiro [cyclopropane-1, 2'-indene] -5'-yl] amino ⁇
  • 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 also includes other isomers, separated isomers, or those 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.
  • 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.
  • NMR1 ⁇ (ppm) in 1 H NMR in DMSO-d 6
  • NMR2 ⁇ (ppm) in 1 H NMR in CDCl 3
  • Structure Structure, TBDMS: tert-butyldimethylsilyl, NMP: N-methyl-2-pyrrolidone, DMSO: dimethyl sulfoxide, THF: tetrahydrofuran, EtOAc: ethyl acetate, DMF: N, N-dimethylformamide, CDI: carbonyldiimidazole, DBU: Diazabicycloundecene.
  • the compound of the formula (I) and a salt thereof can be produced by applying various known synthesis methods utilizing 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.
  • an appropriate protective group a group that can be easily converted into the functional group
  • 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 (8) with sodium azide or trimethylsilyl azide.
  • the compound (8) is mixed with an equal amount or an excess amount of sodium azide or trimethylsilyl azide in a solvent inert to the reaction or in the absence of solvent, from cooling to heating under reflux, preferably from -20 ° C to 200
  • the mixture is stirred at 0 ° C., more preferably 0 ° C. to 150 ° 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, N-methylpyrrolidone, and mixtures thereof. It may be advantageous to carry out the reaction in the presence of ammonium chloride, triethylamine hydrochloride, dibutyltin oxide, etc. in order to make the reaction proceed smoothly.
  • the compound (Ia) of the present invention can be obtained by reacting the compound (7) with the compound (22). In this reaction, an equivalent amount of compound (7) or an excess of compound (22) was used, and these mixtures were heated under reflux from ⁇ 45 ° C. in a solvent inert to the reaction in the presence of a reducing agent.
  • the mixture is preferably stirred at 0 ° C. to 80 ° C. for usually 0.1 hour to 5 days.
  • solvent used here are not particularly limited, but halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, alcohols such as methanol and ethanol, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like. Ethers, N, N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof.
  • the reducing agent include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride and the like.
  • the reaction 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, hydrochloric acid, titanium (IV) isopropoxide complex.
  • a dehydrating agent such as molecular sieves or an acid such as acetic acid, hydrochloric acid, titanium (IV) isopropoxide complex.
  • the imine formed by the condensation of the compound (7) and the compound (22) may be isolated as a stable intermediate. In such a case, this imine intermediate can be produced, isolated once if necessary, and then subjected to a reduction reaction to obtain compound (Id).
  • 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.
  • the compound (Ie) of the present invention can be obtained by reacting the compound (Id) with the compound (23).
  • the leaving group include halogen, methanesulfonyloxy, p-toluenesulfonyloxy group and the like.
  • compound (Id) and an equal amount or an excess amount of compound (23) are used, and these mixtures are heated in a solvent inert to the reaction or in the absence of solvent from cooling to heating under reflux, preferably Stir at 0 to 80 ° C. for usually 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.
  • Aroma 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 reaction is carried out in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, or an inorganic base such as cesium carbonate, potassium phosphate, potassium carbonate, sodium carbonate or potassium hydroxide.
  • an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine
  • an inorganic base such as cesium carbonate, potassium phosphate, potassium carbonate, sodium carbonate or potassium hydroxide.
  • the catalyst used here is not particularly limited, but tris (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium and the like and 4,5-bis (diphenylphosphino) -9,9'-dimethylxanthene (Xantphos ), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (XPhos) and the like can be used in appropriate combinations. . Furthermore, the above reaction can also be performed in the presence of a condensing agent.
  • Examples of the condensing agent used here are not particularly limited, and dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and the like can be used.
  • dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and the like can be used.
  • Compound (7) can be produced from compound (1).
  • Compound (2) can be obtained by boronic esterification reaction of compound (1). In this reaction, compound (1) and a mixture of an equal or excess amount of a boronate esterification reagent and an organic compound in an inert solvent for the reaction are cooled to heated, preferably at ⁇ 20 ° C. to 60 ° C. In the presence of the metal compound, the mixture is usually stirred for 0.1 hour to 5 days.
  • Examples of the solvent used here are not particularly limited, but are 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, dimethoxyethane, DMF, DMSO, EtOAc, acetonitrile or water, and mixtures thereof.
  • Examples of boronic esterification reagents include triisopropyl borate, tributyl borate and the like.
  • Examples of the organometallic compound used in this reaction include organolithium compounds such as n-butyllithium.
  • R B is a compound of H of the compound (2) can be obtained by referring to Wuts et al mentioned above, subjecting the compound (2) to a hydrolysis reaction.
  • compound (5) can be obtained by a coupling reaction of compound (2) and compound (3R).
  • a mixture of the compound (2) and an equal amount or an excess amount of the compound (3R) 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
  • 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, potassium phosphate or potassium hydroxide facilitates the reaction. It may be advantageous for progress.
  • an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine
  • an inorganic base such as potassium carbonate, sodium carbonate, potassium phosphate or potassium hydroxide
  • 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 and the like.
  • a coupling reaction can be performed using metal palladium (0).
  • Compound (6) can be obtained by a reduction reaction of compound (5).
  • compound (5) is usually treated for 0.1 hour to 3 days with an equal or excessive amount of reducing agent in a solvent inert to the reaction under cooling to heating, preferably at -20 ° C to 80 ° C.
  • solvent inert a solvent inert
  • examples of the solvent used here are not particularly limited, but ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, alcohols such as methanol, ethanol and 2-propanol, and aromatics such as benzene, toluene and xylene.
  • 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, ethy
  • reducing agent hydride reducing agents such as lithium aluminum hydride, sodium borohydride or diisobutylaluminum hydride, metal reducing agents such as sodium, zinc, iron and platinum, and other reducing agents in the following documents are preferably used.
  • Compound (7) can be obtained by oxidation reaction of compound (6). In this reaction, compound (6) is usually treated for 0.1 hour to 3 days with an equal or excess amount of an oxidizing agent in a solvent inert to the reaction, under cooling to heating, preferably at -20 ° C to 80 ° C. To do.
  • solvent used here examples are not particularly limited, but ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, benzene, toluene, Aromatic hydrocarbons such as xylene, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, water or a mixture thereof may be mentioned.
  • ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane
  • halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform
  • benzene toluene
  • Aromatic hydrocarbons such as xylene, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, water or
  • the oxidizing agent examples include sodium chlorite, hydrogen peroxide, cumene hydroperoxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, oxone (registered trademark), active manganese dioxide, chromic acid, permanganic acid. Potassium and sodium periodate are preferably used.
  • sodium chlorite is used as the oxidizing agent, a compound such as 2-methyl-2-butene is used to compensate for the chlorine compound generated in the reaction system, and under conditions of acid such as sodium dihydrogen phosphate. In some cases, the reaction can proceed advantageously.
  • DMSO oxidation such as Swern oxidation or oxidation using a Dess-Martin reagent is preferably used.
  • Compound (8a) can be obtained by Mitsunobu reaction between compound (6) and compound (13a). In this reaction, compound (6) is added in an equivalent amount or an excess amount of (13a) in the presence of an azo compound and a phosphorus compound in a solvent inert to the reaction under cooling to heating, preferably at -20 ° C to 80 ° C. ) And usually 0.1 hours to 3 days.
  • solvent used here are not particularly limited, but ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, benzene, toluene, Aromatic hydrocarbons such as xylene, N, N-dimethylformamide, dimethyl sulfoxide, or a mixture thereof.
  • ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane
  • halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform
  • benzene toluene
  • Aromatic hydrocarbons such as xylene, N, N-dimethylformamide, dimethyl sulfoxide, or a mixture thereof.
  • azo compound for example, 1,1 ′-(azodicarbonyl) dipiperidine, diethyl azodicarboxylate, diisopropyl azodicarboxylate can be used, and as the phosphorus compound, for example, tributylphosphine and triphenylphosphine are preferable. Used. Further, instead of the azo compound and the phosphorus compound, for example, a phosphorus ylide compound such as (cyanomethylene) trimethylphosphorane or (cyanomethylene) tributylphosphorane can be used.
  • Compound (11) can be produced by subjecting compound (3 ′) to a substitution reaction, a coupling reaction, and a deprotection reaction.
  • the reaction conditions of the above-mentioned (third production method) can be used for the substitution reaction
  • the reaction conditions of (raw material synthesis 1) can be used for the coupling reaction.
  • the deprotection reaction can be carried out with reference to the aforementioned Utz et al.
  • Compound (12) can be obtained by reacting compound (11) with NH 3 .
  • aqueous ammonia is used with compound (11), and a mixture of these in the presence of a condensing agent, in a solvent inert to the reaction, from cooling to heating, preferably ⁇ 20 ° C. Stir at ⁇ 60 ° C. for usually 0.1 hour to 5 days.
  • a condensing agent in a solvent inert to the reaction, from cooling to heating, preferably ⁇ 20 ° C. Stir at ⁇ 60 ° C. for usually 0.1 hour to 5 days.
  • the solvent used here are not particularly limited, but are 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.
  • 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 may 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
  • a method of reacting with NH 3 after converting the carboxylic acid (11) into a reactive derivative can 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
  • active esters obtained by condensation with benzotriazole and the like include active esters obtained by condensation
  • 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 (8) can be obtained by dehydration reaction of compound (12).
  • the compound (12) is stirred in the presence of a dehydrating agent in a solvent inert to the reaction, from cooling to heating, preferably at -20 ° C. to 60 ° C., usually for 0.1 hour to 5 days. To do.
  • Examples of the solvent used here are not particularly limited, but are 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.
  • Examples of the dehydrating agent include phosphoryl chloride and thionyl chloride, but are not limited thereto.
  • Compound (16) can be obtained by a coupling reaction between compound (15) and a phosphate ester. Although this reaction is not specifically limited, For example, it can carry out by Horner-Emmons (Horner-Emmons) reaction or Wittig (Wittig) reaction. In this reaction, in a solvent inert to the reaction, under cooling to heating, preferably at ⁇ 20 ° C. to 80 ° C., compound (15) is added in the presence of an equal amount or an excess amount of phosphate compound (17). Usually, it is treated for 0.1 hour to 3 days.
  • solvent used here are not particularly limited, but ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, N, N-dimethylformamide and dimethyl Examples thereof include sulfoxide or a mixture thereof. It is advantageous to carry out the reaction 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. There are cases.
  • a base such as sodium bis (trimethylsilyl) amide, n-butyllithium, tert-butoxypotassium, sodium ethoxide, sodium methoxide, sodium hydride, etc.
  • Examples of the phosphate ester compound (17) include diethyl (cyanomethyl) phosphonate.
  • This reaction can also be carried out by using compound (18) in the presence of a phosphorus compound instead of phosphate compound (17).
  • a phosphorus compound an alkyltriphenylphosphonium salt is preferably used, and more specifically, (methoxymethyl) triphenylphosphonium chloride, (methylthiomethyl) triphenylphosphonium and the like can be mentioned.
  • compound (8a) can be obtained by hydrogenation reaction of compound (16). In this reaction, compound (16) is usually stirred for 1 hour to 5 days in the presence of a metal catalyst in a solvent inert to the reaction under a hydrogen atmosphere.
  • 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.
  • 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.
  • hydrogen gas an equivalent to excess amount of formic acid or ammonium formate relative to compound (16) can be used as a hydrogen source. This reaction may also be performed by contacting compound (16) with magnesium in the presence of methanol. This reaction is usually carried out under cooling to heating, preferably at room temperature.
  • 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 (20P) can be obtained by subjecting compound (19P) to a Reformatsky reaction. In this reaction, the compound (19P) and an equivalent amount or an excess amount of the compound (24) are used, and the mixture is heated in the presence of zinc powder in a solvent inert to the reaction, or in the absence of solvent and from under cooling. The mixture is stirred at reflux, preferably 0 ° C. to 200 ° C., more preferably 20 ° C. to 120 ° 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, and mixtures thereof.
  • the zinc powder and the compound (24) can be treated in advance and used in the reaction as a Reformatsky reagent.
  • Compound (21) can be produced by subjecting compound (20P) to a hydrogenation reaction and a deprotection reaction.
  • the hydrogenation reaction can be carried out using the reaction conditions described in (Raw material synthesis 4).
  • 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 method 1 GPR40 agonist activity measurement i) Cloning of human GPR40 A full-length sequence of GPR40 was obtained by PCR using human genomic DNA (Clontech) as a template according to the following procedure. The oligonucleotide consisting of the base sequence represented by SEQ ID NO: 1 was used as a forward primer, and the oligonucleotide consisting of the base sequence represented by SEQ ID NO: 2 was used as a reverse primer. A base sequence including an XbaI recognition site is added to the 5 ′ end of each of the forward primer and the reverse primer.
  • PCR was performed using Taq DNA polymerase (Ex Taq DNA polymerase; Takara Bio Inc.) in the presence of 5% dimethyl sulfoxide (DMSO) at 94 ° C (15 seconds) / 55 ° C (30 seconds) / 72 ° C (1 minute) ) Was repeated 30 times.
  • DMSO dimethyl sulfoxide
  • a DNA fragment of about 0.9 kbp was amplified.
  • This DNA fragment was digested with XbaI and then inserted into the XbaI site of plasmid pEF-BOS-dhfr (Nucleic Acids Research, 18, 5322, 1990) to obtain plasmid pEF-BOS-dhfr-GPR40.
  • the base sequence of the GPR40 gene in the plasmid pEF-BOS-dhfr-GPR40 was determined by the dideoxy terminator method using a DNA sequencer (ABI377 DNA Sequencer; Applied Biosystems).
  • the base sequence of GPR40 gene was as shown in the base sequence represented by SEQ ID NO: 3.
  • the base sequence represented by SEQ ID NO: 3 has an open reading frame (ORF) of 903 bases, and the amino acid sequence (300 amino acids) predicted from this ORF is the amino acid sequence represented by SEQ ID NO: 4. It was as follows.
  • CHO dhfr-cells CHO cells lacking the dihydrofolate reductase (dhfr) gene
  • dhfr dihydrofolate reductase
  • the plasmid pEF-BOS-dhfr-GPR40 obtained in i) was used as an expression plasmid for expressing the GPR40 protein. Inoculate 6-well plates (Asahi Techno Glass) in ⁇ MEM medium containing 10% fetal calf serum (FCS) so that CHO dhfr-cells become 80-90% confluent and culture overnight.
  • FCS fetal calf serum
  • plasmid pEF-BOS-dhfr-GPR40 2 ⁇ g of plasmid pEF-BOS-dhfr-GPR40 per well was introduced using a transfection reagent (Lipofectamine 2000; Invitrogen). After culturing for 24 hours after gene transfer, the cells were diluted and seeded again. At that time, the ⁇ MEM medium containing 10% FCS was changed to the ⁇ MEM medium containing 10% FCS but no nucleic acid. After culturing for 20 days, the formed cell colonies were individually collected and cultured to obtain CHO cells stably expressing GPR40. From these cells, cells having high reactivity to the endogenous ligands oleic acid and linoleic acid were selected.
  • Probenecid (Sigma) (35.68 mg) was dissolved in 1 M NaOH (250 ⁇ l), and HBSS-HEPES buffer (250 ⁇ l) was added to prepare.
  • the fluorescent dye solution was prepared by mixing 16 ml of HBSS-HEPES buffer, 640 ⁇ l of fluorescent dye, and 32 ⁇ l probenecid per plate. The plate medium was removed, and 40 ⁇ l of the fluorescent dye solution was dispensed per well, followed by incubation at room temperature for 2 hours.
  • the test compound was dissolved in DMSO, diluted with HBSS-HEPES buffer, and 10 ⁇ l was dispensed on a plate to start the reaction, and the fluctuation of intracellular calcium concentration was measured by FLIPR.
  • the EC 50 value of the test compound was calculated from the dose response curve of the fluorescence intensity change 1 minute after the measurement. As a result, the compound of the present invention showed GPR40 agonist activity. EC 50 values for some of the compounds of the invention are shown in Table 1. Ex represents an example compound number described later.
  • Test Method 2 Insulin Secretion Promoting Action Using MIN6 Cells
  • MIN6 cells were seeded in a 96-well plate at 5 ⁇ 10 4 cells / hole (200 ⁇ l).
  • the medium used was DMEM (25 mM glucose) containing 10% FBS, 55 ⁇ M 2-mercaptoethanol, 100 U / ml penicillin, 100 ⁇ g / ml streptomycin. After 2 days, the medium was removed with an aspirator and KRB-HEPES containing 2.8 mM glucose (116 mM NaCl, 4.7 mM KCl, 1.2 mM KH 2 PO 4 , 1.2 mM MgSO 4 , 0.25 mM CaCl 2 , 25 mM) warmed to 37 ° C.
  • the plate was washed once with 200 ⁇ l of NaHCO 3 , 0.005% FFA Free BSA, 24 mM HEPES (pH 7.4), and again with 200 ⁇ l of the same buffer, and incubated at 37 ° C. for 1 hour. Remove the above buffer with an aspirator, wash again with buffer (200 ⁇ l), add KRB-HEPES containing 2.8 mM or 22.4 mM glucose, and add a test compound of the specified concentration to each well. In addition, it was incubated at 37 ° C. for 2 hours. The sample was collected, diluted 100 times, and the insulin concentration was quantified using an insulin RIA kit (Amersham RI).
  • Test Method 3 Normal Mouse Single Oral Glucose Tolerance Test
  • a normal mouse was used to examine the inhibitory effect of the test compound on glucose elevation after glucose loading. The test method is shown below. Male ICR mice (6 weeks old) preliminarily raised for 1 week were fasted overnight and used as test animals. The test compound was orally administered 10 mg / kg 30 minutes before loading with glucose (2 g / kg) using 0.01 M sodium hydroxide aqueous solution as the administration solvent. The control group was administered with 0.01 M sodium hydroxide aqueous solution.
  • the rate of inhibition of blood glucose increase (%) relative to the control group at the time of glucose load 30 minutes was calculated.
  • the test results are shown in Table 2. Ex represents an example compound number described later. As a result, it was confirmed that the compound of the present invention has an excellent blood glucose increase inhibitory action.
  • the compound of the formula (I) has an excellent GPR40 agonistic action, and has a potent insulin secretion promoting action and a blood glucose elevation inhibiting action. Therefore, it can be used as an insulin secretion promoter or a prophylactic / therapeutic agent for diabetes.
  • 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 ethanol.
  • the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances, and preservatives.
  • the injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion.
  • 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. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like.
  • ointment bases commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
  • a transmucosal agent such as an inhalant or a nasal agent is used in a solid, liquid, or semi-solid state, and can be produced according to a conventionally known method.
  • 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.
  • 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.
  • the dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. 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.
  • the desiccant was removed by filtration, silica gel (about 10 g) was added to the obtained filtrate, and the mixture was concentrated under reduced pressure.
  • the obtained support was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- ⁇ 4-[(4'-chloro-2'-methylbiphenyl-3-yl) methoxy] phenyl ⁇ propanoic acid Methyl (1.97 g) was obtained as a colorless oil.
  • the reaction mixture was allowed to cool to room temperature, water (300 mL) was added, and the mixture was filtered through celite and washed with ethyl acetate. The filtrate was separated, and the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure.
  • reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added, and the insoluble material was removed by celite filtration. After the filtrate was separated, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure.
  • the reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with a toluene-ethyl acetate solution.
  • the aqueous layer was extracted with a toluene-ethyl acetate solution.
  • the organic layers were combined, washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
  • the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and 5 ′-[(2,2 ′, 6′-trimethylbiphenyl-3-yl) methoxy] spiro [cyclopropane-1,2 ′. -Indene] -1 '(3'H) -one (1.07 g) was obtained as a white solid.
  • the reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with a toluene-ethyl acetate solution.
  • the aqueous layer was extracted with a toluene-ethyl acetate solution.
  • the organic layers were combined, washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
  • the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and ⁇ 5 '-[(2,2', 6'-trimethylbiphenyl-3-yl) methoxy] spiro [cyclopropane-1,2 '-Indene] -1'(3'H) -ylidene ⁇ acetonitrile (729 mg) was obtained as a white amorphous solid.
  • the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and ⁇ 5 '-[(2,2', 6'-trimethylbiphenyl-3-yl) methoxy] -1 ', 3'-dihydro Spiro [cyclopropane-1,2′-indene] -1′-yl ⁇ acetonitrile (702 mg) was obtained as a colorless bowl.
  • the reaction mixture was allowed to cool to room temperature, water, ethyl acetate and toluene were added, and the insoluble material was removed by celite filtration. After the filtrate was separated, the aqueous layer was extracted with a toluene-ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure.
  • the aqueous layer was extracted with a 2-propanol-chloroform solution.
  • the organic layers were combined and dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure to obtain 1 '-(1H-tetrazol-5-ylmethyl) -1', 3'-dihydrospiro [cyclopropane-1,2'-indene. ] -5'-amine (3.11 g) was obtained as a brown amorphous solid.
  • Production Example 38 Add 1M hydrochloric acid (350 mL) to a solution of 2,2 ', 6'-trimethyl-4'-(tetrahydro-2H-pyran-2-yloxy) biphenyl-3-carbaldehyde (35.13 g) in THF (350 mL). And stirred at room temperature for 3.5 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and anhydrous magnesium sulfate and activated carbon (3.00 g) were added.
  • Triethylamine (0.80 mL), acetic anhydride (0.50 mL) and N, N-dimethylpyridin-4-amine (40 mg) were added to the reaction mixture, and the mixture was stirred at 55 ° C. for 17 hours.
  • the reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with 1M hydrochloric acid and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure.
  • Production Example 46 1-1.5 kg of a mixture of 3- (4-nitrophenyl) propanenitrile (7.15 g), ethanol (35 mL), ethyl acetate (35 mL) and 10% palladium-activated carbon (50% water containing product, 1.40 g) The mixture was stirred at room temperature under a hydrogen atmosphere of / cm 2 for 6 hours. The catalyst was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- (4-aminophenyl) propanenitrile (5.76 g) as a pale brown oil.
  • Production Example 47 Dissolve methyl 1- (cyanomethylene) indan-5-carboxylate (1.70 g) in methanol (30 mL) and dioxane (15 mL), add 10% palladium-activated carbon (50% water-containing product, 340 mg), The mixture was stirred at room temperature under a hydrogen atmosphere of 3 kg / cm 2 for 1.5 hours. The catalyst was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give methyl 1- (cyanomethyl) indan-5-carboxylate (1.64 g) as a white solid.
  • the catalyst was removed by Celite filtration, and the filtrate was concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- (4-amino-2-fluorophenyl) propanenitrile (1.85 g) as a yellow oil.
  • the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ⁇ 5-[(4'-hydroxy-2,2 ', 6'-trimethylbiphenyl-3-yl) methoxy] -2,3 -Dihydro-1H-inden-1-yl ⁇ acetonitrile (2.32 g) was obtained as a white amorphous solid.
  • Production Example 53 In the same manner as in Example 1 described later, the compounds of Production Example 53 and Production Examples 53-1 to 53-2 were produced.
  • Tables 3 to 20 show the structures of the production example compounds, and Tables 21 to 23 show the physicochemical data.
  • Example 1 3- ⁇ 4-[(4'-Chloro-2'-methylbiphenyl-3-yl) methoxy] phenyl ⁇ propanenitrile (300 mg), sodium azide (539 mg), triethylamine hydrochloride (1.14 g) and NMP (5 mL) was stirred at 100 ° C. for 6 hours. Thereafter, the reaction mixture was further stirred at 150 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure.
  • the residue was diluted with a toluene-ethyl acetate solution and washed twice with water.
  • the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure.
  • the residue was purified by silica gel column chromatography (chloroform-methanol), and ethyl acetate-diethyl ether was added to the obtained residue and stirred.
  • Example 2 Benzoic acid 2-[(3 '- ⁇ [4- (2-cyanoethyl) phenoxy] methyl ⁇ -2-methylbiphenyl-4-yl) oxy] ethyl (990 mg), sodium azide (523 mg), triethylamine hydrochloride A mixture of salt (1.11 g) and NMP (13 mL) was stirred at 110 ° C. for 33 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate.
  • Example 3 N-[(4 '- ⁇ [(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy ⁇ -2,2', 6'-trimethylbiphenyl-3-yl) methyl]-
  • a mixture of 4- [2- (1H-tetrazol-5-yl) ethyl] aniline (762 mg), 1M hydrochloric acid (4 mL), ethanol (4 mL) and THF (4 mL) was stirred at room temperature for 7 hours.
  • To the reaction mixture were added 1M aqueous sodium hydroxide solution (4.5 mL) and 10% aqueous citric acid solution (20 mL) in this order, and the mixture was extracted with chloroform.
  • the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.
  • the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (chloroform-methanol). To the obtained brown oil (648 mg), THF and 4M hydrogen chloride dioxane solution (1 mL) were added, the solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the precipitated solid was collected by filtration and dried under reduced pressure.
  • Example 4 ⁇ 5 '-[(2,2', 6'-Trimethylbiphenyl-3-yl) methoxy] -1 ', 3'-dihydrospiro [cyclopropane-1,2'-indene] -1'-yl ⁇ acetonitrile (340 mg), sodium azide (270 mg), triethylamine hydrochloride (570 mg) and toluene (10 mL) were stirred at 110 ° C. for 2 hours, and then NMP (5 mL) was added and further stirred at 140 ° C. for 18 hours. Stir for hours.
  • Example 5 5-( ⁇ 5-[(4 '- ⁇ [(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy ⁇ -2,2', 6'-trimethylbiphenyl-3-yl ) Methoxy] -2,3-dihydro-1H-inden-1-yl ⁇ methyl) -1H-tetrazole (506 mg) in methanol (5 mL) and THF (3 mL) was added with 1M hydrochloric acid (3 mL). The mixture was stirred at room temperature for 0.5 hour and then allowed to stand at room temperature for 63.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform.
  • the organic layer was dried over anhydrous magnesium sulfate.
  • the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in methanol (6 mL), 1M aqueous sodium hydroxide solution (2.4 mL) was added, and the mixture was stirred at room temperature for 0.5 hr, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by ODS column chromatography (acetonitrile-water) to obtain a white amorphous solid. Diethyl ether (10 mL) was added to the obtained white amorphous solid, and the mixture was stirred at room temperature for 0.5 hour.
  • the organic layer was dried over anhydrous magnesium sulfate.
  • the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in methanol (6 mL), 1M aqueous sodium hydroxide solution (3 mL) was added, and the mixture was stirred at room temperature for 0.5 hr, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by ODS column chromatography (acetonitrile-water) to obtain a white amorphous solid. Diethyl ether (10 mL) was added to the obtained white amorphous solid, and the mixture was stirred at room temperature for 0.5 hour.
  • Example 6 In the same manner as in Example 6, the compounds of Examples 6-1 to 6-2 shown in the table below were produced.
  • Example 7 4 '- ⁇ [(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy ⁇ -2,2', 6'-trimethylbiphenyl-3-carbaldehyde (220 mg), 1 ' -(1H-tetrazol-5-ylmethyl) -1 ', 3'-dihydrospiro [cyclopropane-1,2'-indene] -5'-amine (150 mg), acetic acid (0.18 mL) and THF (5 mL ) was stirred at room temperature for 2.5 hours.
  • Example 8 (5- ⁇ [4 '-(3-hydroxy-3-methylbutoxy) -2,2', 6'-trimethylbiphenyl-3-yl] methoxy ⁇ -2,3-dihydro-1H-inden-1-yl )
  • Sodium azide (500 mg) and triethylamine hydrochloride (1.05 g) were added to a solution of acetonitrile (572 mg) in NMP (10 mL), and the reaction mixture was stirred at 160 ° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with toluene-ethyl acetate solution.
  • the aqueous layer was extracted with a toluene-ethyl acetate solution and ethyl acetate.
  • the organic layers were combined and dried over anhydrous magnesium sulfate.
  • the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give a brown oil.
  • the obtained oil was dissolved in methanol (5 mL), 1M aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 0.5 hr, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by ODS column chromatography (acetonitrile-water) to obtain a white amorphous solid.
  • Diisopropyl ether (10 mL) was added to the obtained white amorphous solid, and the mixture was stirred at room temperature for 0.5 hour.
  • Example 8 In the same manner as in Example 8, the compound of Example 8-1 shown in the table below was produced.
  • Example 9 4 '-(3-hydroxy-3-methylbutoxy) -2,2', 6'-trimethylbiphenyl-3-carbaldehyde (300 mg), 1 '-(1H-tetrazol-5-ylmethyl) -1', A mixture of 3′-dihydrospiro [cyclopropane-1,2′-indene] -5′-amine (240 mg), acetic acid (0.27 mL) and THF (6 mL) was stirred at room temperature for 2.5 hours. Under ice-cooling, sodium triacetoxyborohydride (300 mg) was added to the reaction mixture, and the mixture was stirred for 15.5 hours while warming to room temperature.
  • Example 10 ⁇ 5 '-[(4'- ⁇ [(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy ⁇ -2,2 ', 6'-trimethylbiphenyl-3-yl) methoxy ] -1 ', 3'-Dihydrospiro [cyclopropane-1,2'-indene] -1'-yl ⁇ acetonitrile (253 mg) in NMP (5 mL) solution with sodium azide (200 mg) and triethylamine hydrochloride Salt (430 mg) was added and the reaction mixture was stirred at 160 ° C. for 17 hours.
  • the reaction mixture was allowed to cool to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with toluene-ethyl acetate solution.
  • the aqueous layer was extracted again with a toluene-ethyl acetate solution.
  • the organic layers were combined, washed with water and a saturated aqueous sodium chloride solution, and anhydrous magnesium sulfate and activated carbon (0.3 g) were added.
  • the desiccant and activated carbon were removed by filtration, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give a brown oil.
  • the desiccant and activated carbon were removed by filtration, and the solvent was distilled off under reduced pressure.
  • 1M hydrochloric acid (3 mL) was added to a solution of the obtained residue in THF (3 mL) and methanol (3 mL), and the mixture was stirred at 50 ° C. for 3 hr.
  • the reaction mixture was allowed to cool to room temperature, 1M aqueous sodium hydroxide solution (5 mL) was added and the mixture was stirred at room temperature for 0.5 hr, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by ODS column chromatography (acetonitrile-water) to obtain a white amorphous solid.
  • Example 11 Benzoic acid 2- ⁇ [3 '-( ⁇ [1'-(cyanomethyl) -1 ', 3'-dihydrospiro [cyclopropane-1,2'-indene] -5'-yl] oxy ⁇ methyl) -2 , 2 ', 6-Trimethylbiphenyl-4-yl] oxy ⁇ ethyl (185 mg) in NMP (4 mL) was added sodium azide (130 mg) and triethylamine hydrochloride (280 mg), and the reaction mixture was added to 160 Stir at 17 ° C. for 17 hours.
  • the reaction mixture was allowed to cool to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with toluene-ethyl acetate solution.
  • the aqueous layer was extracted again with a toluene-ethyl acetate solution.
  • the organic layers were combined, washed with water and a saturated aqueous sodium chloride solution, and anhydrous magnesium sulfate and activated carbon (0.3 g) were added.
  • the desiccant and activated carbon were removed by filtration, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give a brown oil.
  • the desiccant and activated carbon were removed by filtration, and the solvent was distilled off under reduced pressure.
  • To a solution of the obtained residue in methanol (3 mL) was added 1M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 1.5 hours, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by ODS column chromatography (acetonitrile-water) to obtain a white amorphous solid.
  • Diisopropyl ether (10 mL) was added to the obtained white amorphous solid, and the mixture was stirred at room temperature for 0.5 hour.
  • Example 12 N- ⁇ 3- [2- (2- ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ ethoxy) -4,6-dimethylpyrimidin-5-yl] -2-methylbenzyl ⁇ -4- [2- ( To a solution of [1H-tetrazol-5-yl) ethyl] aniline (529 mg) in THF (3 mL) was added 1M hydrochloric acid (6 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1M aqueous sodium hydroxide solution (6.5 mL), and then 10% aqueous citric acid solution (10 mL) was added. The mixture was extracted with 2-propanol-chloroform solution.
  • Example 13 N- [3- (2- ⁇ [(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy ⁇ -4,6-dimethylpyrimidin-5-yl) -2-methylbenzyl]
  • -4- [2- (1H-tetrazol-5-yl) ethyl] aniline 554 mg
  • 1M hydrochloric acid 6 mL
  • Example 14 3- (6- ⁇ [4 '-(2- ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ ethoxy) -2,2', 6'-trimethylbiphenyl-3-yl] methoxy ⁇ pyridin-3-yl 1M hydrochloric acid (1 mL) was added to a solution of propanenitrile (153 mg) in THF (1.5 mL), and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate.
  • the desiccant was removed by filtration, and then the solvent was distilled off under reduced pressure to obtain a colorless bowl (120 mg).
  • a mixture of the obtained colorless rod (120 mg), sodium azide (190 mg), triethylamine hydrochloride (400 mg) and NMP (1.5 mL) was stirred at 160 ° C. for 5 hours.
  • the reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution (5 mL) was added, and 10% aqueous citric acid solution (5 mL) was added.
  • the mixture was extracted with a 2-propanol-chloroform solution, and the organic layer was dried over anhydrous magnesium sulfate.
  • Example 15 3- ⁇ 6-[(4 '- ⁇ [(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy ⁇ -2,2', 6'-trimethylbiphenyl-3-yl) 1M Hydrochloric acid (1 mL) was added to a THF (1.5 ml) solution of methoxy] pyridin-3-yl ⁇ propanenitrile (95 mg), and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate.
  • the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a colorless bowl (83 mg).
  • a mixture of the obtained colorless powder (83 mg), dibutyltin oxide (23 mg), trimethylsilyl azide (0.122 mL) and toluene (3 mL) was stirred at 120 ° C. for 2.5 hours.
  • the reaction mixture was allowed to cool to room temperature, dibutyltin oxide (23 mg) and trimethylsilyl azide (0.122 mL) were added, and the mixture was stirred at 120 ° C. for 1 hr.
  • the reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with a 2-propanol-chloroform solution.
  • the organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure.
  • the residue was purified by silica gel column chromatography (chloroform-methanol), and 1M aqueous sodium hydroxide solution (0.2 mL) was added to a methanol (1 mL) solution of the obtained colorless rod-like material.
  • the residue was purified by ODS column chromatography (acetonitrile-water), and hexane was added to the resulting white amorphous solid and stirred.
  • Example 15-1 In the same manner as in Example 15, the compound of Example 15-1 shown in the table below was produced.
  • the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate.
  • the desiccant was removed by filtration, and then the solvent was distilled off under reduced pressure to obtain a colorless bowl (112 mg).
  • a mixture of the obtained colorless powder (112 mg), dibutyltin oxide (32 mg), trimethylsilyl azide (0.165 mL) and toluene (3 mL) was stirred at 120 ° C. for 4 hours.
  • the reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate.
  • Tables 24 to 30 show the structures of the production example compounds, and Tables 31 to 35 show the physicochemical data.
  • the compound of formula (I) has an excellent GPR40 agonistic action, and is an insulin secretagogue, or diabetes (insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), or borderline type (glucose tolerance).
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • borderline type glucose tolerance
  • -Abnormal fasting blood glucose level Mild diabetes
  • insulin resistance disease obesity and other diseases involving GPR40 can be used as a preventive and / or therapeutic agent.
  • the base sequence represented by the sequence of SEQ ID NO: 1 in the sequence listing is a base sequence of an artificially synthesized primer.
  • the base sequence represented by the sequence number 2 in the sequence listing is the base sequence of an artificially synthesized primer.

Abstract

Disclosed are: a compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and use of the compound or the pharmaceutically acceptable salt thereof for medical purposes. In the formula, RA2 and RA3 independently represent H, or together form -CH2-C(RX1)(RX2)-; RX1 and RX2 independently represent H, or together form an optionally substituted C2-7 alkylene group. The compound or the pharmaceutically acceptable salt thereof has an excellent GPR40 agonistic activity and can be used for medical purposes, such as an insulin secretion promoter and a prophylactic or therapeutic agent for diabetes.

Description

テトラゾール化合物Tetrazole compound
　本発明は、医薬、殊にインスリン分泌促進剤、糖尿病の予防・治療剤として有用な新規なテトラゾール化合物またはその製薬学的に許容される塩に関する。 The present invention relates to a novel tetrazole compound or a pharmaceutically acceptable salt thereof useful as a pharmaceutical, particularly an insulin secretagogue, a prophylactic / therapeutic agent for diabetes.
　糖尿病は、慢性的な高血糖を主徴とする疾患であり、インスリン作用の絶対的または相対的な不足により発症する。臨床においてはその特徴からインスリン依存性糖尿病 (IDDM)とインスリン非依存性糖尿病 (NIDDM)に大別される。インスリン非依存性糖尿病 (NIDDM)において、膵β細胞からのインスリン分泌低下は、主要な発症原因の一つであり、特に初期のインスリン分泌障害による食後高血糖が認められる。 Diabetes is a disease whose main feature is chronic hyperglycemia, and develops due to an absolute or relative lack of insulin action. In clinical practice, it is roughly divided into insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). In non-insulin dependent diabetes mellitus (NIDDM), a decrease in insulin secretion from pancreatic β-cells is one of the main causes of onset, and particularly postprandial hyperglycemia due to early insulin secretion disorder is observed.
　最近、大規模臨床試験により、糖尿病性合併症の発症ならびに進展抑制には食後高血糖の是正が重要であることが確認された。また、食後高血糖のみの時期に動脈硬化が発症すること、食後軽度高血糖の持続が心血管疾患等の原因による死亡率を高めることが報告されている。食後高血糖はたとえ軽度であっても心血管死の独立した危険因子であることを示している。以上のような知見により、食後高血糖に対する薬物治療の必要性が認識されるようになっている。 Recently, large-scale clinical trials confirmed that correction of postprandial hyperglycemia is important for the suppression of the onset and progression of diabetic complications. In addition, it has been reported that arteriosclerosis develops at the time of only postprandial hyperglycemia, and that the persistence of postprandial mild hyperglycemia increases the mortality due to causes such as cardiovascular disease. Postprandial hyperglycemia has been shown to be an independent risk factor for cardiovascular death, even if mild. Based on the above findings, the necessity of drug treatment for postprandial hyperglycemia has been recognized.
　現在、インスリン分泌促進剤としてはスルホニルウレア（SU）剤が主流であるが、低血糖を起こしやすく、長期投与においては膵臓の疲弊により二次無効を引き起こすことが知られている。また、SU剤は食間の血糖コントロールには有効であるが、食後の過血糖を抑制することは困難である。 Currently, sulfonylurea (SU) agents are the mainstream as insulin secretagogues, but they are prone to hypoglycemia and are known to cause secondary ineffectiveness due to pancreatic exhaustion in long-term administration. Moreover, although the SU agent is effective for blood glucose control between meals, it is difficult to suppress hyperglycemia after meals.
　GPR40は、脂肪酸の受容体として同定された膵臓のβ細胞に高発現しているG蛋白質共役型受容体であり、脂肪酸のインスリン分泌作用に関与していることが報告されている（非特許文献１）。
　従って、GPR40受容体アゴニストはインスリン分泌促進作用に基づき、食後高血糖の是正が期待されることから、インスリン依存性糖尿病 (IDDM)、インスリン非依存性糖尿病 (NIDDM)、又は、境界型（耐糖能・空腹時血糖値異常）軽症糖尿病の予防・治療剤として有用である。 GPR40 is a G protein-coupled receptor highly expressed in pancreatic β cells identified as a fatty acid receptor and has been reported to be involved in the insulin secretory action of fatty acids (Non-patent literature). 1).
Therefore, GPR40 receptor agonists are expected to correct postprandial hyperglycemia based on insulin secretion-promoting action, so insulin-dependent diabetes (IDDM), non-insulin-dependent diabetes (NIDDM)・ Abnormal fasting blood glucose level) It is useful as a preventive or therapeutic agent for mild diabetes.
　特許文献１では、広範な化合物を含む式（Ａ）の化合物がGPR40受容体調節作用を有し、インスリン分泌促進薬や糖尿病の予防及び／又は治療薬として有用であることが報告されている。しかしながら、本願発明の構造を有する化合物の具体的開示はない。
Figure JPOXMLDOC01-appb-C000002
 （式中、環Pは置換基を有していてもよい芳香環を、環Qは
Figure JPOXMLDOC01-appb-C000003
 以外にさらに置換基を有していてもよい芳香環を、X及びYはスペーサーを、
Figure JPOXMLDOC01-appb-C000004
 はカチオンを放出しうる基を示す。） In Patent Document 1, it is reported that compounds of formula (A) including a wide range of compounds have a GPR40 receptor modulating action and are useful as insulin secretagogues and diabetes preventive and / or therapeutic agents. However, there is no specific disclosure of the compound having the structure of the present invention.
Figure JPOXMLDOC01-appb-C000002
 (In the formula, ring P represents an aromatic ring which may have a substituent, and ring Q represents
Figure JPOXMLDOC01-appb-C000003
 In addition to the aromatic ring optionally having a substituent, X and Y are spacers,
Figure JPOXMLDOC01-appb-C000004
 Represents a group capable of releasing a cation. )
　特許文献２では、式（Ｂ）の化合物がGPR40受容体調節作用を有し、インスリン分泌促進薬や糖尿病の予防及び／又は治療薬として有用であることが報告されている。
Figure JPOXMLDOC01-appb-C000005
 （式中の記号は当該公報参照。） In Patent Document 2, it is reported that the compound of the formula (B) has a GPR40 receptor modulating action and is useful as an insulin secretagogue and a preventive and / or therapeutic agent for diabetes.
Figure JPOXMLDOC01-appb-C000005
 (See the official gazette for symbols in the formula.)
　特許文献３では、式（Ｃ）のオキサゾリジンジオン化合物が血糖低下作用及び血中脂質低下作用を有し、糖尿病の治療に有用であることが報告されている。
Figure JPOXMLDOC01-appb-C000006
 （式中の記号は当該公報参照。） Patent Document 3 reports that the oxazolidinedione compound of the formula (C) has a blood glucose lowering action and a blood lipid lowering action and is useful for the treatment of diabetes.
Figure JPOXMLDOC01-appb-C000006
 (See the official gazette for symbols in the formula.)
　特許文献４では、式（Ｄ）のオキサジアゾリジンジオン化合物がプラスミノーゲン活性化阻害因子(PAI)-1阻害作用を有し、血栓、心房細動、心筋虚血、糖尿病等の治療に有用であることが報告されている。
Figure JPOXMLDOC01-appb-C000007
 （式中、Ｘは
Figure JPOXMLDOC01-appb-C000008
 を示す。他の記号は当該公報参照。） In Patent Document 4, the oxadiazolidinedione compound of formula (D) has a plasminogen activation inhibitor (PAI) -1 inhibitory action and is useful for the treatment of thrombus, atrial fibrillation, myocardial ischemia, diabetes, etc. It has been reported that.
Figure JPOXMLDOC01-appb-C000007
 (Where X is
Figure JPOXMLDOC01-appb-C000008
 Indicates. For other symbols, see the publication. )
　特許文献５では、式（Ｅ）の化合物がGPR40受容体調節作用を有し、インスリン分泌促進薬や糖尿病の予防及び／又は治療薬として有用であることが報告されている。
Figure JPOXMLDOC01-appb-C000009
 （式中の記号は当該公報参照。） In Patent Document 5, it is reported that the compound of the formula (E) has a GPR40 receptor modulating action and is useful as an insulin secretagogue and a preventive and / or therapeutic agent for diabetes.
Figure JPOXMLDOC01-appb-C000009
 (See the official gazette for symbols in the formula.)
　特許文献６では、式（Ｆ）の化合物がGPR40受容体調節作用を有し、インスリン分泌促進薬や糖尿病の予防及び／又は治療薬として有用であることが報告されている。
Figure JPOXMLDOC01-appb-C000010
 （式中、
Figure JPOXMLDOC01-appb-C000011
 は、
Figure JPOXMLDOC01-appb-C000012
 を、他の記号は当該公報参照。） Patent Document 6 reports that the compound of formula (F) has a GPR40 receptor-modulating action and is useful as an insulin secretion-promoting agent or a prophylactic and / or therapeutic agent for diabetes.
Figure JPOXMLDOC01-appb-C000010
 (Where
Figure JPOXMLDOC01-appb-C000011
 Is
Figure JPOXMLDOC01-appb-C000012
 For other symbols. )
　特許文献７では、式（Ｇ）の化合物がGPR40受容体調節作用を有し、インスリン分泌促進薬や糖尿病の予防及び／又は治療薬として有用であることが報告されている。
Figure JPOXMLDOC01-appb-C000013
 （式中の記号は当該公報参照。） In Patent Document 7, it is reported that the compound of the formula (G) has a GPR40 receptor modulating action and is useful as an insulin secretagogue and a preventive and / or therapeutic agent for diabetes.
Figure JPOXMLDOC01-appb-C000013
 (See the official gazette for symbols in the formula.)
　また、血糖低下作用を有し、糖尿病の治療に有用である化合物として非特許文献２、特許文献８、特許文献９、特許文献１０及び特許文献１１が、GPR40受容体調節作用を有し、糖尿病等の治療に有用である化合物として特許文献１２、特許文献１３、特許文献１４、特許文献１５及び特許文献１６がそれぞれ報告されている。しかし、いずれの文献においても、本発明化合物は具体的に開示されていないし、本発明化合物の示唆もない。 Non-patent document 2, Patent document 8, Patent document 9, Patent document 10 and Patent document 11 have a blood glucose lowering action and are useful for the treatment of diabetes. Patent Literature 12, Patent Literature 13, Patent Literature 14, Patent Literature 15 and Patent Literature 16 have been reported as compounds useful for the treatment of these. However, in any document, the compound of the present invention is not specifically disclosed, and there is no suggestion of the compound of the present invention.
国際公開第2004/041266号パンフレットInternational Publication No. 2004/041266 Pamphlet 国際公開第2005/063729号パンフレットInternational Publication No. 2005/063729 Pamphlet 日本国特許出願　特開平2000-212174号公報Japanese patent application JP-A 2000-212174 国際公開第2005/030203号パンフレットInternational Publication No. 2005/030203 Pamphlet 国際公開第2005/087710号パンフレットInternational Publication No. 2005/087710 Pamphlet 国際公開第2004/106276号パンフレットInternational Publication No. 2004/106276 Pamphlet 国際公開第2008/001931号パンフレットInternational Publication No. 2008/001931 Pamphlet 国際公開第95/30664号パンフレットWO95 / 30664 pamphlet 国際公開第97/41097号パンフレットWO 97/41097 pamphlet 米国特許第5480896号公報US Patent No. 5480896 国際公開第97/41097号パンフレットWO 97/41097 pamphlet 国際公開第2005/063725号パンフレットInternational Publication No. 2005/063725 Pamphlet 国際公開第2008/066097号パンフレットInternational Publication No. 2008/066097 Pamphlet 国際公開第2007/049050号パンフレットInternational Publication No. 2007/049050 Pamphlet 国際公開第2006/083781号パンフレットInternational Publication No. 2006/083781 Pamphlet 国際公開第2006/083612号パンフレットInternational Publication No. 2006/083612 Pamphlet
　本発明は、医薬組成物、例えば、インスリン分泌促進剤、糖尿病の予防・治療剤の有効成分として有用なGPR40アゴニスト作用を有する化合物を提供することを目的とする。 An object of the present invention is to provide a compound having a GPR40 agonistic activity that is useful as an active ingredient of a pharmaceutical composition, for example, an insulin secretagogue and a preventive / therapeutic agent for diabetes.
　本発明者らは、GPR40アゴニスト作用を有する化合物について鋭意検討した結果、２若しくは３環部分にメチレンを介してテトラゾール基が結合し、また、２若しくは３環部分に-O-メチレン若しくは-NH-メチレンを介して６員単環芳香環で置換されたベンゼンが結合する本発明化合物（Ｉ）またはその製薬学的に許容される塩が優れたGPR40アゴニスト活性を有することを見出した。さらに、これらの化合物が優れたインスリン分泌促進作用を有し、糖負荷後の血糖上昇を強力に抑制することを見出し、本発明を完成した。
　即ち、本発明は、下記式（Ｉ）で示されるテトラゾール化合物又はその製薬学的に許容される塩並びに式（Ｉ）で示されるテトラゾール化合物又はその製薬学的に許容される塩を含有する医薬組成物に関する。
Figure JPOXMLDOC01-appb-C000014
 （式中、
RA1は、H、又は、ハロゲンであり、
mは、1、又は、2であり、
RA2及びRA3は、H、又は、
RA2とRA3が一体となって-CH2-C(RX1)(RX2)-であり、
RX1及びRX2は、H、又は、
RX1とRX2が一体となって置換されていてもよいC2-7アルキレンであり、
Zは、N、又は、C-RZであり、
RZは、H、又は、ハロゲンであり、
Lは、O、又は、NHであり、
R1、R2、R3、R4、R5及びR6は、互いに同一又は異なっていてもよい、H、ハロゲン、置換されていてもよい低級アルキル、又は、-O-(置換されていてもよい低級アルキル)であり、
R7は、H、ハロゲン、-O-(置換されていてもよいヘテロ環基)、又は、-O-(CR71R72)p-R73であり、
R71及びR72は、互いに同一又は異なっていてもよい、H、OH、又は、置換されていてもよい低級アルキルであり、
pは、1、2、又は、3であり
R73は、OH、又は、-O-(置換されていてもよい低級アルキル)、又は、置換されていてもよいヘテロ環基であり、
Ya及びYbは、互いに同一又は異なっていてもよい、N、又は、C-RYであり、
RYは、H、ハロゲン、置換されていてもよい低級アルキル、又は、-O-(置換されていてもよい低級アルキル)である。） As a result of intensive studies on compounds having a GPR40 agonistic activity, the present inventors bonded a tetrazole group to the 2 or 3 ring moiety via methylene, and -O-methylene or -NH- to the 2 or 3 ring moiety. It has been found that the compound (I) of the present invention or a pharmaceutically acceptable salt thereof, to which benzene substituted with a 6-membered monocyclic aromatic ring is bonded via methylene has excellent GPR40 agonist activity. Furthermore, the present inventors have found that these compounds have an excellent insulin secretion promoting action and strongly suppress an increase in blood glucose after glucose loading, thereby completing the present invention.
That is, the present invention relates to a tetrazole compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical comprising the tetrazole compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. Relates to the composition.
Figure JPOXMLDOC01-appb-C000014
 (Where
R A1 is H or halogen;
m is 1 or 2,
R A2 and R A3 are H or
R A2 and R A3 are combined to form -CH 2 -C (R X1 ) (R X2 )-
R X1 and R X2 are H or
R X1 and R X2 are C 2-7 alkylene which may be substituted together,
Z is N or CR Z ,
R Z is H or halogen;
L is O or NH;
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be the same or different from each other, H, halogen, optionally substituted lower alkyl, or —O— (substituted Optionally lower alkyl)
R 7 is H, halogen, —O— (optionally substituted heterocyclic group), or —O— (CR 71 R 72 ) p —R 73 ;
R 71 and R 72 are the same or different from each other, H, OH, or optionally substituted lower alkyl,
p is 1, 2 or 3
R 73 is OH or -O- (lower alkyl which may be substituted) or an optionally substituted heterocyclic group;
Y a and Y b may be the same or different from each other, N or CR Y ;
R Y is H, halogen, optionally substituted lower alkyl, or —O— (optionally substituted lower alkyl). )
　なお、特に記載がない限り、本明細書中のある化学式中の記号が他の化学式においても用いられる場合、同一の記号は同一の意味を示す。また、R7における-O-(CR71R72)p-R73のpが2若しくは3のとき、CR71R72は、互いに同一又は異なっていてもよく、例えば、p=2の場合、-O-CH(OH)-CH(CH3)-R73であってもよい。 Unless otherwise specified, when a symbol in a chemical formula in this specification is also used in another chemical formula, the same symbol indicates the same meaning. Further, when p of -O- (CR 71 R 72 ) p -R 73 in R 7 is 2 or 3, CR 71 R 72 may be the same or different from each other, for example, when p = 2 -O-CH (OH) -CH (CH 3 ) -R 73 may also be used.
　更に、本発明は、式（Ｉ）の化合物又はその塩を含有するGPR40が関与する疾患の予防用若しくは治療用医薬組成物、即ち、式（Ｉ）の化合物又はその塩を含有するGPR40が関与する疾患の予防若しくは治療剤に関する。
　また、本発明は、GPR40が関与する疾患の予防用若しくは治療用医薬組成物の製造のための式（Ｉ）の化合物又はその塩の使用、GPR40が関与する疾患の予防若しくは治療のための式（Ｉ）の化合物又はその塩、並びに、式（Ｉ）の化合物又はその塩の有効量を患者に投与することからなるGPR40が関与する疾患の予防若しくは治療方法に関する。 Furthermore, the present invention relates to a pharmaceutical composition for preventing or treating a disease involving GPR40 containing a compound of formula (I) or a salt thereof, that is, GPR40 containing a compound of formula (I) or a salt thereof. The present invention relates to a preventive or therapeutic agent for diseases.
The present 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 a disease involving GPR40, a formula for the prevention or treatment of a disease involving GPR40. The present invention relates to a method for preventing or treating a disease involving GPR40, which comprises administering to a patient an effective amount of a compound of formula (I) or a salt thereof, and a compound of formula (I) or a salt thereof.
　本発明化合物は、優れたGPR40アゴニスト作用を有することから、インスリン分泌促進剤、糖尿病（インスリン依存性糖尿病 (IDDM)、インスリン非依存性糖尿病 (NIDDM)、又は、境界型（耐糖能・空腹時血糖値異常）軽症糖尿病）等のGPR40が関与する疾患の予防・治療剤として有用である。 Since the compound of the present invention has an excellent GPR40 agonistic action, it can be used as an insulin secretagogue, diabetes (insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), or borderline (glucose tolerance / fasting blood glucose It is useful as a prophylactic / therapeutic agent for diseases involving GPR40, such as abnormal values) and mild diabetes.
　以下、本発明を詳細に説明する。尚、本明細書において「式（Ｉ）の化合物又はその塩」を「本発明化合物（Ｉ）」や「化合物（Ｉ）」と表記することがある。 Hereinafter, the present invention will be described in detail. In the present specification, the “compound of formula (I) or a salt thereof” may be referred to as “the present compound (I)” or “compound (I)”.
　本明細書中、「低級アルキル」とは、直鎖又は分枝状の炭素数が１から６（以後、C1-6と略す）のアルキル、例えばメチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ペンチル、n-ヘキシル等である。別の態様としては、C1-4アルキルであり、さらに別の態様としては、C1-3アルキルである。 In the present specification, “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. Another embodiment is C 1-4 alkyl, and yet another embodiment is C 1-3 alkyl.
　「アルキレン」とは、直鎖又は分枝状のアルキレン、例えばメチレン、エチレン、トリメチレン、テトラメチレン、ペンタメチレン、ヘキサメチレン、プロピレン、メチルメチレン、エチルエチレン、1,2-ジメチルエチレン、1,1,2,2-テトラメチルエチレン等である。別の態様としては、C1-6アルキレンであり、さらに別の態様としては、C1-4アルキレンであり、さらに別の態様としては、C1-3アルキレンであり、また、更に別の態様としては、C2-7アルキレンである。 “Alkylene” means linear or branched 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 1-6 alkylene, yet another embodiment is C 1-4 alkylene, and yet another embodiment is C 1-3 alkylene, and yet another embodiment. As C 2-7 alkylene.
　「アリール」とは、C6-14の単環～三環式芳香族炭化水素環基であり、C5-8シクロアルケンとその二重結合部位で縮合した環基を包含する。例えば、フェニル、ナフチル、5-テトラヒドロナフチル、4-インデニル、1-フルオレニル等である。 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 a double bond site thereof. For example, phenyl, naphthyl, 5-tetrahydronaphthyl, 4-indenyl, 1-fluorenyl and the like.
　「ヘテロ環」とは、ｉ）酸素、硫黄及び窒素から選択されるヘテロ原子を１～４個含有する３～８員の、別の態様としては５～７員の単環ヘテロ環、並びに、ｉｉ）当該単環ヘテロ環が、単環へテロ環、ベンゼン環、C5-8シクロアルカン及びC5-8シクロアルケンからなる群より選択される１又は２個の環と縮環し形成される、酸素、硫黄および窒素から選択されるヘテロ原子を１～５個含有する二～三環式ヘテロ環（これら二～三環式ヘテロ環はスピロ環を含む）、から選択される環基を意味する。環原子である硫黄又は窒素が酸化されオキシドやジオキシドを形成してもよい。 “Heterocycle” means i) a 3 to 8 membered, alternatively 5 to 7 membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and ii) The monocyclic heterocycle is formed by condensing 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. A ring group selected from bi to tricyclic heterocycles containing 1 to 5 heteroatoms selected from oxygen, sulfur and nitrogen (these bi to tricyclic heterocycles include spiro rings), means. Ring atoms such as sulfur or nitrogen may be oxidized to form oxides or dioxides.
　「ヘテロ環」として以下の態様が挙げられる。
（１）単環式飽和へテロ環基
（ａ）１～４個の窒素原子を含むもの、例えば、アゼパニル、ジアゼパニル、アジリジニル、アゼチジニル、ピロリジニル、イミダゾリジニル、ピペリジル、ピラゾリジニル、ピペラジニル、アゾカニル、ヘキサメチレンイミノ、ホモピペラジニル等；
（ｂ）１～３個の窒素原子、ならびに１～２個の硫黄原子および／または１～２個の酸素原子を含むもの、例えば、チオモルホリニル、チアゾリジニル、イソチアゾリジニル、オキサゾリジニル、モルホリニル等；
（ｃ）１～２個の硫黄原子を含むもの、例えば、テトラヒドロチオピラニル等；
（ｄ）１～２個の硫黄原子および１～２個の酸素原子を含むもの、例えば、オキサチオラニル等；
（ｅ）１～２個の酸素原子を含むもの、例えば、オキシラニル、オキセタニル、ジオキソラニル、テトラヒドロフラニル、テトラヒドロピラニル、1,4-ジオキサニル等； Examples of the “heterocycle” include the following embodiments.
(1) 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 and 1 to 2 oxygen atoms, such as oxathiolanyl;
(E) those containing 1 to 2 oxygen atoms, such as oxiranyl, oxetanyl, dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl and the like;
（２）単環式不飽和へテロ環基
（ａ）１～４個の窒素原子を含むもの、例えば、ピロリル、2-ピロリニル、イミダゾリル、2-イミダゾリニル、ピラゾリル、2-ピラゾリニル、ピリジル、ジヒドロピリジル、テトラヒドロピリジニル、ピリミジニル、ピラジニル、ピリダジニル、トリアゾリル、テトラゾリル、トリアジニル、ジヒドロトリアジニル、アゼピニル等；
（ｂ）１～３個の窒素原子、ならびに１～２個の硫黄原子および／または１～２個の酸素原子を含むもの、例えば、チアゾリル、イソチアゾリル、チアジアゾリル、ジヒドロチアジニル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、オキサジニル等；
（ｃ）１～２個の硫黄原子を含むもの、例えば、チエニル、チエピニル、ジヒドロジチオピラニル、ジヒドロジチオニル、2H-チオピラニル等；
（ｄ）１～２個の硫黄原子および１～２個の酸素原子を含むもの、具体的には、ジヒドロオキサチオピラニル等；
（ｅ）１～２個の酸素原子を含むもの、例えば、フリル、ジヒドロフリル、ピラニル、2H-ピラニル、オキセピニル、ジオキソリル等； (2) 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) those containing 1 to 2 sulfur atoms, such as thienyl, thiepinyl, dihydrodithiopyranyl, dihydrodithionyl, 2H-thiopyranyl and the like;
(D) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, specifically, dihydrooxathiopyranyl and the like;
(E) those containing 1 to 2 oxygen atoms, such as furyl, dihydrofuryl, pyranyl, 2H-pyranyl, oxepinyl, dioxolyl and the like;
（３）縮合多環式飽和へテロ環基
（ａ）１～５個の窒素原子を含むもの、例えば、キヌクリジニル、7-アザビシクロ[2.2.1]ヘプチル、3-アザビシクロ[3.2.2]ノナニル、2,8-ジアザスピロ[4.5]デカ-8-イル、2,3,6,8-テトラアザスピロ[4.5]デカン-8-イル等；
（ｂ）１～４個の窒素原子、ならびに１～３個の硫黄原子および／または１～３個の酸素原子を含むもの、例えば、トリチアジアザインデニル、ジオキソロイミダゾリジニル、6-オキサ-2,8-ジアザスピロ[4.5]デカン-8-イル、6-チア-2,8-ジアザスピロ[4.5]デカン-8-イル等；
（ｃ）１～３個の硫黄原子および／または１～３個の酸素原子を含むもの、例えば、2,6-ジオキサビシクロ[3.2.2]オクト-7-イル、2-オキサ-6-チアスピロ[4.5]デカン-8-イル等； (3) 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 and the like;
(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-dioxabicyclo [3.2.2] oct-7-yl, 2-oxa-6- Thiaspiro [4.5] decan-8-yl, etc .;
（４）縮合多環式不飽和へテロ環基
（ａ）１～５個の窒素原子を含むもの、例えば、インドリル、イソインドリル、インドリニル、インドリジニル、ベンゾイミダゾリル、ジヒドロベンゾイミダゾリル、テトラヒゾロベンゾイミダゾリル、キノリル、テトラヒドロキノリル、イソキノリル、テトラヒドロイソキノリル、インダゾリル、イミダゾピリジル、ベンゾトリアゾリル、テトラゾロピリダジニル、カルバゾリル、アクリジニル、キノキサリニル、ジヒドロキノキサリニル、テトラヒドロキノキサリニル、フタラジニル、ジヒドロインダゾリル、ベンゾピリミジニル、ナフチリジニル、キナゾリニル、シンノリニル、ピリドピロリジニル、トリアゾロピペリジニル、9, 10-ジヒドロアクリジン、2,8-ジアザスピロ[4.5]デカ-3-エン-8-イル、2,3,6,8-テトラアザスピロ[4.5]デカ-1-エン-8-イル等；
（ｂ）１～４個の窒素原子、ならびに１～３個の硫黄原子および／または１～３個の酸素原子を含むもの、例えば、ベンゾチアゾリル、ジヒドロベンゾチアゾリル、ベンゾチアジアゾリル、イミダゾチアゾリル、イミダゾチアジアゾリル、ベンゾオキサゾリル、ジヒドロベンゾオキサゾリル、ジヒドロベンゾオキサジニル、ベンゾオキサジアゾリル、ベンゾイソチアゾリル、ベンゾイソオキサゾリル、チアゾロピペリジニル、10H-フェノチアジン、6-オキサ-2,8-ジアザスピロ[4.5]デカ-3-エン-8-イル、6-チア-2,8-ジアザスピロ[4.5]デカ-3-エン-8-イル等；
（ｃ）１～３個の硫黄原子を含むもの、例えば、ベンゾチエニル、ベンゾジチオピラニル、クロマニル、ジベンゾ[b,d]チエニル等；
（ｄ）１～３個の硫黄原子および１～３個の酸素原子を含むもの、例えば、ベンゾオキサチオピラニル、フェノキサジニル、2-オキサ-6-チアスピロ[4.5]デカ-3-エン-8-イル等；
（ｅ）１～３個の酸素原子を含むもの、例えば、ベンゾジオキソリル、ベンゾフラニル、ジヒドロベンゾフラニル、イソベンゾフラニル、クロマニル、クロメニル、イソクロメニル、ジベンゾ[b,d]フラニル、メチレンジオキシフェニル、エチレンジオキシフェニル、キサンテニル等；
など。 (4) 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, pyridopyrrolidinyl, triazolopiperidinyl, 9, 10-dihydroacridine, 2,8-diazaspiro [4.5] dec-3-en-8-yl, 2, 3,6,8 -Tetraazaspiro [4.5] dec-1-en-8-yl and the like;
(B) those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, for example benzothiazolyl, dihydrobenzothiazolyl, benzothiadiazolyl, imidazothia Zolyl, imidazothiadiazolyl, benzoxazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, benzooxadiazolyl, benzisothiazolyl, benzisoxazolyl, thiazolopiperidinyl, 10H-phenothiazine 6-oxa-2,8-diazaspiro [4.5] dec-3-en-8-yl, 6-thia-2,8-diazaspiro [4.5] dec-3-en-8-yl;
(C) those containing 1 to 3 sulfur atoms, such as benzothienyl, benzodithiopyranyl, chromanyl, dibenzo [b, d] thienyl, etc .;
(D) those containing 1 to 3 sulfur atoms and 1 to 3 oxygen atoms, such as benzooxathiopyranyl, phenoxazinyl, 2-oxa-6-thiaspiro [4.5] dec-3-en-8- Ill etc .;
(E) those containing 1 to 3 oxygen atoms, such as benzodioxolyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromenyl, dibenzo [b, d] furanyl, methylenedioxy Phenyl, ethylenedioxyphenyl, xanthenyl, etc .;
Such.
　「含窒素へテロ環」基とは、上記の「へテロ環」基のうち、（１）（ａ）、（１）（ｂ）、（２）（ａ）、（２）（ｂ）、（３）（ａ）、（３）（ｂ）、（４）（ａ）及び（４）（ｂ）等のように、１～５個の窒素原子を含んでいるものをいう。 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).
　「含窒素単環式飽和へテロ環」基とは、上記の「単環式飽和へテロ環」基のうち、（１）（ａ）、（１）（ｂ）等のように、１～５個の窒素原子を含んでいるものをいう。 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.
　「含窒素単環式不飽和へテロ環」基とは、上記の「へテロ環」基のうち、（２）（ａ）、（２）（ｂ）等のように、１～５個の窒素原子を含んでいるものをいう。 The “nitrogen-containing monocyclic unsaturated heterocycle” group refers to 1 to 5 of the above “heterocycle” groups, as in (2) (a), (2) (b), etc. The thing containing a nitrogen atom.
　「含窒素縮合多環式飽和へテロ環」基とは、上記の「へテロ環」基のうち、（３）（ａ）、（３）（ｂ）等のように、１～５個の窒素原子を含んでいるものをいう。 The “nitrogen-containing polycyclic saturated heterocycle” group is a group of 1 to 5 of the above “heterocycle” groups, such as (3) (a), (3) (b), etc. The thing containing a nitrogen atom.
　「含窒素縮合多環式不飽和へテロ環」基とは、上記の「へテロ環」基のうち、（４）（ａ）及び（４）（ｂ）等のように、１～５個の窒素原子を含んでいるものをいう。 The “nitrogen-containing fused polycyclic unsaturated heterocycle” group includes 1 to 5 of the above “heterocycle” groups as in (4) (a) and (4) (b) Containing nitrogen atoms.
　「６員単環芳香環」とは、上記「アリール」及び「ヘテロ環」のうち、芳香族性を有する６員環構造の単環式の環基をいう。例えば、フェニル、ピリジル、ピリミジル等である。 The “6-membered monocyclic aromatic ring” refers to a monocyclic ring group of aromatic 6-membered ring structure among the above “aryl” and “heterocycle”. For example, phenyl, pyridyl, pyrimidyl and the like.
　尚、上記の「アリール」及び「ヘテロ環」基は、１価基で記しているが、これらは場合によっては２価以上の基を表してもよい。 In addition, although the above “aryl” and “heterocyclic” groups are described as monovalent groups, they may represent divalent or higher groups depending on circumstances.
　「ハロゲン」は、F、Cl、Br、Iを意味し、好ましくは、F、Br、Clである。 “Halogen” means F, Cl, Br, I, preferably F, Br, Cl.
　「RX1とRX2が一体となってC2-7アルキレン」とは、RX1とRX2が、それらが結合する炭素原子と一体となってC3-8の飽和炭化水素環を形成することを示す。当該飽和炭化水素環としては、例えば、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロオクタン等である。別の態様としては、C2-6アルキレンであり、さらに別の態様としては、C2-4アルキレンである。 "R X1 and R X2 are combined to form C 2-7 alkylene" means that R X1 and R X2 are combined with the carbon atom to which they are bonded to form a C 3-8 saturated hydrocarbon ring. It shows that. Examples of the saturated hydrocarbon ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like. Another embodiment is C 2-6 alkylene, and yet another embodiment is C 2-4 alkylene.
　本明細書において、「置換されていてもよい」とは、無置換、若しくは置換基を１～５個有していることを意味する。なお、複数個の置換基を有する場合、それらの置換基は同一であっても、互いに異なっていてもよい。 In the present specification, “optionally substituted” means unsubstituted or having 1 to 5 substituents. In addition, when it has a some substituent, those substituents may be the same, or may mutually differ.
　R7における「置換されていてもよいヘテロ環」基において許容される置換基のある態様としては、例えば、下記の（a）～（i）に示される基及びオキソ(=O)が挙げられる。また、別の態様としては、例えば、下記の（a）、（b）、（f）及び（i）に示される基及びオキソ(=O)が挙げられる。更に別の態様としては、例えば、下記の（i）に示される基及びオキソ(=O)が挙げられる。
（a）ハロゲン。
（b）-OH、-O-低級アルキル（この低級アルキルは、１個～３個のハロゲンで置換されていてもよい）。
（c）１個又は２個の低級アルキルで置換されていてもよいアミノ、ニトロ。
（d）-SH、-S-低級アルキル（この低級アルキルは、１個～３個のハロゲンで置換されていてもよい）。
（e）-SO2-低級アルキル、-SO2-シクロアルキル、-SO2-ヘテロ環基、-SO2-アリール、１個又は２個の低級アルキルで置換されていてもよいスルファモイル。
（f）-CHO、-CO-低級アルキル、-CO-シクロアルキル、-CO-単環式飽和ヘテロ環基（このヘテロ環基は、ハロゲン、低級アルキル、-O-低級アルキル若しくはオキソ(=O)で置換されていてもよい）、シアノ。
（g）アリール若しくはシクロアルキル。なお、これらの基は、ハロゲン、低級アルキル若しくは-O-低級アルキルでそれぞれ置換されていてもよい。
（h）ヘテロ環基。なお、このヘテロ環基は、ハロゲン、低級アルキル、-O-低級アルキル若しくはオキソ(=O)で置換されていてもよい。
（i）上記（a）～（h）に示される置換基より選択される１個以上の基で置換されていてもよい低級アルキル。 Examples of the substituents allowed in the “optionally substituted heterocycle” group for R 7 include the groups shown in the following (a) to (i) and oxo (═O): . Moreover, as another aspect, the group shown by following (a), (b), (f), and (i) and oxo (= O) are mentioned, for example. Still another embodiment includes, for example, a group shown in the following (i) and oxo (═O).
(A) Halogen.
(B) -OH, -O-lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens).
(C) amino or nitro optionally substituted with 1 or 2 lower alkyls.
(D) -SH, -S-lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens).
(E) sulfamoyl optionally substituted with —SO 2 -lower alkyl, —SO 2 -cycloalkyl, —SO 2 -heterocyclic group, —SO 2 -aryl, 1 or 2 lower alkyls.
(F) -CHO, -CO-lower alkyl, -CO-cycloalkyl, -CO-monocyclic saturated heterocyclic group (this heterocyclic group is halogen, lower alkyl, -O-lower alkyl or oxo (= O ), Cyano.
(G) Aryl or cycloalkyl. These groups may each be substituted with halogen, lower alkyl or —O-lower alkyl.
(H) a heterocyclic group. The heterocyclic group may be substituted with halogen, lower alkyl, —O-lower alkyl or oxo (═O).
(I) Lower alkyl optionally substituted with one or more groups selected from the substituents shown in the above (a) to (h).
　R73における「置換されていてもよいヘテロ環」基において許容される置換基のある態様としては、例えば、上記の（a）～（i）に示される基及びオキソ(=O)が挙げられる。また、別の態様としては、例えば、上記の（a）、（b）、（f）及び（i）に示される基及びオキソ(=O)が挙げられる。更に別の態様としては、例えば、上記の（i）に示される基及びオキソ(=O)が挙げられる。 Examples of the substituent allowed in the “optionally substituted heterocycle” group for R 73 include the groups shown in the above (a) to (i) and oxo (═O). . Moreover, as another aspect, the group shown by said (a), (b), (f) and (i) and oxo (= O) are mentioned, for example. Still another embodiment includes, for example, the group shown in the above (i) and oxo (═O).
　R1、R2、R3、R4、R5及びR6における「置換されていてもよい低級アルキル」において許容される置換基のある態様としては、例えば、上記の（a）～（h）に示される基が挙げられる。また、別の態様としては、例えば、上記の（a）及び(b）に示される基及びオキソ(=O)が挙げられる。更に別の態様としては、例えば、上記の（a）に示される基及びオキソ(=O)が挙げられる。 Examples of the substituents allowed in the “optionally substituted lower alkyl” in R 1 , R 2 , R 3 , R 4 , R 5 and R 6 include, for example, the above (a) to (h ). Moreover, as another aspect, the group shown by said (a) and (b) and oxo (= O) are mentioned, for example. Still another embodiment includes, for example, the group shown in the above (a) and oxo (═O).
　「RX1とRX2が一体となって置換されていてもよいC2-7アルキレン」において許容される置換基のある態様としては、例えば、上記の（a）～（h）に示される基が挙げられる。また、別の態様としては、例えば、上記の（a）、（b）及び（f）に示される基及びオキソ(=O)が挙げられる。更に別の態様としては、例えば、上記の（a）及び（b）に示される基及びオキソ(=O)が挙げられる。 Examples of the substituents allowed in “C 2-7 alkylene in which R X1 and R X2 may be substituted together” include, for example, the groups shown in the above (a) to (h) Is mentioned. Moreover, as another aspect, the group shown by said (a), (b), and (f) and oxo (= O) are mentioned, for example. Still another embodiment includes, for example, the groups shown in the above (a) and (b) and oxo (═O).
　R71及びR72における「置換されていてもよい低級アルキル」において許容される置換基のある態様としては、例えば、上記の（a）～（h）に示される基が挙げられる。また、別の態様としては、例えば、上記の（a）～（e）に示される基及びオキソ(=O)が挙げられる。更に別の態様としては、例えば、上記の（b）に示される基及びオキソ(=O)が挙げられる。 Examples of the substituents allowed in the “optionally substituted lower alkyl” in R 71 and R 72 include the groups shown in the above (a) to (h). As another embodiment, for example, the groups shown in the above (a) to (e) and oxo (═O) can be mentioned. Still another embodiment includes, for example, the group shown in the above (b) and oxo (═O).
　R73における「置換されていてもよい低級アルキル」において許容される置換基のある態様としては、例えば、上記の（a）～（h）に示される基が挙げられる。また、別の態様としては、例えば、上記の（g）及び（h）に示される基及びオキソ(=O)が挙げられる。更に別の態様としては、例えば、上記の（g）に示される基及びオキソ(=O)が挙げられる。 Examples of the substituents allowed in the “optionally substituted lower alkyl” in R 73 include the groups shown in the above (a) to (h). Moreover, as another aspect, the group shown by said (g) and (h) and oxo (= O) are mentioned, for example. Still another embodiment includes, for example, the group shown in the above (g) and oxo (═O).
　RYにおける「置換されていてもよい低級アルキル」において許容される置換基のある態様としては、例えば、上記の（a）～（h）に示される基が挙げられる。また、別の態様としては、例えば、上記の（a）、(b）に示される基及びオキソ(=O)が挙げられる。更に別の態様としては、例えば、上記の（a）に示される基及びオキソ(=O)が挙げられる。 Examples of the substituents allowed in the “optionally substituted lower alkyl” in R Y include groups shown in the above (a) to (h). Moreover, as another aspect, the group shown by said (a) and (b) and oxo (= O) are mentioned, for example. Still another embodiment includes, for example, the group shown in the above (a) and oxo (═O).
　本発明化合物（Ｉ）のある態様として、式（Ｉ’）の化合物又はその塩が示される。
Figure JPOXMLDOC01-appb-C000015
 （式中、
RA1は、H、又は、ハロゲンであり、
mは、1、又は、2であり、
RA2及びRA3は、H、又は、RA2とRA3が一体となって-CH2-C(RX1)(RX2)-であり、
RX1及びRX2は、H、又は、RX1とRX2が一体となってC2-7アルキレンであり、
Zは、N、又は、C-RZであり、
RZは、H、又は、ハロゲンであり、
Lは、O、又は、NHであり、
R1、R2、R3、R4、R5及びR6は、互いに同一又は異なっていてもよい、H、ハロゲン、低級アルキル、又は、-O-低級アルキルであり、
R7は、H、ハロゲン、-O-ヘテロ環基、又は、-O-(CR71R72)p-R73であり、
R71及びR72は、互いに同一又は異なっていてもよい、H、OH、又は、OHで置換されていてもよい低級アルキルであり、
pは、1、2、又は、3であり
R73は、OH、又は、アリール若しくはオキソ(=O)で置換されていてもよい-O-低級アルキル、又は、低級アルキルで置換されていてもよいヘテロ環基であり、
Ya及びYbは、互いに同一又は異なっていてもよい、N、又は、C-RYであり、
RYは、H、ハロゲン、低級アルキル、又は、-O-低級アルキルである。） As an embodiment of the compound (I) of the present invention, a compound of the formula (I ′) or a salt thereof is shown.
Figure JPOXMLDOC01-appb-C000015
 (Where
R A1 is H or halogen;
m is 1 or 2,
R A2 and R A3 are H, or R A2 and R A3 are combined to form —CH 2 —C (R X1 ) (R X2 ) —
R X1 and R X2 are H, or R X1 and R X2 together are C 2-7 alkylene,
Z is N or CR Z ,
R Z is H or halogen;
L is O or NH;
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different from each other, and are H, halogen, lower alkyl, or —O-lower alkyl,
R 7 is H, halogen, -O-heterocyclic group, or -O- (CR 71 R 72 ) p -R 73 ,
R 71 and R 72 may be the same or different from each other, H, OH, or lower alkyl optionally substituted with OH;
p is 1, 2 or 3
R 73 is OH, or -O-lower alkyl which may be substituted with aryl or oxo (= O), or a heterocyclic group which may be substituted with lower alkyl,
Y a and Y b may be the same or different from each other, N or CR Y ;
R Y is H, halogen, lower alkyl, or —O-lower alkyl. )
　本発明化合物（Ｉ）及び（Ｉ’）のある態様を以下に示す。
（１）RA1が、H、又は、Fであり、mが1である化合物。
（２）RA2及びRA3が、Hである化合物。
（３）RA2及びRA3が、一体となって-CH2-C(RX1)(RX2)-であり、RX1及びRX2が、Hである化合物。
（４）RA2及びRA3が、一体となって-CH2-C(RX1)(RX2)-であり、RX1及びRX2が、一体となってC2-7アルキレンである化合物。
（５）RA2及びRA3が、一体となって-CH2-C(RX1)(RX2)-であり、RX1及びRX2が、一体となってエチレンである化合物。
（６）Zが、N、又は、C-RZであり、RZが、Hである化合物。
（７）Lが、NHである化合物。
（８）R1、R2、R3、R4、R5及びR6が、互いに同一又は異なっていてもよい、H、又は、低級アルキルである化合物。
（９）R1、R2及びR3が、Hであり、R4、R5及びR6が、メチルである化合物。
（１０）R7が、-O-(CR71R72)p-R73であり、pが3であり、-(CR71R72)3-が、-CH2-CH(OH)-CH2-であり、R73が、OHである化合物。
（１１）R7が、-O-ヘテロ環基である化合物。
（１２）R7が、-O-ヘテロ環基であり、当該ヘテロ環基が、(テトラヒドロ-2H-ピラン-4-イル)である化合物。
（１３）Ya及びYbが、互いに同一又は異なっていてもよい、N、又は、C-RYであり、RYが、Hである化合物。
　また、本発明化合物（Ｉ）及び（Ｉ’）の別の態様としては、上記（１）～（１３）に記載の基のうち二以上の組み合わせからなる化合物であり、具体的には、以下の化合物があげられる。
（１４）RA1が、H、又は、Fであり、mが1であり、RA2及びRA3がHであり、Zが、N、又は、C-RZであり、RZが、Hであり、Lが、NHであり、R1、R2、R3、R4、R5及びR6が、互いに同一又は異なっていてもよい、H、又は、低級アルキルであり、R7が、-O-(CR71R72)p-R73であり、pが3であり、-(CR71R72)3-が、-CH2-CH(OH)-CH2-であり、R73が、OHであり、Ya及びYbが、互いに同一又は異なっていてもよい、N、又は、C-RYであり、RYが、Hである化合物。
（１５）RA1が、H、又は、Fであり、mが1であり、RA2及びRA3がHであり、Zが、N、又は、C-RZであり、RZが、Hであり、Lが、NHであり、R1、R2及びR3が、Hであり、R4、R5及びR6が、メチルであり、R7が、-O-(CR71R72)p-R73であり、pが3であり、-(CR71R72)3-が、-CH2-CH(OH)-CH2-であり、R73が、OHであり、Ya及びYbが、互いに同一又は異なっていてもよい、N、又は、C-RYであり、RYが、Hである化合物。
（１６）RA1が、Hであり、mが1であり、RA2及びRA3が、一体となって-CH2-C(RX1)(RX2)-であり、RX1及びRX2が、Hであり、Zが、N、又は、C-RZであり、RZが、Hであり、Lが、NHであり、R1、R2、R3、R4、R5及びR6が、H、又は、低級アルキルであり、R7が、-O-ヘテロ環基であり、Ya及びYbが、互いに同一又は異なっていてもよい、N、又は、C-RYであり、RYが、Hである化合物。
（１７）RA1が、Hであり、mが1であり、RA2及びRA3が、一体となって-CH2-C(RX1)(RX2)-であり、RX1及びRX2が、Hであり、Zが、N、又は、C-RZであり、RZが、Hであり、Lが、NHであり、R1、R2及びR3が、Hであり、R4、R5及びR6が、メチルであり、R7が、-O-(CR71R72)p-R73であり、pが3であり、-(CR71R72)3-が、-CH2-CH(OH)-CH2-であり、R73が、OHであり、Ya及びYbが、互いに同一又は異なっていてもよい、N、又は、C-RYであり、RYが、Hである化合物。
（１８）RA1が、Hであり、mが1であり、RA2及びRA3が、一体となって-CH2-C(RX1)(RX2)-であり、RX1及びRX2が、Hであり、Zが、N、又は、C-RZであり、RZが、Hであり、Lが、NHであり、R1、R2、R3、R4、R5及びR6が、H、又は、低級アルキルであり、R7が、-O-(CR71R72)p-R73であり、pが3であり、-(CR71R72)3-が、-CH2-CH(OH)-CH2-であり、R73が、OHであり、Ya及びYbが、N、又は、C-RYであり、RYが、Hである化合物。
（１９）RA1が、Hであり、mが1であり、RA2及びRA3が、一体となって-CH2-C(RX1)(RX2)-であり、RX1及びRX2が、Hであり、Zが、N、又は、C-RZであり、RZが、Hであり、Lが、NHであり、R1、R2及びR3が、Hであり、R4、R5及びR6が、メチルであり、R7が、-O-ヘテロ環基であり、当該ヘテロ環基が、(テトラヒドロ-2H-ピラン-4-イル)であり、Ya及びYbが、互いに同一又は異なっていてもよい、N、又は、C-RYであり、RYが、Hである化合物。
（２０）RA1が、Hであり、mが1であり、RA2及びRA3が、一体となって-CH2-C(RX1)(RX2)-であり、RX1及びRX2が、RX1とRX2が一体となってC2-7アルキレンであり、Zが、N、又は、C-RZであり、RZが、Hであり、Lが、NHであり、R1、R2、R3、R4、R5及びR6が、H、又は、低級アルキルであり、R7が、-O-ヘテロ環基であり、Ya及びYbが、互いに同一又は異なっていてもよい、N、又は、C-RYであり、RYが、Hである化合物。
（２１）RA1が、Hであり、mが1であり、RA2及びRA3が、一体となって-CH2-C(RX1)(RX2)-であり、RX1及びRX2が、RX1とRX2が一体となってエチレンであり、Zが、N、又は、C-RZであり、RZが、Hであり、Lが、NHであり、R1、R2及びR3が、Hであり、R4、R5及びR6が、メチルであり、R7が、-O-(CR71R72)p-R73であり、pが3であり、-(CR71R72)3-が、-CH2-CH(OH)-CH2-であり、R73が、OHであり、Ya及びYbが、互いに同一又は異なっていてもよい、N、又は、C-RYであり、RYが、Hである化合物。
（２２）RA1が、Hであり、mが1であり、RA2及びRA3が、一体となって-CH2-C(RX1)(RX2)-であり、RX1及びRX2が、RX1とRX2が一体となってC2-7アルキレンであり、Zが、N、又は、C-RZであり、RZが、Hであり、Lが、NHであり、R1、R2、R3、R4、R5及びR6が、H、又は、低級アルキルであり、R7が、-O-(CR71R72)p-R73であり、pが3であり、-(CR71R72)3-が、-CH2-CH(OH)-CH2-であり、R73が、OHであり、Ya及びYbが、互いに同一又は異なっていてもよい、N、又は、C-RYであり、RYが、Hである化合物。
（２３）RA1が、Hであり、mが1であり、RA2及びRA3が、一体となって-CH2-C(RX1)(RX2)-であり、RX1及びRX2が、RX1とRX2が一体となってエチレンであり、Zが、N、又は、C-RZであり、RZが、Hであり、Lが、NHであり、R1、R2及びR3が、Hであり、R4、R5及びR6が、メチルであり、R7が、-O-ヘテロ環基であり、当該ヘテロ環基が、(テトラヒドロ-2H-ピラン-4-イル)であり、Ya及びYbが、互いに同一又は異なっていてもよい、N、又は、C-RYであり、RYが、Hである化合物。
　本発明化合物（Ｉ）及び（Ｉ’）の更に別の態様を以下に示す。
（２４）RA1が、Hであり、mが1である化合物。
（２５）RA1が、ハロゲンであり、mが1である化合物。
（２６）RA1が、Fであり、mが1である化合物。
（２７）Zが、Nである化合物。
（２８）Zが、C-RZであり、RZが、Hである化合物。
（２９）Lが、Oである化合物。
（３０）R1、R2及びR3が、Hであり、R4、R5及びR6が、低級アルキルである化合物。
（３１）R7が、-O-(CR71R72)p-R73であり、-(CR71R72)p-が、-CH2-CH2-、-CH2-CH(OH)-CH2-、-CH2-CH(CH2OH)-CH2-、-CH2-CH2-CH(CH3)-、又は、-CH2-CH2-C(CH3)2-であり、R73が、OHである化合物。
（３２）R7が、-O-(CR71R72)p-R73であり、-(CR71R72)p-が、-CH2-CH2-であり、R73が、OHである化合物。
（３３）R7が、-O-(CR71R72)p-R73であり、-(CR71R72)p-が、-CH2-CH2-CH(CH3)-、又は、-CH2-CH2-C(CH3)2-であり、R73が、OHである化合物。
（３４）R7が、-O-(CR71R72)p-R73であり、-(CR71R72) p-が、-(CH2) p-であり、R73が、低級アルキルで置換されていてもよいヘテロ環基である化合物。
（３５）R7が、-O-(CR71R72)p-R73であり、-(CR71R72) p-が、-(CH2) p-であり、R73が、(テトラヒドロ-2H-ピラン-4-イル)である化合物。
（３６）R7が、-O-(CR71R72)p-R73であり、-(CR71R72) p-が、-(CH2) p-であり、R73が、(2,2-ジメチル-1,3-ジオキソラン-4-イル)である化合物。
（３７）Ya及びYbが、Nである化合物。
（３８）Ya及びYbが、C-RYであり、RYが、Hである化合物。
　また、本発明化合物（Ｉ）及び（Ｉ’）の更に別の態様としては、上記（１）～（１３）及び（２４）～（３８）に記載の基のうち二以上の組み合わせからなる化合物であり、具体的には、以下の化合物があげられる。
（３９）RA1が、H、又は、Fであり、mが1である（１０）～（１２）、又は、（３１）～（３６）記載の化合物。
（４０）RA1が、Hであり、mが1である（１０）～（１２）、又は、（３１）～（３６）記載の化合物。
（４１）RA1が、ハロゲンであり、mが1である（１０）～（１２）、又は、（３１）～（３６）記載の化合物。
（４２）RA1が、Fであり、mが1である（１０）～（１２）、又は、（３１）～（３６）記載の化合物。
（４３）Zが、N、又は、C-RZであり、RZが、Hである（１０）～（１２）、（３１）～（３６）、又は、（３９）～（４２）記載の化合物。
（４４）Zが、Nである（１０）～（１２）、（３１）～（３６）、又は、（３９）～（４２）記載の化合物。
（４５）Zが、C-RZであり、RZが、Hである（１０）～（１２）、（３１）～（３６）、又は、（３９）～（４２）記載の化合物。
（４６）Lが、NHである（１０）～（１２）、（３１）～（３６）、又は、（３９）～（４５）記載の化合物。
（４７）Lが、Oである（１０）～（１２）、（３１）～（３６）、又は、（３９）～（４５）記載の化合物。
（４８）R1、R2、R3、R4、R5及びR6が、互いに同一又は異なっていてもよい、H、又は、低級アルキルである（１０）～（１２）、（３１）～（３６）、又は、（３９）～（４７）記載の化合物。
（４９）R1、R2及びR3が、Hであり、R4、R5及びR6が、低級アルキルである（１０）～（１２）、（３１）～（３６）、又は、（３９）～（４７）記載の化合物。
（５０）R1、R2及びR3が、Hであり、R4、R5及びR6が、メチルである（１０）～（１２）、（３１）～（３６）、又は、（３９）～（４７）記載の化合物。
（５１）Ya及びYbが、互いに同一又は異なっていてもよい、N、又は、C-RYであり、RYが、Hである（１０）～（１２）、（３１）～（３６）、又は、（３９）～（５０）記載の化合物。
（５２）Ya及びYbが、Nである（１０）～（１２）、（３１）～（３６）、又は、（３９）～（５０）記載の化合物。
（５３）Ya及びYbが、C-RYであり、RYが、Hである（１０）～（１２）、（３１）～（３６）、又は、（３９）～（５０）記載の化合物。 Certain embodiments of the compounds (I) and (I ′) of the present invention are shown below.
(1) A compound wherein R A1 is H or F and m is 1.
(2) The compound wherein R A2 and R A3 are H.
(3) A compound in which R A2 and R A3 are together —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 are H.
(4) Compound in which R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 are all C 2-7 alkylene. .
(5) A compound in which R A2 and R A3 are integrally —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 are all ethylene.
(6) A compound wherein Z is N or CR Z and R Z is H.
(7) A compound in which L is NH.
(8) The compound in which R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be the same or different from each other and are H or lower alkyl.
(9) The compound wherein R 1 , R 2 and R 3 are H, and R 4 , R 5 and R 6 are methyl.
(10) R 7 is —O— (CR 71 R 72 ) p —R 73 , p is 3, and — (CR 71 R 72 ) 3 — is —CH 2 —CH (OH) —CH 2-The compound in which R 73 is OH.
(11) The compound wherein R 7 is —O-heterocyclic group.
(12) The compound wherein R 7 is —O-heterocyclic group, and the heterocyclic group is (tetrahydro-2H-pyran-4-yl).
(13) The compound wherein Y a and Y b may be the same or different from each other, N or CR Y , and R Y is H.
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 (13). These compounds are mentioned.
(14) R A1 is H or F, m is 1, R A2 and R A3 are H, Z is N or CR Z , and R Z is H , L is NH, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be the same or different from each other, H or lower alkyl, and R 7 is- O- (CR 71 R 72 ) p -R 73 , p is 3,-(CR 71 R 72 ) 3 -is -CH 2 -CH (OH) -CH 2- , and R 73 is , OH, Y a and Y b may be the same or different from each other, N or CR Y , and R Y is H.
(15) R A1 is H or F, m is 1, R A2 and R A3 are H, Z is N or CR Z , and R Z is H , L is NH, R 1 , R 2 and R 3 are H, R 4 , R 5 and R 6 are methyl, and R 7 is —O— (CR 71 R 72 ) p -R 73 , p is 3,-(CR 71 R 72 ) 3 -is -CH 2 -CH (OH) -CH 2- , R 73 is OH, Y a and Y A compound in which b is the same as or different from each other, N or CR Y , and R Y is H.
(16) R A1 is H, m is 1, R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 Is H, Z is N or CR Z , R Z is H, L is NH, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Is H or lower alkyl, R 7 is an —O-heterocyclic group, Y a and Y b may be the same or different from each other, N or CR Y , and R A compound in which Y is H.
(17) R A1 is H, m is 1, and R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 Is H, Z is N or CR Z , R Z is H, L is NH, R 1 , R 2 and R 3 are H, R 4 , R 5 and R 6 are methyl, R 7 is —O— (CR 71 R 72 ) p —R 73 , p is 3, and — (CR 71 R 72 ) 3 — is —CH 2 -CH (OH) -CH 2- , R 73 is OH, Y a and Y b may be the same or different from each other, N or CR Y , and R Y is A compound that is H.
(18) R A1 is H, m is 1, R A2 and R A3 are —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 Is H, Z is N or CR Z , R Z is H, L is NH, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Is H or lower alkyl, R 7 is —O— (CR 71 R 72 ) p —R 73 , p is 3, and — (CR 71 R 72 ) 3 — is —CH A compound in which 2 —CH (OH) —CH 2 —, R 73 is OH, Y a and Y b are N or CR Y , and R Y is H.
(19) R A1 is H, m is 1, R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 Is H, Z is N or CR Z , R Z is H, L is NH, R 1 , R 2 and R 3 are H, R 4 , R 5 and R 6 are methyl, R 7 is an —O-heterocyclic group, the heterocyclic group is (tetrahydro-2H-pyran-4-yl), and Y a and Y b are And N or CR Y which may be the same as or different from each other, and R Y is H.
(20) R A1 is H, m is 1, and R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 R X1 and R X2 together are C 2-7 alkylene, Z is N or CR Z , R Z is H, L is NH, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are H or lower alkyl, R 7 is an —O-heterocyclic group, and Y a and Y b are the same or different from each other. A compound wherein N or CR Y and R Y is H.
(21) R A1 is H, m is 1, R A2 and R A3 are —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 R X1 and R X2 are ethylene together, Z is N or CR Z , R Z is H, L is NH, R 1 , R 2 and R 3 is H, R 4 , R 5 and R 6 are methyl, R 7 is —O— (CR 71 R 72 ) p —R 73 , p is 3, and — (CR 71 R 72 ) 3 — is —CH 2 —CH (OH) —CH 2 —, R 73 is OH, and Y a and Y b may be the same or different from each other, N, or , CR Y and R Y is H.
(22) R A1 is H, m is 1, and R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 R X1 and R X2 together are C 2-7 alkylene, Z is N or CR Z , R Z is H, L is NH, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are H or lower alkyl, R 7 is —O— (CR 71 R 72 ) p —R 73 , and p is 3. ,-(CR 71 R 72 ) 3 -is -CH 2 -CH (OH) -CH 2- , R 73 is OH, and Y a and Y b may be the same or different from each other. , N or CR Y and R Y is H.
(23) R A1 is H, m is 1, and R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 R X1 and R X2 are ethylene together, Z is N or CR Z , R Z is H, L is NH, R 1 , R 2 and R 3 is H, R 4 , R 5 and R 6 are methyl, R 7 is an —O-heterocyclic group, and the heterocyclic group is (tetrahydro-2H-pyran-4-yl And Y a and Y b may be the same or different from each other, N or CR Y , and R Y is H.
Still another embodiment of the compounds (I) and (I ′) of the present invention is shown below.
(24) The compound wherein R A1 is H and m is 1.
(25) The compound wherein R A1 is halogen and m is 1.
(26) The compound wherein R A1 is F and m is 1.
(27) The compound wherein Z is N.
(28) The compound wherein Z is CR Z and R Z is H.
(29) The compound wherein L is O.
(30) The compound wherein R 1 , R 2 and R 3 are H, and R 4 , R 5 and R 6 are lower alkyl.
(31) R 7 is —O— (CR 71 R 72 ) p —R 73 , and — (CR 71 R 72 ) p — is —CH 2 —CH 2 —, —CH 2 —CH (OH) -CH 2 -, - CH 2 -CH (CH 2 OH) -CH 2 -, - CH 2 -CH 2 -CH (CH 3) -, or, -CH 2 -CH 2 -C (CH 3) 2 - And R 73 is OH.
(32) R 7 is —O— (CR 71 R 72 ) p —R 73 , — (CR 71 R 72 ) p — is —CH 2 —CH 2 —, and R 73 is OH. A compound.
(33) R 7 is —O— (CR 71 R 72 ) p —R 73 , and — (CR 71 R 72 ) p — is —CH 2 —CH 2 —CH (CH 3 ) —, or A compound wherein —CH 2 —CH 2 —C (CH 3 ) 2 — and R 73 is OH.
(34) R 7 is —O— (CR 71 R 72 ) p —R 73 , — (CR 71 R 72 ) p — is — (CH 2 ) p —, and R 73 is lower alkyl. The compound which is the heterocyclic group which may be substituted by.
(35) R 7 is —O— (CR 71 R 72 ) p —R 73 , — (CR 71 R 72 ) p — is — (CH 2 ) p —, and R 73 is (tetrahydro -2H-pyran-4-yl).
(36) R 7 is -O- (CR 71 R 72 ) p -R 73 ,-(CR 71 R 72 ) p- is-(CH 2 ) p- , and R 73 is (2 , 2-dimethyl-1,3-dioxolan-4-yl).
(37) The compound wherein Y a and Y b are N.
(38) The compound wherein Y a and Y b are CR Y and R Y is H.
As still another embodiment of the compounds (I) and (I ′) of the present invention, compounds comprising a combination of two or more of the groups described in the above (1) to (13) and (24) to (38) Specific examples include the following compounds.
(39) The compound described in (10) to (12) or (31) to (36), wherein R A1 is H or F and m is 1.
(40) The compound described in (10) to (12) or (31) to (36), wherein R A1 is H and m is 1.
(41) The compound described in (10) to (12) or (31) to (36), wherein R A1 is halogen and m is 1.
(42) The compound described in (10) to (12) or (31) to (36), wherein R A1 is F and m is 1.
(43) The compound described in (10) to (12), (31) to (36), or (39) to (42), wherein Z is N or CR Z and R Z is H .
(44) The compound described in (10) to (12), (31) to (36), or (39) to (42), wherein Z is N.
(45) The compound described in (10) to (12), (31) to (36), or (39) to (42), wherein Z is CR Z and R Z is H.
(46) The compound described in (10) to (12), (31) to (36), or (39) to (45), wherein L is NH.
(47) The compound described in (10) to (12), (31) to (36), or (39) to (45), wherein L is O.
(48) R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be the same or different from each other, H or lower alkyl (10) to (12), (31) (36) or (39) to (47)
(49) (10) to (12), (31) to (36), wherein R 1 , R 2 and R 3 are H, and R 4 , R 5 and R 6 are lower alkyl, or ( 39) to (47).
(50) R 1 , R 2 and R 3 are H, and R 4 , R 5 and R 6 are methyl (10) to (12), (31) to (36), or (39 ) To (47).
(51) Y a and Y b may be the same or different from each other, N or CR Y , and R Y is H (10) to (12), (31) to (36) Or a compound according to (39) to (50).
(52) The compounds described in (10) to (12), (31) to (36), or (39) to (50), wherein Y a and Y b are N.
(53) The compound described in (10) to (12), (31) to (36), or (39) to (50), wherein Y a and Y b are CR Y and R Y is H .
　本発明に包含される具体的化合物の例として、以下の化合物が挙げられる。
(2R)-3-({2,2',6-トリメチル-3'-[({4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]ビフェニル-4-イル}オキシ)プロパン-1,2-ジオール、
2-メチル-4-{[2,2',6-トリメチル-3'-({[1-(1H-テトラゾール-5-イルメチル)-2,3-ジヒドロ-1H-インデン-5-イル]オキシ}メチル)ビフェニル-4-イル]オキシ}ブタン-2-オール、
(2R)-3-{[2,2',6-トリメチル-3'-({[1'-(1H-テトラゾール-5-イルメチル)-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-5'-イル]アミノ}メチル)ビフェニル-4-イル]オキシ}プロパン-1,2-ジオール、
(2R)-3-{[2,2',6-トリメチル-3'-({[1-(1H-テトラゾール-5-イルメチル)-2,3-ジヒドロ-1H-インデン-5-イル]アミノ}メチル)ビフェニル-4-イル]オキシ}プロパン-1,2-ジオール、
2-[(4,6-ジメチル-5-{2-メチル-3-[({4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]フェニル}ピリミジン-2-イル)オキシ]エタノール、
(2R)-3-[(4,6-ジメチル-5-{2-メチル-3-[({4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]フェニル}ピリミジン-2-イル)オキシ]プロパン-1,2-ジオール、
(2R)-3-({3'-[({3-フルオロ-4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]-2,2',6-トリメチルビフェニル-4-イル}オキシ)プロパン-1,2-ジオール、
(2R)-3-[(5-{3-[({3-フルオロ-4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]-2-メチルフェニル}-4,6-ジメチルピリミジン-2-イル)オキシ]プロパン-1,2-ジオール、
4-[2-(1H-テトラゾール-5-イル)エチル]-N-{[2,2',6'-トリメチル-4'-(テトラヒドロ-2H-ピラン-4-イルメトキシ)ビフェニル-3-イル]メチル}アニリン、
4-[2-(1H-テトラゾール-5-イル)エチル]-N-({2,2',6'-トリメチル-4'-[2-(テトラヒドロ-2H-ピラン-4-イル)エトキシ]ビフェニル-3-イル}メチル)アニリン、
(2S)-3-({3'-[({3-フルオロ-4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]-2,2',6-トリメチルビフェニル-4-イル}オキシ)プロパン-1,2-ジオール、
(2S)-3-({2,2',6-トリメチル-3'-[({4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]ビフェニル-4-イル}オキシ)プロパン-1,2-ジオール、
3-フルオロ-4-[2-(1H-テトラゾール-5-イル)エチル]-N-{[2,2',6'-トリメチル-4'-(テトラヒドロ-2H-ピラン-4-イルメトキシ)ビフェニル-3-イル]メチル}アニリン、
4-[2-(1H-テトラゾール-5-イル)エチル]-N-{[2,2',6'-トリメチル-4'-(テトラヒドロ-2H-ピラン-4-イルオキシ)ビフェニル-3-イル]メチル}アニリン、又は、
(2S)-3-({2,2',6-トリメチル-3'-[({5-[2-(1H-テトラゾール-5-イル)エチル]ピリジン-2-イル}オキシ)メチル]ビフェニル-4-イル}オキシ)プロパン-1,2-ジオール。 Examples of specific compounds included in the present invention include the following compounds.
(2R) -3-({2,2 ', 6-Trimethyl-3'-[({4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] biphenyl-4-yl } Oxy) propane-1,2-diol,
2-Methyl-4-{[2,2 ', 6-trimethyl-3'-({[1- (1H-tetrazol-5-ylmethyl) -2,3-dihydro-1H-inden-5-yl] oxy } Methyl) biphenyl-4-yl] oxy} butan-2-ol,
(2R) -3-{[2,2 ', 6-Trimethyl-3'-({[1 '-(1H-tetrazol-5-ylmethyl) -1', 3'-dihydrospiro [cyclopropane-1, 2'-indene] -5'-yl] amino} methyl) biphenyl-4-yl] oxy} propane-1,2-diol,
(2R) -3-{[2,2 ', 6-Trimethyl-3'-({[1- (1H-tetrazol-5-ylmethyl) -2,3-dihydro-1H-inden-5-yl] amino } Methyl) biphenyl-4-yl] oxy} propane-1,2-diol,
2-[(4,6-Dimethyl-5- {2-methyl-3-[({4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] phenyl} pyrimidine-2- Yl) oxy] ethanol,
(2R) -3-[(4,6-Dimethyl-5- {2-methyl-3-[({4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] phenyl} Pyrimidin-2-yl) oxy] propane-1,2-diol,
(2R) -3-({3 '-[({3-Fluoro-4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] -2,2', 6-trimethylbiphenyl -4-yl} oxy) propane-1,2-diol,
(2R) -3-[(5- {3-[({3-Fluoro-4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] -2-methylphenyl} -4 , 6-Dimethylpyrimidin-2-yl) oxy] propane-1,2-diol,
4- [2- (1H-tetrazol-5-yl) ethyl] -N-{[2,2 ', 6'-trimethyl-4'-(tetrahydro-2H-pyran-4-ylmethoxy) biphenyl-3-yl ] Methyl} aniline,
4- [2- (1H-tetrazol-5-yl) ethyl] -N-({2,2 ', 6'-trimethyl-4'-[2- (tetrahydro-2H-pyran-4-yl) ethoxy] Biphenyl-3-yl} methyl) aniline,
(2S) -3-({3 '-[({3-Fluoro-4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] -2,2', 6-trimethylbiphenyl -4-yl} oxy) propane-1,2-diol,
(2S) -3-({2,2 ', 6-Trimethyl-3'-[({4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] biphenyl-4-yl } Oxy) propane-1,2-diol,
3-Fluoro-4- [2- (1H-tetrazol-5-yl) ethyl] -N-{[2,2 ', 6'-trimethyl-4'-(tetrahydro-2H-pyran-4-ylmethoxy) biphenyl -3-yl] methyl} aniline,
4- [2- (1H-tetrazol-5-yl) ethyl] -N-{[2,2 ', 6'-trimethyl-4'-(tetrahydro-2H-pyran-4-yloxy) biphenyl-3-yl ] Methyl} aniline, or
(2S) -3-({2,2 ', 6-Trimethyl-3'-[({5- [2- (1H-tetrazol-5-yl) ethyl] pyridin-2-yl} oxy) methyl] biphenyl -4-yl} oxy) propane-1,2-diol.
　式（Ｉ）の化合物には、置換基の種類によって、互変異性体や幾何異性体が存在しうる。本明細書中、式（Ｉ）の化合物が異性体の一形態のみで記載されることがあるが、本発明は、それ以外の異性体も包含し、異性体の分離されたもの、あるいはそれらの混合物も包含する。
　また、式（Ｉ）の化合物には、不斉炭素原子や軸不斉を有する場合があり、それらに基づく光学異性体が存在しうる。本発明は、式（Ｉ）の化合物の光学異性体の分離されたもの、あるいはそれらの混合物も包含する。 In the compound of the formula (I), tautomers and geometric isomers may exist depending on the type of substituent. In the present specification, the compound of the formula (I) may be described in only one form of an isomer, but the present invention also includes other isomers, separated isomers, or those And mixtures thereof.
In addition, 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.
　さらに、本発明は、式（Ｉ）で示される化合物の製薬学的に許容されるプロドラッグも包含する。製薬学的に許容されるプロドラッグとは、加溶媒分解により又は生理学的条件下で、アミノ基、水酸基、カルボキシル基等に変換されうる基を有する化合物である。プロドラッグを形成する基としては、例えば、Prog. Med., 5, 2157-2161(1985)や、「医薬品の開発」（廣川書店、1990年）第7巻　分子設計163-198に記載の基が挙げられる。 Furthermore, 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. Examples of 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.
　また、式（Ｉ）の化合物の塩とは、式（Ｉ）の化合物の製薬学的に許容される塩であり、置換基の種類によって、酸付加塩又は塩基との塩を形成する場合がある。具体的には、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の無機酸や、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、マンデル酸、酒石酸、ジベンゾイル酒石酸、ジトルオイル酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、アスパラギン酸、グルタミン酸等の有機酸との酸付加塩、ナトリウム、カリウム、マグネシウム、カルシウム、アルミニウム等の無機塩基、メチルアミン、エチルアミン、エタノールアミン、リシン、オルニチン等の有機塩基との塩、アセチルロイシン等の各種アミノ酸及びアミノ酸誘導体との塩やアンモニウム塩等が挙げられる。 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. Specifically, 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 aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine and ammonium salts Etc.
　さらに、本発明は、式（Ｉ）の化合物及びその塩の各種の水和物や溶媒和物、及び結晶多形の物質も包含する。また、本発明は、種々の放射性又は非放射性同位体でラベルされた化合物も包含する。 Furthermore, 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.
　尚、本明細書においては、以下の記号を用いる。
Pr：製造例番号、
Ex：実施例番号、
Data：物理化学的データ、
FAB+：FAB-MS (陽イオン)におけるm/z値を示し、特に明記する場合を除き[M+H]+ピークを示す、
FAB-：FAB-MS (陰イオン)におけるm/z値を示し、特に明記する場合を除き[M-H]-ピークを示す、
ESI+：ESI-MS (陽イオン)におけるm/z値を示し、特に明記する場合を除き[M+H]+ピークを示す、
ESI-：ESI-MS (陰イオン)におけるm/z値を示し、特に明記する場合を除き[M-H]-ピークを示す、
EI：EI-MS (陽イオン)におけるm/z値を示し、特に明記する場合を除きM+ピークを示す、
NMR1：DMSO-d6中の1H NMRにおけるδ(ppm)、
NMR2：CDCl3中の1H NMRにおけるδ(ppm)、
Structure：構造式、
TBDMS：tert-ブチルジメチルシリル、
NMP：N-メチル-2-ピロリドン、
DMSO：ジメチルスルホキシド、
THF：テトラヒドロフラン、
EtOAc：酢酸エチル、
DMF：N,N-ジメチルホルムアミド、
CDI：カルボニルジイミダゾール、
DBU：ジアザビシクロウンデセン。 In the present specification, the following symbols are used.
Pr: Production example number,
Ex: Example number,
Data: Physicochemical data,
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.
NMR1: δ (ppm) in 1 H NMR in DMSO-d 6
NMR2: δ (ppm) in 1 H NMR in CDCl 3
Structure: Structure,
TBDMS: tert-butyldimethylsilyl,
NMP: N-methyl-2-pyrrolidone,
DMSO: dimethyl sulfoxide,
THF: tetrahydrofuran,
EtOAc: ethyl acetate,
DMF: N, N-dimethylformamide,
CDI: carbonyldiimidazole,
DBU: Diazabicycloundecene.
（製造法）
　式（Ｉ）の化合物及びその塩は、その基本構造あるいは置換基の種類に基づく特徴を利用し、種々の公知の合成法を適用して製造することができる。その際、官能基の種類によっては、当該官能基を原料から中間体へ至る段階で適当な保護基（容易に当該官能基に転化可能な基）に置き換えておくことが製造技術上効果的な場合がある。特に、以下の製造例及び実施例化合物うち、R7がOHである化合物を用いるときは、このOH基が副反応を起こさないように適切な保護基を導入して反応を進行させるのが望ましい場合がある。このような保護基としては、例えば、ウッツ(P. G. M. Wuts)及びグリーン(T. W. Greene)著、「Greene’s Protective Groups in Organic Synthesis(第4版、2006年)」に記載の保護基等を挙げることができ、これらの反応条件に応じて適宜選択して用いればよい。このような方法では、当該保護基を導入して反応を行なったあと、必要に応じて保護基を除去することにより、所望の化合物を得ることができる。
　また、式（Ｉ）の化合物のプロドラッグは、上記保護基と同様、原料から中間体へ至る段階で特定の基を導入、あるいは得られた式（Ｉ）の化合物を用いてさらに反応を行なうことで製造できる。反応は通常のエステル化、アミド化、脱水等、当業者に公知の方法を適用することにより行うことができる。
　以下、式（Ｉ）の化合物の代表的な製造法を説明する。各製法は、当該説明に付した参考文献を参照して行うこともできる。なお、本発明の製造法は以下に示した例には限定されない。 (Production method)
The compound of the formula (I) and a salt thereof can be produced by applying various known synthesis methods utilizing 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 using a compound in which R 7 is OH, it is desirable to introduce an appropriate protective group so that the OH group does not cause a side reaction, so that the reaction proceeds. There is a case. Examples of such 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. In such a method, after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group as necessary.
Also, 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. Can be manufactured. 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.
Hereinafter, 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. In addition, the manufacturing method of this invention is not limited to the example shown below.
（第１製法）
Figure JPOXMLDOC01-appb-C000016
 　本発明化合物（Ｉ）は、化合物（８）とアジ化ナトリウムもしくはトリメチルシリルアジドとの反応により得ることができる。
　この反応では、化合物（８）を等量若しくは過剰量のアジ化ナトリウムもしくはトリメチルシリルアジドと、反応に不活性な溶媒中、又は無溶媒下、冷却下から加熱還流下、好ましくは-20℃から200℃、更に好ましくは0℃から150℃において、通常0.1時間～5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、ジクロロメタン、1,2-ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、N-メチルピロリドン及びこれらの混合物が挙げられる。塩化アンモニウム、トリエチルアミン塩酸塩、ジブチルスズオキシド等の存在下で反応を行うのが、反応を円滑に進行させる上で有利な場合がある。 (First manufacturing method)
Figure JPOXMLDOC01-appb-C000016
 The compound (I) of the present invention can be obtained by reacting the compound (8) with sodium azide or trimethylsilyl azide.
In this reaction, the compound (8) is mixed with an equal amount or an excess amount of sodium azide or trimethylsilyl azide in a solvent inert to the reaction or in the absence of solvent, from cooling to heating under reflux, preferably from -20 ° C to 200 The mixture is stirred at 0 ° C., more preferably 0 ° C. to 150 ° C., usually for 0.1 hour to 5 days. Examples of the 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, N-methylpyrrolidone, and mixtures thereof. It may be advantageous to carry out the reaction in the presence of ammonium chloride, triethylamine hydrochloride, dibutyltin oxide, etc. in order to make the reaction proceed smoothly.
（第２製法）
Figure JPOXMLDOC01-appb-C000017
 　本発明化合物（Ｉａ）は、化合物（７）と化合物（２２）との反応により得ることができる。
　この反応では、化合物（７）と等量若しくは一方を過剰量の化合物（２２）を用い、これらの混合物を、還元剤の存在下、反応に不活性な溶媒中、-45℃から加熱還流下、好ましくは0℃～80℃において、通常0.1時間～5日間撹拌する。ここで用いられる溶媒の例としては、特に限定されないが、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、メタノール、エタノール等のアルコール類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、及びこれらの混合物が挙げられる。還元剤としては、シアン化水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム、水素化ホウ素ナトリウム等が挙げられる。モレキュラーシーブス等の脱水剤、又は酢酸、塩酸、チタニウム（IV）イソプロポキシド錯体等の酸存在下で反応を行うことが好ましい場合がある。反応によっては、化合物（７）と化合物（２２）との縮合により生成するイミンが、安定な中間体として単離できる場合がある。そのような場合には、このイミン中間体を生成させ、必要により一旦単離し、次いで、還元反応に付し化合物（Iｄ）を得ることができる。また、前記還元剤での処理の代わりに、メタノール、エタノール、酢酸エチル等の溶媒中、酢酸、塩酸等の酸の存在下又は非存在下で、還元触媒（例えば、パラジウム炭素、ラネーニッケル等）を用いて反応を行うこともできる。この場合、反応を常圧から50気圧の水素雰囲気下で、冷却下から加熱下で行うことが好ましい。
〔文献〕
A. R. Katritzky及びR. J. K. Taylor著、「Comprehensive Organic Functional Group Transformations II」、第2巻、Elsevier Pergamon、2005年
日本化学会編「実験化学講座(第5版)」14巻(2005年)(丸善) (Second manufacturing method)
Figure JPOXMLDOC01-appb-C000017
 The compound (Ia) of the present invention can be obtained by reacting the compound (7) with the compound (22).
In this reaction, an equivalent amount of compound (7) or an excess of compound (22) was used, and these mixtures were heated under reflux from −45 ° C. in a solvent inert to the reaction in the presence of a reducing agent. The mixture is preferably stirred at 0 ° C. to 80 ° C. for usually 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 or chloroform, alcohols such as methanol and ethanol, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like. Ethers, N, N-dimethylformamide, dimethyl sulfoxide, 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, hydrochloric acid, titanium (IV) isopropoxide complex. Depending on the reaction, the imine formed by the condensation of the compound (7) and the compound (22) may be isolated as a stable intermediate. In such a case, this imine intermediate can be produced, isolated once if necessary, and then subjected to a reduction reaction to obtain compound (Id). In place of the treatment with the reducing agent, a reduction catalyst (for example, palladium carbon, Raney nickel, etc.) is used in a solvent such as methanol, ethanol, ethyl acetate, in the presence or absence of an acid such as acetic acid or hydrochloric acid. Can also be used to carry out the reaction. In this case, it is preferable to carry out the reaction under a hydrogen atmosphere at normal pressure to 50 atm and under cooling to heating.
[Reference]
A. R. Katritzky and R. J. K. Taylor, `` Comprehensive Organic Functional Group Transformations II '', Volume 2, Elsevier Pergamon, 2005 The Chemical Society of Japan `` Experimental Chemistry Course (5th Edition) '' Volume 14 (2005) (Maruzen)
（その他の製法）
　式（Ｉ）における種々の置換基は、本発明化合物（Ｉ）を原料として、当業者にとって自明である反応、又はこれらの変法を用いることにより、他の官能基へと容易に変換することができる。例えば、加水分解、アルキル化、ハロゲン化、水素添加等、当業者が通常採用し得る工程を任意に組み合わせて行うことができる。その例をいくつか示す。尚、R7において、ジヒドロキシ基を有する化合物は、メチレンジオキシ基やジメチルメチレンジオキシ基を有する化合物を加水分解することにより得ることができる。 (Other manufacturing methods)
Various substituents in the formula (I) can be easily converted into other functional groups by using the compound (I) of the present invention as a raw material and reactions that are obvious to those skilled in the art or using these modified methods. Can do. For example, processes that can be usually employed by those skilled in the art, such as hydrolysis, alkylation, halogenation, hydrogenation and the like, can be carried out in any combination. Here are some examples. In R 7 , the compound having a dihydroxy group can be obtained by hydrolyzing a compound having a methylenedioxy group or a dimethylmethylenedioxy group.
（第３製法）
Figure JPOXMLDOC01-appb-C000018
 （式中、Jは、脱離基を示す。）
　本発明化合物（Ｉｅ）は、化合物（Ｉｄ）と化合物（２３）との反応により得ることができる。ここで、脱離基の例には、ハロゲン、メタンスルホニルオキシ、p-トルエンスルホニルオキシ基等が含まれる。
　この反応では、化合物（Ｉｄ）と等量若しくは過剰量の化合物（２３）とを用い、これらの混合物を、反応に不活性な溶媒中、又は無溶媒下、冷却下から加熱還流下、好ましくは0℃から80℃において、通常0.1時間～5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、ジクロロメタン、1,2-ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、アセトニトリル及びこれらの混合物が挙げられる。トリエチルアミン、N,N-ジイソプロピルエチルアミン若しくはN-メチルモルホリン等の有機塩基、又は炭酸セシウム、リン酸カリウム、炭酸カリウム、炭酸ナトリウム若しくは水酸化カリウム等の無機塩基の存在下で反応を行うのが、反応を円滑に進行させる上で有利な場合がある。
　また、上記反応は、特に限定はされないが、例えばウルマン（Ullmann）反応やブッフバルト・ハートウィッグ（Buchwald-Hartwig）反応等に使用されるような触媒を用いて行うこともできる。ここで用いられる触媒は、特に限定はされないが、トリス(ジベンジリデンアセトン)パラジウム、テトラキス(トリフェニルホスフィン)パラジウム等と4,5-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン(Xantphos)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル(SPhos)、2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル(XPhos)等を適宜組み合わせて用いることができる。
　更に、上記反応は、縮合剤の存在下で行うこともできる。ここで用いられる縮合剤の例としては、特に限定されないが、ジシクロヘキシルカルボジイミド、ジイソプロピルカルボジイミド、1-エチル-3-（3-ジメチルアミノプロピル）カルボジイミド塩酸塩等を用いることができる。
〔文献〕
S. R. Sandler及びW. Karo著、「Organic Functional Group Preparations」、第2版、第1巻、Academic Press Inc.、1991年
日本化学会編「実験化学講座(第5版)」14巻(2005年)(丸善) (3rd manufacturing method)
Figure JPOXMLDOC01-appb-C000018
 (In the formula, J represents a leaving group.)
The compound (Ie) of the present invention can be obtained by reacting the compound (Id) with the compound (23). Here, examples of the leaving group include halogen, methanesulfonyloxy, p-toluenesulfonyloxy group and the like.
In this reaction, compound (Id) and an equal amount or an excess amount of compound (23) are used, and these mixtures are heated in a solvent inert to the reaction or in the absence of solvent from cooling to heating under reflux, preferably Stir at 0 to 80 ° C. for usually 0.1 hour to 5 days. Examples of the 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 reaction is carried out in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, or an inorganic base such as cesium carbonate, potassium phosphate, potassium carbonate, sodium carbonate or potassium hydroxide. There are cases where it is advantageous to make the process proceed smoothly.
The above reaction is not particularly limited, but it can also be carried out using a catalyst such as that used in the Ullmann reaction, the Buchwald-Hartwig reaction, and the like. The catalyst used here is not particularly limited, but tris (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium and the like and 4,5-bis (diphenylphosphino) -9,9'-dimethylxanthene (Xantphos ), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (XPhos) and the like can be used in appropriate combinations. .
Furthermore, the above reaction can also be performed in the presence of a condensing agent. Examples of the condensing agent used here are not particularly limited, and dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and the like can be used.
[Reference]
SR Sandler and W. Karo, "Organic Functional Group Preparations", 2nd edition, 1st volume, Academic Press Inc., 1991, Chemical Society of Japan "Experimental Chemistry Course (5th edition)", 14th volume (2005) (Maruzen)
（原料合成１）
Figure JPOXMLDOC01-appb-C000019
 （式中、Rは、低級アルキルを、RBは、H、又は、低級アルキル若しくは２つのRBが一体となってC2-7アルキレンを示す。）
　化合物（７）は、化合物（１）から製造できる。
　化合物（２）は、化合物（１）のボロン酸エステル化反応により得ることができる。
　この反応では、反応に不活性な溶媒中、冷却下から加熱下、好ましくは-20℃～60℃で、化合物（１）及び等量若しくは過剰量のとボロン酸エステル化試薬との混合物を有機金属化合物の存在下で通常0.1時間～5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン若しくはキシレン等の芳香族炭化水素類、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、DMF、DMSO、EtOAc、アセトニトリル又は水、及びこれらの混合物が挙げられる。ボロン酸エステル化試薬の例としては、ホウ酸トリイソプロピル、ホウ酸トリブチル等が挙げられる。本反応に用いられる有機金属化合物の例としては、n-ブチルリチウム等の有機リチウム化合物が挙げられる。
　尚、化合物（２）のうちRBがHの化合物は、前述のウッツらの文献を参照して、化合物（２）を加水分解反応に付することにより得ることができる。
　更に、化合物（５）は、化合物（２）と化合物（３Ｒ）とのカップリング反応により得ることができる。
　この反応では、化合物（２）と等量若しくは過剰量の化合物（３Ｒ）の混合物を、反応に不活性な溶媒中、又は無溶媒下、冷却下から加熱還流下、好ましくは0℃から80℃において、通常0.1時間～5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジメチルエーテル、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、ジクロロメタン、1,2-ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、アセトニトリル及びこれらの混合物が挙げられる。トリエチルアミン、N,N-ジイソプロピルエチルアミン若しくはN-メチルモルホリン等の有機塩基、又は炭酸カリウム、炭酸ナトリウム、リン酸カリウム若しくは水酸化カリウム等の無機塩基の存在下で反応を行うのが、反応を円滑に進行させる上で有利な場合がある。
　また、上記反応は、特に限定されないが、例えば鈴木-宮浦クロスカップリング反応に使用されるような触媒を用いて行うこともできる。ここで用いられる触媒は、特に限定はされないが、テトラキス（トリフェニルホスフィン）パラジウム(0)、酢酸パラジウム(ＩＩ)、ジクロロ[1,1’-ビス(ジフェニルホスフェニルホスフィノ)フェロセン]パラジウム(ＩＩ)、塩化ビストリフェニルホスフィンパラジウム(ＩＩ)等を用いることができる。また、金属パラジウム（0）を用いてカップリング反応を行うこともできる。
　化合物（６）は、化合物（５）の還元反応により得ることができる。
　この反応では、反応に不活性な溶媒中、冷却下から加熱下、好ましくは-20℃から80℃で、化合物（５）を等量若しくは過剰量の還元剤で、通常0.1時間～3日間処理する。ここで用いられる溶媒の例としては、特に限定されないが、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、メタノール、エタノール、2-プロパノール等のアルコール類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル及びこれらの混合物が挙げられる。還元剤としては、水素化アルミニウムリチウム、水素化ホウ素ナトリウム若しくはジイソブチルアルミウムヒドリド等のヒドリド還元剤、ナトリウム、亜鉛、鉄、白金等の金属還元剤、その他、下記文献中の還元剤が好適に用いられる。
　化合物（７）は、化合物（６）の酸化反応により得ることができる。
　この反応では、反応に不活性な溶媒中、冷却下から加熱下、好ましくは-20℃から80℃で、化合物（６）を等量若しくは過剰量の酸化剤で、通常0.1時間～3日間処理する。ここで用いられる溶媒の例としては、特に限定されないが、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、水或いはこれらの混合物が挙げられる。酸化剤としては、例えば、亜塩素酸ナトリウム、過酸化水素、クメンヒドロペルオキシド、過酢酸、過安息香酸、m-クロロ過安息香酸、オキソン（登録商標）、活性二酸化マンガン、クロム酸、過マンガン酸カリウム、過ヨウ素酸ナトリウムが好適に用いられる。また、亜塩素酸ナトリウムを酸化剤として用いる場合、反応系中で発生する塩素化合物を補填するために2-メチル-2-ブテンのような化合物を用い、リン二水素ナトリウム等の酸の条件下で行うと反応を有利に進行させることができる場合がある。本反応においては、スワン(Swern)酸化等のDMSO酸化又はデスマーチン(Dess-Martin)試薬を用いた酸化が好適に用いられる。
〔文献〕
M. Hudlicky著、「Reductions in Organic Chemistry, 2nd ed (ACS Monograph :188)」、ACS、1996年
R. C. Larock著、「Comprehensive Organic Transformations」、第2版、VCH Publishers, Inc.、1999年
T. J. Donohoe著、「Oxidation and Reduction in Organic Synthesis (Oxford Chemistry Primers 6)」、Oxford Science Publications、2000年
B. M. Trost著、「Comprehensive Organic Synthesis」、第7巻、1991年
M. Hudlicky著、「Oxidation in Organic Chemistry (ACS Monograph :186)」、ACS、1990年
日本化学会編「実験化学講座(第5版)」17巻(2005年)(丸善)
日本化学会編「実験化学講座(第5版)」14巻(2005年)(丸善) (Raw material synthesis 1)
Figure JPOXMLDOC01-appb-C000019
 (Wherein, R, a lower alkyl, R B represents H, or, lower alkyl or two R B is a C 2-7 alkylene together.)
Compound (7) can be produced from compound (1).
Compound (2) can be obtained by boronic esterification reaction of compound (1).
In this reaction, compound (1) and a mixture of an equal or excess amount of a boronate esterification reagent and an organic compound in an inert solvent for the reaction are cooled to heated, preferably at −20 ° C. to 60 ° C. In the presence of the metal compound, the mixture is usually stirred for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, but are 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, dimethoxyethane, DMF, DMSO, EtOAc, acetonitrile or water, and mixtures thereof. Examples of boronic esterification reagents include triisopropyl borate, tributyl borate and the like. Examples of the organometallic compound used in this reaction include organolithium compounds such as n-butyllithium.
Incidentally, R B is a compound of H of the compound (2) can be obtained by referring to Wuts et al mentioned above, subjecting the compound (2) to a hydrolysis reaction.
Furthermore, compound (5) can be obtained by a coupling reaction of compound (2) and compound (3R).
In this reaction, a mixture of the compound (2) and an equal amount or an excess amount of the compound (3R) 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. Examples of the solvent used here are not particularly limited, but 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. 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, potassium phosphate or potassium hydroxide facilitates the reaction. It may be advantageous for progress.
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 and the like. In addition, a coupling reaction can be performed using metal palladium (0).
Compound (6) can be obtained by a reduction reaction of compound (5).
In this reaction, compound (5) is usually treated for 0.1 hour to 3 days with an equal or excessive amount of reducing agent in a solvent inert to the reaction under cooling to heating, preferably at -20 ° C to 80 ° C. To do. Examples of the solvent used here are not particularly limited, but ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, alcohols such as methanol, ethanol and 2-propanol, and aromatics such as benzene, toluene and xylene. Examples include hydrocarbons, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, and mixtures thereof. As the reducing agent, hydride reducing agents such as lithium aluminum hydride, sodium borohydride or diisobutylaluminum hydride, metal reducing agents such as sodium, zinc, iron and platinum, and other reducing agents in the following documents are preferably used. .
Compound (7) can be obtained by oxidation reaction of compound (6).
In this reaction, compound (6) is usually treated for 0.1 hour to 3 days with an equal or excess amount of an oxidizing agent in a solvent inert to the reaction, under cooling to heating, preferably at -20 ° C to 80 ° C. To do. Examples of the solvent used here are not particularly limited, but ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, benzene, toluene, Aromatic hydrocarbons such as xylene, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, water or a mixture thereof may be mentioned. Examples of the oxidizing agent include sodium chlorite, hydrogen peroxide, cumene hydroperoxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, oxone (registered trademark), active manganese dioxide, chromic acid, permanganic acid. Potassium and sodium periodate are preferably used. In addition, when sodium chlorite is used as the oxidizing agent, a compound such as 2-methyl-2-butene is used to compensate for the chlorine compound generated in the reaction system, and under conditions of acid such as sodium dihydrogen phosphate. In some cases, the reaction can proceed advantageously. In this reaction, DMSO oxidation such as Swern oxidation or oxidation using a Dess-Martin reagent is preferably used.
[Reference]
M. Hudlicky, "Reductions in Organic Chemistry, 2nd ed (ACS Monograph: 188)", ACS, 1996
R. C. Larock, "Comprehensive Organic Transformations", 2nd edition, VCH Publishers, Inc., 1999
T. J. Donohoe, "Oxidation and Reduction in Organic Synthesis (Oxford Chemistry Primers 6)", Oxford Science Publications, 2000
B. M. Trost, "Comprehensive Organic Synthesis", Volume 7, 1991
M. Hudlicky, "Oxidation in Organic Chemistry (ACS Monograph: 186)", ACS, 1990, Chemical Society of Japan, "Experimental Chemistry Course (5th Edition)", Volume 17 (2005) (Maruzen)
The Chemical Society of Japan "Experimental Chemistry Course (5th edition)" Volume 14 (2005) (Maruzen)
（原料合成２）
Figure JPOXMLDOC01-appb-C000020
 　化合物（８ａ）は、化合物（６）と化合物（１３ａ）との光延反応により得ることができる。
　この反応では、反応に不活性な溶媒中、冷却下から加熱下、好ましくは-20℃から80℃で、アゾ化合物及びリン化合物の存在下、化合物（６）を等量若しくは過剰量の（１３ａ）と通常0.1時間～3日間処理する。ここで用いられる溶媒の例としては、特に限定されないが、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、或いはこれらの混合物が挙げられる。アゾ化合物としては、例えば、1,1’-(アゾジカルボニル)ジピペリジン、アゾジカルボン酸ジエチル、アゾジカルボン酸ジイソプロピルを用いることができ、リン化合物としては、例えば、トリブチルホスフィン、トリフェニルホスフィンが好適に用いられる。また、アゾ化合物及びリン化合物の代わりに、例えば、（シアノメチレン）トリメチルホスホランや(シアノメチレン）トリブチルホスホラン等のリンイリド化合物を用いることもできる。 (Raw material synthesis 2)
Figure JPOXMLDOC01-appb-C000020
 Compound (8a) can be obtained by Mitsunobu reaction between compound (6) and compound (13a).
In this reaction, compound (6) is added in an equivalent amount or an excess amount of (13a) in the presence of an azo compound and a phosphorus compound in a solvent inert to the reaction under cooling to heating, preferably at -20 ° C to 80 ° C. ) And usually 0.1 hours to 3 days. Examples of the solvent used here are not particularly limited, but ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, benzene, toluene, Aromatic hydrocarbons such as xylene, N, N-dimethylformamide, dimethyl sulfoxide, or a mixture thereof. As the azo compound, for example, 1,1 ′-(azodicarbonyl) dipiperidine, diethyl azodicarboxylate, diisopropyl azodicarboxylate can be used, and as the phosphorus compound, for example, tributylphosphine and triphenylphosphine are preferable. Used. Further, instead of the azo compound and the phosphorus compound, for example, a phosphorus ylide compound such as (cyanomethylene) trimethylphosphorane or (cyanomethylene) tributylphosphorane can be used.
（原料合成３）
Figure JPOXMLDOC01-appb-C000021
 　化合物（１１）は、化合物（３’）を置換反応、カップリング反応及び脱保護反応に付すことで製造できる。ここで、置換反応は、前述の（第３製法）の反応条件を、カップリング反応は、（原料合成１）の反応条件を用いることができる。脱保護反応は、前述のウッツらの文献を参照して実施できる。
　化合物（１２）は、化合物（１１）とNH3との反応により得ることができる。
　この反応では、化合物（１１）と等量若しくは過剰量のアンモニア水を用い、これらの混合物を、縮合剤の存在下、反応に不活性な溶媒中、冷却下から加熱下、好ましくは-20℃～60℃において、通常0.1時間～5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン若しくはキシレン等の芳香族炭化水素類、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、アセトニトリル又は水、及びこれらの混合物が挙げられる。縮合剤の例としては、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド、ジシクロヘキシルカルボジイミド、1,1’-カルボニルジイミダゾール、ジフェニルリン酸アジド、オキシ塩化リンが挙げられるが、これらに限定されるものではない。添加剤（例えば1-ヒドロキシベンゾトリアゾール）を用いることが反応に好ましい場合がある。トリエチルアミン、N,N-ジイソプロピルエチルアミン若しくはN-メチルモルホリン等の有機塩基、又は炭酸カリウム、炭酸ナトリウム若しくは水酸化カリウム等の無機塩基の存在下で反応を行うことが、反応を円滑に進行させる上で有利な場合がある。
　また、カルボン酸（１１）を反応性誘導体へ変換した後にNH3と反応させる方法も用いることができる。カルボン酸の反応性誘導体の例としては、オキシ塩化リン、塩化チオニル等のハロゲン化剤と反応して得られる酸ハロゲン化物、クロロギ酸イソブチル等と反応して得られる混合酸無水物、1-ヒドロキシベンゾトリアゾール等と縮合して得られる活性エステル等が挙げられる。これらの反応性誘導体とNH3との反応は、ハロゲン化炭化水素類、芳香族炭化水素類、エーテル類等の反応に不活性な溶媒中、冷却下～加熱下、好ましくは、-20℃～60℃で行うことができる。
　化合物（８）は、化合物（１２）の脱水反応により得ることができる。
　この反応では、この反応では、化合物（１２）を脱水剤の存在下、反応に不活性な溶媒中、冷却下から加熱下、好ましくは-20℃～60℃において、通常0.1時間～5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン若しくはキシレン等の芳香族炭化水素類、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、アセトニトリル又は水、及びこれらの混合物が挙げられる。脱水剤の例としては、塩化ホスホリルや塩化チオニル等が挙げられるが、これらに限定されるものではない。トリエチルアミン、N,N-ジイソプロピルエチルアミン若しくはN-メチルモルホリン、ピリジン等の有機塩基、又は炭酸カリウム、炭酸ナトリウム若しくは水酸化カリウム等の無機塩基の存在下で反応を行うことが、反応を円滑に進行させる上で有利な場合がある。
　尚、上記脱保護反応は、例えば、前述のウッツ(P. G. M. Wuts)らの文献を参照して実施することができる。
〔文献〕
S. R. Sandler及びW. Karo著、「Organic Functional Group Preparations」、第2版、第1巻、Academic Press Inc.、1991年
日本化学会編「実験化学講座(第5版)」16巻(2005年)(丸善) (Raw material synthesis 3)
Figure JPOXMLDOC01-appb-C000021
 Compound (11) can be produced by subjecting compound (3 ′) to a substitution reaction, a coupling reaction, and a deprotection reaction. Here, the reaction conditions of the above-mentioned (third production method) can be used for the substitution reaction, and the reaction conditions of (raw material synthesis 1) can be used for the coupling reaction. The deprotection reaction can be carried out with reference to the aforementioned Utz et al.
Compound (12) can be obtained by reacting compound (11) with NH 3 .
In this reaction, an equal amount or an excess amount of aqueous ammonia is used with compound (11), and a mixture of these in the presence of a condensing agent, in a solvent inert to the reaction, from cooling to heating, preferably −20 ° C. Stir at ˜60 ° C. for usually 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, but are 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. Examples of 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 may facilitate the reaction. May be advantageous.
Further, a method of reacting with NH 3 after converting the carboxylic acid (11) into a reactive derivative can be used. Examples of 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 (8) can be obtained by dehydration reaction of compound (12).
In this reaction, the compound (12) is stirred in the presence of a dehydrating agent in a solvent inert to the reaction, from cooling to heating, preferably at -20 ° C. to 60 ° C., usually for 0.1 hour to 5 days. To do. Examples of the solvent used here are not particularly limited, but are 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. Examples of the dehydrating agent include phosphoryl chloride and thionyl chloride, but are not limited thereto. Performing the reaction in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, pyridine, or an inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide makes the reaction proceed smoothly. It may be advantageous above.
The deprotection reaction can be carried out, for example, with reference to the aforementioned P. G. M. Wuts et al.
[Reference]
SR Sandler and W. Karo, "Organic Functional Group Preparations", 2nd edition, 1st volume, Academic Press Inc., 1991, Chemical Society of Japan "Experimental Chemistry Course (5th edition)" 16th volume (2005) (Maruzen)
（原料合成４）
Figure JPOXMLDOC01-appb-C000022
 （式中、RPは、低級アルキルを示す。）
　化合物（１６）は、化合物（１５）とリン酸エステルとのカップリング反応により得ることができる。本反応は、特に限定はされないが、例えば、ホーナー-エモンズ（Horner-Emmons）反応やウィティッヒ（Wittig）反応により行うことができる。
　この反応では、反応に不活性な溶媒中、冷却下から加熱下、好ましくは-20 ℃から80 ℃で、化合物（１５）を等量若しくは過剰量のリン酸エステル化合物（１７）の存在下で、通常0.1時間～3日間処理する。ここで用いられる溶媒の例としては、特に限定されないが、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド或いはこれらの混合物が挙げられる。ナトリウムビス(トリメチルシリル)アミド、n-ブチルリチウム、tert-ブトキシカリウム、ナトリウムエトキシド、ナトリウムメトキシド、水素化ナトリウム等の塩基の存在下で反応を行うのが、反応を円滑に進行させる上で有利な場合がある。リン酸エステル化合物（１７）の例としては、(シアノメチル)ホスホン酸ジエチル等が挙げられる。また、本反応は、リン酸エステル化合物（１７）の代わりにリン化合物の存在下で化合物（１８）を用いることによっても行うことができる。リン化合物の例としては、アルキルトリフェニルホスホニウム塩が好適に用いられ、より具体的には、(メトキシメチル)トリフェニルホスホニウム　クロリド、(メチルチオメチル)トリフェニルホスホニウム等があげられる。
　次に、化合物（８ａ）は、化合物（１６）の水素添加反応により得ることができる。
　この反応では、水素雰囲気下、反応に不活性な溶媒中、化合物（１６）を金属触媒存在下で、通常1時間～5日間撹拌する。この反応は、通常、冷却下から加熱下、好ましくは室温で行われる。ここで用いられる溶媒の例としては、特に限定されないが、メタノール、エタノール、2-プロパノール等のアルコール類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、水、酢酸エチル、N,N-ジメチルホルムアミド、ジメチルスルホキシド及びこれらの混合物が挙げられる。金属触媒としては、パラジウム炭素、パラジウム黒、水酸化パラジウム等のパラジウム触媒、白金板、酸化白金等の白金触媒、還元ニッケル、ラネーニッケル等のニッケル触媒、テトラキストリフェニルホスフィンクロロロジウム等のロジウム触媒、還元鉄等の鉄触媒等が好適に用いられる。水素ガスの代わりに、化合物（１６）に対し等量～過剰量のギ酸またはギ酸アンモニウムを水素源として用いることもできる。
　また、本反応は、化合物（１６）をメタノールの存在下でマグネシウムと接触させることによっても行える場合がある。この反応は、通常、冷却下から加熱下、好ましくは室温で行われる。ここで用いられる溶媒の例としては、特に限定されないが、メタノール、エタノール、2-プロパノール等のアルコール類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、水、酢酸エチル、N,N-ジメチルホルムアミド、ジメチルスルホキシド及びこれらの混合物が挙げられる。
〔文献〕
M. Hudlicky著、「Reductions in Organic Chemistry, 2nd ed (ACS Monograph :188)」、ACS、1996年
日本化学会編「実験化学講座(第5版)」19巻(2005年)(丸善) (Raw material synthesis 4)
Figure JPOXMLDOC01-appb-C000022
 (In the formula, R P represents lower alkyl.)
Compound (16) can be obtained by a coupling reaction between compound (15) and a phosphate ester. Although this reaction is not specifically limited, For example, it can carry out by Horner-Emmons (Horner-Emmons) reaction or Wittig (Wittig) reaction.
In this reaction, in a solvent inert to the reaction, under cooling to heating, preferably at −20 ° C. to 80 ° C., compound (15) is added in the presence of an equal amount or an excess amount of phosphate compound (17). Usually, it is treated for 0.1 hour to 3 days. Examples of the solvent used here are not particularly limited, but ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, N, N-dimethylformamide and dimethyl Examples thereof include sulfoxide or a mixture thereof. It is advantageous to carry out the reaction 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. There are cases. Examples of the phosphate ester compound (17) include diethyl (cyanomethyl) phosphonate. This reaction can also be carried out by using compound (18) in the presence of a phosphorus compound instead of phosphate compound (17). As an example of the phosphorus compound, an alkyltriphenylphosphonium salt is preferably used, and more specifically, (methoxymethyl) triphenylphosphonium chloride, (methylthiomethyl) triphenylphosphonium and the like can be mentioned.
Next, compound (8a) can be obtained by hydrogenation reaction of compound (16).
In this reaction, compound (16) is usually stirred for 1 hour to 5 days in the presence of a metal catalyst in a solvent inert to the reaction under 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. As 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. Instead of hydrogen gas, an equivalent to excess amount of formic acid or ammonium formate relative to compound (16) can be used as a hydrogen source.
This reaction may also be performed by contacting compound (16) with magnesium in the presence of methanol. 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.
[Reference]
M. Hudlicky, `` Reductions in Organic Chemistry, 2nd ed (ACS Monograph: 188) '', ACS, 1996 Chemical Society of Japan, `` Experimental Chemistry Course (5th edition) '' Volume 19 (2005) (Maruzen)
（原料合成５）
Figure JPOXMLDOC01-appb-C000023
 （式中、Pr1は、保護基を示す。）
　化合物（２０Ｐ）は、化合物（１９Ｐ）をリフォマトスキー（Reformatsky）反応に付することにより得ることができる。
　この反応では、化合物（１９Ｐ）と等量若しくは過剰量の化合物（２４）を用い、これらの混合物を、亜鉛粉末の存在下、反応に不活性な溶媒中、又は無溶媒下、冷却下から加熱還流、好ましくは0℃から200℃、更に好ましくは20℃から120℃において、通常0.1時間～5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、ジクロロメタン、1,2-ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド及びこれらの混合物が挙げられる。また、亜鉛粉末と化合物（２４）をあらかじめ処理し、リフォマトスキー試薬として反応に用いることもできる。
　化合物（２１）は、化合物（２０Ｐ）を水素添加反応及び脱保護反応に付することにより製造できる。ここで、水素添加反応は、（原料合成４）記載の反応条件を用いて実施できる。 (Raw material synthesis 5)
Figure JPOXMLDOC01-appb-C000023
 (In the formula, Pr 1 represents a protecting group.)
Compound (20P) can be obtained by subjecting compound (19P) to a Reformatsky reaction.
In this reaction, the compound (19P) and an equivalent amount or an excess amount of the compound (24) are used, and the mixture is heated in the presence of zinc powder in a solvent inert to the reaction, or in the absence of solvent and from under cooling. The mixture is stirred at reflux, preferably 0 ° C. to 200 ° C., more preferably 20 ° C. to 120 ° C., usually for 0.1 hour to 5 days. Examples of the 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, and mixtures thereof. Alternatively, the zinc powder and the compound (24) can be treated in advance and used in the reaction as a Reformatsky reagent.
Compound (21) can be produced by subjecting compound (20P) to a hydrogenation reaction and a deprotection reaction. Here, the hydrogenation reaction can be carried out using the reaction conditions described in (Raw material synthesis 4).
（原料合成６）
Figure JPOXMLDOC01-appb-C000024
 　化合物（２６）は、化合物（１９Ｐ）をカップリング反応、水素添加反応及び脱保護反応に付することにより得ることができる。ここで、カップリング反応及び水素添加反応は、それぞれ前述の（原料合成４）記載の反応条件を用いて実施できる。 (Raw material synthesis 6)
Figure JPOXMLDOC01-appb-C000024
 Compound (26) can be obtained by subjecting compound (19P) to coupling reaction, hydrogenation reaction and deprotection reaction. Here, the coupling reaction and the hydrogenation reaction can be carried out using the reaction conditions described in the above (Raw material synthesis 4).
　式（Ｉ）の化合物は、遊離化合物、その塩、水和物、溶媒和物、あるいは結晶多形の物質として単離され、精製される。式（Ｉ）の化合物の塩は、常法の造塩反応に付すことにより製造することもできる。
　単離、精製は、抽出、分別結晶化、各種分画クロマトグラフィー等、通常の化学操作を適用して行なわれる。
　各種の異性体は、適当な原料化合物を選択することにより製造でき、あるいは異性体間の物理化学的性質の差を利用して分離することができる。例えば、光学異性体は、ラセミ体の一般的な光学分割法（例えば、光学活性な塩基又は酸とのジアステレオマー塩に導く分別結晶化や、キラルカラム等を用いたクロマトグラフィー等）により得られ、また、適当な光学活性な原料化合物から製造することもできる。 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. For example, 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.
　式（Ｉ）の化合物の薬理活性は、以下の試験により確認した。
試験方法１：GPR40アゴニスト活性測定
i)ヒトGPR40のクローニング
　以下に示す手順に従って、ヒトgenomic DNA（Clontech社）をテンプレートとして、PCR法により、GPR40の全長配列を取得した。
　配列番号1で表される塩基配列からなるオリゴヌクレオチドをフォワードプライマーとして、配列番号2で表される塩基配列からなるオリゴヌクレオチドをリバースプライマーとして用いた。なお、前記フォワードプライマー及びリバースプライマーの各々の5’末端には、XbaI認識部位を含む塩基配列が付加されている。PCRは、Taq DNAポリメラーゼ（Ex Taq DNA polymerase；タカラバイオ社）を用いて、5 ％ジメチルスルホキシド（DMSO）存在下で、94℃（15秒間）／55℃（30秒間）／72℃（1分間）からなるサイクルを30回繰り返した。その結果、約0.9kbpのDNA断片が増幅された。このDNA断片をXbaIで消化した後、プラスミドpEF-BOS-dhfr（Nucleic Acids Research, 18, 5322, 1990）のXbaI部位に挿入することにより、プラスミドpEF-BOS-dhfr-GPR40を得た。
　プラスミドpEF-BOS-dhfr-GPR40におけるGPR40遺伝子の塩基配列は、DNAシークエンサー（ABI377 DNA Sequencer; Applied Biosystems社）を用いてジデオキシターミネーター法により決定した。GPR40遺伝子の塩基配列は、配列番号3で表される塩基配列のとおりであった。配列番号3で表される塩基配列は、903塩基のオープンリーディングフレーム（ORF）を有しており、このORFから予測されるアミノ酸配列（300アミノ酸）は、配列番号4で表されるアミノ酸配列のとおりであった。
ii)GPR40安定発現細胞の取得
　GPR40タンパク質を発現させる細胞としてCHO dhfr-細胞(ジヒドロ葉酸レダクターゼ(dhfr)遺伝子欠失のCHO細胞)を使用した。また、GPR40タンパク質を発現させるための発現プラスミドとして、前記i)で得られたプラスミドpEF-BOS-dhfr-GPR40を用いた。6ウェルプレート（旭テクノグラス社）に、CHO dhfr-細胞を、80-90 ％コンフルエントとなるように、10 ％牛胎児血清（FCS）を含むαMEM培地中で播種して一晩培養後、１ウェル当たり2μgのプラスミドpEF-BOS-dhfr-GPR40を、トランスフェクション試薬（Lipofectamine2000; Invitrogen社）を用いて遺伝子導入した。遺伝子導入から24時間培養した後、細胞を希釈して播種し直した。その際、10 ％ FCSを含むαMEM培地から、10％ FCSを含むが、核酸を含まないαMEM培地に変更した。20日間培養したのち、形成された細胞のコロニーを個別に回収して培養してGPR40を安定に発現するCHO細胞を取得した。この中から内在性リガンドであるオレイン酸、リノール酸に反応性の高い細胞を選択した。
iii)GPR40アゴニスト活性測定
　本試験は細胞内カルシウム濃度の変動を指標とし、FLIPR（登録商標、モレキュラーデバイス社）で測定した。以下、試験方法について示す。
　ヒトGPR40を発現させたCHO細胞株を384穴ブラックプレート（ベクトン・デッキンソン社）に1穴あたり6×103個で撒き、CO2インキュベーターで一晩培養した。
発光色素はCalcium-3 アッセイキット（モレキュラーデバイス社）を使用し、1瓶に対してHBSS-HEPESバッファー（PH 7.4、1×HBSS、20 mM HEPES、インビトロジェン社）10 mlに溶解した。プロベネシド（シグマ社）35.68 mgを1 M NaOH 250μlで溶解後、HBSS-HEPESバッファー250μlを加えて調製した。蛍光色素溶液はプレート1枚あたり、HBSS-HEPESバッファー16 ml、蛍光色素640μl、32μlプロベネシドを混合し、調製した。プレートの培地を除き、蛍光色素溶液を１穴あたり40μl分注後、室温で2時間インキュベートした。被検化合物はDMSOで溶解後、HBSS-HEPESバッファーで希釈し、10μlをプレートに分注により、反応を開始し、細胞内カルシウム濃度の変動をFLIPRで測定した。測定1分後の蛍光強度変化の用量反応曲線により、被検化合物のEC50値を算出した。
　その結果、本発明化合物は、GPR40アゴニスト活性を示した。いくつかの本発明化合物について、EC50値を表１に示す。Exは後記実施例化合物番号を示す。
Figure JPOXMLDOC01-appb-T000025
 試験方法２：MIN6細胞を用いたインスリン分泌促進作用
　本試験では、マウス膵β細胞株であるMIN6細胞を用いて被検化合物のインスリン分泌促進作用を検討した。以下、試験方法を示す。
　96穴プレートに5x104個/穴(200μl)になるようにMIN6細胞を撒いた。培地は10%　FBS、55μM　2-メルカプトエタノール、100 U/mlペニシリン、100μg/mlストレプトマイシンを含むDMEM（25 mMグルコース）を用いた。2日後に培地をアスピレーターで除き、37 ℃に暖めた2.8 mMグルコースを含むKRB-HEPES（116 mM NaCl、4.7 mM KCl、1.2 mM KH2PO4、1.2 mM MgSO4、0.25 mM CaCl2、25 mM NaHCO3、0.005 % FFA Free BSA、24 mM HEPES（pH 7.4））200μlで一度洗い、再度、同緩衝液200μlをいれて1時間、37 ℃でインキュベートした。上記緩衝液をアスピレーターで除き、再度、緩衝液で洗浄（200μl）後、2.8 mM または22.4 mM グルコースを含むKRB-HEPESに所定の濃度の被検化合物を添加したものを、各穴に100 μlずつ加え、2時間37℃でインキュベートした。上記サンプルを分取し、100倍希釈して、インスリン濃度をインスリンRIAキット（アマシャムRI社）を用いて定量した。
その結果、本発明化合物は優れたインスリン分泌促進作用を有することが確認された。
試験方法３：正常マウス単回経口糖負荷試験
　本試験では正常マウスを用いて被検化合物の糖負荷後の血糖上昇抑制作用について検討した。以下、試験方法を示す。
　1週間予備飼育した雄性ICRマウス（6週齢）を一晩絶食し、被検動物として用いた。被検化合物は0.01 M 水酸化ナトリウム水溶液を投与溶媒として用い、グルコース（2 g/kg）負荷30分前に10 mg/kg経口投与した。対照群は0.01 M 水酸化ナトリウム水溶液投与とした。グルコース負荷30分時の対照群に対する血糖上昇抑制率（%）を算出した。
　試験結果を、表２に示す。Exは後記実施例化合物番号を示す。その結果、本発明化合物は優れた血糖上昇抑制作用を有することが確認された。
Figure JPOXMLDOC01-appb-T000026
 The pharmacological activity of the compound of formula (I) was confirmed by the following test.
Test method 1: GPR40 agonist activity measurement
i) Cloning of human GPR40 A full-length sequence of GPR40 was obtained by PCR using human genomic DNA (Clontech) as a template according to the following procedure.
The oligonucleotide consisting of the base sequence represented by SEQ ID NO: 1 was used as a forward primer, and the oligonucleotide consisting of the base sequence represented by SEQ ID NO: 2 was used as a reverse primer. A base sequence including an XbaI recognition site is added to the 5 ′ end of each of the forward primer and the reverse primer. PCR was performed using Taq DNA polymerase (Ex Taq DNA polymerase; Takara Bio Inc.) in the presence of 5% dimethyl sulfoxide (DMSO) at 94 ° C (15 seconds) / 55 ° C (30 seconds) / 72 ° C (1 minute) ) Was repeated 30 times. As a result, a DNA fragment of about 0.9 kbp was amplified. This DNA fragment was digested with XbaI and then inserted into the XbaI site of plasmid pEF-BOS-dhfr (Nucleic Acids Research, 18, 5322, 1990) to obtain plasmid pEF-BOS-dhfr-GPR40.
The base sequence of the GPR40 gene in the plasmid pEF-BOS-dhfr-GPR40 was determined by the dideoxy terminator method using a DNA sequencer (ABI377 DNA Sequencer; Applied Biosystems). The base sequence of GPR40 gene was as shown in the base sequence represented by SEQ ID NO: 3. The base sequence represented by SEQ ID NO: 3 has an open reading frame (ORF) of 903 bases, and the amino acid sequence (300 amino acids) predicted from this ORF is the amino acid sequence represented by SEQ ID NO: 4. It was as follows.
ii) Acquisition of GPR40 stably expressing cells CHO dhfr-cells (CHO cells lacking the dihydrofolate reductase (dhfr) gene) were used as cells that express GPR40 protein. Further, the plasmid pEF-BOS-dhfr-GPR40 obtained in i) was used as an expression plasmid for expressing the GPR40 protein. Inoculate 6-well plates (Asahi Techno Glass) in αMEM medium containing 10% fetal calf serum (FCS) so that CHO dhfr-cells become 80-90% confluent and culture overnight. 2 μg of plasmid pEF-BOS-dhfr-GPR40 per well was introduced using a transfection reagent (Lipofectamine 2000; Invitrogen). After culturing for 24 hours after gene transfer, the cells were diluted and seeded again. At that time, the αMEM medium containing 10% FCS was changed to the αMEM medium containing 10% FCS but no nucleic acid. After culturing for 20 days, the formed cell colonies were individually collected and cultured to obtain CHO cells stably expressing GPR40. From these cells, cells having high reactivity to the endogenous ligands oleic acid and linoleic acid were selected.
iii) Measurement of GPR40 agonist activity This test was performed using FLIPR (registered trademark, Molecular Devices) with the variation of intracellular calcium concentration as an index. The test method will be described below.
A CHO cell line expressing human GPR40 was seeded in a 384-well black plate (Becton Dickinson) at 6 × 10 3 per well and cultured overnight in a CO 2 incubator.
The luminescent dye was dissolved in 10 ml of HBSS-HEPES buffer (PH 7.4, 1 × HBSS, 20 mM HEPES, Invitrogen) per bottle using a Calcium-3 assay kit (Molecular Device). Probenecid (Sigma) (35.68 mg) was dissolved in 1 M NaOH (250 μl), and HBSS-HEPES buffer (250 μl) was added to prepare. The fluorescent dye solution was prepared by mixing 16 ml of HBSS-HEPES buffer, 640 μl of fluorescent dye, and 32 μl probenecid per plate. The plate medium was removed, and 40 μl of the fluorescent dye solution was dispensed per well, followed by incubation at room temperature for 2 hours. The test compound was dissolved in DMSO, diluted with HBSS-HEPES buffer, and 10 μl was dispensed on a plate to start the reaction, and the fluctuation of intracellular calcium concentration was measured by FLIPR. The EC 50 value of the test compound was calculated from the dose response curve of the fluorescence intensity change 1 minute after the measurement.
As a result, the compound of the present invention showed GPR40 agonist activity. EC 50 values for some of the compounds of the invention are shown in Table 1. Ex represents an example compound number described later.
Figure JPOXMLDOC01-appb-T000025
 Test Method 2: Insulin Secretion Promoting Action Using MIN6 Cells In this test, the insulin secretion promoting action of the test compound was examined using MIN6 cells, a mouse pancreatic β cell line. The test method is shown below.
MIN6 cells were seeded in a 96-well plate at 5 × 10 4 cells / hole (200 μl). The medium used was DMEM (25 mM glucose) containing 10% FBS, 55 μM 2-mercaptoethanol, 100 U / ml penicillin, 100 μg / ml streptomycin. After 2 days, the medium was removed with an aspirator and KRB-HEPES containing 2.8 mM glucose (116 mM NaCl, 4.7 mM KCl, 1.2 mM KH 2 PO 4 , 1.2 mM MgSO 4 , 0.25 mM CaCl 2 , 25 mM) warmed to 37 ° C. The plate was washed once with 200 μl of NaHCO 3 , 0.005% FFA Free BSA, 24 mM HEPES (pH 7.4), and again with 200 μl of the same buffer, and incubated at 37 ° C. for 1 hour. Remove the above buffer with an aspirator, wash again with buffer (200 μl), add KRB-HEPES containing 2.8 mM or 22.4 mM glucose, and add a test compound of the specified concentration to each well. In addition, it was incubated at 37 ° C. for 2 hours. The sample was collected, diluted 100 times, and the insulin concentration was quantified using an insulin RIA kit (Amersham RI).
As a result, it was confirmed that the compound of the present invention has an excellent insulin secretion promoting action.
Test Method 3: Normal Mouse Single Oral Glucose Tolerance Test In this test, a normal mouse was used to examine the inhibitory effect of the test compound on glucose elevation after glucose loading. The test method is shown below.
Male ICR mice (6 weeks old) preliminarily raised for 1 week were fasted overnight and used as test animals. The test compound was orally administered 10 mg / kg 30 minutes before loading with glucose (2 g / kg) using 0.01 M sodium hydroxide aqueous solution as the administration solvent. The control group was administered with 0.01 M sodium hydroxide aqueous solution. The rate of inhibition of blood glucose increase (%) relative to the control group at the time of glucose load 30 minutes was calculated.
The test results are shown in Table 2. Ex represents an example compound number described later. As a result, it was confirmed that the compound of the present invention has an excellent blood glucose increase inhibitory action.
Figure JPOXMLDOC01-appb-T000026
（比較実験）
　前採血での血糖値、及び被検化合物を30、10、3、1、又は0.3 mg/kgで経口投与した時のグルコース負荷後、5、15、30、60、120分の血糖値から、0～120分の血糖値の血中濃度－時間曲線下面積（AUC）を算出し、対照群に対して有意（Dunnet 多重比較検定）な低下を示した用量及び血糖上昇抑制率が20%になる用量（ED20値）を算出した。その結果、比較化合物（国際公開第2005/087710号パンフレットに記載された実施例37の化合物）のED20値は17.8 mg/kgであった。一方、本発明化合物の中には、ED20値が3 mg/kg以下である化合物があった。 (Comparative experiment)
From the blood glucose level at the previous blood sampling, and the blood glucose level at 5, 15, 30, 60, 120 minutes after the glucose load when the test compound was orally administered at 30, 10, 3, 1, or 0.3 mg / kg, Calculate the area under the blood concentration-time curve (AUC) of blood glucose level from 0 to 120 minutes, and showed a significant (Dunnet multiple comparison test) decrease in the dose and blood glucose elevation inhibition rate to 20% compared to the control group A dose (ED 20 value) was calculated. As a result, the ED 20 value of the comparative compound (the compound of Example 37 described in International Publication No. 2005/087710 pamphlet) was 17.8 mg / kg. On the other hand, among the compounds of the present invention, there was a compound having an ED 20 value of 3 mg / kg or less.
　以上より、式（Ｉ）の化合物は優れたGPR40アゴニスト作用を有し、強力なインスリン分泌促進作用及び血糖上昇抑制作用の効果を有することが確認された。従って、インスリン分泌促進剤若しくは糖尿病の予防・治療剤として利用できる。 From the above, it was confirmed that the compound of the formula (I) has an excellent GPR40 agonistic action, and has a potent insulin secretion promoting action and a blood glucose elevation inhibiting action. Therefore, it can be used as an insulin secretion promoter or a prophylactic / therapeutic agent for diabetes.
　式（Ｉ）の化合物又はその塩の１種又は２種以上を有効成分として含有する医薬組成物は、当分野において通常用いられている賦形剤、即ち、薬剤用賦形剤や薬剤用担体等を用いて、通常使用されている方法によって調製することができる。
　投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、又は、関節内、静脈内、筋肉内等の注射剤、坐剤、点眼剤、眼軟膏、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。 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. Can be prepared by a commonly used method.
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.
　経口投与のための固体組成物としては、錠剤、散剤、顆粒剤等が用いられる。このような固体組成物においては、1種又は2種以上の有効成分を、少なくとも1種の不活性な賦形剤と混合される。組成物は、常法に従って、不活性な添加剤、例えば滑沢剤や崩壊剤、安定化剤、溶解補助剤を含有していてもよい。錠剤又は丸剤は必要により糖衣又は胃溶性若しくは腸溶性物質のフィルムで被膜してもよい。
　経口投与のための液体組成物は、薬剤的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤又はエリキシル剤等を含み、一般的に用いられる不活性な希釈剤、例えば精製水又はエタノールを含む。当該液体組成物は不活性な希釈剤以外に可溶化剤、湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有していてもよい。 As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, 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 ethanol. In addition to the inert diluent, the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances, and preservatives.
　非経口投与のための注射剤は、無菌の水性又は非水性の溶液剤、懸濁剤又は乳濁剤を含有する。水性の溶剤としては、例えば注射用蒸留水又は生理食塩液が含まれる。非水性の溶剤としては、例えばエタノールのようなアルコール類がある。このような組成物は、さらに等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、又は溶解補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを通す濾過、殺菌剤の配合又は照射によって無菌化される。また、これらは無菌の固体組成物を製造し、使用前に無菌水又は無菌の注射用溶媒に溶解又は懸濁して使用することもできる。 The injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion. Examples of the 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. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
　外用剤としては、軟膏剤、硬膏剤、クリーム剤、ゼリー剤、パップ剤、噴霧剤、ローション剤、点眼剤、眼軟膏等を包含する。一般に用いられる軟膏基剤、ローション基剤、水性又は非水性の液剤、懸濁剤、乳剤等を含有する。 External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
　吸入剤や経鼻剤等の経粘膜剤は固体、液体又は半固体状のものが用いられ、従来公知の方法に従って製造することができる。例えば公知の賦形剤や、更に、pH調整剤、防腐剤、界面活性剤、滑沢剤、安定剤や増粘剤等が適宜添加されていてもよい。投与は、適当な吸入又は吹送のためのデバイスを使用することができる。例えば、計量投与吸入デバイス等の公知のデバイスや噴霧器を使用して、化合物を単独で又は処方された混合物の粉末として、もしくは医薬的に許容し得る担体と組み合わせて溶液又は懸濁液として投与することができる。乾燥粉末吸入器等は、単回又は多数回の投与用のものであってもよく、乾燥粉末又は粉末含有カプセルを利用することができる。あるいは、適当な駆出剤、例えば、クロロフルオロアルカン又は二酸化炭素等の好適な気体を使用した加圧エアゾールスプレー等の形態であってもよい。 A transmucosal agent such as an inhalant or a nasal agent is used in a solid, liquid, or semi-solid state, and can be produced according to a conventionally known method. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. For administration, 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. The dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. 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.
　通常経口投与の場合、1日の投与量は、体重当たり約0.001～100 mg/kg、好ましくは0.1～30 mg/kg、更に好ましくは0.1～10 mg/kgが適当であり、これを1回であるいは2回～4回に分けて投与する。静脈内投与される場合は、1日の投与量は、体重当たり約0.0001～10 mg/kgが適当で、1日1回～複数回に分けて投与する。また、経粘膜剤としては、体重当たり約0.001～100 mg/kgを1日1回～複数回に分けて投与する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜決定される。 In general, in the case of oral administration, 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. When administered intravenously, the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day. As 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.
　式（Ｉ）の化合物は、前述の式（Ｉ）の化合物が有効性を示すと考えられる疾患の種々の治療剤又は予防剤と併用することができる。当該併用は、同時投与、或いは別個に連続して、若しくは所望の時間間隔をおいて投与してもよい。同時投与製剤は、配合剤であっても別個に製剤化されていてもよい。 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.
　以下、実施例に基づき、式（Ｉ）の化合物の製造法をさらに詳細に説明する。なお、本発明は、以下に示される具体的実施例及び製造例の製造法のみに限定されるものではなく、式（Ｉ）の化合物はこれらの製造法の組み合わせ、あるいは当業者に自明である方法によっても製造されうる。 Hereinafter, based on an Example, the manufacturing method of the compound of Formula (I) is demonstrated in detail. In addition, this invention is not limited only to the manufacturing method of the specific Example and manufacturing example which are shown below, The compound of a formula (I) is a combination of these manufacturing methods, or is obvious to those skilled in the art. It can also be produced by a method.
製造例１
　3-(4-ヒドロキシフェニル)プロパン酸メチル(5.00 g)のDMF (50 mL)溶液に炭酸カリウム(11.50 g)及び1-ブロモ-3-(ブロモメチル)ベンゼン(7.63 g)を加え、室温で5日間撹拌した。反応混合物に水(100 mL)を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を除き、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより3-{4-[(3-ブロモベンジル)オキシ]フェニル}プロパン酸メチル(9.64 g)を白色固体として得た。 Production Example 1
To a solution of methyl 3- (4-hydroxyphenyl) propanoate (5.00 g) in DMF (50 mL) was added potassium carbonate (11.50 g) and 1-bromo-3- (bromomethyl) benzene (7.63 g), and 5 Stir for days. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give methyl 3- {4-[(3-bromobenzyl) oxy] phenyl} propanoate (9.64 g) as a white solid.
製造例２
　4-ブロモ-3-メチルフェノール(5.00 g)のNMP (30 mL)溶液に炭酸カリウム(5.55 g)及び安息香酸 2-ブロモエチル(5.0 mL)を加え、反応混合物を80 ℃まで昇温し、14時間撹拌後、室温まで放冷した。反応混合物に水(300 mL)を加え、室温で15分間撹拌した。析出物を濾取し、水で洗浄した。得られた固体をTHF (100 mL)に溶解し、減圧下濃縮することにより、薄黄色固体(9.48 g)を得た。得られた薄黄色固体(9.48 g)に酢酸エチル(50 mL)を加え、減圧下で約10 mL程度まで濃縮した。その後、ヘキサン(20 mL)を加え、15分間撹拌した。固体を濾取し、ヘキサンで洗浄後、減圧下加熱乾燥することにより、安息香酸 2-(4-ブロモ-3-メチルフェノキシ)エチル(6.73 g)を白色固体として得た。 Production Example 2
To a solution of 4-bromo-3-methylphenol (5.00 g) in NMP (30 mL) was added potassium carbonate (5.55 g) and 2-bromoethyl benzoate (5.0 mL), and the temperature of the reaction mixture was raised to 80 ° C. After stirring for hours, the mixture was allowed to cool to room temperature. Water (300 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The precipitate was collected by filtration and washed with water. The obtained solid was dissolved in THF (100 mL) and concentrated under reduced pressure to obtain a pale yellow solid (9.48 g). Ethyl acetate (50 mL) was added to the obtained pale yellow solid (9.48 g), and the mixture was concentrated to about 10 mL under reduced pressure. Then, hexane (20 mL) was added and stirred for 15 minutes. The solid was collected by filtration, washed with hexane, and dried by heating under reduced pressure to give 2- (4-bromo-3-methylphenoxy) ethyl benzoate (6.73 g) as a white solid.
製造例３
　4-メチルベンゼンスルホン酸 [(4R)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メチル(129.04 g)、4'-ヒドロキシ-2,2',6'-トリメチルビフェニル-3-カルボン酸メチル(117.34 g)、炭酸セシウム(211.53 g)及びDMF (500 mL)の混合物を75 ℃で4.5時間撹拌し、室温まで放冷した。反応混合物に水を加え、トルエンで抽出した。有機層を水及び飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。乾燥剤を除き、減圧下溶媒を留去することにより、4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-カルボン酸メチル(168.40 g)を薄黄色固体として得た。 Production Example 3
4-Methylbenzenesulfonic acid [(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl (129.04 g), 4'-hydroxy-2,2 ', 6'-trimethylbiphenyl-3 A mixture of methyl carboxylate (117.34 g), cesium carbonate (211.53 g) and DMF (500 mL) was stirred at 75 ° C. for 4.5 hours and allowed to cool to room temperature. Water was added to the reaction mixture and extracted with toluene. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. By removing the desiccant and distilling off the solvent under reduced pressure, 4 '-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2', 6 ' -Methyl trimethylbiphenyl-3-carboxylate (168.40 g) was obtained as a pale yellow solid.
　製造例3の方法と同様にして後記表に示す製造例3-1から3-16の化合物を製造した。 In the same manner as in Production Example 3, the compounds of Production Examples 3-1 to 3-16 shown in the table below were produced.
製造例４
　窒素雰囲気下、3-{4-[(3-ブロモベンジル)オキシ]フェニル}プロパン酸メチル(2.00 g)、4-クロロ-2-メチルフェニルボロン酸(1.17 g)、テトラキストリフェニルホスフィンパラジウム(331 mg)、炭酸ナトリウム(1.82 g)、水(10 mL)、エタノール(10 mL)及びトルエン(100 mL)の混合物を90 ℃で16時間撹拌後、室温まで放冷した。酢酸エチルを加え、水及び飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、得られた濾液にシリカゲル(約10 g)を加え、減圧下濃縮した。得られた担持物をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、3-{4-[(4'-クロロ-2'-メチルビフェニル-3-イル)メトキシ]フェニル}プロパン酸メチル(1.97 g)を無色油状物として得た。 Production Example 4
Under a nitrogen atmosphere, methyl 3- {4-[(3-bromobenzyl) oxy] phenyl} propanoate (2.00 g), 4-chloro-2-methylphenylboronic acid (1.17 g), tetrakistriphenylphosphine palladium (331 mg), sodium carbonate (1.82 g), water (10 mL), ethanol (10 mL) and toluene (100 mL) were stirred at 90 ° C. for 16 hours and then allowed to cool to room temperature. Ethyl acetate was added, washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, silica gel (about 10 g) was added to the obtained filtrate, and the mixture was concentrated under reduced pressure. The obtained support was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- {4-[(4'-chloro-2'-methylbiphenyl-3-yl) methoxy] phenyl} propanoic acid Methyl (1.97 g) was obtained as a colorless oil.
　製造例4の方法と同様にして後記表に示す製造例4-1の化合物を製造した。 In the same manner as in Production Example 4, the compound of Production Example 4-1 shown in the table below was produced.
製造例５
　窒素気流下、[4-(メトキシメトキシ)-2,6-ジメチルフェニル]ボロン酸(86.00 g)、3-ブロモ-2-メチル安息香酸メチル(86.00 g)、リン酸三カリウム(239.07 g)、ジシクロヘキシル(2',6'-ジメトキシビフェニル-2-イル)ホスフィン(1.55 g)及び酢酸パラジウム(II) (0.85 g)を混合した後、トルエン(1290 mL)及び水(129 mL)を加えた。反応混合物を70 ℃まで昇温し、同温で2時間撹拌した。反応混合物を室温まで放冷し、水(300 mL)を加えてセライト濾過後、酢酸エチルで洗浄した。濾液を分液し、有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-トルエン-酢酸エチル)で精製することにより、4'-(メトキシメトキシ)-2,2',6'-トリメチルビフェニル-3-カルボン酸メチル(105.93 g)を薄黄色結晶として得た。 Production Example 5
Under a nitrogen stream, [4- (methoxymethoxy) -2,6-dimethylphenyl] boronic acid (86.00 g), methyl 3-bromo-2-methylbenzoate (86.00 g), tripotassium phosphate (239.07 g), Dicyclohexyl (2 ′, 6′-dimethoxybiphenyl-2-yl) phosphine (1.55 g) and palladium (II) acetate (0.85 g) were mixed, and toluene (1290 mL) and water (129 mL) were added. The reaction mixture was heated to 70 ° C. and stirred at the same temperature for 2 hours. The reaction mixture was allowed to cool to room temperature, water (300 mL) was added, and the mixture was filtered through celite and washed with ethyl acetate. The filtrate was separated, and the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-toluene-ethyl acetate) to give methyl 4 ′-(methoxymethoxy) -2,2 ′, 6′-trimethylbiphenyl-3-carboxylate (105.93 g ) Was obtained as pale yellow crystals.
　製造例5の方法と同様にして後記表に示す製造例5-1から5-2の化合物を製造した。 In the same manner as in Production Example 5, the compounds of Production Examples 5-1 to 5-2 shown in the table below were produced.
製造例６
　5-ブロモ-2-(2-{[tert-ブチル(ジメチル)シリル]オキシ}エトキシ)-4,6-ジメチルピリミジン(7.21 g)、2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)安息香酸メチル(6.10 g)、酢酸パラジウム(II) (242 mg)、ジシクロヘキシル(2',6'-ジメトキシビフェニル-2-イル)ホスフィン(848 mg)、リン酸三カリウム(12.70 g)、トルエン(100 mL)及び水(10 mL)の混合物を窒素雰囲気下、80 ℃で24時間撹拌した。反応混合物を室温まで放冷し、水および酢酸エチルを加え、不溶物をセライト濾過により除去した。濾液を分液した後、水層を酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、3-[2-(2-{[tert-ブチル(ジメチル)シリル]オキシ}エトキシ)-4,6-ジメチルピリミジン-5-イル]-2-メチル安息香酸メチル(7.30 g)を淡黄色油状物として得た。 Production Example 6
5-Bromo-2- (2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) -4,6-dimethylpyrimidine (7.21 g), 2-methyl-3- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) methyl benzoate (6.10 g), palladium (II) acetate (242 mg), dicyclohexyl (2 ', 6'-dimethoxybiphenyl-2-yl) phosphine ( 848 mg), tripotassium phosphate (12.70 g), toluene (100 mL) and water (10 mL) were stirred at 80 ° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added, and the insoluble material was removed by celite filtration. After the filtrate was separated, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- [2- (2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) -4,6-dimethylpyrimidine Methyl -5-yl] -2-methylbenzoate (7.30 g) was obtained as a pale yellow oil.
　製造例6の方法と同様にして後記表に示す製造例6-1から6-4の化合物を製造した。 In the same manner as in Production Example 6, the compounds of Production Examples 6-1 to 6-4 shown in the table below were produced.
製造例７
　3-{4-[(4'-クロロ-2'-メチルビフェニル-3-イル)メトキシ]フェニル}プロパン酸メチル(1.92 g)のTHF (10 mL)及びメタノール(10 mL)溶液に1M水酸化ナトリウム水溶液(10 mL)を加え、室温で13時間撹拌した。反応混合物に1M塩酸(11 mL)を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムにて乾燥後、乾燥剤を除き、溶媒を減圧下留去した。得られた残渣(1.79 g)をジエチルエーテル及びヘキサンより再結晶することにより、3-{4-[(4'-クロロ-2'-メチルビフェニル-3-イル)メトキシ]フェニル}プロパン酸(1.50 g)を無色結晶として得た。 Production Example 7
3- {4-[(4'-Chloro-2'-methylbiphenyl-3-yl) methoxy] phenyl} methyl propanoate (1.92 g) in THF (10 mL) and methanol (10 mL) in 1M hydroxylation Aqueous sodium solution (10 mL) was added, and the mixture was stirred at room temperature for 13 hours. 1M Hydrochloric acid (11 mL) was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. The obtained residue (1.79 g) was recrystallized from diethyl ether and hexane to give 3- {4-[(4′-chloro-2′-methylbiphenyl-3-yl) methoxy] phenyl} propanoic acid (1.50 g) was obtained as colorless crystals.
製造例８
　4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-カルボン酸メチル(168.40 g)、メタノール(500 mL)及びTHF (500 mL)の混合物に5M水酸化ナトリウム水溶液(135 mL)を加え、65 ℃で4時間撹拌後、室温まで放冷した。反応混合物を減圧下濃縮した。残渣に水(500 mL)を加えた後、氷冷下1M塩酸(600 mL)を滴下にて加え、次いで10 %クエン酸水溶液(350 mL)を加えた。酢酸エチルで抽出し、有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去することにより、4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-カルボン酸(160.08 g)を黄色固体として得た。 Production Example 8
4 ′-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2 ′, 6′-trimethylbiphenyl-3-carboxylate methyl (168.40 g), methanol 5M aqueous sodium hydroxide solution (135 mL) was added to a mixture of (500 mL) and THF (500 mL), and the mixture was stirred at 65 ° C. for 4 hours, and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure. Water (500 mL) was added to the residue, 1M hydrochloric acid (600 mL) was added dropwise with ice cooling, and then 10% aqueous citric acid solution (350 mL) was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. By removing the desiccant by filtration and distilling off the solvent under reduced pressure, 4 '-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2' , 6′-Trimethylbiphenyl-3-carboxylic acid (160.08 g) was obtained as a yellow solid.
製造例９
　1-(シアノメチル)インダン-5-カルボン酸メチル(1.78 g)のメタノール(45 mL)溶液に、1M水酸化ナトリウム水溶液(17 mL)を加え、室温で5時間撹拌した。1M水酸化ナトリウム水溶液(8 mL)を加えて、更に室温で3時間撹拌した。反応混合物を減圧下濃縮し、得られた水層をジエチルエーテルで洗浄した。水層に濃塩酸をpH 1になるまで加えた。生じた固体を濾取、水洗後、減圧下加熱乾燥することにより、1-(シアノメチル)インダン-5-カルボン酸(1.60 g)を白色固体として得た。 Production Example 9
To a solution of methyl 1- (cyanomethyl) indan-5-carboxylate (1.78 g) in methanol (45 mL) was added 1M aqueous sodium hydroxide solution (17 mL), and the mixture was stirred at room temperature for 5 hours. 1M Aqueous sodium hydroxide solution (8 mL) was added, and the mixture was further stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the resulting aqueous layer was washed with diethyl ether. Concentrated hydrochloric acid was added to the aqueous layer until pH 1 was reached. The resulting solid was collected by filtration, washed with water, and dried by heating under reduced pressure to obtain 1- (cyanomethyl) indane-5-carboxylic acid (1.60 g) as a white solid.
製造例１０
　3-{4-[(4'-クロロ-2'-メチルビフェニル-3-イル)メトキシ]フェニル}プロパン酸(500 mg)のジクロロメタン(5 mL)溶液に氷冷下、塩化オキサリル(0.14 mL)を加え、室温で1時間撹拌した。反応混合物を氷冷した後、塩化オキサリル(0.14 mL)を加え、室温で1時間撹拌した。反応混合物を減圧下濃縮した後、トルエンを加え、減圧下溶媒を留去した。残渣に再度トルエンを加え、減圧下溶媒を留去した。得られた残渣及びジクロロメタン(5 mL)の混合物に30 %アンモニア水溶液(2.5 mL)を加え、室温で0.5時間撹拌した。反応混合物に水及び酢酸エチルを加え、生じた固体を濾取後、減圧下乾燥することにより、3-{4-[(4'-クロロ-2'-メチルビフェニル-3-イル)メトキシ]フェニル}プロパンアミド(413 mg)を白色粉末固体として得た。 Production Example 10
3-Oxalyl chloride (0.14 mL) in a solution of 3- {4-[(4'-chloro-2'-methylbiphenyl-3-yl) methoxy] phenyl} propanoic acid (500 mg) in dichloromethane (5 mL) under ice-cooling And stirred at room temperature for 1 hour. The reaction mixture was ice-cooled, oxalyl chloride (0.14 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, toluene was added, and the solvent was evaporated under reduced pressure. Toluene was again added to the residue, and the solvent was distilled off under reduced pressure. A 30% aqueous ammonia solution (2.5 mL) was added to a mixture of the obtained residue and dichloromethane (5 mL), and the mixture was stirred at room temperature for 0.5 hr. Water and ethyl acetate were added to the reaction mixture, and the resulting solid was collected by filtration and then dried under reduced pressure to give 3- {4-[(4'-chloro-2'-methylbiphenyl-3-yl) methoxy] phenyl. } Propanamide (413 mg) was obtained as a white powder solid.
製造例１１
　4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-カルボン酸(160.08 g)、1H-ベンゾトリアゾール-1-オール(64.30 g)及びDMF (800 mL)の混合物にトリエチルアミン(70 mL)、N-メトキシメタンアミン 塩酸塩(46.40 g)及びN-[3-(ジメチルアミノ)プロピル]-N'-エチルカルボジイミド 塩酸塩(91.20 g)を順次加え、反応混合物を室温で3時間撹拌した。反応混合物に水(1000 mL)を加え、トルエンで抽出した。有機層を水、5 %クエン酸水溶液、飽和炭酸水素ナトリウム水溶液及び飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣を約70 ℃に加温し、n-ヘプタン(1000 mL)を滴下にて加えた。室温まで放冷し、次いで氷冷下0.5時間撹拌した。固体を濾取し、n-ヘプタンで洗浄後、減圧下乾燥することにより、4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-N-メトキシ-N,2,2',6'-テトラメチルビフェニル-3-カルボキサミド(154.05 g)を白色固体として得た。 Production Example 11
4 '-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2', 6'-trimethylbiphenyl-3-carboxylic acid (160.08 g), 1H- A mixture of benzotriazol-1-ol (64.30 g) and DMF (800 mL) was added to triethylamine (70 mL), N-methoxymethanamine hydrochloride (46.40 g) and N- [3- (dimethylamino) propyl] -N. '-Ethylcarbodiimide hydrochloride (91.20 g) was added sequentially, and the reaction mixture was stirred at room temperature for 3 hours. Water (1000 mL) was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer was washed with water, 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was heated to about 70 ° C., and n-heptane (1000 mL) was added dropwise. The mixture was allowed to cool to room temperature, and then stirred for 0.5 hour under ice cooling. The solid was collected by filtration, washed with n-heptane, and then dried under reduced pressure to give 4 '-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -N- Methoxy-N, 2,2 ′, 6′-tetramethylbiphenyl-3-carboxamide (154.05 g) was obtained as a white solid.
製造例１２
　3-{4-[(4'-クロロ-2'-メチルビフェニル-3-イル)メトキシ]フェニル}プロパンアミド(410 mg)及びピリジン(4 mL)の混合物に氷冷下、塩化ホスホリル(0.11 mL)を加え、室温で1時間撹拌した。反応混合物を減圧下濃縮した後、残渣に0.1M塩酸を加え、2-ブタノン-酢酸エチル溶液で抽出した。有機層を0.1M塩酸及び飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去することにより、3-{4-[(4'-クロロ-2'-メチルビフェニル-3-イル)メトキシ]フェニル}プロパンニトリル(302 mg)を淡黄色飴状物として得た。 Production Example 12
Phosphoryl chloride (0.11 mL) was added to a mixture of 3- {4-[(4'-chloro-2'-methylbiphenyl-3-yl) methoxy] phenyl} propanamide (410 mg) and pyridine (4 mL) under ice-cooling. ) Was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 0.1 M hydrochloric acid was added to the residue, and the mixture was extracted with 2-butanone-ethyl acetate solution. The organic layer was washed with 0.1 M hydrochloric acid and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was removed under reduced pressure to give 3- {4-[(4'-chloro-2'-methylbiphenyl-3-yl) methoxy] phenyl} propanenitrile (302 mg ) Was obtained as a pale yellow rod.
製造例１３
　1-(2-ブロモエチル)-4-ニトロベンゼン(10.00 g)、シアン化カリウム(4.00 g)及びDMSO (100 mL)の混合物を、50 ℃で6時間撹拌した。反応液に水(400 mL)を加えトルエン（200 mL）で抽出した後、有機層を水及び飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。濾過にて不溶物を除去後、濾液を減圧下濃縮して、3-(4-ニトロフェニル)プロパンニトリル(7.16 g)を褐色固体として得た。 Production Example 13
A mixture of 1- (2-bromoethyl) -4-nitrobenzene (10.00 g), potassium cyanide (4.00 g) and DMSO (100 mL) was stirred at 50 ° C. for 6 hours. After adding water (400 mL) to the reaction solution and extracting with toluene (200 mL), the organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 3- (4-nitrophenyl) propanenitrile (7.16 g) as a brown solid.
製造例１４
　安息香酸 2-{[3'-(ヒドロキシメチル)-2-メチルビフェニル-4-イル]オキシ}エチル(800 mg)、3-(4-ヒドロキシフェニル)プロパンニトリル(422 mg)、1,1'-(アゾジカルボニル)ジピペリジン(724 mg)、トリブチルホスフィン(0.7 mL)及びTHF (16 mL)の混合物を室温で14時間撹拌した。不溶物を濾別し、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)により精製し、安息香酸 2-[(3'-{[4-(2-シアノエチル)フェノキシ]メチル}-2-メチルビフェニル-4-イル)オキシ]エチル(998 mg)を淡黄色油状物として得た。 Production Example 14
Benzoic acid 2-{[3 '-(hydroxymethyl) -2-methylbiphenyl-4-yl] oxy} ethyl (800 mg), 3- (4-hydroxyphenyl) propanenitrile (422 mg), 1,1' A mixture of-(azodicarbonyl) dipiperidine (724 mg), tributylphosphine (0.7 mL) and THF (16 mL) was stirred at room temperature for 14 hours. Insoluble matter was filtered off, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane-ethyl acetate), and benzoic acid 2-[(3 '-{[4- (2-cyanoethyl) phenoxy ] Methyl} -2-methylbiphenyl-4-yl) oxy] ethyl (998 mg) was obtained as a pale yellow oil.
　製造例14の方法と同様にして後記表に示す製造例14-1の化合物を製造した。 In the same manner as in Production Example 14, the compound of Production Example 14-1 shown in the table below was produced.
製造例１５
　窒素気流下、4-ブロモ-3,5-ジメチルフェノール(150.00 g)のアセトニトリル(1200 mL)溶液に炭酸カリウム(257.80 g)を加えた。続いてクロロメチルメチルエーテル(68.0 mL)を滴下にて加え、反応混合物を室温で1時間撹拌した。反応混合物に炭酸カリウム(25.80 g)を加え、反応混合物を室温で15分間撹拌した。反応混合物にクロロメチルメチルエーテル(5.6 mL)を滴下にて加え、反応混合物を室温で1.5時間撹拌した。反応混合物に室温でクロロメチルメチルエーテル(2.8 mL)を滴下にて加え、反応混合物を室温で0.5時間撹拌した。反応混合物をろ過し、アセトニトリルで洗浄した。得られた濾液を減圧下濃縮し、得られた残渣をジエチルエーテルで希釈後、1M水酸化ナトリウム水溶液及び飽和塩化ナトリウム水溶液で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、濾過にて乾燥剤を除き、減圧下溶媒を留去することにより、2-ブロモ-5-(メトキシメトキシ)-1,3-ジメチルベンゼン(180.30 g)を薄黄色固体として得た。 Production Example 15
Under a nitrogen stream, potassium carbonate (257.80 g) was added to a solution of 4-bromo-3,5-dimethylphenol (150.00 g) in acetonitrile (1200 mL). Subsequently, chloromethyl methyl ether (68.0 mL) was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added potassium carbonate (25.80 g) and the reaction mixture was stirred at room temperature for 15 minutes. Chloromethyl methyl ether (5.6 mL) was added dropwise to the reaction mixture, and the reaction mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, chloromethyl methyl ether (2.8 mL) was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 0.5 hour. The reaction mixture was filtered and washed with acetonitrile. The obtained filtrate was concentrated under reduced pressure, and the resulting residue was diluted with diethyl ether and washed with 1M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated under reduced pressure to give 2-bromo-5- (methoxymethoxy) -1,3-dimethylbenzene (180.30 g). Obtained as a pale yellow solid.
製造例１６
　窒素気流下、2-ブロモ-5-(メトキシメトキシ)-1,3-ジメチルベンゼン(124.36 g)のTHF (845 mL)溶液に、ドライアイス-アセトン浴で冷却下、1.55M n-ブチルリチウム ヘキサン溶液(360 mL)を滴下し、ドライアイス-アセトン浴冷却下で0.5時間撹拌した。反応混合物にホウ酸トリイソプロピル(135 mL)のTHF (150 mL)溶液を滴下にて加え、同温で0.5時間撹拌した。ドライアイス-アセトン浴をはずし、約5 ℃になるまで昇温させながら1時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液(400 mL)を加え、室温で1時間撹拌した。反応混合物を減圧下濃縮し、得られた残渣に水(300 mL)及びn-ヘプタン(200 mL)を加え、室温で5分間撹拌した。その後、氷冷下0.5時間撹拌後、固体を濾取し、水(100 mL)及びn-ヘプタン(100 mL)で洗浄した。固体を減圧下加熱乾燥することにより、[4-(メトキシメトキシ)-2,6-ジメチルフェニル]ボロン酸(100.53 g)を白色固体として得た。 Production Example 16
In a nitrogen stream, 1.55-M n-butyllithium hexane in a solution of 2-bromo-5- (methoxymethoxy) -1,3-dimethylbenzene (124.36 g) in THF (845 mL) cooled in a dry ice-acetone bath The solution (360 mL) was added dropwise, and the mixture was stirred for 0.5 hr under cooling with a dry ice-acetone bath. A solution of triisopropyl borate (135 mL) in THF (150 mL) was added dropwise to the reaction mixture, and the mixture was stirred at the same temperature for 0.5 hr. The dry ice-acetone bath was removed, and the mixture was stirred for 1 hour while raising the temperature to about 5 ° C. Saturated aqueous ammonium chloride solution (400 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, water (300 mL) and n-heptane (200 mL) were added to the obtained residue, and the mixture was stirred at room temperature for 5 min. Then, after stirring for 0.5 hour under ice cooling, the solid was collected by filtration and washed with water (100 mL) and n-heptane (100 mL). The solid was heated and dried under reduced pressure to obtain [4- (methoxymethoxy) -2,6-dimethylphenyl] boronic acid (100.53 g) as a white solid.
製造例１７
　3-ブロモ-2-メチル安息香酸(112.0 g)及びメタノール(1000 mL)の混合物に撹拌下、濃硫酸(31 mL)を加えた。反応混合物を加熱還流下22時間撹拌した。減圧下溶媒を留去し、得られた残渣に飽和炭酸水素ナトリウム水溶液(110 mL)及び炭酸水素ナトリウム(50 g)を少しずつ加えて、pH 7～8とした。更に水(200 mL)を加えた後、酢酸エチルで抽出した。有機層を水及び飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去することにより、3-ブロモ-2-メチル安息香酸メチル(116.4 g)を淡黄色固体として得た。 Production Example 17
Concentrated sulfuric acid (31 mL) was added to a mixture of 3-bromo-2-methylbenzoic acid (112.0 g) and methanol (1000 mL) with stirring. The reaction mixture was stirred for 22 hours under heating to reflux. The solvent was distilled off under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution (110 mL) and sodium hydrogen carbonate (50 g) were added little by little to the resulting residue to adjust the pH to 7-8. Water (200 mL) was further added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure to obtain methyl 3-bromo-2-methylbenzoate (116.4 g) as a pale yellow solid.
製造例１８
　4'-(メトキシメトキシ)-2,2',6'-トリメチルビフェニル-3-カルボン酸メチル(1167.83 g)のメタノール(5.84 L)溶液に氷冷下、濃塩酸(774 mL)を加え、その後室温で4時間撹拌した。その後、反応混合物を38 ℃まで昇温して1時間撹拌した。反応混合物を室温まで放冷後、水(5.84 L)を滴下にて加えた。反応混合物を氷冷して0.5時間撹拌した。生じた結晶を濾取し、冷含水メタノールで洗浄後、減圧下乾燥することにより、4'-ヒドロキシ-2,2',6'-トリメチルビフェニル-3-カルボン酸メチル(956.05 g)を無色結晶として得た。 Production Example 18
Concentrated hydrochloric acid (774 mL) was added to a methanol (5.84 L) solution of methyl 4 '-(methoxymethoxy) -2,2', 6'-trimethylbiphenyl-3-carboxylate (1167.83 g) under ice-cooling, and then Stir at room temperature for 4 hours. Thereafter, the reaction mixture was heated to 38 ° C. and stirred for 1 hour. The reaction mixture was allowed to cool to room temperature, and water (5.84 L) was added dropwise. The reaction mixture was ice-cooled and stirred for 0.5 hour. The resulting crystals were collected by filtration, washed with cold hydrous methanol, and dried under reduced pressure to give methyl 4'-hydroxy-2,2 ', 6'-trimethylbiphenyl-3-carboxylate (956.05 g) as colorless crystals. Got as.
　製造例18の方法と同様にして後記表に示す製造例18-1から18-2の化合物を製造した。 In the same manner as in Production Example 18, the compounds of Production Examples 18-1 to 18-2 shown in the table below were produced.
製造例１９
　窒素気流下、4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-N-メトキシ-N,2,2',6'-テトラメチルビフェニル-3-カルボキサミド(131.00 g)のトルエン(1000 mL)溶液をドライアイス-アセトン浴にて冷却した。反応混合物に0.99M水素化ジイソブチルアルミニウム トルエン溶液(352 mL)を滴下し、ドライアイス-アセトン浴冷却下で1時間撹拌した。反応混合物に飽和(+)-酒石酸ナトリウムカリウム水溶液を加え、室温まで昇温した。1.5時間撹拌後、酢酸エチルを加え、セライト濾過し、酢酸エチルで洗浄した。得られた濾液を分液し、得られた有機層を水及び飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。濾過にて不溶物を除去後、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-カルバルデヒド(111.51 g)を白色固体として得た。 Production Example 19
4 '-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -N-methoxy-N, 2,2', 6'-tetramethylbiphenyl- under nitrogen flow A solution of 3-carboxamide (131.00 g) in toluene (1000 mL) was cooled in a dry ice-acetone bath. To the reaction mixture was added dropwise a 0.99M diisobutylaluminum hydride toluene solution (352 mL), and the mixture was stirred for 1 hour under cooling with a dry ice-acetone bath. Saturated (+)-potassium sodium tartrate aqueous solution was added to the reaction mixture, and the temperature was raised to room temperature. After stirring for 1.5 hours, ethyl acetate was added, and the mixture was filtered through Celite and washed with ethyl acetate. The obtained filtrate was separated, and the obtained organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4 '-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2 2,2 ', 6'-Trimethylbiphenyl-3-carbaldehyde (111.51 g) was obtained as a white solid.
製造例２０
　2,2',6'-トリメチルビフェニル-3-カルボン酸メチル(2.21 g)のジクロロメタン(20 mL)溶液に、0 ℃で1.0M水素化ジイソブチルアルミニウム トルエン溶液(22 mL)を15分間かけて滴下した後、同温で0.5時間撹拌した。反応液に飽和(+)-酒石酸ナトリウムカリウム水溶液(25 mL）を加え、セライト濾過後酢酸エチル及びジエチルエーテルにて抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、濾過にて乾燥剤を除き、減圧下溶媒を留去して、(2,2',6'-トリメチルビフェニル-3-イル)メタノール(1.90 g)を無色油状物として得た。 Production Example 20
To a solution of methyl 2,2 ', 6'-trimethylbiphenyl-3-carboxylate (2.21 g) in dichloromethane (20 mL), 1.0 M diisobutylaluminum hydride in toluene (22 mL) was added dropwise at 0 ° C over 15 minutes. And stirred at the same temperature for 0.5 hour. Saturated (+)-potassium sodium tartrate aqueous solution (25 mL) was added to the reaction mixture, and the mixture was filtered through celite and extracted with ethyl acetate and diethyl ether. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered to remove the desiccant, and the solvent was distilled off under reduced pressure to give (2,2 ', 6'-trimethylbiphenyl-3-yl ) Methanol (1.90 g) was obtained as a colorless oil.
製造例２１
　6-{[4'-(2-{[tert-ブチル(ジメチル)シリル]オキシ}エトキシ)-2,2',6'-トリメチルビフェニル-3-イル]メトキシ}ニコチノニトリル(1.13 g)及びジクロロメタン(10 mL)の混合物にドライアイス-アセトン浴にて冷却下、1.0M水素化ジイソブチルアルミニウム トルエン溶液(3.0 mL)を加え、同温で3時間撹拌した。反応混合物に同温にて飽和(+)-酒石酸ナトリウムカリウム水溶液(20 mL)及び酢酸エチル(20 mL)を加え、室温で2時間撹拌した。混合物を分液し、水層を酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、6-{[4'-(2-{[tert-ブチル(ジメチル)シリル]オキシ}エトキシ)-2,2',6'-トリメチルビフェニル-3-イル]メトキシ}ニコチンアルデヒド(339 mg)を白色固体として得た。 Production Example 21
6-{[4 '-(2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) -2,2', 6'-trimethylbiphenyl-3-yl] methoxy} nicotinonitrile (1.13 g) and To a mixture of dichloromethane (10 mL) was added 1.0 M diisobutylaluminum hydride toluene solution (3.0 mL) under cooling in a dry ice-acetone bath, and the mixture was stirred at the same temperature for 3 hours. Saturated (+)-potassium sodium tartrate aqueous solution (20 mL) and ethyl acetate (20 mL) were added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 2 hr. The mixture was separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 6-{[4 '-(2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) -2,2', 6 ' -Trimethylbiphenyl-3-yl] methoxy} nicotinaldehyde (339 mg) was obtained as a white solid.
製造例２２
　4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-カルバルデヒド(1.00 g)、3-(4-アミノフェニル)プロパンニトリル(450 mg)及びTHF (10 mL)の混合物に酢酸(0.80 mL)を加え室温で45分間撹拌した後、トリアセトキシ水素化ホウ素ナトリウム(900 mg)を加え同温で更に14時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(20 mL)を加え酢酸エチルで抽出した後、有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。濾過にて不溶物を除去後、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、3-(4-{[(4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-イル)メチル]アミノ}フェニル)プロパンニトリル(1.35 g)を白色アモルファス固体として得た。 Production Example 22
4 '-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2', 6'-trimethylbiphenyl-3-carbaldehyde (1.00 g), 3- Acetic acid (0.80 mL) was added to a mixture of (4-aminophenyl) propanenitrile (450 mg) and THF (10 mL), and the mixture was stirred at room temperature for 45 min. And stirred for a further 14 hours. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- (4-{[(4 '-{[(4S) -2,2-dimethyl-1,3-dioxolane- 4-yl] methoxy} -2,2 ′, 6′-trimethylbiphenyl-3-yl) methyl] amino} phenyl) propanenitrile (1.35 g) was obtained as a white amorphous solid.
製造例２３
　窒素気流下、NMP (250 mL)に氷冷下水素化ナトリウム(ミネラルオイル約40 %添加、21.00 g)を加え、氷冷下で10分間撹拌した。その後、5-フルオロインダン-1-オン(15.00 g)と1,2-ジブロモエタン(30 mL)のNMP (50 mL)溶液を滴下にて加えた。滴下終了後、氷冷下で10分間撹拌した。さらに1,2-ジブロモエタン(10 mL)を滴下し、氷冷下で0.5時間撹拌した。反応混合物に水及び飽和塩化ナトリウム水溶液を加え、トルエン-酢酸エチル溶液で抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、5'-フルオロスピロ[シクロプロパン-1,2'-インデン]-1'(3'H)-オン(10.06 g)を薄黄色固体として得た。 Production Example 23
Under a nitrogen stream, sodium hydride (added about 40% mineral oil, 21.00 g) was added to NMP (250 mL) under ice cooling, and the mixture was stirred for 10 minutes under ice cooling. Thereafter, a solution of 5-fluoroindan-1-one (15.00 g) and 1,2-dibromoethane (30 mL) in NMP (50 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred for 10 minutes under ice cooling. Further, 1,2-dibromoethane (10 mL) was added dropwise, and the mixture was stirred for 0.5 hour under ice cooling. Water and a saturated aqueous sodium chloride solution were added to the reaction mixture, and the mixture was extracted with a toluene-ethyl acetate solution. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 5'-fluorospiro [cyclopropane-1,2'-indene] -1 '(3'H) -one (10.06 g ) Was obtained as a pale yellow solid.
　製造例23の方法と同様にして後記表に示す製造例23-1の化合物を製造した。 In the same manner as in Production Example 23, the compound of Production Example 23-1 shown in the table below was produced.
製造例２４
　窒素気流下、(2,2',6'-トリメチルビフェニル-3-イル)メタノール(912 mg)のDMF (20 mL)溶液を氷冷し、水素化ナトリウム(ミネラルオイル約40 %添加、200 mg)を加え、氷冷下で15分間撹拌した。反応混合物に5'-フルオロスピロ[シクロプロパン-1,2'-インデン]-1'(3'H)-オン(800 mg)を加えて氷浴をはずし、室温まで昇温させながら3時間撹拌した。反応混合物に水素化ナトリウム(ミネラルオイル約40 %添加、200 mg)を加え、65 ℃で4時間撹拌した。反応混合物を室温まで放冷し、水を加えてトルエン-酢酸エチル溶液で抽出した。水層をトルエン-酢酸エチル溶液で抽出した。有機層を合わせ、水及び飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)により精製し、5'-[(2,2',6'-トリメチルビフェニル-3-イル)メトキシ]スピロ[シクロプロパン-1,2'-インデン]-1'(3'H)-オン(1.07 g)を白色固体として得た。 Production Example 24
Under nitrogen flow, (2,2 ', 6'-trimethylbiphenyl-3-yl) methanol (912 mg) in DMF (20 mL) was ice-cooled and sodium hydride (added with about 40% mineral oil, 200 mg ) And stirred for 15 minutes under ice-cooling. 5'-Fluorospiro [cyclopropane-1,2'-indene] -1 '(3'H) -one (800 mg) was added to the reaction mixture, the ice bath was removed, and the mixture was stirred for 3 hours while warming to room temperature. did. Sodium hydride (addition of about 40% mineral oil, 200 mg) was added to the reaction mixture, and the mixture was stirred at 65 ° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with a toluene-ethyl acetate solution. The aqueous layer was extracted with a toluene-ethyl acetate solution. The organic layers were combined, washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and 5 ′-[(2,2 ′, 6′-trimethylbiphenyl-3-yl) methoxy] spiro [cyclopropane-1,2 ′. -Indene] -1 '(3'H) -one (1.07 g) was obtained as a white solid.
　製造例24の方法と同様にして後記表に示す製造例24-1の化合物を製造した。 In the same manner as in Production Example 24, the compound of Production Example 24-1 shown in the table below was produced.
製造例２５
　[4'-(2-{[tert-ブチル(ジメチル)シリル]オキシ}エトキシ)-2,2',6'-トリメチルビフェニル-3-イル]メタノール(1.49 g)のDMF (15 mL)溶液に氷冷下、水素化ナトリウム(ミネラルオイル約40 %添加、150 mg)を加え、氷冷下0.5時間撹拌した後、室温で0.5時間撹拌した。反応混合物に氷冷下、6-クロロニコチノニトリル(520 mg)を加え、氷冷下0.5時間撹拌した後、室温で4時間撹拌した。反応混合物に水(60 mL)を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、6-{[4'-(2-{[tert-ブチル(ジメチル)シリル]オキシ}エトキシ)-2,2',6'-トリメチルビフェニル-3-イル]メトキシ}ニコチノニトリル(1.13 g)を白色固体として得た。 Production Example 25
To a solution of [4 '-(2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) -2,2', 6'-trimethylbiphenyl-3-yl] methanol (1.49 g) in DMF (15 mL) Sodium hydride (addition of about 40% mineral oil, 150 mg) was added under ice cooling, and the mixture was stirred for 0.5 hours under ice cooling and then at room temperature for 0.5 hours. To the reaction mixture was added 6-chloronicotinonitrile (520 mg) under ice cooling, and the mixture was stirred for 0.5 hours under ice cooling, and then stirred at room temperature for 4 hours. Water (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 6-{[4 '-(2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) -2,2', 6 ' -Trimethylbiphenyl-3-yl] methoxy} nicotinonitrile (1.13 g) was obtained as a white solid.
　製造例25の方法と同様にして後記表に示す製造例25-1から25-4の化合物を製造した。 In the same manner as in Production Example 25, the compounds of Production Examples 25-1 to 25-4 shown in the table below were produced.
製造例２６
　窒素気流下、水素化ナトリウム(ミネラルオイル約40 %添加、350 mg)及びDMF (13 mL)の混合物に、氷冷下にて(シアノメチル)ホスホン酸ジエチル(1.30 mL)を少しずつ加え、同温で0.5時間撹拌した。反応混合物に5'-[(2,2',6'-トリメチルビフェニル-3-イル)メトキシ]スピロ[シクロプロパン-1,2'-インデン]-1'(3'H)-オン(1.06 g)及びDMF (7 mL)の混合物を加え、80 ℃で22時間撹拌した。反応混合物を室温まで放冷し、水を加えてトルエン-酢酸エチル溶液で抽出した。水層をトルエン-酢酸エチル溶液で抽出した。有機層を合わせ、水及び飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)により精製し、{5'-[(2,2',6'-トリメチルビフェニル-3-イル)メトキシ]スピロ[シクロプロパン-1,2'-インデン]-1'(3'H)-イリデン}アセトニトリル(729 mg)を白色アモルファス固体として得た。 Production Example 26
Under a stream of nitrogen, sodium hydride (added about 40% mineral oil, 350 mg) and DMF (13 mL) were added in portions with diethyl (cyanomethyl) phosphonate (1.30 mL) under ice cooling. For 0.5 hour. To the reaction mixture was added 5 '-[(2,2', 6'-trimethylbiphenyl-3-yl) methoxy] spiro [cyclopropane-1,2'-indene] -1 '(3'H) -one (1.06 g ) And DMF (7 mL) were added, and the mixture was stirred at 80 ° C. for 22 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with a toluene-ethyl acetate solution. The aqueous layer was extracted with a toluene-ethyl acetate solution. The organic layers were combined, washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and {5 '-[(2,2', 6'-trimethylbiphenyl-3-yl) methoxy] spiro [cyclopropane-1,2 '-Indene] -1'(3'H) -ylidene} acetonitrile (729 mg) was obtained as a white amorphous solid.
　製造例26の方法と同様にして後記表に示す製造例26-1から26-9の化合物を製造した。 In the same manner as in Production Example 26, the compounds of Production Examples 26-1 to 26-9 shown in the table below were produced.
製造例２７
　{5'-[(2,2',6'-トリメチルビフェニル-3-イル)メトキシ]スピロ[シクロプロパン-1,2'-インデン]-1'(3'H)-イリデン}アセトニトリル(729 mg)及びメタノール(15 mL)の混合物にマグネシウム(切削片状、450 mg)を加えた。反応混合物に、マグネシウム(切削片状、0.10 g)、ヨウ素(1欠片)及びメタノール(5 mL)の混合物を室温で0.5時間撹拌したものを3滴加え、室温で1.5時間撹拌した。反応混合物に酢酸エチル及び1M塩酸を加え、室温で0.5時間撹拌後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)により精製し、{5'-[(2,2',6'-トリメチルビフェニル-3-イル)メトキシ]-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-1'-イル}アセトニトリル(702 mg)を無色飴状物として得た。 Production Example 27
{5 '-[(2,2', 6'-Trimethylbiphenyl-3-yl) methoxy] spiro [cyclopropane-1,2'-indene] -1 '(3'H) -ylidene} acetonitrile (729 mg ) And methanol (15 mL) were added magnesium (cut pieces, 450 mg). Three drops of a mixture of magnesium (cut pieces, 0.10 g), iodine (1 piece) and methanol (5 mL) stirred at room temperature for 0.5 hours were added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate and 1M hydrochloric acid were added to the reaction mixture, and the mixture was stirred at room temperature for 0.5 hour and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and {5 '-[(2,2', 6'-trimethylbiphenyl-3-yl) methoxy] -1 ', 3'-dihydro Spiro [cyclopropane-1,2′-indene] -1′-yl} acetonitrile (702 mg) was obtained as a colorless bowl.
　製造例27の方法と同様にして後記表に示す製造例27-1から27-7の化合物を製造した。 The compounds of Production Examples 27-1 to 27-7 shown in the table below were produced in the same manner as in Production Example 27.
製造例２８
　窒素気流下、氷冷下にてTHF (300 mL)に水素化アルミニウムリチウム(4.00 g)を加え、次いで4'-(メトキシメトキシ)-2,2',6'-トリメチルビフェニル-3-カルボン酸メチル(25.00 g)のTHF (100 mL)溶液を滴下にてゆっくり加えた。反応混合物を氷冷下10分間撹拌した後、氷浴をはずし、室温まで昇温させながら40分間撹拌した。反応混合物に氷冷下、硫酸ナトリウム十水和物(35.00 g)を少しずつ加えた後、氷浴をはずし、室温まで昇温させながら0.5時間撹拌した。セライト濾過にて不溶物を除去し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)により精製し、[4'-(メトキシメトキシ)-2,2',6'-トリメチルビフェニル-3-イル]メタノール(21.88 g)を無色飴状物として得た。 Production Example 28
Add lithium aluminum hydride (4.00 g) to THF (300 mL) under nitrogen flow and ice cooling, then 4 '-(methoxymethoxy) -2,2', 6'-trimethylbiphenyl-3-carboxylic acid A solution of methyl (25.00 g) in THF (100 mL) was slowly added dropwise. The reaction mixture was stirred for 10 minutes under ice cooling, then the ice bath was removed, and the mixture was stirred for 40 minutes while warming to room temperature. To the reaction mixture was added sodium sulfate decahydrate (35.00 g) little by little under ice cooling, then the ice bath was removed, and the mixture was stirred for 0.5 hr while warming to room temperature. Insoluble material was removed by Celite filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and [4 ′-(methoxymethoxy) -2,2 ′, 6′-trimethylbiphenyl-3-yl] methanol (21.88 g) was colorless. Obtained as a bowl.
　製造例28の方法と同様にして後記表に示す製造例28-1から28-6の化合物を製造した。 The compounds of Production Examples 28-1 to 28-6 shown in the table below were produced in the same manner as in Production Example 28.
製造例２９
　5'-ブロモスピロ[シクロプロパン-1,2'-インデン]-1'(3'H)-オン(41.00 g)、酢酸パラジウム(II)(3.88 g)、1,3-ビス(ジフェニルホスフィノ)-プロパン(7.13 g)、トリエチルアミン(48.2 mL)、DMF (230 mL)及びメタノール(115 mL)の混合物を一酸化炭素気流下、室温で15分間撹拌した。反応混合物を一酸化炭素雰囲気下、70 ℃で13時間撹拌した。反応混合物を室温まで放冷し、水、酢酸エチルおよびトルエンを加え、不溶物をセライト濾過により除去した。濾液を分液した後、水層をトルエン-酢酸エチル溶液で抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム-メタノール)で精製することにより、1'-オキソ-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-5'-カルボン酸メチル(35.85 g)を淡黄色固体として得た。 Production Example 29
5'-bromospiro [cyclopropane-1,2'-indene] -1 '(3'H) -one (41.00 g), palladium (II) acetate (3.88 g), 1,3-bis (diphenylphosphino) A mixture of propane (7.13 g), triethylamine (48.2 mL), DMF (230 mL) and methanol (115 mL) was stirred at room temperature for 15 minutes under a stream of carbon monoxide. The reaction mixture was stirred at 70 ° C. for 13 hours under a carbon monoxide atmosphere. The reaction mixture was allowed to cool to room temperature, water, ethyl acetate and toluene were added, and the insoluble material was removed by celite filtration. After the filtrate was separated, the aqueous layer was extracted with a toluene-ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give 1'-oxo-1 ', 3'-dihydrospiro [cyclopropane-1,2'-indene] -5'-carboxylic acid Methyl (35.85 g) was obtained as a pale yellow solid.
　製造例29の方法と同様にして後記表に示す製造例29-1の化合物を製造した。 In the same manner as in Production Example 29, the compound of Production Example 29-1 shown in the table below was produced.
製造例３０
　水素化ナトリウム(ミネラルオイル約40 %添加、15.0 g)及びDMF (230 mL)の混合物に氷冷下、シアノメチルホスホン酸ジエチル(59.0 mL)を滴下し、氷冷下45分間撹拌した。反応混合物に1'-オキソ-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-5'-カルボン酸メチル(26.4 g)のDMF (230 mL)溶液を加え、室温で2.5時間撹拌した。反応混合物に5M水酸化ナトリウム水溶液(50 mL)を加え、室温で0.5時間撹拌した。反応混合物に水(500 mL)を加えた後、氷冷下、1M塩酸(300 mL)を加えた。更に水(500 mL)を加え、室温で0.5時間撹拌した。生じた固体を濾取し、水で洗浄後、減圧下加熱乾燥することにより、1'-(シアノメチレン)-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-5'-カルボン酸(30.9 g)を緑褐色固体として得た。 Production Example 30
To a mixture of sodium hydride (addition of about 40% mineral oil, 15.0 g) and DMF (230 mL) was added dropwise cyanomethylphosphonate diethyl ester (59.0 mL) under ice cooling, and the mixture was stirred for 45 minutes under ice cooling. To the reaction mixture was added a solution of methyl 1′-oxo-1 ′, 3′-dihydrospiro [cyclopropane-1,2′-indene] -5′-carboxylate (26.4 g) in DMF (230 mL) at room temperature. Stir for 2.5 hours. To the reaction mixture was added 5M aqueous sodium hydroxide solution (50 mL), and the mixture was stirred at room temperature for 0.5 hr. Water (500 mL) was added to the reaction mixture, and 1M hydrochloric acid (300 mL) was added under ice cooling. Water (500 mL) was further added, and the mixture was stirred at room temperature for 0.5 hour. The resulting solid was collected by filtration, washed with water, and then heated and dried under reduced pressure to give 1 '-(cyanomethylene) -1', 3'-dihydrospiro [cyclopropane-1,2'-indene] -5 '-Carboxylic acid (30.9 g) was obtained as a greenish brown solid.
製造例３１
　1'-(シアノメチレン)-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-5'-カルボン酸(57.60 g)、トリエチルアミン(70.0 mL)、tert-ブタノール(350 mL)及びトルエン(700 mL)の混合物に室温にて、ジフェニルリン酸アジド(75.0 mL)を加え、室温で0.5時間撹拌した。その後、反応混合物を100 ℃で24時間撹拌した。反応混合物を室温まで放冷し、水を加えた後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、tert-ブチル [1'-(シアノメチレン)-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-5'-イル]カルバマート(53.00 g)を淡黄色固体として得た。 Production Example 31
1 '-(cyanomethylene) -1', 3'-dihydrospiro [cyclopropane-1,2'-indene] -5'-carboxylic acid (57.60 g), triethylamine (70.0 mL), tert-butanol (350 mL ) And toluene (700 mL) were added diphenylphosphoric acid azide (75.0 mL) at room temperature, and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was then stirred at 100 ° C. for 24 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give tert-butyl [1 '-(cyanomethylene) -1', 3'-dihydrospiro [cyclopropane-1,2'- Indene] -5'-yl] carbamate (53.00 g) was obtained as a pale yellow solid.
　製造例31の方法と同様にして後記表に示す製造例31-1の化合物を製造した。 In the same manner as in Production Example 31, the compound of Production Example 31-1 shown in the table below was produced.
製造例３２
　tert-ブチル [1'-(1H-テトラゾール-5-イルメチル)-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-5'-イル]カルバマート(4.76 g)のメタノール(20 mL)溶液に4M塩化水素 ジオキサン溶液(70 mL)を加え、室温で1時間撹拌した後、減圧下溶媒を留去した。得られた残渣に1M水酸化ナトリウム水溶液(70 mL)を加えて塩基性とした後、10 %クエン酸水溶液を加えて酸性とし、2-プロパノール-クロロホルム溶液で抽出した。水層を2-プロパノール-クロロホルム溶液で抽出した。有機層を合わせ、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去することにより、1'-(1H-テトラゾール-5-イルメチル)-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-5'-アミン(3.11 g)を褐色アモルファス固体として得た。 Production Example 32
tert-butyl [1 '-(1H-tetrazol-5-ylmethyl) -1', 3'-dihydrospiro [cyclopropane-1,2'-indene] -5'-yl] carbamate (4.76 g) in methanol (4.76 g) 20 mL) solution was added 4M hydrogen chloride dioxane solution (70 mL) and stirred at room temperature for 1 hour, and then the solvent was distilled off under reduced pressure. The resulting residue was basified with 1M aqueous sodium hydroxide solution (70 mL), acidified with 10% aqueous citric acid solution, and extracted with 2-propanol-chloroform solution. The aqueous layer was extracted with a 2-propanol-chloroform solution. The organic layers were combined and dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure to obtain 1 '-(1H-tetrazol-5-ylmethyl) -1', 3'-dihydrospiro [cyclopropane-1,2'-indene. ] -5'-amine (3.11 g) was obtained as a brown amorphous solid.
製造例３３
　tert-ブチル[1-(シアノメチル）-2,3-ジヒドロ-1H-インデン-5-イル]カルバマート(1.65 g)の酢酸エチル(10 mL)溶液に、4M塩化水素 酢酸エチル溶液(10 mL)を加えて、室温で14時間撹拌した。反応混合物を減圧下濃縮して生じた固体を濾取し、酢酸エチルで洗浄後、減圧下加熱乾燥することにより、(5-アミノ-2,3-ジヒドロ-1H-インデン-1-イル）アセトニトリル 塩酸塩(1.17 g)を白色固体として得た。 Production Example 33
To a solution of tert-butyl [1- (cyanomethyl) -2,3-dihydro-1H-inden-5-yl] carbamate (1.65 g) in ethyl acetate (10 mL), add 4M hydrogen chloride in ethyl acetate (10 mL). In addition, the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the resulting solid was collected by filtration, washed with ethyl acetate, and then heated and dried under reduced pressure to give (5-amino-2,3-dihydro-1H-inden-1-yl) acetonitrile. The hydrochloride salt (1.17 g) was obtained as a white solid.
製造例３４
　4-ブロモ-3,5-ジメチルフェノール(50.00 g)、3,4-ジヒドロ-2H-ピラン(47.00 mL)、ピリジン 4-メチルベンゼンスルホン酸塩(12.00 g)及びジクロロメタン(500 mL)の混合物を室温で17.5時間撹拌した。減圧下溶媒を留去し、残渣に水を加えて酢酸エチルで抽出した。有機層を水及び飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)により精製し、2-(4-ブロモ-3,5-ジメチルフェノキシ)テトラヒドロ-2H-ピラン(67.57 g)を無色油状物として得た。 Production Example 34
A mixture of 4-bromo-3,5-dimethylphenol (50.00 g), 3,4-dihydro-2H-pyran (47.00 mL), pyridine 4-methylbenzenesulfonate (12.00 g) and dichloromethane (500 mL). Stir at room temperature for 17.5 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2- (4-bromo-3,5-dimethylphenoxy) tetrahydro-2H-pyran (67.57 g) as a colorless oil.
製造例３５
　窒素気流下、2-(4-ブロモ-3,5-ジメチルフェノキシ)テトラヒドロ-2H-ピラン(67.57 g)のTHF (850 mL)溶液をドライアイス-アセトン浴で冷却した。1.66M n-ブチルリチウム ヘキサン溶液(160 mL)を滴下にて加え、ドライアイス-アセトン浴冷却下で1.5時間撹拌した。反応混合物に2-イソプロポキシ-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン(55 mL)のTHF (150 mL)溶液を滴下にて加えた。ドライアイス-アセトン浴をはずし、室温まで昇温させながら2時間撹拌した。減圧下溶媒を留去し、残渣に水(400 mL)を加えて酢酸エチル(500 mL)で抽出した。有機層を飽和塩化ナトリウム水溶液(300 mL)で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。残渣にメタノール(75 mL)を加え、氷-メタノール浴にて冷却下0.5時間撹拌した。固体を濾取し、減圧下乾燥することにより、2-[3,5-ジメチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノキシ]テトラヒドロ-2H-ピラン(58.53 g)を白色固体として得た。濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)により精製し、2-[3,5-ジメチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノキシ]テトラヒドロ-2H-ピラン(9.16 g)を白色固体として得た。 Production Example 35
Under a nitrogen stream, a solution of 2- (4-bromo-3,5-dimethylphenoxy) tetrahydro-2H-pyran (67.57 g) in THF (850 mL) was cooled in a dry ice-acetone bath. A 1.66M n-butyllithium hexane solution (160 mL) was added dropwise, and the mixture was stirred for 1.5 hours under cooling with a dry ice-acetone bath. To the reaction mixture, a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (55 mL) in THF (150 mL) was added dropwise. The dry ice-acetone bath was removed, and the mixture was stirred for 2 hours while warming to room temperature. The solvent was evaporated under reduced pressure, water (400 mL) was added to the residue, and the mixture was extracted with ethyl acetate (500 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (300 mL) and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. Methanol (75 mL) was added to the residue, and the mixture was stirred for 0.5 hour under cooling in an ice-methanol bath. The solid was collected by filtration and dried under reduced pressure to give 2- [3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] Tetrahydro-2H-pyran (58.53 g) was obtained as a white solid. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2- [3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) phenoxy] tetrahydro-2H-pyran (9.16 g) was obtained as a white solid.
製造例３６
　窒素雰囲気下、3-ブロモ-2-メチル安息香酸メチル(53.00 g)、4,4,4',4',5,5,5',5'-オクタメチル-2,2'-ビ-1,3,2-ジオキサボロラン(88.10 g)、塩化ビストリフェニルホスフィンパラジウム(8.12 g)、トリフェニルホスフィン(6.07 g)、酢酸カリウム(68.10 g)、ジオキサン(530 mL)の混合物を100 ℃で29時間撹拌後、室温まで放冷した。反応混合物をセライト濾過し、酢酸エチルで洗浄した。得られた濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)にて精製し、2-メチル-3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)安息香酸メチル(54.00 g)を無色油状物として得た。 Production Example 36
Under nitrogen atmosphere, methyl 3-bromo-2-methylbenzoate (53.00 g), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi-1, A mixture of 3,2-dioxaborolane (88.10 g), bistriphenylphosphine palladium chloride (8.12 g), triphenylphosphine (6.07 g), potassium acetate (68.10 g), dioxane (530 mL) was stirred at 100 ° C for 29 hours. And allowed to cool to room temperature. The reaction mixture was filtered through celite and washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-methyl-3- (4,4,5,5-tetramethyl-1,3,2 Methyl -dioxaborolan-2-yl) benzoate (54.00 g) was obtained as a colorless oil.
製造例３７
　[2,2',6'-トリメチル-4'-(テトラヒドロ-2H-ピラン-2-イルオキシ)ビフェニル-3-イル]メタノール(35.35 g)のクロロホルム(300 mL)溶液に二酸化マンガン(70.00 g)を加え、反応混合物を60 ℃で19時間撹拌した。反応混合物を室温まで放冷し、セライト濾過にて不溶物を除去後、クロロホルムで洗浄した。濾液に無水硫酸マグネシウムと活性炭(3.00 g)を加えた。濾過にて乾燥剤と活性炭を除去し、減圧下溶媒を留去することにより、2,2',6'-トリメチル-4'-(テトラヒドロ-2H-ピラン-2-イルオキシ)ビフェニル-3-カルバルデヒド(37.82g)を褐色飴状物として得た。 Production Example 37
Manganese dioxide (70.00 g) in chloroform (300 mL) solution of [2,2 ', 6'-trimethyl-4'-(tetrahydro-2H-pyran-2-yloxy) biphenyl-3-yl] methanol (35.35 g) And the reaction mixture was stirred at 60 ° C. for 19 hours. The reaction mixture was allowed to cool to room temperature, insoluble material was removed by Celite filtration, and the mixture was washed with chloroform. Anhydrous magnesium sulfate and activated carbon (3.00 g) were added to the filtrate. The desiccant and activated carbon were removed by filtration, and the solvent was distilled off under reduced pressure to obtain 2,2 ', 6'-trimethyl-4'-(tetrahydro-2H-pyran-2-yloxy) biphenyl-3-carba Rudehydr (37.82 g) was obtained as a brown rod.
　製造例37の方法と同様にして後記表に示す製造例37-1から37-6の化合物を製造した。 In the same manner as in Production Example 37, the compounds of Production Examples 37-1 to 37-6 shown in the table below were produced.
製造例３８
　2,2',6'-トリメチル-4'-(テトラヒドロ-2H-ピラン-2-イルオキシ)ビフェニル-3-カルバルデヒド(35.13 g)のTHF (350 mL)溶液に1M塩酸(350 mL)を加え、室温で3.5時間撹拌した。減圧下溶媒を留去し、残渣に水を加えて酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムと活性炭(3.00 g)を加えた。セライト濾過にて乾燥剤と活性炭を除去し、減圧下溶媒を留去した。残渣にn-ヘプタン(100 mL)を加え、氷冷下0.5時間撹拌した。固体を濾取し、n-ヘプタン(20 mL)で洗浄後、減圧下加熱乾燥することにより4'-ヒドロキシ-2,2',6'-トリメチルビフェニル-3-カルバルデヒド(22.46 g)を淡黄色固体として得た。 Production Example 38
Add 1M hydrochloric acid (350 mL) to a solution of 2,2 ', 6'-trimethyl-4'-(tetrahydro-2H-pyran-2-yloxy) biphenyl-3-carbaldehyde (35.13 g) in THF (350 mL). And stirred at room temperature for 3.5 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and anhydrous magnesium sulfate and activated carbon (3.00 g) were added. The desiccant and activated carbon were removed by Celite filtration, and the solvent was distilled off under reduced pressure. N-Heptane (100 mL) was added to the residue, and the mixture was stirred for 0.5 hour under ice cooling. The solid was collected by filtration, washed with n-heptane (20 mL), and heated and dried under reduced pressure to give 4'-hydroxy-2,2 ', 6'-trimethylbiphenyl-3-carbaldehyde (22.46 g) lightly. Obtained as a yellow solid.
製造例３９
　4'-(3-ヒドロキシ-3-メチルブトキシ)-2,2',6'-トリメチルビフェニル-3-カルバルデヒド(763 mg)のジクロロメタン(10 mL)溶液に氷冷下、トリエチルアミン(0.80 mL)、無水酢酸(0.50 mL)及びN,N-ジメチルピリジン-4-アミン(40 mg)を加えて氷浴をはずし、室温まで昇温させながら8時間撹拌した。反応混合物にトリエチルアミン(0.80 mL)、無水酢酸(0.50 mL)及びN,N-ジメチルピリジン-4-アミン(40 mg)を加え、55 ℃で17時間撹拌した。反応混合物を室温まで放冷し、飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出した。有機層を1M塩酸及び飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)により精製し、酢酸 3-[(3'-ホルミル-2,2',6-トリメチルビフェニル-4-イル)オキシ]-1,1-ジメチルプロピル(676 mg)を無色飴状物として得た。 Production Example 39
4 '-(3-hydroxy-3-methylbutoxy) -2,2', 6'-trimethylbiphenyl-3-carbaldehyde (763 mg) in dichloromethane (10 mL) under ice-cooling, triethylamine (0.80 mL) , Acetic anhydride (0.50 mL) and N, N-dimethylpyridin-4-amine (40 mg) were added, the ice bath was removed, and the mixture was stirred for 8 hours while warming to room temperature. Triethylamine (0.80 mL), acetic anhydride (0.50 mL) and N, N-dimethylpyridin-4-amine (40 mg) were added to the reaction mixture, and the mixture was stirred at 55 ° C. for 17 hours. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and acetic acid 3-[(3'-formyl-2,2 ', 6-trimethylbiphenyl-4-yl) oxy] -1,1- Dimethylpropyl (676 mg) was obtained as a colorless bowl.
製造例４０
　(5-アミノ-2,3-ジヒドロ-1H-インデン-1-イル)アセトニトリル 塩酸塩(209 mg)を飽和炭酸水素ナトリウム水溶液に溶解し、クロロホルムで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、乾燥剤を除き、減圧下溶媒を留去した。得られた油状物のTHF (5 mL)及びジクロロメタン(5 mL)溶液に、4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-カルバルデヒド(356 mg)及び酢酸(0.3 mL)を加えて室温で1時間撹拌した。反応混合物にトリアセトキシ水素化ホウ素ナトリウム(425 mg)を加えて室温で14時間撹拌した。反応混合物に酢酸(0.2 mL)、モレキュラーシーブス4A (2 g)を加えて室温で1時間撹拌した後、トリアセトキシ水素化ホウ素ナトリウム(300 mg)を加えて室温で8時間撹拌した。反応混合物中の不溶物を濾過にて除き、濾液を減圧下濃縮した。残渣をTHF (4 mL)に溶解し、酢酸(0.3 mL)を加えた後、室温で15時間撹拌した。反応混合物にトリアセトキシ水素化ホウ素ナトリウム(330 mg)を加えて、室温で8時間撹拌した。反応混合物に水を加えた後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン-酢酸エチル）で精製することにより、(5-{[(4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-イル)メチル]アミノ}-2,3-ジヒドロ-1H-インデン-1-イル)アセトニトリル(495 mg)を白色アモルファス固体として得た。 Production Example 40
(5-Amino-2,3-dihydro-1H-inden-1-yl) acetonitrile hydrochloride (209 mg) was dissolved in a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, the desiccant was removed, and the solvent was distilled off under reduced pressure. To a solution of the obtained oil in THF (5 mL) and dichloromethane (5 mL), 4 ′-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2, 2 ′, 6′-Trimethylbiphenyl-3-carbaldehyde (356 mg) and acetic acid (0.3 mL) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added sodium triacetoxyborohydride (425 mg), and the mixture was stirred at room temperature for 14 hours. Acetic acid (0.2 mL) and molecular sieves 4A (2 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Sodium triacetoxyborohydride (300 mg) was added, and the mixture was stirred at room temperature for 8 hr. Insoluble matters in the reaction mixture were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (4 mL), acetic acid (0.3 mL) was added, and the mixture was stirred at room temperature for 15 hr. Sodium triacetoxyborohydride (330 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (5-{[(4 '-{[(4S) -2,2-dimethyl-1,3-dioxolane-4- Yl] methoxy} -2,2 ', 6'-trimethylbiphenyl-3-yl) methyl] amino} -2,3-dihydro-1H-inden-1-yl) acetonitrile (495 mg) as a white amorphous solid It was.
製造例４１
　(5-アミノ-2,3-ジヒドロ-1H-インデン-1-イル)アセトニトリル 塩酸塩(205 mg)、安息香酸 2-[(3'-ホルミル-2,2',6-トリメチルビフェニル-4-イル)オキシ]エチル(382 mg)、酢酸ナトリウム(121 mg)及びTHF (4 mL)の混合物に酢酸(0.28 mL)を加え、室温で15時間撹拌した。反応混合物にトリアセトキシ水素化ホウ素ナトリウム(416 mg)を加え、室温で6時間撹拌した。反応混合物に水を加えた後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、安息香酸 2-{[3'-({[1-(シアノメチル)-2,3-ジヒドロ-1H-インデン-5-イル]アミノ}メチル)-2,2',6-トリメチルビフェニル-4-イル]オキシ}エチル(469 mg)を白色アモルファス固体として得た。 Production Example 41
(5-Amino-2,3-dihydro-1H-inden-1-yl) acetonitrile hydrochloride (205 mg), 2-[(3'-formyl-2,2 ', 6-trimethylbiphenyl-4-benzoic acid Acetic acid (0.28 mL) was added to a mixture of (yl) oxy] ethyl (382 mg), sodium acetate (121 mg) and THF (4 mL), and the mixture was stirred at room temperature for 15 hours. Sodium triacetoxyborohydride (416 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give benzoic acid 2-{[3 '-({[1- (cyanomethyl) -2,3-dihydro-1H-indene-5 -Il] amino} methyl) -2,2 ', 6-trimethylbiphenyl-4-yl] oxy} ethyl (469 mg) was obtained as a white amorphous solid.
製造例４２
　5-ブロモ-4,6-ジメチルピリミジン-2-オール(1.00 g)、(2-ブロモエトキシ)(tert-ブチル)ジメチルシラン(1.59 mL)、炭酸カリウム(1.36 g)及びDMF (10 mL)の混合物を100 ℃で3時間撹拌した。反応混合物に室温にて、(2-ブロモエトキシ)(tert-ブチル)ジメチルシラン(0.50 mL)を加え、100 ℃で1時間撹拌した。反応混合物を室温まで放冷した後、水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、5-ブロモ-2-(2-{[tert-ブチル(ジメチル)シリル]オキシ}エトキシ)-4,6-ジメチルピリミジン(1.01 g)を無色油状物として得た。 Production Example 42
5-bromo-4,6-dimethylpyrimidin-2-ol (1.00 g), (2-bromoethoxy) (tert-butyl) dimethylsilane (1.59 mL), potassium carbonate (1.36 g) and DMF (10 mL). The mixture was stirred at 100 ° C. for 3 hours. (2-Bromoethoxy) (tert-butyl) dimethylsilane (0.50 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at 100 ° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 5-bromo-2- (2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) -4,6-dimethyl. Pyrimidine (1.01 g) was obtained as a colorless oil.
　製造例42の方法と同様にして後記表に示す製造例42-1から42-4の化合物を製造した。 The compounds of Production Examples 42-1 to 42-4 shown in the table below were produced in the same manner as in Production Example 42.
製造例４３
　5-ブロモ-2-[(2,2-ジメチル-1,3-ジオキサン-5-イル)メトキシ]-4,6-ジメチルピリミジン(3.62 g)のTHF (30 mL)溶液に1M塩酸(30 mL)を加え、室温で2.5時間撹拌した。反応混合物に1M水酸化ナトリウム水溶液(30 mL)を加えた後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去することにより、2-{[(5-ブロモ-4,6-ジメチルピリミジン-2-イル)オキシ]メチル}プロパン-1,3-ジオール(3.08 g)を白色固体として得た。 Production Example 43
To a solution of 5-bromo-2-[(2,2-dimethyl-1,3-dioxane-5-yl) methoxy] -4,6-dimethylpyrimidine (3.62 g) in THF (30 mL) was added 1M hydrochloric acid (30 mL). ) And stirred at room temperature for 2.5 hours. To the reaction mixture was added 1M aqueous sodium hydroxide solution (30 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure to give 2-{[(5-bromo-4,6-dimethylpyrimidin-2-yl) oxy] methyl} propane-1,3-diol. (3.08 g) was obtained as a white solid.
製造例４４
　2-{[(5-ブロモ-4,6-ジメチルピリミジン-2-イル)オキシ]メチル}プロパン-1,3-ジオール(3.08g)、tert-ブチル(クロロ)ジメチルシラン(4.80 g)、イミダゾール(2.90 g)及びDMF (25 mL)の混合物を室温で2日間撹拌した。反応混合物に水(100 mL)を加え、トルエン-酢酸エチル溶液で抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、5-ブロモ-2-[3-{[tert-ブチル(ジメチル)シリル]オキシ}-2-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)プロポキシ]-4,6-ジメチルピリミジン(5.40 g)を無色油状物として得た。 Production Example 44
2-{[(5-Bromo-4,6-dimethylpyrimidin-2-yl) oxy] methyl} propane-1,3-diol (3.08 g), tert-butyl (chloro) dimethylsilane (4.80 g), imidazole A mixture of (2.90 g) and DMF (25 mL) was stirred at room temperature for 2 days. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with a toluene-ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 5-bromo-2- [3-{[tert-butyl (dimethyl) silyl] oxy} -2-({[tert- Butyl (dimethyl) silyl] oxy} methyl) propoxy] -4,6-dimethylpyrimidine (5.40 g) was obtained as a colorless oil.
　製造例44の方法と同様にして後記表に示す製造例44-1から44-2の化合物を製造した。 In the same manner as in Production Example 44, the compounds of Production Examples 44-1 to 44-2 shown in the table below were produced.
製造例４５
　窒素気流下、2-フルオロ-4-ニトロ安息香酸(5.00 g)のTHF (50 mL)溶液に、氷冷下、1.0Mボラン-THF錯体 THF溶液(54 mL)を滴下した後、室温で14時間撹拌した。反応混合物にメタノール(10 mL)を滴下して反応を停止した後、溶媒を減圧下留去した。残渣に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、(2-フルオロ-4-ニトロフェニル)メタノール(4.55 g)を淡黄色固体として得た。 Production Example 45
Under a nitrogen stream, a 1.0 M borane-THF complex THF solution (54 mL) was added dropwise to a THF (50 mL) solution of 2-fluoro-4-nitrobenzoic acid (5.00 g) under ice-cooling. Stir for hours. Methanol (10 mL) was added dropwise to the reaction mixture to stop the reaction, and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to give (2-fluoro-4-nitrophenyl) methanol (4.55 g) as a pale yellow solid.
製造例４６
　3-(4-ニトロフェニル)プロパンニトリル(7.15 g)、エタノール(35 mL)、酢酸エチル(35 mL)及び10 %パラジウム-活性炭(50 %含水品、1.40 g)の混合物を、1～1.5 kg/cm2の水素雰囲気下室温で6時間撹拌した。触媒をセライト濾過にて除去し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、3-(4-アミノフェニル)プロパンニトリル(5.76 g)を微褐色油状物として得た。 Production Example 46
1-1.5 kg of a mixture of 3- (4-nitrophenyl) propanenitrile (7.15 g), ethanol (35 mL), ethyl acetate (35 mL) and 10% palladium-activated carbon (50% water containing product, 1.40 g) The mixture was stirred at room temperature under a hydrogen atmosphere of / cm 2 for 6 hours. The catalyst was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- (4-aminophenyl) propanenitrile (5.76 g) as a pale brown oil.
製造例４７
　1-(シアノメチレン)インダン-5-カルボン酸メチル(1.70 g)をメタノール(30 mL)及びジオキサン(15 mL)に溶解し、10 %パラジウム-活性炭(50 %含水品、340 mg)を加え、3 kg/cm2の水素雰囲気下室温で1.5時間撹拌した。触媒をセライト濾過にて除去し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、1-(シアノメチル)インダン-5-カルボン酸メチル(1.64 g)を白色固体として得た。 Production Example 47
Dissolve methyl 1- (cyanomethylene) indan-5-carboxylate (1.70 g) in methanol (30 mL) and dioxane (15 mL), add 10% palladium-activated carbon (50% water-containing product, 340 mg), The mixture was stirred at room temperature under a hydrogen atmosphere of 3 kg / cm 2 for 1.5 hours. The catalyst was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give methyl 1- (cyanomethyl) indan-5-carboxylate (1.64 g) as a white solid.
製造例４８
　3-(2-フルオロ-4-ニトロフェニル)アクリロニトリル(2.88 g)のメタノール(15 mL)及びジオキサン(15 mL)溶液に、10 %パラジウム-活性炭(50 %含水品、300 mg)を加え、3 kg/cm2の水素雰囲気下、室温で7時間撹拌した。触媒をセライト濾過にて除去し、濾液を減圧下濃縮した。残渣をメタノール(30 mL)に溶解し、10 %パラジウム-活性炭(50 %含水品、300 mg)を加え、3 kg/cm2の水素雰囲気下、室温で6時間撹拌した。触媒をセライト濾過にて除去し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、3-(4-アミノ-2-フルオロフェニル)プロパンニトリル(1.85 g)を黄色油状物として得た。 Production Example 48
To a solution of 3- (2-fluoro-4-nitrophenyl) acrylonitrile (2.88 g) in methanol (15 mL) and dioxane (15 mL), 10% palladium-activated carbon (50% water-containing product, 300 mg) was added. The mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere of kg / cm 2 . The catalyst was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (30 mL), 10% palladium-activated carbon (50% water-containing product, 300 mg) was added, and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere of 3 kg / cm 2 . The catalyst was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- (4-amino-2-fluorophenyl) propanenitrile (1.85 g) as a yellow oil.
製造例４９
　テトラヒドロ-2H-ピラン-4-オール(1.00 g)のピリジン(10 mL)溶液に、氷冷下、4-メチルベンゼンスルホニルクロリドを加え、反応混合物を室温で3日間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を1M塩酸、飽和炭酸水素ナトリウム水溶液及び飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去することにより、4-メチルベンゼンスルホン酸 テトラヒドロ-2H-ピラン-4-イル(2.72 g)を薄橙色油状物として得た。 Production Example 49
4-methylbenzenesulfonyl chloride was added to a solution of tetrahydro-2H-pyran-4-ol (1.00 g) in pyridine (10 mL) under ice cooling, and the reaction mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was evaporated under reduced pressure to obtain 4-methylbenzenesulfonic acid tetrahydro-2H-pyran-4-yl (2.72 g) as a pale orange oil.
　製造例49の方法と同様にして後記表に示す製造例49-1の化合物を製造した。 In the same manner as in Production Example 49, the compound of Production Example 49-1 shown in the table below was produced.
製造例５０
　4'-(2-{[tert-ブチル(ジメチル)シリル]オキシ}エトキシ)-2,2',6'-トリメチルビフェニル-3-カルバルデヒド(1.50 g)のメタノール(15 mL)溶液に氷冷下、水素化ホウ素ナトリウム(150 mg)を加え、室温で0.5時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去することにより、[4'-(2-{[tert-ブチル(ジメチル)シリル]オキシ}エトキシ)-2,2',6'-トリメチルビフェニル-3-イル]メタノール(1.49 g)を無色飴状物として得た。 Production Example 50
4 '-(2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) -2,2', 6'-trimethylbiphenyl-3-carbaldehyde (1.50 g) in methanol (15 mL) in ice-cooled solution Under the addition of sodium borohydride (150 mg), the mixture was stirred at room temperature for 0.5 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure to obtain [4 '-(2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) -2,2', 6'-trimethyl. Biphenyl-3-yl] methanol (1.49 g) was obtained as a colorless bowl.
　製造例50の方法と同様にして後記表に示す製造例50-1から50-4の化合物を製造した。 In the same manner as in Production Example 50, the compounds of Production Examples 50-1 to 50-4 shown in the table below were produced.
製造例５１
　6-[(4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-イル)メトキシ]ニコチノニトリル(1.06 g)及びジクロロメタンの混合物にドライアイス-メタノール浴にて冷却下、1.0M水素化ジイソブチルアルミニウム トルエン溶液(3.00 mL)を加え、同温で1.5時間撹拌した。反応混合物にドライアイス-メタノール浴にて冷却下、1.0M水素化ジイソブチルアルミニウム トルエン溶液(0.76 mL)を加え、同温で3時間撹拌した。反応混合物にドライアイス-メタノール浴にて冷却下、1.0M水素化ジイソブチルアルミニウム トルエン溶液(0.30 mL)を加え、同温で1時間撹拌した。反応混合物に同温で飽和(+)-酒石酸ナトリウムカリウム水溶液(20 mL)及び酢酸エチル(20 mL)を加え、室温で2時間撹拌した。混合物を分液し、水層を酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去して、得られた残渣、トリエチルアミン(1.30 mL)及びDMSO (10 mL)の混合物に、氷冷下、三酸化硫黄-ピリジン錯体(734 mg)のDMSO (10 mL)溶液を滴下し、室温で3時間撹拌した。反応混合物に水(100 mL)を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製することにより、6-[(4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-イル)メトキシ]ニコチンアルデヒド(564 mg)を淡黄色飴状物として得た。 Production Example 51
6-[(4 ′-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2 ′, 6′-trimethylbiphenyl-3-yl) methoxy] nicochi To a mixture of nononitrile (1.06 g) and dichloromethane, 1.0M diisobutylaluminum hydride toluene solution (3.00 mL) was added while cooling in a dry ice-methanol bath, and the mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture, 1.0 M diisobutylaluminum hydride toluene solution (0.76 mL) was added while cooling in a dry ice-methanol bath, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture was added 1.0 M diisobutylaluminum hydride toluene solution (0.30 mL) while cooling in a dry ice-methanol bath, and the mixture was stirred at the same temperature for 1 hour. Saturated (+)-potassium sodium tartrate aqueous solution (20 mL) and ethyl acetate (20 mL) were added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 2 hr. The mixture was separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was evaporated under reduced pressure, and a mixture of the obtained residue, triethylamine (1.30 mL) and DMSO (10 mL) was added to a mixture of sulfur trioxide-pyridine complex (734 mg) in DMSO (10 mL) was added dropwise and stirred at room temperature for 3 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 6-[(4 '-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] Methoxy} -2,2 ′, 6′-trimethylbiphenyl-3-yl) methoxy] nicotinaldehyde (564 mg) was obtained as a pale yellow rod.
　製造例51の方法と同様にして後記表に示す製造例51-1から51-3の化合物を製造した。 In the same manner as in Production Example 51, the compounds of Production Examples 51-1 to 51-3 shown in the table below were produced.
製造例５２
　(5-{[4'-(メトキシメトキシ)-2,2',6'-トリメチルビフェニル-3-イル]メトキシ}-2,3-ジヒドロ-1H-インデン-1-イリデン)アセトニトリル(2.68 g)及びメタノール(55 mL)の混合物にマグネシウム(切削片状、1.50 g)を加えた。反応混合物に、マグネシウム(切削片状、0.10 g)、ヨウ素(1欠片)及びメタノール(5 mL)の混合物を3滴加え、室温で6時間撹拌した。反応混合物に、マグネシウム(切削片状、0.10 g)、ヨウ素(1欠片)及びメタノール(5 mL)の混合物を室温で0.5時間撹拌したものを3滴加え、室温で1時間撹拌した。反応混合物に酢酸エチル及び1M塩酸を加え、室温で0.5時間撹拌後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をTHF (15 mL)及びメタノール(15 mL)に溶解し、1M塩酸(30 mL)を加えて60 ℃で14時間撹拌した。反応混合物を室温まで放冷し、水を加えて酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)により精製し、{5-[(4'-ヒドロキシ-2,2',6'-トリメチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1H-インデン-1-イル}アセトニトリル(2.32 g)を白色アモルファス固体として得た。 Production Example 52
(5-{[4 '-(Methoxymethoxy) -2,2', 6'-trimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1H-inden-1-ylidene) acetonitrile (2.68 g) And magnesium (cut pieces, 1.50 g) was added to a mixture of methanol (55 mL). Three drops of a mixture of magnesium (cut pieces, 0.10 g), iodine (1 piece) and methanol (5 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. Three drops of a mixture of magnesium (cut pieces, 0.10 g), iodine (1 piece) and methanol (5 mL) stirred at room temperature for 0.5 hour were added to the reaction mixture, and stirred at room temperature for 1 hour. Ethyl acetate and 1M hydrochloric acid were added to the reaction mixture, and the mixture was stirred at room temperature for 0.5 hour and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in THF (15 mL) and methanol (15 mL), 1M hydrochloric acid (30 mL) was added, and the mixture was stirred at 60 ° C. for 14 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain {5-[(4'-hydroxy-2,2 ', 6'-trimethylbiphenyl-3-yl) methoxy] -2,3 -Dihydro-1H-inden-1-yl} acetonitrile (2.32 g) was obtained as a white amorphous solid.
製造例５３
　後述する実施例１の方法と同様にして製造例53及び製造例53-1～53-2の化合物を製造した。 Production Example 53
In the same manner as in Example 1 described later, the compounds of Production Example 53 and Production Examples 53-1 to 53-2 were produced.
　製造例化合物の構造を表３～表２０に、物理化学的データを表２１～表２３にそれぞれ示す。 Tables 3 to 20 show the structures of the production example compounds, and Tables 21 to 23 show the physicochemical data.
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000047
実施例１
　3-{4-[(4'-クロロ-2'-メチルビフェニル-3-イル)メトキシ]フェニル}プロパンニトリル(300 mg)、アジ化ナトリウム(539 mg)、トリエチルアミン 塩酸塩(1.14 g)及びNMP (5 mL)の混合物を100 ℃で6時間撹拌した。その後、さらに反応混合物を150 ℃で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水及び飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去した。残渣をトルエン-酢酸エチル溶液で希釈し、水で2回洗浄した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(クロロホルム-メタノール)で精製し、得られた残渣に酢酸エチル-ジエチルエーテルを加え、撹拌した。固体を濾取後、減圧下乾燥して、5-(2-{4-[(4’-クロロ-2’-メチルビフェニル-3-イル)メトキシ]フェニル}エチル)-1H-テトラゾール(86 mg)を淡黄色粉末固体として得た。 Example 1
3- {4-[(4'-Chloro-2'-methylbiphenyl-3-yl) methoxy] phenyl} propanenitrile (300 mg), sodium azide (539 mg), triethylamine hydrochloride (1.14 g) and NMP (5 mL) was stirred at 100 ° C. for 6 hours. Thereafter, the reaction mixture was further stirred at 150 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure. The residue was diluted with a toluene-ethyl acetate solution and washed twice with water. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol), and ethyl acetate-diethyl ether was added to the obtained residue and stirred. The solid was collected by filtration and dried under reduced pressure to give 5- (2- {4-[(4'-chloro-2'-methylbiphenyl-3-yl) methoxy] phenyl} ethyl) -1H-tetrazole (86 mg). ) Was obtained as a pale yellow powdered solid.
実施例1の方法と同様にして後記表に示す実施例1-1から1-5の化合物を製造した。 In the same manner as in Example 1, the compounds of Examples 1-1 to 1-5 shown in the table below were produced.
実施例２
　安息香酸 2-[(3'-{[4-(2-シアノエチル)フェノキシ]メチル}-2-メチルビフェニル-4-イル)オキシ]エチル(990 mg)、アジ化ナトリウム(523 mg)、トリエチルアミン 塩酸塩(1.11 g)及びNMP (13 mL)の混合物を110 ℃で33時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した後、有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)により精製し、褐色油状物を得た。得られた褐色油状物に1M水酸化ナトリウム水溶液(4 mL)、メタノール(4 mL)及びTHF (4 mL)を加え、50 ℃で2時間撹拌した。減圧下溶媒を留去し、残渣に1M塩酸(5 mL)を加えて酸性とし、クロロホルムで抽出した。有機層を水で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(クロロホルム-メタノール)で精製し、淡黄色泡状物(342 mg)を得た。得られた淡黄色泡状物に1M水酸化カリウム水溶液(0.79 mL)、メタノール(4 mL)及びTHF (4 mL)を加えて室温で5分間撹拌した。減圧下溶媒を留去し、残渣をODSカラムクロマトグラフィー(水-アセトニトリル)により精製して得られた無色泡状物(216 mL)に、塩化カルシウム(25 mg)と水(5 mL)の混合物を加えて撹拌した。析出した固体を濾取し、水で洗浄後、減圧下加熱乾燥し、0.5カルシウム 5-[2-(4-{[4'-(2-ヒドロキシエトキシ)-2'-メチルビフェニル-3-イル]メトキシ}フェニル)エチル]テトラゾール-1-イド(217 mg)を白色固体として得た。 Example 2
Benzoic acid 2-[(3 '-{[4- (2-cyanoethyl) phenoxy] methyl} -2-methylbiphenyl-4-yl) oxy] ethyl (990 mg), sodium azide (523 mg), triethylamine hydrochloride A mixture of salt (1.11 g) and NMP (13 mL) was stirred at 110 ° C. for 33 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain a brown oil. To the obtained brown oil were added 1M aqueous sodium hydroxide solution (4 mL), methanol (4 mL) and THF (4 mL), and the mixture was stirred at 50 ° C. for 2 hr. The solvent was evaporated under reduced pressure, and the residue was acidified with 1M hydrochloric acid (5 mL), and extracted with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain a pale yellow foam (342 mg). To the obtained pale yellow foam, 1M aqueous potassium hydroxide solution (0.79 mL), methanol (4 mL) and THF (4 mL) were added and stirred at room temperature for 5 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by ODS column chromatography (water-acetonitrile) to a colorless foam (216 mL), and a mixture of calcium chloride (25 mg) and water (5 mL). Was added and stirred. The precipitated solid was collected by filtration, washed with water, dried by heating under reduced pressure, and 0.5 calcium 5- [2- (4-{[4 '-(2-hydroxyethoxy) -2'-methylbiphenyl-3-yl]. [Methoxy} phenyl) ethyl] tetrazol-1-id (217 mg) was obtained as a white solid.
実施例３
　N-[(4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-イル)メチル]-4-[2-(1H-テトラゾール-5-イル)エチル]アニリン(762 mg)、1M塩酸(4 mL)、エタノール(4 mL)及びTHF (4 mL)の混合物を室温で7時間撹拌した。反応混合物に1M水酸化ナトリウム水溶液(4.5 mL)及び10 ％クエン酸水溶液(20 mL)を順に加えクロロホルムで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム-メタノール)で精製した。得られた褐色油状物(648 mg)にTHF及び4M塩化水素 ジオキサン溶液(1 mL)を加え減圧下溶媒を留去した後、残渣にジエチルエーテルを加え析出した固体を濾取し減圧下乾燥することにより、(2R)-3-({2,2',6-トリメチル-3'-[({4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]ビフェニル-4-イル}オキシ)プロパン-1,2-ジオール 塩酸塩(533 mg)を褐色固体として得た。 Example 3
N-[(4 '-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2', 6'-trimethylbiphenyl-3-yl) methyl]- A mixture of 4- [2- (1H-tetrazol-5-yl) ethyl] aniline (762 mg), 1M hydrochloric acid (4 mL), ethanol (4 mL) and THF (4 mL) was stirred at room temperature for 7 hours. To the reaction mixture were added 1M aqueous sodium hydroxide solution (4.5 mL) and 10% aqueous citric acid solution (20 mL) in this order, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol). To the obtained brown oil (648 mg), THF and 4M hydrogen chloride dioxane solution (1 mL) were added, the solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the precipitated solid was collected by filtration and dried under reduced pressure. (2R) -3-({2,2 ', 6-trimethyl-3'-[({4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] biphenyl- 4-yl} oxy) propane-1,2-diol hydrochloride (533 mg) was obtained as a brown solid.
実施例４
　{5'-[(2,2',6'-トリメチルビフェニル-3-イル)メトキシ]-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-1'-イル}アセトニトリル(340 mg)、アジ化ナトリウム(270 mg)、トリエチルアミン 塩酸塩(570 mg)及びトルエン(10 mL)の混合物を110℃で2時間撹拌した後、NMP (5 mL)を加え更に140 ℃で18時間撹拌した。反応混合物に水(20 mL)を加えトルエンで抽出した後、有機層を飽和塩化ナトリウム水溶液で洗浄し無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製した後、得られた褐色油状物(30 mg)にアセトニトリル、1M水酸化ナトリウム水溶液(0.07 mL)及び1M塩化カルシウム水溶液(0.035 mL)を順に加え減圧下溶媒を留去した。得られた残渣に水を加え析出した固体を濾取し水洗後、減圧下加熱乾燥することにより、0.5カルシウム 5-({5'-[(2,2',6'-トリメチルビフェニル-3-イル)メトキシ]-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-1'-イル}メチル)テトラゾール-1-イド(20 mg)を褐色固体として得た。 Example 4
{5 '-[(2,2', 6'-Trimethylbiphenyl-3-yl) methoxy] -1 ', 3'-dihydrospiro [cyclopropane-1,2'-indene] -1'-yl} acetonitrile (340 mg), sodium azide (270 mg), triethylamine hydrochloride (570 mg) and toluene (10 mL) were stirred at 110 ° C. for 2 hours, and then NMP (5 mL) was added and further stirred at 140 ° C. for 18 hours. Stir for hours. After adding water (20 mL) to the reaction mixture and extracting with toluene, the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and the resulting brown oil (30 mg) was added to acetonitrile, 1M aqueous sodium hydroxide solution (0.07 mL) and 1M aqueous calcium chloride solution (0.035 mL). ) Were added in order, and the solvent was distilled off under reduced pressure. Water was added to the resulting residue, and the precipitated solid was collected by filtration, washed with water, and dried by heating under reduced pressure to give 0.5 calcium 5-({5 '-[(2,2', 6'-trimethylbiphenyl-3- Yl) methoxy] -1 ′, 3′-dihydrospiro [cyclopropane-1,2′-indene] -1′-yl} methyl) tetrazol-1-ide (20 mg) was obtained as a brown solid.
実施例５
　5-({5-[(4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1H-インデン-1-イル}メチル)-1H-テトラゾール(506 mg)のメタノール(5 mL)及びTHF (3 mL)溶液に1M塩酸(3 mL)を加え、室温で0.5時間撹拌した後、室温で63.5時間静置した。反応混合物に水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をメタノール(6 mL)に溶解し、1M水酸化ナトリウム水溶液(2.4 mL)を加えて室温で0.5時間撹拌した後、減圧下溶媒を留去した。得られた残渣をODSカラムクロマトグラフィー(アセトニトリル-水)で精製し、白色アモルファス固体を得た。得られた白色アモルファス固体にジエチルエーテル(10 mL)を加え、室温で0.5時間撹拌した。固体を濾取し、ジエチルエーテルで洗浄後、減圧下加熱乾燥することにより、ナトリウム 5-({5-[(4'-{[(2R)-2,3-ジヒドロキシプロピル]オキシ}-2,2',6'-トリメチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1H-インデン-1-イル}メチル)テトラゾール-1-イド(367 mg)を白色固体として得た。 Example 5
5-({5-[(4 '-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2', 6'-trimethylbiphenyl-3-yl ) Methoxy] -2,3-dihydro-1H-inden-1-yl} methyl) -1H-tetrazole (506 mg) in methanol (5 mL) and THF (3 mL) was added with 1M hydrochloric acid (3 mL). The mixture was stirred at room temperature for 0.5 hour and then allowed to stand at room temperature for 63.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol (6 mL), 1M aqueous sodium hydroxide solution (2.4 mL) was added, and the mixture was stirred at room temperature for 0.5 hr, and the solvent was evaporated under reduced pressure. The obtained residue was purified by ODS column chromatography (acetonitrile-water) to obtain a white amorphous solid. Diethyl ether (10 mL) was added to the obtained white amorphous solid, and the mixture was stirred at room temperature for 0.5 hour. The solid was collected by filtration, washed with diethyl ether, and then heated and dried under reduced pressure to obtain sodium 5-({5-[(4 '-{[(2R) -2,3-dihydroxypropyl] oxy} -2, 2 ′, 6′-Trimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1H-inden-1-yl} methyl) tetrazol-1-ide (367 mg) was obtained as a white solid.
実施例5の方法と同様にして後記表に示す実施例5-1から5-4の化合物を製造した。 The compounds of Examples 5-1 to 5-4 shown in the table below were produced in the same manner as in Example 5.
実施例６
　安息香酸 2-{[2,2',6-トリメチル-3'-({[1-(1H-テトラゾール-5-イルメチル)-2,3-ジヒドロ-1H-インデン-5-イル]オキシ}メチル)ビフェニル-4-イル]オキシ}エチル(590 mg)のメタノール(6 mL)及びTHF (3 mL)溶液に1M水酸化ナトリウム水溶液(4 mL)を加え、室温で0.5時間撹拌した後、更に室温で63時間静置した。反応混合物に1M塩酸(20 mL)を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をメタノール(6 mL)に溶解し、1M水酸化ナトリウム水溶液(3 mL)を加えて室温で0.5時間撹拌した後、減圧下溶媒を留去した。得られた残渣をODSカラムクロマトグラフィー(アセトニトリル-水)で精製し、白色アモルファス固体を得た。得られた白色アモルファス固体にジエチルエーテル(10 mL)を加え、室温で0.5時間撹拌した。固体を濾取し、ジエチルエーテルで洗浄後、減圧下加熱乾燥することにより、ナトリウム 5-[(5-{[4'-(2-ヒドロキシエトキシ)-2,2',6'-トリメチルビフェニル-3-イル]メトキシ}-2,3-ジヒドロ-1H-インデン-1-イル)メチル]テトラゾール-1-イド(240 mg)を白色固体として得た。 Example 6
Benzoic acid 2-{[2,2 ', 6-trimethyl-3'-({[1- (1H-tetrazol-5-ylmethyl) -2,3-dihydro-1H-inden-5-yl] oxy} methyl ) Biphenyl-4-yl] oxy} ethyl (590 mg) in methanol (6 mL) and THF (3 mL) was added with 1M aqueous sodium hydroxide solution (4 mL), and the mixture was stirred at room temperature for 0.5 hr, and further stirred at Left for 63 hours. 1M Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol (6 mL), 1M aqueous sodium hydroxide solution (3 mL) was added, and the mixture was stirred at room temperature for 0.5 hr, and the solvent was evaporated under reduced pressure. The obtained residue was purified by ODS column chromatography (acetonitrile-water) to obtain a white amorphous solid. Diethyl ether (10 mL) was added to the obtained white amorphous solid, and the mixture was stirred at room temperature for 0.5 hour. The solid was collected by filtration, washed with diethyl ether, and dried by heating under reduced pressure to give sodium 5-[(5-{[4 '-(2-hydroxyethoxy) -2,2', 6'-trimethylbiphenyl- 3-yl] methoxy} -2,3-dihydro-1H-inden-1-yl) methyl] tetrazol-1-id (240 mg) was obtained as a white solid.
実施例6の方法と同様にして後記表に示す実施例6-1から6-2の化合物を製造した。 In the same manner as in Example 6, the compounds of Examples 6-1 to 6-2 shown in the table below were produced.
実施例７
　4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-カルバルデヒド(220 mg)、1'-(1H-テトラゾール-5-イルメチル)-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-5'-アミン(150 mg)、酢酸(0.18 mL)及びTHF (5 mL)の混合物を室温で2.5時間撹拌した。反応混合物に氷冷下、トリアセトキシ水素化ホウ素ナトリウム(220 mg)を加え、室温まで昇温させながら15.5時間撹拌した。反応混合物に水(10 mL)を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)により精製し、N-[(4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-イル)メチル]-1'-(1H-テトラゾール-5-イルメチル)-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-5'-アミン(331 mg)を白色アモルファス固体として得た。 Example 7
4 '-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2', 6'-trimethylbiphenyl-3-carbaldehyde (220 mg), 1 ' -(1H-tetrazol-5-ylmethyl) -1 ', 3'-dihydrospiro [cyclopropane-1,2'-indene] -5'-amine (150 mg), acetic acid (0.18 mL) and THF (5 mL ) Was stirred at room temperature for 2.5 hours. Under ice-cooling, sodium triacetoxyborohydride (220 mg) was added to the reaction mixture, and the mixture was stirred for 15.5 hours while warming to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and N-[(4 '-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2 ', 6'-trimethylbiphenyl-3-yl) methyl] -1'-(1H-tetrazol-5-ylmethyl) -1 ', 3'-dihydrospiro [cyclopropane-1,2'-indene ] -5'-amine (331 mg) was obtained as a white amorphous solid.
実施例7の方法と同様にして後記表に示す実施例7-1から7-8の化合物を製造した。 The compounds of Examples 7-1 to 7-8 shown in the table below were produced in the same manner as in Example 7.
実施例８
　(5-{[4'-(3-ヒドロキシ-3-メチルブトキシ)-2,2',6'-トリメチルビフェニル-3-イル]メトキシ}-2,3-ジヒドロ-1H-インデン-1-イル)アセトニトリル(572 mg)のNMP (10 mL)溶液にアジ化ナトリウム(500 mg)及びトリエチルアミン 塩酸塩(1.05 g)を加え、反応混合物を160 ℃で18時間撹拌した。反応混合物を室温まで放冷し、10 %クエン酸水溶液を加え、トルエン-酢酸エチル溶液で抽出した。水層をトルエン-酢酸エチル溶液及び酢酸エチルで抽出した。有機層を合わせ、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)により精製し、褐色油状物を得た。得られた油状物をメタノール(5 mL)に溶解し、1M水酸化ナトリウム水溶液(2 mL)を加えて室温で0.5時間撹拌した後、減圧下溶媒を留去した。得られた残渣をODSカラムクロマトグラフィー(アセトニトリル-水)で精製し、白色アモルファス固体を得た。得られた白色アモルファス固体にジイソプロピルエーテル(10 mL)を加え、室温で0.5時間撹拌した。固体を濾取し、ジイソプロピルエーテルで洗浄後、減圧下加熱乾燥することにより、ナトリウム 5-[(5-{[4'-(3-ヒドロキシ-3-メチルブトキシ)-2,2',6'-トリメチルビフェニル-3-イル]メトキシ}-2,3-ジヒドロ-1H-インデン-1-イル)メチル]テトラゾール-1-イド(355 mg)を淡黄色固体として得た。 Example 8
(5-{[4 '-(3-hydroxy-3-methylbutoxy) -2,2', 6'-trimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1H-inden-1-yl ) Sodium azide (500 mg) and triethylamine hydrochloride (1.05 g) were added to a solution of acetonitrile (572 mg) in NMP (10 mL), and the reaction mixture was stirred at 160 ° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with toluene-ethyl acetate solution. The aqueous layer was extracted with a toluene-ethyl acetate solution and ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give a brown oil. The obtained oil was dissolved in methanol (5 mL), 1M aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 0.5 hr, and the solvent was evaporated under reduced pressure. The obtained residue was purified by ODS column chromatography (acetonitrile-water) to obtain a white amorphous solid. Diisopropyl ether (10 mL) was added to the obtained white amorphous solid, and the mixture was stirred at room temperature for 0.5 hour. The solid was collected by filtration, washed with diisopropyl ether, and heated and dried under reduced pressure to give sodium 5-[(5-{[4 '-(3-hydroxy-3-methylbutoxy) -2,2', 6 ' -Trimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1H-inden-1-yl) methyl] tetrazol-1-id (355 mg) was obtained as a pale yellow solid.
実施例8の方法と同様にして後記表に示す実施例8-1の化合物を製造した。 In the same manner as in Example 8, the compound of Example 8-1 shown in the table below was produced.
実施例９
　4'-(3-ヒドロキシ-3-メチルブトキシ)-2,2',6'-トリメチルビフェニル-3-カルバルデヒド(300 mg)、1'-(1H-テトラゾール-5-イルメチル)-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-5'-アミン(240 mg)、酢酸(0.27 mL)及びTHF (6 mL)の混合物を室温で2.5時間撹拌した。反応混合物に氷冷下、トリアセトキシ水素化ホウ素ナトリウム(300 mg)を加え、室温まで昇温させながら15.5時間撹拌した。反応混合物に水(10 mL)を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除き、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)により精製し、白色アモルファス固体を得た。得られた白色アモルファス固体をメタノール(5 mL)に溶解し、1M水酸化ナトリウム水溶液(0.87 mL)を加えて室温で0.5時間撹拌した後、減圧下溶媒を留去した。得られた残渣にジイソプロピルエーテル(10 mL)を加え、室温で0.5時間撹拌した。固体を濾取し、ジイソプロピルエーテルで洗浄後、減圧下加熱乾燥することにより、ナトリウム 5-{[5'-({[4'-(3-ヒドロキシ-3-メチルブトキシ)-2,2',6'-トリメチルビフェニル-3-イル]メチル}アミノ)-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-1'-イル]メチル}テトラゾール-1-イド(434 mg)を白色固体として得た。 Example 9
4 '-(3-hydroxy-3-methylbutoxy) -2,2', 6'-trimethylbiphenyl-3-carbaldehyde (300 mg), 1 '-(1H-tetrazol-5-ylmethyl) -1', A mixture of 3′-dihydrospiro [cyclopropane-1,2′-indene] -5′-amine (240 mg), acetic acid (0.27 mL) and THF (6 mL) was stirred at room temperature for 2.5 hours. Under ice-cooling, sodium triacetoxyborohydride (300 mg) was added to the reaction mixture, and the mixture was stirred for 15.5 hours while warming to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain a white amorphous solid. The obtained white amorphous solid was dissolved in methanol (5 mL), 1M aqueous sodium hydroxide solution (0.87 mL) was added, and the mixture was stirred at room temperature for 0.5 hr, and the solvent was evaporated under reduced pressure. Diisopropyl ether (10 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 0.5 hour. The solid was collected by filtration, washed with diisopropyl ether, and then heated and dried under reduced pressure to obtain sodium 5-{[5 '-({[4'-(3-hydroxy-3-methylbutoxy) -2,2 ', 6'-Trimethylbiphenyl-3-yl] methyl} amino) -1 ', 3'-dihydrospiro [cyclopropane-1,2'-indene] -1'-yl] methyl} tetrazol-1-id (434 mg ) Was obtained as a white solid.
実施例9の方法と同様にして後記表に示す実施例9-1から9-6の化合物を製造した。 In the same manner as in Example 9, the compounds of Examples 9-1 to 9-6 shown in the table below were produced.
実施例１０
　{5'-[(4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-イル)メトキシ]-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-1'-イル}アセトニトリル(253 mg)のNMP (5 mL)溶液にアジ化ナトリウム(200 mg)及びトリエチルアミン 塩酸塩(430 mg)を加え、反応混合物を160 ℃で17時間撹拌した。反応混合物を室温まで放冷し、10 %クエン酸水溶液を加え、トルエン-酢酸エチル溶液で抽出した。水層を再度トルエン-酢酸エチル溶液で抽出した。有機層を合わせ、水及び飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムと活性炭(0.3 g)を加えた。濾過にて乾燥剤と活性炭を除去し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)により精製し、褐色油状物を得た。得られた褐色油状物のNMP (5 mL)溶液にアジ化ナトリウム(300 mg)及びトリエチルアミン 塩酸塩(630 mg)を加え、反応混合物を160 ℃で87.5時間撹拌した。反応混合物を室温まで放冷し、10 %クエン酸水溶液を加え、セライト濾過にて不溶物を除去後、濾液をトルエン-酢酸エチル溶液で抽出した。水層を再度トルエン-酢酸エチル溶液で抽出した。有機層を合わせ、水及び飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムと活性炭(0.3 g)を加えた。濾過にて乾燥剤と活性炭を除去し、減圧下溶媒を留去した。得られた残渣のTHF (3 mL)及びメタノール(3 mL)溶液に1M塩酸(3 mL)を加え、50 ℃で3時間撹拌した。反応混合物を室温まで放冷し、1M水酸化ナトリウム水溶液(5 mL)を加えて室温で0.5時間撹拌した後、減圧下溶媒を留去した。得られた残渣をODSカラムクロマトグラフィー(アセトニトリル-水)で精製し、白色アモルファス固体を得た。得られた白色アモルファス固体にジイソプロピルエーテル(10 mL)を加え、室温で0.5時間撹拌した。固体を濾取し、ジイソプロピルエーテルで洗浄後、減圧下加熱乾燥することにより、ナトリウム 5-({5'-[(4'-{[(2R)-2,3-ジヒドロキシプロピル]オキシ}-2,2',6'-トリメチルビフェニル-3-イル)メトキシ]-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-1'-イル}メチル)テトラゾール-1-イド(20 mg)を白色固体として得た。 Example 10
{5 '-[(4'-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2 ', 6'-trimethylbiphenyl-3-yl) methoxy ] -1 ', 3'-Dihydrospiro [cyclopropane-1,2'-indene] -1'-yl} acetonitrile (253 mg) in NMP (5 mL) solution with sodium azide (200 mg) and triethylamine hydrochloride Salt (430 mg) was added and the reaction mixture was stirred at 160 ° C. for 17 hours. The reaction mixture was allowed to cool to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with toluene-ethyl acetate solution. The aqueous layer was extracted again with a toluene-ethyl acetate solution. The organic layers were combined, washed with water and a saturated aqueous sodium chloride solution, and anhydrous magnesium sulfate and activated carbon (0.3 g) were added. The desiccant and activated carbon were removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give a brown oil. Sodium azide (300 mg) and triethylamine hydrochloride (630 mg) were added to a solution of the obtained brown oil in NMP (5 mL), and the reaction mixture was stirred at 160 ° C. for 87.5 hours. The reaction mixture was allowed to cool to room temperature, 10% aqueous citric acid solution was added, insoluble material was removed by Celite filtration, and the filtrate was extracted with toluene-ethyl acetate solution. The aqueous layer was extracted again with a toluene-ethyl acetate solution. The organic layers were combined, washed with water and a saturated aqueous sodium chloride solution, and anhydrous magnesium sulfate and activated carbon (0.3 g) were added. The desiccant and activated carbon were removed by filtration, and the solvent was distilled off under reduced pressure. 1M hydrochloric acid (3 mL) was added to a solution of the obtained residue in THF (3 mL) and methanol (3 mL), and the mixture was stirred at 50 ° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, 1M aqueous sodium hydroxide solution (5 mL) was added and the mixture was stirred at room temperature for 0.5 hr, and the solvent was evaporated under reduced pressure. The obtained residue was purified by ODS column chromatography (acetonitrile-water) to obtain a white amorphous solid. Diisopropyl ether (10 mL) was added to the obtained white amorphous solid, and the mixture was stirred at room temperature for 0.5 hour. The solid was collected by filtration, washed with diisopropyl ether, and heated and dried under reduced pressure to give sodium 5-({5 '-[(4'-{[(2R) -2,3-dihydroxypropyl] oxy} -2 , 2 ', 6'-Trimethylbiphenyl-3-yl) methoxy] -1', 3'-dihydrospiro [cyclopropane-1,2'-indene] -1'-yl} methyl) tetrazol-1-id ( 20 mg) was obtained as a white solid.
実施例１１
　安息香酸 2-{[3'-({[1'-(シアノメチル)-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-5'-イル]オキシ}メチル)-2,2',6-トリメチルビフェニル-4-イル]オキシ}エチル(185 mg)のNMP (4 mL)溶液にアジ化ナトリウム(130 mg)及びトリエチルアミン 塩酸塩(280 mg)を加え、反応混合物を160 ℃で17時間撹拌した。反応混合物を室温まで放冷し、10 %クエン酸水溶液を加え、トルエン-酢酸エチル溶液で抽出した。水層を再度トルエン-酢酸エチル溶液で抽出した。有機層を合わせ、水及び飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムと活性炭(0.3 g)を加えた。濾過にて乾燥剤と活性炭を除去し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)により精製し、褐色油状物を得た。得られた褐色油状物のNMP (4 mL)溶液にアジ化ナトリウム(210 mg)及びトリエチルアミン 塩酸塩(440 mg)を加え、反応混合物を160 ℃で87.5時間撹拌した。反応混合物を室温まで放冷し、10 %クエン酸水溶液を加え、セライト濾過にて不溶物を除去後、濾液をトルエン-酢酸エチル溶液で抽出した。水層をトルエン-酢酸エチル溶液で抽出した。有機層を合わせ、水及び飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムと活性炭(0.3 g)を加えた。濾過にて乾燥剤と活性炭を除去し、減圧下溶媒を留去した。得られた残渣のメタノール(3 mL)溶液に1M水酸化ナトリウム水溶液(2 mL)を加えて室温で1.5時間撹拌した後、減圧下溶媒を留去した。得られた残渣をODSカラムクロマトグラフィー(アセトニトリル-水)で精製し、白色アモルファス固体を得た。得られた白色アモルファス固体にジイソプロピルエーテル(10 mL)を加え、室温で0.5時間撹拌した。固体を濾取し、ジイソプロピルエーテルで洗浄後、減圧下加熱乾燥することにより、ナトリウム 5-[(5'-{[4'-(2-ヒドロキシエトキシ)-2,2',6'-トリメチルビフェニル-3-イル]メトキシ}-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-1'-イル)メチル]テトラゾール-1-イド(19 mg)を白色固体として得た。 Example 11
Benzoic acid 2-{[3 '-({[1'-(cyanomethyl) -1 ', 3'-dihydrospiro [cyclopropane-1,2'-indene] -5'-yl] oxy} methyl) -2 , 2 ', 6-Trimethylbiphenyl-4-yl] oxy} ethyl (185 mg) in NMP (4 mL) was added sodium azide (130 mg) and triethylamine hydrochloride (280 mg), and the reaction mixture was added to 160 Stir at 17 ° C. for 17 hours. The reaction mixture was allowed to cool to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with toluene-ethyl acetate solution. The aqueous layer was extracted again with a toluene-ethyl acetate solution. The organic layers were combined, washed with water and a saturated aqueous sodium chloride solution, and anhydrous magnesium sulfate and activated carbon (0.3 g) were added. The desiccant and activated carbon were removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give a brown oil. Sodium azide (210 mg) and triethylamine hydrochloride (440 mg) were added to a solution of the obtained brown oil in NMP (4 mL), and the reaction mixture was stirred at 160 ° C. for 87.5 hours. The reaction mixture was allowed to cool to room temperature, 10% aqueous citric acid solution was added, insoluble material was removed by Celite filtration, and the filtrate was extracted with toluene-ethyl acetate solution. The aqueous layer was extracted with a toluene-ethyl acetate solution. The organic layers were combined, washed with water and a saturated aqueous sodium chloride solution, and anhydrous magnesium sulfate and activated carbon (0.3 g) were added. The desiccant and activated carbon were removed by filtration, and the solvent was distilled off under reduced pressure. To a solution of the obtained residue in methanol (3 mL) was added 1M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 1.5 hours, and the solvent was evaporated under reduced pressure. The obtained residue was purified by ODS column chromatography (acetonitrile-water) to obtain a white amorphous solid. Diisopropyl ether (10 mL) was added to the obtained white amorphous solid, and the mixture was stirred at room temperature for 0.5 hour. The solid was collected by filtration, washed with diisopropyl ether, and heated and dried under reduced pressure to give sodium 5-[(5 '-{[4'-(2-hydroxyethoxy) -2,2 ', 6'-trimethylbiphenyl]. -3-yl] methoxy} -1 ', 3'-dihydrospiro [cyclopropane-1,2'-indene] -1'-yl) methyl] tetrazol-1-id (19 mg) was obtained as a white solid .
実施例１２
　N-{3-[2-(2-{[tert-ブチル(ジメチル)シリル]オキシ}エトキシ)-4,6-ジメチルピリミジン-5-イル]-2-メチルベンジル}-4-[2-(1H-テトラゾール-5-イル)エチル]アニリン(529 mg)のTHF (3 mL)溶液に1M塩酸(6 mL)を加え、室温で1時間撹拌した。反応混合物に1M水酸化ナトリウム水溶液(6.5 mL)を加えた後、10%クエン酸水溶液(10 mL)を加えた。混合物を2-プロパノール-クロロホルム溶液で抽出した。有機層を無水硫酸マグネシウムで乾燥後、濾過にて乾燥剤を除去し、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(クロロホルム-メタノール)で精製し、得られた白色固体をジエチルエーテルで洗浄し、濾取後、減圧下加熱乾燥して、2-[(4,6-ジメチル-5-{2-メチル-3-[({4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]フェニル}ピリミジン-2-イル)オキシ]エタノール(306 mg)を白色固体として得た。 Example 12
N- {3- [2- (2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) -4,6-dimethylpyrimidin-5-yl] -2-methylbenzyl} -4- [2- ( To a solution of [1H-tetrazol-5-yl) ethyl] aniline (529 mg) in THF (3 mL) was added 1M hydrochloric acid (6 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1M aqueous sodium hydroxide solution (6.5 mL), and then 10% aqueous citric acid solution (10 mL) was added. The mixture was extracted with 2-propanol-chloroform solution. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol), and the resulting white solid was washed with diethyl ether, collected by filtration, and dried by heating under reduced pressure to give 2-[(4,6-dimethyl-5- {2-Methyl-3-[({4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] phenyl} pyrimidin-2-yl) oxy] ethanol (306 mg) as a white solid Got as.
実施例12の方法と同様にして後記表に示す実施例12-1から12-2の化合物を製造した。 In the same manner as in Example 12, the compounds of Examples 12-1 to 12-2 shown in the following table were produced.
実施例１３
　N-[3-(2-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-4,6-ジメチルピリミジン-5-イル)-2-メチルベンジル]-4-[2-(1H-テトラゾール-5-イル)エチル]アニリン(554 mg)のTHF (3 mL)溶液に1M塩酸(6 mL)を加え、室温で12時間撹拌した。反応混合物に1M水酸化ナトリウム水溶液(6.5 mL)を加えた後、10 %クエン酸水溶液(10 mL)を加えた。混合物を2-プロパノール-クロロホルム溶液で抽出した。有機層を無水硫酸マグネシウムで乾燥後、濾過にて乾燥剤を除去し、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(クロロホルム-メタノール)により精製し、得られた白色固体をジエチルエーテルで洗浄し、濾取後、減圧下加熱乾燥して、(2R)-3-[(4,6-ジメチル-5-{2-メチル-3-[({4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]フェニル}ピリミジン-2-イル)オキシ]プロパン-1,2-ジオール(413 mg)を白色固体として得た。 Example 13
N- [3- (2-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -4,6-dimethylpyrimidin-5-yl) -2-methylbenzyl] To a solution of -4- [2- (1H-tetrazol-5-yl) ethyl] aniline (554 mg) in THF (3 mL) was added 1M hydrochloric acid (6 mL), and the mixture was stirred at room temperature for 12 hours. To the reaction mixture was added 1M aqueous sodium hydroxide solution (6.5 mL), and then 10% aqueous citric acid solution (10 mL) was added. The mixture was extracted with 2-propanol-chloroform solution. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol), and the resulting white solid was washed with diethyl ether, collected by filtration, and dried by heating under reduced pressure to give (2R) -3-[(4,6- Dimethyl-5- {2-methyl-3-[({4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] phenyl} pyrimidin-2-yl) oxy] propane-1, 2-Diol (413 mg) was obtained as a white solid.
実施例13の方法と同様にして後記表に示す実施例13-1から13-5の化合物を製造した。 In the same manner as in Example 13, the compounds of Examples 13-1 to 13-5 shown in the table below were produced.
実施例１４
　3-(6-{[4'-(2-{[tert-ブチル(ジメチル)シリル]オキシ}エトキシ)-2,2',6'-トリメチルビフェニル-3-イル]メトキシ}ピリジン-3-イル)プロパンニトリル(153 mg)のTHF (1.5 mL)溶液に1M塩酸(1 mL)を加え、室温で5時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液(5 mL)を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去することにより無色飴状物(120 mg)を得た。得られた無色飴状物(120 mg)、アジ化ナトリウム(190 mg)、トリエチルアミン 塩酸塩(400 mg)及びNMP (1.5 mL)の混合物を160 ℃で5時間撹拌した。反応混合物を室温まで放冷し、飽和炭酸水素ナトリウム水溶液(5 mL)を加えた後、10 %クエン酸水溶液(5 mL)を加えた。混合物を2-プロパノール-クロロホルム溶液で抽出し、有機層を無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去した。残渣に1M水酸化ナトリウム水溶液(0.6 mL)を加え、混合物をODSカラムクロマトグラフィー(アセトニトリル-水)で精製し、得られた黄色アモルファス固体(77 mg)にジエチルエーテルを加え、撹拌した。固体を濾取後、減圧下加熱乾燥することにより、ナトリウム 5-[2-(6-{[4'-(2-ヒドロキシエトキシ)-2,2',6'-トリメチルビフェニル-3-イル]メトキシ}ピリジン-3-イル)エチル]テトラゾール-1-イド(56 mg)を黄褐色粉末固体として得た。 Example 14
3- (6-{[4 '-(2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) -2,2', 6'-trimethylbiphenyl-3-yl] methoxy} pyridin-3-yl 1M hydrochloric acid (1 mL) was added to a solution of propanenitrile (153 mg) in THF (1.5 mL), and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and then the solvent was distilled off under reduced pressure to obtain a colorless bowl (120 mg). A mixture of the obtained colorless rod (120 mg), sodium azide (190 mg), triethylamine hydrochloride (400 mg) and NMP (1.5 mL) was stirred at 160 ° C. for 5 hours. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution (5 mL) was added, and 10% aqueous citric acid solution (5 mL) was added. The mixture was extracted with a 2-propanol-chloroform solution, and the organic layer was dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure. To the residue was added 1M aqueous sodium hydroxide solution (0.6 mL), the mixture was purified by ODS column chromatography (acetonitrile-water), diethyl ether was added to the obtained yellow amorphous solid (77 mg), and the mixture was stirred. The solid was collected by filtration and dried by heating under reduced pressure to give sodium 5- [2- (6-{[4 '-(2-hydroxyethoxy) -2,2', 6'-trimethylbiphenyl-3-yl] Methoxy} pyridin-3-yl) ethyl] tetrazol-1-id (56 mg) was obtained as a tan powder solid.
実施例１５
　3-{6-[(4'-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]メトキシ}-2,2',6'-トリメチルビフェニル-3-イル)メトキシ]ピリジン-3-イル}プロパンニトリル(95 mg)のTHF(1.5ml)溶液に1M塩酸(1 mL)を加え、室温で5時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液(5 mL)を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去し、減圧下溶媒を留去することにより無色飴状物(83mg)を得た。得られた無色飴状物(83 mg)、ジブチルスズオキシド(23 mg)、トリメチルシリルアジド(0.122 mL)及びトルエン(3 mL)の混合物を120 ℃で2.5時間撹拌した。反応混合物を室温まで放冷し、ジブチルスズオキシド(23 mg)およびトリメチルシリルアジド(0.122 mL)を加えた後、120℃で1時間撹拌した。反応混合物を室温まで放冷し、水を加えた後、2-プロパノール-クロロホルム溶液で抽出した。有機層を無水硫酸マグネシウムで乾燥後、濾過にて乾燥剤を除去し、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(クロロホルム-メタノール)により精製し、得られた無色飴状物のメタノール(1 mL)溶液に1M水酸化ナトリウム水溶液(0.2 mL)を加えた。残渣をODSカラムクロマトグラフィー(アセトニトリル-水)で精製し、得られた白色アモルファス固体にヘキサンを加え、撹拌した。固体を濾取後、減圧下加熱乾燥して、ナトリウム 5-(2-{6-[(4’-{[(2R)-2,3-ジヒドロキシプロピル]オキシ}2,2’,6’-トリメチルビフェニル-3-イル)メトキシ]ピリジン-3-イル}エチル)テトラゾール-1-イド(22 mg)を白色粉末固体として得た。 Example 15
3- {6-[(4 '-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2', 6'-trimethylbiphenyl-3-yl) 1M Hydrochloric acid (1 mL) was added to a THF (1.5 ml) solution of methoxy] pyridin-3-yl} propanenitrile (95 mg), and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a colorless bowl (83 mg). A mixture of the obtained colorless powder (83 mg), dibutyltin oxide (23 mg), trimethylsilyl azide (0.122 mL) and toluene (3 mL) was stirred at 120 ° C. for 2.5 hours. The reaction mixture was allowed to cool to room temperature, dibutyltin oxide (23 mg) and trimethylsilyl azide (0.122 mL) were added, and the mixture was stirred at 120 ° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with a 2-propanol-chloroform solution. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol), and 1M aqueous sodium hydroxide solution (0.2 mL) was added to a methanol (1 mL) solution of the obtained colorless rod-like material. The residue was purified by ODS column chromatography (acetonitrile-water), and hexane was added to the resulting white amorphous solid and stirred. The solid was collected by filtration and dried by heating under reduced pressure to give sodium 5- (2- {6-[(4 '-{[(2R) -2,3-dihydroxypropyl] oxy} 2,2', 6'- Trimethylbiphenyl-3-yl) methoxy] pyridin-3-yl} ethyl) tetrazol-1-id (22 mg) was obtained as a white powder solid.
実施例15の方法と同様にして後記表に示す実施例15-1の化合物を製造した。 In the same manner as in Example 15, the compound of Example 15-1 shown in the table below was produced.
実施例１６
　3-{6-[(4'-{[(3S)-3-{[tert-ブチル(ジメチル)シリル]オキシ}ブチル]オキシ}-2,2',6'-トリメチルビフェニル-3-イル)メトキシ]ピリジン-3-イル}プロパンニトリル(152 mg)のTHF (1.5 mL)溶液に1M塩酸(1 mL)を加え、室温で5時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液(5 mL)を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去することにより、無色飴状物(112 mg)を得た。得られた無色飴状物(112 mg)、ジブチルスズオキシド(32 mg)、トリメチルシリルアジド(0.165 mL)及びトルエン(3 mL)の混合物を120 ℃で4時間撹拌した。反応混合物を室温まで放冷し、水を加えた後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。濾過にて乾燥剤を除去後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(クロロホルム-メタノール)で精製することにより、白色アモルファス固体(77 mg)を得た。得られた白色アモルファス固体(77 mg)、THF (3 mL)及びメタノール(3 mL)の混合物に1M水酸化ナトリウム水溶液(0.20 mL)を加え、減圧下溶媒を留去した。残渣をODSカラムクロマトグラフィー(アセトニトリル-水)で精製し、得られた白色アモルファス固体にヘキサンを加え、撹拌した。固体を濾取後、減圧下加熱乾燥することによりナトリウム 5-(2-{6-[(4'-{[(3S)-3-ヒドロキシブチル]オキシ}-2,2',6'-トリメチルビフェニル-3-イル)メトキシ]ピリジン-3-イル}エチル)テトラゾール-1-イド(48 mg)を白色粉末固体として得た。 Example 16
3- {6-[(4 '-{[(3S) -3-{[tert-butyl (dimethyl) silyl] oxy} butyl] oxy} -2,2', 6'-trimethylbiphenyl-3-yl) To a solution of methoxy] pyridin-3-yl} propanenitrile (152 mg) in THF (1.5 mL) was added 1M hydrochloric acid (1 mL), and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and then the solvent was distilled off under reduced pressure to obtain a colorless bowl (112 mg). A mixture of the obtained colorless powder (112 mg), dibutyltin oxide (32 mg), trimethylsilyl azide (0.165 mL) and toluene (3 mL) was stirred at 120 ° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give a white amorphous solid (77 mg). To a mixture of the obtained white amorphous solid (77 mg), THF (3 mL) and methanol (3 mL) was added 1M aqueous sodium hydroxide solution (0.20 mL), and the solvent was evaporated under reduced pressure. The residue was purified by ODS column chromatography (acetonitrile-water), and hexane was added to the resulting white amorphous solid and stirred. After filtering the solid, it was heated and dried under reduced pressure to give sodium 5- (2- {6-[(4 '-{[(3S) -3-hydroxybutyl] oxy} -2,2', 6'-trimethyl Biphenyl-3-yl) methoxy] pyridin-3-yl} ethyl) tetrazol-1-id (48 mg) was obtained as a white powder solid.
実施例16の方法と同様にして後記表に示す実施例16-1から16-2の化合物を製造した。 In the same manner as in Example 16, the compounds of Examples 16-1 to 16-2 shown in the table below were produced.
　製造例化合物の構造を表２４～表３０に、物理化学的データを表３１～表３５にそれぞれ示す。 Tables 24 to 30 show the structures of the production example compounds, and Tables 31 to 35 show the physicochemical data.
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000059
式（Ｉ）の化合物は、優れたGPR40アゴニスト作用を有し、インスリン分泌促進剤、或いは、糖尿病（インスリン依存性糖尿病 (IDDM)、インスリン非依存性糖尿病 (NIDDM)、又は、境界型（耐糖能・空腹時血糖値異常）軽症糖尿病）、インスリン抵抗性疾患及び肥満等のGPR40が関与する疾患の予防及び／又は治療剤として使用しうる。
The compound of formula (I) has an excellent GPR40 agonistic action, and is an insulin secretagogue, or diabetes (insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), or borderline type (glucose tolerance). -Abnormal fasting blood glucose level) Mild diabetes), insulin resistance disease, obesity and other diseases involving GPR40 can be used as a preventive and / or therapeutic agent.
　以下の配列表の数字見出し＜２２３＞には、「Artificial Sequence」の説明を記載する。具体的には、配列表の配列番号１の配列で表される塩基配列は、人工的に合成したプライマーの塩基配列である。また、配列表の配列番号２の配列で表される塩基配列は、人工的に合成したプライマーの塩基配列である。 The description of “Artificial Sequence” is described in the numerical heading <223> of the following sequence listing. Specifically, the base sequence represented by the sequence of SEQ ID NO: 1 in the sequence listing is a base sequence of an artificially synthesized primer. Moreover, the base sequence represented by the sequence number 2 in the sequence listing is the base sequence of an artificially synthesized primer.

Claims (17)

  1. 式（Ｉ）の化合物又はその塩。
    Figure JPOXMLDOC01-appb-C000001
     （式中、
    RA1は、H、又は、ハロゲンであり、
    mは、1、又は、2であり、
    RA2及びRA3は、H、又は、
    RA2とRA3が一体となって-CH2-C(RX1)(RX2)-であり、
    RX1及びRX2は、H、又は、
    RX1とRX2が一体となって置換されていてもよいC2-7アルキレンであり、
    Zは、N、又は、C-RZであり、
    RZは、H、又は、ハロゲンであり、
    Lは、O、又は、NHであり、
    R1、R2、R3、R4、R5及びR6は、互いに同一又は異なっていてもよい、H、ハロゲン、置換されていてもよい低級アルキル、又は、-O-(置換されていてもよい低級アルキル)であり、
    R7は、H、ハロゲン、-O-(置換されていてもよいヘテロ環基)、又は、-O-(CR71R72)p-R73であり、
    R71及びR72は、互いに同一又は異なっていてもよい、H、OH、又は、置換されていてもよい低級アルキルであり、
    pは、1、2、又は、3であり
    R73は、OH、又は、-O-(置換されていてもよい低級アルキル)、又は、置換されていてもよいヘテロ環基であり、
    Ya及びYbは、互いに同一又は異なっていてもよい、N、又は、C-RYであり、
    RYは、H、ハロゲン、置換されていてもよい低級アルキル、又は、-O-(置換されていてもよい低級アルキル)である。）     A compound of formula (I) or a salt thereof.
    Figure JPOXMLDOC01-appb-C000001
     (Where
    R A1 is H or halogen;
    m is 1 or 2,
    R A2 and R A3 are H or
    R A2 and R A3 are combined to form -CH 2 -C (R X1 ) (R X2 )-
    R X1 and R X2 are H or
    R X1 and R X2 are C 2-7 alkylene which may be substituted together,
    Z is N or CR Z ,
    R Z is H or halogen;
    L is O or NH;
    R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be the same or different from each other, H, halogen, optionally substituted lower alkyl, or —O— (substituted Optionally lower alkyl)
    R 7 is H, halogen, —O— (optionally substituted heterocyclic group), or —O— (CR 71 R 72 ) p —R 73 ;
    R 71 and R 72 are the same or different from each other, H, OH, or optionally substituted lower alkyl,
    p is 1, 2 or 3
    R 73 is OH or -O- (lower alkyl which may be substituted) or an optionally substituted heterocyclic group;
    Y a and Y b may be the same or different from each other, N or CR Y ;
    R Y is H, halogen, optionally substituted lower alkyl, or —O— (optionally substituted lower alkyl). )
  2. RX1とRX2が一体となってC2-7アルキレンであり、
    R1、R2、R3、R4、R5及びR6は、互いに同一又は異なっていてもよい、H、ハロゲン、低級アルキル、又は、-O-低級アルキルであり、
    R7は、H、ハロゲン、-O-ヘテロ環基、又は、-O-(CR71R72)p-R73であり、
    R71及びR72は、互いに同一又は異なっていてもよい、H、OH、又は、OHで置換されていてもよい低級アルキルであり、
    R73は、OH、又は、アリール若しくはオキソ(=O)で置換されていてもよい-O-低級アルキル、又は、低級アルキルで置換されていてもよいヘテロ環基であり、
    RYは、H、ハロゲン、低級アルキル、又は、-O-低級アルキルである請求項１記載の化合物又はその塩。     R X1 and R X2 together are C 2-7 alkylene,
    R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different from each other, and are H, halogen, lower alkyl, or —O-lower alkyl,
    R 7 is H, halogen, -O-heterocyclic group, or -O- (CR 71 R 72 ) p -R 73 ,
    R 71 and R 72 may be the same or different from each other, H, OH, or lower alkyl optionally substituted with OH;
    R 73 is OH, or -O-lower alkyl which may be substituted with aryl or oxo (= O), or a heterocyclic group which may be substituted with lower alkyl,
    The compound or a salt thereof according to claim 1, wherein R Y is H, halogen, lower alkyl, or -O-lower alkyl.
  3. RA1が、H、又は、Fであり、mが1であり、R1、R2、R3、R4、R5及びR6が、互いに同一又は異なっていてもよい、H、又は、低級アルキルであり、Zが、N、又は、C-RZであり、RZが、Hであり、Ya及びYbが、互いに同一又は異なっていてもよい、N、又は、C-RYであり、RYが、Hである請求項２記載の化合物又はその塩。 R A1 is H or F, m is 1, and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be the same or different from each other, H or Lower alkyl, Z is N or CR Z , R Z is H, Y a and Y b may be the same or different from each other, N or CR Y ; The compound or a salt thereof according to claim 2, wherein R Y is H.
  4. R1、R2及びR3が、Hであり、R4、R5及びR6が、低級アルキルであり、R7が、-O-(CR71R72)p-R73であり、-(CR71R72)p-が、-CH2-CH2-、-CH2-CH(OH)-CH2-、-CH2-CH(CH2OH)-CH2-、-CH2-CH2-CH(CH3)-、又は、-CH2-CH2-C(CH3)2-であり、R73が、OHである請求項３記載の化合物又はその塩。 R 1 , R 2 and R 3 are H, R 4 , R 5 and R 6 are lower alkyl, R 7 is -O- (CR 71 R 72 ) p -R 73 ,- (CR 71 R 72) p - is, -CH 2 -CH 2 -, - CH 2 -CH (OH) -CH 2 -, - CH 2 -CH (CH 2 OH) -CH 2 -, - CH 2 - CH 2 -CH (CH 3) - , or, -CH 2 -CH 2 -C (CH 3) 2 - a and, R 73 is the compound or a salt according to claim 3, wherein is OH.
  5. R1、R2及びR3が、Hであり、R4、R5及びR6が、低級アルキルであり、R7が、-O-(CR71R72)p-R73であり、pが3であり、-(CR71R72)3-が、-CH2-CH(OH)-CH2-であり、R73が、OHである請求項４記載の化合物又はその塩。 R 1, R 2 and R 3 are H, R 4, R 5 and R 6 are lower alkyl, R 7 is, -O- (CR 71 R 72) is a p -R 73, p 5. The compound according to claim 4, wherein — (CR 71 R 72 ) 3 — is —CH 2 —CH (OH) —CH 2 —, and R 73 is OH.
  6. Lが、NHであり、R1、R2及びR3が、Hであり、R4、R5及びR6が、メチルである請求項５記載の化合物又はその塩。 The compound or a salt thereof according to claim 5, wherein L is NH, R 1 , R 2 and R 3 are H, and R 4 , R 5 and R 6 are methyl.
  7. RA2及びRA3が、Hである請求項４記載の化合物又はその塩。 The compound or a salt thereof according to claim 4, wherein R A2 and R A3 are H.
  8. RA2及びRA3が、一体となって-CH2-C(RX1)(RX2)-であり、RX1及びRX2が、Hである請求項４記載の化合物又はその塩。 5. The compound or a salt thereof according to claim 4, wherein R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 are H.
  9. RA2及びRA3が、一体となって-CH2-C(RX1)(RX2)-であり、RX1及びRX2が、一体となってC2-7アルキレンである請求項４記載の化合物又はその塩。 5. R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 are integrally C 2-7 alkylene. Or a salt thereof.
  10. RA2及びRA3が、一体となって-CH2-C(RX1)(RX2)-であり、RX1及びRX2が、一体となってエチレンである請求項４記載の化合物又はその塩。 5. The compound according to claim 4, wherein R A2 and R A3 are collectively —CH 2 —C (R X1 ) (R X2 ) —, and R X1 and R X2 are all ethylene. salt.
  11. (2R)-3-({2,2',6-トリメチル-3'-[({4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]ビフェニル-4-イル}オキシ)プロパン-1,2-ジオール、
    2-メチル-4-{[2,2',6-トリメチル-3'-({[1-(1H-テトラゾール-5-イルメチル)-2,3-ジヒドロ-1H-インデン-5-イル]オキシ}メチル)ビフェニル-4-イル]オキシ}ブタン-2-オール、
    (2R)-3-{[2,2',6-トリメチル-3'-({[1'-(1H-テトラゾール-5-イルメチル)-1',3'-ジヒドロスピロ[シクロプロパン-1,2'-インデン]-5'-イル]アミノ}メチル)ビフェニル-4-イル]オキシ}プロパン-1,2-ジオール、
    (2R)-3-{[2,2',6-トリメチル-3'-({[1-(1H-テトラゾール-5-イルメチル)-2,3-ジヒドロ-1H-インデン-5-イル]アミノ}メチル)ビフェニル-4-イル]オキシ}プロパン-1,2-ジオール、
    2-[(4,6-ジメチル-5-{2-メチル-3-[({4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]フェニル}ピリミジン-2-イル)オキシ]エタノール、
    (2R)-3-[(4,6-ジメチル-5-{2-メチル-3-[({4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]フェニル}ピリミジン-2-イル)オキシ]プロパン-1,2-ジオール、
    (2R)-3-({3'-[({3-フルオロ-4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]-2,2',6-トリメチルビフェニル-4-イル}オキシ)プロパン-1,2-ジオール、
    (2R)-3-[(5-{3-[({3-フルオロ-4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]-2-メチルフェニル}-4,6-ジメチルピリミジン-2-イル)オキシ]プロパン-1,2-ジオール、
    4-[2-(1H-テトラゾール-5-イル)エチル]-N-{[2,2',6'-トリメチル-4'-(テトラヒドロ-2H-ピラン-4-イルメトキシ)ビフェニル-3-イル]メチル}アニリン、
    4-[2-(1H-テトラゾール-5-イル)エチル]-N-({2,2',6'-トリメチル-4'-[2-(テトラヒドロ-2H-ピラン-4-イル)エトキシ]ビフェニル-3-イル}メチル)アニリン、
    (2S)-3-({3'-[({3-フルオロ-4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]-2,2',6-トリメチルビフェニル-4-イル}オキシ)プロパン-1,2-ジオール、
    (2S)-3-({2,2',6-トリメチル-3'-[({4-[2-(1H-テトラゾール-5-イル)エチル]フェニル}アミノ)メチル]ビフェニル-4-イル}オキシ)プロパン-1,2-ジオール、
    3-フルオロ-4-[2-(1H-テトラゾール-5-イル)エチル]-N-{[2,2',6'-トリメチル-4'-(テトラヒドロ-2H-ピラン-4-イルメトキシ)ビフェニル-3-イル]メチル}アニリン、
    4-[2-(1H-テトラゾール-5-イル)エチル]-N-{[2,2',6'-トリメチル-4'-(テトラヒドロ-2H-ピラン-4-イルオキシ)ビフェニル-3-イル]メチル}アニリン、又は、
    (2S)-3-({2,2',6-トリメチル-3'-[({5-[2-(1H-テトラゾール-5-イル)エチル]ピリジン-2-イル}オキシ)メチル]ビフェニル-4-イル}オキシ)プロパン-1,2-ジオールである請求項１記載の化合物又はその塩。     (2R) -3-({2,2 ', 6-Trimethyl-3'-[({4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] biphenyl-4-yl } Oxy) propane-1,2-diol,
    2-Methyl-4-{[2,2 ', 6-trimethyl-3'-({[1- (1H-tetrazol-5-ylmethyl) -2,3-dihydro-1H-inden-5-yl] oxy } Methyl) biphenyl-4-yl] oxy} butan-2-ol,
    (2R) -3-{[2,2 ', 6-Trimethyl-3'-({[1 '-(1H-tetrazol-5-ylmethyl) -1', 3'-dihydrospiro [cyclopropane-1, 2'-indene] -5'-yl] amino} methyl) biphenyl-4-yl] oxy} propane-1,2-diol,
    (2R) -3-{[2,2 ', 6-Trimethyl-3'-({[1- (1H-tetrazol-5-ylmethyl) -2,3-dihydro-1H-inden-5-yl] amino } Methyl) biphenyl-4-yl] oxy} propane-1,2-diol,
    2-[(4,6-Dimethyl-5- {2-methyl-3-[({4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] phenyl} pyrimidine-2- Yl) oxy] ethanol,
    (2R) -3-[(4,6-Dimethyl-5- {2-methyl-3-[({4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] phenyl} Pyrimidin-2-yl) oxy] propane-1,2-diol,
    (2R) -3-({3 '-[({3-Fluoro-4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] -2,2', 6-trimethylbiphenyl -4-yl} oxy) propane-1,2-diol,
    (2R) -3-[(5- {3-[({3-Fluoro-4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] -2-methylphenyl} -4 , 6-Dimethylpyrimidin-2-yl) oxy] propane-1,2-diol,
    4- [2- (1H-tetrazol-5-yl) ethyl] -N-{[2,2 ', 6'-trimethyl-4'-(tetrahydro-2H-pyran-4-ylmethoxy) biphenyl-3-yl ] Methyl} aniline,
    4- [2- (1H-tetrazol-5-yl) ethyl] -N-({2,2 ', 6'-trimethyl-4'-[2- (tetrahydro-2H-pyran-4-yl) ethoxy] Biphenyl-3-yl} methyl) aniline,
    (2S) -3-({3 '-[({3-Fluoro-4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] -2,2', 6-trimethylbiphenyl -4-yl} oxy) propane-1,2-diol,
    (2S) -3-({2,2 ', 6-Trimethyl-3'-[({4- [2- (1H-tetrazol-5-yl) ethyl] phenyl} amino) methyl] biphenyl-4-yl } Oxy) propane-1,2-diol,
    3-Fluoro-4- [2- (1H-tetrazol-5-yl) ethyl] -N-{[2,2 ', 6'-trimethyl-4'-(tetrahydro-2H-pyran-4-ylmethoxy) biphenyl -3-yl] methyl} aniline,
    4- [2- (1H-tetrazol-5-yl) ethyl] -N-{[2,2 ', 6'-trimethyl-4'-(tetrahydro-2H-pyran-4-yloxy) biphenyl-3-yl ] Methyl} aniline, or
    (2S) -3-({2,2 ', 6-Trimethyl-3'-[({5- [2- (1H-tetrazol-5-yl) ethyl] pyridin-2-yl} oxy) methyl] biphenyl The compound or a salt thereof according to claim 1, which is 4-yl} oxy) propane-1,2-diol.
  12. 請求項１に記載の化合物又はその塩、及び製薬学的に許容される賦形剤を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof, and a pharmaceutically acceptable excipient.
  13. 請求項１に記載の化合物又はその塩を含有するGPR40が関与する疾患の予防用若しくは治療用医薬組成物。 A pharmaceutical composition for preventing or treating a disease involving GPR40, comprising the compound according to claim 1 or a salt thereof.
  14. GPR40が関与する疾患の予防用若しくは治療用医薬組成物の製造のための請求項１に記載の化合物又はその塩の使用。 Use of the compound according to claim 1 or a salt thereof for the manufacture of a pharmaceutical composition for preventing or treating a disease involving GPR40.
  15. GPR40が関与する疾患の予防若しくは治療のための請求項１に記載の化合物又はその塩の使用。 Use of the compound according to claim 1 or a salt thereof for the prevention or treatment of a disease involving GPR40.
  16. 請求項１に記載の化合物又はその塩の有効量を患者に投与することからなるGPR40が関与する疾患の予防若しくは治療方法。 A method for preventing or treating a disease involving GPR40, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to a patient.
  17. GPR40が関与する疾患の予防若しくは治療のための請求項１に記載の化合物又はその塩。 The compound according to claim 1 or a salt thereof for the prevention or treatment of a disease involving GPR40.
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WO2012046869A1 (en) 2010-10-08 2012-04-12 持田製薬株式会社 Cyclic amide derivative
WO2012147518A1 (en) 2011-04-27 2012-11-01 持田製薬株式会社 Novel 3-hydroxyisothiazole 1-oxide derivative
WO2012147516A1 (en) 2011-04-28 2012-11-01 持田製薬株式会社 Cyclic amide derivative
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US10059667B2 (en) 2014-02-06 2018-08-28 Merck Sharp & Dohme Corp. Antidiabetic compounds
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
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