WO2010123017A1 - Composé de tétrazole - Google Patents

Composé de tétrazole 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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compound
methyl
mixture
added
stirred
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PCT/JP2010/057035
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English (en)
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/fr

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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

La présente invention concerne un composé représenté par la formule (I) ou l'un de ses sels pharmaceutiquement acceptables ; et l'utilisation du composé ou de l'un de ses sels pharmaceutiquement acceptables pour des objectifs médicaux. Dans la formule, RA2 et RA3 représentent indépendamment H ou forment ensemble -CH2-C(RX1)(RX2)- ; RX1 et RX2 représentent indépendamment H ou forment ensemble un groupe alkylène en C2 à C7 éventuellement substitué. Le composé ou l'un de ses sels pharmaceutiquement acceptables possède une excellente activité agoniste du GPR40 et peut être utilisé pour des objectifs médicaux, en tant que promoteur de la sécrétion d'insuline et agent prophylactique ou thérapeutique pour le diabète.
PCT/JP2010/057035 2009-04-22 2010-04-21 Composé de tétrazole WO2010123017A1 (fr)

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WO2012147516A1 (fr) 2011-04-28 2012-11-01 持田製薬株式会社 Dérivé d'amide cyclique
WO2012147518A1 (fr) 2011-04-27 2012-11-01 持田製薬株式会社 Nouveau dérivé de 1-oxyde de 3-hydroxyisothiazole
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
US9957219B2 (en) 2013-12-04 2018-05-01 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
US10059667B2 (en) 2014-02-06 2018-08-28 Merck Sharp & Dohme Corp. Antidiabetic compounds
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US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
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US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists

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WO2018138030A1 (fr) * 2017-01-26 2018-08-02 Boehringer Ingelheim International Gmbh Acides benzyloxypyrazinylcyclopropanecarboxyliques, compositions pharmaceutiques et utilisations associées
WO2018138029A1 (fr) * 2017-01-26 2018-08-02 Boehringer Ingelheim International Gmbh Acides benzyloxypyridylcyclopropanecarboxyliques, compositions pharmaceutiques et leurs utilisations

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Publication number Priority date Publication date Assignee Title
WO2012046869A1 (fr) 2010-10-08 2012-04-12 持田製薬株式会社 Dérivé d'amide cyclique
WO2012147518A1 (fr) 2011-04-27 2012-11-01 持田製薬株式会社 Nouveau dérivé de 1-oxyde de 3-hydroxyisothiazole
WO2012147516A1 (fr) 2011-04-28 2012-11-01 持田製薬株式会社 Dérivé d'amide cyclique
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
US9957219B2 (en) 2013-12-04 2018-05-01 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
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
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators

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