WO2014146604A1 - Composé à cycles fusionnés présentant une action de régulation de la fonction du récepteur gpr40 - Google Patents

Composé à cycles fusionnés présentant une action de régulation de la fonction du récepteur gpr40 Download PDF

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WO2014146604A1
WO2014146604A1 PCT/CN2014/073852 CN2014073852W WO2014146604A1 WO 2014146604 A1 WO2014146604 A1 WO 2014146604A1 CN 2014073852 W CN2014073852 W CN 2014073852W WO 2014146604 A1 WO2014146604 A1 WO 2014146604A1
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alkyl
cycloalkyl
hydrogen
heteroaryl
compound
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PCT/CN2014/073852
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English (en)
Chinese (zh)
Inventor
刘希杰
校登明
胡远东
王树龙
刘志华
沈宇
彭勇
王欢
罗鸿
孔凡胜
韩永信
Original Assignee
正大天晴药业集团股份有限公司
北京赛林泰医药技术有限公司
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Publication of WO2014146604A1 publication Critical patent/WO2014146604A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel fused ring compounds having a GPR40 receptor function regulating function, a process for the preparation thereof, a pharmaceutical composition thereof and pharmaceutical use thereof.
  • GPR40 is a member of the G protein-coupled receptor superfamily and can be activated by medium and long-chain fatty acids, hence the name of Free Fat Acid Receptor 1 (FFAR1). Studies have shown that activation of the GPR40 receptor lowers blood sugar and causes little hypoglycemia. GPR40 agonist treatment of type 2 diabetes differs from sulfonylureas (such as Amaryl®) in that it stimulates insulin secretion in a blood glucose-dependent manner, greatly reducing the risk of hypoglycemia.
  • FFAR1 Free Fat Acid Receptor 1
  • the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof -
  • R 2 , R 3 , RR 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, nitro, amino, fluorenyl, decyloxy, cycloalkyl, heterocycloalkyl, aryl group, a heteroaryl group, alkyl with -NHCO-, -NHCO- cycloalkyl, -S0 2 - group embankment, -S0 2 - cycloalkyl, -SO-alkyl with, -SO-cycloalkyl, -N (embankment yl) -S0 2 - group embankment, -N (embankment yl) -S0 2 - cycloalkyl, -N (embankment yl) -S0 2 - aryl, -N (alkyl with) -S0 2 - heteroaryl, -NHS0 2
  • L 1 is -CH 2 0-, -CH 2 NH- or ⁇ ⁇ ;
  • L 2 is -0- or -NR 12 -;
  • R 9 and R 1Q are each independently selected from the group consisting of hydrogen, halogen, fluorenyl, hydroxy, decyloxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyano;
  • n 0, 1, 2, 3, 4 or 5;
  • L 3 is a bond or -NR 13 -;
  • R 12 and R 13 are each independently selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, aryl, heteroaryl, -S0 2 -fluorenyl, -S0 2 -cycloalkyl, -SO-fluorenyl, -SO-cycloalkyl , -CO-fluorenyl, -CO-cycloalkyl, -CO-aryl, -CO-heteroaryl, or R 12 and R 13 together with the atom to which they are attached form a heterocyclic ring containing at least two N atoms Hydrocarbyl group;
  • R 11 is -NR 15 R 16 , halogen, hydroxy, cyano, nitro, decyl, decyloxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or R 11 and R 13 and The attached atoms together form a heterocyclic hydrocarbon group containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom;
  • n 0, 1, 2, 3, 4 or 5;
  • R 19 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
  • Prerequisites are: when L 1 is -CH 2 0- or -CH 2 NH -, L 2 is 0 or -NH -, R 9 and R 1Q are hydrogen, n is 2 or 3, L 3 is a bond, L 4 When -S0 2 -, R 11 is a methyl group or an ethyl group, and R 17 and R 18 are hydrogen, R 19 is selected from the group consisting of a cyclic hydrocarbon group, a heterocyclic hydrocarbon group, an aryl group, and a heteroaryl group.
  • RR 2 , R 3 , RR 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen, Cyano, hydroxy, decyl, decyloxy, amino; In some embodiments, ⁇ RR ⁇ R 6 , R 7 and R 8 are hydrogen, and R 2 and R 3 are methyl.
  • R 9 and R 1Q are selected from hydrogen.
  • R 17 and R 18 are hydrogen. In some embodiments, m is one.
  • L 2 is -0-.
  • R 12 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, aryl, heteroaryl; in some preferred embodiments, R 12 is selected from hydrogen, decyl; in some more preferred embodiments R 12 is selected from the group consisting of hydrogen and d 6 fluorenyl; in some most preferred embodiments, R 12 is selected from hydrogen.
  • L 2 when L 2 is -NR 12 - and L 3 is -NR 13 -, R 12 and R 13 together with the atom to which they are attached form a heterocycloalkyl group containing at least two N atoms; In some preferred embodiments, when L 2 is -NR 12 - and L 3 is -NR 13 -, R 12 and R 13 together with the atoms to which they are attached form a 5 or 6 member having at least two N atoms.
  • Heterocyclic hydrocarbon group when L 2 is -NR 12 - and L 3 is -NR 13 -, R 12 and 1 3 together with the atom to which they are attached form two N atoms 6-membered heterocycloalkyl; in some most preferred embodiments, when L 2 is -NR 12 - and L 3 is -NR 13 -, R 12 and R 13 together with the atom to which they are attached form a piperazine base.
  • n is 2 or 3. In some embodiments, n is 2. In some embodiments, n is 3.
  • R 19 is selected from the group consisting of hydrogen, fluorenyl, and cycloalkyl; preferably, R 19 is selected from the group consisting of hydrogen, d- 6 fluorenyl, C 3 -6 cycloalkyl; more preferably, R 19 is selected from hydrogen, A , ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl; most preferably, R 19 is hydrogen.
  • L 4 is —P(0) (R 14 )—, wherein R 14 is hydrogen or fluorenyl; preferably, R 14 is fluorenyl; more preferably, R 14 is d- 6 fluorenyl; even more preferably, R 14 is d 4 fluorenyl; most preferably, R 14 is methyl.
  • L 3 is -NR 13 -, wherein R 13 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, aryl, heteroaryl; preferably, R 13 is selected from hydrogen, decyl; more preferably, R 13 is selected from hydrogen, d 6 fluorenyl; even more preferably, R 13 is selected from hydrogen.
  • R 11 is —NR 15 R 16 , fluorenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
  • R 11 is -N (embankment yl) 2, -NH (; firing-yl), alkyl with, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
  • R 11 is -N(d- 6 fluorenyl) 2 , -NH C fluorenyl, d 6 fluorenyl, C 3 -6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl.
  • R 11 is -N (d_ 6 embankment yl) 2, -NH C ⁇ embankment yl), C ⁇ alkyl with, C ⁇ cycloalkyl.
  • R 11 is -N(Cw fluorenyl) 2 , -NH(Cw fluorenyl), C hydrazino, C ⁇ cycloalkyl.
  • R 11 is —N(CH 3 ) 2 , —NH(CH 3 ), —CH 3 , —C 2 H 5 , cyclopropyl.
  • L 3 when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A heterocyclic hydrocarbon group of an atom. In some embodiments, when L 3 is -NR 13 -, 1 1 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 3-12 membered heterocycloalkyl group of an atom.
  • L 3 when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 3, 4, 5 or 6 membered heterocycloalkyl group of an atom. In some embodiments, when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 5- or 6-membered heterocycloalkyl group of an atom.
  • L 3 when L 3 is -NR 13 -, 1 1 together with R 13 and the atom to which they are attached form a 5 or 6 membered heterocycloalkyl containing S0 2 - and at least one nitrogen atom. In some embodiments, when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form a 5-membered heterocycloalkyl containing -S0 2 - and a nitrogen atom.
  • L 2 is 0, n is 2 or 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, cycloalkyl; , L 2 is 0, n is 2 or 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NHd_ 6 fluorenyl, -N(d_ 6 fluorenyl) 2 , d_ 6 fluorenyl, _ 6- cycloalkyl; in some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl; in some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -N(fluorenyl) 2 , -NH(fluorenyl), fluorenyl; in some embodiments, L 4 is n
  • L 2 is 0, n is 1, 2, 3 or 4, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, ring a hydrocarbyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or R 11 and R 13 together with the atom to which they are attached form a group containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom Heterocyclic hydrocarbon group;
  • L 2 is 0, n is 2 or 3
  • L 3 is -NR 13 -
  • L 4 is -S0 2 -
  • R 11 is -NR 15 R 16 , fluorenyl, ring a hydrocarbyl group, a heterocyclic hydrocarbon group, or R 11 and R 13 together with the atom to which they are attached form a 3-12 membered heterocycloalkyl group containing -P(0)(R
  • L 2 is 0, n is 2 or 3, L 3 is -NR 13 -, L 4 is -S0 2 -, and R 11 and R 13 together with the atoms to which they are attached form - P(0)(R 14 )- or -S0 2 - and a 3, 4, 5 or 6 membered heterocycloalkyl radical of at least one nitrogen atom, or R 11 is a fluorenyl, cycloalkyl, heterocycloalkyl; in some embodiments in, L 2 is 0, n is 2 or 3, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11 and R 13, and Together with the atoms to which they are attached containing -P (0) (R 14) - or -S0 2 - and at least one 5 or 6-membered heterocycloalkyl nitrogen atom; in some embodiments, L 2 is 0, n is 2, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11
  • L 2 is 0, n is 1, 2, 3 or 4, L 3 is a bond, L 4 is -P(0)(R 14 )-, R 11 is a fluorenyl group, a cyclic hydrocarbon group, a hetero Cycloalkyl, aryl, heteroaryl; In some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is -P(0)(fluorenyl)-, R 11 is a fluorenyl group, cycloalkyl, heterocycloalkyl; in some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is a -PiPXCw embankment yl) -, R 11 is alkyl with D_ 6, 3_ [6 cycloalkyl In some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is -P(0)(CH 3 )-, and R 11 is methyl, ethyl, isopropyl,
  • L 2 is -NR 12 -, L 3 is -NR 13 -, and L 4 is -S0 2 -, and R 12 and R 13 together with the atom to which they are attached form at least two N atoms.
  • Heterocycloalkyl in some embodiments, L 2 is -NR 12 -, L 3 is -NR 13 - and L 4 is -S0 2 -, and R 12 and R 13 together with the atoms to which they are attached form at least a 5- or 6-membered heterocycloalkyl containing two N atoms; in some embodiments, L 2 is -NR 12 -, L 3 is -NR 13 - and L 4 is -S0 2 -, 12 and R 13 and The atoms to which they are attached together form a piperazinyl group.
  • One aspect of the invention isomers -
  • n 0, 1, 2, 3, 4 or 5;
  • L 3 is a bond or -NR 13 -;
  • R 13 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, aryl, heteroaryl;
  • L 4 is -P(0)(R 14 )- or -S0 2 -;
  • R 11 is -NR 15 R 16 , halogen, hydroxy, cyano, nitro, decyl, decyloxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or R 11 and R 13 and The attached atoms together form a heterocyclic hydrocarbon group containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom;
  • R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen, fluorenyl, decyloxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
  • n is 2 or 3. In some embodiments, n is 2. In some embodiments, n is 3.
  • R 19 is selected from the group consisting of hydrogen, fluorenyl, and cycloalkyl; preferably, R 19 is selected from the group consisting of hydrogen, d- 6 fluorenyl, C 3 -6 cycloalkyl; more preferably, R 19 is selected from hydrogen, A , ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl group; most preferably, R 19 is hydrogen.
  • L 4 is -S0 2 -.
  • L 4 is —P(0) (R 14 )—, wherein R 14 is hydrogen or fluorenyl; preferably, R 14 is fluorenyl; more preferably, R 14 is d- 6 fluorenyl; even more preferably, R 14 is d 4 fluorenyl; most preferably, R 14 is methyl.
  • L 4 when L 3 is a bond, L 4 is -S0 2 -.
  • L 3 is -NR 13 -, wherein R 13 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, aryl, heteroaryl; preferably, R 13 is selected from hydrogen, decyl; more preferably, R 13 is selected from hydrogen, d 6 fluorenyl; more preferably, R 13 is selected from hydrogen.
  • R 11 is selected from the group consisting of -NR 15 R 16 , fluorenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl. In some embodiments, R 11 is selected from -N(indenyl) 2 , -NH (;indenyl), fluorenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 11 is selected from -N(Cw fluorenyl) 2 , -NH(Cw fluorenyl), C hydrazino, C ⁇ cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5 or 6-membered heteroaryl.
  • R 11 is selected from the group consisting of -N(d- 6 fluorenyl) 2 , -NH C fluorenyl), d- 6 fluorenyl, -6 cycloalkyl. In some embodiments, R 11 is —N(d 4 fluorenyl) 2 , —NH Cw fluorenyl, C 1-4 fluorenyl, C 3-6 cycloalkyl. In some embodiments, R 11 is —N(CH 3 ) 2 , —NH(CH 3 ), —CH 3 , —C 2 H 5 , cyclopropyl.
  • L 3 when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A heterocyclic hydrocarbon group of an atom. In some embodiments, when L 3 is -NR 13 -, 1 1 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 3-12 membered heterocycloalkyl group of an atom.
  • L 3 when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 3, 4, 5 or 6 membered heterocycloalkyl group of an atom. In some embodiments, when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 5- or 6-membered heterocycloalkyl group of an atom.
  • n is 2 or 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, cycloalkyl; in some embodiments, n is 2 or 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NHd_ 6 fluorenyl, -N(d_ 6 fluorenyl) 2 , C ⁇ fluorenyl, [ 3 -6 cycloalkyl; in some embodiments Wherein n is 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl; in some embodiments, n is 3, L 3 is a bond, and L 4 is - S0 2 -, R 11 is -N(fluorenyl) 2 , -NH(fluorenyl), fluorenyl; in some embodiments, n is 3, L 3 is a bond, and
  • n 1, 2, 3 or 4, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, cycloalkyl, heterocycloalkyl , aryl, heteroaryl, or R 11 and R 13 together with the atom to which they are attached form a heterocycloalkyl containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom;
  • n is 2 or 3 is -NR 13 -, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, cycloalkyl, heterocycloalkyl, or R 11 R 13 and together with the atoms to which they are attached form a 3-12 membered heterocycloalkyl containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom; in some embodiments,
  • n 1, 2, 3 or 4
  • L 3 is a bond
  • L 4 is -P(0)(R 14 )-
  • R 11 is a fluorenyl group, a cyclic hydrocarbon, a heterocycloalkyl group, an aryl group.
  • n is 3, L 3 is a bond, L 4 is -P(0)(fluorenyl)-, 1 is a fluorenyl, cycloalkyl, heterocycloalkyl; in some embodiments Wherein n is 3, L 3 is a bond, L 4 is -PiPXCw ⁇ ) -, R 11 is a C ⁇ fluorenyl group, a C ⁇ cycloalkyl group; in some embodiments, n is 3, L 3 is a bond, L 4 Is -P(0)(CH 3 )-, 1 is methyl, ethyl, isopropyl, -CH 2 -cyclopropyl, cyclopropyl.
  • Another aspect of the invention also relates to a process for the preparation of a compound of formula I or a salt thereof or a stereoisomer thereof, wherein
  • the compound of the formula I or a salt thereof or a stereoisomer thereof can be produced by the following method:
  • the compound of the formula I can be produced by a Mitsunobu reaction of the compound of the formula 1 and the compound of the formula 2.
  • compound 1 and compound 2 are in an azodicarbonyl compound (e.g., diethyl azodicarboxylate, diisopropyl azodicarboxylate, hydrazine, hydrazine-(azodicarbonyl)dipiperidine) and Reaction in the presence of an organophosphine compound such as triphenylphosphine, tributylphosphine;
  • the compound of the formula I can be prepared by reacting a compound of the formula 1 with a compound of the formula 2 in the presence of a base.
  • the leaving group may be a halogen atom, a fluorenylsulfonyloxy group optionally substituted by chlorine.
  • the base used may be an alkali metal hydroxide, an alkali metal carbonate or an organic base.
  • the compound of the formula I or a salt thereof or a stereoisomer thereof can be produced by the following method:
  • X is a leaving group
  • the compound of the formula I can be produced by reacting a compound represented by the formula 1 and a compound represented by the formula 3 in the presence of a base. It is also possible to produce a Schiff base by reacting a compound of the formula 4 with a compound of the formula 3, and then preparing the compound I by reduction with a reducing agent.
  • the compound of the formula I or a salt thereof or a stereoisomer thereof can be produced by the following method -
  • X is a leaving group
  • the compound of the formula I can be produced by a coupling reaction of a compound represented by the formula 5 and a compound represented by the formula 6 in the presence of a palladium catalyst.
  • the compounds represented by Formulas 1, 4 and 5 can be prepared by the following methods:
  • the compound represented by Formulas 1, 4 and 5 can be produced by reacting a compound represented by Formula 7 with a compound represented by Formula 8 in the presence of a base.
  • the compounds of the invention may be asymmetric, for example, having one or more chiral centers and thus having one or more stereoisomers. All stereoisomeric forms are included, such as enantiomers and diastereomers, unless otherwise indicated.
  • the asymmetric carbon atom-containing compound of the present invention can be isolated in optically active pure form or as a racemic mixture.
  • the optically active pure form can be resolved from the racemic mixture or it can be synthesized by using a chiral starting material or a chiral reagent.
  • a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned.
  • metal salts include, but are not limited to, alkali metal salts such as sodium salts, potassium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts and the like.
  • Non-limiting examples of salts formed with organic acids include, but are not limited to, with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzene. a salt formed of a sulfonic acid, p-toluenesulfonic acid or the like.
  • Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, and the like.
  • Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, and the like.
  • Another aspect of the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or II of the invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention or a salt thereof or a stereoisomer thereof with a suitable pharmaceutically acceptable carrier, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation, such as Tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • a suitable pharmaceutically acceptable carrier for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation, such as Tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, Parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous.
  • a preferred route of administration is oral administration.
  • the pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a dragee method, a pulverization method, an emulsification method, a lyophilization method, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by admixing the active compound with a pharmaceutically acceptable carrier well known in the art. These carriers enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules. The core of a tablet or dragee.
  • Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • microcrystalline cellulose glucose solution, gum arabic, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol Sugar alcohol or dicalcium phosphate; silica; croscarmellose sodium, pre-treated starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, carboxymethyl fiber , cross-linked polyvinylpyrrolidone and the like.
  • the core of the dragee can optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • suitable excipients such as fillers, buffers or surfactants can be used.
  • Another aspect of the invention also relates to a compound of formula I or II of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in the treatment and/or prevention of a disease associated with GPR40.
  • Another aspect of the invention also relates to a compound of formula I or hydrazine of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of diabetes, a stereoisomer thereof.
  • Another aspect of the invention also relates to a method of treating and/or preventing a disease associated with GPR40, wherein a therapeutically effective amount of a compound of formula I or hydrazine of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof The body is administered to a mammal in need thereof.
  • Another aspect of the invention also relates to a method of treating and/or preventing diabetes, wherein a therapeutically effective amount of a compound of formula I or II of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is required Mammal administration.
  • the daily dose is preferably 0.01 to 200 mg/kg body weight.
  • the EC 5Q is less than 1000 nM, more preferably the EC 5Q is less than 100 nM, and most preferably the EC 5Q is less than 10 nM.
  • halogen means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
  • cyano refers to a -CN group.
  • nitro refers to a -N0 2 group.
  • mercapto refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which is attached to the remainder of the molecule by a single bond.
  • the fluorenyl group can have from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, and most preferably from 1 to 4 carbon atoms.
  • the thiol group may be unsubstituted or substituted with a substituent.
  • Non-limiting examples of sulfhydryl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, Neopentyl, n-hexyl, 2-methylhexyl, -CH 2 -cyclopropyl, and the like.
  • decyloxy refers to a -0-fluorenyl group, wherein the definition of fluorenyl is the same as defined above.
  • a decyloxy group having 1 to 4 carbon atoms is preferred.
  • the oximeoxy group may be unsubstituted or substituted with a substituent.
  • methoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy , 2-methylbutoxy, neopentyloxy, n-hexyloxy, 2-methylhexyloxy and the like.
  • cycloalkyl refers to a saturated or unsaturated, non-aromatic cyclic hydrocarbon group consisting of carbon atoms and hydrogen atoms, preferably containing 1, 2 or 3 rings, each ring having 3 to 7 ring carbon atoms. More preferably, it is a saturated cyclic fluorenyl group containing 3 to 12 ring carbon atoms in total, and most preferably a saturated cyclic fluorenyl group containing 3 to 6 ring carbon atoms in total.
  • the cyclic hydrocarbon group may be unsubstituted or substituted with a substituent.
  • Non-limiting examples of cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like.
  • alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group having at least one double bond consisting of a carbon atom and a hydrogen atom, preferably a linear or branched alkenyl group having 2 to 4 carbon atoms. .
  • the alkenyl group may be unsubstituted or substituted with a substituent.
  • Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl.
  • alkynyl means a straight or branched unsaturated aliphatic hydrocarbon group having at least one triple bond composed of a carbon atom and a hydrogen atom, preferably a linear or branched alkynyl group having 2 to 4 carbon atoms. .
  • the alkynyl group may be unsubstituted or substituted with a substituent.
  • Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl.
  • amino refers to a -NH 2 group in which a hydrogen atom may be substituted with a substituent.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system, preferably having from 6 to 14 carbon atoms, more preferably from 6 to 10 carbon atoms.
  • the aryl group may be unsubstituted or substituted with a substituent.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system having from 5 to 14 ring atoms containing from 1 to 6 ring atoms selected from N, 0, S, the remaining ring atoms being C, and having at least An aromatic ring.
  • the heteroaryl group preferably has a 5- or 6-membered ring, more preferably a 5-membered ring.
  • the heteroaryl group may be unsubstituted or substituted with a substituent.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , tetrazolyl, triazolyl, triazinyl.
  • heterocycloalkyl refers to a non-aromatic monocyclic or fused polycyclic system group having from 3 to 18 ring atoms, wherein from 1 to 6 ring atoms are selected from N, 0, S( ) n (where n is a hetero atom of 0, 1 or 2), and the remaining ring atoms are [. Such rings may be saturated or unsaturated (eg, having one or more double bonds), but do not have a fully conjugated ⁇ -electron system.
  • the heterocyclic hydrocarbon group may be unsubstituted or substituted with a substituent.
  • Examples of the 3-membered heterocyclic hydrocarbon group include, but are not limited to, an epoxyethyl group, an episulfothyl group, a cyclohexamethylene group, and examples of the 4-membered heterocyclic hydrocarbon group include, but are not limited to, azetidinyl, oxetane, thidium
  • Examples of the cyclic group, 5-membered heterocycloalkyl group include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, 1,1-dioxo
  • Examples of thiazolylhydrazyl, thiazolylhydrazyl, imidazolium, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl, 6-membered heterocycloalkyl
  • terapéuticaally effective amount means that when administered to a mammal, preferably a human, the Formula I or guanidine compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is sufficient to effectively treat a mammal.
  • the amount of (preferably human) a disease associated with GPR40, particularly a diabetes-related disease.
  • the amount of a compound of formula I or hydrazine of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer thereof which constitutes a "therapeutically effective amount” depends on the compound, the state of the disease and its severity, the mode of administration, and the condition to be treated. The age of the mammal varies, but can be routinely determined by one skilled in the art based on its own knowledge and disclosure of the present invention.
  • treating means administering a compound or formulation of the invention to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • pharmaceutical composition refers to one or more of the formula I or indole compounds of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and are generally accepted in the art for use in biologically active compounds.
  • the purpose of the pharmaceutical composition is to facilitate administration of an organism of the formula I or hydrazine compound of the present invention or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, to an organism.
  • pharmaceutically acceptable carrier refers to those carriers and diluents which do not significantly irritate the organism and which do not impair the biological activity and properties of the active compound.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, any carrier, excipient, vehicle, glidant, sweetener, diluent, for human or livestock animals that is approved by the National Food and Drug Administration as acceptable. Preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • the column chromatography was carried out using silica gel (200-300 mesh) produced by Qingdao Chemical Co., Ltd. Thin layer chromatography was carried out using a prefabricated plate manufactured by E. Merck (silica gel 60 PF254, 0.25 mm). Nuclear magnetic resonance chromatography (NMR) was measured using a Varian VNMRS-400 NMR spectrometer; LC/MS was performed using FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 series (column: Waters Symmetry CI 8, ⁇ 4.6 50 mm, 5 micron, 35 °C) in ESI(+) ion mode.
  • NMR nuclear magnetic resonance chromatography
  • Step 2 Synthesis of 4,-(tert-butyldimethylsilyloxy)-2,6,-dimethylbiphenyl-3-carbaldehyde
  • Step 4 2-(6-((4-tert-Butyldimethylsilyloxy)- 2 6 dimethylbiphenyl-3-yl)methoxy)-2,3»dihydrobenzofuran- Synthesis of 3»yl)methyl acetate
  • Step 7 2-(6- ⁇ (4'-(Dimethylphosphono)propoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)-2,3 Synthesis of methyl 2-dibenzofuran-3-yl)acetate
  • Step 8 2-(6-((4'-(3-(Dimethylphosphonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)-2 Synthesis of 3-dihydrobenzofuran-3-yl)acetic acid
  • Step 2 2-(6-((4'-(2-Aminoethoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydro Benzofuran-3-yl)B Synthesis of acid methyl ester
  • Step 3 2-(6-((2,6,-Dimethyl-4,-(2-(methylsulfonylamino)ethoxy)biphenyl-3-yl)methoxy)-2 Synthesis of methyl 3-hydrobenzofuran-3-yl)acetate
  • Step 4 2-(6-((2',6'-Dimethyl-4'-(2-(methylsulfonylamino)ethoxy)biphenyl-3-yl)methoxy)-2, Synthesis of 3-dihydrobenzofuran-3-yl)acetic acid
  • Step 1 2-(6-((4'-(2-(3-Chloropropylsulfonylamino)ethoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy) Synthesis of methyl-2,3-dihydrobenzofuran-3-yl)acetate
  • Step 2 2-(6-((4'-(2-(1,1-dioxo-isothiazol-2-yl)ethoxy) ⁇ 2',6'-dimethylbiphenyl Synthesis of methyl methoxy)- 2,3 ⁇ di-benzobenzopyran-3-yl)acetate
  • Step 3 2-(6-((4'-(2-(1,1-dioxo-isothiazol-2-yl)ethoxy)-2',6'-dimethylbiphenyl- Synthesis of 3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
  • Step 1 Synthesis of sodium 3-(4-bromo-3,5-dimethylphenoxy)propyl-1-sulfonate
  • Step 3 Synthesis of ⁇ V-dimethyl-3-(4-bromo-3,5-dimethylphenoxy)propyl-1-sulfonamide
  • Step 4 Synthesis of 4'-(3-(N,N-dimethylaminosulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-carbaldehyde
  • Step 5-7 2-(6-((2',6'-Dimethyl-4'-(3-(N,N-dimethylaminosulfonyl)propoxy)biphenyl-3-yl) Synthesis of methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
  • reaction mixture was cooled to room temperature, it was filtered, and the filtrate was subjected to reduction under reduced pressure.
  • tetrahydrofuran 50 mL was added, and then 3M: hydrochloric acid (10 mL was added, and the mixture was stirred at room temperature for 2 hours.
  • the reaction mixture was combined and concentrated under reduced pressure, and then dissolved in water (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated.
  • Step 2 02- ⁇ 6-((4'-yl-2,6'-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl) Synthesis of formamidine acetate
  • EtOAc EtOAc 2'6'-Dimethylbiphenyl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (0,82 g, yield 95, 0%).
  • Step 3 >2 ⁇ (6-((4'-(Cyanomethoxy) ⁇ 2 dimethylbiphenyl ⁇ 3-yl)methoxy) ⁇ 2,3-dibenzobenzopyrene- Synthesis of 3-methyl) methyl acetate
  • Potassium carbonate (2.0 g, 14.5 mmol) was added to (5 -2-(6 (4 f -hydroxy',6'-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzene And furan 3-yl)acetic acid formazan (3. () g, 7.2 mm oi) and bromoacetonitrile (1.8 g, 15.0 mmol) in acetonitrile (100 mL). The mixture was stirred at room temperature overnight and filtered.
  • Step 4 '>-2-(6-((2-Aminoethoxy)-2»,6'-dimethylbiphenyl-3-yl)methoxy)-2,3- Synthesis of Methyl Dihydrobenzofuran-3-yl)acetate
  • Step 5 (5)-2 (6-((4' ⁇ (2-(3-(propylsulfonyl)yl)ethoxy) 2',6'-dimethylbiphenyl-3 ⁇ yl Synthesis of methyl methoxy)-2,3-dioxabenzofuran ⁇ 3-yl)acetate
  • Step 6 >2 ⁇ (6-((4'-(2-(1,_-Dioxy'f ⁇ -isothiazolium ⁇ 2-yl)ethoxy)-2',6' ⁇ dimethyl Synthesis of methyl phenyl)methoxy)-2,3-difluorenylbenzofuranylacetate
  • Step 4 Synthesis of 2,6,-dimethyl-4,-(3-(methylsulfonyl)propoxy)-biphenyl-3-phenol
  • Step 5 Synthesis of 2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)-3-trifluoromethanesulfonyloxy-biphenyl
  • reaction mixture was subjected to reduction under reduced pressure, and the obtained dog was separated and purified by silica gel column chromatography to obtain 2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)- 3-Trifluoromethanesulfonyloxy-biphenyl i: 0.43 g, yield 85J:) 3 ⁇ 4).
  • Step 6 2-(6-((2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)ethynyl)-2,3 Synthesis of Methyl-Dihydrobenzofuran-3-yl)acetate
  • Step 7 2-(6-((2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)ethynyl)-2,3- Synthesis of dihydrobenzofuran-3-yl)acetic acid
  • Vector plasmid pcDNA3.1 was purchased from Invitrogen®. Using the two DNA restriction endonuclease sites of BamHI and EcoRV, the fully cloned GPR40 full-length gene was ligated into the pCDNA3.1 vector by T4 DNA ligase, and then transfected into DH5a competent cells, and added Successfully transfected monoclonals were selected on LB agar medium with antibiotic Ampilline (1 g/mL), plasmids were extracted and the gene sequence was determined by DNA sequencing.
  • the present invention uses a calcium flow method to determine the effect of a compound on the intracellular calcium concentration of GPR40 stably expressing cells, thereby reflecting the agonistic effect on GPR40.
  • This agonistic activity is expressed by the index of EC 5Q , which is the concentration of the compound corresponding to the activity of GPR40 which is excited to 50% of the maximum value.
  • Fluo-4 Calcium Flow Kit (Invitrogen®, Cat. No. F10471), including FLuo-4 Calcium Dye, Probenecid and Fluo-4 Calcium Flow Reaction Buffer.
  • DMEM cell culture solution (Gilbco®, Cat.No.C11995500B)
  • fetal bovine serum (Hyclone®, Cat.No.SV30087)
  • GPR40 stably expressing cells were plated into a 96-well black-bottomed cell culture plate coated with polylysine at a density of 2 ⁇ 10 4 cells/well, and DMEM medium was supplemented with 10% fetal bovine serum and 400 g/mL of G418 sulfate was grown overnight in a 37 ° C, 5% carbon dioxide incubator.
  • Table 1 The agonistic activity of the compounds of the examples of the invention on GPR40
  • the present invention uses a method of oral glucose tolerance test (OGTT) in mice to measure the hypoglycemic effect of a compound in vivo.
  • OGTT oral glucose tolerance test
  • mice were weighed and fasted for 16 hours and measured for fasting blood glucose (G Q ), randomized according to G Q , 5 mice per group. 2), the mice were administered with different concentrations of the test compound by intragastric administration, and 25% of the HS-15 was administered to the control mice with 25% polyethylene glycol stearate (HS-15) as a solvent.
  • G Q blood glucose
  • HS-15 polyethylene glycol stearate
  • mice were orally administered with an aqueous solution of glucose at 2.0 g/kg body weight.
  • mice 15 minutes, 30 minutes, 60 minutes, and 120 minutes after oral glucose administration were measured by blood glucose meter, and were recorded as 0 15 , G 30 , G 60 and PG 120 , respectively .
  • Fig. 1 and Fig. 2 show that the compound of Example 11 of the present invention has a significant hypoglycemic effect in normal C57 mice, and the compound of Example 11 of the present invention has a hypoglycemic effect at 30-50 mg/kg. There are significant advantages.

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Abstract

La présente invention concerne un composé à cycles fusionnés présentant une action de régulation de la fonction du récepteur GPR40, et un procédé de préparation et des compositions pharmaceutiques correspondantes, ainsi que son utilisation dans des médicaments destinés à traiter et/ou à prévenir des maladies associées à GPR40, en particulier le diabète.
PCT/CN2014/073852 2013-03-22 2014-03-21 Composé à cycles fusionnés présentant une action de régulation de la fonction du récepteur gpr40 WO2014146604A1 (fr)

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Cited By (10)

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WO2015097713A1 (fr) 2013-11-14 2015-07-02 Cadila Healthcare Limited Nouveaux composés hétérocycliques
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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