WO2008157404A2 - Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators - Google Patents

Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators Download PDF

Info

Publication number
WO2008157404A2
WO2008157404A2 PCT/US2008/066984 US2008066984W WO2008157404A2 WO 2008157404 A2 WO2008157404 A2 WO 2008157404A2 US 2008066984 W US2008066984 W US 2008066984W WO 2008157404 A2 WO2008157404 A2 WO 2008157404A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
cycloalkyl
chr
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2008/066984
Other languages
English (en)
French (fr)
Other versions
WO2008157404A3 (en
Inventor
Jean-Michel Vernier
Samedy Ouk
Martha Alicia De La Rosa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bausch Health Americas Inc
Original Assignee
Valeant Pharmaceuticals International Inc USA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Valeant Pharmaceuticals International Inc USA filed Critical Valeant Pharmaceuticals International Inc USA
Priority to PL08771077T priority Critical patent/PL2170861T3/pl
Priority to BRPI0812564-3A2A priority patent/BRPI0812564A2/pt
Priority to CA002689208A priority patent/CA2689208A1/en
Priority to MX2009013581A priority patent/MX2009013581A/es
Priority to HRP20120857AT priority patent/HRP20120857T1/hr
Priority to CN200880102338A priority patent/CN101868451A/zh
Priority to AU2008266009A priority patent/AU2008266009B2/en
Priority to EP08771077A priority patent/EP2170861B1/en
Priority to DK08771077.8T priority patent/DK2170861T3/da
Priority to ES08771077T priority patent/ES2392774T3/es
Priority to JP2010512399A priority patent/JP2010530002A/ja
Priority to SI200830745T priority patent/SI2170861T1/sl
Publication of WO2008157404A2 publication Critical patent/WO2008157404A2/en
Publication of WO2008157404A3 publication Critical patent/WO2008157404A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention concerns novel compounds that modulate potassium channels.
  • the compounds are useful for the treatment and prevention of diseases and disorders which are affected by activities of potassium ion channels.
  • One such condition is seizure disorders.
  • this invention provides a compound of formula I
  • Amine-Ring is one of Groups A or B below A
  • Ar is a 1,2-fused, six membered ring aromatic group, bearing substituents Ri and R 2 as defined below, and containing zero or one ring nitrogen atom;
  • Ar is a 1,2-fused, six membered ring aromatic group, bearing substituents Ri and R 2 as defined below, and containing zero or one ring nitrogen atom;
  • Amine-Ring is one of Groups A or B below
  • Ar is a 1,2-fused, six membered ring aromatic group, bearing substituents Ri and R 2 as defined below, and containing zero, one, or two ring nitrogen atom;
  • Ar is a 1,2-fused, six membered ring aromatic group, bearing substituents Ri and R 2 as defined below, and containing zero, one, or two ring nitrogen atom;
  • this invention provides a composition
  • a composition comprising a pharmaceutically acceptable carrier and at least one of the following: i) a pharmaceutically effective amount of a compound of formula I and ii) a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • this invention provides a method of preventing or treating a disease or disorder which is affected by modulation of potassium channels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a salt, ester, or prodrug thereof.
  • This invention includes all tautomers and salts, as well as all stereoisomeric forms, of compounds of this invention.
  • This invention also includes all compounds of this invention where one or more atoms are replaced by a radioactive isotope thereof.
  • this invention provides a compound of formula IAl below.
  • this invention provides a compound of formula IA2 below.
  • this invention provides a compound of formula IA3 below.
  • this invention provides a compound of formula IA4 below.
  • this invention provides a compound of formula IA5 below.
  • the invention provides a compound of formula IB 1 below.
  • the invention provides a compound of formula IB2 below.
  • the invention provides a compound of formula IB3 below.
  • the invention provides a compound of formula IB4 below.
  • the invention provides a compound of formula IB5 below.
  • the invention provides a compound of any of formulas IA1-IA5, where W and Z are both N.
  • this invention provides a compound of any of formulas IA1-IA5, where W is N and Z is C.
  • this invention provides a compound of any of formulas IA1-IA5, where W is C and Z is N. In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IA1-IA5, where R' is H, halogen, CF3, or methyl.
  • this invention provides a compound of any of formulas IA1-IA5, where W and Z are both N and R' is H, F, or methyl.
  • the invention provides a compound of any of formulas IB 1 -IB5 , where W and Z are both N.
  • this invention provides a compound of any of formulas IB1-IB5, where W is N and Z is C.
  • this invention provides a compound of any of formulas IB1-IB5, where W is C and Z is N. In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IB1-IB5, where R' is H, halogen, CF3, or methyl. In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IB1-IB5, where W and Z are both N and R' is H, F, or methyl.
  • CH CR 6 -C 3 -C 6 cycloalkyl, (CHR 6 )JC 5 -C 6 cycloalkenyl, CH 2 (CHR 6 )wC 5 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl.
  • Y is O
  • R 5 is Ci-C 6 alkyl or (CHR 6 )JZ 3 -C 6 cycloalkyl.
  • Y is S
  • R 5 is Ci-C 6 alkyl or (CHR6) W C 3 -C 6 cycloalkyl.
  • Y is O
  • R 5 is Ci-C 6 alkyl or (CHR 6 )JZ 3 -C 6 cycloalkyl.
  • Y is S
  • R 5 is Ci-C 6 alkyl or (CHR 6 ) W C 3 -C 6 cycloalkyl.
  • this invention provides or contemplates a compound of formula IAl, IA2, IA3, IA4, IA5, IBl, IB2, IB3, IB4 or IB5, where Ri is halogen; R 2 is H, halogen, or Ci-C 4 alkyl; X is O; and R 5 is Ci-C 6 alkyl, (CHR 6 ) W C 3 -C 6 cycloalkyl, (CHR 6 ) W CH 2 C 3 -C 6 cycloalkyl, or CH 2 (CHR6) W C 3 -C 6 cycloalkyl.
  • this invention provides or contemplates a compound of formula IAl, IA2, IA3, IA4, IA5, IBl, IB2, IB3, IB4 or IB5, where Ri is halogen or halomethyl; R 2 is H, halogen, or Ci-C 4 alkyl; X is O; and R 5 is Ci-C 6 alkyl, (CHR 6 ) W C 3 -C 6 cycloalkyl, (CHR 6 ) W CH 2 C 3 -C 6 cycloalkyl, or CH 2 (CHR6) W C 3 -C 6 cycloalkyl.
  • this invention provides or contemplates a compound of formula IAl, IA2, IA3, IA4, IA5, IBl, IB2, IB3, IB4 or IB5, where Ri is halogen or halomethyl; R 2 is H, halogen, or Ci-C 4 alkyl; R' is halogen, methyl, or halomethyl; X is O; and R 5 is Ci-C 6 alkyl, (CHR6) W C 3 -C 6 cycloalkyl, (CHR 6 ) W CH 2 C 3 -C 6 cycloalkyl, or CH 2 (CHR 6 ) W C 3 - C 6 cycloalkyl.
  • this invention provides or contemplates a compound of formula IAl, IA2, IA3, IA4, IA5, IBl, IB2, IB3, IB4 or IB5, where Ri is halogen or halomethyl; R 2 is H, halogen, or C 1 -C 4 alkyl; X is O; and R 5 is one of the groups above.
  • this invention provides or contemplates a compound of formula IAl, IA2, IA3, IA4, IA5, IBl, IB2, IB3, IB4 or IB5, where Ri is OCi-C 6 alkyl, SCi-C 6 alkyl, C 3 -C 6 cycloalkyl, (CH 2 ) m C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, (CH 2 ) m C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl.
  • Ri is OCi-C 6 alkyl, SCi-C 6 alkyl, C 3 -C 6 cycloalkyl, (CH 2 ) m C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, (CH 2 ) m C 3 -C 6 cycloalkenyl, C 2 -
  • this invention provides or contemplates a compound of formula IAl, IA2, IA3, IA4, IA5, IBl, IB2, IB3, IB4 or IB5, where R 1 is phenyl, pyridyl, pyrrolyl, (CH 2 ) m pyrazyl, (CH 2 ) m imidazolyl, (CH 2 ) m oxazolyl, (CH 2 ) m isoxazolyl, (CH 2 ) m thiazolyl, (CH 2 ) m pyridyl, (CH 2 ) m isothiazolyl, (CH 2 ) ⁇ ,phenyl, (CH 2 ) ⁇ ,pyrrolyl, or (CH 2 ) m pyrimidyl.
  • R 1 is phenyl, pyridyl, pyrrolyl, (CH 2 ) m pyrazyl, (CH 2 ) m imidazolyl, (CH 2 )
  • this invention provides or contemplates a compound of formula IAl, IA2, IA3, IA4, IA5, IBl, IB2, IB3, IB4 or IB5, where Ri is OCi-C 6 alkyl, SCi-C 6 alkyl, C 3 -C 6 cycloalkyl, (CH 2 ) m C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, (CH 2 ) m C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, and R 5 is C 5 -C 6 alkyl or CH 2 -C 3 -C 6 cycloalkyl.
  • this invention provides or contemplates a compound of formula IAl, IA2, IA3, IA4, IA5, IBl, IB2, IB3, IB4 or IB5, where Ri is phenyl, pyridyl, pyrrolyl, (CH 2 ) m imidazolyl, (CH 2 ) m pyrazyl, (CH 2 ) m oxazolyl, (CH 2 ) m isoxazolyl, (CH 2 ) m thiazolyl, (CH 2 ) m isothiazolyl, (CH 2 ) m phenyl, (CH 2 ) m pyrrolyl, (CH 2 ) ⁇ pyridyl, or (CH 2 ) m pyrimidyl, and R 5 is C 5 -C 6 alkyl or CH 2 -C 3 -C 6 cycloalkyl.
  • this invention provides or contemplates a compound of formula IAl, IA2, IA3, IA4, IA5, IBl, IB2, IB3, IB4 or IB5, where Ri is halogen, Ci-C 6 alkyl, mono-halo Ci-C 6 alkyl, CN, di-halo Ci-C 6 alkyl, CF 3 , CN, or 0-Ci-C 6 alkyl, and R 5 is C 5 -C 6 alkyl or CH 2 -C 3 -C 6 cycloalkyl.
  • this invention provides or contemplates a compound of formula IAl, IA2, IA3, IA4, IA5, IBl, IB2, IB3, IB4 or IB5, where Ri is halogen, cyano, CF 3 , or methoxy, R 2 is H or methyl, R' is H, halogen, or methyl, and R 5 is C 5 -C 6 alkyl or CH 2 -C 3 -C 6 cycloalkyl.
  • this invention provides or contemplates a compound of formula IAl, IA2, IA3, IA4, IA5, IBl, IB2, IB3, IB4 or IB5, where R is halogen, CF 3 , or Ci-C 3 alkyl.
  • this invention provides or contemplates a compound of formula IAl, IA2, IA3, IA4, IA5, IBl, IB2, IB3, IB4 or IB5, where Ri is halogen; R 2 is H or methyl, R' is H, halogen, or methyl; and R 5 is C 5 -C 6 alkyl or CH 2 -C 5 -C 6 cycloalkyl.
  • this invention provides or contemplates a compound of formula IAl, IA2, IA3, IA4, IA5, IBl, IB2, IB3, IB4 or IB5, where Ri is halogen; R 2 is H or methyl, R' is H, halogen, or methyl; and R 5 is CH 2 -C 4 -alkyl or CH 2 -C 5 - alkyl.
  • this invention provides a compound of formula I, where Ri or R 5 is CH 2 Ari or CH 2 CH 2 - Ari, where Ari is phenyl, pyridyl, pyrrolyl, imidazolyl, oxazolyl, or thiazolyl.
  • this invention provides a compound of formula I, where Ri and R 2 form pyrrolo, imidazolo, oxazolo, or thiazolo.
  • this invention provides a compound of formula I, where Ri or R 5 is CH 2 Ar i or CH 2 CH 2 - Ari, where Ari is isoxazolyl or iso thiazolyl.
  • this invention provides a compound of formula I, where Ri or R 5 is CH 2 Ar i or CH 2 CH 2 - Ari, where Ari is quinolyl or isoquinolyl.
  • this invention provides a compound of formula I, where Ri or R 5 is CH 2 Ar i or CH 2 CH 2 - Ari, where Ari is pyrimidyl or purinyl.
  • this invention provides a compound of formula I, where Ri or R 5 is CH 2 Ar i or CH 2 CH 2 - Ari, where Ari is indolyl, isoindolyl, or benzimidazolyl. In a more specific embodiment, this invention provides a compound of formula I, where
  • Ri or R 5 is CH 2 Ar i or CH 2 CH 2 - Ari, where Ari is halo phenyl.
  • this invention provides a compound of formula I, where Ri or R 5 is CH 2 Ar i or CH 2 CH 2 - Ari, where Ari is dihalophenyl or dihalopyridyl.
  • invention provides or contemplates a compound of formula I, where Ari is mono- or di-halothienyl, mono- or di-halofuryl, mono-or di- halobenzothienyl, or mono- or di-halobenzofuryl.
  • this invention provides or contemplates a compound of formula I, where Ri or R 5 is CH 2 Ar 1 or CH 2 CH 2 -Ari, where Ari is o-, m-, orp- xylyl or o-, m-, orp-anisyl.
  • this invention provides or contemplates a compound of formula I, where Ri or R5 is CH 2 Ar 1 or CH 2 CH 2 -Ari, where Ari is m- orp- cyanophenyl or m- orp-cyanomethyl phenyl. In another more specific embodiment, this invention provides a compound of formula I, where Ri or R 5 is CH 2 Ar 1 or CH 2 CH 2 - Ari, where Ari is C 2 -C 5 alkylphenyl.
  • this invention provides a compound of formula I, where Ri or R 5 is CH 2 Ari or CH 2 CH 2 -Ar I , where Ari is 3,5-dichlorophenyl or 3,5- difluorophenyl. In a more specific embodiment, this invention provides a compound of formula I, where
  • Ri or R 5 is Ar h (CHR ⁇ w Ari, CH 2 (CHR 6 ) w Ari, or (CHR 6 ) w CH 2 Ari, where Ar 1 is phenyl or pyridyl, R 3 and R 4 are H or Ci-C 6 alkyl, unsubstituted or substituted with one or two groups selected from OH, OMe; Ri is CN, CH 2 CN, or halogen; q is 1 ; and X and Y are both O.
  • this invention provides a compound of formula I, where R 5 is Ari, CH 2 (CHR6) w Ari, or (CHR6) w CH 2 Ari, where Ari is phenyl or pyridyl, Ri is F, CH 2 F, CHF 2 , CF 3 , or CF 2 CF 3 , q is 1, and X and Y are both O.
  • this invention provides a compound of formula I, where Ri or R 5 is Ar h (CHR ⁇ w Ari, CH 2 (CHR 6 ) w Ari, or (CHR 6 ) w CH 2 Ari, where Ari is phenyl or pyridyl, Ri is OCi-C 6 alkyl or alkyl, q is 1, and X and Y are both O.
  • this invention provides a compound of formula I, where
  • this invention provides a compound of formula I, where R 5 is Ari, (CHR 6 ) w Ari, CH 2 (CHR 6 ) W Ar I , or (CHR 6 ) W CH 2 Ar I , where Ari is phenyl or pyridyl, Ri is C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, q is 1 , and X and Y are both O.
  • this invention provides a compound of formula I, where where R 5 is Ari, (CHR 6 ) W Ar I , CH 2 (CHR 6 ) W Ar I , or (CHR 6 ) W CH 2 Ar I , Ari is phenyl or pyridyl, Ri is SCi-C 6 alkyl, q is 1, and X and Y are both O.
  • this invention provides a compound of formula I, where R 5 is Ari, (CHR 6 ) w Ari, CH 2 (CHR 6 ) w Ari, or (CHR6) w CH 2 Ari, where Ari is phenyl or pyridyl, R 3 and R4 are H or C1-C3 alkyl, Ri is Ci-C 6 alkyl, q is zero, and X is O.
  • this invention provides a compound of formula I, where R 5 is Ari, (CHR 6 ) w Ari, CH 2 (CHR 6 ) W Ar I , or (CHR 6 ) W CH 2 Ar I , where Ari is phenyl or pyridyl; R 3 and R 4 are H or Ci-C 3 alkyl; Ri is Ci-C 6 alky; q is 1; and X is O.
  • this invention provides a compound of formula I, where R 5 is Ari, (CHR 6 ) w Ari, CH 2 (CHR 6 ) W Ar I , or (CHR 6 ) W CH 2 Ar I , where Ari is phenyl or pyridyl, R 3 and R 4 are H or Ci-C 3 alkyl, Ri is CN, CH 2 CN, or halogen, q is 1, Y is O, and X is O.
  • this invention provides a compound of formula I, where R 5 is Ari, (CHR 6 ) w Ari, CH 2 (CHR 6 ) W Ar I , or (CHR 6 ) W CH 2 Ar I , where Ari is phenyl or pyridyl, R 3 and R 4 are H or Ci-C 3 alkyl, Ri is CN, CH 2 CN, or halogen, q is 1, Y is O, and X is O.
  • this invention provides a compound of formula I, where R 5 is Ari, (CHR 6 )
  • Ari is thienyl, furyl, benzothienyl, or benzofuryl
  • R 3 and R 4 are, independently, H, methyl, or ethyl
  • R 5 is Ci-C 6 alkyl or (CHR 6 ) W C 3 -C 6 cycloalkyl.
  • this invention provides a compound of formula I, where R 5 is Ari, (CHR 6 ) W ATi, CH 2 (CHR 6 ) W Ar I , or (CHR 6 ) W CH 2 Ar I , where Ari is pyrrolyl, imidazolyl, oxazolyl, or thiazolyl; R 3 and R 4 are, independently, H, methyl, or ethyl; and R 5 is Ci-C 6 alkyl or (CHR 6 ) W C 3 -C 6 cycloalkyl.
  • this invention provides a compound of formula I, where R 5 is Ari, (CHR 6 ) W ATi, CH 2 (CHR 6 ) W Ar I , or (CHR 6 ) W CH 2 Ar I , where Ari is isoxazolyl or isothiazolyl; R 3 and R 4 are, independently, H, methyl, or ethyl; and R 5 is Ci-C 6 alkyl or (CHR 6 ) W C 3 -C 6 cycloalkyl.
  • this invention provides a compound of formula I, in which R 5 is Ci-C 6 alkyl, where the alkyl group is substituted with one or two groups selected, independently, from OH, OMe, OEt, F, CF 3 , Cl, or CN.
  • this invention provides a compound of formula I, in which R 5 is
  • this invention provides a compound of formula I, in which R 5 is (CH 2 ) W -C 5 -C 6 cycloalkyl or (CH 2 ) W -C 5 -C 6 heterocycloalkyl. In another embodiment, this invention provides a compound of formula I, in which R 5 is
  • CH CH-CH 2 -C3-C6 cycloalkyl or heterocycloalkyl, where the carbon-carbon double bond has the E configuration.
  • this invention provides a compound of formula I, in which R 5 is (CHR 6 ) W C 3 -C 6 cycloalkyl or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl group is monosubstituted.
  • this invention provides a compound of formula I, in which R 5 is C 5 -C 6 alkyl.
  • this invention provides a compound of formula I, in which q is zero and R 5 is CH 2 -C 4 -alkyl or CH 2 -C 5 - alkyl.
  • this invention provides a compound of formula I, in which R 5 is C 2 -C 6 alkynyl.
  • this invention provides a compound of formula I, in which R 5 is C 2 -C 6 alkenyl. In a more specific embodiment, this invention provides a compound of formula IAl, IA2,
  • heterocycloalkyl denotes a saturated carbocyclic moiety in which one or more ring carbon atoms is replaced by an atom selected from O, N, and S.
  • heterocycloalkenyl denotes a mono- or poly-unsaturated carbocyclic moiety in which one or more ring carbon atoms is replaced by an atom selected from O, N, and S.
  • heteroaryl denotes a mono- or bi-cyclic aromatic ring system with one or more ring atoms equal to O, N, and/or S.
  • the tube was heated under microwave irradiation (Biotage Initiator®) for 2 hour at 100 0 C.
  • the reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 , concentrated and chromatographed to yield the title product (0.278 g, 0.79 mmol, 79%).
  • the tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100 0 C.
  • the reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 , concentrated and chromatographed to yield the title compound (0.584 g, 1.58 mmol, 73%).
  • the tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100 0 C.
  • the reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 , concentrated and chromatographed to yield the title compound (0.326 g, 0.78 mmol, 63%).
  • Triflic anhydride (4.25 g, 15 mmol) was added to a suspension of tetramethylammonium nitrate (2.04 g, 15 mmol) in dichloromethane (40 ml) at 0 0 C over 15 minutes. The mixture was warmed to room temperature and stirred for 2 hours and then a solution of 2-chloro-4,6- dimethoxypyrimidine (1.75 g in 10 ml, 10 mmol) was added to the mixture over 30 minutes. The mixture was stirred for 2 days. The reaction mixture was poured into ice bath, washed with an aqueous solution of NaHCU 3 and extracted with dichloromethane. The organic layer was washed with brine, concentrated to dryness to yield 4a (2.13 g, 9.73 mmol, 97%).
  • Step 1 Refer to example 4
  • 5b l,8-diazabicyclo[5.4.0]undec-7-ene (0.669 g, 4.4 mmol) was added to a mixture of 4a (0.438 g, 2 mmol) and 6-(trifluoromethyl)-l,2,3,4-tetrahydroisoquinoline hydrochloride (0.487 g, 2.05 mmol) in DMF (5 ml) at 0 0 C over 5 minutes. The mixture was stirred for an additional 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 5b (0.76 g, 1.98 mmol, 99%).
  • the tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100 0 C.
  • the reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 , concentrated and chromatographed to yield the title compound (0.259 g, 0.668 mmol, 87%).
  • the tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100 0 C.
  • the reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 , concentrated and chromatographed to yield the title compound (0.262 g, 0.6 mmol, 95%).
  • PC- 12 cells were grown at 37 0 C and 5 % CO 2 in DMEM/F12 Medium supplemented with 10 % horse serum, 5 % fetal bovine serum, 2 niM glutamine, 100 U/ml penicillin, 100 U/ml streptomycin. They were plated in poly-D-lysine-coated 96-well cell culture microplates at a density of 40,000 cells/well and differentiated with 100 ng/ml NGF-7s for 2-5 days.
  • the medium was aspirated and the cells were washed once with 0.2 ml in wash buffer (25 mM Hepes, pH 7.4, 150 mM NaCl, 1 mM MgCl 2 , 0.8 mM NaH 2 PO 4 , 2 mM CaCl 2 ).
  • the cells were then loaded with 0.2 ml Rb + loading buffer (wash buffer plus 5.4 mM RbCl 2 , 5 mM glucose) and incubated at 37 0 C for 2 h. Attached cells were quickly washed three times with buffer (same as Rb + loading buffer, but containing 5.4 mM KCl instead of RbCl) to remove extracellular Rb + .
  • 0.2 ml of depolarization buffer (wash buffer plus 15 mM KCl) with or without compounds was added to the cells to activate efflux of potassium ion channels. After incubation for 10 min at room temperature, the supernatant was carefully removed and collected. Cells were lysed by the addition of 0.2 ml of lysis buffer (depolarization buffer plus 0.1 % Triton X-100) and the cell lysates were also collected. If collected samples were not immediately analyzed for Rb + contents by atomic absorption spectroscopy (see below), they were stored at 4 0 C without any negative effects on subsequent Rb + analysis.
  • the concentration of Rb + in the supernatants (Rb + Sup ) and cell lysates (Rb + Lys ) was quantified using an ICR8000 flame atomic absorption spectrometer (Aurora Biomed Inc., Vancouver, B.C.) under conditions defined by the manufacturer.
  • ICR8000 flame atomic absorption spectrometer Aurora Biomed Inc., Vancouver, B.C.
  • One 0.05 ml samples were processed automatically from microtiter plates by dilution with an equal volume of Rb + sample analysis buffer and injection into an air-acetylene flame.
  • the amount of Rb + in the sample was measured by absorption at 780 nm using a hollow cathode lamp as light source and a PMT detector.
  • a calibration curve covering the range 0-5 mg/L Rb + in sample analysis buffer was generated with each set of plates.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
PCT/US2008/066984 2007-06-13 2008-06-13 Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators Ceased WO2008157404A2 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
PL08771077T PL2170861T3 (pl) 2007-06-13 2008-06-13 Pochodne 4-(N-azacykloalkilo)anilidów jako modulatory kanałów sodowych
BRPI0812564-3A2A BRPI0812564A2 (pt) 2007-06-13 2008-06-13 Derivados de 4-(n-azacicloalquil) anilidas como moduladores de canal de potássio
CA002689208A CA2689208A1 (en) 2007-06-13 2008-06-13 Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators
MX2009013581A MX2009013581A (es) 2007-06-13 2008-06-13 Derivados de 4-(n-azacicloalquil)anilidas como moduladores del canal de potasio.
HRP20120857AT HRP20120857T1 (hr) 2007-06-13 2008-06-13 Derivati 4-(n-azacikloalkil) anilida kao modulatori kalijevog kanala
CN200880102338A CN101868451A (zh) 2007-06-13 2008-06-13 作为钾通道调节剂的4-(n-氮杂环烷基)苯胺的衍生物
AU2008266009A AU2008266009B2 (en) 2007-06-13 2008-06-13 Derivatives of 4-(N-azacycloalkyl) anilides as potassium channel modulators
EP08771077A EP2170861B1 (en) 2007-06-13 2008-06-13 Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators
DK08771077.8T DK2170861T3 (da) 2007-06-13 2008-06-13 Derivater af 4-(N-azacycloalkyl)anilider som kaliumkanalmodulatorer
ES08771077T ES2392774T3 (es) 2007-06-13 2008-06-13 Derivados de 4-(N-azacicloalquil)anilidas como moduladores de los canales de potasio
JP2010512399A JP2010530002A (ja) 2007-06-13 2008-06-13 カリウムチャネルモジュレーターとしての４−（ｎ−アザシクロアルキル）アニリドの誘導体
SI200830745T SI2170861T1 (sl) 2007-06-13 2008-06-13 Derivati 4-(n-azacikloalkil) anilidov kot kalijevi kanalski modulatorji

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US93439607P 2007-06-13 2007-06-13
US60/934,396 2007-06-13
US12/138,251 US8367684B2 (en) 2007-06-13 2008-06-12 Derivatives of 4-(N-azacycloalkyl) anilides as potassium channel modulators
US12/138,251 2008-06-12

Publications (2)

Publication Number Publication Date
WO2008157404A2 true WO2008157404A2 (en) 2008-12-24
WO2008157404A3 WO2008157404A3 (en) 2009-02-19

Family

ID=40137141

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/066984 Ceased WO2008157404A2 (en) 2007-06-13 2008-06-13 Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators

Country Status (18)

Country Link
US (1) US8367684B2 (enExample)
EP (1) EP2170861B1 (enExample)
JP (1) JP2010530002A (enExample)
KR (1) KR20100018618A (enExample)
CN (1) CN101868451A (enExample)
AU (1) AU2008266009B2 (enExample)
BR (1) BRPI0812564A2 (enExample)
CA (1) CA2689208A1 (enExample)
DK (1) DK2170861T3 (enExample)
ES (1) ES2392774T3 (enExample)
HR (1) HRP20120857T1 (enExample)
MX (1) MX2009013581A (enExample)
PL (1) PL2170861T3 (enExample)
PT (1) PT2170861E (enExample)
RU (1) RU2010100893A (enExample)
SI (1) SI2170861T1 (enExample)
TW (1) TW200914452A (enExample)
WO (1) WO2008157404A2 (enExample)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010122064A1 (en) 2009-04-21 2010-10-28 Neurosearch A/S Substituted naphthyridine derivatives and their medical use
WO2013154109A1 (ja) 2012-04-10 2013-10-17 大日本住友製薬株式会社 新規１位置換インダゾール誘導体
US10702057B2 (en) 2015-07-07 2020-07-07 Colgate-Palmolive Company Oral care implement and monofilament bristle for use with the same
US12157726B2 (en) 2018-05-22 2024-12-03 Shanghai Zhimeng Biopharma Inc. P-phenylenediamine derivative as potassium channel regulator and preparation method and medical application thereof

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8563566B2 (en) * 2007-08-01 2013-10-22 Valeant Pharmaceuticals International Naphthyridine derivatives as potassium channel modulators
US7786146B2 (en) * 2007-08-13 2010-08-31 Valeant Pharmaceuticals International Derivatives of 5-amino-4,6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators
AU2011275393B2 (en) * 2010-07-08 2014-04-10 Pfizer Inc. Piperidinyl pyrimidine amides as Kv7 potassium channel openers
CN108250128A (zh) * 2012-09-27 2018-07-06 江苏先声药业有限公司 作为钾通道调节剂的化合物
TW202333693A (zh) * 2021-12-31 2023-09-01 大陸商上海翰森生物醫藥科技有限公司 苯并哌啶衍生物調節劑、其製備方法和應用
CN116535353A (zh) * 2022-01-25 2023-08-04 上海挚盟医药科技有限公司 作为钾通道调节剂的酰胺类化合物及其制备和应用

Family Cites Families (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4181803A (en) 1973-12-14 1980-01-01 Eisai Co., Ltd. Propiophenone derivatives and preparation thereof
DE3369315D1 (en) 1982-10-27 1987-02-26 Degussa Derivatives of 2-amino-3-acylamino-6-benzylamino pyridine with an anti-epileptic activity
DE3337593A1 (de) 1982-10-27 1984-05-03 Degussa Ag, 6000 Frankfurt 2-amino-3-acylamino-6-benzylamino-pyridin-derivate mit antiepileptischer wirkung
DE3665538D1 (en) 1985-01-23 1989-10-19 Asta Pharma Ag Synergistic combination of flupirtin and non-steroidal anti-phlogistics
ATE43789T1 (de) 1985-02-23 1989-06-15 Asta Pharma Ag Kombination von flupirtin und anticholinergisch wirkenden spasmolytika.
DE3604575A1 (de) 1985-02-23 1986-08-28 Degussa Ag, 6000 Frankfurt Kombination von flupirtin und anticholinergisch wirkenden spasmolytika
JP2583067B2 (ja) 1987-08-04 1997-02-19 住友化学工業株式会社 モノアゾ化合物およびそれを用いて疎水性繊維材料を染色または捺染する方法
GB8800199D0 (en) 1988-01-06 1988-02-10 Beecham Group Plc Pharmaceutical preparation
MC2029A1 (fr) 1988-05-16 1990-04-25 Asta Pharma Ag (n-heterocyclyl)-3 diamino-2,6 pyridines substituees et leurs n-oxydes,preparation de ces composes et leur application comme medicaments
US5629307A (en) 1989-10-20 1997-05-13 Olney; John W. Use of ibogaine in reducing excitotoxic brain damage
US6004945A (en) 1990-05-10 1999-12-21 Fukunaga; Atsuo F. Use of adenosine compounds to relieve pain
IN172468B (enExample) 1990-07-14 1993-08-14 Asta Medica Ag
US5643921A (en) 1990-09-26 1997-07-01 E.R. Squibb & Sons, Inc. Cardiopulmonary bypass and organ transplant using a potassium channel activator
US5234947A (en) 1991-11-07 1993-08-10 New York University Potassium channel activating compounds and methods of use thereof
DE4200259A1 (de) 1992-01-08 1993-07-15 Asta Medica Ag Neue 1,2,4-triaminobenzol-derivate und verfahren zu deren herstellung
US5262419A (en) 1992-06-11 1993-11-16 E. R. Squibb & Sons, Inc. Method for the prophylaxis and/or treatment of ulcerative gastrointestinal conditions using a potassium channel activator
CA2115792C (en) 1993-03-05 2005-11-01 David J. Mayer Method for the treatment of pain
US5428039A (en) 1994-02-20 1995-06-27 The Center For Innovative Technology Method for electively achieving reversible hyperpolarized cardiac arrest
FI971334L (fi) * 1994-08-03 1997-04-01 Asta Medica Ag Indoli-, indatsoli-, pyridopyrroli- ja pyridopyratsolijohdannaiset, joilla on antiastmaattinen, antiallerginen, anti-inflammatorinen ja immunomoduloiva vaikutus
USRE38115E1 (en) 1994-09-22 2003-05-06 Center For Neurologic Study Dextromethorphan and an oxidase inhibitor for treating intractable conditions
US5679706A (en) 1994-09-30 1997-10-21 Bristol-Myers Squibb Company Combination of a potassium channel activator and an antiarrhythmic agent
EP0799051B1 (en) 1994-12-12 2005-07-27 Omeros Corporation Irrigation solution and use thereof for perioperatively inhibiting pain, inflammation and spasm at a wound
DE19539861A1 (de) 1995-10-26 1997-04-30 Asta Medica Ag Verwendung von 4-Amino-4-(4-fluorbenzylamino)-1-ethoxy-carbonylaminobenzen zur Prophylaxe und Behandlung der Folgen der akuten und chronischen zerebralen Minderdurchblutung sowie neurodegenerativer Erkrankungen
DE19701694A1 (de) 1997-01-20 1998-07-23 Asta Medica Ag Neue Modifikationen des 2-Amino-4-(4-fluorbenzylamino)-l-ethoxycarbonyl-aminobenzen sowie Verfahren zu ihrer Herstellung
IN188411B (enExample) * 1997-03-27 2002-09-21 Yuhan Corp
US5760007A (en) 1997-07-16 1998-06-02 Ortho Pharmaceutical Corporation Anticonvulsant derivatives useful in treating neuropathic pain
WO1999007411A1 (fr) 1997-08-08 1999-02-18 Chugai Seiyaku Kabushiki Kaisha Remedes contre les complications du diabete
US6265417B1 (en) 1997-12-18 2001-07-24 Abbott Laboratories Potassium channel openers
US6593335B1 (en) 1997-12-18 2003-07-15 Abbott Laboratories Potassium channel openers
US6211171B1 (en) 1998-05-19 2001-04-03 Dalhousie University Use of antidepressants for local analgesia
JP3441970B2 (ja) 1998-06-30 2003-09-02 株式会社サミー 豆腐の製造方法及び製造装置
JP2000143510A (ja) 1998-11-16 2000-05-23 Taisho Pharmaceut Co Ltd 外用組成物
AU764921B2 (en) 1998-12-14 2003-09-04 Cellegy Pharmaceuticals, Inc. Compositions and methods for the treatment of anorectal disorders
US6281211B1 (en) 1999-02-04 2001-08-28 Euro-Celtique S.A. Substituted semicarbazides and the use thereof
GB9903476D0 (en) 1999-02-17 1999-04-07 Zeneca Ltd Therapeutic agents
JP2002538221A (ja) 1999-03-10 2002-11-12 ワーナー−ランバート・カンパニー 抗てんかん作用を有する化合物を包含する鎮痛組成物およびその使用方法
CA2367895A1 (en) 1999-03-17 2000-09-21 Signal Pharmaceuticals, Inc. Compounds and methods for modulation of estrogen receptors
AT409083B (de) 1999-04-01 2002-05-27 Sanochemia Pharmazeutika Ag Pharmazeutische, tolperison enthaltende zubereitung zur oralen verabreichung
US6610324B2 (en) 1999-04-07 2003-08-26 The Mclean Hospital Corporation Flupirtine in the treatment of fibromyalgia and related conditions
GB9915414D0 (en) 1999-07-01 1999-09-01 Glaxo Group Ltd Medical use
KR20020024300A (ko) 1999-07-06 2002-03-29 피터 지. 스트링거 편두통을 치료하기 위한 선택적 ｉＧｌｕＲ5 수용체 길항제
US6472165B1 (en) 1999-08-03 2002-10-29 Arzneimittelwerk Dresden Gmbh Modulatory binding site in potassium channels for screening and finding new active ingredients
US6495550B2 (en) 1999-08-04 2002-12-17 Icagen, Inc. Pyridine-substituted benzanilides as potassium ion channel openers
JP2003506388A (ja) 1999-08-04 2003-02-18 アイカゲン インコーポレイテッド 疼痛および不安症を処置または予防するための方法
EP1208085B1 (en) 1999-08-04 2007-12-05 Icagen, Inc. Benzanilides as potassium channel openers
US6117900A (en) 1999-09-27 2000-09-12 Asta Medica Aktiengesellschaft Use of retigabine for the treatment of neuropathic pain
US6383511B1 (en) 1999-10-25 2002-05-07 Epicept Corporation Local prevention or amelioration of pain from surgically closed wounds
US6538004B2 (en) 2000-03-03 2003-03-25 Abbott Laboratories Tricyclic dihydropyrazolone and tricyclic dihydroisoxazolone potassium channel openers
US20020015730A1 (en) 2000-03-09 2002-02-07 Torsten Hoffmann Pharmaceutical formulations and method for making
US6348486B1 (en) 2000-10-17 2002-02-19 American Home Products Corporation Methods for modulating bladder function
US6589986B2 (en) 2000-12-20 2003-07-08 Wyeth Methods of treating anxiety disorders
CA2405532A1 (en) * 2001-02-07 2002-08-22 Ortho-Mcneil Pharmaceutical, Inc. Pyridoarylphenyl oxazolidinone antibacterials, and related compositions and methods
US6469042B1 (en) 2001-02-20 2002-10-22 Bristol-Myers Squibb Company Fluoro oxindole derivatives as modulators if KCNQ potassium channels
AR033095A1 (es) 2001-04-04 2003-12-03 Wyeth Corp Metodos para el tratamiento de motilidad gastrica hiperactiva
GB0121214D0 (en) 2001-08-31 2001-10-24 Btg Int Ltd Synthetic method
US6831087B2 (en) * 2001-11-09 2004-12-14 Hoffmann-La Roche Inc. Pyridine substituted isoquinoline derivatives
AU2003244463A1 (en) * 2002-02-05 2003-09-02 Yamanouchi Pharmaceutical Co., Ltd. 2,4,6-triamino-1,3,5-triazine derivative
AU2003202115A1 (en) 2002-02-12 2003-09-04 Pfizer Inc. Non-peptide compounds affecting the action of gonadotropin-releasing hormone (gnrh)
ATE533743T1 (de) 2002-05-17 2011-12-15 Janssen Pharmaceutica Nv Harnstoffderivate von aminotetralin als modulatoren des vanilloid-rezeptors vr1
WO2003106454A1 (en) 2002-06-12 2003-12-24 Orchid Chemicals & Pharmaceuticals Ltd 1h-isoquinoline-oxazolidinone derivaties and their use as antibacterial agents
AUPS312602A0 (en) 2002-06-21 2002-07-18 James Cook University Organ arrest, protection, preservation and recovery
US7419981B2 (en) 2002-08-15 2008-09-02 Pfizer Inc. Synergistic combinations of an alpha-2-delta ligand and a cGMP phosphodieterse 5 inhibitor
US7045551B2 (en) 2002-11-22 2006-05-16 Bristol-Myers Squibb Company 1-aryl-2-hydroxyethyl amides as potassium channel openers
JP4652816B2 (ja) 2002-12-23 2011-03-16 アイシーエージェン インコーポレイテッド カリウムチャネルモジュレータとしてのキナゾリノン
ES2282701T3 (es) 2002-12-27 2007-10-16 H. Lundbeck A/S Derivados de 1,2,4-triaminobenceno utiles para tratar trastornos del sistema nervioso central.
EP1606247A1 (en) 2003-03-14 2005-12-21 H. Lundbeck A/S Substituted aniline derivatives
EP1613303A1 (en) 2003-03-21 2006-01-11 H. Lundbeck A/S Substituted p-diaminobenzene derivatives
US20060264496A1 (en) 2003-04-25 2006-11-23 H. Lundbeck A/S Substituted indoline and indole derivatives
MXPA05012463A (es) 2003-05-27 2006-01-30 Altana Pharma Ag Combinaciones farmaceuticas de un inhibidor de bomba protonica y un compuesto que modifica la motilidad gastrointestinal.
EP1644335A4 (en) * 2003-07-11 2008-06-04 Bristol Myers Squibb Co TETRAHYDROQUINOLINE DERIVATIVES COMPRISING MODULATORS OF CANNABINOID RECEPTORS
JP2007505142A (ja) 2003-09-10 2007-03-08 セダーズ−シナイ メディカル センター 血液脳関門を通過する薬剤のカリウムチャネル媒介性送達
US20050089559A1 (en) 2003-10-23 2005-04-28 Istvan Szelenyi Combinations of potassium channel openers and sodium channel inhibitors or sodium channel-influencing active compounds for treating pains
DE10359335A1 (de) 2003-10-23 2005-05-25 Viatris Gmbh & Co. Kg Kombinationen aus Kaliumkanalöffnern und Natriumkanalinhibitoren oder Natriumkanal beeinflussenden Wirkstoffen zur Behandlung von Schmerzzuständen
ES2235626B1 (es) 2003-11-10 2006-11-01 Almirall Prodesfarma, S.A. Formas de administracion masticables, no comprimidas dosificadas individualmente.
TW200530235A (en) * 2003-12-24 2005-09-16 Renovis Inc Bicycloheteroarylamine compounds as ion channel ligands and uses thereof
TWI357901B (en) 2004-03-12 2012-02-11 Lundbeck & Co As H Substituted morpholine and thiomorpholine derivati
EP1737852A2 (en) 2004-04-13 2007-01-03 Icagen, Inc. Polycyclic pyridines as potassium ion channel modulators
CN1968692A (zh) 2004-05-03 2007-05-23 杜克大学 影响体重减轻的组合物
CA2571133C (en) * 2004-07-15 2011-04-19 Japan Tobacco Inc. Fused benzamide compound and vanilloid receptor 1 (vr1) activity inhibitor
UA89503C2 (uk) 2004-09-13 2010-02-10 Х. Луннбек А/С Заміщені похідні аніліну
KR20070057965A (ko) * 2004-09-21 2007-06-07 신타 파마슈티칼스 코프. 염증 및 면역 관련 용도를 위한 화합물
WO2006054513A1 (ja) 2004-11-19 2006-05-26 Kissei Pharmaceutical Co., Ltd. 神経因性疼痛の予防又は治療剤
EP1688141A1 (en) 2005-01-31 2006-08-09 elbion AG The use of flupirtine for the treatment of overactive bladder and associated diseases, and for the treatment of irritable bowel syndrome
PL2298766T3 (pl) 2005-03-03 2014-09-30 H Lundbeck As Preparaty farmaceutyczne zawierające podstawione pochodne pirydyny
US7683058B2 (en) 2005-09-09 2010-03-23 H. Lundbeck A/S Substituted pyrimidine derivatives
JP5140597B2 (ja) * 2005-10-21 2013-02-06 メルク・シャープ・エンド・ドーム・コーポレイション カリウムチャネル阻害剤
NZ575652A (en) 2006-08-23 2011-08-26 Valeant Pharmaceuticals Int Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators
BRPI0719590A2 (pt) 2006-11-28 2014-01-21 Valeant Pharmaceuticals Int Análogos de retigabina 1,4 diamino bicíclica como modulares de canal de potássio
US8563566B2 (en) * 2007-08-01 2013-10-22 Valeant Pharmaceuticals International Naphthyridine derivatives as potassium channel modulators
JP5798115B2 (ja) * 2009-06-22 2015-10-21 ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． 置換ヒドロキサム酸およびその使用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010122064A1 (en) 2009-04-21 2010-10-28 Neurosearch A/S Substituted naphthyridine derivatives and their medical use
WO2013154109A1 (ja) 2012-04-10 2013-10-17 大日本住友製薬株式会社 新規１位置換インダゾール誘導体
US8765786B2 (en) 2012-04-10 2014-07-01 Dainippon Sumitomo Pharma Co., Ltd. 1-substituted indazole derivative
US9051295B2 (en) 2012-04-10 2015-06-09 Sumitomo Dainippon Pharma Co., Ltd. 1-substituted indazole derivative
US9309221B2 (en) 2012-04-10 2016-04-12 Sumitomo Dainippon Pharma Co., Ltd. 1-substituted indazole derivative
US10702057B2 (en) 2015-07-07 2020-07-07 Colgate-Palmolive Company Oral care implement and monofilament bristle for use with the same
US12157726B2 (en) 2018-05-22 2024-12-03 Shanghai Zhimeng Biopharma Inc. P-phenylenediamine derivative as potassium channel regulator and preparation method and medical application thereof

Also Published As

Publication number Publication date
US8367684B2 (en) 2013-02-05
MX2009013581A (es) 2010-01-26
WO2008157404A3 (en) 2009-02-19
SI2170861T1 (sl) 2012-12-31
EP2170861B1 (en) 2012-08-29
DK2170861T3 (da) 2012-11-26
ES2392774T3 (es) 2012-12-13
JP2010530002A (ja) 2010-09-02
BRPI0812564A2 (pt) 2015-02-10
AU2008266009A1 (en) 2008-12-24
CN101868451A (zh) 2010-10-20
PL2170861T3 (pl) 2013-01-31
PT2170861E (pt) 2012-09-06
TW200914452A (en) 2009-04-01
HRP20120857T1 (hr) 2012-11-30
RU2010100893A (ru) 2011-07-20
CA2689208A1 (en) 2008-12-24
EP2170861A2 (en) 2010-04-07
KR20100018618A (ko) 2010-02-17
AU2008266009B2 (en) 2013-06-06
US20080318979A1 (en) 2008-12-25

Similar Documents

Publication Publication Date Title
EP2170861B1 (en) Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators
KR20080043840A (ko) 히스타민 ｈ4 수용체 활성의 조정자로서 2-아미노피리미딘유도체
CN105503827B (zh) Egfr抑制剂及其制备方法和用途
AU2008341678B2 (en) 4 -aminopyrimidine derivatives as histamine H4 receptor antagonists
CA2817460A1 (en) Substituted 6,6-fused nitrogenous heterocyclic compounds and uses thereof
EP1885369A2 (en) Fused heterocyclic compounds, and compositions and uses thereof
KR20170031778A (ko) 피리딘 아미도피리미딘 유도체, 그의 제조 방법 및 용도
JP7219902B2 (ja) ブルトン型チロシンキナーゼ阻害剤
JP2013509382A (ja) Ｊａｋ３キナーゼ阻害剤としての窒素含有ヘテロアリール誘導体
CA3196068A1 (en) 2,3-dihydro-1h-pyrrolo[3,2-b]pyridine derivative, preparation method therefor, and application thereof
KR20130029756A (ko) Ｎ-7 치환된 퓨린 및 피라졸로피리미딘 화합물, 조성물 및 사용 방법
JP2022500476A (ja) 環状ジヌクレオチド類似体、その医薬組成物及び使用
KR101740085B1 (ko) 히스타민 ｈ４ 수용체 길항제로서의 아미노알킬피리미딘 유도체
CZ142498A3 (cs) Syntéza derivátů sulfonylpyrimidinu s protirakovinným účinkem
WO2008103068A2 (ru) Способ получения 2-aнилинoпиpимидинoв или их солей
CN112341477B (zh) 含有并环基团的咪唑并嘧啶类化合物、其制备方法及用途
WO2017088755A1 (en) Aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activity
CN114126614A (zh) 作为prmt5抑制剂的杂环化合物
TW202430168A (zh) Tyk2假激酶配體及其用途
WO2015145369A1 (en) Process for the preparation of substituted imidazo[4,5-c]quinoline compounds, intermediates and polymorphs thereof
TW202246261A (zh) 作為抗癌劑的化合物
HK40038535A (en) Heterocyclic compounds as prmt5 inhibitors
HK1149003B (en) 4-aminopyrimidine derivatives as histamine h4 receptor antagonists

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200880102338.0

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08771077

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 2689208

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2010512399

Country of ref document: JP

Ref document number: MX/A/2009/013581

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2008266009

Country of ref document: AU

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 4388/KOLNP/2009

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 20107000706

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2008771077

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2010100893

Country of ref document: RU

ENP Entry into the national phase

Ref document number: 2008266009

Country of ref document: AU

Date of ref document: 20080613

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: PI0812564

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20091211