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WO2009021758A1 - Arylsulfonamides ayant un effet analgésique - Google Patents

Arylsulfonamides ayant un effet analgésique Download PDF

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Publication number
WO2009021758A1
WO2009021758A1 PCT/EP2008/052157 EP2008052157W WO2009021758A1 WO 2009021758 A1 WO2009021758 A1 WO 2009021758A1 EP 2008052157 W EP2008052157 W EP 2008052157W WO 2009021758 A1 WO2009021758 A1 WO 2009021758A1
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Prior art keywords
mmol
product
alkyl
hplc
retention time
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PCT/EP2008/052157
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German (de)
English (en)
Inventor
Iris Kauffmann-Hefner
Norbert Hauel
Rainer Walter
Heiner Ebel
Henri Doods
Angelo Ceci
Annette Schuler-Metz
Ingo Konetzki
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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Priority claimed from PCT/EP2007/058408 external-priority patent/WO2008022945A1/fr
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Priority to EP08102044A priority Critical patent/EP2025668A1/fr
Priority to EP08102043A priority patent/EP2025673A1/fr
Priority to DE502008002979T priority patent/DE502008002979D1/de
Priority to JP2010520556A priority patent/JP2011505334A/ja
Priority to KR1020107005536A priority patent/KR20100055469A/ko
Priority to AT08803006T priority patent/ATE502918T1/de
Priority to PCT/EP2008/060562 priority patent/WO2009021944A1/fr
Priority to PCT/EP2008/060563 priority patent/WO2009021945A1/fr
Priority to AU2008288431A priority patent/AU2008288431A1/en
Priority to JP2010520555A priority patent/JP5250627B2/ja
Priority to BRPI0815181 priority patent/BRPI0815181A2/pt
Priority to NZ583815A priority patent/NZ583815A/en
Priority to EA201000296A priority patent/EA201000296A1/ru
Priority to MX2010001664A priority patent/MX2010001664A/es
Priority to US12/672,460 priority patent/US8394805B2/en
Priority to CA2696302A priority patent/CA2696302A1/fr
Priority to US12/672,465 priority patent/US20110077231A1/en
Priority to EP08803005.1A priority patent/EP2188269B1/fr
Priority to CN2008801116296A priority patent/CN101821245B/zh
Priority to PE2008001366A priority patent/PE20090593A1/es
Priority to EP08803006A priority patent/EP2212281B1/fr
Priority to CA2696261A priority patent/CA2696261A1/fr
Priority to TW097130828A priority patent/TW200911744A/zh
Priority to ARP080103538A priority patent/AR068341A1/es
Priority to UY31287A priority patent/UY31287A1/es
Priority to AU2009281472A priority patent/AU2009281472A1/en
Publication of WO2009021758A1 publication Critical patent/WO2009021758A1/fr
Priority to CO10016009A priority patent/CO6331335A2/es
Priority to TNP2010000072A priority patent/TN2010000072A1/fr
Anticipated expiration legal-status Critical
Priority to MA32623A priority patent/MA31613B1/fr
Priority to EC2010009978A priority patent/ECSP109978A/es
Ceased legal-status Critical Current

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to compounds of general formula I. in which A, B, D, Y, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases which have valuable properties, their preparation, the medicaments containing the pharmacologically active compounds, their preparation and their use.
  • A is a bond, d- 4 alkylene or -CH 2 -C (O) -,
  • B is a bond, Ci -3 alkylene, -O- or -C (O) -,
  • Y is an optionally substituted by the radical R 2 Ci_6-alkylene group, wherein a methylene group may be additionally replaced by Y 1 and
  • Y 1 is -O-, -S-, -S (O) -, -N (R 2 ) -, -N (R 2 ) -C (O) -, -C (O) -N (R 2 ) - Represents -C (O) -, -CH (aryl) -, C 3-6 -cycloalkylene or -S (O) 2 -, R 1 is C 3-7 alkyl or -CyClOaIkYl- aryl, heteroaryl or aryl-Ci -3, which may each be substituted by one, two, three or four radicals R 1 1, wherein the radicals R 1 1 is equal to or may be different and
  • R 2 is H or Ci -3 alkyl, wherein each methylene group of up to two and each
  • Methyl group may be substituted with up to three fluorine atoms, or H 3 CC (O) -,
  • R 3 1 a monosubstituted or disubstituted by R 3 1 unsaturated 5- to 7-membered heterocyclic ring which is fused via the unsaturated bonds with one or two phenyl rings, or i) one by R 3 1 simple or doubly substituted saturated 8-bis
  • radicals R 3-1 may each be the same or different and
  • R 3 is also -O-, if B does not represent the group -O-, R 4 a) -O-, b) -C (O) O-, c) -C (O) NR 2 -, d) -NR 2 -, e) -NR 2 -NR 2 -, f) C 3 - 7 cycloalkylene, g) Ci 6 alkylene, h) a a substituted mono- or disubstituted by R 4 1 mono- or di-substituted arylene group, i) a substituted mono- or disubstituted by R 4 1 heteroarylene group, j) by R 4 1 4- to 7-membered saturated heterocyclic ring, k) a saturated 8-bis monosubstituted or disubstituted by R 4 1
  • radicals R 4 1 may each be the same or different and
  • R 4 - 1 is H, F, Cl, Br, I, C 1-3 -alkyl-, HO-, d -3 alkyl-O- or Ci -3 alkyl-OC 2-4 alkylene-O- .
  • R 5 is H, HO-, Cis-alkyl, optionally substituted by d-3-alkyl C 3-7 cycloalkyl, H 2 N-, Ci -4 alkyl-NH-, (C 3 - 6 cycloalkyl ) -NH-, (Ci -4 alkyl) 2 N-,
  • a second embodiment of the present invention consists in the compounds of the above general formula I, in which
  • A is a bond or Ci -4 alkylene
  • B is a bond, d-3-alkylene, -O- or -C (O) -,
  • Y is an optionally substituted by the radical R 2 C- M alkylene group, wherein a methylene group may be additionally replaced by Y 1 and
  • Y 1 is -O-, -S-, -S (O) -, -N (R 2 ) -, -N (R 2 ) -C (O) -, -C (O) -N (R 2 ) - Represents -C (O) -, -CH (aryl) - or -S (O) 2 -,
  • R 1 is C 3-7 alkyl cycloalkyl or aryl, heteroaryl or aryl-Ci -3, which may be substituted 1-1 respectively by one, two, three or four radicals R, where the radicals R 1- 1 may be the same or different and
  • R 2 is H or Ci -3 alkyl, wherein each methylene group of up to two and each methyl group may be substituted with up to three fluoro atoms, R 3 d-6 alkylene group, a substituted mono- or disubstituted by R 3 1 arylene group, a substituted mono- or disubstituted by R 3 1 heteroarylene group, a substituted mono- or disubstituted by R 3 1 saturated 4- to 7-membered heterocyclic ring or a R 3 1 monosubstituted or disubstituted unsaturated 5- to 7-membered heterocyclic ring, wherein the radicals R 3 1 may be the same or different and
  • R 4 is -O-, -C (O) O-, -C (O) NR 2 -, -NR 2 -, -NR 2 -NR 2 -, C 3 - 7 -cycloalkylene, Ci -6- alkylene, a by R 4 1 singly or doubly substituted arylene group, by R 4 1 mono- or di-substituted heteroarylene, a single or double substituted by R 4-1 4- to 7-membered saturated heterocyclic ring or R 4-1 by a single or double substituted 5- to 7-membered unsaturated heterocyclic ring, wherein the radicals R 4 1 may be the same or different and
  • R 4 - 1 is H, F, Cl, Br, I, C 1-3 -alkyl-, HO-, d -3 alkyl-O- or Ci -3 alkyl-OC 2-4 alkylene-O- .
  • R 5 is H, ds-alkyl, optionally substituted by d-3-alkyl
  • R 5 - 1 -3 alkyl-OC represents H, F, Cl, Br, I, d -3 alkyl, HO-, d -3 alkyl-O- or C 2-4 alkylene-O-,
  • a third embodiment of the present invention comprises the compounds of the above general formula I in which A is a bond, d- 4 alkylene or -CH 2 -C (O) -, B is a bond, Ci -2 alkylene, -O - or -C (O) -,
  • D is a group of the general formula II d- 4 -alkylene or a group selected from
  • R 1 aryl or heteroaryl, each of which may be substituted by one, two, three or four radicals R 1 1 , wherein the radicals R 1-1 may be the same or different and
  • R 1 - 1 H, F, Cl, Br, I, C 1-3 -alkyl-, F 3 C-, HO-, d -3 -alkyl-O- or C 1-3 -alkyl-OC 2 - 4 - represents alkylene-O-,
  • R 3 is C- M- alkylene, -N (R 2 ) - or a group selected from
  • R 3 is also -O-, if B does not represent the group -O-,
  • R 4 is d- 4- alkylene, C 3-7 -cycloalkylene, -O- or a group selected from
  • A is a bond or Ci -3 alkylene
  • B is a bond, Ci -2 alkylene, -O- or -C (O) -,
  • Aryl or heteroaryl each of which may be substituted by one, two, three or four radicals R »1 1 .1, wherein the radicals R 1-1 may be the same or different and
  • R 5 is a group selected from
  • A is a bond, d -3 -alkylene or -CH 2 -C (O) -,
  • B is a bond, Ci -2 alkylene, -O- or -C (O) -,
  • R also -O-, if B does not represent the group -O-,
  • R 4 is d- 4- alkylene, C 3-7 -cycloalkylene, -O- or a group selected from
  • A is a bond or C 3 alkylene
  • B is a bond, Ci -2 alkylene, -O- or -C (O) -,
  • D is a group of the general formula II a group selected from
  • R 1 is a group selected from
  • R 4 is d- 4- alkylene, -O- or a group selected from
  • Ci- 5 alkyl H 2 N-, (C 1-2 alkyl) -NH-, (Ci -2 alkyl) 2 N-, H 2 NC (O) -, or
  • R 5 is a group selected from
  • a seventh embodiment of the present invention is the compounds of the above general formula I in which A, B, D, Y, R 2 , R 3 , R 4 and R 5 are as defined above in the first to sixth embodiments, and
  • R 1 is the group means
  • An eighth embodiment of the present invention is the compounds of the above general formula I in which A, B, D, Y, R 2 , R 3 , R 4 and R 5 are as defined above in the first to sixth embodiments, and
  • R 1 is the group means
  • a ninth embodiment of the present invention is the compounds of the above general formula I in which A, B, R 1 , R 3 , R 4 and R 5 are as defined above in the first to eighth embodiments, and
  • R 2 is H or d -3 -alkyl
  • A a bond
  • B is a bond
  • R 1 is the group
  • R 2 is H or Ci -3 alkyl, wherein each methylene group of up to two and each methyl group may be substituted with up to three fluoro atoms,
  • R 3 is a C 4 - 6 cycloalkylene
  • R 4 is a saturated 6- or 7-membered diaza-heterocycle
  • R 5 is d- 3- alkyl or C 3-5 -cycloalkyl
  • Ci are independent of each other. If more than one Ci to be a group, for example, -6 alkyl groups as substituents, one could independently of each other one may represent methyl, one n-propyl and one mean te / f-butyl in the case of three substituents Ci -6 alkyl.
  • the compounds of the invention including their salts, in which one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.
  • C 1-2 -alkyl (even if they are part of other radicals) are alkyl groups having 1 to 2 carbon atoms, by the term “C 1-3 -alkyl” branched and unbranched alkyl groups having 1 to 3 carbon atoms, under the branched term “C 1-4 alkyl” and unbranched alkyl groups having 1 to 4 carbon atoms, branched, the term “Ci -5 alkyl” and unbranched alkyl groups having 1 to 5 carbon atoms, the term “C 1-6 -alkyl” branched and unbranched alkyl groups with 1 to 6 carbon atoms and understood by the term “ds-alkyl” branched and unbranched alkyl groups having 1 to 8 carbon atoms.
  • Examples include: methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl, te / f-butyl, n-pentyl, / so-pentyl, neo-pentyl, Hexyl, heptyl and octyl.
  • the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, t-Bu, etc. are also used for the abovementioned groups.
  • propyl, butyl, pentyl, hexyl, heptyl and octyl include all conceivable isomeric forms of the respective radicals.
  • propyl includes n-propyl and / so-propyl
  • butyl includes / so-butyl, sec-butyl and te / f-butyl, etc.
  • the terms above also include those radicals in which each methylene group contains up to two and each methyl group may be substituted with up to three fluorine atoms.
  • d- 2 alkylene are meant branched and unbranched alkylene groups having 1 or 2 carbon atoms
  • C 1-3 -alkylene (including those which are part of other groups) are branched and unbranched alkylene groups having 1 to 3 carbon atoms , branched
  • C 1-4 alkylene and unbranched alkylene groups with 1 to 4 carbon atoms
  • C 6 alkylene are meant branched and unbranched alkylene groups with 1 to 6 carbon atoms and by the term “C 2-4 -Alkylen "understood branched and unbranched alkylene groups having 2 to 4 carbon atoms.
  • Examples include: methylene, ethylene, ethane-1, 1-diyl, propylene, propane-2,2-diyl, 1-methylethylene, butylene, 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene.
  • propylene and butylene include all conceivable isomeric forms of the same carbon number.
  • propylene also includes 1-methylethylene and butylene includes 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene.
  • each methylene group may be substituted by up to two fluorine atoms.
  • C 3-5 -cycloalkyl are meant cyclic alkyl groups having 3 to 5 carbon atoms
  • C 3 _ 6 -cycloalkyl are meant cyclic alkyl groups having 3 to 6 carbon atoms
  • C 3-7 -cycloalkyl (Even if they are part of other radicals) are understood cyclic alkyl groups having 3 to 7 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl or cycloheptyl.
  • the cyclic alkyl groups may be substituted with one or more groups selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluoro, chloro, bromo and iodo.
  • Cs- ⁇ -cycloalkylene (even if they are part of other radicals) are cyclic alkylene groups having 3 to 6 carbon atoms, by the term “C 3-7 -cycloalkylene” cyclic alkylene groups having 3 to 7 carbon atoms and the term “C 4-6 cycloalkylene” means cyclic alkylene groups having 4 to 6 carbon atoms. Examples include: cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene.
  • the cyclic alkylene groups may be substituted with one or more groups selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
  • a C 4 - or a C 5 -cycloalkylene group may be linked in the 1, 2-position or in the 1, 3-position to the remainder of the molecule, preferably in the 1, 3-position.
  • a Ce or a C 7 -cycloalkylene group may be linked in the 1, 2-position, in the 1, 3-position or in the 1, 4-position to the remainder of the molecule, preferably in the 1, 3-position.
  • C 5-7 -cycloalkenylene means cyclic alkenyl groups having 5 to 7 carbon atoms which contain an unsaturated bond and which are condensed via this unsaturated bond with a phenyl ring. Examples include: cyclopentenyl, cyclohexenyl or cyclohepentyl:
  • the cyclic alkenyl groups may be substituted with one or more groups selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
  • saturated heterocyclic rings is meant four-, five-, six- or seven-membered heterocyclic rings which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen.
  • the ring may be linked to the molecule via a carbon atom and / or, if present, via a nitrogen atom or else via two carbon atoms or via two nitrogen atoms.
  • heterocyclic non-aromatic rings defines five-, six- or seven-membered saturated rings. Examples are:
  • saturated diaza-heterocycles is understood to mean six- or seven-membered heterocyclic rings containing two nitrogen atoms. The ring is linked via both nitrogen atoms with the rest of the molecule. Examples are:
  • saturated aza-heterobicyclene eight-, nine- or ten-membered heterobicyclic rings containing a nitrogen atom. The ring is linked via a carbon atom and the nitrogen atom with the rest of the molecule. Examples are:
  • saturated diaza-heterobicyclene eight-, nine- or ten-membered heterobicyclic rings containing two nitrogen atoms. The ring is linked via both nitrogen atoms with the rest of the molecule. Examples are:
  • heterocyclic rings is understood as meaning five-, six- or seven-membered mono- or diunsaturated heterocyclic rings which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and which are bonded via the unsaturated bonds with one or two phenyl rings are condensed.
  • the heterocyclic ring may be linked to the molecule via a carbon atom and / or, if present, via a nitrogen atom or via two carbon atoms or via two nitrogen atoms. Examples are:
  • saturated diaza spirocycles is understood to mean nine, ten or eleven membered spirocyclic rings containing two nitrogen atoms.
  • the spirocycle is linked via both nitrogen atoms with the rest of the molecule. Examples are:
  • aryl (even if they are part of other radicals) are understood as meaning aromatic ring systems having 6 or 10 carbon atoms.
  • aryl radicals are phenyl and 1-naphthyl; particularly preferred aryl radical is phenyl.
  • the aromatics may be substituted by one or more radicals selected from the group consisting of methyl, ethyl, n-propyl, / so-propyl, te / f-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, Bromine and iodine, where the radicals may be the same or different.
  • heteroaryl is understood to mean five- or six-membered heterocyclic aromatics or 9-11-membered bicyclic heteroaryl rings which may contain one, two or three heteroatoms selected from the group oxygen, sulfur and nitrogen and additionally contain as many conjugated double bonds, that an aromatic system is formed.
  • heterocyclic aromatic compounds there are mentioned:
  • heteroaryls may be substituted with one or more radicals selected from the group consisting from methyl, ethyl, n-propyl, / so-propyl, te / f-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, bromine and iodine, where the radicals may be identical or different.
  • Bicyclic heteroaryl rings may preferably be substituted in the phenyl radical.
  • arylene (even if they are part of other radicals) are understood to mean aromatic ring systems having 6 or 10 carbon atoms.
  • the aromatics may be substituted by one or more radicals selected from the group consisting of methyl, ethyl, n-propyl, / so-propyl, te / f-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, Bromine and iodine.
  • aromatic ring systems are bonded independently of each other via two carbon atoms to the rest of the molecule.
  • heteroarylene are five- or six-membered heterocyclic
  • Understood aromatics or 9-11 membered bicyclic heteroaryl which may contain one, two or three heteroatoms selected from the group oxygen, sulfur and nitrogen, and in addition contain so many conjugated double bonds that an aromatic system is formed.
  • These heterocyclic aromatics are bonded independently of each other either via carbon and / or nitrogen in two places.
  • five- or six-membered heterocyclic aromatic compounds there are mentioned:
  • the heteroaromatics may be substituted by one or more radicals selected from the group consisting of methyl, ethyl, n-propyl, / so-propyl, te / f-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, Bromine and iodine.
  • the substituents in the above-mentioned 5-10 membered bicyclic heteroaryl rings are in the phenyl ring.
  • compounds of the general formula I can be converted, in particular for pharmaceutical applications, into their physiologically tolerated salts with inorganic or organic acids.
  • suitable inorganic acids are, for example, hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, organic acids being, for example, malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid,
  • Tartaric acid or citric acid into consideration. Furthermore, tertiary amino groups optionally present in the molecule can be quaternized. Alkyl halides are used for the reaction. According to the invention, methyl iodide is preferably used for the quartenization.
  • the compounds of the general formula I if they contain suitable carboxylic acid functions, if desired, can be converted into their addition salts with inorganic or organic bases.
  • suitable inorganic bases are, for example, alkali metal or alkaline earth metal hydroxides, for example sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc hydroxides or ammonium hydroxides;
  • suitable organic amines are, for example, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine or dicyclohexylamine.
  • the compounds according to the invention can be present as racemates if they have only one chiral element, but they can also be obtained as pure enantiomers, ie in (R) or (S) form.
  • the application also includes the individual diastereomeric antipode pairs or mixtures thereof, which are present when more than one chirality element is present in the compounds of general formula I, as well as the individual optically active enantiomers which make up the racemates mentioned.
  • the invention relates to the respective compounds optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - such as acid addition salts with hydrohalic acids - for example chlorine or hydrobromic acid - or organic acids - such as oxalic, fumaric, diglycolic or methanesulfonic acid.
  • pharmacologically acceptable acids - such as acid addition salts with hydrohalic acids - for example chlorine or hydrobromic acid - or organic acids - such as oxalic, fumaric, diglycolic or methanesulfonic acid.
  • the compounds of general formula I are obtained by processes known per se, for example by the following processes:
  • the coupling is preferably carried out using methods known from peptide chemistry (see, for example, Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example carbodiimides, such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC ) or ethyl (3-dimethylamino-propyl) -carbodiimide, O- (1 / - / - benzotriazol-1-yl) - ⁇ /, ⁇ / - ⁇ / ', ⁇ /' - tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1 / - / - benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP).
  • DCC dicyclohexylcarbodi
  • the reaction rate can be increased by adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt).
  • the couplings are normally used with equimolar proportions of the coupling components and the coupling reagent in solvents such as dichloromethane, tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), ⁇ / -methylpyrrolidone (NMP) or mixtures thereof and at temperatures between - 30 0 C and +30 0 C, preferably -20 ° C and + 25 ° C performed.
  • DIPEA diisopropylethylamine
  • Hünig's base is preferred as additional auxiliary base.
  • An alternative method of linking is to convert a carboxylic acid of general formula III wherein all of the radicals are as defined above into a carboxylic acid chloride of general formula V in which all radicals are defined as mentioned above, followed by reaction with an amine of general formula IV in which all radicals are defined as mentioned above.
  • the synthesis of a carbonyl chloride of the general formula V is carried out by literature methods (see, for example, Houben-Weyl, Methods of Organic Chemistry, Vol.
  • the sulfonyl chlorides of the general formula VI in which R 1 is defined as mentioned above, are either known from the literature or commercially available. They are reacted according to standard reaction conditions with an amine of the general formulas H 2 NR 2 , Villa or VIIIb to give sulphonic acid amides of the general formulas VII, X or XI, where R 1 and R 2 are defined as mentioned above and n is a number 1, 2 , 3 or 4 and R 6 is a d- 6 -alkyl radical.
  • the reaction is optionally carried out in the presence of a base such as triethylamine, DIPEA or pyridine and an inert solvent such as dichloromethane or tetrahydrofuran at a temperature of 0 0 C to 100 0 C with a typical reaction time of one to 24 hours.
  • a base such as triethylamine, DIPEA or pyridine
  • an inert solvent such as dichloromethane or tetrahydrofuran
  • n is a number 1, 2, 3 or 4 and R 6 is a Ci -3 alkyl group, and R 6 is a Ci -6 alkyl group, is conveniently in a solvent such as toluene, chlorobenzene, dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, acetonitrile or pyridine, for example at temperatures between 0 0 C and 150 0 C and conveniently in the presence of bases such as pyridine, triethylamine, DIPEA, potassium carbonate, potassium tert-butoxide or sodium methoxide, wherein the alkyl sulfonate serves as a leaving group.
  • a solvent such as toluene, chlorobenzene, dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, acetonitrile or pyridine, for example at temperatures between 0 0 C and 150 0 C and conveniently in the presence of bases such as pyridine, triethyl
  • the amino function in the compounds of general formula XXIII is protected by a conventional protecting group PG according to known methods.
  • the selected protecting group is one that can be cleaved under non-hydrogenolytic conditions.
  • a preferred protecting group is the Boc group.
  • the alkylation of a thiol of general formula XXV in which n is a number 1, 2, 3 or 4 and R 6 is a Ci -6 alkyl group means, XXVI to give compounds of the general formula as mentioned above in which R 1 and R 2 defined are n, a number 1, 2, 3 or 4 and R 6 is a C- ⁇ -6-alkyl group, is suitably in a solvent such as toluene, chlorobenzene, DMF, DMSO, dichloromethane, acetonitrile or pyridine, for example at temperatures between 0 0 C and 150 0 C and conveniently in the presence of bases such as pyridine, triethylamine, DIPEA, potassium carbonate, potassium tert-butoxide or sodium methoxide performed, wherein the alkyl sulfonate serves as a leaving group.
  • a solvent such as toluene, chlorobenzene, DMF, DMSO, dichloromethane, acet
  • amines of general formula IV used as starting materials are either commercially available, or they are obtained by processes known per se from the literature, for example by the synthesis routes shown in Schemes 8 to 12, where R 1 1 is defined as mentioned above, HaI 1 is a chlorine radical. or Bromatom and HaI 2 mean a fluorine, chlorine or bromine atom or a radical R 9 .
  • reaction of an amine of general formula XXX, a Ci -3 alkyl group represents in which R 9 is as mentioned above with a halogen-nitrobenzene of the general formula XXXI, in which R 1-1 and Hal 2 defines a fluorine, chlorine or bromine atom or a radical R 9 is carried out by known methods, for example in a solvent such as tetrahydrofuran, dimethylformamide or dimethyl sulfoxide and expediently in the presence of a suitable base such as triethylamine or potassium carbonate, at a temperature of 20 0 C to 160 0 C. If the amine of general formula XXX is liquid, the reaction can also be carried out without solvent and additional base.
  • the reduction of a nitrile of the general formula XXXV to an amine of general formula XXXVI, wherein R 1 1 is as hereinbefore defined and R 9 represents a Ci -3 alkyl group can under standard conditions of catalytic hydrogenolysis with a catalyst such as Raney nickel in a solvent such as ammoniacal methanol or ethanol, or with a reducing agent such as lithium aluminum hydride or sodium borohydride in a solvent such as tetrahydrofuran, optionally in the presence of aluminum chloride.
  • a catalyst such as Raney nickel in a solvent such as ammoniacal methanol or ethanol
  • a reducing agent such as lithium aluminum hydride or sodium borohydride in a solvent such as tetrahydrofuran, optionally in the presence of aluminum chloride.
  • halogen-nitrogen exchange in compounds of the general formulas XXX, in which R 9 is a Ci_3-alkyl group, and XL, in which R 1-1 is defined as mentioned above and HaI 2 is a fluorine, chlorine or bromine atom or a R 9 means, for the preparation of compounds of general formula XLI, in which R 1-1 is defined as mentioned above and R 9 is a Ci -3 alkyl group, is carried out as described under Scheme 8.
  • a reducing agent such as sodium triacetoxyborohydride, sodium borohydride or sodium cyanoborohydride, expediently in a solvent such as Tetra h yd rofu ran or dichloromethane, optionally with the addition of acetic acid.
  • CHO cells expressing the hBK1 receptor are cultured in "Dulbecco's modified medium.” Confluent cultures are used to remove the medium, wash the cells with PBS buffer, scrap and isolate by centrifugation, then homogenize the cells in suspension centrifuging and resuspending the homogenate After determining the protein content, the membrane preparation thus obtained is frozen at -80 ° C.
  • the bound radioactivity is defined in the presence of 1.0 ⁇ M kallidin (DesArg10, Leu9), [3,4-prolyl-3,43H (N)].
  • concentration-binding curve is carried out by means of a computer-aided nonlinear curve fitting. From the data thus obtained, the corresponding K, value is determined for the test substance.
  • novel compounds and their physiologically acceptable salts are useful in the treatment of diseases and disease symptoms caused, at least in part, by the stimulation of bradykinin B 1 receptors. Due to their pharmacological effect, the substances are suitable for treatment
  • intestinal pain e.g. chronic pelvic pain, gynecological pain, pain before and during menses, pain in pancreatitis, peptic ulcer, interstitial cystitis, renal colic, angina pectoris, irritable bowel pain, non-ulcer dyspepsia and gastritis, non-cardiac chest pain and pain in myocardial ischemia and myocardial infarction;
  • intestinal pain e.g. chronic pelvic pain, gynecological pain, pain before and during menses, pain in pancreatitis, peptic ulcer, interstitial cystitis, renal colic, angina pectoris, irritable bowel pain, non-ulcer dyspepsia and gastritis, non-cardiac chest pain and pain in myocardial ischemia and myocardial infarction;
  • neuropathic pain e.g. painful polyneuropathies, pain in diabetic neuropathy, AIDS-associated neuropathic pain, pain in lumbago, in non-herpes associated neuralgia, in post-zoster neuralgia, in nerve injuries, in craniocerebral trauma, in pain
  • tumor pain associated with cancers such as lymphocytic or myeloid leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, lymphogranulomatosis, lymphosarcoma, solid malignant tumors, and extensive metastases;
  • headache disorders e.g. Headaches of various causes, cluster headache, migraine (with or without aura) and tension headache.
  • the compounds are suitable for treatment (g) of inflammatory changes associated with respiratory diseases such as bronchial asthma, including allergic asthma (atopic and non-atopic) and bronchospasm on exertion, occupational asthma, viral or bacterial exacerbation of existing asthma and other non-allergic conditional asthmatic diseases; chronic obstructive pulmonary disease (COPD) including pulmonary emphysema, adult respiratory distress syndrome (ARDS), bronchitis, pneumonia, allergic rhinitis (seasonal and perennial), vasomotor rhinitis and pneumoconiosis diseases such as aluminosis, anthracosis, asbestosis, chalicosis, siderosis, silicosis, Tobacco and Byssinose;
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • ARDS adult respiratory distress syndrome
  • bronchitis pneumonia
  • allergic rhinitis seasonal and perennial
  • diabetes mellitus and its consequences such as diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy
  • diabetic symptoms of insulitis e.g., hyperglycemia, diuresis, proteinuria and increased renal nitrite and kallikrein excretion
  • insulitis e.g., hyperglycemia, diuresis, proteinuria and increased renal nitrite and kallikrein excretion
  • neurodegenerative diseases such as Parkinson 's disease and Alzheimer's disease
  • these substances are also useful in the veterinary treatment of pets, exotic animals and livestock.
  • the compounds according to the invention For the treatment of pain, it may be advantageous to combine the compounds according to the invention with invigorating substances such as caffeine or other pain-relieving active ingredients. If suitable active ingredients are available for the treatment of the cause of the pain, these can be combined with the compounds according to the invention. If, in addition to the pain treatment, other medical treatments are also indicated, for example for hypertension or diabetes, then the active ingredients necessary for this purpose can also be combined with the compounds according to the invention.
  • Non-steroidal anti-inflammatory drugs COX-2 inhibitors such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxinic acid, carprofen, fenhufen, fenoprofen, fiprofen, fulbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen,
  • COX-2 inhibitors such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxinic acid, carprofen, fenhufen, fenoprofen, fiprofen, fulbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen,
  • acetic acid derivatives indomethacin, acemetacin, alcofenac, isoxepac, oxpinax, sulindac, tiopinac, tolmetin, zidometacin, z
  • Cannabinoid agonists such as GW-1000, KDS-2000, SAB-378, SP-104, NVP001-GW-843166, GW-842166X, PRS-211375.
  • Sodium channel blockers such as carbamazepine, mexiletine, lamotrigine, pregabalin, tectin,
  • N-type calcium channel blockers such as e.g. Ziconitide, NMED-160, SP1-860.
  • Serotonergic and noradrenergic modulators such as e.g. SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram.
  • Corticosteroids such as e.g. Betamethasone, budesonide, cortisone, dexamethasone,
  • Hydrocortisone methylprednisolone, prednisolone, prednisone and triamcinolone.
  • Histamine H1 receptor antagonists such as e.g. Bromophtniramint, chlorpheniramine,
  • Cetirizine desloratadine, fexofenadine, levocetirizine.
  • Histamine H2 receptor antagonists such as e.g. Cimetidine, famotidine, and ranitidine.
  • Proton pump inhibitors such as e.g. Omeprazole, pantoprazole, esomeprazole.
  • Leukotriene antagonists and 5-lipoxygenase inhibitors such as e.g. Zafirlukast, Montelukast,
  • Local anesthetics such as Ambroxol, lidocaine.
  • VR1 agonists and antagonists e.g. NGX-4010, WL-1002, ALGRX-4975, WL-
  • Nicotine receptor agonists such as e.g. ABT-202, A-366833, ABT-594, BTG-102, A-85380,
  • P2X3 receptor antagonists such as e.g. A-317491, ISIS-13920, AZD-9056.
  • NGF agonists and antagonists e.g. RI-724, RI-1024, AMG-819, AMG-403, PPH
  • NK1 and N K2 antagonists such as e.g. DA-5018, R-1 16301, CP-728663, ZD-2249.
  • NMDA antagonists such as NER-MD-1 1, CNS-5161, EAA-090, AZ-756, CNP-3381.
  • Potassium channel modulators such as e.g. CL-888, ICA-69673, retigabine.
  • GABA modulators such as e.g. Lacosamide.
  • Serotonergic and noradrenergic modulators such as e.g. SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram, flibanserin.
  • Anti-migraine therapeutics such as e.g. Sumatriptan, zolmitriptan, naratriptan, eletriptan.
  • the dosage required to achieve an analgesic effect is expediently 0.01 to 3 mg / kg body weight, preferably by intravenous administration 0.1 to 1 mg / kg, and when administered orally 0.1 to 8 mg / kg body weight, preferably 0.5 to 3 mg / kg, in each case 1 to 3 times daily.
  • the compounds prepared according to the invention can be administered intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, with aerosol formulations in particular being suitable for inhalation.
  • customary carriers and / or diluents for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol , Water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or their suitable mixtures, in customary pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, metered aerosols or suppositories are incorporated.
  • customary pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, metered aerosols or suppositories are incorporated.
  • IR, 1 H-NMR and / or mass spectra are available for the compounds prepared.
  • the ratios indicated for the flow agents relate to volume units of the respective solvents.
  • the volume units given for ammonia refer to a concentrated solution of ammonia in water.
  • the acid, base and salt solutions used in the workup of the reaction solutions are aqueous systems of the indicated concentrations.
  • silica gel from Millipore 35-70 ⁇ m
  • Alox E. Merck, Darmstadt, aluminum oxide 90 standardized, 63-200 ⁇ m, article no: 1.01097.9050
  • Plasticizer A water / 0.1% formic acid
  • Plasticizer B acetonitrile / 0.1% formic acid
  • Plasticizer A water / 0.1% TFA
  • Plasticizer B acetonitrile / 0.1% TFA gradient:
  • Method 3 Column: XTerra TM MS C18, 3.5 ⁇ M, 4.6 ⁇ 50 mm Detection: 210-420 nm
  • Flow agent A water / 0.1% formic acid flow agent
  • B acetonitrile / 0.1% formic acid gradient:
  • Plasticizer A water / 0.1% formic acid
  • Plasticizer B acetonitrile / 0.1% formic acid
  • Plasticizer A water / 0.1% TFA
  • Plasticizer B acetonitrile
  • Plasticizer A water / 0.1% formic acid
  • Plasticizer B acetonitrile / 0.1% formic acid
  • Method 7 Column: Waters Sunfire C18, 3.5 ⁇ M, 4.6 x 50 mm
  • Plasticizer A water / 0.1% TFA
  • Plasticizer B acetonitrile / 0.1% TFA
  • Method 8 Column: Waters XBridge C18, 3.5 ⁇ M, 4.6 x 50 mm
  • Plasticizer A water / 0.1% TFA
  • Plasticizer B acetonitrile / 0.1% TFA
  • Plasticizer A water / 0.1% formic acid
  • Plasticizer B acetonitrile / 0.1% formic acid
  • Plasticizer A water / 0.1% TFA
  • Plasticizer B acetonitrile / 0.1% TFA gradient:
  • Method 11 Column: Waters XBridge C18, 3.5 ⁇ M, 4.6 x 50 mm
  • Plasticizer A water / 0.1% TFA
  • Plasticizer B acetonitrile / 0.1% TFA
  • Method 12 Column: YMC pack ODS-AQ, 3.0 ⁇ M, 4.6 ⁇ 75 mm Detection: 230-360 nm
  • Plasticizer A water / 0.1% formic acid
  • Plasticizer B acetonitrile / 0.1% formic acid gradient:
  • Example 2 is analogous to 1f from 0.22 g (0.71 mmol) of product from 1c, 0.24 g (1.35 mmol)
  • Example 3 is prepared analogously to 1f from 0.15 g (0.47 mmol) of product from 3c, 0.12 g (0.47 mmol) product of 1 e, 0.2 ml (1.43 mmol) of triethylamine and 0.15 g (0.48 mmol) of TBTU in 8 ml of DMF.
  • C 29 H 37 N 5 O 4 S (551.70) [M + H] + 552
  • Example 4 is analogous to 1f from 0.39 g (1.26 mmol) of product from 1c, 0.24 g (1.26 mmol)
  • 5a is prepared analogously to 1f from 0.39 g (1.26 mmol) of product from 1c, 0.24 g (1.26 mmol) of 4- (4-methylpiperazin-1-yl) -aniline (J. Med. Chem. SIR 48, 7, 2005, 2371 -2387), 0.35 ml (2.51 mmol) triethylamine and 0.50 g (1.32 mmol) HATU in 5 ml DMF.
  • Example 6 is analogous to 1f from 0.22 g (0.71 mmol) of product from 1c, 0.12 g (0.78 mmol) 3
  • Example 7 is analogous to 1f from 0.22 g (0.71 mmol) of product from 1c, 0.14 g (0.71 mmol)
  • Example 8 is analogous to 1f from 0.22 g (0.71 mmol) of product from 1c, 0.16 g (0.71 mmol)
  • Example 9 is analogous to 1f from 0.15 g (0.48 mmol) of product from 1c, 0.14 g (0.51 mmol)
  • 10b is prepared analogously to 1f from 1.85 g (9.10 mmol) of product from 10a, 2.32 g (9.10 mmol).
  • Example 1 1 is prepared analogously to 1 Od from 0.10 g (0.30 mmol) of product from 10c, 0.052 g (0.25 mmol) of 2-chlorobenzenesulfonyl chloride, 0.14 ml (98 mmol) of triethylamine in 5 ml of dichloromethane.
  • C 25 H 28 CIN 5 O 3 S (514.04) [M + H] + 514/516
  • TLC: silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1, Rf-We rt 0.47
  • Example 12 is prepared analogously to 10d from 0.10 g (0.30 mmol) of product from 10c, 0.047 g (0.25 mmol) of p-toluenesulfonyl chloride, 0.14 ml (98 mmol) of triethylamine in 5 ml of dichloromethane.
  • Example 13 is prepared analogously to 10d from 0.10 g (0.30 mmol) of product from 10c, 0.058 g (0.25 mmol) of product from 13a, 0.14 ml (98 mmol) of triethylamine in 5 ml of dichloromethane.
  • Example 14 is prepared analogously to 1Od from 0.10 g (0.30 mmol) of product from 10c, 0.047 g (0.25 mmol) of m-toluenesulfonyl chloride, 0.14 ml (98 mmol) of triethylamine in 5 ml of dichloromethane.
  • Example 15 is prepared analogously to 1 Od from 0.10 g (0.30 mmol) of product from 10c, 0.047 g (0.25 mmol) of o-toluenesulfonyl chloride, 0.14 ml (98 mmol) of triethylamine in 5 ml of dichloromethane.
  • Example 16 is prepared analogously to 1 Od from 0.10 g (0.30 mmol) of product from 10c, 0.043 g (0.25 mmol) of benzenesulfonyl chloride, 0.14 ml (98 mmol) of triethylamine in 5 ml of dichloromethane.
  • Example 17 is analogous to 1f from 0.22 g (0.71 mmol) of product from 1c, 0.34 g (0.78 mmol)
  • 18a is prepared analogously to 1f from 0.20 g (0.64 mmol) of product from 1c, 0.17 g (0.64 mmol) tert-butyl 4- (4-aminobutyl) piperazine-1-carboxylate (J. Med. Chem. 47, 2004, 4300-4315), 0.27 ml (1.92 mmol) of triethylamine and 0.21 g (0.64 mmol) of TBTU in 5 ml of THF.
  • M + H] + 551/553/555
  • Example 19 is analogous to 1f from 0.16 g (0.50 mmol) of product from 1c, 0.10 g (0.50 mmol)
  • Example 20 is prepared analogously to 1f from 0.50 g (1.61 mmol) of product from 1c, 0.55 g (3.22 mmol) product of 20b, 0.67 ml (4.83 mmol) of triethylamine and 0.52 g (1.61 mmol) of TBTU in 30 ml of DMF.
  • Example 21 is analogous to 1f from 0.11 g (0.35 mmol) of product from 1 c, 0.089 g (0.35 mmol)
  • 22b is prepared analogously to 3b from 4.06 g (12.87 mmol) of product from 22a, 2.40 ml (38.62 mmol).
  • the acid is prepared analogously to 1c from 3.83 g (1.63 mmol) of product of 22b, 2.44 g (58.13 mmol) of lithium hydroxide monohydrate in 30 ml of THF and 30 ml of water.
  • Example 22 is prepared analogously to 1f from 0.13 g (0.42 mmol) of product from 22c, 0.089 g (0.35 mmol) of product from 21 b, 0.098 ml (0.70 mmol) of triethylamine and 0.13 g (0.42 mmol) of TBTU in 15 ml of THF.
  • Example 23 is analogous to 1f from 0.30 g (1.00 mmol) of product from 22c, 0.22 g (1.00 mmol)
  • Example 24 is prepared analogously to 1f from 0.25 g (0.80 mmol) of product from 3c, 0.18 g (0.80 mmol) of product from 8b, 0.33 ml (2.39 mmol) of triethylamine and 0.26 g (0.80 mmol) of TBTU in 10 ml of DMF.
  • Example 25 is prepared analogously to 1f from 0.20 g (0.66 mmol) of product from 22c, 0.14 g (0.73 mmol).
  • Example 26 is analogous to 1f from 0.20 g (0.66 mmol) of product from 22c, 0.14 g (0.73 mmol) of 4- (4-methylpiperazin-1-yl) -aniline (J. Med. Chem. SIR 48, 7, 2005, 2371-2387), 0.28 ml (1.99 mmol) triethylamine and 0.21 g (0.66 mmol) TBTU in 5 ml THF.
  • C 24 H 34 N 4 O 4 S x C 2 HF 3 O 2 (588.65) [M + H] + 475
  • 27b is prepared analogously to 8b from 1.50 g (5.99 mmol) of product from 27a, 0.20 g of palladium on carbon (10%) and 15 ml of methanol.
  • Example 28 is analogous to 1f from 0.11 g (0.35 mmol) of product from 22c, 0.082 g (0.35 mmol) of product from 28d, 0.098 ml (0.70 mmol) of triethylamine and 0.13 g (0.42 mmol) of TBTU in 7 ml of THF and 1 ml of DMF produced.
  • 29a is prepared analogously to 28c from 0.12 g (0.80 mmol) of 4-chloropyridine hydrochloride (Aldrich), 0.20 g (0.80 mmol) of ⁇ / -methyl-N- (2-piperidin-4-yl-ethyl) -benzamide (J. Med Chem. 33, 1990, 1880-1887), 0.23 ml (1.68 mmol) of triethylamine in 5 ml of ethanol.
  • C 20 H 25 N 3 O (323.43) [M + H] + 324
  • Extracts are dried over sodium sulfate and concentrated in vacuo to dryness.
  • Example 29 is analogous to 1f from 0.14 g (0.46 mmol) of product from 22c, 0.10 g (0.46 mmol)
  • 30b is prepared analogously to 13a from 4.30 g (23.86 mmol) of product from 30a and 5.60 g (48.06 mmol) of chlorosulfonic acid in 100 ml of dichloromethane.
  • CnH 15 CIO 4 S (278.75) TLC: silica gel, petroleum ether / ethyl acetate 9: 1, R f 0.06
  • 30a is prepared analogously to 3a from 1.70 g (6.10 mmol) of product from 30b, 1.20 g (7.81 mmol) of ⁇ -alanine ethyl ester hydrochloride, 2.60 ml (18.65 mmol) of triethylamine in 30 ml of dichloromethane.
  • CI 6 H 25 NO 6 S (359.44) [M + H] + 360
  • Example 30 is analogous to 1f from 0.14 g (0.39 mmol) of product from 3Oe, 0.10 g (0.39 mmol)
  • Example 31 is analogous to 1f from 0.16 g (0.46 mmol) of product from 3Oe, 0.10 g (0.46 mmol)
  • 32b is analogous to 21 b from 1.93 g (6.74 mmol) of product from 32a and 0.3 g of palladium
  • Example 32 is analogous to 1f from 0.1 1 g (0.35 mmol) of product from 22c, 0.090 g (0.35 mmol) product of 32b, 0.098 ml (0.70 mmol) of triethylamine and 0.13 g (0.42 mmol) of TBTU in 7 ml of THF and 1 ml DMF produced.
  • Example 33 is prepared analogously to 27d from 0.27 g (0.84 mmol) of product from 27c, 0.63 g (2.68 mmol) of product from 33a, 0.22 ml (1.26 mmol) of DIPEA in 3 ml of dichloromethane.
  • Example 34 is analogous to 1f from 0.11 g (0.35 mmol) of product from 22c, 0.076 g (0.35 mmol) product of 34d, 0.098 ml (0.70 mmol) of triethylamine and 0.13 g (0.42 mmol) of TBTU in 7 ml of THF and 1 ml of DMF produced.
  • Example 35 is prepared analogously to 1f from 0.16 g (0.50 mmol) of product from 1c, 0.11 g (0.50 mmol) product of 35b, 0.14 ml (1.00 mmol) of triethylamine and 0.16 g (0.50 mmol) of TBTU in 3 ml of DMF.
  • 36b is prepared analogously to 34b from 4.40 g (15.31 mmol) of product from 36a, 0.7 g of Raney nickel and 45 ml of methanolic ammonia solution.
  • 36c is prepared analogously to 1f from 0.40 g (1.33 mmol) of product from 22c, 0.43 g (1.46 mmol)
  • Example 36 is prepared analogously to 18b from 0.50 g (0.57 mmol) of product from 36c, 0.44 ml of TFA in 5 ml of dichloromethane.
  • Example 37 is prepared analogously to 1f from 0.11 g (0.35 mmol) of product from 22c, 0.072 g (0.35 mmol) of 37b product, 0.098 ml (0.70 mmol) of triethylamine and 0.13 g (0.42 mmol) of TBTU in 7 ml of THF.
  • reaction mixture After stirring for 2 hours at room temperature, the reaction mixture is poured onto a mixture of 6 M HCl and ice. After phase separation, the aqueous
  • 38e is prepared analogously to 1f from 2.00 g (8.27 mmol) of product from 38 d, 18.20 ml (9.10 mmol)
  • Example 38 is analogous to 1f from 0.19 g (0.63 mmol) of product from 22c, 0.12 g (0.63 mmol)
  • Catalyst is then filtered off, the filtrate concentrated in vacuo to dryness.
  • 39c is prepared analogously to 1d from 0.56 g (4.37 mmol) of product from 39b, 0.64 g (4.50 mmol) of 4-fluoro-nitrobenzene (Aldrich), 0.65 ml (4.60 mmol) of triethylamine in 5 ml of DMF.
  • CI 4 H 21 N 3 O 2 (263.34)
  • 39d is analogous to 8b from 0.94 g (3.55 mmol) of product from 39c and 0.10 g of palladium
  • Example 39 is prepared analogously to 1f from 0.30 g (1.00 mmol) of product from 22c, 0.23 g (1.00 mmol) of 39d product, 0.42 ml (3.00 mmol) of triethylamine and 0.32 g (1.00 mmol) of TBTU in 15 ml of DMF.
  • Example 40 is prepared analogously to 1f from 0.16 g (0.50 mmol) of product from 1c, 0.12 g (0.50 mmol)
  • 41a is prepared analogously to 1d from 1.00 g (5.87 mmol) of diethyl-piperidin-4-ylmethyl-amine (Chem.
  • Example 41 is analogous to 1f from 0.40 g (1.34 mmol) of product from 22c, 0.35 g (1.34 mmol)
  • Example 42 is analogous to 1f from 0.33 g (1.08 mmol) of product from 22c, 0.27 g (1.08 mmol) of 42b product, 0.38 ml (2.70 mmol) of triethylamine and 0.35 g (1.08 mmol) of TBTU in 7 ml of THF and 1 ml of DMF produced.
  • Example 44 is analogous to 1f from 0.12 g (0.40 mmol) of product from 22c, 0.10 g (0.40 mmol) of product from 44b, 0.069 ml (0.50 mmol) of triethylamine and 0.14 g (0.44 mmol) of TBTU in 40 ml of THF and 5 ml of DMF produced.
  • 45a is analogous to 44a from 1.00 g (5.87 mmol) of diethyl-piperidin-4-ylmethyl-amine (Chem. Pharm. Bull. 42, 1994, 74-84), 0.93 g (5.87 mmol) of 2-chloro-5-nitropyridine (Fluka) and 1.70 g (12.30 mmol) of potassium carbonate in 100 ml of THF.
  • Ci 5 H 24 N 4 O 2 (292.38) [M + H] + 293
  • Example 45 is analogous to 1f from 0.16 g (0.53 mmol) of product from 22c, 0.14 g (0.53 mmol) of product from 45b, 0.096 ml (0.69 mmol) of triethylamine and 0.19 g (0.58 mmol) of TBTU in 40 ml of THF and 5 ml of DMF produced.
  • C 28 H 43 N 5 O 4 S x 2HCl (618.66) [M + H] + 546
  • 46a is analogous to 1d from 3.00 g (15.21 mmol) of 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone
  • Triethylamine prepared in 25 ml of DMF.
  • Example 46 is analogous to 1f from 0.30 g (1.00 mmol) of product from 22c, 0.27 g (1.00 mmol)
  • Example 47 is prepared analogously to 1f from 0.20 g (0.66 mmol) of product from 22c, 0.14 g (0.66 mmol)
  • 48a is prepared analogously to 1f from 0.24 g (1.45 mmol) 4-nitrobenzoic acid (Aldrich), 0.19 g (1.45 mmol) 4-dimethylamino-piperidine (Alfa Aesar), 0.21 ml (1.52 mmol) triethylamine and 0.49 g (1.52 mmol) TBTU prepared in 8 ml of DMF.
  • Catalyst is then filtered off, the filtrate concentrated in vacuo to dryness.
  • Example 48 is analogous to 1f from 0.15 g (0.50 mmol) of product from 22c, 0.18 g (0.50 mmol)
  • Example 49 is analogous to 1f from 0.15 g (0.50 mmol) of product from 22c, 0.11 g (0.50 mmol) of (4-aminophenyl) - (4-methylpiperazin-1-yl) -methanone (J. Org. Chem. 24, 1959 , 459-463), 0.21 ml (1.49 mmol) of triethylamine and 0.16 g (0.50 mmol) of TBTU in 3 ml of THF.
  • [M + H] + 503
  • 50a is prepared analogously to 1f from 0.60 g (4.34 mmol) of 5-amino-pyridine-2-carboxylic acid (Pharm.
  • the reaction mixture is then concentrated in vacuo to dryness.
  • the product is obtained by preparative HPLC.
  • Example 51 is analogous to 1f from 0.15 g (0.50 mmol) of product from 22c, 0.12 g (0.50 mmol)
  • 52b is prepared analogously to 51 b from 0.17 g (4.51 mmol) of lithium aluminum hydride and 0.58 g (2.34 mmol) of product from 52a in 10 ml of THF.
  • CI 4 H 23 N 3 (233.35) TLC: silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1, Rf-We rt 0.5
  • Example 52 is prepared analogously to 1f from 0.21 g (0.68 mmol) of product from 22c, 0.24 g (0.68 mmol) of 52b product, 0.28 ml (2.04 mmol) of triethylamine and 0.22 g (0.68 mmol) of TBTU in 4 ml of THF.
  • 53a is prepared analogously to 3a from 4.50 g (19.17 mmol) of product from 13a, 1.69 g (21.10 mmol).
  • 53d is prepared analogously to 28c from 1.00 g (6.10 mmol) of 4-chloro-2-methylpyridine hydrochloride (Alfa).
  • Example 53 is analogous to 1f from 0.099 g (0.30 mmol) of product from 53c, 0.066 g (0.30 mmol) of product from 53e, 0.10 ml (0.75 mmol) of triethylamine and 0.12 g (0.36 mmol) of TBTU in 8 ml of THF and 1 ml of DMF produced.
  • 54a is prepared analogously to 1f from 2.00 g (8.27 mmol) of 38d, 8.28 ml (16.55 mmol) product.
  • 54b is prepared analogously to 38f from 1.00 g (4.58 mmol) of product from 54a and 9.00 ml (9.00 mmol)
  • Example 54 is analogous to 1f from 0.099 g (0.30 mmol) of product from 53c, 0.088 g (0.30 mmol) product of 54b, 0.10 ml (0.75 mmol) of triethylamine and 0.12 g (0.36 mmol) of TBTU in 7 ml of THF and 1 ml of DMF produced.
  • 55b is prepared analogously to 27c from 1.7 g (7.14 mmol) of product from 55a and 30 ml of thionyl chloride.
  • 55e is prepared analogously to 38f from 0.80 g (3.13 mmol) of product of 55d and 20.00 ml (20.00 mmol) of lithium aluminum hydride 1 M in THF (Aldrich) in 50 ml of pyridine.
  • Ci 5 Hi 9 N 3 (241.33) [M + H] + 242
  • Example 55 is analogous to 1f from 0.14 g (0.42 mmol) of product from 53c, 0.10 g (0.41 mmol)
  • 56a is prepared analogously to 27c from 1.35 g (5.59 mmol) of i-benzylpyrrolidine-3-carboxylic acid (J. Org. Chem. 33, 1968, 3637-3639) and 10 ml of thionyl chloride.
  • Ci 2 H 14 CINO x HCl (260.16)
  • 56b is prepared analogously to 55c from 1.45 g (5.57 mmol) of product from 56a, 10 ml (50.00 mmol) of methylamine 2M in THF (Aldrich) in 50 ml of THF.
  • Ci 3 H 18 N 2 O (218.29) [M + H] + 219
  • 56d is prepared analogously to 28c from 0.76 g (5.08 mmol) of 4-chloropyridine hydrochloride (Aldrich), 0.65 g (5.07 mmol) of product of 56c and 1.52 ml (10.88 mmol) of triethylamine in 10 ml of ethanol.
  • Aldrich 4-chloropyridine hydrochloride
  • 56e is prepared analogously to 38f from 0.45 g (2.19 mmol) of product of 56 d and 7.00 ml (7.00 mmol) of lithium aluminum hydride 1 M in THF (Aldrich) in 30 ml of THF.
  • CnH 17 N 3 (191.27) [M + H] + 192
  • Example 56 is analogous to 1f from 0.14 g (0.42 mmol) of product from 53c, 0.10 g (0.42 mmol)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule générale (I), dans laquelle A, B, D, Y, R1, R2, R3, R4 et R5 sont tels que définis dans la revendication 1, leurs énantiomères, leurs diastéréoisomères, leurs mélanges et leurs sels, en particulier leurs sels d'acides ou de bases organiques ou inorganiques physiologiquement compatibles et présentant des propriétés utiles, ainsi que leur préparation, les médicaments contenant ces composés pharmacologiquement actifs, leur préparation et leur utilisation.
PCT/EP2008/052157 2007-08-14 2008-02-21 Arylsulfonamides ayant un effet analgésique Ceased WO2009021758A1 (fr)

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EP08102044A EP2025668A1 (fr) 2007-08-14 2008-02-26 Arylsulfonamides ayant activité analgésique
EP08102043A EP2025673A1 (fr) 2007-08-14 2008-02-26 Arylsulfonamides ayant activité analgésique
CA2696261A CA2696261A1 (fr) 2007-08-14 2008-08-12 Nouveaux composes
US12/672,460 US8394805B2 (en) 2007-08-14 2008-08-12 Compounds
EP08803005.1A EP2188269B1 (fr) 2007-08-14 2008-08-12 Arylsulfonamides a effet analgesique
KR1020107005536A KR20100055469A (ko) 2007-08-14 2008-08-12 신규 화합물
AT08803006T ATE502918T1 (de) 2007-08-14 2008-08-12 Arylsulfonamide mit analgetischer wirkung
PCT/EP2008/060562 WO2009021944A1 (fr) 2007-08-14 2008-08-12 Nouveaux composés
PCT/EP2008/060563 WO2009021945A1 (fr) 2007-08-14 2008-08-12 Arylsulfonamides à effet analgésique
AU2008288431A AU2008288431A1 (en) 2007-08-14 2008-08-12 New compounds
JP2010520555A JP5250627B2 (ja) 2007-08-14 2008-08-12 新規化合物
BRPI0815181 BRPI0815181A2 (pt) 2007-08-14 2008-08-12 Compostos
NZ583815A NZ583815A (en) 2007-08-14 2008-08-12 Aryl Sulfonamides with an Analgesic Action
EA201000296A EA201000296A1 (ru) 2007-08-14 2008-08-12 Новые соединения
MX2010001664A MX2010001664A (es) 2007-08-14 2008-08-12 Nuevos compuestos.
DE502008002979T DE502008002979D1 (de) 2007-08-14 2008-08-12 Arylsulfonamide mit analgetischer wirkung
CA2696302A CA2696302A1 (fr) 2007-08-14 2008-08-12 Arylsulfonamides a effet analgesique
US12/672,465 US20110077231A1 (en) 2007-08-14 2008-08-12 Compounds
JP2010520556A JP2011505334A (ja) 2007-08-14 2008-08-12 新規化合物
CN2008801116296A CN101821245B (zh) 2007-08-14 2008-08-12 化合物
PE2008001366A PE20090593A1 (es) 2007-08-14 2008-08-12 Compuestos heterociclos como antagonistas del receptor de bradiquinina b1
EP08803006A EP2212281B1 (fr) 2007-08-14 2008-08-12 Arylsulfonamides à effet analgésique
UY31287A UY31287A1 (es) 2007-08-14 2008-08-13 Antagonistas del receptore de bradiquinina b1. sus procesos de preparación y aplicaciones.
TW097130828A TW200911744A (en) 2007-08-14 2008-08-13 New compounds
ARP080103538A AR068341A1 (es) 2007-08-14 2008-08-13 Derivados heterociclios de sulfonamidas antagonistas del receptor b1 de bradiquinina
AU2009281472A AU2009281472A1 (en) 2007-08-14 2009-02-13 Process for preparing cycloalkyl-substituted piperazine compounds
CO10016009A CO6331335A2 (es) 2007-08-14 2010-02-12 Nuevos compuestos antagonistas de los receptores b1 de bradiquinina
TNP2010000072A TN2010000072A1 (en) 2008-02-21 2010-02-12 New compounds
MA32623A MA31613B1 (fr) 2007-08-14 2010-02-15 Nouveaux composes
EC2010009978A ECSP109978A (es) 2007-08-14 2010-02-19 Nuevos compuestos

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WO2002053516A2 (fr) * 2001-01-08 2002-07-11 Laboratoires Fournier Sa Derives de la n(phenylsulfonyl)glycine et leur utilisation en therapeutique
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WO2006036664A1 (fr) * 2004-09-23 2006-04-06 Amgen Inc. Sulfonamidopropionamides substitues et procedes d'utilisation
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