WO1997024328A1 - 2-amino-heterocycles and therapeutic uses therefor - Google Patents

2-amino-heterocycles and therapeutic uses therefor Download PDF

Info

Publication number
WO1997024328A1
WO1997024328A1 PCT/EP1996/005643 EP9605643W WO9724328A1 WO 1997024328 A1 WO1997024328 A1 WO 1997024328A1 EP 9605643 W EP9605643 W EP 9605643W WO 9724328 A1 WO9724328 A1 WO 9724328A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
structure structure
carbon atoms
chain
optionally
Prior art date
Application number
PCT/EP1996/005643
Other languages
French (fr)
Inventor
Mazen Es-Sayed
Masaru Yamamoto
Klaus Frobel
Chris Poll
Suzanna Grix
Stephen Tudhope
Original Assignee
Bayer Aktiengesellschaft
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 Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to AU13728/97A priority Critical patent/AU1372897A/en
Publication of WO1997024328A1 publication Critical patent/WO1997024328A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • 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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to the use of 2-amino-heterocycles for the preparation of medicaments, in particular for the treatment of airway diseases and inflammatory diseases, new active compounds and process or for their preparation.
  • Leukotrienes are arachidonic acid metabolites produced by the 5-lipoxygenase pathway in activated phagocytes and are important mediators of bronchial asthma and acute inflammation.
  • the pathophysiological importance of leukotrienes suggests that selective inhibitors of leukotriene synthesis may be useful anti ⁇ allergic and an ti -inflammatory therapeutic agents.
  • N,N'-diphenyl-N-(2-pyridinyl)urea derivatives are known as herbicides and plant growth regulators, cholinergic agents, acetylcholine releasing agents as cog ⁇ nition activator or as objects for crystallorgraphic and spectroscopic investigations (J. Crystallorg. Spectrosc. Res. (1988), 18 (6), 729-45; Bioorg. Med. Chem. Lett. (1992), 2(8), 855-60; EP 401 168 A2 or US 4 782 071],
  • R represents hydrogen or methyl or represents a 6 membered aromatic hetero- cycle having up to 2 nitrogen, atoms and to which a phenyl ring can be fused and wherein the rings optionally monosubstituted or disubstituted by identical or different substituents are from the series comprising cyano, halogen, carboxyl, nitro, trifluormethyl, by a straight-chain or branched alk- oxycarbonyl having up to 6 carbon atoms or by a group or a formula -(CO) a -NR 4 R 5 or -NH-CO-R 6 wherein
  • a denotes a number 0 or 1
  • R 4 , R 5 and R 6 are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, which optionally are monosubstituted or disubstituted by pyridyl, benzyl, hydroxyl and/or phenyl, which is optionally substituted by halogen or straight chain or branched alkoxy having up to 4 carbon atoms,
  • R 2 represents adamantyl, cycloalkyl having 3 to 6 carbon atoms, pyridyl, phenyl or benzyl, which optionally are monosubstituted to trisubstituted by halogen, phenyl, carboxyl, cyano, trifluoromethoxy or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or by a residue of a formula -CO-NH-CH(CH 3 )C 6 H 5 , -CO-NH-
  • R and R including the nitrogen atom form together a residue of a formula
  • R represents a group of the formula -A-NR R ,
  • A, D, D' and E are identical or different and denote a bond or straight- chain or branched alkyl having up to 6 carbon atoms,
  • L denotes a nitrogen atom or the CH-group
  • T and T are identical or different and denote halogen or methyl
  • R 7 and R 8 are identical or different and denote hydrogen, cycloalkyl having up to 6 carbon atoms, phenyl, adamantyl, biphenyl or quinidinyl
  • straight-chain or branched alkyl having up to 8 carbon atoms which optionally are up to trisubstituted by identical or different substituents from the series comprising hydroxyl, cyclo ⁇ alkyl having 3 to 6 carbon atoms, pyridyl, thienyl or phenyl, which is optionally up to trisubstituted by identical or different substituents from the series comprising hydroxyl, amino, phenyl, halogen, nitro, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 7 carbon atoms, or by a group of a formula -CO-NR 10 R n or -SO 2 -NH 2 ,
  • R 10 and R 1 1 have the abovementioned meanin 'g3 of R 4 and R 5 , and/or alkyl optionally is substituted by a residue of a formula
  • R and R are identical or different and denote phenyl, which optionally is monosubstituted or disubstituted by halogen, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or
  • R 9 denotes carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or denotes a residue of the formula -CHR R ,
  • R 12 and R lj denote phenyl, which is optionally monosubstituted or disubstituted by halogen,
  • R 9 denotes a residue of the formula -CHR 12 R 1 ' ' ,
  • R 12 and R lj are identical or different and have the abovementioned meaning of R 12 and R lj ,
  • R and R including the nitrogen atom form together a residue of a formula
  • Heterocycle in general represents a 6-membered aromatic ring which can contain up to 2 nitrogen atoms as heteroatoms and to which further aromatic ring can be fused.
  • pyridyl pyrimidyl
  • pyrazinyl pyridazi- nyl
  • quinolyl quinolyl or isoquinolyl.
  • R 1 represents hydrogen or methyl or represents isoquinolyl, pyrazinyl, pyridyl or pyrimidinyl, which optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising cyano, fluorine, chlorine, bromine, trifluormethyl, carboxyl, nitro or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or by a group of the formula -(CO) a -NR 4 R 5 or -NH-CO-R 6 ,
  • a denotes a number 0 or 1
  • R 4 , R 3 and R 6 are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms, which are optionally are monosub ⁇ stituted or disubstituted by pyridyl, benzyl, hydroxyl and/or phenyl, which is optionally substituted by fluorine, chlorine, bromine or straight chain or branched alkoxy having up to 4 carbon atoms,
  • R" represents adamantyl, cyclopentyl, cyclohexyl, pyridyl, phenyl or benzyl, which optionally are monosubstituted to trisubstituted by fluorine, chlorine, bromine, carboxyl, trifluoromethoxy, phenyl, cyano or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, or by a residue of a formula -CO-NH-CH(CH 3 )C 6 H 5 or -CO-NH-
  • R 1 and R 2 including the nitrogen atom form together a residue of a formula
  • R J represents a group of a formula -A-NR 7r R> 8 in which
  • A, D, D' and E are identical or different and denote a bond or a straight- chain or branched alkyl one chain having up to 4 carbon atoms,
  • L denotes a nitrogen atom or the CH-group
  • T and T' are identical or different and denote hydrogen or methyl
  • R 7 and R 8 are identical or different and denote hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, adamantyl, biphenyl or quinudinyl,
  • straight-chain or branched alkyl having up to 6 carbon atoms which optionally are up to trisubstituted by identical or different substituents from the series comprising hydroxyl, cyclo ⁇ propyl, cyclopentyl, cyclohexyl, pyridyl, thienyl or by phenyl, which optionally is up to trisubstituted by identical or different substituents from the series comprising hydroxyl, amino, fluorine, chlorine, bromine, nitro, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 6 carbon atoms, or by a group of a formula -CO-NR 10 R n or SO 2 -NH 2 ,
  • R 10 and R 1 1 have the abovementioned meaning of R 4 and R ⁇ ,
  • alkyl optionally is substituted by a residue of a formula
  • R and R are identidal or different and denote phenyl, which optionally is monosubstituted or disubstituted by fluorine, chlorine, bromine, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, or
  • R denotes carboxyl or straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms, or denotes a residue of a formula -CHR , R " ⁇
  • R n and R 12 denote phenyl, which optionally is monosubstituted or disubstituted by fluorine, chlorine or bromine,
  • R 9 denotes a residue of the formula -CHR ! R lj
  • R and R are identical or different and have the abovementioned meaning of R 12 and R 13 ,
  • R' and R 8 including the nitrosen atom form together a residue of a formula
  • R 1 represents hydrogen or methyl or represents chinolyl, isoquinolyl, pyra ⁇ zinyl, pyridyl or pyrimidinyl, which optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising cyano, fluorine, chlorine, bromine, trifluormethyl, carboxyl, nitro, straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or by a group of a formula -(CO) a -NR 4 R 5 or -NH-CO-R 6 ,
  • a denotes a number 0 or 1
  • R 4 , R 5 and R 6 are identical or different and denote hydrogen, biphenyl, phenyl or adamantyl, straight-chain or branched alkyl or acyl each having up to 3 carbon atoms, which optionally ore monosubstituted or disubstituted by pyridyl, benzyl, hydroxyl and/or phenyl, which is optionally substituted by fluorine, chlorine or methoxy,
  • R 2 represents adamantyl, cyclopentyl, cyclohexyl, pyridyl, phenyl or benzyl, which optionally are monosubstituted to trisubstituted by fluorine, chlorine, bromine, carboxyl, phenyl, cyano, trifluoromethoxy or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, or by a residue of a formula -CO-NH-CH(CH 3 )C 6 H 5 , -CO-NH-
  • R and R" including the nitrogen atom form together a residue of a formula
  • R "5 represents a group of a formula -A-NR 7 R ⁇ , 8 ,
  • A, D, D' and E are identical or different and denote a bond or a straight- chain or branched alkyl having up to 4 carbon atoms,
  • L denotes a nitrogen atom or the CH-group
  • T and T are identical or different and denote hydrogen or methyl
  • R 7 and R 8 are identical or different and denote hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, adamantyl, biphenyl or quinu- clidinyl or denote straight-chain or branched alkyl having up to 5 carbon atoms, which optionally are up to trisubstituted by identical or different substituents from the series comprising hydroxyl, cyclo ⁇ propyl, cyclopentyl, cyclohexyl, pyridyl, thienyl or by phenyl, which optionally is up to trisubstituted by identical or different sub ⁇ stituents from the series comprising hydroxyl, amino, fluorine, chlorine, bromine, nitro, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 5 carbon atoms, or by a group of a formula -CO-NR
  • R 10 and R 11 have the abovementioned meaning of R 4 and R 3 ,
  • alkyl optionally is substituted by a residue of a formula
  • R 9 and R 9' are identical or different and denote phenyl, which optionally is monosubstituted or disubstituted by fluorine, chlorine, bromine, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, or
  • R 9 denotes carboxyl or straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, or denotes a residue of a formula -CHR "R " ⁇ in which
  • R 12 and R 13 denote phenyl, which is optionally monosubstituted to disubstituted by fluorine,
  • R 9 denotes a residue of the formula -CHR 1 R 13 .
  • R ⁇ and R are identical or different and have the abovementioned meaning of R 12 a _ structurind., R n l3
  • the invention additionally relates to new compounds of the formula (X).
  • the compound of the general formula (I) can also be present in the form of their salts.
  • salts with organic or inorganic bases or acids may be mentioned here.
  • Physiologically acceptable salts are preferred in the context of the present invention.
  • Physiologically acceptable salts of the 2-amino-heterocycles and the new compounds can be metal or ammonium salts of the substances according to the invention, which contain a free carboxylic group.
  • Those which are particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or tri ethanol amine, dicyclo- hexylamine, dimethylaminoethanol, arginine, lysine or ethyl enedi amine.
  • Physiologically acceptable salts can also be salts of the compounds according to the invention with inorganic or organic acids.
  • Preferred salts here are those with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
  • the invention relates both to the antipodes and to the racemate forms, as well as the diastereomer mixtures.
  • the racemate forms like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.
  • R 1 and R 2 have the abovementioned meaning
  • R 3 has the abovementioned meaning
  • X denotes halogen, preferably chlorine
  • R J has the abovementioned meaning
  • esters the corresponding acids are etherified, and in the case of carbon acid esters are hydrolysed by customary method and in the case of diamides (-NR R ) the monoamides are reacted with the halogenides in the presence of KHMDS.
  • Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, acetone, dimethyls ⁇ lfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as di- chlormethane, trichlorom ethane or tetrachloromethane. Dioxane is preferred.
  • Suitable bases are generally inorganic or organic bases. These preferably include alkali metal hydroxides such as, for example, sodium hydroxide, sodium hydrogencarbonate or potassium hydroxide, alkaline earth metal hydroxides such as, for example, barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkaline metal, or kaliumhexamethyldisilazid or organic amines (trialky ⁇ C j -C ⁇ amines) such as tri ethyl amine, or heterocycles such as 1,4- diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or amides such as sodium amides, lithium butyl amide or butyllithium, pyridine or methylpiperidine.
  • alkali metal hydroxides such as, for example, sodium hydroxide, sodium hydrogen
  • alkali metals such as sodium or its hydrides such as sodium hydride
  • bases potassium carbonate, tri ethyl amine, sodium hydrogencarbonate, sodiumhydroxide or kaliumhexamethyldisilazid are preferred.
  • the process is in general carried out in a temperature range from 0°C to +100°C, preferably from room temperature to +80°C.
  • the process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
  • the base is employed in an amount from 1 mol to 10 mol, preferably from 1.0 mol to 4 mol, relative to 1 mol of the compounds of the general formulae (III) or (IV).
  • R 1 has the abovementioned meaning
  • Y represents halogen, preferably chlorine
  • R 2 has the abovementioned meaning
  • the process is in general carried out in a temperature range from +60°C to +200°C, preferably from +100°C to +160°C.
  • the process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
  • the 2-amino-heterocycles of the general formula (I) and the new compounds according to the invention can be employed as active compounds in medicaments.
  • the substances can act as inhibitors of enzymatic reactions in the context of arachidonic acid metabolism.
  • the compounds of the general formula (I) surprisingly exhibit a high activity as inhibitors of leukotriene synthesis, specifically inhibit the production of leukotriene B 4 by polymorphonuclear leucocytes (PMN).
  • PMN polymorphonuclear leucocytes
  • Blood was taken from healthy subjects by venous puncture and neutrophils were purified by dextran sedimentation and resuspended in the buffered medium.
  • Internationl pic Percentage inhibition was determined by comparison with vehicle-containing controls.
  • the new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceuti ⁇ cally suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
  • the formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, in the case of the use of water as a diluent, organic solvents can be used as auxiliary solvents if appropriate.
  • Administration is carried out in a customary manner, preferably orally or parenterally, in particular perlingually or intravenously.
  • solutions of the active compound can be employed using suitable liquid vehicles.
  • Table 1 The compounds shown in Table 1 are prepared in analogy to the procedure of example 1 or by the way of the indicated methods. Table 1:

Abstract

2-Amino-heterocycles can be used for the production of medicaments for inhibiting the leukotriene synthesis particularly for the treatment and control of respiratory diseases and inflammatory processes.

Description

2-AMINO-HETEROCYCLES AND THERAPEUTIC USES THEREFOR
The invention relates to the use of 2-amino-heterocycles for the preparation of medicaments, in particular for the treatment of airway diseases and inflammatory diseases, new active compounds and process or for their preparation.
Leukotrienes are arachidonic acid metabolites produced by the 5-lipoxygenase pathway in activated phagocytes and are important mediators of bronchial asthma and acute inflammation. The pathophysiological importance of leukotrienes suggests that selective inhibitors of leukotriene synthesis may be useful anti¬ allergic and an ti -inflammatory therapeutic agents.
Urea,N,N-bis[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]-N'[[3,5-bis(l, ldimeth>'l- ethyl)-4-hydroxyphenylmethyl] and derivatives having an inhibiting effect as antioxidants are described in the publication Neftekhimiya (1987), 27 (5), 703-9.
Also N,N'-diphenyl-N-(2-pyridinyl)urea derivatives are known as herbicides and plant growth regulators, cholinergic agents, acetylcholine releasing agents as cog¬ nition activator or as objects for crystallorgraphic and spectroscopic investigations (J. Crystallorg. Spectrosc. Res. (1988), 18 (6), 729-45; Bioorg. Med. Chem. Lett. (1992), 2(8), 855-60; EP 401 168 A2 or US 4 782 071],
It has been found that 2-amino-heterocycles of the general formula (I)
R1
,2/ M N. W vCO-R3 wherein
R represents hydrogen or methyl or represents a 6 membered aromatic hetero- cycle having up to 2 nitrogen, atoms and to which a phenyl ring can be fused and wherein the rings optionally monosubstituted or disubstituted by identical or different substituents are from the series comprising cyano, halogen, carboxyl, nitro, trifluormethyl, by a straight-chain or branched alk- oxycarbonyl having up to 6 carbon atoms or by a group or a formula -(CO)a-NR4R5 or -NH-CO-R6 wherein
a denotes a number 0 or 1,
R4, R5 and R6 are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, which optionally are monosubstituted or disubstituted by pyridyl, benzyl, hydroxyl and/or phenyl, which is optionally substituted by halogen or straight chain or branched alkoxy having up to 4 carbon atoms,
R2 represents adamantyl, cycloalkyl having 3 to 6 carbon atoms, pyridyl, phenyl or benzyl, which optionally are monosubstituted to trisubstituted by halogen, phenyl, carboxyl, cyano, trifluoromethoxy or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or by a residue of a formula -CO-NH-CH(CH3)C6H5, -CO-NH-
adamantyl, -NH-(CO)2-NH-C6H5 or , or
Figure imgf000004_0001
represents a group of a formula
Figure imgf000004_0002
or
R and R including the nitrogen atom form together a residue of a formula
Figure imgf000004_0003
and
3 7 ft
R represents a group of the formula -A-NR R ,
R
Figure imgf000005_0001
wherein
A, D, D' and E are identical or different and denote a bond or straight- chain or branched alkyl having up to 6 carbon atoms,
L denotes a nitrogen atom or the CH-group,
or
A denotes a C=O group,
T and T are identical or different and denote halogen or methyl,
R7 and R8 are identical or different and denote hydrogen, cycloalkyl having up to 6 carbon atoms, phenyl, adamantyl, biphenyl or quinidinyl
or denote straight-chain or branched alkyl having up to 8 carbon atoms, which optionally are up to trisubstituted by identical or different substituents from the series comprising hydroxyl, cyclo¬ alkyl having 3 to 6 carbon atoms, pyridyl, thienyl or phenyl, which is optionally up to trisubstituted by identical or different substituents from the series comprising hydroxyl, amino, phenyl, halogen, nitro, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 7 carbon atoms, or by a group of a formula -CO-NR10Rn or -SO2-NH2,
in which
R10 and R1 1 have the abovementioned meanin 'g3 of R4 and R5, and/or alkyl optionally is substituted by a residue of a formula
Figure imgf000006_0001
R and R are identical or different and denote phenyl, which optionally is monosubstituted or disubstituted by halogen, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or
R9 denotes carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or denotes a residue of the formula -CHR R ,
in which
R12 and Rlj denote phenyl, which is optionally monosubstituted or disubstituted by halogen,
or
R9 denotes a residue of the formula -CHR12 R1 '' ,
in which
R12 and Rlj are identical or different and have the abovementioned meaning of R12 and Rlj,
or
R and R including the nitrogen atom form together a residue of a formula
Figure imgf000007_0001
and their salts,
suφrisingly have a high activity as inhibitors of leukotriene synthesis and thus and suitable for control and treating airway diseases and inflammatory diseases.
Heterocycle in general represents a 6-membered aromatic ring which can contain up to 2 nitrogen atoms as heteroatoms and to which further aromatic ring can be fused.
The following are mentioned as preferred: pyridyl, pyrimidyl, pyrazinyl, pyridazi- nyl, quinolyl or isoquinolyl.
Preferably used are those compounds of the general formula (I),
wherein
R1 represents hydrogen or methyl or represents isoquinolyl, pyrazinyl, pyridyl or pyrimidinyl, which optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising cyano, fluorine, chlorine, bromine, trifluormethyl, carboxyl, nitro or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or by a group of the formula -(CO)a-NR4R5 or -NH-CO-R6,
in which
a denotes a number 0 or 1,
R4, R3 and R6 are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms, which are optionally are monosub¬ stituted or disubstituted by pyridyl, benzyl, hydroxyl and/or phenyl, which is optionally substituted by fluorine, chlorine, bromine or straight chain or branched alkoxy having up to 4 carbon atoms,
R" represents adamantyl, cyclopentyl, cyclohexyl, pyridyl, phenyl or benzyl, which optionally are monosubstituted to trisubstituted by fluorine, chlorine, bromine, carboxyl, trifluoromethoxy, phenyl, cyano or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, or by a residue of a formula -CO-NH-CH(CH3)C6H5 or -CO-NH-
adamantyl, -NH-(CO)2-NH-C6H5 or or
Figure imgf000008_0001
represents a group of a formula
Figure imgf000008_0002
or
R1 and R2 including the nitrogen atom form together a residue of a formula
Figure imgf000008_0003
and
RJ represents a group of a formula -A-NR 7r R> 8
Figure imgf000009_0001
in which
A, D, D' and E are identical or different and denote a bond or a straight- chain or branched alkyl one chain having up to 4 carbon atoms,
L denotes a nitrogen atom or the CH-group,
or
A denotes a C=O group,
T and T' are identical or different and denote hydrogen or methyl,
R7 and R8 are identical or different and denote hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, adamantyl, biphenyl or quinudinyl,
or denote straight-chain or branched alkyl having up to 6 carbon atoms, which optionally are up to trisubstituted by identical or different substituents from the series comprising hydroxyl, cyclo¬ propyl, cyclopentyl, cyclohexyl, pyridyl, thienyl or by phenyl, which optionally is up to trisubstituted by identical or different substituents from the series comprising hydroxyl, amino, fluorine, chlorine, bromine, nitro, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 6 carbon atoms, or by a group of a formula -CO-NR10Rn or SO2-NH2,
in which
R10 and R1 1 have the abovementioned meaning of R4 and R^,
and/or alkyl optionally is substituted by a residue of a formula
Figure imgf000010_0001
0 0'
R and R are identidal or different and denote phenyl, which optionally is monosubstituted or disubstituted by fluorine, chlorine, bromine, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, or
R denotes carboxyl or straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms, or denotes a residue of a formula -CHR, R "\
in which
Rn and R12 denote phenyl, which optionally is monosubstituted or disubstituted by fluorine, chlorine or bromine,
or
R9 denotes a residue of the formula -CHR! Rlj
in which
R and R are identical or different and have the abovementioned meaning of R12 and R13,
or
R' and R8 including the nitrosen atom form together a residue of a formula
Figure imgf000011_0001
and their salts.
Particularly preferred used are compounds of the general formula (I),
wherein
R1 represents hydrogen or methyl or represents chinolyl, isoquinolyl, pyra¬ zinyl, pyridyl or pyrimidinyl, which optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising cyano, fluorine, chlorine, bromine, trifluormethyl, carboxyl, nitro, straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or by a group of a formula -(CO)a-NR4R5 or -NH-CO-R6,
in which
a denotes a number 0 or 1,
R4, R5 and R6 are identical or different and denote hydrogen, biphenyl, phenyl or adamantyl, straight-chain or branched alkyl or acyl each having up to 3 carbon atoms, which optionally ore monosubstituted or disubstituted by pyridyl, benzyl, hydroxyl and/or phenyl, which is optionally substituted by fluorine, chlorine or methoxy,
R2 represents adamantyl, cyclopentyl, cyclohexyl, pyridyl, phenyl or benzyl, which optionally are monosubstituted to trisubstituted by fluorine, chlorine, bromine, carboxyl, phenyl, cyano, trifluoromethoxy or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, or by a residue of a formula -CO-NH-CH(CH3)C6H5, -CO-NH-
adamantyl, -NH-(CO)2-NH-C6H5 or -O or
Figure imgf000012_0001
represents a group of the formula
Figure imgf000012_0002
or
1 "-
R and R" including the nitrogen atom form together a residue of a formula
Figure imgf000012_0003
R"5 represents a group of a formula -A-NR 7 Rτ, 8 ,
Figure imgf000012_0004
in which
A, D, D' and E are identical or different and denote a bond or a straight- chain or branched alkyl having up to 4 carbon atoms,
L denotes a nitrogen atom or the CH-group,
or A denotes a C=O group,
T and T are identical or different and denote hydrogen or methyl,
R7 and R8 are identical or different and denote hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, adamantyl, biphenyl or quinu- clidinyl or denote straight-chain or branched alkyl having up to 5 carbon atoms, which optionally are up to trisubstituted by identical or different substituents from the series comprising hydroxyl, cyclo¬ propyl, cyclopentyl, cyclohexyl, pyridyl, thienyl or by phenyl, which optionally is up to trisubstituted by identical or different sub¬ stituents from the series comprising hydroxyl, amino, fluorine, chlorine, bromine, nitro, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 5 carbon atoms, or by a group of a formula -CO-NR10Rn or -SO- H-,
in which
R10 and R11 have the abovementioned meaning of R4 and R3,
and/or alkyl optionally is substituted by a residue of a formula
Figure imgf000013_0001
R9 and R9' are identical or different and denote phenyl, which optionally is monosubstituted or disubstituted by fluorine, chlorine, bromine, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, or
R9 denotes carboxyl or straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, or denotes a residue of a formula -CHR "R "\ in which
R12 and R13 denote phenyl, which is optionally monosubstituted to disubstituted by fluorine,
or
R9 denotes a residue of the formula -CHR1 R13.
in which
R ~ and R are identical or different and have the abovementioned meaning of R 12 a _„nd., R n l3
or
7 8 R and R including the nitrosen atom form together a formula
Figure imgf000014_0001
and their salts.
The invention additionally relates to new compounds of the formula (X).
Figure imgf000014_0002
wherein the substituents are of the following meaning:
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
I NH-AtJamanryi
Figure imgf000022_0001
Figure imgf000023_0001
- 11 -
Figure imgf000024_0001
28
- 23 -
Figure imgf000025_0001
Continuation of new compounds:
Structure
Figure imgf000026_0001
Figure imgf000026_0002
Structure
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000027_0003
Structure
Figure imgf000028_0001
Figure imgf000028_0002
Figure imgf000028_0003
Structure
Figure imgf000029_0001
Figure imgf000029_0002
Structure
Figure imgf000030_0001
Figure imgf000030_0002
Structurc
Figure imgf000031_0001
Figure imgf000031_0002
Structure
Figure imgf000032_0001
Figure imgf000032_0002
Figure imgf000032_0003
Structure
Figure imgf000033_0001
Figure imgf000033_0002
-32
Figure imgf000034_0001
- _>_> -
Structure
Figure imgf000035_0001
Figure imgf000035_0002
H.CO
Figure imgf000035_0003
Structure
Figure imgf000036_0001
Figure imgf000036_0002
Figure imgf000036_0003
Structure
Figure imgf000037_0001
Figure imgf000037_0002
Structure
Figure imgf000038_0001
Figure imgf000038_0002
Structure
Figure imgf000039_0001
Figure imgf000039_0002
Structure
Figure imgf000040_0001
Figure imgf000040_0002
- J 9 -
Structure
Figure imgf000041_0001
Figure imgf000041_0002
Structure
Figure imgf000042_0001
Figure imgf000042_0002
H3C
Structure
Figure imgf000043_0001
Figure imgf000043_0002
Structure
Figure imgf000044_0001
Figure imgf000044_0002
Structure
Figure imgf000045_0001
Figure imgf000045_0002
Structure
Figure imgf000046_0001
Figure imgf000046_0002
Structure
Figure imgf000047_0001
Figure imgf000047_0002
Figure imgf000047_0003
Structure
Figure imgf000048_0001
Figure imgf000048_0002
Figure imgf000048_0003
Figure imgf000049_0001
Structure
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000050_0003
Figure imgf000051_0001
Figure imgf000052_0001
Structure
Figure imgf000053_0001
Figure imgf000053_0002
Structure
Figure imgf000054_0001
Figure imgf000054_0002
Structure
Figure imgf000055_0001
Figure imgf000055_0002
œtructure
Figure imgf000056_0001
Figure imgf000056_0002
Figure imgf000056_0003
Figure imgf000056_0004
Structure
Figure imgf000057_0001
Figure imgf000057_0002
Figure imgf000057_0003
Structure
Figure imgf000058_0001
Figure imgf000058_0002
Figure imgf000058_0003
Structure
Figure imgf000059_0001
Figure imgf000059_0002
5S -
Structure
Figure imgf000060_0001
Figure imgf000060_0002
Structure
Figure imgf000061_0001
Cl
Figure imgf000061_0002
Structure
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000062_0003
Structure
Figure imgf000063_0001
Figure imgf000063_0002
Structure
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000064_0003
Structure
Figure imgf000065_0001
Figure imgf000065_0002
Figure imgf000065_0003
Structure
Figure imgf000066_0001
Figure imgf000066_0002
Structure
Figure imgf000067_0001
Figure imgf000067_0002
Figure imgf000067_0003
Structure
Figure imgf000068_0001
Figure imgf000068_0002
Structure
Structure
Figure imgf000070_0001
Figure imgf000070_0002
Structure
Figure imgf000071_0001
Figure imgf000071_0002
Figure imgf000072_0001
Figure imgf000073_0001
Structure
Figure imgf000074_0001
Figure imgf000074_0002
Structure
Figure imgf000075_0001
Figure imgf000075_0002
Structure
Figure imgf000076_0001
Figure imgf000076_0002
Structure
Figure imgf000077_0001
Figure imgf000077_0002
Structure
I
Figure imgf000078_0001
Figure imgf000078_0002
Figure imgf000078_0003
Structure
Figure imgf000079_0001
Figure imgf000079_0002
I
Figure imgf000079_0003
Figure imgf000080_0001
Structure
Figure imgf000081_0001
Structure
Figure imgf000082_0001
Figure imgf000082_0002
Figure imgf000082_0003
Structure
Figure imgf000083_0001
Figure imgf000083_0002
Structure
Figure imgf000084_0001
Figure imgf000084_0002
Structure
Figure imgf000085_0001
Figure imgf000085_0002
S4 -
Structure
H,C.
Figure imgf000086_0001
Figure imgf000086_0002
Figure imgf000086_0003
Structure
Figure imgf000087_0001
Figure imgf000087_0002
Figure imgf000087_0003
Structure
Figure imgf000088_0001
Figure imgf000088_0002
Figure imgf000088_0003
Structure
Figure imgf000089_0001
Figure imgf000089_0002
Figure imgf000089_0003
Structure
Figure imgf000090_0001
Figure imgf000090_0002
H,C,
Figure imgf000090_0003
Figure imgf000091_0001
Structure
Figure imgf000092_0001
Figure imgf000092_0002
H H
H3<Y ΎN
Figure imgf000092_0003
Figure imgf000093_0001
Structure
Figure imgf000094_0001
Figure imgf000094_0002
Figure imgf000094_0003
Structure
Figure imgf000095_0001
Figure imgf000095_0002
Structure
Figure imgf000096_0001
Figure imgf000096_0002
Structure
Figure imgf000097_0001
Figure imgf000097_0002
The compound of the general formula (I) can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
Physiologically acceptable salts are preferred in the context of the present invention. Physiologically acceptable salts of the 2-amino-heterocycles and the new compounds can be metal or ammonium salts of the substances according to the invention, which contain a free carboxylic group. Those which are particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or tri ethanol amine, dicyclo- hexylamine, dimethylaminoethanol, arginine, lysine or ethyl enedi amine.
Physiologically acceptable salts can also be salts of the compounds according to the invention with inorganic or organic acids. Preferred salts here are those with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
Plot as a function of respective substituents compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image
(enantiomers), or which do not behave as image and mirror image (di aster eomers). The invention relates both to the antipodes and to the racemate forms, as well as the diastereomer mixtures. The racemate forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.
A process for the preparation of the compounds of the general formula (I) has additionally been found, characterized in that
[A] compounds of the general formula (II)
R1
| (II)
R — NH in which
R1 and R2 have the abovementioned meaning
are reacted first with trichloromethylchloroformate and compounds of the general formula (III)
R3-H (III)
in which
R3 has the abovementioned meaning
or
[B] compounds of the general formula (II) are
directly reacted with compounds of the general formula (IV)
X-CO-R3 (IV)
in which
X denotes halogen, preferably chlorine
and
RJ has the abovementioned meaning,
in inert solvents, if appropriate in the presence of a base and/or in the presence of an auxiliary,
and in the case of amides the carbon acids are reacted with the corresponding amines optionally in the presence of a base and/or an auxiliary,
and in the case of esters the corresponding acids are etherified, and in the case of carbon acid esters are hydrolysed by customary method and in the case of diamides (-NR R ) the monoamides are reacted with the halogenides in the presence of KHMDS.
The process according to the invention can be illustrated by way of example by the following equations:
[A]
NH trichloromethylchloroformate
HN(CH2-C6H5)2
H3CO -
Figure imgf000100_0001
Figure imgf000101_0001
Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, acetone, dimethylsυlfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as di- chlormethane, trichlorom ethane or tetrachloromethane. Dioxane is preferred.
Suitable bases are generally inorganic or organic bases. These preferably include alkali metal hydroxides such as, for example, sodium hydroxide, sodium hydrogencarbonate or potassium hydroxide, alkaline earth metal hydroxides such as, for example, barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkaline metal, or kaliumhexamethyldisilazid or organic amines (trialky^Cj-C^amines) such as tri ethyl amine, or heterocycles such as 1,4- diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or amides such as sodium amides, lithium butyl amide or butyllithium, pyridine or methylpiperidine. It is also possible to employ alkali metals, such as sodium or its hydrides such as sodium hydride, as bases. Potassium carbonate, tri ethyl amine, sodium hydrogencarbonate, sodiumhydroxide or kaliumhexamethyldisilazid are preferred. The process is in general carried out in a temperature range from 0°C to +100°C, preferably from room temperature to +80°C.
The process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
The base is employed in an amount from 1 mol to 10 mol, preferably from 1.0 mol to 4 mol, relative to 1 mol of the compounds of the general formulae (III) or (IV).
The compounds of the general formula (II) are known or can be prepared by reacting compounds of the general formula (V)
R'-Y (V)
in which
R1 has the abovementioned meaning
and
Y represents halogen, preferably chlorine,
with amines of the general formula (VI)
R2-NH2 (VI)
in which
R2 has the abovementioned meaning,
where the corresponding amines react as solvents simultaneous.
The process is in general carried out in a temperature range from +60°C to +200°C, preferably from +100°C to +160°C. The process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
The compounds of the general formulae (III), (IV), (V) and (VI) are known and in some cases new and can be prepared by customary methods.
The 2-amino-heterocycles of the general formula (I) and the new compounds according to the invention can be employed as active compounds in medicaments. The substances can act as inhibitors of enzymatic reactions in the context of arachidonic acid metabolism.
The compounds of the general formula (I) surprisingly exhibit a high activity as inhibitors of leukotriene synthesis, specifically inhibit the production of leukotriene B4 by polymorphonuclear leucocytes (PMN).
They are therefore preferably suitable for the treatment and prevention of diseases of the respiratory passages, such as allergies/asthma, bronchitis, emphysema, shock lung, pulmonary hypertension, inflammations/rheumatism and oedemas, throm¬ boses and thromboembolism, ischaemis (disturbances in peripheral, cardiac and cerebral circulation), cardiac and cerebral infarctions, disturbances in cardiac rhythm, angina pectoris and arterioscleoris, in the event of tissue, transplants, dermatoses, such as psoriasis, inflammatory dermatoses, for example eczema, dermatophyte infection, infections of the skin by bacteria, metastases and for cytoprotection in the gastrointestinal tract.
Test description
1. Preparation of human PMN
Blood was taken from healthy subjects by venous puncture and neutrophils were purified by dextran sedimentation and resuspended in the buffered medium.
2. Inhibition of thaspsigargin-induced leuktoriene B4 generation Neutrophils (4 x 105 cells/ml) were placed in a 96 well microtitre plate and prewarmed to 37°C. Compounds according to the invention were added in dimethyl sulphoxide (DMSO). Compound concentration ranged from 0.3 to 30 μM, the DMSO concentration was < 0.3% v/v. The plate was incubated for 5 min at 37°C. Neutrophils were then stimulated by addition of 1 μM thapsigargin followed by 1.3 mM Ca~ . The reaction was stopped after 5 minutes and supernatants assayed for the presence of leukotriene (LT) B4 using an LTB4-specific radioimmunoassay kit supplied by Amersham
Internationl pic. Percentage inhibition was determined by comparison with vehicle-containing controls.
The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceuti¬ cally suitable excipients or solvents. In this connection, the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, in the case of the use of water as a diluent, organic solvents can be used as auxiliary solvents if appropriate.
Administration is carried out in a customary manner, preferably orally or parenterally, in particular perlingually or intravenously.
In the case of parenteral administration, solutions of the active compound can be employed using suitable liquid vehicles.
In general, it has proved advantageous on intravenous administration to administer amounts from about 10 to 100 mg/kg, preferably about 10 to 50 mg kg of body weight to achieve effective results, and on oral administration the dosage is about
10 to 100 mg/kg, preferably 10 to 50 mg/kg of body weight.
In spite of this, it may be necessary to depart from the amounts mentioned, in particular depending on the body weight or the type of application route, on individual behaviour towards the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus, in some cases it may be sufficient to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of administration of relatively large amounts, it is advisable to divide these into several individual doses over the course of the day.
Figure imgf000106_0002
Starting compounds
Example I
2-(4-Methoxyanilino)pyridine
Figure imgf000106_0001
A mixture of 1.05 ml (1 1.2 mmol) 2-chloropyridine and 9.5 g (77 mmol) 4- methoxyaniline were heated to 150°C. After 1 hr another 6.15 ml (65.2 mmol) 2- chloropyridine were added. 3 hrs. later the crude product was purified by chromatography (gradient eluation: PE/EE 20:1, 10: 1, 5: 1, 2:1) yielding 12.7 g of the title compound, which was recrystallized from ethylacetate (8.8 g = 57.8% of theory).
Η-NMR (250 MHz, D6-DMSO): δ = 3.71 (s, 3H); 6.62 - 6.67 (ddd, 1H); 6.72 (d, 1H); 6.84 - 6.89 (m, 2H); 7.45 - 7.57 (m, 3H); 8.07 (dt, 1H), 8.75 (s, 1H).
MS (70 eV): m/z (%) = 200 (100) [JvT]. Preparation Examples:
Example 1
N-(l-(4-Methoxyphenyl)-N-2-pyridyl-N'-dibenzyl-urea
Figure imgf000107_0001
To a solution of 500 mg (2.5 mmol) of example I in 25 ml dioxane were added 166 μl (0 55 eq) chlorotrichloromethylformate dropewise. This mixture was kept at 60°C for 17 hrs, followed by addition of 0.58 ml (3.0 mmol) dibenzylamine. After another 24 hrs at 60°C the mixture was cooled to room temperature, the solvent removed under reduced pressure and the residue dissolved in ethylacetate. Aqueous work up yielded an oil, which was purified by chromatography (PE / EA = 5: 1) yielding 302 mg (46.1%) of chloro-N-(4-methoxyphenyl)-N-2-pyridyl- formamide and 1 12 mg (10.5%) of N-(l-(4-Methoxyphenyl)-N-2-pyridyl-N'- dibenzyl-urea.
Example 1 1H-NMR (250 MHz, CDC13): δ = 3.80 (s, 3H); 4.43 (s, 4H), 6.68 (d, 1H), 6.83 -
6.92 (m, 3H); 7.02 - 7.08 (m, 2H); 7.20 - 7.32 (m, 10H); 7.49 (m, 1H); 8.33 - 8.37 (ddd, 1H). MS (FAB)- m/z (%) = 424 (100) [MYl].
chloro-N-(4-methoxyphenyl ,-N-2-pyridylformamide: 1H-NMR (250 MHz, CDC13): δ = 3.81 (s, 3H); 6 84 - 6.97 (m, 2H); 7 18 - 7 23
(ddd, 1H), 7.26 - 7 34 (m, 2H); 7.51 (dd, 1H), 7.77 (ddd, 1H), 8.45 (ddd, 1H) MS (FAB) m/z (%) 263 (55) [MYl].
The compounds shown in Table 1 are prepared in analogy to the procedure of example 1 or by the way of the indicated methods. Table 1:
R1
I • N,
'CO-R'
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
17
Figure imgf000119_0001
IS
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
13:
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
142
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0002
CH2C12 : MeOH = Methylene chloride: Methanol
Cycl. : EE = Cyclohexane : Acid ester
a) in analogy to example 1 b) starting compounds diamine/KHDMS/benzylbromide c) starting compounds
/TBTU/dii sopropyl ethylamin e
Figure imgf000175_0001
d) starting compounds
H2N carbon acid chloride
C6H5- -N — CO — N(CH _-CB6H' V5)2 e) starting compounds ester LiOH f) starting compounds /Buli/Cl-CO-N(CH,C6H5),
Figure imgf000176_0001
H
g) starting compounds amine/Cl-CO-CH2-Cl/ — D-N N — E-R a
h) starting compounds amine/Cl-(CO)2-Cl/H2N(CH2C6H5)2
i) starting compounds amine enzylisocyanate.

Claims

Patent Claims
1. Use of 2-amino-heterocycles of the general formula (I)
R1
. N. (I)
R2/ CO-R3 wherein
R1 represents hydrogen or methyl or represents a 6 membered aromatic hetero¬ cycle having up to 2 nitrogen atoms and to which a phenyl ring can be fused and wherein the rings optionally monosubstituted or disubstituted by identical or different substituents are from the series comprising cyano, halogen, carboxyl, nitro, trifluormethyl, by a straight-chain or branched alk- oxycarbonyl having up to 6 carbon atoms or by a group or a formula
-(CO)a-NR4R5 or -NH-CO-R6
wherein
a denotes a number 0 or 1,
R4, R and R6 are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, which optionally are monosubstituted or disubstituted by pyridyl, benzyl, hydroxyl and/or phenyl, which is optionally substituted by halogen or straight chain or branched alkoxy having up to 4 carbon atoms,
R" represents adamantyl, cycloalkyl having 3 to 6 carbon atoms, pyridyl, phenyl or benzyl, which optionally are monosubstituted to trisubstituted by halogen, phenyl, carboxyl, cyano, trifluoromethoxy or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or by a residue of a formula -CO-NH-CH(CH3)C6H5, -CO-NH-
adamantyl, -NH-(CO)2-NH-C6H5 or " ~" , °r
represents a group of a formula
Figure imgf000178_0001
or
R1 and R2 including the nitrogen atom form together a residue of a formula
Figure imgf000178_0002
and
represents a group of the formula -A-NR 7RD 8,
Figure imgf000178_0003
wherein
A, D, D' and E are identical or different and denote a bond or straight- chain or branched alkyl having up to 6 carbon atoms,
L denotes a nitrogen atom or the CH-group,
or
A denotes a C=O group,
T and T' are identical or different and denote halogen or methyl, R7 and R8 are identical or different and denote hydrogen, cycloalkyl having up to 6 carbon atoms, phenyl, adamantyl, biphenyl or quinidinyl
or denote straight-chain or branched alkyl having up to 8 carbon atoms, which optionally are up to trisubstituted by identical or different substituents from the series comprising hydroxyl, cyclo¬ alkyl having 3 to 6 carbon atoms, pyridyl, thienyl or phenyl, which is optionally up to trisubstituted by identical or different substituents from the series comprising hydroxyl, amino, phenyl, halogen, nitro, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 7 carbon atoms, or by a group of a formula -CO-NR,0Rn or -SO2-NH2,
in which
R10 and Rn have the abovementioned meaning of R4 and R3,
and/or alkyl optionally is substituted by a residue of a formula
Figure imgf000179_0001
R )9 „ a„ndJ R n9' are identical or different and denote phenyl, which optionally is monosubstituted or disubstituted by halogen, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or
R9 denotes carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or denotes a residue of the formula -CHR12Rlj,
in which
7 1 ~\ .
R and R denote phenyl, which is optionally monosubstituted or disubstituted by halogen, or
R denotes a residue of the formula -CH R ,
in which
R and R are identical or different and have the abovementioned meaning of R12 and R13,
or
R and R including the nitrogen atom form together a residue of a formula
Figure imgf000180_0001
and their salts.
2 Use of 2-amino-heterocycles of the formula according to claim (I),
wherein
R1 represents hydrogen or methyl or represents isoquinolyl, pyrazinyl, pyridyl or pyrimidinyl, which optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising cyano, fluorine, chlorine, bromine, trifluormethyl, carboxyl, nitro or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or by a group of the formula -(CO)a-NR R5 or -NH-CO-R6,
in which
a denotes a number 0 or 1 , R4, R5 and R6 are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms, which are optionally are monosub¬ stituted or disubstituted by pyridyl, benzyl, hydroxyl and/or phenyl, which is optionally substituted by fluorine, chlorine, bromine or straight chain or branched alkoxy having up to 4 carbon atoms,
R2 represents adamantyl, cyclopentyl, cyclohexyl, pyridyl, phenyl or benzyl, which optionally are monosubstituted to trisubstituted by fluorine, chlorine, bromine, carboxyl, trifluoromethoxy, phenyl, cyano or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, or by a residue of a formula -CO-NH-CH(CH3)C6H5 or -CO-NH-
adamantyl, -NH-(CO),-NH-C6H5 or
Figure imgf000181_0001
represents a group of a formula
Figure imgf000181_0002
or
R1 and R2 including the nitrogen atom form together a residue of a formula
Figure imgf000181_0003
and
R° represents a group of a formula -A-NR 7 Rt 8'
Figure imgf000182_0001
in which
A, D, D' and E are identical or different and denote a bond or a straight- chain or branched alkyl one chain having up to 4 carbon atoms,
L denotes a nitrogen atom or the CH-group,
or
A denotes a C=O group,
T and T are identical or different and denote hydrogen or methyl,
R7 and R8 are identical or different and denote hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, adamantyl, biphenyl or quinudinyl,
or denote straight-chain or branched alkyl having up to 6 carbon atoms, which optionally are up to trisubstituted by identical or different substituents from the series comprising hydroxyl, cyclo¬ propyl, cyclopentyl, cyclohexyl, pyridyl, thienyl or by phenyl, which optionally is up to trisubstituted by identical or different substituents from the series comprising hydroxyl, amino, fluorine, chlorine, bromine, nitro, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 6 carbon atoms, or by a group of a formula -CO-NR10Rπ or -SO2-NH2,
in which
R10 and R1 1 have the abovementioned meaning of R4 and R5,
and/or alkyl optionally is substituted by a residue of a formula
Figure imgf000183_0001
R9 and R9 are identidal or different and denote phenyl, which optionally is monosubstituted or disubstituted by fluorine, chlorine, bromine, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, or
R9 denotes carboxyl or straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms, or denotes a residue of a formula -CHR12R1;>,
in λvhich
R11 and R12 denote phenyl, which optionally is monosubstituted or disubstituted by fluorine, chlorine or bromine,
or
R9' denotes a residue of the formula -CHR12R13
in which
R12 and Rlj are identical or different and have the abovementioned meaning of R12 and R13,
or
R and R including the nitrogen atom form together a residue of a formula
Figure imgf000184_0001
and their salts.
3. Use of 2-amino-heterocycles of the formula according to claim (I),
wherein
R1 represents hydrogen or methyl or represents chinolyl, isoquinolyl, pyra¬ zinyl, pyridyl or pyrimidinyl, which optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising cyano, fluorine, chlorine, bromine, trifluormethyl, carboxyl, nitro, straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or by a group of a formula -(CO)a-NR4R5 or -NH-CO-R6,
in which
a denotes a number 0 or 1,
R4, R5 and R6 are identical or different and denote hydrogen, biphenyl, phenyl or adamantyl, straight-chain or branched alkyl or acyl each having up to 3 carbon atoms, which optionally ore monosubstituted or disubstituted by pyridyl, benzyl, hydroxyl and/or phenyl, which is optionally substituted by fluorine, chlorine or methoxy,
R" represents adamantyl, cyclopentyl, cyclohexyl, pyridyl, phenyl or benzyl, which optionally are monosubstituted to trisubstituted by fluorine, chlorine, bromine, carboxyl, phenyl, cyano, trifluoromethoxy or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, or by a residue of a formula -CO-NH-CH(CH3)C6H5, -CO-NH-
adamantyl, NH-(CO)2-NH-C6H5 or or
Figure imgf000185_0001
represents a group of the formula
Figure imgf000185_0002
or
R and R" including the nitrogen atom form together a residue of a formuk
Figure imgf000185_0003
RJ represents a group of a formula -A-NR R8
Figure imgf000185_0004
in which
A, D, D' and E are identical or different and denote a bond or a straight- chain or branched alkyl having up to 4 carbon atoms,
L denotes a nitrogen atom or the CH-group,
or A denotes a C=O group,
T and T are identical or different and denote hydrogen or methyl,
R7 and R8 are identical or different and denote hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, adamantyl, biphenyl or quinu- clidinyl or denote straight-chain or branched alkyl having up to 5 carbon atoms, which optionally are up to trisubstituted by identical or different substituents from the series comprising hydroxyl, cyclo¬ propyl, cyclopentyl, cyclohexyl, pyridyl, thienyl or by phenyl, which optionally is up to trisubstituted by identical or different sub¬ stituents from the series comprising hydroxyl, amino, fluorine, chlorine, bromine, nitro, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 5 carbon atoms, or by a group of a formula -CO-NR, 0Rn or -SO-NH2,
in which
R10 and Rπ have the abovementioned meaning of R4 and R3,
and/or alkyl optionally is substituted by a residue of a formula
Figure imgf000186_0001
R9 and R9 are identical or different and denote phenyl, which optionally is monosubstituted or disubstituted by fluorine, chlorine, bromine, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, or
R9 denotes carboxyl or straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, or denotes a residue of a formula -CHR "R , in which
R12 and R1;> denote phenyl, which is optionally monosubstituted to disubstituted by fluorine,
or
R9 denotes a residue of the formula -CHR12R13 .
in which
R and R are identical or different and have the abovementioned meaning of R 12 a „„ndJ r R> 13 ,
or
~J R R and R including the nitrogen atom form together a formula
Figure imgf000187_0001
and their salts.
4. Use according to claims 1 to 3 for the preparation of medicaments for controlling and treating airway diseases.
5. Use according to claims 1 to 3 for the preparation of medicaments for controlling and treating inflammatory processes.
6. 2-amino-heterocycles of the general formula (I) R1
N (I)
R2 ^CO-R3
wherein the substituents R1, R2 and R3 have the meaning in the specific combination according to the following Table:
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0002
Figure imgf000197_0003
Figure imgf000197_0004
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Continuation of new compounds:
Structure
Figure imgf000200_0001
Figure imgf000200_0002
Structure
Figure imgf000201_0001
Figure imgf000201_0002
Figure imgf000201_0003
œtructure
Figure imgf000202_0001
Figure imgf000202_0002
Figure imgf000202_0003
Structure
Figure imgf000203_0001
Figure imgf000203_0002
Structure
Figure imgf000204_0001
Figure imgf000204_0002
Structure
Figure imgf000205_0001
Figure imgf000205_0002
Structure
Figure imgf000206_0001
Figure imgf000206_0002
Figure imgf000206_0003
Structure
Figure imgf000207_0001
Figure imgf000207_0002
Structure
Figure imgf000208_0001
Figure imgf000208_0002
Figure imgf000208_0003
Structure
Figure imgf000209_0001
Figure imgf000209_0002
Figure imgf000209_0003
Structure
Figure imgf000210_0001
Figure imgf000210_0002
Figure imgf000210_0003
Structure
Figure imgf000211_0001
Figure imgf000211_0002
Structure
Figure imgf000212_0001
Figure imgf000212_0002
Structure
Figure imgf000213_0001
Figure imgf000213_0002
Structure
Figure imgf000214_0001
Figure imgf000214_0002
Structure
Figure imgf000215_0001
Figure imgf000215_0002
Structure
Figure imgf000216_0001
Figure imgf000216_0002
Structure
Figure imgf000217_0001
Figure imgf000217_0002
œtructure
Figure imgf000218_0001
Figure imgf000218_0002
Structure
Figure imgf000219_0001
Figure imgf000219_0002
H3C
Structure
Figure imgf000220_0001
Figure imgf000220_0002
Structure
Figure imgf000221_0001
Figure imgf000221_0002
Structure
Figure imgf000222_0001
Figure imgf000222_0002
Figure imgf000222_0003
-221
Figure imgf000223_0001
Structure
Figure imgf000224_0001
Figure imgf000224_0002
Figure imgf000224_0003
Figure imgf000225_0001
Structure
Figure imgf000226_0001
Figure imgf000226_0002
,
Structure
Figure imgf000227_0002
Structure
Figure imgf000228_0001
Figure imgf000228_0002
Structure
Figure imgf000229_0001
Figure imgf000229_0002
Structurc
Figure imgf000230_0001
Figure imgf000230_0002
Figure imgf000230_0003
Figure imgf000230_0004
Structure
Figure imgf000231_0001
Figure imgf000231_0002
Figure imgf000231_0003
Structurc
Figure imgf000232_0001
Figure imgf000232_0002
Figure imgf000232_0003
Structure
Figure imgf000233_0001
Figure imgf000233_0002
Structure
Figure imgf000234_0001
Figure imgf000234_0002
- 233 -
Figure imgf000235_0001
Structure
Figure imgf000236_0001
Figure imgf000236_0002
Figure imgf000236_0003
Structure
Figure imgf000237_0001
Figure imgf000237_0002
Structure
Figure imgf000238_0001
Figure imgf000238_0002
Figure imgf000238_0003
Structure
Figure imgf000239_0001
Figure imgf000239_0002
Figure imgf000239_0003
238
Figure imgf000240_0001
Structure
Figure imgf000241_0001
Figure imgf000241_0002
Figure imgf000241_0003
Structure
Figure imgf000242_0001
Figure imgf000242_0002
-241 -
Figure imgf000243_0001
Structure
Figure imgf000244_0001
Figure imgf000244_0002
Structure
Figure imgf000245_0001
Figure imgf000245_0002
Structure
Figure imgf000246_0001
Figure imgf000246_0002
Figure imgf000246_0003
Structure
Figure imgf000247_0001
Figure imgf000247_0002
Figure imgf000247_0003
Structure
Figure imgf000248_0001
Figure imgf000248_0002
Structure
Figure imgf000249_0001
Figure imgf000249_0002
Structure
Figure imgf000250_0001
Figure imgf000250_0002
Structure
Figure imgf000251_0001
Figure imgf000251_0002
24328 250
Figure imgf000252_0001
Figure imgf000253_0001
œtructure
Figure imgf000254_0001
Figure imgf000254_0002
Structure
Figure imgf000255_0001
Structure
Figure imgf000256_0001
Figure imgf000256_0002
Figure imgf000256_0003
Structure
Figure imgf000257_0001
Figure imgf000257_0002
Structure
Figure imgf000258_0001
Figure imgf000258_0002
Structure
Figure imgf000259_0001
Figure imgf000259_0002
Structure
H.C.
Figure imgf000260_0001
Figure imgf000260_0002
Figure imgf000260_0003
Structure
Figure imgf000261_0001
Figure imgf000261_0002
Figure imgf000261_0003
Structure
Figure imgf000262_0001
Figure imgf000262_0002
Figure imgf000262_0003
Structure
Figure imgf000263_0001
Figure imgf000263_0002
Figure imgf000263_0003
CH, Structure
Figure imgf000264_0001
Figure imgf000264_0002
Figure imgf000264_0003
Structure
Figure imgf000265_0001
Figure imgf000265_0002
Structure
Figure imgf000266_0001
Figure imgf000266_0002
Figure imgf000266_0003
Structure
Figure imgf000267_0001
Figure imgf000267_0002
Figure imgf000267_0003
Figure imgf000267_0004
Structure
Figure imgf000268_0001
Figure imgf000268_0002
Figure imgf000268_0003
CH,
Structure
Figure imgf000269_0001
Figure imgf000269_0002
Structure
Figure imgf000270_0001
Figure imgf000270_0002
Structure
Figure imgf000271_0001
Figure imgf000271_0002
and their salts.
2-Amino-heterocycles according to claim 6 for therapeutic use.
8. Process for the preparation of 2-amino-heterocycles according to claim 6,
characterised in that
[A] compounds of the general formula (II) (II)
R '
in which ■NH
R1 and R" have the abovementioned meaning
are reacted first with trichloromethylchloroformate and compounds of the general formula (III)
R3-H (III)
in which
RJ has the abovementioned meaning
or
[B] compounds of the general formula (II) are
directly reacted with compounds of the general formula (IV)
X-CO-R3 (IV)
in which
X denotes halogen, preferably chlorine
and
R3 has the abovementioned meaning,
in inert solvents, if appropriate in the presence of a base and/or in the presence of an auxiliary, and in the case of amides the carbon acids are reacted with the corresponding amines optionally in the presence of a base and/or an auxiliary,
and in the case of esters the corresponding acids are etherified,
and in the case of carbon acid esters are hydrolysed by customary method and in the case of diamides (-NR R ) the monoamides are reacted with the halogenides in the presence of KHMDS.
9. Medicaments consisting of at least one 2-amino-heterocycle according to claim 6 and an pharmacologically acceptable diluent.
10. Medicaments according to claim 9, and inhibitors of leukotrienes synthesis.
PCT/EP1996/005643 1995-12-27 1996-12-16 2-amino-heterocycles and therapeutic uses therefor WO1997024328A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU13728/97A AU1372897A (en) 1995-12-27 1996-12-16 2-amino-heterocycles and therapeutic uses therefor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9526560.9A GB9526560D0 (en) 1995-12-27 1995-12-27 Use of 2-Amino-Heterocycles
GB9526560.9 1995-12-27

Publications (1)

Publication Number Publication Date
WO1997024328A1 true WO1997024328A1 (en) 1997-07-10

Family

ID=10786100

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/005643 WO1997024328A1 (en) 1995-12-27 1996-12-16 2-amino-heterocycles and therapeutic uses therefor

Country Status (3)

Country Link
AU (1) AU1372897A (en)
GB (1) GB9526560D0 (en)
WO (1) WO1997024328A1 (en)

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6174905B1 (en) * 1996-09-30 2001-01-16 Mitsui Chemicals, Inc. Cell differentiation inducer
WO2002002071A2 (en) * 2000-06-30 2002-01-10 Unilever Plc Cosmetic compositions containing substituted amide derivatives
EP1172359A1 (en) * 1999-04-07 2002-01-16 Santen Pharmaceutical Co., Ltd. N-SUBSTITUTED-N'-SUBSTITUTED UREA DERIVATIVE AND USE THEREOF AS TNF-$g(a) PRODUCTION INHIBITOR
WO2004002481A1 (en) * 2002-06-27 2004-01-08 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
US6794392B1 (en) 1996-09-30 2004-09-21 Schering Aktiengesellschaft Cell differentiation inducer
EP1568692A1 (en) * 2000-05-31 2005-08-31 Santen Pharmaceutical Co., Ltd. (pyridin-4-yl)alkyl-amides as TNF-alpha production inhibitors
WO2005097779A1 (en) * 2004-04-09 2005-10-20 Neuromed Pharmaceuticals Ltd. Diarylamine derivatives as calcium channel blockers
US7064128B2 (en) 1998-06-30 2006-06-20 Neuromed Technologies, Inc. Preferentially substituted calcium channel blockers
US7186726B2 (en) 1998-06-30 2007-03-06 Neuromed Pharmaceuticals Ltd. Preferentially substituted calcium channel blockers
US7332514B2 (en) 2002-08-30 2008-02-19 Japan Tobacco Inc. Dibenzylamine compound and medicinal use thereof
WO2008117862A1 (en) * 2007-03-28 2008-10-02 Santen Pharmaceutical Co., Ltd. Novel (2-aminophenyl)pyridinecarboxamide derivative having urea structure
US7541373B2 (en) 2002-06-27 2009-06-02 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
US7851636B2 (en) 2004-01-06 2010-12-14 Novo Nordisk A/S Heteroaryl-ureas and their use as glucokinase activators
US7884210B2 (en) 2005-07-14 2011-02-08 Novo Nordisk A/S Ureido-thiazole glucokinase activators
US7989462B2 (en) 2003-07-03 2011-08-02 Myrexis, Inc. 4-arylamin-or-4-heteroarylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US7999114B2 (en) 2005-07-08 2011-08-16 Novo Nordisk A/S Dicycloalkylcarbamoyl ureas as glucokinase activators
US8044052B2 (en) 2006-10-18 2011-10-25 Pfizer Inc. Biaryl ether urea compounds
JP4898062B2 (en) * 2000-05-05 2012-03-14 ノバルティス アーゲー Azabicyclic carbamate and its use as an alpha-7 nicotinic acetylcholine receptor agonist
WO2012033069A1 (en) * 2010-09-07 2012-03-15 大鵬薬品工業株式会社 Prostaglandin d synthase inhibitory piperidine compounds
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
CN101130526B (en) * 2002-06-27 2013-07-10 诺沃挪第克公司 Aryl carbonyl derivatives as therapeutic agents
US8513430B2 (en) 2010-07-27 2013-08-20 High Point Pharmaceuticals, Llc Substituted thiazol-2-ylamine derivatives, pharmaceutical compositions, and methods of use as 11-beta HSD1 modulators
US8927549B2 (en) 2008-11-21 2015-01-06 High Point Pharmaceuticals, Llc Adamantyl benzamide derivatives
US11168068B2 (en) 2016-07-18 2021-11-09 Janssen Pharmaceutica Nv Tau PET imaging ligands
US11440898B2 (en) 2016-12-28 2022-09-13 Minoryx Therapeutics S.L. Isoquinoline compounds, methods for their preparation, and therapeutic uses thereof in conditions associated with the alteration of the activity of beta galactosidase
US11833136B2 (en) 2018-06-12 2023-12-05 Vtv Therapeutics Llc Therapeutic uses of glucokinase activators in combination with insulin or insulin analogs

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4782071A (en) * 1986-11-03 1988-11-01 Warner-Lambert Company Tetrasubstituted urea cholinergic agents
EP0401168A2 (en) * 1989-06-02 1990-12-05 Ciba-Geigy Ag Herbicides
US5250693A (en) * 1987-07-31 1993-10-05 American Home Products Corporation Quinolinylmethoxy naphthalenepropionic acid derivatives as anti-inflammatory/antiallergic agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4782071A (en) * 1986-11-03 1988-11-01 Warner-Lambert Company Tetrasubstituted urea cholinergic agents
US5250693A (en) * 1987-07-31 1993-10-05 American Home Products Corporation Quinolinylmethoxy naphthalenepropionic acid derivatives as anti-inflammatory/antiallergic agents
EP0401168A2 (en) * 1989-06-02 1990-12-05 Ciba-Geigy Ag Herbicides

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
E. H. MOERKVED: "On the structure of carbamoylated 2-phenylaminopyridines", J. F PRAKT. CHEMIE, vol. 328, no. 3, 1986, pages 393 - 400, XP000653297 *
E. H. MOERKVED: "Reactions of 2-(N-cyclohexyl)aminopyridine with electrophiles", J. F PRAKT. CHEMIE, vol. 328, no. 3, 1986, pages 401 - 6, XP000653296 *
HISANO ET AL: "Reaction of aromatic N-oxides with...", CHEM. PHARM. BULL, vol. 29, no. 12, 1981, pages 3706 - 12, XP002030188 *

Cited By (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6174905B1 (en) * 1996-09-30 2001-01-16 Mitsui Chemicals, Inc. Cell differentiation inducer
USRE40703E1 (en) 1996-09-30 2009-04-28 Schering Aktiengesellschaft Cell differentiation inducer, benzamide compounds
USRE39754E1 (en) 1996-09-30 2007-07-31 Schering Ag Benzamide derivatives and pharmaceutical compositions containing same
US8026239B2 (en) 1996-09-30 2011-09-27 Bayer Schering Pharma Aktiengesellschaft Cell differentiation inducer
US7317028B2 (en) 1996-09-30 2008-01-08 Schering Aktiengesellschaft Cell differentiation inducer
US7687525B2 (en) 1996-09-30 2010-03-30 Bayer Schering Pharma Aktiengesellschaft Cell differentiation inducer
EP0847992B1 (en) * 1996-09-30 2004-06-23 Schering Aktiengesellschaft Benzamide derivatives, useful as cell differentiation inducers
EP1437346A1 (en) * 1996-09-30 2004-07-14 Schering AG Benzamide derivatives useful as cell differentiation inducers
US6794392B1 (en) 1996-09-30 2004-09-21 Schering Aktiengesellschaft Cell differentiation inducer
US7064128B2 (en) 1998-06-30 2006-06-20 Neuromed Technologies, Inc. Preferentially substituted calcium channel blockers
US7186726B2 (en) 1998-06-30 2007-03-06 Neuromed Pharmaceuticals Ltd. Preferentially substituted calcium channel blockers
EP1172359A1 (en) * 1999-04-07 2002-01-16 Santen Pharmaceutical Co., Ltd. N-SUBSTITUTED-N'-SUBSTITUTED UREA DERIVATIVE AND USE THEREOF AS TNF-$g(a) PRODUCTION INHIBITOR
EP1172359A4 (en) * 1999-04-07 2002-09-11 Santen Pharmaceutical Co Ltd N-SUBSTITUTED-N'-SUBSTITUTED UREA DERIVATIVE AND USE THEREOF AS TNF-$g(a) PRODUCTION INHIBITOR
JP4898062B2 (en) * 2000-05-05 2012-03-14 ノバルティス アーゲー Azabicyclic carbamate and its use as an alpha-7 nicotinic acetylcholine receptor agonist
US7491739B2 (en) 2000-05-31 2009-02-17 Santen Pharmaceutical Co., Ltd. TNF-α production inhibitors
EP1568692A1 (en) * 2000-05-31 2005-08-31 Santen Pharmaceutical Co., Ltd. (pyridin-4-yl)alkyl-amides as TNF-alpha production inhibitors
US7098226B2 (en) 2000-05-31 2006-08-29 Santen Pharmaceutical Co., Ltd. TNF-α production inhibitors
US7345064B2 (en) 2000-05-31 2008-03-18 Santen Pharmaceutical Co., Ltd. TNF-α production inhibitors
US7923461B2 (en) * 2000-05-31 2011-04-12 Santen Pharmaceutical Co., Ltd. TNF-α production inhibitors
WO2002002071A2 (en) * 2000-06-30 2002-01-10 Unilever Plc Cosmetic compositions containing substituted amide derivatives
CN1313072C (en) * 2000-06-30 2007-05-02 荷兰联合利华有限公司 Cosmetic compositions containing substituted amide derivatives
WO2002002071A3 (en) * 2000-06-30 2002-06-20 Unilever Plc Cosmetic compositions containing substituted amide derivatives
USRE45670E1 (en) 2002-06-27 2015-09-15 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
US7897628B2 (en) 2002-06-27 2011-03-01 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
US7541373B2 (en) 2002-06-27 2009-06-02 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
CN101130526B (en) * 2002-06-27 2013-07-10 诺沃挪第克公司 Aryl carbonyl derivatives as therapeutic agents
WO2004002481A1 (en) * 2002-06-27 2004-01-08 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
US8063081B2 (en) 2002-06-27 2011-11-22 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
US7384967B2 (en) 2002-06-27 2008-06-10 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
US7807701B2 (en) 2002-08-30 2010-10-05 Japan Tobacco Inc. Dibenzylamine compounds and pharmaceutical use thereof
US7332514B2 (en) 2002-08-30 2008-02-19 Japan Tobacco Inc. Dibenzylamine compound and medicinal use thereof
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
US7989462B2 (en) 2003-07-03 2011-08-02 Myrexis, Inc. 4-arylamin-or-4-heteroarylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
USRE45183E1 (en) 2004-01-06 2014-10-07 Novo Nordisk A/S Heteroaryl-ureas and their use as glucokinase activators
US7872139B2 (en) 2004-01-06 2011-01-18 Novo Nordisk A/S Heteroaryl-ureas and their use as glucokinase activators
US7851636B2 (en) 2004-01-06 2010-12-14 Novo Nordisk A/S Heteroaryl-ureas and their use as glucokinase activators
WO2005097779A1 (en) * 2004-04-09 2005-10-20 Neuromed Pharmaceuticals Ltd. Diarylamine derivatives as calcium channel blockers
JP2007532492A (en) * 2004-04-09 2007-11-15 ニューロメッド ファーマシューティカルズ リミテッド Diarylamine derivatives as calcium channel blockers
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
US7999114B2 (en) 2005-07-08 2011-08-16 Novo Nordisk A/S Dicycloalkylcarbamoyl ureas as glucokinase activators
US7884210B2 (en) 2005-07-14 2011-02-08 Novo Nordisk A/S Ureido-thiazole glucokinase activators
US8044052B2 (en) 2006-10-18 2011-10-25 Pfizer Inc. Biaryl ether urea compounds
US8012972B2 (en) 2007-03-28 2011-09-06 Santen Pharmaceutical Co., Ltd. Pyridinecarboxylic acid (2-aminophenyl) amide derivative having urea structure
WO2008117862A1 (en) * 2007-03-28 2008-10-02 Santen Pharmaceutical Co., Ltd. Novel (2-aminophenyl)pyridinecarboxamide derivative having urea structure
US8927549B2 (en) 2008-11-21 2015-01-06 High Point Pharmaceuticals, Llc Adamantyl benzamide derivatives
US8513430B2 (en) 2010-07-27 2013-08-20 High Point Pharmaceuticals, Llc Substituted thiazol-2-ylamine derivatives, pharmaceutical compositions, and methods of use as 11-beta HSD1 modulators
JPWO2012033069A1 (en) * 2010-09-07 2014-01-20 大鵬薬品工業株式会社 Piperidine compounds that inhibit prostaglandin D synthase
EP2615084A4 (en) * 2010-09-07 2014-04-09 Taiho Pharmaceutical Co Ltd Prostaglandin d synthase inhibitory piperidine compounds
EP2615084A1 (en) * 2010-09-07 2013-07-17 Taiho Pharmaceutical Co., Ltd. Prostaglandin d synthase inhibitory piperidine compounds
CN103080086B (en) * 2010-09-07 2014-11-05 大鹏药品工业株式会社 Prostaglandin D synthase inhibitory piperidine compounds
CN103080086A (en) * 2010-09-07 2013-05-01 大鹏药品工业株式会社 Prostaglandin D synthase inhibitory piperidine compounds
JP5693591B2 (en) * 2010-09-07 2015-04-01 大鵬薬品工業株式会社 Piperidine compounds that inhibit prostaglandin D synthase
WO2012033069A1 (en) * 2010-09-07 2012-03-15 大鵬薬品工業株式会社 Prostaglandin d synthase inhibitory piperidine compounds
US9181183B2 (en) 2010-09-07 2015-11-10 Taiho Pharmaceutical Co., Ltd. Prostaglandin D synthase inhibitory piperidine compounds
US11168068B2 (en) 2016-07-18 2021-11-09 Janssen Pharmaceutica Nv Tau PET imaging ligands
US11440898B2 (en) 2016-12-28 2022-09-13 Minoryx Therapeutics S.L. Isoquinoline compounds, methods for their preparation, and therapeutic uses thereof in conditions associated with the alteration of the activity of beta galactosidase
US11833136B2 (en) 2018-06-12 2023-12-05 Vtv Therapeutics Llc Therapeutic uses of glucokinase activators in combination with insulin or insulin analogs

Also Published As

Publication number Publication date
GB9526560D0 (en) 1996-02-28
AU1372897A (en) 1997-07-28

Similar Documents

Publication Publication Date Title
WO1997024328A1 (en) 2-amino-heterocycles and therapeutic uses therefor
US5614627A (en) Quinazoline compounds
JP4842963B2 (en) Substituted benzoquinolidines as DPP-IV inhibitors to treat diabetes
US20100256203A1 (en) Benzimidazoles and pharmaceutical compositions thereof
EP0100200A1 (en) 2-Substituted 4-amino-6,7-dimethoxyquinolines
SI9200093A (en) 4-(2-(2-hydroxy-2-phenylethylamino)ethoxy)phenylacetic acid derivatives used in therapy obesity and related state
PL218537B1 (en) Imidazole derivatives and their use as peripherally-selective inhibitors of dopamine-beta-hydroxylase
EP2323735A1 (en) Substituted pyridoxine-lactam carboxylate salts
US6380229B1 (en) 2-(N-cyanoimino)thiazolidin-4-one derivatives
US5432179A (en) Piperazine derivatives and pharmaceuticals containing the same
JP2010024243A (en) Benzo[g]quinoline derivative for treatment of glaucoma and myopia
JPS5989665A (en) Piperazine derivative, manufacture and medicine
NZ260874A (en) Substituted carbonylamino pyridine derivatives, preparation and medicaments thereof
JP4349476B2 (en) Cyanoguanidine as a cytostatic agent
JP2003506432A (en) Carboxamides, their preparation and their use as pharmaceutical compositions
WO1997021678A1 (en) Carbamic acid derivatives as leukotriene antagonists
US4801603A (en) Guanidinobenzoic ester derivative
DK170201B1 (en) 5-Alkylsulfonamido-2- (N-alkylsulfonamidoheterocyclylmethyl-N-methylamino) indane compounds, these compounds for use as drugs, use of the compounds for the preparation of antiarrhythmic drugs and pharmaceutical compositions containing the compounds, and 2- (N-methylamino) ) indan compounds useful as intermediates
US5059613A (en) Topically active ocular benzothiazole sulfonamide carbonic anhydrase inhibitors
US7008955B2 (en) (2-azabicyclo[2.2.1]hept-7yl) methanol derivatives as nicotinic acetylcholine receptor agonists
JP3426242B2 (en) Diazacycloalkane alkylsulfonamide derivatives
PL179032B1 (en) Novel derivatives of hydroxamic acid, pharmaceutic compositions containing them and process for obtaining such derivatives
US20100063035A1 (en) Carbonic anhydrase inhibitors derivatives
WO1997022588A1 (en) Use of hetarylacetic acid derivatives as leukotriene inhibitors
JP2003342265A (en) Triazolidine derivative and its pharmaceutical use

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BG BR BY CA CN CZ EE HU IL IS JP KE KP KR LT LV MX NO NZ PL RO RU SG SI SK UA US VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 97523999

Format of ref document f/p: F

122 Ep: pct application non-entry in european phase