WO2000078728A1 - Novel benzimidazole derivatives and pharmaceutical compositions comprising these compounds - Google Patents

Novel benzimidazole derivatives and pharmaceutical compositions comprising these compounds Download PDF

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Publication number
WO2000078728A1
WO2000078728A1 PCT/DK2000/000333 DK0000333W WO0078728A1 WO 2000078728 A1 WO2000078728 A1 WO 2000078728A1 DK 0000333 W DK0000333 W DK 0000333W WO 0078728 A1 WO0078728 A1 WO 0078728A1
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alkyl
group
piperazinyl
benzimidazole
phenyl
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English (en)
French (fr)
Inventor
Lene Teuber
Frank Wätjen
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NTG Nordic Transport Group AS
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Neurosearch AS
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Priority to NZ515543A priority Critical patent/NZ515543A/en
Priority to AU53910/00A priority patent/AU777961B2/en
Priority to CA002373921A priority patent/CA2373921A1/en
Priority to BR0011823-0A priority patent/BR0011823A/pt
Priority to JP2001504895A priority patent/JP2003502405A/ja
Priority to MXPA02000107A priority patent/MXPA02000107A/es
Priority to IL14640300A priority patent/IL146403A0/xx
Priority to DE60025604T priority patent/DE60025604T2/de
Application filed by Neurosearch AS filed Critical Neurosearch AS
Priority to EP00938584A priority patent/EP1194410B1/en
Publication of WO2000078728A1 publication Critical patent/WO2000078728A1/en
Priority to IL146403A priority patent/IL146403A/en
Priority to US10/012,490 priority patent/US6649609B2/en
Anticipated expiration legal-status Critical
Priority to US10/618,727 priority patent/US6936613B2/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • Agents that bind or interact with the modulatory sites on the GABA A receptor complex can have either enhancing effect on the action of GABA, i.e. a positive modulatory effect of the receptor (agonists, partial agonists), an attenuating effect on the action of GABA, i.e. negative modulation of the receptor (inverse agonists, partial inverse agonists), or they can block the effect of both agonists and inverse agonists (antagonists or ligands without intrinsic activity).
  • anaesthetics many drugs presently available as anaesthetics, and especially pre-anaesthetics, give rise to hang-over effects as well as long awakening times, wherein careful monitoring of the patient is necessary. Anaesthetics with a long half-life may also impose difficulties during incidents of overdosing i.e. prolonged respiratory depression. Furthermore, some currently used drugs cannot be used for anaesthetising children as deaths have been reported in children after prolonged use of Propofol. Some anaesthetics are gasses which inherently possesses a contamination problem for the medical staff. A well known anaesthetic, Propofol, is administered as a mixture of soybean oil, glycerol and purified egg phosphatide, which mixture nourish bacterial growth.
  • EP 616807 describes benzimidazole compounds for use as benzodiazepine receptor ligands.
  • WO 96/33194, WO 96/33191 and WO 96/33192 describe benzimidazole compounds having affinity for the GABA receptor complex.
  • WO 98/34923 describes phenylbenzimidazole derivatives as ligands for the GABA receptor complex.
  • WO 98/17651 describes benzimidazole compounds for use as e.g. 5 anaesthetics. However, the presently disclosed compounds are superior to the compounds previously described.
  • the invention provides a benzimidazole derivative 5 represented by the general Formula I, or a pharmaceutically acceptable salt thereof, wherein,
  • R' represents a group of the formula -(alk) q -R 1 , wherein
  • (alk) represents alkyl, alkenyl or alkynyl, q is 0 or 1 ,
  • R 1 represents a group of the formula -CO 2 R 2 , wherein
  • R 2 represents hydrogen, alkyl, hydroxy-alkyl, alkoxy-alkyl, thioalkoxy-alkyl, alkyl- ⁇ eterocycle", or -alkyl-NR 3 R 4 , wherein
  • Heterocycle represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy- alkyl, alkoxy-alkyl, carboxyl and acyl, and a group of the formula -(alkyl) p -CN, -(alkyl) p - aryl, -(alkyl) p -"Heterocycle", -(alkyl) p -CO 2 -"Heterocycle” or -(alkyl-CO 2 ) s -(alkyl) r COR 5 , in which formulas p, s and t independently of each another is 0 or 1 ,
  • Heterocycle represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy- alkyl, alkoxy-alkyl, carboxyl and acyl,
  • R 5 represents hydroxy, alkoxy, hydroxy-alkoxy, alkoxy-alkoxy, thioalkoxy- alkoxy, or a group of the formula -NR 6 R 7 or -O-alkyl-NR 6 R 7 , in which formulas
  • R 6 and R 7 independently of each another represent hydrogen, alkyl, cycloalkyl or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, or
  • R 3 and R 4 independently of each another represent hydrogen, alkyl or cycloalkyl, or
  • R 3 and R 4 together with the nitrogen to which they are attached form a mono- or poly-cyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl; or
  • R 13 represents hydrogen, hydroxy, alkyl, alkoxy or hydroxy-alkyl
  • R 1 represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, hydroxy-alkyl, alkoxy-alkyl, carboxyl, and acyl, and a group of the formula -(alkyl) p -aryl, -(alkyl) p -"Heterocycle", -(alkyl) p -CN or -(alkyl-CO 2 ) s -(alkyl) t -
  • R 6 and R 7 together with the nitrogen to which they are attached form a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl; and
  • R" represents -(alkyl) 0 -"Heterocycle” or -(alkyl) 0 -CO 2 -(alkyl) u -"Heterocycle", wherein o and u independently of each another is 0 or 1 , and
  • R 5 represents hydrogen, hydroxy, alkyl, alkoxy, hydroxy-alkyl, hydroxy- alkoxy, alkoxy-alkyl, alkoxy-alkoxy, thioalkoxy-alkyl, thioalkoxy-alkoxy, or a group of the formula -NR 6 R 7 or -O-alkyl-NR 6 R 7 , in which formulas R 6 and R 7 independently of each another represent hydrogen, alkyl, cycloalkyl or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, or R 6 and R 7 together with the nitrogen to which they are attached form a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of
  • R" represents -(alkyl) m -CO 2 R 8 , wherein m is 0 or 1 , and
  • R 8 represents hydrogen, alkyl, hydroxy-alkyl, alkoxy-alkyl, thioalkoxy-alkyl, or a group of the formula -(alkyl) p -NR 9 R 10 , wherein p is O o .
  • R 9 and R 10 independently of each another represent hydrogen, alkyl, cycloalkyl, or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, or
  • R 9 and R 10 together with the nitrogen to which they are attached form a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl.
  • the invention provides a use of a benzimidazole derivative according to the invention for the manufacture of a medicament for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to modulation of the GABA receptor complex.
  • the invention provides novel benzimidazole derivatives.
  • the benzimidazole derivatives of the invention are represented by the general Formula I,
  • Heterocycle represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy- alkyl, alkoxy-alkyl, carboxyl, and acyl, and a group of the formula -(alkyl) p -CN, -(alkyl) p - aryl, -(alkyl) p -aralkyl, -(alkyl) p -O-aryl, -(alkyl) p -O-aralkyl, -(alkyl) p -CO 2 -aryl, -(alkyl) p - CO 2 -aralkyl, -(alkyl) p -"Heterocycle", -(alkyl) p -CO 2 -"Heterocycle” or -(alky
  • R 6 and R 7 independently of each another represent hydrogen, alkyl, cycloalkyl or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, or
  • benzimidazole derivative of the invention is a compound of Formula I, wherein
  • N N-Diethylcarbamoylmethyl 2-(3-(3-(5-(3-furanyl)-1 -benzimidazolyl)- phenyl)-4,5-dihydroisoxazole-5-yl)-acetate; or a pharmaceutically acceptable salt thereof.
  • X represents N or CH
  • an alkynyl group designates a carbon chain containing one or more triple bonds, including di-ynes, tri-ynes and poly-ynes.
  • the alkynyl group of the invention comprises of from two to six carbon atoms (C 2-6 -alkynyl), including at least one triple bond.
  • the alkynyl group of the invention is ethynyl, 1 ,2- or 2,3-propynyl, 1 ,2-, 2,3- or 3,4-butynyl.
  • 3-pyrazoline in particular 3-pyrazolin-(1-,3-,4- or 5-)yl.
  • Examples of preferred aromatic heterocyclic tri-cyclic groups of the invention include carbazole, in particular carbazol-(1-,2-,3-,4-,5-,6-,7-,8- or 9-)yl; acridine, in particular acridin-(1-,2-,3-,4-,5-,6-,7-,8- or 9-)yl; phenazine, in particular phenazin-(1-,2-,3-,4-,6-,7-,8- or 9-)yl; phenothiazine, in particular phenothiazin-(1-,2-,3-,4-,6-,7-,8-,9- or 10-)yl; and phenoxazine, in particular phenoxazin-(1-,2-,3-,4-,6-,7-,8-,9- or 10-)yl.
  • Examples of preferred saturated or partially saturated heterocyclic bi- cyclic groups of the invention include
  • 1 H-indazole in particular 1 H-indazol-(3-,4-,5-,6- or 7-)yl; 4H-quinolizine, in particular 4H-quinolizin-(1-,2-,3-,4-6-,7-,8- or 9-)yl; quinuclidine, in particular quinuclidin-(2-,3-,4-,5-,6-,7- or 8-)yl; isoquinuclidine, in particular isoquinuclidin-(1-,2-,3-,4-,5-,6-,7- or 8-)yl; tropane, in particular tropan-(1-,2-,3-,4-, 5-, 6-, 7- or 8-)yl; and nortropane, in particular nortropan-(1-,2-,3-,4-,5-,6- or 7-)yl.
  • Pharmaceutically Acceptable Salts in particular 4H-quinolizin-(1-,2-,
  • optical active compounds can also be prepared from optical active starting materials.
  • IC 50 the concentration ( ⁇ M) of the test substance which inhibits the specific binding of 3 H-FNM by 50%.
  • the dose of PTZ required for inducing convulsion in each mouse is calculated as PTZ kg body weight. Means ⁇ sd for each experimental group of 6 mice is calculated. ED-ioo is calculated by linear regression expressing the dose increasing the PTZ threshold to 100 mg PTZ/kg.

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PCT/DK2000/000333 1999-06-22 2000-06-22 Novel benzimidazole derivatives and pharmaceutical compositions comprising these compounds Ceased WO2000078728A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
IL14640300A IL146403A0 (en) 1999-06-22 2000-06-22 Novel benzimidazole derivatives and pharmaceutical compositions comprising these compounds
CA002373921A CA2373921A1 (en) 1999-06-22 2000-06-22 Novel benzimidazole derivatives and pharmaceutical compositions comprising these compounds
BR0011823-0A BR0011823A (pt) 1999-06-22 2000-06-22 Derivado de benzimidazol, composto, composição farmacêutica, uso de um derivado de benzimidazol, e, método para tratamento, prevenção ou alìvio de uma doença ou de um distúrbio ou de uma condição de um corpo animal vivo
JP2001504895A JP2003502405A (ja) 1999-06-22 2000-06-22 新規ベンズイミダゾール誘導体及びこれらの化合物を含有する薬学的に容認された塩
MXPA02000107A MXPA02000107A (es) 1999-06-22 2000-06-22 Derivados de benzimidazol novedososy composiciones farmaceuticas que comprenden estos compuestos.
DE60025604T DE60025604T2 (de) 1999-06-22 2000-06-22 Benzimidazol-derivate und diese enthaltende pharmazeutische zusammensetzungen
EP00938584A EP1194410B1 (en) 1999-06-22 2000-06-22 Benzimidazole derivatives and pharmaceutical compositions comprising these compounds
NZ515543A NZ515543A (en) 1999-06-22 2000-06-22 Novel benzimidazole derivatives and pharmaceutical compositions comprising these compounds
AU53910/00A AU777961B2 (en) 1999-06-22 2000-06-22 Novel benzimidazole derivatives and pharmaceutical compositions comprising these compounds
IL146403A IL146403A (en) 1999-06-22 2001-11-08 Benzimidazole derivatives and pharmaceutical compositions comprising these compounds
US10/012,490 US6649609B2 (en) 1999-06-22 2001-12-12 Benzimidazole derivatives and pharmaceutical compositions comprising these compounds
US10/618,727 US6936613B2 (en) 1999-06-22 2003-07-15 Benzimidazole derivatives and pharmaceutical compositions comprising these compounds

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DKPA199900888 1999-06-22

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CN (1) CN1167686C (https=)
AT (1) ATE316076T1 (https=)
AU (1) AU777961B2 (https=)
BR (1) BR0011823A (https=)
CA (1) CA2373921A1 (https=)
DE (1) DE60025604T2 (https=)
IL (2) IL146403A0 (https=)
MX (1) MXPA02000107A (https=)
NZ (1) NZ515543A (https=)
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Cited By (28)

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