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EP1926714A1 - Derives de benzimidazole a substitution isotopique - Google Patents

Derives de benzimidazole a substitution isotopique

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Publication number
EP1926714A1
EP1926714A1 EP06792891A EP06792891A EP1926714A1 EP 1926714 A1 EP1926714 A1 EP 1926714A1 EP 06792891 A EP06792891 A EP 06792891A EP 06792891 A EP06792891 A EP 06792891A EP 1926714 A1 EP1926714 A1 EP 1926714A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
alkoxy
hydrogen
hydroxy
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06792891A
Other languages
German (de)
English (en)
Inventor
Bernhard Kohl
Peter Jan Zimmermann
Karl Zech
Peter Zimmermann
Wilm Buhr
Andreas Palmer
Christof Brehm
Maria Vittoria Chiesa
Michael David
Oliver Von Richter
Wolfgang-Alexander Simon
Stefan Postius
Wolfgang Kromer
Hans Christof Holst
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda GmbH
Original Assignee
Nycomed GmbH
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 Nycomed GmbH filed Critical Nycomed GmbH
Priority to EP06792891A priority Critical patent/EP1926714A1/fr
Publication of EP1926714A1 publication Critical patent/EP1926714A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D235/12—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory 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
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D235/08—Radicals containing only hydrogen and carbon atoms

Definitions

  • the invention relates to novel compounds which are used in the pharmaceutical industry as active compounds for the production of medicaments.
  • the International patent application WO 04/087701 discloses tricyclic benzimidazole derivatives having different substituents in 5-position of the benzimidazole moiety which compounds are likewise useful for treating gastrointestinal diseases.
  • the International Patent application WO 05/111000 discloses substituted, bicyclic benzimidazole derivatives which compounds are useful for treating gastrointestinal disorders.
  • the International Patent application WO 05/103057 discloses tricyclic benzimidazole derivatives having oxygen based substituents in 6- and 7-position of the tricyclic core structure. The compounds are likewise useful for treating gastrointestinal disorders.
  • the International Patent application WO 05/121139 discloses tricyclic benzimidazole derivatives having different substituents in 5-, 6- and 7-position of the tricyclic core structure. The compounds inhibit the secretion of gastric acid.
  • the International Patent application WO 06/037748 discloses substituted tricyclic benzimidazole compounds with a certain substitution pattern, which compounds are useful for treating gastrointestinal disorders.
  • the International Patent application WO 06/037759 discloses condensed tricyclic benzimidazole derivatives, which are substituted in 5- and 6-position of the tricyclic core structure.
  • the compounds are likewise useful for treating gastrointestinal disorders.
  • the US Patent 6,818,200 (which corresponds to US Patent Application 2002/094995) describes a method of enhancing the efficiency and increasing the duration of action of drugs (e.g. dihydropyri- dines and anti-bacterials) and particularly of nifedipine and penicillins wherein one or more hydrogen atoms are replaced by Deuterium.
  • drugs e.g. dihydropyri- dines and anti-bacterials
  • nifedipine and penicillins wherein one or more hydrogen atoms are replaced by Deuterium.
  • a deuterated derivative of Omeprazole a compound, which is known to be a proton pump inhibitor, is described by way of example.
  • PPI ' s proton pump inhibitors
  • rPPI ' s reversible proton pump inhibitors
  • APA ' s acid pump antagonists
  • P-CAB ' s potassium competitive acid blockers
  • the invention relates to compounds of the formula 1 in which
  • R1 is hydrogen, halogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alkyl
  • R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, and wherein either R4 and R5 are each hydrogen and R6 is phenyl substituted by R61 and R62 wherein
  • R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl
  • R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl, or wherein R4 and R5 together form a -CHR7-CHR8- group and R6 is phenyl substituted R61 and R62, wherein
  • R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl
  • R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl
  • R7 is hydrogen, hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C- alkoxy
  • R8 is hydrogen, hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C- alkoxy or wherein R4 is hydrogen and R5 and R6 together form a group gp, - A -
  • R9 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl- carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C- alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, I ⁇ C-alkoxy-I ⁇ C-alkoxycarbonylamino or sulfonyl,
  • R10 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy
  • R11 is hydrogen, 1-7C-alkyl, 2-4C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C- alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C- alkoxy-1 -4C-alkoxy, 1 -4C-alkoxy-1 -4C-alkoxy-1 -4C-alkoxy, 3-7C-cycloalkoxy-1 -4C- alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C- alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-
  • R12 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C- alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C- alkoxy-1 -4C-alkoxy, 1 -4C-alkoxy-1 -4C-alkoxy-1 -4C-alkoxy, 3-7C-cycloalkoxy-1 -4C- alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C- alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-
  • R1 is hydrogen, halogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alkyl
  • R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,
  • R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl
  • R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl
  • X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R61 , R62 or of the core structure of the formula 1-a or any combination of R1 , R2, R3, R61 , R62 and the core structure of the formula 1-a is replaced with a deuterium atom, and their salts.
  • R1 is hydrogen, halogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alkyl
  • R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group
  • R6 is phenyl substituted by R61 and R62 wherein
  • R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl
  • R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl
  • R7 is hydrogen, hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C- alkoxy
  • R8 is hydrogen, hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C- alkoxy
  • X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R6, R7, R8 or of the core structure of the formula 1-b or any combination of R1 , R2, R3, R6, R7, R8 and the core structure of the formula 1-b is replaced with a deuterium atom, and their salts.
  • R1 is hydrogen, halogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1- 4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1 -4C-alkyl,
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1 -4C-alkyl or fluoro-2-4C-alkyl
  • R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1 -4C-alkyl,
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,
  • R9 is hydrogen, 1-4C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
  • R10 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy
  • R11 is hydrogen, 1-7C-alkyl, 2-4C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1 -4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1 -4C-alkoxy-1 -4C-alkoxy-1 -4C-alkoxy, 3-7C-cycloalkoxy-1 -4C-alkoxy, 3-7C-cycloalkyl-1 -4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C
  • X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R9, R10, z or of the core structure of the formula 1-c or any combination of R1 , R2, R3, R9, R10, z and the core structure of the formula 1-c is replaced with a deuterium atom, and their salts.
  • 1-4C-Alkyl denotes straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
  • 3-7C-Cycloalkyl denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, among which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
  • 3-7C-Cycloalkyl-1-4C-alkyl denotes one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals. Examples which may be mentioned are the cyclopropylmethyl, the cyclohexylmethyl and the cyclohexylethyl radicals.
  • 1-4C-Alkoxy denotes radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radicals.
  • 1-4C-Alkoxy-1-4C-alkyl denotes one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the methoxymethyl, the methoxyethyl and the butoxyethyl radicals.
  • 1-4C-Alkoxycarbonyl denotes a carbonyl group to which is attached one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the meth- oxycarbonyl (CH 3 O-C(O)-) and the ethoxycarbonyl (CH 3 CH 2 O-C(O)-) radicals.
  • 2-4C-Alkenyl denotes straight-chain or branched alkenyl radicals having 2 to 4 carbon atoms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl and the 2- propenyl (allyl) radicals.
  • 2-4C-Alkynyl denotes straight-chain or branched alkynyl radicals having 2 to 4 carbon atoms. Examples which may be mentioned are the 2-butynyl, the 3-butynyl and, preferably, the 2- propynyl (propargyl radicals).
  • Fluoro-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one or more fluorine atoms.
  • An example which may be mentioned are the trifluoromethyl group, the difluoromethyl, the 2-fluoroethyl, the 2,2-difluoroethyl or the 2,2,2-trifluoroethyl group.
  • Hydroxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by a hydroxy group. Examples which may be mentioned are the hydroxy- methyl, the 2-hydroxyethyl and the 3-hydroxypropyl group. Hydroxy-1-4C-alkyl within the scope of the invention is understood to include 1-4C-alkyl groups with two or more hydroxy groups. Examples which may be mentioned are the 3,4-dihydroxybutyl and in particular the 2,3-dihydroxypropyl group.
  • Fluoro-2-4C-alkyl represents a 2-4C-alkyl group, which is substituted by one or more fluorine atoms. Examples which may be mentioned are the 2-fluoroethyl, the 2,2- difluoroethyl and in particular the 2,2,2-trifluoroethyl group.
  • 3-7C-Cycloalkoxy represents a group, which in addition to the oxygen atom contains one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cyclohep- tyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
  • 3-7C-Cycloalkyl-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclopropylmethoxy, the cyclohexylmethoxy and the 2-cyclohexylethoxy group.
  • Fluoro-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which substituted by one or more fluorine atoms.
  • fluoro-1-4C-alkoxy groups which may be mentioned are the 2-fluoro-ethoxy, 1 ,1 ,1 ,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1 ,1 ,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4-heptafluoro-1-butoxy, the 4,4,4-trifluoro-1-butoxy, the 2,2,3,3,3- pentafluoropropoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy, in particular the 1 ,1 ,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluo
  • Examples which may be mentioned are the 2-(1 ,1 ,2,2-tetrafluoroethoxy)-ethoxy, the 2-(2,2,2-trifluoroethoxy)- ethoxy, the 2-(trifluoromethoxy)-ethoxy and the 2-(difluoromethoxy)-ethoxy group.
  • Hydroxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by a hydroxy group. Examples which may be mentioned are the 2- hydroxyethoxy and the 3-hydroxypropoxy group. Hydroxy-1-4C-alkoxy within the scope of the invention is understood to include 1-4C-alkoxy groups with two or more hydroxy groups. Examples which may be mentioned are the 3,4-dihydroxybutoxy and in particular the 2,3-dihydroxypropoxy group.
  • halogen is bromine, chlorine and fluorine.
  • 1-4C-Alkoxy-1-4C-alkoxy denotes one of the abovementioned 1-4C-alkoxy radicals which is substituted by a further 1-4C-alkoxy radical.
  • examples which may be mentioned are the radicals 2-(methoxy)ethoxy (CH 3 -O-CH 2 -CH 2 -O-) and 2-(ethoxy)ethoxy (CH 3 -CH 2 -O-CH 2 -CH 2 -O-).
  • 1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkyl denotes one of the abovementioned 1-4C-alkoxy-1-4C-alkyl radicals which is substituted by one of the abovementioned 1-4C-alkoxy radicals.
  • An example which may be mentioned is the radical 2- (methoxy)ethoxymethyl (CH 3 -O-CH 2 -CH 2 -O-CH 2 -).
  • Fluoro-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by a fluoro-1-4C-alkoxy group.
  • Fluoro-1-4C-alkoxy in this case represents one of the aforementioned 1-4C-alkoxy groups, which substituted by one or more fluorine atoms.
  • fluoro-substituted 1-4C-alkoxy groups which may be mentioned are the 2-fluoro- ethoxy, 1 ,1 ,1 ,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1 ,1 ,1-trifluoro-2- propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4-heptafluoro-1-butoxy, the 4,4,4-trifluoro-1- butoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy, in particular the 1 ,1 ,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy group.
  • fluoro-1-4C-alkoxy-1-4C-alkyl radicals which may be mentioned are, 1 ,1 ,2,2-tetrafluoroethoxymethyl, the 2,2,2-trifluoroethoxymethyl, the trifluoromethoxymethyl, 2-fluoroethoxyethyl, the 1 ,1 ,2,2-tetrafluoroethoxyethyl, the 2,2,2- trifluoroethoxyethyl, the trifluoromethoxyethyl and preferably the difluoromethoxymethyl and the difluoromethoxyethyl radicals.
  • 1-7C-Alkyl denotes straight-chain or branched alkyl radicals having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl-(5-methylhexyl), hexyl, iso- hexyl-(4-methylpentyl), neohexyl-(3,3-dimethylbutyl), pentyl, isopentyl-(3-methylbutyl), neopentyl-(2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
  • 1-4C-Alkylcarbonyl denotes a radical which, in addition to the carbonyl group, contains one of the abovementioned 1-4C-alkyl radicals.
  • An example which may be mentioned is the acetyl radical.
  • Carboxy-1-4C-alkyl denotes, for example, the carboxymethyl (-CH 2 COOH) or the carboxyethyl (-CH 2 CH 2 COOH) radical.
  • 1-4C-Alkoxycarbonyl-1-4C-alkyl denotes one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned 1-4C-alkoxycarbonyl radicals.
  • An example which may be mentioned is the ethoxycarbonylmethyl (CH 3 CH 2 OC(O)CH 2 -) radical.
  • 1-4C-Alkoxycarbonylamino denotes an amino radical which is substituted by one of the above- mentioned 1-4C-alkoxycarbonyl radicals. Examples which may be mentioned are the ethoxy- carbonylamino and the methoxycarbonylamino radicals.
  • 1-4C-Alkoxy-1-4C-alkoxycarbonyl denotes a carbonyl group to which one of the abovementioned 1-4C-alkoxy-1-4C-alkoxy radicals is attached.
  • Examples which may be mentioned are the 2-(methoxy)ethoxycarbonyl (CH 3 -O-CH 2 CH 2 -O-CO-) and the 2-(ethoxy)ethoxycarbonyl (CH 3 CH 2 -O-CH 2 CH 2 -O-CO-) radicals.
  • 1-4C-Alkoxy-1-4C-alkoxycarbonylamino denotes an amino radical which is substituted by one of the abovementioned 1-4C-alkoxy-1-4C-alkoxycarbonyl radicals. Examples which may be mentioned are the 2-(methoxy)ethoxycarbonylamino and the 2-(ethoxy)ethoxycarbonylamino radicals.
  • 2-4C-Alkenyloxy denotes a radical which, in addition to the oxygen atom, contains a 2-4C- alkenyl radical.
  • An example which may be mentioned is the allyloxy radical.
  • Aryl is phenyl or substituted phenyl with one, two or three identical or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro- methyl, nitro, trifluoromethoxy, hydroxy and cyano.
  • An example which may be mentioned is the phenyl radical.
  • Aryl-1-4C-alkyl denotes an aryl-substituted 1-4C-alkyl radical.
  • An example which may be mentioned is the benzyl radical.
  • Aryl-1-4C-alkoxy denotes an aryl-substituted 1-4C-alkoxy radical.
  • An example which may be mentioned is the benzyloxy radical.
  • Mono- or di-1-4C-alkylamino radicals contain, in addition to the nitrogen atom, one or two of the abovementioned 1-4C-alkyl radicals. Preference is given to di-1-4C-alkylamino and in particular to dimethyl-, diethyl- or diisopropylamino.
  • Mono- or di-1-4C-alkylamino-1-4C-alkyl denotes one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned mono- or di-1-4C-alkylamino radicals.
  • Preferred mono- or di-1-4C-alkylamino-1-4C-alkyl radicals are the mono- or di-1-4C- alkylaminomethyl radicals.
  • An Example which may be mentioned is the dimethylaminomethyl (CHa) 2 N-CH 2 radical.
  • 1-4C-Alkylcarbonylamino denotes an amino group to which a 1-4C-alkylcarbonyl radical is attached.
  • Examples which may be mentioned are the propionylamino (C 3 H 7 C(O)NH-) and the acetylamino (acetamido, CH 3 C(O)NH-) radicals.
  • 1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxy groups.
  • a preferred example which may be mentioned is the methoxyethoxyethoxy group.
  • 3-7C-Cycloalkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkoxy groups. Examples which may be mentioned are the cyclopropoxymethoxy, the cyclobutoxymethoxy and the cyclohexy- loxyethoxy group.
  • 3-7C-Cycloalkyl-1-4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl-1-4C-alkoxy groups. Examples which may be mentioned are the cyclopropylmethoxyethoxy, the cyclobu- tylmethoxyethoxy and the cyclohexylethoxyethoxy group.
  • 1-4C-Alkylcarbonyloxy represents a 1-4C-alkylcarbonyl group which is bonded to an oxygen atom.
  • An example which may be mentioned is the acetoxy group (CH3CO-O-).
  • Halo-1-4C-alkoxy represents 1-4C-alkoxy groups which are completely or mainly substituted by halogen. "Mainly” in this connection means that more than half of the hydrogen atoms in the 1-4C-alkoxy groups are replaced by halogen atoms.
  • Halo-1-4C-alkoxy groups are primarily chloro- and/or in particular fluoro-substituted 1-4C-alkoxy groups.
  • halogen- substituted 1-4C-alkoxy groups which may be mentioned are the 2,2,2-trichloroethoxy, the hexachloroisopropoxy, the pentachloroisopropoxy, the 1 ,1 ,1-trichloro-3,3,3-trifluoro-2- propoxy, the 1 ,1 ,1-trichloro-2-methyl-2-propoxy, the 1 ,1 ,1-trichloro-2-propoxy, the 3-bromo- 1 ,1 ,1 -trifluoro-2-propoxy, the 3-bromo-1 ,1 ,1 -trifluoro-2-butoxy, the 4-bromo-3,3,4,4- tetrafluoro-1-butoxy, the chlorodifluoromethoxy, the 1 ,1 ,1 ,3,3,3-hexafluoro-2-propoxy, the 2- trifluoromethyl-2-propoxy, the 1 ,1 ,1-trifluoro-2-
  • Mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy represents a 1-4C-alkylcarbonyloxy group, which is substituted by one of the aforementioned mono- or di-1-4C-alkylamino groups. Examples, which may be mentioned, are the dimethylamino-methylcarbonyloxy and the dimethylamino-ethylcarbonyloxy group.
  • 1-4C-Alkoxy-1-4C-alkylcarbonyloxy represents one of the aforementioned 1-4C- alkylcarbonyloxy radicals which is substituted by one of the aforementioned 1-4C-alkoxy groups.
  • An example, which may be mentioned, is the methoxymethylcarbonyloxy group.
  • Possible salts of compounds of the formula 1 - depending on substitution - are especially all acid addition salts. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, malonic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naph- thoic acid, where the acids are used in salt preparation - depending on
  • Salts of the compounds of formula I according to the invention can be obtained by dissolving, the free compound in a suitable solvent (for example a ketone such as acetone, me- thylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or di- oxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or to which the desired acid is then added, if necessary upon heating.
  • a suitable solvent for example a ketone such as acetone, me- thylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or di- oxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a
  • the acid can be employed in salt preparation, depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom.
  • the salts are obtained for example by evaporating the solvent or by precipitating upon cooling, by re-precipitating, or by precipitating with a non-solvent for the salt and separation, for example by filtration, of the salt after precipitation.
  • Pharmacologically intolerable salts which can initially be obtained, for example, as process products in the production of the compounds according to the invention on the industrial scale, are converted into the pharmacologically tolerable salts by processes known to the person skilled in the art.
  • the invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula 1 , and also all solvates and in particular all hydrates of the salts of the compounds of the formula 1.
  • the compounds of the formula 1 may have one or more centers of chirality in the skeleton depending on their basic structure and the substitution pattern with deuterium.
  • the invention thus provides all feasible stereoisomers of compounds of the formula 1 in any mixing ratio, including the pure stereoisomers, which are a preferred subject matter of the invention.
  • the pure stereoisomers of the compounds of the formula 1 and salts according to the present invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and by splitting up stereoisomeric mixtures obtained in synthesis.
  • the pure stereoisomers of the compounds of the formula 1 are obtained by using chiral starting compounds.
  • Stereoisomeric mixtures of compounds of the formula 1 can be split up into the pure stereoisomers by methods known to a person skilled in the art. Preferably, the mixtures are separated by chromatography or (fractional) crystallization.
  • the split up is preferably done by forming diastereomeric salts by adding chiral additives like chiral acids, subsequent resolution of the salts and release of the desired compound from the salt.
  • derivatization with chiral auxiliary reagents can be made, followed by diastereomer separation and removal of the chiral auxiliary group.
  • enantiomeric mixtures can be separated using chiral separating columns in chromatography. Another suitable method for the separation of enantiomeric mixtures is the enzymatic separation.
  • the compounds according to the present invention are characterized in that at least one hydrogen atom is replaced by a deuterium atom. This replacement / these replacements can take place in any desired position / positions of the molecule, that is either in any of its substituents R1 , R2, R3, R4, R5, R6 or at the core structure or in any combination thereof.
  • the term "hydrogen atoms of the core structure" according to the present invention is to be understood to be the hydrogen atoms which are not the substituents or part of the substituents R1 , R2, R3, R4, R5 or R6 mentioned above.
  • the hydrogen atoms of the core structures of the compounds of the formulae 1 and 1-a which can be replaced by a deuterium, are indicated below by H/D.
  • the term "at least one of the hydrogen atoms is replaced with a deuterium atom” has the meaning that 1 , 2, 3, 4, 5, 6, 7, 8, 9 or more hydrogen atoms of the compound is / are replaced by a deuterium atom. If more than one hydrogen atom of the compound is replaced by a deuterium atom, this replacement can either lead to a compound where two, three or more deuterium atoms are attached to the same atom (e.g. leading to a - CD 2 -, -CHD 2 or a -CD 3 group) and/or where deuterium atoms are attached to different atoms, for example to 2 or 3 different atoms, within the compound.
  • Preferred compounds according to aspect a of the invention are those compounds of the formula 1-a1 and 1-a2
  • R1 is hydrogen, halogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alkyl
  • R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,
  • R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl
  • R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl
  • X is O (oxygen) or NH whereby optionally one or more further hydrogen atoms of R1 , R2, R3, R61 , R62 or of the core structure of the formulae 1-a1 or 1-a2 or any combination of R1 , R2, R3, R61 , R62 and of the core structure of the formulae 1-a1 or 1-a2 is replaced with a deuterium atom, and their salts.
  • Particularly preferred compounds of the formula 1-a1 and 1-a2 are those in which
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl or hydroxy-1-4C-alkyl,
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or hydroxy-1-4C-alkyl,
  • R3 is carboxyl, 1 -4C-alkoxycarbonyl or the group -CO-NR31 R32, where
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,
  • R61 is 1-4C-alkyl or fluoro-1-4C-alkyl
  • R62 is 1 -4C-alkyl or fluoro-1 -4C-alkyl
  • X is O (oxygen) or NH and whereby optionally one or more further hydrogen atoms of R1 , R2, R3, R61 , R62 or of the core structure of the formulae 1-a1 or 1-a2 or any combination of R1 , R2, R3, R61 , R62 and of the core structure of the formulae 1-a1 or 1-a2 is replaced with a deuterium atom, and their salts.
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R3 is 1 -4C-alkoxycarbonyl or the group -CO-NR31 R32, where
  • R31 is 1-7C-alkyl or hydroxy-1-4C-alkyl
  • R32 is hydrogen or 1-7C-alkyl, R61 is 1-4C-alkyl, R62 is 1-4C-alkyl, X is NH and whereby optionally one or more further hydrogen atoms of R1 , R2, R3, R61 , R62 or of the core structure of the formulae 1-a1 or 1-a2 or any combination of R1 , R2, R3, R61 , R62 and of the core structure of the formulae 1-a1 or 1-a2 is replaced with a deuterium atom, and their salts.
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R3 is 1 -4C-alkoxycarbonyl or the group -CO-NR31 R32, where
  • R31 is 1-7C-alkyl or hydroxy-1-4C-alkyl
  • R32 is hydrogen or 1-7C-alkyl
  • R61 is 1-4C-alkyl
  • R62 is 1-4C-alkyl
  • X is NH and and their salts.
  • Also preferred compounds according to aspect a of the invention are those compounds of the formula 1-a3 in which
  • R1 is hydrogen, halogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1 -4C-alkyl or fluoro-2-4C-alkyl
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C- alkyl and
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group
  • R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl
  • R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl
  • X is O (oxygen) or NH and whereby at least one of the hydrogen atoms in R31 is replaced with a deuterium atom, and whereby optionally one or more further hydrogen atoms of R1 , R2, R31 , R32, R61 , R62 or of the core structure of the formula 1 -a3 or any combination of R1 , R2, R31 , R32, R61 , R62 and of the core structure of the formulae 1-a3 is replaced with a de
  • Particularly preferred compounds of the formula 1-a3 are those in which
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl or hydroxy-1 -4C-alkyl,
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or hydroxy-1 -4C-alkyl,
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C- alkyl and
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group
  • R61 is 1-4C-alkyl or fluoro-1-4C-alkyl
  • R62 is 1 -4C-alkyl or fluoro-1 -4C-alkyl
  • X is O (oxygen) or NH and whereby at least one of the hydrogen atoms in R31 is replaced with a deuterium atom, and whereby optionally one or more further hydrogen atoms of R1 , R2, R31 , R32, R61 , R62 or of the core structure of the formula 1 -a3 or any combination of R1 , R2, R31 , R32, R61 , R62 and of the core structure of the formulae 1-a3 is replaced with a deuterium atom and their salts.
  • R1 is 1 -4C-alkyl or 1 -4C-alkoxy-1 -4C-alkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R31 is 1-7C-alkyl
  • R32 is 1-7C-alkyl
  • R61 is hydrogen or 1-4C-alkyl
  • R62 is 1-4C-alkyl
  • X is NH and whereby at least one of the hydrogen atoms in R31 is replaced with a deuterium atom, and whereby optionally one or more further hydrogen atoms of R1 , R2, R31 , R32, R61 , R62 or of the core structure of the formula 1 -a3 or any combination of R1 , R2, R31 , R32, R61 , R62 and of the core structure of the formulae 1-a3 is replaced with a deuterium atom and their salts.
  • R1 is 1 -4C-alkyl or 1 -4C-alkoxy-1 -4C-alkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R31 is 1-7C-alkyl
  • R32 is 1-7C-alkyl
  • R61 is hydrogen or 1-4C-alkyl
  • R62 is 1-4C-alkyl
  • X is NH and whereby at least one of the hydrogen atom in R31 is replaced with a deuterium atom, and whereby additionally one or more further hydrogen atoms of R31 or R32 or in R31 and R32 is replaced with a deuterium atom and their salts.
  • R1 is 1 -4C-alkyl or 1 -4C-alkoxy-1 -4C-alkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R31 is CD 3 and
  • R32 is CD 3 .
  • R61 is hydrogen or 1-4C-alkyl
  • R62 is 1-4C-alkyl
  • X is NH and and their salts.
  • Preferred compounds according to aspect b of the invention are those compounds of the formula 1-b1
  • R1 is hydrogen, halogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alkyl
  • R6 is phenyl substituted by R61 and R62 wherein
  • R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl
  • R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl
  • R7 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C-alkoxy-1-4C- alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C-alkoxy
  • R8 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C-alkoxy-1-4C- alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C-alkoxy
  • X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R
  • Particularly preferred compounds of the formula 1-b1 are those in which
  • R1 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl
  • R2 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl
  • R6 is phenyl
  • R7 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, 1-4C-alkoxy-1-4C- alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy or hydroxy-1-4C-alkoxy
  • R8 is hydroxyl, 1-4C-alkoxy or hydroxy-1-4C-alkoxy
  • X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R6, R7, R8 or of the core structure of the formula 1-b1 or any combination of R1 , R2, R6, R7, R8 and of the core structure of the formula 1-b1 is replaced with a deuterium atom, and their salts.
  • Also preferred compounds according to aspect b of the invention are those compounds of the formula 1-b2
  • R1 is hydrogen, halogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alkyl
  • R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group
  • R6 is phenyl substituted by R61 and R62 wherein
  • R61 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl
  • R62 is hydrogen, halogen, 1-4C-alkyl or fluoro-1-4C-alkyl
  • X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R6 or of the core structure of the formula 1 -b2 or any combination of R1 , R2, R3, R6 and of the core structure of the formula 1 -b2 is replaced with a deuterium atom, and their salts.
  • Particularly preferred compounds of the formula 1-b2 are those in which
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or fluoro-1-4C-alkyl,
  • R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl
  • R3 is hydrogen, halogen, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31 R32, where
  • R31 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen or 1-7C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,
  • R6 is phenyl
  • X is O (oxygen) or NH
  • at least one of the hydrogen atoms of R1 , R2, R3, R6 or of the core structure of the formula 1-b2 or any combination of R1 , R2, R3, R6 and of the core structure of the formula 1-b2 is replaced with a deuterium atom, and their salts.
  • Preferred compounds according to aspect c of the invention are those compounds of the formula 1-c1
  • R1 is hydrogen, halogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1- 4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1 -4C-alkyl,
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1 -4C-alkyl or fluoro-2-4C-alkyl
  • R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1 -4C-alkyl,
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,
  • R9 is hydrogen, 1-4C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
  • R10 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy
  • R11 is hydrogen, 1-7C-alkyl, 2-4C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1 -4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1 -4C-alkoxy-1 -4C-alkoxy-1 -4C-alkoxy, 3-7C-cycloalkoxy-1 -4C-alkoxy, 3-7C-cycloalkyl-1 -4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C
  • X is O (oxygen) or NH and whereby at least one of the hydrogen atoms of R1 , R2, R3, R9, R10, R11 or of the core structure of the formula 1 -c1 or any combination of R1 , R2, R3, R9, R10, R11 and of the core structure of the formula 1-c1 is replaced with a deuterium atom, and their salts.
  • Particularly preferred compounds according to aspect c of the invention are those compounds of the formula 1-c2
  • R1 is hydrogen, halogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1- 4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1 -4C-alkyl,
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1 -4C-alkyl or fluoro-2-4C-alkyl
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C- alkyl and
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,
  • R9 is hydrogen, 1-4C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
  • R10 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy
  • R11 is hydrogen, 1-7C-alkyl, 2-4C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1 -4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1 -4C-alkoxy-1 -4C-alkoxy-1 -4C-alkoxy, 3-7C-cycloalkoxy-1 -4C-alkoxy, 3-7C-cycloalkyl-1 -4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C
  • Particularly preferred compounds of the formula 1-c2 are those in which
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl or hydroxy-1-4C-alkyl,
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or hydroxy-1-4C-alkyl,
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C- alkyl and
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,
  • R9 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen
  • R10 is hydrogen or 1-4C-alkyl
  • R11 is hydrogen, 1-7C-alkyl, 2-4C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1 -4C-alkoxy-1 -4C-alkoxy-1 -4C-alkoxy, 3-7C-cycloalkoxy-1 -4C-alkoxy, 3-7C-cycloalkyl-1 -4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-
  • Further preferred compounds of the formula 1 , 1-a, 1-b, 1-c, 1-a1 , 1-a2, 1-a3, 1-b1 , 1-b2, 1-c1 and 1- c2 are those wherein at least one of the hydrogen atoms in R2 is replaced with a deuterium atom.
  • particularly preferred substituents R2 in this case are the D, CH 2 D, CHD 2 radicals and in particular the CD 3 radical.
  • Exemplary preferred compounds are those of the formula 1-a in which R1 , R2, R3, R61 and R62 have the meanings given in the following table A and whereby X is NH and the salts of these compounds.
  • Exemplary also preferred compounds are those of the formula 1-a in which R1 , R2, R3, R61 and R62 have the meanings given in the following table A and whereby X is O and the salts of these compounds.
  • Exemplary particularly preferred compounds are those of the formula 1-a1 in which R1 , R2, R3, R61 and R62 have the meanings given in the following table A and whereby X is NH and the salts of these compounds.
  • Exemplary particularly preferred compounds are those of the formula 1-a2 in which R1 , R2, R3, R61 and R62 have the meanings given in the following table A and whereby X is NH and the salts of these compounds.
  • Exemplary also particularly preferred compounds are those of the formula 1-a1 in which R1 , R2, R3, R61 and R62 have the meanings given in the following table A and whereby X is O and the salts of these compounds.
  • Exemplary also particularly preferred compounds are those of the formula 1-a2 in which R1 , R2, R3, R61 and R62 have the meanings given in the following table A and whereby X is O and the salts of these compounds.
  • the compounds of the formula 1 can be prepared in manner known to a person skilled in the art, for example in analogy to the processes disclosed in the patent applications mentioned above for the undeuterated analogues (EP 266326, WO 97/47603, WO 04/054984, WO 04/087701 or WO 05/058893) all of which are incorporated herein by reference, using the corresponding deuterated starting materials or corresponding deuterated reagents.
  • the starting compounds are known from literature.
  • 6-Halo,4-nitro-substituted benzimidazoles can be prepared as described in GiI- lespie et al., J. Org. Chem. 1960, 25, 942 or in WO 04/054984 or they can be prepared using analogous process steps.
  • Suitable deuterated starting materials or deuterated reagents are known to a person skilled in the art or can be prepared by methods known per se.
  • deuterated benzimidazole derivatives of the general formula 1-a1 and 1-a2 can be obtained by reacting benzimidazoles of the formula 2 with deuterated arylmethyl halogenides.
  • benzyl halogenides of the formula 3 as shown in scheme 1 are used, wherein Hal is a halogen atom like for example chlorine or bromine, and which are once or twice deuterated at the benzylic carbon.
  • Hal is a halogen atom like for example chlorine or bromine
  • d 2 -2-methylbenzyl bromide is known from Smith et al., Can. J. Chem. 1986, 64, 1060-1071 or d 2 -2,6-dimethylbenzyl bromide from Luz et al., Phys. Chem. Chem.
  • deuterated reagents can be used for the introduction of deuterium into intermediates or into the final compounds of the formula 1-a4.
  • deuterated amines HNR31 R32 for the synthesis of compounds of the formula 6, wherein at least one of the hydrogen atoms of R31 or R32or of R31 and R32 is replaced with a deuterium atom
  • reagents which allow the introduction of deuterated substituents R2 into compounds of the formula 9 for example deuterated alkylating reagents (e.g.
  • deuterated alky I halides deuterated alky I halides
  • deuterated arylmethyl halogenides or deuterated arylketones especially benzaldehydes, wherein for example one or two hydrogen atoms in the benzyl ic position can be replaced with a deuterium atom.
  • the compound of the formula 5 (3-amino-4,5-dinitrobenzoic acid) is known, inter alia from C. Loring Jackson; M. H. Ittner, Chem. Ber.; 28; 1895; 3063 and C. Loring Jackson; M. H. Ittner, Am. Chem. J.; 19; 1897; 10. and can be transformed to compounds of the formula 6 by methods for converting a carboxylic acid into an amide, which methods are known to a person skilled in the art (e.g. converting the carboxylic acid into a carboxylic acid chloride by chlorination reagents like for example thionyl chloride and further reaction of the carboxylic acid chloride thus obtained with a suitable amine HNR31 R32).
  • One nitro group in compounds of the formula 6 can then be reduced to an amine group leading to compounds of the formula 7 by reactions which are familiar to a person skilled in the art.
  • An example to be mentioned for this reaction is the use molecular hydrogen in the presence of a suitable metal catalyst, like for example Pd, Pt, Rh or Ru catalysts, like for example [RhCI2Cp]2 or RuCI2(PPh3)3 (see for example J. F. Knifton J. Org. Chem. (1975) 40 519), which can optionally be absorbed on a suitable carrier, like for example on BaSO4, AI2O3 or Carbon. Emphasis in this regard is given to the use of a Pd / BaSO4 catalyst.
  • Compounds of the formula 8 can be further derivatized, if desired, by introduction of any desired substituent R2 by an electrophilic substitution of the nitrogen bound hydrogen atom.
  • Any suitable electro- phile which is derived from 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C- alkyl, hydroxy-1-4C-alkyl or fluoro-1-4C-alkyl known to the expert can be used in this reaction, enabling the introduction of any desired substituent R2.
  • the electrophile is used to introduce a 1-4C-alkyl radical, especially a methyl radical, as the R2 substituent by any reaction which is familiar to a person skilled in the art to alkylate amino nitrogen atoms (see for example "The Chemistry of Benzimidazoles” John B. Wright; Chem. Rev. 1951 , 48(3), 397-541), for example by reaction with an alkyl halogenide, such as for example methyliodide, by reaction with a dialkylcar- bonate, especially dimethylcarbonate, or by reaction with dialkylsulfates, especially dimethylsulfate.
  • an alkyl halogenide such as for example methyliodide
  • dialkylcarbonates are used for the alkylation reaction
  • the reactivity of this reagent can be improved by performing the reaction in the presence of an additional base in order to increase reaction rates and yields in this reaction as described for example by Lissel, M. et al in Synthesis, 1986, 382.
  • An example to be mentioned is the use of dimethylcarbonate in the presence of DBU (1 ,8- diazabicyclo[5.4.0]undec-7-ene), DABCO (1 ,4-diazabicylco[2.2.2]octance or DMAP (dimethylamino- pyridine) as additional base in analogy to the process described for example in the US Patent Application US 2003/0073848.
  • reaction conditions as described above for the synthesis of compounds of the formula 7 can be applied.
  • Suitable reaction conditions include, but are not limited to, molecular hydrogen in the presence of a suitable metal catalyst, like for example Raney Nickel, PtO2, Pd or Pt, optionally on a suitable carrier, like for example on charcoal, the use of reducing metals, such as for example zinc, tin, stannous chloride or iron in acidic solution, the use of alternative reducing reagents like for example hydrazine or reducing sulphide reagents or any other method known to the expert.
  • a suitable metal catalyst like for example Raney Nickel, PtO2, Pd or Pt
  • a suitable carrier like for example on charcoal
  • reducing metals such as for example zinc, tin, stannous chloride or iron in acidic solution
  • alternative reducing reagents like for example hydrazine or reducing sulphide reagents or any other method known to the expert.
  • the final conversion of compounds of the formula 10 to compounds of the formula 1-a4 is carried out by methods known to the expert for example for the benzylation of an aromatic amino functionality, for example as described already in the International Patent Application WO 04/054984.
  • One example to be mentioned is the reaction with arylmethyl halogenides (see scheme 1 ).
  • Another example to be mentioned is the reductive amination, which consists in reacting compounds of the formula 10 with arylketones of the formula 12 and subsequent reduction of the resulting imine intermediate by suitable reducing agents, like for example sodium borohydride (NaBH4), cyano borohydride (CN BH3) and especially sodium triacetoxy borohydride NaBH[OC(O)CH3]3.
  • the invention therefore further relates to compounds of the formula 9
  • R1 is hydrogen, halogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hy- droxy-1-4C-alkyl or fluoro-2-4C-alkyl
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, whereby optionally one or more hydrogen atoms of R1 , R2, R31 , R32 or of the core structure of the formula 9 or any combination of R1 , R2, R31 , R32 and of the core structure of the formula 9 is replaced with a deuterium atom, and their salts.
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl or hydroxy-1-4C-alkyl
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or hydroxy-1-4C-alkyl
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, whereby optionally one or more hydrogen atoms of R1 , R2, R31 , R32 or of the core structure of the formula 9 or any combination of R1 , R2, R31 , R32 and of the core structure of the formula 9 is replaced with a deuterium atom, and their salts.
  • R1 is 1-4C-alkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R31 is 1-7C-alkyl
  • R32 is 1-7C-alkyl, whereby optionally one or more hydrogen atoms of R2, R31 or R32 or any combination of R2, R31 and R32 is replaced with a deuterium atom, and their salts.
  • the invention further relates to compounds of the formula 6
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, whereby optionally one or more hydrogen atoms of R31 , R32 or of the core structure of the formula 6 or any combination of R31 , R32 and of the core structure of the formula 6 is replaced with a deuterium atom, and the salts of these compounds.
  • R31 is 1-7C-alkyl
  • R32 is 1-7C-alkyl, whereby optionally one or more hydrogen atoms of R31 or R32 or any combination of R31 and R32 is replaced with a deuterium atom, and the salts of these compounds.
  • the invention further relates to compounds of the formula 7
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, whereby optionally one or more hydrogen atoms of R31 , R32 or of the core structure of the formula 7 or any combination of R31 , R32 and of the core structure of the formula 7 is replaced with a deuterium atom, and the salts of these compounds.
  • the invention further relates to a process for the synthesis of a compound of the formula 10, wherein R1 , R2, R31 and R32 have the meanings as indicated above for compounds of the formula 9,
  • the invention further relates to a process for the synthesis of a compound of the formula 1-a4 wherein R1 , R2, R31 , R32, R61 and R62 have the meanings as indicated above for the compounds of the formula 1-a3, which comprises
  • the invention particularly relates to process for the synthesis of a compound of the formula 1-a4 as described above, wherein R1 , R2, R31 , R32, R61 and R62 have the meanings as indicated above for the compounds of the formula 1-a3, wherein the conversion of an amino compound of the formula 10 to a compound of the formula 1-a4 is either carried out by reaction with an arylmethyl halogenide of the formula 11 , wherein Hal is bromine or chlorine, or by reaction with a compound of the formula 12 and subsequent reduction of the resulting imine intermediate
  • the invention further relates to a process for the synthesis of compounds of the formula 9, wherein R1 , R2, R31 and R32 have the meanings as indicated above, which comprises
  • the invention further relates to a process for the synthesis of compounds of the formula 9, wherein R1 , R2, R31 and R32 have the meanings as indicated above, which comprises
  • the derivatization, if any, of the compounds obtained according to the above scheme 4 is likewise carried out in a manner known to the expert.
  • the derivatization can be performed for example at the stage of the compounds of the formulae 6, 7, 8, 9, 10 or 1-a4.
  • initially obtained compounds with an hydroxy-1-4C-alkyl substituent in R1 , R2, R31 or R32 position can be transformed under standard conditions into the corresponding 1-4C-alkoxy-1-4C-alkyl substituent.
  • the process for the synthesis of compounds of the formula 1 -a4 has several advantages when compared to the processes known from the prior art. Advantages which might be mentioned are inter alia the use of cheap, non-dangerous reagents, the occurance of less side reactions and therefore easier work-up after the benzylation reaction and in particular the possibility to avoid the use of carbon monoxide and costly catalysts like PdCI2(PPh3)2 in a carbonylation reaction.
  • the use of carbon monoxide is a potential safety problem especially when applied on a larger scale.
  • the process according to scheme 4 therefore is particularly applicable for the synthesis of deuterated or un-deuterated compounds of the formula 1-a4 on a larger scale.
  • the compounds of the formula 1 according to the present invention were found, unexpectedly, to possess advantageous properties which make them particularly suitable for use in human and veterinary medicine.
  • the compounds according to the present invention are characterized for example by an advantageous metabolization profile, in particular by an advantageous stability with regard to metabolic degradation.
  • the compounds according to the present invention thus show inter alia an increased effect and an increased duration of action with regard to inhibition of gastric acid secretion and gastric protective activity when compared their un-deuterated analogous.
  • These improved metabolization properties allow for example a reduction of the amount of a compound according to the invention, which is needed for treatment and/or prophylaxis.
  • further advantages such as for example patient safety or economical aspects, e.g. like drug costs etc.
  • the inhibition of the H+/K+-ATPase can be demonstrated for example in investigations using in-vitro systems.
  • the advantageous metabolization profile of the compounds according to the invention can also be demonstrated using suitable in-vitro test systems for example by incubation of isolated liver enzymes of rats, humans or other warm blooded animal.
  • the compounds of the formula 1 according to the invention investigated in the enzymatic assay mentioned below have been provided with numbers which correspond to the numbers of these compounds in the examples.
  • Pipes Sucrose, Nigericin, Na-ATP and Malachite green were purchased from Sigma-Aldrich, Tris, KCI and Ammonium molybdate (Ammoniumheptamolybdate tetrahydrate) from Merck and MgCI 2 from Fluka.
  • Enzyme refers to H+/K+-ATPase-containing vesicles prepared from hog gastric mucosa as described in Rabon, E. C, Bin Im, W., and Sachs, G. Methods Enzymol 1988, 157, 649-654.
  • a PIPES / TRIS buffer based solution with Sucrose and MgCI 2 was prepared. Nigericin and enzyme were added to reach abovementioned final concentrations. 80 ⁇ L/well of this mixture were placed into 96 well flat bottom plates (clear, polystyrol, Greiner bio-one). 10 ⁇ L/well KCI (1mM final) was used for stimulation of H/K ATPase activity. Test substances were dissolved as 1OmM solutions in 100% DMSO. 1 ⁇ L of Substances was added as DMSO solutions in dilutions ranging from IxIO "4 to 1x10 "9 M (final). The enzymatic reaction was started by addition of 10 ⁇ L ATP (1 mM final).
  • the assay was incubated for 30min at room temperature. The reaction was stopped by addition of 150 ⁇ L malachite green reagent and incubated for another 15 min prior to photometric reading of the plate at 680nm in a Pow- erWave HT Microplate spectral photometer (BioTek). Results were analyzed with GraphPad Prism software (Version 4.02) to calculate IC 50 values by sigmoidal curve fitting.
  • the degree of deuteration was determined for several selectivly deuterated compounds of the formula 1 by 1 H NMR spectroscopy.
  • the calculated degree of deuteration applies to the deuterated position with respect to a non-deuterated position within the same molecule (i.e. the value of the integral of a non-deuterated position is calibrated to the number of attached protons). This includes the assumption that non-deuterated positions are substituted by protons ( 1 H) to an extent of 100%.
  • Probe 5 mm BBI with actively shielded z-gradient
  • the present invention relates to compounds wherein at least one of the hydrogen atoms is replaced with a deuterium where in the position of replacement the degree of deuteration is higher than the naturally occurring degree of deuteration.
  • the preferred degree of deuteration in this position is preferably between 60 and 100%, more preferably between 90 and 100% and most preferably between 95 and 100%.
  • the preferred, more preferred and most preferred degree of deuteration in this position is calculated from the preferred, more preferred and most preferred ranges given above multiplied by the exchange rate of hydrogen atoms in that position.
  • An exchange rate of 0.5 is given for example in a -CHD- group, leading to a preferred degree of deuteration in this position between 30 and 50%, more preferred between 45 and 50% and most preferred between 47.5 and 50%.
  • an exchange rate of 0.333 is for example given in the case of a -CH 2 D group.
  • the compounds of the formula 1 , 1-a, 1-b, 1-c, 1-a1 , 1-a2, 1-a3, 1-b1 , 1-b2, 1-c1 and 1-c2 and their pharmaceutically acceptable salts have valuable pharmacological properties which make them commercially utilizable. In particular, they exhibit marked inhibition of gastric acid secretion and an excellent gastric and intestinal protective or curative action in warm-blooded animals, in particular humans.
  • the active compounds according to the invention are distinguished by a high selectivity of action, a fast onset of action, an advantageous duration of action, efficient control of the duration of action by the dosage, a particularly good antisecretory efficacy, the absence of significant side effects and a large therapeutic range.
  • Gastric and intestinal protection or cure in this connection is understood to include, according to general knowledge, the prevention, the treatment and the maintenance treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory diseases and lesions (such as, for example, reflux esophagitis, gastritis, hyperacidic or drug-related functional dyspepsia, and peptic ulcer disease [including peptic ulcer bleeding, gastric ulcer, duodenal ulcer]), which can be caused, for example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins, drugs (e.g. certain antiinflammatories and antirheumatics, such as NSAIDs and COX-inhibitors), chemicals (e.g. ethanol), gastric acid or stress situations.
  • gastrointestinal diseases is understood to include, according to general knowledge,
  • GSD gastroesophageal reflux disease
  • GERD extra-esophageal manifestations of GERD that include, but are not limited to, acid-related asthma, bronchitis, laryngitis and sleep disorders.
  • C) other diseases that can be connected to undiagnosed reflux and/or aspiration include, but are not limited to, airway disorders such as asthma, bronchitis, COPD (chronic obstructive pulmonary disease).
  • gastrointestinal diseases comprise other gastrointestinal conditions that might be related to acid secretion, such as Zollinger-Ellison syndrome, acute upper gastrointestinal bleeding, nausea, vomiting due to chemotherapy or post-operative conditions, stress ulceration, IBD (inflammatory bowel disease) and particularly IBS (irritable bowel syndrome).
  • the active compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art in various models in which the antiulcero- genic and the antisecretory properties are determined.
  • the active compounds according to the invention are outstandingly suitable for use in human and veterinary medicine, where they are used, in particular, for the treatment and/or prophylaxis of disorders of the stomach and/or intestine and/or upper digestive tract, particularly of the abovementioned diseases.
  • a further subject of the invention are therefore the active compounds according to the invention for use in the treatment and/or prophylaxis of the abovementioned diseases.
  • the invention likewise includes the use of the active compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the above- mentioned diseases.
  • the invention furthermore includes the use of the active compounds according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.
  • a further subject of the invention are medicaments which comprise one or more active compounds according to the invention.
  • the active compounds according to the invention are either employed as such, or preferably in combination with suitable pharmaceutical excipients in the form of tablets, coated tablets (e.g. film-coated tablets), multi unit particulate system tablets, capsules, suppositories, granules, powders (e.g. lyophilized compounds), pellets, patches (e.g. as TTS [transdermal therapeutic system]), emulsions, suspensions or solutions.
  • the content of the active compound is advantageously being between 0.1 and 95wt% (weight percent in the final dosage form), preferably between 1 and 60wt%.
  • the active compounds according to the invention can be administered orally, parenterally (e.g. intravenously), rectally or percutaneously. Oral or intravenous administration is preferred.
  • excipients or combinations of excipients which are suitable for the desired pharmaceutical formulations are known to the person skilled in the art on the basis of his/her expert knowledge and are composed of one or more accessory ingredients.
  • solvents antioxidants, stabilizers, surfactants, complexing agents (e.g. cyclodextrins)
  • excipients may be mentioned as examples:
  • gelling agents antifoams, plasticizer, adsorbent agents, wetting agents, colorants, flavorings, sweeteners and/or tabletting excipients (e.g.
  • carriers for intravenous administration, dispersants, emulsifiers, preservatives, solubilizers, buffer substances and/or isotonic adjusting substances.
  • dispersants for intravenous administration, the person skilled in the art may choose as excipients, for example: solvents, gelling agents, polymers, permeation promoters, adhesives, matrix substances and/or wetting agents.
  • a daily dose (given continuously or on-demand) of approximately 0.01 to approximately 20, preferably 0.02 to 5, in particular 0.02 to 1.5, mg/kg of body weight, if appropriate in the form of several, preferably 1 to 2, individual doses to achieve the desired result.
  • a parenteral treatment similar or (in particular in the case of the intravenous administration of the active compounds), as a rule, lower doses can be used.
  • the frequency of administration can be adapted to intermittent, weekly, monthly, even more infrequent (e.g. implant) dosing.
  • the establishment of the optimal dose and manner of administration of the active compounds necessary in each case can easily be carried out by any person skilled in the art on the basis of his/her expert knowledge.
  • the medicaments may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmaceutical science. All methods include the step of bringing the active compounds according to the invention into association with the excipients or a combination of excipients. In general the formulations are prepared by uniformly and intimately bringing into asso- ciation the active compounds according to the invention with liquid excipients or finely divided solid excipients or both and then, if necessary, formulating the product into the desired medicament.
  • the active compounds according to the invention or their pharmaceutical preparations can also be used in combination with one or more pharmacologically active constituents from other groups of drugs [combination partner(s)].
  • “Combination” is understood to be the supply of both the active compound ⁇ ) according to the invention and the combination partner(s) for separate, sequential, simultaneous or chronologically staggered use.
  • a combination is usually designed with the aim of increasing the principal action in an additive or super-additive sense and/or of eliminating or decreasing the side effects of the combination partner(s), or with the aim to obtain a more rapid onset of action and a fast symptom relief.
  • the drug release profile of the components can be exactly adapted to the desired effect, e.g. the release of one compound and its onset of action is chronologically previous to the release of the other compound.
  • a combination can be, for example, a composition containing all active compounds (for example a fixed combination) or a kit-of-parts comprising separate preparations of all active compounds.
  • a "fixed combination” is defined as a combination wherein a first active ingredient and a second active ingredient are present together in one unit dosage or in a single entity.
  • a "fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture of simultaneous administration, such as in a formulation.
  • Another example of a "fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
  • kits-of-parts is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit.
  • a “kit-of-parts” is a combination wherein the said first active ingredient and the said second active ingredient are present separately.
  • the components of the kit-of-parts may be administered separately, sequentially, simultaneously or chronologically staggered.
  • “Other groups of drugs” are understood to include, for example: tranquillizers (for example from the group of the benzodiazepines, like diazepam), spasmolytics (for example butylscopolaminium bromide [Buscopan®]), anticholinergics (for example atropine sulfate, pirenzepine, tolterodine), pain perception reducing or normalizing agents (for example, paracetamol, tetracaine or procaine or especially oxeta- cain), and, if appropriate, also enzymes, vitamins, trace elements or amino acids.
  • tranquillizers for example from the group of the benzodiazepines, like diazepam
  • spasmolytics for example butylscopolaminium bromide [Buscopan®]
  • anticholinergics for example atropine sulfate, pirenzepine, tolterodine
  • pain perception reducing or normalizing agents for example, paraceta
  • histamine-H2 blockers e.g. cimetidine, ranitidine
  • proton pump inhibitors e.g. omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole, tenatoprazole, ilaprazole, leminoprazole, all including their salts and enantiomers
  • other potassium-competitive acid blockers e.g. soraprazan and its stereoisomers, linaprazan, revaprazan, all including their salts]
  • peripheral anticholinergics e.g. pirenzepine
  • gastrin antagonists such as CCK2 antagonists (cholestocystokinin 2 receptor antagonists).
  • antibacterially active substances and especially substances with a bactericidal effect, or combinations thereof.
  • These combination partners are especially useful for the control of Helicobacter pylori infection whose eradication is playing a key role in the treatment of gastrointestinal diseases.
  • suitable antibacterially active combination partner(s) may be mentioned, for example:
  • cephalosporins such as, for example, cifuroximaxetil
  • (B) penicillines such as, for example, amoxicillin, ampicillin
  • (E) macrolide antibiotics such as, for example, erythromycin, clarithromycin, azithromycin
  • glycoside antibiotics such as, for example, gentamicin, streptomycin
  • gyrase inhibitors such as, for example, ciprofloxaxin, gatifloxacin, moxifloxacin
  • I oxazolidines, such as, for example, linezolid
  • nitrofuranes or nitroimidazoles such as, for example, metronidazole, tinidazole, nitrofurantoin
  • K bismuth salts, such as, for example, bismuth subcitrat (L) other antibacterially active substances and combinations of substances selected from (A) to (L), for example clarithromycin + metronidazole.
  • Preferred is the use of two combination partners. Preferred is the use of two combination partners selected from amoxicillin, clarithromycin and metronidazole. A preferred example is the use of amoxicillin and clarithromycin.
  • the active compounds according to the invention are especially suited for a free or fixed combination with drugs, which are known to cause "drug-induced dyspepsia" or are known to have a certain ulcerogenic potency, such as, for example, acetylsalicylic acid, certain antiinflammatories and antirheumatics, such as NSAIDs (non-steroidal antiinflammatory drugs, e.g. etofenamate, diclofenac, indometacin, ibupro- fen, piroxicam, naproxen, meloxicam), oral steroids, bisphosponates (e.g. alendronate), or even NO- releasing NSAIDs, COX-2 inhibitors (e.g. celecoxib, lumiracoxib).
  • drugs which are known to cause "drug-induced dyspepsia” or are known to have a certain ulcerogenic potency, such as, for example, acetylsalicylic acid, certain antiinflammatories and anti
  • the active compounds according to the invention are suited for a free or fixed combination with motility-modifying or -regulating drugs (e.g. gastroprokinetics like mosapride, tegaserod, itopride, metoclopramid), and especially with pharmaceuticals which reduce or normalize the incidence of transient lower esophageal sphincter relaxation (TLESR), such as, for example, pharmaceuticals modulating (activating) directly or indirectly the GABA-B receptor, such as, for example, GABA-B receptor agonists (e.g. baclofen, (2R)-3-amino-2-fluoropropylphosphinic acid), GABA-B receptor positive allos- teric modulators (e.g.
  • motility-modifying or -regulating drugs e.g. gastroprokinetics like mosapride, tegaserod, itopride, metoclopramid
  • GABA-B receptor positive allosteric modulators in combination with GABA-B receptor agonists, or substances that enhance the endogenous GABA tone such as GABA re-uptake inhibitors (e.g. tiagabine), pharmaceuticals antagonising the metabotropic glutamate receptor type 5 (mGluR5), such as metabotropic glutamate receptor type 5 (mGluR5) antagonists (e.g.
  • CB cannabinoid receptor
  • CBD1 cannabinoid receptor type 1
  • CBD1 cannabinoid receptor agonists
  • WIN55.212-2 cannabinoid receptor antagonists
  • CCK1 receptor antagonists e.g. loxiglumide
  • composition partners used for the treatment of IBS or IBD are also suitable combination partner(s), such as, for example: 5-HT4 receptor agonists like mosapride, tegaserod; 5-HT3 receptor antagonists like alosetron, cilansetron; NK2 antagonists like saredutant, nepadutant; ⁇ -opiate agonists like fedotozine.
  • 5-HT4 receptor agonists like mosapride, tegaserod
  • 5-HT3 receptor antagonists like alosetron, cilansetron
  • NK2 antagonists like saredutant, nepadutant
  • ⁇ -opiate agonists like fedotozine.
  • Suitable combination partner(s) also comprise airway therapeutica, for example for the treatment of acid-related asthma and bronchitis.
  • a hypnotic aid such as, for example, Zolpidem [Bikalm®]
  • combination partner(s) may be rational, for example for the treatment of GERD-induced sleep disorders.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés deutériés représentés par la formule (I), dans laquelle les substituants et les symboles correspondent aux définitions indiquées dans la description. Ces composants inhibent la sécrétion d'acide gastrique.
EP06792891A 2005-08-22 2006-08-18 Derives de benzimidazole a substitution isotopique Withdrawn EP1926714A1 (fr)

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EP05107688 2005-08-22
EP06101624 2006-02-14
PCT/EP2006/065447 WO2007023135A1 (fr) 2005-08-22 2006-08-18 Derives de benzimidazole a substitution isotopique
EP06792891A EP1926714A1 (fr) 2005-08-22 2006-08-18 Derives de benzimidazole a substitution isotopique

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CN101309917B (zh) 2005-10-06 2013-09-11 奥斯拜客斯制药有限公司 具有增强治疗性质的胃h+，k+-atp酶氘代抑制剂
WO2007072142A2 (fr) * 2005-12-19 2007-06-28 Pfizer Japan Inc. Dérivés de benzimidazole-5-carboxamide
WO2009094457A2 (fr) * 2008-01-22 2009-07-30 Auspex Pharmaceuticals Benzhydryléthers substitués
CN102470126A (zh) 2009-07-09 2012-05-23 拉夸里亚创药株式会社 用于治疗与异常肠胃运动有关的疾病的酸泵拮抗剂
CN107801396B (zh) 2015-02-02 2021-10-22 福马治疗股份有限公司 作为hdac抑制剂的3-芳基-4-酰氨基-二环[4,5,0]异羟肟酸
WO2016126726A1 (fr) 2015-02-02 2016-08-11 Forma Therapeutics, Inc. Acides hydroxamiques bicycliques [4,6,0] en tant qu'inhibiteurs hdac6
EP3472131B1 (fr) 2016-06-17 2020-02-19 Forma Therapeutics, Inc. Acides hydroxamiques de 2-spiro-indan-5-yl ou de 2-spiro-indan-6-yl utilisés en tant qu'inhibiteurs de hdac
KR20190057569A (ko) * 2017-11-20 2019-05-29 제일약품주식회사 7-아미노-1h-인돌-5-카르복사미드 유도체 및 이의 용도
CN113651663B (zh) * 2021-08-20 2024-03-29 浙大宁波理工学院 一种氘代芳香羰基类化合物的制备方法
WO2024087156A1 (fr) * 2022-10-28 2024-05-02 深圳市华先医药科技有限公司 Procédé de production évolutif de 4-hydroxy-n,n,2-triméthylbenzimidazole-6-carboxamide
WO2024087155A1 (fr) * 2022-10-28 2024-05-02 深圳市华先医药科技有限公司 Procédé de synthèse de 4-hydroxy-n, n, 2-triméthylbenzimidazole-6-carboxamide

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SE9602286D0 (sv) * 1996-06-10 1996-06-10 Astra Ab New compounds
AR043063A1 (es) * 2002-12-13 2005-07-13 Altana Pharma Ag Bencimidazoles 6-sustituidos y su uso como inhibidores de secreciones gastricas
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AU2006283876A1 (en) 2007-03-01

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