+

WO2010038200A1 - Composés d'oxazolidine utilisables en tant qu'antagonistes des récepteurs à orexine - Google Patents

Composés d'oxazolidine utilisables en tant qu'antagonistes des récepteurs à orexine Download PDF

Info

Publication number
WO2010038200A1
WO2010038200A1 PCT/IB2009/054273 IB2009054273W WO2010038200A1 WO 2010038200 A1 WO2010038200 A1 WO 2010038200A1 IB 2009054273 W IB2009054273 W IB 2009054273W WO 2010038200 A1 WO2010038200 A1 WO 2010038200A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
carboxylic acid
thiazole
carbonyl
ylmethyl
Prior art date
Application number
PCT/IB2009/054273
Other languages
English (en)
Inventor
Hamed Aissaoui
Christoph Boss
Christine Brotschi
Jerome Gabillet
Romain Siegrist
Thierry Sifferlen
Jodi T. Williams
Original Assignee
Actelion Pharmaceuticals Ltd
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 Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of WO2010038200A1 publication Critical patent/WO2010038200A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel oxazolidine compounds of formula (I) and their use as pharmaceuticals.
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and especially their use as orexin receptor antagonists.
  • Orexins are novel neuropeptides found in 1998 by two research groups, orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are produced in discrete neurons of the lateral hypothalamus and bind to G-protein-coupled receptors (OX 1 and OX 2 receptors).
  • the orexin-1 receptor (OX 1 ) is selective for OX-A
  • the orexin-2 receptor (OX 2 ) is capable to bind OX-A as well as OX-B.
  • Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behaviour (Sakurai T. et al., Cell, 1998, 92, 573-585). On the other hand, it was also observed that orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches to narcolepsy as well as insomnia and other sleep disorders (Chemelli R. M. et al., Cell, 1999, 98, 437-451 ).
  • Orexin receptors are found in the mammalian brain and may have numerous implications in pathologies as known from the literature.
  • the present invention provides oxazolidine derivatives, which are non-peptide antagonists of human orexin receptors. These compounds are in particular of potential use in the treatment of e.g. eating disorders, drinking disorders, sleep disorders, or cognitive dysfunctions in psychiatric and neurologic disorders.
  • oxazolidine derivatives which are non-peptide antagonists of human orexin receptors. These compounds are in particular of potential use in the treatment of e.g. eating disorders, drinking disorders, sleep disorders, or cognitive dysfunctions in psychiatric and neurologic disorders.
  • Piperidine derivatives useful as orexin receptor antagonists are disclosed in WO01 /96302.
  • Morpholine derivatives useful as orexin receptor antagonists are disclosed in WO02/44172.
  • ⁇ /-Aroyl cyclic amine derivatives useful as orexin receptor antagonists are disclosed in WO02/90355.
  • a first aspect of the invention consists of a compound of the formula (I)
  • A represents aryl or heteroaryl, wherein the aryl or heteroaryl is independently unsubstituted or mono- or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (C 3-6 )cycloalkyl, (Ci -4 )alkoxy, trifluoromethyl, -NR 2 R 3 and halogen;
  • B represents aryl or heteroaryl, wherein the aryl or heteroaryl is independently unsubstituted or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )BIkOXy, fluoroalkyl, fluoroalkoxy, cyano, and halogen;
  • R 1 represents aryl or heteroaryl, wherein the aryl or heteroaryl is independently unsubstituted or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkoxy, halogen, cyano, fluoroalkyl, fluoroalkoxy, and -NR 2 R 3 ; or R 1 represents heterocyclyl wherein said heterocyclyl is unsubstituted or mono- or di-substituted wherein the substituents are independently selected from the group consisting of (Ci -4 )BIkOXy, halogen, and oxo;
  • R 2 represents hydrogen or and R 3 represents hydrogen or
  • a dotted line shows the point of attachment of the radical drawn.
  • halogen means fluorine, chlorine, or bromine, preferably fluorine or chlorine.
  • substituent "A” the term halogen preferably means bromine.
  • alkyl used alone or in combination, refers to a straight or branched chain alkyl group containing one to four carbon atoms.
  • (C x-y )alkyl (x and y each being an integer), refers to an alkyl group as defined before containing x to y carbon atoms. For example a (Ci -4 )alkyl group contains from one to four carbon atoms.
  • Examples of (Ci -4 )alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec. -butyl and tert- butyl. Preferred are methyl and ethyl. Most preferred is methyl.
  • alkoxy refers to an alkyl-O- group wherein the alkyl group is as defined before.
  • (C x-y )alkoxy (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms.
  • a (C 1-4 )alkoxy group means a group of the formula (C 1-4 )alkyl-O- in which the term "(C 1- 4 )alkyl" has the previously given significance.
  • Examples of (C 1-4 )alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert.-butoxy. Preferred is methoxy.
  • fluoroalkyl refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • (C x-y )fluoroalkyl (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example a
  • (Ci -3 )fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • Representative examples of fluoroalkyl groups include trifluoromethyl and 2,2,2-trifluoroethyl. Preferred are (Ci)fluoroalkyl groups such as trifluoromethyl.
  • fluoroalkoxy refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • (C x-y )fluoroalkoxy (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms.
  • a (Ci_3)fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy and 2,2,2-trifluoroethoxy. Preferred are (COfluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy. Most preferred is trifluoromethoxy.
  • (C 3-6 )cycloalkyl means a monocyclic saturated alkyl group with 3 to 6 carbon atoms.
  • Examples of (C 3-6 )cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Preferred is cyclopropyl.
  • -NR 2 R 3 as used fro the substituent "A" means for example -NH 2 or notably -N(CHa) 2 .
  • aryl alone or in combination, means a phenyl or a naphthyl group. Preferred is a phenyl group.
  • the aryl group may be unsubstituted or substituted as explicitly defined.
  • A represents “aryl” the term means the above-mentioned groups, (preferably phenyl) which are unsubstituted or mono- or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (C 3-6 )cycloalkyl, (Ci_ 4 )alkoxy, trifluoromethyl, -NR 2 R 3 and halogen.
  • aryl as used for the substituent "A” means phenyl which is unsubstituted (preferred) or mono-substituted wherein the substituent is selected from (C 1-4 )alkyl.
  • An example is phenyl.
  • the substituent "A” is also substituted by the substituent "B", wherein B is preferably attached in ortho position to the point of attachment of the carbonyl group which links A to the oxazolidine moiety.
  • B represents "aryl”
  • the term means the above-mentioned groups, (preferably phenyl) which are unsubstituted or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of fluoroalkyl, fluoroalkoxy, cyano, and halogen.
  • the substituents are independently selected from the group consisting of (Ci -4 )alkyl, fluoroalkyl, fluoroalkoxy, and halogen.
  • aryl as used for the substituent "B” means phenyl which is unsubstituted or mono-, or di-substituted wherein the substituents are independently selected from the group consisting of (Ci -4 )alkoxy, trifluoromethyl, trifluoromethoxy, and halogen.
  • aryl as used for the substituent "B” means phenyl which is unsubstituted, or mono-substituted in position 3 or 4 (in a sub-embodiment in position 3, in another sub-embodiment in position 4), or di-substituted wherein the substituents are attached in positions 3 and 4; wherein the substituent(s) are independently selected from the group consisting of methyl, methoxy, trifluoromethyl, trifluoromethoxy, chlorine and fluorine (especially selected from methyl, methoxy, and fluorine).
  • aryl groups as used for the substituent "B" are phenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 3,4-dimethylphenyl, 3,5- dimethylphenyl, 4-ethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 3,4- dichlorophenyl, 3-bromophenyl, 4-bromophenyl, 2-chloro-6-fluorophenyl, 3-bromo-4- fluorophenyl, 3-fluoro-2-methylphenyl, 3-fluoro-4-methylphenyl, 2,3-difluoro-4- methylphenyl, 4-cyanophenyl,
  • examples are phenyl, 3-methylphenyl, 3,4-dimethylphenyl, 3-methoxyphenyl, 3-fluorophenyl, and 4-fluorophenyl.
  • the substituent "B” is attached to the substituent "A”.
  • R 1 represents "aryl”
  • the term means the above-mentioned groups which are unsubstituted or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkoxy, halogen, cyano, fluoroalkyl, fluoroalkoxy, and -NR 2 R 3 .
  • the substituents are independently selected from the group consisting of fluoroalkyl, fluoroalkoxy, and halogen.
  • aryl as used for the substituent "R 1 " means unsubstituted naphthyl, or phenyl which is unsubstituted or mono-, or di-substituted wherein the substituents are independently selected from the group consisting of (Ci_ 4 )alkoxy, trifluoromethyl, trifluoromethoxy, and halogen.
  • R 1 " represents "aryl” are 1-naphthyl, 3-methylphenyl, 4-ethylphenyl, 2,3-dimethylphenyl, 2,5- dimethyl-phenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 4-methoxy-2-methylphenyl, A- methoxy-3-methylphenyl, 2-fluoro-5-methylphenyl, 3-fluoro-2-methylphenyl, 2-chloro-3- methylphenyl, 3-chloro-2-methylphenyl, 2-bromo-5-methylphenyl, 4-methyl-3- trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4- dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3- fluoro-6-methoxyphenyl, 5-fluoro
  • heteroaryl means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing 1 , 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur.
  • heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl
  • the term means the above-mentioned groups.
  • the term means a 5- to 6- membered (especially 5-membered) monocyclic heteroaryl as defined above.
  • the term means a 5- to 6-membered (especially 5-membered) monocyclic heteroaryl selected from thiophenyl, oxazolyl, thiazolyl, pyrazolyl, pyrimidyl, pyrazinyl, and pyridyl.
  • heteroaryl is selected from the group consisting of thiophenyl (notably thiophen-2-yl and especially thiophen-3-yl), oxazolyl (notably oxazol-4-yl), thiazolyl (notably thiazol-5-yl and especially thiazol-4-yl), and pyrazinyl (notably pyrazin-2- yl); wherein each of the above-mentioned groups constitute a particular sub-embodiment.
  • heteroaryl groups as used for the substituent "A” are unsubstituted or mono- or di-substituted, wherein the substituents are independently selected from the group consisting of (C 3-6 )cycloalkyl, trifluoromethyl, -NR 2 R 3 and halogen.
  • the above-mentioned heteroaryl groups as used for the substituent "A” are unsubstituted or mono-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (C 3-6 )cycloalkyl, (Ci -4 )alkoxy, trifluoromethyl, -NR 2 R 3 and halogen.
  • the above- mentioned heteroaryl groups as used for the substituent "A” are unsubstituted or mono- substituted, wherein the substituent is selected from the group consisting of (Ci -4 )alkyl, (C 3-6 )cycloalkyl, and -NR 2 R 3 (especially (C 1-4 )alkyl and -NR 2 R 3 ).
  • A represents "heteroaryl” are thiophen-2-yl, thiophen-3-yl, 2-methyl-oxazol-4-yl, 2- methyl-thiazol-5-yl, thiazol-4-yl, 2-methyl-thiazol-4-yl, 2-amino-thiazol-4-yl, 2- dimethylamino-thiazol-4-yl, 2-bromo-thiazol-4-yl, 2-methoxy-thiazol-4-yl 2-cyclopropyl- thiazol-4-yl, and pyrazin-2-yl.
  • particular examples of said groups are 2-methyl-oxazol-4-yl, 2-methyl-thiazol-5-yl, 2-dimethylamino-thiazol-4-yl, and pyrazin- 2-yl.
  • particular examples are 2-methyl-thiazol-4-yl, and 2- dimethylamino-thiazol-4-yl.
  • 2- methyl-oxazol-4-yl is 2- methyl-oxazol-4-yl.
  • a particular example is pyrazin-2-yl.
  • substituent "A” is also substituted by the substituent "B", wherein “B” is preferably attached in ortho position to the point of attachment of the carbonyl group which links A to the oxazolidine moiety.
  • the substituent "B” is preferably attached as follows: in position 5 of thiazol-4-yl groups, in position 4 of thiazol-5-yl groups, in position 3 of thiophen-2-yl groups, in position 2 of thiophen-3-yl groups, in position 5 of oxazol-4-yl groups, and in position 3 of pyrazin-2-yl groups.
  • case “B” represents “heteroaryl” the term means the above-mentioned groups.
  • the term means a 5- to 6-membered monocyclic heteroaryl as defined above.
  • the term means a 5- to 6-membered monocyclic heteroaryl selected from thiophenyl, oxazolyl, thiazolyl, pyrazolyl, pyrimidyl, pyrazinyl, and pyridyl.
  • heteroaryl groups as used for the substituent "B" are unsubstituted or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, fluoroalkyl, fluoroalkoxy, cyano, and halogen.
  • the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, fluoroalkyl, fluoroalkoxy, and halogen.
  • the above-mentioned heteroaryl groups as used for the substituent "B" are unsubstituted or mono-, or di-substituted wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, trifluoromethyl, and halogen (especially methyl, methoxy, trifluoromethyl, chlorine and fluorine).
  • R 1 represents “heteroaryl”
  • the term means the above-mentioned groups.
  • the term means a group selected from the group consisting of furanyl, oxazolyl (notably oxazol-5-yl, oxazol-4-yl), isoxazolyl (notably isoxazol-3-yl, isoxazol-4-yl), oxadiazolyl, thiophenyl, thiazolyl (notably thiazol-2-yl, thiazol-4-yl, thiazol-5-yl), isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl (notably pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl), triazolyl, pyridyl (notably pyridin- 2-yl, pyridin-3
  • R 1 represents "heteroaryl”
  • the term means a group selected from oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl benzotriazolyl, benzo[2,1 ,3]oxadiazolyl, benzo[2,1 ,3]thiadiazolyl, benzo[1 ,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, pyrazolo[1 ,5-a]pyridyl, imidazo[1 ,2-a]pyridyl, 1 H- pyrrolo[
  • R 1 represents "heteroaryl”
  • the term means a group selected from oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyridyl, indolyl, benzofuranyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo[2,1 ,3]oxadiazolyl, benzo[2,1 ,3]thiadiazolyl, benzo[1 ,2,3]thiadiazolyl, quinoxalinyl, imidazo[1 ,2-a]pyridyl, pyrrolo[2,1-b]thiazolyl, and imidazo[2,1-b]thiazolyl; wherein the specific points of attachment of said groups are preferably as mentioned above.
  • R 1 represents "heteroaryl”
  • the term means a group selected from isoxazolyl, pyrazolyl, indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl benzo[1 ,2,3]thiadiazolyl, quinoxalinyl, and imidazo[1 ,2-a]pyridyl; wherein the specific points of attachment of said groups are preferably as mentioned above.
  • heteroaryl groups as used for the substituent "R 1 " are unsubstituted or mono- or di-substituted (especially unsubstituted or mono-substituted) wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, trifluoromethyl, -NR 2 R 3 and halogen.
  • the above- mentioned heteroaryl groups as used for the substituent "R 1 " are unsubstituted or mono- or di-substituted (especially unsubstituted or mono-substituted) wherein the substituents are independently selected from the group consisting of (Ci ⁇ alkoxy, trifluoromethyl, and halogen (especially trifluoromethyl, and halogen).
  • heteroaryl groups as used for the substituent "R 1 " are preferably substituted as follows: isoxazolyl groups are mono-, or di-substituted (preferred) independently with pyrazolyl groups are mono-, di-, or tri-substituted wherein the substituents are independently selected from trifluoromethyl and halogen; indolyl groups are mono-substituted with (d ⁇ alkyl (notably methyl); indazolyl groups are unsubstituted, or mono-substituted with (especially methyl); benzoxazolyl groups are unsubstituted, or mono-substituted with (Ci -4 )alkyl (especially methyl); benzothiazolyl groups are unsubstituted (preferred), or mono-substituted with (Ci- 4 )alkyl (especially methyl); quinoxalinyl, benzisoxazolyl, benzisothiazo
  • R 1 representing "heteroaryl” are 2,5-dimethyl-2H-pyrazol-3-yl, 2- ethyl-5-methyl-2H-pyrazol-3-yl, 1-isopropyl-1 H-pyrazol-4-yl, 1 ,3-dimethyl-1 H-pyrazol-4-yl, 1-ethyl-3-methyl-1 H-pyrazol-4-yl, 1-methyl-5-trifluoromethyl-1 H-pyrazol-4-yl, 1 ,3,5- trimethyl-1 H-pyrazol-4-yl, 5-chloro-1 ,3-dimethyl-1 H-pyrazol-4-yl, 3,5-dimethyl-isoxazol-4- yl, 5-ethyl-3-methyl-isoxazol-4-yl, 3-ethyl-5-methyl-isoxazol-4-yl, 5-fluoro-1-methyl-1 H- indol-2-yl, 1 H-indol-3-yl
  • examples of "R 1 " representing "heteroaryl” are 1-isopropyl-1 H-pyrazol-4-yl, 1 ,3-dimethyl-1 H-pyrazol-4- yl, 1-ethyl-3-methyl-1 H-pyrazol-4-yl, 1-methyl-5-trifluoromethyl-1 H-pyrazol-4-yl, 1 ,3,5- trimethyl-1 H-pyrazol-4-yl, 5-chloro-1 ,3-dimethyl-1 H-pyrazol-4-yl, 3,5-dimethyl-isoxazol-4- yl, 5-ethyl-3-methyl-isoxazol-4-yl, 3-ethyl-5-methyl-isoxazol-4-yl, 1-methyl-1 H-indol-3-yl, 1- methyl-1 H-indol-4-yl, 1-methyl-1 H-indol-5-yl, 1-methyl-1 H-indol-7-yl
  • heterocyclyl alone or in combination, means a phenyl ring fused to a 5- or 6- membered saturated or unsaturated non-aromatic ring containing 1 or 2 heteroatoms independently selected from the group consisting of oxygen and nitrogen.
  • heterocyclyl groups as used for the substituent R 1 are 2,3-dihydro-benzofuranyl (especially 2,3-dihydro-benzofuran-4-yl or 2,3-dihydro-benzofuran-7-yl), AH- benzo[1 ,3]dioxinyl (especially 4H-benzo[1 ,3]dioxin-8-yl or 4H-benzo[1 ,3]dioxin-5-yl), benzo[1 ,3]dioxolyl (especially benzo[1 ,3]dioxol-4-yl), 3,4-dihydro-2H-benzo[1 ,4]oxazinyl (especially 3,4-dihydro-2H-benzo[1 ,4]oxazin-5-yl or 3,4-dihydro-2H-benzo[1 ,4]oxazin-8- yl), 2,3-dihydro-benzo[1 ,
  • heterocyclyl groups are unsubstituted, or mono-, or di-substituted wherein the substituents are independently selected from (Ci -4 )alkyl, halogen and oxo (especially from (Ci -4 )alkyl, halogen and oxo; notably fr and oxo).
  • heterocyclyl groups are substituted as follows: 2,3-dihydro-benzofuranyl- groups are unsubstituted or independently di-substituted with (Ci -4 )alkoxy and halogen (especially unsubstituted, or di-substituted in position 2 with methyl); 4H-benzo[1 ,3]dioxinyl-groups are preferably unsubstituted, or mono-substituted in position 6 with fluoro; benzo[1 ,3]dioxolyl-groups are preferably unsubstituted, or di-substituted in position 2 with fluoro; 3,4-dihydro-2H-benzo[1 ,4]oxazinyl-groups are preferably unsubstituted, or mono- or di-substituted with (especially methyl) or oxo; wherein, in a sub-embodiment, a
  • heterocyclyl groups are 3,4-dihydro-2H-benzo[1 ,4]oxazin-5-yl, 3,4-dihydro-2H- benzo[1 ,4]oxazin-8-yl, 3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-5-yl, 3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-8-yl, 4-methyl-3,4-dihydro-2H-benzo[1 ,4]oxazin-5-yl, 4-methyl-3,4- dihydro-2H-benzo [1 ,4]oxazin-8-yl, 4-methyl-3-oxo-3,4-dihydro-2/-/-benzo[1 ,4]oxazin-5-yl, 4-methyl-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-8-yl
  • particular examples are 2,3-dihydro-benzofuran-4-yl, 2,3-dihydro- benzofuran-7-yl, 2,2-dimethyl-2,3-dihydro-benzofuran-7-yl, 6-fluoro-4H-benzo[1 ,3]dioxin- 8-yl, 2,2-difluoro-benzo[1 ,3]dioxol-4-yl, 2,3-dihydro-benzo[1 ,4]dioxin-5-yl, 2,3-dihydro- benzo[1 ,4]dioxin-6-yl, and chroman-8-yl.
  • a further embodiment of the invention relates to compounds of formula (I) according to embodiment 1 ), which are also compounds of formula (l E i) wherein the stereocenter at position 2 of the oxazolidine moiety is in absolute (S)-configuration:
  • a further embodiment of the invention relates to compounds of formula (I) according to embodiment 1 ), which are also compounds of formula (I E2 ) wherein the stereocenter at position 2 of the oxazolidine moiety is in absolute (R)-configuration:
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 3), wherein A represents aryl or heteroaryl, wherein the aryl or heteroaryl is independently unsubstituted or mono-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 3-6 )cycloalkyl, and -NR 2 R 3 (especially (C 1-4 )alkyl, and -NR 2 R 3 ).
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 4), wherein A represents phenyl which is unsubstituted (preferred) or mono-substituted wherein the substituent is selected from (Ci -4 )alkyl.
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 4), wherein A represents a 5- to 6-membered (especially 5- membered) monocyclic heteroaryl which is unsubstituted or mono-substituted, wherein the substituent is selected from the group consisting of (Ci -4 )alkyl, (C 3-6 )cycloalkyl, and -NR 2 R 3 (especially (C 1-4 )alkyl, and -NR 2 R 3 ).
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 4), wherein A represents heteroaryl selected from the group consisting of thiophenyl (notably thiophen-2-yl and especially thiophen-3-yl), oxazolyl (notably oxazol-4-yl), thiazolyl (notably thiazol-5-yl and especially thiazol-4-yl), and pyrazinyl (notably pyrazin-2-yl); wherein said heteroaryl are unsubstituted or mono- substituted, wherein the substituent is selected from the group consisting of (C- ⁇ -4 )alkyl, (C 3 -6)cycloalkyl, and -NR 2 R 3 (especially and -NR 2 R 3 ).
  • A represents heteroaryl selected from the group consisting of thiophenyl (notably thiophen-2-yl and especially thiophen-3-yl), oxazolyl (notably
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 4), wherein A represents a group selected from the group consisting of thiophen-2-yl, thiophen-3-yl, 2-methyl-oxazol-4-yl, 2-methyl-thiazol-5-yl, thiazol-4-yl, 2-methyl-thiazol-4-yl, 2-amino-thiazol-4-yl, 2-dimethylamino-thiazol-4-yl, 2- bromo-thiazol-4-yl, 2-methoxy-thiazol-4-yl, 2-cyclopropyl-thiazol-4-yl, and pyrazin-2-yl.
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 4), wherein A represents a group selected from the group consisting of 2-methyl-oxazol-4-yl, 2-methyl-thiazol-4-yl, 2-dimethylamino-thiazol-4-yl and pyrazin-2-yl.
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 9), wherein B represents aryl or heteroaryl, wherein the aryl or heteroaryl is independently unsubstituted or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkoxy, fluoroalkyl, fluoroalkoxy, and halogen.
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 10), wherein B represents aryl which is unsubstituted or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of fluoroalkyl, fluoroalkoxy, and halogen (especially (Ci -4 )alkyl, (Ci -4 )alkoxy, and halogen).
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 10), wherein B represents phenyl which is unsubstituted, or mono-substituted in position 3 or 4 (in a sub-embodiment in position 3, in another sub-embodiment in position 4), or di-substituted wherein the substituents are attached in positions 3 and 4; wherein the substituent(s) are independently selected from the group consisting of methyl, methoxy, trifluoromethyl, trifluoromethoxy, chlorine and fluorine (especially methyl, methoxy, and fluorine).
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 12), wherein R 1 represents heteroaryl, which is unsubstituted or mono- or di-substituted (especially unsubstituted or mono-substituted) wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, trifluoromethyl, and halogen (especially (Ci -4 )alkyl, trifluoromethyl, and halogen); or R 1 represents heterocyclyl wherein said heterocyclyl is unsubstituted or mono- or di-substituted wherein the substituents are independently selected from the group consisting of halogen and oxo (especially (Ci -4 )alkyl and halogen).
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 13), wherein R 1 represents heteroaryl, which is unsubstituted or mono- or di-substituted (especially unsubstituted or mono-substituted) wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, trifluoromethyl, and halogen (especially (C 1-4 )alkyl, trifluoromethyl, and halogen).
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 13), wherein R 1 represents heterocyclyl wherein said heterocyclyl is unsubstituted or mono- or di-substituted wherein the substituents are independently selected from the group consisting of halogen and oxo (especially (Ci -4 )alkyl and halogen); 16) A further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 14), wherein, in case R 1 represents heteroaryl, said heteroaryl is selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 14), wherein, in case R 1 represents heterocyclyl, said heterocyclyl is selected from the group consisting of 2,3-dihydro-benzofuranyl, 4H-benzo[1 ,3]dioxinyl, benzo[1 ,3]dioxolyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl, 2,3-dihydro- benzo[1 ,4]dioxinyl, 2H-chromenyl, and chromanyl, wherein said heterocyclyl is unsubstituted or mono- or di-substituted wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, halogen and oxo (especially (Ci -4 )alkyl and halogen).
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 14), wherein, in case R 1 represents heteroaryl, said heteroaryl is selected from the group consisting of 1-isopropyl-1 H-pyrazol-4-yl, 1 ,3- dimethyl-1 H-pyrazol-4-yl, 1 -ethyl-3-methyl-1 H-pyrazol-4-yl, 1 -methyl-5-trifluoromethyl-1 H- pyrazol-4-yl, 1 , 3, 5-trimethyl-1 H-pyrazol-4-yl, 5-chloro-1 ,3-dimethyl-1 H-pyrazol-4-yl, 3,5- dimethyl-isoxazol-4-yl, 5-ethyl-3-methyl-isoxazol-4-yl, 3-ethyl-5-methyl-isoxazol-4-yl, 1- methyl-1 H-indol-3-yl, 1-methyl-1 H-indol-4-yl,
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 13) or 15), wherein, in case R 1 represents heterocyclyl, said heterocyclyl is selected from the group consisting of 2,3-dihydro-benzofuran-4-yl, 2,3- dihydro-benzofuran-7-yl, 2,2-dimethyl-2,3-dihydro-benzofuran-7-yl, 6-fluoro-4H- benzo[1 ,3]dioxin-8-yl, 2,2-difluoro-benzo[1 ,3]dioxol-4-yl, 2,3-dihydro-benzo[1 ,4]dioxin-5-yl, 2,3-dihydro-benzo[1 ,4]dioxin-6-yl, and chroman-8-yl.
  • R 1 represents heterocyclyl
  • said heterocyclyl is selected from the group consisting of 2,3-dihydro
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 12), wherein R 1 represents aryl, wherein the aryl is unsubstituted or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, fluoroalkyl, fluoroalkoxy, and halogen.
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1 ) to 19), wherein, in case R 1 represents a bicyclic heteroaryl group or R 1 represents a heterocyclyl group, the bond with which said bicyclic heteroaryl or said heterocyclyl is attached to the rest of the molecule is positioned on an aromatic carbon atom of said group in alpha position to a bridgehead atom as further illustrated in the following examples:
  • vJ bridgehead atom of the bicyclic ring system
  • ' ⁇ bond with which in these examples the heterocyclyl group may be attached to the rest of the molecule.
  • examples of compounds of formula (I) according to embodiment 1 are selected from the group consisting of:
  • Benzothiazole-7-carboxylic acid [3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)-oxazolidin-2- ylmethyl]-amide; lmidazo[1 ,2-a]pyridine-3-carboxylic acid [3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)- oxazolidin-2-ylmethyl]-amide; 1-Methyl-1 H-indole-3-carboxylic acid [3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)- oxazolidin-2-ylmethyl]-amide;
  • Benzothiazole-7-carboxylic acid ⁇ 3-[2-dimethylamino-5-(3-fluoro-phenyl)-thiazole-4- carbonyl]-oxazolidin-2-ylmethyl ⁇ -amide; Benzothiazole-7-carboxylic acid ⁇ 3-[2-dimethylamino-5-(3-methoxy-phenyl)-thiazole-4- carbonyl]-oxazolidin-2-ylmethyl ⁇ -amide;
  • Benzothiazole-7-carboxylic acid ⁇ 3-[2-dimethylamino-5-(4-fluoro-phenyl)-thiazole-4- carbonyl]-oxazolidin-2-ylmethyl ⁇ -amide; Benzothiazole-7-carboxylic acid ⁇ 3-[3-(3-methoxy-phenyl)-pyrazine-2-carbonyl]-oxazolidin-
  • the present invention also includes isotopically, especially 2 H (deuterium) labelled compounds of formula (I) which compounds are identical to the compound of formula (I) wherein one or more atoms have been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature, lsotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention.
  • Substitution of hydrogen with the heavier isotope 2 H (deuterium) may lead to greater metabolic stability, resulting eg. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile.
  • the compounds of formula (I) are not isotopically labelled, or labelled with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
  • the compounds of formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms.
  • the compounds of formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • pharmaceutically acceptable salts refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parenteral administration.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I).
  • the compounds according to formula (I) are useful in the preparation of a medicament for the prevention or treatment of diseases selected from the group consisting of dysthymic disorders including major depression and cyclothymia, affective neurosis, all types of manic depressive disorders, delirium, psychotic disorders, schizophrenia, catatonic schizophrenia, delusional paranoia, adjustment disorders and all clusters of personality disorders; schizoaffective disorders; anxiety disorders including generalized anxiety, obsessive compulsive disorder, posttraumatic stress disorder, panic attacks, all types of phobic anxiety and avoidance; separation anxiety; all psychoactive substance use, abuse, seeking and reinstatement; all types of psychological or physical addictions, dissociative disorders including multiple personality syndromes and psychogenic amnesias; sexual and reproductive dysfunction; psychosexual dysfunction and addiction; tolerance to narcotics or withdrawal from narcotics; increased anaesthetic risk, anaesthetic responsiveness; hypothalamic-adrenal dysfunctions; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such
  • Compounds of formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of all types of sleep disorders, of stress- related syndromes, of psychoactive substance use, abuse, seeking and reinstatement, of cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders, of eating or drinking disorders.
  • Eating disorders may be defined as comprising metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa.
  • Pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs.
  • Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake.
  • Sleep disorders include all types of parasomnias, insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
  • Insomnias are defined as comprising sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness. Insomnia also include stress-related syndromes including post-traumatic stress disorders as well as other types and subtypes of anxiety disorders such as generalized anxiety, obsessive compulsive disorder, panic attacks and all types of phobic anxiety and avoidance.
  • Psychoactive substance use, abuse, seeking and reinstatement are defined as all types of psychological or physical addictions and their related tolerance and dependence components.
  • Cognitive dysfunctions include deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders.
  • compounds of formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of sleep disorders that comprises all types of insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias, restless leg syndrome, sleep apneas, jet-lag syndrome, shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
  • sleep disorders that comprises all types of insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias, restless leg syndrome, sleep apneas, jet-lag syndrome, shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
  • compounds of formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of cognitive dysfunctions that comprise deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders.
  • compounds of formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of eating disorders that comprise metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa.
  • compounds of formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of psychoactive substance use, abuse, seeking and reinstatement that comprise all types of psychological or physical addictions and their related tolerance and dependence components.
  • a further aspect of the invention is a process for the preparation of compounds of formula (I).
  • Compounds according to formula (I) of the present invention can be prepared according to the general sequence of reactions outlined in the schemes below wherein A, B and R 1 are as defined for formula (I). The compounds obtained may also be converted into salts thereof in a manner known per se.
  • Oxazolidine derivatives of formula (I) may be prepared according to schemes 1 or 2.
  • Acids of formula B-A-COOH and R 1 -COOH are commercially available, synthesized according to methods described below or by the methods given in the experimental part or analogous methods.
  • Carboxylic acid derivatives B-A-COOH wherein B-A represents a thiazole-4-yl derivative are commercially available or can be synthesised according to scheme 3.
  • 2-Bromo-thiazole derivatives may be obtained by reaction of the respective 2-amino-thiazole derivative with isoamylnitrite in the presence of copper(ll)bromide.
  • the bromo substituent may be removed via hydrogenation, or replaced with amines HNR 2 R 3 , sodium alkoxides or a CF 3 group (e.g. TMS-CF 3 , CuI, KF, DMF, NMP; see T. Mano, Bioorg. Med. Chem. 2003, 11, 3879-3887).
  • Saponification of the ester function of (13) using methods known in the art e.g.
  • Carboxylic acid derivatives B-A-COOH wherein B-A represents a thiazole-5-yl derivative are commercially available or synthesised according to scheme 4.
  • the 2-acetamido-3-oxo-propionic acid ester derivative (21) can be synthesized from compounds of structure (20) using acetic anhydride in presence of an acid such as glacial acetic acid and catalytic amounts of metal chlorides such as mercury chloride and zinc powder.
  • Cyclization to the corresponding corresponding oxazole-4-carboxylic acid ester derivative (22) can be achieved under dehydrating conditions such as SOCI 2 in CHCI 3 . Saponification of the ester function using methods known in the art (e.g. NaOH, EtOH/water) provides the corresponding oxazole-4 carboxylic acid derivative (23).
  • Carboxylic acid derivatives B-A-COOH wherein B-A represents a phenyl-2-yl derivative are commercially available or can be synthesised according to scheme 6.
  • Carboxylic acids of formula R 1 -COOH are commercially available or well known in the art (Lit. e.g. WO2001 /96302; T. Eicher, S. Hauptmann “The chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications", 2nd Edition 2003, Wiley, ISBN 978-3- 527-30720-3; A. R. Katrizky, C. W. Rees, E. F. V. Scriven (Eds.) "Comprehensive Heterocyclic Chemistry II” 1996, Elsevier, ISBN 0-08-042072-9).
  • Carboxylic acid derivatives R 1 -COOH which represent an imidazo[2,1-b]thiazole- 2-carboxylic acid derivative are commercially available or can be synthesised according to scheme 8. Pathway A
  • Pathway A By reaction of 2-chloro-3-oxo-butyric acid methyl ester (29) with thiourea the amino-thiazole (30) can be obtained. Transformation to ester (31 ) can be accomplished with bromoacetaldehyde which can be generated in-situ from bromoacetaldehyde diethylacetal under acidic conditions. After saponification with bases such as NaOH the desired acid (32) can be obtained.
  • Pathway B By heating a compound of structure (33) with ⁇ /, ⁇ /-dimethylformamide dimethylacetal in a solvent such as toluene formamidine derivatives (34) can be obtained. They can be alkylated with ethyl bromoacetate yielding the respective thiazolium bromide (35) which can be cyclised with strong bases such as DBU to the ester (36). Saponification of the ester function (e.g. NaOH, EtOH/water) provides the corresponding imidazo[2,1-b]thiazole-2-carboxylic acid derivatives (37).
  • a solvent such as toluene formamidine derivatives (34)
  • Carboxylic acid derivatives R 1 -COOH which represent a pyrrolo[2,1-6]thiazole- 7-carboxylic acid derivative can be synthesised according to scheme 9.
  • Carboxylic acid derivatives R 1 -COOH which represent a 3,4-dihydro-2H- benzo[1 ,4]oxazinyl- or 3-oxo-3,4-dihydro-2/-/-benzo[1 ,4]oxazinyl-carboxylic acid derivative can be synthesised according to the literature according to schemes 10 and 1 1.
  • Carboxylic acid derivatives R 1 -COOH which represent a benzooxazole-4-carboxylic acid derivative can be synthesised according to the literature according to schemes 12 and 13.
  • ester (57) By cyclisation of ethyl 2-amino-3-hydroxybenzoate (56) with acetyl chloride in the presence of PPTS and TEA, the ester (57) can be obtained (Goldstein S.W. et al, Journal of Heterocyclic Chemistry, 1990, 27, 335-336). Saponification of the ester function (e.g. NaOH, EtOH/water) provides the corresponding 2-methyl-benzooxazole-4-carboxylic acid derivative (58).
  • the ester function e.g. NaOH, EtOH/water
  • Carboxylic acid derivatives R 1 -COOH which represent a benzothiazole-7-carboxylic acid derivative can be synthesised according to the literature according to scheme 14.
  • Carboxylic acid derivatives R 1 -COOH which represent a benzofuran-4-carboxylic acid derivative can be synthesised according to the literature according to schemes 15 and 16.
  • the ester (68) By reaction of methyl 3-hydroxybenzoate (67) with 3-chloro-2-butanone, the ester (68) can be obtained. Cyclisation with sulfuric acid provides the 2,3-dimethylbenzofuran derivative (69) (Kawase Y. et al, Bulletin of the Chemical Sociaty of Japan, 1967, 40, 5, 1224-1231. Saponification of the ester function using methods known in the art such as treatment with a base such as NaOH in a solvent such as MeOH/ water provides the corresponding 2,3- dimethylbenzofuran-4-carboxylic acid derivative (70).
  • Carboxylic acid derivatives R 1 -COOH which represent a benzofuran-4-carboxylic acid derivative, wherein R represents one or two substituents selected from Cl, F and CF 3 , can be synthesised according to the literature or according to scheme 17.
  • Derivatives of formula R 1 -COOH wherein R 1 is chroman may be for instance synthesised according to scheme 18.
  • chroman-5-carboxylic acid derivatives can be started with the alkylation of 3-hydroxy-benzoic acid methyl ester (85; commercially available) with propargyl bromide in the presence of K 2 CO 3 to give phenylether (86) which can be cyclised to the chromen derivative (87) by heating to reflux in N,N-diethylaniline.
  • the carboxylic ester may be saponified (e.g. NaOH, MeOH/water) and the obtained chromen derivative (88) can be hydrogenated to give the desired acid (89).
  • the corresponding chroman-8- carboxylic acid derivatives may be synthesized by reduction of 4-chromanone (90; commercially available) with zinc in acetic acid and subsequent orffro-metalation of the intermediate chroman derivative (91 ) with n-BuLi and trapping with carbon dioxide to give the desired acid (92).
  • the enantiomers can be separated using methods known to the one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-O1 (R 1 R) (10 ⁇ m) column, a Daicel ChiralCel OD-H (5-10 ⁇ m) column, or a Daicel ChiralPak IA (10 ⁇ m) or AD-H (5 ⁇ m) column.
  • a chiral stationary phase such as a Regis Whelk-O1 (R 1 R) (10 ⁇ m) column, a Daicel ChiralCel OD-H (5-10 ⁇ m) column, or a Daicel ChiralPak IA (10 ⁇ m) or AD-H (5 ⁇ m) column.
  • Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as TEA, diethylamine) and eluent B (hexane), at a flow rate of 0.8 to 150 mL/min.
  • FCS Foatal calf serum
  • biphenyl-2-carboxylic acid derivative is commercially available: 3',4'-Dimethyl-biphenyl-2-carboxylic acid.
  • A.4 Synthesis of thiazole-5-carboxylic acid derivatives
  • Example compounds were synthesized in racemic form according to the general procedure given above:
  • Example compounds were synthesized in racemic form according to the general procedure given above:
  • the orexin receptor antagonistic activity of the compounds of formula (I) is determined in accordance with the following experimental method.
  • Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptor and the human orexin-2 receptor, respectively, are grown in culture medium (Ham F-12 with L- Glutamine) containing 300 ⁇ g/ml G418, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin and 10 % heat inactivated fetal calf serum (FCS).
  • FCS heat inactivated fetal calf serum
  • the cells are seeded at 20'0OO cells / well into 384-well black clear bottom sterile plates (Greiner). The seeded plates are incubated overnight at 37°C in 5% CO 2 .
  • Human orexin-A as an agonist is prepared as 1 mM stock solution in MeOH: water (1 :1 ), diluted in HBSS containing 0.1 % bovine serum albumin (BSA), NaHCO 3 : 0.375g/l and 20 mM HEPES for use in the assay at a final concentration of 3 nM.
  • BSA bovine serum albumin
  • NaHCO 3 0.375g/l
  • 20 mM HEPES for use in the assay at a final concentration of 3 nM.
  • Antagonists are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates using DMSO followed by a transfer of the dilutions into in HBSS containing 0.1 % bovine serum albumin (BSA), NaHCO 3 : 0.375g/l and 20 mM HEPES.
  • BSA bovine serum albumin
  • 50 ⁇ l of staining buffer HBSS containing 1 % FCS, 20 mM HEPES, NaHCO 3 : 0.375g/l, 5 mM probenecid (Sigma) and 3 ⁇ M of the fluorescent calcium indicator fluo-4 AM (1 mM stock solution in DMSO, containing 10% pluronic) is added to each well.
  • the 384-well cell-plates are incubated for 50 min at 37° C in 5% CO 2 followed by equilibration at rt for 30 - 120 min before measurement.
  • antagonists are added to the plate in a volume of 10 ⁇ l/well, incubated for 10 min and finally 10 ⁇ l/well of agonist is added. Fluorescence is measured for each well at 1 second intervals, and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 3 nM orexin-A with vehicle in place of antagonist.
  • the IC 50 value (the concentration of compound needed to inhibit 50 % of the agonistic response) is determined and normalized using the obtained IC50 value of a on- plate reference compound. Optimized conditions were achieved by adjustment of pipetting speed and cell splitting regime. The calculated IC50 values of the compounds may fluctuate depending on the daily cellular assay performance. Fluctuations of this kind are known to those skilled in the art.
  • Antagonistic activities (IC50 values) of all exemplified compounds are in the range of 2- 5158 nM with an average of 363 nM with respect to the OX1 receptor.
  • IC 50 values of all exemplified compounds are in the range of 2-989 nM with an average of 88 nM with respect to the OX2 receptor.
  • Antagonistic activities of selected compounds are displayed in Table 1.

Landscapes

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

Abstract

La présente invention concerne des dérivés d'oxazolidine de formule (I), A, B et R1 étant tels que définis dans la description, leurs sels et, en particulier, leurs sels pharmaceutiquement acceptables, ainsi que leur utilisation en tant que médicaments, en particulier en tant qu'antagonistes des récepteurs à orexine.
PCT/IB2009/054273 2008-10-01 2009-09-30 Composés d'oxazolidine utilisables en tant qu'antagonistes des récepteurs à orexine WO2010038200A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IBPCT/IB2008/053989 2008-10-01
IB2008053989 2008-10-01

Publications (1)

Publication Number Publication Date
WO2010038200A1 true WO2010038200A1 (fr) 2010-04-08

Family

ID=41328589

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/054273 WO2010038200A1 (fr) 2008-10-01 2009-09-30 Composés d'oxazolidine utilisables en tant qu'antagonistes des récepteurs à orexine

Country Status (1)

Country Link
WO (1) WO2010038200A1 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012085852A1 (fr) 2010-12-22 2012-06-28 Actelion Pharmaceuticals Ltd 3,8-diaza-bicyclo[4.2.0]oct-8-ylamides
WO2012110986A1 (fr) 2011-02-18 2012-08-23 Actelion Pharmaceuticals Ltd Nouveaux dérivés de pyrazole et d'imidazole utiles à titre d'antagonistes d'orexine
WO2013050938A1 (fr) 2011-10-04 2013-04-11 Actelion Pharmaceuticals Ltd Dérivés de 3,7-diazabicyclo[3.3.1]nonane et de 9-oxa-3,7- diazabicyclo[3.3.1]nonane
WO2013182972A1 (fr) 2012-06-04 2013-12-12 Actelion Pharmaceuticals Ltd Dérivés de benzimidazole-proline
WO2014057435A1 (fr) 2012-10-10 2014-04-17 Actelion Pharmaceuticals Ltd Antagonistes des récepteurs de l'orexine, qui sont des dérivés [ortho bi (hetero )aryl]-[2-(meta bi (hetero )aryl)-pyrrolidin-1-yl]-methanone
WO2014141065A1 (fr) 2013-03-12 2014-09-18 Actelion Pharmaceuticals Ltd Dérivés d'amide d'azétidine en tant qu'antagonistes des récepteurs d'oréxine
CN104350053A (zh) * 2012-06-15 2015-02-11 大正制药株式会社 杂芳族甲基环胺衍生物
WO2015083071A1 (fr) 2013-12-03 2015-06-11 Actelion Pharmaceuticals Ltd Forme de sel cristalline de (s)-(2-(6-chloro-7-méthyl-1 h-benzo[d]imidazol- 2-yl)-2-méthylpyrrolidin-1-yl)(5-méthoxy-2-(2h-1,2,3-triazol-2-yl)phényl)méthanone comme antagoniste des récepteurs à l'oréxine
WO2015083094A1 (fr) 2013-12-04 2015-06-11 Actelion Pharmaceuticals Ltd Utilisation de dérivés de benzimidazole-proline
WO2015083070A1 (fr) 2013-12-03 2015-06-11 Actelion Pharmaceuticals Ltd Forme cristalline de (s)-(2-(6-chloro-7-methyl-1h-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1 -yl)(5-methoxy-2-(2h-1,2,3-triazol-2-yl)phenyl)methanone et utilisation de celle-ci en tant qu'antagonistes des recepteurs de l'orexine
WO2016025669A1 (fr) 2014-08-13 2016-02-18 Eolas Therapeutics, Inc. Difluoropyrrolidines en tant que modulateurs des récepteurs de l'orexine
WO2020007964A1 (fr) 2018-07-05 2020-01-09 Idorsia Pharmaceuticals Ltd Dérivés de 2-(2-azabicyclo [3.1.0] hexan-1-yl)-1h-benzimidazole
WO2020099511A1 (fr) 2018-11-14 2020-05-22 Idorsia Pharmaceuticals Ltd Dérivés de benzimidazole-2-méthyl-morpholine
EP3694605A4 (fr) * 2017-10-11 2021-10-27 Cornell University Inhibiteurs peptidomimétiques du protéasome
US11202817B2 (en) 2014-08-18 2021-12-21 Cornell University Dipeptidomimetics as inhibitors of human immunoproteasomes
US11629141B2 (en) 2015-10-15 2023-04-18 Cornell University Proteasome inhibitors and uses thereof
WO2023218023A1 (fr) 2022-05-13 2023-11-16 Idorsia Pharmaceuticals Ltd Dérives d'hydrazine-n-carboxamide cycliques substitués par thiazoloaryl-méthyle
USRE49816E1 (en) 2014-01-10 2024-01-30 Cornell University Dipeptides as inhibitors of human immunoproteasomes

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002090355A1 (fr) * 2001-05-05 2002-11-14 Smithkline Beecham P.L.C. Amines cycliques n-aroyle
WO2004026866A1 (fr) * 2002-09-18 2004-04-01 Glaxo Group Limited Amines cycliques n-aroyle utilisees comme antagonistes du recepteur d'orexine
WO2008065626A2 (fr) * 2006-12-01 2008-06-05 Actelion Pharmaceuticals Ltd Composés piéridines

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002090355A1 (fr) * 2001-05-05 2002-11-14 Smithkline Beecham P.L.C. Amines cycliques n-aroyle
WO2004026866A1 (fr) * 2002-09-18 2004-04-01 Glaxo Group Limited Amines cycliques n-aroyle utilisees comme antagonistes du recepteur d'orexine
WO2008065626A2 (fr) * 2006-12-01 2008-06-05 Actelion Pharmaceuticals Ltd Composés piéridines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CAI J ET AL: "Antagonists of the orexin receptors", EXPERT OPINION ON THERAPEUTIC PATENTS, INFORMA HEALTHCARE, GB, vol. 16, no. 5, 1 May 2006 (2006-05-01), pages 631 - 646, XP002458093, ISSN: 1354-3776 *

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012085852A1 (fr) 2010-12-22 2012-06-28 Actelion Pharmaceuticals Ltd 3,8-diaza-bicyclo[4.2.0]oct-8-ylamides
WO2012085857A1 (fr) 2010-12-22 2012-06-28 Actelion Pharmaceuticals Ltd 3,8-diaza-bicyclo[4.2.0]oct-3-ylamides
WO2012110986A1 (fr) 2011-02-18 2012-08-23 Actelion Pharmaceuticals Ltd Nouveaux dérivés de pyrazole et d'imidazole utiles à titre d'antagonistes d'orexine
US9303023B2 (en) 2011-02-18 2016-04-05 Actelion Pharmaceuticals Ltd. Pyrazole and imidazole derivatives useful as orexin antagonists
WO2013050938A1 (fr) 2011-10-04 2013-04-11 Actelion Pharmaceuticals Ltd Dérivés de 3,7-diazabicyclo[3.3.1]nonane et de 9-oxa-3,7- diazabicyclo[3.3.1]nonane
WO2013182972A1 (fr) 2012-06-04 2013-12-12 Actelion Pharmaceuticals Ltd Dérivés de benzimidazole-proline
US11040966B2 (en) 2012-06-04 2021-06-22 Idorsia Pharmaceuticals Ltd Benzimidazole-proline derivatives
US10329287B2 (en) 2012-06-04 2019-06-25 Idorsia Pharmaceuticals Ltd Benzimidazole-proline derivatives
US9732075B2 (en) 2012-06-04 2017-08-15 Idorsia Pharmaceuticals Ltd Benzimidazole-proline derivatives
CN104350053A (zh) * 2012-06-15 2015-02-11 大正制药株式会社 杂芳族甲基环胺衍生物
EP2862860A4 (fr) * 2012-06-15 2015-11-04 Taisho Pharmaceutical Co Ltd Dérivé d'amine cyclique méthylé hétéroaromatique
RU2639869C2 (ru) * 2012-06-15 2017-12-25 Тайсо Фармасьютикал Ко., Лтд. Гетероароматическое метильное производное циклического амина
US9266870B2 (en) * 2012-06-15 2016-02-23 Taisho Pharmaceutical Co., Ltd Heteroaromatic methyl cyclic amine derivative
WO2014057435A1 (fr) 2012-10-10 2014-04-17 Actelion Pharmaceuticals Ltd Antagonistes des récepteurs de l'orexine, qui sont des dérivés [ortho bi (hetero )aryl]-[2-(meta bi (hetero )aryl)-pyrrolidin-1-yl]-methanone
US9493446B2 (en) 2012-10-10 2016-11-15 Actelion Pharmaceuticals Ltd. Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
WO2014141065A1 (fr) 2013-03-12 2014-09-18 Actelion Pharmaceuticals Ltd Dérivés d'amide d'azétidine en tant qu'antagonistes des récepteurs d'oréxine
US9403813B2 (en) 2013-03-12 2016-08-02 Actelion Pharmaceuticals Ltd. Azetidine amide derivatives as orexin receptor antagonists
WO2015083071A1 (fr) 2013-12-03 2015-06-11 Actelion Pharmaceuticals Ltd Forme de sel cristalline de (s)-(2-(6-chloro-7-méthyl-1 h-benzo[d]imidazol- 2-yl)-2-méthylpyrrolidin-1-yl)(5-méthoxy-2-(2h-1,2,3-triazol-2-yl)phényl)méthanone comme antagoniste des récepteurs à l'oréxine
US10023560B2 (en) 2013-12-03 2018-07-17 Idorsia Pharmaceuticals Ltd Crystalline salt form of (S)-(2-(6 chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone as orexin receptor antagonist
US9790208B2 (en) 2013-12-03 2017-10-17 Idorsia Pharmaceuticals Ltd Crystalline salt form of (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone as orexin receptor antagonist
WO2015083070A1 (fr) 2013-12-03 2015-06-11 Actelion Pharmaceuticals Ltd Forme cristalline de (s)-(2-(6-chloro-7-methyl-1h-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1 -yl)(5-methoxy-2-(2h-1,2,3-triazol-2-yl)phenyl)methanone et utilisation de celle-ci en tant qu'antagonistes des recepteurs de l'orexine
US9914720B2 (en) 2013-12-03 2018-03-13 Idorsia Pharmaceuticals Ltd Crystalline form of (S)-(2-(6-chloro-7-methyl-1H-benzo[D]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and its use as orexin receptor antagonists
WO2015083094A1 (fr) 2013-12-04 2015-06-11 Actelion Pharmaceuticals Ltd Utilisation de dérivés de benzimidazole-proline
US9914721B2 (en) 2013-12-04 2018-03-13 Idorsia Pharmaceuticals Ltd Use of benzimidazole-proline derivatives
USRE49816E1 (en) 2014-01-10 2024-01-30 Cornell University Dipeptides as inhibitors of human immunoproteasomes
WO2016025669A1 (fr) 2014-08-13 2016-02-18 Eolas Therapeutics, Inc. Difluoropyrrolidines en tant que modulateurs des récepteurs de l'orexine
US11202817B2 (en) 2014-08-18 2021-12-21 Cornell University Dipeptidomimetics as inhibitors of human immunoproteasomes
US12016896B2 (en) 2014-08-18 2024-06-25 Cornell University Dipeptidomimetics as inhibitors of human immunoproteasomes
US11629141B2 (en) 2015-10-15 2023-04-18 Cornell University Proteasome inhibitors and uses thereof
EP3694605A4 (fr) * 2017-10-11 2021-10-27 Cornell University Inhibiteurs peptidomimétiques du protéasome
US11203613B2 (en) 2017-10-11 2021-12-21 Cornell University Peptidomimetic proteasome inhibitors
US11732005B2 (en) 2017-10-11 2023-08-22 Cornell University Peptidomimetic proteasome inhibitors
WO2020007964A1 (fr) 2018-07-05 2020-01-09 Idorsia Pharmaceuticals Ltd Dérivés de 2-(2-azabicyclo [3.1.0] hexan-1-yl)-1h-benzimidazole
WO2020099511A1 (fr) 2018-11-14 2020-05-22 Idorsia Pharmaceuticals Ltd Dérivés de benzimidazole-2-méthyl-morpholine
WO2023218023A1 (fr) 2022-05-13 2023-11-16 Idorsia Pharmaceuticals Ltd Dérives d'hydrazine-n-carboxamide cycliques substitués par thiazoloaryl-méthyle

Similar Documents

Publication Publication Date Title
EP2247586B1 (fr) Dérivés de 2-aza-bicyclo[2.2.1]heptane
WO2010038200A1 (fr) Composés d'oxazolidine utilisables en tant qu'antagonistes des récepteurs à orexine
US8106215B2 (en) 3-aza-bicyclo[3.3.0]octane compounds
US20110105491A1 (en) Thiazolidine compounds as orexin receptor antagonists
EP2155739B1 (fr) Dérivés de 2-cyclopropyl-thiazole
US8236964B2 (en) Thiazolidine derivatives as orexin receptor antagonists
EP2185512B1 (fr) Dérivés de trans-3-aza-bicyclo[3.1.0]hexane
EP2069332B1 (fr) Composés d'azétidine en tant qu'antagonistes du recepteur orexin
EP2094690B1 (fr) Derives de 2-aza-bicyclo[3.1.0]hexane comme antagonistes du recepteur de l'orexine
EP2318367B1 (fr) Composés de pipéridine et de pyrrolidine
US8063099B2 (en) Trans-3-aza-bicyclo[3.1.0]hexane derivatives
WO2008038251A2 (fr) Dérivés du 3-aza-bicyclo[3.1.0]hexane

Legal Events

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

Ref document number: 09787326

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09787326

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载