WO2005087708A1 - Derives de phenyle indane - Google Patents

Derives de phenyle indane Download PDF

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Publication number
WO2005087708A1
WO2005087708A1 PCT/DK2005/000152 DK2005000152W WO2005087708A1 WO 2005087708 A1 WO2005087708 A1 WO 2005087708A1 DK 2005000152 W DK2005000152 W DK 2005000152W WO 2005087708 A1 WO2005087708 A1 WO 2005087708A1
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WO
WIPO (PCT)
Prior art keywords
chloro
phenyl
indan
methyl
alk
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PCT/DK2005/000152
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English (en)
Inventor
Garrick Paul Smith
Kim Andersen
Stephen P. Wren
Neil Harris
Guillaume Brandt
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H. Lundbeck A/S
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Publication date
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Priority to EP05706813A priority Critical patent/EP1727785A1/fr
Priority to JP2007502190A priority patent/JP2007528879A/ja
Publication of WO2005087708A1 publication Critical patent/WO2005087708A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to novel compounds which are glycine transporter inhibitors and as such effective in the treatment of disorders in the CNS, such as schizophrenia.
  • Glutamic acid is the major excitatory amino acid in the mammalian central nervous system (CNS), and acts through two classes of receptors, the ionotropic and metabotrobic receptors, respectively.
  • the ionotropic glutamate receptors are divided into three subtypes based on the affinities of agonists for these receptors, namely N-methyl-D-aspartate ( ⁇ MDA), (R,S)- 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMP A) and kainic acid (or kainate) receptors.
  • the ⁇ MDA receptor contains binding sites for modulatory compounds such as glycine and polyamines. Binding of glycine to its receptor enhances the ⁇ MDA receptor activation. Such ⁇ MDA receptor activation may be beneficial for the treatment of schizophrenia and other diseases linked to ⁇ MDA receptor dysfunction. An activation can be achieved by an inhibitor of the glycine transporter.
  • GlyT-1 can be further subdivided into GlyT-la, GlyT-lb and GlyT-lc.
  • the ⁇ MDA receptor is blocked by compounds such as phencyclidine which induce a psychotic state which resembles schizophrenia.
  • the ⁇ MDA antagonists such as ketamine, induce negative and cognitive symptoms similar to schizophrenia. This indicates that ⁇ MDA receptor dysfunction is involved in the pathophysiology of schizophrenia.
  • the ⁇ MDA receptor has been associated with a number of diseases, such as pain (Yaksh Pain 1989, 37, 111-123), spasticity, myuoclonus and epilepsy (Truong et. al. Movement Disorders 1988, 3, 77-87), learning and memory (Rison et. al. Neurosci. Biobehav. Rev. 1995, 19, 533-552), post-traumatic stress disorder (abbreviated: PTSD) (Heresco-levy et. al. The International Journal of Neuropsychopharmacology, 2002, 5:301-307, entitled: "Pilot- controlled trial of D-cycloserine for the treatment of post-traumatic stress disorder").
  • Glycine transporter antagonists or inhibitors are believed to be highly beneficial in the treatment of schizophrenia (Javitt WO 97/20553).
  • Glycine transport antagonists or inhibitors could be useful for the treatment of both the positive and the negative symptoms of schizophrenia and other psychoses, and in the improvement of cognition in conditions where the cognitive processes are diminished, i.e. Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or diseases wherein the brain is damaged by inner or outer influence, such as trauma to the head or stroke.
  • convulsive disorders such as epilepsy, spasticity or myoclonus may benefit from glycine transporter antagonists.
  • the present invention relates to compounds of formula I which are potent inhibiters of the glycine transport.
  • the compounds of formula I also have reduced side effects compared to prior art compounds.
  • the present invention relates to a compound of the formula I
  • the invention provides a compound of formula I as above for use as a medicament.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I as above or a pharmaceutically acceptable salt thereof, e.g. a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutically acceptable carrier or diluent.
  • the invention also provides the use of a compound of formula I as above or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of diseases selected from the group consisting of schizophrenia, including both the positive and the negative symptoms of schizophrenia and other psychoses, and in the improvement of cognition in conditions where the cognitive processes are diminished, i.e. Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or diseases wherein the brain is damaged by inner or outer influence, such as trauma to the head or stroke, and convulsive disorders such as epilepsy, spasticity or myoclonus.
  • diseases selected from the group consisting of schizophrenia, including both the positive and the negative symptoms of schizophrenia and other psychoses, and in the improvement of cognition in conditions where the cognitive processes are diminished, i.e. Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or diseases where
  • the invention also provides the use of a compound of formula I as above or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of post-traumatic stress disorder.
  • the invention also provides a method for the treatment of diseases selected from the group consisting of schizophrenia, including both the positive and the negative symptoms of schizophrenia and other psychoses, and in the improvement of cognition in conditions where the cognitive processes are diminished, i.e. Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or diseases wherein the brain is damaged by inner or outer influence, such as trauma to the head or stroke, and convulsive disorders such as epilepsy, spasticity or myoclonus in a living animal body, including a human, comprising administering a therapeutically effective amount of a compound of formula I as above or a pharmaceutically acceptable acid addition salt thereof.
  • diseases selected from the group consisting of schizophrenia, including both the positive and the negative symptoms of schizophrenia and other psychoses, and in the improvement of cognition in conditions where the cognitive processes are diminished, i.e. Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson'
  • the invention also provides a method for the treatment of post-traumatic stress disorder in a living animal body, including a human, comprising administering a therapeutically effective amount of a compound of formula I as above or a pharmaceutically acceptable acid addition salt thereof.
  • halogen means fluoro, chloro, bromo or iodo.
  • C ⁇ - 6 -alk(en/yn)yl means a C ⁇ - 6 -alkyl, C 2 . 6 -alkenyl or a C 2 . 6 -alkynyl group.
  • C ⁇ - 6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, including but not limited to methyl, ethyl, 1 -propyl, 2-propyl, 1- butyl, 2-butyl, 2-methyl-2-propyl and 2 -methyl- 1 -propyl.
  • C - 6 alkenyl designate such groups having from two to six carbon atoms, including one double bond, including but not limited to ethenyl, propenyl, and butenyl.
  • C 2 _ 6 alkynyl designate such groups having from two to six carbon atoms, including one triple bond, including but not limited to ethynyl, propynyl and butynyl.
  • C ⁇ - 6 -alk(en/yn)yloxy designate such groups in which the d-e-all ⁇ en/yh l is as defined above, and "halo” means halogen, and "aryl” is as defined below.
  • C ⁇ - 6 alk(en/yn)ylsulfanyl-C ⁇ - 6 -alk(en/yn)yl designate such group in which the C ⁇ - 6 alk(en/yn)ylsulfanyl and C ⁇ - 6 -alk(en/yn)yl are as defined above.
  • C ⁇ - 6 -alk(en/yn)yloxycarbonyl refers to groups of the formula Ci- 6 -alk(en/yn)yl-O-CO-, wherein C ⁇ - 6 -alk(en/yn)yl are as defined above.
  • aryl refers to carbocyclic, aromatic systems, such as phenyl and naphthyl.
  • monocyclic heteroaryl refers to 5- to 6- membered aromatic systems containing 1 to 5 carbon atoms and one or more heteroatoms selected from O, S or N, such as 5- membered monocyclic rings such as oxathiazoles, dioxazoles, dithiazoles, oxadiazoles, thiadiazoles, triazoles, isoxazoles, oxazoles, isothiazoles, thiazoles, imidazoles, pyrazoles, pyrroles, furan(s) or thiophene(s), e.g.
  • alkali metal refers to lithium, sodium, potassium, and cesium.
  • phenyl indane derivatives encompassed by the compound of formula I are named in accordance with IUPAC nomenclature, and for illustrative purposes without limiting the invention in any way the numbering system indicated below is applied. 1 7 .
  • C -C in the indane ring system indicates that the carbon referred to as number
  • 1, 2, 3, 4, 5, 6, 7 etc. is indicated as C , C , C , C , C , C , respectively, and this applies similarly to C -C in the phenyl attached to C of the indane ring system.
  • R 2 being 5 -methyl indicates a methyl group attached to C 5 of the indane ring.
  • the (R 2 ) n substituent(s) may be attached to any one of C - C (but not C -C ), and the (R ) m substituent(s) may be attached to any one of C -C of the phenyl group.
  • the asterix adjacent to C 1 of the indane ring system indicates that the compounds of formula I have the R-, or S-configuration, or a mixture thereof in that position.
  • the asterix adjacent to C between the nitrogen and the carbonyl indicates that the compounds of formula I have the R-, or S-configuration, or a mixture thereof in that position.
  • the compounds of formula I may have (R,R)-, (R,S)-, (S,R)-, or (S,S)- configuration or mixtures thereof, all of which are comprised by the phenyl indane compound of formula I.
  • the present invention relates to compounds of formula I which are potent inhibiters of the glycine transporter and consequently they are useful in treating diseases associated with NMDA dysfunction, such as schizophrenia.
  • the present invention relates to a phenyl indane compound of the formula I
  • n 0, 1, or 2
  • m is O, 1, or 2
  • p is 2 or 3
  • R is selected from H, or C ⁇ - 6 -alk(en/yn)yl
  • R 2 is (independently) selected from halogen; C ⁇ - 6 -alk(en/yn)yl; C ⁇ _ 6 -alk(en/yn)yloxy; C ⁇ - 6 - alk(en/yn)ylsulfanyl; halo-C ⁇ - 6 -alk(en/yn)yl; aryl-C ⁇ - 6 -alk(en/yn)yloxy; aryl optionally substituted with a halogen, C ⁇ - 6 -alk(en/yn)yl, C ⁇ _ 6 -alk(en/yn)yloxy, halo-C ⁇ - 6 -alk(en/yn)yl, or halo-C ⁇ _ 6 -alk(en/yn)yloxy; monocyclic heteroaryl optionally substituted with a C ⁇ - 6 - alk(en/yn)yl;
  • R 3 is (independently) selected from halogen; C ⁇ - 6 -alk(en/yn)yl; C ⁇ _ 6 -alk(en/yn)yloxy; C ⁇ - 6 - alk(en/yn)ylsulfanyl; halo-C ⁇ - 6 -alk(en/yn)yl; aryl-C ⁇ - 6 -alk(en/yn)yloxy; aryl optionally substituted with a halogen, C 1 - 6 -alk(en/yn)yl, C ⁇ _ 6 -alk(en/yn)yloxy, halo-C ⁇ - 6 -alk(en/yn)yl, or halo-C 1 . 6 -alk(en/yn)yloxy; monocyclic heteroaryl optionally substituted with a C ⁇ - 6 - alk(en/yn)yl;
  • R is H, or C ⁇ - 6 -alk(en/yn)yl
  • R 5 is H, C ⁇ -6-alk(en/yn)yl, aryl, aryl-C ⁇ - 6 -alk(en/yn)yl, wherein aryl is optionally substituted with a halogen, CF 3 , OCF 3 , CN, NO 2 or C ⁇ - 6 -alk(en/yn)yl; or an alkali metal, such as sodium, potassium or lithium; or a salt thereof, such as a pharmaceutically acceptable salt, disclaiming the following compounds:
  • R 1 is hydrogen (H). In a further embodiment of the compound of formula I R 1 is C ⁇ - 6 -alkyl, such as methyl.
  • n is zero, thus, in a further embodiment of the compound of formula I n is 0.
  • R 2 groups attached to the indane ring, which R 2 groups may be identical or different, and selected from halogen; C ⁇ _ 6 -alk(en/yn)yloxy; C ⁇ - 6 - alk(en/yn)ylsulfanyl; halo-C ⁇ - 6 -alk(en/yn)yl; aryl optionally substituted with a halogen, C ⁇ - 6 - alk(en/yn)yl, or C ⁇ _ 6 -alk(en/yn)yloxy; monocyclic heteroaryl.
  • R 2 groups may be identical or different, and selected from halogen; C ⁇ _ 6 -alk(en/yn)yloxy; C ⁇ - 6 - alk(en/yn)ylsulfanyl; halo-C ⁇ - 6 -alk(en/yn)yl; aryl optionally substituted with a halogen, C ⁇ - 6 - alk(en/yn)
  • R 2 is selected from halogen, such as F, CI, Br, in particular 4-C1, 5-C1, 5-F, 5-Br, or 6-C1.
  • R 2 is selected from C ⁇ _
  • 6 -alkyloxy such as methoxy, in particular 5-methoxy.
  • R 2 is selected from Ci- 6 -alkylsulfanyl, such as methylsulfanyl, in particular 6-methylsulfanyl.
  • R 2 is selected from halo-C ⁇ - 6 -alkyl, such as trifluoromethyl.
  • R 2 when n is 1, R 2 is selected from phenyl, in particular 5 -phenyl. In a further embodiment of the compound of formula I, when n is 1, R 2 is selected from phenyl substituted with a halogen, in particular one or two halogens, such as one or two CI, in particular 5-phenyl substituted with one CI in orto, meta, or para position, or with two CI in meta and para position.
  • R 2 when n is 1, R 2 is selected from phenyl substituted with a C ⁇ - 6 -alkyl, in particular one C ⁇ - 6 -alkyl, such as one methyl, in particular 5-phenyl substituted with one methyl in orto, meta, or para position.
  • R 2 when n is 1, R 2 is selected from phenyl substituted with a C ⁇ _ 6 -alkyloxy, in particular one C ⁇ _ 6 -alkyloxy, such as one methoxy, in particular 5-phenyl substituted with one methoxy in orto, meta, or para position.
  • R 2 when n is 1, R 2 is selected from thiophenyl.
  • R 2 when n is 1, R 2 may be in position 4, 5, or 6.
  • both R are independently selected from halogen, such as F or CI, in particular 5-F and 6-F.
  • R 3 groups attached to the phenyl ring, which R 3 groups may be identical or different, and selected from halogen; C ⁇ - 6 -alk(en/yn)yl; C ⁇ - alk(en/yn)yloxy; halo-C ⁇ - 6 -alk(en/yn)yl; aryl-C ⁇ - 6 -alk(en/yn)yloxy; aryl optionally substituted with a halogen, C ⁇ - 6 -alk(en/yn)yl, Ci_ 6 -alk(en/yn)yloxy, halo-C ⁇ - 6 -alk(en/yn)yl, or halo-C ⁇ - 6 -alk(en/yn)yloxy; monocyclic heteroaryl optionally substituted with a C ⁇ - 6 - alk(en/yn)yl.
  • R 3 groups may be identical or different, and selected from halogen; C ⁇ - 6 -alk(
  • R 3 is selected from halogen, such as CI, or F, in particular 2-F, 4-C1, 4-F.
  • R 3 is selected from - 6 -alkyl, such as methyl, in particular 2-methyl, 3-methyl, or 4-methyl.
  • R 3 is selected from C ⁇ _ 6 -alkyloxy, such as methoxy, in particular 3 -methoxy, or 4-methoxy.
  • R 3 is selected from phenyl-C ⁇ - 6 -alkyloxy, such as phenyl methoxy, in particular 4-phenyl methoxy.
  • R 3 is selected from halo-C ⁇ _ 6 -alkyl, such as trifluoromethyl, in particular 3-trifluoromethyl.
  • R 3 is selected from phenyl, in particular 4-phenyl.
  • R 3 is selected from phenyl substituted with a halogen, such as one CI.
  • the halogen may be in any one of position orto, meta, or para, thus, the CI may be in any one of position orto, meta, or para.
  • the phenyl group is in position 4.
  • R 3 is selected from phenyl substituted with a C t - ⁇ -alkyl (such as one methyl).
  • R 3 is selected from phenyl substituted with a C ⁇ _ 6 -alkyloxy, such as one methoxy.
  • the -e-alkyloxy may be in any one of position orto, meta, or para, thus, the methoxy may be in any one of position orto, meta, or para.
  • the phenyl group is in position 4.
  • R 3 is selected from phenyl substituted with a halo-C ⁇ - 6 -alkyl, such as one trifluoromethyl.
  • the halo-C ⁇ - 6 -alkyl may be in any one of position orto, meta, or para, thus, the trifluoromethyl may be in any one of position orto, meta, or para, e.g. meta.
  • the phenyl group is in position 4.
  • R 3 is selected from phenyl substituted with a halo-C ⁇ - 6 -alkyloxy, such as one trifluoromethoxy.
  • the halo-C ⁇ - ⁇ - alkyloxy may be in any one of position orto, meta, or para, thus, the trifluoromethoxy may be in any one of position orto, meta, or para, e.g. meta.
  • the phenyl group is in position 4.
  • R is selected from a thiophen, optionally substituted with a Ci- ⁇ -alkyl, in particular 4-thiophen.
  • R 3 is selected from a morpholin, optionally substituted with a C ⁇ - 6 -alkyl, in particular 4-morpholin.
  • R 3 is selected from a pyrimidin, optionally substituted with a C ⁇ - 6 -alkyl, in particular 4-pyrimidin.
  • R 3 is selected from a furan, optionally substituted with a C ⁇ - 6 -alkyl, in particular 4-furan.
  • R 3 is selected from an isoxazol, optionally substituted with a - ⁇ -alkyl, such as one or two methyl.
  • the C ⁇ - 6 -alkyl may be in any one of position orto, meta, or para, thus, the one or two methyl groups may be in any one of positions orto, meta, or para.
  • the isoxazol group is in position 4.
  • R 3 when m is 1, R 3 may be in position 2, 3, 4, 5, or 6. Typically, R 3 is in position 2, 3, or 4.
  • both R 3 are independently selected from halogen, such as F or CI, in particular 3-C1 and 4-C1.
  • R 4 is hydrogen
  • R 4 is C ⁇ - 6 -alkyl, such as methyl.
  • R 5 is H.
  • R 5 is C ⁇ - 6 -alkyl
  • R 5 is phenyl optionally substituted with a halogen, CF 3 , OCF 3 , CN, NO 2 or C ⁇ - 6 -alk(en/yn)yl.
  • R 5 is phenyl-C ⁇ - 6 -alkyl, optionally substituted with a halogen, CF 3 , OCF 3 , CN, NO 2 or C ⁇ - 6 -alk(en/yn)yl.
  • R 5 is an alkali metal, such as sodium, potassium or lithium.
  • the compound of formula I is selected from 2-( ⁇ 3 - [5 , 6-Difluoro- 1 -(4-chloro-phenyl)-indan- 1 -yl] -propyl ⁇ -_methyl-amino)-propionic acid,
  • the present invention also comprises salts of the present compounds, typically, pharmaceutically acceptable salts.
  • Such salts include pharmaceutical acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids.
  • suitable inorganic acids include hydrochloric, hydxobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic-.
  • metal salts examples include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium salts and the like.
  • the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
  • the compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers (i.e. enantiomers or diastereomers), as separated, pure or partially purified optical isomers and any mixtures thereof including racemic mixtures are included within the scope of the invention.
  • Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can also be resolved into their optical antipodes, e.g. by fractional crystallization of d- or 1- (tartrates, mandelates or camphorsulphonate) salts. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives.
  • Optically active compounds can also be prepared from optically active starting materials.
  • geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention. Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms that the compounds are able to form are included within the scope of the present invention.
  • the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming pharmacologically active substances.
  • prodrugs will be functional derivatives of the compounds of the general formula (I), which are readily convertible in vivo into the required compound of the formula (I).
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in"Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the invention also encompasses active metabolites of the present compounds.
  • the compounds of formula I are potent inhibiters of the glycine transporter, and accordingly may be applicable for the treatment, including prevention, of schizophrenia, including both the positive and the negative symptoms of schizophrenia and other psychoses, and in the improvement of cognition in conditions where the cognitive processes are diminished, i.e. Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or diseases wherein the brain is damaged by inner or outer influence, such as trauma to the head or stroke, and convulsive disorders such as epilepsy, spasticity or myoclonus.
  • the invention relates to a compound of formula I for use as a medicament.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier or diluent.
  • the composition may comprise any one of the embodiments of formula I described above.
  • the compound of formula I is present in an amount of from about 0.001 to about 100 mg/kg body weight per day.
  • the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of a disease or disorder, wherein an inhibitor of the glycine transport is beneficial.
  • the medicament may comprise any one of the embodiments of formula I described above.
  • the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of schizophrenia.
  • schizophrenia includes both the positive and the negative symptoms of schizophrenia and other psychoses.
  • the present invention relates to use of a compound of formula I for the preparation of a medicament for the treatment of Alzheimer's disease. In a further embodiment the present invention relates to use of a compound of formula I for the preparation of a medicament for the treatment of multi-infarct dementia. In a further embodiment the present invention relates to use of a compound of formula I for the preparation of a medicament for the treatment of AIDS. In a further embodiment the present invention relates to use of a compound of formula I for the preparation of a medicament for the treatment of dementia. In a further embodiment the present invention relates to use of a compound of formula I for the preparation of a medicament for the treatment of Huntington's disease.
  • the present invention relates to use of a compound of formula I for the preparation of a medicament for the treatment of Parkinson's disease. In a further embodiment the present invention relates to use of a compound of formula I for the preparation of a medicament for the treatment of amyotrophic lateral sclerosis. In a further embodiment the present invention relates to use of a compound of formula I for the preparation of a medicament for the treatment of diseases wherein the brain is damaged by inner or outer influence. In a further embodiment the present invention relates to use of a compound of formula I for the preparation of a medicament for the treatment of trauma to the head. In a further embodiment the present invention relates to use of a compound of formula I for the preparation of a medicament for the treatment of stroke.
  • the present invention relates to use of a compound of formula I for the preparation of a medicament for the treatment of convulsive disorders. In a further embodiment the present invention relates to use of a compound of formula I for the preparation of a medicament for the treatment of epilepsy. In a further embodiment the present invention relates to use of a compound of formula I for the preparation of a medicament for the treatment of spasticity. In a further embodiment the present invention relates to use of a compound of formula I for the preparation of a medicament for the treatment of myoclonus. In a further embodiment the present invention relates to the use of a compound of formula I as above or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of post-traumatic stress disorder.
  • the medicament may comprise any one of the embodiments of formula I described above.
  • a further aspect of the invention relates to a method for the treatment of a disease or disorder selected from the group consisting of the positive and the negative symptoms of schizophrenia, including both the positive and the negative symptoms of schizophrenia and other psychoses, and in the improvement of cognition in conditions where the cognitive processes are diminished, i.e.
  • Alzheimer's disease multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or diseases wherein the brain is damaged by inner or outer influence, such as trauma to the head or stroke, and convulsive disorders such as epilepsy, spasticity or myoclonus, in a living animal body, including a human, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I.
  • a further aspect of the invention relates to a method for the treatment of post-traumatic stress disorder in a living animal body, including a human, comprising administering a therapeutically effective amount of a compound of formula I as above or a pharmaceutically acceptable acid addition salt thereof.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral ⁇ including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, t -e oral route being preferred.
  • suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral ⁇ including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, t -e oral route being preferred.
  • suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral ⁇ including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, t -e oral
  • compositions for oral administration include solid dosage form-s such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, sus ensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injetable formulations are also contemplated as being within the scope of the present invention.
  • Suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants, etc.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, a-nd more preferred from about 0.05 to about 10 mg/kg body weight per day administere-d in one or more dosages such as 1 to 3 dosages.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subj ect treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • the formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.01 to about 1000 mg, preferably from about 0.05 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
  • parenteral routes such as intravenous, intrathecal, intramuscular and similar administration
  • typically doses are in the order of about half the dose employed for oral administration.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is a base addition salt of a compound having the utility of a free acid.
  • a compound of the formula (I) contains a free acid such salts are prepared in a conventional manner by treating a solution or suspension of a free acid of the formula (I) with a chemical equivalent of a pharmaceutically acceptable base. Representative examples are mentioned above.
  • solutions of the novel compounds of the formula (I) in sterile aqueous solution may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospho lipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutical acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined, amount of the active ingredient, and which may include a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
  • the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about I g-
  • the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the present invention relates to a method of preparing a compound of formula I, as described below in the section "Methods of preparing the compounds of formula I", in particular methods a, b, and c. Also intended as a further aspect of the invention is the preparation of intermediates disclosed in scemes 1-4, as well as the intermediates themselves.
  • R ⁇ R 5 , n, m, and p are as defined above.
  • LG denotes a leaving group and is typically a halide, methane sulfonate, tosylate or trifluoromethane sulfonate.
  • the reaction is typically performed in a suitable solvent such as ethanol, N,N- dimethylformamide or acetonitrile containing an inorganic base such as potassium or cesium carbonate or an organic base suchN-ethyl diisopropylamine at an elevated temperature of 40-80 °C.
  • Compounds of formula I wherein R 5 is hydrogen may be prepared by hydrolysis of the corresponding esters COOR 5 wherein R 5 is as defined above or an insoluble polymer. This may be performed under basic conditions, for example, using aqueous sodium hydroxide in an alcoholic solvent or under acidic conditions in the hydrolysis of a tertiary-butyl ester or cleavage from an insoluble polymer.
  • Method b Compounds of the invention of formula I can also be prepared from intermediates of formula IN by selective reduction of the amide bond in the presence of an ester using for example borane-methyl sulfide complex in tetrahydrofuran.
  • R'-R 5 , n, m, and p are as defined above, and PG means a protecting group, such as tetrahydropyranyl (THP) or tertbutyldimethylsilyl (TBDSM).
  • THP tetrahydropyranyl
  • TDSM tertbutyldimethylsilyl
  • 3-Phenylindan-l-ones of formula V and 3-Phenylindan-l-ols of formula VI are well known in the literature for example methods of preparation are described by Boegesoe et al Journal of Medicinal Chemistry (1983), 26(7), 935-47 or by Sommer et al, Journal of Organic Chemistry, (1990), 55 (16), 4822-4827.
  • 3-Phenylindan-l-ones can be reduced to the corresponding indanols for example with sodium borohydride in methanol or ethanol or similar reagents for the reduction of ketones known to those skilled in the art.
  • Further reduction of the alcohol VI to the corresponding 1-phenyl-indan of formula VII can be performed by the use of chlorodimethylsilane and indium trichloride using the procedure of Miyai et al, Synlett, 1999,2,182 or the use of hydrogen iodide and red phosphorous in glacial acetic acid.
  • Intermediates of formula Nil can then be alkylated with protected 1-bromo alkyl alcohols using sodium hydride in dimethyl sulfoxide to afford intermediates of formula NIII.
  • the protecting group is typically a silyl protecting group such as tertbutyldimethylsilyl (TBDMS) or tetrahydropyranyl (THP). Removal of the protecting group using tetrabuytlammonium fluoride in tetrahydrofuran yields intermediate alcohol of formula IX. Conversion of the alcohol of formula IX to the bromide of formula II is by standard methods for those skilled in the art for example the use of carbon tetrabromide and polymer supported triphenyl phosphine in dichloromethane.
  • TDMS tertbutyldimethylsilyl
  • THP tetrahydropyranyl
  • the enantiomers of racemic mixtures of intermediates of formula XIII can be prepared as shown in scheme 3. Conversion of intermediates of fo ⁇ nulaXIII to the N-(l-(R)-Phenyl-ethyl)-2-( 1-phenyl- indan-l -yl)-acetamide derivatives of formula XIV are prepared under standard conditions. These can be separated by flash chromatography and the separated diastereisomers can then be hydrolysed to the enantiomerically pure 1-phenyl-indan-l -acetic acid of formula XIII.
  • N-Methyl-L- alanine butyl ester and N-Me-D-alanine butyl ester were prepared according to the method of Van der Auwera et al Intl. J. Pep. Prot. Res. (1988), 31(2), 186-91. Examples
  • Preparative LC-MS-purification was performed on a similar instrument with APCI source.
  • Fraction collection was performed by split-flow MS detection.
  • SCX-columns (1 g) from Varian Mega Bond Elut®, Chrompack cat. No. 220776. Prior to use, the SCX- columns were pre-conditioned with 10% solution of acetic acid in methanol (3 mL). For de- complexation by irradiation, a ultaviolet light source (300 W) from Philipps was used. Preparation of starting material :3-(4-Chlorophenyl)-5,6-difluoroindan-l-ol
  • a 1 :1 mixture of 3-(4-Chloro-phenyl)-5,6-difluoro-indan-l-one and 6-Chloro-3-(3,4- difluoro-phenyl)-indan-l-one (80g) was dissolved in the ethanol (500 mL) and to the solution was added sodium borohydride (5g). The mixture was stirred for 1 hour. The mixture was diluted water and extracted with ether. The ether phase was washed with IM HCL. The ether phase was diluted with cyclohexane (500 mL) and 3-(4-Chlorophenyl)-5,6- difluoroindan-1-ol recrystallised from the solution (lOg). mp. 96-98°C.
  • 3-Amino-6-chloro-l-cyano-l-p-tolyl-lH-indene-2-carboxylic acid methyl ester (32g) was dissolved in acetic acid (100 mL) and heated to 90°C. To the mixture was carefully added a solution of cone. H 2 SO 4 (52 mL) and water (20 mL). The mixture was heated at 115°C for 3 hours, allowed to cool and then poured onto ice. The mixture was then extracted with ether and the organic phase was washed with water and then extracted with 2N NaOH. The aqueous phase was acidified with 2M HC1 and the resulting oil was decanted and dissolved in NMP (100 mL).
  • 6-Fluoro-3-(4-fluorophenyl)-indan-l-ol (l.Og, 4.07 mmol) was dissolved in dichloromethane (2.2 mL) and added over a period of 5 minutes to a solution of indium trichloride (0.045mg, 0.20 mmol) and dimethylchlorosilane (4 mL) at room temperature under a nitrogen atmosphere. After 2.5 hours water and diethyl ether were added and the phases separated. The aqueous phase was extracted with diethyl ether (2X) and the combined organic extracts were dried (MgS0 ), filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with hexane. The product was identified from relevant fractions and the combined fractions combined and concentrated in vacuo.Yield: 937mg, 94%
  • 6-Chloro-indanone (40g, 0.24 mol) was dissolved in toluene (400 mL). To the solution was added ethyl cyanoacetate (108.5g, 0.96 mol), ammonium acetate (18.5g, 0.24 mol), glacial acetic acid (28.8g, 0.48mol) and piperidine (2.37 mL, 0.024 mol). The mixture was placed under nitrogen and heated to reflux for 18 hours. The mixture was then allowed to cool to room temperature. The mixture was washed with water, aquous sodium carbonate and then with brine. The separated organic phase was dried (MgSO 4 ) , filtered and concentrated in vacuo. The product was triturated with diethyl ether and then filtered off. The product was washed with diethyl ether and then methanol. The product was air dried to a constant weight. Yield 36g, 57%.
  • the intermediate product was identified from relevant fractions and concentrated in vacuo to give the 2-( ⁇ 3-[5-(4-methoxy-phenyl)- l-(4-chloro-phenyl)-indan-l-(S)-yl]-ethyl ⁇ -methyl-amino)-acetic acid butyl ester (530 mg, 53%).
  • the butyl ester was then dissolved in IM HCl/AcOH (15 mL) and stirred for 16 hours at room temperature. The solution was then concentrated in vacuo and the crude product was purified by flash chromatography eluting with dichloromethane/methanol/aqueous ammonia (25% v/v) , 90:10:0.5.
  • the HyFlo was then washed with ethyl acetat (5x).
  • the filtrate was then evaporated in vacuo before the crude product was purified on a VacMaster filtration unit using a 5g silica cartridge eluting with cyclohexane/ethyl acetate (90:10) and then cyclohexane/ethyl acetate (70:30).
  • the morpholino substituted intermediate buyl ester was isolated as a colourless residue (40 mg). This was then dissolved in a triluoroacetic acid/water (95:5) (1.5 mL) and the solution was stirred overnight at room temperature.
  • the reaction was irradiated for 40 minutes at 140°C.
  • the reaction mixture was then purified by the direct addition of the reaction mixture to a 5g silica cartridge and was eluted with 10 % ethyl acetate and then 30% ethyl acetate in cyclohexane.
  • the intermediate 2-( ⁇ 3-[5- Chloro- 1 -(4-(3 -methoxyphenyl)-phenyl)-indan- 1 -yl] -ethyll ⁇ -methy l-amino)-acetic acid butyl ester was isolated as a colourless residue (18 mg).
  • test results showed, that the prepared compounds of the indention all showed inhibition below 10000 nM, such as below 2000 nM, as IC 50 in the above-mentioned assay.
  • the compounds of the invention were also tested in a well-recognised and reliable microdialysis test.
  • mice Male Sprague-Dawley rats, initially weighing 275 - 350 g, were used. The animals were housed under a 12-hr light/dark cycle under controlled conditions for regular in-door temperature (21 ⁇ 2°C) and humidity (55 ⁇ 5%) with food and tap water available ad libitum.
  • Rats were anaesthetized with hypnorm/dormicum (2ml/kg) and intracerebral guide cannulas (CMA/12) were stereotaxically implanted into the brain positioning the dialysis probe tip in the ventral hippocampus (co-ordinates 5.6 mm posterior to bregma, lateral -5.0 mm, 7.0 mm ventral to dura). The rats were allowed to recover from surgery for at least 2 days. On the day of the experiment, a microdialysis probe (CMA/12, 0.5 mm diameter, 3 mm length) was inserted through the guide cannula. The probes were connected via a dual channel swivel to a microinj ection pump.
  • CMA/12 intracerebral guide cannulas
  • Perfusion of the microdialysis probe with filtered Ringer solution (145 mM NaCl, 3 mM KCl, 1 mM MgCl 2 , 1.2 mM CaCl 2 ) was begun shortly before insertion of the probe into the brain and continued for the duration of the experiment at a constant flow of 1 ⁇ l/min. After 165 min of stabilization, the experiments were initiated. A 20 or 40 min sampling regime was used throughout the experimental period. Time points were corrected for lag time of the perfusate from the microdialysis site to the probe outlet.
  • the rats were sacrificed by decapitation.
  • the brains were removed, frozen and sectioned (20 ⁇ m), and the position of the probes was verified.
  • the concentration of glycine in the dialysates was analyzed by means of HPLC with fluorescence detection after precolumn online derivatisation with o-phatalaldehyde.
  • the system consisted of a Hypersil AA-ODS column (5 ⁇ m, 2.1 x 200 mm, Agilent) with a Agilent 1100 fluoresence detector (excitation, 266-340 nm; emission, 305-340 mn).
  • Mobile phases consisted of A: 20 mM sodium acetate, 0.018% triethylamine, 0.3 % tetrahydrofuran, pH 7.2.
  • B 20 mM sodium acetate, 40% acetonitrile and 40% methanol, pH 7.2.
  • the oven temperature was set at 40°C and flow rate was 0.45 ml/min. Data were collected and analysed using ChemStation software (Agilent) after calibration with a range of standard glycine solutions (0.1 -10 ⁇ M). Data presentation

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Abstract

L'invention concerne de nouveaux composés qui sont des inhibiteurs des transporteurs de la glycine, et qui, par conséquent, sont efficaces dans le traitement de troubles du SNC tels que la schizophrénie.
PCT/DK2005/000152 2004-03-12 2005-03-08 Derives de phenyle indane WO2005087708A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1871165A2 (fr) * 2005-04-11 2008-01-02 Yale University Corporation Methode de traitement d'un prodrome schizophrenique
WO2010102003A3 (fr) * 2009-03-03 2011-03-10 Vanderbilt University Analogues d'alkylsulfonyl-2,3-dihydrospiro[indène-1,4'-pipéridine] en tant qu'inhibiteurs de glyt1, leurs procédés de fabrication et leur utilisation dans le traitement de troubles psychiatriques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045115A1 (fr) * 1996-05-31 1997-12-04 Trophix Pharmaceuticals, Inc. Produit pharmaceutique pour le traitement de troubles neurologiques et neuropsychiatriques
WO2002008216A1 (fr) * 2000-07-21 2002-01-31 H. Lundbeck A/S Nouveaux composes et leur utilisation comme inhibiteurs du transport de glycine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045115A1 (fr) * 1996-05-31 1997-12-04 Trophix Pharmaceuticals, Inc. Produit pharmaceutique pour le traitement de troubles neurologiques et neuropsychiatriques
WO2002008216A1 (fr) * 2000-07-21 2002-01-31 H. Lundbeck A/S Nouveaux composes et leur utilisation comme inhibiteurs du transport de glycine

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1871165A2 (fr) * 2005-04-11 2008-01-02 Yale University Corporation Methode de traitement d'un prodrome schizophrenique
EP1871165A4 (fr) * 2005-04-11 2009-10-21 Yale University Corp Methode de traitement d'un prodrome schizophrenique
US8492418B2 (en) 2005-04-11 2013-07-23 Yale University Method of treating schizophrenia prodrome
WO2010102003A3 (fr) * 2009-03-03 2011-03-10 Vanderbilt University Analogues d'alkylsulfonyl-2,3-dihydrospiro[indène-1,4'-pipéridine] en tant qu'inhibiteurs de glyt1, leurs procédés de fabrication et leur utilisation dans le traitement de troubles psychiatriques
US8431700B2 (en) 2009-03-03 2013-04-30 Vanderbilt University Alkylsulfonyl-2,3-dihydrospiro[indene-1,4′-piperidine] analogs as GlyT1 inhibitors, methods for making same, and use of same in treating psychiatric disorders

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