EP1727785A1 - Phenyl indan derivatives - Google Patents

Phenyl indan derivatives

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Publication number
EP1727785A1
EP1727785A1 EP05706813A EP05706813A EP1727785A1 EP 1727785 A1 EP1727785 A1 EP 1727785A1 EP 05706813 A EP05706813 A EP 05706813A EP 05706813 A EP05706813 A EP 05706813A EP 1727785 A1 EP1727785 A1 EP 1727785A1
Authority
EP
European Patent Office
Prior art keywords
chloro
phenyl
indan
methyl
alk
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05706813A
Other languages
German (de)
French (fr)
Inventor
Garrick Paul Smith
Kim Andersen
Stephen P. Wren
Neil Harris
Guillaume Brandt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
H Lundbeck AS
Original Assignee
H Lundbeck AS
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 H Lundbeck AS filed Critical H Lundbeck AS
Publication of EP1727785A1 publication Critical patent/EP1727785A1/en
Withdrawn legal-status Critical Current

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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

This 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.

Description

PHENIL INDAN DERIVATIVE
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.
Background of the invention
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 (ΝMDA), (R,S)- 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMP A) and kainic acid (or kainate) receptors.
The ΝMDA receptor contains binding sites for modulatory compounds such as glycine and polyamines. Binding of glycine to its receptor enhances the ΝMDA receptor activation. Such ΝMDA receptor activation may be beneficial for the treatment of schizophrenia and other diseases linked to ΝMDA receptor dysfunction. An activation can be achieved by an inhibitor of the glycine transporter.
Molecular cloning has revealed the existence of two types of glycine transporters, GlyT-1 and GlyT-2, wherein GlyT-1 can be further subdivided into GlyT-la, GlyT-lb and GlyT-lc.
The ΝMDA receptor is blocked by compounds such as phencyclidine which induce a psychotic state which resembles schizophrenia. Likewise, the ΝMDA antagonists, such as ketamine, induce negative and cognitive symptoms similar to schizophrenia. This indicates that ΝMDA receptor dysfunction is involved in the pathophysiology of schizophrenia.
The ΝMDA 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. Likewise, convulsive disorders such as epilepsy, spasticity or myoclonus may benefit from glycine transporter antagonists.
Clinical trials with glycine have been reported, Javitt et. al. Am. J. Psychiatry 1994, 151, 1234-1236 and Leiderman et. al. Biol. Psychiatry 1996, 39, 213-215. The treatment with high-dose glycine is reported to improve the symptoms of schizophrenia. There is a need for more efficient compounds for the treatment of NMD A associated diseases.
Summary of the invention 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. In one aspect the present invention relates to a compound of the formula I
wherein the substituents are as defined below.
Furthermore, the invention provides a compound of formula I as above for use as a medicament.
Moreover, the invention provides 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.
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.
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.
Definitions
The term "halogen" means fluoro, chloro, bromo or iodo.
The expression "Cι-6-alk(en/yn)yl" means a Cι-6-alkyl, C2.6-alkenyl or a C2.6-alkynyl group.
The term "Cι-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.
The term "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.
The term "C2_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.
The terms "Cι-6-alk(en/yn)yloxy", "Cι-6 alk(en/yn)ylsulfanyl", "halo-Cι-6-alk(en/yn)yl", "halo-Cι-6-alk(en/yn)yloxy", "aryl-C1.6-alk(en/yn)yl", "aryl-Cι-6-alk(en/yn)yloxy", etc. 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.
The term "Cι-6 alk(en/yn)ylsulfanyl-Cι-6-alk(en/yn)yl" designate such group in which the Cι-6 alk(en/yn)ylsulfanyl and Cι-6-alk(en/yn)yl are as defined above. As used herein, the term "Cι-6-alk(en/yn)yloxycarbonyl" refers to groups of the formula Ci- 6-alk(en/yn)yl-O-CO-, wherein Cι-6-alk(en/yn)yl are as defined above.
The term "aryl" refers to carbocyclic, aromatic systems, such as phenyl and naphthyl.
The term "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. 3H-l,2,3-oxathiazole, 1,3,2-oxathiazole, 1,3,2- dioxazole, 3H-l,2,3-dithiazole, 1,3,2-dithiazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1H- 1,2,3-triazole, isoxazole, oxazole, isothiazole, thiazole, lH-imidazole, lH-pyrazole, 1H- pyrrole, f ran or thiophene, or 6-membered monocyclic rings such as oxathiazines, dioxazines, dithiazines, oxadiazines, thiadiazines, triazines, oxazines, thiazines, pyrazines, pyridazines, pyrimidines, oxathiins, dioxins, dithiins, pyridines, pyrans or thiins, e.g. 1,2,3- oxathiazine, 1,2,4-oxathiazine, 1,2,5-oxathiazine, 1 ,4,2-oxathiazine, 1,4,3-oxathiazine, 1,2,3-dioxazine, 1,2,4-dioxazine. 4H-l,3,2-dioxazine, 1,4,2-dioxazine, 2H-l,5,2-dioxazine, 1,2,3-dithiazine, 1,2,4-dithiazine, 4H-l,3,2-dithiazine, 1 ,4,2-dithiazine, 2H-l,5,2-dithiazine, 2H-l,2,3-oxadiazine, 2H-l,2,4-oxadiazine, 2H-l,2,5-oxadiazine, 2H-l,2,6-oxadiazine, 2H- 1,3,4-oxadiazine, 2H-l,2,3-thiadiazine, 2H-l,2,4-thiadiazine, 2H-l,2,5-thiadiazine, 2H- 1,2,6-thiadiazine, 2H-l,3,4-thiadiazine, 1,2,3-triazine, 1 ,2,4-triazine, 2H-l,2-oxazine, 2H- 1,3-oxazine, 2H-l,4-oxazine, 2H-l,2-thiazine, 2H-l,3-thiazine, 2H-l,4-thiazine, pyrazine, pyridazine, pyrimidine, 4H-l,3-oxathiin, 1 ,4-oxathiin, 4H-l,3-dioxin, 1,4-dioxin, 4H-1,3- dithiin, 1,4-dithiin, pyridine, 2H-pyran or 2H-thiin.
The term "alkali metal" refers to lithium, sodium, potassium, and cesium.
The 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 .
In particular, 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 , C , respectively, and this applies similarly to C -C in the phenyl attached to C of the indane ring system. Thus, as an example, a specific embodiment of R2 being 5 -methyl indicates a methyl group attached to C5 of the indane ring. Moreover, the (R2)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 C1 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. Thus, 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.
Description of the invention
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.
In one aspect the present invention relates to a phenyl indane compound of the formula I
wherein n is 0, 1, or 2, m is O, 1, or 2, p is 2 or 3,
R is selected from H, or Cι-6-alk(en/yn)yl;
R2 is (independently) selected from halogen; Cι-6-alk(en/yn)yl; Cι_6-alk(en/yn)yloxy; Cι-6- alk(en/yn)ylsulfanyl; halo-Cι-6-alk(en/yn)yl; aryl-Cι-6-alk(en/yn)yloxy; aryl optionally substituted with a halogen, Cι-6-alk(en/yn)yl, Cι_6-alk(en/yn)yloxy, halo-Cι-6-alk(en/yn)yl, or halo-Cι_6-alk(en/yn)yloxy; monocyclic heteroaryl optionally substituted with a Cι-6- alk(en/yn)yl;
R3 is (independently) selected from halogen; Cι-6-alk(en/yn)yl; Cι_6-alk(en/yn)yloxy; Cι-6- alk(en/yn)ylsulfanyl; halo-Cι-6-alk(en/yn)yl; aryl-Cι-6-alk(en/yn)yloxy; aryl optionally substituted with a halogen, C1-6-alk(en/yn)yl, Cι_6-alk(en/yn)yloxy, halo-Cι-6-alk(en/yn)yl, or halo-C1.6-alk(en/yn)yloxy; monocyclic heteroaryl optionally substituted with a Cι-6- alk(en/yn)yl;
R is H, or Cι-6-alk(en/yn)yl; R5 is H, Cι-6-alk(en/yn)yl, aryl, aryl-Cι-6-alk(en/yn)yl, wherein aryl is optionally substituted with a halogen, CF3, OCF3, CN, NO2 or Cι-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:
N-{3-[5-Chloro-l-(4-chloro-phenyl)-indan-l-yl]-propyl}-N-methylglycine, N- { 3 - [5 -Chloro- 1 -(4-chloro-pheny l)-indan- 1 -y 1] -propyl } -N-methylalanine .
In one embodiment of the compound of formula I p is 2. In another embodiment of the compound of formula I p is 3.
In a further embodiment of the compound of formula I R1 is hydrogen (H). In a further embodiment of the compound of formula I R1 is Cι-6-alkyl, such as methyl.
When there are no substituents apart from H in the indane ring then n is zero, thus, in a further embodiment of the compound of formula I n is 0.
Alternatively, there may be one or two R2 groups attached to the indane ring, which R2 groups may be identical or different, and selected from halogen; Cι_6-alk(en/yn)yloxy; Cι-6- alk(en/yn)ylsulfanyl; halo-Cι-6-alk(en/yn)yl; aryl optionally substituted with a halogen, Cι-6- alk(en/yn)yl, or Cι_6-alk(en/yn)yloxy; monocyclic heteroaryl. Thus, in a further embodiment of the compound of formula I n is 1. In a further embodiment of the compound of formula I n is 2.
In a further embodiment of the compound of formula I, when n is 1, R2 is selected from halogen, such as F, CI, Br, in particular 4-C1, 5-C1, 5-F, 5-Br, or 6-C1.
In a further embodiment of the compound of formula I, when n is 1, R2 is selected from Cι_
6-alkyloxy, such as methoxy, in particular 5-methoxy.
In a further embodiment of the compound of formula I, when n is 1, R2 is selected from Ci- 6-alkylsulfanyl, such as methylsulfanyl, in particular 6-methylsulfanyl.
In a further embodiment of the compound of formula I, when n is 1, R2 is selected from halo-Cι-6-alkyl, such as trifluoromethyl.
In a further embodiment of the compound of formula I, when n is 1, R2 is selected from phenyl, in particular 5 -phenyl. In a further embodiment of the compound of formula I, when n is 1, R2 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. In a further embodiment of the compound of formula I, when n is 1, R2 is selected from phenyl substituted with a Cι-6-alkyl, in particular one Cι-6-alkyl, such as one methyl, in particular 5-phenyl substituted with one methyl in orto, meta, or para position. In a further embodiment of the compound of formula I, when n is 1, R2 is selected from phenyl substituted with a Cι_6-alkyloxy, in particular one Cι_6-alkyloxy, such as one methoxy, in particular 5-phenyl substituted with one methoxy in orto, meta, or para position. In a further embodiment of the compound of formula I, when n is 1, R2 is selected from thiophenyl.
In a further embodiment of the compound of formula I, when n is 1, R2 may be in position 4, 5, or 6.
In a further embodiment of the compound of formula I, when n is 2, both R are independently selected from halogen, such as F or CI, in particular 5-F and 6-F.
When there are no substituents apart from H in the phenyl ring then m is zero, thus, in a further embodiment of the compound of formula I m is 0.
Alternatively, there may be one or two R3 groups attached to the phenyl ring, which R3 groups may be identical or different, and selected from halogen; Cι-6-alk(en/yn)yl; C\^- alk(en/yn)yloxy; halo-Cι-6-alk(en/yn)yl; aryl-Cι-6-alk(en/yn)yloxy; aryl optionally substituted with a halogen, Cι-6-alk(en/yn)yl, Ci_6-alk(en/yn)yloxy, halo-Cι-6-alk(en/yn)yl, or halo-Cι-6-alk(en/yn)yloxy; monocyclic heteroaryl optionally substituted with a Cι-6- alk(en/yn)yl. Thus, in a further embodiment of the compound of formula I m is 1. In a further embodiment of the compound of formula I m is 2.
In a further embodiment of the compound of formula I, when m is 1, R3 is selected from halogen, such as CI, or F, in particular 2-F, 4-C1, 4-F. In a further embodiment of the compound of formula I, when m is 1, R3 is selected from - 6-alkyl, such as methyl, in particular 2-methyl, 3-methyl, or 4-methyl. In a further embodiment of the compound of formula I, when m is 1, R3 is selected from Cι_ 6-alkyloxy, such as methoxy, in particular 3 -methoxy, or 4-methoxy. In a further embodiment of the compound of formula I, when m is 1 , R3 is selected from phenyl-Cι-6-alkyloxy, such as phenyl methoxy, in particular 4-phenyl methoxy. In a further embodiment of the compound of formula I, when m is 1, R3 is selected from halo-Cι_6-alkyl, such as trifluoromethyl, in particular 3-trifluoromethyl. In a further embodiment of the compound of formula I, when m is 1, R3 is selected from phenyl, in particular 4-phenyl.
In a further embodiment of the compound of formula I, when m is 1, R3 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. In a particular embodiment the phenyl group is in position 4. In a further embodiment of the compound of formula I, when m is 1, R3 is selected from phenyl substituted with a Ct-β-alkyl (such as one methyl).
In a further embodiment of the compound of formula I, when m is 1, R3 is selected from phenyl substituted with a Cι_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. In a particular embodiment the phenyl group is in position 4.
In a further embodiment of the compound of formula I, when m is 1, R3 is selected from phenyl substituted with a halo-Cι-6-alkyl, such as one trifluoromethyl. The halo-Cι-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. In a particular embodiment the phenyl group is in position 4.
In a further embodiment of the compound of formula I, when m is 1, R3 is selected from phenyl substituted with a halo-Cι-6-alkyloxy, such as one trifluoromethoxy. The halo-Cϊ-δ- 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. In a particular embodiment the phenyl group is in position 4.
In a further embodiment of the compound of formula I, when m is 1, R is selected from a thiophen, optionally substituted with a Ci-β-alkyl, in particular 4-thiophen. In a further embodiment of the compound of formula I, when m is 1, R3 is selected from a morpholin, optionally substituted with a Cι-6-alkyl, in particular 4-morpholin. In a further embodiment of the compound of formula I, when m is 1, R3 is selected from a pyrimidin, optionally substituted with a Cι-6-alkyl, in particular 4-pyrimidin. In a further embodiment of the compound of formula I, when m is 1, R3 is selected from a furan, optionally substituted with a Cι-6-alkyl, in particular 4-furan.
In a further embodiment of the compound of fonr-ula I, when m is 1, R3 is selected from an isoxazol, optionally substituted with a -β-alkyl, such as one or two methyl. The Cι-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. In a particular embodiment the isoxazol group is in position 4.
In a further embodiment of the compound of formula I, when m is 1, R3 may be in position 2, 3, 4, 5, or 6. Typically, R3 is in position 2, 3, or 4.
In a further embodiment of the compound of formula I, when m is 2, both R3 are independently selected from halogen, such as F or CI, in particular 3-C1 and 4-C1.
In a further embodiment of the compound of formula I R4 is hydrogen.
In a further embodiment of the compound of formula I R4 is Cι-6-alkyl, such as methyl.
In a further embodiment of the compound of formula I R5 is H.
In a further embodiment of the compound of formula I R5 is Cι-6-alkyl
In a further embodiment of the compound of formula I R5 is phenyl optionally substituted with a halogen, CF3, OCF3, CN, NO2 or Cι-6-alk(en/yn)yl.
In a further embodiment of the compound of formula I R5 is phenyl-Cι-6-alkyl, optionally substituted with a halogen, CF3, OCF3, CN, NO2 or Cι-6-alk(en/yn)yl. In a further embodiment of the compound of formula I R5 is an alkali metal, such as sodium, potassium or lithium.
In a further embodiment of the compound of formula I the compound is selected from 2-( { 3 - [5 , 6-Difluoro- 1 -(4-chloro-phenyl)-indan- 1 -yl] -propyl } -_methyl-amino)-propionic acid,
( { 3 -[5 , 6-Difluoro- 1 -(4-chloro-phenyl)-indan- 1 -yl] -propyl} -methyl-amino)-acetic acid,
2-( { 3 - [1 -(3 ,4-Dichloro-phenyl)-indan- 1 -yl]-propyl} -methyl-amino)-propionic acid,
({3-[5-Fluoro-l-(4-fluoro-phenyl)-indan-l-yl]-propyl}-methyl-amino)-acetic acid,
2-({3-[6-Chloro-l-(4-Fluoro-phenyl)-indan-l-yl]-propyl}-methyl-amino)-propionic acid, 2-({3-[6-Chloro- 1 -(4-methyl-phenyl)-indan- 1 -yl]-propyl} -methyl-amino)-propionic acid,
({2(R)-[6-Chloro-l-(4-chloro-phenyl)-indan-l(S)-yl]-propyl} -methyl-amino)-propionic acid,
({2(S)-[6-Chloro-l-(4-chloro-phenyl)-indan-l(R)-yl]-propyl} -methyl-amino)-propionic acid, ( { 2(R)- [6-Chloro- 1 -(4-chloro-phenyl)-indan- 1 (R)-yl] -propyl} -methyl-amino)-propionic acid,
({2(S)-[6-Chloro-l-(4-chloro-phenyl)-indan-l(S)-yl]-propyl} -methyl-amino)-propionic acid,
( {2- [5 -Chloro- 1 -(4-chloro-phenyl)-indan- 1 (S)-yl] -ethyl} -met y l-amino)-acetic acid, ({2-[5-Chloro- 1 -(4-chloro-phenyl)-indan- 1 (R)-yl] -ethyl} -methy l-amino)-acetic acid,
2(R)-({3-[5-Chloro-l-(4-methoxy-phenyl)-indan-l-yl]-propyl}-methyl-amino)-propionic acid,
2-(S)-( { 3 - [5 -Chloro- 1 -(4-methoxy-phenyl)-indan- 1 -yl]-propyl } -methyl-amino)-propionic acid, ( {2- [5 -Methoxy- 1 -(4-chloro-phenyl)-indan- 1 -yl] -ethyl } -methyl-amino)-acetic acid,
2-( { 3 - [5 -Chloro- 1 -(4-methoxy-pheny l)-indan- 1 -yl] -ethyl } -methy l-amino)-acetic acid,
2-({3-[5-Chloro-l-(4-benzyloxy-phenyl)-indan-l-yl]-ethyll}-methyl-amino)-acetic acid,
({2-[5-Fluoro-l-(4-chloro-phenyl)-indan-l-yl]-ethyl}-methyl-amino)-acetic acid,
2-( { 3 - [5 -(4-methoxy-phenyl)- 1 -(4-chloro-phenyl)-indan- 1 -(S)-yl] -ethyl} -methyl-amino)- acetic acid,
2-( { 3 - [5 -(4-Methoxy-phenyl)- 1 -(4-chloro-phenyl)-indan- 1 (R)-yl] -propyl } -methyl-amino)- acetic acid, 2(S)-({3-[5 -Chloro- 1 -(4-(N-morpholino)-pheny l)-indan- 1 -yl] -propyl } -methyl- amino)- propionic acid,
2-( { 3 - [5 -Chloro- 1 -(4-(3-methoxyphenyl)-phenyl)-indan- 1 -yl]-ethyll } -methyl-amino)-acetic acid, 2-( { 3 - [5 -Chloro- 1 -(4-(3-thienyl)-phenyl)-indan- 1 -yl]-ethyll} -methyl-amino)-acetic acid, or a salt thereof, such as a pharmaceutically acceptable salt. Each of these compounds is considered a specific embodiment and may be subject to individual claims.
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.
Representative examples of suitable inorganic acids include hydrochloric, hydxobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic-. propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, rnaleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8- halotheophyllines, for example 8-bromotheophylline and the like. Further examples of pharmaceutical acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977,66,2, which is incorporated herein by reference.
Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like.
Examples of ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium salts and the like. Further, 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.
Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981).
Optically active compounds can also be prepared from optically active starting materials.
Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule 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. In general, such 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.
As mentioned above, 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.
Accordingly, in a further aspect the invention relates to a compound of formula I for use as a medicament.
The present invention also relates to 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.
In an embodiment of the pharmaceutical composition, 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.
In particular the present invention also relates to use of a compound of formula I for the preparation of a medicament for the treatment of schizophrenia. Such schizophrenia includes both the positive and the negative symptoms of schizophrenia and other psychoses.
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 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. 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 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. 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 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.
Pharmaceutical compositions
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. The pharmaceutical 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. It will be appreciated that the preferred route will depend on thie general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
Pharmaceutical 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.
Pharmaceutical 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.
Other 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.
For 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. When 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.
For parenteral administration, solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such 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. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospho lipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, 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 pharmacy.
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. Furthermore, 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.
If a solid carrier is used for oral administration, 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-
If a liquid carrier is used, 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.
In a further aspect 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.
Methods of preparing the compounds of formula I The compounds of the invention are prepared by the following general methods:
Method a: Reaction of an alkylating agent of formula II with an amine of formula III. (ii) (III)
The substituents R^R5, 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 R5 is hydrogen may be prepared by hydrolysis of the corresponding esters COOR5 wherein R5 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.
(IV) Method c: Compounds of formula I can also be prepared from intermediates of the same formula I where R5 is as defined above but excluding hydrogen, R2 and R3 are as defined above, typically R2 and/or R3 is a halide, trifluoromethanesulfonyloxy (triflate) or nonaflate, R4, n, and m are as defined above, and s is 1 or 2. These compounds can then be used for C- C for and C-N couplings.
Intermediates of formula II where the substituents R -R5, n, m, and p are as defined above may be prepared as depicted in scheme 1.
Scheme 1
The substituents R'-R5, n, m, and p are as defined above, and PG means a protecting group, such as tetrahydropyranyl (THP) or tertbutyldimethylsilyl (TBDSM). 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.
Intermediates of formula IV may be prepared as depicted in scheme 2
Scheme 2 Intermediates of formula IV may be prepared using the synthetic sequence described in scheme 2. Substituted indan-1-ones of formula X are commercially available or their preparation are well described in the literature. Indanones of formula X are converted using cyano acetic acid ethyl ester in a Knoevenagel reaction to give the 2-cyano-2-( indan-1- ylidene) acetic acid ethyl ester of formula XL 1,4 copper catalysed addition of a substituted phenylmagensium bromide gives the intermediate XII Hydrolysis of the ethyl ester under basic conditions followed by acidic hydrolysis of the nitrile group and subsequent decarboxylation yields the 1-phenyl-indan-l -acetic acid of formula XIII. The enantiomers of racemic mixtures of intermediates of formula XIII can be prepared as shown in scheme 3. Conversion of intermediates of foπnulaXIII 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.
(Xlllla) (Xlllb)
Scheme 3 For the preparation of intermediates of formula IV where s is 1 it is necessary to homologate the intermediate of formula XIII by the sequence shown in scheme 4.
Scheme 4
Carboxylic acid intermediates of formula XIII where s isl are reduced using standard conditions such as borane-tetrahydrofuran complex to give the corresponding alcohol of formula IX. Bromination of the alcohol using carbon tetrabromide and triphenyl phosphine in tetrahydrofuran gives the bromide of formula XII. Treatment with a alkaline metal cyanide salt gives the nitrile of foπnula XV. Hydrolysis of intermediates of formula XV under acidic conditions gives the homologated carboxylic acid of formula XIII. It should be noted that intermediates of formula II generated in scheme 4 can also be used in method a.
Intermediates acids formula XIII can then be coupled with amino acid derivatives of formula III using standard peptide coupling conditions for example using l-ethyl-3-(3- dimethylaminopropyl)carbodiimide and 4-dimethylaminopyridine in tetrahydrofuran to give intermediates of formula IV.
Amino acid derivatives of formula III are commercially available or their syntheses are described in the literature .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
General Methods
Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with APPI source and Shimadzu LC-8A SLC-10A LC system. Column: 30 X 4.6 mm Waters Symmmetry CI 8 column with 3.5 μm particle size; Solventsystem: A = water/trifluoroacetic acid (100:0.05) and B = water/acetonitrile/trif uoroacetic acid (5:95:0.03); Method: Linear gradient elution with 90% A to 100% B in 4 min and with a flow rate of 2 mL/min. Purity was determined by integration of the UV (254 nm) and ELSD trace. The retention times (RT) are expressed in minutes.
Preparative LC-MS-purification was performed on a similar instrument with APCI source. Column: 50 X 20 mm YMC ODS-A with 5 μm particle size; Method: Linear gradient elution with 80% A to 100%o B in 7 min and with a flow rate of 22.7 mL/min. Fraction collection was performed by split-flow MS detection.
1H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500 instrument, Varian Unity Inova 400 spectrometer or at 250.13 MHz on a Bruker AC 250 instrument. Deuterated methylenchloride (99.8%D), chloroform (99.8%D) or dimethyl sulfoxide (99.8%D) were used as solvents. TMS was used as internal reference standard. Chemical shift values are expressed in ppm- values. The following abbreviations are used for multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = heptet, dd = double doublet, dt = double triplet, dq = double quartet, tt = triplet of triplets, m = multiplet and b = broad singlet.
For ion-exchange chromatography, the following material was used: 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
Preparation of 3-(4-Chloro-phenyl)-3-(3,4-difluoro-phenyl)-propionic acid 3,4-Bisfluoro-bromobenzene (154g, 0.8 mol) and magnesium (21g, 0.875mol) was dissolved in dry ether (500 mL) and heated at reflux for thirty minutes and thereafter was added 3-(4-Chloro-p enyl)-2-cyano-acrylic acid ethyl ester (189g, 0.8 mol) dissolved in toluene (500 mL) and ether was continuously distilled off from the reaction. The distillation was continued until the solution temperature reached 80°C. The mixture was then heated at reflux for 30 minutes and then poured into ice and 12 M HC1 (100 mL). The organic phase was separated and to this was added 9M NaOH (100 mL) and water (200 mL). The mixture was refluxed for 30 minutes and then allowed to cool to room temperature. The phases were separated and the aqueous layer was separated and then acidified with cone. HC1. Toluene was added and the phases separated. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The intermediate 3-(4-Chloro-phenyl)-2-cyano-3-(3,4-difluoro- phenyl)-propionic acid (250g) was then dissolved in acetic acid (300mL), water (300 mL) and sulphuric acid (300 mL). The mixture was heated at reflux for 5 hours and then poured into ice. The crystalline acid was filtered, dissolved in ether and dried (MgSO4). The ether solution was transferred to a beaker and evaporated in a steam bath with addition of hexane (1.5L) to give the title acid. Yield 134g.
Preparation of 3-(4-Chloro-phenyl)-5, 6-difluoro-indan-l-one
3-(4-Chloro-phenyl)-3-(3,4-difluoro-phenyl)-propionic acid (134g, 0.45 mol) dissolved in DMF (0.5 L) containing thionyl chloride (100 mL) was heated for one hour on a steam batch. The solution was concentrated on a rotary evaporator and then dissolved in dichloromethane (500 mL) which was then solowly added to a solution of aluminium trichloride (78g) in dichloromethane (1 L). The mixture was heated at reflux for 1 hour and then poured onto ice and the phases were separated. The organic phase was separated and washed with water and IN NaOH. The organic phase was then filtered through a silica plug eluting with dichloromethane. The organic phase was dried (MgSO4), filtered and concentrated in vacuo and the product was recrystallised from cyclohexane to give the title product and 6-Chloro-3-(3,4-difluoro-phenyl)-indan-l-one as a 1:1 mixture Preparation of 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.
Preparation of starting material: 3-(4-Methyl-phenyl)-6-chIoro-indan-l-one
Preparation of 3-Amino-6-chloro-l-cyano-l-p-tolyl-lH-indene-2-carboxylic acid methyl ester
4-Methyl-benzyl nitrile (23g, 0.17 mol) and and 4-chloro-2-fluoro-benzene nitrile (23g, 0.16 mol) were added at room temperature to a solution of potassium tert-butoxide (37g,
0.33mol) in DMF (250 mL). The mixture was stirred for 45 minutes before chloroacetate methyl ester (20 ML) was added dropwise. The reaction was stirred for 4 hours at ambient temperature and then poured onto ice. The title product crystallised and was filtered and then washed with water and ether. Yield 34g, 64%.
Preparation of 3-(4-Methyl-phenyl)-6-chloro-indan-l-one
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. H2SO4 (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). The solution was heated for 90 minutes at 140°C. The solution was allowed to cool and poured into ice containing a little 2N NaOH. The title product precipitated ,filtered and then redissolved in dichloromethane. This was then dried (MgSO4) and heptane added. The title product recrystallised 20g m.p. 112-114°C. Preparation of Intermediates of Formula VI
3- (3, 4-Dichloro-phenyl)-indan- l-ol
3-(3,4-Dichloro-phenyl)-indan-l-one (Boegesoe et al Journal of Medicinal Chemistry (1983), 26(7), 935-47 ) (2.14 g) was dissolved in ethanol (15 mL). Sodium borohydride (95 mg, 2.51 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated and then dissolved in a mixture of diethyl ether and water. The layers were separated and the aqueous layer was reextracted with diethyl ether (x2). The combined diethyl ether extracts were dried (MgSO4) , filtered and concentrated in vacuo to give the product as an orange viscous oil. Yield: 2.14g, 100%).
Preparation of Intermediates of Formula VII
l-(4-Chlorophenyl)-5, 6-difluoroindan
3-(4-Chlorophenyl)-5,6-difluoroindan-l-ol (3.0g, 10.7 mmol) was dissolved in glacial acetic acid (3 mL), red phosphorous (431 mg, 13.9 mmol) and aquous hydriodic acid (57%) (3 mL) was added under a nitrogen atmosphere. The reaction was heated at reflux for 18 hours before being allowed to cool to room temperature. The solution was then poured into water and diluted with diethyl ether. The biphasic mixture was filtered to remove insoluble by products. The organic layer was then separated and the aqueous layer was re-extracted with diethyl ether. The combined organic extracts were then washed with water and then dried over magnesium sulfate, filtered and evaporated in vacuo to yield a pale yellow oil. Yield: 2.6g, 92%
the following intermediates were prepared in an analogous fashion: l-(3, 4-Dichloro-phenyl)-indanfrom 3-(3, 4-Dichloro-phenyl)-indan-l-ol l-(4-Fluoro-phenyl)-6-chloro-indanfrom 3-(4-Fluoro-phenyl)-6-chloro-indan-ol l-(4-Methyl-phenyl)-6-chloro-indanfrom 3-(4-Methyl-phenyl)-6-chloro-indan-l-ol 5-Fluoro-l-(4-Fluorophenyl)-indan
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%
Preparation of Intermediates of Formula VIII
tert-Butyl-{3-[l-(4-chloro-phenyl)-5,6-difluoro-indan-l-yl]-propoxy}-dimethyl-silane
Sodium hydride (456 mg, 11.4 mmol) was stirred in dry DMSO (8 mL) at 50°C under a nitrogen atmosphere for 1 hour.The suspension was then allowed to cool to room temperature before 3 -(4-chlorophenyl)-5, 6-difluoroindan (2.6g, 9.83 mmol) dissolved in DMSO (1 mL) was added to the reaction over a one minute period. The solution was then allowed to stir for 1 hour at room temperature before 1-bromo- propoxy-tertbutyl-dimethyl- silane (2.83 g, 11.2 mmol) dissolved in DMSO (1 mL) was added over 3 minutes. The solution was then allowed to stir for 21 hours after which time a thin suspension was formed. The mixture was poured into water, extracted with ethyl acetate, washed with water and the separated organic layer was evaporated in the presence of a small amount of toluene to give the product. Yield: 4.6g, 107%
The following intermediates were prepared in an analogous fashion tert-Butyl-{3-[l-(3,4-dichlorophenyl)-indan-l-yl]-propoxy}-dimethyl-silane from l-(3,4-dichlorophenyl)-indan and 1-bromo- propoxy-tertbutyl-dimethyl-silane
tert-Butyl-{3-[l-(4-fluoro-phenyl)-5-fluoro-indan-l-yl]-propoxy}-dimethyl-silane from l-(4-fluoro-phenyl)-5-fluoro-indan and 1 -bromo- propoxy-tertbutyl-dimethyl-silane tert-Butyl-{3-[l-(4-fluoro-phenyl)-6-chloro-indan-l-yl]-propoxy}-dimethyl-silane from l-(4-fluoro-phenyl)-6-chloro-indan and 1-bromo- propoxy-tertbutyl-dimethyl-silane
tert-Butyl-{3-[l-(4-methyl-phenyl)-6-chloro-indan-l-yl]-propoxy}-dimethyl-silanefrom 1- (4-methyl-phenyl)-6-chloro-indan and 1-bromo- propoxy-tertbutyl-dimethyl-silane
Preparation of Intermediates of Formula IX
3-[l-(4-Chloro-phenyl)-5,6-difluoro-indan-l-yl]-propan-l-ol
tert-Butyl- { 3 - [ 1 -(4-chloro-phenyl)-5 ,6-difluoro-indan- 1 -yl] -propoxy } -dimethyl-silane (4.29g, 9.83 mmol) was dissolved in dry tetrahydrofuran (90 mL) and tetrabutylammonium fluoride (IM in THF, 10.8 mmol, 10 mL) was added. The solution was then stirred at room temperature for 5 hours. The solution was then evaporated in avcuo and then purified by flash chromatography eluting with ethyl acetate/cyclohexane in the proportions 20:80 and then 33:67. The desired product was identified from relevant fractions and then the fractions were combined and evaporated in vacuo to give the product as a colourless oil. Yield 2.1g, 66%.
The following intermediates were prepared in an analogous fashion
3-[l-(3, 4 Dichloro-phenyl)-indan-l-yl]-propan-l-ol from tert-Butyl-{3-[l-(3, 4-dichlorophenyl)-indan-l-yl]-propoxy}-dimethyl-silane
3-[l - (4-Fluoro-phenyl)-5-fluoro-indan-l-yl]-propan-l-ol from tert-Butyl-{3-[l-(4-fluoro-phenyl)-5-fluoro-indan-l-yl]-propoxy}-dimethyl-silane
3-[l-(4-Fluoro-phenyl)-6-chloro—indan-l-yl]-propan-l-ol from tert-Butyl-{3-[l-(4-fluoro-phenyl)-6-chloro-indan-l~yl]-propoxy}-dimethyl-silane
3-[l-(4-Methyl-phenyl)-6-chloro—indan-l-yl]-propan-l-ol from tert-Butyl-{3-[l-(4-methyl-phenyl)-6-chloro-indan-l-yl]-propoxy}-dimethyl-silane
Preparation of Intermediates of Formula II
l-(3-Bromo-propyl)-5, 6-bisfluoro-l-(4-fluoro-phenyl)-indan
3-[l-(4-Chloro-phenyl)-5,6-difluoro-indan-l-yl]-propan-l-ol (2.1g_, 6.51 mmol) and carbon tetrabromide (2.16g, 6.51 mmol) was dissolved in dichloromethane (60 mL) at room temperature. To the solution was added triphenylphosphine (2.76g- 10.55 mmol) over two minutes. The solution was stirred at room temperature for 18 hours . A further quantity of carbon tetrabromide (400mg, 1.3 mmol) was added and the solution was 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 and then dichloromethane/methanol (19:1). The product was identified by tic from relevant fractions. These were then combined and concentrated in vacuo to give an oil. Yield : 1.5g, 60%.
The following compounds were prepared in an analogous fashion
1 ~(3-Bromo-propyl)-l -(3,4-dichloro-phenylJ-indan from l-(3-Hydroxy-propyl)-l-(3,4-dichloro-phenyl)-indan
l-(3-Bromo-propyl)-5-fluoro-l-(4-fluoro-phenyl)-indan from l-(3-hydroxy-propyl)-5-fluoro-l-(4-fluoro-phenyl)-indan l-(3-Bromo-propyl)-6-chloro-l-(4-fluoro-phenyl)-indan from l-(3-Hydroxy-propyl)-6-chloro-l-(4-fluoro-phenyl)-indan
1 - (3-Bromo-propyl)-6-chloro-l-(4-methyl-phenyl)-indan from l-(3-Hydroxy-propyl)-6-chloro-l-(4-methyl-phenyl)-indan
1 (R)-(2-Bromo-ethyl)-6-chloro-l-(4-chlorl-phenyl)-indan from 1 (R)-(2-Hydroxy-ethyl)-6-chloro-l-(4-chlorl-phenyl)-indan
l(S)-(2-Bromo-ethyl)-6-chloro-l-(4-chloro-phenyl)-indan from l(S)-(2-Hydroxy-ethyl)-6-chloro-l-(4-chloro-phenyl)-indan
l-(2-Bromo-ethyl)-5-chloro-l-(4-methoxy-phenyl)-indan from 1 - (2-Hydroxy-ethyl)-5-chloro-l-(4-methoxy-phenyl)-indan
l-(2-Bromo-ethyl)-5-chloro-l- (4-benzyloxy-phenyl)-indan from l-(2-Hydroxy-ethyl)-5-chloro-l-(4-benzyloxy-phenyl)-indan
Preparation of Intermediates of Formula XI
(6-Chloro-indan-l-ylidene)-cyano-acetic acid ethyl ester
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 (MgSO4) , 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%.
And in an analogous fashion were prepared
(5-Chloro-indan-l-ylidene)-cyano-acetic acid ethyl ester from 5-chloro-indan-l-one
(5-Methoxy-indan-l-ylidene)-cyano-acetic acid ethyl ester from 5-methoxy-indan-l-one
(5-Fluoro-indan-l-ylidene)-cyano-acetic acid ethyl ester from 5-fluoro-indan-l -one (5-Bromo-indan-l-ylidene)-cyano-acetic acid ethyl ester from 5-Bromo-indan-l-one
Preparation of Intermediates of Formula XII
(6-Chloro-l-(4-chloro-phenyl)-indan-l-yl)-cyano-ac&tic acid ethyl ester
Copper cyanide (31.1 g, 0.348 mmol) was stirred in dry THF (700 mL) under a nitrogen atmosphere.Over a ten minute period was added 4-cb-lorophenyl magnesium bromide (444 mL, 0.444 mol, 1.0M in diethyl ether). The mixture was allowed to stir for 30 minutes. A solution of (6-Chloro-indan-l-ylidene)-cyano-acetic- acid ethyl ester (50.6g, 0.193 mol) in THF (900 mL) was added and the mixture was heated at reflux for 18 hours. The mixture was allowed to cool to room temperature and then poured into cold aqueous ammonium chloride. The product was then extracted with ethyl -acetate and then filtered to remove insoluble impurities. The filtrate was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by medium pressue liquid chromatography eluting with ethyl acetate/cyclohex-ane (15:85) The product was isolated from relevant fractions. Yield 37g, 81%.
And in an analogous fashion were prepared
(5-Chloro-l-(4-chloro-phenyl)-indan-l-yl)-cyano-acetic acid ethyl ester from (5-Chloro-indan-l-ylidene)-cyano-acetic acid ethyl ester and 4-chlorophenyl magnesium bromide
(6-Chloro-l-(4-methoxy-phenyl)-indan-l-yl)-cyano— acetic acid ethyl ester from (6-Chloro-indan-l-ylidene)-cyano-acetic acid ethyl ester and 4-methoxyphenyl magnesium bromide
(5-Chloro-l-(4-methoxy-phenyl)-indan-l-yl)-cyano— acetic acid ethyl ester from (5 -Chloro-indan-l-ylidene)-cyano-acetic acid ethyl ester and 4-methoxyphenyl magnesium bromide
(5-Methoxy-l-(4-chloro-phenyl)-indan-l-yl)-cyano-acetic acid ethyl ester from (5 -Methoxy-indan-l-ylidene)-cyano-acetic acid ethyl ester and 4-chlorophenyl magnesium bromide
(5-Fluoro-l-(4-chloro-phenyl)-indan-l-yl)-cyano-acetic acid ethyl ester from (5 -Fluoroy-indan-l-ylidene)-cyano-acetic acid ethyl ester and 4-chloro-phenyl magnesium bromide
(5-Chloro-l-(4-benzyloxy-phenyl)-indan-l-yl)-cyano-acetic acid ethyl ester from (5-Chloro-indan-l-ylidene)-cyano-acetic acid ethyl ester and 4-benzyloxyphenyl magnesium bromide
(5-Bromo-l -(4-chloro-phenyl)-indan-l -yl)-cyano-acetic acid ethyl ester (5-Bromo-indan-l-ylidene)-cyano-acetic acid ethyl ester and 4-chloro-phenyl magnesium bromide
Preparation of Intermediates of Formula XIII
[6-Chloro-l-(4-chloro-phenyl)-indan-l~yl]-acetic acid
(6-Chloro- l-(4-chloro-phenyl)-indan-l-yl)-cyano-acetic acid ethyl ester (23.4 g) was dissolved in a solution of potassium hydroxide (70g, 1.25 mol), ethylene glycol (150 mL) and water (70 mL). The solution was heated at reflux for 40 hours and then allowed to cool to room temperature. The product was extracted with ethyl acetate which was washed with brine. The separated organic layer was dried (MgSO4), filtered and concentrated in vacuo. Yield 20g, 100%
and in an analagous fashion were prepared
[5 -Methoxy- 1 - (4-chloro-phenyl)-indan-l-yl) '-acetic acid from (5-Methoxy-l-(4-chloro-phenyl)-indan-l-yl)-cyano-acetic acid ethyl ester [5-Bromo-l -(4-chloro-phenyl) -indan-1-yl] -acetic acid from (5-Bromo-l-(4-chloro-phenyl)-indan-l-yl)-cyano-acetic acid ethyl ester
[5-Chloro l-(4-methoxy-phenyl)~indan-l-yl]-acetic acid from (5-Chloro-l-(-4methoxy-phenyl)-indan-l-yl)-cyano-acetic acid ethyl ester
[6-Chloro-l-(4-methoxy-phenyl)-indan-l-yl] -acetic acid from (6-Chloro- l-(4-methoxy-phenyl)-indan-l-yl)-cyano-acetic acid ethyl ester
[5-Chloro-l-(4-benzyloxy-phenyl)-indan-l-yl]-acetic acid from (5-Chloro-l-(4-benzyloxy-phenyl)-indan-l-yl)-cyano-acetic acid ethyl ester
[5-Fluoro-l-(4-chloro-phenyl)-indan-l-yl] -acetic acid from (5-Fluoro-l-(4-chloro-phenyl)-indan-l-yl)-cyano-acetic acid ethyl ester
[5-Chloro-l-(4-chloro-phenyl)-indan-l-yl] '-acetic acid (5-Chloro-l-(4-chloro-phenyl)-indan-l-yl)-cyano-acetic acid ethyl ester
[6-Chloro-l-(4-chloro-phenyl)-indan-l (R)-yl] -acetic acid
2-[6-Chloro- 1 -(4-chloro-phenyl)-indan- 1 (R)-yl]-N- 1 (R)-phenyl-ethyl)-acetamide (9.6g, 0.023 mmol) was dissolved in glacial acetic acid (300 mL). To the stirred solution was added concentrated hydrochloric acid (600 mL). The resulting mixture was heated to reflux for 60 hours. The reaction was allowed to cool to room temperature and then diluted with water and ethyl acetate. The organic phase was separated before and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give an amber coloured oil. Yield 8.8g.
and in an analogous fashion was prepared
[6-Chloro-l-(4-chloro-phenyl)~indan-l (S)-ylJ -acetic acid from 2-[6-Chloro-l-(4-chloro-phenyl)-indan-l(S)-yl]-N-l(R)-phenyl-ethyl)-acetamide [5-Bromo-l-(4-chloro-phenyl)-indan-l (S)-ylJ -acetic acid from 2-[5-Bromo-l-(4-chloro-phenyl)-indan-l(S)-yl]-N-l(R)-phenyl-ethyl)-acetamide
[5-Bromo-l-(4-chloro-phenyl)-indan-l (R)-yl] -acetic acid from 2-[5-Bromo-l-(4-chloro-phenyl)-indan-l (R)-yl]-N-l (R)-phenyl-ethyl)-acetamide
3-[6-Chloro-l-(4-chloro-phenyl)-indan-l (R)-yl]-propionic acid from 2-[6-Chloro-l-(4-chloro-phenyl)-indan-l (R)-yl]-N-l (R)-phenyl-ethyl)-acetamide
l-(2-Cyano-ethyl)-6-chloro-l(R)-(4-chloro-phenyl)-indan (2.3g, 7.28 mmol) was stirred in water (60 mL) and concentrated sulphuric acid (lOOmL) was slowly added to the mixture. The resulting mixture was stirred at 150°C for 3 hours and then allowed to cool to room temperature. The mixture was diluted with water and then extracted with ethyl acetate. The separated organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purfied by flash chromatography eluting with pentane/ethyl acetate 4: 1 and then pentane/ethyl acetate 1 :1. The product was identified from relevant fractions which were combined and concentrated to give an oil. Yield 1.5g, 61%
and in analogous fashion were prepared 3-[6-Chloro-l-(4-chloro-phenyl)-indan-l (S)-ylJ-propionic acid from l-(2-Cyano-ethyl)-6-chloro-l(S)-(4-chloro-phenyl)-indan
3-[5-Chloro-l-(4-methoxy-phenyl)-indan-l-yl]-propionic acid from l-(2-Cyano-ethyl)-5-chloro-l-(4-methoxy-phenyl)-indan
3-[5-Chloro-l-(4-benzyloxy-phenyl)-indan-l-yl]-propionic acid from l-(2-Cyano-ethyl)-5-chloro-l-(4-benzyloxy-phenyl)-indan Preparation of Intermediates of Formula XV
2-[6-Chloro-l-(4-chloro-phenyl)-indan-l(R)-yl]-ethanol
[6-Chloro- l-(4-chloro-phenyl)-indan-l(R)-yl] -acetic acid (2.6g, 8.1 mmol) was dissolved in THF (25 mL) and cooled to below 10°C. Borane-tetrahydrofuran complex (1.0 M in THF, 24.3 mmol, 24.3 mL) was added dropwise to the solution over 15 minutes and the reaction was allowed to warm to room temperature and stirred for 4 hours at room temperature. The solution was then cooled to below 10°C and methanol (10 mL) was added dropwise over 10 minutes. The mixture was stirred at room temperature overnight and then the solvent was removed in vacuo and the residue dissolved in ethyl acetate. The solution was then washed with 5% aqueous sodium bicarbonate solution. The separated organic phase was dried (MgSO4), filtered and concentrated in vacuo to give a colourless oil. Yield 2.48g, 96%
and in an analogous fashion were prepared
2-[6-Chloro-l -(4-chloro-phenyl)-indan-l (S)-ylJ -ethanol from -[6-Chloro-l-(4-chloro~phenyl)-indan-l (S)-ylJ -acetic acid
2-[5-Chloro-l-(4-methoxy-phenyl)-indan-l-yl] -ethanol from [5-Chloro-l-(4-methoxy-phenyl)-indan-l-yl]-acetic acid
2-[5-Chloro-l-(4-benzyloxy-phenyl)-indan-l-yl] -ethanol from -[5-Chloro-l -(4-benzyloxy-phenyl)-indan-l -ylj-acetic acid
Preparation of Intermediates of Formula XVI
l-(2-Cyano-ethyl)-6-chloro-l(R)-(4-chloro-phenyl)-indan
l-(2-Bromo-ethyl)-6-chloro-l(R)-(4-chloro-phenyl)-indan (2.8 g, 7.57 mmol) was dissolved in dimethyl sulfoxide (100 mL). To the solution was added sodium cyanide (3.15g, 64.3 mmol). The resulting mixture was then heated at 120°C with stirring for one hour. The solution was allowed to cool to room temperature and then poured in water and the product extracted with ethyl acetate. The separated organic phase was then washed with brine solution, and then the solvent was removed in vacuo in the presence of a little toluene to give the product as a red oil. Yield 2.3g, 96%
and in an analogous fashion were prepared:
1 -(2-Cyano-ethyl)-6-chloro- 1 (S)-(4-chloro-phenyl)-indan from l-(2-Bromo-ethyl)-6-chloro-l (S)-(4-chloro-phenyl)-indan
1 -(2-Cyano-ethyl)-5-chloro- 1 -(4-methoxy-phenyl)-indan from l-(2-Bromo-ethyl)-5-chloro-l-(4-methoxy-phenyl)-indan
1 -(2-Cyano-ethyl)-5-chloro- 1 -(4-benzyloxy-phenyl)-indan from 1 - (2-Bromo-ethyl)-5-chloro-l-(4-benzyloxy-phenyl)-indan
Preparation of Intermediates of Formula XIV
2-[6-Chloro-l-(4-chloro-phenyl)-indan-l-yl]-N-l(R)-phenyl-ethyl)-acetamide
(R)-alpha-methylbenzylamine (3.73g, 30.8 mmol) was dissolved in dichloromethane (60 mL), placed under a nitrogen atmosphere and cooled to 0°C. 4-Dimethylaminopyridine (2.5g, 20.6 mmol) was added followed by a solution of [6-Chloro- 1 -(4-chloro-phenyl)- indan-1-yl] -acetic acid (3.3g, 10.28 mmol) dissolved in dichloromethane (190 mL), maintaining the temperature of the reaction at 5°C. l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) was added (2.36g, 12.3 mmol) whilst maintaining the reaction temperature below 5 °C. The mixture was stirred at room temperature for 3 days, then washed with water, IM HC1 and then again with water. The separated organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo to give a brown oil yield 4.5 g. Purification by flash chromatography eluting with 10% ethyl acetate in cyclohexane afforded two products. The first eluting product is:
2-[6-Chloro-l-(4-chloro-phenyl)-indan-l(R)-yl]-N-l(R)-phenyl-ethyl)-acetamide
Yield 630 mg The second eluting product is:
2-[6-Chloro-l-(4-chloro-phenyl)-indan-l(S)-yl]-N-l(R)-phenyl-ethyl)-acetamide
Yield l.Og
and the following intermediates were prepared in an analogous fashion:
2-[5-Bromo-l-(4-chloro-phenyl)-indan-l (R)-yl]-N-l (R)-phenyl-ethyl)-acetamide 2-[5-Bromo-l-(4-chloro-phenyl)-indan-l(S)-yl]-N-l(R)-phenyl-ethyl)-acetamide
from [5-Bromo-l-(4-chloro-phenyl)-indan-l-yl]-acetic acid
Preparation of Intermedates of Formula IV
2(S)(-({3-[6-Chloro-l-(4-chloro-phenyl)-indan l(R)-l-yl]-propionyl}-methyl-amino)- propionic acid tert-butyl ester
(S)-N-Methyl alanine-tert-butylester (920mg, 4.7 mmol) was dissolved in dichloromethane and placed under a nitrogen atmosphere. 4-Dimethylamino pyridine (874 mg, 7.17 mmol) was added and a solution of3-[6-Chloro-l-(4-chloro-phenyl)-indan-l(R)-yl]-propionic acid (0.75g, 2.24 mmol) dissolved in dichloromethane (20 mL)) was added and then l-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (515 mg, 2.69 mmol). The mixture was allowed to stir for 18 hours and then the mixture was washed with IM HCl and then brine. The separated organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo to give the product. Yield: 1.12g
and in an analogous fashion were prepared
2(S)(-({3-[6-Chloro-l-(4-chloro-phenyl)-indan-l(S)-yl]-propionyl}-methyl-amino)- propionic acid tert-butyl ester from 3-[6-Chloro-l -(4-chloro-phenyl)-indan-l (S)-ylJ-propionic acid and (S)-N-methyl alanine-tert butyl ester 2(R)(-({3-[6-Chloro-l-(4-chloro-phenyl)-indan -l(R)-yl]-propionyl}-methyl-amino)- propionic acid tert-butyl ester from 3-[6-Chloro-l ~(4-chloro-phenyl)-indan-l (R)-yl]-propionic acid and (R)-N-methyl alanine-tert butyl ester
2(R)(-({3-[6-Chloro-l-(4-chloro-phenyl)-indan -l(S)-yl]-propionyl}-methyl-amino)- propionic acid tert-butyl ester from 3-[6-Chloro-l-(4-chloro-phenyl)-indan-l(R)-yl]-propionic acid and (S)-N-methyl alanine-tert butyl ester
({2-[5-Chloro-l-(4-chloro-phenyl)-indan-l (R)-yl]-acetyl}-methyl-amino) -acetic acid tert- butyl ester from [5-Chloro-l-(4-chloro-phenyl)-indan-l (R)-ylJ -acetic acid and sarcosine butyl ester
({2-[5-Chloro-l-(4-chloro-phenyl)-indan-l (S)-yl]-acetyl}-methyl-amino) -acetic acid tert- butyl ester from [5-Chloro-l-(4-chloro-phenyl)-indan-l(S)-yl]-acetic acid and sarcosine butyl ester
2(S)(-({3-[5-Chloro-l-(4-methoxy-phenyl)-indan-l-yl]-propionyl}-methyl-amino)-propionic acid tert-butyl ester from 3-[5-Chloro-l-(4-methoxy-phenyl)-indan-l-yl]-propionic acid and (S)-N-methyl alanine tert butyl ester
2(R)(-({3-[5-Chloro-l-(4-methoxy-phenyl)-indan -l-yl]-propionyl}-methyl-amino)- propionic acid tert-butyl este from 3-[5-Chloro-l-(4-methoxy-phenyl)-indan-l-yl]-propionic acid and (R)-N-methyl alanine tert butyl ester
({2-[l-(4-Chloro-phenyl)-5-methoxy-indan-l -yl]-acetyl}-methyl-amino) -acetic acid tert- butyl ester from [5 -Methoxy- l-(4-chloro-phenyl)-indan-l-yl] -acetic acid and sarcosine tert butyl ester ({2-[l-(4-Chloro-phenyl)-5-bromo-indan-l (R)-yl]-acetyl}-methyl-amino) -acetic acid tert- butyl ester from 5-Bromo-l -(4-chloro-phenyl)-indan-l (R)-yl] -acetic acid and sarcosine tert butyl ester
({2-[l-(4-Chloro-phenyl)-5-bromo-indan-l (S)-yl]-acetyl}-methyl-amino) -acetic acid tert- butyl ester from 5-Bromo-l -(4-chloro-phenyl)-indan-l (S)-yl] -acetic acid and sarcosine tert butyl ester
({2-[l-(4-Benzyloxy-phenyl)-5-chloro-indan-l-yl]-acetyl}-methyl-amino)-acetic acid tert- butyl ester from 5 -Chloro-l-(4-benzyloxy-phenyl)-indan-l-yl] -acetic acid and sarcosine tert butyl ester
Preparation of Compounds of the Invention
Example 1
la 2-({3-[5,6-Difluoro-l -(4-chloro-phenyl)-indan-l -yl]-propyl}-methyl-amino)-propionic acid hydrochloride
l-(3-Bromo-propyl)-l-(4-chloro-phenyl)-5,6-difluoro-indan (75 mg, 0.195 mmol) was dissolved in acetonitrile (5 mL). To the solution was added N-Methyl alanine tert-butyl ester (90 mg, 0.566 mmol) and polymer supported diisopropyl ethylamine (18 mg, 0.566 mmol base). The suspension was then heated at 80°C for 6 hours , allowed to cool, filtered and evaporated in vacu. The crude product was purified by flash chromatography eluting with dichloromethane/methanol , 9:1. The tert-butyl ester was isolated from evaporation of relevant fractions as an oil (lOmg, 11%). The ester was then dissolved in a mixture of trifluoroacetic acid (1ml) and water (0.05ml) and allowed to stand for 18 hours at room temperature. The solution was then evaporated and to the residue was added 2M HCl (3 mL). The solution was then freeze dried to give the product as a colourless solid. Yield 7 mg, 73%. 1H NMR, LC-MS (m/z) (MH)+ 408.3 RT=2.44 (UV, ELSD) 83%, 99% and the following compounds were prepared in an analogous fashion:
lb ({3-[5, 6-Difluoro- l-(4-chloro-phenyl)-indan-l-yl]-propyl}-methyl-amino)-acetic acid, hydrochloride
Yield 19 mg, 52% 1H NMR (CD3OD, 400 MHz) 1.82 (m, 2H), 2.00 (m, IH), 2.09 (m, IH), 2.17 (m, IH), 2.24 (m, IH), 2.9-3.0 (m, 5H), 3.02-3.18 (m, 2H), 4.0 (s, 2H), 7.05 (m, 2H), 7.13 (m, 4H) LC-MS (m/z) (MH)+ 394 RT=2.48 (UV,ELSD) 91%, 99%
lc 2-({3-[l-(3, 4-Dichloro-phenyl)-indan-l-yl]-propyl}-methyl-amino)-propionic acid
Yield 42mg, 22% 1H NMR (CD3OD, 400 MHz) 1.54 (d, 3H) 1.6-1.8 (m, 2H), 2.03 (m, IH), 2.20 (m, IH), 2.45 (m, 2H), 2.83 (s, 3H) 2.-3.0 (m, 2H), 3.02-3.18 (m, 2H), 4.0 (br s, IH), 7.2-7.30 (m, 5H), 7.35 (s, IH), 7.40 (d, IH) LC-MS (m/z) (MH)+ 406.3 RT=2.48 (UV,ELSD) 72%, 99%
1 d ({3-[5-Fluoro-l- (4-fluoro-phenyl)-indan-l-yl]-propyl}-methyl-amino)-acetic acid
Yield 17.4 mg, 54% 1H NMR (CD3OD, 400 MHz) 1.64 (m, 2H), 2.03 (m, IH), 2.18 (m, IH), 2.36 (m, IH), 2.45 (m, IH), 2.85 (s, 3H), 2.8-2.95 (m, 2H), 3.1-3.22 (br m, IH), 4-4.06 (br s, 2H), 6.95-7.03 (m, 4H), 7.20 (dd, IH), 7.25 (m, 2H) LC-MS (m/z) (MH)+ 360.1 RT=2.18 (UV, ELSD) 79%, 95%
le 2-({3-[6-Chloro-l -(4-Fluoro-phenyl)-indan-l -yl]-propyl}-methyl-amino)-propionic acid
Yield 37 mg, 100% 1H NMR (CD3OD, 400 MHz) 1.56 (d, 3H) 1.60-1.76 (m, 2H), 2.05 (m, IH), 2.20 (m, IH), 2.35 (m, IH), 2.50 (m, IH), 2.84 (s, 3H), 2.90 (m, 2H), 3.0-3.20 (m, 2H), 4.18 (m, 2H) LC-MS (m/z) (MH)+ 2.37 (UV, ELSD) 78%, 87%
lϊ2-({3-[6-Chloro-l-(4-methyl-phenyl)-indan-l-yl]-propyl}-methyl-amino)-propionic acid Yield 24mg , 80% 1H NMR (CD3OD, 400 MHz) 1.58 (d, 3H), 1.66-1.74 (m, 2H), 2.0 (m, IH), 2.20 (m, IH), 2.30-2.38 (m, 4H), 2.5 (m, IH), 2.80 (s, 3H), 2.82-2.95 (m, 3H), 3.18 (m, IH), 4.18 (m, IH), LC-MS (m/z) (MH)+2.48 (UV, ELSD) 86%, 100%
Example 2
2a ({2(R)-[6-Chloro-l-(4-chloro-phenyl)-indan-l(S)-yl]-propyl}-methyl-amino)-propionic acid
2(R)(-({3-[6-Chloro-l-(4-chloro-phenyl)-indan l(S)-l-yl]-propionyl}-methyl-amino)- propionic acid tert-butyl ester (1.34g, 2.73 mmol) was dissolved in anhydrous tetrahydrofuran and under an inert atmosphere with cooling (0-5°C) was added borane- tetrahydrofuran complex (IM solution in THF) (75 mL, 75 mmol) at a rate so that the temperature remained at 0-5°C. After the addition the reaction was heated to reflux for 16 hours. The reaction was cooled to room temperature before the careful addition of 10% (w/v) of aqueous sodium carbonate solution. The mixture was then stirred for another 16 hours. Water (100 mL) was added and the product was extracted with ethyl acetate (3 X 50 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the intermediate butyl ester (1.26 g, 100%). The compound (1.09, 2.37 mmol) was then stirred in trifluoroacetic acid (31.8 mL) and water (1.6 mL) at room temperature for 18 hours. The solution was then concentrated in vacuo followed by reevaporation in the presence of toluene. The crude product was purified by preparative reverse phase HPLC eluting with 30:70:0.01 MeCN/H2O/TFA to 98:2:0.01 MeCN/H O/TFA over 45 minutes. The compound was then isolated from relevant fractions and the compound was freezes dried to give a white solid. Yield 196mg, 18%
1H NMR (CD3OD, 400 MHz) 1.55 (d, 3H), 1.67 (m, 2H), 2.03 (m, IH), 2.20 (m, IH), 2.38 (m, IH), 2.46 (m, IH), 2.83 (d, 3H), 2.9-3.05 (m, 3H), 3.18 (m, IH), 4.2 (dt, IH), 7.25 (m, 7H) LC-MS (m/z) (MH)+406 (UV/ELSD) 92%, 97%.
and the following compounds were prepared in an analogous fashion
2b ({2(S)-[6-Chloro-l-(4-chloro-phenyl)-indan-l(R)-yl]-propyl}-methyl-amino)-propionic acid
Yield (50mg) 1H MR (CD3OD, 400 MHz) 1.55 (d, 3H), 1.63 (m, 2H), 2.03 (m, IH), 2.20 (m, IH), 2.38 (m, IH), 2.46 (m, IH), 2.83 (s,3H), 2.9-3.2 (m, 4H), 4.08 (m, IH), 7.25 (m, 7H) LC-MS (m/z) (MH)+ 406 (UV/ELSD) 89%, 94%.
2c ({2(R)-[6-Chloro-l-(4-chloro-phenyl)-indan-l(R)-yl]-propyl}-methyl-amino)-propionic acid
Yield 30mg
1H NMR (CD3OD, 400 MHz) 1.55 (d, 3H), 1.63 (m, 2H), 2.03 (m, IH), 2.20 (m, IH), 2.38 (m, IH), 2.46 (m, IH), 2.83 (d, 3H), 2.9-3.0 (m, 2H), 3.0-3.20 (m, 2H), 4.20 (dt, IH), 7.25 (m, 7H)
LC-MS (m/z) (MH)+406 (UV/ELSD) 88%, 98%.
2d ({2(S)-[6-Chloro-l-(4-chloro-phenyl)-indan-l(S)-yl]-propyl}-methyl-amino)~propionic acid
Yield 53mg.
1H NMR (CD3OD, 400 MHz) 1.55 (d, 3H), 1.63 (m, 2H), 2.03 (m, IH), 2.20 (m, IH), 2.38 (m, IH), 2.46 (m5 IH), 2.83 (s, 3H), 2.9-3.0 (m, 2H), 3.0-3.20 (m, 2H), 4.18 (br s, IH), 7.25 (m, 7H)
LC-MS (m/z) (MH)+ 406 (UV/ELSD) 72%, 100%
2e ({2-[5-Chloro-l-(4-chloro-phenyl)-indan-l (S)-yl] -ethyl} -methyl-amino) -acetic acid
Yield: 7mg, 49% 'H NMR (CD3OD- 400 MHz) 2.36 (m, IH), 2.5 (m, 2H), 2.6 (m, IH), 2.8-3.0 (m, 2H), 2.9 (s, 3H),3.0-3.2 (m, 2H), 4.05 (br s, IH), 7.25 (m, 7H)
LC-MS (m/z) (MH)+378 RT=2.36 (UV/ELSD) 83%, 100%.
2i ({2-[5-Chloro-l-(4-chloro-phenyl)-indan-l(R)-yl]-ethyl}-methyl-amino)-acetic acid
Yield 28mg , 95%
1H NMR (CD3OD, 400 MHz) 2.36 (m, IH), 2.5 (m, 2H), 2.6 (m, IH), 2.8-3.0 (m, 2H), 2.9 (s, 3H), 3.0-3.2 (br m, 2H), 4.05 (br s, IH), 7.25 (m, 7H) )
LC-MS (m/z) (MH)+ 378, RT=2.36 (UV/ELSD) 81%, 100%.
2g 2(R)-({3-[5-Chloro-l-(4-methoxy-phenyl)-indan-l-yl]-propyl}-methyl-amino)-propionic acid
Yield 87mg, 96%
1H NMR (CD3OD, 400 MHz) 1.55 (d, 3H), 1.63 (br m, 2H), 2.0 (m, IH), 2.15 (m, IH), 2.26 (m, IH), 2.80 (br s, 3H), 2.8-2.95 (m, 2H), 3.18 (m, 2H), 3.77 (s, 3H), 4.18 (br s, IH), 6.83 (d, 2H), 7.20 (m, 4H), 7.24 (s,lH)
LC-MS (m/z) (MH)+ 402.2 RT=2.31 (UV/ELSD) 79%, 98%
2h 2-(S)-({3-[5-Chloro-l-(4-methoxy-phenyl)-indan-l-yl]-propyl}-methyl-amino)-propionic acid
Yield 75mg, 100%. 1H NMR (CD3OD, 400 MHz) 1.55 (d, 3H), 1.63 (br m, 2H), 2.0 (m, IH), 2.15 (m, IH), 2.26 (m, IH), 2.80 (br s, 3H), 2.8-2.95 (m, 2H), 3.18 (m, 2H), 3.77 (s, 3H), 4.18 (br s, IH), 6.83 (d, 2H), 7.20 (m- 4H), 7.24 (s,lH) LC-MS (m/z) (MH)+ 402.2 R =2.31 (UV/ELSD) 82%, 99%
2i ( {2- [5 -Methoxy- 1 -(4-chloro-phenyl)-indan-l-yl]-ethyl}-methyl-amino)-acetic acid
Yield 70mg, 68%.
1H NMR (CD3OD, 400 MHz) 2.30 (m, IH), 2.44 (m, 2H), 2.55 (m, IH), 2.83 (m, 2H), 2.90 (s, 3H), 3.78 (s, 3H), 3.98 (s, 2H), 6.8 (m, 2H), 7.1 (d, IH), 7.25 (m, 4H)
LC-MS (m z) (MH)+ 374.0 RT=2.18 (UV/ELSD) 61%, 92%
2j 2-({3-[5-Chloro-l-(4-methoxy-phenyl)-indan-l-yl]-ethyl}-methyl-amino)-acetic acid hydrochloride
Yield: 0.36g, 98%
1H NMR (CD3OD, 400 MHz) 2.23 (m, IH), 2.4-2.6 (m, 3H), 2.9-3.0 (m, 5H), 3.05 (m, IH), 3.2 (m, IH), 3.78 (s, 3H), 4.05 (dd, 2H), 6.92 (d, 2H), 7.2-7.3 (m, 5H)
LC-MS (m z) (MH)+ 374.1 RT=2.21 (UV/ELSD) 90%, 97%
2k 2-({3-[5-Chloro-l -(4-benzyloxy-phenyl)-indan-l -yl]-ethyll}-methyl-amino)-acetic acid
Yield 5mg, 10%
1H NMR (CD3OD, 400 MHz) 2.23 (m, IH), 2.4-2.6 (m, 3H), 2.9-3.0 (m, 5H), 3.04 (br m, 2H), 3.83 (s, 2H), 5.05 (s, 2H), 6.93 (d, 2H), 7.17-7.4 (m, 10H)
LC-MS (m z) (MH)+ 449.9 RT=2.72 (UV/ELSD) 88%, 99%
21 ({2-[5-Fluoro-l-(4-chloro-phenyl)-indan-l-yl]-ethyl}-methyl-amino)-acetic acid ({2-[l-(4-Chloro-phenyl)-5-fluoro-indan-l-yl]-acetyl}-methyl-amino)-acetic acid tert-butyl ester (4.3g, 10 mmol) was dissolved in anhydrous tetrahydrofuran (125 mL) and cooled to 0°C. Borane tetrahydrofuran complex (50ml, 50mmol,lM in THF) was added and the reaction was refluxed for 16 hours and then cooled to room temperature.. Aqueous IM NaOH (100ml) was added and the solution was heated to reflux for 2 hours. The solution was then cooled and water (50 m-L) was added. The phases were then separated. The aqueous phase was extracted with ethyl acetate (3 X 50 mL). The combined organic extracts were washed with saturated brine and then the organic extracts were dried over MgSO . The organic extracts were then filtered and concentrated in vacuo to give the crude tert-butyl ester (3.1 g). This was then purified by flash chromatography eluting with dichloromethane/ethyl acetate 95 :5. The purified compound was identified from relevant fractions before being combined and evaporated to give the product (2.0g). To the intermediate butyl ester (0.5g, 12 mmol) was added IM HCl/AcOH (50 mL) and the solution was stirred for 16 hours at room temperature. The solution was evaporated in vacuo and the crude product was purified by preparative reverse HPLC eluting with 30:70:0.01 MeCN /H2O/TFA to 98:2:0.01 MeCN /H2O/TFA over 45 minutes. The purified fractions were then evaporated and the product was treated with 2M HCl and extratcted with ethyl acetate (3 X 20mL). The combined organic extracts were dried over magnesium sulphate , filtered and evaporated.
Yield 210mg, 96%
Example 3
3a 2-({3-[5-(4-methoxy-phenyl)-l-(4-chloro-phenyl)-indan-l-(S)-yl]-ethyl}-methyl-amino)- acetic acid hydrochloride
({2-[l-(4-Chloro-phenyl)-5-brorno-indan-l(S)-yl]-acetyl}-methyl-amino)-acetic acid tert- butyl ester (3.1 g, 8.4 mmol) was dissolved in tetrahydrofuran at 0°C and borane tetrahydrofuran complex (IM in THF) was added under an inert atmosphere. The solution was then heated at reflux for 1.5 hoxirs and then for 16 hours at room temperature. IN NaOH (100 mL) was slowly added to the reaction and after addition the mixture was heated at reflux for two hours. The mixture was allowed to cool and then diluted with ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2X). The combined organic extracts were dried (MgSO4), filtered anc concentrated in vacuo. The crude product was purified by flash chromatograph eluting with a gradient of 10% to 50% ethyl acetate in hexane. The product, ({2-[5-Bromo-l-(4-chloro-phenyl)-indan- l(S)-yl]-ethyl}-methyl-amino)-acetic acid tert-butyl ester , was isolated from relvant fractions Yield: l.lg, (27%).
({2-[5-Bromo-l-(4-chloro-phenyl)-indan-l(S)-yl]-ethyl}-methyl-amino)-acetic acid tert- butyl ester was then dissolved in dimethoxy ethane (20 mL) and placed under a nitrogen at room temperature. To the solution was added tetrakis palladium (70 mg), 2M aqueous Na2CO3 and 4-methoxyphenyl boronic acid (530 mg, 30 mmol) dissolved in ethanol (2 mL). The solution was then heated to reflux for 16 hours, allowed to cool and then ethyl acetate (30 mL) and IM aqueous NaOH (10 mL) was added. The organic layer was separated and then washed with water and brine. The separated organic layer was then dried (MgS04), filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with a gradient elution starting with heptane/ethyl acetate 5:1 and finishing with heptane/ethyl acetate 2.1 over a 20 minute period. 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 relevant fractions were evaporated and to the product -was then added 4M HCl (20 mL). The product was then extracted with ethyl acetate (3 X 30 mL). The organic extracts were then evaporated in vacuo and the residue redissolved in dichloromethane and evaporated in vacuo to give the product as a colourless foam. Yield : 190 mg, 37%.
1H NMR (DMSO-d6, 500 MHz) 2.3 (m, IH), 2.37 (m, IH), 2.5 (m, 2H), 2.7 (m, IH), 2.8 (s, 3H), 2.87 (m, IH), 3.0 (m, 2H), 4.05 (br 2, 2H), 7.0 (d, 2H), 7.40 (br m, 5H), 7.5 (m, 2H), 7.6 (m, 2H) LC-MS (m/z) (MH)+ 450.0685 RT=2.59 (UV/ELSD) 99%, 100%
The following compounds were prepared in an analagous fashion
3b 2-({3-[5-(4-Methoxy-phenyl)-l-(4-chloro-phenyl)-indan-l (R)-yl] -propyl} -methyl- amino) -acetic acid hydrochloride
Yield: 230 mg
1H NMR (DMSO-d6, 500 MHz) 2.25 (m, IH), 2.4 (m, IH, 2.5 (m, IH), 2.7 (m, IH), 2.8 (s, 3H), 2.83 (s, 3H), 2.9 (m -IH), 3.0 (m, 3H), 3.8 (s, 3H), 4.08 (br s, 2H), 7.0 (d, 2H), 7.38 (m, 5H), 7.48 (dd, 2H), 7.57 (d, 2H)
LC-MS (m/z) (MH)+ 450.1705 RT=2.61 (UV/ELSD) 99%, 100%
Example 4
4n 2(S)-({3~[5-Chloro-l-(4-(N-morpholino)-phenyl)-indan-l-yl]-propyl}~methyl-amino)- propionic acid dihydrochloride
(Debenzylation of example 2k butyl ester)
2(S)-( { 3 - [5 -Chloro- 1 -(4-benzyloxy-phenyl)-indan- 1 -yl]-ethyll } -methyl-amino)-propionic acid tert butyl ester (0.875g, 1.64 mmol) was dissolved in ethanol (60 mL) and ethyl acetate (29 mL) and 1,2 dichlorobenzene (9.7 mL). Argon gas was bubbled through the solution and stirred for 10 minutes. Palladium hydroxide on carbon (20%) (0.365g) and acetic acid (6 mL) was added at room temperature. The reaction was placed under a hydrogen atmosphere (1 atmosphere) for 85 minutes after which time the mixture was filtered through celite and the filter cake was washed with ethanol. The filtrate was concentrated in vacuo and the product 2(S)-( { 3 - [5 -Chloro- 1 -(4-hydroxy-pheny l)-indan- 1 -yl] -propyl} -methyl-amino)- propionic acid tert butyl ester was recrystallised from ethyl acetate/cyclohexane. Yield 0.627g, 86%
(Conversion to triflate) 2(S)-({3-[5-Chloro-l-(4-hydroxy-phenyl)-indan-l-yl]-propyl}-methyl-amino)-propionic acid tert butyl ester (0.610g, 1.37 mmol) was dissolved in dichloromethane and placed under a nitrogen atmosphere.. N-phenyltriflimide (0.982g, 2.75 mmol) dissolved in dichloromethane (20mL) was added to the solution under a nitrogen atmosphere. Then triethylamine (0.19mL, 1.37 mmol) was added and the solution was stiorred for 2 hours at 0°C and then for 5 days at room temperature.The solution was then concentrated in vacuo and diluted with diethyl ether and then washed with water. The separated organic layer was washed withlΝ ΝaOH, and then washed with water. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with cycohexane/ethyl acetate 9:1 then 1:3. The product was identified from relevant fractions which were combined and concentrated in vacuo to give 2(S)-({3-[5-Chloro-l-(4-trifluoromethanesulfonyloxy-phenyl)-indan-l-yl]-propyl}-methyl- amino)-propionic acid butyl ester . Yield (0.5g, 63%)
2(S)-({3-[5-Chloro-l-(4-trifluoromethanesulfonyloxy-phenyl)-indan-l-yl]-propyl}-methyl- amino)-propionic acid butyl ester (80 mg, 0.14 mmol), potassium phosphate (41 mg, 0.194 mmol), and morpholine (14.5 μL, 0.166 mmol) were dissolved in tetrahydrofuran (0.7 mL) and placed in a sealed vial and subjected to microwave irradiation at 110°C for 60 minutes. The reaction vial was then allowed to cool to room temperature before the reaction mixture was filtered through HyFlo . 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 solution was then diluted with In HCl (5 ml) and then freeze dried.The crude product was purfied by preparative HPLC eluting with a acetonitrile/water gradient (30%-63% acetonitrile in water over 70 minutes). The relevant fractions were combined and evaporated, the product redissolved in IN HCl (5mL) and then freeze dried to afford the product as a white solid.
Yield 35 mg, 85% 1H NMR (CD3OD, 400 MHz) 1.58 (s, 3H), 1.6-1.7 (m, 2H), 2.08 (m, IH), 2.3 (m, IH), 2.4 (m, IH), 2.5 (m, IH), 2.83 (d, 3H), 2.9 (m, 1H),3.0 (m, IH), 3.2 (m, 2H), 3.72 (br s, 4H), 4.17 (br s, 4H),4.25 (m, IH), 7.25 (m, 2H), 7.3 (s, IH), 7.55 (m, 2H), 7.65 (d, 2H)
LC-MS (m/z) (MH)+ 457.0617 RT=2.01 (UV/ELSD) 95%, 100%
4b 2-({3-[5-Chloro-l-(4-(3-methoxyphenyl)-phenyl)-indan-l-yl]-ethyll}-methyl-amino)- acetic acid hydrochloride
( {2- [5-Chloro- 1 -(4-trifluoromethanesulfonyloxy-phenyl)-indan- 1 -yl]-ethyl } -methyl-amino)- acetic acid butyl ester (30mg, 0.055 mmol), 3 -methoxy benzene boronic acid and potassium carbonate (11.4 mg, 0.082 mmol) were dissolved in toluene (0.75 mL) and placed in a microwave vial and sealed. Nitrogen was bubbled through the solution before tetrakis (triphenylphosphine) palladium (3.1 mg, 0.0026 mmol) and ethanol (0.75 mL) were added. 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). This was then dissolved in a triluoroacetic acid/water (95:5) (1.5 mL) and the solution was stirred for 8 hours at room temperature. The solution was then diluted with IN HCl (5 ml) and then freeze dried.The crude product was purfied by preparative HPLC eluting with a acetonitrile/water gradient (30%-63% acetonitrile in water over 70 minutes). The relevant fractions were combined and evaporated, the product redissolved in IN HCl (5mL) and then freeze dried to afford the product as a white solid.
Yield 14 mg, 82%
1H NMR (CD3OD, 400 MHz) 2.38 (m, IH), 2.5 (m, IH), 2.6 (m, IH), 2.66 (m, IH), 2.87- 3.0 (br m, 5H), 3.1 (br m, 2H), 3.82 (s, 3H), 4.07 ( br s, 2H), 6.83 (d, IH), 7.1 (s, IH), 7.18 (d, IH), 7.25-7.4 (m, 6H), 7.58 (d, 2H)
LC-MS (m/z) (MH)+450.106 RT=2.64 (UV/ELSD) 100%, 100% The following compounds were prepared in an analagous fashion:
4c 2-({3-[5-Chloro-l-(4-(3-thienyl)-phenyl)-indan-l-yl]-ethyll}-methyl-amino)-acetic acid hydrochloride
Yield: 22.6 mg, 84%
1H NMR (CD3OD, 400 MHz) 2.38 (m, IH), 2.5 (m, IH), 2.6 (m, IH), 2.66 (m, IH), 2.87- 3.0 (br m, 5H), 3.1 (br m, 2H), 4.05 (br s, IH), 7.22-7.35 (m, 5H), 7.45 (m, 2H), 7.6 (m, 6H)
LC-MS (m/z) (MH)+ 426.0583 RT=2.59 (UV/ELS) 100%, 100%
Pharmacological testing
The compounds of the invention were tested in a well-recognised and reliable test measuring glycine uptake:
[3H]-Glycine uptake
Cells transfected with the human GlyT-lb were seeded in 96 well plates. Prior to the experiment the cells were washed twice in HBS (10 mM Hepes-tris (pH 7,4), 2,5 mM KCl,
1 mM CaCl2, 2,5 mM MgSO4,) and pre-incubated with test compound for 6 minutes.
Afterwards, 10 nM 3H-glycine was added to each well and the incubation was continued for
15 minutes. The cells were washed twice in HBS. Scintillation fluid was added and the
Plates were counted on a Trilux (Wallac) scintillation counter.
The test results showed, that the prepared compounds of the indention all showed inhibition below 10000 nM, such as below 2000 nM, as IC50 in the above-mentioned assay. The compounds of the invention were also tested in a well-recognised and reliable microdialysis test.
Method
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. Perfusion of the microdialysis probe with filtered Ringer solution (145 mM NaCl, 3 mM KCl, 1 mM MgCl2, 1.2 mM CaCl2) 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 μl/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.
After the experiments, the rats were sacrificed by decapitation. The brains were removed, frozen and sectioned (20 μm), and the position of the probes was verified.
Analysis of glycine in the dialysates
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 μm, 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 μM). Data presentation
The mean value of 3 consecutive glycine samples immediately preceding compound administration served as the basal level for each experiment and data were converted to percentage of basal (mean basal pre-inj ection values normalized to 100%).

Claims

We Claim:
1. A phenyl indane compound of the formula I
wherein n is 0, 1, or 2, m is O, 1, or 2, p is 2 or 3,
R is selected from H, or Cι-6-alk(en/yn)yl;
R is (independently) selected from halogen; Cι-6-alk(en/yn)yl; Cι-6- alk(en/yn)ylsulfanyl; halo-Cι-6-alk(en/yn)yl; aryl-C1.6-alk(en/yn)yloxy; aryl optionally substituted with a halogen, Cι-6-alk(en yn)yl, Cι_6-alk(en yn)yloxy, halo-C]-6-alk(en/yn)yl, or halo-Cι-g-alk(en/yn)yloxy; or monocyclic heteroaryl optionally substituted with a Cι-6- alk(en yn)yl;
R is (independently) selected from halogen; Cι-6-alk(en yn)yl; Cι_6-alk(en/yn)yloxy; Cι-6- alk(en/yn)ylsulfanyl; halo-Cι-6-alk(en/yn)yl; aryl-C1.6-alk(en/yn)yloxy; aryl optionally substituted with a halogen, Cι-6-alk(en/yn)yl, Cι_6-alk(en yn)yloxy, halo-Cι-6-alk(en/yn)yl, or halo-Cι-6-alk(en/yn)yloxy; or monocyclic heteroaryl optionally substituted with a C].6- alk(en/yn)yl; R4 is H, or Cι-6-alk(en/yn)yl;
R5 is H, Ci-6-alk(en/yn)yl, aryl, aryl-Cι-6-alk(en/yn)yl, wherein aryl is optionally substituted with a halogen, CF3, OCF3, CN, N02 or Cι-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:
N- { 3 -[5 -Chloro- 1 -(4-chloro-phenyl)-indan- 1 -yl] -propyl } -N-methyl glycine,
N- { 3 - [5 -Chloro- 1 -(4-chloro-phenyl)-indan- 1 -yl] -propyl -N-methylalanine .
2. The compound of claim 1 wherein p is 2.
3. The compound of claim 1 wherein p is 3.
4. The compound of any one of claims 1-3 wherein R1 is Cι-6-alkyl, such as methyl
5. The compound of any one of claim 1-4 wherein n is O.
6. The compound of any one of claim 1-4 wherein n is 1 or 2.
7. The compound of claim 6 wherein R2 is independently selected from halogen; Cι_6- alk(en/yn)yloxy; Cι-6-alk(en yn)ylsulfanyl; halo-Cι-6-alk(en yn)yl; aryl optionally substituted with a halogen, Cι-6-alk(en/yn)yl, or Cι_6-alk(en/yn)yloxy; or monocyclic heteroaryl.
8. The compound of claim 7 wherein n is 1 and R2 is selected from halogen, such as F, CI, Br; Cι_6-alkyloxy, such as methoxy; Cι-6-alkylsulfanyl, such as methylsulfanyl; halo-Cι-6- alkyl, such as trifluoromethyl; phenyl optionally substituted with a halogen (such as one or two CI), Cι-6-alkyl (such as one methyl), or Cι_6-alkyloxy (such as one methoxy); or thiophenyl.
9. The compound of claim 7 wherein n is 2 and R2 is independently selected from halogen, such as F.
10. The compound of any one of claim 1-9 wherein m is 0.
11. The compound of any one of claim 1-9 wherein m is 1 or 2.
12. The compound of claim 11 wherein R3 is independently selected from halogen; Cι-6- alk(en yn)yl; Cι-_6-alk(en/yn)yloxy; halo-Cι-6-alk(en/yn)yl; aryl-Cι-6-alk(en yn)yloxy; aryl optionally substituted with a halogen, Cι-6-alk(en/yn)yl, Cι_6-alk(en yn)yloxy, halo-Cι-6- alk(en/yn)yl, or halo-Cι-6-alk(en/yn)yloxy; or monocyclic heteroaryl optionally substituted with a C i -6-alk(en/yn)yl.
13. The compound of claim 12 wherein m is 1 and R is selected from halogen, such as CI, or F; Cι-6-alkyl, such as methyl; Ci-e-alkyloxy, such as methoxy; halo-Cι-6-alkyl, such as trifluoromethyl; phenyl-Cι-6-alkyloxy, such as phenyl methoxy; phenyl optionally substituted with a halogen (such as one Chloro), C^-allcyl (such as one methyl), Cι_6- alkyloxy (such as one methoxy), halo-Cι-6-alkyl (such as one trifluoromethyl), or halo-Cι-6- alkyloxy (such as one trifluoromethoxy); thiophen optionally substituted with a Cι-6-alkyl, such as one or two methyl; morpholin optionally substituted with a Cι-6-alkyl, such as one or two methyl; pyrimidin optionally substituted with a Cι-6-alkyl, such as one or two methyl; furan optionally substituted with a Cι-6-alkyl, such as one or two methyl; or isoxazol optionally substituted with a Cι-6-alkyl, such as one or two methyl.
14. The compound of claim 12 wherein m is 2 and R3 is independently selected from halogen, such as CI.
15. The compound of any one of claims 1-14 wherein R4 is Cι-6-alkyl, such as methyl.
16. The compound of any one of claims 1-15 wherein R5 is H.
17. The compound of claim 1 selected from
2-( { 3- [5 ,6-Difluoro- 1 -(4-chloro-phenyl)-indan- 1 -y 1] -propyl} -methyl-amino)-propionic acid, ( { 3 - [5 ,6-Difluoro- 1 -(4-chloro-phenyl)-indan- 1 -yl] -propyl} -methyl-amino)-acetic acid, 2-({ 3 - [ 1 -(3 ,4-Dichloro-phenyl)-indan- 1 -yl]-propyl } -methy l-amino)-propionic acid, ({3-[5-Fluoro-l-(4-fluoro-phenyl)-indan-l-yl]-propyl}-methyl-amino)-acetic acid,
2-({3-[6-Chloro-l-(4-Fluoro-phenyl)-indan-l-yl]-propyl}-methyl-amino)-propionic acid,
2-( { 3 -[6-Chloro- 1 -(4-methyl-phenyl)-indan- 1 -yl] -propyl } -methyl-amino)-propionic acid,
({2(R)-[6-Chloro-l-(4-chloro-phenyl)-indan-l(S)-yl]-propyl}-methyl-amino)-propionic acid,
({2(S)-[6-Chloro-l-(4-chloro-phenyl)-indan-l(R)-yl]-propyl}-methyl-amino)-propionic acid,
({2(R)- [6-Chloro- 1 -(4-chloro-phenyl)-indan- 1 (R)-y 1] -propyl } -methyl-amino)-propionic acid, ({2(S)-[6-Chloro-l-(4-chloro-phenyl)-indan-l(S)-yl]-propyl}-methyl-amino)-propionic acid,
({2-[5-Chloro-l-(4-chloro-phenyl)-indan-l(S)-yl]-ethyl}-methyl-amino)-acetic acid,
({2-[5-Chloro-l-(4-chloro-phenyl)-indan-l(R)-yl]-ethyl}-methyl-amino)-acetic acid,
2(R)-({3-[5-Chloro-l-(4-methoxy-phenyl)-indan-l-yl]-propyl}-methyl-amino)-propionic acid,
2-(S)-({3-[5-Chloro-l-(4-methoxy-phenyl)-indan-l -yl]-propyl}-methyl-amino)-propionic acid,
({2-[5-Methoxy-l-(4-chloro-phenyl)-indan-l-yl]-ethyl}-methyl-amino)-acetic acid,
2-({3-[5-Chloro-l-(4-methoxy-phenyl)-indan-l-yl]-ethyl}-methyl-amino)-acetic acid, 2-({3-[5-Chloro-l-(4-benzyloxy-phenyl)-indan-l-yl]-ethyll}-methyl-amino)-acetic acid,
( { 2- [5 -Fluoro- 1 -(4-chloro-pheny l)-indan- 1 -yl] -ethyl } -methyl-amino)-acetic acid,
2-({3-[5-(4-methoxy-phenyl)-l-(4-chloro-phenyl)-indan-l-(S)-yl]-ethyl}-methyl-amino)- acetic acid,
2-( { 3 -[5 -(4-Methoxy-phenyl)- 1 -(4-chloro-pheny l)-indan- 1 (R)-yl] -propyl } -methyl-amino)- acetic acid,
2(S)-( {3 -[5-Chloro- 1 -(4-(N-morpholino)-phenyl)-indan- 1 -yl] -propyl } -methyl-amino)- propionic acid,
2-( { 3 - [5-Chloro- 1 -(4-(3 -methoxyphenyl)-phenyl)-indan- 1 -yl] -ethy 11} -methyl-amino)-acetic acid, 2-({3-[5 -Chloro- 1 -(4-(3 -thienyl)-phenyl)-indan- 1 -y 1] -ethy 11 } -methyl-amino)-acetic acid, or a salt thereof, such as a pharmaceutically acceptable salt.
18. A pharmaceutical composition comprising a compound of any one of claims 1-17 and a pharmaceutically acceptable carrier or diluent.
19. The use of a compound of any one of claims 1-17 for the preparation of a medicament for the treatment of post-traumatic stress disorder or a disease 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.
20. A method for the treatment of a disease or disorder selected from the group consisting of post-traumatic stress disorder, 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 according to any one of claims 1-17.
EP05706813A 2004-03-12 2005-03-08 Phenyl indan derivatives Withdrawn EP1727785A1 (en)

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