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WO1999041227A1 - Tricyclic compounds as glycine transport inhibitors - Google Patents

Tricyclic compounds as glycine transport inhibitors Download PDF

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Publication number
WO1999041227A1
WO1999041227A1 PCT/US1999/003012 US9903012W WO9941227A1 WO 1999041227 A1 WO1999041227 A1 WO 1999041227A1 US 9903012 W US9903012 W US 9903012W WO 9941227 A1 WO9941227 A1 WO 9941227A1
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fluoren
phenyl
serine
threonine
methylphenyl
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Vassil I. Ognyanov
Stanley C. Bell
Allen Hopper
Jing Zhang
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Allelix Neuroscience Inc
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Allelix Neuroscience Inc
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    • 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
    • C07C229/26—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 more than one amino group bound to the carbon skeleton, e.g. lysine
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    • 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
    • C07C229/22—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 the carbon skeleton being further substituted by oxygen atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/61—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C07D311/86—Oxygen atoms, e.g. xanthones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/64—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/10—Dibenzothiopyrans; Hydrogenated dibenzothiopyrans
    • C07D335/12—Thioxanthenes
    • C07D335/14—Thioxanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C07D335/16—Oxygen atoms, e.g. thioxanthones
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/24—Anthracenes; Hydrogenated anthracenes
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
    • C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes

Definitions

  • the present invention relates to a class of substituted amino acids, pharmaceutical compositions and methods of treating neurological and neuropsychiatric disorders.
  • Synaptic transmission is a complex form of intercellular communication that involves a considerable array of specialized structures in both the pre- and post-synaptic terminal and surrounding glial cells (Kanner and Schuldiner, CRC Critical Reviews in Biochemistry, 22, 1987:1032).
  • Transporters sequester neurotransmitter from the synapse, thereby regulating the concentration of neurotransmitter in the synapse, as well as its duration therein, which together influence the magnitude of synaptic transmission. Further, by preventing the spread of transmitter to neighbouring synapses, transporters maintain the fidelity of synaptic transmission. Last, by sequestering released transmitter into the presy ⁇ aptic terminal, transporters allow for transmitter reutilization.
  • Neurotransmitter transport is dependent on extracellular sodium and the voltage difference across the membrane; under conditions of intense neuronal firing, as, for example, during a seizure, transporters can function in reverse, releasing neurotransmitter in a calcium-independent non-exocytotic manner (Attwell et al., Neuron, 11 , 1993:401-407). Pharmacologic modulation of neurotransmitter transporters thus provides a means for modifying synaptic activity, which provides useful therapy for the treatment of neurological and psychiatric disturbances.
  • the amino acid glycine is a major neurotransmitter in the mammalian central nervous system, functioning at both inhibitory and excitatory synapses. By nervous system, both the central and peripheral portions of the nervous system are intended. These distinct functions of glycine are - 2 -
  • glycine receptors that are sensitive to the convulsant alkaloid strychnine, and are thus referred to as "strychnine-sensitive".
  • strychnine-sensitive glycine receptors contain an intrinsic chloride channel that is opened upon binding of glycine to the receptor; by increasing chloride conductance, the threshold for firing of an action potential is increased.
  • Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brainstem, and pharmacological agents that enhance the activation of such receptors will thus increase inhibitory neurotransmission in these regions.
  • Glycine also functions in excitatory transmission by modulating the actions of glutamate, the major excitatory neurotransmitter in the central nervous system. See Johnson and Ascher, Nature, 325, 1987:529-531 ; Fletcher et al., Glycine Transmission, Otterson and Storm- athisen, eds., 1990:193-219.
  • glycine is an obligatory co-agonist at the class of glutamate receptor termed N-methyl-D-aspartate (NMDA) receptor. Activation of NMDA receptors increases sodium and calcium conductance, which depolarizes the neuron, thereby increasing the likelihood that it will fire an action potential.
  • NMDA receptors are widely distributed throughout the brain, with a particularly high density in the cerebral cortex and hippocampal formation.
  • GlyT-1 is found predominantly in the forebrain and its dist ⁇ bution corresponds to that of glutaminergic pathways and NMDA receptors (Smith, et al., Neuron, 8, 1992:927-935).
  • GlyT-la is found predominantly in the forebrain and its dist ⁇ bution corresponds to that of glutaminergic pathways and NMDA receptors (Smith, et al., Neuron, 8, 1992:927-935).
  • GlyT-la three variants of GlyT-1 , termed GlyT-la, GlyT-1 b and GlyT-1 c (Kim, et al., Molecular Pharmacology, 45, 1994:608-617), each of which displays a unique distribution in the brain and peripheral tissues. The variants arise by - 3 -
  • GlyT-2 in contrast, is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors [Liu et ai, J. Biological Chemistry, 268, 1993:22802-220808; Jursky and Nelson, J. Neurochemistry, 64, 1995:1026-1033).
  • Another distinguishing feature of glycine transport mediated by GlyT-2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GlyT-1.
  • GlyT-2 can be used to diminish the activity of neurons having strychnine-sensitive glycine receptors via increasing synaptic levels of glycine, thus diminishing the transmission of pain-related (i.e., nociceptive) information in the spinal cord, which has been shown to be mediated by these receptors (Yaksh, Pain, 37, 1989:111 -123).
  • enhancing inhibitory glycinergic transmission through strychnine-sensitive glycine receptors in the spinal cord can be used to decrease muscle hyperactivity, which is useful in treating diseases or conditions associated with increased muscle contraction, such as spasticity, myoclonus, and epilepsy (Truong er a/., Movement Disorders, 3, 1988:77-89; Becker, FASEB J, 4, 1990:2767-2774).
  • Spasticity that can be treated via modulation of glycine receptors is associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord injury, dystonia, and other conditions of illness and injury of the nervous system.
  • neurodegenerative diseases such as amyotrophic lateral sclerosis can be treated. 4 -
  • the invention provides a class of compounds of Formula I:
  • R 1 is independently selected from the group consisting of H, C 1-4 alkyl and the counter ion for a basic addition salt
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H and dialkyl;
  • R 5 and R 6 are independently selected from the group consisting of H, C ⁇ - 4 alkyl and phenyl;
  • X is selected from the group consisting of CH 2 , S, O, SO, SO 2 , NH and
  • R 7 is selected from the group consisting of Formula ll-V:
  • R 8 is selected from the group consisting of H, d- 6 alkyl, benzyl, cycloalkyi, indanyl and an optionally substituted aromatic or heteroaromatic, 5-10-membered mono- or bicyclic ring wherein the optional substituents are independently selected from 1-4 members of the group consisting of C ⁇ -4 alkyl, halo, phenyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono-d.
  • Z is selected from the group consisting of CH 2 , O, S, NH and NC ⁇ - 4 alkyl when
  • a pharmaceutical composition comprising a compound of Formula VI in an 6 - amount effective to inhibit glycine transport, and a pharmaceutically acceptable carrier.
  • R 1 is independently selected from the group consisting of H, C ⁇ . 4 alkyl and the counter ion for a basic addition salt
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H and d. 4 alkyl;
  • R 5 and R 6 are independently selected from the group consisting of H, C ⁇ . alkyl and phenyl;
  • X is selected from the group consisting of CH 2 , S, O, SO, SO 2 , NH and NC 1-4 alkyl;
  • R 7 is selected from the group consisting of Formula ll-V:
  • R 8 is selected from the group consisting of H, d- 6 alkyl, benzyl, cycloalkyi, indanyl and an optionally substituted aromatic or heteroaromatic,
  • Z is selected from the group consisting of CH 2 , O, S, NH and NCi ⁇ alkyl when is a single bond;
  • Z is selected from the group consisting of CH and N when is a double bond.
  • compositions containing the present compounds in amounts for pharmaceutical use to treat medical conditions for which a glycine transport inhibitor is useful.
  • Particularly amenable are those medical conditions for which inhibition of glycine transport mediated by GlyT-2 is indicated, such as the treatment of diseases or conditions associated with increased muscle contraction; for example, spasticity, myoclonus and epilepsy.
  • Spasticity that can be treated by modulation of glycine receptor activity, via inhibition of glycine reuptake is associated with epilepsy, stroke, head trauma, cerebral palsy, multiple sclerosis, spinal cord injury, dystonia, and other conditions of illness and injury of the nervous system.
  • Chalky as used herein means straight and branched chain alkyl radicals containing from one to four carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.
  • C 1-6 alkyl as used herein means straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl, ⁇ -hexyl and the like.
  • d ⁇ alkoxy as used herein means branched chain alkoxy radicals containing from one to four carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
  • cycloalkyi as used herein means saturated carbocycles containing from 3-7 carbon atoms and includes cyclopropyl, cyclohexyi and the like.
  • aromatic or heteroaromatic, 5-10-membered mono- or bicyclic ring as used herein means a 5-10- membered mono- or bicyclic fully saturated ring optionally containing from one to four heteroatoms optionally selected from O, S and N and includes phenyl, pyridyl, indolyl, napthtyl, thienyl, furanyl, thiazolyl, imidazolyl, benzothienyl and the like.
  • halo means halogen and includes fluoro, chloro, bromo and the like.
  • pharmaceutically acceptable salt means either an acid addition salt or a basic addition salt which is compatible with the treatment of patients.
  • a "pharmaceutically acceptable acid addition salt” is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formulae I and VI or any of its intermediates.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids.
  • Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid.
  • Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form.
  • the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • a "pharmaceutically acceptable basic addition salt” is any non-toxic organic or inorganic base addition salt of the acid compounds represented by Formulae I and VI or any of its intermediates.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxides.
  • salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoline or ammonia.
  • the selection of the appropriate salt may be important so that an ester functionality elsewhere in the molecule is not hydrolyzed.
  • the selection criteria for the appropriate salt will be known to one skilled in the art.
  • Solvate means a compound of Formula I or II or the pharmaceutically acceptable salt of a compound of Formula I or II wherein molecules of a suitable solvent are incorporated in a crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered as the solvate. Examples of suitable solvents are ethanol and the like.
  • stereoisomers is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral centre that are not mirror images of one another (diastereomers).
  • treat or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
  • terapéuticaally effective amount means an amount of the compound which is effective in treating the named disorder or condition.
  • pharmaceutically acceptable carrier means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient.
  • such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration.
  • the present invention includes within its scope prodrugs of the compounds of Formulae I and VI.
  • prodrugs will be functional derivatives of the compounds of Formula I or VI which are readily convertible in vivo into the required compound of Formula I or VI.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985.
  • Suitable values for R 1 are H, dialkyl and the counter ion for a basic addition salt, in particular H, methyl and sodium.
  • R 1 is H or sodium.
  • R 2 , R 3 and R 4 are H and dialkyl, in particular H and methyl.
  • R 2 , R 3 and R 4 are all H.
  • R 5 and R 6 are independently selected from H, C ⁇ -4 alkyl and phenyl, particularly H, methyl and phenyl. In a preferred embodiment, one of R 4 and R 5 is H and the other is methyl.
  • X is selected from O, S, NH and CH 2 .
  • X is O.
  • the compounds of the invention suitably include those where R 7 is selected from one of the groups defined by Formula II, III, IV or V which can be optionally substituted at nodes other than R 8 with 1-4 groups selected from - 12 -
  • C ⁇ -4 alkyl halo, phenyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono-C ⁇ . 4 alkylamino, di-C 1-4 alkylamino, C 1-4 alkoxycarbonyl, d- 4 alkylcarbonyl, d- 4 alkoxythiocarbonyl, C 1-4 alkylthiocarbonyl, C ⁇ . 4 alkoxy, C 1-4 alkylS-, phenoxy, -SO 2 NH2, -SO 2 NHd. 4 alkyl, -SO 2 N(C ⁇ . 4 alkyl) 2 and 1 ,2-methylenedioxy, suitably
  • Y is O.
  • Z is selected from the group consisting of CH 2 , O, S, NH and NCi ⁇ alkyl when is a single bond and Z is selected from the group consisting of CH and N when is a double bond.
  • Suitable groups for R 7 include 9-(R 8 )-9H-fluoren-9-yl, 2-fluoro-9-(R 8 )- 9H-fluoren-9-yl, 9-(R 8 )-9H-xanthen-9-yl, 5-(R 8 )-5H-dibenzo[a.
  • R 7 is unsubstituted 9-(R 8 )-9H-fluoren-9-yl.
  • suitable values for R 8 are selected from H, d- 6 alkyl, benzyl, cycloalkyi, indanyl and an optionally substituted aromatic or heteroaromatic, 5-10-membered mono- or bicyclic ring.
  • Suitable aromatic or heteroaromatic rings include thienyl, furanyl, imidazolyl, thiazolyl, phenyl, pyridyl, naphthyl, indolyl, benzothienyl and the like.
  • substituents on the aromatic or heteroaromatic ring there may be 1-4 substituents on the aromatic or heteroaromatic ring and these substituents are optionally selected from 1-4 members of the group consisting of C ⁇ - alkyl, halo, phenyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono-Ci ⁇ alkylamino, - 13 - di-C ⁇ . alkylamino, C ⁇ . alkoxycarbonyl, C ⁇ alkylcarbonyl, d. 4 alkoxythiocarbonyl, C ⁇ . alkylthiocarbonyl, C ⁇ . 4 alkoxy, C ⁇ . 4 alkylS-, phenoxy, - SO 2 NH 2 ,
  • R 8 is selected from H, C ⁇ -4 alkyl, benzyl, cyclohexyi, and thienyl, phenyl and naphthyl which are optionally substituted with 1-3 substituents selected from methyl, ethyl, bromo, chloro, fluoro, phenyl, trifluoromethyl and methoxy.
  • R 8 Particular values for R 8 include H, phenyl, thien-2-yl, 3-methylphenyl,
  • R 8 is phenyl and thien-2-yl both optionally substituted with one substituent selected from methyl, ethyl, methoxy, chloro, fluoro and trifluoromethyl.
  • the compounds of Formulae I and VI include:
  • the compounds of Formulae I and VI include:
  • Formulae I and VI include:
  • the compounds of Formulae I and VI include:
  • the compounds of Formulae I and VI include: - 21 -
  • the compounds in labeled form can be used to identify GlyT-2 transporter ligands by techniques common in the art. This can be achieved by incubating the tissue or cells that express the transporter in the presence of a ligand candidate and an equimolar amount of radiolabeled compound of the invention such as 0-(9-phenyl-9/- -fluoren-9-yl)-L- threonine. GlyT-2 ligands are thus revealed as those that significantly prevent the binding of the radiolabeled compound of the present invention.
  • GlyT-2 transporter ligands may be identified by first incubating a radiolabeled form of a compound of the invention and then incubating the resulting preparation in the presence of a candidate ligand. A more potent GlyT-2 transporter ligand will, at equimolar concentration, displace the radiolabeled compound of the invention.
  • Further uses of the radiolabeled compound of the invention include identification of allosteric modulators of GlyT-2 and measuring the rate constants (ko ⁇ and koff) of ligands that bind to GlyT-2. Allosteric modulators will be identified as compounds that inhibit GlyT-2 function (i.e. inhibit glycine transport) but do not displace the radiolabeled compound of the present invention.
  • the on and off rate constants of the radiolabeled compound of the invention can be assessed by incubating the radiolabeled compound with tissues or cells expressing the transporter and then diluting the mix such that the concentration of radiolabeled compound is reduced below its equilibrium dissociation constant (Kd).
  • Kd equilibrium dissociation constant
  • the rate of association and dissociation can then be calculated by techniques common in the art.
  • the rate constants of GlyT-2 transporter ligand candidates may also be - 22 -
  • the radiolabeled compound of interest will be useful for tissues that express GlyT-2 by either standard membrane binding techniques or autoradiography. These techniques can also be used to identify pathophysiol ⁇ gical conditions that result in a change in expression level of GlyT-2.
  • Acid addition salts of the compounds of Formula I and VI are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids e.g. hydrochloric, sulphuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic orfumaric acid.
  • Other non- pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I and VI for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • solvates and hydrates of the invention are also included within the scope of the invention.
  • Basic addition salts of the compounds of Formula I and VI are most suitably formed from pharmaceutically acceptable bases and include for example, those formed with inorganic bases, e.g. sodium, potassium, calcium, magnesium or barium hydroxides, or aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoline or ammonia.
  • inorganic bases e.g. sodium, potassium, calcium, magnesium or barium hydroxides
  • aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoline or ammonia.
  • the selection of the appropriate salt may be important so that the ester is not hydroiyzed.
  • the selection criteria for the appropriate salt will be known to one skilled in the art.
  • aqueous solution of the given salt is treated with a solution of base, e.g. sodium carbonate or potassium hydroxide, until the desired pH is reached to liberate the free base but not deprotonate the carboxylic acid if present.
  • base e.g. sodium carbonate or potassium hydroxide
  • the free base is then extracted into an appropriate solvent, such as ether, and then separated from the aqueous - 23 -
  • an aqueous solution of the basic addition given salt is treated with a solution of acid, e.g. hydrochloric acid or sulfuric acid, until the desired pH is reached to liberate the free base but not protonate the amine.
  • the free base is then extracted into an appropriate solvent, such as ether, and then separated from the aqueous portion, dried, and treated with the requisite base to give the desired basic addition salt.
  • All of the compounds of the present invention have at least one chiral center.
  • the invention extends to cover all structural and optical isomers of the various compounds, as well as racemic mixtures thereof.
  • the compounds of the present invention can be prepared by processes analogous to those established in the art.
  • compounds of Formulae I and VI may be prepared as shown in Scheme 1.
  • Suitable acids include sulfuric acid, trifluoroacetic acid, p- toluenesulfonic acid, camphor sulfonic acid or various Lewis acids such as BF 3 OEt 2 , with p-toluenesulfonic acid being preferred.
  • Suitable aprotic solvents include toluene, benzene, methylene chloride, chloroform and 1 ,2- dichloroethane, with toluene being preferred. This reaction can be carried out at a temperature in the range of 0-120 °C, preferably 20-120 °C. Removal of the nitrogen protecting group (PG 1 ) can be performed using standard 24
  • R 4 -R 7 are as defined above, R 1 is d- 4 alkyl and one of R 2 and R 3 is selected from H and C ⁇ . 4 alkyl and the other is H (Formula C below).
  • removal of the Fmoc protecting group may be achieved using piperidine either neat or in an inert solvent such as DMF, toluene, benzene or methylene chloride at temperatures in the range of 0 to 100 °C.
  • Preferred conditions are neat piperidine at about room temperature.
  • a amino acid derivative of Formula F wherein X is selected from O, NH or NC ⁇ . alkyl, R is d. 4 alkyl, one of R 2 and R 3 is selected from H and C ⁇ . 4 alkyl and the other is PG 2 , wherein PG 2 is an appropriate protecting group such as f-BOC, and R 4 -R 6 are as defined in Formulae I and VI, under standard alkylating conditions, for example sodium bicarbonate, potassium carbonate or trialkylamine, in an inert solvent such as acetone or acetonitrile at temperatures in the range of 0 to 100 °C. Preferred conditions are potassium carbonate in acetonitrile at room temperature.
  • the reaction may be conducted in the presence of an iodide salt such as potassium iodide.
  • an iodide salt such as potassium iodide.
  • Removal of the protecting group (PG 2 ) can be performed under standard conditions to provide compounds of Formulae I and VI wherein R 1 , R -R 7 are as defined above and one of R 2 and R 3 is selected from H and C ⁇ -4 alkyl and the other is H (Formula G below).
  • Hydrolysis of the ester function can be performed as described above to provide compounds of Formulae I and VI wherein R 1 is H.
  • toluenesulfonic acid camphorsulfonic acid and the like and suitable solvents include methylene chloride, chloroform, toluene and the like.
  • suitable solvents include methylene chloride, chloroform, toluene and the like.
  • Preferred reaction conditions are neat trifluoroacetic acid at room temperature.
  • R 1 is C 1-4 alkyl
  • the ester functionality of the compounds of Formula J may be hydrolyzed as described above to provide compounds of Formulae I and VI wherein R 1 is H.
  • Compounds of Formula J can be oxidized under standard conditions, for example either 1 or 2 equivalents of t ⁇ -chloroperbenzoic acid in methylene chloride, to provide compounds of Formula I and VI wherein X is SO and SO 2 respectively.
  • ⁇ -aminonitriles K wherein R 2 -R 7 are as defined in Formula I and VI, may be hydrolyzed to the desired free ⁇ -amino acid L, wherein R 2 -R 7 are as defined in Formula I and VI, by any well known hydrolysis reaction for nitriles, for example, with a base (preferably a hydroxide, e.g.
  • Compounds of Formula L may be esterified using standard esterification methods (e.g. SOCI 2 and d. 4 alkanol) to provide compounds of Formula I and VI wherein R 1 is d. alkyl, or these compounds - 27 - may be isolated directly from the hydrolysis of the nitrile by substituting a Ci. alkanol for water as the solvent.
  • standard esterification methods e.g. SOCI 2 and d. 4 alkanol
  • hydrolysis of hydantoin compounds M, wherein R 2 -R 7 are as defined in Formula I and VI using well known methods provides the corresponding amino acids N (compounds of Formulae I and VI wherein one of R 2 and R 3 is H and the other is selected from H and dialkyl, R 1 is H and R 4 -R 7 are as defined above).
  • This hydrolysis is effected, for example, by treatment of compounds of Formula M with most alkali or alkaline earth hydroxides (preferably sodium hydroxide).
  • Compounds of Formula N may be esterified using standard esterification methods (e.g. SOCI 2 and Ci ⁇ alkanol) to provide compounds of Formula I and VI wherein R 1 is C ⁇ -4 alkyl.
  • ⁇ -aminonitriles K or hydantoins M are both conveniently prepared from the corresponding aldehydes or ketones of Formula P, wherein X is selected from CH 2 , S and O and R -R 7 are as defined in Formulae I and VI, as shown in Scheme 6.
  • nitriies are available by reaction of compounds of Formula P under well-known Strecker conditions, such as reaction with a mixture of sodium or potassium cyanide and ammonia, Ci ⁇ alkylamines (ethylamine, butylamine and the like), di-C 1-4 alkylamines (dimethylamine, ethylpropylamine and the like), phenylamine or phenyl C 1-4 alkylamines (phenethylamine, phenyl-methylamine and the like) at any suitable temperature, preferably at or near room temperature.
  • Strecker conditions such as reaction with a mixture of sodium or potassium cyanide and ammonia, Ci ⁇ alkylamines (ethylamine, butylamine and the like), di-C 1-4 alkylamines (dimethylamine, ethylpropylamine and the like), phenylamine or phenyl C 1-4 alkylamines (phenethylamine, phenyl-methylamine and the like)
  • Hydantoins M are prepared using any well known method for converting compounds of Formula P to a hydantoin, for example, reaction in an inert solvent such as d- alkanols with a mixture of an alkali cyanide and ammonium carbonate at elevated temperatures and optionally in a sealed tube.
  • Preferred conditions are potassium cyanide and ammonium carbonate in aqueous ethanol in a sealed tube at a temperature in the range of 20-120 °C (preferably 50-120 °C).
  • Conditions suitable to affect the transformation of Q to P include treating reagents Q with sodium in a lower alkanol followed by addition of reagents R or S at temperatures in the range of -80 °C to room temperature. Deprotection of the resulting intermediates may be performed in the presence of acid in an inert solvent at a temperature in the range of 20-100 °C. During this latter reaction, care must be taken so as not to hydrolyze the "R 7 -X-" functionality.
  • reagents U wherein R 7 is as defined in Formulae I and VI, is treated with a strong base such as an alkyl lithium, in an inert solvent such as tetrahydrofuran or hexanes, at temperatures in the range of -80 to 20 °C, followed by the addition of either reagents V (when R 4 is H) or reagents W, (when R 4 is d- 4 alkyl), wherein X is CH 2 , R 4 -R 6 are as defined in Formulae I and VI, Y is an appropriate leaving group, such as halo or tosylate and PG 3 is as defined in Formula R.
  • a strong base such as an alkyl lithium
  • an inert solvent such as tetrahydrofuran or hexanes
  • Preferred reaction conditions are n-butyllithium in hexanes at 0 °C.
  • Deprotection of the resulting intermediate in the presence of acid in an inert solvent at a temperature in the range of 20-100 °C , preferably p- toluenesulfonic acid in acetone at a refluxi ⁇ g temperature, provides compounds of Formula P, wherein X is CH 2 and R -R 7 are as defined in - 32 -
  • reagents U wherein R 7 is as defined in Formulae I and VI, are treated with a strong base such as an alkyl lithium, in an inert solvent such as tetrahydrofuran or hexanes, at temperatures in the range of -80 to 20 °C, followed by the addition of reagents Z, wherein Y is an appropriate leaving group, such as halo or tosylate, X is CH 2 and PG 4 is as defined in Formula T, followed by deprotection in the presence of a suitable acid (e.g. HCI) and oxidation using standard conditions (for example Swern oxidation) to provide compounds of Formula P, wherein X is CH 2 and R 4 -R 7 are as defined in Formulae I and VI.
  • a strong base such as an alkyl lithium
  • an inert solvent such as tetrahydrofuran or hexanes
  • alkyl amine derivatives of the compounds of Formulae I and VI are readily formed by the reaction of primary or secondary amines of, for example, compounds of Formulae D, G and J, with compounds of Formula - 33 -
  • R 2 3 -Y wherein Y is an appropriate leaving group and R /3 is C ⁇ . alkyl, under standard alkylation conditions.
  • Primary amines of compounds of Formulae D, G and J may also be treated under standard reductive alkylation conditions with aldehydes of Formula R 2/3 -C(O)H to provide monoalkylated compounds of Formulae I and VI which may be further alkylated under standard conditions with compounds of Formula R 23 -Y, to provide the corresponding secondary amines.
  • Compounds of Formulae B, F and H are well known amino acids and derivatives thereof. These compounds are commercially available in both racemic and enantiomerically pure forms or can be prepared using methods known to one skilled in the art (for example see Carpino, L. A.; Han, G. Y. J. Am. Chem. Soc. 92, 1970:5748-5749 and Paquet, A. Can. J. Chem. 60, 1982:976).
  • Reagents R, S, T, U, V and W are all well known alkanols and derivatives thereof which are either commercially available or readily prepared from commercially available materials using methods known to one skilled in the art.
  • Reagents of Formula A, wherein R 8 is not H are readily available from the addition of appropriately substituted Grignard reagents or alkyl and aryl lithiums, wherein R 8 is as defined in Formulae I and VI and Y is, for example, halo, preferably bromo or chloro, to the corresponding ketones under standard conditions as shown in Scheme 9 for compounds of Formulae I and VI wherein R 7 is a group of Formula II and R 8 is as defined in Formulae I and VI (other than H).
  • Reagents of Formula A wherein R 8 is H are readily available by reduction of the corresponding ketone using any well known reducing agent, for example metal hydrides, such as lithium aluminum hydride, in an inert solvent, such as tetrahydrofuran, and at temperatures in the range of -50-100 °C, suitably -20-60 °C.
  • metal hydrides such as lithium aluminum hydride
  • inert solvent such as tetrahydrofuran
  • Reagents of Formula A may be converted to reagents of Formula E, T and Q using well known chemistries as shown in Scheme 10 for compounds of Formulae E, T and Q wherein R 7 is a group of Formula II.
  • compounds of Formula A may be treated with hydrogen sulfide in the presence of an acid or an alkali or alkali earth hydrosulfide (preferably sodium hydrosulfide) in an inert solvent (preferably Ci ⁇ alkanols) at elevated temperatures, preferably at or near the reflux temperature of the system.
  • Y is an appropriate leaving group, for example halo or tosylate
  • Y is bromo or chloro
  • Y is bromo or chloro
  • Y can be any appropriate leaving group which is available using standard chemistries.
  • Compounds of Formula T may be prepared by the reduction of - 35 -
  • ketone precursors to compounds of Formula A may be purchased or prepared using standard procedures known to those skilled in the art.
  • the chemistries outlined above may have to be modified, for instance by use of protecting groups, to prevent side reactions due to reactive groups, such as reactive groups attached as substituents.
  • R 1 can be a residue other than hydrogen representing functionalized resin or suitably selected linker attached to - 36 -
  • the linker should be stable under the conditions employed for the above-described reactions.
  • the compounds of the invention where R 1 is hydrogen are then cleaved from the resin or the linker leaving the remainder of the molecule intact.
  • solid-phase synthesis of peptoids [oligo(N-substituted glycines)] using a robotic synthesizer was described by Zuckermann et al., J. Am. Chem. Soc. 114, 1992:10646-10647 and Spellmeyer et al. WO 95/04072.
  • the present compounds are useful as pharmaceuticals for the treatment of various conditions in which the use of a glycine transport inhibitor is indicated.
  • Particularly amenable are those medical conditions for which inhibition of glycine transport mediated by GlyT-2 is needed, such as the treatment of diseases or conditions associated with increased muscle contraction; for example, spasticity, myoclonus and epilepsy.
  • GlyT-2 refers to those glycine transporters found predominantly in the brain stem and spinal cord and the distribution of which corresponds closely to that of strychnine-sensitive glycine receptors (Liu et al. J. Biological Chemistry, 268, 1993:22802-22808; Jursky and Nelson, J. Neurochemistry, 64, 1995: 1026-1033).
  • Another distinguishing feature of glycine transport mediated by GlyT-2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GlyT-1.
  • the compounds of the present invention can be administered in a standard pharmaceutical composition.
  • the present invention therefore provides, in a further aspect, pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a Formula VI compound or a pharmaceutically acceptable salt, solvate or hydrate thereof, in an amount effective to treat the target indication.
  • the compounds of the present invention may be administered by any convenient route, for example by oral, parenteral, buccal, sublingual, nasal, - 37 -
  • Compounds of Formula I and VI and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, or as solid forms such as tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutical liquid carrier for example, ethanol, glycerine, non- aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier, for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension filled into a soft gelatin capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically - 38 -
  • aqueous or non-aqueous solvent are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • the physician or other health care professional can select the appropriate dose and treatment regimen based on the subject's weight, age and physical condition. Dosages will generally be selected to maintain a serum level of compounds in the invention between about 0.01 ⁇ g/cc and about 1000 ⁇ g/cc, preferably between about 0.1 ⁇ g/cc and 100 ⁇ g/cc.
  • an alternative measure of preferred amount is from about 0.001 mg/kg to about 10 mg/kg (alternatively, from about 0.01 mg/kg to about 10 mg/kg), more preferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg), will be administered.
  • an alternative measure of preferred administration amount is from about 0.001 mg/kg to about 10 mg/kg (from about 0.1 mg/kg to about 10 mg/kg), more preferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg).
  • an alternative measure of preferred administration amount is from about 0.1 mg/kg to about 10 mg/kg, more preferably from about 0.1 mg/kg to about 1 mg/kg.
  • the reaction mixture was stirred at room temperature for 1 h, poured into a saturated solution of ammonium chloride (5 mL) and extracted with dichloromethane (3 x 20 mL). The combined dichloromethane extracts were washed with brine (10 mL), dried (MgSO 4 ), the solvent evaporated and the residue chromatographed on silica gel column with 10% ethyl acetate in hexanes to give the title compound as an oil.
  • Step 1 ⁇ ⁇ -(9-Fluorenylmethoxycarbonyl)-O-(9-phenyl-9H -fluoren-9-yl)-L- serine methyl ester:
  • Step 2 0-(9-Phenyl-9H-fluoren-9-yl)-L-serine methyl ester:
  • Step 3 O-(9-Phenyl-9H-fluoren-9-yl)-L-serine: - 45 -
  • Step 1
  • Step 2 - 52 -
  • the alkaline aqueous phase was acidified with 20% acetic acid by cooling with an ice bath the white precipitate was filtered, washed with water and dried in vacuo over P 2 O 5 to give 0.027 g (yield 90%) ⁇ /-methyl-0-(9-phenyl-9H-fluoren-9-yl)-L- serine as a white powder.
  • Step 1
  • Step 2 - 53 -
  • Step 1 ⁇ / ⁇ -(9-Fuorenylmethoxycarbo ⁇ yl)- ⁇ / ⁇ -(9-phenyl-9H-fluoren-9-yl)-DL- ⁇ , ⁇ -diaminopropionic acid methyl ester
  • Step 2 ⁇ / ⁇ -(9-Phenyl-9/-/-fluoren-9-yl)-DL- ⁇ , ⁇ -diaminopropionic acid methyl ester
  • Step 2 deprotection of the 9- fluorenylmethoxycarbonyl (Fmoc) group of ⁇ / ⁇ -(9-fluorenylmethoxycarbonyl)- N ⁇ -(9-phenyl-9H-fluoren-9-yl)-DL- ⁇ , ⁇ -diaminopropionic acid methyl ester from Step 1 gave ⁇ / ? -(9-phenyl-9H-fluoren-9-yl)- ⁇ , ⁇ -DL-propionic acid methyl - 56 -
  • Step 3 Hydrolysis of the methyl ester from Step 2 with methanolic sodium hydroxide (like in Example 4a, Step 3) provided /V*-(9-phenyl-9H-fluoren-9- yl)-DL- ⁇ , ⁇ -diaminopropionic acid as a yellow powder.
  • Step 1 3-(9-Phenyl-9H-fluoren-9-yl)propanol
  • Step 4 4-(9-Phenyl-9H-fluoren-9-yl)-DL-2-aminobutyric acid hydrochloride
  • This example illustrates a method for the measurement of glycine uptake by transfected cultured cells.
  • Cells transiently transfected with human GlyT-1 C see Kim, et al., Molecular
  • HBS HEPES buffered saline
  • a concentration of a candidate drug was added.
  • a range of concentrations of the candidate drug was used to generate data for calculating the concentration resulting in 50% of the effect (e.g., the ICso's which are the concentration of drug inhibiting glycine uptake by 50%).
  • the cells were then incubated another 10 minutes at 37 °C, after which the cells were aspirated and washed three times with ice-cold HBS. The cells were harvested, scintilla ⁇ t was added to the cells, the cells were shaken for 30 minutes, and the radioactivity in the cells was counted using a scintillation counter. Data were compared between the same cells contacted and not contacted by the candidate agent, and between cells having GlyT-1 activity versus cells having GlyT-2 activity, depending on the assay being conducted.

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Abstract

The present invention relates to a class of substituted amino acids, pharmaceutical compositions and methods of treating neurological and neuropsychiatric disorders.

Description

Tricyclic Compounds As Glycine Transport Inhibitors
The present invention relates to a class of substituted amino acids, pharmaceutical compositions and methods of treating neurological and neuropsychiatric disorders.
Synaptic transmission is a complex form of intercellular communication that involves a considerable array of specialized structures in both the pre- and post-synaptic terminal and surrounding glial cells (Kanner and Schuldiner, CRC Critical Reviews in Biochemistry, 22, 1987:1032). Transporters sequester neurotransmitter from the synapse, thereby regulating the concentration of neurotransmitter in the synapse, as well as its duration therein, which together influence the magnitude of synaptic transmission. Further, by preventing the spread of transmitter to neighbouring synapses, transporters maintain the fidelity of synaptic transmission. Last, by sequestering released transmitter into the presyπaptic terminal, transporters allow for transmitter reutilization.
Neurotransmitter transport is dependent on extracellular sodium and the voltage difference across the membrane; under conditions of intense neuronal firing, as, for example, during a seizure, transporters can function in reverse, releasing neurotransmitter in a calcium-independent non-exocytotic manner (Attwell et al., Neuron, 11 , 1993:401-407). Pharmacologic modulation of neurotransmitter transporters thus provides a means for modifying synaptic activity, which provides useful therapy for the treatment of neurological and psychiatric disturbances.
The amino acid glycine is a major neurotransmitter in the mammalian central nervous system, functioning at both inhibitory and excitatory synapses. By nervous system, both the central and peripheral portions of the nervous system are intended. These distinct functions of glycine are - 2 -
mediated by two different types of receptor, each of which is associated with a different class of glycine transporter. The inhibitory actions of glycine are medicated by glycine receptors that are sensitive to the convulsant alkaloid strychnine, and are thus referred to as "strychnine-sensitive". Such receptors contain an intrinsic chloride channel that is opened upon binding of glycine to the receptor; by increasing chloride conductance, the threshold for firing of an action potential is increased. Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brainstem, and pharmacological agents that enhance the activation of such receptors will thus increase inhibitory neurotransmission in these regions.
Glycine also functions in excitatory transmission by modulating the actions of glutamate, the major excitatory neurotransmitter in the central nervous system. See Johnson and Ascher, Nature, 325, 1987:529-531 ; Fletcher et al., Glycine Transmission, Otterson and Storm- athisen, eds., 1990:193-219. Specifically, glycine is an obligatory co-agonist at the class of glutamate receptor termed N-methyl-D-aspartate (NMDA) receptor. Activation of NMDA receptors increases sodium and calcium conductance, which depolarizes the neuron, thereby increasing the likelihood that it will fire an action potential. NMDA receptors are widely distributed throughout the brain, with a particularly high density in the cerebral cortex and hippocampal formation.
Molecular cloning has revealed the existence in mammalian brains of two classes of glycine transporters, termed GlyT-1 and GlyT-2. GlyT-1 is found predominantly in the forebrain and its distπbution corresponds to that of glutaminergic pathways and NMDA receptors (Smith, et al., Neuron, 8, 1992:927-935). Molecular cloning has further revealed the existence of three variants of GlyT-1 , termed GlyT-la, GlyT-1 b and GlyT-1 c (Kim, et al., Molecular Pharmacology, 45, 1994:608-617), each of which displays a unique distribution in the brain and peripheral tissues. The variants arise by - 3 -
differential splicing and exon usage, and differ in their N-terminal regions. GlyT-2, in contrast, is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors [Liu et ai, J. Biological Chemistry, 268, 1993:22802-220808; Jursky and Nelson, J. Neurochemistry, 64, 1995:1026-1033). Another distinguishing feature of glycine transport mediated by GlyT-2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GlyT-1. These data are consistent with the view that, by regulating the synaptic levels of glycine, GlyT-1 and GlyT-2 selectively influence the activity of NMDA receptors and strychnine-sensitive glycine receptors, respectively.
Compounds that inhibit or activate glycine transporters would thus be expected to alter receptor function, and provide therapeutic benefits in a variety of disease states. For example, inhibition of GlyT-2 can be used to diminish the activity of neurons having strychnine-sensitive glycine receptors via increasing synaptic levels of glycine, thus diminishing the transmission of pain-related (i.e., nociceptive) information in the spinal cord, which has been shown to be mediated by these receptors (Yaksh, Pain, 37, 1989:111 -123). Additionally, enhancing inhibitory glycinergic transmission through strychnine-sensitive glycine receptors in the spinal cord can be used to decrease muscle hyperactivity, which is useful in treating diseases or conditions associated with increased muscle contraction, such as spasticity, myoclonus, and epilepsy (Truong er a/., Movement Disorders, 3, 1988:77-89; Becker, FASEB J, 4, 1990:2767-2774). Spasticity that can be treated via modulation of glycine receptors is associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord injury, dystonia, and other conditions of illness and injury of the nervous system. In addition, neurodegenerative diseases such as amyotrophic lateral sclerosis can be treated. 4 -
Summary of the Invention
According to one aspect of the invention, there are provided compounds that inhibit glycine transport via the GlyT-2 transporters, or are precursors, such as prodrugs, to compounds that inhibit such transport. Thus, the invention provides a class of compounds of Formula I:
Figure imgf000006_0001
OR1
R5 R3^ ^R2
or a prodrug or pharmaceutically acceptable salt, solvate or hydrate thereof wherein:
R1 is independently selected from the group consisting of H, C1-4alkyl and the counter ion for a basic addition salt;
R2, R3 and R4 are independently selected from the group consisting of H and dialkyl;
R5 and R6 are independently selected from the group consisting of H, Cι-4alkyl and phenyl;
X is selected from the group consisting of CH2, S, O, SO, SO2, NH and
NC^alkyl; R7 is selected from the group consisting of Formula ll-V:
Figure imgf000006_0002
Figure imgf000006_0003
Figure imgf000006_0004
IV V - 5 -
which are all optionally substituted, at nodes other than R8, with 1-4 substituents independently selected from the group consisting of C1-4alkyl, halo, phenyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono-Ci. 4alkylamino, di-Cι.4alkylamino, Cι-4alkoxycarbonyl, Cι. alkylcarbonyl, d- alkoxythiocarbonyl, d.4alkylthiocarbonyl, Cι_4alkoxy, d.4alkylS-, phenoxy, -
SO2NH2,
-SO2NHCι-4alkyl, -SO2N(C1-4alkyl)2 and 1 ,2-methylenedioxy; and wherein R8 is selected from the group consisting of H, d-6alkyl, benzyl, cycloalkyi, indanyl and an optionally substituted aromatic or heteroaromatic, 5-10-membered mono- or bicyclic ring wherein the optional substituents are independently selected from 1-4 members of the group consisting of Cι-4alkyl, halo, phenyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono-d.4alkylamino, di-Ci^alkylamino, d^alkoxycarbonyl, C1-4alkylcarbonyl, Cι-4alkoxythiocarbonyl, Cι.4alkylthiocarbonyl, Cι-4alkoxy, Ci^alkylS-, phenoxy, -SO2NH2, -SO2NHCι-4alkyl, -SO2N(C1-4alkyl)2 and 1 ,2-methylenedioxy;
— represents a single or double bond;
Y is selected from the group consisting of O, S, SO, NH, NC1-4alkyl, CH2, CH-C^alkyl, C(C1-4alkyl)2, and C=O; Z is selected from the group consisting of CH2, O, S, NH and NCι-4alkyl when
— is a single bond;
Z is selected from the group consisting of CH and N when is a double bond; and with the provisos that: when X is S, R8 is not H; when X is S and R7 is a group of Formula II, then R8 is not optionally substituted phenyl; and when X is S and R7 is a group of Formula III with X = O, then R8 is not unsubstituted phenyl.
According to another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of Formula VI in an 6 - amount effective to inhibit glycine transport, and a pharmaceutically acceptable carrier.
R6 o
Figure imgf000008_0001
OR1 VI
R5 R3/ \R2
or a prodrug or pharmaceutically acceptable salt, solvate or hydrate thereof wherein:
R1 is independently selected from the group consisting of H, Cι.4alkyl and the counter ion for a basic addition salt; R2, R3 and R4 are independently selected from the group consisting of H and d.4alkyl;
R5 and R6 are independently selected from the group consisting of H, Cι. alkyl and phenyl;
X is selected from the group consisting of CH2, S, O, SO, SO2, NH and NC1-4alkyl;
R7 is selected from the group consisting of Formula ll-V:
Figure imgf000008_0002
II III IV v which are all optionally substituted, at nodes other than R8, with 1 -4 substituents independently selected from the group consisting of d.4alkyl, halo, phenyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono-Ci- 4alkylamino, - 7 - di-Cι-4alkylamino, Cι. alkoxycarbonyl, Cι.4alkylcarbonyl, Ci- alkoxythiocarbonyl,
Cι. alkylthiocarbonyl, Cι.4alkoxy, Cι.4alkylS-, phenoxy, -SO2NH2, -SO2NHCι.
4alkyl, -SO2N(Cι. alkyl)2 and 1 ,2-methylenedioxy; and wherein R8 is selected from the group consisting of H, d-6alkyl, benzyl, cycloalkyi, indanyl and an optionally substituted aromatic or heteroaromatic,
5-10-membered mono- or bicyclic ring wherein the optional substituents are independently selected from 1-4 members of the group consisting of d- alkyl, halo, phenyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono-Ci^alkylamino, di-d- alkylamiπo, C -4alkoxycarbonyl, Cι- alkylcarbonyl,
Cι- alkoxythiocarbonyl, Cι- alkylthiocarbonyl, d^alkoxy, C1- alkylS-, phenoxy,
-SO2NH2, -SO2NHCι-4alkyl, -SO2N(C1-4alkyl)2 and 1 ,2-methylenedioxy;
— represents a single or double bond;
Y is selected from the group consisting of O, S, SO, NH, NC^alkyl, CH2, CH-C1-4alkyl, C(d-4alkyl)2l and C=O;
Z is selected from the group consisting of CH2, O, S, NH and NCi^alkyl when is a single bond; and
Z is selected from the group consisting of CH and N when is a double bond.
In another aspect of the present invention there are provided compositions containing the present compounds in amounts for pharmaceutical use to treat medical conditions for which a glycine transport inhibitor is useful. Particularly amenable are those medical conditions for which inhibition of glycine transport mediated by GlyT-2 is indicated, such as the treatment of diseases or conditions associated with increased muscle contraction; for example, spasticity, myoclonus and epilepsy. Spasticity that can be treated by modulation of glycine receptor activity, via inhibition of glycine reuptake, is associated with epilepsy, stroke, head trauma, cerebral palsy, multiple sclerosis, spinal cord injury, dystonia, and other conditions of illness and injury of the nervous system. In addition, neurodegenerative - 8 -
diseases such as amyotrophic lateral sclerosis can be treated. These and other aspects of the present invention are described in greater detail hereinbelow.
Definitions
The term "Chalky!" as used herein means straight and branched chain alkyl radicals containing from one to four carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.
The term "C1-6alkyl" as used herein means straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl, π-hexyl and the like.
The term "d^alkoxy" as used herein means branched chain alkoxy radicals containing from one to four carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
The term "cycloalkyi" as used herein means saturated carbocycles containing from 3-7 carbon atoms and includes cyclopropyl, cyclohexyi and the like.
The term "optionally substituted aromatic or heteroaromatic, 5-10-membered mono- or bicyclic ring" as used herein means a 5-10- membered mono- or bicyclic fully saturated ring optionally containing from one to four heteroatoms optionally selected from O, S and N and includes phenyl, pyridyl, indolyl, napthtyl, thienyl, furanyl, thiazolyl, imidazolyl, benzothienyl and the like.
The term "1 ,2-methylenedioxy" as used herein means "-O-CH2-O-" attached to adjacent nodes of a ring. The term halo as used herein means halogen and includes fluoro, chloro, bromo and the like.
The term "pharmaceutically acceptable salt" means either an acid addition salt or a basic addition salt which is compatible with the treatment of patients.
A "pharmaceutically acceptable acid addition salt" is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formulae I and VI or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
A "pharmaceutically acceptable basic addition salt" is any non-toxic organic or inorganic base addition salt of the acid compounds represented by Formulae I and VI or any of its intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxides. Illustrative organic bases which form suitable - 10 -
salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoline or ammonia. The selection of the appropriate salt may be important so that an ester functionality elsewhere in the molecule is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
"Solvate" means a compound of Formula I or II or the pharmaceutically acceptable salt of a compound of Formula I or II wherein molecules of a suitable solvent are incorporated in a crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered as the solvate. Examples of suitable solvents are ethanol and the like.
The term "stereoisomers" is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral centre that are not mirror images of one another (diastereomers).
The term "treat" or "treating" means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
The term "therapeutically effective amount" means an amount of the compound which is effective in treating the named disorder or condition.
The term "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One - 1 1 -
example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration.
The present invention includes within its scope prodrugs of the compounds of Formulae I and VI. In general, such prodrugs will be functional derivatives of the compounds of Formula I or VI which are readily convertible in vivo into the required compound of Formula I or VI. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs" ed. H. Bundgaard, Elsevier, 1985.
Detailed Description and Preferred Embodiments
Suitable values for R1 are H, dialkyl and the counter ion for a basic addition salt, in particular H, methyl and sodium. Preferably, R1 is H or sodium.
Suitable values for R2, R3 and R4 are H and dialkyl, in particular H and methyl. Preferably R2, R3 and R4 are all H.
In embodiments of the invention, R5 and R6 are independently selected from H, Cι-4alkyl and phenyl, particularly H, methyl and phenyl. In a preferred embodiment, one of R4 and R5 is H and the other is methyl.
The values for X are suitably selected from the group consisting of
CH2, S, O, SO, SO2, NH and NCι-4alkyl. In specific embodiments, X is selected from O, S, NH and CH2. Preferably X is O.
The compounds of the invention suitably include those where R7 is selected from one of the groups defined by Formula II, III, IV or V which can be optionally substituted at nodes other than R8 with 1-4 groups selected from - 12 -
Cι-4alkyl, halo, phenyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono-Cι.4alkylamino, di-C1-4alkylamino, C1-4alkoxycarbonyl, d-4alkylcarbonyl, d-4alkoxythiocarbonyl, C1-4alkylthiocarbonyl, Cι.4alkoxy, C1-4alkylS-, phenoxy, -SO2NH2, -SO2NHd.4alkyl, -SO2N(Cι.4alkyl)2 and 1 ,2-methylenedioxy, suitably
1-2 groups selected from methyl, bromo, flouro, chloro or methoxy. Within the group of Formula III, Y is suitably selected from O, S, SO, NH, NCι. alkyl, CH2, CH-Cι-4alkyl, C(Cι-4alkyl)2, and C=O, specifically O, S and CMe2. In preferred embodiments, Y is O. Within the group of Formula IV, represents a single or double bond and Z is selected from the group consisting of CH2, O, S, NH and NCi^alkyl when is a single bond and Z is selected from the group consisting of CH and N when is a double bond. In specific embodiments, is a single bond and Z is CH2 or is a double bond and Z is CH.
Suitable groups for R7 include 9-(R8)-9H-fluoren-9-yl, 2-fluoro-9-(R8)- 9H-fluoren-9-yl, 9-(R8)-9H-xanthen-9-yl, 5-(R8)-5H-dibenzo[a. ]cyclohepten- 5-yl, 9-(R8)-9H-thioxantheπ-9-yl, 10,10-dimethyl-9-(R8)-9,10-dihydroanthracen-9-yl, 10,11 -dihydro-5-(R8)-5/-/-dibenzo[a,d]cyclohepten-5-yl, 2,7-dibromo-9-(R8)- 9H-fluoren-9-yl and 2,7-dichloro-9-(R8)-9H-fluoren-9-yl. Preferably, R7 is unsubstituted 9-(R8)-9H-fluoren-9-yl.
Within R7, suitable values for R8 are selected from H, d-6alkyl, benzyl, cycloalkyi, indanyl and an optionally substituted aromatic or heteroaromatic, 5-10-membered mono- or bicyclic ring. Suitable aromatic or heteroaromatic rings include thienyl, furanyl, imidazolyl, thiazolyl, phenyl, pyridyl, naphthyl, indolyl, benzothienyl and the like. There may be 1-4 substituents on the aromatic or heteroaromatic ring and these substituents are optionally selected from 1-4 members of the group consisting of Cι- alkyl, halo, phenyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono-Ci^alkylamino, - 13 - di-Cι. alkylamino, Cι. alkoxycarbonyl, C^alkylcarbonyl, d. 4alkoxythiocarbonyl, Cι. alkylthiocarbonyl, Cι.4alkoxy, Cι.4alkylS-, phenoxy, - SO2NH2,
-SO2NHCι. alkyl, -SO2N(Cι-4alkyl)2 and 1 ,2-methylenedioxy. More specifically, R8 is selected from H, Cι-4alkyl, benzyl, cyclohexyi, and thienyl, phenyl and naphthyl which are optionally substituted with 1-3 substituents selected from methyl, ethyl, bromo, chloro, fluoro, phenyl, trifluoromethyl and methoxy.
Particular values for R8 include H, phenyl, thien-2-yl, 3-methylphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-methylphenyl, cyclohexyi, 2,4.6-trimethylphenyl, 2-fluorophenyl, 3,4-methylenedioxyphenyl, 3- methylthien-2-yl, 3-chlorophenyl, 3-methoxyphenyl, butyl, 3,4- dimethoxyphenyl, 5-chlorothien-2-yl, 3-trifluoromethylphenyl, 4-methoxyphenyl, 4-ethylpheπyl, 3-ethylphenyI, naphth-2-yl and 3-biphenyl. Preferably, R8 is phenyl and thien-2-yl both optionally substituted with one substituent selected from methyl, ethyl, methoxy, chloro, fluoro and trifluoromethyl.
In embodiments of the invention, the compounds of Formulae I and VI include:
O-(9-Phenyl-9H-fluoren-9-yl)-L-serine;
0-[9-(2-Thienyl)-9/-/-fluoren-9-yl]-L-serine; O-(2-Fluoro-9-phenyl-9H-fluoren-9-yl)-L-serine;
0-(9-Phenyl-9H-fluoren-9-yl)-L-threonine
O-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-threonine;
0-(9-Phenyl-9H-xanthen-9-yl)-L-serine;
0-[9-(3-Methylphenyl)-9H-fluoren-9-yl]-L-serine; 0-[9-(4-Fluorophenyl)-9/-/-fluoren-9-yl]-L-serine;
0-[9-(4-Fluorophenyl)-9H-fluoren-9-yl]-L-threonine; - 14 -
O-(9-Pheπyl-9/-/-xanthen-9-yl)-L-threonine;
O-[9-(4-Chlorophenyl)-9/-/-fluoren-9-yl]-L-serine;
0-[5-(2-Thienyl)-5/-/-dibenzo[a,d]cyclohepten-5-yl]-L-serine;
0-[9-(3-Methylphenyl)-9H-xanthen-9-yl]-L-serine; O-[9-(4-Methylphenyl)-9H-fluoren-9-yl]-L-serine;
O-[9-(2-Methylthien-5-yl)-9H-fluoren-9-yl]-L-serine;
O-(9-Phenyl-9H-thioxanthen-9-yl)-L-serine;
O-[9-(3-Methylphenyl)-9H-xanthen-9-yl]-L-threonine;
O-(10,10-Dimethyl-9-phenyl-9,10-dihydroanthracen-9-yl)-L-serine; O-[9-(3-Methylphenyl)-9H-thioxanthen-9-yl]-L-serine;
O-[9-(4-Chlorophenyl)-9H-fluoren-9-yl]-L-threonine;
0-(2,7-Dichloro-9-phenyl-9/-/-fluoren-9-yl)-L-serine; β-(9-Phenyl-9H-fluoren-9-yl)oxy-DL-norvaline;
O-(9-Pheπyl-9H-fluoren-9-yl)-L-allothreonine; O-[9-(4-Fluorophenyl)-9/-/-xanthen-9-yl]-L-threonine;
O-(10,11-Dihydro-5-phenyl-5/-/-dibenzo[a,d]cyclohepten-5-yl)-L-serine;
O-(5-Phenyl-5H-dibenzo[a, ]cyclohepten-5-yl)-L-serine;
O-[9-(4-Methylphenyl)-9/-/-thioxanthen-9-yl]-L-serine;
O-[9-(4-Methylphenyl)-9/-/-xanthen-9-yl]-L-serine; 0-(9-Phenyl-9H-fluoren-9-yl)-DL-f 7reo-3-phenylserine;
O-[9-(4-Fluorophenyl)-9/-/-xanthen-9-yl]-L-serine;
O-[10, 11 -Dihydro-5-(2-thienyl)-5/-/-dibenzo[a,c]cyclohepten-5-yl]-L-serine;
0-(9-Cyclohexyl-9H-fluoren-9-yl)-L-serine;
0-(9-Phenyl-9/-/-xanthen-9-yl)-D-threonine; O-[5-(3-Methylphenyl)-5H-dibenzo[a, ]cyclohepten-5-yl]-ι_-serine;
O-[5-(4-Methylphenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-L-serine;
O-(9-Phenyl-9/-/-xanthen-9-yl)-D-serine;
0-[9-(4-Methylphenyl)-9H-xanthen-9-yl]-D-serine;
0-[9-(3-Methylρhenyl)-9H-xanthen-9-yl]-D-serine; 0-(9-Phenyl-9H-fluoren-9-yl)-D-serine; 15
O-(2,7-Dibromo-9-phenyl-9H-fluoren-9-yl)-L-serine;
O-[9-(2,4,6-Trimethylphenyl)-9H-fluoren-9-yl]-L-serine;
O-[9-Phenylmethyl-9H-fluoren-9-yl]-L-serine;
0-[9-(2-Fluorophenyl)-9/-/-fluoren-9-yl]-L-threonine; O-[9-(3,4-Methylenedioxyphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Chlorophenyl)-9/-/-fluoren-9-yl]-L-threonine;
O-[9-(3-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Methylphenyl)-9/-/-fluoren-9-yl]-L-threonine;
O-(9-Butyl-9/-/-fluoren-9-yl)-L-threonine; O-[9-(3,4-Dimethoxyphenyl)-9/-/-fluoren-9-yl]-L-threonine;
O-[9-(3-Methylthien-2-yl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Methoxyphenyl)-9/-/-fluoren-9-yl]-L-threonine;
O-[9-(5-Chlorothien-2-yl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Trifluoromethylphenyl)-9/-/-fluoren-9-yl]-L-threonine; O-[9-(4-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(4-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Naphthyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Biphenyl)-9H-fluoren-9-yl]-L-threonine; Λ/-Methyl-O-(9-phenyl-9/-/-fluoren-9-yl)-L-serine;
Λ/,Λ/-Dimethyl-O-(9-phenyl-9H-fluoren-9-yl)-L-serine;
S-(9-Phenyl-9H-thioxanthen-9-yl)-D,L-cysteine;
S-[9-(3-Methylphenyl)-9H-thioxanthen-9-yl]-DL-cysteine;
S-[9-(4-Methylphenyl)-9/-/-thioxanthen-9-yl]-D,L-cysteine; S-(5-Phenyl-5/-/-dibenzo[a,d]cyclohepten-5-yl)-D,L-cysteine;
S-[5-(3-Methylphenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-D,L-cysteine;
S-[5-(4-Methylphenyl)-5H-dibenzo[a, ]cyclohepten-5-yl]-D,L-cysteine;
S-(10,11-Dihydro-5-phenyl-5H-dibenzo[a,cf]cyclohepten-5-yl)-D,L-cysteine;
S-[9-(3-Methylphenyl)-9H-fluoren-9-yl]-D,L-cysteine; S-[9-(4-Methylphenyl)-9/-/-fluoren-9-yl]-D,L-cysteine;
S-(10,10-Dimethyl-9-phenyl-9,10-dihydroanthracen-9-yl)-D,L-cysteine; - 16 -
S-(7-Phenyl-7H-benz[d,e]anthracen-7-yl )-D,L-cysteine; S-(2,7-Dibromo-9-phenyl-9/-/-fluoren-9-yl)-D,L-cysteine; S-(9-Phenyl-9H-fluoren-9-yl)-D,L-cysteine; Λ α-(9-Phenyl-9H-fluoren-9-yl)-DL-α,β-diaminopropionic acid; 4-(9-Phenyl-9/-/-fluoren-9-yl)-DL-2-aminobutyric acid ;
O-(10, 11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-L-serine; O-(9H-fluoren-9-yl)-L-serine; and O-(9-f-butyl-9H-fluoren-9-yl)-L-serine.
In specific embodiments of the invention, the compounds of Formulae I and VI include:
0-(9-Phenyl-9H-fluoren-9-yl)-L-serine;
O-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-serine; O-(2-Fluoro-9-phenyl-9H-fluoren-9-yl)-L-serine;
O-(9-Phenyl-9H-fluoren-9-yl)-L-threonine
O-[9-(2-Thienyl)-9/-/-fluoren-9-yl]-L-threonine;
O-(9-Phenyl-9H-xanthen-9-yl)-L-serine;
0-[9-(3-Methylphenyl)-9H-fluoren-9-yl]-L-serine; O-[9-(4-Fluorophenyl)-9/-/-fluoren-9-yl]-L-seriπe;
O-[9-(4-Fluorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-(9-Phenyl-9H-xanthen-9-yl)-L-threonine;
O-[9-(4-Chlorophenyl)-9/-/-fluoren-9-yl]-L-serine;
O-[5-(2-Thienyl)-5/-/-dibenzo[a, ]cyclohepten-5-yl]-L-serine; 0-[9-(3-Methylphenyl)-9/-/-xanthen-9-yl]-L-serine;
O-[9-(4-Methylphenyl)-9H-fluoren-9-yl]-L-serine;
0-[9-(2-Methylthien-5-yl)-9H-fluoren-9-yl]-L-serine;
O-(9-Phenyl-9/-/-thioxanthen-9-yl)-L-serine;
0-[9-(3-Methylphenyl)-9H-xanthen-9-yl]-L-threonine; O-(10,10-Dimethyl-9-phenyl-9,10-dihydroanthracen-9-yl)-L-serine; - 17 -
O-[9-(3-Methylphenyl)-9H-thioxanthen-9-yl]-L-serine; 0-[9-(4-Chlorophenyl)-9H-fluoren-9-yl]-L-threonine; 0-(2,7-Dichloro-9-phenyl-9/-/-fluoren-9-yl)-L-serine; β-(9-Phenyl-9H-fluoren-9-yl)oxy-DL-norvaline; 0-(9-Phenyl-9H-fluoren-9-yl)-L-allothreonine;
O-[9-(4-Fluorophenyl)-9/-/-xanthen-9-yl]-L-threonine; O-(10, 11 -Dihydro-5-phenyl-5H-dibenzo[a,d]cyclohepten-5-yl)-ι_-serine; O-(5-Phenyl-5/-/-dibenzo[a,d]cyclohepten-5-yl)-L-serine; O-[9-(4-Methylphenyl)-9H-thioxanthen-9-yl]-L-serine; O-[9-(4-Methylphenyl)-9f/-xanthen-9-yl]-L-serine;
O-(9-Pheπyl-9/-/-fluoren-9-yl)-DL-f/7reo-3-phenylserine; 0-[9-(4-Fluorophenyl)-9H-xanthen-9-yl]-L-serine;
O-[10, 11 -Dihydro-5-(2-thienyl)-5H-dibenzo[a,c]cyclohepten-5-yl]-L-serine;
O-[9-(2-Fluorophenyl)-9/-/-fluoren-9-yl]-L-threonine; O-[9-(3-Chlorophenyl)-9H-fluoren-9-yl]-L-threoniπe;
0-[9-(3-Methoxyphenyl)-9W-fluoren-9-yl]-L-threoπine;
O-[9-(2-Methylphenyl)-9H-fluoren-9-yl]-L-threonine;
0-[9-(3-Methylthien-2-yl)-9H-fluoren-9-yl]-L-threonine;
0-[9-(2-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine; 0-[9-(5-Chlorothien-2-yl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Trifluoromethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(4-Methoxyphenyl)-9/-/-fluoren-9-yl]-L-threonine;
O-[9-(4-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine; 0-[9-(2-Naphthyl)-9H-fluoren-9-yl]-L-threonine;
0-[9-(3-Biphenyl)-9H-fluoren-9-yl]-L-threonine;
Λ/-Methyl-O-(9-phenyl-9/-/-fluoren-9-yl)-L-serine;
S-(9-Phenyl-9H-thioxanthen-9-yl)-D,L-cysteine;
S-[9-(3-Methylphenyl)-9H-thioxanthen-9-yl]-DL-cysteine; S-[9-(4-Methylphenyl)-9H-thioxanthen-9-yl]-D,L-cysteine; - 18 -
S-(5-Phenyl-5/-/-dibenzo[a, ]cyclohepten-5-yl)-D,L-cysteine; S-[5-(3-Methylphenyl)-5/-/-dibenzo[a, ]cyclohepten-5-yl]-D,L-cysteine; S-[9-(3-Methylρhenyl)-9H-fluoren-9-yl]-D,L-cysteiπe; S-(9-Phenyl-9H-fluoren-9-yl)-D,L-cysteine; S-(7-Phenyl-7H-benz[ ,e]anthracen-7-yl)-D,L-cysteine;
Na -(9-Phenyl-9H-f luoren-9-yl)-DL-α, β-diaminopropionic acid; 4-(9-Phenyl-9/-/-fluoren-9-yl)-DL-2-aminobutyric acid; and the sodium salts thereof.
In more specific embodiments of the invention, the compounds of
Formulae I and VI include:
0-(9-Phenyl-9H-fluoren-9-yl)-L-serine;
0-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-serine; O-(2-Fluoro-9-phenyl-9H-f luoren-9-yl)-L-serine;
0-(9-Phenyl-9H-fluoren-9-yl)-L-threonine
0-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-threonine;
0-(9-Phenyl-9H-xanthen-9-yl)-L-serine;
0-[9-(3-Methylphenyl)-9H-fluoren-9-yl]-L-serine; 0-[9-(4-Fluorophenyl)-9H-fluoren-9-yl]-L-serine;
0-[9-(4-Fluorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-(9-Phenyl-9H-xanthen-9-yl)-L-threonine;
0-[9-(4-Chlorophenyl)-9H-fluoren-9-yl]-L-serine;
0-[9-(4-Methylphenyl)-9H-fluoren-9-yl]-L-serine; 0-[9-(2-Methylthien-5-yl)-9H-fluoren-9-yl]-L-serine;
0-(9-Phenyl-9/-/-thioxanthen-9-yl)-L-serine;
0-[9-(3-Methylphenyl)-9H-xanthen-9-yl]-L-threonine;
O-(10,10-Dimethyl-9-phenyl-9,10-dihydroanthracen-9-yl)-L-serine;
0-[9-(3-Methylphenyl)-9H-thioxanthen-9-yl]-L-serine; 0-(2,7-Dichloro-9-phenyl-9/-/-fluoren-9-yl)-L-serine; - 19 -
β-(9-Phenyl-9H-fluoren-9-yl)oxy-DL-norvaline; 0-[9-(4-Fluorophenyl)-9H-xanthen-9-yl]-L-threoπine; 0-(5-Phenyl-5H-dibenzo[a, ]cyclohepten-5-yl)-L-serine; 0-[9-(4-Methylphenyl)-9H-thioxanthen-9-yl]-L-serine; O-[9-(4-Methylphenyl)-9/-/-xantheπ-9-yl]-L-seriπe;
0-(9-Phenyl-9H-fluoren-9-yl)-DL-#7reo-3-phenylserine;
O-[10, 11 -Dihydro-5-(2-thienyl)-5H-dibenzo[a,c]cyclohepten-5-yl]-L-serine;
0-[9-(2-Fluorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Chloroρhenyl)-9H-fluoren-9-yl]-L-threonine; O-[9-(3-Methoxyρhenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Methylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Methylthien-2-yl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Methoxyphenyl)-9/-/-fluoren-9-yl]-L-threoπine;
O-[9-(5-Chlorothien-2-yl)-9H-fluoren-9-yl]-L-threonine; O-[9-(3-Trifluoromethylphenyl)-9 - -fluoren-9-yl]-L-threonine;
O-[9-(4-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine;
0-[9-(4-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Naphthyl)-9H-fluoren-9-yl]-L-threonine; 0-[9-(3-Biphenyl)-9H-fluoren-9-yl]-L-threonine;
S-(9-Phenyl-9H-thioxanthen-9-yl)-D,L-cysteine;
S-[9-(3-Methylρhenyl)-9H-thioxanthen-9-yl]-DL-cysteine;
S-[9-(4-Methylphenyl)-9/-/-thioxanthen-9-yl]-D,L-cysteine;
S-(5-Phenyl-5H-dibenzo[a,σ]cyclohepten-5-yl)-D,L-cysteine; S-[5-(3-Methylphenyl)-5H-dibenzo[a,o cyclohepten-5-yl]-D,L-cysteine;
S-[9-(3-Methylρheπyl)-9H-fluoren-9-yl]-D,L-cysteine;
S-(9-Phenyl-9H-fluoren-9-yl)-D,L-cysteine
ΛT -(9-Phenyl-9/-/-fluoren-9-yl)-DL-α, β-diaminopropionic acid;
4-(9-Phenyl-9H-fluoren-9-yl)-DL-2-aminobutyric acid; and the sodium salts thereof. - 20 -
ln even more specific embodiments of the invention, the compounds of Formulae I and VI include:
0-(9-Phenyl-9H-fluoren-9-yl)-L-threonine
O-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-threonine;
O-(9-Phenyl-9/-/-xanthen-9-yl)-L-serine;
O-[9-(4-Fluorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-(9-Phenyl-9H-xanthen-9-yl)-L-threonine; O-[9-(3-Methylphenyl)-9H-xanthen-9-yl]-L-threonine;
? β-(9-Phenyl-9H-fluoren-9-yl)oxy-DL-nontaline;
O-[9-(4-Fluorophenyl)-9/-/-xanthen-9-yl]-L-threonine;
0-(9-Phenyl-9H-fluoren-9-yl)-DL-f 7reo-3-phenylserine;
O-[9-(2-Fluorophenyl)-9L/-fluoren-9-yl]-L-threonine; O-[9-(3-Chlorophenyl)-9H-f luoren-9-yl]-L-threonine;
O-[9-(3-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine;
0-[9-(2-Methylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Methylthien-2-yl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine; O-[9-(5-Chlorothien-2-yl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Trifluoromethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(4-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine;
S-[9-(3-Methylphenyl)-9H-thioxanthen-9-yl]-DL-cysteine;
S-[9-(4-Methylphenyl)-9H-thioxanthen-9-yl]-D,L-cysteine; S-(5-Phenyl-5H-dibenzo[a,o cyclohepten-5-yl)-D,L-cysteine; and the sodium salts thereof.
In the most specific embodiments of the invention, the compounds of Formulae I and VI include: - 21 -
O-(9-Phenyl-9H-fluoreπ-9-yl)-L-threonine 0-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-threonine; 0-[9-(3-Chlorophenyl)-9/-/-fluoren-9-yl]-L-threonine; 0-[9-(3-Methoxyphenyl)-9/-/-fluoren-9-yl]-L-threonine; 0-[9-(2-Methylphenyl)-9H-fluoren-9-yl]-L-threonine; O-[9-(3-Methylthien-2-yl)-9H-fluoren-9-yl]-L-threonine; and the sodium salts thereof.
In another aspect of the invention, the compounds in labeled form can be used to identify GlyT-2 transporter ligands by techniques common in the art. This can be achieved by incubating the tissue or cells that express the transporter in the presence of a ligand candidate and an equimolar amount of radiolabeled compound of the invention such as 0-(9-phenyl-9/- -fluoren-9-yl)-L- threonine. GlyT-2 ligands are thus revealed as those that significantly prevent the binding of the radiolabeled compound of the present invention.
Alternatively, GlyT-2 transporter ligands may be identified by first incubating a radiolabeled form of a compound of the invention and then incubating the resulting preparation in the presence of a candidate ligand. A more potent GlyT-2 transporter ligand will, at equimolar concentration, displace the radiolabeled compound of the invention. Further uses of the radiolabeled compound of the invention include identification of allosteric modulators of GlyT-2 and measuring the rate constants (koπ and koff) of ligands that bind to GlyT-2. Allosteric modulators will be identified as compounds that inhibit GlyT-2 function (i.e. inhibit glycine transport) but do not displace the radiolabeled compound of the present invention. The on and off rate constants of the radiolabeled compound of the invention can be assessed by incubating the radiolabeled compound with tissues or cells expressing the transporter and then diluting the mix such that the concentration of radiolabeled compound is reduced below its equilibrium dissociation constant (Kd). The rate of association and dissociation can then be calculated by techniques common in the art. The rate constants of GlyT-2 transporter ligand candidates may also be - 22 -
assessed by measuring the rate at which the ligands displace the radiolabeled compound of interest. Finally, the radiolabeled compound of interest will be useful for tissues that express GlyT-2 by either standard membrane binding techniques or autoradiography. These techniques can also be used to identify pathophysiolσgical conditions that result in a change in expression level of GlyT-2.
Acid addition salts of the compounds of Formula I and VI are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids e.g. hydrochloric, sulphuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic orfumaric acid. Other non- pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I and VI for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included within the scope of the invention are solvates and hydrates of the invention.
Basic addition salts of the compounds of Formula I and VI are most suitably formed from pharmaceutically acceptable bases and include for example, those formed with inorganic bases, e.g. sodium, potassium, calcium, magnesium or barium hydroxides, or aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoline or ammonia. The selection of the appropriate salt may be important so that the ester is not hydroiyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, in which an aqueous solution of the given salt is treated with a solution of base, e.g. sodium carbonate or potassium hydroxide, until the desired pH is reached to liberate the free base but not deprotonate the carboxylic acid if present. The free base is then extracted into an appropriate solvent, such as ether, and then separated from the aqueous - 23 -
portion, dried, and treated with the requisite acid to give the desired acid addition salt. Alternatively, an aqueous solution of the basic addition given salt is treated with a solution of acid, e.g. hydrochloric acid or sulfuric acid, until the desired pH is reached to liberate the free base but not protonate the amine. The free base is then extracted into an appropriate solvent, such as ether, and then separated from the aqueous portion, dried, and treated with the requisite base to give the desired basic addition salt.
All of the compounds of the present invention have at least one chiral center. The invention extends to cover all structural and optical isomers of the various compounds, as well as racemic mixtures thereof.
In accordance with other aspects of the invention, the compounds of the present invention can be prepared by processes analogous to those established in the art. For example, when X = O, compounds of Formulae I and VI may be prepared as shown in Scheme 1. Condensation of appropriately aryl-substituted carbinols A, wherein R7 is as defined in Formulae I and VI, with a serine derivative of Formula B, wherein R4, R5 and R6 are as defined in Formula I and VI, R1 is dialkyl and one of R2 and R3 is selected from H and dialkyl and the other is PG1, wherein PG1 is any protecting group which is acid stable (for example the 9- fluorenylmethoxycarbonyl or Fmoc protecting group), in the presence of an acid in an aprotic solvent and optionally under standard conditions for affecting the azeotropic removal of water (e.g. Dean Stark apparatus or molecular sieves). Suitable acids include sulfuric acid, trifluoroacetic acid, p- toluenesulfonic acid, camphor sulfonic acid or various Lewis acids such as BF3OEt2, with p-toluenesulfonic acid being preferred. Suitable aprotic solvents include toluene, benzene, methylene chloride, chloroform and 1 ,2- dichloroethane, with toluene being preferred. This reaction can be carried out at a temperature in the range of 0-120 °C, preferably 20-120 °C. Removal of the nitrogen protecting group (PG1) can be performed using standard 24
deprotection conditions to provide compounds of Formulae I and VI wherein R4-R7 are as defined above, R1 is d-4alkyl and one of R2 and R3 is selected from H and Cι.4alkyl and the other is H (Formula C below). For example, removal of the Fmoc protecting group may be achieved using piperidine either neat or in an inert solvent such as DMF, toluene, benzene or methylene chloride at temperatures in the range of 0 to 100 °C. Preferred conditions are neat piperidine at about room temperature. When compounds of Formula C are treated with inorganic bases, for example sodium hydroxide or lithium hydroxide in a polar solvent such as methanol or ethanol (with methanol being preferred), followed by acidification to a pH of around 4-5 using a standard mineral acid such as hydrochloric acid, compounds of Formulae I and VI wherein R4-R7 are as defined above, R1 is H and one of R2 and R3 is selected from H and d-4alkyl and the other is H (Formula D below) are obtained.
Scheme 1
R -OH + HO-
Figure imgf000026_0001
OR1 1) acid (- H2O)t R7— O'
Figure imgf000026_0003
OR1
R5 R5
N- 2) deprotection N.
\
R23 PG 1 -' "H
B C
1)-OH
R7— O'
Figure imgf000026_0002
OH
2) H+
R2/3 H
D
Compounds of Formulae I and VI, wherein X is O, NH or NCι. alkyl, may be prepared using the method shown in Scheme 2. A compound of Formula E, wherein R7 is as defined in Formulae I and VI and Y is an appropriate leaving group such as chloro, bromo, iodo or mesylate, - 25 -
preferably bromo, is reacted with a amino acid derivative of Formula F, wherein X is selected from O, NH or NCι. alkyl, R is d.4alkyl, one of R2 and R3 is selected from H and Cι.4alkyl and the other is PG2, wherein PG2 is an appropriate protecting group such as f-BOC, and R4-R6 are as defined in Formulae I and VI, under standard alkylating conditions, for example sodium bicarbonate, potassium carbonate or trialkylamine, in an inert solvent such as acetone or acetonitrile at temperatures in the range of 0 to 100 °C. Preferred conditions are potassium carbonate in acetonitrile at room temperature. When the leaving group, Y, is a halide, the reaction may be conducted in the presence of an iodide salt such as potassium iodide. Removal of the protecting group (PG2) can be performed under standard conditions to provide compounds of Formulae I and VI wherein R1, R -R7 are as defined above and one of R2 and R3 is selected from H and Cι-4alkyl and the other is H (Formula G below). Hydrolysis of the ester function can be performed as described above to provide compounds of Formulae I and VI wherein R1 is H.
Scheme 2
R6 ™ O R6 O
R7— Y + HX-
Figure imgf000027_0001
ORI 1 ) base R7— X'
Figure imgf000027_0002
OR1 R5 ili 2) deprotection R5 N
R23 PG R23 H
Compounds of Formulae I and VI wherein X is S are readily prepared utilizing the method shown in Scheme 3. An alcohol of Formula A, wherein R7 is as defined in Formulae I and VI, is condensed with cysteine or cysteine derivative of Formula H, wherein R1-R6 are as defined in Formulae I and VI, in the presence of an acid either neat or in an inert solvent and at temperatures in the range of 0-50 °C, to provide compounds of Formula J where R1-R7 are as defined in Formulae I and VI. Suitable acids include trifluoroacetic acid, p- - 26 -
toluenesulfonic acid, camphorsulfonic acid and the like and suitable solvents include methylene chloride, chloroform, toluene and the like. Preferred reaction conditions are neat trifluoroacetic acid at room temperature. When R1 is C1-4alkyl, the ester functionality of the compounds of Formula J may be hydrolyzed as described above to provide compounds of Formulae I and VI wherein R1 is H. Compounds of Formula J can be oxidized under standard conditions, for example either 1 or 2 equivalents of tπ-chloroperbenzoic acid in methylene chloride, to provide compounds of Formula I and VI wherein X is SO and SO2 respectively.
Scheme 3
R6 R6 R< O
R7-OH + HS-
Figure imgf000028_0001
OR1 acid
R7— S'
R5 OR1
A ,N R5 I
.N.
R2 y R3 R2^ " R3
H J
Compounds of Formulae I and VI are also conveniently prepared from the corresponding α-aminonitriles or hydantoin compounds. These methods, described below, are particularly amenable to the preparation of compounds of Formulae I and VI wherein X is O, S or CH2. As shown in Scheme 4, α-aminonitriles K, wherein R2-R7 are as defined in Formula I and VI, may be hydrolyzed to the desired free α-amino acid L, wherein R2-R7 are as defined in Formula I and VI, by any well known hydrolysis reaction for nitriles, for example, with a base (preferably a hydroxide, e.g. sodium hydroxide) in the presence of water at elevated temperatures (preferably at or near the reflux temperature of the mixture). Compounds of Formula L may be esterified using standard esterification methods (e.g. SOCI2 and d.4alkanol) to provide compounds of Formula I and VI wherein R1 is d. alkyl, or these compounds - 27 - may be isolated directly from the hydrolysis of the nitrile by substituting a Ci. alkanol for water as the solvent.
Scheme 4
°
OH
R7-X R -X'
Figure imgf000029_0002
OH
R5
N- N.
Figure imgf000029_0001
R " R3
K
As shown in Scheme 5, hydrolysis of hydantoin compounds M, wherein R2-R7 are as defined in Formula I and VI, using well known methods provides the corresponding amino acids N (compounds of Formulae I and VI wherein one of R2 and R3 is H and the other is selected from H and dialkyl, R1 is H and R4-R7 are as defined above). This hydrolysis is effected, for example, by treatment of compounds of Formula M with most alkali or alkaline earth hydroxides (preferably sodium hydroxide). Compounds of Formula N may be esterified using standard esterification methods (e.g. SOCI2 and Ci^alkanol) to provide compounds of Formula I and VI wherein R1 is Cι-4alkyl.
- 28 -
Scheme 5
R6
Figure imgf000030_0001
NH base ^
Figure imgf000030_0002
OH
R5 R5
N-
R23 4 O R2/3 H
M N
The α-aminonitriles K or hydantoins M are both conveniently prepared from the corresponding aldehydes or ketones of Formula P, wherein X is selected from CH2, S and O and R -R7 are as defined in Formulae I and VI, as shown in Scheme 6. The nitriies are available by reaction of compounds of Formula P under well-known Strecker conditions, such as reaction with a mixture of sodium or potassium cyanide and ammonia, Ci^alkylamines (ethylamine, butylamine and the like), di-C1-4alkylamines (dimethylamine, ethylpropylamine and the like), phenylamine or phenyl C1-4alkylamines (phenethylamine, phenyl-methylamine and the like) at any suitable temperature, preferably at or near room temperature. Hydantoins M are prepared using any well known method for converting compounds of Formula P to a hydantoin, for example, reaction in an inert solvent such as d- alkanols with a mixture of an alkali cyanide and ammonium carbonate at elevated temperatures and optionally in a sealed tube. Preferred conditions are potassium cyanide and ammonium carbonate in aqueous ethanol in a sealed tube at a temperature in the range of 20-120 °C (preferably 50-120 °C). - 29 -
Scheme 6
Figure imgf000031_0002
NH
R5
R6 N /
Figure imgf000031_0003
R23 O
R4
Figure imgf000031_0001
M
O
R7-X
Figure imgf000031_0004
K
When X is S or O, compounds of Formula P may be prepared as shown below in Scheme 7. Reagents Q, wherein R7 is as defined in Formulae I and VI, and X is S or O, are reacted either with reagents R (when R4 is H) or reagents S, (when R4 is C1-4alkyl), wherein R5 and R6 are as defined in Formulae I and VI, Y is an appropriate leaving group such as chloro, bromo, iodo or mesylate, preferably bromo, and PG3 may be for example, methyl or together form a cyclic acetal which provides suitable protection for the aldehyde functionality. Conditions suitable to affect the transformation of Q to P include treating reagents Q with sodium in a lower alkanol followed by addition of reagents R or S at temperatures in the range of -80 °C to room temperature. Deprotection of the resulting intermediates may be performed in the presence of acid in an inert solvent at a temperature in the range of 20-100 °C. During this latter reaction, care must be taken so as not to hydrolyze the "R7-X-" functionality. When X is O, compounds of Formula P are also available, as shown in Scheme 7, from by the addition of reagents Q, wherein R7 is as defined in Formulae I and VI, to reagents T, wherein R4-R6 are as defined in Formulae I and VI and PG4 is a suitable - 30 -
protecting group such as tetrahydropyranyl or methoxymethyl, using the same conditions described above for the addition and deprotection of reagents Q and R (or S). Oxidation of the resulting alcohol under standard conditions, such as Swern oxidation (oxalyl chloride, DMSO, triethylamine), in an inert solvent such as dichloromethane provides compounds of Formula P, wherein R4-R7 are as defined in Formulae I and VI.
- 31 - Scheme 7
R6
OPG3
Figure imgf000033_0001
OPG3 R6
R R4
1 ) base
R7-XH + or
Figure imgf000033_0002
2) deprotection O
Q R6 X = S, O R4
Y'
R5 O S
R6 R6 4 base R4
R7-XH + H O G
R5 2) deprotection
Figure imgf000033_0003
RY5 R4
Q 3) oxidation
T X = O P
When X is CH2, compounds of Formula P are available using the methods depicted in Scheme 8. In the first instance, reagents U, wherein R7 is as defined in Formulae I and VI, is treated with a strong base such as an alkyl lithium, in an inert solvent such as tetrahydrofuran or hexanes, at temperatures in the range of -80 to 20 °C, followed by the addition of either reagents V (when R4 is H) or reagents W, (when R4 is d-4alkyl), wherein X is CH2, R4-R6 are as defined in Formulae I and VI, Y is an appropriate leaving group, such as halo or tosylate and PG3 is as defined in Formula R. Preferred reaction conditions are n-butyllithium in hexanes at 0 °C. Deprotection of the resulting intermediate in the presence of acid in an inert solvent at a temperature in the range of 20-100 °C , preferably p- toluenesulfonic acid in acetone at a refluxiπg temperature, provides compounds of Formula P, wherein X is CH2 and R -R7 are as defined in - 32 -
Formulae I and VI. Alternatively, reagents U, wherein R7 is as defined in Formulae I and VI, are treated with a strong base such as an alkyl lithium, in an inert solvent such as tetrahydrofuran or hexanes, at temperatures in the range of -80 to 20 °C, followed by the addition of reagents Z, wherein Y is an appropriate leaving group, such as halo or tosylate, X is CH2 and PG4 is as defined in Formula T, followed by deprotection in the presence of a suitable acid (e.g. HCI) and oxidation using standard conditions (for example Swern oxidation) to provide compounds of Formula P, wherein X is CH2 and R4-R7 are as defined in Formulae I and VI.
Scheme 8
R6
Y OPG3
Figure imgf000034_0001
OPG3 R6
V R4
1 ) strong base
R7-H or ^.
Figure imgf000034_0002
2) deprotection
U R6
Y. R4 X'
R5 O W
R6 R6
Y 0PG4 1 ) strong base^ R4
R7-H
Figure imgf000034_0003
2) deprotection
Figure imgf000034_0004
R4 0
U 3) oxidation P
Various alkyl amine derivatives of the compounds of Formulae I and VI are readily formed by the reaction of primary or secondary amines of, for example, compounds of Formulae D, G and J, with compounds of Formula - 33 -
R2 3-Y, wherein Y is an appropriate leaving group and R /3 is Cι. alkyl, under standard alkylation conditions. Primary amines of compounds of Formulae D, G and J may also be treated under standard reductive alkylation conditions with aldehydes of Formula R2/3-C(O)H to provide monoalkylated compounds of Formulae I and VI which may be further alkylated under standard conditions with compounds of Formula R23-Y, to provide the corresponding secondary amines.
Compounds of Formulae B, F and H are well known amino acids and derivatives thereof. These compounds are commercially available in both racemic and enantiomerically pure forms or can be prepared using methods known to one skilled in the art (for example see Carpino, L. A.; Han, G. Y. J. Am. Chem. Soc. 92, 1970:5748-5749 and Paquet, A. Can. J. Chem. 60, 1982:976).
Reagents R, S, T, U, V and W are all well known alkanols and derivatives thereof which are either commercially available or readily prepared from commercially available materials using methods known to one skilled in the art.
Reagents of Formula A, wherein R8 is not H, are readily available from the addition of appropriately substituted Grignard reagents or alkyl and aryl lithiums, wherein R8 is as defined in Formulae I and VI and Y is, for example, halo, preferably bromo or chloro, to the corresponding ketones under standard conditions as shown in Scheme 9 for compounds of Formulae I and VI wherein R7 is a group of Formula II and R8 is as defined in Formulae I and VI (other than H). - 34 -
Scheme 9
R8-MgY HO R8
+ or
Figure imgf000036_0002
Figure imgf000036_0001
R8Li —
A
Reagents of Formula A wherein R8 is H are readily available by reduction of the corresponding ketone using any well known reducing agent, for example metal hydrides, such as lithium aluminum hydride, in an inert solvent, such as tetrahydrofuran, and at temperatures in the range of -50-100 °C, suitably -20-60 °C.
Reagents of Formula A, wherein R8 is as defined in Formulae I and VI, may be converted to reagents of Formula E, T and Q using well known chemistries as shown in Scheme 10 for compounds of Formulae E, T and Q wherein R7 is a group of Formula II. For the preparation of reagents of Formula Q, wherein X is S, compounds of Formula A may be treated with hydrogen sulfide in the presence of an acid or an alkali or alkali earth hydrosulfide (preferably sodium hydrosulfide) in an inert solvent (preferably Ci^alkanols) at elevated temperatures, preferably at or near the reflux temperature of the system. The preparation of reagents of Formula E, wherein Y is an appropriate leaving group, for example halo or tosylate, is readily accomplished using either standard halogenating conditions, for example CBr P sP or SOCI2, when Y is bromo or chloro, or via the addition of, for example tosyl or mesyl halide in the presence of a base in an inert solvent, when Y is toslyate or mesylate. It should be understood that Y can be any appropriate leaving group which is available using standard chemistries. Compounds of Formula T may be prepared by the reduction of - 35 -
compounds of Formula A using standard conditions, for example zinc in the presence of an acid as described in Ullmann et al. Ber. 73, 904:37.
Scheme 10
HS 8
H2S/acid or H2S/NaSH
Figure imgf000037_0002
HO 8
Halogenation or mesyl/tosyl halide
Figure imgf000037_0001
—
Figure imgf000037_0003
— y^y
Figure imgf000037_0004
—
T
The ketone precursors to compounds of Formula A may be purchased or prepared using standard procedures known to those skilled in the art.
In some cases, the chemistries outlined above may have to be modified, for instance by use of protecting groups, to prevent side reactions due to reactive groups, such as reactive groups attached as substituents.
Compounds of the invention may also be prepared by adapting the classical solution chemistries outlined above into solid-phase synthetic techniques. For example, R1 can be a residue other than hydrogen representing functionalized resin or suitably selected linker attached to - 36 -
functionalized resin. The linker should be stable under the conditions employed for the above-described reactions. The compounds of the invention where R1 is hydrogen are then cleaved from the resin or the linker leaving the remainder of the molecule intact. For example, solid-phase synthesis of peptoids [oligo(N-substituted glycines)] using a robotic synthesizer was described by Zuckermann et al., J. Am. Chem. Soc. 114, 1992:10646-10647 and Spellmeyer et al. WO 95/04072.
The present compounds are useful as pharmaceuticals for the treatment of various conditions in which the use of a glycine transport inhibitor is indicated. Particularly amenable are those medical conditions for which inhibition of glycine transport mediated by GlyT-2 is needed, such as the treatment of diseases or conditions associated with increased muscle contraction; for example, spasticity, myoclonus and epilepsy. As used herein, GlyT-2 refers to those glycine transporters found predominantly in the brain stem and spinal cord and the distribution of which corresponds closely to that of strychnine-sensitive glycine receptors (Liu et al. J. Biological Chemistry, 268, 1993:22802-22808; Jursky and Nelson, J. Neurochemistry, 64, 1995: 1026-1033). Another distinguishing feature of glycine transport mediated by GlyT-2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GlyT-1.
For use in medicine, the compounds of the present invention can be administered in a standard pharmaceutical composition. The present invention therefore provides, in a further aspect, pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a Formula VI compound or a pharmaceutically acceptable salt, solvate or hydrate thereof, in an amount effective to treat the target indication.
The compounds of the present invention may be administered by any convenient route, for example by oral, parenteral, buccal, sublingual, nasal, - 37 -
rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly.
Compounds of Formula I and VI and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, or as solid forms such as tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutical liquid carrier for example, ethanol, glycerine, non- aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier, for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension filled into a soft gelatin capsule.
Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration.
Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically - 38 -
acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer.
Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
The physician or other health care professional can select the appropriate dose and treatment regimen based on the subject's weight, age and physical condition. Dosages will generally be selected to maintain a serum level of compounds in the invention between about 0.01 μg/cc and about 1000 μg/cc, preferably between about 0.1 μg/cc and 100 μg/cc. For parenteral administration, an alternative measure of preferred amount is from about 0.001 mg/kg to about 10 mg/kg (alternatively, from about 0.01 mg/kg to about 10 mg/kg), more preferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg), will be administered. For oral administrations, an alternative measure of preferred administration amount is from about 0.001 mg/kg to about 10 mg/kg (from about 0.1 mg/kg to about 10 mg/kg), more preferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg). For administrations in suppository form, an alternative measure of preferred administration amount is from about 0.1 mg/kg to about 10 mg/kg, more preferably from about 0.1 mg/kg to about 1 mg/kg. - 39 -
Specific Examples
Example 1 (a): 9-(3-Methylphenyl)-9H-fiuoren-9-ol
A 1.0M solution of m-tolylmagnesium chloride in tetrahydrofuran (10 mL, 10 mmol) (Aldrich) was added dropwise to a solution of 9-fluorenone (1.8 g, 10mmol) (Aldrich) in anhydrous tetrahydrofuran (5 mL) with stirring under argon at 0 °C. The mixture was stirred at room temperature for 1 h, anhydrous diethyl ether (20 mL) was added and the formed precipitate was filtered and dissolved in chloroform (50 mL). The chloroform solution was washed with a saturated solution of ammonium chloride (10 mL), brine (10 mL), dried (MgSO4), the solvent evaporated and the residue recrystallized from diethyl ether/hexane to give the title compound as a white solid (2.42 g, 89%).
In a like manner, the following additional compounds were prepared:
(b) 9-Phenyl-9H-fluoren-9-ol (yield 57%): from phenylmagnesium chloride and 9-fluorenone; (c) 9-(4-Methylphenyl)-9/-/-fluoren-9-ol (yield 39%): from p-tolylmagnesium bromide and 9-fluorenone;
(d) 9-(2,4,6-Trimethylphenyl)-9tf-fluoren-9-ol (yield 82%): from 2- mesitylmagnesium bromide and 9-fluorenone;
(e) 2-Fluoro-9-phenyl-9H-fluoren-9-ol: from phenylmagnesium bromide and 2- fluoro-9-fluorenone;
(f) 9-Phenyl-9H-xaπthen-9-ol: from phenylmagnesium chloride and xanthone;
(g) 9-(4-Chlorophenyl)-9/-/-fluoren-9-ol: from 4-chlorophenylmagπesium bromide and 9-fluorenone;
(h) 9-(3-Methylphenyl)-9H-xanthen-9-ol: from m-tolylmagnesium chloride and xanthone; - 40 -
(i) 9-Phenyl-9H-thioxanthen-9-ol: from phenylmagnesium chloride and thioxanthen-9-one;
(j) 10,10-Dimethyl-9-pheπyl-9,10-dihydroanthracen-9-ol: from phenylmagnesium chloride andl 0, 10-dimethyl-9, 10-dihydroanthracen-9-one; (k) 9-(3-Methylphenyl)-9H-thioxanthen-9-ol: from m-tolylmagnesium chloride and thioxanthen-9-one;
(I) 2,7-Dichloro-9-pheπyl-9/-/-fluoren-9-ol: from phenylmagnesium chloride and 2,7-dichloro-9-fluorenone;
(m) 9-(4-Fluorophenyl)-9H-xanthen-9-ol: from 4-fluorophenylmagnesium bromide and xanthone;
(n) 10,11-Dihydro-5-phenyl-5H-dibenzo[a,d]cyclohepten-5-ol: from phenylmagnesium chloride and dibenzosuberone;
(o) 5-Phenyl-5H-dibenzo[a,d]cyclohepten-5-ol: from phenylmagnesium chloride and dibenzosuberenone; (p) 9-(4-Methylphenyl)-9H-thioxanthen-9-ol: from p-tolylmagnesium bromide and thioxanthen-9-one;
(q) 9-(4-Methylphenyl)-9H-xanthen-9-ol: from p-tolylmagnesium bromide and xanthone;
(r) 9-Cyclohexyl-9H-fluoren-9-ol: from cyclohexylmagnesium chloride and 9- fluorenone;
(s) 5-(3-Methylphenyl)-5H-dibenzo[a,d]cyclohepten-5-ol: m-tolylmagnesium chloride and dibenzosuberenone;
(t) 5-(4-Methylphenyl)-5H-dibenzo[a, ]cyclohepten-5-ol: from p- tolylmagnesium bromide and dibenzosuberenone; (u) 2,7-Dibromo-9-phenyl-9/-/-fluoren-9-ol: from phenylmagnesium chloride and 2,7-dibromo-9-fluorenone;
(v) 7-phenyl-7H-benz[c/,e]anthracen-7-ol: from phenylmagnesium chloride and benzanthrone;
(w) 9-Phenylmethyl-9H-fluoren-9-ol: from benzylmagnesium chloride and 9- fluorenone; - 41 -
(x) 9- -Butyl-9/-/-fluoren-9-ol: from f-butylmagnesium chloride and 9- fluorenone; and
(y) 9-(4-Fluorophenyl)-9/-/-fluoren-9-ol: from 4-fluoromagnesium bromide and
9-fluorenone.
Example 2(a): 9-(2-Methylthien-5-yl)-9/-/-fluoren-9-ol
A 2.5M solution of butyllithium in hexanes (9.6 mL, 24 mmol), (Aldrich) was added dropwise to a solution of 2-methylthiophene (1.96 g, 20 mmol) in anhydrous tetrahydrofuran (10 mL) with stirring under argon at 0 °C. The mixture was stirred at room temperature for 0.5 h and then cooled to 0 °C. A solution of 9-fluorenone (3.6 g, 20 mmol), (Aldrich) in anhydrous tetrahydrofuran (5 mL) was added dropwise to the mixture with stirring and cooling at 0 °C. The reaction mixture was stirred at room temperature for 1 h, poured into a saturated solution of ammonium chloride (5 mL) and extracted with dichloromethane (3 x 20 mL). The combined dichloromethane extracts were washed with brine (10 mL), dried (MgSO4), the solvent evaporated and the residue chromatographed on silica gel column with 10% ethyl acetate in hexanes to give the title compound as an oil.
In a like manner, the following additional compounds were prepared:
(b) 9-(2-Thienyl)-9H-fluoren-9-ol: from thiophene and 9-fluorenone;
(c) 5-(2-Thienyl)-5/-/-dibenzo[a,d]cyclohepten-5-ol: from thiophene and dibenzosuberenone;
(d) 10,11-Dihydro-5-(2-thienyl)-5H-dibenzo[a,d]cyclohepten-5-ol: from thiophene and dibenzosuberone.
Example 3(a): 9-(3-Chlorophenyl)-9H-fluoren-9-ol - 42 -
A 2.5M solution of butyllithium in hexanes (1.8 eq), (Aldrich) was added dropwise to a solution of 1-bromo-3-chlorobenzene (1.5 eq) in anhydrous diethyl ether with stirring under argon at -40 °C. After stirring at room temperature for 0.5 h, a solution of 9-fluorenone (1 eq), (Aldrich) in anhydrous diethyl ether was added dropwise to the mixture with stirring and cooling at 0 °C. The reaction mixture was stirred at room temperature for 1 h, poured into a saturated solution of ammonium chloride and extracted with dichloromethane. The combined dichloromethane extracts were washed with brine, dried (MgSO ), the solvent evaporated and the residue chromatographed on silica gel column with 10% ethyl acetate in hexanes to give the title compound as an oil.
In a like manner, the following additional compounds were prepared:
(b) 10,11-Dihydro-5-(2-thienyl)-5H -dibenzo[a,d]cyclohepten-5-ol: from 2- bromothiophene and dibenzosuberone;
(c) 9-(2-Fluorophenyl)-9H-fluoren-9-ol: from 1-bromo-2-fluorobenzene and 9- fluorenone;
(d) 9-(3,4-Methylenedioxyphenyl)-9H-fluoren-9-ol: from 4-bromo-1 ,2- (methylenedioxy)benzene and 9-fluorenone;
(e) 9-(3-Chlorophenyl)-9H-fluoren-9-ol: from 1-bromo-3-chlorobenzene and 9- fluorenone;
(f) 9-(3-Methoxyphenyl)-9H-fiuoren-9-ol: from 3-bromoanisole and 9- fluorenone; (g) 9-(2-Methylphenyl)-9H-fluoren-9-ol: from 2-bromotoluene and 9- fluorenone;
(h) 9-Butyl-9/-/-fluoren-9-ol: from butyllithium and 9-fluorenone;
(i) 9-(3,4-Dimethoxyphenyl)-9H-fluoren-9-ol: from 4-bromoveratrole and 9- fluorenone; (j) 9-(3-Methylthien-2-yl)-9/-/-fluoren-9-ol: from 2-bromo-3-methylthiophene and 9-fluorenone; - 43 -
(k) 9-(2-Methoxyphenyl)-9H-fluoren-9-ol: from 2-bromoanisole and 9- fluorenone;
(I) 9-(5-Chlorothien-2-yl)-9H-fluoren-9-ol: from 2-bromo-5-chlorothiophene and 9-fluorenone; (m) 9-(3-Trifluoromethylphenyl)-9H-fluoren-9-ol: from 3-bromobenzotrifluoride and 9-fluorenone;
(n) 9-(4-Methoxyphenyl)-9/-/-fiuoren-9-ol: from 4-bromoanisole and 9- fluorenone;
(o) 9-(4-Ethylphenyl)-9/-/-fluoren-9-ol: from 1-bromo-4-ethylbenzene and 9- fluorenone;
(p) 9-(2-Naphthyl)-9H-fluoren-9-ol: from 2-bromonaphthalene and 9- fluorenone;
(q) 9-(3-Biphenyl)-9H-fluoren-9-ol: from 3-bromobipheπyl and 9-fluorenone.
(r) 9-(3-Ethylphenyl)-9H-fluoren-9-ol: from 1-bromo-3-ethylbenzene and 9- fluorenone;
Example 4(a): O-(9-Phenyl-9H-fluoren-9-yl)-L-serine
Step 1 : Λ α-(9-Fluorenylmethoxycarbonyl)-O-(9-phenyl-9H -fluoren-9-yl)-L- serine methyl ester:
Method A:
A solution of 6.2 g (24 mmol) of 9-phenyl-9H-fluoren-9-ol (Example 1 b) and
6.8 g (20 mmol) of Λ/α-(9-fluorenylmethoxycarbonyl)-L-serine methyl ester in benzene (150 mL) was placed in a round bottomed flask fitted with a Dean- Stark trap. Two drops of concentrated sulfuric acid were added and the mixture heated under reflux with stirring for 1 h. Removal of the solvent under vacuo gave the crude Λ/α-(9-fluorenylmethoxycarbonyl)-O-(9-phenyl- 9H-fluoren-9-yl)-L-serine methyl ester which was subjected to the Fmoc deprotection in Step 2 without further purification. - 44 -
Method B:
To a mixture of 0.17 g (0.5 mmol) Λ/α-(9-fluorenylmethoxycarbonyl)-L-serine methyl ester, 0.043 g (0.6 mmol) potassium carbonate and 0.083 g (0.5 mmol) potassium iodide in acetonitrile (2 mL) was added 0.16 g (0.5 mmol) of 9-bromo-9-phenyl-9/-/-fluorene (Aldrich), and the mixture stirred at 40 °C for 2 h. Filtration and removal of the solvent under vacuo gave the crude Λ/"-(9- fluorenylmethoxycarboπyl)-O-(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester which was subjected to the Fmoc deprotection in Step 2 without further purification.
Step 2: 0-(9-Phenyl-9H-fluoren-9-yl)-L-serine methyl ester:
The crude Λ/or-(9-fluorenylmethoxycarbonyl)-O-(9-phenyl-9/-/-fluoren-9-yl)-L- serine methyl ester from Step 1 (Method A) was dissolved in piperidine (5 mL) and the mixture stirred at 60 °C for 0.5 h. After evaporation of the solvent the residue was chromatographed on silica gel with ethyl acetate to give 6.96 g (yield 97%) 0-(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester as a viscous oil. 1H NMR (CDCI3l 300 MHz) δ: 7.65 (d, 2 H), 7.40-7.05 (m, 11 H), 3.65 (s, 3 H), 3.46 (t, 1 H), 3.30-3.10 (m, 2 H), 1.80 (br s, 2 H); 13C NMR (CDCI3, 75 MHz) δ: 174.1 , 146.4, 146.2, 142.7, 140.4, 129.0, 128.9, 128.1 , 127.9, 126.9, 125.2, 125.1 , 124.9, 119.8, 119.7, 88.1 , 65.1 , 54.6, 51.8, 51.7, 13.9.
Analogous Fmoc deprotection of the crude Λ/α-(9-fluorenylmethoxycarbonyl)- 0-(9-phenyl-9/-/-fluoren-9-yl)-L-serine methyl ester from Step 1 (Method B) gave product identical with the 0-(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester prepared in Step 2, after comparison of the NMR spectra and TLC (60% ethyl acetate in hexanes, Rf = 0.3)
Step 3: O-(9-Phenyl-9H-fluoren-9-yl)-L-serine: - 45 -
To a solution of 6.4 g (17.8 mmol) of O-(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester from step 2 in methanol (20 mL) was added 20% sodium hydroxide (10 mL) and the mixture stirred at room temperature for 1 h. Most of the methanol was evaporated under vacuo, the residue suspended in water (200 mL) and extracted with diethyl ether (2 x 50 mL). The alkaline aqueous phase was added dropwise into 20% acetic acid (30 mL) with stirring and cooling with an ice bath, the white precipitate was filtered, washed with water and dried in vacuo over P2O5 to give 5.3 g (yield 90%) of 0-(9-phenyl-9H-fluoren-9-yl)-L-serine as a white powder. 13C NMR (DMSO-d6, 75 MHz) δ: 167.0, 146.4, 146.1 , 143.3, 140.3, 140.0, 129.4, 129.2, 128.4, 128.2, 128.0, 127.2, 125.6, 125.5, 125.1 , 120.5, 120.4, 88.4, 63.2, 54.8.
In a like manner, the following additional compounds were prepared:
(b) 0-(9-Phenyl-9H-fluoren-9-yl)-L-threonine: from 9-phenyl-9H-fluoren-9-ol (Example 1 b) and /\T-(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(c) 0-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-serine: from 9-(2-thienyl)-9H-fluoren-9- ol (Example 2b) and AT-(9-fluorenylmethoxycarbonyl)-L-serine methyl ester; (d) O-(2-Fluoro-9-phenyl-9H-fluoren-9-yl)-L-serine: from 2-fluoro-9-phenyl- 9H-fluoren-9-ol (Example 1e) and Λ/α-(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
(e) O-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-threonine: from 9-(2-thienyl)-9H- fluoren-9-ol (Example 2b) and Λ/α-(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(f) O-(9-Phenyl-9H-xanthen-9-yl)-L-serine: from 9-phenyl-9H-xanthen-9-ol (Example 1f) and Λ/α-(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
(g) 0-[9-(3-Methylphenyl)-9/-/-fluoren-9-yl]-L-serine: from 9-(3-methylρhenyl)-9/-/-fluoreπ-9-ol (Example 1a) and ΛT-(9- fluorenylmethoxycarbonyl)-L-serine methyl ester. - 46 -
(h) O-[9-(4-Fluorophenyl)-9/-/-fluoren-9-yl]-L-serine: from 9-(4-fluσrophenyl)-
9H-fluoren-9-ol (Example 1 ) and ΛT-(9-flu9renylmethoxycarbonyl)-L-serine methyl ester;
(i) 0-[9-(4-Fluorophenyl)-9/-/-fluoren-9-yl]-L-threonine: from 9-(4- fluorophenyl)-9f/-fluoren-9-ol (Example 1y) and Λ/α-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(j) O-(9-Phenyl-9/-/-xanthen-9-yl)-L-threonine: from 9-phenyl-9/-/-xanthen-9-ol
(Example 2f) and Λ/α-(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(k) O-[9-(4-Chlorophenyl)-9H-fluoren-9-yl]-L-serine: from 9-(4-chlorophenyl)- 9/-/-fluoren-9-ol (Example 2g) and ΛT-(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
(I) 0-[5-(2-Thienyl)-5H-dibenzo[a, ]cyclohepten-5-yl]-L-serine: from 5-(2- thienyl)-5/-/-dibenzo[a,c/]cyclohepten-5-ol (Example 2c) and Λ/α-(9- fluorenylmethoxycarbonyl)-L-serine methyl ester; (m) O-[9-(3-Methylphenyl)-9H-xanthen-9-yl]-L-serine: from 9-(3- methylphenyl)-9/-/-xanthen-9-ol (Example 1h) and Λ -(9- fluorenylmethoxycarbonyl)-L-serine methyl ester;
(n) O-[9-(4-Methylphenyl)-9H-fluoren-9-yl]-L-serine: from 9-(4-methylphenyl)-
9/-/-fluoren-9-ol (Example 1c) and ΛT-(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
(o) O-[9-(2-Methylthien-5-yl)-9H-fluoren-9-yl]-L-serine: from 9-(2-methylthien-
5-yl)-9H-fluoren-9-ol (Example 2a) and A/a-(9-fluorenylmethoxycarbonyl)-L- serine methyl ester;
(p) O-(9-Phenyl-9H-thioxanthen-9-yl)-L-serine: from 9-phenyl-9H- thioxanthen-9-ol (Example 1 i) and Λ/α-(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
(q) 0-[9-(3-Methylphenyl)-9H-xanthen-9-yl]-L-threonine: from 9-(3- methylphenyl)-9H-xanthen-9-ol (Example 1 h) and Na-(9- fluorenylmethoxycarboπyl)-L-threonine methyl ester; - 47 -
(r) O-( 10, 10-Dimethyl-9-phenyl-9, 10-dihydroanthracen-9-yl)-i_-serine: from
10,10-dimethyl-9-phenyl-9,10-dihydroanthracen-9-ol (Example 1j) Λ/α-(9- fluorenylmethoxycarbonyl)-L-serine methyl ester;
(s) 0-[9-(3-Methylphenyl)-9H-thioxanthen-9-yl]-L-seriπe: from 9-(3- methylphenyl)-9/-/-thioxanthen-9-ol (Example 1 k) and ΛT-(9- fluorenylmethoxycarbonyl)-L-serine methyl ester;
(t) O-[9-(4-Chlorophenyl)-9H-fluoren-9-yl]-L-threonine: from 9-(4- chlorophenyl)-9/-/-fluoren-9-ol (Example 1g) and Λ/α-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester; (u) O-(2,7-Dichloro-9-phenyl-9H-fluoren-9-yl)-L-serine: from 2,7-dichloro-9- phenyl-9H-fluoren-9-ol (Example 11) and A/a-(9-fluorenylmethoxycarbonyl)-L- serine methyl ester;
(v) β-(9-Phenyl-9H-fluoren-9-yl)oxy-DL-norvaline: from 9-phenyl-9H-fluoren-
9-ol (Example 1b) and ΛT-(9-fluorenylmethoxycarbonyl)-DL-norvaline methyl ester;
(w) O-(9-Phenyl-9/- -fluoren-9-yl)-L-allothreonine: from 9-phenyl-9 -/-fluoren-
9-ol (Example 1b) and Λ/α-(9-fluorenylmethoxycarbonyl)-L-allothreonine methyl ester;
(x) 0-[9-(4-Fluorophenyl)-9 -/-xanthen-9-yl]-L-threonine: from 9-(4- fluorophenyl)-9H-xanthen-9-ol (Example 1m) and ΛT-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(y) O-(10,11-Dihydro-5-phenyl-5H-dibenzo[a,d]cyclohepten-5-yl)-L-serine: from 10,11-dihydro-5-phenyl-5H-dibenzo[a, ]cyclohepten-5-ol (Example 1 n) and Λ/α-(9-fluorenylmethoxycarbonyl)-L-sehne methyl ester;
(z) O-(5-Phenyl-5H-dibenzo[a,d]cyclohepten-5-yl)-L-serine: from 5-phenyl-5H- dibenzo[a,cf]cyclohepten-5-ol (Example 1o) and Λ/α-(9- fluorenylmethoxycarbonyl)-L-serine methyl ester; - 48 -
(aa) O-[9-(4-Methylphenyl)-9H-thioxanthen-9-yl]-L-serine: from 9-(4- methylphenyl)-9H-thioxanthen-9-ol (Example 1 p) and Λ/α-(9- fluorenylmethoxycarboπyl)-L-serine methyl ester;
(bb) 0-[9-(4-Methylphenyl)-9/-/-xanthen-9-yl]-L-serine: from 9-(4- methylphenyl)-9H-xanthen-9-ol (Example 1 q) and Λ/α-(9- fluoreπylmethoxycarbonyl)-L-serine methyl ester;
(cc) O-(9-Phenyl-9/-/-fluoren-9-yl)-DL-threo-3-phenylserine: from 9-phenyl-9 -/- fluoren-9-ol (Example 1 b) and Λ/°-(9-fluorenylmethoxycarboπyl)-DL-threo-3- phenylserine methyl ester; (dd) O-[9-(4-Fluorophenyl)-9H-xanthen-9-yl]-L-serine: from 9-(4- fluorophenyl)-9H-xanthen-9-ol (Example 1 m) and Λ/a-(9- fluorenylmethoxycarbonyl)-L-serine methyl ester;
(ee) 0-[10, 11 -Dihydro-5-(2-thienyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-L- serine: from 10,11-dihydro-5-(2-thienyl)-5H-dibenzo[a,d]cyclohepten-5-ol (Example 2d) and Λ/α-(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
(ff) O-(9-Cyclohexyl-9H-fluoren-9-yl)-L-serine: from 9-cyclohexyl-9H-fluoren-
9-ol (Example 1r) and Λ α-(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
(gg) O-(9-Phenyl-9H-xanthen-9-yl)-D-threonine: from 9-phenyl-9H-xanthen-9- ol (Example 1f) and Λ/α-(9-fluorenylmethoxycarbonyl)-D-threoπine methyl ester;
(hh) 0-[5-(3-Methylρhenyl)-5H-dibenzo[a, yclohepten-5-yl]-L-serine: from 5-
(S-methylpheny -SH-dibenzof^ lcyclohepten-S-ol (Example 1s) and Λ/α-(9- fluorenylmethoxycarbonyl)-L-serine methyl ester;
(ii) O-[5-(4-Methylphenyl)-5H-dibenzo[a, ]cyclohepten-5-yl]-L-serine: from 5- (4-methylphenyl)-5H-dibenzo[a,d]cyclohepten-5-ol (Example 1t) and ΛT-(9- fluorenylmethoxycarbonyl)-L-serine methyl ester;
(jj) O-(9-Phenyl-9H-xanthen-9-yl)-D-sehne: from 9-phenyl-9H-xanthen-9-ol
(Example 1f) and Λ/α-(9-fluorenylmethoxycarbonyl)-D-serine methyl ester; - 49 -
(kk) 0-[9-(4-Methylphenyl)-9H-xanthen-9-yl]-D-serine: from 9-(4- methylphenyl)-9/-/-xanthen-9-ol (Example 1q) and Λ/°-(9- fluorenylmethoxycarbonyl)-D-serine methyl ester;
(II) 0-[9-(3-Methylphenyl)-9H-xanthen-9-yl]-D-serine: from 9-(3- methylphenyl)-9H-xanthen-9-ol (Example 1 h) and Na-(9- fluorenylmethoxycarbonyl)-D-serine methyl ester;
(mm) O-(9-Phenyl-9/-/-fluoren-9-yl)-D-serine: from 9-phenyl-9/-/-fluoren-9-ol
(Example 1 b) and Λ/α-(9-fluorenylmethoxycarbonyl)-D-serine methyl ester;
(nn) 0-(2,7-Dibromo-9-phenyl-9/-/-fluoren-9-yl)-L-serine: from 2,7-dibromo-9- phenyl-9H-fluoren-9-ol (Example 1u) and Λ/α-(9-fluorenylmethoxycarbonyl)-L- serine methyl ester;
(oo) 0-[9-(2,4,6-Trimethylphenyl)-9H-fluoren-9-yl]-L-serine: from 9-(2,4,6- trimethylphenyl)-9/- -fluoren-9-ol (Example 1d) and Na-(9- fluorenylmethoxycarbonyl)-L-serine methyl ester; (pp) O-[9-Phenylmethyl-9H-fluoren-9-yl]-L-serine: from 9-phenylmethyl-9H- fluoren-9-ol (Example 1w) and /Va-(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
(qq) O-[9-(2-Fluorophenyl)-9H-fluoren-9-yl]-L-threonine: from 9-(2- fluorophenyl)-9/-/-fluoren-9-ol (Example 3c) and ΛT-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(rr) O-[9-(3,4-Methylenedioxyphenyl)-9H-fluoren-9-yl]-L-threonine: from 9-3,4- methylenedioxyphenyl-ΘW-fluoren-θ-ol (Example 3d) and ΛT-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(ss) O-[9-(3-Chlorophenyl)-9H-fluoren-9-yl]-L-threonine: from 9-(3- chlorophenyl)-9H-fluoren-9-ol (Example 3e) and Na-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(tt) O-[9-(3-Methoxyphenyl)-9/-/-fluoren-9-yl]-L-threonine: from 9-(3- methoxyphenyl)-9/-/-fluoren-9-ol (Example 3f) and Λ/°-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester; - 50 -
(uu) O-[9-(2-Methylphenyl)-9H-fluoren-9-yl]-L-threonine: from 9-(2- methylphenyl)-9H-fluoren-9-ol (Example 3g) and ΛT-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(vv) 0-(9-Butyl-9H-fluoren-9-yl)-L-threonine: from 9-butyl-9H-fluoren-9-ol (Example 3h) and Λ/α-(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(ww) O-[9-(3,4-Dimethoxypheπyl)-9H-fluoren-9-yl]-L-threonine: from 9-(3,4- dimethoxyphenyl)-9 -/-fluoren-9-ol (Example 3i) and Λ/α-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(xx) O-[9-(3-Methylthien-2-yl)-9H-fluoren-9-yl]-L-threonine: from 9-(3- methylthien-2-yl)-9H-fluoren-9-ol (Example 3j) and ΛT-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(yy) O-[9-(2-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine: from 9-(2- methoxyphenyl)-9tf-fluoren-9-ol (Example 3k) and Na-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester; (zz) O-[9-(5-Chlorothien-2-yl)-9H-fluoren-9-yl]-L-threonine: from 9-(5- chlorothien-2-yl)-9H-fluoren-9-ol (Example 31) and ΛT-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(aaa) 0-[9-(3-Trifluoromethylphenyl)-9H-fluoren-9-yl]-L-threonine: from 9-(3- trifluoromethylpheny -ΘH-fluoren-θ-ol (Example 3m) and ^-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(bbb) O-[9-(4-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine: from 9-(4- methoxyphenyl)-9H-fluoren-9-ol (Example 3n) and ^"-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(ccc) O-[9-(4-Ethylρhenyl)-9H-fluoren-9-yl]-L-threonine: from 9-(4- ethylphenyl)-9H-fluoren-9-ol (Example 3o) and ΛT-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(ddd) O-[9-(3-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine: from 9-(3- ethylphenyl)-9H-fluoren-9-ol (Example 3r) and ^-(9- fluorenylmethoxycarbonyl)-L-threonine methyl ester; - 51 -
(eee) O-[9-(2-Naphthyl)-9H-fluoren-9-yl]-ι_-threonine: from 9-(2-naphthyl)-9H- fluoren-9-ol (Example 3p) and ΛT-(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(fff) O-[9-(3-biphenyl)-9H-fluoren-9-yl]-L-threonine: from 9-(3-biphenyl)-9H- fluoren-9-ol (Example 3q) and Λ/α-(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
(ggg) O-(10,11-Dihydro-5H-dibenzo[a,c]cyclohepten-5-yl)-L-serine: from dibenzosuberol (Aldrich) and Λ/α-(9-fluorenylmethoxycarbonyl)-L-serine methyl ester; (hhh) O-(9H-fluoren-9-yl)-L-serine: from 9-hydroxyfluorene (Aldrich) and ΛT- (9-fluorenylmethoxycarbonyl)-L-serine methyl ester; and (iii) O-(9- -butyl-9H-fluoren-9-yl)-L-serine: from 9-f-butyl-9H-fluoren-9-ol (Example 1x) and Λ/α-(9-fluorenylmethoxycarbonyl)-L-serine methyl ester.
Example 5(a): Λ/-Methyl-O-(9-phenyl-9H-fluoren-9-yl)-L-serine
Step 1 :
To a mixture of 0.8 g (2.2 mmol) of O-(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester (Example 4a, Step 2) and 1.2 g (8.9 mmol) of potassium carbonate in acetonitrile (5 mL) was added 0.17 mL (2.7 mmol) iodomethane and the mixture stirred at room temperature for 16 h. The mixture was dissolved in dichloromethane, filtered and after evaporation of the solvent the residue was chromatographed on silica gel with 60% ethyl acetate in hexanes to give 0.038 g (yield 4.5%) Λ/-Methyl-O-(9-pheπyl-9H- fluoren-9-yl)-ι_-serine methyl ester as an oil. 1H NMR (CDCI3, 300 MHz) δ: 7.67 (d, 2 H), 7.45-7.10 (m, 11 H), 3.73 (s, 3 H), 3.35-3.15 (m, 3 H), 2.37 (s, 3 H), 2.06 (s, 1 H); 13C NMR (CDCI3, 75 MHz) δ: 173.2, 146.6, 146.4, 143.1 , 140.6, 129.2, 129.1 , 128.3, 128.1 , 128.0, 127.1 , 125.4, 125.3, 125.1 , 119.9, 88.3, 63.8, 62.9, 51.7.
Step 2: - 52 -
To a solution of 0.032 g (0.085 mmol) /V-methyl-O-(9-phenyl-9H-fluoren-9-yl)- L-serine methyl ester from Step 1 in methanol (1 mL) was added 20% sodium hydroxide (1 mL) and the mixture stirred at room temperature for 1 h. Most of the methanol was evaporated under vacuo, the residue suspended in water (5 mL) and extracted with diethyl ether (2 x 1 mL). The alkaline aqueous phase was acidified with 20% acetic acid by cooling with an ice bath the white precipitate was filtered, washed with water and dried in vacuo over P2O5 to give 0.027 g (yield 90%) Λ/-methyl-0-(9-phenyl-9H-fluoren-9-yl)-L- serine as a white powder.
Example 6(a): Λ/,Λ/-Dimethyl-O-(9-phenyl-9H-fluoren-9-yl)-L-serine
Step 1 :
To a stirred solution of 0.57 g (1.6 mmol) 0-(9-ρhenyl-9H-fluoren-9-yl)-L- serine methyl ester (Example 4a, Step 2), 0.150 g (5 mmol) paraformaldehyde and water (0.4 mL) in methanol (5 mL) was added dropwise a solution of 0.11 g (0.8 mmol) zinc chloride and 0.1 g (1.6 mmol) sodium cyanoborohydride in methanol (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h, the solvent was evaporated, water (50 mL) was added and the mixture extracted with dichloromethane (3 x 20 mL). The combined dichloromethane extracts were washed with brine, dried (MgSO4), the solvent evaporated and the residue chromatographed on silica gel with 30% ethyl acetate in hexanes to give 0.5 g (yield 81.6%) N,N- dimethyl-0-(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester as an oil. 1H NMR (CDCI3, 300 MHz) δ: 7.68 (d, 2 H), 7.40-7.10 (m, 11 H), 3.73 (s, 3 H), 3.40-3.15 (m, 3 H), 2.29 (s, 6 H); 13C NMR (CDCI3, 75 MHz) δ: 171.3, 146.6, 146.5, 143.2, 140.7, 140.5, 129.1 , 129.0, 128.2, 128.1 , 128.0, 127.0, 125.5, 125.4, 125.3, 120.0, 119.9, 88.7, 67.7, 61.9, 51.4, 42.6, 14.2.
Step 2: - 53 -
To a solution of 0.39 g (1 mmol) Λ/,Λ/-Dimethyl-O-(9-phenyl-9H-fluoren-9-yl)- L-serine methyl ester from Step 1 in methanol (4 mL) was added 20% sodium hydroxide (2 mL) and the mixture stirred at room temperature for 1 h. Most of the methanol was evaporated in vacuo, the residue suspended in water (10 mL) and extracted with diethyl ether (2 x 2 mL). The alkaline aqueous phase was acidified with 20% acetic acid by cooling with an ice bath, the white precipitate was filtered, washed with water and dried in vacuo over P2O5 to give 0.314 g (yield 84%) Λ/,Λ/-dimethyl-O-(9-phenyl-9H-fluoren-9-yl)-L-serine as a white powder. 1H NMR (CD3OD, 300 MHz) δ: 7.87 (br s, 2 H), 7.70-7.10 (m, 11 H), 3.70-3.45 (m, 3 H), 2.95 (s, 6H).
Example 7(a)1: S-(9-Phenyl-9H-thioxanthen-9-yl)-D,L-cysteine
A mixture of 0.29 g (1 mmol) of 9-phenyl-9H-thioxanthen-9-ol (Example 1 i) and 0.12 g (1 mmol) of D,L-cysteine were combined in a dry 50 mL flask flushed with argon. 2 mL of anhydrous trifluoroacetic acid was added and the flask was stoppered and gently swirled by hand until all the material went into solution. The dark brown solution stood for 10 to 15 minutes and was then concentrated to an oil, which was taken up in 30 mL of ether and neutralized with 15 mL of saturated NaHCO3 solution. A thick precipitate formed upon shaking the mixture, which was filtered, washed with 2 x 15 mL of H2O, 2 x 5 mL of acetone and 2 x 10 mL of ether to give light yellow powder after drying in vacuo. 1H NMR (dmso-d6) δ: 7.51-7.15 (m, 13 H), 3.31 (t, J = 5.7 Hz, 1 H), 2.64-2.50 (m, 2 H).
In a like manner, the following additional compounds were prepared:
(b) S-[9-(3-Methylphenyl)-9H-thioxantheπ-9-yl]-DL-cysteiπe: from 9-(3- methylphenyl)-9/-/-thioxanthen-9-ol (Example 1 k) and D,L-cysteiπe as a yellow powder. - 54 -
(c) S-[9-(4-Methylρhenyl)-9H-thioxanthen-9-yl]-D,L-cysteine: from 9-(4- methylphenyl)-9/-/-thioxanthen-9-ol (Example 1 p) and D,ι_-cysteine as a yellow powder.
(d) S-(5-Phenyl-5/-/-dibenzo[a;c/]cyclohepten-5-yl)-D,L-cysteine: from 5-phenyl-5H-dibenzo[a,d]cyclohepten-5-ol (Example 1 o) and D,L-cysteine as a yellow powder.
(e) S-[5-(3-Methylphenyl)-5/-/-dibenzo[a, ]cycloheρteπ-5-yl]-D,L-cysteiπe: from 5-(3-methylphenyl)-5/-/-dibenzo[a, ]cyclohepten-5-ol (Example 1s) and D,L- cysteine as a yellow powder. (f) S-[5-(4-Methylphenyl)-5H-dibeπzo[a,d]cyclohepten-5-yl]-D,L-cysteine: from
5-(4-methylphenyl)-5/-/-dibenzo[a,d]cyclohepteπ-5-ol (Example 1t) and D,L- cysteine as a yellow powder.
(g) S-(10, 11 -Dihydro-5-phenyl-5H-dibenzo[a, /]cyclohepten-5-yl)-D,L-cysteine: from 10,11-dihydro-5-phenyl-5/-/-dibenzo[a,d]cyclohepten-5-ol (Example 1 n) and D,L-cysteine as a yellow powder.
(h) S-[9-(3-Methylphenyl)-9H-fluoren-9-yl]-D,L-cysteine: from 9-(3- methylphenyl)-9/-/-fluoren-9-ol (Example 1a) and D,L-cysteine as a yellow powder.
(i) S-(9-Phenyl-9H-fluoren-9-yl)-D,L-cysteine: from 9-phenyl-9H-fluoren-9-ol (Example 1 b) and D,L-cysteine as a yellow powder.
(j) S-[9-(4-Methylphenyl)-9H-fluoren-9-yl]-D,L-cysteine: from 9-(4- methylphenyl)-9H-fluoren-9-ol (Example 1c) and D,L-cysteine as a yellow powder.
(k) S-(10, 10-Dimethyl-9-phenyl-9, 10-dihydroaπthracen-9-yl)-D,L-cysteine: from 10,10-dimethyl-9-phenyl-9,10-dihydroanthracen-9-ol (Example 1j) and
D,L-cysteiπe as a yellow powder.
(I) S-(7-phenyl-7H-benz[d,e]anthracen-7-yl )-D,L-cysteine: from 7-phenyl-7H- benz[c,e]anthracen-7-ol (Example 1v) as a yellow powder.
(m) S-(2,7-Dibromo-9-phenyl-9H-fluoren-9-yl)-D,L-cysteine: from 2,7-dibromo- 9-phenyl-9/-/-fluoren-9-ol (Example 1 u) and D,L-cysteine as a yellow powder. - 55 -
1Photaki, I.; Taylor-Papadimitriou, J.; Sakarellos, C; Mazarakis, P.; Zervas, L, On Cysteine and Cystine Peptides. Part V. S-Trityl- and S-Diphenylmethyl cysteine and cystine peptides., J. Chem. Soc. (c), 1970:2683-2697.
Example 8(a): Nα-(9-Phenyl-9/-/-fluoren-9-yl)-DL-α,β-diaminopropionic acid
Step 1 : Λ/α-(9-Fuorenylmethoxycarboπyl)-Λ/^-(9-phenyl-9H-fluoren-9-yl)-DL- α,β-diaminopropionic acid methyl ester
To a stirred solution of 0.100 g (0.36 mmol) 9-chloro-9H-fluorene (prepared by treatment of 9-phenyl-9H-fluoren-9-ol (Example 1 b) with SOCI2) in anhydrous dichloromethane (2 mL) was added 0.124 g of (0.36 mmol) Na-(9- fluorenylmethoxycarbonyl)-DL-α,β-diaminopropionic acid methyl ester hydrochloride (prepared by esterification of Λ/°-(9-fluorenylmethoxycarbonyl)- DL-α,β-diaminopriopionic acid (Bachem) with methanol in the presence of 2.5 eq chlorotrimethylsilane and 0.138 g (1.08 mmol) Λ/,Λ/-diisopropylethylamine. The mixture was stirred at room temperature for 48 h, the solvent evaporated and the residue purified by preparative TLC with 30% ethyl acetate in hexanes to give 0.016 g (8%) Λ/α-(9-fluorenylmethoxycarbonyl)-Λ/^-(9-phenyl- 9H-fluoren-9-yl)-DL-α,β-diaminopropionic acid methyl ester as a pale yellow oil. 1H NMR (CDC.3,300 MHz) δ: 7.80-6.90 (m, 21 H), 5.60 (br s, 1 H), 4.50- 4.00 (m, 4 H), 3.60 (s, 3 H), 2.44 (br s, 2 H).
Step 2: Λ/^-(9-Phenyl-9/-/-fluoren-9-yl)-DL-α,β-diaminopropionic acid methyl ester
Analogous to Example 4a, Step 2 deprotection of the 9- fluorenylmethoxycarbonyl (Fmoc) group of Λ/α-(9-fluorenylmethoxycarbonyl)- N^-(9-phenyl-9H-fluoren-9-yl)-DL-α,β-diaminopropionic acid methyl ester from Step 1 gave Λ/?-(9-phenyl-9H-fluoren-9-yl)- α,β-DL-propionic acid methyl - 56 -
ester. 13C NMR (CDCI3, 75 MHz) δ: 175.5, 149.7. 144.7, 140.7, 128.5, 128.2, 128.1 , 127.4, 126.4, 125.0, 124.9, 120.2, 72.9, 55.0, 52.3, 46.8.
Step 3: Hydrolysis of the methyl ester from Step 2 with methanolic sodium hydroxide (like in Example 4a, Step 3) provided /V*-(9-phenyl-9H-fluoren-9- yl)-DL-α,β-diaminopropionic acid as a yellow powder.
Example 9(a): 4-(9-Phenyl-9H-fluoren-9-yl)-DL-2-aminobutyric acid hydrochloride
Step 1 : 3-(9-Phenyl-9H-fluoren-9-yl)propanol
To a stirred solution of 2.42 g (10 mmol) 9-phenylfluorene (prepared by reduction of 9-phenyl-9H-fluoren-9-ol (Example 1 b) with Zn in acetic acid according to the method of F. Ullmann, and R. von Wurstemberger, Ber., 73, 1904:37) in anhydrous tetrahydrofuran (20 mL) was added dropwise 4.8 mL (12 mmol) of a 2.5 M solution of butyllithium in hexanes at 0 °C under Ar. The mixture was stirred at room temperature for 0.5 h during which a white precipitate separated from the orange-colored solution. A solution of 2.7 g (12 mmol) of 2-(3-bromopropoxy)tetrahydro-2H-pyran (Aldrich) was then added dropwise at 0 °C, stirring was continued for 0.5 h at room temperature and the solvent evaporated. The residue was dissolved in 80% acetic acid (10 mL), the solution stirred for 16 h at 80 °C, most of the solvent removed under vacuo and the residue chromatographed on silica gel with dichloromethane to provide 1.4 g (yield 48%) of 3-(9-phenyl-9/-/-fluoren-9- yl)propanol as an oil. 1H NMR (CDCI3, 300 MHz) δ: 7.68 (d, 2H), 7.35-7.00 (m, 11 H), 3.26 (t, 2 H), 2.47 (dt, 2 h), 1.86 (s, 1 H), 0.87 (dt, 2 H); 13C NMR (CDCIa, 75 MHz) δ: 151.4, 144.6, 140.5, 128.2, 127.5, 127.1 , 126.5, 126.3, 124.1 , 119.8, 62.6, 58.2, 33.7, 27.1. - 57 -
Step 2: 3-(9-Phenyl-9H-fluoren-9-yl)propanal
A solution of 0.68 mL (9.6 mmol) dimethylsulfoxide in anhydrous dichloromethane (2 mL) was added dropwise to a solution of 0.4 mL (4.6 mmol) oxalyl chloride in anhydrous dichloromethane (10 mL) with stirring and cooling at -50 °C. Stirring was continued for 10 min and a solution of 1.2 g (4 mmol) of 3-(9-phenyl-9tf-fluoren-9H-yl)propanol (from Step 2) in anhydrous dichloromethane (2 mL) was then added dropwise at -50 °C over 10 minutes. The mixture was stirred at -50 °C for another 10 minutes, triethylamine (2.8 mL) was added dropwise and the mixture was left to reach room temperature. After addition of water (14 mL), the organic phase was separated, the water phase extracted with dichloromethane (2 x 3 mL), the dichloromethane phases combined, washed with brine and dried (MgSO ). Evaporation of the solvent and silica gel column chromatography of the residue with 10% ethyl acetate in hexanes gave 1.0 g (yield 84%) of 3-(9-phenyl-9/-/-fluoren-9- yl)propanal as an oil. 1H NMR (CDCI3, 300 MHz) δ: 9.4 (s, 1 H), 7.76 (d, 2 H), 7.50-7.00 (m, 11 H), 2.84 (d, 2 H), 1.79 (t, 2 H); 13C NMR (CDCI3, 75 MHz) δ: 201.7, 150.5, 144.0, 140.6, 128.4, 127.9, 127.6, 126.6, 126.4, 124.2, 120.0, 57.5, 45.7, 39.0, 29.4.
Step 3: 5-[2-(9-Phenyl-9H-fluoren-9-yl)ethyl]hydantoin
A mixture of 0.3 g (1 mmol) of 3-(9-phenyl-9H-fluoren-9-yl)propanal (from Step 2), 0.07 g (1.1 mmol) potassium cyanide and 0.23 g (2.4 mmol) ammonium carbonate in 50% aqueous ethanol (5 mL) was placed in a pressure tube and heated at 60 °C for 16 h with stirring. The reaction was then cooled to room temperature, quenched with 30% acetic acid (5 mL) and most of the solvent removed under vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with water (3 x 10 mL), dried (MgS04) and the solvent evaporated. The residue was chromatographed on silica gel with ethyl acetate to provide 0.11 g (yield 30%) of 5-[2-(9-phenyl-9H-fluoren-9- - 58 -
yl)ethyl]hydantoin as a white solid. 1H NMR (CD3OD, 300 MHz) δ: 7.79 (d, 2 H), 7.40-7.00 (m, 11 H), 3.86 (dd, 1 h), 2.75-2.50 (m, 2 H), 1.98 (d, 1 H), 1.35- 0.8 (m, 3 H); 13C NMR (CD3OD, 75 MHz) δ: 177.8, 159.8, 152.3, 146.0, 142.1 , 129.4, 128.9, 128.7, 127.6, 127.5, 125.4 121.1 , 59.7, 59.4, 33.6, 27.8.
Step 4: 4-(9-Phenyl-9H-fluoren-9-yl)-DL-2-aminobutyric acid hydrochloride
A mixture of 0.1 g (0.27 mmol) of 5-[2-(9-phenyl-9W-fluoren-9- yl)ethyl]hydantoin (from Step 3) and 2N sodium hydroxide (10 mL) was heated under reflux at 120 °C for 40 h. The reaction mixture was cooled, acidified with concentrated hydrochloric acid and extracted with chloroform (3 x 10 mL). The combined chloroform extracts were washed with brine, dried (MgS0 ) and the solvent evaporated. The solid residue was washed with anhydrous diethyl ether and dried under vacuo to give 0.04 g (yield 40%) of 4-(9-phenyl-9H-fluoren-9-yl)-DL-2-aminobutyric acid hydrochloride as a pale yellow powder. 1H NMR (CD3OD, 300 MHz) δ: 7.67 (d, 2 H), 7.30-6.90 (m, 11 h), 3.56 (br s, 1 H), 2.75-2.55 (m, 1 H), 2.55-2.35 (m, 1 H), 1.20-0.95 (m, 2 H); 13C NMR (CD3OD, 75 MHz) δ: 152.0, 145.8, 142.2, 142.1 129.4, 129.0, 128.8, 127.7, 127.6, 125.4, 125.3, 121.1 , 59.3, 54.4, 33.7, 26.6.
Example 10: Assay of Transport Via GlyT-1 or GlyT-2 Transporters
This example illustrates a method for the measurement of glycine uptake by transfected cultured cells. Cells transiently transfected with human GlyT-1 C (see Kim, et al., Molecular
Pharmacology, 45, 1994:608-617) and human GlyT-2 (the sequence of the human GLYT-2 is described by Albert et al. in co-pending US Application No.
08/700,013, filed August 20, 1996; the rat GlyT-2 is described by Liu et al., J.
Biological Chemistry, 268, 1993:22802-22808) were washed three times with HEPES buffered saline (HBS). The cells were then incubated 10 minutes at 37
°C, after which a solution containing 50 nM [3H]glycine (17.5 Ci/mmol) and either - 59 -
(a) no potential competitor, (b) 10 mM nonradioactive glycine or (c) a concentration of a candidate drug was added. A range of concentrations of the candidate drug was used to generate data for calculating the concentration resulting in 50% of the effect (e.g., the ICso's which are the concentration of drug inhibiting glycine uptake by 50%). The cells were then incubated another 10 minutes at 37 °C, after which the cells were aspirated and washed three times with ice-cold HBS. The cells were harvested, scintillaπt was added to the cells, the cells were shaken for 30 minutes, and the radioactivity in the cells was counted using a scintillation counter. Data were compared between the same cells contacted and not contacted by the candidate agent, and between cells having GlyT-1 activity versus cells having GlyT-2 activity, depending on the assay being conducted.
All exemplified compounds of the invention were tested for inhibition of glycine transport via GlyT-2 and displayed a pICso in the range of about 4.0-8.5. Selectivity for inhibition of glycine transport via GlyT-2 versus GlyT-1 was at least about 1/2 to 4.5 log units for all of the exemplified compounds.

Claims

- 60 - We Claim:
1. A compound according to Formula
Figure imgf000062_0001
OR1
R5 R3^ \R2
or a prodrug or pharmaceutically acceptable salt, solvate or hydrate thereof wherein:
R1 is independently selected from the group consisting of H, Ci^alkyl and the counter ion for a basic addition salt;
R2, R3 and R4 are independently selected from the group consisting of H and dialkyl;
R5 and R6 are independently selected from the group consisting of H, dialkyl and phenyl;
X is selected from the group consisting of CH2, S, O, SO, SO2, NH and
NC1-4alkyl;
R7 is selected from the group consisting of Formula ll-V:
Figure imgf000062_0002
I I III IV V which are all optionally substituted, at nodes other than R8, with 1-4 substituents independently selected from the group consisting of Cι-4alkyl, halo, phenyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono-C1- alkylamino, di-Ci^alkylamino, d.4alkoxycarbonyl, Cι.4alkylcarbonyl, C1-4alkoxythiocarbonyl, Cι-4alkylthiocarbonyl, Cι-4alkoxy, Cι-4alkylS-, phenoxy, -SO2NH2, -SO2NHd^alkyl, - 61 -
-SO2N(d- alkyl)2 and 1 ,2-methylenedioxy; and wherein R8 is selected from the group consisting of H, Cι-6alkyl, benzyl, cycloalkyi, indanyl and an optionally substituted aromatic or heteroaromatic, 5-10-membered mono- or bicyclic ring wherein the optional substituents are independently selected from 1-4 members of the group consisting of C1-4alkyl, halo, phenyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono-Cι-4alkylamino, di-d- alkylamino, Cι- alkoxycarbonyl, Cι.4alkylcarbonyl, d- alkoxythiocarbonyl, C1-4alkylthiocarbonyl, C1-4alkoxy, C1-4alkylS-, phenoxy, -SO2NH2, -SO2NHCι.4alkyl, -SO2N(C1-4alkyl)2 and 1 ,2-methylenedioxy; represents a single or double bond;
Y is selected from the group consisting of O, S, SO, NH, NC1-4alkyl, CH2, CH-C^alkyl, C(d^alkyl)2, and C=O;
Z is selected from the group consisting of CH2, O, S, NH and NC1-4alkyl when is a single bond;
Z is selected from the group consisting of CH and N when is a double bond; and with the provisos that: when X is S, R8 is not H; when X is S and R7 is a group of Formula II, then R8 is not optionally substituted phenyl; and when X is S and R7 is a group of Formula III with X = O, then R8 is not unsubstituted phenyl.
2. A compound according to claim 1 , wherein R1, R2, R3 and R4 are independently selected from the group consisting of H and methyl.
3. A compound according to claim 2, wherein R1, R2, R3 and R4 are all H.
4. A compound according to claim 1 , wherein R1 is Na. - 62 -
5. A compound according to claim 1 , wherein R5 and R6 independently selected from the group consisting of H and methyl.
6. A compound according to claim 5, wherein one of R5 and R6 is H and the other is methyl.
7. A compound according to claim 1 , wherein X is selected from the group consisting of CH2, S, O, and NH.
8. A compound according to claim 7, wherein X is O.
9. A compound according to claim 1 , wherein R7 is a group of Formula II which is optionally substituted, at nodes other than R8, with 1-2 groups independently selected from the group consisting of methyl, bromo, fluoro, chloro and methoxy.
10. A compound according to claim 1 , wherein R7 is a group of Formula III wherein Y is selected from the group consisting of O, S and C(Me)2 and which is optionally substituted, at nodes other than R8, with 1-2 groups independently selected from the group consisting of methyl, bromo, flouro, chloro and methoxy.
11. A compound according to claim 10 wherein R7 is unsubstituted at nodes other than R8 and Y is O.
12. A compound according to claim 1 , wherein R7 is a group of Formula IV which is optionally substituted at nodes other than R8 with 1-2 groups independently selected from the group consisting of methyl, bromo, flouro, chloro and methoxy and wherein Z is CH when is a double bond and Z is CH2 when is a single bond.
13. A compound according to claim 12 wherein R7 is unsubstituted at nodes other than R8 and — is a single bond. - 63 -
14. A compound according to claim 1 , wherein R7 is a group of Formula V which is optionally substituted at nodes other than R8 with 1-2 groups independently selected from the group consisting of methyl, bromo, flouro, chloro and methoxy.
15. A compound according to claim 14 wherein R7 is unsubstituted at nodes other than R8.
16. A compound according to claim 1 , wherein R7 is selected from the group consisting of 9-(R8)-9H-fluoren-9-yl, 2-fluoro-9-(R8)-9H-fluoren-9-yl 9-(R8)-9H- xanthen-9-yl, 5-(R8)-5/-/-dibenzo[a,d]cyclohepten-5-yl, 9-(R8)-9/-/-thioxanthen-9-yl, 10, 10-dimethyl-9-(R8)-9, 10-dihydroanthracen-9-yl, 10, 11 -dihydro-5-(R8)-5H- dibenzo[a,d]cyclohepten-5-yl, 2,7-dibromo-9-(R8)-9/- -fluoren-9-yl and 2,7-dichloro-9- (R8)-9H-fluoren-9-yl.
17. A compound according to claim 16, wherein R7 is unsubstituted 9-(R8)-9H- fluoren-9-yl.
18. A compound according to claim 1 , wherein R8 is selected from the group consisting of H, methyl, butyl, t-butyl, benzyl, cyclohexyi, indanyl and optionally substituted thienyl, furanyl, phenyl, indolyl, naphthyl and pyridyl wherein the optional substituents are independently selected from 1-4 members of the group consisting of Cι.4alkyl, halo, phenyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono-Ci^alkylamino, di-Ci^alkylamino, Cι-4alkoxycarbonyl, Cι-4alkylcarbonyl, Cι-4alkoxythiocarbonyl, Cι.4alkylthiocarbonyl, Cι.4alkoxy, C1-4S- and
1 ,2-methylenedioxy.
19. A compound according to claim 18 wherein R8 is selected from the group consisting of phenyl and thienyl which are optionally substituted with 1 -3 substituents independently selected from the group consisting of methyl, ethyl, bromo, chloro, fluoro, phenyl, trifluoromethyl and methoxy. - 64 -
20. A compound according to claim 18 wherein R8 is selected from the group consisting of H, phenyl, thien-2-yl, 3-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-methylphenyl, cyclohexyi, 2,4,6-trimethylphenyl, 2-fluoroρhenyl, 3,4-methyleπedioxyphenyl, 3-methylthien-2yl, 3-chlorophenyl, 3-methoxyphenyl, butyl, 3,4-dimethoxyphenyl, 5-chlorothieny-2-yl, 3-trifluoromethylphenyl, 4- methoxypheπyl,
4-ethylphenyl, 3-ethylphenyl, naphthyl-2-yl and 3-biphenyl.
21. A compound according to claim 20, wherein R8 is selected from the group consisting of phenyl and thien-2-yl both optionally substituted with one substituent selected from methyl, ethyl, methoxy, chloro, fluoro and trifluoromethyl.
22. A compound according to claim 21 wherein R7 is a group of Formula II.
23. A compound according to claim 22 wherein R7 is unsubstituted at nodes other than R8.
24. A compound according to claim 23, wherein X is O.
25. A compound according to claim 24, wherein one of R5 and R6 is H and the other is methyl.
26. A compound according to claim 1 , wherein the compound is selected from the group consisting of:
O-(9-Phenyl-9H-fluoreπ-9-yl)-L-serine;
0-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-serine;
O-(9-Phenyl-9H-fluoren-9-yl)-L-threonine
O-(2-Fluoro-9-phenyl-9H-fluoren-9-yl)-L-serine;
0-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-threonine; - 65 -
O-(9-Phenyl-9H-xanthen-9-yl)-L-serine;
O-[9-(3-Methylphenyl)-9H-fluoren-9-yl]-L-serine;
O-[9-(4-Fluorophenyl)-9H-fluoren-9-yl]-L-serine;
O-[9-(4-Fluorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-(9-Phenyl-9H-xanthen-9-yl)-L-threonine;
O-[9-(4-Chlorophenyl)-9H-fluoren-9-yl]-L-serine;
0-[5-(2-Thienyl)-5H-dibenzo[a, ]cyclohepten-5-yl]-L-serine;
O-[9-(3-Methylphenyl)-9H-xanthen-9-yl]-L-serine;
O-[9-(4-Methylphenyl)-9/-/-fluoren-9-yl]-L-serine;
O-[9-(2-Methylthien-5-yl)-9H-fluoren-9-yl]-L-serine;
O-(9-Phenyl-9H-thioxanthen-9-yl)-L-serine;
O-[9-(3-Methylphenyl)-9H-xanthen-9-yl]-L-threonine;
O-(10,10-Dimethyl-9-phenyl-9,10-dihydroanthracen-9-yl)-L-serine;
O-[9-(3-Methylphenyl)-9H-thioxanthen-9-yl]-L-serine;
O-[9-(4-Chlorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-(2,7-Dichloro-9-phenyl-9H-fluoren-9-yl)-L-serine; β-(9-Phenyl-9H-fluoren-9-yl)oxy-DL-norvaline;
O-(9-Phenyl-9H-fluoren-9-yl)-L-allothreonine;
O-[9-(4-Fluorophenyl)-9H-xanthen-9-yl]-L-threonine;
O-(10, 11 -Dihydro-5-phenyl-5/-/-dibenzo[a, ]cyclohepten-5-yl)-L-serine;
O-(5-Phenyl-5/-/-dibenzo[a,d]cyclohepten-5-yl)-L-serine;
O-[9-(4-Methylphenyl)-9H-thioxanthen-9-yl]-L-serine;
O-[9-(4-Methylphenyl)-9/-/-xanthen-9-yl]-L-serine;
O-(9-Phenyl-9H-fluoren-9-yl)-DL-threo-3-phenylserine;
O-[9-(4-Fluorophenyl)-9H-xanthen-9-yl]-L-serine;
O-[10,11-Dihydro-5-(2-thieπyl)-5H-dibenzo[a,c/]cyclohepteπ-5-yl]-L-serine;
0-(9-Cyclohexyl-9H-fluoren-9-yl)-L-serine;
0-(9-Phenyl-9/-/-xanthen-9-yl)-D-threonine;
O-[5-(3-Methylphenyl)-5H-dibenzo[a,o]cyclohepten-5-yl]-L-serine;
O-[5-(4-Methylphenyl)-5/-/-dibenzo[a,d]cyclohepten-5-yl]-L-serine;
O-(9-Phenyl-9H-xanthen-9-yl)-D-serine; - 66 -
O-[9-(4-Methylρhenyl)-9/-/-xaπthen-9-yl]-D-serine;
O-[9-(3-Methylphenyl)-9H-xanthen-9-yl]-D-serine;
O-(9-Phenyl-9H-fluoren-9-yl)-D-serine;
0-(2,7-Dibromo-9-phenyl-9/-/-fluoren-9-yl)-L-serine;
O-[9-(2,4,6-Trimethylphenyl)-9j4-fluoren-9-yl]-L-serine;
O-[9-Phenylmethyl-9H-fluoren-9-yl]-L-serine;
O-[9-(2-Fluorophenyl)-9/-/-fluoren-9-yl]-L-threonine;
O-[9-(3,4-Methylenedioxyphenyl)-9/-/-fluoren-9-yl]-L-threonine;
O-[9-(3-Chlorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Methylphenyl)-9/-/-fluoren-9-yl]-L-threonine;
0-(9-Butyl-9H-fluoren-9-yl)-L-threoπine;
0-[9-(3,4-Dimethoxyρhenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Methylthien-2-yl)-9H-fluoren-9-yl]-L-threonine;
0-[9-(2-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine;
0-[9-(5-Chlorothien-2-yl)-9/-/-fluoren-9-yl]-L-threonine;
O-[9-(3-Trifluoromethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(4-Methoxyphenyl )-9/-/-f I uoren-9-y l]-L-threon i ne ;
O-[9-(4-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine;
0-[9-(3-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Naphthyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Biρhenyl)-9H-fluoren-9-yl]-L-threonine;
Λ/-Methyl-O-(9-phenyl-9H-fluoren-9-yl)-L-serine;
Λ/,Λ/-Dimethyl-0-(9-phenyl-9H-fluoren-9-yl)-L-serine;
S-(9-Phenyl-9H-thioxanthen-9-yl)-D,L-cysteine;
S-[9-(3-Methylphenyl)-9H-thioxanthen-9-yl]-DL-cysteine;
S-[9-(4-Methylphenyl)-9H-thioxanthen-9-yl]-D,L-cysteiπe;
S-(5-Phenyl-5/-/-dibenzo[a/d]cyclohepten-5-yl)-D,L-cysteine;
S-[5-(3-Methylρhenyl)-5H-dibenzo[a,cf]cyclohepten-5-yl]-D,L-cysteine;
S-[5-(4-Methylphenyl)-5/-/-dibenzo[a,cf]cyclohepten-5-yl]-D,L-cysteine;
S-(10,11-Dihydro-5-phenyl-5/-/-dibenzo[a, ]cyclohepten-5-yl)-D,L-cysteine; - 67 -
S-[9-(3-Methylphenyl)-9H-fluoren-9-yl]-D,L-cysteine;
S-(10,10-Dimethyl-9-phenyl-9,10-dihydroanthracen-9-yl)-D,L-cysteine;
S-(7-Pheπyl-7/-/-benz[d,e]anthracen-7-yl )-D,L-cysteine;
S-(2,7-Dibromo-9-phenyl-9H-fluoren-9-yl)-D,L-cysteine;
Na -(9-Phenyl-9H-fluoren-9-yl)-DL-α, β-diaminopropionic acid;
4-(9-Phenyl-9H-fluoren-9-yl)-DL-2-aminobutyric acid .
O-(10, 11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-L-serine;
O-(9H-fluoren-9-yl)-L-sehne; and
O-(9-f-butyl-9/-/-fluoren-9-yl)-L-serine.
27. A compound according to claim 1 , wherein the compound is selected from the group consisting of:
O-(9-Phenyl-9H-fluoren-9-yl)-L-serine;
O-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-serine;
O-(2-Fluoro-9-phenyl-9H-fluoren-9-yl)-L-serine;
O-(9-Phenyl-9H-fluoren-9-yl)-L-threonine
O-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-threonine;
O-(9-Phenyl-9/-/-xanthen-9-yl)-L-serine;
O-[9-(3-Methylphenyl)-9H-fluoren-9-yl]-L-serine;
O-[9-(4-Fluorophenyl)-9 -/-fiuoren-9-yl]-L-serine;
O-[9-(4-Fiuorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-(9-Phenyl-9H-xanthen-9-yl)-L-threonine;
O-[9-(4-Chlorophenyl)-9H-fluoren-9-yl]-L-serine;
O-[5-(2-Thienyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-L-serine;
O-[9-(3-Methylphenyl)-9H-xanthen-9-yl]-L-serine;
O-[9-(4-Methylphenyl)-9H-fluoren-9-yl]-L-serine;
O-[9-(2-Methylthien-5-yl)-9H-fluoren-9-yl]-L-serine;
O-(9-Phenyl-9H-thioxanthen-9-yl)-L-serine;
O-[9-(3-Methylphenyl)-9H-xaπthen-9-yl]-L-threonine;
O-(10,10-Dimethyl-9-phenyl-9,10-dihydroanthracen-9-yl)-L-serine; - 68 -
0-[9-(3-Methylphenyl)-9H-thioxanthen-9-yl]-L-serine;
0-[9-(4-Chlorophenyl)-9H-fluoren-9-yl]-L-threonine;
0-(2,7-Dichloro-9-phenyl-9L -fluoren-9-yl)-L-serine; β-(9-Phenyl-9/-/-fluoren-9-yl)oxy-DL-norvaline;
0-(9-Phenyl-9H-fluoren-9-yl)-L-allothreonine;
0-[9-(4-Fluoropheπyl)-9/-/-xanthen-9-yl]-L-threonine;
O-(10,11-Dihydro-5-phenyl-5H-dibenzo[a,cIcyclohepten-5-yl)-L-serine;
0-(5-Phenyl-5H-dibenzo[a,cf]cyclohepten-5-yl)-L-serine;
0-[9-(4-Methylphenyl)-9/Ly-thioxanthen-9-yl]-L-serine;
0-[9-(4-Methylphenyl)-9H-xanthen-9-yl]-L-serine;
0-(9-Phenyl-9H-fluoren-9-yl)-DL-threo-3-phenylserine;
0-[9-(4-Fluorophenyl)-9H-xanthen-9-yl]-L-serine;
O-[10,11-Dihydro-5-(2-thienyl)-5H-dibenzo[a,cf]cyclohepten-5-yl]-L-serine;
O-[9-(2-Fluorophenyl)-9H-fluoren-9-yl]-L-threonine;
0-[9-(3-Chlorophenyl)-9H-fluoren-9-yl]-L-threonine;
0-[9-(3-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine;
0-[9-(2-Methylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Methylthien-2-yl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Methoxyphenyl)-9 - -fluoren-9-yl]-L-threonine;
O-[9-(5-Chlorothien-2-yl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Trifluoromethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(4-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(4-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Naphthyl)-9/-/-fluoren-9-yl]-L-threonine;
O-[9-(3-Biphenyl)-9H-fluoren-9-yl]-L-threonine;
Λ/-Methyl-O-(9-phenyl-9/-/-fluoren-9-yl)-L-serine;
S-(9-Phenyl-9H-thioxanthen-9-yl)-D,L-cysteine;
S-[9-(3-Methylphenyl)-9H-thioxanthenr9-yl]-DL-cysteine;
S-[9-(4-Methylphenyl)-9 -/-thioxanthen-9-yl]-D,L-cysteine;
S-(5-Phenyl-5H-dibenzo[a,d]cyclohepten-5-yl)-D,L-cysteine; - 69 -
S-[5-(3-Methylphenyl)-5/-/-dibenzo[a,c]cyclohepten-5-yl]-D,L-cysteine; S-[9-(3-Methylphenyl)-9H-fluoren-9-yl]-D,L-cysteine; S-(7-Phenyl-7H-benz[d,e]anthracen-7-yl )-D,L-cysteine; Λ/Qr-(9-Phenyl-9/-/-fluoren-9-yl)-DL-α,β-diaminopropionic acid; and 4-(9-Phenyl-9H-fluoren-9-yl)-DL-2-aminobutyric acid.
28. A compound according to claim 1 , wherein the compound is selected from the group consisting of:
O-(9-Phenyl-9H-fluoren-9-yl)-L-serine;
O-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-serine;
O-(2-Fluoro-9-pheπyl-9H-fiuoren-9-yl)-L-serine;
O-(9-Phenyl-9H-fluoren-9-yl)-L-threonine
O-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-threonine;
O-(9-Phenyl-9H-xanthen-9-yl)-L-serine;
O-[9-(3-Methylphenyl)-9H-fluoren-9-yl]-L-serine;
0-[9-(4-Fluorophenyl)-9H-fluoren-9-yI]-L-serine;
O-[9-(4-Fluorophenyl)-9/-/-fluoren-9-yl]-L-threonine;
O-(9-Phenyl-9H-xanthen-9-yl)-L-threonine;
O-[9-(4-Chlorophenyl)-9H-fluoren-9-yl]-L-serine;
O-[9-(4-Methylphenyl)-9H-fluoren-9-yl]-L-serine;
O-[9-(2-Methylthien-5-yl)-9H-fluoren-9-yl]-L-serine;
O-(9-Phenyl-9H-thioxanthen-9-yl)-L-serine;
O-[9-(3-Methylphenyl)-9H-xanthen-9-yl]-L-threonine;
O-(10, 10-Dimethyl-9-phenyl-9, 10-dihydroanthracen-9-yl)-L-serine;
O-[9-(3-Methylphenyl)-9H-thioxanthen-9-yl]-L-serine;
O-(2,7-Dichloro-9-phenyl-9H-fluoren-9-yl)-L-serine; β-(9-Phenyl-9H-fluoren-9-yl)oxy-DL-norvaline;
O-[9-(4-Fluorophenyl)-9/-/-xanthen-9-yl]-L-threonine;
O-(5-Phenyl-5/-/-dibenzo[a,d]cyclohepten-5-yl)-L-serine; - 70 -
O-[9-(4-Methylphenyl)-9H-thioxanthen-9-yl]-L-serine;
O-[9-(4-Methylphenyl)-9/-/-xanthen-9-yl]-L-serine;
O-(9-Phenyl-9/- -fluoren-9-yl)-DL-threo-3-phenylserine;
O-[10,11-Dihydro-5-(2-thienyl)-5/-/-dibenzo[a;c]cyclohepten-5-yl]-L-serine;
0-[9-(2-Fluorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Chlorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Methylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Methylthien-2-yl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(5-Chlorothien-2-yl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Trifluoromethylphenyl)-9H-fluoren-9-yl]-L-threonine;
0-[9-(4-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(4-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Ethylphenyl)-9H-fluoreπ-9-yl]-L-threonine;
O-[9-(2-Naphthyl)-9H-fluoren-9-yl]-L-threonine;
0-[9-(3-Biphenyl)-9H-fiuoren-9-yl]-L-threonine;
S-(9-Phenyl-9H-thioxanthen-9-yl)-D,L-cysteine;
S-[9-(3-Methylphenyl)-9H-thioxanthen-9-yl]-DL-cysteine;
S-[9-(4-Methylphenyl)-9/- -thioxanthen-9-yl]-D,L-cysteine;
S-(5-Phenyl-5/-/-dibenzo[a,d]cyclohepten-5-yl)-D,L-cysteine;
S-[5-(3-Methylphenyl)-5H-dibenzo[a,cf]cyclohepten-5-yl]-D,L-cysteine;
S-[9-(3-Methylphenyl)-9H-fluoren-9-yl]-D,L-cysteine;
Λ/α-(9-Phenyl-9H-fluoren-9-yl)-DL-α,β-diaminopropionic acid; and
4-(9-Phenyl-9/-/-fluoren-9-yl)-DL-2-aminobutyric acid.
29. A compound according to claim 1 , wherein the compound is selected from the group consisting of:
0-(9-Phenyl-9H-fluoren-9-yl)-L-threonine O-[9-(2-Thienyl)-9/-/-fluoren-9-yl]-L-threonine; - 71 -
O-(9-Phenyl-9H-xanthen-9-yl)-L-serine;
O-[9-(4-Fluorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-(9-Phenyl-9H-xanthen-9-yl)-L-threonine;
0-[9-(3-Methylphenyl)-9/-/-xanthen-9-yl]-L-threonine; β-(9-Phenyl-9/-/-fluoren-9-yl)oxy-DL-norvaline;
O-[9-(4-Fluorophenyl)-9H-xanthen-9-yl]-L-threonine;
O-(9-Phenyl-9H-fluoren-9-yl)-DL-threo-3-phenylserine;
O-[9-(2-Fluorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Chlorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Methylphenyl)-9H-fiuoren-9-yl]-L-threonine;
O-[9-(3-Methylthien-2-yl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Methoxypheπyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(5-Chlorothien-2-yl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Trifluoromethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(4-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine;
S-[9-(3-Methylphenyl)-9H-thioxanthen-9-yl]-DL-cysteine;
S-[9-(4-Methylphenyl)-9H-thioxanthen-9-yl]-D,L-cysteine; and
S-(5-Phenyl-5/-/-dibenzo[a,cT|cyclohepten-5-yl)-D,L-cysteine.
30. A compound according to claim 1 , wherein the compound is selected from the group consisting of:
0-(9-Phenyl-9H-fluoren-9-yl)-L-threonine
O-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Chlorophenyl)-9H-fluoreπ-9-yl]-L-threonine;
O-[9-(3-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Methylρhenyl)-9H-fluoren-9-yl]-L-threonine; and
O-[9-(3-Methylthien-2-yl)-9H-fluoren-9-yl]-L-threonine.
31. The sodium salt of a compound according to claim 26. - 72
32. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and, in a therapeutically effective amount, a compound of Formula VI.
R6 o
Figure imgf000074_0001
OR1 VI
R5
/ .N,
R3 R2
or a prodrug or pharmaceutically acceptable salt, solvate or hydrate thereof wherein:
R1 is independently selected from the group consisting of H, Ci^alkyl and the counter ion for a basic addition salt;
R2, R3 and R4 are independently selected from the group consisting of H and dialkyl;
R5 and R6 are independently selected from the group consisting of H, Cι- alkyl and phenyl;
X is selected from the group consisting of CH2, S, O, SO, SO2, NH and
NC^alkyl;
R7 is selected from the group consisting of Formula ll-V:
Figure imgf000074_0002
which are all optionally substituted, at nodes other than R , with 1-4 substituents independently selected from the group consisting of C1-4alkyl, halo, phenyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono-C1-4alkylamino, di-Cι-4alkylamino, Ci^alkoxycarbonyl, Ci^alkylcarbonyl, Cι.4alkoxythiocarbonyl, Cι.4alkylthiocarbonyl, d^alkoxy, Ci^alkylS-, phenoxy, -SO2NH2, -SO2NHCι. alkyl, - 73 -
-SO2N(Cι-4alkyl)2 and 1 ,2-methylenedioxy; and wherein R8 is selected from the group consisting of H, d-6alkyl, benzyl, cycloalkyi, indanyl and an optionally substituted aromatic or heteroaromatic, 5-10-membered mono- or bicyclic ring wherein the optional substituents are independently selected from 1-4 members of the group consisting of Cι. alkyl, halo, phenyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono-Cι-4alkylamino, di-Ci^alkylamino,
Cι.4alkoxycarbonyl, Cι-4alkylcarbonyl, Cι- alkoxythiocarbonyl, C1-4alkylthiocarbonyl,
Cι-4alkoxy, Cι- alkylS-, phenoxy, -SO2NH2, -SO2NHC1-4alkyl, -SO2N(C1-4alkyl)2 and
1 ,2-methylenedioxy;
— represents a single or double bond;
Y is selected from the group consisting of O, S, SO, NH, NC1-4alkyl, CH2,
CH-C1-4aIkyl, C(Cι.4alkyl)2, and C=O;
Z is selected from the group consisting of CH2, O, S, NH and NC^alkyl when is a single bond; and
Z is selected from the group consisting of CH and N when is a double bond.
33. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and, in a therapeutically effective amount, a compound selected from the group consisting of:
O-(9-Phenyl-9H-fluoren-9-yl)-L-serine;
O-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-serine;
O-(9-Phenyl-9H-fluoren-9-yl)-L-threonine
O-(2-Fluoro-9-phenyl-9/-/-fluoren-9-yl)-L-serine;
O-[9-(2-Thienyl)-9H-fluoren-9-yl]-L-threonine;
O-(9-Phenyl-9H-xanthen-9-yl)-L-serine;
0-[9-(3-Methylphenyl)-9H-fluoren-9-yl]-L-serine;
O-[9-(4-Fluorophenyl)-9/-/-fluoren-9-yl]-L-serine;
0-[9-(4-Fluorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-(9-Phenyl-9H-xanthen-9-yl)-L-threonine;
0-[9-(4-Chlorophenyl)-9/-/-fluoren-9-yl]-L-sehne; - 74 -
O-[5-(2-Thienyl)-5L -dibenzo[a, ]cyclohepten-5-yl]-L-serine;
O-[9-(3-Methylphenyl)-9H-xanthen-9-yl]-L-serine;
O-[9-(4-Methylphenyl)-9H-fluoren-9-yl]-L-serine;
O-[9-(2-Methylthien-5-yl)-9W-fluoreπ-9-yl]-L-serine;
O-(9-Phenyl-9H-thioxanthen-9-yl)-L-serine;
O-[9-(3-Methylphenyl)-9H-xaπthen-9-yl]-L-threonine;
O-(10, 10-Dimethyl-9-phenyl-9, 10-dihydroanthracen-9-yl)-L-serine;
O-[9-(3-Methylphenyl)-9H-thioxanthen-9-yl]-L-serine;
O-[9-(4-Chlorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-(2,7-Dichloro-9-phenyl-9/-/-fluoren-9-yl)-L-serine; β-(9-Phenyl-9/-/-fluoren-9-yl)oxy-DL-norvaline;
O-(9-Phenyl-9H-fluoren-9-yl)-L-allothreonine;
O-[9-(4-Fluorophenyl)-9/-/-xanthen-9-yl]-L-threonine;
O^I O.I I-Dihydro-S-phenyl-SH-dibenzota^ jcyclohepten-S-ylJ-L-serine;
O-(5-Phenyl-5/-/-dibenzo[a,d]cyclohepten-5-yl)-L-serine;
O-[9-(4-Methylphenyl)-9H-thioxanthen-9-yl]-L-serine;
0-[9-(4-Methylphenyl)-9H-xanthen-9-yl]-L-serine;
O-(9-Phenyl-9/-/-fluoren-9-yl)-DL-threo-3-phenylserine;
O-[9-(4-Fluorophenyl)-9/-/-xanthen-9-yl]-L-serine;
O-[10, 11 -Dihydro-5-(2-thienyl)-5/- -dibenzo[a,cf]cyclohepten-5-yl]-L-serine;
O-(9-Cyclohexyl-9H-fluoren-9-yl)-L-serine;
O-(9-Phenyl-9H-xanthen-9-yl)-D-threonine;
O-[5-(3-Methylphenyl)-5W-dibenzo[a, ]cyclohepten-5-yl]-ι_-serine;
O-[5-(4-Methylphenyl)-5H-dibenzo[a, ]cyclohepten-5-yl]-L-serine;
O-(9-Phenyl-9H-xanthen-9-yl)-D-serine;
O-[9-(4-Methylphenyl)-9H-xanthen-9-yl]-D-serine;
O-[9-(3-Methylphenyl)-9H-xanthen-9-yl]-D-serine;
0-(9-Phenyl-9H-fluoren-9-yl)-D-serine;
O-(2,7-Dibromo-9-phenyl-9/-/-fluoren-9-yl)-L-serine;
O-[9-(2,4,6-Trimethylphenyl)-9H-fluoren-9-yl]-L-serine;
0-[9-Phenylmethyl-9W-fluoren-9-yl]-L-serine; - 75 -
O-[9-(2-Fluorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3,4-Methylenedioxyρhenyl)-9H-fluoren-9-yl]-L-threonine;
0-[9-(3-Chlorophenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Methylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-(9-Butyl-9H-fluoren-9-yl)-L-threonine;
O-[9-(3,4-Dimethoxyphenyl)-9H-fluoreπ-9-yl]-L-threonine;
O-[9-(3-Methylthien-2-yl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Methoxyphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(5-Chlorothien-2-yl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Trifluoromethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(4-Methoxyphenyl)-9/7-fluoren-9-yl]-L-threonine;
0-[9-(4-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Ethylphenyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(2-Naphthyl)-9H-fluoren-9-yl]-L-threonine;
O-[9-(3-Biphenyl)-9H-fluoren-9-yl]-L-threonine;
Λ/-Methyl-O-(9-phenyI-9H-fluoren-9-yl)-L-serine;
N,/V-Dimethyl-O-(9-phenyl-9tf-fluoren-9-yl)-L-serine;
S-(9-Phenyl-9H-thioxanthen-9-yl)-D,L-cysteine;
S-[9-(3-Methylρhenyl)-9H-thioxaπthen-9-yl]-DL-cysteine;
S-[9-(4-MethyIphenyl)-9H-thioxanthen-9-yl]-D,L-cysteine;
S-(5-Phenyl-5H-dibenzo[a, ]cyclohepten-5-yl)-D,L-cysteine;
S-[5-(3-Methylphenyl)-5/-/-dibenzo[a, ]cyclohepten-5-yl]-D,L-cysteine;
S-[5-(4-Methylphenyl)-5H-dibenzo[a ]cyclohepten-5-yl]-D,L-cysteine;
S-(10,11-Dihydro-5-phenyl-5H-dibenzo[a,d]cyclohepten-5-yl)-D,L-cysteine;
S-[9-(3-Methylphenyl)-9H-fluoren-9-yl]-D,L-cysteine;
S-[9-(4-Methylphenyl)-9H-fluoren-9-yl]-D,L-cysteine;
S-(10,10-Dimethyl-9-phenyl-9,10-dihydroanthracen-9-yl)-D,L-cysteine;
S-(7-Phenyl-7H-benz[ ,e]anthracen-7-yl )-D,L-cysteine;
S-(2,7-Dibromo-9-phenyl-9H-fluoren-9-yl)-D,L-cysteine;
S-(9-Phenyl-9H-fluoren-9-yl)-D,L-cysteine - 76 -
Λ/α-(9-Phenyl-9H-fluoren-9-yl)-DL-α,β-diaminopropionic acid;
4-(9-Phenyl-9H-fluoren-9-yl)-DL-2-aminobutyric acid.
0-(10, 11 -Dihydro-5H-dibenzo[a, ]cyclohepten-5-yl)-L-serine;
O-(9H-fluoren-9-yl)-L-serine; and
0-(9-f-butyl-9H-fluoren-9-yl)-L-serine
34. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and, in a therapeutically effective amount, the sodium salt of a compound according to claim 33.
35. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and, in a therapeutically effective amount, the compound according to claim 30.
36. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and, in a therapeutically effective amount, the compound according to claim 31.
37. A method for treating a patient having a medical condition for which inhibition of glycine transport mediated by GlyT-2 is indicated, comprising the step of administering to the patient a pharmaceutical composition as defined in claim 32.
38. A method for treating a patient according to claim 37, wherein the medical condition is associated with increased or decreased muscle contraction.
PCT/US1999/003012 1998-02-12 1999-02-11 Tricyclic compounds as glycine transport inhibitors Ceased WO1999041227A1 (en)

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US09/022,617 1998-02-12

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CN107698490A (en) * 2017-09-04 2018-02-16 上海珂力恩特化学材料有限公司 A kind of organic luminescent compounds and its preparation method and application
CN114685255A (en) * 2020-12-30 2022-07-01 重庆圣华曦药业股份有限公司 Preparation method of melitracen hydrochloride intermediate

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Title
ZEE-CHENG K.-Y., CHENG C. C.: "EXPERIMENTAL ANTILEUKEMIC AGENTS. PREPARATION AND STRUCTURE-ACTIVITY STUDY OF S-TRITYLEYSTEINE AND RELATED COMPOUNDS.", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 13., no. 03., 1 January 1970 (1970-01-01), US, pages 414 - 417., XP002919020, ISSN: 0022-2623, DOI: 10.1021/jm00297a019 *

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JP6092513B2 (en) * 2009-03-12 2017-03-08 味の素株式会社 Fluorene compound
US8569453B2 (en) 2009-03-12 2013-10-29 Ajinomoto Co., Inc. Fluorene compound
EP2415744A4 (en) * 2009-03-12 2014-03-19 Ajinomoto Kk Fluorene compound
US9029504B2 (en) 2009-03-12 2015-05-12 Ajinomoto Co., Inc. Fluorene compound
WO2010104169A1 (en) * 2009-03-12 2010-09-16 味の素株式会社 Fluorene compound
WO2013141264A1 (en) * 2012-03-21 2013-09-26 一般社団法人ファルマバレープロジェクト支援機構 Novel cysteine compound and salt thereof
JP5662618B2 (en) * 2012-03-21 2015-02-04 一般社団法人ファルマバレープロジェクト支援機構 Novel cysteine compounds and salts thereof
CN105085162A (en) * 2015-09-06 2015-11-25 河南省商业科学研究所有限责任公司 One-pot method for preparing 2-bromo-9,9-diphenylfluorene
CN105085163A (en) * 2015-09-06 2015-11-25 河南省商业科学研究所有限责任公司 Synthesis method of 2-bromo-9,9-diphenylfluorene
CN107698490A (en) * 2017-09-04 2018-02-16 上海珂力恩特化学材料有限公司 A kind of organic luminescent compounds and its preparation method and application
CN107698490B (en) * 2017-09-04 2020-12-22 奥来德(上海)光电材料科技有限公司 Organic light-emitting compound and preparation method and application thereof
CN114685255A (en) * 2020-12-30 2022-07-01 重庆圣华曦药业股份有限公司 Preparation method of melitracen hydrochloride intermediate
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