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WO1999041227A1 - Composes tricycliques comme inhibiteurs de transport de glycine - Google Patents

Composes tricycliques comme inhibiteurs de transport de glycine Download PDF

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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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    • 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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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • 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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    • 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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    • 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
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    • 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
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    • 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
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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
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    • 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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    • 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
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    • 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
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    • 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

L'invention concerne une classe d'acides aminés substitués, des compositions pharmaceutiques et des procédés permettant de traiter des troubles neurologiques et neuropsychiatriques.
PCT/US1999/003012 1998-02-12 1999-02-11 Composes tricycliques comme inhibiteurs de transport de glycine Ceased WO1999041227A1 (fr)

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WO2010104169A1 (fr) * 2009-03-12 2010-09-16 味の素株式会社 Composé fluorène
WO2013141264A1 (fr) * 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 Nouveau composé de cystéine et sel de celui-ci
CN105085162A (zh) * 2015-09-06 2015-11-25 河南省商业科学研究所有限责任公司 一锅法制备2-溴-9,9-二苯基芴
CN105085163A (zh) * 2015-09-06 2015-11-25 河南省商业科学研究所有限责任公司 2-溴-9,9-二苯基芴的合成方法
CN107698490A (zh) * 2017-09-04 2018-02-16 上海珂力恩特化学材料有限公司 一种有机发光化合物及其制备方法和应用
CN114685255A (zh) * 2020-12-30 2022-07-01 重庆圣华曦药业股份有限公司 一种盐酸美利曲辛中间体的制备方法

Non-Patent Citations (1)

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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 (ja) * 2009-03-12 2017-03-08 味の素株式会社 フルオレン化合物
US8569453B2 (en) 2009-03-12 2013-10-29 Ajinomoto Co., Inc. Fluorene compound
EP2415744A4 (fr) * 2009-03-12 2014-03-19 Ajinomoto Kk Composé fluorène
US9029504B2 (en) 2009-03-12 2015-05-12 Ajinomoto Co., Inc. Fluorene compound
WO2010104169A1 (fr) * 2009-03-12 2010-09-16 味の素株式会社 Composé fluorène
WO2013141264A1 (fr) * 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 Nouveau composé de cystéine et sel de celui-ci
JP5662618B2 (ja) * 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 新規システイン化合物及びその塩
CN105085162A (zh) * 2015-09-06 2015-11-25 河南省商业科学研究所有限责任公司 一锅法制备2-溴-9,9-二苯基芴
CN105085163A (zh) * 2015-09-06 2015-11-25 河南省商业科学研究所有限责任公司 2-溴-9,9-二苯基芴的合成方法
CN107698490A (zh) * 2017-09-04 2018-02-16 上海珂力恩特化学材料有限公司 一种有机发光化合物及其制备方法和应用
CN107698490B (zh) * 2017-09-04 2020-12-22 奥来德(上海)光电材料科技有限公司 一种有机发光化合物及其制备方法和应用
CN114685255A (zh) * 2020-12-30 2022-07-01 重庆圣华曦药业股份有限公司 一种盐酸美利曲辛中间体的制备方法
CN114685255B (zh) * 2020-12-30 2023-12-26 重庆圣华曦药业股份有限公司 一种盐酸美利曲辛中间体的制备方法

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