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WO1996040141A1 - Quinoxalinediones et quinolones pontees en position 4 et 5, et leur emploi comme antagonistes de recepteurs d'acides amines excitateurs - Google Patents

Quinoxalinediones et quinolones pontees en position 4 et 5, et leur emploi comme antagonistes de recepteurs d'acides amines excitateurs Download PDF

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Publication number
WO1996040141A1
WO1996040141A1 PCT/US1996/010118 US9610118W WO9640141A1 WO 1996040141 A1 WO1996040141 A1 WO 1996040141A1 US 9610118 W US9610118 W US 9610118W WO 9640141 A1 WO9640141 A1 WO 9640141A1
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substimted
alkyl
arylalkyl
aryl
alkenyl
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Sui Xiong Cai
John F. W. Keana
Vladimir V. Martin
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Oregon State Board of Higher Education
Acea Pharmaceuticals Inc
Oregon State
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Oregon State Board of Higher Education
Acea Pharmaceuticals Inc
Oregon State
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Priority to AU61726/96A priority Critical patent/AU6172696A/en
Publication of WO1996040141A1 publication Critical patent/WO1996040141A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems

Definitions

  • the present invention is in the field of medicinal chemistry and relates to compounds that exhibit high affinity for the strychnine-insensitive glycine binding site and that do not exhibit PCP side effects.
  • the present invention relates to novel 4,5-bridged tricyclic quinoxaline-2,3-diones and pyridine (N-oxide) analogs thereof, and their use to treat or prevent neuronal degeneration associated with ischemia, pathophysiologic conditions associated with neuronal degeneration,, convulsions, anxiety, chronic pain, and to induce anesthesia.
  • EAAs excitatory amino acids
  • ALS amyotrophic lateral sclerosis
  • Glutamate is thought to be the major excitatory amino acid in the brain. There are three major subtypes of glutamate receptors in the CNS.
  • NMDA receptors are found in the membranes of virtually every neuron in the brain. NMDA receptors are ligand-gated cation channels that allow Na + , K + , and Ca + + to permeate when they are activated by glutamate or aspartate (non-selective, endogenous agonists) or by NMDA (a selective, synthetic agonist) (Wong and Kemp, Ann. Rev. Pharmacol. Toxicol. 31:401- 425 (1991)).
  • the NMDA receptor channel In order to become activated by glutamate, the NMDA receptor channel must first bind glycine at a specific, high affinity, glycine binding site that is separate from the glutamate/NMDA binding site on the receptor protein (Johnson and Ascher, Nature 325:329-331 (1987)). Glycine is therefore an obligatory co- agonist at the NMDA receptor/channel complex (Kemp, J.A., et al. , Proc. Natl. Acad. Sci. USA 55:6547-6550 (1988)).
  • the NMDA receptor In addition to the binding sites for glutamate/NMDA and glycine, the NMDA receptor carries a number of other functionally important binding sites. These include binding sites for Mg ++ , Zn ++ , polyamines, arachidonic acid, and phencyclidine (PCP) (Reynolds and Miller, Adv. in Pharmacol. 27:101-126 (1990); Miller, B., et al. , Nature 355:122-125 (1992)).
  • the PCP binding site now commonly referred to as the PCP receptor—is located inside the pore of the ionophore of the NMDA receptor/channel complex (Wong, E.H.F., et al. , Proc. Natl. Acad. Sci.
  • PCP In order for PCP to gain access to the PCP receptor, the channel must first be opened by glutamate and glycine. In the absence of glutamate and glycine, PCP cannot bind to the PCP receptor although some studies have suggested that a small amount of PCP binding can occur even in the absence of glutamate and glycine (Sircar and Zukin, Brain Res. 556:280-284 (1991)). Once PCP binds to the PCP receptor, it blocks ion flux through the open channel. Therefore, PCP is an open channel blocker and a non-competitive glutamate antagonist at the NMDA receptor/channel complex.
  • One of the most potent and selective drugs that bind to the PCP receptor is the anticonvulsant drug MK801. This drug has a K d of approximately 3nM at the PCP receptor (Wong, E.H.F., et al , Proc. Natl.
  • PCP and MK801 as well as other PCP receptor ligands, e.g. , dextromethorphan, ketamine, and N,N' -disubstituted guanidines, have neuroprotective efficacy both in vitro and in vivo (Gill, R., et al. , J. Neurosci. 7:3343-3349 (1987); Keana, J.F.W., et al , Proc. Natl. Acad. Sci. USA
  • PCP PCP receptor ligands
  • PCP and related PCP receptor ligands cause a behavioral excitation (hyperlocomotion) in rodents (Tricklebank, M.D., et al., Eur. J. Pharmacol.
  • Drugs acting as competitive antagonists at the glutamate binding site of the NMDA receptor such as, CGS 19755 and LY274614, also have neuroprotective efficacy because these drugs— like the PCP receptor ligands— can prevent excessive Ca ++ flux through NMDA receptor/channels in ischemia (Boast, C.A., et al, Brain Res. 442:345-348 (1988); Schoepp,
  • NMDA receptor channel activation is by using antagonists at the glycine binding site of the NMDA receptor. Since glycine must bind to the glycine site in order for glutamate to effect channel opening (Johnson and Ascher, Nature 325:329-331 (1987); Kemp, J.A., et al, Proc. Natl Acad. Sci. USA 55:6547-6550 (1988)), a glycine antagonist can completely prevent ion flux through the NMDA receptor channel-even in the presence of a large amount of glutamate.
  • glycine antagonists should be very powerful neuroprotective agents because they can prevent the opening of NMDA channels by glutamate non- competitively and, therefore, unlike competitive NMDA antagonists, do not have to overcome the large concentrations of endogenous glutamate that are released in the ischemic brain region.
  • glycine antagonists act at neither the glutamate/NMDA nor the PCP binding sites to prevent NMDA channel opening, these drugs might not cause the PCP-like behavioral side effect seen with both PCP receptor ligands and competitive NMDA receptor antagonists
  • glycine antagonists as clinically useful neuroprotective agents: A. Most available glycine antagonists with relatively high receptor binding affinity in vitro such as 7-Cl-kynurenic acid (Kemp, J.A., et al , Proc. Natl. Acad. Sci. USA
  • X represents alkyl, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, alkylamino, alkoxy, alkanoyl, alkoxycarbonyl, sulfamoyl, carbamoyl, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alk lsulfamoyl, alkylsulfonyl, amino, or acylamino;
  • - R 1 represents hydrogen, alkyl, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, alkylamino, alkoxy, alkanoyl, alkoxycarbonyl, sulfamoyl, carbamoyl, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfamoyl,
  • W represents hydrogen, CO 2 R 3 , CO 2 Y, CONR 3 R 4 , CONR 3 Y,
  • These compounds are disclosed as selective antagonists of glutamate receptors for the treatment and prevention of various diseases such as minimizing damage to the central nervous system induced by ischemic or hypoxic conditions, treatment and/or prevention of neurodegenerative disorders, as analgesics, antidepressants, anxiolytics and anti-schizophrenics.
  • U.S. Patent Nos. 4,812,458 and 4,948,794 discloses 1,4- dihydroquinoxaline-2,3-dione compounds reportedly useful for treatment of indications caused by hyperactivity of the excitatory neurotransmitters, particularly the quisqualate receptors, and as neuroleptics.
  • International Application Publication No. WO91/13878 discloses N- substituted l,4-dihydroquinoxaline-2,3-diones, which bind to the glycine receptor, and pharmaceutically acceptable salts thereof.
  • the present invention is broadly directed to methods of treating, preventing, or decreasing neuronal degeneration associated with ischemia, pathophysiologic conditions associated with neuronal degeneration, convulsions, anxiety, chronic pain, and inducing anesthesia by administering a tricyclic quinoxalinedione represented by Formula /:
  • X represents one of C(R ! ) or N(O) n ;
  • Y represents one of C(R 2 ) or N(O) n ;
  • Z represents one of C(R 3 ) or N(O) n , with the proviso that when either or both of X and Z are N(O) n , then Y is C(R 2 );
  • R 1 and R 2 independently represent hydrogen, halogen, cyano, azido, nitro, hydroxy, amino, alkyl, haloalkyl, alkenyl, alkynyl, alkylamino, alkoxy, haloalkoxy, trialkylsilyl-substituted alkoxy, alkanoyl, alkoxycarbonyl, sulfamoyl, carbamoyl, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfamoyl, alkylsulfonylamino, or acylamino;
  • R 3 represents hydrogen or fluorine
  • E represents one of — C(R 4a )(R 4b )— , — O- or — N(R 9 )— ;
  • G represents one of — C(R 6a )(R 6b )— , — O— or — N(R")— ;
  • R 5a and R 5b (i) independently represent hydrogen, alkyl, substimted alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, arylalkyl, substituted arylalkyl, aryl or substitute
  • R 9 independently represents hydrogen or lower alkyl, or (ii) R 9 together with R 5a form a double bond; n is zero or one; and p is zero or one.
  • the present invention is also drawn to the following novel sub ⁇ classes of compounds falling within the definition of Formula /. These novel compounds are represented by Formulae IA, IB, IC and ID. One subclass of novel compounds according to the present invention is represented by compounds of Formula IA:
  • R 1 , R 2 , R 3 , E, G, R 4a , R 4b , R 5a , R 5b , R 6 ⁇ R 6b , R 7 , R 8 , R 9 and p are defined as above for Formula /; preferably
  • R 6a and R 6b do not represent hydrogen, alkyl or substimted alkyl.
  • Another sub-class of novel compounds according • to the present invention are aza and aza(N-oxy) compounds represented one of Formulae IB, IC or ID:
  • R R 2 , R 3 , E, G, R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7 , R 8 , R 9 and p are defined as above for Formula /; and n is zero or one.
  • An additional aspect of the present invention relates to tricyclic systems based upon l,2,3,4-tetrahydroquinoline-2,3-dione-3-oximes. These compounds have the following generalized formula:
  • X, Y, Z, R 1 , R 2 , R ⁇ E, G, R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7 , R 8 , R 9 , n and p are defined as above for Formula /;
  • R' is one of hydrogen, alkyl, aryl, heteroaryl, acyl, halogen-substituted acyl or aryloyl.
  • An additional aspect of the present invention relates to tricyclic systems based upon 4-hydroxy-3-nitro-2-quinolones.
  • the 4 and 5 carbons of a 4-hydroxy-3-nitro-2-quinolone are bridged to form compounds having the following generalized structure:
  • X represents one of C(R') or N(O) n ;
  • Y represents one of C(R 2 ) or N(O) n ;
  • Z represents one of C(R 3 ) or N(O) n with the proviso that when either or both of X and Z are N(O) n , then Y is C(R 2 );
  • R, and R 2 independently represent hydrogen, halogen, cyano, azido, nitro, hydroxy, amino, alkyl, haloalkyl, alkenyl, alkynyl, alkylamino, alkoxy, haloalkoxy, trialkylsilyl-substituted alkoxy, alkanoyl, alkoxycarbonyl, sulfamoyl, carbamoyl, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfamoyl, alkylsulfonylamino, or acylamino;
  • R 3 represents one of hydrogen or flourine
  • E represents one of — C(R 4a )(R 4b )— , — O— or — N(R 9 )— ;
  • R 4b is hydrogen or alkyl, and R 4a together with R 5a forms a double bond;
  • R 5 and R 5b (i) independently represent hydrogen, alkyl, substimted alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, arylalkyl, substimted arylalkyl, aryl or substimted aryl, (ii) together represent oxo or thiooxo, or
  • R 5b represents hydrogen or alkyl when R 5a together with R 4a or R 5a together with R 9 form a double bond
  • R 9 independently represents hydrogen or lower alkyl, or (ii) R 9 together with R 5a form a double bond; n is zero or one.
  • R ⁇ R 2 , R 3 , E, R 4a , R 4b , R 5a , R 5b and R 9 are defined as above for Formula ///; and n is zero or one.
  • a further embodiment of the invention relates to tricyclic quinoxalinediones which incorporate a nitrone group in the bridge between C- 5 and N-4 of a quinoxalinedione.
  • These compounds have the one of the following formulae:
  • R 1 and R 2 independently represent hydrogen, halogen, cyano, azido, nitro, hydroxy, amino, alkyl, haloalkyl, alkenyl, alkynyl, alkylamino, alkoxy, haloalkoxy, trialkylsilyl-substimted alkoxy, alkanoyl, alkoxycarbonyl, sulfamoyl, carbamoyl, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfamoyl, alkylsulfonylamino, or acylamino;
  • R 3 represents hydrogen or fluorine
  • W represents one of C(R 4 ) or N(O) tripod; .
  • N represents one of C(R 5 ) or ⁇ (O) n with the proviso that one of W and V is N(O) n , and the other of W and V is C(R 4 ) or C(R 5 ), respectively;
  • R 4 and R 5 independently represent hydrogen, alkyl, substimted alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, arylalkyl, substimted arylalkyl, aryl or substimted aryl;
  • R 6 represents hydrogen, CO 2 R 7 , CONR 7 R 8 , CON(OR 7 )R 8 , COR 7 , CN, tetrazolyl, alkyl, substimted alkyl, alkenyl, cycloalkylalkyl, arylalkyl, substimted arylalkyl, heteroarylalkyl, substimted heteroarylalkyl or heterocycloalkyl;
  • R 7 and R 8 independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, arylalkyl, substimted arylalkyl, aryl, substimted aryl, heteroarylalkyl, heteroarylalkenyl, heteroaryl, substituted heteroaryl, substimted heteroarylalkyl, substimted heteroarylalkenyl, or heterocycloalkyl;
  • R 26 represents alkyl, substituted alkyl, alkenyl, cycloalkylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substimted heteroarylalkyl or heterocycloalkyl; and n is zero or one.
  • the dashed line between W and Z indicates that the bond between W and Z can be either a single or double bond.
  • the present invention relates to novel tricylic compounds having Formulae I, II, III, IVA and IVB, tautomers or pharmaceutically acceptable salts thereof.
  • the present invention relates to a method of treating or preventing (A) neuronal loss associated with stroke, ischemia, CNS trauma, or hypoglycemia or (B) the adverse neurological consequences of surgery, comprising administering to an animal in need of such treatment or prevention an effective amount of a compound defined by one of Formulae 7, 77, 777, IVA and IVB, or a tautomer or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method of treating a neurodegenerative disease selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Down's syndrome, comprising administering to an animal in need of such treatment an effective amount of a compound defined by one of Formulae /, //, III, IVA and IVB, or a tautomer or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method of antagonizing excitatory amino acids at the NMDA receptor complex, comprising administering to an animal in need thereof an effective amount of a compound defined by one of Formulae I, II, III, IVA and IVB, or a tautomer or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method of treating or preventing the adverse consequences of the hyperactivity of the NMDA receptor, comprising administering to an animal in need of such treatment or prevention an effective amount of a compound defined by one of Formulae I, II, III, IVA and IVB, or a tautomer or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method of treating chronic pain, comprising administering to an animal in need of such treatment an effective amount of a compound defined by one of Formulae 7, 77, 777, IVA and IVB, or a tautomer or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method of treating or preventing anxiety, comprising administering to an animal in need of such treatment or prevention an effective amount of a compound defined by one of Formulae 7, 77, 777, IVA and IVB, or a tautomer or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method of treating or preventing convulsions, comprising administering to an animal in need of such treatment or prevention an effective amount of a compound defined by one of Formulae I, II, III, IVA and IVB, or a tautomer or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method of inducing anesthesia, comprising administering to an animal in need of such anesthesia an effective amount of a compound defined by one of Formulae I,
  • the present invention relates to a method of treating or preventing NMDA receptor-ion channel related psychosis, comprising administering to an animal in need of such treatment or prevention an effective amount of a compound defined by one of Formulae 7, 77, 777, IVA and IVB, or a tautomer or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method of inducing a hypnotic effect, comprising administering to an animal in need of such treatment an effective amount of a compound defined by one of
  • -the present invention relates to a radiolabelled compound having one of Formulae 7, 77, 777, IVA and IVB, or a tautomer or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method of preventing opiate tolerance, comprising administering to an animal in need of such prevention an effective amount of a compound having one of
  • the present invention relates to a pharmaceutical compositions comprising a compound having one of Formulae
  • the present invention provides novel quinoxalinediones depicted by Formula 7 above and tautomers and pharmaceutically acceptable salts thereof.
  • the tricyclic compounds provided for by the following formulae are included in this aspect of the present invention:
  • R 1 , R 2 and R 3 are each as defined for Formula 7 above;
  • R 16 represents hydrogen, CO 2 R 7 , CONR 7 R 8 , CON(OR 7 )R 8 , COR 7 , CN, tetrazolyl, alkyl, substituted alkyl, alkenyl, cycloalkylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl or heterocycloalkyl;
  • R 7 and R 8 independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, arylalkyl, substimted arylalkyl, aryl, substimted aryl, heteroarylalkyl, heteroarylalkenyl, heteroaryl, substimted heteroaryl, substimted heteroarylalkyl, substimted heteroarylalkenyl, or heterocycloalkyl;
  • R 19 represents hydrogen or alkyl; and n is zero or one.
  • a second aspect of the present invention relates to tricyclic compounds based upon l,2,3,4-tetrahydroquinoline-2,3-dione-3-oximes having Formula 77 above.
  • Preferred compounds for this aspect of the invention include compounds having the formulae:
  • R 1 , R 2 and R 3 are each as defined for Formula 7 above; and n is zero or one.
  • An additional aspect of the present invention relates to tricyclic compounds based upon 4-hydroxy-3-nitro-2-quinolones.
  • the 4 and 5 carbons of a 4-hydroxy-3-nitro-2-quinolone are bridged to form compounds of the general structure of Formula 777 above.
  • Preferred compounds for this aspect of the invention have the following structures:
  • R ⁇ R 2 and R 3 are each as defined for Formula 777 above, and R 19 represents hydrogen or alkyl.
  • a further embodiment of the invention relates to tricyclic quinoxalinediones which incorporate a nitrone group in the bridge between C- 5 and N-4 of a quinoxalinedione.
  • These compounds have the general Formulae IVA and IVB shown above.
  • Preferred compounds within this embodiment have the following structure: XXVIII
  • R 1 and R 2 are defined as above for Formula 7;
  • R 16 represents hydrogen, CO 2 R 7 , CONR 7 R 8 , CON(OR 7 )R 8 , COR 7 .
  • CN tetrazolyl, alkyl, substimted alkyl, alkenyl, cycloalkylalkyl.
  • R 26 represents alkyl, substimted alkyl, alkenyl, cycloalkylalkyl, arylalkyl, substimted arylalkyl, heteroarylalkyl, substimted heteroarylalkyl or heterocycloalkyl.
  • aryl as used herein includes aryl groups having 6 to 14 carbon atoms. Typical examples are phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups.
  • aryloxy as used herein includes any of the . ⁇ aryl groups linked by oxygen, e.g., phenoxy and 1-naphthyloxy groups.
  • substituted aryl as used herein includes any of the C ⁇ aryl groups substimted by one or more halo, nitro, cyano, alkyl, haloalkyl, alkenyl, and alkynyl groups, e.g., 2-chlorophenyl, 2,4-dibromophenyl, and the like.
  • substituted aryloxy includes any of the C ⁇ aryl groups substimted by one or more halo, nitro, cyano, alkyl, haloalkyl, alkenyl, and alkynyl groups, and linked by oxygen, e.g., 2-chlorophenoxy, 2,4-dibromophenoxy, and the like.
  • aryloyl as used herein includes any of the above-mentioned aryl groups substimted by a carbonyl group.
  • amino as used herein includes NH 2 , NHR 11 , and NR n R 12 , wherein R ⁇ and R 12 are C M alkyl groups.
  • alkyl as used herein includes straight-chained or branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples are methyl, ethyl, /i-propyl, isopropyl, sec-butyl, tert-butyl, neopentyl, w-pentyl, and /z-hexyl.
  • alkylamino as used herein includes mono- and dialkylamino groups, wherein an alkyl group contains from 1 to 6 carbon atoms which may be straight-chained or branched. Typical examples are methylamino, methylethylamino, diethylamino, propylamino, diisopropylamino, and hexylamino.
  • halogen or “halo” as used herein include fluorine, chlorine, bromine, and iodine. Typical examples are chlorine and bromine.
  • alkoxy as used herein includes straight-chained or branched alkoxy groups containing from 1 to 6 carbon atoms. Typical examples are methoxy, ethoxy, propoxy, isopropoxy, sec-butoxy, terr-butoxy, neopentoxy, pentoxy, and hexoxy.
  • alkanoyl as used herein includes straight-chained or branched alkanoyl groups containing from 1 to 6 carbon atoms. Typical examples are formyi, acetyl, propanoyl, n-butanoyl, and pivaloyl.
  • alkoxycarbonyl as used herein includes straight-chained or branched alkoxycarbonyl groups containing from 1 to 6 carbon atoms. Typical examples are methoxy carbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl, and tert-butoxy carbonyl.
  • alkylthio as used herein includes straight-chained or branched alkylthio groups containing from 1 to 6 carbon atoms. Typical examples are methylthio, ethylthio, ⁇ -propylthio, isopropylthio, sec-butylthio, r -butylthio, neopentylthio, ⁇ -pentylthio, and w-hexylthio.
  • alkylsulfinyl as used herein includes straight-chained or branched alkylsulfinyl groups containing from 1 to 6 carbon atoms. Typical examples are methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, sec-butylsulfinyl, rt-butylsulfinyl, neopentylsulfinyl, n-pentylsulfinyl, and n- hexylsulfinyl.
  • alkylsulfonyl as used herein includes straight-chained or branched alkylsulfonyl groups containing from 1 to 6 carbon atoms. Typical examples are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, rec-butylsulfonyl, /T-butylsulfonyl, neopentylsulfonyl, n- pentylsulfonyl, and /i-hexylsulfonyl.
  • alkylcarbamoyl as used herein includes mono- and dialkylcarbamoyl, wherein an alkyl moiety contains from 1 to 6 carbon atoms which may be straight-chained or branched. Typical examples are methyl- carbamoyl, methylethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, diisopropylcarbamoyl, and hexylcarbamoyl.
  • alkylsulfamoyl as used herein includes sulfamoyl groups substimted with 1 or 2 alkyl groups containing from 1 to 6 carbon atoms which may be straight-chained or branched. Typical examples are methylsulfamoyl, methylethylsulfamoyl, diethylsulfamoyl, propylsulfamoyl, diisopropylsulfamoyl, and hexylsulfamoyl.
  • alkylsulfonylamino as used herein includes straight-chained or branched alkylsulfonylamino groups containing from 1 to 6 carbon atoms. Typical examples are methylsulfonylamino, ethylsulfonylamino, n- propylsulfonylamino, isopropylsulfonylamino, sec-butylsulfony lamino, tert- butylsulfonylamino, neopentylsulfonylam.no, n-pentylsulfony lamino, and n- hexy lsulf ony lamino .
  • acy lamino as used herein includes straight-chained or branched alkanoylamino groups containing from 1 to 6 carbon atoms.
  • acy lamino as used herein also includes aroy lamino groups containing from 7 to 11 carbon atoms. Typical examples are formy lamino, acety lamino, propanoy lamino, butanoy lamino, sec-butanoy lamino, /i-pentanoy lamino, n- hexanoy lamino, benzoy lamino, and 1- or 2-naphthoy lamino.
  • cycloalkyl as used herein includes cycloalkyl groups containing from 3 to 8 carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • alkenyl as used herein includes straight-chained or branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples are vinyl, allyl, 1-propenyl, and 1-, 2- or 3-butenyl.
  • alkynyl as used herein includes straight-chained or branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples are ethynyl, propargyl, 1- or 2-propynyl, 1- or 2-butynyl, and pentynyl.
  • cycloalkylalkyl as used herein includes straight-chained or branched alkyl groups attached with cycloalkyl groups, which contains up to 13 carbon atoms. Typical examples are cyclopropylmethyl, cyclopentylethyl, cyclohexylmethyl, and cyclohexylpropyl.
  • arylalkyl as used herein includes straight-chained or branched alkyl groups attached with aryl groups, which contains up to 15 carbon atoms. Typical examples are benzyl, phenylethyl, 1- or 2- naphthylmethyl, and 1- or 2-naphthylpropyl.
  • haloalkyl as used herein includes C M alkyl groups substimted by one or more fluorine, chlorine, bromine, or iodine atoms, e.g., fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1- difluoroethyl, and trichloromethyl groups.
  • haloalkoxy includes one of the alkoxy groups mentioned above substimted by one or more fluoro, chloro, bromo, or iodo groups, e.g., trifluoromethoxy, trichloromethoxy, 2-chloroethoxy, 2- bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, 4,4,4-trichlorobutoxy, and the like.
  • Trialkylsilyl-substimted alkoxy includes any one of the C alkoxy groups substimted by a C 3-6 trialkylsilyl group, e.g. 2-trimethylsilylethoxy, 2-triethylsilylethoxy and 2-(t-butyldimethylsilyl)ethoxy, and the like.
  • Preferred heterocyclic groups are those having 3 to 10 carbon atoms and having one or more 4, 5, 6, or 7 member samrated or unsamrated rings containing 1, 2, or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heterocyclic radicals are: tetrahydrofuran, 1,4-dioxane, 1,3,5-trioxane, pyrrolidine, piperidine, piperazine, imadazoline, isoindoline, chromane, isochromane, pyrazolidine, quinuclidine, pyridine, pyrrole, oxazole, indole, purine, pyrimidine, 1,3-dithiane, azetidine, tetrahydropyran, imidazole, thiazole, isoxazole, pyrazole, quinoline, cytosine, thymine, uracil, adenine, guanine, pyrazine, l-methyl-l,
  • heteroaryl as used herein includes groups which have 3 to 14 ring atoms; 6, 10 or 14 - ⁇ electrons shared in a cyclic array; and contain carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 277-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 37 -indolyl, indolyl, indazolyl, purinyl, 4H-quinoliziny
  • heteroarylalkyl as used herein includes straight-chained or branched alkyl groups containing up to 6 carbon atoms, which is attached with a heteroaryl group.
  • the heteroaryl group is as defined above. Typical examples are pyridylmethyl, - quinolylethyl, isoquinolylpropyl, pyridazinylmethyl, pyrimidinylethyl, pyrazinylpropyl, pyrrolylmethyl, indolylethyl, pyranylpropyl, furylmethyl, benzofurylethyl, thienylpropyl, benzothienylmethyl, imidazolylethyl, oxazolylpropyl, thiazolylmethyl, isoxazolylmethyl, isothiazolylethyl, oxadiazolylethyl, thiadiazolylproyl, tetrazolylmethyl, benzoxazolylmethyl,
  • heterocycloalkyl as used herein includes heterocycloalkyl groups containing up to 6 carbon atoms together with 1 or 2 heteroatoms which are selected from nitrogen, oxygen and sulfur atoms. Typical examples are piperidyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, and dithianyl.
  • heterocycloalkyl as used herein also includes heterocycloalkyl groups fused with benzene-ring containing up to 10 carbon atoms together with 1 or 2 heteroatoms which are selected from nitrogen, oxygen and sulfur atoms. Typical examples are indolinyl, isoindolinyl, tetrahydro- 1 -quinolinyl, and tetrahydro-2-quinolinyl, tetrahydroquinoxaliny 1.
  • alkyl groups of the term "substimted alkyl" as used in R 4 , R 5 , R 6 , R 6a and R 6b include straight-chained or branched alkyl groups containing from 1 to 4 carbon atoms. Typical examples are methyl, ethyl, propyl, and butyl.
  • the substituent of the term "substimted alkyl" as used in R 4 , R 5 , R 6 , R 63 , R 6b , and R 16 includes CO 2 R 3 , CONR 13 R 14 , CON(OR 13 )R 14 , COR 15 , CN, NR 13 CO 2 R 14 , NR 13 CONR 14 R 15 , phthalimido, heteroaryl, substimted heteroaryl, heterocycloalkyl, NR 13 R 14 , NR ,3 SO 2 R 14 , NR ,3 COR 14 , NR ,3 COCO 2 R 14 , NR 13 COCONR ,4 R 15 , NR 13 COCOR 14 , OR 13 , OCOR 13 , OCOY, OCO 2 R 13 ,
  • OCONR 13 R 14 OCOCO 2 R 13 , OCOCOR 13 , OCOCONR 13 R 14 , OSO 2 R 13 , PO(OR 13 ) 2 , SR 13 , SOR 13 , SO 2 R 13 , SO 3 R 13 , SO 2 NR 13 R 14 , F, Cl, Br, and I; wherein R 13 , R 14 , and R 15 independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, arylalkyl, substimted arylalkyl, aryl, substimted aryl, heteroarylalkyl, heteroaryl, substimted heteroaryl, substimted heteroarylalkyl or heterocycloalkyl; and
  • the number of the substituents on substimted aryl, substimted arylalkyl, substimted heteroaryl, or substimted heteroarylalkyl, respectively, as used herein may be one, two, or three, up to the maximum number permitted, and the substituents include alkyl, halogen, cyano, trifluoromethyl, nitro, hydroxy, mercapto, amino, alkylamino, alkoxy, alkanoyl, alkoxycarbonyl, carboxy, sulfamoyl, carbamoyl, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfamoyl, alkylsulfonylamino, acy lamino, substimted alkyl, substimted alkenyl, and substimted alkynyl.
  • the compounds of the present invention exist as tautomeric isomers.
  • the present invention is also directed to such tautomeric isomers and mixmres of such isomers. It is to be understood that all tautomeric forms of the compounds of Formulae 7, 77, 777, IVA and IVB, as well as all possible mixmres thereof, are included within the scope of the present invention.
  • the compounds according to the invention have at least one asymmetric center, they may accordingly exist as enantiomers.
  • the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixmres thereof are encompassed within the scope of the present invention.
  • the pyridine(N-oxide) analogs of the present invention are expected to have increased water solubility compared to glycine receptor antagonists in the prior art. As such, the compounds overcome problems encountered with many known glycine receptor antagonists: difficulty in formulating injectable solutions and a low bioavailability.
  • the invention also relates to a method of treating or preventing the adverse consequences of the overstimulation of the excitatory amino acids; treating anxiety, convulsions, chronic pain, or psychosis; preventing opiate tolerance; or inducing a hypnotic effect or anesthesia treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia, and surgery; treating neurodegenerative diseases, including, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, and Down's syndrome; comprising administering to an animal in need of such treatment or prevention a tricyclic quinoxalinedione, a tricyclic 3-nitro-2-quinolone, or pyridine(N-oxide) or nitrone analogs thereof, as defined herein, having high affinity for the glycine binding site and the capability of crossing the blood brain barrier at high levels, while lacking PCP side effects.
  • the compounds disclosed herein are active in treating or preventing neuronal loss, neurodegenerative diseases, and chronic pain and are active as anticonvulsants and in inducing anesthesia without untoward side effects caused by non-selective binding with other receptors, particularly, kainate, AMPA, and quisqualate receptors and the PCP and glutamate receptors associated with the NMDA receptor.
  • these compounds are effective in treating or preventing the adverse consequences of the hyperactivity of the excitatory amino acids, e.g. , those that are involved in the
  • NMDA receptor system by blocking the glycine receptors and preventing the ligand-gated cation channels from opening and allowing excessive influx of Ca ++ into neurons, as occurs during ischemia.
  • Neurodegenerative diseases that may be treated with the disclosed compounds include those selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Down's syndrome.
  • These compounds also find particular utility in the treatment or prevention of neuronal loss associated with multiple strokes that give rise to dementia. After a patient has been diagnosed as suffering from a stroke, the compounds can be administered to ameliorate the immediate ischemia and prevent further neuronal damage that may occur from recurrent strokes.
  • these compounds are able to cross the blood/brain barrier, in contrast to 6-cyano-7-nitro-l,4-dihydroquinoxaline-2,3-dione, 6,7-dinitro- l,4-dihydroquinoxaline-2,3-dione, and other 6,7-disubstituted 1,4- dihydroquinoxaline-2,3-diones that are incapable of crossing the blood/brain barrier after i.p. administration (see Turski, L. et al, J. Pharm. Exp. Ther. 260: 742-747 (1992)). See also, Sheardown et al, Eur. J. Pharmacol.
  • the compound should exhibit an ED 50 of less than about 100 mg/kg body weight of the animal.
  • the compounds of the present invention exhibit an ED 50 of less than about 20 mg/kg and, more preferably, less than about 10 mg/kg.
  • the compounds find particular utility in treating or preventing the adverse neurological consequences of surgery.
  • coronary bypass surgery requires the use of heart-lung machines, which tend to introduce air bubbles into the circulatory system that may lodge in the brain. The presence of such air bubbles robs neuronal tissue of oxygen, resulting in anoxia and ischemia.
  • Pre- or post- surgical admimstration of the 1 ,4-dihydroquinoxalines of the present invention will treat or prevent the resulting ischemia.
  • the compounds are administered to patients undergoing cardiopulmonary bypass surgery or carotid endarterectomy surgery. These compounds also find utility in treating or preventing pain, e.g., chronic pain.
  • Such chronic pain can be the result of surgery, trauma, headache, arthritis, or other degenerative disease.
  • the compounds of the present invention find particular utility in the treatment of phantom pain that results from amputation of an extremity.
  • the compounds of the invention are also useful in inducing anesthesia, either general or local anesthesia, as, for example, during surgery.
  • Especially preferred compounds within the scope of Formulae 7A-7C include 8-aza-l,4,6-trihydropyrazino[l,2,3-fie]quinoxaline-2,3,5-trione, 8-(N- oxy)aza-l,4,6-trihydropyrazino[l,2,3-de]quinoxaline-2,3,5-trione, 8-aza-4- (ethoxycarbonyl)-l,4,6-trihydropyrazino[l,2,3-rfe]quinoxaline-2,3,5-trione, 8- (N-oxy)aza-4-(ethoxycarbonyl)-l,4,6-trihydropyrazino[l,2,3- ⁇ t?]quinoxaline- 2,3,5-trione, 8-aza-4-(phenylcarbamoyl)-l ,4,6-trihydropyrazino[l ,2,3- - ⁇ 'e]quinoxaline-2,3,5-trione, 8-(N-
  • preferred compounds include 8- chloro-3-nitro-l,6-dihydro ⁇ 4-oxopyrido[2,3,4- ⁇ ]quinoline-2,5-dione, 8-bromo- 3-nitro-l,6-dihydro-4-oxopyrido[2,3,4-rfe]quinoline-2,5-dione, 8-methyl-3- nitro-l,6-dihydro-4-oxopyrido[2,3,4-rf£?]quinoline-2,5-dione, 8-fluoro-3-nitro- l,6-dihydro-4-oxopyrido[2,3,4--7-?]quinoline-2,5-dione, 8-nitro-3-nitro-l ,6- dihydro-4-oxopyrido[2,3,4-de]quinoline-2,5-dione, 7,8-dichloro-3-nitro-l ,6- dihydro-4-
  • the aza(N-oxy) group of the (N-oxy) pyridine analogs is considered to function as an electron withdrawing substiment similar to NO 2 , and can replace a -CH- group on the aromatic ring. It is therefore expected that the (N-oxy)pyridine analogs of tricyclic dihydroquinolin-2-ones and tetrahydroquinaline-2, 3-diones described herein should behave similarly to the corresponding tricyclic dihydroquinolin-2-ones and tetrahydroquinaline-2,3- diones that have high binding to the glycine receptor.
  • N-oxide pyridine analogs of the tricyclic dihydroquinolin-2-ones and tetrahydroquinoline-2,3-diones will have a lower log P and will be more water soluble compared to the corresponding tricyclic (4,5 bridged) dihydroquinolin-2-ones and tetrahydroquinoline-2 , 3-diones .
  • the compounds of Formula V can be prepared by the following synthetic route:
  • R 1 , R 2 , R 3 and R 16 are defined as above.
  • R 1 , R 2 and R 16 are as defined above.
  • An example of the substimted sodium glucinate is the following aspartic acid derivative:
  • R 1 , R 2 and R 16 are defined as above.
  • the starting amine 4 is prepared from the corresponding 5-nitro derivative by SnCl 2 reduction. See, PCT Published Application WO94/00124.
  • the amine 4 is acylated by heating in excess of an appropriate ⁇ -dicarbonyl compound 5a-c to give an acyl derivative 6a-c.
  • the acyl derivative 6a,b is then reacted with bromine in DMF to give the corresponding bromo derivative 7a,b. Cyclization of the bromide 7a,b into the final tricyclic compound 1 a,b is performed with potassium tert-butoxide in DMF.
  • the compounds of Formula VI can be prepared by the route outlined below:
  • R 1 is defined above.
  • R 1 and R 2 are defined above.
  • N-amino-l,4-dihydroquinoxaline-2,3-dione starting material is prepared by N-nitrosylating one of the amide nitrogen atoms of 1,4- dihydroquinoxaline-2,3-dione, followed by reduction. See International Published application WO94/00124, which is fully incorporated by reference herein.
  • R 1 and R 2 are defined above.
  • R 1 and R 2 may preferably be Cl.
  • R 1 and R 2 are defined above.
  • R 1 and R 2 may preferably be Cl.
  • R 1 and R 2 are defined above.
  • R 1 may preferably be hydrogen and R 2 may preferably be Cl.
  • R ⁇ R 2 and R 19 are defined above.
  • R 1 and R 2 are defined above.
  • R 1 and R 2 are defined above.
  • R 1 and R 2 are defined above.
  • R 1 and R 2 may preferably be Cl.
  • the 5-nitro-QX starting material for Scheme XIV can be prepared according to the method disclosed in International Published application WO94/00124, supra.
  • R 1 and R 2 are defined above.
  • R 1 and R 2 may preferably be Cl.
  • Aza and aza(N-oxy) compounds having a strucmre represented by Formula .YV777 can be prepared as illustrated in the following scheme:
  • R 16 is defined as above.
  • R 36 represents hydrogen, alkyl, substimted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, substimted aryl, arylalkyl, substimted arylalkyl, heteroaryl, heteroarylalkyl, substimted heteroaryl, substimted heteroarylalkyl or heterocycloalkyl.
  • R 16 is defined as above.
  • Equation 2 shows the pprreeppaarraattiioonn o ⁇ f the starting materials for Scheme XX.
  • R 16 is defined as above.
  • R 16 is defined as above.
  • Equation 3 shows the preparation of compound e, the starting material for Scheme XXI and compound f, the starting material for Scheme XXII.
  • Equation 3 shows the preparation of compound e, the starting material for Scheme XXI and compound f, the starting material for Scheme XXII.
  • R 16 is defined as above.
  • Bridged pyrazinopyridines of Formula 7C can be formed by the following scheme:
  • 4-Aminopyridine 24 is reacted with diethylethoxymethylene maleate (Ethoxy Methylene Malonic Ester, EMME) to give a dicarboxyl derivative 25.
  • Compound 25 is heated in Dowtherm A resulting in thermal cyclization to form a 1,6-naphtyridine system in compound 26.
  • Compound 26 was previously prepared by this route and after hydrolysis and decarboxylation was used for synthesis of the unsubstimted parent heterocycle (Czuba, W., Chem. Heterocycl. Comp 1 (1979) (Engl. transl.); Hauser and Reynolds, J. Org. Chem 15:1224 (1950); Albert, J. Chem. Soc: 1790 (I960)).
  • R 16 is defined as above.
  • R 16 is defined as above.
  • R 16 is defined as above.
  • Tricyclic compounds having a 3-oxime substiment can be formed by the following general reaction scheme.
  • R 1 and.R 2 are defined as above.
  • aza- and (N-oxy)aza derivatives of 3-oxime substimted tricyclic compounds are formed by the following scheme:
  • R 1 is defined as above.
  • R 1 and R 2 are defined above.
  • R 1 and R 2 may preferably be Cl.
  • R 1 , R 2 and R 4 are defined above.
  • R 1 and R 2 may preferably be Cl.
  • Scheme B shows a synthetic route that employs a diaz ⁇ nium salt of a quinoxalinedione to form compounds of Formula 7.
  • the reaction of a diazonium salt with acrylic acid is well " l iown and is called a Meerwein arylation.
  • a diazonium salt with acrylic acid is well " l iown and is called a Meerwein arylation.
  • the compounds of the present invention can be tested for potential glycine antagonist activity by observing the inhibition of binding of 1 ⁇ M glycine-stimulated [ 3 H]-MK-801 in rat or guinea pig brain membrane homogenates.
  • the binding affinities of the compounds at NMDA receptor glycine sites may also be estimated by electrophysiological assays with either cloned rat NMDA receptors expressed in Xenopus oocytes, or non-NMDA receptors expressed in oocytes by whole rat brain poly(A) + RNA.
  • Kj values were estimated by assuming competitive inhibition and assaying suppression of membrane current responses elicited by fixed concentrations of agonist: ImM glycine and 100 mM glutamate for NMDA receptors; 20 mM kainic acid for non-NMDA receptors.
  • KjS were approximated by averaging values at three subtype combinations (NR1A / NR2A, NR1A /
  • K about 10 ⁇ M or less, more preferably, 1 ⁇ M or less, and more preferably, 500 nM or less, and more preferably, 100 nM or less, and most preferably, about 10 nM or less.
  • compounds that exhibit binding at the kainate and AMPA sites of not less than K; 1 ⁇ M and, more preferably, not less than 10 ⁇ M.
  • novel glycine antagonists can be tested for in vivo activity after intraperitoneal injection using a number of anticonvulsant tests in mice
  • Preferred compounds exhibit ataxia side effects in the rotorod ataxia test at dosage levels of greater than about 100 mg/kg, more preferably, greater than about 200 mg/kg.
  • the compounds can also be tested in drug discrimination tests in rats trained to discriminate PCP from saline. It is expected that most of the compounds will not generalize to PCP at any dose. In addition, it is also expected that none of the compounds will produce a behavioral excitation in locomotor activity tests in the mouse.
  • the glycine and excitatory amino acid antagonists are also expected to show potent activity in vivo after intraperitoneal injection suggesting that these compounds can penetrate the blood/brain barrier.
  • the present invention is directed to compounds having high binding to the glycine receptor and low binding to the kainate and AMPA sites.
  • the glycine antagonist potency in vitro can be determined using a l ⁇ M glycine-stimulated [ 3 H]-MK801 binding assay. This assay takes advantage of the dependence of the binding of [ 3 H]-MK801 to the PCP receptor inside the pore of the NMDA channel on the presence of both glutamate and glycine.
  • the assay is conducted using rat brain membrane homogenates that are enriched in NMDA receptors.
  • the membranes are prepared as follows. Frozen rat brains (obtained from Pel-Freez, Rogers, Arkansas) are homogenized in 15 volumes (w/v) of ice cold 0.32 M sucrose. The homogenate is spun at 1 ,000 x g for ten minutes. The supernatant is collected and spun for 20 minutes at 44,000 x g. The pellet is suspended in 15 volumes of water (relative to original brain weight). The homogenate is again spun at 44,000 x g for twenty minutes. The pellet is resuspended in 5 volumes of water and the suspension is freeze-thawed 2 times.
  • the suspension is brought to 15 volumes with water and spun at 44,000 x g for twenty minutes.
  • the pellet is resuspended in 5 volumes of ice-cold 10 mM HEPES, and is titrated to pH 7.4 with KOH containing 0.04% Triton X-100.
  • Membranes are incubated with the Triton/HEPES buffer at 37 °C for 15 minutes. The volume is then brought to 15 with ice-cold 10 mM HEPES, pH 7.4, and spun/washed three times with spins of 44,000 x g between washes.
  • the final pellet is suspended in three volumes of 50 mM HEPES, pH 7.4, and the protein concentration is determined with a standard dye-binding protein assay (Bio-Rad, Richmond, CA). The suspension is stored at -80 °C until used. Only HPLC grade water is used for all buffers and suspensions/ washings. The extensive washings are necessary to remove as much endogenous glycine from the membrane preparation as possible.
  • Nonspecific binding is defined as the difference in binding that occurs in the absence or presence of PCP (final concentration: 100 ⁇ M).
  • PCP final concentration: 100 ⁇ M.
  • bound radioactivity in the presence of 10 ⁇ M glutamate alone (final concentration) is subtracted from the bound radioactivity in the presence of both 10 ⁇ M glutamate and 1 ⁇ M glycine (final concentration).
  • DCK 5,7-dichlorokynurenic
  • the assays are incubated for 120 minutes at room temperature after which time the membrane-bound radioactivity is isolated from the free radioactivity by vacuum filtration through Whatman glass fiber filters that had been pretreated with 0.3% polyethyleneimine. Filtration is accomplished using a Brandel 48 well cell harvester. Filtered membranes are washed three times with 3 mL each of ice cold buffer. Filters are transferred to scintillation vials and 5 mL of scintillation cocktail is added. The vials are shaken overnight and the radioactivity is counted by liquid scintillation spectroscopy. The assays are done in triplicate and all experiments are conducted at least three times.
  • Inhibition dose response curves are constructed using increasing concentrations of glycine antagonists from 5 nM to 330 ⁇ M. IC 50 values are determined for compounds active in inhibiting 1 ⁇ M glycine-stimulated [ 3 H]- MK801 binding by computer-assisted plotting of the inhibition curves and interpolation. When compounds are found to inhibit glycine-stimulated [ 3 H]-
  • Kj values for the glycine antagonists are calculated using the Cheng and Prusoff equation employing the experimentally determined IC 50 values, the known concentration of glycine in the assay (l ⁇ M) and the known affinity of glycine for the glycine binding site of the NMDA receptor (100 nM).
  • the same rat brain membrane homogenates used for the 1 ⁇ M glycine- stimulated [ 3 H]-MK801 binding assay are used for the [ 3 H]-AMPA radioligand binding assay.
  • the frozen membranes (prepared as described above) are thawed and diluted with 30mM Tris/HCl buffer containing 2.5 mM CaCl 2 and 100 mM KSCN, pH 7.4, to yield a final membrane concentration of 1.25 mg/mL membrane protein.
  • 0.8 mL of membrane homogenate is added to polypropylene tubes followed by 0.033 mL drug and 0.067 mL buffer (or, for controls, by 0.1 mL buffer alone) and 0.1 mL buffer containing 200,000 cpm of [ 3 H]-AMPA.
  • the assay is incubated for 30 minutes on ice.
  • Bound radioactivity is separated from free radioactivity by filtration over Whatman glass fiber filters (pretreated with 0.3% polyethyleneimine) using a Brandel 48 well cell harvester. Filtered membranes are washed three times with 3 mL each of ice cold buffer. The filters are transferred to scintillation vials and 5 mL of scintillation cocktail is added.
  • the vials are shaken overnight and radioactivity is counted by liquid scintillation spectroscopy. Nonspecific binding is determined by the radioactivity that remains bound to the membranes in the presence 10 mM glutamate. Inhibition dose response curves are constructed by adding increasing concentrations of drug from 10 nM to 100 ⁇ M.
  • Tris/HCl buffer, pH 7.4, is added to yield a final concentration of 0.5 mg/mL membrane protein.
  • 0.8 mL of membrane homogenate is added to polypropylene tubes followed by 0.033 mL drug and 0.067 mL buffer (or, for controls, by 0.1 mL buffer alone) and 0.1 mL buffer containing 200,000 cpm of [ 3 H] -kainate. The assay is incubated for 2 hours on ice.
  • Bound radioactivity is separated from free radioactivity by filtration over Whatman glass fiber filters (pretreated with 0.3% polyethyleneimine) using a Brandel 48 well cell harvester. Filtered membranes are washed three times with 3 mL each of ice cold buffer. The filters are transferred to scintillation vials and 5 mL of scintillation cocktail is added. The vials are shaken overnight and radioactivity is counted by liquid scintillation spectroscopy. Nonspecific binding is determined by the radioactivity that remains bound to the membranes in the presence 10 mM glutamate. Inhibition dose response curves are constructed by adding increasing concentrations of drug from 250 nM to 330 ⁇ M.
  • the anxiolytic activity of any particular compound of the present invention can be determined by use of any of the recognized animal models for anxiety.
  • a preferred model is described by Jones, B.J. et al, Br. J. Pharmacol. 95:985-993 (1988).
  • This model involves administering the compound in question to mice that have a high basal level of anxiety.
  • the test is based on the finding that such mice find it aversive when taken from a dark home environment in a dark testing room and placed in an area that is painted white and brightly lit.
  • the test box has two compartments, one white and brightly illuminated and one black and non-illuminated. The mice have access to both compartments via an opening at floor level in the divider between the two compartments.
  • mice are placed in the center of the brightly illuminated area. After locating the opening to the dark area, the mice are free to pass back and forth between the two compartments. Control mice tend to spend a larger proportion of time in the dark compartment. When given an anxiolytic agent, the mice spend more time exploring the more novel brightly lit compartment and exhibit a delayed latency to move to the dark compartment. Moreover, the mice treated with the anxiolytic agent exhibit more behavior in the white compartment, as measured by exploratory rearings and line crossings. Since the mice can habituate to the test situation, naive mice should always be used in the test.
  • the administration of the compounds of the present invention is expected to result in the mice spending more time in the larger, brightly lit area of the test chamber.
  • the anxiolytic activity of a putative agent can be identified by the increase of the numbers of line crossings and rears in the light compartment at the expense of the numbers of line crossings and rears in the dark compartment, in comparison with control mice.
  • a second preferred animal model is the rat social interaction test described by Jones, B.J. et al, supra, wherein the time that two mice spend in social interaction is quantified.
  • the anxiolytic activity of a putative agent can be identified by the increase in the time that pairs of male rats spend in active social interaction (90% of the behaviors are investigatory in nature). Both the familiarity and the light level of the test arena can be manipulated.
  • Undrugged rats show the highest level of social interaction when the test arena is familiar and is lit by low light. Social interaction declines if the arena is unfamiliar to the rats or is lit by bright light. Anxiolytic agents prevent this decline. The overall level of motor activity can also be measured to allow detection of drug effects specific to social behaviors.
  • the efficacy of the glycine and excitatory amino acid antagonists to inhibit glutamate neurotoxicity in a rat brain cortex neuron cell culmre system can be determined as follows. An excitotoxicity model modified after that developed by Choi (Choi, D.W., J. Neuroscience 7:357 (1987)) can be used to test anti-excitotoxic efficacy of the glycine and excitatory amino acid antagonists.
  • Femses from rat embryonic day 19 are removed from time-mated pregnant rats.
  • the brains are removed from the femses and the cerebral cortex is dissected.
  • Cells from the dissected cortex are dissociated by a combination of mechanical agitation and enzymatic digestion according to the method of Landon and Robbins (Methods in Enzymology 124:412 (1986)).
  • the dissociated cells are passed through an 80 micron nitex screen and the viability of the cells are assessed by Trypan Blue.
  • the cells are plated on poly-D-lysine coated plates and incubated at 37 °C in an atmosphere containing 91 % O 2 /9% CO 2 .
  • fluoro-d-uracil is added for two days to suppress non-neural cell growth.
  • the primary neuron cultures are exposed to 100 ⁇ M glutamate for 5 minutes with or without increasing doses of glycine and excitatory amino acid antagonist or other drugs. After 5 minutes, the cultures are washed and incubated for 24 hours at 37°C.
  • Neuronal cell damage is quantitated by measuring lactate dehydrogenase (LDH) activity that is released into the culmre medium.
  • LDH lactate dehydrogenase
  • LDH activity is measured according to the method of Decker et al (Decker et al , J. Immunol. Methods 15:16 (1988)).
  • the anticonvulsant activity of the glycine and excitatory amino acid antagonists can be assessed in the audiogenic seizure model in DBA-2 mice as follows.
  • DBA-2 mice can be obtained from Jackson Laboratories, Bar
  • mice at an age of ⁇ 27 days develop a tonic seizure within 5-10 seconds and die when they are exposed to a sound of 14 kHz (sinus wave) at 110 dB (Lonsdale, D., Dev. Pharmacol. Ther. 4:28 (1982)).
  • Seizure protection is defined when animals injected with drug 30 minutes prior to sound exposure do not develop a seizure and do not die during a 1 minute exposure to the sound. 21 day old DBA-2 mice are used for all experiments.
  • Compounds are given intraperitoneally in either saline, DMSO, or polyethyleneglycol-400. Appropriate solvent controls are included in each experiment. Dose response curves are constructed by giving increasing doses of drug from 1 mg/kg to 100 mg/kg. Each dose group (or solvent control) consists of at least six animals.
  • the anticonvulsant efficacy of the glycine receptor antagonists can be assessed in the pentylenetetrazol (PTZ)-induced seizure test as follows. Swiss/Webster mice, when injected with 50 mg/kg PTZ (i.p.) develop a minimal clonic seizure of approximately 5 seconds in length within 5-15 minutes after drug injection.
  • Anticonvulsant efficacy of a glycine/excitatory amino acid antagonist (or other) drug is defined as the absence of a seizure when a drug is given 30 minutes prior to PTZ application and a seizure does not develop for up to 45 minutes following PTZ administration.
  • Glycine/excitatory amino acid antagonist or other drugs are given intraperitoneally in either saline, DMSO, or polyethyleneglycol-400.
  • Dose response curves are constructed by giving increasing doses of drug from 1 mg/kg to 100 mg/kg.
  • Each dose group (or solvent control) consists of at least six animals.
  • the efficacy of glycine/excitatory amino acid antagonists to protect mice from NMDA-induced death can be assessed as follows. When mice are injected with 200 mg/kg N-methyl-D-aspartate (NMDA) i.p., the animals will develop seizures followed by death within 5-10 minutes. Glycine/excitatory amino acid antagonists are tested for their ability to prevent NMDA-induced death by giving the drugs i.p. 30 minutes prior to the NMDA application.
  • NMDA N-methyl-D-aspartate
  • Glycine/excitatory amino acid antagonist or other drugs are given intraperitoneally in either saline, DMSO, or polyethyleneglycol-400. Appropriate solvent controls are included in each experiment. Dose response curves are constructed by giving increasing doses of drug from 1 mg/kg to 100 mg/kg. Each dose group (or solvent control) consists of at least six animals. - The anticonvulsant activity of the glycine antagonists can be assessed in the MES assays in mice. Electroshock was applied to male Swiss/Webster mice (20-30 g, Simonsen) through corneal electrodes (Swinyard, E.A., in Anticonvulsant Drugs, Mercier, J., ed., Pergamon Press, Oxford (1973), pp.
  • the seizure stimulus parameters were: 50 mA, 60 Hz, rectangular pulse, width 0.8 msec, duration 200 msec. Tonic hind limb extension observed after application of the electrical stimulus was recorded as occurrence of seizure.
  • the drug was applied i.v. as an aqueous Tris (Tromethamine) solution.
  • a series of different evaluations can be conducted on doses of the glycine/excitatory amino acid antagonists of the invention to determine the biological activity of the compounds both in normal gerbils and in animals exposed to 5 minutes of bilateral carotid occlusion. See Scheme XXX.
  • mice are conscious and have no other pharmacological agents administered to them. Gerbils are preinstrumented 48-hours prior to ischemia to allow for the complete elimination of the pentobarbital anesthetic that is employed.
  • animals are given i.p. injections of the glycine/excitatory amino acid antagonist or vehicle. In the case of multiple injections, animals are given i.p. injections 2 hours apart and the final injection is given 30 minutes prior to the ischemic period or in the case of post treatment, the animals are given injections at 30 minutes, 2 hours, 4 hours, and 6 hours post-ischemic reperfusion.
  • naive gerbils are injected with either saline or differing doses of the antagonist.
  • the behavioral changes are assessed using a photobeam locomotor activity chamber, which is a two foot circular diameter arena with photobeam detection. Animals are individually placed in the 2 foot diameter chambers. The chambers are housed in a cabinet that is closed and noise is abated using both a background white noise generator and a fan. Animals are placed in these chambers in the case of the initial pharmacological evaluation for a period of 6 hours and the total activity during each successive hour is accumulated using the computer control systems.
  • mice Following the initiation of reperfusion, animals are placed into the circular locomotor activity testing apparams and the activity at the beginning of the first hour following reperfusion is monitored for the subsequent four hours.
  • Control animals not exposed to ischemia and given injections of saline prior to being placed in the locomotor activity chamber show a characteristic pattern of activity, which in the first hour of locomotor activity is substantially higher than during all other hours and progressively declines over the four hours to a very low value.
  • control animals that are exposed to five minutes of cortical ischemia demonstrate a completely different pattern of locomotor activity.
  • gerbils are pretreated with the glycine/excitatory amino acid antagonists of the invention 30 minutes before the onset of carotid occlusion and then placed into the locomotor activity following one hour of reperfusion. It is expected that pretreatment of the gerbils with the glycine/- excitatory amino acid antagonists of the invention will prevent both the post- ischemic decrease and increase in activity. Post-ischemic decreases in activity are expected to be near zero during the first hour following reperfusion. Pretreatment with the glycine/excitatory amino acid antagonists of the invention is expected to reduce or prevent this early depression of behavior. In addition, the glycine/excitatory amino acid antagonists of the invention are expected to prevent the post-ischemic stimulation of behavior.
  • gerbils are also evaluated with multiple injections of the glycine/excitatory amino acid antagonists of the invention. Doses are administered i.p. at 6 hours, 4 hours, 2 hours, and 30 minutes prior to the onset of 5 minutes of ischemia.
  • the lesion with 5 minutes of ischemia is essentially restricted within the hippocampus to the CA1 region of the dorsal hippocampus.
  • the intermedial lateral zone of the horn is unaffected and the dentate gyrus and/or cells in CA3 do, not show pathology.
  • Gerbils are anesthetized on day 7 following ischemia with 60 mg/kg of pentobarbital.
  • Brains are perfused transcardiac with ice-cold saline followed by buffered paraformaldehyde (10%). Brains are removed, imbedded, and sections made. Sections are stained with hematoxylin-eosin and neuronal cell counts are determined in terms of the number of neuronal nuclei/ 100 micrometers.
  • NMDA receptors are critically involved in the development of persistent pain following nerve and tissue injury.
  • Tissue injury such as that caused by injecting a small amount of formalin subcutaneously into the hindpaw of a test animal, has been shown to produce an immediate increase of glutamate and aspartate in the spinal cord (Skilling, S.R., et al , J. Neurosci. 70:1309-1318 (1990)).
  • Administration of NMDA receptor blockers reduces the response of spinal cord dorsal horn neurons following formalin injection (Dickenson and Aydar, Neuroscience Lett. 727:263-266 (1991); Haley, J.E., et al , Brain Res. 518:218-226 (1990)).
  • dorsal horn neurons are critical in carrying the pain signal from the spinal cord to the brain and a reduced response of these neurons is indicative of a reduction in pain perceived by the test animal to which pain has been inflicted by subcutaneous formalin injection.
  • NMDA receptor antagonists can block dorsal horn neuron response induced by subcutaneous formalin injection, NMDA receptor antagonists have potential for the treatment of chronic pain, such as, pain caused by surgery, by amputation (phantom pain), or by infliction of other wounds (wound pain).
  • chronic pain such as, pain caused by surgery, by amputation (phantom pain), or by infliction of other wounds (wound pain).
  • conventional NMDA antagonists such as, MK801 or CGS 19755, in preventing or treating chronic pain is severely limited by the adverse PCP-like behavioral side effects that are caused by these drugs.
  • the glycine receptor antagonists that are the subject of this invention will be highly effective in preventing chronic pain in mice induced by injecting formalin subcutaneously into the hindpaw of the animals. Because the glycine/excitatory amino acid antagonists of this invention are expected to be free of PCP-like side effects, these drugs are highly useful in preventing or treating chronic pain without causing PCP-like adverse behavioral side effects.
  • mice Male Swiss/Webster mice weighing 25-35 grams are housed five to a cage with free access to food and water and are maintained on a.12 hour light cycle (light onset at 0800h).
  • the glycine receptor antagonist is dissolved in DMSO at a concentration of 1-40 and 5-40 mg/mL, respectively. DMSO is used as vehicle control. All drugs are injected intraperitoneally (1 ⁇ l/g). The formalin test is performed as described (Dubuisson and Dennis, Pain 4: H 161-174 (1977)). Mice are observed in a plexiglass cylinder, 25 cm in diameter and 30 cm in height.
  • the plantar surface of one hindpaw is injected subcutaneously with 20 ⁇ l of 5% formalin.
  • the degree of pain is determined by measuring the amount of time the animal spends licking the formalin-injected paw during the following time intervals: 0-5 ' (early phase); 5 '-10', 10 '-15 ' and 15 '-50' (late phase).
  • DMSO methyl methyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-administra dose-induced chronic pain in a dose-dependent manner as determined by the reduction of the time the mouse spends licking the formalin injected hindpaw, caused by increasing doses of glycine/excitatory amino acid antagonist.
  • opiates e.g., morphine
  • the term "opiates” is intended to mean any preparation or derivative of opium, especially the alkaloids namrally contained therein, of which there are about twenty, e.g. , morphine, noscapine, codeine, papaverine, and thebaine, and their derivatives.
  • morphine noscapine
  • codeine codeine
  • papaverine papaverine
  • thebaine and their derivatives.
  • compositions within the scope of this invention include all composi ⁇ tions wherein the compounds of the present invention are contained in an amount effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
  • the compounds may be administered to mammals, e.g., humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for anxiety disorders, e.g., generalized anxiety disorder, phobic disorders, obsessional compulsive disorder, panic disorder, and post traumatic stress disorders.
  • anxiety disorders e.g., generalized anxiety disorder, phobic disorders, obsessional compulsive disorder, panic disorder, and post traumatic stress disorders.
  • about 0.01 to about 10 mg/kg is orally administered to treat or prevent such disorders.
  • the dose is generally about one-half of the oral dose.
  • a suitable intramuscular dose would be about 0.0025 to about 15 mg/kg, and most preferably, from about 0.01 to about 10 mg/kg.
  • the pharmaceutical compositions of the invention can comprise the compounds of the present invention at a unit dose level of about 0.01 to about 50 mg/kg of body weight, or an equivalent amount of the pharmaceutically acceptable salt thereof, on a regimen of 1-4 times per day.
  • the compounds of the invention When used to treat chronic pain or to induce anesthesia, the compounds of the invention may be administered at a unit dosage level of from about 0.01 to about 50 mg/kg of body weight, or an equivalent amount of a pharmaceutically acceptable salt thereof, on a regimen of 1-4 times per day.
  • a unit dosage level of from about 0.01 to about 50 mg/kg of body weight, or an equivalent amount of a pharmaceutically acceptable salt thereof, on a regimen of 1-4 times per day.
  • the exact treatment level will depend upon the case history of the animal, e.g., human being, that is treated. The precise treatment level can be determined by one of ordinary skill in the art without undue experimentation.
  • the unit oral dose may comprise from about 0.01 to about 50 mg, preferably about 0.1 to about 10 mg of the compound.
  • the unit dose may be administered one or more times daily as one or more tablets each containing from about 0.1 to about 10, conveniently about 0.25 to 50 mg, of the compound or its solvates.
  • the compounds of the invention can be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the compounds into preparations that can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the compounds into preparations that can be used pharmaceutically.
  • the preparations particularly those preparations that can be administered orally and that can be used for the preferred type of administration, such as tablets, dragees, and capsules, and preparations that can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.01 to 99 percent, preferably from about 0.25 to 75 percent of active compound(s), together with the excipient.
  • non- toxic pharmaceutically acceptable salts of the compounds of the present invention are also included within the scope of the present invention.
  • Basic salts are formed by mixing a solution of a particular tricyclic compound of the present invention with a solution of a pharmaceutically acceptable non-toxic base, such as, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, or an amino compound, such as, choline hydroxide, Tris, bis-Tris, N-methylglucamine, arginine, and the like. See, U.S. Application Serial No. 08/148,268, supra.
  • compositions of the invention can be administered to any animal that may experience the beneficial effects of the compounds of the invention.
  • animals Foremost among such animals are humans, although the invention is not intended to be so limited.
  • compositions of the present invention can be administered by any means that achieve their intended purpose.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular routes.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • compositions of the invention When the compositions of the invention are administered ocularly, one may achieve either local or systemic administration.
  • the compositions of the present invention may be administered in the form of eye drops that are substantially isotonic with tear fluid to achieve systemic administration.
  • such compositions will also comprise a permeation-enhancing agent, which aids the systemic absorption of the compounds of the present invention. See, U.S. Patent No. 5,182,258.
  • the compositions of the invention may be administered ocularly to treat or prevent optic nerve degeneration.
  • the compounds of the present invention are administered in the form of eye drops, as disclosed above, or may be injected into the vicinity of the optic nerve.
  • thin ocular implants may be employed that slowly release the compounds of the present invention.
  • the new pharmaceutical preparations can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • the pharmaceutical preparations of the present invention are manufacmred in a manner that is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixmre and processing the mixmre of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers, such as, saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as, saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin,
  • disintegrating agents can be added, such as, the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as, sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as, magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings that, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixmres.
  • suitable cellulose preparations such as, acetylcellulose phthalate or hydroxypropylmethyl- cellulose phthalate, are used.
  • Dye smffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations that can be used orally include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as, glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules that may be mixed with fillers, such as, lactose, binders, such as, starches, and/or lubricants, such as, talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as, fatty oils or liquid paraffin.
  • stabilizers may be added.
  • Possible pharmaceutical preparations that can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water- soluble salts and alkaline solutions.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • the glycine ligands of the present invention can be used to characterize the glycine binding site.
  • the particularly preferred compounds that can be used for this purpose are isotopically radiolabelled derivatives, e.g., where one or more of the atoms are replaced with 3 H, ⁇ C, 14 C, 15 N, or 18 F.
  • Examples of preferred photoaffmity ligands are 3 H or ,8 F-substituted 6-azido-5,7-difluoro-l,4- dihydroquinoxaline-2,3-dione and 3 H-substituted 6-azido-5,7-dichloro-l,4- dihydroquinoxaline-2,3-dione.
  • Example 12 4-Acyl-7, 8-dichloro-l,2,3,3a,4,5, 6-hexahydropyrazino[l,2,3- de]quinoxaline-2,3,5'triones (14a,b) (general procedure)
  • Example 18 6, 7-Dichloro-4-(2 ' -ethoxy carbonyl)ethyledene-l, 2, 3, 3a, 4, 5- hexahydroimidazo[l,2,3-de]quinox ⁇ line-2,3-dione (22)

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Abstract

La présente invention concerne des quinoxalinediones tricycliques qui ont une liaison élevée avec le récepteur de glycine. Beaucoup des composés ont la structure (1), dans laquelle chacune des variables est définie dans le descriptif. L'invention révèle des méthodes de traitement ou de prévention de la dépopulation neuronale associée à l'ictus, à l'ischémie, aux traumatismes du système nerveux central, à l'hypoglycémie et aux opérations chirurgicales, ainsi que des méthodes de traitement des affections de dégénérescence neurologique, dont la maladie d'Alzheimer, la sclérose latérale amyotrophique, la chorée de Huntington et la syndrome de Down, des méthodes de traitement ou de prévention des conséquences néfastes de l'hyperactivité des acides aminés excitateurs ainsi que de traitement de l'anxiété, des douleurs chroniques, des convulsions et d'induction de l'anesthésie. Lesdites méthodes consistent à administrer à un animal ayant besoin d'un traitement de ce genre un composé de formule (I) ou un sel pharmaceutiquement acceptable de ce composé.
PCT/US1996/010118 1995-06-07 1996-06-06 Quinoxalinediones et quinolones pontees en position 4 et 5, et leur emploi comme antagonistes de recepteurs d'acides amines excitateurs Ceased WO1996040141A1 (fr)

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AU61726/96A AU6172696A (en) 1995-06-07 1996-06-06 4,5-bridged quinoxalinediones and quinolones and the use thereof as excitatory amino acid receptor antagonists

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US08/486,199 1995-06-07

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6737423B2 (en) 2000-12-19 2004-05-18 Aventis Pharma Deutschland Gmbh Substituted heterocyclo-norbornylamino derivatives, processes for their preparation, their use as medicaments or diagnostics, and medicaments comprising them

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5436240A (en) * 1989-06-09 1995-07-25 The Upjohn Company Heterocyclic amines having central nervous system activity

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5436240A (en) * 1989-06-09 1995-07-25 The Upjohn Company Heterocyclic amines having central nervous system activity

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6737423B2 (en) 2000-12-19 2004-05-18 Aventis Pharma Deutschland Gmbh Substituted heterocyclo-norbornylamino derivatives, processes for their preparation, their use as medicaments or diagnostics, and medicaments comprising them

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