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WO1998005651A1 - Nouveaux antagonistes de recepteurs du glutamate sous forme de quinoxalinediones fusionnees avec cycloalkyle - Google Patents

Nouveaux antagonistes de recepteurs du glutamate sous forme de quinoxalinediones fusionnees avec cycloalkyle Download PDF

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WO1998005651A1
WO1998005651A1 PCT/US1997/010504 US9710504W WO9805651A1 WO 1998005651 A1 WO1998005651 A1 WO 1998005651A1 US 9710504 W US9710504 W US 9710504W WO 9805651 A1 WO9805651 A1 WO 9805651A1
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Christopher Franklin Bigge
Daniel Martin Retz
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Warner-Lambert Company
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    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
    • C07F9/650994—Six-membered rings having the nitrogen atoms in the positions 1 and 4 condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • This invention is directed to 2 , 3 -quinoxaline- diones with a substituted C5-C7 cycloalkyl ring fused to the quinoxaline system.
  • the substituted C5-C7 cycloalkyl ring fused 2 , 3-quinoxalinediones are active as excitatory amino acid receptor antagonists acting at glutamate receptors, including either or both N-methyl- D-aspartate (MNDA) receptors and nonNMDA receptors such as the ⁇ -amino-3 -hydroxy-5-methyl-4 -isoxazole propionic acid (AMPA) receptor and the kainate receptor.
  • MNDA N-methyl- D-aspartate
  • AMPA ⁇ -amino-3 -hydroxy-5-methyl-4 -isoxazole propionic acid
  • the invention also relates to the use of those quinoxalinediones as neuroprotective agents for treating conditions such as cerebral ischemia or cerebral infarction resulting from a range of phenomena, such as thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma, as well as to treat chronic neurodegenerative disorders such as lathyrism, Alzheimer's Disease, Parkinsonism, and Huntington's Disease, and as anticonvulsants .
  • the compounds of the present invention may also be useful in the treatment of schizophrenia, epilepsy, anxiety, pain, and drug addiction.
  • EAA excitatory amino acid
  • NMDA N-methyl-D- aspartate
  • AMPA ⁇ -amino-3-hydroxy-5-methyl-4- isoxazole propionic acid
  • This excitotoxic action is responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma, as well as lathyrism, Alzheimer's, Parkinson's and Huntington's disease.
  • EAA glutamate
  • United States Patent No. 4,889,855 is directed to compounds of formula
  • R- R 2 , and R3 are independently H, halogen, CN, NH 2 , N0 2 , SO3H, S0 2 NH 2 , and CONH 2 .
  • This reference specifically discloses 6-amino, 6-cyano, 5-carbamoyl, 6-nitro, and 5, 6-dinitro- , 8 , 9, 10-tetrahydro-2, 3- dihydroxybenzo (f) quinolxalines .
  • the compounds are disclosed as useful for treating conditions caused by the hyperactivity of the excitatory neurotransmitter .
  • the reference does not disclose any compounds with substitution of the fused cyclohexyl ring, i.e., where R is other than hydrogen. Nor does the reference disclose or suggest any methods which would allow substitution of the cyclohexyl ring.
  • R is hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy, cycloalkoxy, or acyloxy; R and R together form a further fused ring, which is substituted with hydrogen, halogen, or CN, and R' and R independently are hydrogen, N0 2 , halogen, CN,
  • R 7 and RR together form a further fused ring, which is substituted with hydrogen, halogen, or CN, and R and R 6 independently are hydrogen, N0 2 , halogen, CN, S02NR'R', S0 2 R', CF 3 , or OR', wherein R' is hydrogen or C ⁇ _ ⁇ -alkyl.
  • the compounds are disclosed as useful in the treatment of indications caused by hyperactivity of the excitatory neurotrans itters, particularly the quisqualate receptors and especially as neuroleptics . Again, however, these references do not suggest or illustrate any examples of substituted cyclohexyl rings.
  • NMDA and nonNMDA antagonists may provide a superior pharmacological profile.
  • Combinations of NMDA and nonNMDA receptor antagonists have shown synergistic activity in focal and global ischemia (K. Lippert, M. Welsch, and J. Krieglstein, Rnr. iT. Pharmacol . s 1994;253 (3) :207-13) , as anticonvulsants ( . Loescher, C. Rundfelt, and D. Hoenack, Fur. J Nenr-ngrH ,
  • AMPA receptor antagonists recognized for usefulness in the treatment of disorders are those that block AMPA receptors (C.F. Bigge and T.C. Malone, r ⁇ r-r Op-i ⁇ . Thfir. Pat . r 1993:951; M.A. Rogawski, Ti PS 1993 ;14 :325) .
  • AMPA receptor antagonists have prevented neuronal injury in several models of global cerebral ischemia (H. Li and A.M. Buchan, .T . Tprehr . Blond Flnw MPtah., 1993 ; 13 : 933 ; B. Nellgard and T. ieloch, J. Cprehr.
  • AMPA receptor antagonists have demonstrated promise in chronic neurodegenerative disorders such as Parkinsonism, too (T. Klockgether, L. Turski, T. Honore, et al . , Ann ⁇ Neural . , 1993;34; (4) :585-93) .
  • the present invention is directed to 2,3-quino- xalinediones with a substituted C5-C7 cycloalkyl ring fused angularly to the quinoxaline system.
  • the compounds of the subject invention act as excitatory amino acid receptor antagonists at glutamate receptors.
  • the glutamate receptors include the N-methyl-D- aspartate (NMDA) receptors and nonNMDA receptors such as the ⁇ -amino-3-hydroxy-S-methyl-4-isoxazde proprionic acid (AMPA) receptor and the kainate receptor. More particularly, the present invention is directed to compound represented by the formula (I) :
  • Z is a carbocyclic fused ring having 5 to 7 carbon atoms ;
  • X and Y are independently hydrogen, halogen, nitro, cyano, -CF3, -COOH, -CONR ⁇ -R 2 , -COR 3 , -SQ 2 R 3 , imidazolyl or imidazolidinyl, wherein R-*- and R 2 are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl, aralkyl or join together to form a heterocyclic ring and wherein R is alkyl, haloalkyl, cycloalkyl, aryl or aralkyl ;
  • pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as the hydrochloride , hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, oxalate, and the acetate.
  • pharmaceutically acceptable inorganic and organic base addition salts may be used such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like.
  • Alkyl means a straight chained or branched chain of from 1 to 6 carbon atoms or cyclic alkyl of from 3 to 7 carbon atoms including, but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Alkenyl means a straight chained or branched chain alkenyl group of 2 to 6 carbon atoms or a cyclic alkenyl group of 3 to 7 carbon atoms, for example, but not limited to ethylene, 1,2- or 2 , 3 -propylene, 1,2-, or 3 , 4-butylene, cyclopentene, or cyclohexene.
  • Alkynyl means a straight chained or branched chain alkynyl group of 2 to 6 carbon atoms, for example, but not limited to ethynyl , 2 , 3 -propynyl , 2,3- or 3,4- butynyl .
  • Alkylene means a divalent group having 1 to 6 methylene units .
  • Aryl means a monocyclic or bicyclic carbocyclic aromatic ring system, for example, but not limited to phenyl, 2-naphthyl, or 1-naphthyl.
  • Aralkyl mean aryl as defined above and alkyl as defined above, for example, but not limited to benzyl, 2-phenylethyl, 3 -phenylpropyl ; a preferred group is benzyl.
  • Halogen is fluorine, chlorine, bromine, or iodine; fluorine, chlorine, and bromine are preferred groups.
  • Heterocyclic means an aromatic or nonaromatic ring structure having 5 or 6 members in which one or more of the elements in the ring is an element other than carbon, e.g., nitrogen, sulfur, or oxygen.
  • Typical nonaromatic heterocyclic groups include any of the following which may be optionally substituted with one or more alkyl, halo, or hydroxy groups: tetrahydrofuranyl, pyranyl, piperidinyl, piperizinyl, pyrrolidinyl, imidazolindinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, and pyrazolinyl groups .
  • Typical aromatic heterocyclic (heteroaryl) groups include any one of the following which may be optionally substituted with one or more alkyl, halo, or hydroxy groups: thienyl, benzo [b] thienyl, naphtho[2,3- b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl
  • heteroaryl group contains a nitrogen atom in a ring
  • nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide, and the like.
  • the instant invention is also related to a pharmaceutical composition containing the compound defined by formula I in an amount effective to treat cerebrovascular disorders responsive to the blockade of glutamate receptors, including either or both NMDA receptors and nonNMDA receptors (such as the ⁇ -amino-3- hydroxy-5 -methyl-4 -isoxazole propionic acid (AMPA) receptor and the kainate receptor) , and a pharmaceutically acceptable carrier.
  • NMDA receptors and nonNMDA receptors such as the ⁇ -amino-3- hydroxy-5 -methyl-4 -isoxazole propionic acid (AMPA) receptor and the kainate receptor
  • AMPA ⁇ -amino-3- hydroxy-5 -methyl-4 -isoxazole propionic acid
  • kainate receptor a pharmaceutically acceptable carrier.
  • disorders responsive to such treatment include cerebral ischemia caused by cerebral trauma, stroke, hypoglycemia, heart attack, and surgery; anxiety and schizophrenia; and chronic neurodegenerative disorders such as Huntington's disease
  • the pharmaceutical composition of this invention may also be employed as an analgesic or for the treatment of epilepsy.
  • the invention further relates to a method of treating cerebrovascular disorders responsive to antagonism of glutamate receptors including either or both NMDA receptors and nonNMDA receptors by administering a compound of above-defined formula I in a unit dosage form.
  • X and Y are independently hydrogen, bromo, and nitro. It is also preferred that Z is a cyclopentyl fused ring or a cyclohexyl fused ring.
  • A is a bond, NR , NR 4 CO or CO, R 4 is hydrogen or alkyl having 1 to 6 carbon atoms, and m is 0 or 1. It is also preferred that B is COR 5 , CN, PO3R 2 , or heterocylic.
  • B is a heterocyclic, more prefereably a heterocyclic group selected from the group represented by the following formulae:
  • Particularly preferred compounds of the present invention include, without limitation: 6-Nitro-2,3-dioxo-2, 3,4,7,8, 9-hexahydro-lH- cyclopenta [f] quinoxaline-8-carboxylic acid pyridin-2-ylamide; 1- (6-Nitro-2, 3-dioxo-2 , 3 , 4 , 7, 8, 9-hexahydro-lH- cyclopenta [f] quinoxalin-8-yl) -3-phenyl-thiourea; 6-Nitro-2,3-dioxo-2,3,4, 7,8, 9-hexahydro-lH- cyclopenta [f] quinoxaline-8-carboxyclic acid [1,3,4] thiadiazol-2-ylamide; 6-Nitro-2,3-dioxo-2, 3,4,7,8, 9-hexahydro-lH- cyclopenta [f] quinoxaline-8-carbox
  • G is a substituent of the aromatic ring.
  • Typical substituents include OH, N0 , acid amide, methyl groups, or a halogen atom and q is 1 to 3.
  • the indanones and tetralones are readily reduced to alcohols using standard hydride reagents (lithium aluminum hydride, sodium borohydride, and their derivatives) , or catalytic hydrogenation. They can also undergo reductive amination to form amines; the keto group is treated with a primary or secondary amine under dehydrating conditions, and the resulting imine can be reduced by a hydride reagent (sodium cyanoborohydride , for example) or catalytic hydrogenation to give the amine.
  • a hydride reagent sodium cyanoborohydride , for example
  • Both the indanones and tetralones can be homologated via several procedures known in the literature to give either nitriles or carboxylic acid functionality in place of the ketone.
  • Cyanohydrin formation by classical methodology, or by using trimethylsilylcyanide, followed by elimination of the alcohol and reduction of the double bond can give the nitrile moiety in place of the ketone.
  • Subsequent hydrolysis gives the carboxylic acid derivative, or reduction of the nitrile gives the aminomethyl derivative.
  • Each of these intermediates, alcohols, amines, nitriles, or carboxylic acid derivatives can be separately processed according to procedures known to those skilled in the art to give the desired side chains described within this invention.
  • the reactions and methodologies described can be performed at a number of different stages of the sequence, and the preferred order of reaction may be optimally dependent upon each individual substrate and product that is generated.
  • keto group can be displaced directly via treatment with a variety of known Wittig reagents (such as 3- (2-thienyl)propyltriphenylphosphonium bromide) or Horner-Emmons reagents (triethylphosphonoacetate) , with subsequent catalytic hydrogenation of the double bond formed in the condensation process.
  • Wittig reagents such as 3- (2-thienyl)propyltriphenylphosphonium bromide
  • Horner-Emmons reagents triethylphosphonoacetate
  • aldol-like and Knoevenagel condensations can be performed with the indanone or tetralone substrate to give similar products.
  • Scheme 1 illustrates two methods of electrophilic aromatic substitution that were used to obtain regiospecific substitution of the aromatic ring and enabled formation of the desired quinoxalinediones .
  • Z represents the side chain substitutent of the indane or tetralin system, and may be either a precursor side chain or the final side chain as previously described herein.
  • the acetamide is used as a directing group for the aromatic substitution and a protecting group for the aniline nitrogen.
  • the aromatic substitution proceeds in a similar manner, but the quinoxalinedione can be formed via intramolecular condensation without the deprotection step.
  • the substitution pattern of the aromatic ring can be elaborated from an acetamidotetralin or acetamidoindane derivative as illustrated in Scheme 1. Electrophilic aromatic substitution occurs preferentially ortho and para to the acetamido group.
  • the substituent that is introduced (halide, sulfate, etc.) may act as a protecting group, to be removed later, to block a specific position on the aromatic ring and allow the subsequent regioselective introduction of another functional group, such as nitro.
  • the substituent can also be retained in the final quinoxalinedione, and allows each of the positions of the aromatic ring to be selectively substituted.
  • Nitration of the aromatic ring ortho to the acetamido functionality provides a diamino derivative that can be condensed with an oxalic acid derivative (free acid, dimethyl ester, diphenyl ester, etc.) to form a quinoxalinedione.
  • oxalic acid derivative free acid, dimethyl ester, diphenyl ester, etc.
  • Y acts as a protecting group, such as bromine or sulfate
  • conditions can be used that simultaneously reduce the nitro functionality and give hydrogenolysis of the bromine, or reverse sulfonylation, to give a hydrogen atom in its place.
  • Subsequent aromatic electrophilic substitution will give the X-substitution preferentially, and some of the Y-substitution.
  • X and Y are previously described substitutents for Formula I.
  • Scheme 2 illustrates an alternative substrate that enables the necessary regioselectivity of substitution of the aromatic ring to be established using similar methodology as previously described.
  • Conversion to the quinoxalinedione can proceed from the ortho diamine with condensation with an oxalic acid derivative, or from an ortho amino oxamide derivative by intramolecular condensation.
  • Compounds of this invention can be prepared using the methods described in Schemes 1 or 2 with elaboration of the side chain as described in Scheme 3 , There is no restriction as to the order in which the methods may be used to generate the compounds of this invention, i.e., the side chains may be elaborated before or after the aromatic substitution pattern is set .
  • compositions and unit dosages thereof may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing 10 mg of active ingredients or, more broadly, 0.1 to 100 mg per tablet, are accordingly suitable representative unit dosage forms .
  • Solid forms of pharmaceutical compositions for PO administration and injectable solutions are preferred.
  • the compounds of this invention are extremely useful in the treatment of central nervous system disorders related to their biological activity.
  • the compounds of this invention may accordingly be administered to a subject, including a human, in need of treatment, alleviation, or elimination of an indication associated with the biological activity of the compounds.
  • This includes especially excitatory amino-acid-dependent psychosis, excitatory amino-acid- dependent anoxia, excitatory amino-acid-dependent ischemia, excitatory amino-acid-dependent Parkinsonism, excitatory amino-acid-dependent convulsions, and excitatory amino-acid-dependent migraine.
  • Suitable dosage ranges are 0.1 to 1000 mg daily, dependent as usual upon the exact mode of administration, the form in which administered, the indication toward which the administration is directed, the subject involved, and the body weight of the subject involved, and further, the preference and experience of the physician or veterinarian in charge.
  • the compounds of the invention exhibit valuable biological properties because of their strong excitatory amino acid (EAA) antagonizing properties at one of several binding sites on glutamate receptors: the AMPA ( (RS) - -amino-3-hydroxy-5-methyl-4-isoxazole- propionic acid (or kainic acid) binding site on AMPA (nonNMDA) receptors or the glycine site of NMDA receptors.
  • the compounds generally have activity at both NMDA and nonNMDA receptors, and thus may act in disorders arising from overexcitation of either receptor family.
  • the compounds of the present invention exhibit binding affinity for the AMPA receptor as described by Honore T. , et al., Nen n.rH e cp T.Pt-f s 1985;54:27-32. Preferred compounds demonstrate IC50 values ⁇ 100 ⁇ M in this assay. Values for selected compounds are found in Table 1.
  • the compounds of the present invention exhibit binding affinity for the kainate site (nonNMDA receptor) as described by London E.D. and Coyle J, Mol . Pha macol . f 1979; 15: 492.
  • the compounds of the present invention exhibit binding affinity for the glycine site of the NMDA receptor as described by Jones S.M., et al., Pharmacol ⁇ Methods, 1989;2l:161.
  • AMPA antagonist activity To functionally measure AMPA antagonist activity, the effects of the agent on AMPA-induced neuronal damage in primary cortical neuronal cultures was examined using techniques similar to those outlined by Koh, J.-Y. et al., J. Neurosri . , 1990; 10:693.
  • the neuronal damage produced by long-term exposure to 100 ⁇ M AMPA is measured by the release of the cytosolic enzyme lactate dehydrogenase (LDH) .
  • LDH lactate dehydrogenase
  • AMPA given ICV (intracerebroventricular) (15 ⁇ g/kg) to NMRI mice induces clonic seizures which should be inhibited by nonNMDA receptor antagonists .
  • Test compound was given IV 5 minutes (or PO 30 minutes) before a 0.3 ⁇ g ICV administration of AMPA to ten female NMRI mice (weighing 24-26 g) per dose. The number of mice experiencing clonic seizures within the next 5 minutes was noted. An ED Q value was calculated as the dose inhibiting 50% of the mice from having clonic seizures.
  • 1, 7-Bis (N -methyl) acetamido-4-bromo-2 -nitro- 5, 6, 7, 8-tetrahydronaphthalene was hydrolyzed in 3 N HCI (100 mL) and acetic acid (20 mL) at 100°C for 72 hours. The mixture was cooled in an ice bath for 1 hour, and the orange precipitate collected by filtration and dried (7.6 g) .
  • 1, 2 , 3,4-tetrahydronaphthalen-2-yl ester (2.6 g, 8 mmol) in 40 mL of trifluoroacetic acid was cooled in an ice bath. Fuming nitric acid (2 mL) was added dropwise and the mixture was stirred for 2.5 hours. The solvent was removed by rotoevaporation, and water was added to the residue which induced solidification. The solid was collected by filtration, washed with ether, and dried to give the product (2.4 g) in 81% yield.
  • Raney nickel was deactivated prior to use by washing twice with acetone, and then washed twice with tetrahydrofuran.
  • a mixture of 8-amino-5-bro ⁇ no-7-nitro- 1, 2, 3,4-tetrahydronaphthalen-2-ol (1.8 g) and Raney nickel (4 g) in tetrahydrofuran (100 mL) was stirred under a hydrogen atmosphere (1 atm) for 1 hour.
  • the catalyst was removed by filtration, and filtrate evaporated.
  • the solid residue was washed with diethyl ether and then dried to give the desired product .
  • the title compound was obtained by an identical procedure to Example 27 except that the racemate was cocrystallized with (S) -mandelic acid.
  • EXAMPLE 38 6-Ni ro-2,3-dir>xo-2,3,4,7, 8, 9-hexahyriro-lH- r-yrloppnta ⁇ f1 qninoxal i ne-fi -o hoyyr-l i r. a id (thiophen- 7-ylmpthyl ) -ami e;
  • EXAMPLE 40 6 -Ni ro- 2, -di nxo- 2. ,4, 7, 8, -hexahyriro-lH- ⁇ yclo- ppnt [fl quinoxal ne-8-carboxyrl ic aci (thi phen-7- ylmpthyl ) -am e;
  • the title compound was prepared in a manner similar to Example 38, except the 5-aminotetrazole was replaced by thienylmethyl amide.
  • the title compound was prepared in a manner similar to Example 38, except the 5-aminotetrazole was replaced by methylthioltriazole amide.
  • the title compound was prepared in a manner similar to Example 38, except the 5-aminotetrazole was replaced by piperidine amide.
  • the title compound was prepared in a manner similar to Example 38, except the 5-aminotetrazole was replaced by isoxazole amide .
  • EXAMPLE 46 fi-N f-ro-7, -d yo-2, 3,4 , 7. fl, q -heyahydro- 1 H-oyol o- ppnta ff1 q ⁇ inoxal i ne-8-carhoyycl i r. acid thia ol-7- yl mi dp;
  • the title compound was prepared in a manner similar to Example 38, except the 5-aminotetrazole was replaced by thiazole amide.
  • EXAMPLE 60 7 - ( 7 - ( 5 -TPt ra ⁇ ol yl ) pt hyl ) - 5 -n i roi ndariP
  • N-Indan-2-yl-acetamide 14 g, 80 mmol was dissolved in trifluoroacetic acid (150 mL) and cooled in an ice bath to 0°C. Fuming nitric acid (20 mL) was added slowly via a pipette, and the mixture was stirred for 2 hours while maintaining the temperature at 0°C. After evaporating the solvent in vacuo, the residue was dissolved in a mixture of ether and water. The water layer was extracted several times with ether, and the combined organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated to give the nitrated adduct(s) as a syrupy solid (20.5 g) . This material (7:1 mixture by NMR) was used without further purification.

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Abstract

Nouvelles 2,3-quinoxalinediones à noyau alicyclique substitué fusionné, compositions pharmaceutiques les contenant et leur procédé d'utilisation pour bloquer les récepteurs du glutamate, dont un ou les deux récepteurs de N-méthyl-D-aspartate (NMDA) et les récepteurs non NMDA tels que le récepteur d'acide α-amino-3-hydroxy-5-méthyl-4-isoxazole propionique et le récepteur de kainate. Lesdites 2,3-quinoxalinediones peuvent être utilisées, par exemple, en tant qu'agents neuroprotecteurs, pour le traitement des troubles neurodégénératifs chroniques, en tant qu'anticonvulsifs, et dans le traitement de la schizophrénie, de l'épilepsie, de l'anxiété, de la douleur et de la toxicomanie.
PCT/US1997/010504 1996-08-01 1997-06-18 Nouveaux antagonistes de recepteurs du glutamate sous forme de quinoxalinediones fusionnees avec cycloalkyle WO1998005651A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2000032183A1 (fr) * 1998-12-03 2000-06-08 Ortho-Mcneil Pharmaceutical, Inc. Topiramate et derives associes destines au traitement de la schizophrenie
WO2006074884A1 (fr) * 2005-01-14 2006-07-20 F.Hoffmann-La Roche Ag Derives de thiazole-4-carboxamide en tant qu'antagonistes du mglur5
JP2007509846A (ja) * 2003-10-15 2007-04-19 バイエル・ヘルスケア・アクチェンゲゼルシャフト テトラヒドロ−ナフタレンおよび尿素誘導体
US7659401B2 (en) 2005-11-08 2010-02-09 Hoffmann-La Roche Inc. Thiazolo[4,5-C]pyridine derivatives
WO2010074089A1 (fr) 2008-12-24 2010-07-01 第一三共株式会社 Composés indanyle
US7951824B2 (en) 2006-02-17 2011-05-31 Hoffman-La Roche Inc. 4-aryl-pyridine-2-carboxyamide derivatives

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WO1996028445A1 (fr) * 1995-03-14 1996-09-19 Warner-Lambert Company Nouveaux antagonistes de recepteurs de glutamate (acide amp/kainate): azacycloalkylquinoxalinediones fusionnees a substitution n
WO1996040649A1 (fr) * 1995-06-07 1996-12-19 Warner-Lambert Company Derives de la quinoxaline 2,3-dione substitues par des derives d'acides amines, utilises comme antagonistes des recepteurs du glutamate

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000032183A1 (fr) * 1998-12-03 2000-06-08 Ortho-Mcneil Pharmaceutical, Inc. Topiramate et derives associes destines au traitement de la schizophrenie
JP2007509846A (ja) * 2003-10-15 2007-04-19 バイエル・ヘルスケア・アクチェンゲゼルシャフト テトラヒドロ−ナフタレンおよび尿素誘導体
WO2006074884A1 (fr) * 2005-01-14 2006-07-20 F.Hoffmann-La Roche Ag Derives de thiazole-4-carboxamide en tant qu'antagonistes du mglur5
KR100905810B1 (ko) * 2005-01-14 2009-07-02 에프. 호프만-라 로슈 아게 Ｍｇｌｕｒ5 길항제로서의 싸이아졸-4-카복스아마이드유도체
US7678815B2 (en) 2005-01-14 2010-03-16 Hoffmann-La Roche Inc. Thiazole-4-carboxyamide derivatives
CN101137653B (zh) * 2005-01-14 2012-05-09 弗·哈夫曼-拉罗切有限公司 作为mglur5拮抗剂的噻唑-4-甲酰胺衍生物
US7659401B2 (en) 2005-11-08 2010-02-09 Hoffmann-La Roche Inc. Thiazolo[4,5-C]pyridine derivatives
US7951824B2 (en) 2006-02-17 2011-05-31 Hoffman-La Roche Inc. 4-aryl-pyridine-2-carboxyamide derivatives
WO2010074089A1 (fr) 2008-12-24 2010-07-01 第一三共株式会社 Composés indanyle

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