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WO1998005651A1 - Novel glutamate receptor antagonists: fused cycloalkyl quinoxalinediones - Google Patents

Novel glutamate receptor antagonists: fused cycloalkyl quinoxalinediones 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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    • C07—ORGANIC CHEMISTRY
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • 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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    • C07D401/02—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
    • C07D401/12—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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    • 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
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    • 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
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    • 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

Novel substituted alicyclic fused ring 2,3-quinoxalinediones, pharmaceutical compositions containing the same and the method of using the same, for the blockade of glutamate receptors, including either or both N-methyl-D-aspartate (NMDA) receptors and nonNMDA receptors such as the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor and the kainate receptor, are described. The novel substituted alicyclic fused ring 2,3-quinoxalinediones may be used, for example, as neuroprotective agents, for treatment of chronic neurodegenerative disorders, as anticonvulsants and in the treatment of schizophrenia, epilepsy, anxiety, pain and drug addiction.

Description

NOVEL GLUTAMATE RECEPTOR ANTAGONISTS: FUSED CYCLOALKYL
QUINOXALINEDIONES
FIELD OF THE INVENTION
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 α-amino-3 -hydroxy-5-methyl-4 -isoxazole propionic acid (AMPA) receptor and the kainate receptor. 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. RELATED BACKGROUND ART
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acid (EAA) glutamate and aspartate at the N-methyl-D- aspartate (NMDA) , the α-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid (AMPA) receptor, and the kainate receptor. 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. Several classes of quinoxalinedione derivatives have been disclosed as glutamate (EAA) receptor antagonists. For example, United States Patent No. 4,889,855 is directed to compounds of formula
Figure imgf000004_0001
wherein A together with the 2 carbon atoms denoted as 1 and 2 is selected from
Figure imgf000004_0002
wherein R- R2, and R3 are independently H, halogen, CN, NH2, N02, SO3H, S02NH2, and CONH2. 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, however, 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.
United States Patent No. 5,308,845 and United States Patent No. 5,081,123 are directed to compounds of formula
Figure imgf000005_0001
wherein 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, N02, halogen, CN,
S0 NR'R', S02R', CF , or OR', wherein R' is hydrogen or
C1_4~alkyl; or R 7 and RR together form a further fused ring, which is substituted with hydrogen, halogen, or CN, and R and R6 independently are hydrogen, N02, halogen, CN, S02NR'R', S02R', CF3, 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.
Cyclohexyl-fused and cyclopentyl- fused quinoxalinediones and a method for preparing the same are described in copending application No. 08/350,765, filed December 7, 1994, the disclosure of which is incorporated by reference herein.
Having both NMDA and nonNMDA antagonist properties in a single entity 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 ,
1993 ,-5 (11) : 1545-50) , and in protection of neuronal degeneration in retina (J. Mosinger, M. Price, H. Bai,
H. Xiao, D. Wozniak, and J. Olney, Exp__ Np.nrnl . ,
1991;113 :10-17) . Among excitatory amino acid 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-iπ. 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. Rlnnd Flow Mfftah. f 1992,-12: 2) and focal cerebral ischemia (R. Bullock, D.I. Graham, S. Swanson, and J. McCulloch, ,τ. Pprphr Ptl nnH Flow Metah.. 1994 ; 14 : 466 ; D. Xue, Z.-G. Huang, K. Barnes, H.J. Lesiuk, K.E. Smith, and A.M. Buchan, ,T. Pfirp.hr. Blond Flow Mel-abl., 1994 ;14 :251) . AMPA antagonists have also shown efficacy in models for analgesia (X.-J. Xu, J.-X. Hao, A. Seiger, and Z. Wiesenfeld-Hallin, _I_ Pha macol . yp . Ther. , 1993;267:140) , and epilepsy (T. Na ba, K. Morimoto, K. Stao, N. Yamada, and S. Kuroda, Brain Re_s___, 1994;638:36. S.E. Browne and J. McCulloch, Brain Re.q . , 1994,-641: 10; S.I. Yamaguchi , S.D. Donevan, and M.A. Rogawski, Fpilppsy Rp.g r 1993; 15: 179; S.E. Smith,
N. Durnuller, and B.S. Meldrum, Eu.r ■ J Pharmacol . ,
1991;201 : 179) . 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) .
.qTTMMARV OF TWF T VFNT TON
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 α-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) :
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof wherein
Z is a carbocyclic fused ring having 5 to 7 carbon atoms ; X and Y are independently hydrogen, halogen, nitro, cyano, -CF3, -COOH, -CONR^-R2, -COR3, -SQ2R3, imidazolyl or imidazolidinyl, wherein R-*- and R2 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 ; A is a bond, 0, S, NR , NR4C0, NR CS, CONR4, CSNR , CO or CS wherein R4 is hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl, aralkyl or when n = 0 then R and B may join together to form a heterocyclic ring; B is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, R5, CN, COR5, P0 R5 , S0 R5, or heterocyclic, wherein R is hydroxy, alkoxy, aralkoxy, aryloxy or R^2; and m and n are independently 0, 1, and 2, provided that (i) m is not 0 when A is 0, CN, tetrazole or CO, except when A is CO and B is a heterocyclic or when A is 0 and B is COR5, P03R5 2 or S02R5; (ii) m is not 0 or 1 when A is NR , except when B is COR5, P03R5 2 or S02R5; and (iii) n is not 0 when A is 0, S, NR4 , CONR4 and B is NR1R2, CN, COR5, or P03R5 2.
Examples of 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. Alternatively, 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, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl , β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl , phenothiazinyl, isoxazolyl, furazanyl phenoxazinyl groups, 1, 4-dihydroquinoxaline-2 , 3 -dione, 7-amino isocoumarin, pyrido [1, 2-a] pyrimidin-4 -one, 1,2- benzoisoxazol-3-yl , benzimidazolyl , 2-oxobenz- imidazolyl, 2-oxindolyl, and 4-nitrobenzofurazan. Where the heteroaryl group contains a nitrogen atom in a ring, such 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 α-amino-3- hydroxy-5 -methyl-4 -isoxazole propionic acid (AMPA) receptor and the kainate receptor) , and a pharmaceutically acceptable carrier. Exemplary 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, ALS, Parkinsonism, and
Alzheimer'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.
DFTATT.Fn D SCRI TTON OF THF. T VFNTTON
The substituted C5-C7 cycloalkyl ring fused 2,3- quinoxalinediones are represented by previously defined formula I.
Preferably, 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.
More preferably, A is a bond, NR , NR4CO or CO, R4 is hydrogen or alkyl having 1 to 6 carbon atoms, and m is 0 or 1. It is also preferred that B is COR5, CN, PO3R 2, or heterocylic.
In a particularly preferred embodiment of the present invention B is a heterocyclic, more prefereably a heterocyclic group selected from the group represented by the following formulae:
Figure imgf000012_0001
Examples of compounds of this invention are represented by the formulae listed below:
■11-
Figure imgf000013_0001
Figure imgf000014_0001
10
Figure imgf000014_0002
Figure imgf000014_0003
30 -13-
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000016_0001
Figure imgf000016_0003
Figure imgf000016_0002
Figure imgf000016_0004
■15-
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000018_0001
Figure imgf000018_0002
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-carboxyclic acid (1H-
[1,2,4] triazol-3-yl) -amide; 6-Ni ro-2,3-dioxo-2,3,4,7, 8, 9-hexahydro-lH- cyclopenta [f] quinoxaline-8-carboxyclic acid thiazol-2 -ylamide; 6-Nitro-2,3-dioxo-2,3,4, 7,8, 9-hexahydro-lH- cyclopenta [f] quinoxaline-8-carboxyclic acid (5- methylsulfanyl-lH- [1, 2, 4] triazol-3-yl) -amide; 6-Nitro-2, 3-dioxo-2, 3,4,7,8, 9-hexahydro-lH- cyclopenta [f] quinoxaline-8-carboxyclic acid (3- methyl-isoxazol-5-yl) -amide; 6-Nitro-2, 3-dioxo-2, 3,4,7,8, 9-hexahydro-lH- cyclopenta [f] quinoxaline-8-carboxyclic acid (1H- tetrazol-5-yl) -amide;
6-Nitro-2, 3-dioxo-2, 3,4,7,8, 9-hexahydro-lH- cyclopenta [f] quinoxaline-8-carboxyclic acid
(thiophen-2-ylmethyl) -amide; 6-Nitro-8- (piperidine-1-carbonyl) -4,7,8, 9-tetrahydro- 1H-cyclopenta [f] quinoxaline-2 , 3 -dione;
(6-Nitro-2, 3-dioxo-2, 3,4,7,8, 9-hexahydro-lH- cyclopenta [f] quinoxalin-8-yl) -acetic acid; [Methyl- (6-Nitro-2, 3-dioxo-2, 3,4,7,8, 9-hexahydro-lH- cyclopenta [f] quinoxalin-8-yl) -amino] -acetic acid; 8- (lH-Tetrazol-5-ylmethyl) -4,7,8, 9-tetrahydro-lH- cyclopenta [f] quinoxaline-2 , 3 -dione ; 6-Nitro-8- (lH-tetrazol-5-ylmethyl) -4,7,8, 9-tetrahydro- lH-cyclopenta [f] quinoxaline-2, 3 -dione; 2- (6-Nitro-2, 3 -dioxo-2 , 3 , 4 , 7,8, 9-hexahydro-lH- cyclopenta [f] quinoxalin-8-yl) -N- (lH-tetrazol-5- yl) -acetamide; 6-Nitro-8- [2- (lH-tetrazol-5-yl) -ethyl] -4,7,8,9- tetrahydro-lH-cyclopenta [f] quinoxaline-2 , 3-dione; 8- [2- (lH-Tetrazol-5-yl) -ethyl] -4,7,8, 9-tetrahydro-lH- cyclopenta [f] quinoxaline-2 , 3 -dione; 8- [Methyl- (lH-tetrazol-5-ylmethyl) -amino] -6-nitro-
4,7,8, 9-tetrahydro-lH-cyclopenta [f] quinoxaline-
2, 3 -dione; { [Methyl- (6-nitro-2, 3-dioxo-2 , 3 , 4 , 7,8, 9-hexahydro-lH- cyclopenta [f] quinoxalin-8-yl) -amino] -methyl }- phosphonic acid diethyl ester; { [Methyl- (6-nitro-2, 3-dioxo-2,3 ,4,7,8, 9-hexahydro-lH- cyclopenta [f] quinoxalin-8-yl) -amino] -methyl} - phosphonic acid; and pharmaceutically acceptable salts thereof.
Several precursors are available commercially or via known chemical transformations that are starting materials for the compounds disclosed in the present invention. For example, several tetrahydronapthalene and indane derivatives which are substituted on the saturated ring are available. Example of substituents on the saturated ring include, but are not limited to the following, OH, NHR, CH2NHR, CN, N3, and COOH, wherein R is hydrogen or alkyl having 1 to 6 carbon atoms.
Illustrated below are several indane and tetrahydronaphthalene derivatives with substitution on the saturated ring that are readily available or can be prepared by those skilled in the art. Such compounds may be employed as precursors in preparation of the compounds of this invention.
Figure imgf000020_0001
Figure imgf000021_0001
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. 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.
Figure imgf000022_0001
When the substituent of the saturated ring is hydroxy it can be transformed into a good leaving group such as a mesylate, tosylate, halide, or the like, or a variety of ether derivatives may be prepared by the Williamson ether synthesis. The above transformations can be performed either before or after establishing the substitution pattern of the aromatic ring. Standard chemistry methodologies can be used to further elaborate the side chain from derivatives of the indanone and tetralone systems. Enolate chemistry (formed by treatment with an appropriate base, such as lithium diisopropylamide) or enamine chemistry (formed by treatment with pyrrolidine under dehydrating conditions) can result in substitution of the α-carbon atom when treated with an electrophile . Subsequent reductive methods, known to those skilled in the art (Wulff Kishner reduction, Clemmenson reduction, catalytic hydrogenation, metal hydrides) are used to provide the deoxygenated species.
Figure imgf000022_0002
b — "co- The 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. Alternatively, aldol-like and Knoevenagel condensations can be performed with the indanone or tetralone substrate to give similar products.
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000023_0003
SCHEME 1 Establishing Regiochemistry of Aromatic Ring and Conversion to Quinoxalinedione
Figure imgf000024_0001
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. In the first method the acetamide is used as a directing group for the aromatic substitution and a protecting group for the aniline nitrogen. When the aniline is protected as the oxamide, 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, followed by hydrolysis and reduction provides a diamino derivative that can be condensed with an oxalic acid derivative (free acid, dimethyl ester, diphenyl ester, etc.) to form a quinoxalinedione. Several alternative methodologies known to those skilled in the art exist, including starting with an oxalyamide, introduction of the nitro functionality, selective reduction of the nitro moiety to the amine, and subsequent ring closure. When 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 Alternate methods of establishing regiochemistry of the aromatic ring and subsequent conversion to quinoxalinedone
Figure imgf000027_0001
Figure imgf000027_0002
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 .
SCHEME 3
Figure imgf000029_0001
NH2NH: RaNi
Equation 1. RCOOEt RCONHNH2
EtOH H2(g)
RCONH2
Equation 2. RCONHNH2
Figure imgf000029_0002
1. CDI
Equation 3. RCOOH RCOCH2COOEt
KOOCCHzCOOEt Base NH2NHZ EtOH
Figure imgf000029_0003
Equation 4. RCN
Figure imgf000029_0004
PHARMACEUTICAL COMPOSITIONS
The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, 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.
METHOD OF TREATING
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.
BIOLOGICAL ACTIVITY
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 μM 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. 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 μM AMPA is measured by the release of the cytosolic enzyme lactate dehydrogenase (LDH) .
As a preliminary indicator of in vivo CNS activity related to anticonvulsant activity and potential neuroprotection, a maximal electroshock assay in CF-1 strain mice (20-25 g) is performed with corneal electrodes by conventional methods as described previously (Krall et al . , Kpi is si ar 1988;19:409-28. The claimed compounds generally demonstrated ED50 values of <50 mg/kg. Also, compounds of the present invention when administered IV or IP in the in vivo AMPA seizure test, as described below, inhibit the clonic seizures induced by AMPA.
AMPA- Induced Clonic Seizures
AMPA given ICV (intracerebroventricular) (15 μg/kg) to NMRI mice induces clonic seizures which should be inhibited by nonNMDA receptor antagonists .
METHOD
Test compound was given IV 5 minutes (or PO 30 minutes) before a 0.3 μg 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.
Table 1.
Figure imgf000034_0001
X AMPA Kainate Glycine LDH
Et203PCH2NME NO- 1.6 1.9
H203PCH2NME NO- 1.7 1.4
Figure imgf000034_0002
Figure imgf000034_0003
Figure imgf000034_0004
Figure imgf000034_0005
TABLE 1 (continued)
R X AMPA Kainate Glycine LDH
Figure imgf000035_0001
HOOCCH2 NO- 0.65 1.45 >10 HOOCCH2NME N02 0.24 0.23 >10
Figure imgf000035_0002
Figure imgf000035_0003
Figure imgf000035_0004
Figure imgf000035_0005
Figure imgf000035_0006
TABLE 1 (continued)
Figure imgf000036_0003
Figure imgf000036_0001
Figure imgf000036_0002
N02 1.71 1.64
O-"" co- The examples which follow (particularly the examples of the final products of this invention: 9, 10, 17, 23, 24, 38, 39, 40, 41, 42, 44, 45, 46, 54, 54, 55, 65, 66, 75, and 76) are intended as an illustration j of certain preferred embodiments of the invention, and no limitation of the invention is implied.
EXAMPLE 1 ft-Are arrnrio-3-rnethoxynaphthalerιe
e
Figure imgf000037_0001
A mixture of 8-Acetamido-2 -naphthol (21 g,
0.104 mol), dimethyl sulfate (15.1 g, 0.12 mol) and potassium carbonate (41 g, 0.3 mol) in acetone (200 mL) was stirred at room temperature for 48 hours. Solids were removed by filtration and washed with methanol, and the filtrate evaporated. The residue was washed in 1:1 hexane : toluene , collected by filtration and dried (24.7 g) .
EXAMPLE 2 B-Αcp.taττn o-2-t-.frt.ral np
Figure imgf000037_0002
Ammonia (300 mL) was condensed in a flask containing 8-Acetamido-2-me hoxynaphthalene (24.5 g, 115 mmol), ϋ-butyl alcohol (34 g. 0.46 mol) and THF (300 mL) . Sodium (8 g, 0.35 mol) was added in portions and the mixture was stirred for 3 hours and allowed to warm to room temperature . The mixture was poured onto ice and saturated sodium chloride, and then extracted with tetrahydrofuran (THF) (3x) . The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to give a dark solid. The residue was dissolved in 50% acetic acid and heated at 95°C for 18 hours. After evaporation, the residue was suspended in diethyl ether and collected by filtration and dried. The filtrate was purified by silica gel chromatography (3:2 EtOAc:hexane) and combined with the other product to give a tan solid (10 g) .
EXAMPLE 3 1 -A(-etami o-7-benzylamino-5f 6f 7r 8- tetrahy rn- naphthalene
Figure imgf000038_0001
A solution of 8-acetamido-2-tetralone (15.5 g, 76 mmol), benzylamine (16.3 g, 150 mmol) and tosic acid (0.2 g) in benzene (200 mL) and dimethylformamide (DMF) (50 mL) was refluxed with a Dean-Stark trap attached for 18 hours. The solvent was evaporated and the residue dissolved in 1:1 methanol:THF (250 mL) . After cooling in an ice bath, sodium cyanoborohydride was added and the mixture warmed to room temperature and stirred for 5 hours. The mixture was basified with 12.5% NaOH and the solvent concentrated. The residue was dissolved in methylene chloride : water and filtered through a celite pad. The aqueous layer was extracted with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The dark residue was purified by column chromatography (9:1 EtOAc :methanol) to give the product (15 g) .
EXAMPLE 4 1 - Αcetami o- 7 -hen:zyl rnethy1 rn-i no- f 6 f 7 f ft - tetrahydro- naphtha l ene
Figure imgf000039_0001
A mixture of l-acetamido-7-benzylamino-5, 6 , 7, 8- tetrahydronaphtahlene (14.3 g, 50 mmol), para- formaldehyde (15 g, 0.5 mol) and sodium cyanoboro- hydride (15.7 g;, 0.25 mol) in acetic acid (250 mL) was stirred at room temperature for 48 hours. The solvent was removed and the residue taken up in water: diethyl ether. The aqueous phase was basified with 12.5% NaOH and back extracted with ether. The combined ether layers were washed with saturated NaCl, dried over magnesium sulfate, filtered and evaporated to give a viscous syrup (16 g) .
EXAMPLE 5
1 , 7 -Bi s fN τ7_-mP yl ) acet am i do - ς r 6 r 7 r fi - t- et- ra hyHrn - nfφhf.hal ine
Figure imgf000040_0001
A mixture of l-acetamido-7-benzylmethylamino- 5, 6, 7, 8 -tetrahydronaphthalene (14 g, 45 mmol) and 20% Pd/C (3 g) in acetic acid (200 mL) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (50 psi) for several hours (hydrogen replaced periodically). After removing the catalyst, the solvent was evaporated and the residue portioned between methylene chloride and water. The aqueous layer was basified with 12.5% NaOH and back extracted. The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography (gradient from 30%-100% methanol in EtOAc) to give the methylamine adduct (7.4 g) as clear solid. The methylamine (5 g, 23 mmol) was dissolved in THF (50 mL) and treated with acetic anydride (6 g, 60 mmol) and the mixture stirred at room temperature for 1 hour. The solvent was removed, and the residue triturated with diethyl ether and the solid collected by filtration and dried (5.6 g) . EXAMPLE 6
1 , 7-Bis (N τj7_-methyl ) aπetamido-4-brnmo r 5f 6,7, 8-tetrahydro- naphthalene
Figure imgf000041_0001
A solution of 1 , 7-Bis (N τ7-methyl) acetamido-5 , 6 , 7 , 8- tetrahydronaphthalene (7 g, 27 mmol) and sodium acetate trihydrate (5.5 g, 41 mmol) in acetic acid (100 mL) was treated with bromine (5.2 g, 32 mmol) and stirred at room temperature for 18 hours. Sodium bisulfite was added and the solvent removed. The residue was taken up in water : methylene chloride and the aqueous phase back extracted. The combined organic layer were evaporated to give an off-white solid. This was washed with diethyl ether and dried to give the product (8.5 g) as a white solid.
EXAMPLE 7 1, 7 -Bis (N^-methy ) acetamido-4 -bromo-7.-nitro-5 , 6 , 7,8- tetrahyd nnaph hal ne
Figure imgf000041_0002
-7
A mixture of 1, 7-bιs (N -methyl) acetamido-4 -bromo- 2 -nitro- 5, 6, 7, 8 -tetrahydronaphthalene (8.5 g, 25 mmol) in trifluoroacetic acid (100 mL) was cooled in an ice bath and treated with fuming nitric acid (10 mL) . The reaction mixture was warmed to room temperature after 1 hour and stirred for 3 hours longer. The solvent was removed and the residue taken up in methylene chloride : ater . The aqueous layer was back extracted and the combined organic layers were dried over sodium sulfate, filtered and evaporated to give the product as a yellow syrup (9.2 g) .
EXAMPLE 8 1.7-Di (N^-methyl ) ami no- -hrnmn-9 -ni trn- 5 r 6.7, ft- tp rahydronaph halenp hydrochl nri p
Figure imgf000042_0001
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) .
EXAMPLE 9
Figure imgf000042_0002
quinoxa1.infi-2,.3-d πrip. hyrirochlorid,
Figure imgf000042_0003
A mixture of 1 , 7-di (N τ7-methyl) amino-4-bromo-2- nitro-5, 6,7, 8-tetrahydronaphthalene hydrochloride (7.6 g, 23 mmol) and 20% Pd/C (1 g) in methanol (250 mL) was shaken on a Parr hydrogenator under a hydrogen atmosphere (52 psi) for 18 hours. After removing the catalyst , the solvent was removed and the residue dissolved in 2 N HCI (100 mL) . Oxalic acid
(6.3 g, 50 mmol) was added and the reaction heated at 100°C for 3 hours. After cooling to room temperature, the precipitate was collected by filtration and dried.
EXAMPLE 10 q-Methylaminn-6-n-i tro-1 ,7,3,4,7,8,9,1 Ω-nrt.ahyrlm-hpn n- f1 ginnnxal ine-2, 3 -dione
Figure imgf000043_0001
9-Methylamino-6-nitro-l,2, 3,4,7,8,9, 10-octahydro- benzo [f] quinoxaline-2 , 3-dione hydrochloride (1 g, 3.5 mmol) was nitrated using fuming nitric acid (1 mL) and trifluoroacetic acid (30 mL) from 0°C to room temperature for 1 hour. The solvent was removed and the residue triturated in acetone : water and collected by filtration and dried to give the product (1.1 g) .
EXAMPLE 11 Preparation of N- (7-hydroxy-5 , 6 f , 8 -tetrahydro- naphtalen-1 -yl ) -ace ami e
Figure imgf000043_0002
A mixture of l-amino-7-hydroxynaphthalene (16.5 g, 0.1 mol), lithium hydroxide hydrate (4.3 g) , and 20% palladium on carbon (4 g) was suspended in 600 mL) 4:1 methanol and water and shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (52 psi) for about 1 hour, the hydrogen atmosphere recharged, and then shaken an additional hour. After filtration through celite, the filtrate was concentrated and the pH adjusted with aqueous HCI to seven. Acetic anhydride (15 g) was added and swirled for 15 minutes. The solution was saturated with sodium chloride and extracted with ethyl acetate (3x) . The combined organic layer was dried over magnesium sulfate.
EXAMPLE 12
Preparation of acetic acid λ-aπe y.aminn-l , 2, λ, 4-t..r.ra- hydronaphthal en-2-yl este
Figure imgf000044_0001
A mixture of N- (7-hydroxy-5 , 6 , 7, 8-tetra-hydro- naphthalen-1-yl) -acetamide (3 g, 15 mmol) , acetic anhydride (2 g, 200 mmol) in pyridine (50 L) was stirred at room temperature for 18 hours. Solvent was removed by rotoevaporation and the residue was purified by column chromatography on silica gel (1:1 ethyl acetate : hexane as eluant) to give the product (2.2 g) as a tan solid in 59% yield. EXAMPLE 13 Preparation of acetic acid 8-acety] m no-5-hromo- 1 , r 3,4-tptrahydronaphthalen-7-yl ester
Figure imgf000045_0001
A mixture of acetic acid 8-acetylamino-l, 2 , 3 , 4- tetrahydronaphthalen-2-yl ester (2.2 g, 8.9 mmol) and bromine (1.7 g, 10.7 mmol) in 50 mL of acetic acid was stirred at room temperature for 18 hours. The solvent was removed by rotoevaporation, and the residue was taken up in an diethyl ether/water mixture . The resulting solid was collected by filtration, and washed with diethyl ether. After drying the product (2.75 g) was obtained in 95% yield.
EXAMPLE 14 Preparation of acetic acid R-acetyl ami no- -bromo-7- ni tro-1 ,2,3 , 4 - etrahydronaphth l en- -yl mr r
Figure imgf000045_0002
A solution of acetic acid 8-acetylamino-5-bromo-
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.
EXAMPLE 15 Preparati on of 8 -amino- 5-bromo- 7-ni ro- 1 , , 3 , 4 - t-et- rahydronaphtha l en- 7-ol
Figure imgf000046_0001
A mixture of acetic acid 8-acetylamino-5-bromo-7- nitro-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester (2 g, 5.4 mmol), acetic acid (15 L) , and 6 N HCI (30 mL) was stirred at 90°C for 18 hours. The solvent was removed by rotoevaporation to give the product (1.6 g) as an orange solid in a quantitative yield.
EXAMPLE 16
Preparat i on of 7 , 8 -diamino- 5 -bromo- 1 , , , 4 -tetra - hydronaphtha l pn - 7 -ol
Figure imgf000046_0002
Raney nickel was deactivated prior to use by washing twice with acetone, and then washed twice with tetrahydrofuran. A mixture of 8-amino-5-broτno-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 . EXAMPLE 17 Preparation of 6-bromo-9-hydroxy-1 , 4 , 7 , 8 , , 10- hPxahydro-ben7:o [ ] qni noxali ηe-2 , 3-dionp
Figure imgf000047_0001
A mixture of 7, 8-diamino-5-bromo-l , 2 , 3 , 4-tetra- hydronaphthalen-2-ol (0.5 g, 2 mmol) and oxalic acid (0.5 g, 4 mmol) in 2 N HCI (20 mL) was heated at 90°C for 3 hours. A solid was collected by filtration, washed consecutively with water and diethyl ether, and dried to give the quinoxalinedione product (0.33 g) . Analysis calculated for C12Hι:LBRN θ3- 1.5H20-C, 42.62; H, 4.17; N, 8.29. Found: C, 42.87; H, 3.73; N, 8.29.
EXAMPLE 18
Preparation of methanesul oni acid 8 -acptyl mi no- 1,2,3 , 4-t.p.t.rahydrnnaphr.halen-2-yl es ar
Figure imgf000047_0002
A solution of N- (7-hydroxy-5 , 6 , 7 , 8-tetrahydro- naphthalen-1-yl) -acetamide (5 g, 24 mmol), methyl- sulfonylchloride (6.9 g, 60 mmol) and pyridine (4.7 g, 60 mmol) in methylene chloride (100 mL) was heated at reflux for 8 hours. The mixture was then cooled and washed with water. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The resulting solid was washed with diethyl ether and dried (3.8 g, 51% yield) and used without further purification.
EXAMPLE 19 Preparation of N- (7-azido-5 , 6 , 7 , R-tetrahydronaphthal en-
1-yl) -aπer.amidfi
Figure imgf000048_0001
A mixture of methanesulfonic acid 8-acetylamino- 1,2, 3, 4-tetrahydronaphthalen-2-yl ester (3.8 g, 13 mmol) and sodium azide (1.7 g, 27 mmol) in dimethylformamide (70 mL) was heated at 50°C for 6 hours. The solvent was removed by rotoevaporation in vacuo and the residue partitioned between methylene chloride and water. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated to give a dark solid. The product was purified by column chromatography on silica gel (1:1 ethyl acetate :hexane as eluant) to give a white solid (2.9 g) in 97% yield.
EXAMPLE 20 Preparation of N- (7-azido-4 -bromo-5 , , 7, 8 -tetrahydro- naphtha Ten - ] -yl ) -acetami de
Figure imgf000048_0002
A solution of N- (7-azido-4-bromo-5, 6, 7, 8- tetrahydronaphthalen-1-yl) -acetamide (1 g, 4.3 mmol) in acetic acid (40 mL) was treated dropwise with bromine (1 g, 6.5 mmol) and stirred at room temperature for 3 hours. The solvent was evaporated and the solid residue was washed with ether, collected by filtration, and dried to give the product (1.5 g) in 89% yield.
EXAMPLE 21 Preparation of N- (7-a7.i do-4 -hromo-2 -ni tro-5 , 6 , 7 , 6- t-pr- -rahydro-naph ha! en-1 -yl ) -acetamide
Figure imgf000049_0001
A solution of N- (7-azido-4-bromo-5 , 6 , 7 , 8-tetra- hydronaphthalen-1-yl) -acetamide (1.5 g) was cooled in an ice bath and treated with fuming nitric acid (2 mL) , After stirring for 2 hours the solvent was removed by rotoevaporation and water was added to the residue to give a solid. The product was collected by filtration and dried (1.1 g, 81% yield) .
EXAMPLE 22 Preparat i on of 7 -az ido-4 -bromo- ?. -ni tro- 5 , 6 , 7 , 8 - tetrahydro-naphthal n-l-ylamine
Figure imgf000049_0002
A mixture of N- (7-azido-4-bromo-2-nitro-5, 6, 7, 8- tetrahydro-naphthalen- 1-yl) acetamide, 2 N HCI (150 mL) and acetic acid (30 mL) was heated at 85°C for 48 hours. The mixture was concentrated by rotoevaporation in vacuo, and the resulting solid was collected by filtration, washed with water, and then dried to give the desired aniline (4.25 g) in 86% yield.
EXAMPLE 23 Preparation of 9-amino-l r 4 f 7r 8 , 9 , 10 -hexahydro- ben o \f 1 uinoxal ine-2 , 3-di one
Figure imgf000050_0001
A solution of 7-azido-4-broτno-2-nitro-5, 6 , 7 , 8- tetrahydro-naphthalen-1-ylamine (1.7 g, 5.4 mmol) in tetrahydrofuran (50 mL) and methanol (50 mL) was treated with 20% palladium on charcoal (0.5 g) and shaken in a Parr apparatus under a hydrogen atmosphere
(50 psi) for 15 hours. The catalyst was removed by filtration, the filtrate was evaporated and the residue was dissolved in 2 N HCI and treated with oxalic acid
(1.7 g) . After heating at 85°C for 2.5 hours, the solid that formed was collected by filtration and washed with methanol and dried in vacuo to give the product (1.02 g, 82% yield) .
EXAMPLE 24
Preparation of 9-amlno-6 -ni ro-1 , .7 , 8 , , in-hexahydro- benzo ff 1 quinoxal ine-2. -di ne
Figure imgf000050_0002
A mixture of 9-amino-6-nitro-l, 4 , 7, 8, 9, 10- hexahydro-benzo [f] quinoxaline-2, 3-dione and trifluoro- acetic acid (10 mL) was cooled in an ice bath and then treated with fuming nitric acid (0.5 mL) and stirred for 3 hours at 0°C and then 1 hour at room temperature. After removing the solvent by rotoevaporation, the residue was triturated with acetone and the resulting solid collected by filtration to give the product (0.22 g, 93% yield). The solid was stirred in 2 N HCI for 15 minutes, collected by filtration, and dried to give the hydrochloride salt .
Analysis calculated for C12H12N404 -HCI -H20-C, 43.58; H, 4.57; N, 16.94. Found: C, 43.56; H, 4.08: N, 16.51.
EXAMPLE 25
Pr-eparar-ion of TJ- ( 6 -ni tro- 7 , 3 -d i oxo- 1 , 7 , 3 , 4 , 7 , R , Q , 10 ■ nrt-.ahy ro-hanzQ Tf 1 quinoxal in-9-yl ) -aretami dp
Figure imgf000051_0001
hexahydro-benzo [f] quinoxaline-2 , 3-dione (0.15 g,
0.5 mmol), acetic anhydride (0.1 g, 1 mmol), and triethylamine (0.2 g, 2 mmol) in dimethylformamide
(5 mL) was stirred at room temperature for 3 hours.
The solvent was removed by rotoevaporation, and the residue suspended in water and 2 N HCI. The solid which formed was collected by filtration, washed with diethyl ether, and dried to give the acetamide (0.14 g) in 88% yield.
Analysis calculated for C14H14N θ5-H20: C, 50.00;
H, 4.80; N, 16.66.
Found: C, 49.92; H, 4.77; N, 16.04. EXAMPLE 26 Preparat i on of N7 -henzyl - 4 -bromo- 7 -n i ro- 5 , 6 t 7 f fl - t-pt-r-ahydronaphtha l ene- 1 , 7 -d am p
Figure imgf000052_0001
A solution of 1 , 7-diamino-2-nitro-4-bromotetralin hydrochloride (0.32 g, 1 mmol) and benzaldehyde (0.16 g, 1.5 mmol) in 2:1 methanol :water (10 mL) was stirred at room temperature and treated with sodium cyanoborohydride (0.19 g, 3 mmol). After stirring for 18 hours, the mixture was concentrated and extracted with methylene chloride. The organic layer was dried over magnesium sulfate, filtered, and evaporated to give a yellow solid. Purification was accomplished by silica gel chromatography (chloroform, then 2% methanol in chloroform as eluant) to give the benzylamine derivative (0.18 g) .
EXAMPLE 27 Resolution of 7 , 5 -di mi nn-fi -hromo- -ni ro ndane
Figure imgf000052_0002
The amine (10.1 g) was dissolved in 185 mL of 4:1 isopropanol :water . (R) -Mandelic acid (2.8 g, 0.5 eq) was added and the mixture allowed to crystallize at room temperature for 18 hours. The crystals were collected by filtration and dried. The solid was partitioned between methylene chloride:! N NaOH, and the aqueous layer was back extracted. The combined organic layers were dried over sodium sulfate, and evaporated to give a solid (3.2 g) . The recrystal- lization with (R) -mandelic acid was repeated a total of four times to give an enantiomeric excess of 99% of
(R) -2, 5-diamino-6-bromo-4-nitroindane as determined by chiral HPLC. Absolute configuration was determined by x-ray crystallography. The (R) - and (S) -enantiomers were carried individually through the remaining synthesis to give chiral quinoxalinedione adducts .
EXAMPLE 28 (fi) -2, -di am no-6-bromo-4-ni roi dane
Figure imgf000053_0001
The title compound was obtained by an identical procedure to Example 27 except that the racemate was cocrystallized with (S) -mandelic acid.
EXAMPLE 29 -Carboxyethyl- 1 - i ndannne
Figure imgf000053_0002
A mixture of 1-indanone (26.4 g, 0.2 mol), diethyl carbonate (35.4 g, 0.3 mol) and sodium hydride (16 g, 0.4 mol, 60% in oil) in THF (600 mL) was stirred at 40°C for 2 hours. The mixture was then poured onto 500 mL of 2 N HCI and ice. The organic phase was separated, and the aqueous phase extracted with ether. The combined organic layers were washed with saturated NaCl, dried over magnesium sulfate, filtered and evaporated to give the product as a syrup (38.3 g) .
EXAMPLE 30
7 - r hoxye hyl i ndape
Figure imgf000054_0001
A mixture of 2-carboxyethyl-l-idanone (38.3 g, 0.19 mol), 20% Pd/C (4 g) and concentrated sulfuric acid (4 drops) in ethanol (400 mL) was shaken on a Parr hydrogenation apparatus under hydrogen atmosphere (50.5 psi) for 15 hours. After removal of the catalyst by filtration, the solvent was evaporated and the residue purified by silica gel chromatography (4:1 hexane:EtOAc) to give the product 28.8 g) .
EXAMPLE 31 7 -C boxyethyl- 5 -nitroindane
Figure imgf000054_0002
A mixture of 2 -carboxyethylindane (28.8 g, 0.15 mol) and trifluoroacetic acid (300 mL) was cooled in an ice bath and then treated with fuming nitric acid (50 mL) . The reaction mixture was slowly warmed to room temperature and allowed to sit for 18 hours. After removing the solvent, the residue was dissolved in an ether:water mixture. The ether layer was separated and washed with water, and then saturated NaCl, and dried over magnesium sulfate. The filtrate was evaporated to give a dark syrup (34.3 g, 3:1 ratio of iso ers) .
EXAMPLE 32 5-Acet mi o- 2 -carhoxyethyl indane
OOEt
Figure imgf000055_0001
A mixture of 2-carboxyethyl-5-nitroindane (34 g, 0.15 mol), Raney nickel (5 g) , acetic anhydride (25 mL) and acetic acid (225 mL) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (50 psi) for 30 hours. After removing the catalyst, the filtrate was evaporated to give a dark syrup. The residue was purified by column chromatography (3:2 hexane : EtOAc) .
EXAMPLE 33 5-Aoetamido-6-bromo-2-carboxyethyl i ndane
Figure imgf000055_0002
A solution of 5 -acetamido-2 -carboxyethylindane
(18 g, 73 mmol) , sodium acetate (9 g, 110 mmol) in acetic acid (300 mL) was treated dropwise with bromine (14.1 g, 88 mmol) and then stirred for 18 hours. After removing the solvent, the residue was dissolved in ether-.water mixture, and sodium bisulfite was added. The ether layer was separated and the aqueous layer back extracted. The combined organic layers were washed with saturated NaCl, dried over magnesium sulfate, filtered and evaporated. The syrup was purified by silica gel chromatography (3:2 hexane : EtOAc) to give the product.
EXAMPLE 34 -Acetamido-6-bromo-2-carboxyethyl - -ni roi πdane
ooEt
Figure imgf000056_0001
A mixture of 5-acetamido-6-bromo-2-carboxyethyl- inadane (7 g, 20 mmol) and trifluoroacetic acid (150 mL) was cooled in an ice bath and treated with fuming nitric acid (10 mL) . After 2 hours at 0°C, the solvent was removed and the residue solidified upon addition of water. The solid was collected by filtration, washed with ether, and dried. Crystallization from hot toluene gave the pure product (7 g) .
EXAMPLE 35 - Ami no- 6 -hromo-4 -n i t.roi ndane - 2 -rarboxyl ac i
Figure imgf000056_0002
A mixture of 5-acetamindo-6-bromo-2-carboxyethyl- 4-nitroindane (7.1 g, 19 mmol) in acetic acid (25 mL) and 3 N HCI (100 mL) was heated at 100°C for 18 hours. The mixture was concentrated by rotoevaporation, and the resulting orange solid was collected by filtration, washed with ether and dried to give the product (5.5 g) .
EXAMPLE 36
7, 3-nioyo-7.r 3 ,4.7.8.9-hexahydro-l H-cyl oppnta Tfl - gninoxal i ne-9-carhoxyl i.c acid
Figure imgf000057_0001
A mixture of 5-amino-6-bromo-4-nitroindane-2- carboxylic acid (5.5 g, 18 mmol) and 20% Pd/C (0.5 g) in 95% ethanol (250 mL) and tetrahydrofuran (250 mL) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (51 psi) for 30 hours. After removing the catalyst, the solvent was evaporated to give a solid. The solid was dissolved in 2 N HCI
(150 mL) and treated with oxalic acid (4.6 g) , and then the mixture was heated at 90°C for 5 hours. After cooling to room temperature, the precipitate was collected by filtration and dried in vacuo (4.0 g) .
EXAMPLE 37 6-Nitro-?r -dioxo-7.3.4.7.R, 9-hpχahydro-l H-cycl o- penta f f 1 qninaoxal ne-8-carboxyli c aoi d
Figure imgf000057_0002
A mixture of 2 , 3-dioxo-2 , 3 , 4 , 7 , 8 , 9-hexahydro-lH- cyclopenta [f ] quinoxaline- 8 -carboxylic acid (4 g, 16 mmol) in trifluoroacetic acid (75 mL) was cooled to
0°C and then treated with fuming nitric acid (5 mL) .
After stirring in an ice bath for 3 hours, the mixture was warmed to room temperature for 1 hour, the solvent evaporated, and the residue was suspended in water. A solid precipitate was collected by filtration, washed with ether and dried in vacuo (4 g) .
Calculated for C-^Hg^Og- 0.5 H20 : C, 48.00; H, 3.36;
N, 14.00.
Found: C, 48.64; H, 3.13; N, 13.86, ms M+l (292).
EXAMPLE 38 6-Ni ro-2,3-dir>xo-2,3,4,7, 8, 9-hexahyriro-lH- r-yrloppnta ϊf1 qninoxal i ne-fi -o hoyyr-l i r. a id (thiophen- 7-ylmpthyl ) -ami e;
Figure imgf000058_0002
Figure imgf000058_0001
mixture of t e car oxy in Example 37 (0.29 g. 1 mmol), 5-aminotetrazole (0.13 g, 1.5 mmol) and EDAC [What is EDAC?] (0.29 g, 1.5 mmol) in DMF (15 mL) was treated with dimethylaminopyridine (10 mg) and then heated at 50°C for 18 hours. The solvent was removed and the residue suspended in water and acidified with 2 N HCI. The precipitate was collected by filtration and dried. Analysis Calculated for -L3H-LQN305 -H20: C, 39.60; H, 3.58; N,28.42. Found: C, 38.90, H, 3.05, N, 27.15, ms MS M+CH4 (372). EXAMPLE 39 6-Ni tro-7 , -di oxo-7.3.4,7.8. -hexahydro-l H-cycl o- ppnta [f1 quinoxal i ne-R-carhoxycl i acid [1,3,4]- thi a zol -7-yl mi e;
Figure imgf000059_0001
The title compound was prepared in a manner similar to Example 38, except the 5-aminotetrazole was replaced by thiadiazole amide. Analysis Calculated for C1 H10 N6°5S: C' 44.92; H, 2.69; N, 22.45. Found: C, 44.88, H, 3.62, N, 22.89.
EXAMPLE 40 6 -Ni ro- 2, -di nxo- 2. ,4, 7, 8, -hexahyriro-lH-πyclo- ppnt [fl quinoxal ne-8-carboxyrl ic aci (thi phen-7- ylmpthyl ) -am e;
Figure imgf000059_0002
The title compound was prepared in a manner similar to Example 38, except the 5-aminotetrazole was replaced by thienylmethyl amide.
Analysis Calculated for C-L H-L4N4O5S: C, 52.85; H, 3.65;
N, 14.50. Found: C, 53.37, H, 3.87, N, 14.47, ms M+l (387) . EXAMPLE 41 fi-Ni ro-7, 3-dioyo-7.3.4.7. fl . Q-heyahyd-ro-π-T- yr-1 o- penta \f1 quinoxaline-8-carhoxycl ic acid MM- p, 7,41- triazol -3-yl ) -amide
Figure imgf000060_0001
The title compound was prepared in a manner similar to Example 38, except the 5-aminotetrazole was replaced by triazole amide . Analysis Calculated for -^H- N-^ • 0.5 H20: C, 45.90; H, 3.30; N, 26.77. Found: C, 46.29, H, 3.40, N, 23.97, ms M+l (358).
EXAMPLE 42 fi-Ni -ro-7, 3-di vo-7.r4.7rR. Q-heyahydro- 1 H- yr-1 o- penta [f 1 qni oxal ine-R-carhoxycl i c acid (5-methyl- snl fanyl -1H- M ,7, 1 ri zol -3-yl ) -amide;
Figure imgf000060_0002
The title compound was prepared in a manner similar to Example 38, except the 5-aminotetrazole was replaced by methylthioltriazole amide.
Analysis Calculated for C-^H-^N-^S : C, 44.66; H, 3.25;
N, 24.31. Found: C, 44.30; H, 3.27; N, 20.55. EXAMPLE 43 6-Ni tro-8- (p.i peridine-1-carbonyl. ) -4,7,8, 9-tetrahydro- IH-cyclopenta f1 uinoxal ine-2, -di ne;
Figure imgf000061_0001
The title compound was prepared in a manner similar to Example 38, except the 5-aminotetrazole was replaced by piperidine amide.
Analysis Calculated for C17H18N θ5- 1.2 H20: C, 53.73; H, 5.41; N, 14.75.
Found: C, 53.34, H, 5.45, N, 15.46, ms M+l (358).
Exampl 44
6-Ni tro-7.3-di oxo-2.3.4.7.8, 9-hexahydro-l H-ryr-1 o- penta [f1 uinoxal i ne-8-carboyyrl i r. aoi d (3-mpthyl - i soxa7.ol -5-yl ) -amide;
Figure imgf000061_0002
The title compound was prepared in a manner similar to Example 38, except the 5-aminotetrazole was replaced by isoxazole amide .
Analysis Calculated for C^H^^Og- 1.3 H20: C, 48.68;
H,3.98; N, 17.74.
Found: C, 48.83, H, 4.04, N, 1619.1 EXAMPLE 45 -Ni tro-2 , -di nxn-2 , .3,4,7,8, 9-hex ydro- 1 H- yπl n- ppnt Tf 1 quinoyal inp-8-carhoxyl ic acid pyridin-7- ylamide;
Figure imgf000062_0001
The title compound was prepared in a manner similar to Example 38, except the 5-aminotetrazole was replaced by pyridine amide . Analysis Calculated for 11H13N)θ^ • l .2H 0 : C, 52.49; H, 3.99; N, 18.01. Found: C, 52.56, H, 3.69, N, 17.55, ms M+l (369).
EXAMPLE 46 fi-N f-ro-7, -d yo-2, 3,4 , 7. fl, q -heyahydro- 1 H-oyol o- ppnta ff1 qπinoxal i ne-8-carhoyycl i r. acid thia ol-7- yl mi dp;
Figure imgf000062_0002
The title compound was prepared in a manner similar to Example 38, except the 5-aminotetrazole was replaced by thiazole amide.
Analysis Calculated for C-L5H- N505S -H 0: C, 46.03;
H, 3,35; N, 17.90. Found: C, 45.99, H, 3.39, N, 17.40, ms M+l (374). EXAMPLE 47 2- (π boerhoyymethyl i pne) indane
Figure imgf000063_0001
A solution of 2-indanone (26.4 g, 0.2 mol) in benzene (400mL) was treated with carbethoxy- methylene) tri-phenylphosphorane and then heated at reflux for 4 hours . The solvent was removed and the residue triturated in diethyl ether. The mixture was filtered through a celite pad, and the filtrate was evaporated. The resulting syrup was purified by silica gel chromatography (20% EtOAc in hexane) to give a reddish syrup (21.2 g) .
EXAMPLE 48 7- (Carbop hoxym thyl ) indane
_ COOEt
A mixture of 2- (carboethoxymethylidene) indane (21.2 g, 0.105 mol) and 20% Pd/C (1.78 g) in ethanol (lOOmL) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (51 psi) for 8.4 hours. After removing the catalyst, the filtrate was evaporated and the residue purified by silica gel chromatography (9:1 hexane :EtOAC) to give the product (76% yield) . EXAMPLE 49 2- (farboethoxymethyl ) -5- i ro ndane
OEt
Figure imgf000064_0001
A mixture of 2- (carboethoxymethyl) indane (16.2 g, 80 mmol) in trifluoroacetic acid (200 mL) was cooled in an ice bath and treated with fuming nitric acid (20 mL) . After stirring for 4 hours, the solvent was removed and the residue partitioned between methylene chloride :water. The aqueous layer was back extracted, and the combined organic layers were dried over sodium sulfate, filtered, and evaporated to give a brown syrup (19.5 g) .
EXAMPLE 50 5-Aretamido-2- (carboethoyympthyl ) i ndanp
Figure imgf000064_0002
A mixture of 2- (carboethoxymethyl) -5-nitroindane (19.5 g, 80 mmol) and Raney nickel (5 g) in THF (200 mL) was stirred under a hydrogen atmosphere (1 atm) at room temperature for 24 hours. Fresh Raney nickel and hydrogen were added and reaction continued for 24 hours. After removing the catalyst, the filtrate was evaporated and the residue purified by silica gel chromatography (3:2 hexane:EtOAc) to give product as a brownish syrup (17 g) . EXAMPLE 51 5-Aoetamido-6-hromo-2- (carboethoxymethyl ) indane
OOEt OOEt
Figure imgf000065_0001
Figure imgf000065_0002
A mixture of 5-acetamido-2- (carboethoxymethyl) - indane (17 g, 65 mmol) and sodium acetate (17.7 g, 0.13 mol) in acetic acid (300 mL) was treated with bromine (12.5 g, 78 mmol) and stirred at room temperature for 5 hours. Sodium bisulfite was added until the mixture cleared. The solvent was evaporated, and the residue partitioned between water and methylene chloride. The aqueous layer was back extracted, and the combined organic layers were washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated (26 g solid) . The product was purified by silica gel chromatography (chloroform) to give separation of the product and its regioisomer.
EXAMPLE 52 -Acetamido-6-bromo-2- (carboethoxymethyl ) -4- nitroindanee
Figure imgf000065_0003
A mixture of 5-acetamido-6-bromo-2- (carboethoxymethyl) indane (5.2 g, 15 mmol) in trifluoroacetic acid (100 mL) was cooled in an ice bath and then treated with fuming nitric acid (5 mL) . After stirring for 1 hour in the ice bath and 4 hours at room temperature, the solvent was removed and the residue partitioned between methylene chloride and water. The organic layer was dried over sodium sulfate, filtered, and evaporated to give a white solid (6.2 g) .
EXAMPLE 53 5-Amino-fi-hromo-2- (c hoxym hyl ) -4 -n oi dane
Figure imgf000066_0001
A solution of 5-acetamido-6-bromo-2- (carboethoxymethyl) -4 -nitroindane (2 g, 5.2 mmol) in acetic acid (20 mL) and 3 N HCI (50 mL) was heated at 100°C for 3 hours. The solvent was evaporated and the residue purified by silica gel chromatography (3% methanol in chloroform) to give a reddish syrup (1.5 g) .
EXAMPLE 54
2, 3-ni yo-7.3,4.7.8.9 -hexahydro- 1 H-ycl openta \ f1 - qninoyal ine-8-aceti c. acid
Figure imgf000066_0002
A mixture of 5-amino-6-bromo-2- (carboxy ethyl) -4- nitroindane (4.1 g, 13 mmol), 20% Pd/C (0.4 g) , and triethylamine (10 L) in THF (100 mL) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (51 psi) for 15 hours. After removing the catalyst, the solvent was evaporated and the residue dissolved in 2 N HCI (150 L) and treated with oxalic acid (3.3 g, 2 eq) . After heating at 100°C for 3 hours, the reaction was cooled to room temperature, and the resulting precipitate collected by filtration and dried (2.9 g) .
EXAMPLE 55
2 , -Di oxo- 2 , . 4 . 7 . ft . 9-hexahydro- -ni tro- 1 H-oyol - penta f ] qn i noxal i ne - R -aceti c aci d
Figure imgf000067_0001
A mixture of 2 , 3-dioxo-2 , 3 , 4 , 7 , 8 , 9-hexahydro-lH- cyclopenta [f] quinoxaline- 8-acetic acid (2.9 g) in triflouroacetic acid (75 L) was cooled in an ice bath and treated with fuming nitric acid (5 mL) . After stirring 1 hour at 0°C and then 2 hours at room temperature, the solvent was removed, and the residue suspended in 2 N HCI. The resulting solid was collected by filtration and dried (2.9 g) .
EXAMPLE 56 2-Hydroxyethyl ndane
Figure imgf000067_0002
A solution of 2- (carboethoxymethyl) indane (10.5 g, 51 mmol) in diethyl ether (250 mL) was cooled in an ice bath and treated with lithium aluminum hydride (3.8 g, 100 mmol) . After stirring for 18 hours at room temperature, the mixture was cooled and then quenched successively with water (4 mL) , 12.5% NaOH (3 mL) and water (5 L) . The white solid was removed by filtration, and the filtrate evaporated. The residue was purified by silica gel chromatography (9:1 hexane: EtOAc) to give the product as a clear syrup.
EXAMPLE 57 2- (2-Methanesulfonylhydroxyethyl ) indanp
Figure imgf000068_0001
A solution of 2-hydroxyethylindane (7.8 g, 48 mmol) in methylene chloride (200 mL) was cooled in an ice bath and then treated with methanesulfonyl chloride, (6.6 g, 58 mmol) and triethylamine (7.3 g, 72 mmol) . After stirring at room temperature for 4 hours, the reaction mixture was washed with water and then saturated sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and evaporated to give a syrup (12 g) .
EXAMPLE 58 2 - f 2 - ryartoethyl ) i ndane
Figure imgf000068_0002
A mixture of 2- (2-methanesulfonylhydroxy- ethyl) indane (12.1 g, 50 mmol) and sodium cyanide (4.9 g, 100 mmol) in DMF (100 mL) was heated at 40°C for 16 hours. The solvent was removed and the residue partitioned between methylene chloride and water. The aqueous phase was back extracted, and the combined organic layers were dried over sodium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (20:1 hexane : EtOAc) to give the product as a white solid (6.2 g) .
EXAMPLE 59 2- (2- (5-Ter.rar.olyl ) ethyl ) indane
Figure imgf000069_0001
A mixture of 2- (2-cyanoethyl) indane (6 g, 35 mmol) and tri-n-butyl tin azide (10 mL) was heated in a sealed tube at 90°C for 4 days. The mixture was cooled to room temperature and poured into diethyl ether saturated with HCI (g) , and stirred for 1 hour. A white precipitate formed and was collected by filtration, washed with heptane, and dried (7.5 g) .
EXAMPLE 60 7 - ( 7 - ( 5 -TPt ra ^ol yl ) pt hyl ) - 5 -n i roi ndariP
Figure imgf000069_0002
A mixture of 2- (2- (5-tetrazolyl) ethyl) indane (7.5 g, 35 mmol) and triflouroacetic acid (150 mL) was cooled in an ice bath and treated with fuming nitric acid (10 mL) . After stirring at 0°C for 1 hour, and then room temperature overnight, the solvent was removed and the residue partitioned between methylene chloride and water. The aqueous layer was back extracted, and the combined organic layers were dried over sodium sulfate, filtered, and evaporated to give a syrup (8.5 g) .
EXAMPLE 61 5-Acetamido-2- (2- (5-tetrazol yl ) ethyl ) i ndane
Figure imgf000070_0001
A mixture of 2- (2- (5-tetrazolyl) ethyl) -5- nitroindane (8.5 g, 33 mmol) and Raney nickel (5 g) in THF (200 mL) under hydrogen (g, 1 atm) was stirred at room temperature for 18 hours. After removing the catalyst, the filtrate was treated with acetic anhydride (10 g) and evaporated to give a syrup (9.0 g) .
EXAMPLE 62 -Aoet-ami o-6-bromo-2- (2- (5- te raτ:ol yl ethyl ) i ndane
Figure imgf000070_0002
A mixture of 5-acetamido-2- (2- (5-tetrazolyl) - ethyl) indane (9 g, 33 mmol) and sodium acetate (5.4 g, 66 mmol) in acetic acid (150 mL) was treated dropwise with bromine (6.4 g, 40 mmol) and then stirred at room temperature for 18 hours. Excess bromine was quenched with sodium bisulfite, and the solvent removed. The residue was triturated with isopropyl alcohol and the resulting solid was collected by filtration.
EXAMPLE 63 5 -Aretami do- 6 -hromo-7 - ( 7 - ( 5 -tetra7.ol yl ) ethyl ) ni troi dane
Figure imgf000071_0001
A mixture of 5-acetamido-6-bromo-2- (2- (5- tetrazolyl) ethyl) indane (2.3 g, 6.6 mmol) in trifluoro- acetic acid (50 mL) was cooled in an ice bath and treated with fuming nitric acid (3 mL) . After stirring for 1 hour at 0°C and then warming to room temperature for 5 hours, the solvent was removed. The residue was partitioned between THF and water, and the aqueous phase back extracted. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to give a yellow solid (2.5 g) .
EXAMPLE 64 5 -Ami no- 6 -bromo- 2 - ( 2 - ( 5 -tetrazol yl ) ethyl - -n i roi ndane
Figure imgf000071_0002
A solution of 5-acetamido-6-bromo-2- (2- (5- tetrazolyl) ethyl) -4-nitroindane (2.5 g) in 3 N HCI (100 mL) and acetic acid (25 L) was heated at 100°C for 18 hours. After cooling to room temperature, the mixture was extracted with methylene chloride . The organic layer was dried over sodium sulfate, filtered, and evaporated to give a red syrup .
EXAMPLE 65 7.3-D oxo-8- (7- ( -tetra olyl ) ethyl , -2.3. .7. ft. Q- hpχahydro-1H- cyclopenta ϊf 1 quinoxal i p
Figure imgf000072_0001
A mixture of 5-amino-6-bromo-2- (2- (5-tetrazolyl) - ethyl) -4 -nitroindane (2.4 g, 6.8 mmol) and 20% Pd/C (0.25 g) in water (100 mL) and 50% NaOH (2 g) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (50 psi) for 18 hours. After removing the catalyst, the mixture was acidified with concentrated HCI, the mixture treated with oxalic acid (2 g) an then heated at 100°C for 4 hours. The mixture was cooled to room temperature and the precipitate was collected by filtration and dried (0.8 g) .
EXAMPLE 66 7f -ni vo-R- (7- (5-tetra olyl ) ethyl ) -7,3,4.7,8.9- heyahydro-IH-6-ni trocycl open Tf 1 qni oyal i np
Figure imgf000072_0002
A mixture of 2, 3-Dioxo-8- (2- (5-tetrazolyl) ethyl) - 2,3,4,7,8, 9-hexahydro-lH-cyclopenta [f] quinoxaline (0.8 g) in trifluoroacetic acid (20 mL) was cooled in an ice bath and treated with fuming nitric acid (1 mL) After stirring for 1 hour at 0°C and 18 hours at room temperature, the solvent was removed and the residue suspended in water. The solid was collected by filtration, then dissolved in saturated sodium bicarbonate and filtered. The filtrate was acidified, the precipitate collected by filtration, and dried (0.5 g) .
EXAMPLE 67 2- ( Cyaπn) ethyl ideneindane
Figure imgf000073_0001
A solution of diisopropyl cyanomethlyphosphonate (12.3 g, 60 mmol) in THF (100 L) was cooled in an ice bath and treated with sodium hydride (60% in oil, 2.4 g, 60 mmol) . After stirring for 30 minutes, 2-indanone (6.5, 50 mmol) was added and the mixture stirred at room temperature for 18 hours. A precipitate formed. The mixture was partitioned between diethyl ether and 2 N HCI . The ether layer was washed with saturated sodium bicarbonate and then saturated sodium chloride, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (30% EtOAc in hexane) to give the product as a brown solid (5 g) . EXAMPLE 68
7 -Cyanomethyl i ndane
Figure imgf000074_0001
A mixture of 2- (cyano)methylideneindane (4.8 g, 31 mmol) and 5% Pd/C (0.5 g) in THF (150 mL) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (51 psi) for 2 hours. After removing the catalyst, the solvent was evaporated and the residue purified by silica gel chromatography (9:1 hexane: EtOAc) to give the product as a crystalline solid (3.9 g) .
EXAMPLE 69 7- ( -Tetra7:olyl ) methyl indane
Figure imgf000074_0002
A mixture of 2 -cyanomethylindane (3.9 g, 25 mmol) and tri-n-butyl tin azide (15 L) was heated at 90°C in a sealed tube for 48 hours. The mixture was cooled to room temperature and poured into diethyl ether (200 mL) saturated with HCI (g) , and then stirred for 2 hours at room temperature. The resulting precipitate was collected by filtration (4.5 g) . EXAMPLE 70 7 - ( ς -Tetra ol yl ) methyl - 5 -ni.troi ndanp
Figure imgf000075_0001
A mixture of 2- (5-Tetrazolyl)methylindane (4.5 g, 23 mmol) in trifluoroacetic acid (100 mL) was cooled in an ice bath and treated with fuming nitric acid (5 mL) . After stirring for 1 hour at 0°C and 2 hours at room temperature, the solvent was removed and the residue partition between water and methylene chloride. The aqueous phase was back extracted and the combined organic layers were dried over sodium sulfate, filtered, and evaporated to give a yellow solid.
EXAMPLE 71 -Acetami do-7- (5-tetrazolyl ) ethyl i ndane
Figure imgf000075_0002
A mixture of 2- (5-tetrazolyl) methyl-5-nitroindane (5.5 g) and Raney nickel (1 g) in THF (150 mL) was stirred under hydrogen (1 atm) at room temperature for 18 hours. After removing the catalyst, the filtrate was treated with acetic anhydride (10 g) and evaporated to give the product as a syrup. EXAMPLE 72 6-Acetamido-5-bromo-2- (5-tetraτ:ol yl ) methyl indane
Figure imgf000076_0001
A solution of 5-acetamido-2- (5-tetrazolyl) - methylindane (5.9 g, 23 mmol) and sodium acetate (3.8 g, 46 mmol) in acetic acid (200 mL) was treated dropwise with bromine (4.4 g, 27 mmol) and then stirred at room temperature for 16 hours. The excess bromine was quenched with sodium bisulfite, and the solvent evaporated. The residue was partitioned between water and THF. A solid precipitate (3 g) was removed by filtration. The organic layer was dried over magnesium sulfate, filtered, and evaporated to give the product as a solid (2.5 g) .
EXAMPLE 73 5-Aoe ami o-6-bromo-2- ( 5 -tetrazol yl ) methyl -4- ni troi ndane
Figure imgf000076_0002
A mixture of 6-acetamido-5-bromo-2- (5-tetrazolyl) methylindane (6.2 g) in trifluoroacetic acid (100 mL) was cooled in an ice bath and treated with fuming nitric acid (7 mL) . After stirring for 1 hour at 0°C and then 3 hours at room temperature, the solvent was removed and the residue triturated with water. The resulting solid was collected by filtration, washed with diethyl ether, and dried.
EXAMPLE 74 5-Amino-fi-bromo-2- (5- tetrazol yl ) ethyl -4-ni tro ndane
Figure imgf000077_0001
A solution of 5-acetamido-6-bromo-2- (5- tetrazolyl) -methyl-4 -nitroindane (3.5 g) in 3 N HCI (80 mL) and acetic acid (20 mL) was stirred at 100 °C for 3 hours . The solvent was removed and the solid collected by filtration and dried.
EXAMPLE 75
7. -D yo-ft- ( 7 - C5-t.Ptra7.olyl ϊ erhyl ) -7, 1,4, 7, ft.9-
Figure imgf000077_0002
A mixture of 5-amino-6-bromo-2- (5-tetrazolyl) - methyl-4 -nitroindane (2.6 g, 7.7 mmol), 20% Pd/C (0.3 g) and triethylamine (2.5 mL) in methanol (250 mL) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (50 psi) for 18 hours. After removing the catalyst, the solvent was removed and the residue dissolved in 2 N HCL and treated with oxalic acid (2.9 g) , and then heated at 90°C for 3 hours. The reaction was cooled to room temperature and the resulting precipitate was collected by filtration and dried (1.2 g) .
EXAMPLE 76 2, -n oyo-ft- (2- (5-t trazol yl ϊmpthyl ^-2,3,4,7,8,9- hexahydro- 1H- 6 -nitrocycl opent \f qu i nox 1 i ne
Figure imgf000078_0001
A mixture of 2, 3-Dioxo-8- (2- (5- tetrazolyl) methyl) 2,3,4,7,8, 9 -hexahydro-lH-cyclopenta [f] quinoxaline
(1.2 g) in triflouroacetic acid (30 mL) was cooled in an ice bath and then treated with fuming nitric acid (2 mL) . After stirring at 0°C for 1 hour and room temperature for 3 hours, the solvent was removed and the residue triturated in water. The resulting precipitate was collected by filtration and dried (1.2 g) .
EXAMPLE 77 g- ethylamino-6-ni tro-1.4.7.8.9.10-hpyahydro-hpn7.o ffl - qninoy l ine-2. -dione
[How was it prepared?}
Analysis Calculated for C13H-L O4 -HCI : C, 47.79;
H, 4.63; N, 17.15. Found: C, 43.36; H, 4,22; N. 18.85, ms M+l (291). EXAMPLE 78 2 -Ethyl arbamoyl i ndane
Figure imgf000079_0001
A mixture of 2-aminoindane hydrochloride (25 g, 0.15 mol) and ethyl chloroformate (21.7 g, 0.2 mol) in saturated sodium bicarbonate (200 mL) and ether (200 mL) was stirred at room temperature for 1 hour. The ether layer was separated and the aqueous layer back extracted. The combined ether extracts were washed with saturated NaCl, dried over magnesium sulfate, filtered, and evaporated to give a white solid (27 g) .
EXAMPLE 79 2- (N-Methyl ) cptami doindane
HCOOEt
Figure imgf000079_0002
Figure imgf000079_0003
A solution of 2-ethylcarbamoylindane (20.5 g, 0.1 mol) in diethyl ether (250 mL) was cooled in an ice bath and then treated portionwise with lithium aluminum hydride (7.6 g, 0.2 mol) . The reaction mixture was stirred over 18 hours while warming to room temperature. The reduction was incomplete, and the reaction mixture was then heated at reflux for an additional 24 hours. The mixture was cooled to 0°C and treated cautiously with water (8 mL) , followed by 12.5% NaOH (6.5 mL) and water (16 mL) . The white precipitate was removed by filtration and washed with ether and THF. The filtrate was treated with acetic anhydride (13 g) and the filtrate evaporated to a syrup. Silica gel chromatography (1:1 hexane : EtOAc) gave the product (12.2 g) . 5
EXAMPLE 80 2- (N-Methyl ) acetami.do-5-ni troi ndane
Figure imgf000080_0001
A mixture of 2- (N-methyl) acetamidoindane (16 g, 85 mmol) in trifluoroacetic acid (200 mL) was cooled in 5 an ice bath and then treated with fuming nitric acid (20 mL) . After stirring for 1 hour in the ice bath, the reaction was stirred for an additional 3 hours at room temperature. The solvent was removed and the residue taken up in methylene chloride : water . The 0 aqueous phase was extracted with methylene chloride and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to give the product (20 g) .
5 EXAMPLE 81
N^-Met-hyl -2 , 5 -diacetamidoi ndanp
Figure imgf000080_0002
A mixture of 2- (N-methyl) acetamido-5-nitroindane (20.1 g, 85 mmol) and Raney Nickel (10 g) in THF (100 mL) and methanol (100 L) was stirred under a 5 hydrogen atmosphere (balloon) at room temperature for 18 hours. The catalyst was removed, and the filtrate was treated with acetic anhydride (18 g) , and then evaporated to a brown syrup (22 g) .
EXAMPLE 82 τ^-Methyl - 2 , -di cetami do-5-bromoi dane
Figure imgf000081_0001
A mixture of N -methyl-2, 5-diacetamidoindane (22 g, 85 mmol) and sodium acetate trihydrate (23 g, 0.17 mol) in acetic acid (250 L) was treated dropwise with bromine (17 g, 0.11 mol) and stirred for 18 hours at room temperature . The mixture was treated with sodium bisulfite and evaporated. The residue was taken up in methylene chloride :water , and the aqueous layer was back extracted with additional methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and evaporated to give a syrup
(26 g) . The syrup was triturated with diethyl ether to give the product as a white solid.
EXAMPLE 83 K_-Methyl -2 , 5 -di acetami do-6 -bromo-4 -ni troi ndane
Figure imgf000081_0002
A mixture of N -methyl-2, 6 -diacetamido-5- bromoindane (21.8 g, 67 mmol) in trifluoroacetic acid (200 mL) was cooled in an ice bath and treated with fuming nitric acid (25 L) . After stirring for 1 hour, the mixture was warmed to room temperature and stirred for an additional 3 hours . The solvent was removed and the residue taken up in water. The mixture was triturated in diethyl ether to give a precipitate, which was collected by filtration and dried to give the product (22.5 g) .
EXAMPLE 84 N^-Methyl -2, 5-dι mi no-6-hromo- -ni froindanp hydrochlori e
Figure imgf000082_0001
A mixture of N -methyl-2 , 5-diacetamido-6-bromo-4- nitroindane (22.5 g, 61 mmol) in 3 N HCI (150 mL) and acetic acid (50 mL) was heated at 100°C for 24 hours. The mixture was cooled in an ice bath and the orange precipitate was collected by filtration and dried (17.2 g) .
EXAMPLE 85
Figure imgf000082_0002
A mixture of N -methyl-2, 5-diamino-6-bromo-4- nitroindane hydrochloride (17.2 g, 53 mmol) and 20% Pd/C (1 g) in methanol (250 mL) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (50 psi) for 6 hours. After removing the catalyst, the filtrate was evaporated and the residue taken up in 2 N HCI (250 mL) and oxalic acid (13 g, 0.1 mol) and heated at 100°C for 5 hours. The mixture was cooled in a refrigerator overnight, and the resulting precipitate was collected by filtration and washed with water and then diethyl ether and dried to give the product (9.9 g) .
EXAMPLE 86 R -Mpthyl ami o- 6 -ni ro-4 , 7 , ft , - tetrahydro- 1 H- cycl o- pent f fl qni noxa J ne-2 , -di one methane sul f onate sal t
Figure imgf000083_0001
A mixture of 8-methylamino-4 , 7 , 8 , 9-tetrahydro-lH- cyclopenta [f] quinoxaline-2, 3 -dione (9.9 g) in trifluoroacetic acid was cooled in an ice bath and treated with fuming nitric acid (10 mL) . After stirring at 0°C for 1 hour, the reaction mixture was warmed to room temperature for an additional hour. The solvent was removed and the residue taken up in acetone :water. The yellow solid was collected by filtration, washed with water, and dried (9.8 g) . One gram was taken up in water and NaOH (1 eq) and stirred at room temperature for 3 hours. The solid was collected by filtration an dried. The solid was suspended in methanol and treated with methanesulfonic acid and stirred for 15 minutes. A tan solid was collected by filtration and dried.
8-Methylamino-6-nitro-4, 7,8, 9-tetrahydro-lH- cyclopenta [f] quinoxaline-2, 3-dione hydrochloride
(0.39 g) in trifluouroacetic acid was cooled in an ice bath and then treated with fuming nitric acid (1 mL) . After stirring for 1 hour, the mixture was warmed to room temperature for 3 hours . The solvent was evaporated and the residue suspended in methanol. The resulting yellow solid was collected by filtration and dried.
Analysis Calculated for C12 H12N4° " H4°3S : c> 41.93; H, 4.33; N, 15.05. Found: C, 39.56; H, 4.11; N, 13.61, ms M+l (277).
EXAMPLE 87
Figure imgf000084_0001
A mixture of N -methyl-2, 5-diamino-6-bromo-4 - nitroindane hydrochloride (2 g, 6.2 mmol), ethyl bromoacetate (1.1 g, 6.8 mmol) and diisopropylethylamine (2.4 g, 18.6 mmol) in DMF (60 mL) was heated at 50°C for 24 hours. After removing the solvent, the residue was partitioned between methylene chloride :water, basified with 12.5% NaOH. The aqueous phase was back extracted, and the combined organic layers were dried over sodium sulfate, filtered, and evaporated to give a dark syrup.
Figure imgf000084_0002
A mixture of the product of example 87 (0.38 g, 1 mmol) and 20% Pd/C (0.1 g) in methanol (75 mL) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (52 psi) for 14.5 hours. After removing the catalyst, the filtrate was evaporated and the residue dissolved in 2 N HCI (20 mL) and treated with oxalic acid (0.37 g, 3 mmol) . The reaction was heated at reflux for 3 hours. After cooling to room temperature, the solid was collected by filtration and dried to give the product (0.25 g) .
EXAMPLE 89
H
Figure imgf000085_0001
A mixture of the product of example 88 (0.24 g) and trifluoroacetic acid (15 mL) was cooled in an ice bath and then treated with fuming nitric acid 0.5 mL . After stirring for 1 hour, the reaction mixture was warmed to room temperature and stirred for an additional 3 hours. The solvent was removed, and the syrup was triturated with acetone. The resulting precipitate was collected by filtration and dried (0.24 g) .
EXAMPLE 90
Preparation of N- ndan-2-yl -acetami e
Figure imgf000085_0002
A mixture of 2-aminoindan hydrochloride (13.3 g, 78 mmol), acetic anhydride (6 g, 0.157 mol), and saturated sodium bicarbonate (100 mL) in ether (100 mL) was stirred at room temperature for 1 hour. The organic phase was separated, and the aqueous layer back washed with ether. The combined organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated to give the acetamide (13.6 g) in quantitative yield.
EXAMPLE 91 Preparation of N- (5-ni o- i ndan- -yl ) -acet mi e
Figure imgf000086_0001
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.
EXAMPLE 92 Preparation of N- (5-acetyl amino- i ndan-2-yl ) -acetamide
Figure imgf000086_0002
The mixture of N- (5-nitro-indan-2-yl) -acetamide
(20.5 g, 93 mmol) in tetrahydrofuran (200 mL) was combined with acetic anhydride (10 mL) and Raney nickel (5 g) and stirred under an atmosphere of hydrogen gas (in a balloon) at room temperature for 24 hours. Additional Raney nickel was added and the balloon recharged with hydrogen gas and stirred an additional 24 hours. After removing the Raney nickel by filtration through a celite pad and washing with methanol several times, the filtrate was evaporated to a syrup. The residue was triturated with ether: ater and the resulting white solid collected by filtration
(9.2 g, 52% yield overall from 2-aminoindan prepared in Example 20) .
EXAMPLE 93 Preparation of N- ( -acetylam o- -bromo- i dan-7 -yl - acetamide
Figure imgf000087_0001
A solution of N- (5-acetylamino-indan-2-yl) - acetamide (9.8 g, 42 mmol) and bromine (8.5 g, 53 mmol) in acetic acid (200 mL) was stirred at room temperature for 3 hours. After evaporation of the solvent, the syrupy residue was dissolved in ether and washed with water. The organic layer was washed with aqueous sodium bisulfite and dried over magnesium sulfate . The solvent was concentrated and the resulting solid collected by filtration (10 g, 77% yield) . EXAMPLE 94 Preparation of N- (5-acetyl ami o-fi-bromo-4 -ni ro- i dan- 2-yl ) -acetamide
Figure imgf000088_0001
A solution of N- (5-acetylamino-6-bromo-indan-2 - yl) -acetamide (10 g, 32 mmol) in trifluoroacetic acid (175 mL) was cooled in an ice bath to 0°C and then treated with fuming nitric acid (25 mL) . After stirring for 2 hours at 0°C, the reaction mixture was warmed to room temperature and stirred for an additional 2 hours. The solvent was removed by rotoevaporation and the residue was triturated with an ether :water mixture. The resulting solid was collected by filtration and washed consecutively with water and ether, and then dried in vacuo to give the product (10 g) in 87% yield.
EXAMPLE 95 Preparation of N- ( 5-ami no-6-hromo-4 -ni tro- i ndan- 2-yl ) - acetam e
Figure imgf000088_0002
N- (5-Acetylamino-6-bromo-4-nitro-indan-2-yl) - acetamide (1 g, 2.8 mmol) was suspended in a 2:1 mixture of sulfuric acid and water (30 mL) and heated at 90°C for 12 hours. The mixture was poured onto ice and the resulting yellow solid was collected by filtration and dried in vacuo to give (0.7 g, 80% yield) . EXAMPLE 96 Preparat i on of 6-bromo-4 -nι t o- i dan- 2 , 5 - diam e monohydrochl or ide
Figure imgf000089_0001
N- (5-Acetylamino-6-bromo-4-nitro-indan-2-yl) - acetamide (1 g, 2.8 mmol) was stirred in 3 N HCI
(80 mL) at reflux for 3 hours. The resulting solid was collected by filtration and dried in vacuo. Additional material was obtained by evaporation of the filtrate to give a combined yield of 93% of the yellow orange product (0.8 g) .
EXAMPLE 97
Preparafion of N- (4.5-di ami no- 6 -hrn o- dan- 7 -yl ) - acetamide
Figure imgf000089_0002
N- (5-Amino-6-bromo-4-nitro-indan-2-yl) -acetamide
(0.7 g, 2.2 mmol) was dissolved in tetrahydrofuran (20 L) and then treated with Raney nickel and stirred under a hydrogen atmosphere (1 atm) at room temperature for 1 hour. The catalyst was removed by filtration through a celite pad, and washed repeatedly with methanol. The combined organic filtrate was removed by rotoevaporation to give a syrup that solidified upon standing. This product was used without further purification. EXAMPLE 98 Preparation of N- ( -bromo-7.3.4.7. ft Q-hpyahydr-o- 1 H- oycl pent-a If1 qninoxali n-8-yl ) -acetami e
Figure imgf000090_0001
N- (4 , 5-Diamino-6-bromo-indan-2-yl) -acetamide (~2.2 mmol) was combined with oxalic acid (0.5 g) in 2 N HCI (15 mL) and heated at 80°C for 3 hours. The resulting precipitate was collected by filtration and washed consecutively with methanol, water and ether, and then dried in vacuo to give the quinoxalinedione (0.37 g) in 50% yield for the hydrolysis and condensation steps. Analysis Caluclated for C-^H-^Br^O • 2.2H20: C, 41.33; H, 4.37; N, 11.12.
Found: C, 41.12; H, 3.91; N, 11.24.
EXAMPLE 99 Preparation of N- (5 -bromo-6 -ni ro-2 , -di oyo-2 , , 4 , 7 , 8 , 9-hexahydro-IH-cycl pentaff 1 qu noxal i -ft-yl -acetami e
Figure imgf000090_0002
ahydro-lH- cyclopenta [f] quinoxalin-8-yl) -acetamide (0.24 g, 0.7 mmol) was dissolved in trifluoroacetic acid (10 mL) , cooled in an ice bath to 0°C, and then treated with fuming nitric acid (0.5 mL) and stirred for 4 hours at 0°C. After removing the solvent by rotoevaporation, the syrupy residue was triturated with water and the resulting solid was collected by filtration, washed with water and then ether and dried in vacuo (0.22 g, 81% yield).
Analysis Calculated for C]_ H]_-]_BrN4θ5-H2θ:
C, 38.92; H, 3.27; N, 13.94.
Found: C, 38.60; H, 3.00; N, 13.66.
EXAMPLE 100
Preparation of - ( 7 .3-di oyo- f . , 7. ft .9 -heyahydro-1 H- cyπlopenta [f1 qu.inoxalin-8-yl) -acetamide
Figure imgf000091_0001
A mixture of N- (5-amino-6-bromo-4 -nitro--indan-2- yl) -acetamide (0.5 g, 1.6 mmol), 5% palladium on carbon (0.2 g) and sodium acetate (0.16 g) in methanol (75 mL) was placed on a Parr hydrogenation apparatus under a hydrogen atmosphere (51 psi) and shaken for 18 hours. After removing the catalyst by filtration, the solvent was evaporated and the residue was suspended in 2 N
HCI, treated with oxalic acid (0.5 g) and then heated at 80°C for 4 hours. The water was evaporated and the residue dissolved in saturated sodium bicarbonate and acetic anhydride (1 mL) was added. The resulting solid was collected by filtration and dried in vacuo to give a brown solid (0.15 g) in 36% yield. EXAMPLE 101 Preparation of 1ST- (2.3 -di oyo-2.3.4.7 ft Q-heyahydro- 1 H- oyolopent Ff1 quinoxal in-8-yl ) -acetamide
Figure imgf000092_0001
N- (5-Bromo-2,3-dioxo-2, 3,4,7,8, 9-hexahydro-lH- cyclopenta [f] quinoxalin- 8 -yl) -acetamide (1 g, 3 mmol) was dissolved in dimethylformamide (75 mL) and treated with potassium acetate (0.33 g) and 20% palladium on carbon (0.2 g) and shaken on a Parr apparatus under a hydrogen atmosphere (51 psi) for 7 min. The catalyst was removed by filtration, the filtrate evaporated and the residue triturated in water. The resulting solid was collected by filtration and dried in vacuo to give the debrominated product (0.75 g) in 98% yield. Analysis Calculated for ^3^3^03 • 1.7 H20 : C, 53.85; H, 5.70; N, 14.49. Found: C, 53.87; H, 5.04; N, 14.15.
EXAMPLE 102
Preparation of N- ( fi-ni tro-2 f 3 -d oyo-2 , , , 7 , ft , 9- hexahydro-IH-cyclopent ff1 quinoxal in-8-yl ) -acetamide
Figure imgf000092_0002
A mixture of N- (2 , 3-dioxo-2 , 3 , 4 , 7, 8 , 9-hexahydro- lH-cyclopenta [f] quinoxalin-8 -yl) -acetamide (0.15 g, 0.6 mmol), potassium nitrate (0.07 g, 0.7 mmol), and sulfuric acid (5 mL) was stirred at room temperature for 3 hours. After pouring onto ice, the aqueous solution was saturated with sodium chloride and allowed to stand overnight. The resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give a solid (35 mg, 19% yield) . Analysis Calculated for
Figure imgf000093_0001
• 0.75 NaCl: C, 44.85; H, 3.47; N, 16.09. Found: C, 45.18; H, 3.87; N, 15.87.
Example 103
Preparation of fi-ami o- , 7 , ft , -te ahydro-1 H- cyclopent IT1 quinoxal i ne-2 , 3-dione hydrochl ri de
Figure imgf000093_0002
N- (2,3-Dioxo-2, 3,4,7,8, 9-hexahydro-lH- cyclopenta [f] quinoxalin-8-yl) -acetamide (0.5 g, 1.9 mmol) was stirred in 2 N HCI (20 mL) at reflux for 72 hours. The solid was collected by filtration and dried in vacuo to give the product (0.4 g, 83% yield) .
Other variations and modifications of this invention will be obvious to those skilled in this art. This invention is not to be limited except as set forth in the following claims.

Claims

1. A compound represented by the formula (I) :
Figure imgf000094_0001
or a pharmaceutically acceptable salt thereof wherein
Z is a carbocyclic fused ring having 5 to 7 carbon atoms ;
X and Y are independently hydrogen, halogen, nitro, cyano, -CF3, -COOH, -CONR1R2, -COR3, -S02R , imidazolyl or imidazolidinyl , wherein R 1 and R7 are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl, aralkyl or join together to form a
3 heterocyclic ring and wherein R is alkyl, haloalkyl, cycloalkyl, aryl or aralkyl;
A is a bond, O, S, NR4, NR4C0, NR4CS, CONR4,
CSNR4, CO or CS wherein R4 is hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl, aralkyl or when n = 0 then R and B may join together to form a heterocyclic ring;
B is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, R5, CN, COR5, P03R5 2, S02R5, or heterocyclic, wherein R is hydroxy, alkoxy, aralkoxy, aryloxy or NR 1-'-R7 ; and m and n are independently 0, 1 and 2, provided that (i) m is not O when A is 0, CN, tetrazole or CO, except when A is CO and B is a heterocyclic or when A is O and B is COR5, P03R5 2 or
S02R5; (ii) m is not O or 1 when A is NR , except when B is COR5, P03R5 2 or S02R5; and (iii) n is not O when A is 0, S, NR4 , CONR4 and B is NR^2, CN, COR5 or P03R5 2.
2. A compound according to Claim 1, wherein Z is a cyclopentyl fused ring or cyclohexyl fused ring, and X and Y are independently hydrogen, nitro or halogen.
3. A compound according to Claim 2, wherein A is a bond, NR4 , NR4C0 or CO, R4 is hydrogen or alkyl having 1 to 6 carbon atoms and m is 0 or 1.
4. A compound according to Claim 3, wherein B is COR5, CN, P03R5 2 or heterocylic.
5. A compound according to Claim 4, wherein X is nitro.
6. A compound according to Claim 5, wherein the B is a heterocyclic selected from the group consisting of the formulae:
Figure imgf000096_0003
Figure imgf000096_0001
7. A compound selected from the group consisting of:
Figure imgf000096_0002
■95-
Figure imgf000097_0001
15
Figure imgf000097_0002
25
Figure imgf000098_0003
Figure imgf000098_0001
Figure imgf000098_0002
Figure imgf000099_0001
Figure imgf000099_0002
Figure imgf000099_0004
Figure imgf000099_0003
Figure imgf000099_0005
Figure imgf000100_0001
Figure imgf000100_0002
Figure imgf000101_0001
or a pharmaceutically acceptable salt thereof,
8. A pharmaceutical composition useful for treating disorders responsive to the blockade of aspartate, glutamate or kainate receptors such as epilepsy, anxiety, schizophrenia, depression, neuropathic pain, central nervous systems degenerative disorders, cerebral hypoxia/ischemic conditions or stress related psychiatric disorders, said composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of at least one compound of Claim 1.
9. A method for treating disorders responsive to the blockade of aspartate, glutamate or kainate receptors in a human suffering thereof which comprises administering at least one compound of Claim 1 in unit dosage form.
10. A method for treating anxiety which comprises adminstering at least one compound of Claim 1 in unit dosage form.
11. A method for treating cerebral hypoxy/ ischemia which comprises administering at least one compound of Claim 1 in unit dosage form.
12. A method for treating Parkinsonism which comprises administering at least one compound of Claim 1 in unit dosage form.
13. A method for treating disorders responsive to anticonvulsants in a human suffering thereof which comprises administering at least one compound of Claim 1 in unit dosage form.
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