| PATENT ASSIGNEE'S COUNTRY | USA |
| UPDATE | 08.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 29.08.00 |
| PATENT TITLE |
Cyclic amine derivatives of substituted quinoxaline 2,3-diones as glutamate receptor antagonists |
| PATENT ABSTRACT |
A novel series of substituted quinoxaline 2,3-diones useful as neuroprotective agents are taught. Novel intermediates, processes of preparation, and pharmaceutical compositions containing the compounds are also taught. The compounds are glutamate antagonists and are useful in the treatment of stroke, cerebral ischemia, or cerebral infarction resulting from thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia, seizure disorders, pain, Alzheimer's, Parkinson's, and Huntington's Diseases. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 19.03.99 |
| PATENT REFERENCES CITED |
C.F. Bigge, and T.C. Malone, "Agonists, Antagonists and Modulators of the N-methyl-D-aspartic acid (NMDA) and .sub.I -amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) Subtypes of Glutamate Receptors", Current Opinion in Therapeutic Patents, 1993, pp 951-989. M. Rogawski, "Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines", TiPS, vol. 14, 1993, pp 325-331. H. Li and A.M. Buchan, "Treatment with an AMPA Antagonist 12 Hours Following Severe Normothermic Forebrain Ischemia Prevents CA.sub.1 Neuronal Injury", Journal of Cerebral Blood Flow and Metabolism, vol. 13, No. 6, 1993, pp 933-939. B. Nellg.ang.rd and T. Wieloch, "Postischemic Blockade of AMPA but not NMDA Receptors Mitigates Neuronal Damage in the Rat Brain Following Transient Severe Cerebral Ischemia", Journal of Cerebral Blood Flow and Metabolism, vol. 12, No. 1, 1992, pp 2-11. R. Bullock et al., "Neuroprotective Effect of the AMPA Receptor Antagonist LY-293558 in Focal Cerebral Ischemia", Journal of Cerebral Blood Flow and Metabolism, vol. 14, No. 3, 1994, pp 466-471. D. Xue et al., "Delayed Treatment with AMPA, but Not NMDA, Antagonists Reduces Neocortical Infarction", Journal of Cerebral Blood Flow and Metabolism, vol. 14, No. 2, 1994, pp 251-261. X.-J. Xu et al., "Systemic Excitatory Amino Acid Receptor Antagonists of the .sub.I- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor and of the N-methyl-D-aspartate (NMDA) Receptor Relieve Mechanical Hypersensitives After Transient Spinal Cord Ischemia in Rats", The Journal of Pharmacology and Experimental Therapeutics, vol. 267, No. 1, 1993, pp 140-144. T. Namba et al., "Antiepileptic and anticonvulsant effects of NBQX, a selective AMPA receptor antagonist, in the rat kindling model of epilepsy", Brain Research, vol. 638, 1994, pp 36-44. S.E. Browne and J. McCulloch, "AMPA receptor antagonists and local cerebral glucose utilization in the rat", Brain Research, vol. 641, 1994, pp 10-20. S. Yamaguchi et al., "Anticonvulsant activity of AMPA/kainate antagonists: comparison of GYKI 52466 and NBQX in maximal electroshock and chemoconvulsant seizure models", Epilepsy Research, vol. 15, 1993, pp 179-184. S. Smith et al., "The non-N-methyl-D-aspartate receptor antagonists, BYKI 52466 and NBQX are anticonvulsant in two animal models of reflex epilepsy", European Journal of Pharmacology, vol. 201, 1991, pp 179-183. T. Klockgether et al., "The AMPA Receptor Antagonist NMQX Has Antiparkinsonian Effects in Monoamine-depleted Rats and MPTP-treated Monkeys", Annals of Neurology, vol. 30, No. 5, 1991, pp 717-723. T. Klockgether and L. Turski, "Toward and Understanding of the Role of Glutamate in Experimental Parkinsonism: Agonist-Sensitive Sites in the Basal Ganglia", Annals of Neurology, vol. 34, No. 4, 1993, pp 585-593. P. Francis et al., "Cortical Pyramidal Neurone Loss May Cause Glutamatergic Hypoactivity and Cognitive Impairment in Alzheimer's Disease: Investigative and Therapeutic Perspectives", Journal of Neurochemistry, vol. 60, No. 5, 1993, pp 1589-1604. S. Lipton, "Prospects for clinically tolerated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide", TINS, vol. 16, No. 12, 1993, pp 527-532. S. Lipton and P. Rosenberg, "Excitatory Amino Acids as a Final Common Pathway for Neurologic Disorders", Review Article in Mechanism of Disease, F. Epstein, Editor, vol. 330, No. 9, 1993, pp 613-622. C. Bigge, "Structural Requirements for the Development of Potent N-methyl-D-aspartic Acid (NMDA) Receptor Antagonists", Biochemical Pharmacology, vol. 45, No. 8, 1993, pp 1547-1561. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
N-Me-N-(6-methyl-7-nitro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxa lin-5-ylmethyl)-methanesulfonamide |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION This invention is for novel glutamate receptor antagonists which are new compounds of the 5,6,7,8-substituted quinoxaline 2,3-diones type. The fused ring system is substituted at the a or b position by amino acid derivatives. The compounds are active as excitatory amino acid receptor antagonists acting at glutamate receptors, including either or both N-methyl-D-aspartate (NMDA) receptors and non-NMDA receptors such as the .alpha.-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor and the kainate receptor. The invention also relates to the use of those quinoxaline-2,3-diones 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 Alzheimer's Disease, Parkinsonism, and Huntington's Disease, and seizure disorders and pain. Therefore, the compounds of the present invention may also be useful in the treatment of schizophrenia, epilepsy, anxiety, pain, and drug addiction. 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 acids (EAA) glutamate and aspartate at the N-methyl-D-aspartate (NMDA) receptor, the .alpha.-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, and the kainate receptor. AMPA/kainate receptors may be referred to jointly as non-NMDA receptors. This excitotoxic action is considered 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 vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma, as well as lathyrism, Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease. Several classes of quinoxalinedione derivatives have been disclosed as glutamate (EAA) receptor antagonists. For example, among excitatory amino acid receptor antagonists recognized for usefulness in the treatment of disorders are those that block AMPA receptors (Bigge C. F. and Malone T. C., Curr. Opin. Ther. Pat., 1993:951; Rogawski M. A., TiPS, 1993;14:325). AMPA receptor antagonists have prevented neuronal injury in several models of global cerebral ischemia (Li H. and Buchan A. M., J. Cerebr. Blood Flow Metab., 1993;13:933; Nellgard B. and Wieloch T., J. Cerebr. Blood Flow Metab., 1992;12:2) and focal cerebral ischemia (Bullock R., Graham D. I., Swanson S., McCulloch J., J. Cerebr. Blood Flow Metab., 1994;14:466; Xue D., Huang Z.-G., Barnes K., Lesiuk H. J., Smith K. E., Buchan A. M., J. Cerebr. Blood Flow Metab., 1994;14:251). AMPA antagonists have also shown efficacy in models for analgesia (Xu X.-J., Hao J.-X, Seiger A., Wiesenfeld-Hallin Z., J. Pharmacol. Exp. Ther., 1993;267:140), and epilepsy (Namba T., Morimoto K., Sato K., Yamada N., Kuroda S., Brain Res., 1994;638:36; Brown S. E., McCulloch J., Brain Res., 1994;641:10; Yamaguchi S. I., Donevan S. D., Rogawski M. A., Epilepsy Res., 1993;15:179; Smith S. E., Durmuller N., Meldrum B. S., Eur. J. Pharmacol., 1991;201:179). AMPA receptor antagonists have also demonstrated promise in chronic neurodegenerative disorders such as Parkinsonism (Klockgether T., Turski L., Honore T., Zhang Z., Gash D. M., Kurlan R., Greenamyre J. T., Ann. Neurol., 1993;34(4):585-593). Excitatory amino acid receptor antagonists that block NMDA receptors are also recognized for usefulness in the treatment of disorders. NMDA receptors are intimately involved in the phenomenon of excitotoxicity, which may be a critical determinant of outcome of several neurological disorders. Disorders known to be responsive to blockade of the NMDA receptor include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, neuropathic pain, and anxiety, and may be a significant causal factor in chronic neurodegenerative disorders such as Parkinson's Disease (Klockgether T., Turski L., Ann. Neurol., 1993;34:585-593), human immunodeficiency virus (HIV) related neuronal injury, amyotrophic lateral sclerosis (ALS), Alzheimer's Disease (Francis P. T., Sims N. R., Procter A. W., Bowen D. M., J. Neurochem., 1993;60(5):1589-1604), and Huntington's Disease. (See Lipton S., TINS, 1993;16(12):527-532; Lipton S. A., Rosenberg P. A., New Eng. J. Med., 1994;330(9):613-622; and Bigge C. F., Biochem. Pharmacol., 1993;45:1547-1561 and references cited therein.) NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control withdrawal symptoms from addictive drugs (Eur. Pat. Appl. 488,959A). Copending U.S. Ser. No. 08/124,770 discloses glutamate receptor antagonist quinoxalinedione derivatives represented by the formula: ##STR1## wherein A is a 5 to 7 atom containing ring having a nitrogen which may be substituted by hydrogen, alkyl, or CH.sub.2 CH.sub.2 OH. This application does not disclose or suggest compounds having the instant amino as substituents, or the requisite methodology to prepare the same. Copending application U.S. Ser. No. 08/404,400 teaches glutamate receptor antagonists which are quinoxalinediones of formula ##STR2## or a pharmaceutically acceptable salt thereof wherein R.sub.1 is hydrogen, an alkyl, or an alkylaryl; X and Y are independently hydrogen, halogen, nitro, cyano, trifluoromethyl, COOH, CONR.sub.4 R.sub.5, SO.sub.2 CF.sub.3, SO.sub.2 R.sub.4, SONR.sub.4 R.sub.5, alkyl, alkenyl, (CH.sub.2).sub.z CONR.sub.4 R.sub.5, (CH.sub.2).sub.z COOR.sub.4, or NHCOR.sub.4, wherein R.sub.4 and R.sub.5 are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl, or alkylaryl, and z is an integer from 0 to 4; R.sub.2 is alkylCOOR.sub.3, alkylamine, alkylquanidine, aryl, alkylaryl, COalkyl, COalkylaryl, CONR.sub.3 alkyl, CONR.sub.3 aryl, CONR.sub.3 alkylaryl, CSNR.sub.3 alkyl, CSNR.sub.3 alkylaryl or a common amino acid moiety joined by an amide bond, wherein R.sub.3 is hydrogen, alkyl, or alkylaryl; and m and n are independently 0, 1, or 2 provided that m+n is >1. This application does not disclose or suggest the compounds of the instant invention having cyclic amines as substituents at the a- or b-positions nor the methodology to prepare them. JP06228112-A discloses glutamate receptor antagonists which are quinoxaline-2,3(1H,4H)-dione derivatives of formula ##STR3## wherein R.sub.1 is H, NO.sub.2, or CF.sub.3 ; Ring A is a nitrogen-containing saturated heterocyclic group which may contain sulfur or oxygen; R.sub.2 is H, OH, lower alkoxy, COOH, lower alkoxy carbonyl, NH.sub.2, or lower alkoxy carbonyl-amino. This reference does not teach or suggest the instant compounds which must be attached to the quinoxaline dione fused ring system by an alkylene. WO 93/08188 covers a tricyclic quinoxalinedione of formula ##STR4## as useful or selective antagonists of glutamate receptors. European Patent Application 0627434 covers tricyclic quinoxalinedione of Formula I below which are selective antagonists of glycine binding site of the NMDA receptor ##STR5## wherein X represents hydrogen, alkyl, halogen, cyano, trifluoromethyl, or nitro; R.sub.1 represents hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl; G represents --CONR.sub.2 -- or --NR.sub.2 CO--, wherein R.sub.2 represents hydrogen or alkyl; J represents an acidic group or a group which is convertible thereto in vivo; E represents a basic group or a group which is convertible thereto in vivo; Y represents a single bond, alkylene, alkenylene, substituted alkylene, or Y.sub.1 --Q--Y.sub.2, wherein Y.sub.1 represents a single bond or alkylene, Y.sub.2 represents alkylene, and Q represents a heteroatom selected from oxygen or sulfur; and Z represents alkylene. WO 94/26747 discloses compounds of Formula I below as useful in the treatment of cerebrovascular disorder ##STR6## wherein R.sub.1 is hydrogen, alkyl or benzyl; X is O or NOR.sub.2, wherein R.sub.2 is hydrogen, alkyl, or benzyl; Y is N--R.sub.4, wherein R.sub.4 is hydrogen, OH, or alkyl; n is 0 or 1; R.sub.6 is phenyl, naphthyl, thienyl, pyridyl, all of which may be substituted one or more times with substituents selected from the group consisting of halogen; CF.sub.3, NO.sub.2, amino, alkyl, alkoxy, and phenyl; and A is a ring of 5 to 7 atoms fused with the benzo ring at the positions marked a and b. The compounds of the instant invention differ from the art in that they provide noncoplanar compounds with greater solubility and, therefore, better ability to penetrate the blood-brain barrier. These are important attributes in pharmaceuticals. An object of this invention is to provide novel quinoxalinediones with cyclic amines at the a- or b-positions which function as antagonists. SUMMARY OF THE INVENTION The present invention is directed to compounds represented by Formula I: ##STR7## or a pharmaceutically acceptable salt thereof wherein R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and n are as described below. 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 (such as the .alpha.-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 the treatment of epilepsy. The invention further relates to a method of treating cerebrovascular disorders responsive to antagonism of glutamate receptors NMDA by administering a compound of above-defined Formula I in a unit dosage form. Another object of this invention is to provide a method of treating disorders responsive to the antagonism of glutamate or aspartate receptors in a human by administering a pharmaceutically effective amount of the 2,3-quinoxalinediones of this invention. Another object of this invention is to provide novel methods of preparing the 2,3-quinoxalinediones. A further object of this invention is directed to novel intermediates useful in the preparation of the 2,3-quinoxalinediones of this invention. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1. Maximal Electroshock Time Course with Compound 1, Compound 2, and PNQX is 1,4,7,8,9,10-hexahydro-7-methyl-6-nitro-pyrido[3,4-f]quinoxaline-2,3-dione in Mice IV FIG. 2. Maximal Electroshock Dose-Response with PNQX, Compounds 4 and 1 in Mice IV DETAILED DESCRIPTION OF THE INVENTION The substituted quinoxaline-2,3-diones of the instant invention are those of Formula I ##STR8## or a pharmaceutically acceptable salt thereof wherein R is a cyclic amine; n is an integer of from 1 to 4; R.sub.1 is hydrogen, alkyl, aralkyl, carboxyalkyl, phosphoroalkyl, or phosphonoalkyl; R.sub.2 is hydrogen, hydroxy, or amino; R.sub.3 and R.sub.4 are each independently hydrogen, alkyl, cycloalkyl, alkenyl, halogen, haloalkyl, nitro, cyano, SO.sub.2 CF.sub.3, CH.sub.2 SO.sub.2 R.sub.6, (CH.sub.2).sub.m CO.sub.2 R.sub.6, (CH.sub.2).sub.m CONR.sub.7 R.sub.8, (CH.sub.2).sub.m SO.sub.2 NR.sub.7 R.sub.8, or NHCOR.sub.6 wherein m is an integer of from 0 to 4, and R.sub.6, R.sub.7, and R.sub.8 are each independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl; R.sub.5 is hydrogen, alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, aryl, aralkyl, heteroaryl, nitro, cyano, SO.sub.2 CF.sub.3, (CH.sub.2).sub.m CO.sub.2 R.sub.9, (CH.sub.2).sub.m CONR.sub.9 R.sub.10, SONR.sub.9 R.sub.10, or NHCOR.sub.9 ; m is an integer of from 0 to 4; R.sub.9 and R.sub.10 are each independently hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl; and R.sub.5 may be at the a-position and R--(CH.sub.2).sub.n -- at the b-position on the ring. Preferred compounds are those of Formula I wherein R is a mono- or bi-cyclic ring unsubstituted or substituted by from 1 to 4 substituents, R is attached to the quinoxaline ring through N(--CH.sub.2).sub.n and at the a- or b-position and R is ##STR9## of from 4 to 7 atoms or ##STR10## of from 8 to 12 atoms wherein R.sub.11 is from 1 to 4 substituents independently selected from hydrogen, hydroxy, hydroxyalkyl, alkyl, alkoxy, alkoxyalkyl, --NR.sub.13 R.sub.14, aminoalkyl, alkenyl, alkynyl, thiol, thioalkyl, alkylthioalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, --SO.sub.2 R.sub.15, --SO.sub.2 NR.sub.13 R.sub.14, --(CH.sub.2).sub.n SO.sub.2 NR.sub.13 R.sub.14, and --(CH.sub.2).sub.n SO.sub.2 R.sub.15 ; wherein R.sub.13 and R.sub.14 are independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, and aryl; R.sub.15 is hydroxy, alkoxy, --NR.sub.13 R.sub.14, or haloalkyl; R.sub.11 may be 2 substituents attached at the same carbon; X and Y are each independently carbon which is substituted by hydrogen, halogen, haloalkyl, alkyl, alkoxy, alkoxyalkyl, NR.sub.13 R.sub.14, aminoalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, hydroxy, and hydroxyalkyl, --O--, --S--, --SO--, --SO.sub.2 --, --NR.sub.16 --, wherein R.sub.16 is alkyl, hydrogen, aralkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, --C(O)OR.sub.17, --C(O)R.sub.17, --SO.sub.2 R.sub.18, --SO.sub.2 NR.sub.19 R.sub.20, --CH.sub.2 SO.sub.2 R.sub.18, --CH.sub.2 SO.sub.2 NR.sub.19 R.sub.20, wherein R.sub.17 is alkyl, aralkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R.sub.18 is alkyl, aralkyl, hydroxyl, or alkoxy; R.sub.19 and R.sub.20 are each independently hydrogen and alkyl. Bicyclic structures encompassed in this invention include spiro ring structures, wherein both ends of a second ring are attached to the same carbon unit on the parent ring. For monocyclic and bicyclic structures wherein X or Y represent a carbon atom, the structure may also include an integral double bond. More preferred are those of Formula I wherein R is ##STR11## of from 4 to 7 atoms where X is carbon substituted by hydrogen, haloalkyl, alkyl, alkoxy, alkoxyalkyl, NR.sub.13 R.sub.14, aminoalkyl, cycloalkyl, heterocycloalkyl, hydroxy, and hydroxyalkyl, --O--, --NR.sub.16 --, and --C(O)--; R.sub.11 is absent, hydrogen, alkyl, alkoxy, alkoxyalkyl, NR.sub.13 R.sub.14, aminoalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, hydroxy, or hydroxyalkyl, R.sub.11 may also represent two independent alkyl substituents to form a gem-dialkyl arrangement, where X represents carbon, an integral double bond may be located between the C.sub.3 and C.sub.4 carbons of 5- to 7-membered rings. Still more preferred are those of Formula I wherein R is ##STR12## of from 4 to 7 atoms where X is carbon substituted by hydrogen, alkyl, NR.sub.13 R.sub.14, aminoalkyl, cycloalkyl, and heterocycloalkyl, --O--, --NR.sub.16 --, and --C(O)--; R.sup.11 is absent, hydrogen, hydroxy, hydroxyalkyl, alkyl, alkoxy, alkoxyalkyl, --NR.sub.13 R.sub.14, aminoalkyl, cycloalkyl, or heterocycloalkyl; R.sub.11 may also represent two independent alkyl substituents to form a gem-dialkyl arrangement, where X represents carbon, an integral double bond may be located between the C.sub.3 and C.sub.4 carbons of 5- to 7-membered rings. R.sub.1 is hydrogen; R.sub.2 is hydrogen or hydroxy; R.sub.3 and R.sub.4 are each independently hydrogen, alkyl, or nitro; R.sub.5 is hydrogen, alkyl, cycloalkyl, halo, or nitro. Most preferred are selected from 6-Methyl-5-pyrrolidin-1-ylmethyl-7-nitro-1,4-dihydroquinoxaline-2,3-dione, 6-Methyl-5-(2-methyl-pyrrolidin-1-ylmethyl)-7-nitro-1,4-dihydroquinoxaline- 2,3-dione, 5-(2,5-Dimethyl-pyrrolidin-1-ylmethyl)-6-methyl-7-nitro-1,4-dihydroquinoxal ine-2,3-dione, 6-Methyl-7-nitro-5-piperidin-1-ylmethyl-1,4-dihydroquinoxaline-2,3-dione, 6-Methyl-5-(2-methyl-piperidin-1-ylmethyl)-7-nitro-1,4-dihydroquinoxaline-2 ,3-dione, 6-Methyl-5-(4-methyl-piperidin-1-ylmethyl)-7-nitro-1,4-dihydroquinoxaline-2 ,3-dione, 5-(3,5-Dimethyl-piperidin-1-ylmethyl)-6-methyl-7-nitro-1,4-dihydroquinoxali ne-2,3-dione, 5-(3-Azaspiro[5.5]undec-3-ylmethyl)-6-methyl-7-nitro-1,4-dihydroquinoxaline -2,3-dione, 5-(1,4-Dioxa-8-azaspiro[4,5]dec-8-ylmethyl)-6-methyl-7-nitro-1,4-dihydroqui noxaline-2,3-dione, 6-Methyl-5-morpholin-4-ylmethyl-7-nitro-1,4-dihydroquinoxaline-2,3-dione, 6-Methyl-5-(4-methyl-piperazin-1-ylmethyl)-7-nitro-1,4-dihydroquinoxaline-2 ,3-dione, 5-Azepan-1-ylmethyl-6-methyl-7-nitro-1,4-dihydroqinoxaline-2,3-dione, 6-Methyl-7-nitro-5-(octahydroquinolin-1-ylmethyl)-1,4-dihydroquinoxaline-2, 3-dione, 6-Methyl-7-nitro-5-(octahydroisoquinolin-2-ylmethyl)-1,4-dihydroquinoxaline -2,3-dione, and 6-Chloro-7-nitro-5-piperidin-1-ylmethyl-1,4-dihydro-quinoxaline-2,3-dione sulfate salt. Other preferred compounds of the invention are those of Formula I wherein R is ##STR13## of from 8 to 12 atoms; X and Y are each independently as described above; R.sub.11 is absent, hydrogen, alkyl, alkoxy, alkoxyalkyl, NR.sub.13 R.sub.14, aminoalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, hydroxy, and hydroxyalkyl; R.sub.1 is hydrogen; R.sub.2 is hydrogen or hydroxy; R.sub.3 and R.sub.4 are each independently hydrogen, alkyl, and nitro; R.sub.5 is hydrogen, alkyl, cycloalkyl, halogen, and nitro. The compounds of Formula I are capable of further forming pharmaceutically acceptable acid addition salts. These forms are within the scope of the present invention. Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, isethionate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S. M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977;66:1-19). The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention. Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain of the compounds of the present invention may exist as a mixture of cis and trans isomers or as the individual cis and trans isomers or R and S stereoisomers. The mixture of isomers as well as the individual isomers are intended to be encompassed within the scope of the present invention. In the compounds of Formula I, the term "alkyl" means a straight or branched hydrocarbon radical having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. The term "carboxyalkyl" means alkyl as above and attached to a carboxy group. The term "phosphoroalkyl" means alkyl as above and attached to a phosphoro group. The term "phosphonoalkyl" means alkyl as above and attached to a phosphono group. The term "alkenyl" means a straight or branched unsaturated hydrocarbon radical having from 3 to 6 carbon atoms and includes, for example, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, and the like. Alkynyl means a straight or branched unsaturated hydrocarbon radical of from 2 to 6 carbon atoms and includes but is not limited to ethynyl, 2,3-propynyl, 1,2-propynyl, and 3,4-butynyl. "Alkoxy" is O-alkyl of from 1 to 6 carbon atoms as defined above for "alkyl". The term "aryl" means an aromatic radical which is a phenyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined above for alkyl, dialkylamino as defined for alkyl, or 1,3-benzodioxol-5-yl. The term "aralkyl" means aryl and alkyl as defined above and includes but is not limited to benzyl, 2-phenylethyl, and 3-phenylpropyl; a preferred group is phenyl. The term "heteroaryl" means a heteroaromatic radical which is 2-, 3-, or 4-pyridinyl, 2-, 4-, or 5-pyrimidinyl, 2- or 3-thienyl, isoquinolines, quinolines, imidazolines, pyrroles, indoles, and thiazoles. "Halogen" is fluorine, chlorine, bromine, or iodine. The term "haloalkyl" means halogen and alkyl as defined above, for example, but not limited to, trifluoromethyl and trichloromethyl. "Alkylaryl" means 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. The term "heterocycloalkyl" means a nonaromatic ring with from 4 to 7 members, with up to 4 heteroatoms for example, N, O, and S. Spiro rings include but are not limited to 5- to 7-membered carbocyclic or heterocyclic ring with up to 4 heteroatoms. R in Formula I may be defined as follows. These groups are merely illustrative of the invention. ##STR14## 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-isoxazolepropionic acid (or kainic acid) binding site on AMPA (non-NMDA) receptors or the glycine site of NMDA receptors. The compounds of the present invention exhibit binding affinity for the AMPA receptors measured as described in Honore T., et al., Neuroscience Letters, 1985;54:27-32. Preferred compounds demonstrate IC.sub.50 values <100 .mu.M in this assay. The compounds of the present invention exhibit binding affinity for the kainate site (non-NMDA receptor) measured as described in London E. D. and Coyle J., Mol. Pharmacol., 1979;15:492. The compounds of the present invention exhibit binding affinity for the glycine site of the NMDA receptor measured as described in Jones S. M., et al., Pharmacol. Methods, 1989;21:161. To measure functional 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. Neurosci, 1990;10:693. In addition, the neuronal damage produced by long-term exposure to 100 .mu.M AMPA may be measured by the release of the cytosolic enzyme lactate dehydrogenase (LDH). Selected compounds of the present invention were tested by one or more of the above-described assays. The data obtained in the assays is set forth in Tables 1-4 below. The IC.sub.50 values set forth in Tables 1-4 are a measure of the concentration (.mu.M) of the test substance which inhibits 50% of an induced release from the tested receptors. TABLE 1 |
| PATENT PHOTOCOPY | Available on request |
|
Want more information ? Interested in the hidden information ? Click here and do your request. |