NZ241986A - Imidazo(1,5-a)quinoxaline-1,3,(2h,5h)-dione derivatives - Google Patents

Description

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No.: Date: NEW ZEALAND PATENTS ACT, 1953 / 6A 'AR ipyj COMPLETE SPECIFICATION CERTAIN IMIDAZOQUINOXALINES; A NEW CLASS OF GABA BRAIN RECEPTOR LIGANDS We, NEUROGEN CORPORATION, a corporation organised and existing under the laws of the State of Delaware, United States of America, having a place of business at 35 N.E. Industrial Road, Branford, Connecticut 06405, United States of America, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- (followed by page la) BAfKGROrND OF THF INVENTION Field ol Ltif Invention This invention relates to certain imidazoquinoxalines which 10 selectively bind to GABAa receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating anxiety, sleep and seizure disorders, and overdoses of benzodiazepine-type drugs, and enhancing alertness. The interaction of imidazoquinoxalines of the invention with a 15 GABA binding site, the benzodiazepines (BDZ) receptor, is described. This interaction results in the pharmacological activities of these compounds.

Description of the Related All y-Aminobuty ric acid (GABA) is regarded as one of the major 20 inhibitory amino acid transmitters in the mammalian brain. Over 30 years have elapsed since us presence in the brain was demonstrated (Roberts &: Frankcl. J. Biol. Chem 187: 55-63. 1950; Udcnfriend. J. Biol. Chem. 187: 65-69. 1950). Sincc that time, an enormous amount of effort has been devoted to implicating GABA in the etiology of seizure disorders, sleep, anxiety and 25 cognition (Tallman and Gallager. Ann. Rev. Neuroscience £.: 21-44, 1985). Widely, although unequally, distributed through the mammalian brain. GABA is said to be a transmitter at approximately 30Tr of the synapses in the brain. In most regions of the brain, GABA is associated with local inhibitory neurons and only in two regions is GABA associated with longer projections. 30 GABA mediates many of its actions through a complex of proteins localized both on cell bodies and nerve endings; these are called GABAa receptors Postsynaptic responses to GABA arc mediated through alterations in chloride conductance that generally, although not invariably. lead to hyperpolarization of the cell. Recent investigations have indicated that the 35 complex of proteins associated with postsynaptic GABA responses is a major site of action for a number of structurally unrelated compounds capable ot modifying postsynaptic responses to GABA. Depending on the mode ot interaction, these compounds arc capable of producing a spectrum of activities (either sedative, anxiolytic, and anticonvulsant, or wakefulness. 40 seizures, and anxiety). 1,4-Benzodiazepmes continue to be among the most widely used drug^ in the world. Principal among the benzodiazepines marketed are chlordiazepoxide. diazepam, flurazepam. and triazolam. These compounds are widely used as anxiolytics, sedative-hypnotics, muscle relaxants, and 5 anticonvulsants. A number of these compounds are extremely potent drugs, such potency indicates a site of action with a high affinity and specificity for individual receptors. Early electrophysiological studies indicated that a major action of benzodiazepines was enhancement of GABAergic inhibition The benzodiazepines were capable of enhancing presynaptic inhibition of a 10 monosynaptic ventral root reflex, a GABA-mediated event (Schmidt et al.. 1967, Arch. Exp. Path. Pharmakol. 2 5 8: 69-82). All subsequent electrophysiological studies (reviewed in Tallman et al. 1980, Science 202:274-81. Haefley et al.. 1981. Handb. Exptl. Pharmacol, H; 95-102) have generally confirmed this finding, and by the mid-1970s, there was a general 15 consensus among electrophy siologists that the benzodiazepines could enhance the actions of GABA.

With the discovery of the "receptor" for the benzodiazepines and the subsequent definition of the nature of the interaction between GABA and the benzodiazepines, it appears that the bchaviorally important interactions 20 of the benzodiazepines with different neurotransmitter systems are due in a large part to the enhanced ability of GABA itself to modify these systems Each modified system, in turn, may be associated with the expression of a behavior.

Studies on the mechanistic nature of these interactions depended on 25 the demonstration of a high-affinity benzodiazepine binding site (receptor). Such a receptor is present in the CNS of all vertebrates phy logenetically newer than the boncy fishes (Squires & Braestrup 1977. Nature 1M: 732-34, Mohler & Okada. 1977, Science 12&: 854-51, Mohler & Okada, 1977. Br. J. Psychiatry 1 3 3: 261-68). By using tritiatcd diazepam, and a 30 variety of other compounds, it has been demonstrated that these benzodiazepine binding sites fulfill many of the criteria of pharmacological receptors; binding to these sites in vitro is rapid, reversible, stereospecific. and saturable. More importantly, highly significant correlations have been shown between the ability of benzodiazepines to displace diazepam from its 35 binding site and activity in a number of animal behavioral tests predictive of benzodiazepine potency (Braestrup & Squires 1978. Br. J. Psychiatry 133' 249-60. Mohlcr & Okada. 1977. Scicncc 121: 854-51. Mohler & Okada. 1977. Br J. Psychiatry 1 3 3: 261-68). The average therapeutic doses of these drugs in ? k i o 9 man also correlate with receptor potency (Tallnian et al. 1980. Science 2 0" 274-281 ).

In 1978, it became clear that GABA and related analogs could interact at the low affinity (1 mM) GABA binding site to enhance the binding of 5 benzodiazepines to the clonazepan-sensitive site (Tallman et al. 1978. Nature. 274; 383-85). This enhancement was caused by an increase in the affinity of the benzodiazepine binding site due to occupancy of the GABA site. The data were interpreted to mean that both GABA and benzodiazepine sites were allosterically linked in the membrane as part of a complex of proteins. For a 10 number of GABA analogs, the ability to enhance diazepam binding by 509c of maximum and the ability to inhibit the binding of GABA to brain membranes by 509c could be directly correlated. Enhancement of benzodiazepine binding by GABA agonists is blocked by the GABA receptor antagonisi( + ) bicuculline; the stereoisomer (-) bicuculline is much less 15 active (Tallman et al.. 1978. Nature. 27-4; 383-85).

Soon after the discovery of high affinity binding sites for the benzodiazepines, it was discovered that a triazolopyridazine could interact with benzodiazepine receptors in a number of regions of the brain in a manner consistent with receptor heterogeneity or negative cooperativity. 20 In these studies, Hill coefficients significantly less than one were observed in a number of brain regions, including cortex, hippocampus, and striatum. In ccrebellum. triazolopyridazine interacted with benzodiazepine sites with a Hill coefficient of 1 (Squires et al.. 1979. Pharma. Biochem. Behav. J_Q.: 825-30, Klepner et al. 1979, Pharmacol. Biochem. Behav. 1 1 : 457-62). Thus. 25 multiple benzodiazepine receptors were predicted in the cortex, hippocampus, striatum, but not in the cerebellum.

Based on these studies, extensive receptor autoradiographic localization studies were carried out at a light microscopic level. Although receptor heterogeneity has been demonstrated (Young & Kuhar 1980, J. 30 Pharmacol. Exp. Ther. 2 12: 337-46. Young el al.. 1981 J. Pharmacol Exp. ther 216: 425-430. Niehoff et al. 1982. J. Pharmacol. Exp. Ther. 22 1: 670-75). no simple correlation between localization of receptor subtypes and the behaviors associated with the region has emerged from the early studies. In addition, in the ccrcbellum. where one rcceptor was predicted from binding 35 studies, autoradiography revealed heterogeneity of receptors (Niehoff et al.. 1982, J. Pharmacol. Exp. Ther. 221: 670-75).

A physical basis for the differences in drug specificity for the two apparent subtypes of benzodiazepine sites has been demonstrated by 7 .< 1 G & fc i S* <v \t Sieghan & Karobath. 1980, Nature 2 86: 285-87. Using gel electrophoresis in the presence of sodium dodecyl sulfate, the presence of several molecular weight receptors for the benzodiazepines has been reported. The receptors were identified by the covalent incorporation of radioactive flunitrazepam, 5 a benzodiazepine which can covalently label all receptor types. The major labeled bands have moelcular weights of 50,000 to 53.000. 55.000, and 57,000 and the triazolopyridazines inhibit labeling of the slightly higher molecular weight forms (53.000. 55.000, 57.000) (Seighart et al. 1983, Eur. J. Pharmacol. M; 291-99).

At that lime, the possibility was raised that the multiple forms of the rcceptor represent "isoreccptors" or multiple allelic forms of the receptor (Tallman & Gallager 1985. Ann. Rev. Neurosci. &, 21-44). Although common for enzymes, genetically distinct forms of receptors have not generally been described. As we begin to study receptors using specific radioactive 15 probes and elcctrophorctic techniques, it is almost certain that isoreccptors will emerge as important in investigations of the etiology of psychiatric disorders in people.

The GABAa receptor subunns have been cloned from bovine and human cDNA libraries (Schoenficld et al., 1988: Duman et al.. 1989). A 20 number of distinct cDNAs were identified as subunits of the GABAa rcceptor complex by cloning and expression. These arc categorized into «, p, y, 5, 6. and provide a molecular basis for the GABAa receptor heterogeneity and distinctive regional pharmacology (Shivvcrs et al.. 1980; Levitan et al.. 1989). The y subunit appears to enable drugs like benzodiazepines to modify 2 5 the GABA responses (Pritchett et al.. 1989). The presence of low Hill coefficients in the binding of ligands to the GABAa receptor indicates unique profiles of subtype specific pharmacological action.

Drugs that interact at the GABAa receptor can possess a spectrum of pharmacological activities depending on their abilities to modify the actions 30 of GABA. For example, the beta-carbolines were first isolated based upon their ability to inhibit .competitively the binding of diazepam to its binding site (Nielsen et al., 1979. Life Sci ZL' 679-86). The receptor binding assay is not totally predictive about the biological activity of such compounds; agonists, partial agonists, inverse agonists, and antagonists can inhibit 3 5 binding. When the bcta-carboline structure was determined, it was possible to synthesize a number of analogs and test these compounds behaviorally. It was immediately realized that the beta-carbolines could antagonize the actions of diazepam behaviorally (Tenen & Hirsch, 1980. Nature 288: 609-10). ' .. 3 6 In addition to this antagonism, beta-carbolines possess intrinsic activity of their own opposite to that of the benzodiazepines: they become known as inverse agonists.

In addition, a number of other specific antagonists of the 5 benzodiazepine receptor were developed based on their ability to inhibit the binding of benzodiazepines. The best studied of these compounds is an imidazodiazepine, (Hunkeler et al., 1981. Nature 2 90: 514-516). This compound is a high affinity competitive inhibitor of benzodiazepine and beta-carboline binding and is capable of blocking the pharmacological 10 actions of both these classes of compounds. By itself, it possesses little intrinsic pharmacological activity in animals and humans (Hunkeler et al.. 1981. Nature 290: 514-16; Darragh et al.. 1983. Eur. J. Clin. Pharmacol. j_4: 569-70). When a radiolabeled form of this compound was studied (Mohler & Richards, 1981, Nature 294: 763-65), it was demonstrated that this compound 15 would interact with the same number of sites as the benzodiazepines and beta-carbolines. and that the interactions of these compounds were purely competitive. This compound is the ligand of choice for binding to GABAa receptors because it does not possess receptor subtype specificity and measures each state of the receptor.

The study of the interactions of a wide variety of compounds similar to the above has led to the categorizing of these compounds. Presently, those compounds possessing activity similar to the benzodiazepines are called agonists. Compounds possessing activity opposite to benzodiazepines are called inverse agonists, and the compounds blocking both types of 25 activity have been termed antagonists. This categorization has been developed to emphasize the fact that a wide variety of compounds can produce a spectrum of pharmacological effects, to indicate that compounds can interact at the same rcceptor to produce opposite effects, and to indicate that beta-carbolines and antagonists with intrinsic anxiogenic effects are 30 not synonymous. A biochemical test for the pharmacological and behavioral properties of compounds that interact with the benzodiazepine rcceptor continues to emphasize the interaction with the GABAergic system. In contrast to the benzodiazepines, which show an increase in their affinity due to GABA (Tallman et al., 1978, Nature 2 74: 383-85, Tallman et al., 1980. 35 Science 207: 274-81), compounds with antagonist properties show little GABA shift (i.e.. change in rcceptor affinity due to GABA) (Mohlcr & Richards 1981. Nature 294: 763-65). and the inverse agonists actually show a decrease in affinity due to GABA (Braestrup & Nielson 1981. Nature 294: 472-474). > '9 8 6 Thus. the GABA shift predicts generally the expected behavioral properties of the compounds.

Various compounds have been prepared as benzodiazepine agonists and antagonists. For example, U.S. Patents Nos. 4,312,870 and 4,713,383. and 5 European Patent Application EP 181.282 disclose assorted compounds useful in treating anxiety or depression. U.S. Patent No. 4.713.383 teaches compounds of the formula: wherein Rj = (un)substituted Ph, (dihydro)furanyl, tetrahydrofuranyl, (dihydro)thienyl, tetrahydrothienyl, pyranyl. ribofuranosyl, all C-attached; Rt = H, alkyl; X = O, S. R3N; R3 = H. alkenyl, alkynyl, C3.20 cycloalkyl, (un)substituted alkyl, aryl. aralkyl, where aryl is Ph, pyridinyl, thienyl, furanyl; ring A may be substituted by alkyl. alkoxy. halo, amino, alkylthio, etc.

European Patent Application EP 181,282 discloses compounds of the formula: wherein Rj = (substituted) Ph or heterocycle; R2 = H, alkyl, alkenyl. hydroxyalkyl. aralkyl. aralkenyl, aryl; R3 = H, alkyl, alkoxy, HO, halo, F3C. O3N, HtN. alkylthio, alkylsulfinyl, alkylsulfonyl, aralkoxy; X = O. S. NR4; and R4 = H, alkyl. aralkyl. cycloalkyl. alkenyl, alkynyl. aryl. (substituted) aminoaklyl. hydroxyalkyl. 2 4 19 8 6 U.S Patent No. 4,312,870 teaches compounds of formulas: n-n' n-n' It' R, . R/ R2 and 11 where Ph is 1,2-phenylene. unsubsiituted or substituted by up to 3 identical or different members selected from lower alkyk. lower alkoxy, lower alkylthio, hydroxy, halogeno. trifluoromethyl, nitro, amino, mono- or di-lower alkylamino, 10 cyano. carbamoyl and carboxy; R is unsubstituted or substituted phenyl as defined by H-Ph, pyridyl. lower alkylpvridyl, or halogenopyridyl; R) is hydrogen, lower alkyl or lower (hydroxy, dialkylamino or H-Ph) -alkyl; and Ri is hydrogen or lower alkyl alkyl; their 3-hydroxy-tautomers; lower alkanoyl, 15 carbamoyl, mono- or di-lower alkyl-carbamoyl derivatives of said (hydroxy or amino)-(phenyl or phenylcnc) compounds; and <y n-n H ii i where R" is hydrogen, alkyl or alkoxy with up to 4 carbon atoms each, hydroxy, fluoro. chloro, bromo, or trifluoromethyl; and R' is hydrogen, o- or m-fluoro; or it is p-fluoro when R" is chloro.

The compounds of the present invention differ from these compounds. These compounds are not imidazoquinoxalines and lack the various ring substituents of the compounds of the present invention. ^419 3 0 SI'MNlARV OF THF. INVENTION This invention provides novel compounds of Formula I which interact with a GABAa binding site, the benzodiazepine receptor.

The invention provides pharmaceutical compositions comprising compounds of Formula 1. The invention also provides compounds useful in enhancing alertness, treatment of seizure, anxiety, and sleep disorders, and treatment of benzodiazepine overdoses. Accordingly, a broad embodiment of the invention is directed to compounds of Formula I: W °v / r, N I and the pharmaceutical^ acceptablc non-toxic salts thereof wherein: R i and R4 are the same or different and represent hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; X is hydrogen, halogen, hydroxy, or amino: or mono- or dialkylamino where each alkyl is lower alkyl having 1-6 carbon atoms: W is phenyl, thienyl, or pyridyl. or phenyl, thienyl. or pyridyl. each of which may be mono or disubstituted with halogen, .hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; X 4 19 3 8 and R3 are the same or different and represent hydrogen, halogen, hydroxy, amino, 1-indanyl. 4-(thio)chromanyl, l-(1.2,3,4-tetrahydronaphthyl); 1-indanyl, 4-(thio)chromany 1, 1 -(1,2.3,4-tetrahydronaphthy 1), each of which is monosubstituted with halogen, straight or branched chain lower alkyl having 1-6, carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms: OR5. COR5, CO2R5. OCOR5. or R5. where R5 is hydrogen, phenyl, pyridyl. straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalky 1 or pyridylalkvl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; -CONR6R7 or -(CH2)nNR6R7 where n is 0, 1. or 2; R6 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms; R7 is hydrogen, phenyl, pyridyl. straight or branched chain lower alkyl having 1-6 carbon atoms, or phcnylalkyl or pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or NR6R7 forms a heterocyclic group which is morpholyl, pipcridyl, pyrrolidyl. or N-alkyl piperazyl; -NR8CO2R9 where Rs and R9 arc the same or different and represent hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or C(OH)Ri()R|l where Rjo and R1 1 are the same or different and represent straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms.

These compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, sleep, and seizure disorders, overdose with benzodiazepine drugs, and enhancement of memory. -) h. < BR1F.F DESCRIPTION OF THF. DRAWING Figures 1A-E show representative imidazoquinoxalines of the present invention. -1 ? nF.TAII F.D DF.SCRIPTION OF THE INVENTION The novel compounds encompassed by the instant invention can be described by the following general formula I: W ov Ri r in and pharmaceutical acceptable non-toxic salts thereof wherein: R i and R4 are the same or different and represent hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; X is hydrogen, halogen, hydroxy, or amino; or mono- or dialkylamino where each alkyl is lower alkyl having 1-6 carbon atoms; W is phenyl, thienyl, or pyridyl, or phenyl, thienyl. or pyridyl, each of which may be mono or disubstitutcd with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; Rt and R3 are the same or different and represent hydrogen, halogen. hydroxy. amino. 1-indanyl. 4-(thio)chromanyl, I -(1,2,3.4-tetrahydronaphthyl); 1 -indany 1. 4-(thio)chromanyl. 1 -(1. 2.3.4-let rah yd ronaphth> I >. each of which is monosubstituted with halogen, straight or branched chain lower alkyl having 1-6. carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon 5 atoms; OR5, COR5. CO2R5, OCOR5, or R5. where R5 is hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl 10 is straight or branched chain lower alkyl having 1-6 carbon atoms; -CONR6R7 or -(CH2)nNR6R7 where n is 0. 1. or 2; R6 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms; R7 is hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl .having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl is 20 straight or branched chain lower alkyl having 1-6 carbon atoms; or NR6R7 forms a heterocyclic group which is morpholyl. piperidyl. pyrrolidyl. or N-alkyl piperazyl; -NR8CO2R9 where Rg and R9 arc the same or different and represent hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or C(OH)Ri()Rii where Rio and R1 j are the same or different and represent straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon 35 atoms.

V ' 1 Q P5 •«*' 'V* In addition, the present invention encompasses compounds o! Formula II.

II whe re: Rj and R4 are the same or different and represent hydrogen, halogen or straight or branched chain lower alkyl having 1-6 carbon atoms; X is W is hydrogen, halogen, hydroxy, or amino; or mono- or dialkylamino where cach alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; phenyl or a phenyl group mono or disubstituted with halogen, hydroxy, amino, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms. •- ^ 8 The present invention also cncompases compounds of Formula 111. w H III where: W is phenyl or a phenyl group mono or disubstituled with halogen, hydroxy, amino, straight or branched chain lower alkyl 10 having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms.

The present invention also encompascs compounds of Formula IV: where: W is IV phenyl or a phenyl group mono or disubstituted with halogen, hydroxy, amino, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; and ? ■' ' Q B 6 and R3 are the same or different and represent hydrogen, halogen, hydroxy. amino, 1-indanyl, 4-(thio)chromanyl. 1 - (1,2.3.4-tetrahydronaphthyl); 1-indanyl. 4-(thio)chromanyI. 1 - (1,2.3.4-tetrahydronaphthyl). each of which is monosubstituted with halogen, straight or branched chain lower alkyl having 1-6. carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms: OR5. COR5. CO2R5. OCOR5, or R5. where R5 is hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; -CONR6R7 or -(Cl-b)nNR6R7 where n is 0, 1. or 2; R6 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms: R 7 is hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms: or NR6R7 forms a heterocyclic group which is morpholyl. piperidyI. pyrrolidyl. or N-alkyl piperazyl; -NR8CO2R9 where Rs and R9 arc the same or different and represent hydrogen, phenyl, pyridyl. straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or C(OH)RioRll where Rio and Rj 1 are the same or different and represent straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms. a '1 ' 9 b 5 Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic. formic, toluene sulfonic, hydroiodic, acetic and the like. Those skilled in the art will 5 recognize a wide variety of non-toxic pharmaceuticaily acceptable addition salts.

Representative compounds of the present invention, which are encompassed by Formula I. include, but are not limited to the compounds in • Figure I and their pharmaceuticaily acceptable salts. The present invention 10 also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will rccognizwe various synthetic methodologies which may be employed to prepare non-toxic pharmaceuticaily acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.

By lower alkyl in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as. for example, methyl, ethyl, propyl, isopropvl. n-butyl. sec-butyl, ten-butyl, peniyl, 2-pentyl. isopentyl, ncopentyl. hexyl, 2-hexyl, 3-hexyl, and 3-methylpeniyl.

By lower alkoxy in the present invention is meant straight or 20 branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy. propoxy. isopropoxy, n-butoxy, sec-butoxy, tert-butoxy. pentoxy. 2-pentyl. isopentoxy, neopentoxy, hexoxy. 2-hexoxy, 3-hexoxy. and 3-methylpcntoxy.

By halogen in the present invention is meant fluorine, bromine. 25 chlorine, and iodine.

By N-alkylpiperazyl in the invention is meant radicals of the formula: N N—R \ / where R is a straight or branched chain lower alkyl as defined above. By 4-(thio)chromanyl is meant a radical of the formula: CO r\ 4+ 9 Thc pharmaceutical utilitv ot" compounds ot" this invention arc indicated by the following assay for GABAa receptor activity.

Assays are carried out as described in Thomas and Tallman (J. Bio Chem. 156: 9838-9842 . J. Neurosci. 2.:433-440, 1983). Rat cortical tissue is 5 dissected and homogenized in 25 volumes (w/v) of 0.05 M Tris HCl buffer (pH 7.4 at 4°C). The tissue homogenaie is centrifuged in the cold (4°) at 20.000 x g for 20'. The supernatant is decanted and the pellet is rehomogenized in the same volume of buffer and again centrifuged at 20,000 x g. The supernatant is decanted and the pellet is frozen at -20°C 10 overnight. The pellet is then thawed and rehomogenized in 25 volume (original wt/vol) of buffer and the procedure is carried out twice. The pellet is finally resuspended in 50 volumes (w/vol of 0.05 M Tris HCl buffer (pH 7.4 at 40°C).

Incubations contain 100 fa 1 of tissue homogenaie, 100 n I ol 15 radioligand 0.5 nM (3 H-RO15-1 788 (3 H-Flumazenil] specific activity 80 Ci/mmolh drug or blocker and buffer to a total volume of 500 ja 1. Incubations are carried for 30 min at 4°C then arc rapidly filtered through GFB fillers to separate free and bound ligand. Filters are washed twicc with fresh 0.05 M Tris HCl buffer (pH 7.4 at 4°C) and counted in a liquid 20 scintillation counter. 1.0 niM diazepam is added to some tubes to determine nonspecific binding. Data arc collected in triplicate determinations, averaged and % inhibition of total specific binding is calculated. Total Specific Binding = Total - Nonspecific. In some cases, the amounts of unlabeled drugs is varied and total displacement curves of binding are 25 carried out. Data are converted to a form for the calculation of IC50 ar>d Hill Coefficient (nH). Data for the compounds of this invention arc listed in Table I.

TABLE I Compound Number1 ic^uM) 1 0.0095 3 0.015 4 0.0095 0.016 33 0.0024 'Compound numbers relate to compounds shown in Figure I.

Compounds 1. 3 and 4 are particularly preferred embodiments of the present invention.

Thc compounds of general formula I may be administered oraih. topically, parenterally, by inhalation or spray or rectaily in dosage unit formulations containing conventional non-toxic pharmaceuticaily acceptable carriers, adjuvants and vehicles. The term parenteral as used 5 herein includes subcutaneous injections, intravenous. intramuscular, intrastemal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general formula 1 and a pharmaceuticaily acceptable carrier. One or more compounds of general formula I may be present in association with one or more non-toxic 10 pharmaceuticaily acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general formula I may be in a form suitable for oral use. for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft 15 capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents. 20 coloring agents and preserving agents in order to provide pharmaceuticaily elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceuticaily acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate. 25 lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearaic. stearic acid or talc. The tablets may be uncoated or they may be coatcd by known techniques to delay disintegration 30 and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsulcs wherein the active ingredient is mixed with an inert solid diluent. 35 for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsulcs wherein the active ingredient is mixed with water or an oil medium, for example peanut oil. liquid paraffin or olive oil. • ■ (i " Q w-4 < Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents. for example sodium carboxymethylcellulose. methvlcellulose, hydro propylmethylcellulose. sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia: dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example 10 heptadecaethyleneoxycetanol. or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as poUoxyethylene sorbitol monooleate. or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may 15 also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil. for example arachis oil. olive oil. sesame oil or 20 coconut oil. or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cctyl alcohol. Sweetening agents such as those set forth above, and flavoring agents nvay be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as 25 ascorbic acid.

Dispcrsiblc powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and 30 suspending agents arc exemplified by those already mentioned above. Additional excipients. . for example sweetening, flavoring and coloring agents, may also be present Pharmaceutical compositions of the invention may also be in the form of oil-in-waier emulsions. The oily phase may be a vegetable oil. for 35 example olive oil or arachis oil. or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth. naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial r>:' 1 Q 8 6 esters derived from fatty acids and hexitol. anhydrides, for example sorbitan monoleate. and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitor or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be 10 formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and 15 solvents that may be employed are water. Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of 20 injectables.

The compounds of general formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the 25 rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

Compounds of general formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vchicle. Advantageously. 30 adjuvants such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the abovc-indicated conditions (about 0.5 mg to about 7 g per patient per day). The 35 amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will ?4198 generally contain between from about 1 mg to about 500 mg of an active ingredient.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the 5 activity of the specific compound employed, the age. body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

An illustration of the preparation of compounds of the present 10 invention is given in Scheme I and Scheme II. Those having skill in the an will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples.

Scheme 1 R4 H * **V C l" ! *7 NCO -24-Scheme II WNH, Et,N / DMF l, n T a, R4 RJ H whe re: Rl and R4 are the same or different and represent hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy haying 1-6 carbon atoms; X is hydrogen, halogen, hydroxy, or amino; or mono- or dialkylamino where each alkyl is lower alkyl having 1-6 carbon atoms; phenyl, thienyl. or pyridyl, or phenyl, thienyl. or pyridyl. each of which may be mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; and R3 are the same or different and represent hydrogen, halogen, hydroxy, amino, 1-indanyl. 4-(thio)chromany I, 1 - (1,2.3,4-tetrahydronaphthy 1): 1 -indanyl. 4-(thio)chromanyl, l-( 1,2.3.4-tetrahydronaphthyl), each of which is monosubstiluted with halogen, straight or branched chain lower alkyl having 1-6, carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; OR5, COR5. CO2R5. OCOR5, or R5, where R5 is hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; -CONR6R7 or -(CH2)nNR6R7 where n is 0. 1. or 2; R6 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms; R7 is hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or NR6R7 forms a heterocyclic group which is morpholyl. piperidyl. pyrrolidyl. or N-alkyl ; '19 8 -NRgC02R9 where R8 and R9 are the same or different and represent hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl is straight or branched chain 5 lower alkyl having 1-6 carbon atoms; or C(OH)RioRll where Rio and Rj 1 are the same or different and represent straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where each alkyl is 10 straight or branched chain lower alkyl having 1-6 carbon atoms.

In some cases protection of certain reactivc functionalities may be necessary to achieve some of the above transformations. In general the 15 need for such protecting groups will be obvious to those skilled in the art of organic synthesis as well as the conditions necessary to attach and remove such groups. £419 86 .->1.

EXAMPLE I To a solution of 2-Niirophenyl isocyanaie (3.34 g) in 100 mL of toluene was added aniline (2 g). The mixture was stirred at 20°C for 30 min. Hexane (300 mL) was added and the resulting solid was filtered and dried to yield N-(2-Nitrophenyl)-N'-phenyl-urca as a light yellow solid.

To a solution of Diethyl nitroterephthalate (17.9 g) in 300 mL ethanol 15 was added IN NaOH (70 mL) and stirred overnight. IN HCl (70 mL) was added and the reaction -was partitioned between methylene chloride (200 mL) and water (200 mL). The aqueous layer was extracted an additional three times. The combined organic extracts were dried and the solvent removed in vacuo to afford Ethy!-3-nitro-4-carboxybenzoate as a white solid. < s 1 EXAMPLE III H N H EtO. 0 To Diphenylphosphoryl azide (5.75 g) in anhydrous toluene (50 mL) at 100 °C under nitrogen was added dropwise a solution containing Ethyl-3-nitro-4-carboxybenzoate (5 g) and triethylamine (4 mL) in anhydrous toluene (50 mL). The mixture was stirred for 1 h followed by the addition of aniline (5 mL). and the reaction was allowed to cool to room temperature (40 10 min). Ethyl acetate (300 mL) was added and the solution was washed successively with IN HCl (300 mL), water (300 mL), IN NaOH (300 mL) and water (300 mL). The organic layer was dried and the solvent was removed in vacuo. To the resulting oil was added diethyl ether (50 mL), and the resulting solid was collected and dried yielding N-(2-Nitro-5-15 melhylphcnyl)-N'-phcnyl-urea as a white solid.

A solution containing N-(2-Nitrophcnyl)-N'-phcny 1-urea (5.76 g) and chloroacetyl chloride (40 mL) was refluxed under nitrogen for 30 min. After the excess chloroacetyl chloride was removed in vacuo, diethyl ether (50 mL) was added and the resulting solid was filtered and dried to yield N'-(2-25 chloroacetyl)-N-(2-nitrophenyl)-N'-phenyl-urea as a white solid.

EXAMPLE IV CI EXAMPLE V A solution of N'-(2-Chloroacetyl)-N-(2-nitrophenyl)-N"-phenyl-urea (3.7 g). dimeihylformamide (15 mL) and diisopropylethylamine (15 mL) was refluxed for 5 min. The hot mixture was allowed to cool to room temperature and precipitated by adding the mixture to 200 mL of water. The precipitate was collected and dried to yield l-(2-Nitrophenyl)-3-phenyl-imidazoline-2.4( 1 H.3H)-dione.

~\ EXAMPLE VI (Compound 1) To a solution of l-(2-Nitrophenyl)-3-phenyl-imidazoIine-2,4(lH.3H)-dionc (2.7 g) in anhydrous dimcthylformamide (2 mL) under nitrogen was added N.N-dimethylformamide dimethyl acetal (2.7 g). The reaction was stirred at 80°C for 2 h. and the solvent was removed in vacuo. To the 10 resulting oil was added iron powder (5 g) and acetic acid (250 mL). This mixture was carefully heated to reflux for 3 min followed by stirring the reaction for an additional 30 min. The heterogeneous mixture was diluted with 10% methanol-methylene chloride (200 mL) and filtered through silica gel using 10% methanol/methylene chloride as eluant. The solvent 15 was removed in vacuo and hot ethanol (200 mL) was added . To this mixture was added water (200 mL) and the resulting solid was filtered and washed successively with ethanol, ethyl acetate, diethyl ether and dried to yield 2-Phenyl-imidazo[ 1,5-a]quinoxaIine-1,3(2H.5H)-dionc as a yellow solid. (Compound 1) melting at 231-234°C.

EXAHPLE VII (Compound 2) To a solution containing 1-(2-Nitrophenyl)-3-(2-fluorophenyl)-imidazolinc-2,4( 1 H,3H)-dionc (1.18 g) in anhydrous methylene chloride (5 mL) under nitrogen was added tris(dimcthy lamino)methane (1 mL). The reaction was stirred at room temperature for 20 min and the solvent was 10 removed in vacuo. The resulting solid was dissolved in dimethylformamide (100 mL) and a slurry of Raney nickel (50% solution in water, 1 mL) was added. The mixture was hydrogenated at 50 psi for 45 min. After filtration through cclite. the solvent was concentrated in vacuo to 30 mL and water (50 mL) was added. The resulting solid was collected and washed successively 15 with ethanol, ethyl acetate and diethyl ether and air dried to yield 2-(2-Fluorophenyl)-imidazo[ 1,5.a)quinoxaline-1,3-(2H,5H)-dione as a yellow solid (Compound 2), m.p. 261-264°C.

EXAMPLE VIII OEt To a solution containing DMF (100 mL). PbO (15 mL) , 5% Pd-carbon (1.25 g) and l-(2-Nitrophcnyl)-3-(4-ethoxyphcnyl)-imidazoline-2.4(lH,3H)-dione (25 g) at 60°C. was added dropwise a solution containing sodium hypophosphite (15 g) in H2O (40 mL) . After 3 hours the mixture was cooled to room temperature, and filtered through celite. The filtrate was poured 10 into 500 mL of HoO and filtered and dried to yield l-(2-Aminophcnyl)-3-(4- ethoxyphenyl)-imidazo!ine-2.4(lH.3H)-dione.

Example IX OEt H (Compound 3) To l-(2-Aminophcnyl)-3-(4-ethoxyphenyl)-imidazoline-2.4(lH.3H)-dione (2 g) was added DMF (5 mL), acetic acid (5 mL) and N.N-dimethylformamide dimethyl acetal (5 mL) The reaction mixture was 20 heated to 60°C for 16 h, cooled and filtered. The resulting orange solid was washed with isopropanol and rccrystallized from acetic acid to give 2-(4-ethoxyphenyl)-imidazo[ l,5,a]quinoxaline-l,3(2H,5H)-dione. m.p. 268-269°C (Compound 3).

P 8 6 EXAMPLE X The following compounds were prepared essentially according to the procedures described in Examples VI, VII, and IX. 1. 2-(4-Methoxypheny!)-imidazo[ 1,5,a Jquinoxaline-1,3(2H,5H)-dione (Compound 4), m.p. 240-242°C. 2. 2-(4-Methylphenyl)-imidazo[ 1.5.a]quinoxaline-l ,3(2H.5H)-dione (Compound 5). m.p. 305-308°C. 3. 2-(4-Fluorophenyl)-imidazo[l,5,a]quinoxaline-1.3(2H,5H)-dione (Compound 6). m.p. 235-238°C. 4. 2-(2- Aminophenyl)-imidazo[l,5,a]quinoxaline-l,3(2H.5H)-dione (Compound 7), m.p.247-249°C . 2-(3-F1 uoropheny 1)-im idazo [ 1,5, a Jquinoxaline -1,3(2H.5H)-dionc (Compound 8). m.p. 265-266°C. 6. 2-(4-Chlorophcnyl)-imidazo[ 1,5.a Jquinoxaline -1,3(2H.5H)-dionc (Compound 9). m.p. 235-238°C. 7. 2-(3-Meihylphenyl)-imidazo[ 1,5,a Jquinoxaline -1,3(2H,5 H)-dione (Compound 10). m.p. 263-265°C. 8. 2-(2 -Fluoro-4-ethoxyphenyl)-imidazo[ 1.5. a Jquinoxaline - 1,3(2H.5H)-dione (Compound 11). m.p. 264-267°C. 9. 2-(3-Chlorophenyl)-imidazo[ 1.5. a Jquinoxaline-1,3 (2H,5H)-dionc (Compound 12). m.p.235-239°C. . 2-( 2-Mcthoxyphcnyl)-imidazo[ 1.5.a]quinoxaline-l ,3(2H,5H)-dione (Compound 13). m.p.270-272°C. 11. 2-(4-Ethylphenyl)-imidazo[I,5,a]quinoxaline-l ,3(2H,5H)-dione (Compound 14), m.p. 215-216°C. 12. 2-(2-Fluoro-4-methylphenyl)-imidazo[1.5.a]quinoxaline-1.3(2H.5Hj-dione (Compound 15). m.p. 280-284°C. 13. 2-(3-Methoxyphenyl)-imidazo[l,5.a]quinoxaline-1.3(2H.5H)-dione 5 (Compound 16), m.p.. 212-214°C. 14. 2-(3-Ethoxvphenyl)-imidazo[ 1,5.a]quinoxaline-l .3(2H.5H)-dione (Compound 17). m.p. 197-200°C. 15. 2-(4-n-PropyIoxyphenyl)-imidazo[ 1.5.a]quinoxaline -1,3(2H.5H)-dione (Compound 18). m.p. 182-185°C. 16. 2-(4-n-Butoxyphenyl)-imidazo[ 1.5. a Jquinoxaline-1,3(2H.5H)-dione (Compound 19). m.p. 155- 156°C. 17. 2-(4-Isopropoxyphenyl)-imida/o[ 1,5, a Jquinoxaline -1,3(2H.5H)-dione (Compound 20). m.p. I64-167°C. 18. 7-Chloro-2-(4-meihylphenyl)-imidazo[1.5.a]quinoxaline-1.3(2H.5H)-20 dione (Compound 21). m.p. 200-204°C. 19. 7.8-Dimethyl-2-(4-eihoxyphcnyl)-imidazo[ 1,5,a]quinoxaline-1,3(2H,5H)-dione (Compound 22). 20. 8-Mcthyl-2-phcnyl-i m idazo [ 1.5. ajquinox aline - 1.3(2H.5H)-dione (Compound 23), m.p. 240-244°C. 21. 8-Carboethoxy-2-(4-ethoxyphcnyl)-imidazo[1.5,a]quinoxaline-1.3-(2H,5H)-dione (Compound 24). 22. 7-Carbocthoxy-2r(4-cthoxyphenyl)-imidazo[l,5,a]quinoxalinc-l,3-(2H,5H)-dione (Compound 25). 23. 8-Bromo-2-(4-ethoxyphenyl)-imidazo[ 1,5.ajquinox aline -1.3(2H.5H)-35 dione (Compound 26). m.p. 152-155°C. 24. 2-(4-PropylphenyI)-imidazo[1.5.a]quinoxaline-1.3(2H.5H)-dione (Compound 27). m.p. 185-I86°C. <1' 19 8 6 . 7-Methyl-2-(4-ethoxyphenyI)-imidazo[1.5.a]quinoxaline-l,3(2H.5H)-dione (Compound 28), m.p. 200-203°C. 26. 2-(3-Bromo-4-ethoxyphenyl)-imidazo[l,5.a]quinoxaline-l,3(2H.5H)-dione (Compound 29). m.p. 147-150°C. 27. 2-( 3-Thieny l)-imidazo[ 1.5. a Jquinoxaline -1.3(2H.5H)-dione (Compound ). 28. 2-(2-Thienyl)-imidazo[ 1.5,a]quinoxaline-1.3(2H.5H)-dione (Compound 31). 29. 2-(4- Ace toxy phenyi)-imidazo[ 1,5,a]quinox aline-1.3(2 H,5H)-di one. (Compound 32), m.p. 210-211°C. ) 3 Example XI OMe Br . 0 ^ N N H (Compound 33) To a suspension of 2-(4-McthoxyphenyI)-imidazo[ 1,5,a]quinoxaline-1,3(2H.5H)-dione (100 mg) in anhydrous dioxane (4mL) was added bromine (200 mg). The reaction was stirred at 20° C for 15 min, and was then poured directly into boiling acetic acid (50 mL) containing zinc powder (500 mg). 10 The reaction was refluxed for 5 min and allowed to cool to room temperature. After dilution with 10% methanol/methylene chloridc (100 mL). the mixture was filtered through silica gel. the solvent was removed in vacuo, and the resulting solid was treated with boiling ethanol (25 mL) followed by dilution with water (100 mL). The mixture was cooled to 0°C and the solid was filtered 15 and dried to yield 8-Bromo-2-(4-methoxyphenyl)-imidazo[ 1,5,a]quinoxalinc-l,3(2H.5H)-dione (Compound 33) as a yellow solid, m.p.l54°(dcc).

Example XII The following compound was made essentially according to the procedure described in Example XI. 1. 8-Bromo-2-(3-bromo-4-ethoxyphenyl)-imidazo[1.5.a]quinoxaline-l,3(2H,5H)-dione (Compound 34). m.p. 146-149°C.

V 9 Example XIII OEt A solution containing 1-(2-Nitrophenyl)-3-(4-ethoxypheny 1) 5 imidazoline-2,4(lH,3H)-dione (5 g) in anhydrous THF (50 mL) was added dropwise over 30 min to a solution of 0.5 M LDA in THF (29 mL) at -78°C. After 20 min ethyl chloroformate (1.2 mL) in THF (5mL) was added in a single portion. The reaction was warmed to room temperature over 30 min and quenched with saturated ammonium chloridc solution. The reaction mixture 10 was partitioned between ethyl acetate and water, and the organic layer was dried, and the solvent was removed in vacuo. Column chromatography using silica gel with 507c ethyl acctatc/hcxanc as the eluent yielded 5-Carbocthoxy-l-(2-nitrophenyl)-3-(4-ethoxyphenyl)-imidazoline-2,4( 1 H,3H)-dionc.

Example XIV OEt 0 \—N r^T^OH H (Compound 35) To a suspension containing zinc dust (6 g) in acetic acid (250 ml) was added 5-Carboethoxy-l-(2-nitrophenyl)-3-(4-ethoxyphenyl)-imidazoline-2.4( 1 H.3H)-dione (2.5 g). The mixture was heated to reflux for 15 min. cooled to room temperature and filtered, the solvent was removed in vacuo, and the resulting solid was stirred with ethanol (50 mL) and filtered to yield 4-Hydroxy-2-(4-ethoxyphenyl)-imidazo[l,5,a]quinoxaline-1.3(2H,5H)-dione (Compound 35).

A solution of 4-Hydroxy-2-(4-ethoxyphenyl )-imidazo[ 1,5 .a] -quinoxaline-1,3(2H.5H)-dionc (3.2 g) in phosphorous oxychloride (40 mL) was refluxed for 16 h. The solvent was removed in vacuo and water (15 mL) was added. The pH was adjusted to 7.0 using ammonium hydroxide and the resulting solid was filtered and dried to yield 4-Chloro-2-(4-cthoxyphcnyI)-imidazo[l,5.a]quinoxalinc-1.3(2H.5H)-dione (Compound 36).

Example XV OEt H (Compound 36) o Example XVI OEt (Compound 37) A solution of THF (lOmL). ammonia (lOmL) and 4-Chloro-2-(4- ethoxy phcnyl)-imidazo[ 1,5,a]quinoxaline-1,3(2H,5H)-dionc (100 mg) was heated to 100° C in a scaled tube for 4 hours. After cooling to room temperature the solvent was removed in vacuo. The solid was slurried in 50% EtOH-H20 and filtered to yield 4-Amino-2-(4-ethoxyphenyl- imidazo[ 1,5.a]quinoxaline-1,3(2H.5H)-dionc (Compound 37).

Example XVII The following compounds were prepared essentially according to the procedure described in example XVI: 1. 4-Dimethylamino-2-(4-ethoxyphenvl)-imidazo[l,5.a]quinoxaline-1,3(2H.5H)-dione. (Compound 38). 2. 4-n-Propylamino-2-(4-ethoxyphenyl)-imidazo[l,5.a]quinoxaline-20 1,3(2H.5H)-dionc (Compound 39). 3. 4-N-Mcihylamino-2-(4-cihoxyphcnyl)-imidazo[1.5,a]quinoxalinc-1,3(2H.5H)-dionc (Compound 40). n 19 Example X V111 oh h 2-(4-Acetoxypheny I)-imidazo[ 1,5.a Jquinoxaline-1,3(2H,5H)-dione (250 5 mg) was added to an ethanol solution (50 mL) saturated with HCl. The solution was stirred for 2 hours and the solvent was removed in vacuo to yield 2-(4-Hydroxyphenyl)-imidazo[1.5.a]quinoxaline-1.3(2H.5H)-dione (Compound 41). m.p. 318-322°C.

Fsamplf XIX OEt ch3 (Compound 42) 2-(4-Ethoxyphenyl)-imidazo[1.5,a]quinoxaline-1,3(2H.5H)-dione (100 15 mg) was added to a solution of dimethylformamide dimethylacetal (10 mL) and DMF (5mL). and the rcaciion mixture was heated to 100°C for 4 h. The solution was cooled to room temperature and poured onto water (200 mL). The resulting precipitate was collected and dried to yield 5-N-Methyl-2-(4-ethoxyphenyl)-imidazo[ I.5.a]quinoxaline-l,3(2H.5H)-dione (Compound 42). 20 m.p. 263-266°C. ' 1 9 Fxample XX OEt (Compound 43) 2-(4-Ethoxyphenyl)-imidazo[ l,5,a]quinoxalinc-1.3(2H.5H)-dione was added to a solution of anhydrous DMF (5 mL) and potassium tcrt-butoxide (125 mg) at 50°C. After 5 min trimethylacety 1 chloride (150 mg) was added. The reaction was stirred for 15 min and then poured into water (25 mL). The 10 resulting precipitate was collected, washed with EtOH and dried to yield 3-Trimethylecetoxy-2-(4-ethoxyphenyl)-imidazo[1.5,a]quinoxalinc-1,3(2H.5H)-dione (Compound 43).

Example XXI The following compounds were prepared essentially according to the procedure described in Example XX: 1. 3-n-Propyloxy-2-(4-cthoxyphcnyl)-imidazo[l,5,a]quinoxaline-l(2H,5H)-one (Compound 44). 2. 5-Propionyl-2-(4-ethoxyphenyl)-imidazo[l,5.a]quinoxaIine-1,3(2H,5H)-dione (Compound 45).

The invention and the manner and process of making and using it. 25 are now described in such full, clear, concise and exact terms as to enable any person skilled in the an to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in 30 the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.

Claims (5)

WHAT WE CLAIM IS: 1. A compound of the formula I: W and the pharmaceuticaily acceptable non-toxic salts wherein: 10 Rj and R4 are the same or different and each represents hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; X is 15 hydrogen, halogen, hydroxy, or amino; or mono- or dialkylamino where cach alkyl is lower alkyl having 1-6 carbon atoms; W is 20 phenyl, thienyl, or pyridyl; or phenyl, thienyl, or pyridyl, cach of which may be mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, amino, mono or 25 dialkylamino where cach alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; R2 and R3 arc the same or different and each represents 30 hydrogen. halogen, hydroxy, amino, 1-indanyl, 4-(thio)chromanyl, 1 - (1,2,3.4-tctrahydronaphlhyl); -43- 24 1 9 6 10 15 20 25 30 1 -indanyl. 4-( thio)chromanyl. l-( 1.2,3,4-ietrahydronaphthy I), cach of which is monosubstiiutcd with halogen, straight or branched chain lower alkyl having 1-6, carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms: OR5, COR5. CO2R5. OCOR5, or R5. where R5 is hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; -CONR6R7 or -(CH2)nNR<jR7 where n is 0, 1, or 2: R<5 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms; R7 is hydrogen, phenyl, pyridyl. straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where cach alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or NR6R7 forms a heterocyclic group which is morpholyl, piperidyl. pyrrolidyl, or N-alkyl piperazyl; -NR8CO2R9 where Rg and R9 arc the same or different and cach represents hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where cach alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or C(OH)RiqRii where Rjq and R[ j are the same or dilTcrcnt and cach represents straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where cach alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms. 1 A compound according to claim 1. which is 5 where: R ] and R4 are the same or different and cach represents hydrogen, halogen or straight or branched chain lower alkyl having 1-6 carbon atoms; X is hydrogen, halogen, hydroxy, or amino; or 15 20 W is mono- or dialkylamino where cach alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; phenyl or a phenyl group mono or disubstituted with halogen, hydroxy, amino, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms. 2S 30 3. A compound according to claim 1, which is: where: W is t W ^ Q :K *25 ntf®95 phenyl or a phenyl group mono or disubstituted with halogen, hydroxy, amino, straight or branched chain lower alkyl -45- V 1 S 3 6 having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms. 4. A compound according to claim 1. which is: whe re: 15 W is phenyl or a phenyl group mono or disubstituted with halogen, hydroxy, amino, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; and R2 and R3 are the same or different and cach represents hydrogen. halogen, hydroxy, amino, 1-indanyl, 4-(thio)chromanyl. l-( 1,2,3.4-tetrahydronaphthyl); 20 25 30

1-indanyl, 4-(thio)chromanyl, l-( 1,2,3,4-tctrahydronaphthyI), each of which is monosubstitutcd with halogen, straight or branched chain lower alkyl having 1-6, carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; OR5, COR5, CO2R5, OCOR5, or R5, where R5 is hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where cach alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; -CONR6R7 or -(CH2)nNR6R7 where n is 0, 1, or 2; R6 is hydrogen, straight or branched chain k. V having 1-6 carbon atoms; |rJ K *2 R7 is hydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 5 carbon atoms: or NR6R7 forms a heterocyclic group which is morpholyl, piperidyl. pyrrolidyl, or N-alkyl piperazyl: -NR3CO2R9 where Rs and R9 are the same or different and each 10 represents hydrogen, phenyl, pyridyl. straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or 15 C(OH)Ri()Rll where Rio and R1 1 arc the same or different and cach represents straight or branched chain iower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms. 20 5. A compound according to claim 1, wherein W is phenyl. 6. A compound according to claim I. wherein Rt is bromine. 25 7. A compound according to claim 1, wherein W is 4-niethoxyphcnyl. 8. A compound according to claim 1, wherein W is

2-tluorophcnyl. 9. A compound according to claim 1, wherein W is 4-ethoxyphcnyl. 30 10. A compound according to claim 1, wherein W is 2-thicnyl. 11. A compound according to claim 1, which is 2-phenyl- imida/o| 1,5,a]ciuinoxaI ine-1,3(2 H,5 H)-dionc. 35 12. A compound according to claim 1, which is 2-(2-fluorophcnyl)- imida/ol 1,5.a]quinoxaline-1.3(2H.5H)-dionc. • ' ' 0 13. A compound according to claim 1. which is 2- phenyl)- -47- .36 imida/o[ 1,5,a Jquinoxaline -1,3(2 H.5 H)-dione. 14. A compound according to claim 1, which is 2-(4-methoxyphenyl)-5 imidazo[ l,5,aJquinoxaline-l,3(2H,5H)-dionc. 15. A compound according to claim 1. which is 2-(4-mcthylphenyl)-imida/.o[ 1,5, a Jquinoxaline -1.3(2 H, 5 H)-dione. 10 16. A compound according to claim 1. which is 2-(4-fluorophcnyl)-im idazo [ 1,5,aJquinox aline -1,3(2H,5H)-dione. 17. A compound according to claim 1, which is 2-(2-aminophenyl)-imidazol 1,5,a] qui nox aline -1,3(2H,5 H)-dionc. 15 18. A compound according to claim 1, which is 2-(

3-fluorophenyl)-imida/.of 1,5,a]quinoxaIine-1,3(2H,5 H)-dione. 19. A compound according to claim 1, which is 2-(

4-chlorophenyl)-20 imida/ol 1,5.a J qui nox aline -1,3(2H,5 H)-dionc. 20. A compound according to claim 1, which is 2-(3-methyIphcnyl)-imida/.o[ 1,5.a]quinoxaline -1,3(2H,5 H)-dione. 25 21. A compound according to claim 1, which is 2-(2-fluoro-4-ethoxy phenyl )-imidazo[ 1,5,a]quinoxalinc-l ,3(2H,5H)-dionc. 22. A compound according to claim 1, which is 2-(3-chloropheny 1)-imida/o[ 1,5,a Jquinoxaline -1,3(2H,5 H)-dionc. 23. A compound according to claim 1, which is 2-(2-mcthoxyphenyl)-imida/.ol 1,5,a]quinoxaline-1,3(2H,5H)-dionc. 24. A compound according to claim 1, which is 2-(4-cthylphenyl)-35 imida/ol 1,5,a]quinoxaline-1,3(2H,5H)-dionc. 30 I *»i—•.'* 26. A compound according to claim 1, which is 2-(3-nicthoxyphenyl)-im idazo [ 1.5 .ajqui nox aline-1,3(2H,5 H)-dionc. 27. A compound according to claim 1, which is 2-(3-ethoxyphenyl)-imidazo[ 1,5,a Jquinoxaline -1,3(2H,5H)-dione. 28. A compound according to claim 1. which is 2-(4-n-propyloxyphenyl)-imidaz.o[1.5,a]quinoxaline-l,3(2H,5H)-dionc. 29. A compound according to claim 1. which is 2-(4-n-butoxyphenyl)-imidazol 1,5, a [qui nox aline -1,3(2H,5H)-dione. 30. A compound according to claim I, which is 2-(4-isopropoxyphenyl)-iinida/o[ 1.5,a Jquinoxaline -1,3(2H,5H)-dione. 31. A compound according to claim 1, which is 7-chloro-2-(4-nicthy 1 phony l)-im idazoj 1.5, a Jquinoxaline -1,3(2H.5H)-dionc. 32. A compound according to claim 1, which is 7,8-dimethy!-2-(4-cthoxyphenyl)-imidazo[1.5,a]quinoxaline-l,3(2H.5H)-dione. 33. A compound according to claim 1, which is 8-mcthyl-2-phenyl-imidazo[ 1,5.a]quinoxaline-l ,3(2H,5H)-dionc. 34. A compound according to claim 1, which is 8-carbocthoxy-2-(4-cihoxy phenyl )-im idazo 11,5, a Jquinoxaline-1,3(2 H,5H)-dionc. 35. A compound according to claim 1. which is 7-carbocthoxy-2-(4-ethoxypheny!)- ini idazo (1,5, a Jquinoxaline -1,3 (2H,5H)-dione. 36. A compound according to claim 1, which is 8-bromo-2-(4-elhoxyphcny I )-imidazo[ i ,5, a Jquinoxaline -1,3(2H,5H)-dionc. 37. A compound according to claim I, which is 2-(4-propy!phenyl)-imida/o[ 1,5.a Jquinoxaline -1,3(2H,5H)-dionc. -49- 3S. A compound according to claim 1. which is 7-methvl-2-(4-ethoxy phony I )-imida/o[ 1,5.a Jquinoxaline -1.3(2 H.5H)-dionc. 39. A compound according to claim 1. which is 2-(3-bromo-4-ethoxyphenyl)-imidazo[ 1.5,a Jquinoxaline -1,3(2H,5H)-dione. 40. A compound according to claim 1. which is 2-(3-thienyl)-i m idazo] 1.5. a Jquinoxaline -1,3(2 H.5H)-dionc. 41. A compound according to claim 1, which is 2-(2-th ieny 1)-i m idazo [ 1,5,a]qui nox aline-1.3(2 H.5H)-dione. 42. A compound according to claim 1. which is 2-(4-acetoxyphenyl)-iniidazo[1.5,aJquino.xaline-l,3(2H.5H)-dione. 43. A compound according to claim 1, which is 8-bromo-2-(4-met ho xy phenyl )-im idazo [ 1,5. a J qui nox aline -1,3(2H,5H)-dionc. 44. A compound according to claim 1. which is 8-bromo-2-(3-bromo-4 ethox y phony l)-im idazo [ 1.5. ajqui nox aline -1,3(2H,5H)-dionc. 45. A compound according to claim 1, which is 4-hydroxy-2-(4-ethoxyphenyl)-imidazo[ 1.5. a Jquinoxaline -1,3(2H,5H)-dionc. 46. A compound according to claim I, which is 4-chioro-2-(4-ci h ox y phony I)-imidazol 1.5. a Jquinoxaline -1,3(2H.5H)-dionc. 47. A compound according to claim 1. which is 4-amino-2-(4-ethoxy phony l)-i m id azof 1.5, a Jquinoxaline -1,3(2 H.5H)-dione. 4S. A compound according to claim 1. which is 4-dimcthylamino-2-(4-othoxyphenyI )-imidazo[ 1,5. ajqui nox aline -1,3{2H,5H)-dione. 49. A compound according to claim 1. which is 4-n-propylamino-2-(4-e thoxy phenyl)-imidazo[ 1,5 .ajqui nox aline -1,3(2H,5H)-dionc. 50. A compound according to claim 1, which is 4-mcthylamino-2-(4-ethoxy phony I)- imidazol 1.5 .ajqui nox aline -1,3(2H.5H)-dione. /' -50- 241986 51. A compound according to claim 1, which is 2-(4-hydroxyphenyl )-imida/o[ 1.5 ,a]quinox aline-1,3(2H,5 H)-dionc. 5 52. A compound according to claim 1, which is

5-methyl-2-(4-etho.xyphenyl)-imidazo[l,5,a]quinoxaIine-1.3(2H,5H)-dionc. 53. A compound according to claim 1, which is 3-trimcthylacetoxy-2-(4-ethoxyphcnyl)-imidazo[l,5.a]quinoxaline-l(2H.5H)-onc. 10 54. A compound according to claim 1, which is 3-n-propyioxy-2-(4-cthoxyphenyl)-imidazo[l,5,a]quinoxalinc-l(2H,5H)-onc. 55. A compound according to claim 1. which is 5-propionyl-2-(4-15 ethoxypheny l)-imida/.o[ 1,5.a]quinox aline -1,3(2H.5H)-dione. 56. A compound of the formula I as claimed in claim 1, substantially as herein described with reference to any example thereof and/or the accompanying drawings. «