NOVEL FUSED PYRROLECARBOXAMIDES; A NEW CLASS OF GABA BRAIN RECEPTOR LIGANDS

Abstract: The present invention encompasses structures of formula (I) or the pharmaceutically acceptable non-toxic salts thereof wherein G represents (1) where Q is aryl substituents optionally mono or disubstituted with hydroxy or halogen; T is halogen, hydrogen, hydroxyl, amino or alkoxy having 1-6 carbon atoms; W is oxygen, nitrogen, sulfur, or optionally substituted methylene; X is hydrogen, hydroxyl, or alkyl; Z is an organic or inorganic substituent optionally forming a ring with substituents on Q; (2), (3) and (4) independently represent optionally substituted carbon chains; wherein k, m, and n are independently 0, or an integer of from 1-3; R3, R4, R5, and R6 are the same or different and represent organic or inorganic substituents. 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 for enhancement of memory.

Description: NOVEL FUSED PYRROLECARBOXAMIDES; A NEW CLASS OF GABA BRAIN RECEPTOR LIGANDS BACKGROUND OF THE INVENTION Field of the Invention This invention relates to novel fused pyrrolecarboxamides which 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. Description of the Related Art γ-Aminobutyric acid (GABA) is regarded as one of the major inhibitory amino acid transmitters in the mammalian brain. Over 30 years have elapsed since its presence in the brain was demonstrated (Roberts & Frankel, J. Biol. Chem JLS1: 55-63, 1950; Udenfriend, J. Biol. Chem. jLSZ: 65-69, 1950). Since that time, an enormous amount of effort has been devoted to implicating GABA in the etiology of seizure disorders, sleep, anxiety and cognition (Talirnan and Gallager, Ann. Rev. Neuroscience S.: 21-44, 1985). Widely, although unequally, distributed through the mammalian brain, GABA is said to be a transmitter at approximately 30% 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. 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 are mediated through alterations in chloride conductance that generally, although not invariably, lead to hyperpolarization of the cell. Recent investigations have indicated that the complex of proteins associated with postsynaptic GABA responses is a major site of action for a number of structurally unrelated compounds capable of modifying postsynaptic responses to GABA. Depending on the mode of interaction, these compounds are capable of producing a spectrum of activities (either sedative, anxiolytic, and anϋconvulsant, or wakefulness, seizures, and anxiety). 1,4-Benzodiazepines continue to be among the most widely used drugs in the world. Principal among the benzodiazepines marketed are chlordiazepoxide, diazepam, flurazepam, and triazolarn. These compounds are widely used as anxiolytics, sedative-hypnotics, muscle relaxants, and 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 monosynaptic ventral root reflex, a GABA-mediated event (Schmidt et al., 1967, Arch. Exp. Path. Pharmakol. 258: 69-82). All subsequent electrophysiological studies (reviewed in Tallman et al. 1980, Science 201: 274-81, Haefley et al., 1981, Handb. Exptl. Pharmacol. 21' 95-102) have generally confirmed this finding, and by the mid-1970s, there was a general consensus among electrophysiologists 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 behaviorally important interactions 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 the demonstration of a high-affinity benzodiazepine binding site (receptor). Such a receptor is present in the CNS of all vertebrates phylogenetically newer than the boney fishes (Squires & Braestrup 1977, Nature 166: 732-34, Mohler & Okada, 1977, Science 12i_: 854-51 , Mohler & Okada, 1977, Br. J. Psychiatry 133: 261-68). By using tritiated diazepam, and a 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 binding site and activity in a number of animal behavioral tests predictive of benzodiazepine potency (Braestrup & Squires 1978, Br. J. Psychiatry Jϋ: 249-60, Mohler & Okada, 1977, Science J ≥__: 854-51, Mohler & Okada, 1977, Br. J. Psychiatry 13_3_: 261-68). The average therapeutic doses of these drugs in man also correlate with receptor potency (Tallman et al. 1980, Science ΩZ: 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 benzodiazepines to the clonazepam- 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 number of GABA analogs, the ability to enhance diazepam binding by 50% of maximum and the ability to inhibit the binding of GABA to brain membranes by 50% could be directly correlated. Enhancement of benzodiazepine binding by GABA agonists is blocked by the GABA receptor antagonist (+) bicuculline; the stereoisomer (-) bicuculline is much less active (Tallman et al., 1978, Nature, 224: 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. In these studies, Hill coefficients significantly less than one were observed in a number of brain regions, including cortex, hippocampus, and striatum. In cerebellum, triazolopyridazine interacted with benzodiazepine sites with a Hill coefficient of 1 (Squires et al., 1979, Pharma. Biochem. Behav. IQ: 825-30, Klepner et al. 1979, Pharmacol. Biochem. Behav. ϋ: 457-62). Thus, multiple benzodiazepine receptors were predicted in the conex, 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. Pharmacol. Exp. Ther. 212: 337-46, Young et al., 1981 J. Pharmacol Exp. ther 16: 425-430, Niehoff et al. 1982, J. Pharmacol. Exp. Ther. 221: 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 cerebellum, where one receptor was predicted from binding 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 Sieghart & Karobath, 1980, Nature 2&& 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, a benzodiazepine which can covalently label all receptor types. The major labeled bands have molecular 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. 8j_: 291-99). At that time, the possibility was raised that the multiple forms of the receptor represent "isoreceptors" 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 probes and electrophoretic techniques, it is almost certain that isoreceptors will emerge as important in investigations of the etiology of psychiatric disorders in people. The GABAa receptor subunits have been cloned from bovine and human cDNA libraries (Schoenfield et al., 1988; Duman et al., 1989). A number of distinct cDNAs were identified as subunits of the GABAa receptor complex by cloning and expression. These are categorized into α, β, γ, δ, € , and provide a molecular basis for the GABAa receptor heterogeneity and distinctive regional pharmacology (Shiwers et al., 1980; Levitan et al., 1989). The γ subunit appears to enable drugs like benzodiazepines to modify 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 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. 2__: 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 binding. When the beta-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). 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 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 290: 514-516). This compound is a high affinity competitive inhibitor of benzodiazepine and beta-carboline binding and is capable of blocking the pharmacological actions of both these classes of compounds. By itself, it possesses little intrinsic pharmacological activity in animals and humans (Hunkeler et al., 1981, Nature 2____: 514-16; Darragh et al., 1983, Eur. J. Clin. Pharmacol. 14 569-70). When a radiolabeled form of this compound was studied (Mohler & Richards, 1981, Nature 294: 763- 65), it was demonstrated that this compound 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 iigand 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 activity have been termed antagonists. This categorization has been developed to emphasize the faα that a wide variety of compounds can produce a spectrum of pharmacological effects, to indicate that compounds can interact at the same receptor to produce opposite effects, and to indicate that beta- carbolines and antagonists with intrinsic anxiogenic effects are not synonymous. A biochemical test for the pharmacological and behavioral properties of compounds that interact with the benzodiazepine receptor 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 224: 383-85, Tallman et al., 1980, Science 202: 274- 81), compounds with antagonist properties show little GABA shift (i.e., change in receptor affinity due to GABA) (Mohler & Richards 1981, Nature 224: 763-65), and the inverse agonists actually show a decrease in affinity due to GABA (Braestrup & Nielson 1981, Nature 294: 472- 474). Thus, the GABA shift predicts generally the expected behavioral propeπies of the compounds. Various compounds have been prepared as benzodiazepine agonists and antagonists. For Example, U.S. Patents Nos. 3.455,943, 4,435,403, 4,596,808, 4,623,649, and 4,719.210, German Patent No. DE 3,246,932, and Liebigs Ann. Chem. 1986, 1749 teach assoπed benzodiazepine agonists and antagonists and related anti-depressant and central nervous system active compounds. U.S. Patent No. 3,455,943 discloses compounds of the formula: wherein Ri is a member of the group consisting of hydrogen and lower alkoxy; R2 is a member of the group consisting of hydrogen and lower alkoxy; R3 is a member of the group consisting of hydrogen and lower alkyl; and X is a divalent radical selected from the group consisting of Other references, such as U.S. Patent No. 4,435,403 and German patent DE 3,246,932 disclose compounds containing the following structural skeleton: where A is carbon or nitrogen. A variety of indole-3-carboxamides are described in the literature. For example, J. Org. Chem., 42: 1883-1885 (1977) discloses the following compounds. J. Heterocylic Chem., 14 519-520 (1977) discloses a compound of the following formula: None of these indole-3-carboxamides includes an oxy substiuent at the 4-position of the indole ring. STFMMARY OF THE INVFNTTON This invention provides novel compounds of Formula 1 which interact with a GABAa binding site, the benzodiazepine receptor. The invention provides pharmaceutical compositions comprising compounds of Formula I. The invention also provides compounds useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory. Accordingly, a broad embodiment of the invention is directed to compounds of general Formula I: I or the pharmaceutically acceptable non-toxic salts thereof wherein: G represents where Q is phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, all of which may be mono or disubstituted with hydroxy or halogen; T is halogen, hydrogen, hydroxyl, amino or straight or branched chain lower alkoxy having 1-6 carbon atoms; W is oxygen, nitrogen, sulfur, or CR7R8 where R7 and ^8 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, or 7- 8 may be taken together to represent a cyclic moiety having 3-7 carbon atoms; X is hydrogen, hydroxyl, or straight or branched chain lower alkyl having 1-6 carbon atoms; Z is hydroxy, straight or branched chain lower alkoxy having 1-6 carbon atoms, cycloaikyl alkoxy having 3-7 carbon atoms, amino, mono, or clialkylamino where each alkyl is independendy straight or branched chain lower alkyl having 1-6 carbon atoms or cycloaikyl having 3-7 carbon atoms, or NR9COR10 where R9 and Rio are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms or cycloaikyl having 3-7 carbon atoms; or Z is connected, optionally through W, to Q to from a 1-6 membered ring; , , and independently represent a carbon chain optionally substituted with hydrogen, halogen, or straight or branched chain lower alkyl having 1-6 carbon atoms; wherein k is 0, 1, 2, or 3; m is O, 1, 2, or 3; and n is 0, 1, 2, or 3; R3, R4, R5, and Rβ are the same or different and are selected from hydrogen, straight or branched lower alkyl having 1-6 carbon atoms, -CORi 1 or -CO2R11 where Ri 1 is straight or branched lower alkyl having 1-6 carbon atoms or cycloaikyl having 3-7 carbon atoms; or -CONR12 13 where R12 and l3 are selected independently from hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, cycloaikyl having 3-7 carbon atoms, phenyl, 2-, 3-, or 4-pyridyl, or NR12R13 forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or R3-R4 taken together forms a cyclic moiety having 3-7 carbon atoms; or R5- 6 may be taken together to form a cyclic moiety having 3-7 carbon atoms; and where each alkyl group forming an R3, R4, R5. or R6 substitutent or portion tiiereof may be substituted independently with hydroxy or mono- or dialkylamino where each alkyl is independently straight or branched chain lower alkyl having 1-6 carbon atoms or cycloaikyl having 3-7 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. In other words, while the compounds of the invention all interact with GABAa brain receptors, they do not display identical physiologic activity. Thus, these compounds are useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory. For example, these compounds can be used to treat overdoses of benzodiazepine-type drugs as they would competitively bind to the benzodiazepine receptor. DETAILED DESCRIPTION OF THE TNVFNTTON The novel compounds encompassed by the instant invention can be described by general formula I set forth above or the pharmaceutically acceptable non-toxic salts thereof. In addition, the present invention encompasses compounds of Formula U. π wherein Y is hydrogen, halogen, or hydroxy; and W, Y, Z, k, m, n, R3, R4, R5, and R6 are defined as above. The present invention also encompasses compounds of Formula ITJ wherein Y is hydrogen, halogen, or hydroxy; and W, Y, Z, k, m, n, R3, R4, R5, and R6 are defined as above. The present invention also encompasses compounds of Formula IV. IV wherein Y is hydrogen, halogen, or hydroxy; and W, Y, Z, k, m, n, R3, R4, R5. and R6 are defined as above. The present invention also encompasses compounds of Formula V. wherein Y is hydrogen, halogen, or hydroxy; and W, Y, Z, k, m, n, R3, R4, R5, and R are defined as above. The present invention also encompasses compounds of Formula VI. VI wherein Y is hydrogen, halogen, or hydroxy; and W, Y, Z, k, m, n, R3, R4, R5, and R6 are defined as above. The present invention also encompasses compounds of Formula VH. vπ wherein W, Z, m, n, R3, R4, R5, and R6 are defined as above. The present invention also encompasses compounds of Formula VHI. vm wherein W, Z, m, n, R3, R4, R5, and R6 are defined as above. The present invention also encompasses compounds of Formula DC. IX wherein W, Z, k, m, n, R3, R4, R5, and R6 are defined as above. The present invention also encompasses compounds of Formula X. wherein W, Z, k, m, n, R3, R4, R5, and R6 are defined as above. Preferred G substituents of the invention include the following: where R a represents hydrogen or alkyl where the alkyl is optionally halogenated; and e is an integer of 1-3. More preferred G substituents of formula A include diose where e is 1, 2, or 3, and R a is hydrogen, methyl, ethyl, isopropyl, or cyclopropyl. Particularly preferred G substituents of formula A include those where e is 1, 2, or 3, and R a is hydrogen or methyl. Another preferred G substituent is the following formula: B where Ra represents hydrogen or alkyl where the alkyl is optionally halogenated; and e is an integer of 1-3. More preferred G substituents of formula B include those where e is 1, 2, or 3; and Ra is hydrogen, methyl or ethyl. Particularly preferred G substituents of formula B include those where e is 1 or 2, and R is hydrogen or methyl. Another preferred G substituent is the following formula: C where Ra and Rb independently represent hydrogen or alkyl; and e is an integer of 2-3. More preferred G substituents of formula C include those where R a is hydrogen, methyl or ethyl; and Rb is hydrogen. Particularly preferred G substituents of formula C include those where e is 2; R a is hydrogen or methyl; and Rb is hydrogen. Another preferred G substituent is the following formula: D where Ra represents hydrogen, alkyl, or C3.7 cycloaikyl; Rb represents hydrogen, alkyl, or acyl; Y represents hydrogen or halogen; and e is an integer of 1-3. More preferred G substituents of formula D are those where Y is hydrogen or fluorine; and e is 1 or 2. Particularly preferred G substituents of formula D are those where Y is hydrogen or fluorine; e is 1 or 2; R a is hydrogen, C1-3 alkyl, or cyclopropyl, and Rb is hydrogen, methyl, or acyl. Another preferred G substituent is the following formula: E where Z is oxygen, nitrogen, or methylene; and m is 1 or 2. Particularly preferred G substituents of formula E are those where Z is oxygen, and m is 1 or 2. Other particularly preferred G substituents of formula E are those where Z is nitrogen, and m is 1 or 2. Another preferred G substituent is the following formula: F where Z is oxygen or nitrogen; and m is 1 or 2. Particularly preferred G substituents of formula F are those where Z is nitrogen, and m is l or 2. Another preferred G substituent is the following formula: H where Z is oxygen, nitrogen, or methylene; and m is 1 or 2. Particularly preferred G substituents of formula H are those where Z is nitrogen, and m is l or 2. Another preferred G substituent is the following formula: J where R a represents hydrogen, alkyl, or C3-7 cycloaikyl; Rb represents hydrogen, .alkyl, or acyl; Y and Y' independently represent hydrogen or halogen; and e is an integer of 1-3. More preferred G substituents of formula J are those where Y and Y' are independently hydrogen or fluorine; and e is 1 or 2. Particularly preferred G substituents of formula J are those where and Y' are independently hydrogen or fluorine; e is 1 or 2; R a is hydrogen, C1.3 alkyl, or cyclopropyl, and Rb is hydrogen, methyl, or acyl. Representative compounds of the invention are shown below in Table 1. Table 1 Compound 1 Compound 3 Compound 4 Compound 5 Compound 6 Compound 7 Compound 9 Compound 10 Compound 11 Compound 12 Compound 13 Compound 15 The following numbering system is used to identify positions on the pyrrole ring portion of the compounds of the invention: Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable salts. Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maieic, hydroiodic, alkanoic such as acetic, HOOC-(CH2)n-COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts. Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table 1 and their pharmaceutically acceptable salts. The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I. By "alkyl" or "lower alky in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n- butyi, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. By "alkoxy" or "lower alkoxy" in the present invention is meant straight or 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-methylpentoxy. By "benzoxaz-nyl" as used herein is meant a moiety of the formula: A benzoxazin-6-yl group is depicted. By "halogen" in the present invention is meant fluorine, bromine, chlorine, and iodine. By "2-hydroxyethoxy" is meant a group of the formula: -OCH2CH2OH. 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. The pharmaceutical utility of compounds of this invention are indicated by the following assay for GAB Aa receptor binding 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 dissected and homogenized in 25 volumes (w/v) of 0.05 M Tris HC1 buffer (pH 7.4 at 4°C). The tissue homogenate 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 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 HC1 buffer (pH 7.4 at 40 >C). Incubations contain 100 ml of tissue homogenate, 100 ml of radioligand 0.5 nM (^H- RO15-1788 [^H-Rumazenil] specific activity 80 Ci/mmol), drug or blocker and buffer to a total volume of 500 ml. Incubations are carried for 30 min at 4°C then are rapidly filtered through GFB filters to separate free and bound ligand. Filters are washed twice with fresh 0.05 M Tris HC1 buffer (pH 7.4 at 4°C) and counted in a liquid scintillation counter. 1.0 mM diazepam is added to some tubes to determine nonspecific binding. Data are 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 carried out. Data are converted to Ki's; results for compounds of this invention are listed in Table 2. The compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non- toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of general formula I may be present in association with one or more non-toxic pharmaceutically 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 capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the an 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, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in -admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, 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 stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as giyceryl monosterate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. 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, methy .cellulose, hydropropylmethylcellulose, sodium alginate, poiyvinylpyrrolidone, 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 heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene 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 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 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 cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible 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 suspending agents are 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- water emulsions. The oily phase may be a vegetable oil, for 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 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 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 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 oieic acid find use in the preparation of 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 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 vehicle. Advantageously, 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 above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The 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 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 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 d e present invention is given in Scheme I. Scheme I K 2 CO3, CS 2 CO 3 EtI,DMF where: Ar is where Q, W, k, m,n, Z, R3, R4, R5, and R6 are as defined above. Those having skill in the art 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. In some cases protection of certain reactive functionalities may be necessary to achieve some of the above transformations. In general the need for such protecting groups will be apparent to those skilled in the art of organic synthesis as well as the conditions necessary to attach and remove such groups. Representative examples of the preparation of various protected aniline derivatives are shown in Schemes II (1), (2) and (3). Scheme II I Pyridine, TFAA CH 2 C1 2 , 0° (2) 10% Pd/C, H 2 EtOH I^R.oNH, i-PrOH sealed tube, 100° AA, (for R l0 = H) The disclosures in this application of all articles and references, including patents, are incorporated herein by reference in their entirety. One skilled in the art will recognize that modifications may be made in the present invention without deviating from the spirit or scope of the invention. The invention is illustrated further by the following examples which are not to be construed as limiting the invention or scope of the specific procedures or compositions described herein. Example 1 Preparation of starting materials and intermediates The starting materials -and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods. Representative examples of methods for preparing intermediates of the invention are set forth below. 1. 4-oxo-4.5.6.7-tetrahvdrobenzofuran-3-carboxvlic acid 4-Oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid is prepared according to the following procedure. Potassium hydroxide (345 g, 6.15 mol) is dissolved in methyl alcohol (1.2 L) then cooled in an ice water bath. A solution of cyclohexanedione (714 g, 6.15 mol) in methyl alcohol (1.2 L), dissolved using gende heat, is added dropwise to the cold, stirred KOH solution over 2 h. A solution of ethyl bromopyruvate (1200 g, 6.15 mol) in methyl alcohol (1.5 L) is then added dropwise over 3 h. The reaction mixture is allowed to reach ambient temperature and stirred an additional 14.5 h. While cooling the reaction mixture via a water bath, a solution of sodium hydroxide (492 g, 12.4 mol) in water (984 mL) is added dropwise over 2.5 h. After stirring at ambient temperature for 15.5 h, the reaction mixture is cooled in an ice water bath, 500 g of ice added, and the resulting mixture is then acidified with concentrated hydrochloric acid (ca IL) to pH 1. The reaction mixture is concentrated in vacua, IL of ice is added, and the precipitate filtered, washed with ice water (3 X 200 mL), and then dried in a vacuum oven at 75° C to afford 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (560 g). m.p. 137-138° C. - 4-oxo-4.5.6.7-tetrahvdroindole-3-carboxvlate To a stirred mixture of 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (640 g, 3.55 mol), potassium carbonate (1.7 kg, 10.65 mol) and cesium carbonate (100 g, 0.32 mol) in N,N-dimethylformamide (9.0 L) is added iodoethane (1250 g, 8.01 mol). The mixture is heated at 60° C for 2 h. After cooling to ambient temperature, the mixture is filtered, the solid is rinsed with ethyl acetate, and the filtrate concentrated in vacua . Water (2 L) is added then extracted with ethyl acetate (2 X 2L); the combined organic extracts are washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacua to give ethyl 4-oxo-4,5,6,7- tetrahydrobenzofuran-3-carboxylic acid (642 g). A mixture of this ester (640 g, 3.07 mol) and ammonium acetate (426 g, 5.53 mol) in N,N-dimethylformamide (320 mL) is heated to 100° C for 2 h. The reaction mixture is concentrated in vacua , ice water (2.5L) is added, and extracted with dichloromethane (2 X 3L) ; the combined organic extract.; are washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacua to give ethyl 4-oxo-4,5,6,7- tetrahydroindole-3-carboxylate (357 g). A rnixture of this ester (170 g, 0.82 mol) in ethyl alcohol (250 mL) and a solution of sodium hydroxide (165 g, 4.1 mol) in water (1 L) is heated at reflux for 1 h, then cooled in an ice water bath. Concentrated hydrochloric acid (350 mL) is added dropwise, the precipitate collected by filtration, rinsed with ice water (3 X), and dried in a vacuum oven at 75° C to afford 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate (125 g). m.p. 269-270° C. 1. 4-rN-trifluoro-Cetvl-(rnethvlaminornethvnaniline A solution of p-nitrobenzylbromide (5.40 g, 25 mmol) in acetonitrile (60 ml) is added dropwise to a stirred solution of aqueous methylamine (65 mL, 40 wt.%, 0.75 mol) in acetonitrile (50 mL) at 0°. After stirring an additional 15 minutes, the solution is poured into brine and extracted 2X with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4- (methylaminomethyl)nitrobenzene (4.04g). A solution of trifluoracetic anhydride (4.46 mL, 31.6 mmol) in dichloromediane (10 mL) is added dropwise to a stirred solution of 4-(methylaminomethyl)nitrobenzene (4.04g, 24.3 mmol) and pyridine (2.16 mL, 26.7 mmol) in dichloromethane (25 mL) at 0°. After stirring an additional 30 minutes, the solution is poured into aqueous 3.6N hydrochloric acid and extracted with dichloromethane. The organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-[N-trifluoroacetyl-(meΛylam omemyl)]nitrobenzene (6.55 g). Crude 4-[N-trifluoroacetyl-(methylaminomethyl)]nitrobenzene (6.55 g) is dissolved in ethyl alcohol (75 mL) , added to 10% Pd/C (655 mg) in a Parr bottie and shaken under Hydrogen (50 PSI) for 4 hours. The mixture is filtered through Celite and concentrated in vacuo to give 4- ( -trifluoroacetyl-(rnethylaπtinomethyl)aniline (5.75 g). The 3-aminoalkylanilines are prepared in a similar fashion according to the procedure generally set forth in part (1) of Scheme π above. 4. 4-arr-mo-fl^-triflucroacetyl-2-methylaminoethoxy)benzene A mixture of p-nitrophenol (1.39 g, 10 mmol), 2-chloroethoxytrimethylsilane (3.2 ml, 20 mmol), potassium carbonate (4.15 g, 30 mmol), cesium carbonate (163 mg, 0.5 mmol), and sodium iodide (149 mg, 1 mmol) in N,N-dimethylformamide ( 10 ml) is heated at 75° for 19.5 hours. After cooling to ambient temperature, the mixture is diluted with ethyl acetate and filtered. The filtrate is washed with saturated aqueous sodium bicarbonate, then washed 2X with water, dried over magnesium sulfate, filtered, concentrated in vacuo, and purified on Silica gel ( 1 : 1 ethyl acetate / hexanes) to give 4-nitro-(2-Hydroxye_hoxy)benzene (1.25 g). 4-Nitro-(2-Hydroxyethoxy)benzene (1.13 g, 6.2 mmol) in thionyl chloride (10 mL) is heated at reflux for 3 hours then concentrated in vacuo . After cooling the residue in an ice water bath, saturated aqueous sodium bicarbonate is added and the precipitate collected, rinsed with water, and dried to give 4-nitro-(2-chloroethoxy)benzene (909 mg). A mixture of 4-nitro-(2-chloroethoxy)benzene (781 mg, 3.9 mmol) and aqueous methylarnine (15 mL, 40 wt. %) in isopropyl alcohol (15 mL) is heated in a sealed tube at 100° for 4 hours. After cooling in an ice water bath, die mixtured is poured into brine and extracted 2X with dichloromethane, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4- nitro-(2-methylaminoethoxy)benzene (697 mg). To a solution of 4-nitro-(2-methylaminoethoxy)benzene (766 mg, 3.9 mmol) and pyridine (0.35 mL, 4.29 mmol) in dichloromethane (5 mL) at 0° C is added dropwise trifluroacetic anhydride (0.72 mL, 5.08 mmol). After stirring at 0° C for 3.5 hours, the rnixture is poured into aqueous 1.2 N hydrochloric acid and extracted with dichloromethane. The organic layer is washed with saturated aqueous sodium bicarbonate then brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-mtro-(N-triflucflOacetyl-2-rτιemylaιninoethoxy)benzene (1.06 g). Treatment of this nitro compound with 10% Palladium on carbon in ethyl alcohol (18 mL) in a Parr bottle under Hydrogen (55 PSI) for 2.25 hours affords 4-amino-(N-trifluoroacetyl-2- methylaminoethoxy)benzene (709 mg). Example 2 Compound 1 To a stirred solution of 4-oxo-4,5,6,7-tetrahydro-lH-indole-3-carboxylic acid (100 mg, 0.6 mmol) and triethylamine (0.15 mL, 1.1 mmol) in N,N-dimethylformamide (5 mL) at 0° C is added ethyl chloroformate (0.1 mL, 1.1 mmol). After stirring an additional 1 hour, 3-(N- trifluoroacetyl-(methylaminomethyl)aniline (0.3 g, 1.3 mmol ) is added. The reaction mixture is stirrred for 4 hours, then poured into saturated aqueous ammonium chloride and extracted 2X with ethyl acetate. The combined organic layers are washed sequentially with brine, aqueous 2N hydrochloric acid, then brine, dried over sodium sulfate, filtered, and concentrated in vacuo . To the residue is added 15% aqueous potassium bicarbonate (5 mL) and methyl alcohol (3 mL), then heated at reflux for 3 hours. After cooling, the reaction mixture is extracted with ethyl acetate, the organic layer dried over sodium sulfate, filtered, and concentrated in vacuo to give N-[3- (methylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro- lH-indole-3-carboxamide. m.p. 130- 132°C. Example 3 The following compounds are prepared essentially according to the procedures described in Examples 1-5: (a) N-[3-(Methylaιιώc^nethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro- lH-indole-3- carboxamide (Compound 1); mp 130-132° C. (b) N-[4-(Hydroxyethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro- lH-indole-3- carboxamide; mp 245-247° C. (c) N-[4-(Methoxyethoxy)phenyl]-4-oxo- 4,5,6,7-tetrahydro- 1 H-indole-3- carboxamide (Compound 2). (d) N-[-4-(3-Memylaπύnoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro- lH-indole-3- carboxamide; mp 233-236° C. (e) N-[4-(Memoxymethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-lH-indole-3- carboxamide; mp 164-165° C. (0 N-[4-(A-iiinomethyl)phenyl]-4-oxo-4,5,6,7-tetrahyc_ro- lH-indole-3-carboxamide (Compound 6); mp >200° C (d). (g) N-{4-(Methylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-lH-indole-3- carboxamide; mp 217-219° C. (h) N-[2-Fluoro-4-(methylaminomethyl)phenyl]-4-oxo- 4,5,6,7-tetrahydro-lH- indole-3-carboxamide (Compound 3); mp 186-188°C. (i) N-(4-[N-acetyl-(rr«thylaminonτethyl)phenyl]}-4-oxcr-4,5,6,7-tetrahydro-lH- indole-3-carboxamide; mp 204-206° C. (j) N-[4-0 thylammomemyl)phenyl]-4-oxo-4,5,6,7-teoahydro- lH-indole-3- carboxamide; mp 194-195° C. (k) N-[4-(Isopropylaιιιmomethyl)phenyl]-4-oxo-4,5,6,7-tet-ahydro- lH-indole-3- carboxamide; mp 164- 166° C. 0) N-[4-(Cyclopropylarnmomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro- lH-indole-3- carboxamide (Compound 5); mp 171-173° C. (m) N-[4-0 irrιethylaminomethyl)phenyl]-4-oxo- 4,5,6,7 -tetrahydro-lH-indole- 3- carboxamide; mp 216-218°C. (n) N-[4-(2-An oethyl)phenyl]-4-oxo- 4,5,6,7-tetrahycuτ)-lH-ndole-3-cartθxaπ-ide; mp 85-90° C. (o) N-[4-(2-Methylaminoethyl)phenyl]-4-oxo- 4,5,6,7-tetrahydro- 1 H-indole-3- carboxamide (Compound 4); mp 197-200° C. (p) N-[4-(Methoxyιrιeϋ^yl)phenyl]-4-oxo-5,5-dimethyl-4,5,6,7-tetrahyc_r^ lH-indole- 3-carboxamide. (q) N-[4-(Methylaminomethyl)phenyl-4-oxo- 1 ,4,5,6,7,8-hexahydro- cyclohepta[b]pyrrole-3-carboxamide (Compound 7); mp 173-175° C. (r) N-{4-[N-aceryl-(memylaπιinomethyl)phenyl]}-4-oxo-6-methyl-4-5,6,7- teπahyd- lH-indole-3-carboxamide; mp 159-161° C. (s) N-[4-(Methyla_mnomemyl)phenyl]-4-oxo-6-r^ 3-carboxamide; mp 217-219° C. (t) N-[4-(Hydroxymethyl)phenyl]-4-oxo-6-methyl-4,5,6,7-tetrahydro-lH-indole-3- carboxamide; mp 260-262° C. (u) N-[4-(2-Hyα^xyemoxy)phenyl]-4-oxo-6-methyl-4,5,6,7-tetrahydro-lH-indole- 3-carboxamide (Compound 9); mp 245-247° C. (v) N-[3-(Methylaminomethyl)phenyl]-4-oxo-6-methyl-4,5,6,7-tetraydro-lH-indole- 3-carboxamide; mp 172-174° C. (w) N-[4-(2-Hydroxyethoxy)phenyl]-4-oxo-6,6-dime-hyl-4,5,6,7-tetrahydro-lH- indole-3-carboxamide; mp 268-270° C. (x) N-[3-(Hydroxymethyl)phenyl]-4-oxch6,6-α^emyl-4,5,6,7-tetrahydro- lH-indole- 3-carboxamide (Compound 8); mp 233-235°C. (y) N-[4-(Hydroxymethyl)phenyl]-4-oxcr-6,6-dimethyl-4,5,6,7-te-rahydro- 1 H-indole- 3-carboxamide; mp 245-247°C. (z) N-[4-(Memylammomemyl)phenyl]-4-oxo-6,6-dime yl-4,5,6,7-tetrahydro- 1H- indoie-3-carboxamide; mp 230-232°C. (aa) N-( 1 ,3-Benzodioxol-5-yl)-4-oxo-4,5,6,7-tetrahydro- lH-indole-3-carboxamide (Compound 10); mp 248-249° C. (bb) N-(2,3-Whyώx)-l,4-benzocUoxm-6-yl)-4-oxo-4,5,6,7-tet-^ydro-lH-indole-3- carboxamide (Compound 11); mp 254-256° C. (cc) N-(3,4-Dihydro-2H- 1 ,4-benzoxazin-6-yl)-4-oxo-4,5,6,7-tetrahydro- lH-indole-3- carboxamide; mp 216°C. (dd) N-(2^-Dimemyl-l,3-benzodioxol-5-yl)-4-oxo-4,5,6,7-tetrahydro-lH-indole-3- carboxamide. (ee) N-(2,3-Dihydro- lH-indol-5-yl)-4-oxo-4,5,6,7-tetrahydro- lH-indole-3- carboxamide; mp 283-286°C (ff) N-(2,3-Dmydro-lH-indol-6-yl)-4-oxo-4,5,6,7-tetrahydro- lH-indole-3- carboxamide (Compound 13); mp 322-323°C. (gg) N-( 1 t 3-Benzomoxol-5-yl)-4-oxo-5,5-dimethyl-4,5,6,7-tetrahydro- 1 H-indole-3- carboxamidc. (hh) N-(2,3-Dihydro- 1 ,4-benzodioxin-6-yl)-4-oxo-5,5-dimethyl-4,5,6,7-tetrahydro- lH-indole-3-carboxamide; mp 241-243°C. (ϋ) N-(4H- l,3-Benzodioxin-7-yl)-4-oxo-5,5-dimethyl-4,5,6,7-tetrahydro- IH-indole- 3-carboxamide; mp 251-252°C. (jj) N-(l ,3-Benzodioxol-5-yl)-4-oxo- 1 ,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3- carboxamide; mp 210-212° C. (kk) N-(2,3-Dihydro-l,4-benzodioxin-6-yl)-4-oxo-l,4,5,6,7,8-hexahydro- cyclohep [b]pyrrole-3-carboxamide (Compond 12); mp 222-223° C. (U) N-(2,2-Dimethyl- 1 ,3-benzodioxol-5-yl)-4-oxo-6-memyl-4,5,6,7-tetrahydro- 1H- indole-3-carboxamide; mp 155-157°C. (mm) N-(l,3-Benzodioxol-5-yl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-lH-indole-3- carboxamide; mp 297-299°C. (nn) N-(2,3-Dihydro- 1 ,4-benzodioxin-6-yl)-4-oxo-6-rr» yl-4,5,6,7-tetrahydro-lH- -ndole-3-carboxamide; mp 290-292°C. (oo) N-( 1 ,3-Benzodioxol-5-yl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro- lH-indole-3- carboxamide; mp 245-246° C. (pp) N-(2,3-Dihydrcr-l,4-ben_»dioxin-6-yl)-4-oxo-6,6-dimethyl-4,5,6,7-tet_ahyc-ro- lH-indole-3-carboxamide. (qq) N-(4H- 1 ,3-Ben-Xidioxin-7-yl)-4-oxo-6,6-dimedιyl-4,5,6,7-tetrahydro- lH-indole- 3-carboxamide; mp 234-236° C. (rr) N-[(2-Hydroxyeu^oxy)pyrid-5-yl]-4-oxo-6-meu yl-4,5,6,7-tetrahydπ>- lH-indole- 3-carboxamide (Compound 15); mp 221-223° C. (ss) N-(3,4-I_Hhydro-2H-l,4-ben-»xa--m-7-yl)-4-oxo-4,5,6,7-tet-^ydro-lH-indole-3- c-crboxamide. Example 4 Water solubility for various compounds within the invention was determined and compared with that for compounds outside the scope of the invention. The compounds evaluated are encompassed within formula II: π Bx. R Water Solubility (μ rol) The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art 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 depaning from the spirit or scope of the present invention as set fonh in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.

Claims: WHAT IS CLAIMED IS: 1. A compound of the formula: or the pharmaceutically acceptable non-toxic salts thereof wherein: G represents where Q is phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, all of which may be mono or disubstituted with hydroxy or halogen; T is halogen, hydrogen, hydroxyl, amino or alkoxy having 1-6 carbon atoms; W is oxygen, nitrogen, sulfur, or CR7R8 where R7 and R8 are the same or different and represent hydrogen, alkyl, or R7-R8 taken together represents a cyclic moiety having 3-7 carbon atoms; X is hydrogen, hydroxyl, or alkyl; Z is hydroxy, alkoxy, cycloaikyl alkoxy having 3-7 carbon atoms, amino, mono, or dialkylamino where each alkyl is independentiy alkyl or cycloaikyl having 3-7 carbon atoms, or NR9COR10 where R9 and Rio are the same or different and represent hydrogen or alkyl or cycloaikyl having 3-7 carbon atoms; or Z is connected, optionally through W, to Q to from a 1-6 membered ring; , independently represent a carbon chain optionally substituted with hydrogen, halogen, or straight or branched chain lower alkyl having 1-6 carbon atoms; wherein is O, 1, 2, or 3; m is O, 1, 2, or 3; and n is 0, 1, 2, or 3; R3, R4, R5, and R6 are the same or different and are selected from hydrogen, alkyl , -CORi i or -CO2R11 where R_ 1 is alkyl or cycloaikyl having 3-7 carbon atoms; or -CONR12R13 where R 12 and Rl 3 are selected independently from hydrogen, alkyl, cycloaikyl having 3-7 carbon atoms, phenyl, 2-, 3-, or 4-pyridyl, or NR l2Rl3 forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or R3-R4 may be taken together to form a cyclic moiety having 3-7 carbon atoms; or R5-R6 may be taken together to form a cyclic moiety having 3-7 carbon atoms; and where each alkyl group forming an R3, R4, R5, or R6 substitutent or portion thereof may be substituted independently with hydroxy or mono- or dialkylamino where each alkyl is independently alkyl or cycloaikyl having 3-7 carbon atoms. 2. A compound according to claim l .which is: wherein Y is hydrogen, halogen, or hydroxy. 3. A compound according to claim 1.which is: wherein Y is hydrogen, halogen, or hydroxy. 4. A compound according to claim 1.which is: wherein Y is hydrogen, halogen, or hydroxy. A compound according to claim 1, which is: wherein Y is hydrogen, halogen, or hydroxy 6. A compound according to claim 1.which is: wherein Y is hydrogen, halogen, or hydroxy. A compound according to claim 1, which is: 8. A compound of the formula: 9. A compound of the formula: 10. A compound of the formula: 11. A compound according to claim 1 , which is N-[3-(Methylaminomethyl)phenyl]-4- oxch4,5,6,7--etrahydro-lH-mdole-3-carboxan-ide . 12. A compound according to claim 1 , which is N-[4-(Hydroxyeώoxy)phenyl]-4-oxo- 4,5,6,7-tetrahydro- lH-indole-3-carboxamide. 13. A compound according to claim 1, which is N-[4-(Methoxyethoxy)phenyl]-4-oxo- 4,5,6,7-tetrahydro- lH-indole-3-c-.rboxam.de. 14. A compound according to claim 1, which is N-[-4-(3- Methylaminoeϋ oxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-lH-mdole-3-carboxar__ide. 15. A compound according to claim 1 , which is N-[4-(Methoxymethyl)phenyl]-4-oxo- 4,5,6,7-tetrahydro- lH-indole-3-carboxamide. 16. A compound according to claim 1, which is N-[4-(Armnomethy.)phenyl]-4-oxo- 4,5,6,7-tetrahydro-lH-irιdole-3-carboxamide. 17. A compound according to claim 1, which is N-[4-(Methyl_-_ninomethyl)phenyl]-4- oxo-4,5,6,7-tetrahydiXHlH-indole-3-carboxamide. 18. A compound according to claim 1 , which is N-[2-Fluoro-4- (me-hyl-_-_dnotnethyl)phenyl]-4-oxo- 4,5,6,7-tetrahydro- lH-indole-3-carboxamide. 19. A compound according to claim 1 , which is N- { 4-[N-acetyl- (methylaιi- orrιethyl)phenyl]}-4-oxo-4,5,6,7-te -hydro-lH-indole-3-carD^ 20. A compound according to claim 1, which is N-[4-03thylaminomethyl)phenyl]-4- oxo-4,5,6,7-tetrahydro-lH-indole-3-carboxamide. 21. A compound according to claim 1 , which is N-[4-(Isopropylaminomethyl)phenyl]- 4 >xcr-4,5,6,7-tetrahydro-lH-indole-3-carboxamide. 22. A compound according to claim 1, which is N-{4- (Cycloproyla-r-momemyl)phenyl]-4-oxo-4,5,6,7-tetrahydro- lH-indole-3-carboxamide . 23. A compound according to claim 1, which is N-[4- (Dimeu ylarr-inomethyl)phenyl]4-oxo- 4,5,6,7-tetrahydro- lH-indole-3-carboxamide. 24. A compound according to claim 1 , which is N-[4-(2-Aminoethyl)phenyl]-4-oxo- 4,5,6,7-tetrahydro- 1 H-indole-3-carboxamide. 25. A compound according to claim 1 , which is N-[4-(2-Methylaminoethyl)phenyl]- 4oxo-4,5,6,7-tetrahydro-lH-indole-3-carboxamide. 26. A compound according to claim 1 , which is N-[4-(Methoxymethyl)phenyl]-4-oxo- 5,5-dimethyl-4,5,6,7-tetrahydro-lH-indole-3-carboxamide. 27. A compound according to claim 1, which is N-[4-(Methylaminomethyl)phenyl-4- oxo- 1 ,4,5,6,7,8-hexahydro-cyclohepta| ]pyrrole-3-carboxamide. 28. A compound according to claim 1 , which is N- {4-[N-acetyl- (meuιyl-ur_ ornethyl)phenyl])-4-oxo-6-rre 29. A compound according to claim 1, which is N-[4-(Meώyla-r_inomethyl)phenyl]-4- oxo-6-methyl-4,5,6,7-tetrahydιx>-lH-mdole-3-car-x>xa-nide. 30. A compound according to claim 1 , which is N-[4-(Hydroxymethyl)phenyl]-4-oxo- 6-methyl-4,5,6,7-tett^ydrc^lH-indole-3-carboxamide. 31. A compound according to claim 1 , which is N-[4-(2-Hydroxyethoxy)pheny l]-4- oxo-6-methyl-4,5,6,7-tetrahydπ>lH- dole-3-carboxamide . 32. A compound according to claim 1 , which is N-[3-(Methylaminomethyl)phenyl]-4- oxo-6-meu^yl-4,5,6,7-tetrahdπ>-lH- dole-3-carboxam-de. 33. A compound according to claim 1 , which is N-[4-(2-Hydroxyethoxyphenyl]-4- oxc>-6,6 -i-r-ethyl-4,5,6,7-tetrahyc_ro-lH-indole-3-carix)xan ide. 34. A compound according to claim 1 , which is N-[3-(Hydroxymethyl)phenyl] -4-oxo- 6,6-dimethyl-4-5,6,7-tetrahydro- lH-indole-3-carboxamide . 35. A compound according to claim 1, which is N-[4-(Hydroxymethyl)phenyl]-4-oxo- 6,6-dimethyl-4,5,6,7-tetrahydro-lH-indole-3-carboxamide. 36. A compound according to claim 1, which is N-[4-(Methylaminomethyl)phenyl]-4- oxo-6,6-dimethyl-4,5,6,7-tetrahydπ lH-indole-3-carboxamide. 37. A compound according to claim 1 , which is N-( 1 ,3-Benzodioxol-5-yl)-4-oxo- 4,5,6,7-tetrahydro-lH-indole-3-carboxamide. 38. A compound according to claim 1 , which is N-(2,3-Dihydro- 1 ,4-benzodioxin-6- yl)-4-oxo-4,5,6,7-tetrahydro-lH-indole-3-carboxamide. 39. A compound according to claim 1 , which is N-(3,4-Dihydro-2H- 1 ,4-benzoxazin- 6^y!)-4-oxo-4,5,6,7-tetrahydro-lH-indole-3-carboxamide. 40. A compound according to claim 1, which is N-(2,2-Diιnethyl-l,3-benzodioxol-5- yl)-4-oxo-4,5,6,7-tetrahydro- lH-indole-3-carboxamide. 41. A compound according to claim 1 , which is N-(2,3-Dihydro- 1 H-indol-5-yl)-4- oxo-4,5,6,7-tetrahydro- 1 H-indole-3-carboxamide. 42. A compound according to claim 1, which is N-(2,3-Dihydro-lH-indol-6-yl)-4- oxo-4,5,6,7-tetrahydro-lH-indole-3-carboxamide. 43. A compound according to claim 1, which is N-(l,3-Benzodioxol-5-yl)-4-oxo-5,5- dimethyl-4,5,6,7-tetπ-hydro-lH-indole-3-carboxamide. 44. A compound according to claim 1 , which is N-(2,3-Dihydro- 1 ,4-benzodioxin-6- yl)-4-oxo-5,5-o^ethyl-4,5,6,7-tetrahydix>-lH- dole-3-carboxamide. 45. A compound according to claim 1, which is N-(4H-l,3-Benzodioxin-7-yl)-4-oxo- 5,5-dimethyl-4,5,6,7-tetrahydro-lH-indole-3-carrx>xamide. 46. A compound according to claim 1 , which is N-(l,3-Benzodioxol-5-yl)-4-oxo- l,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide. 47. A compound according to claim 1 , which is N-(2,3-Dihydro- 1 ,4-benzodioxin-6- yl)-4-oxo- 1 ,4^,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide. 48. A compound according to claim 1 , which is N-(2,2-Dimethyl- 1 ,3-benzodioxol-5- yl)-4-oxo-6-rr-ed yl-4,5,6,7-tetrahydro- 1 H-indole-3-carixwamide. 49. A compound according to claim 1 , which is N-(l,3-Benzodioxol-5-yl)-4-oxo-6- me yl-4,5,6,7-tetrahydro-lH-indole-3-carboxamide. 50. A compound according to claim 1 , which is N-(2,3-Dihydro- 1 ,4-benzodioxin-6- yl)-4-oxo-6-rnethyl-4,5,6,7-tetrahydro-lH-indole-3-ca-toxamide. 51. A compound according to claim 1 , which is N-( 1 ,3-Benzodioxol-5-y l)-4-oxo-6,6- climethyl-4,5,6,7-tet-^ydro-lH--ndole-3-carboxamide. 52. A compound according to claim 1, which is N-(2,3-Dihydro-l,4-benzodioxin-6- yl)-4-oxo-6,6-dime yl-4,5,6,7-tetrahydro-lH-indole-3-carboxa.r-ide. 53. A compound according to claim 1, which is N-(4H-l,3-Benzodioxin-7-yl)-4-oxo- 6,6-dimethyl-4,5,6,7-teu^ydro-lH-indole-3-cart»xarnide. 54. A compound according to claim 1, which is N-[(2-Hydroxyethoxy)pyτid-5-yl]-4- oxo-6-methyl-4,5,6,7-tetrahydro- lH-indole-3-carboxaιnide. 55. A compound of the formula: where R3, R5, and R independently represent hydrogen, or alkyl; Ra represents hydrogen or alkyl where the alkyl is optionally halogenated; and e is an integer of 1-3. where R3, R5, and R independently represent hydrogen, or alkyl; Ra and Rb independently represent hydrogen or alkyl; and e is an integer of 2-3. 57. A compound of the formula: where R3, R5, and R independently represent hydrogen, or alkyl; R a represents hydrogen, alkyl, or C3-7 cycloaikyl; Rb represents hydrogen, alkyl, or acyl; Y represents hydrogen or halogen; and e is an integer of 1-3. 58. A compound of the formula: where R3, R5, and R independently represent hydrogen, or alkyl; Ra represents hydrogen or alkyl where the alkyl is optionally halogenated; and e is an integer of 1-3. 59. A compound of the formula: where G represents where Ra represents hydrogen, alkyl, or C3.7 cycloaikyl; Rb represents hydrogen, alkyl, or acyl; Y and Y' independently represent hydrogen or halogen; and e is an integer of 1-3. 60. A compound of the formula: where G represents: where Z is oxygen, nitrogen, or methylene; and m is 1 or 2.

Inventors: ALBAUGH PAMELA, HUTCHISON ALAN, LIU GANG, SHAW KENNETH, ALBAUGH, PAMELA, HUTCHISON, ALAN, LIU, GANG, SHAW, KENNETH
Applicants: ALBAUGH PAMELA, HUTCHISON ALAN, LIU GANG, NEUROGEN CORP, SHAW KENNETH, ALBAUGH, PAMELA, HUTCHISON, ALAN, LIU, GANG, NEUROGEN CORPORATION, SHAW, KENNETH
Application year: 1997
Main classification: C07D209
IPC codes: A61K31, A61P25, A61P43, C07D209, C07D401, C07D403, C07D405, C07D413