MXPA98007730A - Certain pirrolcarboxamidas fusionadas, a new lingandos of the receiver gaba del cere - Google Patents

Abstract

The present invention relates to structures of formula (I) and pharmaceutically acceptable non-toxic salts wherein (a) represents (b), (c), (d), or (e), wherein W represents substituted aryl groups or unsubstituted, X is hydrogen, hydroxy or lower alkyl, T is hydrogen, halogen, hydroxyl, amino or alkyl, R3 is hydrogen or an organic group, R4 is hydrogen or substituted or unsubstituted organic substituent, R5 and R6 represent organic and inorganic substituents and is 1, 2, 3 or 4. These compounds are agonists, highly selective antagonists or inverse agonists for brain GABAa receptors or prodrugs or agonists, antagonists or inverse agonists for brain GABAa receptors. These compounds are useful in the diagnosis and treatment of anxiety, sleep disorders, seizures, overdoses with benzodiazepine drugs and for the improvement of memory.

Description

CERTAIN PI ROLCARBQXAMIDAS FUSIONADAS; A NEW CLASS OF LIGANDQS OF THE GABA RECEIVER OF THE BRAIN.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention relates to certain fused pyrrolecarboxar.ilides that selectively bind to the GABAa receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It is also related to the use of such compounds to treat anxiety, sleep and access disorders, and overdoses of drugs of the benzodiazepine type, and increased attention, and overdoses of benzodiazepine-type drugs, and increased attention .

DESCRIPTION OF THE RELATED TECHNIQUE The α-aminobutyric acid (GABA) is considered as one of the main inhibitors of amino acid transmitters in the mammalian brain. During the 30 years that have elapsed, since then its presence has been demonstrated in the REF .: 28524 brain. (Roberts &Frankel, J. Biol. Chem 187, 55-63, 1950, Udenfried, J. Biol. Chem. 187 65-69, 1950). Since that time, a great deal of effort has been devoted to involving GABA in the etiology of 1 access, sleep, anxiety and perception disorders (Tallman and - Galager, Ann. Rev. Neuroscience 8_; 21-44, 1985). Broadly, although unequally, distributed through the mammary brain, GABA is mentioned to be a transmitter in approximately 30% of the brain's synapses. In most regions of the brain, GABA is associated with local inhibitory neurons and in only two regions, GABA is associated with larger projections. GABA mediates many of its actions through a complex of proteins located both in cell bodies and in nerve terminals; these are called GABAa receptors. Postsynaptic responses to GABA are mediated through alterations in the. conductance or conductive power of the chloride that generally, although not invariably, lead to the h'iperpolarization of the cell. Recent research has indicated that the protein complex, associated with postsynaptic GABAa responses, is a primary site of action for a number of structurally unrelated compounds, capable of modifying the postsynaptic responses to GABA. Depending on the form of interaction, these compounds are capable of producing a spectrum, of activities (either sedative, anxiolytic and anticonvulsant, or insomnia, access and anxiety). The 1,4-benzodiazepines continue to be the most widely used prodrugs in the world. Among the main benzodiazepines sold are chlordiazepoxide, diazepam, flurazepam and trazol-am. These compounds are widely used as anxiolytics, hypnotics-sedatives, 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. Previous electrophysiological studies indicate that a major action of benzodiazepines had increased GABAergic inhibition. The benzodiazepines are capable of improving the presynaptic inhibition of a monosynaptic ventral root reflex, an event mediated with GABA (Schmidt et al., 1967, Arch. Exp. Path. Pharmakol. 258: 69-82). All subsequent electrophysiological studies (reviewed in Tallman et al., 1980, Science 207; 274-81, Haefley et al., 1981, Handb. Expt. Pharmacol. 33_: 95-102) have generally confirmed this discovery, and approximately In the mid-1970s, there was a general consensus among electrophysiologists that benzodiazepines could increase the actions of G-ABA. With the discovery of the "receptor" for benzodiazepines and the subsequent definition of the nature of the interaction between GABA and benzodiazepines, he suffers that the important behavioral interactions of benzodiazepines with different neurotransmitter systems are due in large part to the increased capacity of GABA itself to modify these systems. Each modified system, in turn, may be associated with the expression of a behavior. Studies on the mechanical nature of these interactions depend on the demonstration of a high affinity benzodiazepine binding site (receptor). Such a receptor is present in the CNS of all vertebrates phylogenetically more recent than the fish with spines (Squires & amp;; Braestrup 1977, -Nature 1966: 732-34, Mohler & Okada, 1977, Science 198: 854-51, Mohler & Okada, 1977, Br. J. Psychiatry 133: 261-68). Using tritiated diacepam, and a variety of other compounds, it has been shown that these benzodiazepine binding sites meet many of the criteria of pharmacological receptors; The union of these sites in vi is fast, reversible, tereospecific, and saturable. More importantly, extremely important correlations have been shown between the ability of benzodiazepines to displace diazepam from its site and binding activity in a number of predicted animal behavior tests of benzodiazepine potency (Braestrup &Squires 1978, Br J. Psychiatry 133; 249-60, Mohler &Okada, 1977. Science 198: 854-51, Mohler &Okada, 1977, Br J. Psychiatry 133: 261-68). The average therapeutic doses of these drugs in man also correlate with the potency of the receptor (Tallman et al., 1980, Science 207: 274-281). In 1978, it is clear that GABA and related analogs could interact at the binding site of lower affinity GABA (1 mM) to increase the binding of benzodiazepines to the sensitive site of clonazepam (Tallman et al., 1978, Nature, 274 : 383-85). This increase is caused by an increase in the affinity of the benzodiazepine binding site due to the occupation of the GABA site. The data are interpreted to mean that both GABA and benzodiazepine sites are thermally bound in the membrane as part of a protein complex. For a number of GABA analogues, the ability to increase the binding of diazepam by 50% of maximum and the ability to inhibit the binding of GABA to brain membranes by 50% could be directly correlated. The increased binding of benzodiazepine by the agonists and GABA is blocked by the (+) bicuculline antagonist of the GABA receptor; the stereoisomer (-) bicuculline is much less active (Tallman et al., 1978, Nature, 274; 383-85). Shortly after the discovery of high-affinity binding sites for benzodiazepines, it was discovered that a triazolopyrazine might interact with banzodiazepine receptors in a number of regions of the brain in a manner consistent with the heterogeneity or negative cooperativity of the receptor. In these studies, Hill coefficients significantly less than 1 were observed in a number of brain regions, including the cortex, the hippocampus and the striatum. In the cerebellum, the triazolopyridazine interacts with the benzodiazepine sites with a Hill coefficient of 1 (Squires et al., 1979, Pharma, Biochem Behav 10_: 825-30, Klepner et al., 1979, -Pharmacol. Biochem. Behav .11: 457-62). In this way, multiple benzodiazepine receptors are predicted in the cortex, hippocampus, striatum, but not in the cerebellum. Based on these studies, studies of autoradiographic localization of the extensive receptor are carried out at a microscopic level of light. Although receptor heterogeneity has been demonstrated (Young &Kuhar 1980, J. Pharmacol.Exp.Ther. 212: 337-46, Young et al., 1981, J. Pharmacol.Exp.Ther.St.216: 425-430, Niehoff et al., 1982, J. Pharmacol. Exp. Ther. 221: 670-75), it has emerged from previous studies that there is no simple correlation between the location of the receptor subtypes and the behaviors associated with the region. In addition, in the cerebellum, where a receptor was predicted from the binding studies, autoradiography revealed heterogeneity of receptors (Niehoff et al., 1982, J. Pharmacol.Exp.t. 221: 670-75). A physical basis for differences in drug specificity for the two apparent subtypes of benzodiazepine sites has been demonstrated by Sieghart & Karobath, 1980, Nature 286: 285-87. Using gel electrophoresis in the presence of sodium dodecyl sulfate, the presence of various molecular weight receptors for benzodiazepines has been reported. The receptors are identified by the covalent incorporation of radioactive f-luni t racepam, a benzodiazepine that can covalently classify all types of receptors. The main classified bands have molecular weights of 50,000 to 53,000, 55,000 and 57,000 and the thiazolopyridazines inhibit the classification of slightly larger molecular weight forms (53,000, 55,000, 57,000) (Seighart et al., 1983, Eur. Pharmacol. 8_8_: 291-99). At that time, the possibility arose that multiple forms of the receiver represent "iso-receptors" or multiple allelic forms of the receptor (Tallman &; Callager 1985, Ann. Rev. Nurosci. 8_, 21-44). Although the genetically distinct forms of the receptors, common for enzymes, have not been generally described. As we begin to study receptors using specific radioactive probes and electrophoretic techniques, it is almost certain that receptors will emerge as important in the investigation of the etiology of psychiatric disorders in people. GABAa receptor subunits have been cloned from bovine and human cDNA libraries (Schoenfield et al., 1988; Duman, et al., 1989). A number of different cDNAs have been identified as subunits of the GABAa receptor complex by cloning and expression. These are categorized into a, ß,?, D, e, and provide a molecular basis for the heterogeneity of the GABAa receptor and distinctive regional pharmacology (Shivvers et al., 1980; Levitan et al., 1989). The subunit? it seems to allow drugs, similar to benzodiazepines, to modify the responses to GABA (Pritchett et al, 1989). The presence of low Hill coefficients in the binding of the ligands to the GABAa receptor indicates unique profiles of subtype-specific pharmacological action. The drugs that interact in the GABAa receptor may possess a spectrum of pharmacological activities that depend on their abilities to modify the actions of GABA. For example, beta-carbolines were the first isolated based on their ability to competitively inhibit the binding of diacepam to its binding site (Nielsen et al., 1979, Life Sci. 2_5: 679-86). The receptor binding assay does not completely predict the biological activity of such compounds; antagonists, partial agonists, inverse agonists and antagonists can inhibit the union. When beta-carboline was determined, it was possible to determine a number of analogs and test these co-taxes for their behavior. It was immediately understood that beta-carbolines could antagonize the actions of diazepam by their behavior (Teñen &Hirsch, 1980, Nature 288: 609-10). Furthermore, for this antagonism, beta-carbolines possess intrinsic activity of their own opposites for those benzodiazepines; they become known as inverse agonists. In addition, a number of other benzodiazepine receptor specific antagonists were developed based on their ability to inhibit benzodiazepine binding. The most studied of these compounds is an imidazodiazepine (Hunkeler et al., 1981, Nature 290: 514-516). This compound is a competitive inhibitor of high binding affinity of benzodiazepine and beta-carboline and is capable of blocking the pharmacological actions of both classes of compounds. By itself, it possesses small intrinsic pharmacological activity in animals and humans (Hunkeler et al., 1981, Nature 290: 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 shown that this compound could interact with the same number of sites as benzodiazepines and beta-carbolines, and that Interactions of these compounds were purely competitive. This compound is the ligand of choice for the binding of GABAa receptors because it has no receptor subtype specificity and measurements of each receptor state. The study of the interactions of a wide variety of compounds similar to the previous ones has led to the categorization of these compounds. Currently, those compounds that have activity similar to benzodiazepines are called agonists. Compounds that have opposite activity to benzodiazepines are called inverse agonists and compounds that block both types of activity have been called 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 in the same receptor to produce opposite effects and to indicate that beta-carbolines and antagonists with intrinsic .ansiogenic effects are not synonymous. A biochemical test for the pharmacological and behavioral properties of the compounds that interact with the benzodiazepine receptor continues to emphasize the interaction with the GABAergic system. In contrast to benzodiazepines, which show an increase in their affinity due to GABA (Tallman et al., 1978, Nature 274, 383-85, T'allman et al., 1980, Science 207: 274-81), compounds with antagonistic properties show small change in GABA (ie, change in receptor affinity due to GABA) (Mohler &Richards 1981, Nature- 294: 763-65), and inverse agonists currently show a decrease in the affinity due to GABA (Braestrup &Nielson 1981, Nature 294: 472-474). In this way, the change in GABA generally predicts the expected behavior properties of the compounds. Various compounds have been prepared as benzodiazepine agonists and antagonists. for example, U.S. Patent Nos. 3,455,943, 4,435,403 ', 4,596,808, 4,623,649, • and 4,719,210, German Patent No. 3,246,932, and Liebigs Ann. Chem. 1986, 1949 teach the antagonists and antagonists of benzodiazepine and active compounds of the central nervous system and antidepressants. U.S. Patent No. 3,455,943 discloses compounds of the formula: wherein Rx 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 bivalent radical selected from the group consisting of \ ^ NH ^ 1 ^ N - lower alkyl lower alkyl lower alkyl ^ ^? N lower alkyl the non-toxic acid addition salts thereof.

Other references, such as U.S. Patent No. 4,435,403 and German Patent DE 3,246,932 describe compounds that contain the following structural scheme: where A is a carbon or nitrogen. A variety of indole-3-carboxamides is described in the literature. For example, J. Org. Chem., 42: 1883-1885 (1977) describes the following compounds.

J. Heterocylic Chem., 14_ 519-520 (1977 describes a compound of the following formula.

None of these indole-3-carboxamides includes an oxy substituent at the 4-position of the indole ring. U.S. Patent No. 5,484,944, the description of which is incorporated herein in its entirety, describes c-omponents of the general formula: or the non-toxic pharmaceutically acceptable salts thereof wherein: T is halogen, hydrogen, hydroxyl, amino or straight or branched chain lower alkoxy having 1-6 carbon atoms; X is hydrogen, hydroxyl or straight or branched chain lower alkyl having 1.6 carbon atoms; W is phenyl, 2- or 3-thienyl, 2-, 3-, or 4-pyridyl or 6-quinolinyl, each of which may be mono- or di-substituted by halogen, cyano, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms; amino, mono or dialkylamino wherein each alkyl is independently straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, or NR? C0R2, COR2, CONR R2, or CO2R2 where Ri and R2 are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms; Y It represents wherein: Y represents nitrogen 'or C-R; Z represents N-R7 or a carbon atom substituted with R8 and R9, that is, C (R8) (Rg); n is 1, 2, 3 or 4; R3 is hydrogen, phenyl, 2-, 3-, or 4-pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or 2-, 3-, or 4-pyridylalkyl where each alkyl is alkyl lower straight or branched chain having 1-6 carbon atoms; R4 is halogen or trifluoromethyl; u -ORÍO, -COR10, -CO2R10 / -OCOR10, or -Rio, where Rio is hydrogen, phenyl, 2-, 3, or 4-pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or 2-, 3-, or- pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or -CONR11R12 or - (CH2) mNRn i2, where m is 0, 1, or 2; R11 represents hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms; and R12 is hydrogen, phenyl, 2-, 3-, or 4-pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or 2-, 3-, or 4-pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or NRpRp forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl or N-alkyl-piperazinyl; R5 and Re 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; R7 is hydrogen, phenyl, 2-, 3-, or 4-pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or 2-, 3, or 4-pyridylalkyl where each alkyl is alkyl lower straight or branched chain having 1-6 carbon atoms; Rg is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, and R9 is -COR? 3 -CO2R13, or -R13, where Rx3 is hydrogen, phenyl, 2-, 3-, or 4- pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or 2-, 3-, or 4-pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or -CONR14R15 or - (CH2) NR? 4Ri5, where k is 0, 1, or 2; R 4 represents hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms; and R15 is hydrogen, phenyl, 2-, 3-, or 4-pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or 2-, 3-, or 4-pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or NR14R15 forms a. heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl or N-alkyl-piperazinyl. International Application No. PCT / US94 / 12300, filed on October 26, 1994 and published on May 4, 1995, the description of which is incorporated herein in its entirety, also discloses pyrrole derivatives of the formula g generally described in U.S. Patent No. 5,484,944, that is, Substitutes on this general formula are as defined in U.S. Patent No. 5,484,944. In addition, the Application of the United States S.N. 08 / 473,509, filed June 7, 1995, the description of which is hereby incorporated in its entirety, discloses compounds of the general formula set forth in U.S. Patent No. 5,484,944.

BRIEF DESCRIPTION OF THE INVENTION The invention provides novel compounds of Formula I that 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 access disorders, overdoses with benzodiazepine drugs and to increase memory. Accordingly, a broad embodiment of the invention is directed to compounds of the general Formula I: or the pharmaceutically acceptable non-toxic salts thereof wherein: W is aryl or heteroaryl; and T is halogen, hydrogen, hydroxyl, amino or straight or branched chain lower alkoxy having 1-6 carbon atoms; -X is hydrogen, hydroxyl, or straight or branched chain lower alkyl having 1-6 carbon atoms; m e s 0, 1 or 2; n is O, 1, OR 2; and R3, and R4 are the same or different and are selected from hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms or cycloalkyl having 3-7 carbon atoms, CONR6R7 wherein R6 and R7 are independently selected from hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, phenyl, 2-, 3-, or 4-pyridyl, or NR6R7 forms a heterocyclic group which is morpholinyl , piperidinyl, pyrrolidinyl, or N-alkyl-piperazinyl; or R3-R4 together represent a cyclic portion having 3-7 carbon atoms; and wherein each alkyl substituent in Formula I is optionally substituted with at least one group independently selected from hydroxy, mono- or dialkylamino, phenyl or pyridyl. These compounds are highly selective inverse agonists, antagonists or agonists for brain GABAa receptors or prodrugs of agonists, antagonists or inverse agonists for brain GABAa receptors. In other words, while all of the compounds of the invention interact with the brain receptors of GABAa, they do not exhibit identical physiological activity. In this way, these compounds are useful in the diagnosis and treatment of anxiety, sleep and access disorders, overdoses with benzodiazepine drugs and to increase memory. For example, these compounds can be used to treat overdoses of benzodiazepine-like drugs and could bind competitively to the benzodiazepine receptor.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "aryl" refers to aromatic carbocyclic groups having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple co-condensed rings in which less one is aromatic, (eg, 1, 2, 3, 4, -tetrahydronaphthyl, naphthyl, anthryl or phenanthryl), which may be optionally substituted with, for example, halogen, lower alkyl, lower alkylthio, trifluoromethyl, lower acyloxy , aryl and heteroaryl. A preferred aryl group is phenyl optionally substituted with up to five groups independently selected from halogen, cyano, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms or cycloalkyl having 3-7 carbon atoms, amino, mono or dialkylamino wherein each alkyl is independently straight or branched chain lower alkyl having 1-6 carbon atoms or cycloalkyl having 3-7 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms or cycloalkylalkoxy which has 3-7 carbon atoms, or NRxCOR2, COR2, CONR2 or C02R2 where Rx and R2 are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms or cycloalkyl having 3-7 carbon atoms. By "heteroaryl" is meant aromatic ring system having at least one and up to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Examples of heteroaryl groups are pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl, naphthyridinyl, isoxazolyl, phthalazinyl, furanyl, quinolinyl, isoquinolinyl, thiazolyl and thienyl, which can be optionally substituted with, for example, halogen. , lower alkyl, lower alkoxy, lower alkylthio, rifluoromethyl, lower acyloxy, aryl, heteroaryl and hydroxy. The aryl and heteroaryl groups herein are systems characterized by 4n + 2 p electrons, where n is' an integer. In addition, for those mentioned in the above, other examples of the aryl and heteroaryl groups included in the invention are the following: As noted above, each of these groups may optionally be mono- or polysubstituted with groups independently selected from, for example, halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl and hydroxy. Still other examples of various aryl and heteroaryl groups are known in Diagram D of the published International Application WO 93/17025. By "alkyl" and "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, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. Unless otherwise indicated, the substituents of the alkyl group herein are optionally substituted with at least one group independently selected from hydroxy, mono- or dialkylamino, phenyl or pyridyl. Where R3 and R4 are both alkyl, each alkyl is independently selected from lower alkyl. By "alkoxy" and "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. As used herein "cycloalkylalkoxy" refers to groups of the formula (CH2) to CH - (CR'R-JBO ' where a is an integer from 2 to 6. R 'and R "independently represent hydrogen or alkyl, and b is an integer from 1 to 6. By the term" halogen "in the present invention is meant fluorine, bromine, chlorine and iodine By "N-alkylpiperazyl" in the invention is meant radicals of the formula: N-R where R is alkyl as defined above. By "monoalkylamino" as used herein is meant an aminq substituent substituted with one (1) alkyl group, wherein the alkyl group is lower alkyl as defined above or cycloalkyl having 3-7 carbon atoms. By "dialkylamino" as used herein is meant an amino substituent substituted with two (2) alkyl groups, wherein the alkyl groups are independently lower alkyl groups as defined in the foregoing or cycloalkyl having from 3-7 atoms of carbon. The novel compounds encompassed by the present invention can be described by the general formula I set forth above or the non-toxic pharmaceutically acceptable salts thereof. In addition, the present invention encompasses compounds of Formula II.

II wherein R3 and R4 are the same or different and represent hydrogen, alkyl, COR5 or C02R5, where R5 is alkyl or cycloalkyl having 3-7 carbon atoms. CONReR7, where Rβ and R7 are independently selected from hydrogen, alkyl, cycloalkyl having 3-7 carbon atoms, phenyl, 2-, 3- or 4-pyridyl or NR6R7 forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl or N-alkyl-piperazinyl; or R3-R4 together represent a cyclic portion having 3-7 carbon atoms; Rβ is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkylalkoxy having 3-7 carbon atoms, amino, mono- or dialkylamino; and R9 is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycloalkylalkoxy having 3-7 carbon atoms, amino, mono- or dialkylamino, RN1COR2, COR2 or C02R2, where R and R2 are the same or different and represent hydrogen, alkyl, or cycloalkyl having 3-7 carbon atoms, and Rio is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or dialkylamino; m is 0, 1 or 2; and n 'is 0, 1 or 2. Preferred compounds of Formula II are those wherein the phenyl group is mono-, di- or trisubstituted at positions 2, 4 and / or 5 relative to the point of attachment of the ring of phenyl to the amide nitrogen. In addition, the present invention encompasses the compounds of Formula III.

III wherein R3 and R are the same or different and represent hydrogen or alkyl; R is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkylalkoxy having 3-7 carbon atoms, amino, mono- or dialkylamino; and Rg is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycloalkylalkoxy having 3-7 carbon atoms, amino, mono- or dialkylamino, NR? COR2, COR2 or C02R2, where Ri and R2 are the same or different and represent hydrogen, alkyl or cycloalkyl that has 3-7 carbon atoms; and Rio is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or dialkylamino. Preferred compounds of Formula III are those in which the phenyl group is mono-, di or trisubstituted at positions 2, 4 and / or 5 relative to the point of attachment of the phenyl ring to the amide nitrogen. Particularly preferred compounds of formula III are those where the phenyl group is trisubstituted at the 2-positions, 4. and 5 relative to the point of attachment of the phenyl ring to the amide nitrogen, and Rs, R9 and Rio are independently selected from hydrogen, halogen, hydroxy, alkoxy and alkyl, with the proviso that none of Rs, R9 and R or be hydrogen In addition, the present invention encompasses the compounds of Formula IV IV wherein R3 represents alkyl; Rs is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkylalkoxy having 3-7 carbon atoms, amino, mono- or dialkylamino; and Rg is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycloalkylalkoxy having. 3-7 carbon atoms, amino, mono- or di-alkylamino, NR? COR2, COR2 or CO2R2, where Rx and R2 are the same or different and represent hydrogen, alkyl or cycloalkyl having 3-7 carbon atoms; and Rio is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or dialkylamino. Preferred compounds of Formula IV are those wherein R8, Rg and Rio are independently selected from hydrogen, halogen, hydroxy, alkoxy and alkyl, with the proviso that none of R8, Rg and Rio are hydrogen. In addition, the present invention encompasses the compounds of Formula V wherein R3 and R are the same or different and represent alkyl; R s is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkylalkoxy having 3-7 carbon atoms, amino, mono- or dialkylamino; and Rg is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycloalkylalkoxy having 3-7 carbon atoms, amino, mono- or dialkylamino, NR1COR2, COR2 or CO2R2, where Rx and R2 are the same or different and represent hydrogen, alkyl or cycloalkyl having 3-7 carbon atoms; and Rio is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or dialkylamino. Preferred compounds of Formula V are those wherein Rs, R9 and Rio are independently selected from hydrogen, halogen, hydroxy, alkoxy and alkyl, with the proviso that none of Ra, R9 and Rio are hydrogen. Particularly preferred compounds of Formula V are those where R3 and R4 are both methyl, and Rs, R_ and Rio are independently selected from hydrogen, halogen, hydroxy, alkoxy and alkyl, with the proviso that none of Ra, R9 and Rio be hydrogen In addition, the present invention encompasses the compounds of Formula VI.

SAW where q is an integer from 2-6; Rs is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkylalkoxy having 3-7 carbon atoms, amino, mono- or dialkylamino; and Rg is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycloalkylalkoxy having 3-7 carbon atoms, amino, mono- or alkylamino, RN? COR2 / COR or CO2R2, where RL and R? are the same or different and represent hydrogen, alkyl, or cycloalkyl that has 3-7 carbon atoms, and Rio is. hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or dialkylamino; m is 0, 1 or 2; and n is O, 1 or 2. Preferred compounds of the Formula VI are those in which R 8, R 9 and Rio are independently selected from hydrogen, halogen, hydroxy, alkoxy and alkyl, with the proviso that none of Rs, Rg and Rio are hydrogen. In addition, the present invention encompasses the compounds of Formula VII. vp where G represents aryl or heteroaryl such as, for example, thienyl, thiazolyl, pyridyl, naphthyridinyl, quinolinyl or phenyl, each of which is optionally mono-, di- or trisubstituted with halogen, alkyl, alkoxy or hydroxy; and R? and R4 are the same or different and represent hydrogen or alkyl, with the proviso that none of R3 and R4 are hydrogen. Preferred compounds of Formula VII are those wherein R3 and R4 are C3_3 alkyl, and most preferably methyl. Other preferred compounds of Formula VII are those wherein R3 is hydrogen and R4 is C3_3alkyl, and most preferably R4 is methyl. Preferred compounds of Formula VII include a group G selected from the following: CO N-4-, In groups G above, the following definitions apply: R_ is halogen; Rb is hydroxy; Rc represents alkoxy; R represents alkyl; Re represents hydrogen or R ^; Rf represents hydrogen or Rc; and Rq represents hydrogen, Ra or Rc. In those formulas where more than one of the same substituent appears, those substituents are the same or different. Particularly preferred Ra groups in G- are fluorine. Particularly preferred Rc groups in G are methoxy and ethoxy. Particularly preferred groups R_ in G are methyl and ethyl. Representative compounds of the invention are shown in the following Table 1.

Table 1 Item 9 Compound 10 The following numbering system is used to identify the positions in the pyrrole ring portion of the compounds of the invention: Compounds representative 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. The non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, s-ulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, iohydric, alkanoic such as acetic, HOOC- ( CH2) n-C00H, where n is 0-4 and the like. Those. Those skilled in the art will recognize a wide variety of pharmaceutically acceptable n-or toxic addition salts. The present invention also encompasses the prodrugs, preferably acylated prodrugs, of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies that can be employed to prepare non-toxic pharmaceutically acceptable addition salts and prodrugs of the compounds encompassed for Formula I. The pharmaceutical utility of the compounds of this invention is indicated by the following assays for the binding activity of the GABAa receptor. The assays are carried out as described in Thomas and Tallman (J. Bio, Chem. 156: 9838-9842, J. Neurosci. 3_: 433-440, 1983). The rat cortical tissue is dissected and homogenized in 25 volumes (w / v) of 0.05M Tris HCl buffer (pH 7.4 at 4 ° C). The homogenate tissue is centrifuged in the cold (4 ° C) at 20,000 x g for 20 '. The supernatant is decanted and the pellet is rehomogenized in the same volume of the 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 volumes (original p / v) buffer and the procedure is carried out twice. The pellet is finally resuspended in 50 volumes (p / v of tris buffer HCl 0.C5 M (pH of -4 to 40 ° C).

Incubations contain 100 ml of homogenate tissue, 100 ml of 0.5 nM radioligand (specific activity 3H-R015-1788 [3H-Flumazenil] 80 Ci / mmol), drug or blocker and buffer for a total volume of 500 ml. Incubations are carried out for 30 minutes at 4 ° C, then filtered rapidly through GFB filters to separate the free and bound ligand. The filters are washed twice with freshly prepared 0.05 M Tris HCl buffer (pH 7.4 at 4 ° C) and counted in a liquid scintillation counter. 1.0 mM of diazepam is added in some tubes to determine non-specific binding. Data are collected in triplicate determinations, the percentage of total inhibition of the specific binding is averaged and calculated. Specific Union Total = Total - Not specified. In some cases, the amounts of unlabeled drugs are varied and the total binding displacement curves are carried out. The data is converted to Ki, the results for the compounds of this invention are listed in Table 2.

TABLE 2 Compound Number Kx (nM) 1 21 2 12 3 13 4 1 5 0.5 6 1 7 10 8 80 9 4 10 12 The compounds of the general formula I can be administered ocally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional, pharmaceutically acceptable non-toxic carriers, adjuvants and vehicles. The term "parenteral" as used herein includes subcutaneous injections, injection techniques or intravenous, intramuscular, intrasternal infusion. In addition, a pharmaceutical formulation comprising a compound of the general formula I and a pharmaceutically acceptable carrier is provided. One or more compounds of the general formula I may be present in association with one or more pharmaceutically acceptable non-toxic carriers and / or diluents and / or adjuvants, and if desired, other active ingredients. The pharmaceutical compositions containing the compounds of the general formula I can be in a form suitable for oral use, for example as tablets, troches, lozenges, oily or aqueous suspensions, dispersible powders or granules, emulsion, hard or soft capsules or syrups or elixirs. The compositions intended for oral use can be prepared according to any method known in the art for the manufacture of the pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, s-aborising agents, coloring agents .and conservative agents for. to provide pharmaceutically elegant and pleasant preparations. The tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic 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 for disintegration and delayed absorption in the gastrointestinal tract and thereby provide a sustained action over a long period. For example, a time-delayed material such as glyceryl monostearate or slitty 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 oily 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 carboxymethyl cellulose, methyl cellulose, hydropropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum and acacia gum; the dispersing agents or humectants may be a phosphatide which exists in a natural form, 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, 5 heptadecaethylene oxyketanol, 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 • II 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. 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 can be added to provide pleasant oral preparations. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for the 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 in the foregoing. Additional excipients may also be present, for example sweetening, flavoring and coloring agents. The 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 peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be naturally occurring gums, for example acacia gum or tragacanth gum, naturally occurring phosphatides, for example soy, lecithin and esters or partial esters derived from fatty acids and hexitol, anhydrides, example sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, for example polyoxyethylenediobitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol 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 or oleaginous injectable aqueous suspension. This suspension can be formulated according to the known art using those dispersing agents or suitable humectants and suspending agents that have been mentioned in the foregoing. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, sterile oils are conventionally employed as a solvent or suspending medium. Any soft fixed oil including synthetic mono- or diglycerides can be used for this purpose. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of the general formula I can 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 fuse in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

The compounds of the general formula I 'can be administered parenterally in a sterile medium. The drug, which depends on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and deadening agents can be dissolved in the vehicle. The dose levels of the order from approximately 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of. conditions indicated in the above (approximately 0.5 mg to approximately 7- g per patient per day). The amount of the active ingredient that can be combined with the carrier materials to produce an individual dosage form will vary depending on the host treated and the particular mode of administration. Dosage unit forms will generally contain between about 1 mg to about 500 mg of an active ingredient. Nevertheless, it will be understood that the specific dose level for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration and speed of excretion, combination of drug and the severity of the therapy that the particular disease suffers from. An illustration of the preparation of the compounds of the present invention is given in Scheme I. Scheme 1 MsCL £ t, N CH £ l3.0aC where, m, n, R3 and R4 are as defined in the above. Those of skill in the art will recognize that the initial materials can be varied and the additional steps employed to produce the compounds encompassed by the present invention, as demonstrated by the following examples. In some cases, the protection of certain reactive functionalities may be necessary to achieve some of the above transformations. ' In general, the need for such protective groups will be apparent to those skilled in the art of organic synthesis, as well as the conditions necessary to unite and eliminate such groups Descriptions in this application of all articles and references, including patents, are hereby incorporated by reference in their entirety The invention is further illustrated by the following examples, which are not to be construed as limiting the scope or spirit of the invention for the specific procedures described therein.

Example 1 Preparation of initial and intermediate materials The starting materials and various intermediates can be obtained from commercial sources, prepared from commercially available organic compounds or prepared using well-known synthetic methods. Representative examples of methods for preparing the intermediates of the invention are set forth in the following.

J 3 -Hydroxy-4 -oxo-6-methyl-2, 3,4,5,6,7-hexahydrobenzofuran-3-carboxylate ethyl To a stirred mixture of 5-methyl-1-, 3-cyclohexanedione (10.25 g, 81 mmol) and potassium carbonate (22.46 g, 162 mmol) in dichloromethane (200 ml) at 0 ° C was added a bromopyruvate solution of ethyl (10.7 ml, 85 mmol) in dichloromethane (50 ml). The reaction is allowed to reach room temperature, stirred for 18 hours, then emptied into saturated aqueous ammonium chloride. After adjusting to neutral pH with aqueous hydrochloric acid, the mixture is extracted 2X with dichloromethane, the combined organic layers are dried over sodium sulfate, filtered and concentrated in vacuo to give 3-hydroxy-4-oxo-6-. methyl-2, 3, 4, 5, 6, 7-hexahydrobenzofuran-3-carboxylic acid ethyl ester (18.48 g). __. 4-Oxo-6-methyl-4, 5, 6, 7-tetrahydrobenzofuran-3-carboxylate ethyl A solution of methanesulfonyl chloride (6.1 ml, 78.5 mmol) in dichloromethane (50 ml) is added to a stirred solution of 3-hydroxy-4-oxo-6-methyl-2, 3, 4, 5, 6 , 7-hexahydrobenzo-furan-3-carboxylic acid ethyl ester (18.48 g, 76 mmol) and triethylamine (21.4 ml, 154 mmol) in dichloromethane (150 ml) at 0 ° C. The mixture is allowed to reach room temperature, is stirred for 2 hours, then is poured into 1N aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 4-oxo-β-methyl-4,5,6,7-tet ethyl rahydrobenzofuran-3-carboxylate ( 16.86 g). 3_. 4-oxo-6-methyl-4,5,6,7-tetrahydro-l-indole-3-carboxylic acid A mixture of ethyl 4-oxo-6-met il-4, 5, 6, 7-tet rahydrobenzofuran-3-carboxylate (15.7 g, 71 mmol) and ammonium acetate (9.54 g, 124 mmol) in N, N , -dimet ilformamide (75 ml) is heated at 100 ° C for 2 hours. The reaction mixture is concentrated in vacuo, water is added with ice, and the precipitate is collected, rinsed with water then diethyl ether and dried to give 4-oxo-6-met il-4, 5, 6, 7-ethyl tetrahydro-lH-indol-3-carboxylate (5.94 g). To this ester is added 5N aqueous sodium hydroxide (50 ml) and ethyl alcohol (10 ml) and the mixture is refluxed for 40 minutes. The reaction mixture is cooled in an ice water bath, acidified with aqueous hydrochloric acid, and the precipitate is collected, rinsed with water then diethyl ether and dried to give 4-oxo-6-methyl-4,5 acid. , 6, 7-tetrahydro-lH-indole-3-carboxylic acid (5.2 g), mp 210-211 ° C. 4_. Essentially, 4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (mp 231-232 ° C) is prepared according to the procedures described in Parts 1- 3 of these examples.

Example 2 It is added to a solution of 4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-l-indole-3-carboxylic acid (155 mg, 0.75 mmol) and triethylamine (209 μl, 1.5 mmoles) in dimethylformamide (4 ml) at 0 ° C ethyl chloroformate (143 μl, 1.5 mmol). After stirring an additional 45 minutes, 2-fluoroaniline (145 μl, 1.5 mmol) is added. The reaction mixture is stirred for 30 minutes, then it is drained in 3.6N hydrochloric acid and 2X extracted with ethyl acetate. The combined organic layers are washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. 5N sodium hydroxide (5 ml) and ethyl alcohol (1 ml) are added to the residue, and the mixture is refluxed for 30 minutes. After cooling in a water bath with ice, the reaction mixture is acidified with hydrochloric acid, the precipitate is collected, rinsed with water, and dried to give 55 mg of N-82-fluorophenyl) -4-oxo- 6,6-Dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 2).

EXAMPLE 3 The following compounds are essentially prepared according to the procedures described in Examples 1 and 2. (a) N-Phenyl-4-oxo-6,6-dimethyl-4, 5, 6, 7-tet rahydro- lH-indole-3-carboxamide (Compound 1) (b) N- (2-Fluorophenyl) -4-oxo-6,6-dimet i 1- 4, 5, 6, 7-tetrahydro-lH-indol- 3- carboxamide; mp 259-2.61 ° C. (c) N- (3-Fluorophenyl) -4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-lH-indole-3-carboxamide; 268-270 ° C. (D) N- (2,4-Difluorophenyl) -4-oxo-6,6-dimet and 1-4,5,6,7-tetrahydro-lH-indole-3-carboxamide. (e) N- (2,4-Difluorophenyl) -4-oxo-6,6-dimethyl-4,5,6,7-hephydro-lH-indole-3-carboxamide. (f) N- (3-Methoxyphenyl) -4-OXO-6,6-dimethyl-4,5,6,7-tetrahydro-lH-indo-3-carboxamide. (g) N- (2-Hydroxy-4-methoxyphenyl) -4-oxo-d, 6-dimethyl-4,5,6,7-tetrahydro-1 H-indole-3-carboxamide; p.f. 190-192 ° C. (h) N- (3-Hydroxy-4-methoxy phenyl) -4-oxo-6,6-dimethyl-4,5,6,7-dihydro-1H-indole-3-carboxamide; p.f. 282-284 ° C. (i) N- (2-Fluoro-4-methoxyphenyl) -4-oxo-6 > 6-dimethyl-4, 5, 6, 7 -tet rahydro-lH-indole-3-carboxamide; p.f. 213-215 ° C. (j) N- (2-Fluoro-4-methoxyphenyl) -4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-lH-indole-3-carboxamide. (k) N- (2-Fluoro-5-methoxyphenyl) -4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide. (1) N- (2-Fluoro-4-methoxy phenyl) -4-oxo-6,6-dimethyl-4,5,6,7-dihydro-1H-indole-3-carboxamide; p.f. 225-227 ° C. (m) N- (2-Methoxyphenyl) -4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-lH-indole-3-carboxamide (Compound 3) (n) N- (4-Ethoxyphenyl) -4-oxo-6,6-dimet and 1-4,5,6,7-tetrahydro-lH-indole-3-carboxamide. (o) N- (4-Methoxyphenyl) -4-oxo-6,6-dimethyl-4,5,6,7-tet rahydro-1H-indole-3-carboxamide. (p) N- (2-Hydroxy-4-methylphenyl) -4-oxo-6,6-dimethyl-4,5,6,7-tet -hydro-1H-indole-3-carboxamide; p.f. 201-203 ° C. (q) N-Phenyl-4-oxo-6-methyl-4,5,6,7-tet -hydro-1H-indole-3-carboxamide (Compound 4); p.f. 278-279 ° C. (r) N- (2-Fluorophenyl) -4 -oxo-6-met il-4, 5,6,7-tet rahydro-lH-? ndol-3-carboxamide (Compound 5); p.f. 264-265 ° C. (s) N- (3-Fluorophenyl) -4 -oxo-6-met il-4, 5,6,7-t and rahydro-lH-indole-3-carboxamide; p.f. 302-303 ° C. (t) N- (4-Fluorophenyl) -4 -oxo-6-methyl-4,5,6,7-tetrahydro-lH-indole-3-carboxamide; p.f. 262-264 ° C. (u) N- (3-Methoxyphenyl) -4 -oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; p.f. 234-235 ° C. (v) N- (4-Hydroxyphenyl) -4 -oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; p.f. 320 ° C. (w) N- (2-Fluoro-4-hydroxyphenyl) -4-OXO-6-methyl-4,5,6,7-tetrahydro-1H-indol-3-carboxamide; p.f. 330 ° C. (x) N- (2-Hydroxy-4-methoxyphenyl) -4-oxo-6-methyl-4,5,6,7-ethohydro-1H-indole-3-carboxamide; p.f. 236-238 ° C. (y) N- (4-Methoxyphenyl) -4-oxo-6-methyl-1-4,5,6,7-tetrahydro-lH-indole-3-carboxamide; p.f. 260-261 ° C. (z) N- (2-Fluoro-4-methoxyphenyl) -4-oxo-6-met il-4, 5,6,7-ethohydro-1H-indol-3-carboxamide (Compound 6); p.f. 217-219 ° C. (aa) N- (4-Ethoxyphenyl) -4 -oxo-6-met-il-4,5,6,7-tetrahydro-lH-indole-3-carboxamide; p.f. 269 ° C. (bb) N- (2-Fluoro-4-ethoxyphenyl) -4-oxo-6-methyl-4,5,6,7-tetrahydro-lH-indole-3-carboxamide; p.f. 224-225 ° C. (ce) N- (3,4-Dihydroxyphenyl) -4-oxo-6-methyl-4,5,6,7-tetrahydro-lH-indole-3-carboxamide; p.f. 267-269 ° C. (dd) N- (2-Hydroxy-methyl-phenyl) -4-oxo-6-methyl-4, 5, 6, 7-t and rahydro-1H-indole-3-carboxamide; mp, 258-260 ° C. (ee) N- (2-Thienyl) -4-oxo-6,6-dimethyl-4,5,6,7-tet rahydro-lH-indole-3-carboxamide (Compound 7). (ff) N- (2-Thiazoyl) -4 -oxo-6,6-dimethyl-4,5,6,7-tetrahydro-lH-indole-3-carboxamide. (gg) N- (5-Methyl-2-thiazolyl) -4-oxo-6,6-dimethyl-4,5,6,6-7 -hydrohydro-1H-indole-3-carboxamide. (hh) N- (3-Pyridyl) -4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; p.f. 237-239 ° C. (ii) N- (4-Methoxy-3-pyridyl) -4-oxo-6,6-dimethyl-4,6,6,7-tetrahydro-1H-indole-3-carboxamide; p.f. 217-218 ° C. (jj) N- (2-Chloro-l, 8-naphthyridin-7-yl) -4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-lH-indole-3-carboxamide; p.f. 278-280 ° C. (kk) N- (1, 8-Naphthyridin-2-yl) -4-oxo-6,6-dimethyl-4,5,6-7 -hydrohydro-1-indole-3-carboxamide (Compound 8); p.f. 389-390 ° C. (11) N- (3-Pyridyl) -oxo-6-met i 1-4,5,6,6,7-tet rahydro-lH-indole-3-carboxamide; p.f. 2'25-227 ° C. (mm) N- (4-Pyridyl) - - oxo - 6 - met il - 4, 5, 6, 7. tetrahydro-lH-indole-3-carboxamide; p.f. 280-290 ° C. (nn) N- (1, 8-Naphthyridin-2-yl) -4-oxo-6-methyl-4,5,6,7-tet rahydro-l-indol-3-carboxamide (Compound 9). (oo) N- (6-Methyl-l, 8-naphthyridin-2-yl) -4-oxo-6-methyl-4,5,6,7-tetrahydro-lH-indole-3-carboxamide; p. F. 338-340 ° C (d). (pp) N- (2-Quinolinyl) -4 -oxo-6-methyl-4,5,6,7-tetrahydro-lH-indole-3-carboxamide (Compound 10); p.f. 273-275 ° C. (qq) N- (4-Pyridyl) -oxo-6,6-dimet i 1-4,5,6,7-tetrahydro-lH-indole-3-carbo-amide.

The invention and the manner and process of making and using it are now described in such complete, clear, concise and exact terms as they allow any person with experience in the technique to which it belongs to make and use it. This is to understand that the foregoing describes the preferred embodiments of the present invention and that the modifications can be made herein without departing from the spirit and scope of the present invention as set forth in the claims. For the particularly pointed and clear claim, the subject matter is considered as an invention, the following claims conclude this specification. It is noted that with regard to this date, the best method known to the applicant for carrying out said invention is the conventional one for the manufacture of the objects or products to which the same refers. Having described the invention as above, property is claimed as contained in the following:

Claims (15)

1. A compound of the formula or the non-toxic pharmaceutically acceptable salts thereof, characterized in that:. is aryl or heteroaryl, each of which is optionally substituted with up to five groups independently selected from halogen, cyano, hydroxy, alkyl or cycloalkyl having 3-7 carbon atoms, aminc or mono- or dialkylamino, where each alkyl is independently lower alkyl or cycloalkyl having 3-7 carbon atoms, alkoxy or cycloalkyl having 3-7 carbon atoms, or NR? C0R2, C0R2, CONR1R2 or CO2R2, where Ri and R2 • are the same or different and represent hydrogen or alkyl or cycloalkyl having 3-7 carbon atoms; and T is halogen, hydrogen, hydroxyl, amino or alkoxy; X is hydrogen, hydroxyl or alkyl; m is 0, 1 or 2; n is O, 1 6 2; and R3 and R4 are the same or different and represent hydrogen, alkyl, COR5 or CO2R5, where R5 'is alkyl or cycloalkyl having 3-7 carbon atoms, CONR6R7, where Re and R7 are independently selected from hydrogen, alkyl, cycloalkyl, has 3-7 carbon atoms, phenyl, 2-, 3- or 4-pyridyl or NR6R7 forms a heterocyclic group which is -morpholinyl, 'piperidinyl, pyrrolidinyl or N-alkyl-piperazinyl; or R3-R4 together represent a cyclic portion having 3-7 carbon atoms.

2. A compound of the formula characterized in that 3 and R4 are the same or different and represent hydrogen, alkyl, COR5 or CO2R5, where R5 is alkyl or cycloalkyl having 3-7 carbon atoms, CONR6R7, where R6 and R are independently selected from hydrogen, alkyl, cycloalkyl, has 3-7 carbon atoms, phenyl, 2-, 3- or 4-pyridyl or NR6R7 forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl or N-alkyl-piperazinyl; or

R3-R4 together represent a cyclic portion having 3-7 carbon atoms; R8 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkylalkoxy having 3-7 carbon atoms, amino, mono- or dialkylamino; and Rg is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycloalkylalkoxy having 3-7 carbon atoms, amino, mono- or dialkylamino, RN1COR2, COR2 or CO2R2, where Ri and R2 are the same or different and represent hydrogen, alkyl, or cycloalkyl having 3-7 carbon atoms; and Rio is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or dialkylamino; m is O, 1 6 2; and n is O, 1 or 23. A compound of the formula characterized in that G represents thienyl, thiazolyl, pyridyl, naphthyridinyl, quinolinyl or phenyl, each of which is optionally mono-, di- or trisus-t with halogen, alkyl, alkoxy or hydroxy; and R3 and R4 are the same or different and represent hydrogen or alkyl, with the proviso that none of R3 and R4 are hydrogen.

4. A compound according to claim 3, characterized in that R3 and R4 are hydrogen or C? _3 alkyl, with the proviso that none of R3 and R are hydrogen.

5. A compound according to claim 3, characterized in that R3 and R are methyl.

6. A compound according to claim 3, characterized in that R3 is methyl and R4 is hydrogen.

7. A compound according to claim 1, characterized in that it is N-Phenyl-4-oxo-6,6-dimethyl-l, 4,5,6,7-tetrahydro-lH-indole-3-carboxamide.

8. A compound according to claim 1, characterized in that it is N- (2-Fluoro-phenyl) -4 -oxo-6,6-dimethyl-4,5,6,7-tetrahydro-lH-indole-3-carboxamide.

9. A compound according to claim 1, characterized in that it is N- (3-Fluorophenyl) -4-oxo-6,6-dimethyl-l, 4,5,6,7-tetrahydro-lH-indole-3-carboxamide.

10. A compound according to claim 1, characterized in that it is N- (4-Fluoro-phenyl) -4-oxo-d, 6-dimethyl-l, 4,6,6,7-tetrahydro-lH-indole-3-carboxamide.

11. A compound according to claim 1, characterized in that it is. N- (2,4-Difluorophenyl) -4-oxo-6,6-dimet i 1-4, 5,6,7-tetrahydro-lH-indol-3-carboxamide.

12. A compound according to claim 1, characterized in that it is N- (2,6-Difluorophenyl) -4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.

13. A compound according to claim 1, characterized in that it is N- (3-Methoxyphenyl) -4-oxo-6,6-dimethyl-l, 4,5,6,7-tetrahydro-lH-indole-3-carboxamide.

14. A compound according to claim 1, characterized in that it is N- (2-Hydroxy-4-methoxyphenyl) -4-oxo-6,6-dimet i 1-4,5,6,7-tet rahydro-lH-indole - 3 -carboxamide.

15. A compound according to claim 1, characterized in that it is N- (3-hydroxy-4-methoxyphenyl) -4-OXO-6,6-dimet i 1-4,5,6,7-. t et rahydro-1H-indole-3-carboxamide.