MXPA00008364A - Substituted cycloalkyl-4-oxonicotinic carboxamides;gaba brain receptor ligands - Google Patents

Abstract

Disclosed are compounds of Formula (a) or the pharmaceutically acceptable non-toxic salts thereof wherein:the C ring is a(n) (un)substituted carbocycle;X is hydrogen, hydroxyl or lower alkyl;and W is (un)substituted alkyl, aryl, arylalkyl, or heteroaryl, which 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

Carboxamides substituted cycloalkyl- -Oxonicotinics; Ligands of the GABA Receptor of the Brain BACKGROUND OF THE INVENTION Field of the invention This invention relates to certain substituted cycloalkyl-4-oxonicotinic carboxamides. In particular, it relates to such compounds that selectively bind to GABAa receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It is also related to the use of such compounds in the treatment of anxiety, sleep disorders and stroke, overdose of benzodiazepine-type drugs, and increased liveliness.

Description of the Related Art (-aminobutyric acid (GABA) is considered as one of the main transmitters of amino acid inhibitors in the brain of mammals.40 years have elapsed since its presence in the brain was demonstrated (Robert & Frankel, J Biol. Chem 187: 55-63, 1950: Udenfriend, J. Biol .. Chem, 187: 65-69, 1950) During this time, a great deal of effort has been devoted to the involvement of GABA in the etiology of apoplectic disorders, sleep, anxiety, and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8: 21-44, 1985) Wide, though unequally, distributed in the mammals' brain, it is said that GABA is a transmitter in approximately 30% of the synapses in the brain GABA mediates many of its actions through a complex of localized proteins, both in the bodies of cells and nerve endings, these are called receptors GABAa.The answers pos tsinápticas to the GABA are mediated through alterations in the conductance of chloride that generally, although, not invariably, leads to hyperpolarization of the cell. Recent research has indicated that the protein complex associated with postsynaptic GABA responses is the main site of action of a nr of structurally unrelated compounds, capable of modifying postsynaptic responses by GABA. 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. 1,4-Benzodiazepines, such as diazepam, flurazepa, and trizolam continue to be among the most widely used as anxiolytics, sedative-hypnotics, muscle relaxants, and anticonvulsants. A nr of these compounds are extremely potent drugs; such power indicates a site of action with a high affinity and specificity for individual receptors. The first electrophysiological studies indicated that a major action of the benzodiazepines was the elevation of GABAergic inhibition. Currently, those compounds that possess activity such as the elevation of the effect of GABA are called agonists, those compounds that decrease the effect of GSBA are called antagonists.

The subunits of the GABA receptor have been cloned from bovine and human cDNA libraries (Schoenfield et al., 1998, Duman et al., 1989). A nr of different cDNAs were 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 its distinctive regional pharmacology (Shivers et al., 1980; Leviatán et al., 1989). The subunits? They seem to allow drugs such as benzodiazepines to modify GABA responses (Pritchett et al., 1989). The presence of low Hill coefficients in the binding of the GABAa receptor ligands indicates unique profiles of the pharmacological action of the subtype specific.

With the discovery of the "receptor" for benzodiazepines and the subsequent definition of the nature of the interaction between GABA and benzodiazepines, it seems that the important interactions of benzodiazepine behavior with different neurotransmitter systems are due in large part to the elevation of the ability of GABA itself to modify these systems. Each modified system, in turn, can be associated with the expression of a behavior. Depending on the mode of interaction, these compounds are capable of producing a spectrum of activities (any, sedative, anxiolytic, and anticonvulsant, or insomnia, stroke, and anxiety).BRIEF DESCRIPTION OF THE INVENTION This invention provides new compounds of formula I 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 disorders of anxiety, sleep and stroke, overdose with benzodiazepine drugs and for the elevation of memory. Accordingly, a broad mode of the invention is directed to the compounds of formula I: wherein: ring C represents a carbocyclic group having from 5-7 members, wherein any member of the carbocyclic group is optionally mono-, di-, or trisubstituted with lower alkyl, Ci-Cβ alkoxy. hydroxyl, halogen, amino, mono- or dialkylamino (Ci-Cß), or trifluoromethyl; X is hydrogen, hydroxyl or lower alkyl; Y is lower alkyl optionally substituted with halogen, hydroxyl, lower alkoxy, amino or mono- or dialkylamino, wherein each alkyl portion is lower alkyl; or W is aryl, arylalkyl, or heteroaryl, wherein each aryl is optionally substituted with one or two groups independently selected from halogen, trifluoromethyl, cyano, hydroxyl, lower alkyl, lower alkoxy, amino, mono- or dialkylamino, wherein each alkyl portion is lower alkyl, mono- or dialkylaminoalkyl wherein each alkyl portion is lower alkyl, or NR? COR2, COR2, CNR1R2 or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl, or NR? R2 forms a ring of , 6 or 7 members having a ring member optionally replaced with oxygen or nitrogen.

These compounds are highly selective inverse agonists, antagonists or inverse agonists for GABAa receptors in the brain. These compounds are useful in the diagnosis and treatment of sleep disorders, anxiety and seizures, overdoses of benzodiazepine drugs and for the elevation of memory.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds encompassed by the present invention can be described by the general Formula I described above of the non-toxic pharmaceutically acceptable salts thereof.

In addition, the present invention also comprises compounds of Formula II, wherein: Ra is hydrogen, lower alkyl, Ci-Cβ alkoxy, hydroxyl, halogen, amino, mono- or dialkylamino (C? -C6), or trifluoromethyl; R is hydrogen, lower alkyl, C? -C6 alkoxy, hydroxyl, halogen, amino, mono- or dialkylamino (C? -C6), or trifluoromethyl; n is an integer of 1-3; and X is hydrogen or C? -C6 alkyl; W is lower alkyl optionally substituted with halogen, hydroxyl, lower alkoxy, amino, or mono or dialkyl amino, wherein each alkyl portion is lower alkyl; or W is aryl, arylalkyl or heteroaryl, wherein each aryl is optionally substituted with one or two groups independently selected from halogen, trifluoromethyl, cyano, hydroxyl, lower alkyl, lower alkoxy, amino mono or dialkylamino, where each alkyl portion is lower alkyl, alkylated inoalkyl, preferably methylaminoalkyl, wherein each alkyl portion is lower alkyl, or NR1COR2, COR2, CONR2R2 or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

Preferred compounds of Formula II are where W is an optionally substituted aryl, arylalkyl or heteroaryl. Other preferred compounds of II are those wherein one of Ra and Rb may be non-hydrogenous substituents; preferably the groups Ra and b are independently C 1 -C 2 alkyl, or more preferably, hydrogen, yet other preferred compounds of Formula II are those wherein X is C 1 -C 6 alkyl or hydrogen, preferably hydrogen.

More preferably the compounds of Formula II are where W is phenyl, benzyl, thienyl, thiazolyl, or pyridyl each of which is optionally substituted with one or more groups independently selected from halogen, trifluoromethyl, cyano, hydroxyl, lower alkyl, alkoxy lower, amino mono or dialkylamino, wherein each alkyl portion is a lower alkyl or NR? COR2, COR2, CONR1R2 or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

Even more preferred compounds of Formula II are where W is phenyl, benzyl, thienyl, thiazolyl, or pyridinyl, each of which is optionally substituted with one or two groups independently selected from halogen, hydroxyl, lower alkyl, lower alkoxide.

Other more preferred compounds of Formula II are those where the group W is mono- or di-substituted with a halogen, selected from chlorine, bromine or fluorine, amino, mono- or dialkylamino (C? -C2), C? -C3 alkoxide, C-C3 alkyl, or hydroxyl.

In addition, the present invention encompasses the compounds of formula III: where: Ra is hydrogen, lower alkyl, C? -C6 alkoxide. hydroxyl, halogen, amino, mono- or dialkylamino (Ci-Cß), or trifluoromethyl; W is lower alkyl optionally substituted with halogen, hydroxyl, lower alkoxide, amino or mono or dialkylamino where each alkyl portion is lower alkyl; or W is aryl, arylalkyl or heteroaryl, wherein each aryl is optionally substituted with one or two groups independently selected from halogen, trifluoromethyl, cyano, hydroxyl, lower alkyl, lower alkoxy, amino, mono or dialkylamino, wherein each alkyl portion is lower alkyl or NR? COR2, COR2, CONR? R2 or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

Preferred compounds of Formula II are where W is an optionally substituted aryl, arylalkyl or heteroaryl.

The most preferred compounds of Formula II are where it is phenyl, benzyl, thiophene, thiazolyl, pyridinyl or piperonyl, each of which is optionally substituted with one or two groups independently selected from halogen, trifluoromethyl, cyano, hydroxyl, lower alkyl, lower alkoxy, amino, ono-or dialkylamino, wherein each alkyl portion is lower alkyl, or NR? COR2, COR2, CONR] R2 or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

Even more preferred compounds of Formula III are where W is phenyl, benzyl, thiophene, thiazolyl, or pyridinyl, each of which is optionally substituted with one or more groups independently selected from C? -C3 alkyl, more preferably methyl , fluoride, or methoxide.

In addition, the present invention encompasses the compounds of Formula IV: IV where: Ra is hydrogen, lower alkyl, Ci-C6 alkoxide, hydroxyl, halogen, amino, mono- or dialkylamino (Ci-Cd), or trifluoromethyl; W is lower alkyl optionally substituted by halogen, hydroxyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl; W is aryl, arylalkyl, or heteroaryl, wherein each aryl is optionally substituted with one or two groups independently selected from halogen, trifluoromethyl, cyano, hydroxyl, lower alkyl, lower alkoxy, amino, mono or dialkylamino where each alkyl portion is lower alkyl, or NR? COR, COR2, CONR? R2 or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

Preferred compounds of Formula IV are where W is an optionally substituted aryl, arylalkyl, or heteroaryl.

The most preferred compounds of formula IV are where W is phenyl, benzyl, thiophene, thiazolyl, pyridinyl, or piperonyl, each of which is optionally substituted with one or two groups independently selected from halogen, trifluoromethyl, cyano, hydroxyl, alkyl lower, lower alkoxy, amino, mono- or dialkylamino, where each alkyl portion is lower alkyl, methyl or ethyl aminoalkyl where each alkyl portion is lower alkyl or NR1COR2, COR2, CONR1R2 or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

The still more preferred compounds of Formula IV are where W is phenyl, benzyl, thiophene, thiazolyl or pyridinyl each of which is optionally substituted with one or two groups independently selected from methyl, fluoride, hydroxyl or methoxy or C1- alkyl. C3, preferably methyl.

In addition, the present invention encompasses the compounds of Formula V. wherein: Ra is hydrogen, lower alkyl, Ci-Cβ alkoxy, hydroxyl, halogen, amino, mono- or dialkylamino (C? -C6), or trifluoromethyl; R b is lower alkyl, C 1 -C 6 alkoxide, hydroxyl, halogen, amino, mono- or dialkylamino (C 1 -C 69 or trifluoromethyl; W is lower alkyl optionally substituted by halogen, hydroxyl, lower alkoxy, amino, or mono- or dialkylamino, wherein each alkyl portion is lower alkyl; or W is aryl, arylalkyl, or heteroaryl, wherein each aryl is optionally substituted with one or two groups independently selected from halogen, trifluoromethyl, cyano, hydroxyl, lower alkyl, lower alkoxy, amino, mono or dialkylamino, wherein each alkyl portion is alkyl lower methylaminoalkyl, wherein each alkyl portion is lower alkyl or NR? COR2, COR2, CONR? R2 or CO2R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

Preferred compounds of Formula V where W is an optionally substituted aryl, arylalkyl or heteroaryl.

The most preferred compounds of Formula V are where W is phenyl, benzyl, thiazolyl, pyridinyl, or piperonyl each of which is optionally substituted with one or two groups independently selected from halogen, trifluoromethyl, cyano, hydroxyl, lower alkyl, lower alkoxy, amino, mono- or dialkylamino, wherein each alkyl portion is a lower alkyl methylaminoalkyl, wherein each alkyl portion is lower alkyl, or NR1COR2, COR2, CONR2R2 or CO2R2 where Ri and R2 are the same or different and represent and they represent hydrogen or lower alkyl.

Even more preferred compounds of Formula IV are where W is phenyl, benzyl, or thiazolyl each of which is optionally substituted with one or two groups independently selected from chloro, fluoro, ethoxide or methoxide.

Preferred compounds of the invention are encompassed by the following formulas: wherein: Ra is hydrogen, lower alkyl, C? -C6 alkoxide, hydroxyl, halogen, amino, mono- or dialkylamino (Ci-C?) Or trifluoromethyl, R3 and R4 they are the same or different and represent hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, amino, mono- or dialkylamino where each alkyl portion is lower alkyl, methylaminoalkyl, wherein each alkyl portion is lower alkyl, or NR1COR2, COR2, CONR1R2 or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

The most preferred compounds of Formula VI are where Ra is hydrogen, methyl or ethyl, R 3 is hydrogen or halogen and R 4 is halogen, hydroxyl, or lower alkyl. where : Ra is hydrogen, lower alkyl, C? -C6 alkoxide, hydroxyl, halogen, amino, mono- or dialkylamino (C? -C6), or trifluoromethyl; R3 and R4 are the same or different and represent hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, amino, mono- or dialkylamino where each alkyl portion is lower alkyl or methylaminoalkyl where each alkyl portion is lower alkyl, or NR1COR2, COR2, CONR? R2 or CO2R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

The most preferred compounds of Formula VII are where R3 is hydrogen or halogen, Ra is hydrogen, methyl or ethyl, and R is halogen, hydroxyl, or lower aleoxido. where : Ra is hydrogen, lower alkyl, C? -C? Alkoxide, hydroxyl, halogen, amino, mono- or dialkylamino (C? -C6), or trifluoromethyl; R5 and R6 are the same or different and represent hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, amino, mono- or dialkylamino, where each alkyl portion is lower alkyl, methylaminoalkyl where each alkyl portion is lower alkyl or NR? COR2, COR2, CONR2 or C02R2 where Ri and R are the same or different and represent hydrogen or lower alkyl.

The most preferred compounds of Formula VIII are where R5 is hydrogen or halogen, hydroxyl, or lower alkoxide. wherein: Ra is hydrogen, lower alkyl, Ci-Cβ alkoxy, hydroxyl, halogen, amino, mono- or dialkylamino (C? -C6), or trifluoromethyl; R5 and Re are the same or different and represent hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, amino, mono- or dialkylamino, where each alkyl portion is lower alkyl, methylaminoalkyl where each alkyl portion is lower alkyl or NR? COR2, COR2, CONR2 or CO2R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

The most preferred compounds of Formula IX are where R 5 is hydrogen or halogen and Rβ is halogen, hydroxyl, or lower alkoxide. wherein: Ra is hydrogen, lower alkyl, Ci-Cβ alkoxy, hydroxyl, halogen, amino, mono- or dialkylamino (C? -C6), or trifluoromethyl; W is 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-thiazolyl, each of which can be independently substituted with halogen, hydroxyl, lower alkyl, lower alkoxy, amino, methylaminoalkyl, where each alkyl portion is lower alkyl or NR? COR2, COR2, CONR? R2 or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

The most preferred compounds of Formula X are where W is 2-, 3- or 4-pyridyl, 2- or 3-thienyl, or 2-thiazolyl, each of which may be independently substituted with halogen, lower alkyl or alkoxy lower. wherein: Ra is hydrogen, lower alkyl, C? -C6 alkoxide, hydroxyl, halogen, amino, mono- or dialkylamino (Ci-C?), or trifluoromethyl, W is 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-thiazolyl, each of which can be independently substituted with halogen, hydroxyl, lower alkyl, lower alkoxy, amino, methylaminoalkyl, where each alkyl portion is lower alkyl or NR? COR2, COR2 / CONR? R2 or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl. The most preferred compounds of Formula X are where it is 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-thiazolyl, each of which may be independently substituted with halogen lower alkyl or lower alkoxide .

"Alkyl" and "lower alkyl" in the present invention refers to linear or branched alkyl groups having from 1-6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, ter -butyl, pentyl, 2-pentyl, isopentyl, neopentyl hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

"Alkoxide" and "Lower alkoxide", this invention refers to straight or branched chain alkoxide groups having 1-6 carbon atoms, such as, methoxide, ethoxide, propoxide, isopropoxide, n-butoxide, sec-butoxide, ter-butoxide, pentoxide, 2-pentyl, isopentoxide, neopentoxide, hexoxido, 2-hexoxido, 3-hexoxido, and 3-methylpentoxide.

The term "halogen" refers in the present invention to fluoride, bromide, chloride and iodide.

"Heteroaryl" refers to one or more aromatic ring systems of 5, 6 or 7 members that contain at least one or up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (is) oxazolyl, pyridyl, pyrimidinyl, (iso) quinolinyl, naphthyridinyl, benzimidazolyl, benzoxazolyl. Preferred heteroaryl groups are optionally substituted pyridyl, pyrimidinyl, naphthyridinyl, benzimidazolyl, and -imidazolyl.

By "aryl" is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl) or condensed multiple rings in which at least one is aromatic (e.g., 1, 2, 3 , -tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which is optionally mono-, di-, or trisubstituted with, for example, halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy, Preferred aryl groups are the optionally substituted phenyl and naphthyl groups. Representative compounds of the invention are shown below in Table 1.

. Table 1 Representative compounds of the present invention which are encompassed by Formula I, include, but are not limited to, the compounds of Table 1 and their pharmaceutically acceptable salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basification of a solution of the acid salt, particularly a pharmaceutically acceptable salt of addition, can be produced by dissolution of the free base in a suitable organic solvent and treatment of the solution with an acid, according to conventional procedures for the preparation of acid addition salts from base compounds.

Non-toxic pharmaceutically acceptable salts include the salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, 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 pharmaceutically acceptable non-toxic acid addition 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 that can be employed to prepare non-toxic, pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I The compounds of Formula I and their salts are suitable for the diagnosis and treatment of anxiety, Down syndrome, sleep disorders, cognitive and stroke, and overdose with benzodiazepine drugs and for the elevation of the liveliness, both in humans in non-human animals and in domestic pets, especially dogs and cats and farm animals such as sheep, pigs and cattle. The compounds of general Formula I can be administered orally, topically, parenterally, by inhalation or atomization or rectally in formulations of dosage units containing conventional, non-toxic, pharmaceutically acceptable carriers, auxiliaries and vehicles. The term parenteral as used herein includes subcutaneous techniques, injections, injection or intravenous, intramuscular or intrasternal infusion. In addition there is provided a pharmaceutical formulation comprising a compound of the general Formula I and a pharmaceutically acceptable carrier. One or more compounds of the general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or auxiliaries and if desired other active ingredients. The pharmaceutical compositions containing the compounds of the general Formula I may be in a form suitable for oral use, for example as tablets, sachets, lozenges, aqueous or oily dispersible suspensions, powders or granules, emulsions, rigid and 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 pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives. to provide pharmaceutically elegant and acceptable preparations. The tablets contain the active ingredient in a mixture 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 gelatin or acacia starch, 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 for a longer period of time. For example, a retarding material such as glyceryl monostearate or glyceryl disterate may be employed.

Formulations for oral use can also be presented as rigid 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 it is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in mixtures with excipients suitable for the manufacture of aqueous suspensions, such excipients are suspending agents for example, sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, pilivinylpyrrolidine, gum tragacanth and acacia gum, dispersing agents or wetting agents may be a phosphatin present in nature, for example, lecithin, or products of the condensation of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or products of the condensation of ethylene oxide aliphatic chain alcohols long, for example heptadecaethyleneoxycetanol, or the condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monoleate, or the condensation products of ethylene oxide with partial esters derived from the fatty acids and anh dridos hexitol, for example sorbitan monooleate polyethylene. 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.

Only suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil or coconut oil, or 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 described above, | and the flavoring agents can be added to provide acceptable 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 a mixture with a dispersing and wetting agent, the suspending agent and one or more preservatives. Suitable dispersants 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.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be gums present in nature, for example acacia gum or tragacanth gum, phosphatides present in nature, for example soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and products of the condensation of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.

The syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitor or sucrose. Such formulations may also contain a demulcent, a preservative and coloring and flavoring agents. The pharmaceutical compositions may be in the form of a sterile aqueous or oleoginous injectable suspension. This suspension can be formulated according to known techniques using those suitable dispersing or humidifying agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic perenterally acceptable diluent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, the sterile, fixed oils are conventionally employed as a solvent or suspension medium. For this purpose any fixed soft oil may be employed, including mono- or diglycerides. In addition, fatty acids such as oleic acid find their 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 must therefore melt 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, depending on the vehicle and the concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuncts such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

The dose levels in the order of about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the conditions indicated 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 a single dosage form can vary depending on the hosts treated and the particular mode of administration. Dosage unit forms should generally contain from about 1 mg to about 500 mg of an active ingredient.

This should be understood, however, that the dose level for any particular patient depends 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, the proportion of the excretion, the combination of the drug and the severity of the individual in particular undergo therapy.

For the administration of non-human animals, the composition must also be added to the animal's feed or to the drinking water. It should be convenient to formulate the feed and water compositions with a mixed dose of the drug so that the animal takes in an appropriate amount of the composition throughout its diet. This should also be convenient to present the composition as a premix to add to the food or drink water.

An illustration of the preparation of the compounds of the present invention is given in Scheme I. The pyridin-4-one-3-carboxylic acid is prepared essentially according to the procedures described in J. Het. Chem. 1975, 1245.

Where the c-ring, X and W have the definitions given above by formula I.

Those having experience in the art should recognize that the initiator materials can be employed in varied and optional steps to produce the compounds encompassed in the present invention, as demonstrated in the following examples.

As shown in Scheme I, the pyridin-4-one-3-carboxylic acid is treated with an acid chloride, such as, for example, ethyl chloroformate, in the presence of a base similar to triethylamine. The resulting mixed anhydride is subsequently treated with an amine to give the desired amide.

The invention is also illustrated by the following examples that are not constructed as a limit of the invention in the scope or spirit of the specific procedures described therein.

The initiator materials and various intermediates can be obtained by commercial routes, prepared from the appropriate organic compounds, or prepared using well-known synthetic methods.

Representative examples of the methods for preparing intermediates of the invention are described below.

Example 1 N- (4-methoxybenzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxyamide An amount of 100 mg (0.61 mmol, 1.0 eq) of acid -4, 5, 6, 7, -tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxylic acid dissolved in 5 ml of THF and 1 ml of DMF and treated at 0 ° C with 0.18 ml (1, 2 mmol, 2.2. eq) TEA followed by 0.12 ml (1.2 mmol, 2.2 eq) of ethyl chloroformate. The resulting solution was stirred for 30 minutes at the same time as 0.17 ml (1.2 mmol, 2.2 eq) of 4-methoxybenzylamine was added. The solution was allowed to warm to room temperature for 1 hour before the addition of 20 ml of H20, the THF was removed under reduced pressure, and the resulting solid was filtered and washed with H20 and then with Et20. The resulting solid was suspended in 1 mL of EtOH and 5 mL of 10% NaOH, heated at 90 ° C for 10 minutes, cooled to 0 ° C, and the pH adjusted to 9.0 with 3N HCl. The resulting solid was filtered, washed with H20, Et20, and purified by chromatography (silica gel, 10% CH3OH / CH2Cl2), to yield 89 mg of N- (4-methoxybenzyl) -4.5.6, 7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide (compound 1), mp 240-241 ° C.

Example 2 N- (2-fluorophenyl) -1,4,5,6,7,8-hexahydr-x-? Uinoli-n-4-one-3-carboxamide An amount of 100 mg (0.52 mmol, 1.0 eq) of .4,5,6,7,8-hexahydroquinolin-4-one-3-carboxylic acid was dissolved in 5 ml of THF and 1 ml of DMF was treated at 0 ° C with 0.16 ml (1.14 mmol, 2.2 eq) of TEA followed by 0.11 ml (1.14 mmol, 2. 2 eq) of ethyl chloroformate. The resulting solution was stirred for 30 minutes at the same time, 0.15 ml (1.14 mmol, 2.2 eq) of 4-methoxybenzyl amine was added. The solution was allowed to warm to room temperature for 1 hour before the addition of 20 ml of H20, the THF was removed under reduced pressure, and the resulting solid was filtered and washed with H20, then, purified by chromatography (gel of silica, 10% CH30H / CH2C12), to yield 102 mg of N- (fluorophenyl) -1, 4, 5, 6, 7, 8, -hexahydroquinolin-4-one-3-carboxamide (compound 5), mp 241-244 °.

Example 3 The following compounds are prepared essentially according to the procedures described in Examples 1 and 2. (a) N- (4-methoxybenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one- 3-carboxamide; p.f. = 241-244 ° C (Compound 2) (b) N- (2-thiazolyl) -1,4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide, m.p. 305 ° (dec.) (Compound 3). (c-) N- (phenyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-2-carboxamide; p.f. 295-296 ° C (Compound 4). (d) N- (piperonyl) -1, 4, 5, 6,7, 8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 263-265 ° C (Compound 6). (e) N- (3-fluorophenyl) -4,5,6,8,8-hexahydroquinolin-4-one-3-carboxamide, m.p. = 319-320 ° c (Compound 7). (f) N- (phenyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 299-300 ° C (Compound 2). (g) N- (2-thiazolyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 260 ° C (dec.) (Compound 9) (h) N- (4-methoxyphenyl) -1,, 5, 6, 7, 8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 287-290 ° C (Compound 10) (i) N- (4-methyl-2-thiazolyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 350-352 ° C (Compound 11). (j) N- (4-fluorophenyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 324-326 ° C (Compound 12). (k) N- (3-pyridyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 308 ° C (dec.) (Compound 13). (1) N- (2-hydroxyphenyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 295 ° C (dec.) (Compound 14). (m) N- (4-methoxypyrid-3-yl) -1, 4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 292 ° C (dec.) (Compound 15). (n) N- (3-methoxyphenyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 275-280 ° C (Compound 16). (o) N- (4-methoxypyrid-2-yl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 212 ° C (dec.) (Compound 17). (p) N- (3-hydroxybenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide, m.p. = 133-136 ° C (Compound 18). (q) N- (benzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 257-259 ° C (Compound 19). (r) N- (2-thienyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-9-carboxamide; p.f. = 306 ° C (dec.) (Compound 20). (s) N- (2-chlorophenyl) -1,, 5, 6, 7, 8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 339-341 ° C (Compound 21). (t) N- (3-thienyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 321-324 ° C (Compound 22). (u) N- (2,6-difluorophenyl) -1,4,5,8,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 278-286 ° C (Compound 23). (v) N- (2-methoxybenzyl) -1,4,5,8,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 217-219 ° C (Compound 24). (w) N- (3-methoxybenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 210-212 ° C (Compound 25). (x) N- (2-fluorobenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 206-209 ° C (Compound 26). (y) N- (2-fluoro-4-methoxyphenyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; mp = 257-259 ° C (Compound 27). (z) N- (2-pyridyl) -4,5,6,7-tetrahydro-lH-cyclopentan- [b] pyridin-4-one-3-carboxamide; p.f. = 294-295 ° C (Compound 28). (aa) N- (4-methyl-2-thiazolyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; mp = 304-305 ° C (Compound 29). (bb) N- (3-fluorophenyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carbaxamide; p.f. = 340 ° C (dec.) (Compound 30). (ce) N- (2-fluorophenyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; p.f. = 330 ° C (dec.) (Compound 31). (dd) N- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; p.f. 328 ° C (dec.) (Compound 32). (ee) N- (2,6-difluorophenyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide, m.p. 297 ° C (dec) (Compound 33) (ff) N- (benzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; p. f .149-150 ° C (Compound 34). (gg) N- (3-methoxybenzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; p.f. 204-205 ° C (Compound 25). (hh) N- (2-methoxybenzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; p.f. = 243-244 ° C (Compound 36). (ii) N- (2,6-difluorobenzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; p.f. = 294-295 ° C (Compound 37). (j j) N- (2-thienyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; p.f. = 210 ° C (dec.) (Compound 38) (kk) N-butyl-4, 5, 6,7,6, 9-hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide; p.f. = 138-143 ° C (Compound 39). (11) N- (2-thiazolyl) -4,5,6,7,8,8-hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide; p.f. 301 ° C (dec.) (Compound 40). (mm) N- (4-methoxyphenyl) -4, 5, 6, 7, 8, 9-hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide; p.f. = 240-242 ° C (Compound 41). (nn) N- (benzyl) -4, 5, 6, 7, 8, 9-hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide; p.f. 224-226 ° C (Compound 42) (oo) N- (4-methoxyphenyl) -4, 5, 6,, 8, 9-hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide; p.f. = 203-205 ° C (Compound 43). (pp) N- (4-fluorobenzyl) -4,5,6,7,8,9-hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide; p.f. = 219-222 ° C (Compound 44). (qq) N- (3-fluorobenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 267-270 ° C (Compound 45). (rr) N- (4-fluorobenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 278-280 ° C (Compound 46). (ss) N- (3-chlorobenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 247-249 ° C (Compound 47). (tt) N- (4-chlorobenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-2-carboxamide; p.f. = 283-285 ° C (Compound 48). (uu) N- (2-fluoro-4-methoxybenzyl) -1,, 5, 6, 7, 8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 257-259 ° C (Compound 49). (vv) N- (4-ethoxybenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 241-243 ° C (Compound 50) (ww) N- (4-methylbenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 270-273 ° C (Compound 51). (xx) N- (3-methylbenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 242-245 ° C (Compound 52). (yy) N- (2-fluoro-4-ethoxybenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 178-181 ° C (Compound 53). (zz) N- (2-fluoro-4-isopropoxybenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 197-200 ° C (Compound 54). (aaa) N- (2-fluoro-4-propyl) -1, 4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. 189-191 ° C (Compound 55). (bbb) N- (2-thienylmethyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; p.f. = 245-248 ° C (Compound 56) (ccc) N- (4-methoxyphenyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; p.f. = 330-332 ° C (Compound 57). (ddd) N- (3-methoxyphenyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; p.f. = 320 ° C (dec) (Compound 58) (eee) N- (4- (2-hydroxyethoxy) phenyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3 -carboxamide; p.f. = 220-222 ° C (Compound 59). (fff) N- ((4- (dimethylamino) phenyDmethyl) -4,5,6,7,6-tetrahydro-lH-cyclopentan [b] pyridin-4-one-4-3-carboxamide; mp 269-270 ° C (Compound 60). (Ggg) N- (2-fluoro-4-methoxybenzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-4-3-carboxamide, mp 238-240 ° C (Compound 61). (Hhh) N- (4-ethoxybenzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-4-3-carboxamide; mp = 243- 245 ° C (compound 62). (Iii) N- (2-fluoro-4-ethoxybenzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-4-3-carboxamide; mp = 217-219 ° C (compound 63) (j jj) N- (2-fluoro-4-isopropoxybenzyl) -4,5,6,7,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one- 3-carboxamide, mp = 214 ° C (dec) (Compound 64). (kkk) N- (2-fluoro-4-propoxybenzyl) -4,5,6,7, -tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; p. f. 209-211 ° C (Compound 65). (111) N- (2-fluorobenzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; p.f. = 259-261 ° C (Compound 66).

Example 4 The utility of the compounds of this invention is indicated by the following assays for the activity of the GABAa receptor.

The assays were carried out as described in Thomas and Tallman (J. Bio, Chem. 156: 9838-9842, J. Neurosci.3: 433-440, 1983). Rat cortical tissue was dissected and homogenized in 25 volumes (w / v) of 0.05 M Tris HCl buffer (pH 7.4 at 4 ° C). The homogenized tissue was centrifuged cold (4 °) at 20.00 x g 20 '. The supernatant was decanted and the pellet was rehomogenized in the same volume of buffer and again centrifuged at 20.00 x g. The supernatant was decanted and the pellet was cooled to -20 ° C overnight. The pellet was then dissolved and rehomogenized in 25 volumes (original weight / vol) of buffer and the procedure was carried out twice. The pellet was finally resuspended in 50 volumes (weight / volume of 0.05 M Tris HCl buffer (pH 7.4 at 40 ° C).

Incubations contain 100 ml of homogenized tissue, 100 ml of 0.5 nM radioligand (3H-R015-17788 [3H-Flumazenil] specific activity 80 Ci / mmol), the drug or blocker and buffer for a total volume of 500 ml. Incubations were carried out for 30 minutes at 4 ° C then they were quickly filtered through GFB filters for free-separate and linkage binding. The filters were washed twice with fresh 0.05 M Tris HCl buffer (pH 7.4 at 4 ° C) and counted in a liquid scintillation counter. The 1.0 mM diazepam was added to some tubes to determine non-specific binding. The data are collected in triplicate determinations, averaging-and% inhibition of the total specific binding was calculated. The total specific binding = Total - not specific. In some cases, the quantities of unlabeled drugs are varied and the total displacement curves of the linkage are carried out. The data is converted to a form for calculating the ICso and the Hill coefficient (nH). In the compounds of the described assays, Ki's of at least 1 μM are present.

Example 5 In sum, the following assays can be used to determine whether the compounds of the invention are agonists, antagonists, or inverse agonists, and, therefore, their specific pharmaceutical utilities. The following assay can be used to determine the specific activity of the GABAa receptor.

The assays are carried out as described in White and Gurley (NeuroReport 6: 1313: 1316, 1995) and Whithw, Hartnett, Stirling, and Gregory (receptors and Channels 3j_ 1-5, 1995) with modifications. The Xenopus Laevis oocysts are enzymatically isolated and grafted with the non-polyadenylated cRNA mixed in a ratio of 4: 1: 4 to the subunits derived from human a, β, and α, respectively. For each subunit combination, the sufficient message is grafted to result in current amplitudes of Z10 nA when 1 μM GABA is applied.

The electrophysiological recordings are carried out using both the electrode voltage plug technique at a membrane retention potential of -70 mV.

The compounds are evaluated against a GABA concentration that evokes < 10% of the current maximum evocable GABA. Each oocyte was exposed to increased concentrations of compounds to evaluate a concentration / effect relationship. The efficiency of the compound is expressed as a percentage change in the current amplitude: 100 * ((Ice / I) -1 where Ice is the current amplitude GABA evoked observed in the presence of the compound and I is the current amplitude GAMBA evoked observed in absence of the compound.

The specificity of a compound for the Rol5-1788 site was determined following the completion of the concentration / effect curve. After washing the oocyte enough to remove the previously applied compound, the oocyte was exposed to GABA + 1 μM Rol5-1788, followed by exposure. The percentage change due to the addition of the compound was calculated as described above. Any percentage change observed in the presence of Rol5-1788 was subtracted from the percentage changes in the current amplitude observed in the absence of Rol5-1788 1 μM. These net values are used for calculating average efficiency and EC50 values.

To evaluate the average efficiency and EC50 values, the concentration / effect data are averaged across the cells and fixed to the logistic equation.

The invention and the way and the process of making and using it, are now described in such terms of totals, clear, concise and exact for any way that expert person in the matter to which it belongs, to make and use the same, It is understood that the above described preferred embodiments of the present invention and the modifications can be made in that regard without departing from the spirit and scope of the present invention as described in the claims. To clarify and claim in a different manner the subject matter of the invention in relation to the invention, the following claims of this specification are included.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the result is clear from the manufacture of the objects to which it refers. Having described the invention as above, property is claimed as contained in the following:

Claims (21)

Claims

1. A compound of the formula or pharmaceutically acceptable non-toxic salts thereof characterized in that: Ring c represents a carbocyclic group having 5-7 members, wherein any member of the carbocyclic group is optionally substituted with a lower alkyl, C? -C6 alkoxide, hydroxide, halogen , amino, mono- or di (C? -6) alkylamino, or trifluoromethyl; X is hydrogen, hydroxy or lower alkyl; and W is a lower alkyl optionally substituted with halogen, hydroxide, lower alkoxide, amino, mono or dialkyl amino wherein each alkyl portion is a lower alkyl; or W is aryl, arylalkyl, heteroaryl, wherein each aryl is optionally substituted with one or two groups independently selected from halogen, trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxy, amino, mono- or dialkylamino where each alkyl moiety is a lower alkyl, methylaminoalkyl where each alkyl portion is a lower alkyl, or NR? COR2, COR2, CONR? R2, or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

2. A compound of the formula: characterized in that: W is a lower alkyl optionally substituted with halogen, hydroxide, lower alkoxide, amino, or mono- or dialkyl amino wherein each alkyl portion is a lower alkyl; or W is an aryl, arylalkyl, or heterooryl, wherein each aryl is optionally substituted with one or two groups independently selected from halogen, trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxy, amino, mono- or dialkyl where each portion of alkyl is a lower alkyl, or NR? COR2, COR2, CONR? R2, or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

3. A compound of the formula: Or pharmaceutically acceptable non-toxic salts thereof characterized in that: W is a lower alkyl optionally substituted by halogen, hydroxide, lower alkoxy, amino, or mono- or dialkyl amino wherein each alkyl portion is a lower alkyl; or W is aryl, arylalkyl, heteroaryl, wherein each aryl is optionally substituted with one or two groups independently selected from halogen, trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxy, amino, mono- or dialkylamino wherein each alkyl portion is a lower alkyl, methylaminoalkyl wherein each alkyl portion is a lower alkyl, or NR? COR2, C0R2, CONR1R2, or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

4. A compound according to claim 1 which is: Or non-toxic pharmaceutically acceptable salts thereof characterized in that: wherein R3 and R4 are the same or different and represent hydrogen, halogen, hydroxide, lower alkyl, lower alkoxy, amino, mono- or dialkylamino where each alkyl portion is a lower alkyl , methylaminoalkyl wherein each alkyl portion is a lower alkyl, or NR? COR2, COR2, CONR1R2, or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

A code according to claim 1 which is: 0 pharmaceutically acceptable non-toxic salts thereof characterized in that: where R3 and R4 are the same or different and represent hydrogen, halogen, hydroxide, lower alkyl, lower alkoxy, amino, mono- or dialkylamino where each alkyl portion is a lower alkyl, methylaminoalkyl where each alkyl portion is a lower alkyl, or NR? COR2, COR2, CONR? R2, or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

6. A compound according to claim 1 which is: Or pharmaceutically acceptable non-toxic salts thereof characterized in that: wherein R5 and R6 are the same or different and represent hydrogen, halogen, hydroxide, lower alkyl, lower alkoxy, amino, mono- or dialkylamino where each alkyl portion is a lower alkyl , methylaminoalkyl wherein each alkyl portion is a lower alkyl, or NR1COR2, COR2, CONR2, or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

7. A compound according to claim 1 which is: Or non-toxic pharmaceutically acceptable salts thereof characterized in that: wherein R5 and Rb are the same or different and represent hydrogen, halogen, hydroxide, lower alkyl, lower alkoxy, amino, mono- or dialkylamino where each alkyl portion is a lower alkyl , methylaminoalkyl wherein each alkyl portion is a lower alkyl, or NR? C0R2, COR2, CONR? R2, or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

8. A compound according to claim 1 which is: Or pharmaceutically acceptable non-toxic salts thereof characterized in that: W is 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-thiazolyl, each of which can be independently substituted with halogen, hydroxide , lower alkyl, lower alkoxy, amino, methylaminoalkyl wherein each alkyl portion is a lower alkyl, or NR? COR2, COR2, CONR1R2, or C02R2 where Rx and R2 are the same or different and represent hydrogen or lower alkyl.

9. A compound according to claim 1 which is: O pharmaceutically acceptable non-toxic salts thereof characterized in that: W is 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-thiazolyl, each of which it can be independently substituted with halogen, hydroxide, lower alkyl, lower alkoxide, amino, methylaminoalkyl where each alkyl portion is a lower alkyl, or NR? COR2, COR2, CONR1R2, or C02R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

10. A compound according to claim 1 characterized in that it is N- (4-methoxybenzyl) -4,5,6,7,7-tetrahydro-lH-cyclopentan [b] pyridine-3-carboxamide.

11. A compound according to claim 1, characterized in that it is selected from N- (2-fluorophenyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (4-methoxybenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (2-thiazolyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide, N- (phenyl) -4,5,6,7-tetrahydro- lH- cyclopentan [b] pyridin-4-one-3-carboxamide; N- (piperonyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (3-fluorophenyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (phenyl) -1,, 5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; and N- (2-thiazolyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide.

12. A compound according to claim 1 characterized in that it is selected from N- (4-methoxyphenyl) -1,, 5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (4-methyl-2-thiazolyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (4-fluorophenyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (3-Pyridyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (2-hydroxyphenyl) -1,4,5,6,7,9-hexahydroquinolin-4-one-3-carboxamide; N- (4-methoxypyrid-3-yl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (3-methoxyphenyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; and N- (4-methoxypyrid-2-yl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide.

13. A compound according to claim 1, characterized in that it is selected from N- (3-hydroxybenzyl) -1,4,5,6,7,8-hexahydroquinolin-3-carboxamide; N- (benzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (2-thienyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (2-chlorophenyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; • - N- (3-thienyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide, N- (2,6-difluorophenyl) -1,4,5,6,6 7,8-hexahydroquinolin-α-2-carboxamide; N- (2-methoxybenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; and N- (3-methoxybenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide.

14. A compound according to claim 1 characterized in that it is selected from N- (2-fluorobenzyl-1, 5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (2-fluoro-4-methoxyphenyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (2-pyridyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-2-carboxamide; N- (4-methyl-2-thiazolyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide, N- (3-fluorophenyl) -4,5, 6,7-tetrahydro-1H-cyclopentan [b] pyridine-3-carboxamide; N- (2-fluorophenyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; N- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide, and N- (2,6-difluorophenyl) -4.5 , 6, 7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide.

15. A compound according to claim 1, characterized in that it is selected from N- (benzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; N- (3-methoxybenzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; N- (2-methoxybenzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; N- (2,6-difluorobenzyl) -4,5,6,7-tetrahydro-lH-Cyclopentan [b] pyridin-4-one-3-carboxamide; and N- (2-thienyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide.

16. A compound according to the formula: Or pharmaceutically acceptable non-toxic salts thereof characterized in that: Ra is hydrogen, lower alkyl, lower alkoxide, hydroxide, halogen, amino, mono- or di (C? -C6) alkylamino or trifluoromethyl; Rb is hydrogen, lower alkyl, lower alkoxide, hydroxide, halogen, amino, mono- or di (C? -C6) alkylamino or trifluoromethyl; N is an integer of 1-3; and W is a lower alkyl optionally substituted with halogen, hydroxide, lower alkoxide, amino, mono or dialkyl amino wherein each alkyl portion is a lower alkyl; or W is aryl, aryl alkyl, heteroaryl, wherein each aryl is optionally substituted with one or two groups independently selected from halogen, trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxy, amino, mono- or dialkylamino where each alkyl moiety is a lower alkyl, methylaminoalkyl where each alkyl portion is a lower alkyl, or NR? COR2, COR2, CONR? R2, or C02R2 where Rx and R2 are the same or different and represent hydrogen or lower alkyl.

17. A compound of formula O non-toxic pharmaceutically acceptable salts thereof characterized in that: W is a lower alkyl optionally substituted with halogen, hydroxide, lower alkoxide, amino, mono or dialkyl amino wherein each alkyl portion is a lower alkyl; or W is aryl, aryl alkyl, heteroaryl, wherein each aryl is optionally substituted with one or two groups independently selected from halogen, trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxide, amino, mono- or dialkylamino where each alkyl portion is a lower alkyl, methylaminoalkyl wherein each alkyl portion is a lower alkyl, or NR1COR2, COR2, CONR2, or CO2R2 where Ri and R2 are the same or different and represent hydrogen or lower alkyl.

18. A compound according to claim 1, characterized in that it is selected from: N-butyl-4,5,6,7,9-hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide; N- (2-thiazolyl) -4,5,6,7,8,9-hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide; N- (4-methoxyphenyl) -4,5,6,7,8,9-hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide; N- (benzyl) -4, 5, 6, 7, 8, -hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide; N- (4-methoxybenzyl) -4,5,6,7,8,9-hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide, N- (4-fluorobenzyl) -4,5 6,7,8,9-hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide; N-butyl-4,5,6,7,8,9-hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide; N- (2-thiazolyl) -4,5,6,7,8,9-hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide; and N- (4-methoxyphenyl) -4,5,6,7,8,9-hexahydro-lH-cycloheptan [b] pyridin-4-ene-3-carboxamide.

19. A compound according to claim 1 characterized in that it is selected from N- (benzyl) -4,5,7,7,8,9-hexahydro-lH-cycloheptan [bj pyridin-4-one-3-carboxamide; N- (4-methoxybenzyl) -4, 5, 6, 7, 8, 9-hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide; N- (4-fluorobenzyl) -4,5,6,7,8,9-hexahydro-lH-cycloheptan [b] pyridin-4-one-3-carboxamide; N- (3-fluorobenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (4-fluorobenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (3-chlorobenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one -3-carboxamide; N- (4-chlorobenzyl) -1,4,6,7,7,8-hexahydroquinolin-4-one-3-carboxamide; and N- (2-fluoro-4-methoxybenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide.

20. A compound according to claim 1 characterized in that it is selected from N- (4-ethoxybenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (4-methylbenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (3-methylbenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (2-fluoro-4-ethoxybenzyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (2-fluoro-4-isopropoxybenzyl) -1, 4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (2-fluoro-4-propyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (2-thienylmethyl) -1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide; N- (4-methoxyphenyl) -4,5,9,7-tetrahydro-lH-cyclopentan [b] pyridine-3-carboxamide.

21. A compound according to claim 1 characterized in that it is selected from N- (3-methoxyphenyl) -4,5,6,7-tetrahydro-1H-cyclopentan [b] pyridin-4-one-3-carboxamide; N- (4- (2-hydroxyethoxy) phenyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; N - ((4- (dimethylamino) phenyl) methyl) -4,5,6,7-tetrahydro-1-cyclopentan [b] pyridin-4-one-3-carboxamide; N- (2-fluoro-4-methoxybenzyl) -4,5,6,7,7-tetrahydro-lH-tetrahydro-lH-pentan [b] pyridin-4-one-3-carboxamide; N- (4-ethoxybenzyl) -4,5,9,7-tetrahydro-lH-cyclopentan [b] pyridine-2-carboxamide; N- (2-fluoro-4-ethoxybenzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; N- (2-fluoro-4-isopropoxybenzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; N- (2-fluoro-4-propoxybenzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide; N- (2-fluorobenzyl) -4,5,6,7-tetrahydro-lH-cyclopentan [b] pyridin-4-one-3-carboxamide.