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WO1996039404A1 - Nouvelles imidazolones d'aryle et de cycloalkyle substituees; nouvelle classe de ligands du recepteur gaba du cerveau - Google Patents

Nouvelles imidazolones d'aryle et de cycloalkyle substituees; nouvelle classe de ligands du recepteur gaba du cerveau Download PDF

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Publication number
WO1996039404A1
WO1996039404A1 PCT/US1996/010214 US9610214W WO9639404A1 WO 1996039404 A1 WO1996039404 A1 WO 1996039404A1 US 9610214 W US9610214 W US 9610214W WO 9639404 A1 WO9639404 A1 WO 9639404A1
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WIPO (PCT)
Prior art keywords
compound according
lower alkyl
alkyl
compounds
fluorobenzoxazyl
Prior art date
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PCT/US1996/010214
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English (en)
Inventor
Robert W. Desimone
Charles A. Blum
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Neurogen Corporation
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Filing date
Publication date
Priority claimed from US08/461,641 external-priority patent/US5637724A/en
Priority claimed from US08/462,674 external-priority patent/US5637725A/en
Application filed by Neurogen Corporation filed Critical Neurogen Corporation
Priority to AU61743/96A priority Critical patent/AU717630B2/en
Priority to EP96919393A priority patent/EP0830359A1/fr
Priority to CA002223936A priority patent/CA2223936C/fr
Publication of WO1996039404A1 publication Critical patent/WO1996039404A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to novel imidazolone derivatives which selectively bind to GABAa receptors. More specifically it relates to substituted aryl and cycloalkyl imidazolones and to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating anxiety, sleep and seizure disorders, and overdoses of benzodiazepine- type drugs, and enhancing alertness.
  • GABA ⁇ -Aminobutyric acid
  • GABA Global System for Mobile Communications
  • 1,4-Benzodiazepines continue to be among the most widely used drugs in the world. Principal among the benzodiazepines marketed are chlordiazepoxide, diazepam, flurazepam, and triazolam. These compounds are widely used as anxiolytics, sedative-hypnotics, muscle relaxants, and anticonvulsants.
  • a number of these compounds are extremely potent drugs; such potency indicates a site of action with a high affinity and specificity for individual receptors.
  • the benzodiazepines were capable of enhancing presynaptic inhibition of a monosynaptic ventral root reflex, a GABA-mediated event (Schmidt et al., 1967, Arch. Exp. Path. Pharmakol. 258: 69-82).
  • All subsequent electrophysiological studies (reviewed in Tallman et al. 1980, Science 207: 274-81 , Haefley et al., 1981 , Handb. Exptl. Pharmacol. 33: 95-102) have generally confirmed this finding, and by the mid-1970s, there was a general consensus among electrophysiologists that the benzodiazepines could enhance the actions of GABA.
  • a high-affinity benzodiazepine binding site receptor
  • Such a receptor is present in the CNS of all vertebrates phylogenetically newer than the boney fishes (Squires & Braestrup 1977, Nature 166: 732-34, Mohler & Okada, 1977, Science 198: 854-51 , Mohler & Okada, 1977, Br. J. Psychiatry 133: 261-68).
  • the major labeled bands have molecular weights of 50,000 to 53,000, 55,000, and 57,000 and the triazolopyridazines inhibit labeling of the slightly higher molecular weight forms (53,000, 55,000, 57,000) (Seighart et al. 1983, Eur. J. Pharmacol. 88: 291-99).
  • the GABAa receptor subunits have been cloned from bovine and human cDNA libraries (Schoenfield et al., 1988; Duman et al., 1989). A number of distinct cDNAs were identified as subunits of the GABAa receptor complex by cloning and expression. These are categorized into ° ⁇ , ⁇ , ⁇ , e , and provide a molecular basis for the GABAa receptor heterogeneity and distinctive regional pharmacology (Shiwers et al., 1980; Levitan et al., 1989). The ⁇ subunit appears to enable drugs like benzodiazepines to modify the GABA responses (Pritchett et al., 1989). The presence of low Hill coefficients in the binding of ligands to the GABAa receptor indicates unique profiles of subtype specific pharmacological action.
  • Drugs that interact at the GABAa receptor can possess a spectrum of pharmacological activities depending on their abilities to modify the actions of GABA.
  • the beta- carbolines were first isolated based upon their ability to inhibit competitively the binding of diazepam to its binding site (Nielsen et al., 1979, Life Sci. 25: 679-86).
  • the receptor binding assay s not tota y pre ct ve a out t e o og ca act v ty o suc compoun s; agon sts, part a agonists, inverse agonists, and antagonists can inhibit binding.
  • beta-carboline structure When the beta-carboline structure was determined, it was possible to synthesize a number of analogs and test these compounds behaviorally. It was immediately realized that the beta-carbolines could antagonize the actions of diazepam behaviorally (Tenen & Hirsch, 1980, Nature 288: 609-10). In addition to this antagonism, beta-carbolines possess intrinsic activity of their own opposite to that of the benzodiazepines; they become known as inverse agonists.
  • Rl 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
  • X is a divalent radical selected from the group consisting of
  • U.S. Patent No. 4,435,403 teaches compounds of the formula: wherein R ⁇ is hydrogen, lower alkyl, alkoxyalkyl of up to 6 C-atoms, cycloalkyl of 3-6 C- atoms, arylalkyl of up to 8 C-atoms, or (CH2)nOR2 wherein R20 i alkyl of up to 6 C-atoms, cycloalkyl of 3-6 C-atoms or arylalkyl of up to 8 C-atoms and n is an integer of 1 to 3; Y is oxygen, two hydrogen atoms or NORi, wherein R] is hydrogen, lower alkyl, aryl or arylalkyl of up to 6 C-atoms, COR2, wherein R2 is lower alkyl of up to 6 C-atoms, or Y is CHCOOR3, wherein R3 is hydrogen or lower alkyl or Y is NNR4R5, wherein R4 and R5 can be the same or different and each is hydrogen, lower
  • R and R7 can be the same or different and each is hydrogen or lower alkyl or R4 and R5 together with the connecting N-atom, form a 5- or 6-membered heterocyclic ring which optionally may also contain an O-atom or up to 3 N-atoms and which optionally may be substituted by a lower alkyl group;
  • Z is hydrogen, or alkoxy or aralkoxy each of up to 10 C- atoms and each optionally substituted by hydroxy, or Z is alkyl of up to 6 C-atoms, C6-10- ar y' or C7_i ⁇ -arylalkyl each of which may optionally be substituted by a COORg or a CONR9R10 group, wherein Rg is alkyl of up to 6 C-atoms, and R9 and RJO can be the same or different and each is hydrogen or alkyl of up to 6 C-atoms; or Z is NR9R10, wherein R9 and R j r j are as defined above; or Z is
  • R13 is Ci-io-alkyl or NR14R15, wherein R14 and R15 are the same or different and each is hydrogen, OH or alkyl or alkoxy each of up to 6 C-atoms, or wherein R12 and R13 together are oxygen, in which case, R ⁇ ⁇ is hydrogen
  • Z is COOR2 wherein R2 is as defined above; or Y and Z, together with the connecting C-atom, may form a 5- or 6-membered heterocyclic ring which contains an O-atom, adjoining O- and N-atoms or up to 4 N atoms and which optionally may be substituted by a lower alkyl group, hydroxy or oxo.
  • U.S. Patent No. 4,596,808 discloses compounds of the formula: wherein R A is H, F, Cl, Br, I, NO2, CN, CH3, CF3, SCH3, NR ⁇ 6 R ⁇ 7 or NHCOR ⁇ 6 , wherein R1 g of Rj ⁇ are the same or different and each is hydrogen or alkyl, alkenyl or alkynyl each of up to 6 C-atoms, arylalkyl or cycloalkyl each of up to 10 C-atoms, or wherein R ⁇ and Rj7 together form a saturated or unsaturated 3-7 membered heterocyclic ring.
  • R3 is an oxadiazolyl residue of the formula
  • R5 stands for lower alkyl of up to 3 carbon atoms or an ester -CO2R6 with ⁇ 6 being hydrogen or lower alkyl of up to 3 carbon atoms
  • R4 is hydrogen, lower alkyl of up to 3 carbon atoms
  • CH2OR9 wherein R9 is lower alkyl of up to 3 carbon atoms
  • R A is phenyl or a hydrocarbon residue containing 2-10 carbon atoms which can be cyclic or acyclic, saturated or unsaturated, branched or unbranched, and which can optionally be substituted by oxo, formyl OH, O-alkyl of up to 3 carbon atoms or phenyl, and wherein in a cyclic hydrocarbon residue, a CH2-group can be replaced by oxygen.
  • Ri is hydrogen or a protecting group
  • R4 is hydrogen o halogen
  • R3 is hydrogen, lower alkyl or lower alkoxyalkyl
  • R A is, inter alia, hydrogen
  • R7 is lower alkyl, optionall substituted aryl or arylalkyl, and each compound can contain one or more R A radicals which ar not hydrogen.
  • Patents teach carbocyclic compounds having pyridine or piperidine rings but lack the imidazolon ring present in the compounds of the present invention.
  • German Patent No. DE 3,246,932 discloses compounds of the formula:
  • R ⁇ aryl
  • This invention provides novel compounds of Formula I which interact with a GABAa binding site, the benzodiazepine receptor.
  • the invention provides pharmaceutical compositions comprising compounds of Formula I.
  • the invention also provides compounds useful in the diagnosis and treatment of anxiety, sleep, and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory. Accordingly, a broad embodiment of the invention is directed to compounds of Formula I:
  • T is NH, O, or S
  • X is hydrogen, hydroxyl, lower alkyl, or CONR1R2 where Ri and R2 independently represent hydrogen or lower alkyl;
  • n 0, 1, 2, or 3;
  • R3 5 R4, R5 and R6 are the same or different and represent hydrogen, halogen, lowe alkyl, lower alkoxy, phenyl, or 2-, 3-, or 4-pyridyl; or phenylalkyl or 2-, 3-, or 4-pyridylalkyl where each alkyl is lower alkyl, each o which is mono or disubstituted with halogen, hydroxyl, lower alkyl or alkoxy lower alkyl; and R7, R8, R9, Rio independently represents hydrogen, lower alkyl; or R7 and Rs together may represent a group of the formula
  • These compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory.
  • T is NH, O, or S
  • X is hydrogen, hydroxyl, lower alkyl, or CONR1R2 where Ri and R2 independently represe hydrogen or lower alkyl;
  • each alkyl represents benzo, thieno, or pyrido, each of which is optionally mono o disubstituted with halogen, hydroxyl, lower alkyl, amino, mono- or dialkylamino wher each alkyl is lower alkyl, or lower alkoxy;
  • n 0, 1, 2, or 3
  • R3 s R4, R5 and R6 are the same or ferent and represent hy rogen, a ogen, ow alkyl, lower alkoxy, phenyl, or 2-, 3-, or 4-pyridyl; or phenylalkyl or 2-, 3-, or 4-pyridylalkyl where each alkyl is lower alkyl, each which is mono or disubstituted with halogen, hydroxyl, lower alkyl or alkox lower alkyl; R7, R ⁇ , R9, Rio independently represents hydrogen, lower alkyl; or R7 and Rg together may represent a group of the formula
  • nl 0, 1, 2.
  • the present invention encompasses compounds of the Formula II.
  • the “W ring” represents benzo, thieno, or pyrido, each of which i optionally mono or disubstituted with halogen, hydroxyl, lower alkyl, lowe alkoxy, amino, or mono- or dialkylamino where each alkyl is lower alkyl;
  • R is hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy.
  • Preferred compounds of Formula II are those where the W ring is benzo or pyrido, each of which is mono or disubstituted with halogen, hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or a y am no w ere eac a y s ower a y .
  • R is hydrogen or halogen
  • W ring is benzo or pyrido, each of which i mono or disubstituted with halogen, hydroxyl, lower alkyl, lower alkoxy, amino, or mono- o dialkylamino where each alkyl is lower alkyl.
  • the present invention encompasses compounds of the Formula III.
  • Y ring represents benzo or pyrido, each of which is optionally mono or disubstituted with halogen, hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where each alkyl is lower alkyl; and R is hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy.
  • Preferred compounds of Formula III are those where the Y ring is benzo or pyrido, each of which is mono or disubstituted with halogen, hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where each alkyl is lower alkyl.
  • More preferred compounds of Formula III are those where R is hydrogen or halogen; and the Y ring is benzo or pyrido each of which is mono or disubstituted with halogen, hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where each alkyl is lower alkyl.
  • the present invention encompasses compounds of the Formula IV.
  • Preferred compounds of Formula IV are those where the Y ring is benzo or pyrido, eac of which is mono or disubstituted with halogen, hydroxyl, lower alkyl, lower alkoxy, amino, o mono- or dialkylamino where each alkyl is lower alkyl. More preferred compounds of Formul
  • Y ring is benzo or pyrido, each of which is mono or disubstituted wit halogen, hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where eac alkyl is lower alkyl.
  • Preferred compounds of Formula V are those where the Y ring is benzo or pyrido, eac of which is mono or disubstituted with halogen, hydroxyl, lower alkyl, lower alkoxy, amino, o mono- or dialkylamino where each alkyl is lower alkyl. More preferred compounds of Formul
  • V are those where the Y ring is benzo or pyrido, each of which is mono or disubstituted with halogen, hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where each alkyl is lower alkyl.
  • Non-toxic pharmaceutically acceptable salts include salts o acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluen sulfonic, hydroiodic, acetic and the like. Those skilled in the art will recognize a wide variety o non-toxic pharmaceutically acceptable addition salts.
  • the present invention also encompasses the acylated prodrugs of the compounds o Formula I.
  • acylated prodrugs of the compounds o Formula I Those skilled in the art will recognize various synthetic methodologies which can b employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
  • each alkyl is lower alkyl, or lower alkoxy.
  • thieno as used herein is meant a group of the formula
  • each alkyl is lower alkyl, or lower alkoxy.
  • pyrido as used herein is meant a group of the formula
  • each alkyl is lower alkyl, or lower alkoxy.
  • 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 methylpentyl.
  • lower alkoxy in the present invention is meant straight or branched chain alkox 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.
  • halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
  • N-alkylpiperazyl in the invention is meant radicals of the formula:
  • Ra is lower alkyl as defined above.
  • Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) of 0.05 M Tris HCl buffer (pH 7.4 at 4°C). The tissue homogenate is centrifuged in the cold (4°) at 20,000 x g for 20'. The supernatant is decanted and the pellet is rehomogenized in the same volume of buffer and again centrifuged at 20,000 x g. The supernatant is decanted and the pellet is frozen at -20°C overnight.
  • RO15-1788 [ ⁇ H-Flumazenil] specific activity 80 Ci/mmol), drug or blocker and buffer to a tota volume of 500 ml. Incubations are carried for 30 min at 4°C then are rapidly filtered throug GFB filters to separate free and bound ligand. Filters are washed twice with fresh 0.05 M Tri HCl buffer (pH 7.4 at 4°C) and counted in a liquid scintillation counter. 1.0 mM diazepam i added to some tubes to determine nonspecific binding. Data are collected in triplicat determinations, averaged and % inhibition of total specific binding is calculated. Total Specifi Binding Total - Nonspecific. In some cases, the amounts of unlabeled drugs is varied and tota displacement curves of binding are carried out. Data are converted to a form for the calculation o IC50 and Hill Coefficient (nH). Data for compounds of this invention are listed in Table 2.
  • the compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier. ne or more compoun s o genera ormu a may e present n assoc at on w t one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
  • compositions containing compounds of general formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation product of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, o condensation products of ethylene oxide with partial esters derived from fatty acids and a hexito such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide wit partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbita monooleate.
  • dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or
  • the aqueous suspensions may also contain one or more preservatives, for exampl ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavorin agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and e x rs may e ormu ate w t sweeten ng agents, or examp glycerol, propylene glycol, sorbitor or sucrose.
  • Such formulations may also contain demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspensio may be formulated according to the known art using those suitable dispersing or wetting agent and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent o solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parentally acceptable diluent o solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvent that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. Fo this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of general formula I may also be administered in the form o suppositories for rectal administration of the drug.
  • These compositions can be prepared b mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures bu liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Suc materials are cocoa butter and polyethylene glycols.
  • Compounds of general formula I may be administered parenterally in a steril medium.
  • the drug depending on the vehicle and concentration used, can either be suspended o dissolved in the vehicle.
  • adjuvants such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day).
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body we g t, genera ealth, sex, diet, time of a m n strat on, route o administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • CDI means carbonyl di-imidazole.
  • a mixture of 2-bromocyclohexanone (6.23g, 0.035 moi) and urea (2.1g, 0.035 moi) is refluxed in a solution of ammonium acetate (lOg), acetic acid (15mL) and water (50mL) for 4h.

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Abstract

Composés de la formule (I) dans laquelle T représente NH, O ou S; X représente hydrogène, hydroxyle, alkyle inférieur ou un amide éventuellement substitué; le noyau W est un groupe aryle ou hétéroaryle éventuellement substitué; et (a) représente un groupe benzo éventuellement substitué ou un noyau éventuellement substitué à 5, 6, 7 ou 8 chaînons. Ces composés sont des agonistes, antagonistes ou agonistes inverses à haute sélectivité pour les récepteurs GABAa du cerveau ou des promédicaments d'agonistes, antagonistes ou agonistes inverses des récepteurs GABAa du cerveau. Ces composés peuvent être utilisés dans le cadre du diagnostic ou du traitement de l'anxiété, de troubles du sommeil, des attaques et d'une surdose de médicaments à base de benzodiazépine ainsi que pour améliorer la mémoire.
PCT/US1996/010214 1995-06-05 1996-06-04 Nouvelles imidazolones d'aryle et de cycloalkyle substituees; nouvelle classe de ligands du recepteur gaba du cerveau WO1996039404A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU61743/96A AU717630B2 (en) 1995-06-05 1996-06-04 Novel substituted aryl and cycloalkyl imidazolones; a new class of GABA brain receptor ligands
EP96919393A EP0830359A1 (fr) 1995-06-05 1996-06-04 Nouvelles imidazolones d'aryle et de cycloalkyle substituees; nouvelle classe de ligands du recepteur gaba du cerveau
CA002223936A CA2223936C (fr) 1995-06-05 1996-06-04 Nouvelles imidazolones d'aryle et de cycloalkyle substituees; nouvelle classe de ligands du recepteur gaba du cerveau

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US08/461,641 US5637724A (en) 1995-06-05 1995-06-05 Substituted aryl and cycloalkyl imidazolones; a new class of GABA brain receptor ligands
US08/462,674 US5637725A (en) 1995-06-05 1995-06-05 Substituted aryl and cycloalkyl imidazolones; a new class of GABA brain receptor ligands
US08/461,641 1995-06-05
US08/462,674 1995-06-05

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6271241B1 (en) 1999-04-02 2001-08-07 Neurogen Corporation Cycloalkyl and aryl fused aminoalkyl-imidazole derivatives: modulators and GLP-1 receptors
US6281237B1 (en) 1999-04-02 2001-08-28 Neurogen Corporation N-phenyl benzimidazolecarboxamide and N-phenyl indolecarboxamide derivatives
US6380210B1 (en) 1999-04-02 2002-04-30 Neurogen Corporation Heteroaryl fused aminoalkyl-imidazole derivatives: selective modulators of GABAa receptors
US6627624B1 (en) 1999-04-02 2003-09-30 Neurogen Corporation Aryl fused aminoalkyl-imidazole derivatives: selective modulators of GABAa receptors
WO2003097643A1 (fr) * 2002-05-17 2003-11-27 Neurogen Corporation Derives d'imidazole a cycles fusionnes se fixant aux recepteurs gabaa, ligands des recepteurs gabaa
WO2005070906A1 (fr) * 2004-01-21 2005-08-04 Novartis Ag Composes organiques

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US6271241B1 (en) 1999-04-02 2001-08-07 Neurogen Corporation Cycloalkyl and aryl fused aminoalkyl-imidazole derivatives: modulators and GLP-1 receptors
US6281237B1 (en) 1999-04-02 2001-08-28 Neurogen Corporation N-phenyl benzimidazolecarboxamide and N-phenyl indolecarboxamide derivatives
US6380210B1 (en) 1999-04-02 2002-04-30 Neurogen Corporation Heteroaryl fused aminoalkyl-imidazole derivatives: selective modulators of GABAa receptors
US6583169B2 (en) 1999-04-02 2003-06-24 Neurogen Corporation N-phenyl benzimidazolecarboxamide and N-phenyl indolecarboxamide derivatives
US6627624B1 (en) 1999-04-02 2003-09-30 Neurogen Corporation Aryl fused aminoalkyl-imidazole derivatives: selective modulators of GABAa receptors
US6972293B2 (en) 1999-04-02 2005-12-06 Neurogen Corporation Heteroaryl fused aminoalkyl-imidazole derivatives: selective modulators of GABAa receptors
WO2003097643A1 (fr) * 2002-05-17 2003-11-27 Neurogen Corporation Derives d'imidazole a cycles fusionnes se fixant aux recepteurs gabaa, ligands des recepteurs gabaa
US6916827B2 (en) 2002-05-17 2005-07-12 Neurogen Corporation Substituted ring-fused imidazole derivative: GABAA receptors ligands
WO2005070906A1 (fr) * 2004-01-21 2005-08-04 Novartis Ag Composes organiques
CN100567273C (zh) 2004-01-21 2009-12-09 诺瓦提斯公司 有机化合物
EP2281819A1 (fr) * 2004-01-21 2011-02-09 Novartis AG Dérivés du benzimidazole ou du benzoxazole

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EP0830359A1 (fr) 1998-03-25
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AU6174396A (en) 1996-12-24
CA2223936C (fr) 2004-01-20

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