US20030092912A1 - Heteroaryl fused aminoalkyl-imidazole derivatives: selective modulators of GABAa Receptors - Google Patents

Heteroaryl fused aminoalkyl-imidazole derivatives: selective modulators of GABAa Receptors Download PDF

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US20030092912A1
US20030092912A1 US10/115,361 US11536102A US2003092912A1 US 20030092912 A1 US20030092912 A1 US 20030092912A1 US 11536102 A US11536102 A US 11536102A US 2003092912 A1 US2003092912 A1 US 2003092912A1
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methylbutyl
methylpropyl
fluorophenyl
methylphenyl
propyl
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Robert DeSimone
Alan Hutchison
Kenneth Shaw
Daniel Rosewater
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Neurogen Corp
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Neurogen Corp
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Publication of US20030092912A1 publication Critical patent/US20030092912A1/en
Priority to US10/609,941 priority patent/US6972293B2/en
Priority to US11/295,173 priority patent/US7348326B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to heteroaryl fused aminoalkylimidazole derivatives which when appropriately substituted selectively bind to GABA A receptors.
  • This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in enhancing alertness and treating anxiety, overdoses of benzodiazepine-type drugs, Down Syndrome, depression, sleep, seizure and cognitive disorders both in human as well as domestic pets and livestock.
  • the compounds of this invention are also useful as probes for the localization of cell surface receptors.
  • the GABA A receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, ⁇ -aminobutyric acid, or GABA, acts. Widely, although unequally, distributed through the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABA A receptor, which causes alteration in chloride conductance and membrane polarization.
  • GABA A receptor subunits A number of cDNAs for GABA A receptor subunits have been characterized. To date at least 6 ⁇ , 3 ⁇ , 3 ⁇ , 1 ⁇ , 1 ⁇ and 2 ⁇ subunits have been identified. It is generally accepted that native GABA A receptors are typically composed of 2 ⁇ , 2 ⁇ , and 1 ⁇ subunits (Pritchett & Seeburg Science 1989; 245:1389-1392 and Knight et. al., Recept. Channels 1998; 6:1-18).
  • Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABA A receptor.
  • the GABA A receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and the barbiturate site.
  • the benzodiazepine site of the GABA A receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for GABA or for other classes of drugs that bind to the receptor (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6 th ed., 1991, pp. 145-148, Oxford University Press, New York).
  • GABA A selective ligands may also act to potentiate the effects of certain other CNS active compounds.
  • selective serotonin reuptake inhibitors SSRIs
  • SSRIs selective serotonin reuptake inhibitors
  • This invention relates to heteroaryl fused aminoalkyl-derivatives.
  • Preferred compounds of the invention that bind with high affinity to the benzodiazepine site of the GABA A receptor, including human GABA A receptors.
  • Preferred compounds of the invention also bind with high selectivity to the benzodiazepine site of the GABA A receptor.
  • the invention provides novel compounds of Formula I (shown below), and pharmaceutical compositions comprising compounds of Formula I.
  • the invention further comprises methods of treating patients suffering from certain CNS disorders with an effective amount of a compound of the invention.
  • the patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering such conditions with an effective amount of a compound of the invention is contemplated by the invention.
  • the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention with another CNS active compound.
  • this invention relates to the use of the compounds of the invention as probes for the localization of GABA A receptors in tissue sections.
  • probes are useful for in vitro studies, such as binding assays and autoradiography of tissue sections and for in vivo techniques such as PET and SPECT scans.
  • the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention with another CNS active compound.
  • the invention furthermore provides methods of using compounds of this invention as positive controls in assays for receptor activity and using appropriately labeled compounds of the invention as probes for the localization of receptors, particularly GABA A receptors, in tissue sections.
  • probes are useful for in vitro studies, such as binding assays and autoradiography of tissue sections and for in vivo techniques such as PET and SPECT scans.
  • Z is O, or S
  • R 1 represents phenyl, C 1 -C 6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
  • R 3 represents C 1 -C 6 alkyl, allyl, cyclopropylmethyl, cyclopentyl;
  • X represents a bond, CH 2 , or CHCH
  • A,B,C,D are the same or different and represent CH or N with the proviso that not more than two of A,B,C, or D represent N.
  • Preferred compounds of the invention are highly selective agonists, antagonists or inverse agonists for GABA A brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors, the benzodiazepine receptor. These compounds are useful in the diagnosis and treatment of anxiety, Down Syndrome, depression, sleep and seizure disorders, cognitive disorders overdose with benzodiazepine drugs, and enhancement of alertness, both in human and non-human animals and domestic pets, especially dogs and cats and farm animals such as sheep, swine and cattle.
  • the invention also provides methods and compositions for treating and diagnosing anxiety, Down Syndrome, depression, sleep, cognitive and seizure disorders, and overdose with benzodiazepine drugs.
  • the invention encompasses compounds that are intermediates in the synthesis of the compounds of Formula I.
  • Z is O, or S
  • R 1 represents phenyl, C 1 -C 6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
  • R 2 represents
  • C 1 -C 6 alkyl or C 1 -C 6 alkoxy each of which are optionally substituted with amino, mono or di(C 1 -C 6 ) alkylamino, a C 5 -C 7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
  • NR 8 R 9 forms a 5-, 6-, or 7-membered heterocyclic ring
  • R 3 represents
  • C 1 -C 6 alkyl or C 1 -C 6 alkoxy each of which is optionally substituted with amino, mono or di(C 1 -C 6 ) alkylamino, a C 5 -C 7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
  • NR 8 R 9 forms a 5-, 6-, 7-membered heterocyclic ring
  • R 4 , R 5 and R 6 are the same or different and represent
  • C 1 -C 6 alkyl or C 1 -C 6 alkoxy each of which is optionally substituted with amino, mono or di(C 1 -C 6 ) alkylamino, a C 5 -C 7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion, C 1 -C 6 alkylthiol, or halogen;
  • NR 8 R 9 forms a 5-, 6-, or 7-membered heterocyclic ring
  • R 4 and R 5 can form a 1,3-dioxolene ring
  • X represents a bond, CH 2 , or CHCH
  • A, B, C, and D are the same or different and represent CH or N with the proviso that not more than two of A,B,C, or D represent N.
  • R 2 may also represent
  • R n and R k independently represent C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 cycloalkyl (C 1 -C 6 ) alkyl, benzoyl where the phenyl portion is optionally substituted with halgoen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • p, s, and t independently represent 1 or 2;
  • J is CH, N, O, S, or a carbon atom substituted with C 1 -C 6 alkyl; or
  • NR k R n represents
  • Preferred compounds of the invention are represented by Formula II.
  • R 1 represents phenyl, C 1 -C 6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
  • X represents a bond, CH 2 , CHCH
  • A,B,C,D are the same or different and represent CH or N with the proviso that not more than two of A,B,C, or D represent N.
  • Z is O, or S
  • R 1 represents phenyl, C 1 -C 6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
  • X represents a bond, CH 2 , CHCH
  • A,B,C,D are the same or different and represent CH or N with the proviso that not more than two of A,B,C, or D represent N.
  • R 4 , R 5 , and R 6 are as defined above for Formula I;
  • R 1 and R 3 are independently C 1 -C 6 alkyl; and R a and R b are independently
  • R n and R k independently represent C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 cycloalkyl (C 1 -C 6 ) alkyl, benzoyl where the phenyl portion is optionally substituted with halgoen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • p, s, and t independently represent 1 or 2;
  • J is CH, N, O, or a carbon atom substituted with C 1 -C 6 alkyl; or
  • NR k R n represents
  • Preferred compounds of Formula IV include those where R 1 is propyl and R 3 is C 3 -C 5 alkyl, preferably isobutyl. More preferred compounds of IV are those where R b is hydrogen and R a is —NHR n where R n is defined as above or —NR k R n where both R n and R k are allyl or C 1 -C 6 alkyl.
  • Preferred —NR k R n groups include diallylamino, dimethylamino, diethylamino, and N-ethyl-N-cyclopropylmethylamino.
  • Preferred NHR n groups include those where R n is allyl, C 1 -C 6 alkyl, or a group of IV-a.
  • Preferred IV-a groups include pyrrolidinyl, morpholinyl and piperidinyl.
  • Particularly preferred compounds of IV are those where R 1 is propyl, R 3 is isobutyl, R b is hydrogen, and R a is
  • the compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
  • These compounds can be, for example, racemates or optically active forms.
  • the single enantiomers, i.e., optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
  • Representative compounds of the present invention include, but are not limited to the compounds described in the Examples and their pharmaceutically acceptable acid addition salts.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH 2 ) n -COOH where n is 0-4, and the like.
  • acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH 2 ) n -COOH where n is 0-4, and the like.
  • acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,
  • the present invention also encompasses the acylated prodrugs of the compounds of Formula I.
  • acylated prodrugs of the compounds of Formula I include those skilled in the art and various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
  • alkyl or “lower alkyl” in the present invention is meant C 1 -C 6 alkyl, i.e., 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.
  • Preferred C 1 -C 6 alkyl groups are methyl, ethyl, propyl, butyl, cyclopropyl or cyclopropylmethyl.
  • alkoxy or “lower alkoxy” in the present invention is meant C 1 -C 6 alkoxy, i.e., 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.
  • (hetero) cyclic ring is meant a ring that is either aliphatic or aromatic and optionally contains at least one hetero atom. Hetero atoms include nitrogen, sulfur, and oxygen. Examples of such (hetero) cyclic rings are cyclohexyl, cyclopenyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, etc.
  • heteroaryl in the present invention is meant one or more aromatic ring systems of 5-, 6-, or 7-membered rings containing at least one and up to four hetero atoms selected from nitrogen, oxygen, or sulfur.
  • heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl, imidazolyl, (iso)quinolinyl, naphthyridinyl, benzimidazolyl, and benzoxazolyl.
  • heteroaryl groups are the following:
  • L is nitrogen or —CR 11 ;
  • T is —NR 19 , oxygen, or sulfur
  • R 11 and R 11i are the same or different and are selected from hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, (C 1 -C 6 )alkoxy, amino, or mono- or di(C 1 -C 6 )alkylamino;
  • R 12 , R 12i , and R 13 are the same or different and are selected from hydrogen, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, amino, mono- or di(C 1 -C 6 )alkylamino, hydroxy, or trifluoromethyl; and
  • R 19 is hydrogen, lower alkyl having 1-6 carbon atoms.
  • the invention encompasses all possible tautomers and rotamers represented by Formula I.
  • halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
  • Aryl and heteroaryl fused aminoalkyl-imidazoles of Formula I and their salts are suitable for the diagnosis and treatment of anxiety, Down Syndrome, sleep and seizure disorders, overdoses of benzodiazepine-type drugs, depression and cognitive disorders and for the enhancement of alertness, both in human and non-human animals and domestic pets, especially dogs and cats and farm animals such as sheep, swine and cattle. These interactions result in the pharmacological activites of these compounds.
  • 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.
  • One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
  • 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.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • 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 products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoo
  • 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.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., sodium EDTA
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium EDTA, sodium bicarbonate, sodium bicarbonate
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, 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 injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents 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.
  • 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 of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • Compounds of general Formula I may be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anesthetics, 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.
  • Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of anxiety or depression a dosage regimen of 1 or 2 times daily is particularly preferred. For the treatment of sleep disorders a single dose that rapidly reaches effective concentrations is desirable.
  • Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lifes. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat periphereal disorders are often preferred.
  • Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously. Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcová, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27).
  • Compound half-life is inversely proportional to the frequency of dosage of a compound.
  • In vitro half-lifes of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).
  • the present invention also pertains to packaged pharmaceutical compositions for treating disorders responsive to GABA A receptor modulation, e.g., treatment of cognitive deficits, anxiety or depression by GABA A receptor modulation.
  • the packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one GABA A receptor modulator as described supra and instructions (e.g., labeling) indicating the contained GABA A receptor ligand is to be used for treating a disorder responsive to GABA A receptor modulation in the patient.
  • the present invention also pertains to methods for altering the signal-tranducing activity of GABA A receptors, said method comprising exposing cells expressing such receptor to an effective amount of a compound of the invention.
  • a method of inhibiting the binding of a benzodiazepine compound to the benzodiazepine site of the GABA A receptor comprising contacting a compound of Formula I with cells expressing such a receptor in the presence of a the benzodiazepine compound, wherein the compound is present at a concentration sufficient to inhibit benzodiazepine compound binding to cells expressing a cloned human GABA A receptor in vitro is provided by a separate aspect of the invention.
  • the invention provides a method of potentiating the actions of other CNS active compounds, which comprises administering an effective amount of a compound of the invention in combination with another CNS active compound.
  • CNS active compounds include, but are not limited to the following: for anxiety, serotonin receptor (e.g. 5-HT 1A ) agonists and antagonists; for anxiety and depression, neurokinin receptor antagonists or corticotropin releasing factor receptor (CRF 1 ) antagonists; for sleep disorders, melatonin receptor agonists; and for neurodegenerative disorders, such as Alzheimer's dementia, nicotinic agonists, muscarinic agents, acetylcholinesterase inhibitors and dopamine receptor agonists.
  • SSRIs selective serotonin reuptake inhibitors
  • Combination administration can be carried out in an analogous fashion to that disclosed in Da-Rocha, et al., J. Psychopharmacology (1997) 11(3) 211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10) 1339-45; and Le, et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132.
  • a solution of 150 mL (2.37 mole) of chloroacetonitrile, 139 mL (2.37 mole) of ethanol in 1,200 mL of dry benzene is cooled to 0° C. in an ice/ethanol bath. Dry HCl gas is bubbled through the vigorously stirred solution for approximately 30 min. while the internal temperature is maintained below 10° C. The solution is allowed to stand at rt. overnight. The resulting solid is filtered and washed with 2L of dry ether and allowed to air dry to afford 328 g (88%) of imidate hydrochloride.
  • a solution of 11.25 g (0.07 mole) of 2-n-Propyl-5-fluorophenelyenediamine in 200 mL of anhydrous CHCl 13 is treated with 11.06 g (0.07 mole) of imidate at room temperature.
  • the heterogeneous reaction mixture is allowed to stir for 45 min. at which time no starting material is detectable by TLC.
  • 100 mL of saturated NaHCO 3 is added and extracted 3 ⁇ 50 mL of CH 2 Cl 2 .
  • a solution of 20 g (0.095 mole) of [3-nitro-4-(propylamino)phenyl]methan-1-ol and 19.2 g (0.28 mole) of imidazole in 200 mL of anhydrous DMF is treated with 19 g (0.13 mole) of t-butyldimethylsilyl chloride at room temperature for 30 min.
  • the resulting mixture is diluted with 400 mL of ethyl acetate and washed 3 ⁇ 200 mL of water and 1 ⁇ 200 mL of brine.
  • the resulting orgainc layer is dried over anhydrous Na 2 SO 4 and the solvent removed in vacuo.
  • 2,5-difluorobenzoylchloride 1.5 eq is treated with 1.0 eq 1.25 g (3.3 mmole) of propyl ( ⁇ 1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl ⁇ methyl) amine in dichloromethane at room temperature for 1 hr.
  • the reaction is quenched with 1 N NaOH and partitioned between dichloromethane and water.
  • the organic layer is dried over anhydrous Na 2 SO 4 and the solvent removed in vacuo.
  • a solution of 0.2 mL of 0.2M (2,5-difluorophenyl)-N- ⁇ ([5-(chloromethyl)-1-propylbenzimidazol-2-yl]methyl ⁇ -N-propylcarboxamide in 1-methyl-2-pyrrolidinone is treated at room temperature for 16 hr with 0.3 mL of 0.2M solution of morpholine in toluene.
  • the resulting mixture is diluted with 2 mL of ethyl acetate and washed 2 ⁇ 2 mL of water 1 ⁇ 2 mL brine.
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 1 Methyl 3-Fluorophenyl 2 Allyl 3-Fluorophenyl 3 Propyl 3-Fluorophenyl 4 Allyl 3-Fluorophenyl 5 Propyl 3-Fluorophenyl 6 Propyl 3,4-Difluorophenyl 7 Allyl 2,5-Difluorophenyl 8 Propyl 2,5-Difluorophenyl 9 Propyl 1,3-Benzodioxol-5-yl 10 Allyl 3-Chloro-4-fluorophenyl 11 Propyl 3-Chloro-4-fluorophenyl 12 Methyl 5-Chloro-2-methoxyphenyl 13 3-Methylbutyl 3- ⁇ 2-[(3- Methoxypropyl)amino]ethoxy ⁇ phenyl 14 3-Methylbutyl
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 273 2-Methylpropyl 2,4,6-Trifluorophenyl 274 3-Methylbutyl 2,4,6-Trifluorophenyl 275 2-Methylpropyl 2,3,6-Trifluorophenyl 276 Pentyl 2,3,6-Trifluorophenyl 277 3-Methylbutyl 2,3,6-Trifluorophenyl 278 Pentyl 2-Chloro-6-fluorophenyl 279 3-Methylbutyl 2-Chloro-6-fluorophenyl 280 Pentyl 2-Fluoro-6- trifluoromethylphenyl 281 3-Methylbutyl 2-Fluoro-6- trifluoromethylphenyl 282 Pentyl 3-Bromo-4-fluorophenyl 283 2-Methylpropyl 4-Hexylphen
  • R 2 and R 3 are specified in the following table.
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 Propyl 3-Chlorophenyl 558 Propyl Phenyl 559 Allyl 2-Fluorophenyl 560 Propyl 2-Fluorophenyl 561 Propyl 3-Fluoro-4- methylphenyl 562 Methyl 2,5-Dichlorophenyl 563 Propyl 2,5-Dichlorophenyl 564 Propyl 4-Pentylphenyl 565 Propyl 3-Bromophenyl 566 Propyl 3-Methyl-2-thienyl
  • R 2 and R 3 are specified in the following table.
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 683 Allyl 3-Fluorophenyl 684 Allyl 3,4-Difluorophenyl 685 Propyl 1,3-Benzodioxol-5-yl 686 Allyl 5-Chloro-2-methoxyphenyl 687 Propyl 3-Methyl-2-Thienyl 688 Propyl 3-Fluoro-4-methylphenyl 689 Propyl 3-Fluorophenyl 690 Propyl 3,4-Difluorophenyl 691 Allyl 3-Chloro-4-fluorophenyl 692 Propyl 5-Chloro-2-methoxyphenyl 693 Allyl Phenyl 694 Allyl 5-Fluoro-2-methylphenyl 695 Propyl 4-Fluorophenyl 696 Allyl 2,5-Difluorophenyl 697
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 715 Methyl 3-Fluorophenyl 716 Methyl 5-Fluoro-2-methylphenyl 717 Methyl 3-Chlorophenyl 718 Methyl 5-Chloro-2-methoxyphenyl 839 2-Methylpropyl 2,3,6-Trifluorophenyl 840 Pentyl 2,3,6-Trifluorophenyl 841 3-Methylbutyl 2,3,6-Trifluorophenyl 938 Butyl Phenyl 939 2-Methylpropyl Phenyl 940 Pentyl Phenyl 941 3-Methylbutyl Phenyl 942 Butyl 3-Methylphenyl 943 2-Methylpropyl 3-Methylphenyl 944 3-Methylbutyl 3-Methylphenyl 945 2-Met
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 719 Propyl 3-Fluorophenyl 720 Propyl 1,3-Benzodioxol-5-yl 721 Propyl 5-Fluoro-2-methylphenyl 722 Allyl 2-Fluorophenyl 723 Propyl 3-Chloro-4-fluorophenyl 724 Propyl 3-Chlorophenyl 725 Propyl 2-Fluorophenyl 726 Allyl 5-Chloro-2-methoxyphenyl 727 Allyl 3-Chlorophenyl 728 Methyl 3-Fluorophenyl 729 Methyl 2,5-Difluorophenyl 730 Propyl Phenyl 731 Propyl 3-Chlorophenyl 732 Allyl 3-Fluorophenyl 733 Propyl 2,5-Difluorophenyl 734 Propyl
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 800 Propyl Phenyl 801 Methyl 3-Chlorophenyl 802 Allyl 3-Chlorophenyl 803 Propyl 3-Chlorophenyl 804 Propyl 5-Chloro-2-methoxyphenyl 805 Propyl 3-Trifluoromethylphenyl 806 Propyl 2,5-Dichlorophenyl 807 Propyl 3-Bromophenyl 808 Propyl 3-Bromo-4-fluorophenyl 809 Methyl 3-Iodophenyl 810 Allyl 3-Iodophenyl 811 Propyl 3-Iodophenyl 888 Allyl 5-Chloro-2-methoxyphenyl 931 Propyl 3-Fluorophenyl 932 Propyl 2-Fluorophenyl 1092 Propyl 3-Fluorophenyl 1093 Propyl
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 889 Methyl 2,5-Difluorophenyl 890 Methyl 2,5-Dichlorophenyl 891 Propyl 3-Bromophenyl 892 Methyl 3-Iodophenyl 893 Allyl 3-Iodophenyl 894 Propyl 3-Iodophenyl 1126 Propyl 2,5-Dichlorophenyl 1127 Methyl 3-Bromophenyl 1128 Allyl 3-Bromophenyl 1432 Propyl 3-Bromo-4-fluorophenyl 1517 2-Methylpropyl 3-Fluorophenyl 1518 2-Methylpropyl 3,4-Dimethylphenyl 1519 2-Methylpropyl 3-Methoxyphenyl 1520 2-Methylpropyl 3-Fluoro-4-methylphenyl 1521 Cyclo
  • R 2 and R 3 are specified in the following table.
  • R 2 and R 3 are specified in the following table.
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 902 Allyl 3-Bromo-4-methylphenyl 903 Propyl 3-Bromo-4-methylphenyl 904 Allyl 3-Bromo-4-fluorophenyl 905 Propyl 3-Bromo-4-fluorophenyl 906 Methyl 3-Iodophenyl 907 Allyl 3-Iodophenyl 908 Propyl 3-Iodophenyl 909 Propyl 3-Iodo-4-methylphenyl 910 Methyl 2-Thienyl 911 Methyl 3-Thienyl 912 Methyl 3-Methyl-2-thienyl 913 Propyl 5-Methyl-2-thienyl 914 Propyl Phenyl 915 Methyl 3-Methylphenyl 916 Propyl 3-Fluorophenyl 917 Propyl 2-Fluor
  • R 2 and R 3 are specified in the following table.
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 818 Propyl 3-Fluorophenyl 819 Propyl 2-Fluorophenyl 820 Propyl 3,4-Difluorophenyl 821 Methyl 2,5-Difluorophenyl 822 Allyl 2,5-Difluorophenyl 823 Propyl 2,5-Difluorophenyl 824 Propyl 1,3-Benzodioxol-5-yl 825 Propyl 3-Chloro-4-fluorophenyl 826 Methyl 5-Chloro-2-methoxyphenyl 827 Ethyl 5-Chloro-2-methoxyphenyl 828 Allyl 5-Chloro-2-methoxyphenyl 829 Propyl 5-Chloro-2-methoxyphenyl 830 Methyl 2,5-Dichlorophenyl 831 Allyl 2,5
  • R 2 and R 3 are specified in the following table.
  • R 2 and R 3 are specified in the following table.
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 955 Methyl Phenyl 956 Propyl Phenyl 957 Methyl 3-Methylphenyl 958 Propyl 3-Methylphenyl 959 Methyl 3-Fluorophenyl 960 Propyl 3-Fluorophenyl 961 Methyl 2-Fluorophenyl 962 Allyl 2-Fluorophenyl 963 Propyl 2-Fluorophenyl 964 Methyl 5-Fluoro-2-methylphenyl 965 Methyl 3-Chlorophenyl 966 Propyl 3-Chlorophenyl 989 Propyl 3-Chloro-4-fluorophenyl 994 Methyl 2-Thienyl 995 Propyl 2-Thienyl 996 Methyl 3-Thienyl 997 Methyl 3-Methyl
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 967 Propyl Phenyl 968 Propyl 3-Methylphenyl 969 Propyl 4-Methylphenyl 970 Propyl 3-Fluorophenyl 971 Propyl 2-Fluorophenyl 972 Propyl 5-Fluoro-2-methylphenyl 973 Ethyl 3-Chlorophenyl 974 Allyl 3-Chlorophenyl 975 Propyl 3-Chlorophenyl 990 Propyl 1,3-Benzodioxol-5-yl 991 Allyl 3-Chloro-4-fluorophenyl 992 Propyl 3-Chloro-4-fluorophenyl 1103 Propyl 5-Chloro-2-methoxyphenyl 1104 Propyl 3-Trifluoromethylphenyl 1105 Propyl 3,4-Dichlorophenyl 1106 Allyl 2,
  • R 2 and R 3 are specified in the following table.
  • Compound No R 2 R 3 1220 2-Methylpropyl Phenyl 1221 2-Methylpropyl 3-Methylpropyl 1222 2-Methylpropyl 4-Methylpropyl 1223 2-Methylpropyl 2-Fluorophenyl 1224 2-Methylpropyl 4-Ethylphenyl 1225 2-Methylpropyl 3,4-Dimethylphenyl 1227 2-Methylpropyl 2,5-Difluorophenyl 1228 2-Methylpropyl 2,4-Difluorophenyl 1229 2-Methylpropyl 1,3-Benzodioxol-5-yl 1230 2-Methylpropyl 4-Bromophenyl 1251 2-Methylpropyl 3-Bromo-4-methylphenyl 1272 2-Methylpropyl 3-Chloro
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 1226 Propyl 2-Fluorophenyl 1231 Allyl 5-Chloro-2-methoxyphenyl 1232 Propyl 5-Chloro-2-methoxyphenyl 1233 Methyl 2,5-Dichlorophenyl 1234 Allyl 2,5-Dichlorophenyl 1235 Propyl 2,5-Dichlorophenyl 1236 Methyl 3-Bromophenyl 1237 Allyl 3-Bromophenyl 1238 Propyl 3-Bromophenyl 1252 Propyl 3-Iodophenyl 1748 2-Methylpropyl 2,3,6-Trifluorophenyl 1749 3-Methylbutyl 2,3,6-Trifluorophenyl 1750 2-Methylpropyl 3-Chloro-4-phenyl 1751 3-Methylbutyl 3-Chloro-4-phenyl 1751 3-Methylbut
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 1250 Propyl 3-Iodophenyl 1616 2-Methylpropyl 3-Chloro-4-fluorophenyl 1617 2-Methylpropyl 3-Bromophenyl 1618 3-Methylbutyl 3-Bromophenyl 1634 2-Methylpropyl 3-Bromo-4-methylphenyl 1635 2-Methylpropyl 3-Bromo-4-fluorophenyl 1636 3-Methylbutyl 3-Bromo-4-fluorophenyl 1637 2-Methylpropyl 3-Iodophenyl 1638 3-Methylbutyl 3-Bromo-4-fluorophenyl 1639 2-Methylpropyl Phenyl 1640 3-Methylbutyl Phenyl 1641 2-Methylpropyl 3-Methylphenyl 1642 3-Met
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 1276 2-Methylpropyl Phenyl 1277 Pentyl Phenyl 1278 3-Methylbutyl Phenyl 1279 3-Methylbutyl 3-Methylphenyl 1280 2-Methylpropyl 4-Methylphenyl 1281 2-Methylpropyl 3-Fluorophenyl 1282 3-Methylbutyl 3-Fluorophenyl 1283 2-Methylpropyl 4-Fluorophenyl 1284 Butyl 2-Fluorophenyl 1285 2-Methylpropyl 2-Fluorophenyl 1286 Pentyl 2-Fluorophenyl 1287 3-Methylbutyl 2-Fluorophenyl 1288 2-Methylpropyl 3-Methoxyphenyl 1289 3-Methylbut
  • R 2 and R 3 are specified in the following table.
  • R 2 and R 3 are specified in the following table.
  • R 2 and R 3 are specified in the following table.
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 2004 2-Methylpropyl 2-(4-Chlorophenyl)ethenyl
  • R 2 and R 3 are specified in the following table.
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 2025 3-Pyrrolinyl 2,5-Difluorophenyl 2026 3-Pyrrolinyl 3-Fluorophenyl 2027 Pyrrolidinyl 2,5-Difluorophenyl 2028 Pyrrolidinyl 3-Fluorophenyl 2029 1,2,5,6-Tetrahydro 2,5-Difluorophenyl pyridyl 2030 1,2,5,6-Tetrahydro 3-Fluorophenyl pyridyl 2031 Piperidyl 2,5-Difluorophenyl 2032 Piperidyl 3-Fluorophenyl 2039 Morpholinyl 2,5-Difluorophenyl 2040 Morpholinyl 3-Fluorophenyl 2043 4-Methyl 2,5-Difluorophenyl piperidyl
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 4 R 3 2033 Pyrrolidinyl 2,5-Difluorophenyl 2034 Pyrrolidinyl 3-Fluorophenyl 2035 1,2,5,6-Tetrahydro 2,5-Difluorophenyl pyridyl 2036 1,2,5,6-Tetrahydro 3-Fluorophenyl pyridyl 2037
  • Piperidyl 2,5-Difluorophenyl 2038 Morpholinyl 3-Fluorophenyl 2041
  • 4-Methyl 2,5-Difluorophenyl piperidyl 2042 4-Methyl 3-Fluorophenyl piperidyl 2045 Azaperhydro 3-Fluorophenyl Epinyl 2048 1,4-Thiazaper 3-Fluorophenyl hydroin-4-yl 2051 3,3-dimethyl 2,
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 2147 3-Methylbutyl 3-Chlorophenyl 2219 3-Methylbutyl 3-Trifluoromethylphenyl 2220 Butyl 3-Bromophenyl 2221 2-Methylpropyl 3-Bromophenyl 2222 3-Methylbutyl 3-Bromophenyl
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 2186 Butyl 2,5-Dimethoxyphenyl 2187 2-Methylpropyl 2,5-Dimethoxyphenyl 2188 3-Methylbutyl 2,5-Dimethoxyphenyl 2189 Butyl 3-Chloro-4-methoxyphenyl 2190 2-Methylpropyl 3-Chloro-4-methoxyphenyl 2191 3-Methylbutyl 3-Chloro-4-methoxyphenyl 2192 Butyl 5-Chloro-2-methoxyphenyl 2193 2-Methylpropyl 5-Chloro-2-methoxyphenyl 2194 3-Methylbutyl 5-Chloro-2-methoxyphenyl 2195 2-Methylpropyl 4-Chloro-2-methoxyphenyl 2196 Butyl 3-Trifluoromethylphenyl 2197 2-Methylpropyl
  • R 2 and R 3 are specified in the following table.
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 2380 2-Methylpropyl 2,4-Difluorophenyl 2381 2-Methylpropyl 2H-Benzo[d]1,3-dioxolane 2382 2-Methylpropyl 3-Chloro-4-methylphenyl
  • R 2 and R 3 are specified in the following table.
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 2383 2-Methylpropyl 3-Chloro-4-methylphenyl 2384 2-Methylpropyl 2,4-Difluorophenyl 2385 2-Methylpropyl 2H-Benzo [d]1,3-dioxolane
  • R 2 and R 3 are specified in the following table.
  • Compound No. R 2 R 3 2389 Pentyl 3-Fluoro-4-methylphenyl
  • the following assay is a standard assay for GABA A receptor binding.
  • Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) of Buffer A (0.05 M Tris HCl buffer, pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4° C.) at 20,000 ⁇ g for 20 minutes. The supernatant is decanted, the pellet rehomogenized in the same volume of buffer, and centrifuged again at 20,000 ⁇ g. The supernatant of this centrifugation step is decanted and the pellet stored at ⁇ 20° C. overnight.
  • Buffer A 0.05 M Tris HCl buffer, pH 7.4 at 4° C.
  • the pellet is then thawed and resuspended in 25 volumes of Buffer A (original wt/vol), centrifuged at 20,000 ⁇ g and the supernatant decanted. This wash step is repeated once. The pellet is finally resuspended in 50 volumes of Buffer A.
  • Buffer A original wt/vol
  • a competition binding curve is obtained with up to 11 points spanning the compound concentration range from 10 ⁇ 12 M to 10 ⁇ 5 M obtained per curve by the method described above for determining percent inhibition.
  • K i values are calculated according the Cheng-Prussof equation. When tested in this assay compounds of the invention exihibit K i values of less than 1 uM, preferred compounds of the invention have K i values of less than 500 nM and more compounds of the invention have K i values of less than 100 nM.
  • the following assay is used to determine if a compound of the invention act as an agonist, an antagonist, or an inverse agonist at the benzodiazepine site of the GABA A receptor.
  • Assays are carried out as described in White and Gurley (NeuroReport 6: 1313-1316, 1995) and White, Gurley, Hartnett, Stirling, and Gregory (Receptors and Channels 3: 1-5, 1995) with modifications. Electrophysiological recordings are carried out using the two electrode voltage-clamp technique at a membrane holding potential of ⁇ 70 mV. Xenopus Laevis oocytes are enzymatically isolated and injected with non-polyadenylated cRNA mixed in a ratio of 4:1:4 for , and subunits, respectively. Of the nine combinations of , and subunits described in the White et al. publications, preferred combinations are 1 2 2, 2 3 2, 3 3 2, and 5 3 2.
  • each combination Preferably all of the subunit cRNAs in each combination are human clones or all are rat clones.
  • the sequence of each of these cloned subunits is available from GENBANK, e.g., human 1, GENBANK accession no. X14766, human 2, GENBANK accession no. A28100; human 3, GENBANK accession no. A28102; human 5, GENBANK accession no. A28104; human 2, GENBANK accession no. M82919; human 3, GENBANK accession no. Z20136; human 2, GENBANK accession no. X15376; rat 1, GENBANK accession no. L08490, rat 2, GENBANK accession no.
  • Compounds are evaluated against a GABA concentration that evokes ⁇ 10% of the maximal evokable GABA current (e.g. 1 M -9 M). Each oocyte is exposed to increasing concentrations of compound in order to evaluate a concentration/effect relationship. Compound efficacy is calculated as a percent-change in current amplitude: 100*((Ic/I) ⁇ 1), where Ic is the GABA evoked current amplitude observed in the presence of test compound and I is the GABA evoked current amplitude observed in the absence of the test compound.
  • Specificity of a compound for the benzodiazepine site is determined following completion of a concentration/effect curve. After washing the oocyte sufficiently to remove previously applied compound, the oocyte is exposed to GABA+1 ⁇ M RO15-1788, followed by exposure to GABA+1 ⁇ M RO15-1788+test compound. Percent change due to addition of compound is calculated as described above. Any percent change observed in the presence of RO15-1788 is subtracted from the percent changes in current amplitude observed in the absence of 1 ⁇ M RO15-1788. These net values are used for the calculation of average efficacy and EC 50 values by standard methods. To evaluate average efficacy and EC 50 values, the concentration/effect data are averaged across cells and fit to the logistic equation.
  • the compounds of the invention are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope.
  • the radioisotope is preferably selected from of at least one of carbon (preferably 14 C), hydrogen (preferably 3 H), sulfur (preferably 35 S), or iodine (preferably 125 I).
  • Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, Ill.; Cambridge Isotope Laboratories, Inc.
  • Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.
  • Receptor autoradiography (receptor mapping) of NK-3 or GABA A receptors in cultured cells or tissue samples is carried out in vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York, using radiolabeled compounds of the invention prepared as described in the preceding Example.

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Abstract

Disclosed are compounds of the formula:
Figure US20030092912A1-20030515-C00001
or the pharmaceutically acceptable non-toxic salts thereof wherein the A, B, C, D, X, R1, R2, R3, R4, R5, and R6, are variables defined herein, 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, and are therefore useful in the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, depression, overdose with benzodiazepine drugs, and enhancement of memory and alertness.

Description

  • This application claims the benefit of U.S. Provisional Application No. 60/127,526, filed Apr. 2, 1999.[0001]
    • FIELD OF THE INVENTION
  • This invention relates to heteroaryl fused aminoalkylimidazole derivatives which when appropriately substituted selectively bind to GABA[0002] A receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in enhancing alertness and treating anxiety, overdoses of benzodiazepine-type drugs, Down Syndrome, depression, sleep, seizure and cognitive disorders both in human as well as domestic pets and livestock.
  • The compounds of this invention are also useful as probes for the localization of cell surface receptors. [0003]
    • BACKGROUND
  • The GABA[0004] A receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, γ-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed through the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABAA receptor, which causes alteration in chloride conductance and membrane polarization.
  • A number of cDNAs for GABA[0005] A receptor subunits have been characterized. To date at least 6α, 3β, 3γ, 1ε, 1δ and 2ρ subunits have been identified. It is generally accepted that native GABAA receptors are typically composed of 2α, 2β, and 1γ subunits (Pritchett & Seeburg Science 1989; 245:1389-1392 and Knight et. al., Recept. Channels 1998; 6:1-18). Evidence such as message distribution, genome localization and biochemical study results suggest that the major naturally occurring receptor combinations are α1β2γ2, α2β3γ2, α3β3γ2, and α5β3γ2 (Mohler et. al. Neuroch. Res. 1995; 20(5): 631-636).
  • Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABA[0006] A receptor. In addition to the benzodiazepine site, the GABAA receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and the barbiturate site. The benzodiazepine site of the GABAA receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for GABA or for other classes of drugs that bind to the receptor (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6th ed., 1991, pp. 145-148, Oxford University Press, New York). Early electrophysiological studies indicated that a major action of the benzodiazepines was enhancement of GABAergic inhibition. Compounds that selectively bind to the benzodiazepine site and enhance the ability of GABA to open GABAA receptor channels are agonists of GABA receptors. Other compounds that interact with the same site but negatively modulate the action of GABA are called inverse agonists. Compounds belonging to a third class bind selectively to the benzodiazepine site and yet have little or no effect on GABA activity, but can block the action of GABAA receptor agonists or inverse agonists that act at this site. These compounds are referred to as antagonists.
  • The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early and the distribution of activities at different receptor subtypes has been an area of intense pharmacological discovery. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative, and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects. While benzodiazepines have a long history of pharmaceutical use as anxiolytics, these compounds often exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence. [0007]
  • GABA[0008] A selective ligands may also act to potentiate the effects of certain other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when when used in combination with GABAA selective ligands than when used alone.
    • SUMMARY OF THE INVENTION
  • This invention relates to heteroaryl fused aminoalkyl-derivatives. Preferred compounds of the invention that bind with high affinity to the benzodiazepine site of the GABA[0009] A receptor, including human GABAA receptors. Preferred compounds of the invention also bind with high selectivity to the benzodiazepine site of the GABAA receptor.
  • The invention provides novel compounds of Formula I (shown below), and pharmaceutical compositions comprising compounds of Formula I. [0010]
  • The invention further comprises methods of treating patients suffering from certain CNS disorders with an effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering such conditions with an effective amount of a compound of the invention is contemplated by the invention. [0011]
  • In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention with another CNS active compound. [0012]
  • Additionally this invention relates to the use of the compounds of the invention as probes for the localization of GABA[0013] A receptors in tissue sections. Such probes are useful for in vitro studies, such as binding assays and autoradiography of tissue sections and for in vivo techniques such as PET and SPECT scans.
  • Packaged pharmaceutical compositions including instructions for use of the composition are also included. [0014]
  • In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention with another CNS active compound. [0015]
  • The invention furthermore provides methods of using compounds of this invention as positive controls in assays for receptor activity and using appropriately labeled compounds of the invention as probes for the localization of receptors, particularly GABA[0016] A receptors, in tissue sections. Such probes are useful for in vitro studies, such as binding assays and autoradiography of tissue sections and for in vivo techniques such as PET and SPECT scans.
  • Accordingly, a broad embodiment of the invention is directed to compounds of Formula I: [0017]
    Figure US20030092912A1-20030515-C00002
  • or the pharmaceutically acceptable non-toxic salts thereof wherein: [0018]
  • W represents [0019]
    Figure US20030092912A1-20030515-C00003
  • where Z is O, or S; [0020]
  • R[0021] 1 represents phenyl, C1-C6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
  • R[0022] 2 represents hydroxyl, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6) alkylamino, additionally the alkyl portion can form a 5,6,7 member ring; or O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl, additionally R8 and R9 can be a 5,6,7 member heterocyclic ring;
  • R[0023] 3 represents C1-C6 alkyl, allyl, cyclopropylmethyl, cyclopentyl;
  • or benzyl optionally mono-, di-, or trisubstituted independently with halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C[0024] 1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6) alkylamino, additionally the alkyl portion can form a 5,6,7 member ring; or O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl, additionally R8 and R9 can be a 5,6,7 member heterocyclic ring, additional substitution on the benzyl ring can be directly bound or O(CH2)n (where n=1,2,3,4) linked SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8, as well as tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, and pyridyl;
  • R[0025] 4, R5 and R6 are the same or different and represent hydrogen, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6) alkylamino, additionally the alkyl portion can form a 5,6,7 member ring, C1-C6 alkylthiol, or halogen, or O(CH2)nco2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, additionally R8 and R9 can be a 5,6,7 member heterocyclic ring, additionally R4 and R5 can form a 1,3-dioxolene ring;
  • X represents a bond, CH[0026] 2, or CHCH;
  • A,B,C,D are the same or different and represent CH or N with the proviso that not more than two of A,B,C, or D represent N. [0027]
  • Preferred compounds of the invention are highly selective agonists, antagonists or inverse agonists for GABA[0028] A brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors, the benzodiazepine receptor. These compounds are useful in the diagnosis and treatment of anxiety, Down Syndrome, depression, sleep and seizure disorders, cognitive disorders overdose with benzodiazepine drugs, and enhancement of alertness, both in human and non-human animals and domestic pets, especially dogs and cats and farm animals such as sheep, swine and cattle.
  • Thus, the invention also provides methods and compositions for treating and diagnosing anxiety, Down Syndrome, depression, sleep, cognitive and seizure disorders, and overdose with benzodiazepine drugs. [0029]
  • In another aspect, the invention encompasses compounds that are intermediates in the synthesis of the compounds of Formula I. [0030]
    • DETAILED DESCRIPTION OF THE INVENTION
  • The compounds encompassed by the instant invention are represented by the general formula I: [0031]
    Figure US20030092912A1-20030515-C00004
  • or pharmaceutically acceptable non-toxic salts thereof wherein: [0032]
  • W represents [0033]
    Figure US20030092912A1-20030515-C00005
  • where [0034]
  • Z is O, or S; [0035]
  • R[0036] 1 represents phenyl, C1-C6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
  • R[0037] 2 represents
  • hydroxyl; [0038]
  • C[0039] 1-C6 alkyl or C1-C6 alkoxy, each of which are optionally substituted with amino, mono or di(C1-C6) alkylamino, a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
  • O(CH[0040] 2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl; or
  • NR[0041] 8R9 forms a 5-, 6-, or 7-membered heterocyclic ring;
  • R[0042] 3 represents
  • C[0043] 1-C6 alkyl, allyl, cyclopropylmethyl, cyclopentyl; or
  • benzyl optionally mono-, di-, or trisubstituted independently with [0044]
  • halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, or hydroxy; [0045]
  • C[0046] 1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino, mono or di(C1-C6) alkylamino, a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
  • O(CH[0047] 2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl;
  • NR[0048] 8R9 forms a 5-, 6-, 7-membered heterocyclic ring;
  • SO[0049] 2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8 where R8 is defined as above;
  • O(CH[0050] 2)n-G where n=1,2,3,4 and G is SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, or CONHSO2R8, where R8 is as defined above; or
  • tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, or pyridyl; [0051]
  • R[0052] 4, R5 and R6 are the same or different and represent
  • hydrogen; or [0053]
  • C[0054] 1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino, mono or di(C1-C6) alkylamino, a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion, C1-C6 alkylthiol, or halogen;
  • O(CH[0055] 2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl;
  • NR[0056] 8R9 forms a 5-, 6-, or 7-membered heterocyclic ring; or
  • R[0057] 4 and R5 can form a 1,3-dioxolene ring;
  • X represents a bond, CH[0058] 2, or CHCH; and
  • A, B, C, and D are the same or different and represent CH or N with the proviso that not more than two of A,B,C, or D represent N. [0059]
  • In formula I, R[0060] 2 may also represent
  • hydrogen or [0061]
  • a group of the formula [0062]
    Figure US20030092912A1-20030515-C00006
  • where [0063]  
  • R[0064] n and Rk independently represent C1-C6 alkyl, C2-C6 alkenyl, C1-C6 cycloalkyl (C1-C6) alkyl, benzoyl where the phenyl portion is optionally substituted with halgoen, C1-C6 alkyl, or C1-C6 alkoxy;
  • a group of the formula IV-a [0065]
    Figure US20030092912A1-20030515-C00007
  • where [0066]  
  • p, s, and t independently represent 1 or 2; [0067]
  • J is CH, N, O, S, or a carbon atom substituted with C[0068] 1-C6 alkyl; or
  • NR[0069] kRn represents
    Figure US20030092912A1-20030515-C00008
  • where s, t, and J are as defined above. [0070]  
  • Preferred compounds of the invention are represented by Formula II. [0071]
    Figure US20030092912A1-20030515-C00009
  • R[0072] 1 represents phenyl, C1-C6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
  • R[0073] 2 represents hydroxyl, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6) alkylamino, additionally the alkyl portion can form a 5,6,7 member ring; or O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl, additionally R8 and R9 can be a 5,6,7 member heterocyclic ring;
  • R[0074] 3 represents C1-C6 alkyl, allyl, cyclopropylmethyl, cyclopentyl; or benzyl optionally mono-, di-, or trisubstituted independently with halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6) alkylamino, additionally the alkyl portion can form a 5,6,7 member ring; or O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl, additionally R8 and R9 can be a 5,6,7 member heterocyclic ring, additional substitution on the benzyl ring can be directly bound or O(CH2)n (where n=1,2,3,4) linked SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8, as well as tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, and pyridyl;
  • R[0075] 4, R5 and R6 are the same or different and represent hydrogen, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6) alkylamino, additionally the alkyl portion can form a 5,6,7 member ring, C1-C6 alkylthiol, or halogen, or O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, additionally R8 and R9 can be a 5,6,7 member heterocyclic ring, additionally R4 and R5 can form a 1,3-dioxolene ring;
  • X represents a bond, CH[0076] 2, CHCH;
  • A,B,C,D are the same or different and represent CH or N with the proviso that not more than two of A,B,C, or D represent N. [0077]
  • Other preferred compounds of the invention are represented by Formula III. [0078]
    Figure US20030092912A1-20030515-C00010
  • where [0079]
  • Z is O, or S; [0080]
  • R[0081] 1 represents phenyl, C1-C6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
  • R[0082] 2 represents hydroxyl, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6) alkylamino, additionally the alkyl portion can form a 5,6,7 member ring; or O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl, additionally R8 and R9 can be a 5,6,7 member heterocyclic ring;
  • R[0083] 3 represents C1-C6 alkyl, allyl, cyclopropylmethyl, cyclopentyl; or benzyl optionally mono-, di-, or trisubstituted independently with halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6) alkylamino, additionally the alkyl portion can form a 5,6,7 member ring; or O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl, additionally R8 and R9 can be a 5,6,7 member heterocyclic ring, additional substitution on the benzyl ring can be directly bound or O(CH2)n (where n=1,2,3,4) linked SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8, as well as tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, and pyridyl;
  • R[0084] 4, R5 and R6 are the same or different and represent hydrogen, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6) alkylamino, additionally the alkyl portion can form a 5,6,7 member ring, C1-C6 alkylthiol, or halogen, or O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, additionally R8 and R9 can be a 5,6,7 member heterocyclic ring, additionally R4 and R5 can form a 1,3-dioxolene ring;
  • X represents a bond, CH[0085] 2, CHCH;
  • A,B,C,D are the same or different and represent CH or N with the proviso that not more than two of A,B,C, or D represent N. [0086]
  • More preferred compounds of Formula I are represented by Formula IV [0087]
    Figure US20030092912A1-20030515-C00011
  • where [0088]
  • R[0089] 4, R5, and R6 are as defined above for Formula I;
  • R[0090] 1 and R3 are independently C1-C6 alkyl; and Ra and Rb are independently
  • hydrogen or [0091]
  • a group of the formula [0092]
    Figure US20030092912A1-20030515-C00012
  • where [0093]  
  • R[0094] n and Rk independently represent C1-C6 alkyl, C2-C6 alkenyl, C1-C6 cycloalkyl (C1-C6) alkyl, benzoyl where the phenyl portion is optionally substituted with halgoen, C1-C6 alkyl, or C1-C6 alkoxy;
  • a group of the formula IV-a [0095]
    Figure US20030092912A1-20030515-C00013
  • where [0096]  
  • p, s, and t independently represent 1 or 2; [0097]
  • J is CH, N, O, or a carbon atom substituted with C[0098] 1-C6 alkyl; or
  • NR[0099] kRn represents
    Figure US20030092912A1-20030515-C00014
  • where s, t, and J are as defined above. [0100]  
  • Preferred compounds of Formula IV include those where R[0101] 1 is propyl and R3 is C3-C5 alkyl, preferably isobutyl. More preferred compounds of IV are those where Rb is hydrogen and Ra is —NHRn where Rn is defined as above or —NRkRn where both Rn and Rk are allyl or C1-C6 alkyl.
  • Preferred —NR[0102] kRn groups include diallylamino, dimethylamino, diethylamino, and N-ethyl-N-cyclopropylmethylamino.
  • Preferred NHR[0103] n groups include those where Rn is allyl, C1-C6 alkyl, or a group of IV-a. Preferred IV-a groups include pyrrolidinyl, morpholinyl and piperidinyl.
  • Particularly preferred compounds of IV are those where R[0104] 1 is propyl, R3 is isobutyl, Rb is hydrogen, and Ra is
  • In certain situations, the compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column. [0105]
  • Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds described in the Examples and their pharmaceutically acceptable acid addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. [0106]
  • Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH[0107] 2)n-COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
  • The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I. [0108]
  • By “alkyl” or “lower alkyl” in the present invention is meant C[0109] 1-C6 alkyl, i.e., 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. Preferred C1-C6 alkyl groups are methyl, ethyl, propyl, butyl, cyclopropyl or cyclopropylmethyl.
  • By “alkoxy” or “lower alkoxy” in the present invention is meant C[0110] 1-C6 alkoxy, i.e., straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
  • By (hetero) cyclic ring is meant a ring that is either aliphatic or aromatic and optionally contains at least one hetero atom. Hetero atoms include nitrogen, sulfur, and oxygen. Examples of such (hetero) cyclic rings are cyclohexyl, cyclopenyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, etc. [0111]
  • By heteroaryl (aromatic heterocycle) in the present invention is meant one or more aromatic ring systems of 5-, 6-, or 7-membered rings containing at least one and up to four hetero atoms selected from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl, imidazolyl, (iso)quinolinyl, naphthyridinyl, benzimidazolyl, and benzoxazolyl. [0112]
  • Specific examples of heteroaryl groups are the following: [0113]
    Figure US20030092912A1-20030515-C00015
  • wherein [0114]
  • L is nitrogen or —CR[0115] 11;
  • T is —NR[0116] 19, oxygen, or sulfur;
  • R[0117] 11 and R11i are the same or different and are selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, (C1-C6)alkoxy, amino, or mono- or di(C1-C6)alkylamino;
  • R[0118] 12, R12i, and R13 are the same or different and are selected from hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, amino, mono- or di(C1-C6)alkylamino, hydroxy, or trifluoromethyl; and
  • R[0119] 19 is hydrogen, lower alkyl having 1-6 carbon atoms.
  • The invention encompasses all possible tautomers and rotamers represented by Formula I. [0120]
  • By the term “halogen” in the present invention is meant fluorine, bromine, chlorine, and iodine. [0121]
  • Aryl and heteroaryl fused aminoalkyl-imidazoles of Formula I and their salts are suitable for the diagnosis and treatment of anxiety, Down Syndrome, sleep and seizure disorders, overdoses of benzodiazepine-type drugs, depression and cognitive disorders and for the enhancement of alertness, both in human and non-human animals and domestic pets, especially dogs and cats and farm animals such as sheep, swine and cattle. These interactions result in the pharmacological activites of these compounds. [0122]
  • The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. [0123]
  • 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. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed. [0124]
  • 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. [0125]
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, 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 products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. [0126]
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. [0127]
  • 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. [0128]
  • Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents. [0129]
  • Syrups and elixirs may 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 injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. [0130]
  • The compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. [0131]
  • Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. [0132]
  • 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. [0133]
  • Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of anxiety or depression a dosage regimen of 1 or 2 times daily is particularly preferred. For the treatment of sleep disorders a single dose that rapidly reaches effective concentrations is desirable. [0134]
  • It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. [0135]
  • Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lifes. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat periphereal disorders are often preferred. [0136]
  • Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously. Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcová, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27). [0137]
  • Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lifes of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127). [0138]
  • The present invention also pertains to packaged pharmaceutical compositions for treating disorders responsive to GABA[0139] A receptor modulation, e.g., treatment of cognitive deficits, anxiety or depression by GABAA receptor modulation. The packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one GABAA receptor modulator as described supra and instructions (e.g., labeling) indicating the contained GABAA receptor ligand is to be used for treating a disorder responsive to GABAA receptor modulation in the patient.
  • The present invention also pertains to methods for altering the signal-tranducing activity of GABA[0140] A receptors, said method comprising exposing cells expressing such receptor to an effective amount of a compound of the invention.
  • A method of inhibiting the binding of a benzodiazepine compound to the benzodiazepine site of the GABA[0141] A receptor, comprising contacting a compound of Formula I with cells expressing such a receptor in the presence of a the benzodiazepine compound, wherein the compound is present at a concentration sufficient to inhibit benzodiazepine compound binding to cells expressing a cloned human GABAA receptor in vitro is provided by a separate aspect of the invention.
  • In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds, which comprises administering an effective amount of a compound of the invention in combination with another CNS active compound. Such CNS active compounds include, but are not limited to the following: for anxiety, serotonin receptor (e.g. 5-HT[0142] 1A) agonists and antagonists; for anxiety and depression, neurokinin receptor antagonists or corticotropin releasing factor receptor (CRF1) antagonists; for sleep disorders, melatonin receptor agonists; and for neurodegenerative disorders, such as Alzheimer's dementia, nicotinic agonists, muscarinic agents, acetylcholinesterase inhibitors and dopamine receptor agonists. Particularly the invention provides a method of potentiating the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) by administering an effective amount of a GABA agonist compound of the invention in combination with an SSRI.
  • Combination administration can be carried out in an analogous fashion to that disclosed in Da-Rocha, et al., [0143] J. Psychopharmacology (1997) 11(3) 211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10) 1339-45; and Le, et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132. Also see, the discussion of the use of the GABAA receptor ligand 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-alphthalzine in combination with nicotinic agonists, muscarinic agonists, and acetylcholinesterase inhibitors, in PCT International publications Nos. WO 99/47142, WO 99/47171, and WO 99/47131, respectively. Also see in this regard PCT International publication No. WO 99/37303 for its discussion of the use of a class of GABAA receptor ligands, 1,2,4-triazolo[4,3-b]pyridazines, in combination with SSRIs.
  • The disclosures of all articles and references mentioned in in this application, including patents, are incorporated herein by reference. [0144]
  • The invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them. Compounds of the invention can be prepared using the reactions depicted in Schemes I to VI. [0145]
    Figure US20030092912A1-20030515-C00016
    Figure US20030092912A1-20030515-C00017
    Figure US20030092912A1-20030515-C00018
    Figure US20030092912A1-20030515-C00019
    Figure US20030092912A1-20030515-C00020
    • Scheme VI
  • Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples. [0146]
  • The following examples illustrate the general procedures for the preparation of compounds of the invention using the reactions outlined above in Schemes I-VI. These examples are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them. [0147]
  • Analysis is performed on a Hewlett Packard 6890 GC, equipped with a dual cool on-column inlets and flame ionization detectors or mass spec detectors. All gas flows are regulated via electronic pneumatic control. The analytical column used is a Supelco PTE-5 QTM, 15 m×0.53 mm ID×0.50 μm film. GC instrument control and data collection are handled using a Perkin Elmer TurboChrom Client/Server data system. GC conditions: On-column injector 163 C. for 2.5 min., ramp at 40 C./min to 323 C. Oven program 100 C. for 1 minute, ramp at 40 C./min to 320 C. Detector temperature is set at 325 C. GC conditions: for compounds 7-12 initial temperature 200 C., ramp to 300 C. at 20 C./min on a 12 m, DB-5 column. [0148]
    • EXAMPLE 1 General Procedure for the Preparation of Chloromethylbenzimidazoles as Outlined in Scheme I
  • 1. Imidate Hydrochloride: [0149]
  • A solution of 150 mL (2.37 mole) of chloroacetonitrile, 139 mL (2.37 mole) of ethanol in 1,200 mL of dry benzene is cooled to 0° C. in an ice/ethanol bath. Dry HCl gas is bubbled through the vigorously stirred solution for approximately 30 min. while the internal temperature is maintained below 10° C. The solution is allowed to stand at rt. overnight. The resulting solid is filtered and washed with 2L of dry ether and allowed to air dry to afford 328 g (88%) of imidate hydrochloride. [0150]
  • 2. 1-n-Propyl-2-(chloromethyl)-5-fluorobenzimidazole: [0151]
    Figure US20030092912A1-20030515-C00021
  • A solution of 11.25 g (0.07 mole) of 2-n-Propyl-5-fluorophenelyenediamine in 200 mL of anhydrous CHCl[0152] 13 is treated with 11.06 g (0.07 mole) of imidate at room temperature. The heterogeneous reaction mixture is allowed to stir for 45 min. at which time no starting material is detectable by TLC. 100 mL of saturated NaHCO3 is added and extracted 3×50 mL of CH2Cl2. The extracts are dried over anhydrous MgSO4, the solvent removed in vacuo, and the residue chromatgraphed (SiO2) with 50% ethyl acetate/hexane to afford 15 g (95%) of 1-n-Propyl-2-(chloromethyl)-5-fluorobenzimidazole.
    • EXAMPLE 2 General Procedure for the Preparation of Benzimidazoles as Shown in Scheme II
  • N-[benzoyl]-N-methyl-1-n-propyl-2-(methanamine)-5-fluorobenzimidazole [0153]
    Figure US20030092912A1-20030515-C00022
  • A solution of 8 mmole of 1-n-Propyl-2-(chloromethyl)-5-fluorobenzimidazole (alternatively named 2-(chloromethyl)-5-fluoro-1-propylbenzimidazole) in 20 mL of dry Acetonitrile is treated with 10 mL of 40% aqueous methylamine for 16 hr at room temperature. The solvent is removed in vacuo and the residue is partitioned between 30 mL of ethyl acetate and 10 mL of 1 N NaOH. The ethyl acetate layer is dried over anhydrous Na[0154] 2SO4 and solvent removed in vacuo to afford 1.68 g 95% of 1-n-Propyl-2-(methanamine)-5-fluorobenzimidazole. Benzoylchloride 1.5 eq is treated with of 1-n-Propyl-2-(methanamine)-5-fluorobenzimidazole 1.0 eq in dichloromethane at room temperature for 1 hr. The reaction is quenched with 1 N NaOH and partitioned between dichloromethane and water. The organic layer is dried with Na2SO4 and the solvent removed in vacuo. The residue is chromatographed (SiO2) with ethyl acetate to afford 95% of N-[benzoyl]-N-methyl-1-n-propyl-2-(methanamine)-5-fluorobenzimidazole [alternatively named N-((5-fluorobenzimidazol-2-yl)methyl)-N-methylbenzamide] (Compound A1).
    • EXAMPLE 3 General Procedure for the Preparation of Benzimidazoles as Shown in Scheme 3
  • (2,5-difluorophenyl)-N-{[5-(morpholin-4-ylmethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide [0155]
    Figure US20030092912A1-20030515-C00023
  • A solution of 20 g (0.095 mole) of [3-nitro-4-(propylamino)phenyl]methan-1-ol and 19.2 g (0.28 mole) of imidazole in 200 mL of anhydrous DMF is treated with 19 g (0.13 mole) of t-butyldimethylsilyl chloride at room temperature for 30 min. The resulting mixture is diluted with 400 mL of ethyl acetate and washed 3×200 mL of water and 1×200 mL of brine. The resulting orgainc layer is dried over anhydrous Na[0156] 2SO4 and the solvent removed in vacuo. The resulting oil is column chromatographed 5% ethyl acetate/hexanes to afford 11 g (35%) of {2-nitro-4-[(1,1,2,2-tetramethy-1-silapropoxy)methyl]phenyl} propylamine.
  • A solution of 11 g (0.033 mole) of {2-nitro-4-[(1,1,2,2-tetramethy-1-silapropoxy)methyl]phenyl} propylamine in 100 mL of ethanol and 1 g 10% Pd/C is treated with 50 psi of H[0157] 2 at room temperature for 2 hr. The resulting mixture is filtered through celite, washed with 200 mL of ethanol and the solvent removed in vacuo. The crude material is treated with 9.7 g (0.06 mole) of imidate hydrochloride in 250 mL of chloroform at room temperature for 1 hr. The reaction mixture is partitioned between 200 mL sat NaHCO3 and 200 mL of chloroform. The organic layer is dried over anhydrous anhydrous Na2SO4 and the solvent removed in vacuo. The resulting oil is column chromatographed 50% ethyl acetate/hexanes to afford 6 g (52% for 2 steps) of 1-{[2-(chloromethyl)-1-propylbenzimidazol-5-yl]methoxy}-1,1,2,2-tetramethyl-1-silapropane.
  • A solution of 2.0 g (5.6 mmole) of 1-{[2-(chloromethyl)-1-propylbenzimidazol-5-yl]methoxy}-1,1,2,2-tetramethyl-1-silapropane in 20 mL of anhydrous acetonitrile is treated with 10 mL of propylamine for 16 hr at room temperature. The solvent is removed in vacuo and the residue is partitioned between 30 mL of ethyl acetate and 10 mL of 1 N NaOH. The ethyl acetate layer is dried over anhydrous Na[0158] 2SO4 and solvent removed in vacuo to afford 2.1 g (99%) of propyl ({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)amine.
  • 2,5-difluorobenzoylchloride 1.5 eq is treated with 1.0 eq 1.25 g (3.3 mmole) of propyl ({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl) amine in dichloromethane at room temperature for 1 hr. The reaction is quenched with 1 N NaOH and partitioned between dichloromethane and water. The organic layer is dried over anhydrous Na[0159] 2SO4 and the solvent removed in vacuo. The residue is chromatographed (SiO2) with ethyl acetate to afford 74% of (2,5-difluorophenyl)-N-propyl-N-({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)carboxamide.
  • A solution 1.25 g (2.4 mmole) of (2,5-difluorophenyl)-N-propyl-N-({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)carboxamide in 20 mL of THF is treated at room temperature with 3 mL of 1M tetrabutylammonium fluoride for 1 hr. The reaction solution is diluted with 20 mL of sat NaHCO[0160] 3 and extracted with 3×100 mL of dichloromethane. The organic extracts are dried over anhydrous Na2SO4 and the solvent removed in vacuo to afford 0.96 g (99%) of (2,5-difluorophenyl)-N-{[5-(hydroxymethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide.
  • (2,5-difluorophenyl)-N-{[5-(hydroxymethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide 0.96 g (2.3 mmole) is treated with 30 mL of thionyl chloride for 15 min a room temperature. The resulting mixture is concentrated in vacuo and partitioned between 100 mL sat NaHCO[0161] 3 and 100 mL of ethyl acetate. The ethyl acetate layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting oil is chroamtoagraphed 50% ethyl acetate/hexanes to afford 0.9 g (93%) of (2,5-difluorophenyl)-N-{[5-(chloromethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide.
  • A solution of 0.2 mL of 0.2M (2,5-difluorophenyl)-N-{([5-(chloromethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide in 1-methyl-2-pyrrolidinone is treated at room temperature for 16 hr with 0.3 mL of 0.2M solution of morpholine in toluene. The resulting mixture is diluted with 2 mL of ethyl acetate and washed 2×2 mL of water 1×2 mL brine. The ethyl acetate layer is dried over anhydrous Na[0162] 2SO4 and concentrated in vacuo to afford 70% of (2,5-difluorophenyl)-N-{[5-(morpholin-4-ylmethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide.
    • EXAMPLE 4
  • The following compounds are prepared essentially according to the procedure described in Examples 1-5, and as shown in Schemes 1-6: [0163]
    Figure US20030092912A1-20030515-C00024
  • (a) (2,5-difluorodifluorophenyl)-N-methyl-N-((1-propylbenzimidazol-2-yl)methyl)carboxamide (Compound A5); GC retention time=5.26 minutes. [0164]
    Figure US20030092912A1-20030515-C00025
  • (b) N-((3-cyclopropylmethylimidazolo[5,4-b]pyridin-2-yl)methyl) (3-fluorophenyl)-N-propylcarboxamide (Compound A6); GC retention time=5.07 minutes. [0165]
    Figure US20030092912A1-20030515-C00026
  • (c) N-[(3-cyclopropylmethylimidazolo[5,4-b]pyridin-2-yl) methyl](2, 5-difluorophenyl)-N-propylcarboxamide (Compound A7); GC retention time=4.80 minutes. [0166]
    Figure US20030092912A1-20030515-C00027
  • (d) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](2,5-difluorophenyl)-N-propylcarboxamide (Compound A8); GC retention time=MS (CI) M+ 453 amu. [0167]
    Figure US20030092912A1-20030515-C00028
  • (e) N-({5-(diethylamino)methyl]-1-butylbenzimidazol-2-yl}methyl) (3-f luorophenyl)-N-propylcarboxamide (Compound A9); GC retention time=5.96 minutes. [0168]
    Figure US20030092912A1-20030515-C00029
  • (f) N-((3-n-butyl-imidazolo[5,4-b]pyridin-2-yl)methyl](3-iodophenyl)-N-propylcarboxamide (Compound A10); GC retention time=6.12 minutes. [0169]
  • (g) N-[(7-chloro-1-propylbenzimidazol-2-yl)methyl](3-fluorophenyl)-N-methylcarboxamide M+ 361 amu [0170]
  • (h) N-[(7-chloro-1-propylbenzimidazol-2-yl)methyl](3-fluorophenyl)-N-propylcarboxamide M+ 389 amu [0171]
  • (i) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]{3-[(methylamino)methyl]phenyl}-N-propylcarboxamide M+ 414 amu [0172]
  • (j) (3-fluorophenyl)-N-[(4-fluoro-1-propylbenzimidazol-2-yl)methyl]-N-propylcarboxamide M+ 372 amu [0173]
  • (k) (2,5-difluorophenyl)-N-{[1-(cyclopropylmethyl)benzimidazol-2-yl]methyl}-N-propylcarboxamide M+ 384 amu [0174]
  • (l) N-{[5-(N,N-diethylcarbamoyl)-1-propylbenzimidazol-2-yl]methyl}(3-fluorophenyl)-N-propylcarboxamide M+ 454 amu [0175]
  • (m) (2,5-difluorophenyl)-N-[(4-fluoro-1-propylbenzimidazol-2-yl)methyl]-N-propylcarboxamide M+ 391 amu [0176]
  • (n) N-{[6-chloro-1-(cyclopropylmethyl)benzimidazol-2-yl]methyl}(3-fluorophenyl)-N-propylcarboxamide M+ 401 amu [0177]
  • (o) (2,5-difluorophenyl)-N-({5-[(ethylamino)methyl]-1-propylbenzimidazol-2-yl}methyl)-N-propylcarboxamide M+ 430 amu [0178]
  • (p) (2,5-difluorophenyl)-N-propyl-N-({1-propyl-5-[(propylamino)methyl]benzimidazol-2-yl}methyl)carboxamide M+ 444 amu [0179]
  • (q) (2,5-difluorophenyl)-N-({5-[(methylamino)methyl]-1-propylbenzimidazol-2-yl}methyl)-N-propylcarboxamide M+ 416 amu [0180]
  • (r) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]{4-[2-(ethylamino)ethoxy]phenyl}-N-(3-methylbutyl)carboxamide M+ 486 amu [0181]
  • (s) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]-N-(3-methylbutyl){4-[2-(propylamino)ethoxy]phenyl}carboxamide M+ 500 amu [0182]
  • (t) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](2-methyl(1,3-thiazol-4-yl))-N-(2-methylpropyl)carboxamide M+ 406 amu [0183]
  • (u) (5-bromo(2-thienyl))-N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]-N-(2-methylpropyl)carboxamide M+ 470 amu [0184]
  • (v) [3-(2-bromoethoxy)phenyl]-N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]-N-(2-methylpropyl)carboxamide M+ 508 amu [0185]
  • (w) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]-N-(2-methylpropyl){3-[2-(propylamino)ethoxy]phenyl}carboxamide M+ 486 amu [0186]
  • (x) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](3-{2-[(2-methoxyethyl)amino]ethoxy}phenyl)-N-(2-methylpropyl)carboxamide M+ 502 amu [0187]
  • (y) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](3-{2-[(2-ethoxyethyl)amino]propoxy}phenyl)-N-(2-methylpropyl)carboxamide M+ 530 amu [0188]
  • (z) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](3-(2-{[2-(methylethoxy)ethyl]amino}propoxy)phenyl]-N-(2-methylpropyl)carboxamide M+ 544 amu [0189]
    • EXAMPLES 5-41
  • The compounds of Examples 5-41 are prepared essentially according to the procedure described in Examples 1-3, and as shown in Schemes 1-6. These compounds are represented by the formulae presented in each of the examples with the definitions of the substituents found within the table. It is noted for the reader that the R[0190] 2 and R3 groups used in these formulae are not the same R2 and R3 groups used in Formula I.
  • Structures for the compounds of Examples 5-42 are shown in Appendices 1 and 2 hereto. [0191]
    • EXAMPLE 5
  • [0192]
    Figure US20030092912A1-20030515-C00030
  • For each compound, the definitions of R[0193] 2 and R3 are specified in the following table.
    Compound
    No. R2 R3
    1 Methyl 3-Fluorophenyl
    2 Allyl 3-Fluorophenyl
    3 Propyl 3-Fluorophenyl
    4 Allyl 3-Fluorophenyl
    5 Propyl 3-Fluorophenyl
    6 Propyl 3,4-Difluorophenyl
    7 Allyl 2,5-Difluorophenyl
    8 Propyl 2,5-Difluorophenyl
    9 Propyl 1,3-Benzodioxol-5-yl
    10 Allyl 3-Chloro-4-fluorophenyl
    11 Propyl 3-Chloro-4-fluorophenyl
    12 Methyl 5-Chloro-2-methoxyphenyl
    13 3-Methylbutyl 3-{2-[(3-
    Methoxypropyl)amino]ethoxy}
    phenyl
    14 3-Methylbutyl 3-{2-[(3-
    Ethoxypropyl)amino]ethoxy}
    phenyl
    15 3-Methylbutyl 3-{2-[(3-
    Ethoxypropyl)amino]ethoxy}
    phenyl
    16 3-Methylbutyl 3-[2-(Benzylamino)
    ethoxy]phenyl
    17 3-Methylbutyl 3-[2-(Benzylamino)
    ethoxy]phenyl
    18 2-Methylpropyl 3-{2-[(3-i-
    Propoxypropyl)amino]ethoxy}
    phenyl
    19 3-Methylbutyl 3-{2-[(3-i-
    Propoxypropyl)amino]ethoxy}
    phenyl
    20 Benzyl 3-Chloro-2-thienyl
    21 4-Fluorobenzyl 3-Chloro-2-thienyl
    22 Benzyl 3-Chloro-4-methylphenyl
    23 2-Fluorobenzyl 3-Chloro-4-methylphenyl
    24 4-Fluorobenzyl 3-Chloro-4-methylphenyl
    25 4-Fluorobenzyl 2-Fluoro-6-trifluoromethyl
    phenyl
    26 4-Fluorobenzyl 3,5-Dibromophenyl
    27 Pentyl 3-Bromophenyl
    28 3-Methylbutyl 3-Bromophenyl
    29 2-Methylpropyl 4-Bromophenyl
    30 3-Methylbutyl 4-Bromophenyl
    31 Butyl 2-Bromophenyl
    32 Pentyl 2-Bromophenyl
    33 3-Methylbutyl 2-Bromophenyl
    34 3-Methylbutyl 3-Methoxyphenyl
    35 3-Methylbutyl 2-Methoxyphenyl
    36 3-Methylbutyl 3-Chlorophenyl
    37 3-Methylbutyl 2-Chlorophenyl
    38 3-Methylbutyl 2-Chlorophenyl
    39 Ethyl 5-Chloro-2-methoxyphenyl
    40 Allyl 5-Chloro-2-methoxyphenyl
    41 Propyl 5-Chloro-2-methoxyphenyl
    42 Methyl 2,5-Dichlorophenyl
    43 Allyl 2,5-Dichlorophenyl
    44 Propyl 2,5-Dichlorophenyl
    45 Propyl 5-Methyl-2-thienyl
    46 Propyl Phenyl
    47 Propyl 3-Methylphenyl
    48 Propyl 3-Fluoro-4-methylphenyl
    49 Allyl 5-Fluoro-2-methylphenyl
    50 Propyl 5-Fluoro-2-methylphenyl
    51 Benzyl 2,3,5,6-Tetrafluoro
    phenyl
    52 4-Fluorobenzyl 2,3,5,6-Tetrafluoro
    phenyl
    53 Benzyl 2,4,6-Trifluoro
    phenyl
    54 Benzyl 2,3,6-Trifluoro
    phenyl
    55 4-Fluorobenzyl 2,3,6-Trifluoro
    phenyl
    56 4-Fluorobenzyl 2-Chloro-6-fluorophenyl
    57 Benzyl 2-Fluoro-6-trifluoromethyl
    phenyl
    58 2-Methylpropyl 3-(2-{[(4-Methylphenyl)
    methyl]amino}
    ethoxy)phenyl
    59 3-Methylbutyl 3-{2-[(2-Cyclohex-1-enylethyl)
    amino]ethoxy}
    phenyl
    60 2-Methylpropyl 3-(2-{[(2-Methylphenyl)
    methyl]amino}
    ethoxy)phenyl
    61 2-Methylpropyl 3-(2-{[(3-Methylphenyl)
    methyl]amino}
    ethoxy)phenyl
    62 2-Methylpropyl 3-(2-{[(2-Methoxyphenyl)
    methyl]amino}
    ethoxy)phenyl
    63 2-Fluorobenzyl 3-Iodo-4-methylphenyl
    64 4-Fluorobenzyl 3-Iodo-4-methylphenyl
    65 4-Fluorobenzyl 2-Thienyl
    66 Benzyl 2-Thienyl
    67 4-Fluorobenzyl 2-Thienyl
    68 Benzyl 3-Methyl-2-thienyl
    69 4-Fluorobenzyl 3-Methyl-2-thienyl
    70 Benzyl 5-Methyl-2-thienyl
    71 2-Fluorobenzyl 5-Methyl-2-thienyl
    72 4-Fluorobenzyl 5-Methyl-2-thienyl
    73 4-Fluorobenzyl 4,5-Dimethyl-2-furyl
    74 2-Methylpropyl 3,4-Dichlorophenyl
    75 Pentyl 3,4-Dichlorophenyl
    76 3-Methylbutyl 3,4-Dichlorophenyl
    77 3-Methylbutyl 3,5-Dichlorophenyl
    78 3-Methylbutyl 2,3-Dichlorophenyl
    79 Butyl 2,5-Dichlorophenyl
    80 2-Methylpropyl 2,5-Dichlorophenyl
    81 Pentyl 2,5-Dichlorophenyl
    82 3-Methylbutyl 2,5-Dichlorophenyl
    83 Butyl 2,4-Dichlorophenyl
    84 2-Methylpropyl 2,4-Dichlorophenyl
    85 3-Methylbutyl 2,4-Dichlorophenyl
    86 Allyl 3-Chlorophenyl
    87 Propyl 3-Chlorophenyl
    88 Propyl 2,3,6-Trifluorophenyl
    89 Methyl 5-Chloro-2-methoxyphenyl
    90 Ethyl 5-Chloro-2-methoxyphenyl
    91 Allyl 5-Chloro-2-methoxyphenyl
    92 Methyl 2,5-Dichlorophenyl
    93 Methyl 3-Bromophenyl
    94 Ethyl 3-Bromophenyl
    95 Propyl 3-Bromophenyl
    96 Methyl 3-Bromo-4-fluorophenyl
    97 Methyl 3-Iodophenyl
    98 3-Methylbutyl 3-(2-{[(2-Methoxyphenyl)
    methyl]amino}
    ethoxy)phenyl
    99 2-Methylpropyl 3-(2-{[(3-Methoxyphenyl)
    methyl]amino}
    ethoxy)phenyl
    100 2-Methylpropyl 3-(2-{[(4-Methoxyphenyl)
    methyl]amino}
    ethoxy)phenyl
    101 2-Methylpropyl 3-(2-{[(2-Chlorophenyl)
    methyl]amino}
    ethoxy)phenyl
    102 Benzyl 2,5-Dimethoxyphenyl
    103 2-Fluorobenzyl 2,5-Dimethoxyphenyl
    104 4-Fluorobenzyl 2,5-Dimethoxyphenyl
    105 Butyl 4-Pentylphenyl
    106 2-Methylpropyl 4-Pentylphenyl
    107 3-Methylbutyl 4-Pentylphenyl
    108 Butyl 3-Bromophenyl
    109 2-Methylpropyl 3-Bromophenyl
    110 Pentyl 3-Bromophenyl
    111 3-Methylbutyl 3-Bromophenyl
    112 2-Methylpropyl 4-Bromophenyl
    113 3-Methylbutyl 4-Bromophenyl
    114 Butyl 2-Bromophenyl
    115 Pentyl 2-Bromophenyl
    116 3-Methylbutyl 2-Bromophenyl
    117 Ethyl 3-Iodophenyl
    118 Allyl 3-Iodophenyl
    119 Propyl 3-Chloro-4-methylphenyl
    120 Propyl 5-Bromo-2-thienyl
    121 Ethyl Phenyl
    122 Allyl Phenyl
    123 Propyl Phenyl
    124 Allyl 3-Methylphenyl
    125 Propyl 3-Methylphenyl
    126 Propyl 4-Methylphenyl
    127 Methyl 3-Fluorophenyl
    128 Propyl 3-Fluorophenyl
    129 Butyl 3-Chloro-4-methoxyphenyl
    130 2-Methylpropyl 3-Chloro-4-methoxyphenyl
    131 3-Methylbutyl 3-Chloro-4-methoxyphenyl
    132 Butyl 5-Chloro-2-methoxyphenyl
    133 2-Methylpropyl 5-Chloro-2-methoxyphenyl
    134 Pentyl 5-Chloro-2-methoxyphenyl
    135 3-Methylbutyl 5-Chloro-2-methoxyphenyl
    136 Butyl 3-Trifluoromethylphenyl
    137 Pentyl 3-Trifluoromethylphenyl
    138 3-Methylbutyl 3-Trifluoromethylphenyl
    139 3-Methylbutyl 2-Trifluoromethylphenyl
    140 Butyl 3,4-Dichlorophenyl
    141 Propyl 4-Fluorophenyl
    142 Methyl 2-Fluorophenyl
    143 Allyl 2-Fluorophenyl
    144 Propyl 2-Fluorophenyl
    145 Propyl 3-Fluoro-4-methylphenyl
    146 Methyl 5-Fluoro-2-methylphenyl
    147 Propyl 5-Fluoro-2-methylphenyl
    148 Methyl 3-Chlorophenyl
    149 Allyl 3-Chlorophenyl
    150 Propyl 3-Chlorophenyl
    151 3-Methylbutyl 4-Hexylphenyl
    152 3-Methylbutyl 2-Fluoro-3-
    trifluoromethylphenyl
    153 Butyl 2,5-Dichlorophenyl
    154 2-Methylpropyl 2,5-Dichlorophenyl
    155 Pentyl 2,5-Dichlorophenyl
    156 3-Methylbutyl 2,5-Dichlorophenyl
    157 Butyl 2,4-Dichlorophenyl
    158 2-Methylpropyl 2,4-Dichlorophenyl
    159 3-Methylbutyl 2,4-Dichlorophenyl
    160 Butyl 4-Pentylphenyl
    161 2-Methylpropyl 4-Pentylphenyl
    162 3-Methylbutyl 4-Pentylphenyl
    163 Butyl 3-Bromophenyl
    164 2-Methylpropyl 3-Bromophenyl
    165 2-Methylpropyl 3-Bromo-4-methylphenyl
    166 3-Methylbutyl 3-Bromo-4-methylphenyl
    167 Butyl 3-Bromo-4-fluorophenyl
    168 2-Methylpropyl 3-Bromo-4-fluorophenyl
    169 3-Methylbutyl 3-Bromo-4-fluorophenyl
    170 Butyl 3-Iodophenyl
    171 2-Methylpropyl 3-Iodophenyl
    172 Pentyl 3-Iodophenyl
    173 3-Methylbutyl 3-Iodophenyl
    174 2-Methylpropyl 4-Iodophenyl
    175 3-Methylbutyl 3-Iodo-4-methylphenyl
    176 Butyl 2-Thienyl
    177 Pentyl 2-Thienyl
    178 3-Methylbutyl 2-Thienyl
    179 Butyl 3-Thienyl
    180 Pentyl 3-Thienyl
    181 3-Methylbutyl 3-Thienyl
    182 3-Methylbutyl Benzyl
    183 Butyl 3-Methyl-2-thienyl
    184 Pentyl 3-Methyl-2-thienyl
    185 3-Methylbutyl 3-Methyl-2-thienyl
    186 Pentyl 3-Methyl-5-thienyl
    187 3-Methylbutyl 3-Methyl-5-thienyl
    188 3-Methylbutyl 3-Methylphenyl
    189 2-Methylpropyl 5-Chloro-2-methoxyphenyl
    190 Pentyl 5-Chloro-2-methoxyphenyl
    191 3-Methylbutyl 5-Chloro-2-methoxyphenyl
    192 Butyl 3-Trifluoromethylphenyl
    193 Pentyl 3-Trifluoromethylphenyl
    194 3-Methylbutyl 3-Trifluoromethylphenyl
    195 3-Methylbutyl 2-Trifluoromethylphenyl
    196 Butyl 3,4-Dichlorophenyl
    197 2-Methylpropyl 3,4-Dichlorophenyl
    198 3-Methylbutyl 3,4-Dichlorophenyl
    199 3-Methylbutyl 3,5-Dichlorophenyl
    200 3-Methylbutyl 2,3-Dichlorophenyl
    201 Butyl Phenyl
    202 Pentyl Phenyl
    203 3-Methylbutyl Phenyl
    204 Pentyl 3-Methylphenyl
    205 3-Methylbutyl 3-Methylphenyl
    206 2-Methylpropyl 4-Methylphenyl
    207 3-Methylbutyl 4-Methylphenyl
    208 Pentyl 2-Methylphenyl
    209 3-Methylbutyl 2-Methylphenyl
    210 Butyl 3-Fluorophenyl
    211 2-Methylpropyl 3-Fluorophenyl
    212 Pentyl 3-Fluorophenyl
    213 3-Methylbutyl 3-Fluorophenyl
    214 Pentyl 4-Fluorophenyl
    215 3-Methylbutyl 4-Fluorophenyl
    216 Pentyl 2-Fluorophenyl
    217 3-Methylbutyl 2-Fluorophenyl
    218 2-Methylpropyl 3,4-Dimethylphenyl
    219 3-Methylbutyl 3,4-Dimethylphenyl
    220 Pentyl 2,5-Dimethylphenyl
    221 3-Methylbutyl 2,5-Dimethylphenyl
    222 2-Methylpropyl 2,4-Dimethylphenyl
    223 3-Methylbutyl 2,4-Dimethylphenyl
    224 2-Methylpropyl 3-Methoxyphenyl
    225 Pentyl 3-Methoxyphenyl
    226 3-Methylbutyl 3-Methoxyphenyl
    227 2-Methylpropyl 4-Methoxyphenyl
    228 3-Methylbutyl 4-Methoxyphenyl
    229 Pentyl 2-Methoxyphenyl
    230 3-Methylbutyl 2-Methoxyphenyl
    231 2-Methylpropyl 3-Fluoro-4-methylphenyl
    232 Pentyl 3-Fluoro-4-methylphenyl
    233 3-Methylbutyl 3-Fluoro-4-methylphenyl
    234 3-Methylbutyl 3-Fluoro-2-methylphenyl
    235 2-Methylpropyl 5-Fluoro-2-methylphenyl
    236 Pentyl 5-Fluoro-2-methylphenyl
    237 2-Methylpropyl 3-Chloro-4-fluorophenyl
    238 Pentyl 3-Chloro-4-fluorophenyl
    239 3-Methylbutyl 3-Chloro-4-fluorophenyl
    240 3-Methylbutyl 3,4,5-Trifluorophenyl
    241 3-Methylbutyl 4-Butylphenyl
    242 Pentyl 4-i-propylphenyl
    243 3-Methylbutyl 4-i-propylphenyl
    244 Butyl 4-Ethylthiophenyl
    245 2-Methylpropyl 4-Ethylthiophenyl
    246 3-Methylbutyl 4-Ethylthiophenyl
    247 3-Methylbutyl 3-Chloro-4-methoxyphenyl
    248 Butyl 5-Chloro-2-methoxyphenyl
    249 3-Methylbutyl 5-Fluoro-2-methylphenyl
    250 2-Methylpropyl 2-Fluoro-3-methylphenyl
    251 Pentyl 2-Fluoro-3-methylphenyl
    252 3-Methylbutyl 2-Fluoro-3-methylphenyl
    253 2-Methylpropyl 3-Chlorophenyl
    254 Pentyl 3-Chlorophenyl
    255 3-Methylbutyl 3-Chlorophenyl
    256 2-Methylpropyl 4-Chlorophenyl
    257 3-Methylbutyl 4-Chlorophenyl
    258 3-Methylbutyl 2-Chlorophenyl
    259 3-Methylbutyl 3,4-Difluorophenyl
    260 3-Methylbutyl 1,2-Difluorophenyl
    261 Pentyl 2,5-Difluorophenyl
    262 3-Methylbutyl 2,5-Difluorophenyl
    263 Pentyl 2,4-Difluorophenyl
    264 3-Methylbutyl 2,4-Difluorophenyl
    265 3-Methylbutyl 4-Propylphenyl
    266 Pentyl 1,3-Benzodioxol-5-yl
    267 3-Methylbutyl 1,3-Benzodioxol-5-yl
    268 3-Methylbutyl 4-Methylthio
    phenyl
    269 3-Methylbutyl 3-Fluoro-4-methoxyphenyl
    270 2-Methylpropyl 4-Chloro-3-methylphenyl
    271 3-Methylbutyl 4-Chloro-3-methylphenyl
    272 Butyl 3-Chloro-4-fluorophenyl
    • EXAMPLE 6
  • [0194]
    Figure US20030092912A1-20030515-C00031
  • For each compound, the definitions of R[0195] 2 and R3 are specified in the following table.
    Compound
    No. R2 R3
    273 2-Methylpropyl 2,4,6-Trifluorophenyl
    274 3-Methylbutyl 2,4,6-Trifluorophenyl
    275 2-Methylpropyl 2,3,6-Trifluorophenyl
    276 Pentyl 2,3,6-Trifluorophenyl
    277 3-Methylbutyl 2,3,6-Trifluorophenyl
    278 Pentyl 2-Chloro-6-fluorophenyl
    279 3-Methylbutyl 2-Chloro-6-fluorophenyl
    280 Pentyl 2-Fluoro-6-
    trifluoromethylphenyl
    281 3-Methylbutyl 2-Fluoro-6-
    trifluoromethylphenyl
    282 Pentyl 3-Bromo-4-fluorophenyl
    283 2-Methylpropyl 4-Hexylphenyl
    284 Butyl 4-Pentoxyphenyl
    285 2-Methylpropyl 4-Pentoxyphenyl
    286 Butyl 2-Fluoro-3-
    trifluoromethylphenyl
    287 2-Methylpropyl 2-Fluoro-3-
    trifluoromethylphenyl
    288 3-Methylbutyl 3-Bromo-4-fluorophenyl
    289 2-Methylpropyl 4-heptylphenyl
    290 Butyl 3-Iodophenyl
    291 2-Methylpropyl 3-Iodophenyl
    292 Pentyl 3-Iodophenyl
    293 3-Methylbutyl 3-Iodophenyl
    294 Butyl 4-Iodophenyl
    295 2-Methylpropyl 4-Iodophenyl
    296 2-Methylpropyl 4-Pentylphenyl
    297 3-Methylbutyl 2-Fluoro-3-
    trifluoromethylphenyl
    298 Butyl 3-Bromo-4-methylphenyl
    299 2-Methylpropyl 3-Bromo-4-methylphenyl
    300 Pentyl 3-Bromo-4-methylphenyl
    301 3-Methylbutyl 3-Bromo-4-methylphenyl
    302 Butyl 3-Bromo-4-fluorophenyl
    303 2-Methylpropyl 3-Bromo-4-fluorophenyl
    304 3-Methylbutyl 3,4-Dichlorophenyl
    305 Butyl 2,3-Dichlorophenyl
    306 2-Methylpropyl 2,3-Dichlorophenyl
    307 3-Methylbutyl 2,3-Dichlorophenyl
    308 Butyl 2,5-Dichlorophenyl
    309 Butyl 3-Bromophenyl
    310 2-Methylpropyl 3-Bromophenyl
    311 Pentyl 3-Bromophenyl
    312 3-Methylbutyl 3-Bromophenyl
    313 Butyl 4-Bromophenyl
    314 2-Methylpropyl 4-Bromophenyl
    315 3-Methylbutyl 4-Bromophenyl
    316 Butyl 2-Bromophenyl
    317 Pentyl 2-Bromophenyl
    318 3-Methylbutyl 2-Bromophenyl
    319 Pentyl 4-Hexylphenyl
    320 2-Methylpropyl 4-Chloro-2-methoxyphenyl
    321 2-Methylpropyl 2,5-Dichlorophenyl
    322 Pentyl 2,5-Dichlorophenyl
    323 3-Methylbutyl 2,5-Dichlorophenyl
    324 Butyl 2,4-Dichlorophenyl
    325 2-Methylpropyl 2,4-Dichlorophenyl
    326 Pentyl 2,4-Dichlorophenyl
    327 3-Methylbutyl 2,4-Dichlorophenyl
    328 2-Methylpropyl 2,5-Dimethoxyphenyl
    329 Pentyl 2,5-Dimethoxyphenyl
    330 3-Methylbutyl 2,5-Dimethoxyphenyl
    331 2-Methylpropyl 2,4-Dimethoxyphenyl
    332 3-Methylbutyl 2,4-Dimethoxyphenyl
    333 Pentyl 4-Chloro-2-methoxyphenyl
    334 3-Methylbutyl 4-Chloro-2-methoxyphenyl
    335 Butyl 3-Trifluoromethylphenyl
    336 2-Methylpropyl 3-Trifluoromethylphenyl
    337 Pentyl 3-Trifluoromethylphenyl
    338 3-Methylbutyl 3-Trifluoromethylphenyl
    339 2-Methylpropyl 4-Trifluoromethylphenyl
    340 Butyl 2-Trifluoromethylphenyl
    341 3-Methylbutyl 2-Trifluoromethylphenyl
    342 Butyl 3,4-Dichlorophenyl
    343 2-Methylpropyl 3,4-Dichlorophenyl
    344 Butyl 4-Methylthio
    phenyl
    345 Butyl 3-Chloro-4-methoxyphenyl
    346 2-Methylpropyl 3-Chloro-4-methoxyphenyl
    347 3-Methylbutyl 3-Chloro-4-methoxyphenyl
    348 Butyl 5-Chloro-2-methoxyphenyl
    349 2-Methylpropyl 5-Chloro-2-methoxyphenyl
    350 Pentyl 5-Chloro-2-methoxyphenyl
    351 3-Methylbutyl 5-Chloro-2-methoxyphenyl
    352 Butyl 2,5-Difluorophenyl
    353 2-Methylpropyl 2,5-Difluorophenyl
    354 Pentyl 2,5-Difluorophenyl
    355 3-Methylbutyl 2,5-Difluorophenyl
    356 Butyl 2,4-Difluorophenyl
    357 2-Methylpropyl 4-Methylthio
    phenyl
    358 Butyl 3-Fluoro-4-methoxyphenyl
    359 2-Methylpropyl 3-Fluoro-4-methoxyphenyl
    360 3-Methylbutyl 3-Fluoro-4-methoxyphenyl
    361 2-Methylpropyl 4-Chloro-3-methylphenyl
    362 Butyl 3-Chloro-4-fluorophenyl
    363 2-Methylpropyl 3-Chloro-4-fluorophenyl
    364 Pentyl 3-Chloro-4-fluorophenyl
    365 3-Methylbutyl 3-Chloro-4-fluorophenyl
    366 2-Methylpropyl 4-Ethylthiophenyl
    367 Butyl 2,5-Dimethoxyphenyl
    368 Butyl 2-Chlorophenyl
    369 2-Methylpropyl 2,4-Difluorophenyl
    370 Pentyl 2,4-Difluorophenyl
    371 3-Methylbutyl 2,4-Difluorophenyl
    372 Butyl 1,3-Benzodioxol-5-yl
    373 2-Methylpropyl 1,3-Benzodioxol-5-yl
    374 Pentyl 1,3-Benzodioxol-5-yl
    375 3-Methylbutyl 1,3-Benzodioxol-5-yl
    376 3-Methylbutyl 3-Fluoro-2-methylphenyl
    377 Butyl 5-Fluoro-2-methylphenyl
    378 2-Methylpropyl 5-Fluoro-2-methylphenyl
    379 Pentyl 5 Fluoro-2-methylphenyl
    380 3-Methylbutyl 5-Fluoro-2-methylphenyl
    381 2-Methylpropyl 2-Chlorophenyl
    382 Pentyl 2-Chlorophenyl
    383 3-Methylbutyl 2-Chlorophenyl
    384 Butyl 3,4-Difluorophenyl
    385 2-Methylpropyl 3,4-Difluorophenyl
    386 Pentyl 3,4-Difluorophenyl
    387 3-Methylbutyl 3,4-Difluorophenyl
    388 Butyl 2,3-Difluorophenyl
    389 2-Methylpropyl 2,3-Difluorophenyl
    390 Pentyl 2,3-Difluorophenyl
    391 3-Methylbutyl 2,3-Difluorophenyl
    392 2-Methylpropyl 4-Methoxyphenyl
    393 Butyl 3-Chlorophenyl
    394 2-Methylpropyl 3-Chlorophenyl
    395 Pentyl 3-Chlorophenyl
    396 3-Methylbutyl 3-Chlorophenyl
    397 Butyl 4-Chlorophenyl
    398 2-Methylpropyl 4-Chlorophenyl
    399 3-Methylbutyl 4-Chlorophenyl
    400 Butyl 2,5-Dimethylphenyl
    401 2-Methylpropyl 2,5-Dimethylphenyl
    402 Pentyl 2,5-Dimethylphenyl
    403 3-Methylbutyl 2,5-Dimethylphenyl
    404 Butyl 2,4-Dimethylphenyl
    405 3-Methylbutyl 4-Methoxyphenyl
    406 Butyl 2-Methoxyphenyl
    407 2-Methylpropyl 2-Methoxyphenyl
    408 Pentyl 2-Methoxyphenyl
    409 3-Methylbutyl 2-Methoxyphenyl
    410 Butyl 3-Fluoro-4-methylphenyl
    411 2-Methylpropyl 3-Fluoro-4-methylphenyl
    412 Pentyl 3-Fluoro-4-methylphenyl
    413 3-Methylbutyl 3-Fluoro-4-methylphenyl
    414 Butyl 3-Fluoro-2-methylphenyl
    415 2-Methylpropyl 3-Fluoro-2-methylphenyl
    416 Butyl 4-Fluorophenyl
    417 2-Methylpropyl 2,4-Dimethylphenyl
    418 3-Methylbutyl 2,4-Dimethylphenyl
    419 Butyl 3-Methoxyphenyl
    420 2-Methylpropyl 3-Methoxyphenyl
    421 Pentyl 3-Methoxyphenyl
    422 3-Methylbutyl 3-Methoxyphenyl
    423 Butyl 4-Methoxyphenyl
    424 3-Methylbutyl 3-Methylphenyl
    425 Butyl 4-Methylphenyl
    426 2-Methylpropyl 4-Methylphenyl
    427 Pentyl 4-Methylphenyl
    428 3-Methylbutyl 4-Methylphenyl
    429 2-Methylpropyl 4-Fluorophenyl
    430 Pentyl 4-Fluorophenyl
    431 3-Methylbutyl 4-Fluorophenyl
    432 Butyl 2-Fluorophenyl
    433 2-Methylpropyl 2-Fluorophenyl
    434 Pentyl 2-Fluorophenyl
    435 3-Methylbutyl 2-Fluorophenyl
    436 2-Methylpropyl 4-Ethylphenyl
    437 Butyl 3,4-Dimethylphenyl
    438 2-Methylpropyl 3,4-Dimethylphenyl
    439 3-Methylbutyl 3,4-Dimethylphenyl
    440 Butyl 2-Methylphenyl
    441 Pentyl 2-Methylphenyl
    442 3-Methylbutyl 2-Methylphenyl
    443 Butyl 3-Fluorophenyl
    444 2-Methylpropyl 3-Fluorophenyl
    445 Pentyl 3-Fluorophenyl
    446 3-Methylbutyl 3-Fluorophenyl
    447 Butyl Phenyl
    448 2-Methylpropyl Phenyl
    449 Pentyl Phenyl
    450 3-Methylbutyl Phenyl
    451 Butyl 3-Methylphenyl
    452 2-Methylpropyl 3-Methylphenyl
    453 Pentyl 3-Methylphenyl
    • EXAMPLE 7
  • [0196]
    Figure US20030092912A1-20030515-C00032
  • For each compound, the definitions of R[0197] 2 and R3 are specified in the following table.
    Compound
    No. R2 R3
    454 Allyl 2,5-Dichlorophenyl
    455 Propyl 2,5-Dichlorophenyl
    456 Propyl 2,4-Dichlorophenyl
    457 Propyl 4-Pentylphenyl
    458 Allyl 3-Bromophenyl
    459 Propyl 3-Bromophenyl
    460 Propyl 4-Bromophenyl
    461 Propyl 2-Chlorophenyl
    462 Methyl Phenyl
    463 Propyl Phenyl
    464 Methyl 3-Methylphenyl
    465 Propyl 3-Methylphenyl
    466 Propyl 2-Chlorophenyl
    467 Propyl 3,4-Difluorophenyl
    468 Methyl 2,3-Difluorophenyl
    469 Propyl 2,3-Difluorophenyl
    470 Methyl 2,5-Difluorophenyl
    471 Allyl 2,5-Difluorophenyl
    472 Propyl 2,5-Difluorophenyl
    473 Propyl 2,4-Difluorophenyl
    474 Allyl 1,3-Benzodioxol-5-yl
    475 Propyl 1,3-Benzodioxol-5-yl
    476 Propyl 4-Methylthio
    phenyl
    477 Propyl 4-Chloro-3-methylphenyl
    478 Propyl 4-Methylphenyl
    479 Propyl 3-Fluorophenyl
    480 Propyl 4-Fluorophenyl
    481 Methyl 2-Fluorophenyl
    482 Allyl 2-Fluorophenyl
    483 Propyl 2-Fluorophenyl
    484 Propyl 3,4-Dimethylphenyl
    485 Propyl 3-Fluoro-4-methylphenyl
    486 Propyl 2-Fluoro-3-methylphenyl
    487 Allyl 3-Chlorophenyl
    488 Propyl 3-Chlorophenyl
    489 Propyl 4-Chlorophenyl
    490 2-Methylpropyl 3-Chloro-2-thienyl
    491 Pentyl 3-Chloro-2-thienyl
    492 3-Methylbutyl 3-Chloro-2-thienyl
    493 Butyl 3-Ethoxy-2-thienyl
    494 Pentyl 3-Ethoxy-2-thienyl
    495 3-Methylbutyl 2-Methoxybenzyl
    496 3-Methylbutyl 2-(2-Fluorophenyl)
    ethenyl
    497 2-Methylpropyl 2-(2-Chlorophenyl)
    ethenyl
    498 3-Methylbutyl 2-(2-Chlorophenyl)
    ethenyl
    499 Pentyl 2-Fluoro-6-
    trifluoromethylphenyl
    500 3-Methylbutyl 3-Ethoxy-2-thienyl
    501 Butyl 5-Methylthio-2-thienyl
    502 2-Methylpropyl 5-Methylthio-2-thienyl
    503 3-Methylbutyl 5-Methylthio-2-thienyl
    504 3-Methylbutyl 4-Fluorophenyl
    505 3-Methylbutyl 2-Fluorophenyl
    506 3-Methylbutyl 3-Methoxyphenyl
    507 3-Methylbutyl 2,3,5,6-Tetrafluoro phenyl
    508 2-Methylpropyl 2,4,6-Trifluoro
    phenyl
    509 3-Methylbutyl 2,4,6-Trifluoro
    phenyl
    510 Butyl 2,3,6-Trifluoro
    phenyl
    511 2-Methylpropyl 2,3,6-Trifluoro
    phenyl
    512 3-Methylbutyl 2-Fluoro-6-
    trifluoromethylphenyl
    513 2-Methylpropyl 2,4,6-Trichlorophenyl
    514 Pentyl 2,5-Dimethyl-3-furyl
    515 3-Methylbutyl 4,5-Dimethyl-2-furyl
    516 Butyl 3,4-Dimethyl-2-furyl
    517 2-Methylpropyl 3,4-Dimethyl-2-furyl
    518 Pentyl 3,4-Dimethyl-2-furyl
    519 3-Methylbutyl 3,4-Dimethyl-2-furyl
    520 Butyl 4-Methoxy-3-thienyl
    521 3-Methylbutyl 4-Methoxy-3-thienyl
    522 Butyl 3-Chloro-2-thienyl
    523 Allyl 3-Bromo-4-fluorophenyl
    524 Propyl 3-Bromo-4-fluorophenyl
    525 Methyl 3-Iodophenyl
    526 Ethyl 3-Iodophenyl
    527 Allyl 3-Iodophenyl
    528 Propyl 3-Iodophenyl
    529 Propyl 3-Methyl-2-thienyl
    530 Propyl 3-Fluorobenzyl
    531 Pentyl 2,3,6-Trifluoro
    phenyl
    532 3-Methylbutyl 2,3,6-Trifluoro
    phenyl
    533 Butyl 2-Chloro-6-fluorophenyl
    534 2-Methylpropyl 2-Chloro-6-fluorophenyl
    535 Pentyl 2-Chloro-6-fluorophenyl
    536 3-Methylbutyl 2-Chloro-6-fluorophenyl
    537 Butyl 2-Fluoro-6-
    trifluoromethylphenyl
    538 3-Methylbutyl 3-Chlorobenzyl
    539 2-Methylpropyl 4-Chlorobenzyl
    540 3-Methylbutyl 2-Chlorobenzyl
    541 Butyl 2,3,5,6-Tetrafluoro phenyl
    542 2-Methylpropyl 2,3,5,6-Tetrafluoro phenyl
    543 Pentyl 2,3,5,6-Tetrafluoro phenyl
    544 Allyl 3-Chloro-4-fluorophenyl
    545 Propyl 3-Chloro-4-fluorophenyl
    546 Propyl 4-Butylphenyl
    547 Propyl 3-Chloro-4-methoxyphenyl
    548 Allyl 5-Chloro-2-methoxyphenyl
    549 Propyl 5-Chloro-2-methoxyphenyl
    550 Propyl 3,4-Dichlorophenyl
    551 Propyl 4-Hexylphenyl
    552 Methyl 3-Bromo-4-methylphenyl
    553 Allyl 3-Bromo-4-methylphenyl
    554 Propyl 3-Bromo-4-methylphenyl
    555 Methyl 3-Bromo-4-fluorophenyl
    556 Butyl 2-Methoxybenzyl
    • EXAMPLE 8
  • [0198]
    Figure US20030092912A1-20030515-C00033
  • For each compound, the definitions of R[0199] 2 and R3 are specified in the following table.
    Compound
    No. R2 R3
    557 Propyl 3-Chlorophenyl
    558 Propyl Phenyl
    559 Allyl 2-Fluorophenyl
    560 Propyl 2-Fluorophenyl
    561 Propyl 3-Fluoro-4-
    methylphenyl
    562 Methyl 2,5-Dichlorophenyl
    563 Propyl 2,5-Dichlorophenyl
    564 Propyl 4-Pentylphenyl
    565 Propyl 3-Bromophenyl
    566 Propyl 3-Methyl-2-thienyl
  • Compound No. 567: (5-Chloro-2-methoxyphenyl)-N-({3-[(2-chlorophenyl)methyl]imidazolo[5,4-b]pyridin-2-yl}methyl-N-pentylcarboxamide. [0200]
    • EXAMPLE 9
  • [0201]
    Figure US20030092912A1-20030515-C00034
  • For each compound, the definitions of R[0202] 2 and R3 are specified in the following table.
    Compound
    No. R2 R3
    568 Methyl Phenyl
    569 Methyl 3-Chlorophenyl
    570 Butyl 2,5-Dimethylphenyl
    571 Butyl 5-Fluoro-2-methylphenyl
    572 Butyl 2,3-Dimethylphenyl
    573 Propyl 3-Fluorophenyl
    574 Butyl 3-Methylphenyl
    575 Butyl 4-Fluorophenyl
    576 Butyl 3-Methoxyphenyl
    577 Butyl 2,5-Difluorophenyl
    578 Methyl 2-Fluorophenyl
    579 Butyl 4-Methylphenyl
    580 Butyl 2-Fluorophenyl
    581 Butyl 4-Methoxyphenyl
    582 Butyl 3-Chlorophenyl
    583 Methyl 2,5-Dimethylphenyl
    584 Butyl 2-Methylphenyl
    585 Butyl 4-Ethylphenyl
    586 Butyl 2-Methoxyphenyl
    587 Butyl 3-Chlorophenyl
    588 Propyl 3-Fluoro-4-methylphenyl
    589 Butyl 3-Fluorophenyl
    590 Butyl 3,4-Dimethylphenyl
    591 Butyl 3-Fluoro-4-methylphenyl
    592 Butyl 3,4-Difluorophenyl
    593 Propyl 2,4-Dimethoxyphenyl
    594 Methyl 2,5-Dichlorophenyl
    595 Butyl 5-Chloro-2-methoxyphenyl
    596 Butyl 3-Methyl-2-thienyl
    597 Butyl 3-Methylphenyl
    598 Pentyl 3-Fluorophenyl
    599 Pentyl 2,5-Dimethylphenyl
    600 Propyl 2,5-Dichlorophenyl
    601 Butyl 3-Methyl-2-thienyl
    602 Pentyl 3-Methylphenyl
    603 Butyl 2-Fluorophenyl
    604 Pentyl 3-Methoxyphenyl
    605 Methyl 3-Bromophenyl
    606 Butyl 3-Iodophenyl
    607 Butyl 4-Fluorophenyl
    608 2-Methylpropyl 4-Methylphenyl
    609 2-Methylpropyl 2-Fluorophenyl
    610 2-Methylpropyl 4-Methoxyphenyl
    611 Propyl 3-Bromophenyl
    612 Allyl 4-Octylphenyl
    613 Butyl Phenyl
    614 Pentyl 2-Methylphenyl
    615 Pentyl 2-Fluorophenyl
    616 Butyl 2-Methoxyphenyl
    617 Butyl 3-Chloro-4-methoxyphenyl
    618 Propyl 4-Octylphenyl
    619 Pentyl Phenyl
    620 Butyl 3-Fluorophenyl
    621 2-Methylpropyl 3,4-Dimethylphenyl
    622 Pentyl 2-Methoxyphenyl
    623 Butyl 3-Fluoro-4-methylphenyl
    624 Butyl 2-Fluoro-3-methylphenyl
    625 2-Methylpropyl 4-Chlorophenyl
    626 2-Methylpropyl 2,3-Difluorophenyl
    627 2-Methylpropyl 1,3-Benzodioxol-5-yl
    628 2-Methylpropyl 3-Chloro-4-methoxyphenyl
    629 2-Methylpropyl 3-Fluoro-4-methylphenyl
    630 Pentyl 2-Fluoro-3-methylphenyl
    631 Pentyl 2-Chlorophenyl
    632 Pentyl 2,3-Difluorophenyl
    633 Butyl 4-Methylthio
    phenyl
    634 2-Methylpropyl 3-Chloro-4-methoxyphenyl
    635 Butyl 5-Fluoro-2-methylphenyl
    636 Butyl 3-Chlorophenyl
    637 Butyl 3,4-Difluorophenyl
    638 Butyl 2,5-Difluorophenyl
    639 Butyl 3-Chloro-4-fluorophenyl
    640 Butyl 5-Chloro-2-methoxyphenyl
    641 2-Methylpropyl 5-Fluoro-2-methylphenyl
    642 2-Methylpropyl 3-Chlorophenyl
    643 2-Methylpropyl 3,4-Difluorophenyl
    644 Pentyl 2,5-Difluorophenyl
    645 2-Methylpropyl 4-Ethylthiophenyl
    646 2-Methylpropyl 5-Chloro-2-methoxyphenyl
    647 Pentyl 5-Fluoro-2-methylphenyl
    648 Pentyl 3-Chlorophenyl
    649 Butyl 2,3-Difluorophenyl
    650 2-Methylpropyl 2,4-Difluorophenyl
    651 Butyl 3-Chloro-4-methoxyphenyl
    652 Pentyl 5-Chloro-2-methoxyphenyl
    653 3-Methylbutyl 5-Chloro-2-methoxyphenyl
    654 3-Methylbutyl 2,5-Dichlorophenyl
    655 2-Methylpropyl 4-Bromophenyl
    656 Butyl 2-Thienyl
    657 3-Methylbutyl 3-Thienyl
    658 2-Methylpropyl 3-Methyl-2-thienyl
    659 3-Methylbutyl 3-Trifluoromethylphenyl
    660 Butyl 3-Bromophenyl
    661 3-Methylbutyl 2-Bromophenyl
    662 Pentyl 2-Thienyl
    663 Butyl 5-Methyl-2-thienyl
    664 3-Methylbutyl 3-Methyl-2-thienyl
    665 2-Methylpropyl 3,4-Dichlorophenyl
    666 2-Methylpropyl 3-Bromophenyl
    667 3-Methylbutyl 3-Bromo-4-fluorophenyl
    668 3-Methylbutyl 2-Thienyl
    669 Pentyl 5-Methyl-2-thienyl
    670 Butyl 3-Fluorophenyl
    671 Butyl 2,5-Dichlorophenyl
    672 Pentyl 3-Bromophenyl
    673 Pentyl 3-Iodophenyl
    674 Butyl 3-Thienyl
    675 3-Methylbutyl 5-Methyl-2-thienyl
    676 3-Methylbutyl 3-Fluorophenyl
    677 Pentyl 2,5-Dichlorophenyl
    678 3-Methylbutyl 3-Bromophenyl
    679 3-Methylbutyl 3-Iodophenyl
    680 Pentyl 3-Thienyl
    681 Butyl 3-Methyl-2-thienyl
    682 2-Methylpropyl 2-Chlorophenyl
    815 2-Methylpropyl 3,5-Difluorophenyl
    816 3-Methylbutyl 3,5-Difluorophenyl
    817 Butyl 3,5-Difluorophenyl
    2238 Benzyl 3-Fluorophenyl
    2242 Benzyl 2-Fluorophenyl
    2253 Benzyl 2-Methoxyphenyl
    2257 Benzyl 5-Fluoro-2-methylphenyl
    2260 Benzyl 3-Chlorophenyl
    2268 Benzyl 2,3-Difluorophenyl
    2271 Benzyl 2,5-Difluorophenyl
    • EXAMPLE 10
  • [0203]
    Figure US20030092912A1-20030515-C00035
  • For each compound, the definitions of R[0204] 2 and R3 are specified in the following table.
    Compound
    No. R2 R3
    683 Allyl 3-Fluorophenyl
    684 Allyl 3,4-Difluorophenyl
    685 Propyl 1,3-Benzodioxol-5-yl
    686 Allyl 5-Chloro-2-methoxyphenyl
    687 Propyl 3-Methyl-2-Thienyl
    688 Propyl 3-Fluoro-4-methylphenyl
    689 Propyl 3-Fluorophenyl
    690 Propyl 3,4-Difluorophenyl
    691 Allyl 3-Chloro-4-fluorophenyl
    692 Propyl 5-Chloro-2-methoxyphenyl
    693 Allyl Phenyl
    694 Allyl 5-Fluoro-2-methylphenyl
    695 Propyl 4-Fluorophenyl
    696 Allyl 2,5-Difluorophenyl
    697 Propyl 3-Chloro-4-fluorophenyl
    698 Methyl 2,5-Dichlorophenyl
    699 Propyl Phenyl
    700 Propyl 5-Fluoro-2-methylphenyl
    701 Allyl 2-Fluorophenyl
    702 Propyl 2,5-Difluorophenyl
    703 Methyl 5-Chloro-2-methoxyphenyl
    704 Allyl 2,5-Dichlorophenyl
    705 Allyl 3-Methylphenyl
    706 Allyl 3-Chlorophenyl
    707 Propyl 2-Fluorophenyl
    708 Allyl 1,3-Benzodioxol-5-yl
    709 Ethyl 5-Chloro-2-methoxyphenyl
    710 Propyl 2,5-Dichlorophenyl
    711 Propyl 3-Methylphenyl
    712 Propyl 3-Chlorophenyl
    713 Propyl 4-Methylthio
    phenyl
    714 Propyl 3-Iodo-4-methylphenyl
    887 Propyl 2,3,6-Trifluorophenyl
    2306 3-Methylbutyl 2,3,6-Trifluorophenyl
    2347 3-Methylbutyl 3-(2-1,2,3,4-Teterahydro
    isoquinolinyl
    methyl)
    phenyl
    2348 3-Methylbutyl 3-(Diethylamino
    methyl)phenyl
    2349 3-Methylbutyl 3-(Hexylmethyl
    amino
    methyl)phenyl
    2351 3-Methylbutyl 3-(Dibutylamino
    methyl)phenyl
    2364 3-Methylbutyl 3-[(1-methylethyl)
    methylamino
    methyl]phenyl
    2365 3-Methylbutyl 3-(Cyclohexyl
    ethylamino
    methyl)phenyl
    2367 3-Methylbutyl 3-[bis(2-Methoxyethyl)
    aminomethyl]
    phenyl
    2369 3-Methylbutyl 3-[(3,3,5-Trimethylaza
    perhydroepinyl)methyl]phenyl
    • EXAMPLE 11
  • [0205]
    Figure US20030092912A1-20030515-C00036
  • For each compound, the definitions of R[0206] 2 and R3 are specified in the following table.
    Compound
    No. R2 R3
    715 Methyl 3-Fluorophenyl
    716 Methyl 5-Fluoro-2-methylphenyl
    717 Methyl 3-Chlorophenyl
    718 Methyl 5-Chloro-2-methoxyphenyl
    839 2-Methylpropyl 2,3,6-Trifluorophenyl
    840 Pentyl 2,3,6-Trifluorophenyl
    841 3-Methylbutyl 2,3,6-Trifluorophenyl
    938 Butyl Phenyl
    939 2-Methylpropyl Phenyl
    940 Pentyl Phenyl
    941 3-Methylbutyl Phenyl
    942 Butyl 3-Methylphenyl
    943 2-Methylpropyl 3-Methylphenyl
    944 3-Methylbutyl 3-Methylphenyl
    945 2-Methylpropyl 4-Methylphenyl
    946 Butyl 3-Fluorophenyl
    947 Pentyl 3-Fluorophenyl
    948 3-Methylbutyl 3-Fluorophenyl
    949 3-Methylbutyl 4-Fluorophenyl
    950 Butyl 2-Fluorophenyl
    951 2-Methylpropyl 2-Fluorophenyl
    952 Pentyl 2-Fluorophenyl
    953 3-Methylbutyl 2-Fluorophenyl
    954 2-Methylpropyl 3,4-Dimethylphenyl
    1002 Butyl 2-Chlorophenyl
    1003 Pentyl 2-Chlorophenyl
    1004 3-Methylbutyl 2-Chlorophenyl
    1005 Butyl 3,4-Difluorophenyl
    1006 2-Methylpropyl 3,4-Difluorophenyl
    1007 Pentyl 3,4-Difluorophenyl
    1008 3-Methylbutyl 3,4-Difluorophenyl
    1009 Butyl 2,3-Difluorophenyl
    1010 2-Methylpropyl 2,3-Difluorophenyl
    1011 Pentyl 2,3-Difluorophenyl
    1012 3-Methylbutyl 2,3-Difluorophenyl
    1013 Butyl 2,5-Difluorophenyl
    1014 2-Methylpropyl 2,5-Difluorophenyl
    1015 Pentyl 2,5-Difluorophenyl
    1016 3-Methylbutyl 2,5-Difluorophenyl
    1017 Butyl 2,4-Difluorophenyl
    1018 2-Methylpropyl 2,4-Difluorophenyl
    1019 3-Methylbutyl 2,4-Difluorophenyl
    1020 2-Methylpropyl 3-Ethoxyphenyl
    1021 Butyl 1,3-Benzodioxol-5-yl
    1022 2-Methylpropyl 1,3-Benzodioxol-5-yl
    1023 3-Methylbutyl 1,3-Benzodioxol-5-yl
    1024 2-Methylpropyl 4-Methylthio
    phenyl
    1025 3-Methylbutyl 4-Methylthio
    phenyl
    1026 2-Methylpropyl 3-Fluoro-4-methoxyphenyl
    1027 3-Methylbutyl 3-Fluoro-4-methoxyphenyl
    1028 2-Methylpropyl 4-Chloro-3-methylphenyl
    1029 Butyl 3-Chloro-4-fluorophenyl
    1030 2-Methylpropyl 3-Chloro-4-fluorophenyl
    1031 Pentyl 3-Chloro-4-fluorophenyl
    1032 3-Methylbutyl 3-Chloro-4-fluorophenyl
    1033 2-Methylpropyl 3,4,5-Trifluorophenyl
    1034 3-Methylbutyl 3,4,5-Trifluorophenyl
    1035 2-Methylpropyl 4-Butylphenyl
    1036 2-Methylpropyl 4-Ethylthiophenyl
    1109 Cyclopropyl Phenyl
    methyl
    1110 Cyclopropyl 3-Methylphenyl
    Methyl
    1111 Cyclopropyl 4-Methylphenyl
    Methyl
    1112 Cyclopropyl 3-Fluorophenyl
    Methyl
    1113 Cyclopropyl 2-Fluorophenyl
    Methyl
    1114 Cyclopropyl 3-Methoxyphenyl
    Methyl
    1115 Cyclopropyl 3-Fluoro-4-methylphenyl
    Methyl
    1116 Cyclopropyl 5-Fluoro-2-methylphenyl
    methyl
    1130 Cyclopropyl 5-Chloro-2-methoxyphenyl
    Methyl
    1131 Cyclopropyl 2,5-Dichlorophenyl
    Methyl
    1132 Cyclopropyl 3-Bromophenyl
    Methyl
    1133 3-Methylbutyl 5-Chloro-2-methoxyphenyl
    1134 Butyl 2,5-Dichlorophenyl
    1135 2-Methylpropyl 2,5-Dichlorophenyl
    1136 Pentyl 2,5-Dichlorophenyl
    1137 3-Methylbutyl 2,5-Dichlorophenyl
    1138 2-Methylpropyl 2,4-Dichlorophenyl
    1139 2-Methylpropyl 4-Pentylphenyl
    1140 Butyl 3-Bromophenyl
    1141 2-Methylpropyl 3-Bromophenyl
    1142 Pentyl 3-Bromophenyl
    1143 3-Methylbutyl 3-Bromophenyl
    1144 2-Methylpropyl 4-Bromophenyl
    1256 Cyclopropyl 3,4-Difluorophenyl
    Methyl
    1257 Cyclopropyl 2,4-Difluorophenyl
    Methyl
    1258 Propyl 1,3-Benzodioxol-5-yl
    1259 Cyclopropyl 1,3-Benzodioxol-5-yl
    Methyl
    1260 Cyclopropyl 3-Chloro-4-fluorophenyl
    Methyl
    1261 3-Methylbutyl 3-Iodo-4-methylphenyl
    1262 3-Methylbutyl 2-Thienyl
    1263 3-Methylbutyl 3-Thienyl
    1264 2-Methylpropyl 5-Methyl-2-thienyl
    1265 Pentyl 5-Methyl-2-thienyl
    1266 3-Methylbutyl 5-Methyl-2-thienyl
    1267 3-Methylbutyl 3-Fluorobenzyl
    1448 Methyl 2,5-Difluorophenyl
    1449 Methyl 2,5-Dichlorophenyl
    2005 3-Methylbutyl 5-Bromo-2-thienyl
    2239 Benzyl 3-Fluorophenyl
    2243 Benzyl 2-Fluorophenyl
    2245 Benzyl 3,4-Dimethylphenyl
    2251 Benzyl 3-Methoxyphenyl
    2254 Benzyl 2-Methoxyphenyl
    2258 Benzyl 5-Fluoro-2-methylphenyl
    2261 Benzyl 3-Chlorophenyl
    2266 Benzyl 3,4-Difluorophenyl
    2269 Benzyl 2,3-Difluorophenyl
    2272 Benzyl 2,5-Difluorophenyl
    2281 Benzyl 5-Chloro-2-methoxyphenyl
    2289 Benzyl 2,5-Dichlorophenyl
    2292 Benzyl 3-Bromophenyl
    2295 Benzyl 2-Bromophenyl
    2298 Benzyl 3-Iodophenyl
    2302 Benzyl 2,5-Dimethylpyrrol-3-yl
    2305 Benzyl 3-Methylbutyl
    2320 3-Methylbutyl 3-(Methylamino
    methyl)phenyl
    2321 3-Methylbutyl 3-(Ethylamino
    methyl)phenyl
    2322 3-Methylbutyl 3-(Cyclobutyl
    amino
    methyl)phenyl
    2323 3-Methylbutyl 3-[(1-Methylpropyl)
    amino
    methyl]phenyl
    2324 3-Methylbutyl 3-(Cyclopentyl
    amino
    methyl)phenyl
    2350 3-Methylbutyl 3-(Dibutylamino
    methyl)phenyl
    2366 3-Methylbutyl 3-[bis(2-Methoxyethyl)
    aminomethyl]
    phenyl
    2368 3-Methylbutyl 3-[(3,3,5-Trimethylaza
    perhydroepinyl)methyl]phenyl
    2391 Methyl 2,5-Difluorophenyl
    • EXAMPLE 12
  • [0207]
    Figure US20030092912A1-20030515-C00037
  • For each compound, the definitions of R[0208] 2 and R3 are specified in the following table.
    Compound
    No. R2 R3
    719 Propyl 3-Fluorophenyl
    720 Propyl 1,3-Benzodioxol-5-yl
    721 Propyl 5-Fluoro-2-methylphenyl
    722 Allyl 2-Fluorophenyl
    723 Propyl 3-Chloro-4-fluorophenyl
    724 Propyl 3-Chlorophenyl
    725 Propyl 2-Fluorophenyl
    726 Allyl 5-Chloro-2-methoxyphenyl
    727 Allyl 3-Chlorophenyl
    728 Methyl 3-Fluorophenyl
    729 Methyl 2,5-Difluorophenyl
    730 Propyl Phenyl
    731 Propyl 3-Chlorophenyl
    732 Allyl 3-Fluorophenyl
    733 Propyl 2,5-Difluorophenyl
    734 Propyl 3-Fluoro-4-methylphenyl
    735 Propyl 4-Methylthio
    phenyl
    736 3-Methylbutyl 3-Fluorophenyl
    737 2-Methylpropyl 2-Fluorophenyl
    738 Butyl 3,4-Difluorophenyl
    739 2-Methylpropyl 2,5-Difluorophenyl
    740 3-Methylbutyl 1,3-Benzodioxol-5-yl
    741 Butyl 4-Fluorophenyl
    742 Pentyl 2-Fluorophenyl
    743 2-Methylpropyl 3,4-Difluorophenyl
    744 Pentyl 2,5-Difluorophenyl
    745 Butyl 3-Chloro-4-fluorophenyl
    746 Butyl 3-Fluorophenyl
    747 2-Methylpropyl 4-Fluorophenyl
    748 3-Methylbutyl 2-Fluorophenyl
    749 Pentyl 3,4-Difluorophenyl
    750 3-Methylbutyl 2,5-Difluorophenyl
    751 2-Methylpropyl 3-Chloro-4-fluorophenyl
    752 2-Methylpropyl 3-Fluorophenyl
    753 3-Methylbutyl 4-Fluorophenyl
    754 2-Methylpropyl 2,5-Dimethylphenyl
    755 3-Methylbutyl 3,4-Difluorophenyl
    756 Butyl 1,3-Benzodioxol-5-yl
    757 Pentyl 3-Chloro-4-fluorophenyl
    758 Pentyl 3-Fluorophenyl
    759 Butyl 2-Fluorophenyl
    760 3-Methylbutyl 2,5-Dimethylphenyl
    761 Butyl 2,5-Difluorophenyl
    762 2-Methylpropyl 1,3-Benzodioxol-5-yl
    763 3-Methylbutyl 3-Chloro-4-fluorophenyl
    764 Butyl 5-Chloro-2-methoxyphenyl
    765 2-Methylpropyl 2,5-Dichlorophenyl
    766 Pentyl 5-Methyl-2-thienyl
    767 3-Methylbutyl Phenyl
    768 2-Methylpropyl 2-Methylphenyl
    769 3-Methylbutyl 5-Fluoro-2-methylphenyl
    770 2-Methylpropyl 5-Chloro-2-methoxyphenyl
    771 Pentyl 2,5-Dichlorophenyl
    772 3-Methylbutyl 5-Methyl-2-thienyl
    773 Butyl 3-Methylphenyl
    774 3-Methylbutyl 2-Methylphenyl
    775 Butyl 3-Chlorophenyl
    776 Pentyl 5-Chloro-2-methoxyphenyl
    777 3-Methylbutyl 2,5-Dichlorophenyl
    778 Butyl Phenyl
    779 2-Methylpropyl 3-Methylphenyl
    780 2-Methylpropyl 3-Fluoro-4-methylphenyl
    781 2-Methylpropyl 3-Chlorophenyl
    782 3-Methylbutyl 5-Chloro-2-methoxyphenyl
    783 Butyl 5-Methyl-2-thienyl
    784 2-Methylpropyl Phenyl
    785 Pentyl 3-Methylphenyl
    786 3-Methylbutyl 3-Fluoro-4-methylphenyl
    787 Pentyl 3-Chlorophenyl
    788 Butyl 2,5-Dichlorophenyl
    789 2-Methylpropyl 5-Methyl-2-thienyl
    790 Pentyl Phenyl
    791 3-Methylbutyl 3-Methylphenyl
    792 Pentyl 5-Fluoro-2-methylphenyl
    793 3-Methylbutyl 3-Chlorophenyl
    794 2-Methylpropyl 4-Methylthio
    phenyl
    795 2-Methylpropyl 3-Fluoro-4-methoxyphenyl
    796 3-Methylbutyl 3-Fluoro-4-methoxyphenyl
    797 2-Methylpropyl 2,4,6-Trifluorophenyl
    798 Butyl 2,3,6-Trifluorophenyl
    799 2-Methylpropyl 2,3,6-Trifluorophenyl
    885 Methyl 2,3,6-Trifluorophenyl
    886 Propyl 2,3,6-Trifluorophenyl
    933 Propyl Phenyl
    934 Propyl 3-Fluorophenyl
    935 Propyl 4-Fluorophenyl
    936 Allyl 2-Fluorophenyl
    937 Propyl 2-Fluorophenyl
    1037 Butyl 3-Chlorophenyl
    1038 2-Methylpropyl 3-Chlorophenyl
    1039 Pentyl 3-Chlorophenyl
    1040 3-Methylbutyl 3-Chlorophenyl
    1041 Butyl 3,4-Difluorophenyl
    1042 2-Methylpropyl 3,4-Difluorophenyl
    1043 Pentyl 3,4-Difluorophenyl
    1044 3-Methylbutyl 3,4-Difluorophenyl
    1045 Butyl 2,3-Difluorophenyl
    1046 2-Methylpropyl 2,3-Difluorophenyl
    1047 Pentyl 2,3-Difluorophenyl
    1048 3-Methylbutyl 2,3-Difluorophenyl
    1049 Butyl 2,5-Difluorophenyl
    1050 2-Methylpropyl 2,5-Difluorophenyl
    1051 Pentyl 2,5-Difluorophenyl
    1052 3-Methylbutyl 2,5-Difluorophenyl
    1053 Butyl 2,4-Difluorophenyl
    1054 2-Methylpropyl 2,4-Difluorophenyl
    1055 Pentyl 2,4-Difluorophenyl
    1056 3-Methylbutyl 2,4-Difluorophenyl
    1057 2-Methylpropyl 4-Propylphenyl
    1058 2-Methylpropyl 4-Ethoxyphenyl
    1059 Butyl 1,3-Benzodioxol-5-yl
    1060 2-Methylpropyl 1,3-Benzodioxol-5-yl
    1061 Pentyl 1,3-Benzodioxol-5-yl
    1062 3-Methylbutyl 1,3-Benzodioxol-5-yl
    1063 Butyl 4-Methylothio
    phenyl
    1064 2-Methylpropyl 4-Methylothio
    phenyl
    1065 Butyl 3-Fluoro-4-methoxyphenyl
    1066 2-Methylpropyl 3-Fluoro-4-methoxyphenyl
    1067 3-Methylbutyl 3-Fluoro-4-methoxyphenyl
    1068 2-Methylpropyl 4-Chloro-3-methylphenyl
    1069 3-Methylbutyl 4-Chloro-3-methylphenyl
    1070 Butyl 3-Chloro-4-fluorophenyl
    1071 2-Methylpropyl 3-Chloro-4-fluorophenyl
    1072 Pentyl 3-Chloro-4-fluorophenyl
    1073 3-Methylbutyl 3-Chloro-4-fluorophenyl
    1074 2-Methylpropyl 3,4,5-Trifluorophenyl
    1075 3-Methylbutyl 3,4,5-Trifluorophenyl
    1076 2-Methylpropyl 4-Ethylthiophenyl
    1077 3-Methylbutyl 2,3,6-Trifluorophenyl
    1078 Allyl 5-Chloro-2-methoxyphenyl
    1079 Propyl 5-Chloro-2-methoxyphenyl
    1080 Propyl 3-Trifluoromethylphenyl
    1081 Allyl 2,5-Dichlorophenyl
    1082 Propyl 2,5-Dichlorophenyl
    1083 Methyl 3-Bromophenyl
    1084 Allyl 3-Bromophenyl
    1085 Propyl 3-Bromo-4-fluorophenyl
    1086 Methyl 3-Iodophenyl
    1087 Allyl 3-Iodophenyl
    1088 Propyl 3-Iodophenyl
    1089 2-Methoxy 2,5-Difluorophenyl
    ethyl
    1090 2-Methoxy 2,5-Dichlorophenyl
    ethyl
    1091 2-Methoxy 3-Bromophenyl
    ethyl
    1145 2-Methylpropyl 3-Chloro-4-methoxyphenyl
    1146 3-Methylbutyl 3-Chloro-4-methoxyphenyl
    1147 2-Methylpropyl 5-Chloro-2-methoxyphenyl
    1148 Pentyl 5-Chloro-2-methoxyphenyl
    1149 3-Methylbutyl 5-Chloro-2-methoxyphenyl
    1150 Pentyl 3-Trifluoromethylphenyl
    1151 3-Methylbutyl 3-Trifluoromethylphenyl
    1152 Butyl 2-Trifluoromethylphenyl
    1153 3-Methylbutyl 2-Trifluoromethylphenyl
    1154 Butyl 3,4-Dichlorophenyl
    1155 2-Methylpropyl 3,4-Dichlorophenyl
    1156 3-Methylbutyl 3,4-Dichlorophenyl
    1157 2-Methylpropyl 2,5-Dichlorophenyl
    1158 Pentyl 2,5-Dichlorophenyl
    1159 3-Methylbutyl 2,5-Dichlorophenyl
    1160 2-Methylpropyl 2,4-Dichlorophenyl
    1161 2-Methylpropyl 3-Bromophenyl
    1162 Pentyl 3-Bromophenyl
    1163 3-Methylbutyl 3-Bromophenyl
    1164 2-Methylpropyl 4-Bromophenyl
    1165 2-Methylpropyl 2-Bromophenyl
    1166 Pentyl 2-Bromophenyl
    1167 3-Methylbutyl 2-Bromophenyl
    1194 2-Methylpropyl 3-Phenoxyphenyl
    1195 2-Methylpropyl 4-Phenoxyphenyl
    1196 Butyl 3-Bromo-4-methylphenyl
    1197 2-Methylpropyl 3-Bromo-4-methylphenyl
    1198 Butyl 3-Bromo-4-fluorophenyl
    1199 2-Methylpropyl 3-Bromo-4-fluorophenyl
    1200 Pentyl 3-Bromo-4-fluorophenyl
    1201 3-Methylbutyl 3-Bromo-4-fluorophenyl
    1202 Butyl 3-Iodophenyl
    1203 Pentyl 3-Iodophenyl
    1204 3-Methylbutyl 3-Iodophenyl
    1205 2-Methylpropyl 4-Iodophenyl
    1206 Methyl 3-Iodophenyl
    1239 Cyclopentyl 4-Methylphenyl
    1240 Cyclopentyl 3-Fluoro-4-methylphenyl
    1241 Cyclopropyl 5-Chloro-2-methoxyphenyl
    Methyl
    1242 Cyclopropyl 3-Trifluoromethylphenyl
    Methyl
    1243 Cyclopropyl 2,5-Dichlorophenyl
    Methyl
    1244 Cyclopropyl 3-Bromophenyl
    Methyl
    1245 Cyclopentyl 3-Methoxybenzyl
    1246 Cyclopentyl 2-(2-Chlorophenyl)
    ethenyl
    1247 Cyclopropyl 3-Bromo-4-methylphenyl
    Methyl
    1248 Cyclopropyl 3-Bromo-4-fluorophenyl
    Methyl
    1249 Cyclopropyl 3-Iodophenyl
    Methyl
    1253 Cyclopentyl 3-Chloro-4-methoxyphenyl
    1254 Cyclopropyl 5-Chloro-2-methoxyphenyl
    Methyl
    1255 Cyclopentyl 2,4-Dichlorophenyl
    1268 Cyclopentyl 3-Fluorobenzyl
    1269 Cyclopentyl 2-(2-
    Trifluoromethylphenyl)ethenyl
    1270 Cyclopentyl 2-(2-Bromophenyl)
    ethenyl
    1271 Cyclopropyl 2,3,6-Trifluorophenyl
    Methyl
    1274 Cyclopentyl 3-Chloro-4-methylphenyl
    1275 Cyclopropyl 2,4,5-Trifluorophenyl
    Methyl
    1425 Propyl 3-Fluoro-4-methylphenyl
    1426 Propyl 3-Chlorophenyl
    1427 Allyl 3-Bromo-4-fluorophenyl
    1428 Propyl 3-Bromo-4-fluorophenyl
    1429 Allyl 3-Iodophenyl
    1430 Propyl 3-Iodophenyl
    1431 Propyl 3-Iodo-4-methylphenyl
    1433 Propyl 3,4-Difluorophenyl
    1434 Propyl 2,3-Difluorophenyl
    1435 Propyl 2,4-Difluorophenyl
    1436 Propyl 1,3-Benzodioxol-5-yl
    1437 Propyl 3-Chloro-4-fluorophenyl
    1438 Propyl 5-Chloro-2-methoxyphenyl
    1439 Methyl 2,5-Dichlorophenyl
    1440 Allyl 2,5-Dichlorophenyl
    1441 Propyl 2,5-Dichlorophenyl
    1442 Propyl 2,4-Dichlorophenyl
    1443 Methyl 3-Bromophenyl
    1444 Allyl 3-Bromophenyl
    1445 Propyl 3-Bromophenyl
    1446 Propyl 5-Methyl-2-thienyl
    1447 Propyl 2,6-Difluorophenyl
    1977 3-Methylbutyl 4,5-Dimethyl-2-furyl
    1978 3-Methylbutyl 3-Chloro-4-methylphenyl
    1980 3-Methylbutyl 2,4,5-Trifluorophenyl
    1982 3-Methylbutyl 2,6-Difluorophenyl
    1983 3-Methylbutyl 2-Bromo-5-methoxyphenyl
    1984 3-Methylbutyl 3,5-Difluorophenyl
    2006 3-Methylbutyl 5-Bromo-2-thienyl
    2008 3-Methylbutyl 3-Bromo-2-thienyl
    • EXAMPLE 13
  • [0209]
    Figure US20030092912A1-20030515-C00038
  • For each compound, the definitions of R[0210] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    800 Propyl Phenyl
    801 Methyl 3-Chlorophenyl
    802 Allyl 3-Chlorophenyl
    803 Propyl 3-Chlorophenyl
    804 Propyl 5-Chloro-2-methoxyphenyl
    805 Propyl 3-Trifluoromethylphenyl
    806 Propyl 2,5-Dichlorophenyl
    807 Propyl 3-Bromophenyl
    808 Propyl 3-Bromo-4-fluorophenyl
    809 Methyl 3-Iodophenyl
    810 Allyl 3-Iodophenyl
    811 Propyl 3-Iodophenyl
    888 Allyl 5-Chloro-2-methoxyphenyl
    931 Propyl 3-Fluorophenyl
    932 Propyl 2-Fluorophenyl
    1092 Propyl 3-Fluorophenyl
    1093 Propyl 2-Fluorophenyl
    1094 Allyl 2,5-Difluorophenyl
    1095 Propyl 2,5-Difluorophenyl
    1096 Propyl 1,3-Benzodioxol-5-yl
    1097 Methyl 5-Chloro-2-methoxyphenyl
    1098 Allyl 5-Chloro-2-methoxyphenyl
    1099 Methyl 2,5-Dichlorophenyl
    1168 Methyl 5-Chloro-2-methoxyphenyl
    1169 Allyl 5-Chloro-2-methoxyphenyl
    1170 Propyl 5-Chloro-2-methoxyphenyl
    1171 Propyl 3,4-Dichlorophenyl
    1172 Allyl 2,5-Dichlorophenyl
    1173 Propyl 2,5-Dichlorophenyl
    1174 Propyl 2,4-Dichlorophenyl
    1175 Methyl 3-Bromophenyl
    1176 Allyl 3-Bromophenyl
    1177 Propyl 3-Bromophenyl
    1178 Cyclopropyl 5-Chloro-2-methoxyphenyl
    methyl
    1179 Cyclopropyl 2,5-Dichlorophenyl
    methyl
    1180 Propyl 3-Bromophenyl
    1181 Cyclopropyl 3-Bromophenyl
    methyl
    1182 Pentyl 3-Bromo-4-fluorophenyl
    1183 3-Methylbutyl 3-Bromo-4-fluorophenyl
    1184 Pentyl 3-Iodophenyl
    1185 Cyclopropyl 3-Bromo-4-fluorophenyl
    Methyl
    1186 Cyclopropyl 3-Iodophenyl
    Methyl
    1756 Butyl 2-Thienyl
    1757 2-Methylpropyl 2-Thienyl
    1758 Pentyl 2-Thienyl
    1759 3-Methylbutyl 2-Thienyl
    1760 Butyl 3-Thienyl
    1761 2-Methylpropyl 3-Thienyl
    1762 Pentyl 3-Thienyl
    1763 3-Methylbutyl 3-Thienyl
    1764 3-Methylbutyl Benzyl
    1765 Butyl 5-Methyl-2-thienyl
    1766 2-Methylpropyl 5-Methyl-2-thienyl
    1767 Pentyl 5-Methyl-2-thienyl
    1768 3-Methylbutyl 5-Methyl-2-thienyl
    1769 3-Methylbutyl 3-Fluorobenzyl
    1770 3-Methylbutyl 4-Fluorobenzyl
    1771 3-Methylbutyl 3-Methoxybenzyl
    1787 3-Methylbutyl 2,3,6-Trifluorophenyl
    1788 2-Methylpropyl 2,3,6-Trifluorophenyl
    1789 3-Methylbutyl 2,3,6-Trifluorophenyl
    1790 3-Methylbutyl 2-Chloro-6-fluorophenyl
    1791 Butyl Phenyl
    1792 2-Methylpropyl Phenyl
    1793 Pentyl Phenyl
    1794 3-Methylbutyl Phenyl
    1795 Butyl 3-Methylphenyl
    1796 2-Methylpropyl 3-Methylphenyl
    1797 Pentyl 3-Methylphenyl
    1798 3-Methylbutyl 3-Methylphenyl
    1799 Butyl 4-Methylphenyl
    1800 2-Methylpropyl 4-Methylphenyl
    1801 Butyl 3-Fluorophenyl
    1802 2-Methylpropyl 3-Fluorophenyl
    1803 Pentyl 3-Fluorophenyl
    1804 3-Methylbutyl 3-Fluorophenyl
    1805 Butyl 4-Fluorophenyl
    1806 3-Methylbutyl 4-Fluorophenyl
    1807 Butyl 2-Fluorophenyl
    1808 2-Methylpropyl 2-Fluorophenyl
    1809 Pentyl 2-Fluorophenyl
    1810 3-Methylbutyl 2-Fluorophenyl
    1811 2-Methylpropyl 4-Ethylphenyl
    1812 2-Methylpropyl 3,4-Dimethylphenyl
    1813 3-Methylbutyl 3-Methoxyphenyl
    1814 2-Methylpropyl 3-Fluoro-4-methylphenyl
    1815 3-Methylbutyl 3-Fluoro-4-methylphenyl
    1816 2-Methylpropyl 5-Fluoro-2-methylphenyl
    1817 Pentyl 5-Fluoro-2-methylphenyl
    1818 3-Methylbutyl 5-Fluoro-2-methylphenyl
    1857 Butyl 2,5-Dichlorophenyl
    1858 2-Methylpropyl 2,5-Dichlorophenyl
    1859 Pentyl 2,5-Dichlorophenyl
    1860 3-Methylbutyl 2,5-Dichlorophenyl
    1861 2-Methylpropyl 4-Pentylphenyl
    1862 Butyl 3-Bromophenyl
    1863 2-Methylpropyl 3-Bromophenyl
    1864 Pentyl 3-Bromophenyl
    1865 3-Methylbutyl 3-Bromophenyl
    1866 2-Methylpropyl 4-Bromophenyl
    1922 Butyl 3,4-Dimethylphenyl
    1923 2-Methylpropyl 3-Iodo-4-methylphenyl
    1924 3-Methylbutyl 3-Iodo-4-methylphenyl
    1986 Butyl 4,5-Dimethyl-2-furyl
    1987 2-Methylpropyl 4,5-Dimethyl-2-furyl
    1988 3-Methylbutyl 4,5-Dimethyl-2-furyl
    1989 3-Methylbutyl 4-Methoxy-3-thienyl
    1990 Butyl 3-Chloro-2-thienyl
    1991 2-Methylpropyl 3-Chloro-2-thienyl
    1992 Pentyl 3-Chloro-2-thienyl
    1993 3-Methylbutyl 3-Chloro-2-thienyl
    1994 2-Methylpropyl 3-Chloro-4-methylphenyl
    1995 3-Methylbutyl 3-Chloro-4-methylphenyl
    1996 3-Methylbutyl 2,4,5-Trifluorophenyl
    1997 Pentyl 2,6-Difluorophenyl
    1998 3-Methylbutyl 2,6-Difluorophenyl
    1999 Pentyl 2-Bromo-5-methoxyphenyl
    2000 3-Methylbutyl 2-Bromo-5-methoxyphenyl
    2001 3-Methylbutyl 3,5-Difluorophenyl
    2002 2-Methylpropyl 5-Bromo-2-thienyl
    2003 3-Methylbutyl 5-Bromo-2-thienyl
    2009 Butyl 5-Ethyl-2-thienyl
    2010 2-Methylpropyl 5-Ethyl-2-thienyl
    2011 3-Methylbutyl 5-Ethyl-2-thienyl
    2012 2-Methylpropyl 5-Propyl-2-thienyl
    2013 2-Methylpropyl 5-Butyl-2-thienyl
    2014 2-Methylpropyl 5-Pentyl-2-thienyl
    2015 2-Methylpropyl 5-Hexyl-2-thienyl
    • EXAMPLE 14
  • [0211]
    Figure US20030092912A1-20030515-C00039
  • For each compound, the definitions of R[0212] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    889 Methyl 2,5-Difluorophenyl
    890 Methyl 2,5-Dichlorophenyl
    891 Propyl 3-Bromophenyl
    892 Methyl 3-Iodophenyl
    893 Allyl 3-Iodophenyl
    894 Propyl 3-Iodophenyl
    1126 Propyl 2,5-Dichlorophenyl
    1127 Methyl 3-Bromophenyl
    1128 Allyl 3-Bromophenyl
    1432 Propyl 3-Bromo-4-fluorophenyl
    1517 2-Methylpropyl 3-Fluorophenyl
    1518 2-Methylpropyl 3,4-Dimethylphenyl
    1519 2-Methylpropyl 3-Methoxyphenyl
    1520 2-Methylpropyl 3-Fluoro-4-methylphenyl
    1521 Cyclopentyl 3-Fluoro-4-methylphenyl
    1522 2-Methylpropyl 5-Fluoro-2-methylphenyl
    1523 2-Methylpropyl 2-Fluoro-3-methylphenyl
    1524 2-Methylpropyl 3-Chlorophenyl
    1525 2-Methylpropyl 4-Chlorophenyl
    1567 2-Methylpropyl 1,3-Benzodioxol-5-yl
    1568 Cyclopentyl 4-Methoxyphenyl
    1569 Cyclopentyl 4-Butylphenyl
    1570 3-Methylbutyl 3-Chloro-4-methoxyphenyl
    1571 Cyclopentyl 3-Chloro-4-methoxyphenyl
    1572 2-Methylpropyl 3,4-Dichlorophenyl
    1573 3-Methylbutyl 2,5-Dichlorophenyl
    1574 Cyclopentyl 2,4-Dichlorophenyl
    1575 Cyclopentyl 4-Pentylphenyl
    1576 3-Methylbutyl 3-Bromophenyl
    1619 2-Methylpropyl 4-Hexylphenyl
    1620 Cyclopentyl 4-Hexylphenyl
    1621 2-Methylpropyl 3-Bromo-4-methylphenyl
    1622 2-Methylpropyl 3-Bromo-4-fluorophenyl
    1623 3-Methylbutyl 3-Bromo-4-fluorophenyl
    1624 2-Methylpropyl 3-Iodophenyl
    1625 3-Methylbutyl 3-Iodophenyl
    1653 2-Methylpropyl 3-Iodo-4-methylphenyl
    1654 3-Methylbutyl 2-Thienyl
    1655 3-Methylbutyl Benzyl
    1656 2-Methylpropyl 5-Methyl-2-thienyl
    1657 3-Methylbutyl 5-Methyl-2-thienyl
    1658 3-Methylbutyl 3-Fluorobenzyl
    1659 Cyclopentyl 3-Fluorobenzyl
    1678 Cyclopentyl 2-Chlorobenzyl
    1682 2-Methylpropyl 2-(2-Chlorophenyl)
    ethenyl
    1683 Cyclopentyl 2-(2-Chlorophenyl)
    ethenyl
    1701 2-Methylpropyl 2,3,6-Trifluorophenyl
    1702 2-Methylpropyl 4,5-Dimethyl-2-furyl
    • EXAMPLE 15
  • [0213]
    Figure US20030092912A1-20030515-C00040
  • For each compound, the definitions of R[0214] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    895 Propyl 5-Bromo-2-thienyl
    993 Propyl 1,3-Benzodioxol-5-yl
    • EXAMPLE 16
  • [0215]
    Figure US20030092912A1-20030515-C00041
  • For each compound, the definitions of R[0216] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    896 Propyl 3-Bromo-4-fluorophenyl
    897 Allyl 3-Iodophenyl
    898 Propyl 3-Iodophenyl
    899 Propyl 3-Iodo-4-methylphenyl
    900 Methyl 2-Thienyl
    901 Methyl 5-Methyl-2-thienyl
    923 Propyl 3-Methylphenyl
    1117 Propyl 5-Chloro-2-methoxyphenyl
    1118 Propyl 2,5-Dichlorophenyl
    1119 Propyl 3-Bromophenyl
    1979 3-Methylbutyl 3-Chloro-4-methylphenyl
    1981 3-Methylbutyl 2,4,5-Trifluorophenyl
    1985 3-Methylbutyl 3,5-Difluorophenyl
    2007 3-Methylbutyl 5-Bromo-2-thienyl
    2386 2-(2- 2,5-Dichlorophenyl
    Fluorophenyl)
    ethyl
    2387 2-(2- 3-Bromophenyl
    Fluorophenyl)
    ethyl
    2388 2-(2- 3-Iodophenyl
    Fluorophenyl)
    ethyl
    • EXAMPLE 17
  • [0217]
    Figure US20030092912A1-20030515-C00042
  • For each compound, the definitions of R[0218] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    902 Allyl 3-Bromo-4-methylphenyl
    903 Propyl 3-Bromo-4-methylphenyl
    904 Allyl 3-Bromo-4-fluorophenyl
    905 Propyl 3-Bromo-4-fluorophenyl
    906 Methyl 3-Iodophenyl
    907 Allyl 3-Iodophenyl
    908 Propyl 3-Iodophenyl
    909 Propyl 3-Iodo-4-methylphenyl
    910 Methyl 2-Thienyl
    911 Methyl 3-Thienyl
    912 Methyl 3-Methyl-2-thienyl
    913 Propyl 5-Methyl-2-thienyl
    914 Propyl Phenyl
    915 Methyl 3-Methylphenyl
    916 Propyl 3-Fluorophenyl
    917 Propyl 2-Fluorophenyl
    918 Methyl 5-Fluoro-2-methylphenyl
    919 Allyl 5-Fluoro-2-methylphenyl
    920 Methyl 3-Chlorophenyl
    921 Propyl 3-Chlorophenyl
    976 Propyl 2-Chlorophenyl
    977 Allyl 3,4-Difluorophenyl
    978 Propyl 3,4-Difluorophenyl
    979 Methyl 2,3-Difluorophenyl
    980 Allyl 2,3-Difluorophenyl
    981 Propyl 2,3-Difluorophenyl
    982 Methyl 2,5-Difluorophenyl
    983 Allyl 2,5-Difluorophenyl
    984 Propyl 2,5-Difluorophenyl
    985 Propyl 2,4-Difluorophenyl
    986 Propyl 1,3-Benzodioxol-5-yl
    987 Allyl 3-Chloro-4-fluorophenyl
    988 Propyl 3-Chloro-4-fluorophenyl
    1120 Allyl 5-Chloro-2-methoxyphenyl
    1121 Propyl 5-Chloro-2-methoxyphenyl
    1122 Allyl 2,5-Dichlorophenyl
    1123 Propyl 2,5-Dichlorophenyl
    1124 Allyl 3-Bromophenyl
    1125 Propyl 3-Bromophenyl
    1516 Methyl 5-Ethoxy-2-thienyl
    1706 2-Methylpropyl 2,4,6-Trifluorophenyl
    1707 2-Methylpropyl 2,3,6-Trifluorophenyl
    1708 3-Methylbutyl 2,3,6-Trifluorophenyl
    1709 2-Methylpropyl 4,5-Dimethyl-2-furyl
    1710 3-Methylbutyl 4,5-Dimethyl-2-furyl
    1711 2-Methylpropyl 3-Chloro-2-thienyl
    1712 3-Methylbutyl 3-Chloro-2-thienyl
    1713 2-Methylpropyl 5-Methylthio-2-thienyl
    1719 2-Methylpropyl 3-Chlorophenyl
    1720 3-Methylbutyl 2,4,5-Trifluorophenyl
    1725 2-Methylpropyl 2,6-Difluorophenyl
    1727 3-Methylbutyl Phenyl
    1728 2-Methylpropyl 3-Methylphenyl
    1729 3-Methylbutyl 3-Methylphenyl
    1730 2-Methylpropyl 4-Methylphenyl
    1731 3-Methylbutyl 4-Methylphenyl
    1732 2-Methylpropyl 2-Methylphenyl
    1733 3-Methylbutyl 2-Methylphenyl
    1734 2-Methylpropyl 3-Fluorophenyl
    1735 3-Methylbutyl 3-Fluorophenyl
    1736 2-Methylpropyl 3-Fluorophenyl
    1737 3-Methylbutyl 4-Fluorophenyl
    1738 2-Methylpropyl 2-Fluorophenyl
    1739 3-Methylbutyl 2-Fluorophenyl
    1740 2-Methylpropyl 4-Ethylphenyl
    1741 2-Methylpropyl 3,4-Dimethylphenyl
    1742 2-Methylpropyl 3-Fluoro-4-methylphenyl
    1743 Cyclopentyl 3-Fluoro-4-methylphenyl
    1744 2-Methylpropyl 4-Chlorophenyl
    1745 Cyclopentyl 4-Methoxyphenyl
    1746 3-Methylbutyl 3-Chloro-4-fluorophenyl
    1747 3-Methylbutyl 2-Thienyl
    • EXAMPLE 18
  • [0219]
    Figure US20030092912A1-20030515-C00043
  • For each compound, the definitions of R[0220] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    812 Methyl 2,5-Difluorophenyl
    813 Propyl 2,5-Dichlorophenyl
    814 Propyl 3-Iodophenyl
    • EXAMPLE 19
  • [0221]
    Figure US20030092912A1-20030515-C00044
  • For each compound, the definitions of R[0222] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    818 Propyl 3-Fluorophenyl
    819 Propyl 2-Fluorophenyl
    820 Propyl 3,4-Difluorophenyl
    821 Methyl 2,5-Difluorophenyl
    822 Allyl 2,5-Difluorophenyl
    823 Propyl 2,5-Difluorophenyl
    824 Propyl 1,3-Benzodioxol-5-yl
    825 Propyl 3-Chloro-4-fluorophenyl
    826 Methyl 5-Chloro-2-methoxyphenyl
    827 Ethyl 5-Chloro-2-methoxyphenyl
    828 Allyl 5-Chloro-2-methoxyphenyl
    829 Propyl 5-Chloro-2-methoxyphenyl
    830 Methyl 2,5-Dichlorophenyl
    831 Allyl 2,5-Dichlorophenyl
    832 Propyl 2,5-Dichlorophenyl
    833 Propyl Phenyl
    834 Propyl 3-Fluoro-4-methylphenyl
    835 Propyl 5-Fluoro-2-methylphenyl
    836 Methyl 3-Chlorophenyl
    837 Allyl 3-Chlorophenyl
    838 Propyl 3-Chlorophenyl
    842 Methyl 5-Chloro-2-methoxyphenyl
    843 Ethyl 5-Chloro-2-methoxyphenyl
    844 Allyl 5-Chloro-2-methoxyphenyl
    845 Propyl 5-Chloro-2-methoxyphenyl
    846 Methyl 3-Trifluorophenyl
    847 Propyl 3-Trifluorophenyl
    848 Methyl 2,5-Dichlorophenyl
    849 Allyl 2,5-Dichlorophenyl
    850 Propyl 2,5-Dichlorophenyl
    851 Methyl 3-Bromophenyl
    852 Allyl 3-Bromophenyl
    853 Propyl 3-Bromophenyl
    854 Propyl 3-Bromo-4-fluorophenyl
    855 Methyl 3-Iodophenyl
    856 Allyl 3-Iodophenyl
    857 Propyl 3-Iodophenyl
    859 Allyl 2-Fluorophenyl
    860 Propyl 2-Fluorophenyl
    861 Propyl 2-Chlorophenyl
    862 Propyl 3,4-Difluorophenyl
    863 Propyl 2,3-Difluorophenyl
    864 Methyl 2,5-Difluorophenyl
    865 Propyl 4-Methylthiophenyl
    866 Propyl 3-Fluoro-4-methoxyphenyl
    867 Propyl 4-Chloro-3-methylphenyl
    868 Methyl 3-Chloro-4-fluorophenyl
    869 Allyl 3-Chloro-4-fluorophenyl
    870 Propyl 3-Chloro-4-fluorophenyl
    871 Propyl 3,4,5-Trifluorophenyl
    872 Propyl 4-Butylphenyl
    873 Propyl 4-Methylthiophenyl
    1772 Butyl 2-Thienyl
    1773 2-Methylpropyl 2-Thienyl
    1774 Pentyl 2-Thienyl
    1775 3-Methylbutyl 2-Thienyl
    1776 Butyl 3-Thienyl
    1777 2-Methylpropyl 3-Thienyl
    1778 Pentyl 3-Thienyl
    1779 3-Methylbutyl 3-Thienyl
    1780 3-Methylbutyl Benzyl
    1781 Butyl 5-Methyl-2-thienyl
    1782 2-Methylpropyl 5-Methyl-2-thienyl
    1783 Pentyl 5-Methyl-2-thienyl
    1784 3-Methylbutyl 5-Methyl-2-thienyl
    1785 3-Methylbutyl 3-Fluorobenzyl
    1786 3-Methylbutyl 3-Methoxybenzyl
    1819 Butyl Phenyl
    1820 2-Methylpropyl Phenyl
    1821 Pentyl Phenyl
    1822 3-Methylbutyl Phenyl
    1823 Butyl 3-Methylphenyl
    1824 2-Methylpropyl 3-Methylphenyl
    1825 Pentyl 3-Methylphenyl
    1826 3-Methylbutyl 3-Methylphenyl
    1827 Butyl 4-Methylphenyl
    1828 2-Methylpropyl 4-Methylphenyl
    1829 3-Methylbutyl 4-Methylphenyl
    1830 Butyl 3-Fluorophenyl
    1831 2-Methylpropyl 3-Fluorophenyl
    1832 Pentyl 3-Fluorophenyl
    1833 3-Methylbutyl 3-Fluorophenyl
    1834 Butyl 4-Fluorophenyl
    1835 2-Methylpropyl 4-Fluorophenyl
    1836 Pentyl 4-Fluorophenyl
    1837 3-Methylbutyl 4-Fluorophenyl
    1838 Butyl 2-Fluorophenyl
    1839 2-Methylpropyl 2-Fluorophenyl
    1840 Pentyl 2-Fluorophenyl
    1841 3-Methylbutyl 2-Fluorophenyl
    1842 2-Methylpropyl 4-Ethylphenyl
    1843 2-Methylpropyl 3,4-Dimethylphenyl
    1844 3-Methylbutyl 2,5-Dimethylphenyl
    1845 2-Methylpropyl 2,4-Dimethylphenyl
    1846 2-Methylpropyl 3-Methoxyphenyl
    1847 3-Methylbutyl 3-Methoxyphenyl
    1848 3-Methylbutyl 2-Methoxyphenyl
    1849 2-Methylpropyl 3-Fluoro-4-methylphenyl
    1850 3-Methylbutyl 3-Fluoro-4-methylphenyl
    1851 Butyl 5-Fluoro-2-methylphenyl
    1852 2-Methylpropyl 5-Fluoro-2-methylphenyl
    1853 Pentyl 5-Fluoro-2-methylphenyl
    1854 3-Methylbutyl 5-Fluoro-2-methylphenyl
    1855 2-Methylpropyl 4-Chlorophenyl
    1856 3-Methylbutyl 4-Chlorophenyl
    1867 2-Methylpropyl 2,5-Dichlorophenyl
    1868 Pentyl 2,5-Dichlorophenyl
    1869 3-Methylbutyl 2,5-Dichlorophenyl
    1870 2-Methylpropyl 4-Pentylphenyl
    1871 2-Methylpropyl 3-Bromophenyl
    1872 Pentyl 3-Bromophenyl
    1873 3-Methylbutyl 3-Bromophenyl
    1925 2-Methylpropyl 3-Iodo-4-methylphenyl
    1926 3-Methylbutyl 3-Iodo-4-methylphenyl
    1928 Butyl 2-Chlorophenyl
    1929 2-Methylpropyl 2-Chorophenyl
    1930 Pentyl 2-Chlorophenyl
    1931 Butyl 3,4-Difluorophenyl
    1932 2-Methylpropyl 3,4-Difluorophenyl
    1933 Pentyl 3,4-Difluorophenyl
    1934 3-Methylbutyl 3,4-Difluorophenyl
    1935 Butyl 2,3-Difluorophenyl
    1936 2-Methylpropyl 2,3-Difluorophenyl
    1937 Pentyl 2,3-Difluorophenyl
    1938 3-Methylbutyl 2,3-Difluorophenyl
    1939 Butyl 2,5-Difluorophenyl
    1940 2-Methylpropyl 2,5-Difluorophenyl
    1941 Pentyl 2,5-Difluorophenyl
    1942 3-Methylbutyl 2,5-Difluorophenyl
    1943 Butyl 2,4-Difluorophenyl
    1944 2-Methylpropyl 2,4-Difluorophenyl
    1945 Pentyl 2,4-Difluorophenyl
    1946 3-Methylbutyl 2,4-Difluorophenyl
    1947 2-Methylpropyl 4-Propylphenyl
    1948 2-Methylpropyl 4-i-Propylphenyl
    1949 Butyl 1,3-Benzodioxol-5-yl
    1950 2-Methylpropyl 1,3-Benzodioxol-5-yl
    1951 Pentyl 1,3-Benzodioxol-5-yl
    1952 3-Methylbutyl 1,3-Benzodioxol-5-yl
    1953 Butyl 3-Bromo-4-methylphenyl
    1954 2-Methylpropyl 3-Bromo-4-methylphenyl
    1955 Pentyl 3-Bromo-4-methylphenyl
    1956 3-Methylbutyl 3-Bromo-4-methylphenyl
    1957 2-Methylpropyl 4-Heptylphenyl
    1958 Butyl 3-Iodophenyl
    1959 2-Methylpropyl 3-Iodophenyl
    1960 Pentyl 3-Iodophenyl
    1961 3-Methylbutyl 3-Iodophenyl
    1962 2-Methylpropyl 4-Iodophenyl
    2016 Butyl 5-Ethyl-2-thienyl
    2017 2-Methylpropyl 5-Ethyl-2-thienyl
    2018 3-Methylbutyl 5-Ethyl-2-thienyl
    2019 2-Methylpropyl 5-Propyl-2-thienyl
    • EXAMPLE 20
  • [0223]
    Figure US20030092912A1-20030515-C00045
  • For each compound, the definitions of R[0224] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    874 Methyl 3-Fluorophenyl
    875 Allyl 3-Fluorophenyl
    876 Propyl 3-Fluorophenyl
    877 Propyl 4-Fluorophenyl
    878 Methyl 3-Chloro-4-methylphenyl
    879 Allyl 3-Chloro-4-methylphenyl
    880 Propyl 3-Chloro-4-methylphenyl
    881 Allyl 5-Bromo-2-thienyl
    882 Propyl 5-Bromo-2-thienyl
    883 Propyl 3-Fluoro-4-methylphenyl
    884 Propyl 5-Fluoro-2-methylphenyl
    922 Propyl 3-Methoxyphenyl
    1450 Propyl 3-Bromo-4-methylphenyl
    1451 Allyl 3-Bromo-4-fluorophenyl
    1452 Propyl 3-Bromo-4-fluorophenyl
    1453 Allyl 3-Iodophenyl
    1454 Propyl 3-Iodophenyl
    1455 Allyl 5-Chloro-2-methoxyphenyl
    1456 Propyl 5-Chloro-2-methoxyphenyl
    1457 Propyl 3,4-Dichlorophenyl
    1458 Ethyl 2,5-Dichlorophenyl
    1459 Allyl 2,5-Dichlorophenyl
    1460 Propyl 2,5-Dichlorophenyl
    1461 Propyl 2,4-Dichlorophenyl
    1462 Ethyl 3-Bromophenyl
    1463 Allyl 3-Bromophenyl
    1464 Propyl 3-Bromophenyl
    1465 Propyl 5-Methyl-2-thienyl
    1466 Propyl 4-Chloro-3-methylphenyl
    1467 Propyl 3-Chloro-4-fluorophenyl
    1526 2-Methylpropyl Phenyl
    1527 3-Methylbutyl Phenyl
    1528 2-Methylpropyl 3-Methylphenyl
    1529 3-Methylbutyl 3-Methylphenyl
    1530 2-Methylpropyl 4-Methylphenyl
    1531 Cyclopentyl 4-Methylphenyl
    1532 2-Methylpropyl 2-Methylphenyl
    1533 3-Methylbutyl 2-Methylphenyl
    1534 2-Methylpropyl 3-Fluorophenyl
    1535 3-Methylbutyl 3-Fluorophenyl
    1536 2-Methylpropyl 4-Fluorophenyl
    1537 3-Methylbutyl 4-Fluorophenyl
    1538 2-Methylpropyl 2-Fluorophenyl
    1539 Cyclopentyl 2-Fluorophenyl
    1540 2-Methylpropyl 4-Ethylphenyl
    1541 2-Methylpropyl 3,4-Dimethylphenyl
    1542 2-Methylpropyl 2,3-Dimethylphenyl
    1543 2-Methylpropyl 2,5-Dimethylphenyl
    1544 3-Methylbutyl 2,5-Dimethylphenyl
    1545 2-Methylpropyl 2,4-Dimethylphenyl
    1546 3-Methylbutyl 2,4-Dimethylphenyl
    1547 Cyclopentyl 2,4-Dimethylphenyl
    1548 2-Methylpropyl 3-Methoxyphenyl
    1549 3-Methylbutyl 3-Methoxyphenyl
    1550 2-Methylpropyl 4-Methoxyphenyl
    1551 3-Methylbutyl 4-Methoxyphenyl
    1552 Cyclopentyl 4-Methoxyphenyl
    1553 2-Methylpropyl 2-Methoxyphenyl
    1554 3-Methylbutyl 2-Methoxyphenyl
    1555 2-Methylpropyl 3-Fluoro-4-methylphenyl
    1556 Cyclopentyl 3-Fluoro-4-methylphenyl
    1557 2-Methylpropyl 3-Fluoro-2-methylphenyl
    1558 3-Methylbutyl 3-Fluoro-2-methylphenyl
    1559 2-Methylpropyl 5-Fluoro-2-methylphenyl
    1560 3-Methylbutyl 5-Fluoro-2-methylphenyl
    1561 2-Methylpropyl 2-Fluoro-3-methylphenyl
    1562 2-Methylpropyl 3-Chlorophenyl
    1563 3-Methylbutyl 3-Chlorophenyl
    1564 Cyclopentyl 3-Chlorophenyl
    1565 2-Methylpropyl 4-Chlorophenyl
    1566 Cyclopentyl 4-Chlorophenyl
    1577 3-Methylbutyl 2-Chlorophenyl
    1578 Cyclopentyl 2-Chlorophenyl
    1579 2-Methylpropyl 3,4-Difluorophenyl
    1580 3-Methylbutyl 3,4-Difluorophenyl
    1581 2-Methylpropyl 2,3-Difluorophenyl
    1582 3-Methylbutyl 2,3-Difluorophenyl
    1583 Cyclopentyl 2,3-Difluorophenyl
    1584 2-Methylpropyl 2,5-Difluorophenyl
    1585 3-Methylbutyl 2,5-Difluorophenyl
    1586 2-Methylpropyl 2,4-Difluorophenyl
    1587 3-Methylbutyl 2,4-Difluorophenyl
    1588 Cyclopentyl 2,4-Difluorophenyl
    1589 2-Methylpropyl 1,3-Benzodioxol-5-yl
    1590 3-Methylbutyl 1,3-Benzodioxol-5-yl
    1591 Cyclopentyl 1,3-Benzodioxol-5-yl
    1592 2-Methylpropyl 4-Methylthio
    phenyl
    1593 Cyclopentyl 4-Methylthio
    phenyl
    1594 Cyclopentyl 3-Fluoro-4-methoxy
    1595 Cyclopentyl 4-Butylphenyl
    1596 Cyclopentyl 4-Ethylthiophenyl
    1597 2-Methylpropyl 3-Chloro-4-methoxyphenyl
    1598 3-Methylbutyl 3-Chloro-4-methoxyphenyl
    1599 Cyclopentyl 3-Chloro-4-methoxyphenyl
    1600 2-Methylpropyl 2-Trifluoromethylphenyl
    1601 3-Methylbutyl 2-Trifluoromethylphenyl
    1602 2-Methylpropyl 3,4-Dichlorophenyl
    1603 3-Methylbutyl 3,4-Dichlorophenyl
    1604 2-Methylpropyl 2,3-Dichlorophenyl
    1605 2-Methylpropyl 2,5-Dichlorophenyl
    1606 3-Methylbutyl 2,5-Dichlorophenyl
    1607 2-Methylpropyl 2,4-Dichlorophenyl
    1608 Cyclopentyl 2,4-Dichlorophenyl
    1609 2-Methylpropyl 3-Bromophenyl
    1610 3-Methylbutyl 3-Bromophenyl
    1611 Cyclopentyl 3-Bromophenyl
    1612 2-Methylpropyl 4-Bromophenyl
    1613 Cyclopentyl 4-Bromophenyl
    1614 2-Methylpropyl 2-Bromophenyl
    1615 3-Methylbutyl 2-Bromophenyl
    1626 2-Methylpropyl 3-Bromo-4-methylphenyl
    1627 3-Methylbutyl 3-Bromo-4-methylphenyl
    1628 Cyclopentyl 3-Bromo-4-methylphenyl
    1629 2-Methylpropyl 3-Bromo-4-fluorophenyl
    1630 3-Methylbutyl 3-Bromo-4-fluorophenyl
    1631 2-Methylpropyl 3-Iodophenyl
    1632 3-Methylbutyl 3-Iodophenyl
    1633 2-Methylpropyl 4-Iodophenyl
    1660 2-Methylpropyl 3-Iodo-4-methylphenyl
    1661 2-Methylpropyl 4-Iodobenzyl
    1662 2-Methylpropyl 2-Thienyl
    1663 3-Methylbutyl 2-Thienyl
    1664 2-Methylpropyl Benzyl
    1665 3-Methylbutyl Benzyl
    1666 Cyclopentyl Benzyl
    1667 2-Methylpropyl 5-Methyl-2-thienyl
    1668 3-Methylbutyl 5-Methyl-2-thienyl
    1669 Cyclopentyl 5-Methyl-2-thienyl
    1670 Cyclopentyl 3-Methylbenzyl
    1671 2-Methylpropyl 3-Fluorobenzyl
    1672 3-Methylbutyl 3-Fluorobenzyl
    1673 Cyclopentyl 3-Fluorobenzyl
    1679 3-Methylbutyl 2-Methoxybenzyl
    1680 Cyclopentyl 1-(4-Fluorophenyl)
    ethyl
    1681 Cyclopentyl 2-Chlorobenzyl
    1684 Cyclopentyl 2-(2-Chlorophenyl)
    ethenyl
    1703 2-Methylpropyl 2,4,6-Trifluorophenyl
    1704 2-Methylpropyl 2,3,6-Trifluorophenyl
    1705 2-Methylpropyl 2-Chloro-6-fluorophenyl
    1714 2-Methylpropyl 3-Chloro-4-methylphenyl
    • EXAMPLE 21
  • [0225]
    Figure US20030092912A1-20030515-C00046
  • For each compound, the definitions of R[0226] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    923 Propyl Phenyl
    924 Propyl 3-Methylphenyl
    925 Propyl 4-Methylphenyl
    926 Propyl 3-Fluorophenyl
    927 Methyl 2-Fluorophenyl
    928 Allyl 2-Fluorophenyl
    929 Propyl 2-Fluorophenyl
    1000 Methyl 2,3-Difluorophenyl
    1001 Methyl 2,5-Difluorophenyl
    1129 Ethyl 5-Chloro-2-methoxyphenyl
    2307 3-Methylbutyl 2,3,6-Trifluorophenyl
    • EXAMPLE 22
  • [0227]
    Figure US20030092912A1-20030515-C00047
  • For each compound, the definitions of R[0228] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    955 Methyl Phenyl
    956 Propyl Phenyl
    957 Methyl 3-Methylphenyl
    958 Propyl 3-Methylphenyl
    959 Methyl 3-Fluorophenyl
    960 Propyl 3-Fluorophenyl
    961 Methyl 2-Fluorophenyl
    962 Allyl 2-Fluorophenyl
    963 Propyl 2-Fluorophenyl
    964 Methyl 5-Fluoro-2-methylphenyl
    965 Methyl 3-Chlorophenyl
    966 Propyl 3-Chlorophenyl
    989 Propyl 3-Chloro-4-fluorophenyl
    994 Methyl 2-Thienyl
    995 Propyl 2-Thienyl
    996 Methyl 3-Thienyl
    997 Methyl 3-Methyl-2-thienyl
    998 Methyl 5-Methyl-2-thienyl
    999 Propyl 5-Methyl-2-thienyl
    1100 Propyl 5-Chloro-2-methoxyphenyl
    1101 Methyl 3-Bromophenyl
    1102 Propyl 3-Bromophenyl
    • EXAMPLE 23
  • [0229]
    Figure US20030092912A1-20030515-C00048
  • For each compound, the definitions of R[0230] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    967 Propyl Phenyl
    968 Propyl 3-Methylphenyl
    969 Propyl 4-Methylphenyl
    970 Propyl 3-Fluorophenyl
    971 Propyl 2-Fluorophenyl
    972 Propyl 5-Fluoro-2-methylphenyl
    973 Ethyl 3-Chlorophenyl
    974 Allyl 3-Chlorophenyl
    975 Propyl 3-Chlorophenyl
    990 Propyl 1,3-Benzodioxol-5-yl
    991 Allyl 3-Chloro-4-fluorophenyl
    992 Propyl 3-Chloro-4-fluorophenyl
    1103 Propyl 5-Chloro-2-methoxyphenyl
    1104 Propyl 3-Trifluoromethylphenyl
    1105 Propyl 3,4-Dichlorophenyl
    1106 Allyl 2,5-Dichlorophenyl
    1107 Allyl 3-Bromophenyl
    1108 Propyl 3-Bromophenyl
    1187 Propyl 3-Bromo-4-methylphenyl
    1188 Methyl 3-Bromo-4-fluorophenyl
    1189 Allyl 3-Bromo-4-fluorophenyl
    1190 Propyl 3-Bromo-4-fluorophenyl
    1191 Methyl 3-Iodophenyl
    1192 Allyl 3-Iodophenyl
    1193 Propyl 3-Iodophenyl
    1207 Propyl 3-Bromo-4-fluorophenyl
    1208 Methyl 3-Bromo-4-fluorophenyl
    1209 Allyl 3-Bromo-4-fluorophenyl
    1210 Propyl 3-Bromo-4-fluorophenyl
    1211 Methyl 3-Iodophenyl
    1212 Ethyl 3-Iodophenyl
    1213 Allyl 3-Iodophenyl
    1214 Propyl 3-Iodophenyl
    1215 Propyl 3-Iodo-4-methylphenyl
    1216 Methyl 2-Thienyl
    1217 Propyl 2-Thienyl
    1218 Allyl 5-Methyl-2-thienyl
    1219 Propyl 5-Methyl-2-thienyl
    • EXAMPLE 24
  • [0231]
    Figure US20030092912A1-20030515-C00049
  • For each compound, the definitions of R[0232] 2 and R3 are specified in the following table.
    Compound No R2 R3
    1220 2-Methylpropyl Phenyl
    1221 2-Methylpropyl 3-Methylpropyl
    1222 2-Methylpropyl 4-Methylpropyl
    1223 2-Methylpropyl 2-Fluorophenyl
    1224 2-Methylpropyl 4-Ethylphenyl
    1225 2-Methylpropyl 3,4-Dimethylphenyl
    1227 2-Methylpropyl 2,5-Difluorophenyl
    1228 2-Methylpropyl 2,4-Difluorophenyl
    1229 2-Methylpropyl 1,3-Benzodioxol-5-yl
    1230 2-Methylpropyl 4-Bromophenyl
    1251 2-Methylpropyl 3-Bromo-4-methylphenyl
    1272 2-Methylpropyl 3-Chloro-4-methylphenyl
    1273 2-Methylpropyl 2,4,5-Trifluorophenyl
    • EXAMPLE 25
  • [0233]
    Figure US20030092912A1-20030515-C00050
  • For each compound, the definitions of R[0234] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    1226 Propyl 2-Fluorophenyl
    1231 Allyl 5-Chloro-2-methoxyphenyl
    1232 Propyl 5-Chloro-2-methoxyphenyl
    1233 Methyl 2,5-Dichlorophenyl
    1234 Allyl 2,5-Dichlorophenyl
    1235 Propyl 2,5-Dichlorophenyl
    1236 Methyl 3-Bromophenyl
    1237 Allyl 3-Bromophenyl
    1238 Propyl 3-Bromophenyl
    1252 Propyl 3-Iodophenyl
    1748 2-Methylpropyl 2,3,6-Trifluorophenyl
    1749 3-Methylbutyl 2,3,6-Trifluorophenyl
    1750 2-Methylpropyl 3-Chloro-4-phenyl
    1751 3-Methylbutyl 3-Chloro-4-phenyl
    1752 2-Methylpropyl 2,4,5-Trifluorophenyl
    1753 3-Methylbutyl 2,4,5-Trifluorophenyl
    1754 2-Methylpropyl 2,6-Difluorophenyl
    1755 3-Methylbutyl 2,6-Difluorophenyl
    1881 Butyl Phenyl
    1882 2-Methylpropyl Phenyl
    1883 Pentyl Phenyl
    1884 3-Methylbutyl Phenyl
    1885 Butyl 3-Methylphenyl
    1886 2-Methylpropyl 3-Methylphenyl
    1887 Pentyl 3-Methylphenyl
    1888 3-Methylbutyl 3-Methylphenyl
    1889 2-Methylpropyl 4-Methylphenyl
    1890 3-Methylbutyl 4-Methylphenyl
    1891 Butyl 3-Fluorophenyl
    1892 2-Methylpropyl 3-Fluorophenyl
    1893 Pentyl 3-Fluorophenyl
    1894 3-Methylbutyl 3-Fluorophenyl
    1895 2-Methylpropyl 4-Fluorophenyl
    1896 3-Methylbutyl 4-Fluorophenyl
    1897 Butyl 2-Fluorophenyl
    1898 2-Methylpropyl 2-Fluorophenyl
    1899 Pentyl 2-Fluorophenyl
    1900 3-Methylbutyl 2-Fluorophenyl
    1901 2-Methylpropyl 3,4-Dimethylphenyl
    1902 Butyl 2-Chlorophenyl
    1903 2-Methylpropyl 2-Chlorophenyl
    1904 Pentyl 2-Chlorophenyl
    1905 3-Methylbutyl 2-Chlorophenyl
    1906 Butyl 3,4-Difluorophenyl
    1907 2-Methylpropyl 3,4-Difluorophenyl
    1908 Pentyl 3,4-Difluorophenyl
    1909 3-Methylbutyl 3,4-Difluorophenyl
    1910 Butyl 2,3-Difluorophenyl
    1911 2-Methylpropyl 2,3-Difluorophenyl
    1912 Pentyl 2,3-Difluorophenyl
    1913 3-Methylbutyl 2,3-Difluorophenyl
    1914 Butyl 2,5-Difluorophenyl
    1915 2-Methylpropyl 2,5-Difluorophenyl
    1916 Pentyl 2,5-Difluorophenyl
    1917 3-Methylbutyl 2,5-Difluorophenyl
    1918 2-Methylpropyl 2,4-Difluorophenyl
    1919 3-Methylbutyl 2,4-Difluorophenyl
    1920 2-Methylpropyl 1,3-Benzodioxol-5-yl
    1921 3-Methylbutyl 1,3-Benzodioxol-5-yl
    1927 3-Methylbutyl 3-Iodo-4-methylphenyl
    1963 2-Methylpropyl 2-(2-Chlorophenyl)
    ethenyl
    1964 Butyl 2-Thienyl
    1965 Pentyl 2-Thienyl
    1966 3-Methylbutyl 2-Thienyl
    1967 Pentyl 3-Thienyl
    1968 3-Methylbutyl 3-Thienyl
    1969 3-Methylbutyl Benzyl
    1970 Butyl 5-Methyl-2-thienyl
    1971 2-Methylpropyl 5-Methyl-2-thienyl
    1972 Pentyl 5-Methyl-2-thienyl
    1973 3-Methylbutyl 5-Methyl-2-thienyl
    1974 3-Methylbutyl 3-Fluorobenzyl
    1975 3-Methylbutyl 3-Methoxybenzyl
    • EXAMPLE 26
  • [0235]
    Figure US20030092912A1-20030515-C00051
  • For each compound, the definitions of R[0236] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    1250 Propyl 3-Iodophenyl
    1616 2-Methylpropyl 3-Chloro-4-fluorophenyl
    1617 2-Methylpropyl 3-Bromophenyl
    1618 3-Methylbutyl 3-Bromophenyl
    1634 2-Methylpropyl 3-Bromo-4-methylphenyl
    1635 2-Methylpropyl 3-Bromo-4-fluorophenyl
    1636 3-Methylbutyl 3-Bromo-4-fluorophenyl
    1637 2-Methylpropyl 3-Iodophenyl
    1638 3-Methylbutyl 3-Bromo-4-fluorophenyl
    1639 2-Methylpropyl Phenyl
    1640 3-Methylbutyl Phenyl
    1641 2-Methylpropyl 3-Methylphenyl
    1642 3-Methylbutyl 3-Methylphenyl
    1643 2-Methylpropyl 4-Methylphenyl
    1644 2-Methylpropyl 3-Fluorophenyl
    1645 3-Methylbutyl 3-Fluorophenyl
    1646 2-Methylpropyl 4-Fluorophenyl
    1647 2-Methylpropyl 2-Fluorophenyl
    1648 3-Methylbutyl 2-Fluorophenyl
    1649 2-Methylpropyl 3,4-Dimethylphenyl
    1650 2-Methylpropyl 3-Fluoro-4-methylphenyl
    1651 2-Methylpropyl 3-Chlorophenyl
    1652 3-Methylbutyl 3-Chlorophenyl
    1674 2-Methylpropyl 3-Iodo-4-methylphenyl
    1675 2-Methylpropyl 5-Methyl-2-thienyl
    1676 3-Methylbutyl 5-Methyl-2-thienyl
    1677 3-Methylbutyl 3-Fluorobenzyl
    1715 2-Methylpropyl 3-Chloro-4-methylphenyl
    1716 2-Methylpropyl 2,4,5-Trifluorophenyl
    1874 Butyl 3,4-Dimethylphenyl
    1875 2-Methylpropyl 3,4-Dimethylphenyl
    1876 3-Methylbutyl 3,4-Dimethylphenyl
    1877 3-Methylbutyl 2,3-Dimethylphenyl
    1878 2-Methylpropyl 2,5-Dimethylphenyl
    1879 3-Methylbutyl 2,5-Dimethylphenyl
    1880 2-Methylpropyl 1,3-Benzodioxol-5-yl
    1976 3-Methylbutyl 3-Methoxybenzyl
    2262 Benzyl 3-Chlorophenyl
    2282 Benzyl 5-Chloro-2-methoxyphenyl
    2293 Benzyl 3-Bromophenyl
    2299 Benzyl 3-Iodophenyl
    • EXAMPLE 27
  • [0237]
    Figure US20030092912A1-20030515-C00052
  • For each compound, the definitions of R[0238] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    1276 2-Methylpropyl Phenyl
    1277 Pentyl Phenyl
    1278 3-Methylbutyl Phenyl
    1279 3-Methylbutyl 3-Methylphenyl
    1280 2-Methylpropyl 4-Methylphenyl
    1281 2-Methylpropyl 3-Fluorophenyl
    1282 3-Methylbutyl 3-Fluorophenyl
    1283 2-Methylpropyl 4-Fluorophenyl
    1284 Butyl 2-Fluorophenyl
    1285 2-Methylpropyl 2-Fluorophenyl
    1286 Pentyl 2-Fluorophenyl
    1287 3-Methylbutyl 2-Fluorophenyl
    1288 2-Methylpropyl 3-Methoxyphenyl
    1289 3-Methylbutyl 3-Methoxyphenyl
    1290 3-Methylbutyl 4-Methoxyphenyl
    1291 2-Methylpropyl 3-Fluoro-4-methylphenyl
    1292 3-Methylbutyl 2-Fluoro-3-methylphenyl
    1293 Butyl 3-Chlorophenyl
    1294 2-Methylpropyl 3-Chlorophenyl
    1295 Pentyl 3-Chlorophenyl
    1296 3-Methylbutyl 3-Chlorophenyl
    1297 2-Methylpropyl 3,4-Difluorophenyl
    1298 2-Methylpropyl 2,3-Difluorophenyl
    1299 3-Methylbutyl 2,3-Difluorophenyl
    1300 3-Methylbutyl 2,5-Difluorophenyl
    1301 2-Methylpropyl 1,3-Benzodioxol-5-yl
    1302 2-Methylpropyl 1,3-Benzodioxol-5-yl
    1386 3-Methylbutyl 5-Chloro-2-methoxyphenyl
    1387 3-Methylbutyl 3-Bromophenyl
    1388 2-Methylpropyl 4-Bromophenyl
    1389 2-Methylpropyl 5-Methyl-2-thienyl
    1390 3-Methylbutyl 5-Methyl-2-thienyl
    1685 3-Methylbutyl 2,3,6-Trifluorophenyl
    • EXAMPLE 28
  • [0239]
    Figure US20030092912A1-20030515-C00053
  • For each compound, the definitions of R[0240] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    1303 Butyl Phenyl
    1304 2-Methylpropyl Phenyl
    1305 Pentyl Phenyl
    1306 3-Methylbutyl Phenyl
    1307 Butyl 3-Methylphenyl
    1308 2-Methylpropyl 3-Methylphenyl
    1309 Pentyl 3-Methylphenyl
    1310 3-Methylbutyl 3-Methylphenyl
    1311 Butyl 4-Methylphenyl
    1312 2-Methylpropyl 4-Methylphenyl
    1313 3-Methylbutyl 4-Methylphenyl
    1314 3-Methylbutyl 2-Methylphenyl
    1315 Butyl 3-Fluorophenyl
    1316 2-Methylpropyl 3-Fluorophenyl
    1317 Pentyl 3-Fluorophenyl
    1318 3-Methylbutyl 3-Fluorophenyl
    1319 2-Methylpropyl 4-Fluorophenyl
    1320 3-Methylbutyl 4-Fluorophenyl
    1321 Butyl 2-Fluorophenyl
    1322 2-Methylpropyl 2-Fluorophenyl
    1323 Pentyl 2-Fluorophenyl
    1324 3-Methylbutyl 2-Fluorophenyl
    1325 2-Methylpropyl 4-Ethylphenyl
    1326 Butyl 3,4-Dimethylphenyl
    1327 2-Methylpropyl 3,4-Dimethylphenyl
    1328 3-Methylbutyl 3,4-Dimethylphenyl
    1329 2-Methylpropyl 2,4-Dimethylphenyl
    1330 Butyl 3-Methoxyphenyl
    1331 2-Methylpropyl 3-Methoxyphenyl
    1332 Pentyl 3-Methoxyphenyl
    1333 3-Methylbutyl 3-Methoxyphenyl
    1334 Butyl 4-Methoxyphenyl
    1335 2-Methylpropyl 4-Methoxyphenyl
    1336 3-Methylbutyl 4-Methoxyphenyl
    1337 Pentyl 2-Methoxyphenyl
    1338 3-Methylbutyl 2-Methoxyphenyl
    1339 Butyl 3-Fluoro-4-methylphenyl
    1340 Pentyl 3-Fluoro-4-methylphenyl
    1341 3-Methylbutyl 3-Fluoro-4-methylphenyl
    1342 3-Methylbutyl 3-Fluoro-2-methylphenyl
    1343 Butyl 2-Fluoro-3-methylphenyl
    1344 2-Methylpropyl 2-Fluoro-3-methylphenyl
    1345 Pentyl 2-Fluoro-3-methylphenyl
    1346 3-Methylbutyl 2-Fluoro-3-methylphenyl
    1347 Butyl 3-Chlorophenyl
    1348 2-Methylpropyl 3-Chlorophenyl
    1349 Pentyl 3-Chlorophenyl
    1350 3-Methylbutyl 3-Chlorophenyl
    1351 2-Methylpropyl 4-Chlorophenyl
    1352 Pentyl 4-Chlorophenyl
    1353 3-Methylbutyl 4-Chlorophenyl
    1354 Butyl 2-Chlorophenyl
    1355 2-Methylpropyl 2-Chlorophenyl
    1356 Pentyl 2-Chlorophenyl
    1357 3-Methylbutyl 2-Chlorophenyl
    1358 Butyl 3,4-Difluorophenyl
    1359 2-Methylpropyl 3,4-Difluorophenyl
    1360 Pentyl 3,4-Difluorophenyl
    1361 3-Methylbutyl 3,4-Difluorophenyl
    1362 Butyl 2,3-Difluorophenyl
    1363 2-Methylpropyl 2,3-Difluorophenyl
    1364 Pentyl 2,3-Difluorophenyl
    1365 3-Methylbutyl 2,3-Difluorophenyl
    1366 Butyl 2,5-Difluorophenyl
    1367 2-Methylpropyl 2,5-Difluorophenyl
    1368 Pentyl 2,5-Difluorophenyl
    1369 3-Methylbutyl 2,5-Difluorophenyl
    1370 Butyl 2,4-Difluorophenyl
    1371 2-Methylpropyl 2,4-Difluorophenyl
    1372 Pentyl 2,4-Difluorophenyl
    1373 3-Methylbutyl 2,4-Difluorophenyl
    1374 2-Methylpropyl 3-Ethoxyphenyl
    1375 3-Methylbutyl 3-Ethoxyphenyl
    1376 Butyl 1,3-Benzodioxol-5-yl
    1377 2-Methylpropyl 1,3-Benzodioxol-5-yl
    1378 Pentyl 1,3-Benzodioxol-5-yl
    1379 3-Methylbutyl 1,3-Benzodioxol-5-yl
    1380 Butyl 4-Methylthio
    phenyl
    1381 2-Methylpropyl 4-Methylthio
    phenyl
    1382 3-Methylbutyl 3-Fluoro-4-methoxyphenyl
    1383 Butyl 3-Chloro-4-fluorophenyl
    1384 2-Methylpropyl 3-Chloro-4-fluorophenyl
    1385 3-Methylbutyl 3-Chloro-4-fluorophenyl
    1391 3-Methylbutyl 3-Chloro-4-methoxyphenyl
    1392 Pentyl 5-Chloro-2-methoxyphenyl
    1393 3-Methylbutyl 5-Chloro-2-methoxyphenyl
    1394 2-Methylpropyl 3,4-Dichlorophenyl
    1395 3-Methylbutyl 3,4-Dichlorophenyl
    1396 Butyl 2,5-Dichlorophenyl
    1397 2-Methylpropyl 2,5-Dichlorophenyl
    1398 Pentyl 2,5-Dichlorophenyl
    1399 3-Methylbutyl 2,5-Dichlorophenyl
    1400 2-Methylpropyl 2,4-Dichlorophenyl
    1401 3-Methylbutyl 2,4-Dichlorophenyl
    1402 Butyl 3-Bromophenyl
    1403 2-Methylpropyl 3-Bromophenyl
    1404 Pentyl 3-Bromophenyl
    1405 3-Methylbutyl 3-Bromophenyl
    1406 2-Methylpropyl 4-Bromophenyl
    1407 3-Methylbutyl 4-Bromophenyl
    1408 3-Methylbutyl 2-Bromophenyl
    1409 3-Methylbutyl 3-Bromo-4-methylphenyl
    1410 Butyl 3-Bromo-4-fluorophenyl
    1411 2-Methylpropyl 3-Bromo-4-fluorophenyl
    1412 Pentyl 3-Bromo-4-fluorophenyl
    1413 3-Methylbutyl 3-Bromo-4-fluorophenyl
    1414 Butyl 3-Iodophenyl
    1415 2-Methylpropyl 3-Iodophenyl
    1416 Pentyl 3-Iodophenyl
    1417 3-Methylbutyl 3-Iodophenyl
    1418 Butyl 5-Methyl-2-thienyl
    1419 2-Methylpropyl 5-Methyl-2-thienyl
    1420 Pentyl 5-Methyl-2-thienyl
    1421 3-Methylbutyl 5-Methyl-2-thienyl
    1422 3-Methylbutyl 3-Fluorobenzyl
    1423 3-Methylbutyl 3-Methoxybenzyl
    1424 3-Methylbutyl 2-Methoxybenzyl
    1686 2-Methylpropyl 2,4,6-Trifluorophenyl
    1687 Butyl 2,3,6-Trifluorophenyl
    1688 2-Methylpropyl 2,3,6-Trifluorophenyl
    1689 Pentyl 2,3,6-Trifluorophenyl
    1690 3-Methylbutyl 2,3,6-Trifluorophenyl
    1691 3-Methylbutyl 2,5-Dimethyl-3-furyl
    1692 Butyl 4,5-Dimethyl-2-furyl
    1693 2-Methylpropyl 4,5-Dimethyl-2-furyl
    1694 Pentyl 4,5-Dimethyl-2-furyl
    1695 3-Methylbutyl 4,5-Dimethyl-2-furyl
    1696 2-Methylpropyl 2-(3-Thienyl)ethenyl
    1697 Pentyl 3-Chloro-2-thienyl
    1698 3-Methylbutyl 3-Chloro-2-thienyl
    1699 2-Methylpropyl 5-Methylthio-2-thienyl
    1700 3-Methylbutyl 5-Methylthio-2-thienyl
    1721 Butyl 3-Chloro-4-methylphenyl
    1722 2-Methylpropyl 3-Chloro-4-methylphenyl
    1723 3-Methylbutyl 3-Chloro-4-methylphenyl
    1724 2-Methylpropyl 2,4,5-Trichlorophenyl
    • EXAMPLE 29
  • [0241]
    Figure US20030092912A1-20030515-C00054
  • For each compound, the definitions of R[0242] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    1468 Methyl Phenyl
    1469 Allyl Phenyl
    1470 Propyl Phenyl
    1471 Methyl 3-Methylphenyl
    1472 Allyl 3-Methylphenyl
    1473 Propyl 3-Methylphenyl
    1474 Propyl 4-Methylphenyl
    1475 Methyl 3-Fluorophenyl
    1476 Allyl 3-Fluorophenyl
    1477 Propyl 3-Fluorophenyl
    1478 Propyl 4-Fluorophenyl
    1479 Methyl 2-Fluorophenyl
    1480 Allyl 2-Fluorophenyl
    1481 Propyl 2-Fluorophenyl
    1482 Propyl 3,4-Dimethylphenyl
    1483 Propyl 3-Methoxyphenyl
    1484 Propyl 3-Fluoro-4-methylphenyl
    1485 Allyl 3-Chlorophenyl
    1486 Propyl 3-Chlorophenyl
    1487 Propyl 2-Chlorophenyl
    1488 Propyl 3,4-Difluorophenyl
    1489 Methyl 2,3-Difluorophenyl
    1490 Propyl 2,3-Difluorophenyl
    1491 Methyl 2,5-Difluorophenyl
    1492 Allyl 2,5-Difluorophenyl
    1493 Propyl 2,5-Difluorophenyl
    1494 Propyl 2,4-Difluorophenyl
    1495 Propyl 1,3-Benzodioxol-5-yl
    1496 Propyl 3-Chloro-4-fluorophenyl
    1497 Methyl 5-Chloro-2-methoxyphenyl
    1498 Methyl 3-Trifluoromethylphenyl
    1499 Propyl 3-Trifluoromethylphenyl
    1500 Methyl 2,5-Dichlorophenyl
    1501 Propyl 2,5-Dichlorophenyl
    1502 Methyl 3-Bromophenyl
    1503 Allyl 3-Bromophenyl
    1504 Propyl 3-Bromophenyl
    1505 Propyl 3-Bromo-4-methylphenyl
    1506 Methyl 3-Bromo-4-fluorophenyl
    1507 Allyl 3-Bromo-4-fluorophenyl
    1508 Propyl 3-Bromo-4-fluorophenyl
    1509 Methyl 3-Iodophenyl
    1510 Ethyl 3-Iodophenyl
    1511 Allyl 3-Iodophenyl
    1512 Propyl 3-Iodophenyl
    1513 Propyl 5-Methyl-2-thienyl
    1514 Propyl 3-Fluorobenzyl
    1515 Methyl 5-Ethoxy-2-thienyl
    • EXAMPLE 30
  • [0243]
    Figure US20030092912A1-20030515-C00055
  • For each compound, the definitions of R[0244] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    1717 Propyl 3-Chloro-4-methylphenyl
    1718 Propyl 2,4,5-Trifluorophenyl
    2237 Benzyl Phenyl
    2240 Benzyl 3-Fluorophenyl
    2241 Benzyl 4-Fluorophenyl
    2244 Benzyl 2-Fluorophenyl
    2246 Benzyl 3,4-Dimethylphenyl
    2247 Benzyl 3,5-Dimethylphenyl
    2248 Benzyl 2,3-Dimethylphenyl
    2249 Benzyl 2,5-Dimethylphenyl
    2250 Benzyl 2,4-Dimethylphenyl
    2252 Benzyl 3-Methoxyphenyl
    2255 Benzyl 2-Methoxyphenyl
    2256 Benzyl 3-Fluoro-4-methylphenyl
    2259 Benzyl 5-Fluoro-2-methylphenyl
    2263 Benzyl 3-Chlorophenyl
    2264 Benzyl 4-Chlorophenyl
    2265 Benzyl 2-Chlorophenyl
    2267 Benzyl 3,4-Difluorophenyl
    2270 Benzyl 2,3-Difluorophenyl
    2273 Benzyl 2,5-Difluorophenyl
    2274 Benzyl 2,4-Difluorophenyl
    2275 Benzyl 3-Ethoxyphenyl
    2276 Benzyl 1,3-Benzodioxol-5-yl
    2277 Benzyl 4-Chloro-3-methylphenyl
    2278 Benzyl 3-Chloro-4-fluorophenyl
    2279 Benzyl 3,4,5-Trifluorophenyl
    2280 Benzyl 2,5-Dimethoxyphenyl
    2283 Benzyl 5-Chloro-2-methoxyphenyl
    2284 Benzyl 4-Chloro-2-methoxyphenyl
    2285 Benzyl 3-Trifluoromethylphenyl
    2286 Benzyl 2-Trifluoromethylphenyl
    2287 Benzyl 3,4-Dichlorophenyl
    2288 Benzyl 2,3-Dichlorophenyl
    2290 Benzyl 2,5-Dichlorophenyl
    2291 Benzyl 2,4-Dichlorophenyl
    2294 Benzyl 3-Bromophenyl
    2296 Benzyl 2-Bromophenyl
    2297 Benzyl 3-Bromo-4-fluorophenyl
    2300 Benzyl 3-Iodophenyl
    2301 Benzyl 2-Methoxyphenyl
    2303 Benzyl 2,5-Dimethylpyrrol-3-yl
    2308 Benzyl 2,3,6-Trifluorphenyl
    2309 3-Methylbutyl 2-Chloro-6-fluorophenyl
    2325 3-Methylbutyl 3-(Methylamino
    methyl)phenyl
    2326 3-Methylbutyl 3-(Ethylamino
    methyl)phenyl
    2327 3-Methylbutyl 3-(allylamino
    methyl)phenyl
    2328 3-Methylbutyl 3-(propylamino
    methyl)phenyl
    2329 3-Methylbutyl 3-[(Cyclopropyl
    methyl)amino
    methyl]phenyl
    2330 3-Methylbutyl 3-(butylamino
    methyl)phenyl
    2331 3-Methylbutyl 3-[(2-Methylpropyl)
    amino
    methyl]phenyl
    2332 3-Methylbutyl 3-(Pentylamino
    methyl)phenyl
    2333 3-Methylbutyl 3-[(3-Methylbutyl)
    amino
    methyl]phenyl
    2334 3-Methylbutyl 3-[(2-Methylbutyl)
    amino
    methyl]phenyl
    2335 3-Methylbutyl 3-(Hexylamino
    methyl)phenyl
    2336 3-Methylbutyl 3-(Cyclopropyl
    amino
    methyl)phenyl
    2337 3-Methylbutyl 3-[(1-Methylethyl)
    aminomethyl]
    phenyl
    2338 3-Methylbutyl 3-(Cyclobutyl
    amino
    methyl)phenyl
    2339 3-Methylbutyl 3-[(1-Methylpropyl)
    aminomethyl]
    phenyl
    2340 3-Methylbutyl 3-[(1,1-Dimethylethyl)
    aminomethyl]
    phenyl
    2341 3-Methylbutyl 3-(Cyclopentyl
    amino
    methyl)phenyl
    2342 3-Methylbutyl 3-[(1-Methylbutyl)
    aminomethyl]
    phenyl
    2343 3-Methylbutyl 3-[(1,2-Dimethylpropyl)
    aminomethyl]
    phenyl
    2344 3-Methylbutyl 3-[(1-Ethylpropyl)
    aminomethyl]
    phenyl
    2345 3-Methylbutyl 3-[(1,1-Dimethylpropyl)
    aminomethyl]
    phenyl
    2346 3-Methylbutyl 3-(Cyclohexyl
    amino
    methyl)phenyl
    2352 3-Methylbutyl 3-(Piperidyl
    methyl)phenyl
    2353 3-Methylbutyl 3-(Morpholin-4-yl
    methyl)phenyl
    2354 3-Methylbutyl 3-(Azaperhydro
    epinylmethyl)
    phenyl
    2355 3-Methylbutyl 3-(Azaperhydro
    ocinylmethyl)
    phenyl
    2356 3-Methylbutyl 3-(2-1,2,3,4-Teterahydro
    isoquinolinyl
    methyl)
    phenyl
    2357 3-Methylbutyl 3-(Methylpropyl
    aminomethyl)
    phenyl
    2358 3-Methylbutyl 3-(i-propylethyl
    aminomethyl)
    phenyl
    2359 3-Methylbutyl 3-(Diethyl
    aminomethyl)
    phenyl
    2360 3-Methylbutyl 3-(Butylethyl
    aminomethyl)
    phenyl
    2361 3-Methylbutyl 3-[(Cyclopropyl
    methyl)propyl
    aminomethyl]
    phenyl
    2362 3-Methylbutyl 3-(Hexylmethyl
    aminomethyl)
    phenyl
    2363 3-Methylbutyl 3-(Dibutyl
    aminomethyl)
    phenyl
    2370 3-Methylbutyl 3-[(1-methylethyl)
    methyl
    aminomethyl]
    phenyl
    2371 3-Methylbutyl 3-[(2-Methyl
    piperidyl)
    methyl]phenyl
    2372 3-Methylbutyl 3-[Ethyl(2-Methylprop-2-enyl)amino
    methyl]phenyl
    2373 3-Methylbutyl 3-[(2-Ethyl
    piperidyl)
    methyl]phenyl
    2374 3-Methylbutyl 3-(Cyclohexyl
    ethyl
    aminomethyl)
    phenyl
    2375 3-Methylbutyl 3-[bis(2-Methoxyethyl)
    aminomethyl]
    phenyl
    2376 3-Methylbutyl 3-[(3,3,5-Trimethylaza
    perhydroepinyl)methyl]phenyl
    2377 3-Methylbutyl 3-[(8-Aza-1,4-dioxaspiro[4.5]dec-8-
    yl)methyl]
    phenyl
    2378 3-Methylbutyl 3-(Dipentylamino
    methyl)phenyl
    2379 3-Methylbutyl 3-(Dihexylamino
    methyl)phenyl
    • EXAMPLE 31
  • [0245]
    Figure US20030092912A1-20030515-C00056
  • For each compound, the definitions of R[0246] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    2004 2-Methylpropyl 2-(4-Chlorophenyl)ethenyl
    • EXAMPLE 32
  • [0247]
    Figure US20030092912A1-20030515-C00057
  • For each compound, the definitions of R[0248] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    2020 Methyl 3-Thienyl
    2021 i-Propyl 3-Methyl-2-thienyl
    2022 Methyl 4-Methylbenzyl
    2023 Methyl 2-Methylbenzyl
    2024 Methyl 3-Fluorobenzyl
    • EXAMPLE 33
  • [0249]
    Figure US20030092912A1-20030515-C00058
  • For each compound, the definitions of R[0250] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    2025 3-Pyrrolinyl 2,5-Difluorophenyl
    2026 3-Pyrrolinyl 3-Fluorophenyl
    2027 Pyrrolidinyl 2,5-Difluorophenyl
    2028 Pyrrolidinyl 3-Fluorophenyl
    2029 1,2,5,6-Tetrahydro 2,5-Difluorophenyl
    pyridyl
    2030 1,2,5,6-Tetrahydro 3-Fluorophenyl
    pyridyl
    2031 Piperidyl 2,5-Difluorophenyl
    2032 Piperidyl 3-Fluorophenyl
    2039 Morpholinyl 2,5-Difluorophenyl
    2040 Morpholinyl 3-Fluorophenyl
    2043 4-Methyl 2,5-Difluorophenyl
    piperidyl
    2044 4-Methyl 3-Fluorophenyl
    piperidyl
    2046 Azaperhydro 2,5-Difluorophenyl
    epinyl
    2047 Azaperhydro 3-Fluorophenyl
    Epinyl
    2049 1,4-Thiazaper 2,5-Difluorophenyl
    hydroin-4-yl
    2050 1,4-Thiazaper 3-Fluorophenyl
    hydroin-4-yl
    2053 3,3-dimethyl 2,5-Difluorophenyl
    piperidyl
    2054 3,3-dimethyl 3-Fluorophenyl
    piperidyl
    2057 Azaperhydro 2,5-Difluorophenyl
    ocinyl
    2058 Azaperhydro 3-Fluorophenyl
    Ocinyl
    2061 2-(1,2,3,4-Tetrahydroiso 2,5-Difluorophenyl
    quinolyl)
    2062 2-(1,2,3,4-Tetrahydroiso 3-Fluorophenyl
    quinolyl)
    2065 Methylprop-2-enylamino 2,5-Difluorophenyl
    2066 Methylprop-2-enylamino 3-Fluorophenyl
    2068 Diethylamino 2,5-Difluorophenyl
    2069 Diethylamino 3-Fluorophenyl
    2072 Methylpropyl 2,5-Difluorophenyl
    amino
    2073 Methylpropyl 3-Fluorophenyl
    Amino
    2076 Butylmethyl 2,5-Difluorophenyl
    amino
    2077 Butylmethyl 3-Fluorophenyl
    Amino
    2080 i-Propylethyl 2,5-Difluorophenyl
    amino
    2081 i-Propylethyl 3-Fluorophenyl
    amino
    2084 Diallylamino 2,5-Difluorophenyl
    2085 Diallylamino 3-Fluorophenyl
    2088 Dipropylamino 2,5-Difluorophenyl
    2089 Dipropylamino 3-Fluorophenyl
    2092 Butylethyl 2,5-Difluorophenyl
    Amino
    2093 Butylethyl 3-Fluorophenyl
    Amino
    2096 (Cyclo 2,5-Difluorophenyl
    propylmethyl)
    propylamino
    2097 (Cyclo 3-Fluorophenyl
    propylmethyl)
    propylamino
    2100 Hexylmethyl 2,5-Difluorophenyl
    amino
    2101 Hexylmethyl 3-Fluorophenyl
    Amino
    2104 Dibutylamino 2,5-Difluorophenyl
    2105 Dibutylamino 3-Fluorophenyl
    2107 Methylamino 2,5-Difluorophenyl
    2108 Methylamino 3-Fluorophenyl
    2110 Ethylamino 2,5-Difluorophenyl
    2111 Ethylamino 3-Fluorophenyl
    2114 Allylamino 2,5-Difluorophenyl
    2115 Allylamino 3-Fluorophenyl
    2118 Propylamino 2,5-Difluorophenyl
    2119 Propylamino 3-Fluorophenyl
    2122 (Cyclopropyl 2,5-Difluorophenyl
    methyl)amino
    2123 (Cyclopropyl 3-Fluorophenyl
    methyl)amino
    2126 Butyl 2,5-Difluorophenyl
    2127 Butyl 3-Fluorophenyl
    2130 (2-Methylpropyl) 2,5-Difluorophenyl
    amino
    2131 (2-Methylpropyl) 3-Fluorophenyl
    amino
    2134 Pentylamino 2,5-Difluorophenyl
    2135 Pentylamino 3-Fluorophenyl
    2138 (3-Methylbutyl) 2,5-Difluorophenyl
    amino
    2139 (3-Methylbutyl) 3-Fluorophenyl
    amino
    2141 (2-Methylbutyl) 2,5-Difluorophenyl
    amino
    2142 (2-Methylbutyl) 3-Fluorophenyl
    amino
    2145 Hexylamino 2,5-Difluorophenyl
    2146 Hexylamino 3-Fluorophenyl
    2148 [2-(Dimethyl 2,5-Difluorophenyl
    amino)ethyl]
    amino
    2149 [2-(Dimethyl 3-Fluorophenyl
    amino)ethyl]
    amino
    2150 [3-(Dimethyl 2,5-Difluorophenyl
    amino)propyl]
    amino
    2151 [3-(Dimethyl 3-Fluorophenyl
    amino)propyl]
    amino
    2153 (2-Pyrrolidinyl 2,5-Difluorophenyl
    ethyl)amino
    2154 (2-Pyrrolidinyl 3-Fluorophenyl
    ethyl)amino
    2157 [2-(Diethyl 2,5-Difluorophenyl
    amino)ethyl]
    amino
    2158 [2-(Diethyl 3-Fluorophenyl
    amino)ethyl]
    amino
    2161 (2-Piperidyl 2,5-Difluorophenyl
    ethyl)amino
    2162 (2-Piperidyl 3-Fluorophenyl
    ethyl)amino
    2164 [2-(1-Methyl 2,5-Difluorophenyl
    pyrrolidin-2-yl)ethyl]amino
    2165 [2-(1-Methyl 3-Fluorophenyl
    pyrrolidin-2-yl)ethyl]amino
    2168 [2-(Diethyl 2,5-Difluorophenyl
    amino)propyl]
    amino
    2169 [2-(Diethyl 3-Fluorophenyl
    amino)propyl]
    amino
    2172 (2-Morpholin-4-yl 2,5-Difluorophenyl
    ethyl)amino
    2173 (2-Morpholin-4-yl 3-Fluorophenyl
    ethyl)amino
    2176 (3-Morpholin-4-yl 2,5-Difluorophenyl
    propyl)amino
    2177 (3-Morpholin-4-yl 3-Fluorophenyl
    propyl)amino
    2180 [3-(2-Methyl 2,5-Difluorophenyl
    piperidyl)
    propyl]amino
    2181 [3-(2-Methyl 3-Fluorophenyl
    piperidyl)
    propyl]amino
    2184 [3-(2-Oxo 2,5-Difluorophenyl
    pyrrolidinyl)
    propyl]amino
    2185 [3-(2-Oxo 3-Fluorophenyl
    pyrrolidinyl)
    propyl]amino
    • EXAMPLE 34
  • [0251]
    Figure US20030092912A1-20030515-C00059
  • For each compound, the definitions of R[0252] 2 and R3 are specified in the following table.
    Compound No. R4 R3
    2033 Pyrrolidinyl 2,5-Difluorophenyl
    2034 Pyrrolidinyl 3-Fluorophenyl
    2035 1,2,5,6-Tetrahydro 2,5-Difluorophenyl
    pyridyl
    2036 1,2,5,6-Tetrahydro 3-Fluorophenyl
    pyridyl
    2037 Piperidyl 2,5-Difluorophenyl
    2038 Morpholinyl 3-Fluorophenyl
    2041 4-Methyl 2,5-Difluorophenyl
    piperidyl
    2042 4-Methyl 3-Fluorophenyl
    piperidyl
    2045 Azaperhydro 3-Fluorophenyl
    Epinyl
    2048 1,4-Thiazaper 3-Fluorophenyl
    hydroin-4-yl
    2051 3,3-dimethyl 2,5-Difluorophenyl
    piperidyl
    2052 3,3-dimethyl 3-Fluorophenyl
    piperidyl
    2055 Azaperhydro 2,5-Difluorophenyl
    ocinyl
    2056 Azaperhydro 3-Fluorophenyl
    Ocinyl
    2059 2-(1,2,3,4- 2,5-Difluorophenyl
    Tetrahydroiso
    quinolyl)
    2060 2-(1,2,3,4- 3-Fluorophenyl
    Tetrahydroiso
    quinolyl)
    2063 Methylprop-2- 2,5-Difluorophenyl
    enylamino
    2064 Methylprop-2- 3-Fluorophenyl
    enylamino
    2067 Diethylamino 3-Fluorophenyl
    2070 Methylpropyl 2,5-Difluorophenyl
    amino
    2071 Methylpropyl 3-Fluorophenyl
    Amino
    2074 Butylmethyl 2,5-Difluorophenyl
    amino
    2075 Butylmethyl 3-Fluorophenyl
    Amino
    2078 i-Propylethyl 2,5-Difluorophenyl
    amino
    2079 i-Propylethyl 3-Fluorophenyl
    amino
    2082 Diallylamino 2,5-Difluorophenyl
    2083 Diallylamino 3-Fluorophenyl
    2086 Dipropylamino 2,5-Difluorophenyl
    2087 Dipropylamino 3-Fluorophenyl
    2090 Butylethyl 2,5-Difluorophenyl
    Amino
    2091 Butylethyl 3-Fluorophenyl
    Amino
    2094 (Cyclo 2,5-Difluorophenyl
    propylmethyl)
    propylamino
    2095 (Cyclo 3-Fluorophenyl
    propylmethyl)
    propylamino
    2098 Hexylmethyl 2,5-Difluorophenyl
    Amino
    2099 Hexylmethyl 3-Fluorophenyl
    Amino
    2102 Dibutylamino 2,5-Difluorophenyl
    2103 Dibutylamino 3-Fluorophenyl
    2106 Methylamino 3-Fluorophenyl
    2109 Ethylamino 3-Fluorophenyl
    2112 Allylamino 2,5-Difluorophenyl
    2113 Allylamino 3-Fluorophenyl
    2116 Propylamino 2,5-Difluorophenyl
    2117 Propylamino 3-Fluorophenyl
    2120 (Cyclopropyl 2,5-Difluorophenyl
    methyl)amino
    2121 (Cyclopropyl 3-Fluorophenyl
    methyl)amino
    2124 Butyl 2,5-Difluorophenyl
    2125 Butyl 3-Fluorophenyl
    2128 (2-Methylpropyl) 2,5-Difluorophenyl
    amino
    2129 (2-Methylpropyl) 3-Fluorophenyl
    amino
    2132 Pentylamino 2,5-Difluorophenyl
    2133 Pentylamino 3-Fluorophenyl
    2136 (3-Methylbutyl) 2,5-Difluorophenyl
    amino
    2137 (3-Methylbutyl) 3-Fluorophenyl
    amino
    2140 (2-Methylbutyl) 3-Fluorophenyl
    amino
    2143 Hexylamino 2,5-Difluorophenyl
    2144 Hexylamino 3-Fluorophenyl
    2152 (2-Pyrrolidinyl 3-Fluorophenyl
    ethyl)amino
    2155 [2-(Diethyl 2,5-Difluorophenyl
    amino)ethyl]
    amino
    2156 [2-(Diethyl 3-Fluorophenyl
    amino)ethyl]
    amino
    2159 (2-Piperidyl 2,5-Difluorophenyl
    ethyl)amino
    2160 (2-Piperidyl 3-Fluorophenyl
    ethyl)amino
    2163 [2-(1-Methyl 3-Fluorophenyl
    pyrrolidin-2-
    yl)ethyl]amino
    2166 [2-(Diethyl 2,5-Difluorophenyl
    amino)propyl]
    amino
    2167 [2-(Diethyl 3-Fluorophenyl
    amino)propyl]
    amino
    2170 (2-Morpholin-4-yl 2,5-Difluorophenyl
    ethyl)amino
    2171 (2-Morpholin-4-yl 3-Fluorophenyl
    ethyl)amino
    2174 (3-Morpholin-4-yl 2,5-Difluorophenyl
    propyl)amino
    2175 (3-Morpholin-4-yl 3-Fluorophenyl
    propyl)amino
    2178 [3-(2-Methyl 2,5-Difluorophenyl
    piperidyl)
    propyl]amino
    2179 [3-(2-Methyl 3-Fluorophenyl
    piperidyl)
    propyl]amino
    2182 [3-(2-Oxo 2,5-Difluorophenyl
    pyrrolidinyl)
    propyl]amino
    2183 [3-(2-Oxo 3-Fluorophenyl
    pyrrolidinyl)
    propyl]amino
    • EXAMPLE 35
  • [0253]
    Figure US20030092912A1-20030515-C00060
  • For each compound, the definitions of R[0254] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    2147 3-Methylbutyl 3-Chlorophenyl
    2219 3-Methylbutyl 3-Trifluoromethylphenyl
    2220 Butyl 3-Bromophenyl
    2221 2-Methylpropyl 3-Bromophenyl
    2222 3-Methylbutyl 3-Bromophenyl
    • EXAMPLE 36
  • [0255]
    Figure US20030092912A1-20030515-C00061
  • For each compound, the definitions of R[0256] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    2186 Butyl 2,5-Dimethoxyphenyl
    2187 2-Methylpropyl 2,5-Dimethoxyphenyl
    2188 3-Methylbutyl 2,5-Dimethoxyphenyl
    2189 Butyl 3-Chloro-4-methoxyphenyl
    2190 2-Methylpropyl 3-Chloro-4-methoxyphenyl
    2191 3-Methylbutyl 3-Chloro-4-methoxyphenyl
    2192 Butyl 5-Chloro-2-methoxyphenyl
    2193 2-Methylpropyl 5-Chloro-2-methoxyphenyl
    2194 3-Methylbutyl 5-Chloro-2-methoxyphenyl
    2195 2-Methylpropyl 4-Chloro-2-methoxyphenyl
    2196 Butyl 3-Trifluoromethylphenyl
    2197 2-Methylpropyl 3-Trifluoromethylphenyl
    2198 3-Methylbutyl 3-Trifluoromethylphenyl
    2199 Butyl 2-Trifluoromethylphenyl
    2200 3-Methylbutyl 2-Trifluoromethylphenyl
    2201 Butyl 3,4-Dichlorophenyl
    2202 2-Methylpropyl 3,4-Dichlorophenyl
    2203 3-Methylbutyl 3,4-Dichlorophenyl
    2204 Butyl 2,5-Dichlorophenyl
    2205 2-Methylpropyl 2,5-Dichlorophenyl
    2206 Pentyl 2,5-Dichlorophenyl
    2207 3-Methylbutyl 2,5-Dichlorophenyl
    2208 Butyl 2,4-Dichlorophenyl
    2209 2-Methylpropyl 2,4-Dichlorophenyl
    2210 3-Methylbutyl 2,4-Dichlorophenyl
    2211 Butyl 3-Bromophenyl
    2212 2-Methylpropyl 3-Bromophenyl
    2213 Pentyl 3-Bromophenyl
    2214 3-Methylbutyl 3-Bromophenyl
    2215 2-Methylpropyl 4-Bromophenyl
    2216 Butyl 2-Bromophenyl
    2217 2-Methylpropyl 2-Bromophenyl
    2218 3-Methylbutyl 2-Bromophenyl
    2223 2-Methylpropyl 3-Phenoxyphenyl
    2224 2-Methylpropyl 4-Phenoxyphenyl
    2225 2-Methylpropyl 3-Bromo-4-methylphenyl
    2226 Pentyl 3-Bromo-4-methylphenyl
    2227 3-Methylbutyl 3-Bromo-4-methylphenyl
    2228 Butyl 3-Bromo-4-methylphenyl
    2229 2-Methylpropyl 3-Bromo-4-methylphenyl
    2230 Pentyl 3-Bromo-4-methylphenyl
    2231 3-Methylbutyl 3-Bromo-4-methylphenyl
    2232 Butyl 3-Iodophenyl
    2233 2-Methylpropyl 3-Iodophenyl
    2234 Pentyl 3-Iodophenyl
    2235 3-Methylbutyl 3-Iodophenyl
    2236 2-Methylpropyl 4-Iodophenyl
    2310 2-Methylpropyl 2,3,5,6-Tetrafluoro
    phenyl
    2311 2-Methylpropyl 2,4,6-Trifluorophenyl
    2312 Butyl 2,3,6-Trifluorophenyl
    2313 2-Methylpropyl 2,3,6-Trifluorophenyl
    2314 Pentyl 2,3,6-Trifluorophenyl
    2315 3-Methylbutyl 2,3,6-Trifluorophenyl
    2316 Butyl 3-Chloro-6-fluorophenyl
    2317 Pentyl 3-Chloro-6-fluorophenyl
    2318 3-Methylbutyl 3-Chloro-6-fluorophenyl
    2319 Butyl 2-Fluoro-6-
    trifluoromethylphenyl
    • EXAMPLE 37
  • [0257]
    Figure US20030092912A1-20030515-C00062
  • For each compound, the definitions of R[0258] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    2304 2-Methylpropyl 5-Methyl-2-thienyl
    • EXAMPLE 38
  • [0259]
    Figure US20030092912A1-20030515-C00063
  • For each compound, the definitions of R[0260] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    2380 2-Methylpropyl 2,4-Difluorophenyl
    2381 2-Methylpropyl 2H-Benzo[d]1,3-dioxolane
    2382 2-Methylpropyl 3-Chloro-4-methylphenyl
    • EXAMPLE 39
  • [0261]
    Figure US20030092912A1-20030515-C00064
  • For each compound, the definitions of R[0262] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    2390 2-Methylpropyl 5-Methyl-2-thienyl
    • EXAMPLE 40
  • [0263]
    Figure US20030092912A1-20030515-C00065
  • For each compound, the definitions of R[0264] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    2383 2-Methylpropyl 3-Chloro-4-methylphenyl
    2384 2-Methylpropyl 2,4-Difluorophenyl
    2385 2-Methylpropyl 2H-Benzo [d]1,3-dioxolane
    • EXAMPLE 41
  • [0265]
    Figure US20030092912A1-20030515-C00066
  • For each compound, the definitions of R[0266] 2 and R3 are specified in the following table.
    Compound No. R2 R3
    2389 Pentyl 3-Fluoro-4-methylphenyl
    • EXAMPLE 42 Assay for GABAA Receptor Binding
  • The following assay is a standard assay for GABA[0267] A receptor binding.
  • The high affinity and high selectivity of compounds of this invention for the benzodiazepine site of the GABA[0268] A receptor is confirmed using the binding assay described in Thomas and Tallman (J. Bio. Chem. 1981; 156:9838-9842, and J. Neurosci. 1983; 3:433-440).
  • Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) of Buffer A (0.05 M Tris HCl buffer, pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4° C.) at 20,000× g for 20 minutes. The supernatant is decanted, the pellet rehomogenized in the same volume of buffer, and centrifuged again at 20,000× g. The supernatant of this centrifugation step is decanted and the pellet stored at −20° C. overnight. The pellet is then thawed and resuspended in 25 volumes of Buffer A (original wt/vol), centrifuged at 20,000× g and the supernatant decanted. This wash step is repeated once. The pellet is finally resuspended in 50 volumes of Buffer A. [0269]
  • Incubations containi 100 l of tissue homogenate, 100 l of radioligand, (0.5 nM [0270] 3H-Rol5-1788 [3H-Flumazenil], specific activity 80 Ci/mmol), and test compound or control (see below), and are brought to a total volume of 500 l with Buffer A. Incubations are carried for 30 min at 4° C. and then rapidly filtered through Whatman GFB filters to separate free and bound ligand. Filters are washed twice with fresh Buffer A and counted in a liquid scintillation counter. Nonspecific binding (control) is determined by displacement of 3H Rol5-1788 with 10 M Diazepam (Research Biochemicals International, Natick, Mass.). Data were collected in triplicate, averaged, and percent inhibition of total specific binding (Total Specific Binding=Total−Nonspecific) was calculated for each compound.
  • A competition binding curve is obtained with up to 11 points spanning the compound concentration range from 10[0271] −12M to 10−5M obtained per curve by the method described above for determining percent inhibition. Ki values are calculated according the Cheng-Prussof equation. When tested in this assay compounds of the invention exihibit Ki values of less than 1 uM, preferred compounds of the invention have Ki values of less than 500 nM and more compounds of the invention have Ki values of less than 100 nM.
    • EXAMPLE 43 Assay for GABAA Receptor Functional Activity Electrophysiology
  • The following assay is used to determine if a compound of the invention act as an agonist, an antagonist, or an inverse agonist at the benzodiazepine site of the GABA[0272] A receptor.
  • Assays are carried out as described in White and Gurley (NeuroReport 6: 1313-1316, 1995) and White, Gurley, Hartnett, Stirling, and Gregory (Receptors and Channels 3: 1-5, 1995) with modifications. Electrophysiological recordings are carried out using the two electrode voltage-clamp technique at a membrane holding potential of −70 mV. [0273] Xenopus Laevis oocytes are enzymatically isolated and injected with non-polyadenylated cRNA mixed in a ratio of 4:1:4 for , and subunits, respectively. Of the nine combinations of , and subunits described in the White et al. publications, preferred combinations are 1 2 2, 2 3 2, 3 3 2, and 5 3 2. Preferably all of the subunit cRNAs in each combination are human clones or all are rat clones. The sequence of each of these cloned subunits is available from GENBANK, e.g., human 1, GENBANK accession no. X14766, human 2, GENBANK accession no. A28100; human 3, GENBANK accession no. A28102; human 5, GENBANK accession no. A28104; human 2, GENBANK accession no. M82919; human 3, GENBANK accession no. Z20136; human 2, GENBANK accession no. X15376; rat 1, GENBANK accession no. L08490, rat 2, GENBANK accession no. L08491; rat 3, GENBANK accession no. L08492; rat 5, GENBANK accession no. L08494; rat 2, GENBANK accession no. X15467; rat 3, GENBANK accession no. X15468; and rat 2, GENBANK accession no. L08497. For each subunit combination, sufficient message for each constituent subunit is injected to provide current amplitudes of >10 nA when 1 μM GABA is applied.
  • Compounds are evaluated against a GABA concentration that evokes <10% of the maximal evokable GABA current (e.g. 1 M -9 M). Each oocyte is exposed to increasing concentrations of compound in order to evaluate a concentration/effect relationship. Compound efficacy is calculated as a percent-change in current amplitude: 100*((Ic/I)−1), where Ic is the GABA evoked current amplitude observed in the presence of test compound and I is the GABA evoked current amplitude observed in the absence of the test compound. [0274]
  • Specificity of a compound for the benzodiazepine site is determined following completion of a concentration/effect curve. After washing the oocyte sufficiently to remove previously applied compound, the oocyte is exposed to GABA+1 μM RO15-1788, followed by exposure to GABA+1 μM RO15-1788+test compound. Percent change due to addition of compound is calculated as described above. Any percent change observed in the presence of RO15-1788 is subtracted from the percent changes in current amplitude observed in the absence of 1 μM RO15-1788. These net values are used for the calculation of average efficacy and EC[0275] 50 values by standard methods. To evaluate average efficacy and EC50 values, the concentration/effect data are averaged across cells and fit to the logistic equation.
    • EXAMPLE 44 Preparation of Radiolabeled Probe Compounds of the Invention
  • The compounds of the invention are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. The radioisotope is preferably selected from of at least one of carbon (preferably [0276] 14C), hydrogen (preferably 3H), sulfur (preferably 35S), or iodine (preferably 125I). Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRI International, Menlo Park, Calif.; Wizard Laboratories, West Sacramento, Calif.; ChemSyn Laboratories, Lexena, Kans.; American Radiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif.
  • Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate. [0277]
    • EXAMPLE 45 Use of Compounds of the Invention as Probes for GABAA Receptors in Cultured Cells and Tissue Samples
  • Receptor autoradiography (receptor mapping) of NK-3 or GABA[0278] A receptors in cultured cells or tissue samples is carried out in vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York, using radiolabeled compounds of the invention prepared as described in the preceding Example.
  • The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification. [0279]
    Figure US20030092912A1-20030515-P00001
    Figure US20030092912A1-20030515-P00002
    Figure US20030092912A1-20030515-P00003
    Figure US20030092912A1-20030515-P00004
    Figure US20030092912A1-20030515-P00005
    Figure US20030092912A1-20030515-P00006
    Figure US20030092912A1-20030515-P00007
    Figure US20030092912A1-20030515-P00008
    Figure US20030092912A1-20030515-P00009
    Figure US20030092912A1-20030515-P00010
    Figure US20030092912A1-20030515-P00011
    Figure US20030092912A1-20030515-P00012
    Figure US20030092912A1-20030515-P00013
    Figure US20030092912A1-20030515-P00014
    Figure US20030092912A1-20030515-P00015
    Figure US20030092912A1-20030515-P00016
    Figure US20030092912A1-20030515-P00017
    Figure US20030092912A1-20030515-P00018
    Figure US20030092912A1-20030515-P00019
    Figure US20030092912A1-20030515-P00020
    Figure US20030092912A1-20030515-P00021
    Figure US20030092912A1-20030515-P00022
    Figure US20030092912A1-20030515-P00023
    Figure US20030092912A1-20030515-P00024
    Figure US20030092912A1-20030515-P00025
    Figure US20030092912A1-20030515-P00026
    Figure US20030092912A1-20030515-P00027
    Figure US20030092912A1-20030515-P00028
    Figure US20030092912A1-20030515-P00029
    Figure US20030092912A1-20030515-P00030
    Figure US20030092912A1-20030515-P00031
    Figure US20030092912A1-20030515-P00032
    Figure US20030092912A1-20030515-P00033
    Figure US20030092912A1-20030515-P00034
    Figure US20030092912A1-20030515-P00035
    Figure US20030092912A1-20030515-P00036
    Figure US20030092912A1-20030515-P00037
    Figure US20030092912A1-20030515-P00038
    Figure US20030092912A1-20030515-P00039
    Figure US20030092912A1-20030515-P00040
    Figure US20030092912A1-20030515-P00041
    Figure US20030092912A1-20030515-P00042
    Figure US20030092912A1-20030515-P00043
    Figure US20030092912A1-20030515-P00044
    Figure US20030092912A1-20030515-P00045
    Figure US20030092912A1-20030515-P00046
    Figure US20030092912A1-20030515-P00047
    Figure US20030092912A1-20030515-P00048
    Figure US20030092912A1-20030515-P00049
    Figure US20030092912A1-20030515-P00050
    Figure US20030092912A1-20030515-P00051
    Figure US20030092912A1-20030515-P00052
    Figure US20030092912A1-20030515-P00053
    Figure US20030092912A1-20030515-P00054
    Figure US20030092912A1-20030515-P00055
    Figure US20030092912A1-20030515-P00056
    Figure US20030092912A1-20030515-P00057
    Figure US20030092912A1-20030515-P00058
    Figure US20030092912A1-20030515-P00059
    Figure US20030092912A1-20030515-P00060
    Figure US20030092912A1-20030515-P00061
    Figure US20030092912A1-20030515-P00062
    Figure US20030092912A1-20030515-P00063
    Figure US20030092912A1-20030515-P00064
    Figure US20030092912A1-20030515-P00065
    Figure US20030092912A1-20030515-P00066
    Figure US20030092912A1-20030515-P00067
    Figure US20030092912A1-20030515-P00068
    Figure US20030092912A1-20030515-P00069
    Figure US20030092912A1-20030515-P00070
    Figure US20030092912A1-20030515-P00071
    Figure US20030092912A1-20030515-P00072
    Figure US20030092912A1-20030515-P00073
    Figure US20030092912A1-20030515-P00074

Claims (26)

What is claimed is:
1. A compound of the formula:
Figure US20030092912A1-20030515-C00067
or pharmaceutically acceptable non-toxic salts thereof wherein:
W represents
Figure US20030092912A1-20030515-C00068
 where
Z is O, or S;
R1 represents phenyl, C1-C6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
R2 represents
hydroxyl;
C1-C6 alkyl or C1-C6 alkoxy, each of which are optionally substituted with amino, mono or di(C1-C6) alkylamino, a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl; or
NR8R9 forms a 5-, 6-, or 7-membered heterocyclic ring;
or R2 represents
hydrogen or
a group of the formula
Figure US20030092912A1-20030515-C00069
 where
Rn and Rk independently represent C1-C6 alkyl, C2-C6 alkenyl, C1-C6 cycloalkyl (C1-C6) alkyl, benzoyl where the phenyl portion is optionally substituted with halgoen, C1-C6 alkyl, or C1-C6 alkoxy;
a group of the formula IV-a
Figure US20030092912A1-20030515-C00070
 where
p, s, and t independently represent 1 or 2;
J is CH, N, O, or a carbon atom substituted with C1-C6 alkyl; or
NRkRn represents
Figure US20030092912A1-20030515-C00071
 where s, t, and J are as defined above;
R3 represents
C1-C6 alkyl, allyl, cyclopropylmethyl, cyclopentyl; or
benzyl optionally mono-, di-, or trisubstituted independently with halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, or hydroxy;
C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino, mono or di(C1-C6) alkylamino, a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl;
NR8R9 forms a 5-, 6-, 7-membered heterocyclic ring;
SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8 where R8 is defined as above;
O(CH2)n-G where n=1,2,3,4 and G is SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, or CONHSO2R8, where R8 is as defined above; or
tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, or pyridyl;
R4, R5 and R6 are the same or different and represent hydrogen; or
C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino, mono or di(C1-C6) alkylamino, a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion, C1-C6 alkylthiol, or halogen;
O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl;
NR8R9 forms a 5-, 6-, or 7-membered heterocyclic ring; or
R4 and R5 can form a 1,3-dioxolene ring;
X represents a bond, CH2, or CHCH; and
A, B, C, and D are the same or different and represent CH or N with the proviso that at least one, but not more than two of A,B,C, or D represent N.
2. A compound according to claim 1, which is N-((3-cyclopropylmethylimidazolo[5,4-b]pyridin-2-yl)methyl)(3-fluorophenyl)-N-propylcarboxamide.
3. A compound according to claim 1, which is N-[(3-cyclopropylmethylimidazolo[5,4-b]pyridin-2-yl)methyl](2,5-difluorophenyl)-N-propylcarboxamide.
4. A compound according to claim 1, which is N-((3-n-butyl-imidazolo[5,4-b]pyridin-2-yl)methyl](3-iodophenyl)-N-propylcarboxamide.
5. A compound according to claim 1 for use in therapeutic treatment of a disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABAA receptor.
6. A pharmaceutical composition comprising a compound according to claim 1 combined with at least one pharmaceutically acceptable carrier or excipient.
7. A method for the treatment or prevention of a disease or disorder associated with pathogenic associated with pathogenic agonism, inverse agonism or antagonism of the GABAA receptor, the method comprising administering to a patient in need of such treatment or prevention an effective amount of a compound of claim 1.
8. The use of a compound according to claim 1 for the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABAA receptor.
9. The use of a compound according to claim 1 for the manufacture of a medicament for the treatment or prevention of anxiety, depression, sleep disorders, or cognitive impairment.
10. A method according to claim 7 wherein the disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABAA receptor is anxiety, depression, a sleep disorder, or cognitive impairment.
11. A method for localizing GABAA receptors in a tissue sample comprising: contacting the sample with a detectably-labeled compound of claim 1 under conditions that permit binding of the compound to GABAA receptors, washing the sample to remove unbound compound, and detecting the bound compound.
12. A method for altering the signal-transducing activity of GABAA receptors, the method comprising exposing cells expressing GABAA receptors to a compound according to claim 1 at a concentration sufficient to inhibit RO15-1788 binding to cells expressing a cloned human GABAA receptor in vitro.
13. A packaged pharmaceutical composition comprising the pharmaceutical composition of claim 6 in a container and instructions for using the composition to treat a patient suffering from a disorder responsive to agonism, inverse agonism or antagonism of the GABAA receptor.
14. The packaged pharmaceutical composition of claim 13, wherein the patient is suffering from anxiety, depression, a sleep disorder, or cognitive impairment.
15. A compound according to claim 1 wherein the compound exhibits an IC50 of 1 micromolar or less in a standard assay of GABAA receptor binding.
16. A compound according to claim 1 wherein the compound exhibits an IC50 of 100 nanomolar or less in a standard assay of GABAA receptor binding.
17. A compound according to claim 1 wherein the compound exhibits an IC50 of 10 nanomolar or less in a standard assay of GABAA receptor binding.
18. A compound according to claim 1 which has the formula
Figure US20030092912A1-20030515-C00072
where R2 and R3 are defined in the following table:
R2 R3 Methyl 3-Fluorophenyl Allyl 3-Fluorophenyl Propyl 3-Fluorophenyl Allyl 3-Fluorophenyl Propyl 3-Fluorophenyl Propyl 3,4-Difluorophenyl Allyl 2,5-Difluorophenyl Propyl 2,5-Difluorophenyl Propyl 1,3-Benzodioxol-5-yl Allyl 3-Chloro-4-fluorophenyl Propyl 3-Chloro-4-fluorophenyl Methyl 5-Chloro-2-methoxyphenyl 3-Methylbutyl 3-{2-[(3- Methoxypropyl)amino]ethoxy}phenyl 3-Methylbutyl 3-{2-[(3-Ethoxypropyl)amino]ethoxy}phenyl 3-Methylbutyl 3-{2-[(3-Ethoxypropyl)amino]ethoxy}phenyl 3-Methylbutyl 3-[2-(Benzylamino)ethoxy]phenyl 3-Methylbutyl 3-[2-(Benzylamino)ethoxy]phenyl 2-Methylpropyl 3-{2-[(3-i- Propoxypropyl)amino]ethoxy}phenyl 3-Methylbutyl 3-{2-[(3-i- Propoxypropyl)amino]ethoxy}phenyl Benzyl 3-Chloro-2-thienyl 4-Fluorobenzyl 3-Chloro-2-thienyl Benzyl 3-Chloro-4-methylphenyl 2-Fluorobenzyl 3-Chloro-4-methylphenyl 4-Fluorobenzyl 3-Chloro-4-methylphenyl 4-Fluorobenzyl 2-Fluoro-6-trifluoromethylphenyl 4-Fluorobenzyl 3,5-Dibromophenyl Pentyl 3-Bromophenyl 3-Methylbutyl 3-Bromophenyl 2-Methylpropyl 4-Bromophenyl 3-Methylbutyl 4-Bromophenyl Butyl 2-Bromophenyl Pentyl 2-Bromophenyl 3-Methylbutyl 2-Bromophenyl 3-Methylbutyl 3-Methoxyphenyl 3-Methylbutyl 2-Methoxyphenyl 3-Methylbutyl 3-Chlorophenyl 3-Methylbutyl 2-Chlorophenyl 3-Methylbutyl 2-Chlorophenyl Ethyl 5-Chloro-2-methoxyphenyl Allyl 5-Chloro-2-methoxyphenyl Propyl 5-Chloro-2-methoxyphenyl Methyl 2,5-Dichlorophenyl Allyl 2,5-Dichlorophenyl Propyl 2,5-Dichlorophenyl Propyl 5-Methyl-2-thienyl Propyl Phenyl Propyl 3-Methylphenyl Propyl 3-Fluoro-4-methylphenyl Allyl 5-Fluoro-2-methylphenyl Propyl 5-Fluoro-2-methylphenyl Benzyl 2,3,5,6-Tetrafluorophenyl 4-Fluorobenzyl 2,3,5,6-Tetrafluorophenyl Benzyl 2,4,6-Trifluorophenyl Benzyl 2,3,6-Trifluorophenyl 4-Fluorobenzyl 2,3,6-Trifluorophenyl 4-Fluorobenzyl 2-Chloro-6-fluorophenyl Benzyl 2-Fluoro-6-trifluoromethylphenyl 2-Methylpropyl 3-(2-{[(4- Methylphenyl)methyl]amino}ethoxy)phenyl 3-Methylbutyl 3-{2-[(2-Cyclohex-1- enylethyl)amino]ethoxy}phenyl 2-Methylpropyl 3-(2-{[(2- Methylphenyl)methyl]amino}ethoxy)phenyl 2-Methylpropyl 3-(2-{[(3- Methylphenyl)methyl]amino}ethoxy)phenyl 2-Methylpropyl 3-(2-{[(2- Methoxyphenyl)methyl]amino}ethoxy)phenyl 2-Fluorobenzyl 3-Iodo-4-methylphenyl 4-Fluorobenzyl 3-Iodo-4-methylphenyl 4-Fluorobenzyl 2-Thienyl Benzyl 2-Thienyl 4-Fluorobenzyl 2-Thienyl Benzyl 3-Methyl-2-thienyl 4-Fluorobenzyl 3-Methyl-2-thienyl Benzyl 5-Methyl-2-thienyl 2-Fluorobenzyl 5-Methyl-2-thienyl 4-Fluorobenzyl 5-Methyl-2-thienyl 4-Fluorobenzyl 4,5-Dimethyl-2-furyl 2-Methylpropyl 3,4-Dichlorophenyl Pentyl 3,4-Dichlorophenyl 3-Methylbutyl 3,4-Dichlorophenyl 3-Methylbutyl 3,5-Dichlorophenyl 3-Methylbutyl 2,3-Dichlorophenyl Butyl 2,5-Dichlorophenyl 2-Methylpropyl 2,5-Dichlorophenyl Pentyl 2,5-Dichlorophenyl 3-Methylbutyl 2,5-Dichlorophenyl Butyl 2,4-Dichlorophenyl 2-Methylpropyl 2,4-Dichlorophenyl 3-Methylbutyl 2,4-Dichlorophenyl Allyl 3-Chlorophenyl Propyl 3-Chlorophenyl Propyl 2,3,6-Trifluorophenyl Methyl 5-Chloro-2-methoxyphenyl Ethyl 5-Chloro-2-methoxyphenyl Allyl 5-Chloro-2-methoxyphenyl Methyl 2,5-Dichlorophenyl Methyl 3-Bromophenyl Ethyl 3-Bromophenyl Propyl 3-Bromophenyl Methyl 3-Bromo-4-fluorophenyl Methyl 3-Iodophenyl 3-Methylbutyl 3-(2-{[(2- Methoxyphenyl)methyl]amino}ethoxy)phenyl 2-Methylpropyl 3-(2-{[(3- Methoxyphenyl)methyl]amino}ethoxy)phenyl 2-Methylpropyl 3-(2-{[(4- Methoxyphenyl)methyl]amino}ethoxy)phenyl 2-Methylpropyl 3-(2-{[(2- Chlorophenyl)methyl]amino }ethoxy)phenyl Benzyl 2,5-Dimethoxyphenyl 2-Fluorobenzyl 2,5-Dimethoxyphenyl 4-Fluorobenzyl 2,5-Dimethoxyphenyl Butyl 4-Pentylphenyl 2-Methylpropyl 4-Pentylphenyl 3-Methylbutyl 4-Pentylphenyl Butyl 3-Bromophenyl 2-Methylpropyl 3-Bromophenyl Pentyl 3-Bromophenyl 3-Methylbutyl 3-Bromophenyl 2-Methylpropyl 4-Bromophenyl 3-Methylbutyl 4-Bromophenyl Butyl 2-Bromophenyl Pentyl 2-Bromophenyl 3-Methylbutyl 2-Bromophenyl Ethyl 3-Iodophenyl Allyl 3-Iodophenyl Propyl 3-Chloro-4-methylphenyl Propyl 5-Bromo-2-thienyl Ethyl Phenyl Allyl Phenyl Propyl Phenyl Allyl 3-Methylphenyl Propyl 3-Methylphenyl Propyl 4-Methylphenyl Methyl 3-Fluorophenyl Propyl 3-Fluorophenyl Butyl 3-Chloro-4-methoxyphenyl 2-Methylpropyl 3-Chloro-4-methoxyphenyl 3-Methylbutyl 3-Chloro-4-methoxyphenyl Butyl 5-Chloro-2-methoxyphenyl 2-Methylpropyl 5-Chloro-2-methoxyphenyl Pentyl 5-Chloro-2-methoxyphenyl 3-Methylbutyl 5-Chloro-2-methoxyphenyl Butyl 3-Trifluoromethylphenyl Pentyl 3-Trifluoromethylphenyl 3-Methylbutyl 3-Trifluoromethylphenyl 3-Methylbutyl 2-Trifluoromethylphenyl Butyl 3,4-Dichlorophenyl Propyl 4-Fluorophenyl Methyl 2-Fluorophenyl Allyl 2-Fluorophenyl Propyl 2-Fluorophenyl Propyl 3-Fluoro-4-methylphenyl Methyl 5-Fluoro-2-methylphenyl Propyl 5-Fluoro-2-methylphenyl Methyl 3-Chlorophenyl Allyl 3-Chlorophenyl Propyl 3-Chlorophenyl 3-Methylbutyl 4-Hexylphenyl 3-Methylbutyl 2-Fluoro-3-trifluoromethylphenyl Butyl 2,5-Dichlorophenyl 2-Methylpropyl 2,5-Dichlorophenyl Pentyl 2,5-Dichlorophenyl 3-Methylbutyl 2,5-Dichlorophenyl Butyl 2,4-Dichlorophenyl 2-Methylpropyl 2,4-Dichlorophenyl 3-Methylbutyl 2,4-Dichlorophenyl Butyl 4-Pentylphenyl 2-Methylpropyl 4-Pentylphenyl 3-Methylbutyl 4-Pentylphenyl Butyl 3-Bromophenyl 2-Methylpropyl 3-Bromophenyl 2-Methylpropyl 3-Bromo-4-methylphenyl 3-Methylbutyl 3-Bromo-4-methylphenyl Butyl 3-Bromo-4-fluorophenyl 2-Methylpropyl 3-Bromo-4-fluorophenyl 3-Methylbutyl 3-Bromo-4-fluorophenyl Butyl 3-Iodophenyl 2-Methylpropyl 3-Iodophenyl Pentyl 3-Iodophenyl 3-Methylbutyl 3-Iodophenyl 2-Methylpropyl 4-Iodophenyl 3-Methylbutyl 3-Iodo-4-methylphenyl Butyl 2-Thienyl Pentyl 2-Thienyl 3-Methylbutyl 2-Thienyl Butyl 3-Thienyl Pentyl 3-Thienyl 3-Methylbutyl 3-Thienyl 3-Methylbutyl Benzyl Butyl 3-Methyl-2-thienyl Pentyl 3-Methyl-2-thienyl 3-Methylbutyl 3-Methyl-2-thienyl Pentyl 3-Methyl-5-thienyl 3-Methylbutyl 3-Methyl-5-thienyl 3-Methylbutyl 3-Methylphenyl 2-Methylpropyl 5-Chloro-2-methoxyphenyl Pentyl 5-Chloro-2-methoxyphenyl 3-Methylbutyl 5-Chloro-2-methoxyphenyl Butyl 3-Trifluoromethylphenyl Pentyl 3-Trifluoromethylphenyl 3-Methylbutyl 3-Trifluoromethylphenyl 3-Methylbutyl 2-Trifluoromethylphenyl Butyl 3,4-Dichlorophenyl 2-Methylpropyl 3,4-Dichlorophenyl 3-Methylbutyl 3,4-Dichlorophenyl 3-Methylbutyl 3,5-Dichlorophenyl 3-Methylbutyl 2,3-Dichlorophenyl Butyl Phenyl Pentyl Phenyl 3-Methylbutyl Phenyl Pentyl 3-Methylphenyl 3-Methylbutyl 3-Methylphenyl 2-Methylpropyl 4-Methylphenyl 3-Methylbutyl 4-Methylphenyl Pentyl 2-Methylphenyl 3-Methylbutyl 2-Methylphenyl Butyl 3-Fluorophenyl 2-Methylpropyl 3-Fluorophenyl Pentyl 3-Fluorophenyl 3-Methylbutyl 3-Fluorophenyl Pentyl 4-Fluorophenyl 3-Methylbutyl 4-Fluorophenyl Pentyl 2-Fluorophenyl 3-Methylbutyl 2-Fluorophenyl 2-Methylpropyl 3,4-Dimethylphenyl 3-Methylbutyl 3,4-Dimethylphenyl Pentyl 2,5-Dimethylphenyl 3-Methylbutyl 2,5-Dimethylphenyl 2-Methylpropyl 2,4-Dimethylphenyl 3-Methylbutyl 2,4-Dimethylphenyl 2-Methylpropyl 3-Methoxyphenyl Pentyl 3-Methoxyphenyl 3-Methylbutyl 3-Methoxyphenyl 2-Methylpropyl 4-Methoxyphenyl 3-Methylbutyl 4-Methoxyphenyl Pentyl 2-Methoxyphenyl 3-Methylbutyl 2-Methoxyphenyl 2-Methylpropyl 3-Fluoro-4-methylphenyl Pentyl 3-Fluoro-4-methylphenyl 3-Methylbutyl 3-Fluoro-4-methylphenyl 3-Methylbutyl 3-Fluoro-2-methylphenyl 2-Methylpropyl 5-Fluoro-2-methylphenyl Pentyl 5-Fluoro-2-methylphenyl 2-Methylpropyl 3-Chloro-4-fluorophenyl Pentyl 3-Chloro-4-fluorophenyl 3-Methylbutyl 3-Chloro-4-fluorophenyl 3-Methylbutyl 3,4,5-Trifluorophenyl 3-Methylbutyl 4-Butylphenyl Pentyl 4-i-propylphenyl 3-Methylbutyl 4-i-propylphenyl Butyl 4-Ethylthiophenyl 2-Methylpropyl 4-Ethylthiophenyl 3-Methylbutyl 4-Ethylthiophenyl 3-Methylbutyl 3-Chloro-4-methoxyphenyl Butyl 5-Chloro-2-methoxyphenyl 3-Methylbutyl 5-Fluoro-2-methylphenyl 2-Methylpropyl 2-Fluoro-3-methylphenyl Pentyl 2-Fluoro-3-methylphenyl 3-Methylbutyl 2-Fluoro-3-methylphenyl 2-Methylpropyl 3-Chlorophenyl Pentyl 3-Chlorophenyl 3-Methylbutyl 3-Chlorophenyl 2-Methylpropyl 4-Chlorophenyl 3-Methylbutyl 4-Chlorophenyl 3-Methylbutyl 2-Chlorophenyl 3-Methylbutyl 3,4-Difluorophenyl 3-Methylbutyl 1,2-Difluorophenyl Pentyl 2,5-Difluorophenyl 3-Methylbutyl 2,5-Difluorophenyl Pentyl 2,4-Difluorophenyl 3-Methylbutyl 2,4-Difluorophenyl 3-Methylbutyl 4-Propylphenyl Pentyl 1,3-Benzodioxol-5-yl 3-Methylbutyl 1,3-Benzodioxol-5-yl 3-Methylbutyl 4-Methylthiophenyl 3-Methylbutyl 3-Fluoro-4-methoxyphenyl 2-Methylpropyl 4-Chloro-3-methylphenyl 3-Methylbutyl 4-Chloro-3-methylphenyl Buty 3-Chloro-4-fluorophenyl
19. A compound according to claim 1 which has the formula
Figure US20030092912A1-20030515-C00073
where R2 and R3 are defined in the following table:
R2 R3 2-Methylpropyl 2,4,6-Trifluorophenyl 3-Methylbutyl 2,4,6-Trifluorophenyl 2-Methylpropyl 2,3,6-Trifluorophenyl Pentyl 2,3,6-Trifluorophenyl 3-Methylbutyl 2,3,6-Trifluorophenyl Pentyl 2-Chloro-6-fluorophenyl 3-Methylbutyl 2-Chloro-6-fluorophenyl Pentyl 2-Fluoro-6- trifluoromethylphenyl 3-Methylbutyl 2-Fluoro-6- trifluoromethylphenyl Pentyl 3-Bromo-4-fluorophenyl 2-Methylpropyl 4-Hexylphenyl Butyl 4-Pentoxyphenyl 2-Methylpropyl 4-Pentoxyphenyl Butyl 2-Fluoro-3- trifluoromethylphenyl 2-Methylpropyl 2-Fluoro-3- trifluoromethylphenyl 3-Methylbutyl 3-Bromo-4-fluorophenyl 2-Methylpropyl 4-heptylphenyl Butyl 3-Iodophenyl 2-Methylpropyl 3-Iodophenyl Pentyl 3-Iodophenyl 3-Methylbutyl 3-Iodophenyl Butyl 4-Iodophenyl 2-Methylpropyl 4-Iodophenyl 2-Methylpropyl 4-Pentylphenyl 3-Methylbutyl 2-Fluoro-3- trifluoromethylphenyl Butyl 3-Bromo-4-methylphenyl 2-Methylpropyl 3-Bromo-4-methylphenyl Pentyl 3-Bromo-4-methylphenyl 3-Methylbutyl 3-Bromo-4-methylphenyl Butyl 3-Bromo-4-fluorophenyl 2-Methylpropyl 3-Bromo-4-fluorophenyl 3-Methylbutyl 3,4-Dichlorophenyl Butyl 2,3-Dichlorophenyl 2-Methylpropyl 2,3-Dichlorophenyl 3-Methylbutyl 2,3-Dichlorophenyl Butyl 2,5-Dichlorophenyl Butyl 3-Bromophenyl 2-Methylpropyl 3-Bromophenyl Pentyl 3-Bromophenyl 3-Methylbutyl 3-Bromophenyl Butyl 4-Bromophenyl 2-Methylpropyl 4-Bromophenyl 3-Methylbutyl 4-Bromophenyl Butyl 2-Bromophenyl Pentyl 2-Bromophenyl 3-Methylbutyl 2-Bromophenyl Pentyl 4-Hexylphenyl 2-Methylpropyl 4-Chloro-2-methoxyphenyl 2-Methylpropyl 2,5-Dichlorophenyl Pentyl 2,5-Dichlorophenyl 3-Methylbutyl 2,5-Dichlorophenyl Butyl 2,4-Dichlorophenyl 2-Methylpropyl 2,4-Dichlorophenyl Pentyl 2,4-Dichlorophenyl 3-Methylbutyl 2,4-Dichlorophenyl 2-Methylpropyl 2,5-Dimethoxyphenyl Pentyl 2,5-Dimethoxyphenyl 3-Methylbutyl 2,5-Dimethoxyphenyl 2-Methylpropyl 2,4-Dimethoxyphenyl 3-Methylbutyl 2,4-Dimethoxyphenyl Pentyl 4-Chloro-2-methoxyphenyl 3-Methylbutyl 4-Chloro-2-methoxyphenyl Butyl 3-Trifluoromethylphenyl 2-Methylpropyl 3-Trifluoromethylphenyl Pentyl 3-Trifluoromethylphenyl 3-Methylbutyl 3-Trifluoromethylphenyl 2-Methylpropyl 4-Trifluoromethylphenyl Butyl 2-Trifluoromethylphenyl 3-Methylbutyl 2-Trifluoromethylphenyl Butyl 3,4-Dichlorophenyl 2-Methylpropyl 3,4-Dichlorophenyl Butyl 4-Methylthiophenyl Butyl 3-Chloro-4-methoxyphenyl 2-Methylpropyl 3-Chloro-4-methoxyphenyl 3-Methylbutyl 3-Chloro-4-methoxyphenyl Butyl 5-Chloro-2-methoxyphenyl 2-Methylpropyl 5-Chloro-2-methoxyphenyl Pentyl 5-Chloro-2-methoxyphenyl 3-Methylbutyl 5-Chloro-2-methoxyphenyl Butyl 2,5-Difluorophenyl 2-Methylpropyl 2,5-Difluorophenyl Pentyl 2,5-Difluorophenyl 3-Methylbutyl 2,5-Difluorophenyl Butyl 2,4-Difluorophenyl 2-Methylpropyl 4-Methylthiophenyl Butyl 3-Fluoro-4-methoxyphenyl 2-Methylpropyl 3-Fluoro-4-methoxyphenyl 3-Methylbutyl 3-Fluoro-4-methoxyphenyl 2-Methylpropyl 4-Chloro-3-methylphenyl Butyl 3-Chloro-4-fluorophenyl 2-Methylpropyl 3-Chloro-4-fluorophenyl Pentyl 3-Chloro-4-fluorophenyl 3-Methylbutyl 3-Chloro-4-fluorophenyl 2-Methylpropyl 4-Ethylthiophenyl Butyl 2,5-Dimethoxyphenyl Butyl 2-Chlorophenyl 2-Methylpropyl 2,4-Difluorophenyl Pentyl 2,4-Difluorophenyl 3-Methylbutyl 2,4-Difluorophenyl Butyl 1,3-Benzodioxol-5-yl 2-Methylpropyl 1,3-Benzodioxol-5-yl Pentyl 1,3-Benzodioxol-5-yl 3-Methylbutyl 1,3-Benzodioxol-5-yl 3-Methylbutyl 3-Fluoro-2-methylphenyl Butyl 5-Fluoro-2-methylphenyl 2-Methylpropyl 5-Fluoro-2-methylphenyl Pentyl 5-Fluoro-2-methylphenyl 3-Methylbutyl 5-Fluoro-2-methylphenyl 2-Methylpropyl 2-Chlorophenyl Pentyl 2-Chlorophenyl 3-Methylbutyl 2-Chlorophenyl Butyl 3,4-Difluorophenyl 2-Methylpropyl 3,4-Difluorophenyl Pentyl 3,4-Difluorophenyl 3-Methylbutyl 3,4-Difiluorophenyl Butyl 2,3-Difluorophenyl 2-Methylpropyl 2,3-Difluorophenyl Pentyl 2,3-Difluorophenyl 3-Methylbutyl 2,3-Difluorophenyl 2-Methylpropyl 4-Methoxyphenyl Butyl 3-Chlorophenyl 2-Methylpropyl 3-Chlorophenyl Pentyl 3-Chlorophenyl 3-Methylbutyl 3-Chlorophenyl Butyl 4-Chlorophenyl 2-Methylpropyl 4-Chlorophenyl 3-Methylbutyl 4-Chlorophenyl Butyl 2,5-Dimethylphenyl 2-Methylpropyl 2,5-Dimethylphenyl Pentyl 2,5-Dimethylphenyl 3-Methylbutyl 2,5-Dimethylphenyl Butyl 2,4-Dimethylphenyl 3-Methylbutyl 4-Methoxyphenyl Butyl 2-Methoxyphenyl 2-Methylpropyl 2-Methoxyphenyl Pentyl 2-Methoxyphenyl 3-Methylbutyl 2-Methoxyphenyl Butyl 3-Fluoro-4-methylphenyl 2-Methylpropyl 3-Fluoro-4-methylphenyl Pentyl 3-Fluoro-4-methylphenyl 3-Methylbutyl 3-Fluoro-4-methylphenyl Butyl 3-Fluoro-2-methylphenyl 2-Methylpropyl 3-Fluoro-2-methylphenyl Butyl 4-Fluorophenyl 2-Methylpropyl 2,4-Dimethylphenyl 3-Methylbutyl 2,4-Dimethylphenyl Butyl 3-Methoxyphenyl 2-Methylpropyl 3-Methoxyphenyl Pentyl 3-Methoxyphenyl 3-Methylbutyl 3-Methoxyphenyl Butyl 4-Methoxyphenyl 3-Methylbutyl 3-Methylphenyl Butyl 4-Methylphenyl 2-Methylpropyl 4-Methylphenyl Pentyl 4-Methylphenyl 3-Methylbutyl 4-Methylphenyl 2-Methylpropyl 4-Fluorophenyl Pentyl 4-Fluorophenyl 3-Methylbutyl 4-Fluorophenyl Butyl 2-Fluorophenyl 2-Methylpropyl 2-Fluorophenyl Pentyl 2-Fluorophenyl 3-Methylbutyl 2-Fluorophenyl 2-Methylpropyl 4-Ethylphenyl Butyl 3,4-Dimethylphenyl 2-Methylpropyl 3,4-Dimethylphenyl 3-Methylbutyl 3,4-Dimethylphenyl Butyl 2-Methylphenyl Pentyl 2-Methylphenyl 3-Methylbutyl 2-Methylphenyl Butyl 3-Fluorophenyl 2-Methylpropyl 3-Fluorophenyl Pentyl 3-Fluorophenyl 3-Methylbutyl 3-Fluorophenyl Butyl Phenyl 2-Methylpropyl Phenyl Pentyl Phenyl 3-Methylbutyl Phenyl Butyl 3-Methylphenyl 2-Methylpropyl 3-Methylphenyl Pentyl 3-Methylphenyl
20. A compound according to claim 1 which has the formula
Figure US20030092912A1-20030515-C00074
where R2 and R3 are defined in the following table:
R2 R3 Allyl 2,5-Dichlorophenyl Propyl 2,5-Dichlorophenyl Propyl 2,4-Dichlorophenyl Propyl 4-Pentylphenyl Allyl 3-Bromophenyl Propyl 3-Bromophenyl Propyl 4-Bromophenyl Propyl 2-Chlorophenyl Methyl Phenyl Propyl Phenyl Methyl 3-Methylphenyl Propyl 3-Methylphenyl Propyl 2-Chlorophenyl Propyl 3,4-Difluorophenyl Methyl 2,3-Difluorophenyl Propyl 2,3-Difluorophenyl Methyl 2,5-Difluorophenyl Allyl 2,5-Difluorophenyl Propyl 2,5-Difluorophenyl Propyl 2,4-Difluorophenyl Allyl 1,3-Benzodioxol-5-yl Propyl 1,3-Benzodioxol-5-yl Propyl 4-Methylthiophenyl Propyl 4-Chloro-3-methylphenyl Propyl 4-Methylphenyl Propyl 3-Fluorophenyl Propyl 4-Fluorophenyl Methyl 2-Fluorophenyl Allyl 2-Fluorophenyl Propyl 2-Fluorophenyl Propyl 3,4-Dimethylphenyl Propyl 3-Fluoro-4-methylphenyl Propyl 2-Fluoro-3-methylphenyl Allyl 3-Chlorophenyl Propyl 3-Chlorophenyl Propyl 4-Chlorophenyl 2-Methylpropyl 3-Chloro-2-thienyl Pentyl 3-Chloro-2-thienyl 3-Methylbutyl 3-Chloro-2-thienyl Butyl 3-Ethoxy-2-thienyl Pentyl 3-Ethoxy-2-thienyl 3-Methylbutyl 2-Methoxybenzyl 3-Methylbutyl 2-(2-Fluorophenyl)ethenyl 2-Methylpropyl 2-(2-Chlorophenyl)ethenyl 3-Methylbutyl 2-(2-Chlorophenyl)ethenyl Pentyl 2-Fluoro-6-trifluoromethylphenyl 3-Methylbutyl 3-Ethoxy-2-thienyl Butyl 5-Methylthio-2-thienyl 2-Methylpropyl 5-Methylthio-2-thienyl 3-Methylbutyl 5-Methylthio-2-thienyl 3-Methylbutyl 4-Fluorophenyl 3-Methylbutyl 2-Fluorophenyl 3-Methylbutyl 3-Methoxyphenyl 3-Methylbutyl 2,3,5,6-Tetrafluoro phenyl 2-Methylpropyl 2,4,6-Trifluorophenyl 3-Methylbutyl 2,4,6-Trifluorophenyl Butyl 2,3,6-Trifluorophenyl 2-Methylpropyl 2,3,6-Trifluorophenyl 3-Methylbutyl 2-Fluoro-6-trifluoromethylphenyl 2-Methylpropyl 2,4,6-Trichlorophenyl Pentyl 2,5-Dimethyl-3-furyl 3-Methylbutyl 4,5-Dimethyl-2-furyl Butyl 3,4-Dimethyl-2-furyl 2-Methylpropyl 3,4 -Dimethyl-2-furyl Pentyl 3,4-Dimethyl-2-furyl 3-Methylbutyl 3,4-Dimethyl-2-furyl Butyl 4-Methoxy-3-thienyl 3-Methylbutyl 4-Methoxy-3-thienyl Butyl 3-Chloro-2-thienyl Allyl 3-Bromo-4-fluorophenyl Propyl 3-Bromo-4-fluorophenyl Methyl 3-Iodophenyl Ethyl 3-Iodophenyl Allyl 3-Iodophenyl Propyl 3-Iodophenyl Propyl 3-Methyl-2-thienyl Propyl 3-Fluorobenzyl Pentyl 2,3,6-Trifluorophenyl 3-Methylbutyl 2,3,6-Trifluorophenyl Butyl 2-Chloro-6-fluorophenyl 2-Methylpropyl 2-Chloro-6-fluorophenyl Pentyl 2-Chloro-6-fluorophenyl 3-Methylbutyl 2-Chloro-6-fluorophenyl Butyl 2-Fluoro-6-trifluoromethylphenyl 3-Methylbutyl 3-Chlorobenzyl 2-Methylpropyl 4-Chlorobenzyl 3-Methylbutyl 2-Chlorobenzyl Butyl 2,3,5,6-Tetrafluoro phenyl 2-Methylpropyl 2,3,5,6-Tetrafluoro phenyl Pentyl 2,3,5,6-Tetrafluoro phenyl Allyl 3-Chloro-4-fluorophenyl Propyl 3-Chloro-4-fluorophenyl Propyl 4-Butylphenyl Propyl 3-Chloro-4-methoxyphenyl Allyl 5-Chloro-2-methoxyphenyl Propyl 5-Chloro-2-methoxyphenyl Propyl 3,4-Dichlorophenyl Propyl 4-Hexylphenyl Methyl 3-Bromo-4-methylphenyl Allyl 3-Bromo-4-methylphenyl Propyl 3-Bromo-4-methylphenyl Methyl 3-Bromo-4-fluorophenyl Butyl 2-Methoxybenzyl
21. A compound according to claim 1 which has the formula
Figure US20030092912A1-20030515-C00075
where R2 and R3 are defined in the following table:
R2 R3 Propyl 3-Chlorophenyl Propyl Phenyl Allyl 2-Fluorophenyl Propyl 2-Fluorophenyl Propyl 3-Fluoro-4-methylphenyl Methyl 2,5-Dichlorophenyl Propyl 2,5-Dichlorophenyl Propyl 4-Pentylphenyl Propyl 3-Bromophenyl Propyl 3-Methyl-2-thienyl
22. A pharmaceutical composition comprising a compound according to claim 1, together with at least one pharmaceutically acceptable carrier or excipient.
23. A method for the treatment or prevention of physiological disorders associated with modulation of the GABAa receptor complex by selective interaction with the benzodiazepine receptor, the method comprising administering to a patient in need thereof a GABAa receptor complex agonist, antagonist or inverse agonist of a compound according to claim 1.
24. A method according to claim 23 for the treatment of enhancing alertness and treating anxiety, overdoses of benzodiazepine-type drugs, Down Syndrome, depression, sleep, seizure and cognitive disorders both in human and non-human animals and domestic pets, especially dogs and cats and farm animals such as sheep, swine and cattle.
25. The use of a compound as claimed in claim 1 for the manufacture of a medicament for the treatment of enhancing alertness and treating anxiety, overdoses of benzodiazepine-type drugs, Down Syndrome, depression, sleep, seizure and cognitive disorders both in human and non-human animals and domestic pets, especially dogs and cats and farm animals such as sheep, swine and cattle.
26. A process for the preparation of a compound as claimed in claim 1.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007139818A2 (en) 2006-05-22 2007-12-06 The Board Of Trustees Of The Leland Stanford Junior University Pharmacological treatment of cognitive impairment
US8937087B2 (en) 2013-04-18 2015-01-20 Astellas Pharma Inc. Heterocyclic acetamide compound
US8946206B2 (en) 2010-12-17 2015-02-03 The Board Of Trustees Of The Leland Stanford Junior University Methods for improving cognitive function
AU2013204190B2 (en) * 2006-05-22 2016-09-22 The Board Of Trustees Of The Leland Stanford Junior University Pharmacological treatment of cognitive impairment

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6455734B1 (en) * 2000-08-09 2002-09-24 Magnesium Diagnostics, Inc. Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states
DE60014339T8 (en) * 1999-04-02 2006-04-27 Neurogen Corp., Branford ARYL AND HETEROARYL-CONDENSED AMINOALKYL-IMIDAZOLE DERIVATIVES: SELECTIVE MODULATORS OF GABAA RECEPTORS
US6380210B1 (en) * 1999-04-02 2002-04-30 Neurogen Corporation Heteroaryl fused aminoalkyl-imidazole derivatives: selective modulators of GABAa receptors
WO2002076987A1 (en) 2001-03-27 2002-10-03 Neurogen Corporation (oxo-pyrazolo[1,5a]pyrimidin-2-yl)alkyl-carboxamides
IL159811A0 (en) 2001-07-13 2004-06-20 Neurogen Corp Heteroaryl substituted fused bicyclic heteroaryl compounds as gabaa receptor ligands
JP2005526709A (en) 2002-01-10 2005-09-08 ニューロジェン・コーポレーション Melanin-concentrating hormone receptor ligand: substituted benzimidazole analogs
US7271271B2 (en) * 2004-06-28 2007-09-18 Amgen Sf, Llc Imidazolo-related compounds, compositions and methods for their use
US20060128777A1 (en) * 2004-11-05 2006-06-15 Bendall Heather H Cancer treatments
US8436190B2 (en) 2005-01-14 2013-05-07 Cephalon, Inc. Bendamustine pharmaceutical compositions
DE202005011043U1 (en) * 2005-07-06 2006-11-16 Mapa Gmbh Gummi- Und Plastikwerke Sucking and chewing articles for babies or toddlers
AR072777A1 (en) 2008-03-26 2010-09-22 Cephalon Inc SOLID FORMS OF BENDAMUSTINE CHLORHYDRATE
CN104224703A (en) * 2008-09-25 2014-12-24 赛福伦公司 Liquid Formulations Of Bendamustine
UA109109C2 (en) * 2009-01-15 2015-07-27 Сефалон, Інк. Crystalline forms of bendamustine free base (variants) and pharmaceutical composition for treatment of cancer (variants)
WO2020065642A1 (en) * 2018-09-25 2020-04-02 Pepticom Ltd. Positive allosteric modulators of gabaa receptor

Family Cites Families (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3255202A (en) 1963-08-23 1966-06-07 Union Carbide Corp Process for the preparation of 2-(acylamidoalkyl)benzimidazoles
US3455940A (en) 1965-12-07 1969-07-15 Herbert C Stecker Certain halo and dihalo n-substituted salicylamides
DE2300018C2 (en) 1973-01-02 1983-01-20 Knoll Ag, 6700 Ludwigshafen 1- [N-methyl-N - (β-phenylethyl) -3-aminopropyl] benzimidazole derivatives
HU168095B (en) 1973-05-09 1976-02-28
DE2428673A1 (en) 1974-06-14 1976-01-02 Bayer Ag CARBON ACID AMIDE, THE PROCESS FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT
JPH03200961A (en) 1989-10-03 1991-09-02 Fuji Photo Film Co Ltd Silver halide color photographic sensitive material
JPH04274425A (en) 1991-03-01 1992-09-30 Fuji Photo Film Co Ltd Processing method for silver halide color photographic sensitive material
US5296493A (en) 1991-05-23 1994-03-22 Neurosearch A/S 1-substituted-2-(N-phenyl-N-(phenylmethyl)methanamine)-4,5-dihydro-imidazoles and related compounds and their use in treating calcium overload in brain cells
US5877195A (en) 1992-11-06 1999-03-02 Bayer Aktiengesellschaft 2-perhalogenalkyl-substituted benzimidazoles, and their use as pesticides
AU675484B2 (en) 1993-03-24 1997-02-06 Neurosearch A/S Benzimidazole compounds, their use and preparation
JPH07133224A (en) 1993-11-10 1995-05-23 Kyowa Hakko Kogyo Co Ltd Medicine for arteriosclerosis
CZ382496A3 (en) 1994-06-29 1997-12-17 Smithkline Beecham Corp Compounds representing antagonists of vitronectin receptors, process of their preparation, intermediates of such process, pharmaceutical composition containing the compounds and their use
UA49805C2 (en) 1994-08-03 2002-10-15 Куміаі Кемікал Індастрі Ко., Лтд amino acid amide derivative, method of its producing (versions), AGROHORTICULTURAL fungicide and method of fungi DESTRUCtion
CA2218552C (en) 1995-04-21 2002-04-16 Neurosearch A/S Benzimidazole compounds and their use as modulators of the gabaa receptor complex
EE04310B1 (en) 1995-04-21 2004-06-15 Neurosearch A/S Benzimidazole compounds, pharmaceutical compositions containing these compounds and their use
EP0830359A1 (en) 1995-06-05 1998-03-25 Neurogen Corporation Novel substituted aryl and cycloalkyl imidazolones; a new class of gaba brain receptor ligands
US5955613A (en) 1995-10-13 1999-09-21 Neurogen Corporation Certain pyrrolopyridine derivatives; novel CRF1 specific ligands
AU722514B2 (en) 1995-12-28 2000-08-03 Fujisawa Pharmaceutical Co., Ltd. Benzimidazole derivatives
IL125033A0 (en) 1995-12-29 1999-01-26 Smithkline Beecham Corp Vitronectin receptor antagonists
NZ334868A (en) 1996-10-21 2001-02-23 Neurosearch As 1-Phenyl-benzimidazole compounds and their use as BAGA-a receptor modulators
DE19702130C1 (en) 1997-01-22 1998-04-23 Siemens Ag Sintered armature design e.g. for contactors
GB9801538D0 (en) 1998-01-23 1998-03-25 Merck Sharp & Dohme Pharmaceutical product
GB9805557D0 (en) 1998-03-16 1998-05-13 Merck Sharp & Dohme A combination of therapeutic agents
GB9805559D0 (en) 1998-03-16 1998-05-13 Merck Sharp & Dohme A combination of therapeutic agents
GB9805561D0 (en) 1998-03-16 1998-05-13 Merck Sharp & Dohme A combination of therapeutic agents
US6380210B1 (en) 1999-04-02 2002-04-30 Neurogen Corporation Heteroaryl fused aminoalkyl-imidazole derivatives: selective modulators of GABAa receptors

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007139818A2 (en) 2006-05-22 2007-12-06 The Board Of Trustees Of The Leland Stanford Junior University Pharmacological treatment of cognitive impairment
US20080009475A1 (en) * 2006-05-22 2008-01-10 Garner Craig C Pharmacological treatment of cognitive impairment
US8729067B2 (en) 2006-05-22 2014-05-20 The Board Of Trustees Of The Leland Stanford Junior University Pharmacological treatment of cognitive impairment
EP3050562A1 (en) 2006-05-22 2016-08-03 The Board of Trustees of the Leland Stanford Junior University Pharmacological treatment of cognitive impairment using gabaa receptor antagonists
AU2013204190B2 (en) * 2006-05-22 2016-09-22 The Board Of Trustees Of The Leland Stanford Junior University Pharmacological treatment of cognitive impairment
AU2013204190B9 (en) * 2006-05-22 2016-10-06 The Board Of Trustees Of The Leland Stanford Junior University Pharmacological treatment of cognitive impairment
US10172825B2 (en) 2006-05-22 2019-01-08 The Board Of Trustees Of The Leland Stanford Junior University Pharmacological treatment of cognitive impairment
US8946206B2 (en) 2010-12-17 2015-02-03 The Board Of Trustees Of The Leland Stanford Junior University Methods for improving cognitive function
US9789119B2 (en) 2010-12-17 2017-10-17 The Board Of Trustees Of The Leland Stanford Junior University Cognitive function
US8937087B2 (en) 2013-04-18 2015-01-20 Astellas Pharma Inc. Heterocyclic acetamide compound
US9708307B2 (en) 2013-04-18 2017-07-18 Astellas Pharma Inc. Heterocyclic acetamide compound

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