WO2002014275A2 - Derives sulfonamides heterocycliques - Google Patents

Derives sulfonamides heterocycliques Download PDF

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Publication number
WO2002014275A2
WO2002014275A2 PCT/US2001/021122 US0121122W WO0214275A2 WO 2002014275 A2 WO2002014275 A2 WO 2002014275A2 US 0121122 W US0121122 W US 0121122W WO 0214275 A2 WO0214275 A2 WO 0214275A2
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alkyl
compound
methyl
fluoro
methylethyl
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PCT/US2001/021122
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English (en)
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WO2002014275A3 (fr
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Scott Louis Forman
Winton Dennis Jones
Daryl Lynn Smith
Hamideh Zarrinmayeh
Dennis Michael Zimmerman
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Eli Lilly And Company
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Priority to US10/332,941 priority Critical patent/US20030220369A1/en
Priority to AU2001280470A priority patent/AU2001280470A1/en
Priority to EP01958860A priority patent/EP1313719A2/fr
Publication of WO2002014275A2 publication Critical patent/WO2002014275A2/fr
Publication of WO2002014275A3 publication Critical patent/WO2002014275A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • 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
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2

Definitions

  • EAA receptors excitatory amino acid receptors
  • Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell o membrane of the neurons are termed "ionotropic". This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists ⁇ /-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA).
  • NMDA ⁇ /-methyl-D-aspartate
  • AMPA alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
  • KA kainic acid
  • the second general type of receptor is the G-protein or second 5 messenger-linked "metabotropic" excitatory amino acid receptor.
  • This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in c-AMP formation, and changes in ion channel function.
  • Schoepp and Conn Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors o appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11 , 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
  • AMPA receptors are assembled from four protein sub-units known as GluR1 to GluR4, while kainic acid receptors are assembled from the sub-units GluR5 to GluR7, and KA-1 and KA-2. Wong and Mayer, Molecular
  • AMPA and kainic acid receptors are distinctive properties of AMPA and kainic acid receptors. Yamada and Tang, The Journal of Neuroscience, September 1993, 13(9): 3904-3915 and Kathryn M. Partin, J. Neuroscience, November 1 , 1996, 16(21): 6634-6647.
  • sulfonamide derivatives which are useful, for example, for treating psychiatric and neurological disorders, for example cognitive disorders; neuro-degenerative disorders such as Alzheimer's disease; age-related dementias; age-induced memory impairment; movement disorders such as tardive dyskinesia, Huntington's chorea, myoclonus, and Parkinson's disease; reversal of drug-induced states (such as cocaine, amphetamines, alcohol-induced states); depression; attention deficit disorder; attention deficit hyperactivity disorder; psychosis; cognitive deficits associated with psychosis, and drug-induced psychosis.
  • cognitive disorders for example cognitive disorders
  • neuro-degenerative disorders such as Alzheimer's disease; age-related dementias; age-induced memory impairment
  • movement disorders such as tardive dyskinesia, Huntington's chorea, myoclonus, and Parkinson's disease
  • drug-induced states such as cocaine, amphetamines, alcohol-induced states
  • depression attention deficit disorder
  • attention deficit hyperactivity disorder such as depression
  • psychosis attention deficit hyperactivity
  • R 1 represents (1-6C)alkyl, (2-6C)alkenyl, or NR 7 R 8 ;
  • R 2 and R 3 each independently represent hydrogen, F, (1-4C)alkyl, or
  • R 4a and R 4b each independently represent hydrogen, (1-4C) alkyl, (1-4C)alkoxy, I,
  • Q is selected from the following:
  • R represents hydrogen or (1-6C)alkyl
  • Y represents CH 2 CH 2 , CR 10 R 11 , NR 6 , S, or O;
  • Z represents O, S, or NH
  • R 6 represents hydrogen or (1-6C)alkyl
  • R 7 and R 8 each independently represent hydrogen or (1-4C)alkyl
  • R 9 represents hydrogen or (1-4C)aIkyl
  • R 10 and R 11 each independently represent hydrogen or (1-4C)alkyl; or a pharmaceutically acceptable salt thereof; with the proviso, that at least one of R 2 and R 3 represents F, and with the further proviso that the compound of formula I is other than (+)-5-[4-(1-fluoro-1-methyl-2- ⁇ [(methyIethyl)sulfonyl]amino ⁇ ethylphenyl]-indolin-2-one or (+)-6-[4-(1 -fluoro-1 - methyl- ⁇ [(methylethyl)sulfonyl]amino ⁇ ethylphenyl]-indolin-2-one.
  • the present invention further provides a method of potentiating glutamate receptor function in a patient, which comprises administering to said patient an effective amount of a compound of formula I.
  • the present invention provides a method of treating cognitive disorders in a patient, which comprises administering to said patient an effective amount of a compound of formula I.
  • the present invention further provides a method of treating cognitive deficits associated with psychosis in a patient, which comprises administering to said patient an effective amount of a compound of formula I.
  • the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for potentiating glutamate receptor function.
  • the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for potentiating glutamate receptor function.
  • the invention further provides pharmaceutical compositions comprising, a compound of formula I and a pharmaceutically acceptable diluent or carrier.
  • This invention also encompasses novel intermediates, and processes for the synthesis of the compounds of formula I.
  • glutamate receptor function refers to any increased responsiveness of glutamate receptors, for example AMPA receptors, to glutamate or an agonist, and includes but is not limited to inhibition of rapid desensitization or deactivation of AMPA receptors to glutamate.
  • AMPA receptor potentiator refers to a compound which inhibits the rapid desensitization or deactivation of AMPA receptors to glutamate. A wide variety of conditions may be treated or prevented by compounds of formula I and their pharmaceutically acceptable salts through their action as potentiators of glutamate receptor function.
  • Such conditions include those associated with glutamate hypofunction, such as psychiatric and neurological disorders, for example cognitive disorders and neuro-degenerative disorders such as Alzheimer's disease; age-related dementias; age-induced memory impairment; cognitive deficits due to autism, Down's syndrome and other central nervous system disorders with childhood onset, cognitive deficits post electroconvulsive therapy, movement disorders such as tardive dyskinesia, Hungtington's chorea, myoclonus, dystonia, spasticity, and Parkinson's disease; reversal of drug-induced states (such as cocaine, amphetamines, alcohol- induced states); depression; attention deficit disorder; attention deficit hyperactivity disorder; psychosis; cognitive deficits associated with psychosis, drug-induced psychosis, stroke, and sexual dysfunction.
  • Compounds of formula I may also be useful for improving memory (both short term and long term) and learning ability.
  • the present invention provides the use of compounds of formula I for the treatment of each of these conditions.
  • the present invention includes the pharmaceutically acceptable salts of the compounds defined by formula I.
  • a compound of this invention can possess a sufficiently acidic group, a sufficiently basic group, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
  • Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2-19 (1977) which are known to the skilled artisan.
  • Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and
  • salts examples include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprate, caprylate, acrylate, ascorbate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, propionate, phenylpropionate, salicylate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, mandelate, nicotinate, isonicotinate, cinnamate, hippurate, nitrate, phthalate, teraphthalate, butyne-1 ,4-dioate, butyne-1 ,
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the potassium and sodium salt forms are particularly preferred. It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that the above salts may form hydrates or exist in a substantially anhydrous form.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three- dimensional structures which are not interchangeable. The three-dimensional structures are called configurations.
  • enantiomer refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • chiral center refers to a carbon atom to which four different groups are attached.
  • diastereomers refers to stereoisomers which are not enantiomers.
  • two diastereomers which have a different configuration at only one chiral center are referred to herein as “epimers”.
  • racemate racemic mixture
  • racemic modification refer to a mixture of equal parts of enantiomers.
  • enantiomeric enrichment refers to the increase in the amount of one enantiomer as compared to the other.
  • a convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee”, which is found using the following equation:
  • E 1 is the amount of the first enantiomer and E 2 is the amount of the second enantiomer.
  • the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 70:30 is achieved
  • the ee with respect to the first enantiomer is 40%.
  • the final ratio is 90:10
  • the ee with respect to the first enantiomer is 80%.
  • An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred.
  • Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art.
  • the specific stereoisomers and enantiomers of compounds of formula I can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by J. Jacques, et al., “Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981 , and E.L. Eliel and S.H. Wilen," Stereochemistry of Organic Compounds", (Wiley- Interscience 1994), and European Patent Application No. EP-A-838448, published April 29, 1998. Examples of resolutions include recrystallization techniques or chiral chromatography.
  • Some of the compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.
  • the terms "R” and "S” are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
  • R rectus
  • S sinister
  • the priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice", (J.H. Fletcher, et al., eds., 1974) at pages 103-120.
  • ⁇ [(methylethyl)sulfonyl]amino ⁇ ethylphenyl]-indolin-2-one refers to the racemic mixture of a compound with the following structure:
  • (+)-6-[4-(1-fluoro-1-methyl- ⁇ [(methylethyl)sulfonyl]amino ⁇ ethylphenyl]-indolin-2-one refers to the racemic mixture of a compound with the following structure:
  • (1-6C)alkyl refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl.
  • the term "(1-6C)alkyl” includes within its definition the term "(1-4C)alkyl”.
  • (2-6C)alkenyl refers to a straight or branched, monovalent, unsaturated aliphatic chain having from two to six carbon atoms and includes, but is not limited to, ethenyl (also known as vinyl), 1-methylethenyl, 1- methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2- propenyl, 2-butenyl, 2-pentenyl, and the like.
  • (1-4C)alkoxy refers to a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom, and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, and the like.
  • halogen include fluorine, chlorine, bromine and iodine unless otherwise specified.
  • bis(pinacolato)diboron refers to the following structure:
  • the compounds of formula I can be prepared by one of ordinary skill in the art following, for example, the various procedures set forth in the Schemes below.
  • the reagents and starting materials are readily available to one of ordinary skill in the art, for example, see International Patent Application Publications: WO 98/33496 published August 6, 1998, and WO 00/06148 and WO 00/06158, both published February 10, 2000. All substituents, unless otherwise specified are as previously defined.
  • step A the compound of structure (1) is combined with the compound of structure (2) under conditions well known in the art to provide the compound of structure (3).
  • the compound (1 ) is dissolved in a suitable organic solvent.
  • suitable organic solvents include methylene chloride, tetrahydrofuran, and the like.
  • the solution is treated with a slight excess of a suitable base, and then cooled to about -78°C to about 0°C.
  • suitable bases include triethylamine, pyridine, 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU),and the like.
  • DBU diazabicyclo[5.4.0]undec-7-ene
  • Suitable leaving groups include, Cl, Br, and the like.
  • Cl is the preferred leaving group.
  • the reaction mixture is stirred at about 0°C to about 50°C for about 0.5 hours to about 16 hours.
  • the compound (3) is then isolated and purified by techniques well known in the art, such as extraction techniques and chromatography. For example, the mixture is washed with 10% sodium bisulfate, the layers separated and the aqueous extracted with several times with a suitable organic solvent, such as methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is then purified by flash chromatography on silica gel with a suitable eluent such as ethyl acetate/hexane to provide the compound (3).
  • step B the compound of structure (3) is fluorinated under conditions well known in the art to provide the compound of formula la.
  • compound (3) is dissolved in a suitable organic solvent, such as methylene chloride and the solution is cooled to about -78°C under an inert atmosphere, such as nitrogen.
  • DAST diethylaminosulfur trifluoride
  • a suitable organic solvent such as methylene chloride with stirring.
  • the reaction is then allowed to warm to room temperature (about 22°C) and the compound of formula la is then isolated and purified using techniques and procedures well known in the art, such as extraction techniques and chromatography.
  • the reaction is diluted with water and methylene chloride.
  • the layers are separated and the organic layer is washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude compound of formula la.
  • This crude material can then be purified by standard techniques, such as recrystallization from a suitable eluent, or chromatography on silica gel, with a suitable eluent, such as hexane/ethyl acetate to provide purified compound of formula la.
  • step B' the compound (1) is fluorinated in a manner analogous to the procedure described in step B above with DAST to provide the compound of structure (4).
  • step A' compound (4) is converted to the compound of formula la in a manner analogous to the procedure described in step A above.
  • the compounds of formula la can be prepared following the procedure described in Scheme II.
  • the reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.
  • step A the compound of structure (5) is coupled with compound of structure (6) under standard Suzuki coupling conditions to provide compound of structure (7).
  • Suzuki A., Journal of Organometallic Chemistry, 576, 147-168 (1999), and Miyaura and Suzuki, Chemical Reviews, 95, 2457- 2483 (1995) for examples of Suzuki-type coupling reactions and conditions.
  • compound (5) is combined with about 1.5 equivalents of compound (6), about 1.5 equivalents of potassium carbonate, and about 0.06 equivalents of tetrakis(triphenyl phosphine)palladium(O) in a suitable solvent or solvent mixture, such as dioxane/water (3:1). The mixture is then heated at about 100°C for about 18 hours.
  • reaction is then cooled and compound (7) is isolated and purified using standard techniques and procedures, such as extraction techniques and chromatography.
  • a suitable organic solvent such as ethyl acetate
  • the organic extracts are combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum.
  • the crude material is then purified by chromatography on silica gel with a suitable eluent, such as hexane/ethyl acetate to provide purified compound (15).
  • step B compound (7) is fluorinated under standard conditions to provide the compound of formula la.
  • compound (7) is dissolved in a suitable organic solvent, such as methylene chloride is added to about one equivalent of DAST at about -78°C with stirring under an atmosphere of nitrogen.
  • a suitable organic solvent such as methylene chloride
  • the reaction is allowed to warm to room temperature and the compound of formula la is isolated and purified using standard techniques, such as extraction techniques and chromatography.
  • the reaction mixture is diluted with water and a suitable organic solvent, such as methylene chloride.
  • the layers are separated and the organic layer is washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • the crude material is then purified by chromatography on silica gel with a suitable eluent, such as hexane/ethyl acetate to provide the purified compound of formula la.
  • step B' the compound (5) is fluorinated to provide the compound (8) in a manner analogous to the procedure described above in step B.
  • step A' the compound (8) is converted to the compound of formula la in a manner analogous to the procedure described above in step A.
  • step A the compound of structure (1) is combined with a compound of formula CIS0 2 NR 7 R 8 under standard conditions to provide the compound of structure (9).
  • compound (1 ) is dissolved in a suitable organic solvent, such as tetrahydrofuran and treated with about one equivalent of a suitable base, such as DBU at about 0°C.
  • a suitable base such as DBU at about 0°C.
  • the solution is then treated with about one equivalent of a compound of formula CIS0 2 NR 7 R 8 .
  • the reaction is then allowed to warm to room temperature and stirred for about 4 to 16 hours.
  • the reaction is then concentrated under vacuum to provide the crude product (9) which can then be purified by chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane.
  • step B compound (9) is converted to the compound of formula lb in a manner analogous to the procedure set forth in Scheme I, step B.
  • step B' the compound (1) is fluorinated in a manner analogous to the procedure described in Scheme I, step B with DAST to provide the compound of structure (4).
  • step A' compound (4) is converted to the compound of formula lb in a manner analogous to the procedure described above in step A.
  • the compounds of structure (5) can be prepared following the procedure described in Scheme IV.
  • the reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.
  • step A the compound of structure (10) is converted to the compound of structure (11 ) under standard conditions.
  • compound (10) is dissolved in a suitable organic solvent, such as dry tetrahydrofuran, containing excess 18-crown-6, and excess potassium cyanide.
  • a suitable organic solvent such as dry tetrahydrofuran, containing excess 18-crown-6, and excess potassium cyanide.
  • To this mixture at room temperature is added dropwise about 1.2 equivalents of cya ⁇ otrimethylsilane.
  • the reaction mixture is allowed to stir for about 1 to 4 hours to provide compound (11 ).
  • Compound (11 ) is then carried on directly to step B without isolation.
  • step A for example, compound (10) is combined with a catalytic amount of zinc iodide followed by slow addition of excess trimethylsilyl cyanide with the generation of heat.
  • the resulting solution is stirred at room temperature under nitrogen for about 8 to 16 hours.
  • the mixture is then diluted with a suitable organic solvent, such as chloroform, washed with saturated sodium bicarbonate, water, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide compound (11 ).
  • step B compound (11 ) is converted to compound of structure (12).
  • compound (11 ) prepared above, still in solution is treated with a solution of about 1.4 equivalents of borane in dimethylsulfide.
  • the reaction mixture is then heated to reflux for about 16 hours and then cooled to room temperature.
  • the reaction mixture is then cautiously treated with anhydrous HCI in methanol and allowed to stir for about one hour.
  • the product (12) is then isolated and purified using standard techniques and procedures. For example, the solvent is removed under vacuum and the residue triturated with a suitable organic solvent, such at methy t-butyl ether and the solid is collected by filtration.
  • the solid is then suspended in methylene chloride/tetrahydrofuran mixture (1 :2.4) and treated with 1 N NaOH until about pH 12.3 is reached.
  • the phases are separated and the organic phase is rinsed with brine.
  • the organic phase is then concentrated under vacuum and the residue triturated with diethyl ether to provide the purified compound (12).
  • step C compound (12) is then sulfonylated to provide compound (5) in a manner analogous to the procedure described in Scheme I, step A.
  • NBS N-bromosuccinimde
  • Me Me
  • Et methyl
  • Pr propyl
  • iPr isopropyl
  • RT room temperature
  • 6-Bromo-3,4-dihydro-1 H-quinolin-2-one (0.35 g, 1.35 mmol) was combined with pinacol borane (0.30 g, 2.33 mmol), [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (0.04 g, 0.05 mmol) and triethylamine (0.65 mL, 4.65 mmol) in dry acetonitrile (7 mL) and heated at reflux under N 2 for 4 hours then cooled to ambient temperature. The reaction mixture was dumped into diethyl ether and washed with water and saturated NaCI, dried (MgS0 4 ), filtered, and concentrated to give the title compound (0.44 g) as a light yellow oil which was used without purification.
  • 5-Bromo-1 ,3-dihydro-indol-2-one can be prepared following the procedure described by Sun et al., J. Med. Chem., 4 . , 2588-2603 (1998).
  • oxindole (1.30 g, 10 mmol) in dry acetonitrile(22.0 mL) at -10° C
  • NBS portionwise recrystallized NBS (2.00 g, 11.0 mmol) and the resulting suspension was stirred at -10 to 0° C for 3 hours.
  • the suspension was allowed to warm to ambient temperature and the mixture was filtered to give a white solid which was recrystallized (EtOH) to provide the title compound (1.47, 43%) as a slightly pink solid; mp 212-214° C.
  • 2-Bromo-6-nitro-phenyl acetic acid can be prepared according to the procedure of Magnus et al Tetrahedron Letters, 2,000, 835-838.
  • pyrrolidine (1.10 mL, .013 mol) was added to a stirred solution of 2-bromo-6- nitrotoluene (3.24 g, .015 mol) and dimethylformamide dimethyl acetal in dry DMF (20 mL) at ambient temperature under N 2 .
  • the resulting mixture heated and stirred for 3h at 110° C.
  • the dark brown reaction mixture was poured into Et 2 0- H 2 O.
  • step A The trimethylsilyl-protected cyanohydrin derivative of 4-iodoacetophenone was prepared in situ following generally the method disclosed by Greenlee and Hangauer, Tetrahedron Lett., 24(42), 4559 (1983). Accordingly, cyanotrimethylsilane (21.4 g, 0.216 mol) was added dropwise over 5 minutes to a dry, room temperature solution containing 4-iodoacetophenone (44.3 g, 0.180 mol), 18- resulting semi-solid was purified via silica crown-6 (1.6 g, 6.1 mmoles) and KCN (1.17g, 0.018 mol) in THF (100 mL). The resulting solution was allowed to stir for 2.5 h. TLC analysis (3:7 EtOAc / Hexanes) showed consumption of starting acetophenone.
  • step B A 10M solution of borane in dimethylsulfide (25 mL, 0.25 mol) was added rapidly to the reaction solution and the resulting mixture was heated at reflux for 16 h. The mixture was cooled to room temperature and anhydrous 10% (by wt) HCI in methanol was added slowly over 1 h (GAS)
  • step C Into a 250 mL 3 necked flask fitted with a stirrer and thermometer, was added dropwise 2-propanesulfonyl chloride (1.60 g, 0.011 mol) to 1-amino-2-(4-iodophenyl)propan-2-ol (2.77 gm, 0.01 mol) in 125 mL
  • step C In a 250 mL-3 neck flask fitted with a stirrer and thermometer, 2.10 g. of propanesulfonyl chloride was added dropwise to 2.77 g. of 1-amino-2-(4-iodophenyl)propan-2-ol and 2.30 g. of DBU in CH 2 CI 2 (150 mL) while stirring at 0°C under a nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred overnight at this temperature.
  • step B Into a 10 mL single neck flask, a solution of [2-hydroxy-2- (4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (158 mg, 0.41 mmol) in 1.7 mL CH 2 CI 2 was added syringe wise slowly to a solution of DAST (66 mg, 0.41 mmol) in 0.3 mL CH 2 CI 2 while stirring at -78°C under nitrogen. The reaction was then allowed to warm to room temperature and the mixture was diluted with H 2 O and CH 2 CI 2 .
  • step B Into a 100 mL 3-neck flask fitted with a stirrer and thermometer, 1.0 g. of [2-hydroxy-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine in CH 2 CI 2 (15 mL) was added dropwise to 0.3 mL DAST in CH 2 CL 2 (10 mL) while stirring at -78°C under a nitrogen atmosphere. Reaction was allowed to warm to room temperature and diluted with CH 2 CI 2 (50 mL). This organic layer was washed with H 2 O, dried over anhydrous Na 2 S0 4 , filtered, and concentrated under reduced vacuum to yield an oil. This material was purified via silica gel chromatography employing the
  • Example 1a Preparation of (+)-r2-fluoro-2-(4-iodophenyl)propyl1[(methylethyl)sulfonv ⁇ amine and (-)-[2-fluoro-2-(4-iodophenyl)propyll[(methylethyl)sulfonvnamine.
  • [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (2.0 g, prepared in example 1) was dissolved into 3A ethanol (30 mL) and was further diluted with heptane (20 mL).
  • 3A ethanol refers to ethanol containing 5% methanol.
  • the mixture was agitated via ultrasound to form a clear, colorless solution. This lot was loaded upon a 8 x 28 cm preparative Chiralpak AD chromatographic column that was pre-equilibrated with 60% 3A ethanol/40% heptane. Eluent flow was 300 mL/min and detection wavelength was 240 nm.
  • step A' (+)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine.(0.219 g, 0.57 mmol) bis(pinacolato)diboron (0.165 g, 0.65 mmol), PdCI 2 (dppf).CH 2 CI 2 (.024 g, .029 5 mmol) and potassium acetate (0.200 g, 2.0 mmol) were heated and stirred at 80° C in dry DMF (14.0 mL) for 3 hours under N 2 .
  • the reaction mixture was allowed to cool to ambient temperature and 5-bromo-1 ,3-dihydro-indol-2-one (0.138 g, 0.651 mmol), PdCI 2 (dppf).CH 2 CI 2 (.025 g, .031 mmol), and 2M Na 2 CO 3 (1.5, 3.0 mmol) were added respectively. Additional DMF (3.0 mL) was added . The o resulting mixture was stirred and heated at 80° C for 7 hours. The reaction mixture was allowed to cool to ambient temperature and poured into EtOAc(100 mL) and extracted with H 2 O. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, washed with brine and dried
  • step A' (-)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine(0.438g, 1.14mmol) bis(pinacolato)diboron (0..330 g, 1.30 mmol), PdCI 2 (dppf).CH 2 CI 2 (0.045 g, 0.055 mmol) and potassium acetate (0.400 g, 4.08 mmol) were heated and stirred at 80° C in dry DMF (35.0 mL) for 3 hours under N 2 .
  • the reaction mixture was allowed to cool to ambient temperature and 5-bromo-1 ,3-dihydro-indol-2-one (0.138 g, 0.651 mmol), PdCI 2 (dppf).CH 2 CI 2 (0.025 g, 0.031 mmol), and 2M Na 2 CO 3 (1.5, 3.0 mmol) were added respectively. Additional DMF (3.0 mL) was added. The resulting mixture was stirred and heated at 80° C for 7 hours. The reaction mixture was allowed to cool to ambient temperature and poured into EtOAc(100 mL) and extracted with H 2 O. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, washed with brine and dried (MgSO ).
  • step A' (+)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine.(10.2, 26.47 mmol) bis(pinacolato)diboron (0.7.40 g, 29.14 mmol), PdCI 2 (dppf).CH 2 CI 2 (0.86 g, 1.05 mmol) and potassium acetate (9.04 g, 92.13 mmol) were heated and stirred at 80° C in dry DMF (150.0 L) for 6 hours under N 2 . The reaction mixture was allowed to cool to ambient temperature and 6-bromo-1 ,3-dihydro-indol-2-one
  • step A' (-)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine (0.345 g, 0.896 mmol) bis(pinacolato)diboron (0.250 g, 0.984 mmol), PdCI 2 (dppf).CH 2 CI 2 (0.024 g, 0.029 mmol) and potassium acetate (0.338 g, 3.44 mmol) were heated and stirred at 80° C in dry DMF (25.0 mL) for 3 hours under N 2 .
  • step A' (+)-[2-fluoro-2-(4- iodophenyl)propyI][(methylethyl)sulfonyl]amine (0.310 g, 0.81 mmol) bis(pinacolato)diboron (0.224 g, 0.581 mmol), PdCI 2 (dppf).CH 2 CI 2 (0.020 g, 0.024 mmol) and potassium acetate (0.276 g, 2.81 mmol) were heated and stirred at 80° C in dry DMF (25.0 mL) for 3 hours under N 2 .
  • the reaction mixture was allowed to cool to ambient temperature and 6-bromo-3-methyl-1 ,3-dihydro-indol- 2-one (0.200 g, 0.885 mmol), PdCI 2 (dppf).CH 2 CI 2 (0.020 g, 0.024 mmol), and 2M Na 2 CO 3 (1.5, 3.0 mmol) were added respectively.
  • the resulting mixture was stirred and heated at 80° C for 6 hours.
  • the reaction mixture was allowed to cool to ambient temperature and poured into EtOAc and extracted with H 2 O. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, washed with brine and dried (MgS0 4 ).
  • racemate of example 6 and the opposite enantiomer of example 6, 6-[4-(1 -fluoro-1 -methyl- ⁇ [(methylethyl)sulfonyl]amino ⁇ ethylphenyl]-indolin-2-one and 6-[4-(1 -fluoro-1 - methyl- ⁇ [(methylethyl)sulfonyl]amino ⁇ ethylphenyl]-indolin-2-one (enantiomer 2) are readily prepared in a manner analogous to the procedure described in example 6 from racemic starting material and (-)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine, respectively.
  • Example 7 Preparation of 7-[4-(1 -fluoro-1 -methyl-2- ⁇ rmethylethv0sulfonyl1amino)- ethv
  • step A' [2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine (0.54 g, 0.1.4 mmol), bis(pinacolato)diboron (0.40 g, 0.1.6 mmol), PdCI 2 (dppf).CH 2 CI 2 (0.10 g, 0.12 mmol) and potassium acetate (0.69 g, 7.0 mmol) were heated and stirred at 80° C in dry DMF (10.0 mL) for 3 hours under nitrogen then stirred at 23° C for 22 h.
  • (+)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine 0.512 g, 0 1.33 mmol
  • bis(pinacolato)diboron 0.387 g, 1.53 mmol
  • PdCI 2 dppf
  • CH 2 CI 2 0.057 g, 0.070 mmol
  • potassium acetate (0.47g, 4.79 mmol
  • enantiomer 2 of example 10 is readily prepared in a manner analogous to the procedure described therein from (+)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine.
  • the ability of compounds of formula I to potentiate glutamate receptor- mediated response may be determined using fluorescent calcium indicator dyes (Molecular Probes, Eugene, Oregon, Fluo-3) and by measuring glutamate- evoked efflux of calcium into GluR4 transfected HEK293 cells, as described in more detail below.
  • 96 well plates containing confluent monolayers of HEK 293 cells stably expressing human GluR4B (obtained as described in European Patent Application Publication Number EP-A1-583917) are prepared.
  • the tissue culture medium in the wells is then discarded, and the wells are each washed once with 200 ⁇ l of buffer (glucose, 10mM, sodium chloride, 138mM, magnesium chloride, 1mM, potassium chloride, 5mM, calcium chloride, 5mM, N-[2- hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid], 10mM, to pH 7.1 to 7.3).
  • the plates are then incubated for 60 minutes in the dark with 20 ⁇ M Fluo3-AM dye (obtained from Molecular Probes Inc., Eugene, Oregon) in buffer in each well. After the incubation, each well is washed once with 100 ⁇ l buffer, 200 ⁇ l of buffer is added and the plates are incubated for 30 minutes.
  • 20 ⁇ M Fluo3-AM dye obtained from Molecular Probes Inc., Eugene, Oregon
  • Solutions for use in the test are also prepared as follows. 30 ⁇ M, 10 ⁇ M, 3 ⁇ M and 1 ⁇ M dilutions of test compound are prepared using buffer from a 10 mM solution of test compound in DMSO. 100 ⁇ M cyclothiazide solution is prepared by adding 3 ⁇ l of 100 mM cyclothiazide to 3 ml of buffer. Control buffer solution is prepared by adding 1.5 ⁇ l DMSO to 498.5 ⁇ l of buffer.
  • test is then performed as follows. 200 ⁇ l of control buffer in each well is discarded and replaced with 45 ⁇ l of control buffer solution. A baseline fluorescent measurement is taken using a FLUOROSKAN II fluorimeter (Obtained from Labsystems, Needham Heights, MA, USA, a Division of Life
  • test compounds and cyclothiazide solutions are determined by subtracting the second from the third reading (fluorescence due to addition of glutamate in the presence or absence of test compound or cyclothiazide) and are expressed relative to enhance fluorescence produced by 100 ⁇ M cyclothiazide.
  • HEK293 cells stably expressing human GluR4 are used in the electrophysiological characterization of AMPA receptor potentiators.
  • recording pipettes have a resistance of 2-3 M ⁇ .
  • whole-cell voltage clamp technique Hamill et al.(1981)Pfl ⁇ gers Arch., 391 : 85-100
  • cells are voltage-clamped at -60mV and control current responses to 1 mM glutamate are evoked.
  • the potentiation of these responses by 100 ⁇ M cyclothiazide is determined by its inclusion in both the bathing solution and the glutamate-containing . solution. In this manner, the efficacy of the test compound relative to that of cyclothiazide can be determined.
  • the present invention provides a pharmaceutical composition, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
  • compositions are prepared by known procedures using well-known and readily available ingredients.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragcanth, gelatin, calcium silicate, micro-crystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
  • compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 mg to about 500 mg, more preferably about 5 mg to about 300 mg (for example 25 mg) of the active ingredient.
  • unit dosage form refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.
  • Capsules are prepared by mixing the compound with a suitable diluent and filling the proper amount of the mixture in capsules.
  • suitable diluents include inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like.
  • Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
  • a lubricant is generally necessary in a tablet formulation to prevent the tablet and punches from sticking in the die.
  • the lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
  • Tablet disintegrators are substances which swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, may be used, as well as sodium lauryl sulfate.
  • Enteric formulations are often used to protect an active ingredient from the strongly acidic contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in acidic environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.
  • Tablets are often coated with sugar as a flavor and sealant, or with film- forming protecting agents to modify the dissolution properties of the tablet.
  • the compounds may also be formulated as chewable tablets, by using large amounts of pleasant-tasting substances such as mannitol in the formulation, as is now well-established practice.
  • Instantly dissolving tablet-like formulations are also now frequently used to assure that the patient consumes the dosage form, and to avoid the difficulty in swallowing solid objects that bothers some patients.
  • Cocoa butter is a traditional suppository base, which may be modified by addition of waxes to raise its melting point slightly.
  • Water- miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use, also.
  • Transdermal patches have become popular recently. Typically they comprise a resinous composition in which the drugs will dissolve, or partially dissolve, which is held in contact with the skin by a film which protects the composition. Many patents have appeared in the field recently. Other, more complicated patch compositions are also in use, particularly those having a membrane pierced with pores through which the compound of formula I is pumped by osmotic action.
  • Hard gelatin capsules are prepared using the following ingredients:
  • the above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
  • Formulation 2 Tablets each containing 60 mg of active ingredient are made as follows:
  • active ingredient refers to a compound of formula I.
  • the active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • patient refers to a mammal, such as a mouse, guinea pig, rat, dog, horse, or human. It is understood that the preferred patient is a human.
  • the terms “treating” or “to treat” each mean to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder.
  • the methods of this invention encompass both therapeutic and prophylactic administration.
  • the term "effective amount” refers to the amount of a compound of formula I which is effective, upon single or multiple dose administration to a patient, in treating the patient suffering from the named disorder.
  • an effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
  • determining the effective amount or dose a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • the compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, bucal or intranasal routes. Alternatively, the compound may be administered by continuous infusion.
  • a typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of the active compound of this invention. Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.
  • R 2 compounds of formula I wherein R 2 is hydrogen, methyl or ethyl are preferred, with hydrogen or methyl being most preferred.
  • R 2 when R 2 is methyl, it is most preferred that R 3 is hydrogen, and when R 2 is hydrogen, it is most preferred that R 3 is methyl.
  • R 4a and R 4b compounds of formula I wherein R 4a and R 4b are each independently hydrogen, methyl, ethyl, methoxy, ethoxy, Br, Cl or F are preferred, with hydrogen, methyl, methoxy and F being most preferred.
  • R 6 compounds of formula I wherein R 6 is hydrogen or methyl are preferred.
  • R 7 and R 8 compounds of formula I wherein R 7 and R 8 are each independently hydrogen, methyl, or ethyl are preferred, with methyl being most preferred.
  • R 9 compounds of formula I wherein R 9 is hydrogen, methyl, or ethyl are preferred, with methyl being most preferred.
  • R 10 and R 11 compounds of formula I wherein R 10 is hydrogen or methyl are preferred, and R 11 is hydrogen or methyl are preferred. It is most preferred that R 10 and R 11 each represent hydrogen.
  • Y and Z compounds of formula 1 wherein Y is N when Z is CH 2 when Z is O and Y is CH 2 CH 2 when Z is O are preferred.

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Abstract

La présente invention concerne certains dérivés sulfonamides hétérocycliques représentés par la formule (I) qui permettent de potentialiser la fonction de récepteur du glutamate chez un patient et qui conviennent bien pour le traitement de diverses pathologies, dont des troubles psychiatriques et neurologiques.
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US6596716B2 (en) 1997-02-04 2003-07-22 Eli Lilly And Company 2-propane-sulphonamide derivatives
EP1958947A1 (fr) 2007-02-15 2008-08-20 Ranbaxy Laboratories Limited Inhibiteurs de la phosphodiestérase de type 4
WO2011097337A1 (fr) * 2010-02-04 2011-08-11 Advanced Neural Dynamics, Inc. Nouveaux sulfamides présentant une action neuroprotectrice et leurs procédés d'utilisation
WO2011109277A1 (fr) * 2010-03-04 2011-09-09 Merck Sharp & Dohme Corp. Modulateurs allostériques positifs de mglur2
WO2012020424A1 (fr) 2010-08-12 2012-02-16 Arch Pharmalabs Limited Procédé court pour la préparation de ziprasidone et de ses intermédiaires
WO2012021382A1 (fr) * 2010-08-12 2012-02-16 Merck Sharp & Dohme Corp. Modulateurs allostériques positifs de mglur2
WO2013016411A1 (fr) * 2011-07-28 2013-01-31 Garry Robert Smith Nouveaux sulfamides cycliques fluorés présentant une action neuroprotectrice et leur procédé d'utilisation
EP2579717A2 (fr) * 2010-06-09 2013-04-17 Merck Sharp & Dohme Corp. Modulateurs allostériques positifs de mglur2
WO2013093928A1 (fr) 2011-12-20 2013-06-27 Arch Pharmalabs Limited Procédé amélioré de préparation de 2-oxindoles de formule i, une matière première clé pour la fabrication de médicaments et de leurs intermédiaires
US8609849B1 (en) 2010-11-30 2013-12-17 Fox Chase Chemical Diversity Center, Inc. Hydroxylated sulfamides exhibiting neuroprotective action and their method of use
EP3311842A1 (fr) 2013-06-13 2018-04-25 VeroScience LLC Compositions et procédés de traitement des troubles métaboliques

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EP0976744A1 (fr) * 1998-07-31 2000-02-02 Eli Lilly And Company Dérivés amides, de carbamates et de l'urée ayant une activité stimulatrice de la fonction des récepteurs de glutamate
WO2000066546A2 (fr) * 1999-04-30 2000-11-09 Eli Lilly And Company Derives de monofluoralkyle

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Publication number Priority date Publication date Assignee Title
EP0976744A1 (fr) * 1998-07-31 2000-02-02 Eli Lilly And Company Dérivés amides, de carbamates et de l'urée ayant une activité stimulatrice de la fonction des récepteurs de glutamate
WO2000066546A2 (fr) * 1999-04-30 2000-11-09 Eli Lilly And Company Derives de monofluoralkyle

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7135487B2 (en) 1997-02-04 2006-11-14 Eli Lilly And Company Sulphonamide derivatives
US6596716B2 (en) 1997-02-04 2003-07-22 Eli Lilly And Company 2-propane-sulphonamide derivatives
EP1958947A1 (fr) 2007-02-15 2008-08-20 Ranbaxy Laboratories Limited Inhibiteurs de la phosphodiestérase de type 4
WO2011097337A1 (fr) * 2010-02-04 2011-08-11 Advanced Neural Dynamics, Inc. Nouveaux sulfamides présentant une action neuroprotectrice et leurs procédés d'utilisation
WO2011109277A1 (fr) * 2010-03-04 2011-09-09 Merck Sharp & Dohme Corp. Modulateurs allostériques positifs de mglur2
US9108937B2 (en) 2010-03-04 2015-08-18 Merck Sharp & Dohme Corp. Positive allosteric modulators of mGluR2
EP2579717A2 (fr) * 2010-06-09 2013-04-17 Merck Sharp & Dohme Corp. Modulateurs allostériques positifs de mglur2
EP2579717A4 (fr) * 2010-06-09 2013-12-11 Merck Sharp & Dohme Modulateurs allostériques positifs de mglur2
WO2012021382A1 (fr) * 2010-08-12 2012-02-16 Merck Sharp & Dohme Corp. Modulateurs allostériques positifs de mglur2
US8993779B2 (en) 2010-08-12 2015-03-31 Merck Sharp & Dohme Corp. Positive allosteric modulators of MGLUR2
WO2012020424A1 (fr) 2010-08-12 2012-02-16 Arch Pharmalabs Limited Procédé court pour la préparation de ziprasidone et de ses intermédiaires
US8609849B1 (en) 2010-11-30 2013-12-17 Fox Chase Chemical Diversity Center, Inc. Hydroxylated sulfamides exhibiting neuroprotective action and their method of use
WO2013016411A1 (fr) * 2011-07-28 2013-01-31 Garry Robert Smith Nouveaux sulfamides cycliques fluorés présentant une action neuroprotectrice et leur procédé d'utilisation
WO2013093928A1 (fr) 2011-12-20 2013-06-27 Arch Pharmalabs Limited Procédé amélioré de préparation de 2-oxindoles de formule i, une matière première clé pour la fabrication de médicaments et de leurs intermédiaires
EP3311842A1 (fr) 2013-06-13 2018-04-25 VeroScience LLC Compositions et procédés de traitement des troubles métaboliques

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