WO2002066426A2 - Fluoro oxindole derivatives as modulators of kcnq potassium channels - Google Patents

Fluoro oxindole derivatives as modulators of kcnq potassium channels Download PDF

Info

Publication number
WO2002066426A2
WO2002066426A2 PCT/US2002/004304 US0204304W WO02066426A2 WO 2002066426 A2 WO2002066426 A2 WO 2002066426A2 US 0204304 W US0204304 W US 0204304W WO 02066426 A2 WO02066426 A2 WO 02066426A2
Authority
WO
WIPO (PCT)
Prior art keywords
chloro
fluoro
phenyl
indol
dihydro
Prior art date
Application number
PCT/US2002/004304
Other languages
English (en)
French (fr)
Other versions
WO2002066426A3 (en
Inventor
Piyasena Hewawasam
Pierre Dextraze
Valentin K. Gribkoff
Gene G. Kinney
Steven I. Dworetzky
Original Assignee
Bristol-Myers Squibb Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to JP2002565943A priority Critical patent/JP2004531483A/ja
Priority to HU0400063A priority patent/HUP0400063A2/hu
Priority to EP02714888A priority patent/EP1363624A2/en
Priority to CA002438805A priority patent/CA2438805A1/en
Publication of WO2002066426A2 publication Critical patent/WO2002066426A2/en
Publication of WO2002066426A3 publication Critical patent/WO2002066426A3/en

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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

Definitions

  • the present invention is directed to novel 3-fluoro-3-phenyl oxindole derivatives which are modulators of KCNQ potassium channels and are therefore useful in treating disorders responsive to the modulation of the potassium channels.
  • the present invention also provides a method of treatment with the novel 3-fluoro oxindole derivatives and to pharmaceutical compositions thereof.
  • K + channels are considered to be the most diverse class of ion channels and have several critical roles in cell function. This has been demonstrated in neurons where K + channels are responsible, in part, for determining cell excitability by contributing to membrane repolarization following depolarization, resting membrane potential, and regulation of neurotransmitter release.
  • the M-current has long been described, by electrophysiology recording methods and by pharmacology, as a dominant conductance in controlling neuronal excitability. Pharmacological activation or suppression of M-currents by small molecules could have profound effects in controlling neuronal excitability. Recently, Wang et al.
  • KCNQ2 and KCNQ3 potassium channels underlies the native M-current in neurons.
  • Activation or opening of the KCNQ channel(s), particularly the KCNQ2 or KCNQ2/3 channel(s), mutated or wild type may prove to be beneficial in increasing hyperpolarization of neurons, thereby resulting in protection from abnormal synchronous firing during a migraine attack.
  • the present invention provides a solution to the problem of abnormal synchronous firing of neurons related to migraine headache by demonstrating that modulators, preferably openers, of KCNQ potassium channels increases hyperpolarization of neurons which protects against abnormal synchronous neuron firing involved in migraine attacks.
  • migraine migraine
  • anti- migraine agents which are effective in the treatment of acute migraine, as well as in the prodrome phase of a migraine attack.
  • migraine afflicts a large percentage of the population, there is a need to discover compounds and agents that are useful in therapeutics and treatments, and as components of pharmaceutical compositions, for reducing, ameliorating, or alleviating the pain and discomfort of migraine headache and other symptoms of migraine.
  • the present invention satisfies such a need by providing compounds that function as openers of the KCNQ family of potassium channel proteins to serve as anti-migraine agents or drugs and to comprise compositions to treat migraine, as described herein.
  • a number of substituted oxindoles have been disclosed as neuroanabolic agents by H. Kuch et al. in U.S. Patent Nos. 4,542,148, issued Sep. 17, 1985 and 4,614,739, issued Sep. 30, 1986.
  • the present invention provides novel 3-fluoro oxindole derivatives having the general Formula I
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and Y are as defined below, or a nontoxic pharmaceutically acceptable salt, solvate or hydrate thereof which are openers or activators of KCNQ potassium channels.
  • the present invention also provides pharmaceutical compositions comprising said 3-fluoro oxindole derivatives and to the method of treatment of disorders sensitive to KCNQ potassium channel opening activity such as migraine.
  • the present invention provides novel 3-fluoro oxindole derivatives which are modulators of the KCNQ potassium channels and which have the general Formula I
  • R 1 , R 2 , R 3 and R 4 each are independently hydrogen, C,_ 4 alkyl, halogen, fluoromethyl, trifluoromethyl, phenyl, 4-methylphenyl or 4- trifluoromethylphenyl;
  • R 5 is C-, .3 alkyl optionally substituted with one to three same or different groups selected from fluoro and chloro, provided R 5 is not C 1 - 6 alkyl when Y is O; Y is O or S; and R 6 and R 7 each are independently hydrogen, chloro, bromo or trifluoromethyl.
  • the present invention also provides a method for the treatment or alleviation of disorders associated with KCNQ potassium channel polypeptides and, in particular, human KCNQ potassium channel polypeptides which are especially involved in reducing or alleviating migraine or a migraine attack, which comprises administering together with a conventional adjuvant, carrier or diluent a therapeutically effective amount of a compound of Formula I.
  • C 1 - 6 alkyl as used herein and in the claims means straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, te/ ⁇ -butyl, pentyl, 4-methylbutyl, hexyl and the like.
  • C ⁇ - alkyl as used herein and in the claims means straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and fetf-butyl.
  • halogen as used herein and in the claims is intended to include bromine, chlorine, iodine and fluorine.
  • the present invention includes the racemate as well as the individual enantiomeric forms of the compounds of Formula I as described herein and in the claims.
  • Preferred embodiments of compounds of Formula I are the racemate and the single enantiomer which includes mostly the one stereoisomer having a (+) optical rotation is most preferred.
  • Mixtures of isomers of the compounds of the examples or chiral presursors thereof can be separated into individual isomers according to methods which are known per se, e.g. fractional crystallization, adsorption chromatography or other suitable separation processes.
  • Resulting racemates can be separated into antipodes in the usual manner after introduction of suitable salt-forming groupings, e.g. by forming a mixture of diastereosiomeric salts with optically active salt-forming agents, separating the mixture into diastereomeric salts and converting the separated salts into the free compounds.
  • suitable salt-forming groupings e.g. by forming a mixture of diastereosiomeric salts with optically active salt-forming agents, separating the mixture into diastereomeric salts and converting the separated salts into the free compounds.
  • the enantiomeric forms may also be separated by fractionation through chiral high pressure liquid chromatography columns, according to procedures described herein.
  • Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms including hydrated forms such as monohydrate, dihydrate, trihydrate, hemihydrate, tetrahydrate and the like.
  • the products may be true solvates, while in other cases, the products may merely retain adventitious solvent or be a mixture of solvate plus some adventitious solvent. It should be appreciated by those skilled in the art that solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • the term "therapeutically effective amount” means the total amount of each active component of the method that is sufficient to show a meaningful patient benefit, i.e., amelioration or healing of conditions which respond to modulation of the KCNQ potassium channels.
  • a meaningful patient benefit i.e., amelioration or healing of conditions which respond to modulation of the KCNQ potassium channels.
  • the term refers to that ingredient alone.
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • KCNQ as used herein and in the claims means the family of KCNQ2, KCNQ3, KCNQ4, and KCNQ5 potassium channel polypeptides as well as heteromultimers of different individual family members which include but are not limited to KCNQ2/3, KCNQ2/5 and KCNQ3/5.
  • Preferred compounds for use in the method of the present invention include the compounds of Formula I listed below:
  • the starting material isatins of Formula III, used in Reaction Scheme 1 were obtained from either commercial sources or prepared by well-known literature procedures such as those described by Hewawasam, P. et al. in U.S. Patent Nos. 5,565,483 and 5,602,169; Hewawasam, P., et al., Tetrahedron Lett., 1994, 35, 7303; Gassman, P. et al., J. Org. Chem., 1977, 42, 1344; Stolle, R., J. Prakt. Chem., 1922, 105, 137; and Sandmeyer, T., Helv. Chim. Ada, 1919, 2, 234.
  • Reaction Scheme 1 , Step A, (i) shows the desired substituted isatin of Formula III is first treated with a suitable base in an aprotic solvent at approximately 0°C in order to generate the corresponding isatin salt.
  • Preferred bases include metal hydride bases, particularly sodium hydride, and a preferred aprotic solvent is THF.
  • the isatin salt is then reacted with an appropriate 2- magnesium bromide aryloxy ether of Formula IV in an appropriate solvent, such as THF within the temperature range of -20°C to room temperature (rt) to provide the 3-hydroxyoxindoles of Formula V.
  • a preferred method for the fluorination is to treat the 3-hydroxyoxindole of Formula V with diethylaminosulfur trifluoride (DAST) in an aprotic solvent, such as dichloromethane (as described in Example 1 ) to afford the 3- fluorooxindole of Formula la.
  • DAST diethylaminosulfur trifluoride
  • an aprotic solvent such as dichloromethane (as described in Example 1 )
  • Reaction Scheme 2 depicts the reaction of a magnesium phenolate (prepared by mixing an appropriate phenol and ethyl magnesium bromide) with the desired isatins of Formula III in CH 2 C to afford the desired 3- hydroxyoxindoles of Formula VI (as described in Preparation 5).
  • Selective alkylation of the phenolic hydroxyl moiety of the 3-hydroxyoxindole derivatives of Formula VI is accomplished by treating the compound of Formula VI with R 5 X (wherein X is a leaving group such as bromo or iodo) in the presence of a base, such as potassium carbonate, in 2-butanone at approximately 80°C to afford the 3-hydroxyoxindole ethers of Formula V.
  • Step (a) Diazotization of the 2-bromoanilines of Formula VII as shown in Reaction Scheme 3, Step (a), is carried out by treatment with sodium nitrite and hydrogen tetrafluoroborate in ethanol to provide the diazonium tetrafluoroborate of Formula VIII (as described for the preparation of 2-bromo-4-chlorobenzenediazonium tetrafluoroborate in Preparation 7).
  • Step (b) Thioalkylation of the 2-bromobenzene diazonium salts of Formula VIII is carried out in Step (b) by treating an acetonitrile solution of the diazonium salt with a sodium thioalkoxide at 0°C (as described for the preparation of 2-bromo-4-chloro-1-methylthiobenzene in Preparation 8).
  • 2-Bromobenzene disulfides of Formula IX are prepared by treating a hot aqueous solution of potassium ethyl xanthate with the diazonium salt of Formula VIII followed by treatment with potassium hydroxide and ethanol (as described for the preparation of 2-bromo-4-chlorobenzene disulfide in Preparation 9).
  • 2-Bromobenzenethiols of Formula XI are prepared by reduction of the disulfide of Formula IX with sodium borohydride in THF (as described for the preparation of 2-bromo-4-chlorobenzenethioI in Preparation 10).
  • 2-Bromo-1-(tetrahydropyran-2-ylthio)benzene derivatives of Formula XII are prepared from the thiols of Formula XI by treatment with para-toluenesulfonic acid (p-TSA) and 3,4-dihydro-2-H- pyran in CH 2 CI 2 as described for the preparation of 2-bromo-4-chloro-1- (tetrahydropyran-2-ylthio)benzene in Preparation 11.
  • p-TSA para-toluenesulfonic acid
  • Reaction Scheme 4 depicts the preparation of compounds of Formula lb. Lithiation of 2-bromo-1-(tetrahydropyran-2-ylthio)benzene derivatives is effected by treatment with a strong base, such as tert- butyllithium in anhydrous THF at approximately -78°C.
  • a strong base such as tert- butyllithium in anhydrous THF at approximately -78°C.
  • the resultant aryl lithium intermediate of Formula Xlla is added to the sodium salt of the desired isatin of Formula III (prepared by treatment of isatin with NaH in THF) in THF to provide intermediates of Formula XIV (as described for the preparation of 3-(5-chloro-2-(tetrahydropyran-2-ylthio)phenyl)-3-hydroxy- 1 -/-6-trifluoromethyl-1 ,3-dihydroindol-2-one in Preparation 12).
  • the intermediate of Formula XIV is then treated with silver nitrate in a polar solvent, such as DMF, to provide the silver salt of Formula XV.
  • the silver salt of the compound of Formula XV is then alkylated by treatment with an appropriate electrophile, R 5 X (e.g. ethyl iodide as used for the synthesis of 3-(5-chloro-2-ethylthiophenyl)-3-hydroxy-1 H-6-trifluoromethyl-1 ,3- dihydroindol-2-one in Preparation 14).
  • R 5 X e.g. ethyl iodide as used for the synthesis of 3-(5-chloro-2-ethylthiophenyl)-3-hydroxy-1 H-6-trifluoromethyl-1 ,3- dihydroindol-2-one in Preparation 14
  • hydroxyindolones of Formula XVI can be prepared by addition of a Grignard reagent of Formula Xa to the desired isatins of Formula III as described in Preparation 13.
  • fluorination of 3-hydroxyindole derivatives of Formula XVI is carried out using diethylaminosulfur trifluoride in an aprotic solvent such as CH 2 CI 2 at approximately -78°C to provide the fluoro derivatives of Formula lb (as described in Example 5).
  • K + channels are structurally and functionally diverse families of K + -selective channel proteins which are ubiquitous in cells, indicating their central importance in regulating a number of key cell functions [Rudy, B., Neuroscience, 25: 729-749 (1988)]. While widely distributed as a class, K + channels are differentially distributed as individual members of this class or as families. [Gehlert, D.R., et al.,
  • K + channels can respond to important cellular events such as changes in the intracellular concentration of ATP or the intracellular concentration of calcium (Ca2 + ).
  • K + channels The central role of K + channels in regulating numerous cell functions makes them particularly important targets for therapeutic development. [Cook, N.S., Potassium channels: Structure, classification, function and therapeutic potential. Ellis Horwood, Chinchester (1990)].
  • KCNQ2 the KCNQ family exemplified by KCNQ2, KCNQ2/3 heteromultimeres, and KCNQ5
  • KCNQ2 the KCNQ family exemplified by KCNQ2, KCNQ2/3 heteromultimeres, and KCNQ5
  • KCNQ5 the KCNQ family exemplified by KCNQ2, KCNQ2/3 heteromultimeres, and KCNQ5
  • KCNQ channels such as the KCNQ2 and KCNQ2/3 channel opener retigabine, exerts its cellular effects by increasing the open probability of these channels [Main J., Mol Pharmacol 58(2):253-62 (2000); Wickenden, A. iaL Mol. Pharm. 58:591-600 (2000)].
  • This increase in the opening of individual KCNQ channels collectively results in the hyperpolarization of cell membranes, particularly in depolarized cells, produced by significant increases in whole-cell KCNQ-mediated conductance.
  • KCNQ- mediated currents The ability of compounds described in the present invention to open KCNQ channels and increase whole-cell outward (K + ) KCNQ- mediated currents was assessed under voltage-clamp conditions by determining their ability to increase cloned mouse KCNQ2 (mKCNQ2)- mediated, heteromultimeric KCNQ2/3 (m ⁇ KCNQ2/3)-mediated, and human KCNQ5 (hKCNQ ⁇ )-mediated outward currents heterologously expressed in Xenopus oocytes. Oocytes were prepared and injected using standard techniques; each oocyte was injected with approximately 50 nl of mKCNQ2, or hKCNQ ⁇ cRNA.
  • oocytes were maintained at 17° in ND96 medium consisting of (in mM): NaCI, 90; KCI, 1.0; CaCI 2> 1.0; MgCI 2 , 1.0; HEPES, 5.0; pH 7.5. Horse serum (5%) and penicillin/streptomycin (5%) were added to the incubation medium. Recording commenced 2-6 days following mRNA injection.
  • MBS Modified Barth's Solution
  • Rats Male Long-Evans rats (Harlan, 250-400g) were used in the experiments described in this example. Prior to testing, rats were allowed access to food and water ad libitum and were maintained on a 12:12-h light/dark cycle. Rats were group housed in an Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) accredited facility and cared for in strict compliance with all applicable regulations.
  • AAA Laboratory Animal Care
  • Superior sagital sinus (SSS) stimulation and recording were performed in a manner consistent with previously published methods using cat (Hoskin et al., 1996) and rat (Cumberbatch et al., 1998; 1999) animal models. Rats were anesthetized with 1.2 g/kg i.p. urethane (#U- 2500, Sigma Chemical Company, St. Louis, MO) and given supplemental urethane as needed. In the case of intravenous (i.v.) drug administration, the jugular veins of the rats were cannulated using sylastic tubing pre- filled with vehicle.
  • Rats were placed in a stereotaxic device (#1730, David Kopf Instruments, Tujunga, CA) and an incision was made to expose the entire skull that continued caudally to the level of the C1/C2 vertebral juncture.
  • a microdrill #770, Dremel, Racine, Wl
  • #4 carbide burr Henry Schein, Melville, NY
  • a square section of skull was removed extending from the bregma position, rostrally, to the lambda position, caudally.
  • the underlying dura mater was incised bilateral to the SSS and a small section of Parafilm® (American National Can, Neenah, WI) was placed under the SSS to isolate the stimulation electrode.
  • the SSS was stimulated using insulated silver electrodes bent at their ends to form a hook.
  • the dorsal region of the vertebra corresponding to C2 was removed for access to the trigeminal nucleus caudalis.
  • Stimulated field responses were recorded in the trigeminal nucleus caudalis using Teflon coated stainless-steel microelectrodes (5 megaohms impedance, Frederick Haer, Brunswick, ME) and amplified and filtered (0.1 Hz - 10 kHz) using a differential amplifier (#lsoDAM8, World Precision Instruments, Sarasota, FL). Stimulation voltage (250 ⁇ sec, 40-130V) was delivered using a Grass S88 (Grass Medical Instruments, Quincy, MA) stimulator and stimulus isolation unit (Grass #SIU5) at a rate of 0.3 Hz.
  • Grass S88 Grass Medical Instruments, Quincy, MA
  • Amplified potentials were captured with an analog-to-digital converter (#1401 plus, Cambridge Electronic Design, Cambridge, UK) and commercially available software (#Signal, Cambridge Electronic Design). Low temperature wax was applied to both the recording and stimulation sites to prevent dehydration.
  • openers or activators of the KCNQ2 potassium channel protein have been found to be effective in the above-described model of migraine involving vasculo-trigeminal systems which are integrally involved in the transmission of migraine pain.
  • a non-limiting representative compound used in the SSS-stimulated trigeminal model for migraine as described in Example 2 produced a dose-dependent reduction in the SSS-stimulated trigeminal field response (overall ANOVA, p ⁇ 0.001 ).
  • the results of the KCNQ potassium channel openers described above demonstrate that the compounds of the present invention results in the hyperpolarization of cell membranes and for the in vivo SSS-field potential experiments demonstrate that the KCNQ2 openers are useful for modulating neuronal activity and may result in protection from abnormal synchronous firing during a migraine attack.
  • the KCNQ opener or activator compounds described according to the present invention are capable of limiting neuronal activity within the trigeminovascular system and are thus particularly useful for the treatment of migraine headache and migraine attack in individuals suffering from the pain and discomfort of migraine.
  • the compounds of the present invention are therefore useful in the treatment of acutemigraine, as well as the potential for prophylactic treatment of migraine as demonstrated by efficacy in a model of cortical spreading depression.
  • the compounds of the present invention could reduce, ameliorate, eliminate or prevent one, or a number of, the characteristic cluster of symptoms, namely, nausea, photophobia, phonophobia and basic functional disabilities, that are further associated with migraine and migraine pain that occur after the prodrome phase of a migraine headache.
  • this invention includes pharmaceutical compositions comprising at least one compound of Formula I in combination with a pharmaceutical adjuvant, carrier or diluent.
  • this invention relates to a method of treatment or prevention of disorders responsive to opening of KCNQ potassium channels in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I.
  • Formula I will normally be administered as a pharmaceutical composition
  • a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in association with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjutants and excipients employing standard and conventional techniques.
  • the pharmaceutical compositions include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous) bronchial or nasal administration.
  • parenteral including subcutaneous, intramuscular, intradermal and intravenous
  • nasal administration if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge.
  • the solid carrier may contain conventional excipients such as binding agents, fillers, tableting lubricants, disintegrants, wetting agents and the like.
  • the tablet may, if desired, be film coated by conventional techniques.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile vehicle for injection, an aqueous or r _ ⁇ . ⁇
  • non-aqueous liquid suspension may be a dry product for reconstitution with water or other suitable vehicle before use.
  • Liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous vehicle (including edible oils), preservatives, as well as flavoring and/or coloring agents.
  • a vehicle normally will comprise sterile water, at least in large part, although saline solutions, glucose solutions and like may be utilized.
  • injectable suspensions also may be used, in which case conventional suspending agents may be employed.
  • Conventional preservatives, buffering agents and the like also may be added to the parenteral dosage forms. Particularly useful is the administration of a compound of Formula I directly in parenteral formulations.
  • the pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation containing appropriate amounts of the active ingredient, that is, the compound of Formula I according to the invention. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 17th edition, 1985.
  • the dosage of the compounds of Formula I to achieve a therapeutic effect will depend not only on such factors as the age, weight and sex of the patient and mode of administration, but also on the degree of potassium channel activating activity desired and the potency of the particular compound being utilized for the particular disorder of disease concerned. It is also contemplated that the treatment and dosage of the particular compound may be administered in unit dosage form and that the unit dosage form would be adjusted accordingly by one skilled in the art to reflect the relative level of activity. The decision as to the particular dosage to be employed (and the number of times to be administered per day) is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect.
  • a suitable dose of a compound of Formula I or pharmaceutical composition thereof for a mammal, including man, suffering from, or likely to suffer from any condition as described herein is an amount of active ingredient from about 0.01 ⁇ g/kg to 10 mg/kg body weight.
  • the dose may be in the range of 0.1 ⁇ g/kg to 1 mg/kg body weight for intravenous administration.
  • the dose may be in the range of 0.1 ⁇ g/kg to 5 mg/kg body weight.
  • the active ingredient will preferably be administered in equal doses from one to four times a day. However, usually a small dosage is administered, and the dosage is gradually increased until the optimal dosage for the host under treatment is determined.
  • the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound of be administered, the chosen route of administration, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.
  • Step A Neat methanesulfonyl chloride (28 mL, 0.36 mol) was added dropwise to a stirred cold (0°C) solution of 2,2,2-trifluoroethanol (30 g, 0.3 mol) and triethylamine (50 mL, 0.36 mol) in CH 2 CI 2 (60 mL). The reaction mixture was allowed to warm to ambient temperature and maintained at room temperature for 1-2 hours. The reaction mixture was quenched with 1 N HCI (50 mL) and the organic layer was separated and then washed consecutively with water and brine.
  • Step B To a stirred cold (0°C) suspension of oil free NaH (0.12 mol, 4.8 g of 60% NaH in mineral oil) in anhydrous DMF (50 mL), a solution of 2-bromo-4-chlorophenol in DMF (50 mL) was added over 30 minutes under nitrogen. The resultant gray suspension of the sodium salt of 2- bromo-4-chlorophenol was treated with neat 2,2,2-trifluoroethylmethane sulfonate (21.4 g, 0.12 mol). The stirred mixture was heated at reflux temperature for 2-3 days. The mixture was cooled in an ice water bath and extracted with diethyl ether (2 x 100 mL).
  • Step A To a stirred suspension of magnesium turnings in dry THF (30 mL), was added dibromoethane (0.77 mL) under nitrogen and allowed to react for 10-15 minutes. Neat 2-bromo-4-chloro(2,2,2- trifluoroethoxy)benzene (13.0 g, 45 mmol) was then added. Once the ensuing exothermic reaction had subsided the reaction mixture was heated to reflux for 2-3 hours then was allowed to cool to room temperature.
  • Step B In a separate flask, neat 6-(trifluoromethyl)isatin (6.45g, 30 mmol) was added to a cold (0°C) suspension of oil free NaH (60% in oil, 1.44 g, 36 mmol) in dry THF (30 mL) under nitrogen. The mixture was stirred until gas evolution ceased. The sodium salt of the 6-(trifluoromethyl)isatin was cooled to -20°C and then the Grignard reagent 2-(magnesium bromide)- 4-chloro(2,2,2-trifluoroethoxy)benzene (from Step A, above) was added via syringe. The reaction mixture was allowed to warm to room temperature and maintained at room temperature for 30 minutes.
  • the reaction mixture was diluted with diethyl ether and then quenched with 1 N HCI.
  • the organic layer was separated and washed consecutively with 0.5N NaOH (2 x 50 mL), 1 N HCI, water, brine and then dried over Na 2 S0 4 and filtered.
  • the filtrate was concentrated in vacuo to provide a light brown solid (16.3 g) which was triturated with CH 2 CI 2 to afford the titled compound (8.92 g, 70%) as a white solid: mp 226-228°C.
  • Neat diethylaminosulfur trifluoride (3.66 mL, 0.03 mol) was added dropwise to a cold (-78°C) stirred partial solution of ( ⁇ )-3-[5-chloro-2- [(2,2,2-trifluoroethoxy)phenyl]-1 ,3-dihydro-3-hydroxy-6-(trifluoromethyl)- 2H-indol-2-one (Preparation 4, 6.4 g, 0.015 mol) in anhydrous CH 2 CI 2 (45 mL) under a nitrogen atmosphere. The resultant mixture was allowed to warm in an ice-bath and maintained at 0°C. After 1 hour, TLC showed absence of starting material.
  • Example 1 The racemic compound (+)-3-[5-chIoro-2-[(2,2,2- trifluoroethoxy)phenyl]-1 ,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2- one obtained in Example 1 was separated into its enantiomers using a Chiracel-OD analytical HPLC column (250 x 4 mm) using 9:1 hexanes/isopropyl alcohol as the eluting solvent at a flow rate of 0.7 mL/min.
  • the detection method employed a HP 1090 UV detector with diode array at a wavelength of 220 nm.
  • the first enantiomer which eluted from the column had a retention time of about 8.64 minutes and was determined to be the (+)-enantiomer of the title compound.
  • On a preparative scale up to two grams of the racemate may be resolved with a single injection on a 5 x 50 cm Chiracel-OD preparative HPLC column using 9:1 hexanes/isopropyl alcohol at a flow rate of 60 mL/min with baseline separation.
  • the (+)-enantiomer was identical to the racemate with respect to NMR, mass spectra, TLC and IR.
  • the second enantiomer eluted from the same column at a retention time of about 15.19 minutes was determined to be the (-)-enantiomer of the title compound.
  • the (-)-enantiomer was identical to the racemate with respect to NMR, mass spectra, TLC and IR.
  • Examples 6-11 were prepared by reacting the Grignard reagent derived from 2-bromo-4-chloro(2,2,2-trifluoroethoxy)benzene (Preparation 1 ) and an appropriately substituted 2,3-indolinedione according to the methods described previously for Preparation 4.
  • the resulting intermediate ( ⁇ )-3-[5-chloro-2-[(2,2,2-trifluoroethoxy)phenyl]-1 ,3-dihydro- 3-hydroxy-2/-/-indol-2-one derivative was then fluorinated using diethylaminosulfur trifluoride according to the method as described for Example 1 to provide the compounds of Examples 6-11.
  • Examples 12 and 13 were obtained from Example 11 by separation of the enantiomers according to the methods as previously described for Examples 2 and 3.
  • Examples 14 and 15 were prepared by reacting the Grignard reagent derived from either 2-bromo-4-chloro(2-fluoroethoxy)benzene (Preparation 3, for Example 14) or 2-bromo-4,5-dichloro(2- fluoroethoxy)benzene (for Example 15), respectively, and the sodium salt of 6-trifluoromethyl 2,3-indolinedione according to the methods described previously for Preparation 4.
  • Example 14 or ( ⁇ )-3-[4,5-dichloro-2-[(2-fluoroethoxy)phenyl]-1 ,3-dihydro- 3-hydroxy-2H-indol-2-one (for Example 15) was then fluorinated using diethylaminosulfur trifluoride according to the method as described for Example 1 to provide the title compounds of Examples 14 and 15, respectively.
  • Examples 16 - 22 were prepared by fluorination of the 3-hydroxy moiety of the corresponding 3-[5-chloro-2-(alkylthio)phenyl]-1 ,3-dihydro-3- hydroxy-6-(trifluoromethyl)-2H-indol-2-one with diethylaminosulfur trifluoride according to the procedure as previously described in Example 5.
  • 3-[5- chloro-2-(2-fluoroethylthio)phenyl]-1 ,3-dihydro-3-fluoro-6-(trifluoromethyl)- 2H-indol-2-one (compound of Example 16) was prepared by alkylation of the thiol silver salt (of Preparation 14) with 1-bromo-2-fluoroethane followed by fluorination with diethylaminosulfur trifluoride.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/US2002/004304 2001-02-20 2002-02-14 Fluoro oxindole derivatives as modulators of kcnq potassium channels WO2002066426A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2002565943A JP2004531483A (ja) 2001-02-20 2002-02-14 Ｋｃｎｑカリウムチャネルのモジュレーターとしてのフルオロオキシンドール誘導体
HU0400063A HUP0400063A2 (hu) 2001-02-20 2002-02-14 Fluor-oxo-indolszármazékok mint KCNQ káliumcsatorna modulátorok, alkalmazásuk és ezeket tartalmazó gyógyszerkészítmények
EP02714888A EP1363624A2 (en) 2001-02-20 2002-02-14 Fluoro oxindole derivatives as modulators of kcnq potassium channels
CA002438805A CA2438805A1 (en) 2001-02-20 2002-02-14 Fluoro oxindole derivatives as modulators of kcnq potassium channels

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US27011201P 2001-02-20 2001-02-20
US60/270,112 2001-02-20

Publications (2)

Publication Number Publication Date
WO2002066426A2 true WO2002066426A2 (en) 2002-08-29
WO2002066426A3 WO2002066426A3 (en) 2002-11-21

Family

ID=23029954

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/004304 WO2002066426A2 (en) 2001-02-20 2002-02-14 Fluoro oxindole derivatives as modulators of kcnq potassium channels

Country Status (5)

Country Link
EP (1) EP1363624A2 (3Den)
JP (1) JP2004531483A (3Den)
CA (1) CA2438805A1 (3Den)
HU (1) HUP0400063A2 (3Den)
WO (1) WO2002066426A2 (3Den)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072088A3 (en) * 2001-02-20 2004-05-27 Bristol Myers Squibb Co Modulators of kcnq potassium channels and use thereof in treating migraine and mechanistically related diseases
WO2004096767A1 (en) * 2003-04-25 2004-11-11 H. Lundbeck A/S Sustituted indoline and indole derivatives
WO2005035498A1 (ja) * 2003-10-08 2005-04-21 Dainippon Sumitomo Pharma Co., Ltd. 含窒素二環性化合物の摂食調節剤としての用途
WO2006074991A1 (en) * 2005-01-11 2006-07-20 Neurosearch A/S Novel 2-amino benzimidazole derivatives and their use as modulators of small-conductance calcium-activated potassium channels
CN110240558A (zh) * 2019-07-10 2019-09-17 上海华理生物医药股份有限公司 一种Flindokalner消旋体的新合成方法
EP2723336B1 (en) * 2011-06-27 2020-04-08 Centre National De La Recherche Scientifique Compositions for the treatment of fragile x syndrome
EP3912625A1 (en) 2020-05-20 2021-11-24 Kaerus Bioscience Limited Novel maxi-k potassium channel openers for the treatment of fragile x associated disorders

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5565483A (en) * 1995-06-07 1996-10-15 Bristol-Myers Squibb Company 3-substituted oxindole derivatives as potassium channel modulators
JP2002531552A (ja) * 1998-12-04 2002-09-24 ニューロサーチ、アクティーゼルスカブ イオンチャネル調節剤としての新規ベンズイミダゾロン−、ベンズオキサゾロン−又はベンゾチアゾロン−誘導体
US6372767B1 (en) * 1999-08-04 2002-04-16 Icagen, Inc. Benzanilides as potassium channel openers

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072088A3 (en) * 2001-02-20 2004-05-27 Bristol Myers Squibb Co Modulators of kcnq potassium channels and use thereof in treating migraine and mechanistically related diseases
US6855829B2 (en) 2001-02-20 2005-02-15 Bristol-Myers Squibb Company 3-fluoro-2-oxindole modulators of KCNQ potassium channels and use thereof in treating migraine and mechanistically related disease
WO2004096767A1 (en) * 2003-04-25 2004-11-11 H. Lundbeck A/S Sustituted indoline and indole derivatives
WO2005035498A1 (ja) * 2003-10-08 2005-04-21 Dainippon Sumitomo Pharma Co., Ltd. 含窒素二環性化合物の摂食調節剤としての用途
WO2006074991A1 (en) * 2005-01-11 2006-07-20 Neurosearch A/S Novel 2-amino benzimidazole derivatives and their use as modulators of small-conductance calcium-activated potassium channels
US7842817B2 (en) 2005-01-11 2010-11-30 Neurosearch A/S 2-amino benzimidazole derivatives and their use as modulators of small-conductance calcium-activated potassium channels
EP2319512A1 (en) * 2005-01-11 2011-05-11 NeuroSearch AS Novel 2-amino benzimidazole derivatives and their use as modulators of small-conductance calcium-activated potassium channels.
EP2723336B1 (en) * 2011-06-27 2020-04-08 Centre National De La Recherche Scientifique Compositions for the treatment of fragile x syndrome
CN110240558A (zh) * 2019-07-10 2019-09-17 上海华理生物医药股份有限公司 一种Flindokalner消旋体的新合成方法
CN110240558B (zh) * 2019-07-10 2022-05-27 上海华理生物医药股份有限公司 一种Flindokalner消旋体的新合成方法
EP3912625A1 (en) 2020-05-20 2021-11-24 Kaerus Bioscience Limited Novel maxi-k potassium channel openers for the treatment of fragile x associated disorders
WO2021234084A1 (en) 2020-05-20 2021-11-25 Kaerus Bioscience Limited Maxi-k potassium channel openers for the treatment of fragile x associated disorders

Also Published As

Publication number Publication date
EP1363624A2 (en) 2003-11-26
CA2438805A1 (en) 2002-08-29
JP2004531483A (ja) 2004-10-14
HUP0400063A2 (hu) 2004-04-28
WO2002066426A3 (en) 2002-11-21

Similar Documents

Publication Publication Date Title
US6469042B1 (en) Fluoro oxindole derivatives as modulators if KCNQ potassium channels
RU2328483C2 (ru) Индолы, обладающие противодиабетической активностью
US5843972A (en) Heterocyclic β-adrenergic agonists
AU719663B2 (en) Antidiabetic agents
JP4521463B2 (ja) 疼痛の治療に有用なｎ−（ｎ−スルホニルアミノメチル）シクロプロパンカルボキサミド誘導体
EP1133474B1 (en) 3-substituted-4-arylquinolin-2-one derivatives as potassium channel modulators
NO152837B (no) Analogifremgangsmaate ved fremstilling av terapeutisk aktive allylaminderivater
JP2005507853A (ja) Ｋｃｎｑカリウムチャンネルモジュレーター並びに片頭痛および機構的に関連する疾患の治療におけるそれらの使用
WO2002066036A1 (en) 2,4-disubstituted pyrimidine-5-carboxamide derivatives as kcnq potassium channel modulators
EP1259505B1 (fr) Derives de 1,3-dihydro-2h-indol-2-one et leur utilisation en tant que ligands des recepteurs v1b ou v1b et v1a de l'arginine-vasopressine
AU2002336311B8 (en) Bicyclic compound
US20120309786A1 (en) 3-amino-pyridine derivatives for the treatment of metabolic disorders
EP1937653A1 (en) Pyrimidine derivatives and their use as kcnq potassium channels openers
EP1363624A2 (en) Fluoro oxindole derivatives as modulators of kcnq potassium channels
US6160000A (en) Antidiabetic agents based on aryl and heteroarylacetic acids
JP2000309534A (ja) 血管新生阻害剤
AU2002247126A1 (en) Fluoro oxindole derivatives as modulators of KCNQ potassium channels
FR2543952A1 (fr) Composes hydrocarbones heterocycliques appartenant aux series indoliques et leur application pharmacologique
JP4008059B2 (ja) 松果体ホルモン作用薬
US6515015B1 (en) Antidiabetic agents based on aryl and heteroarylacetic acids
NO970183L (no) (1H-Indol-4-yl)-piperidin- eller tetrahydropyridin-etylaminer og -etylkarboksamider
CN101528734B (zh) 治疗代谢障碍的3-氨基吡啶衍生物
AU2002243998A1 (en) 2,4-Disubstituted pyrimidine-5-carboxamide derivatives as KCNQ potassium channel modulators

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

WWE Wipo information: entry into national phase

Ref document number: 2002714888

Country of ref document: EP

Ref document number: 2438805

Country of ref document: CA

Ref document number: 2002247126

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2002565943

Country of ref document: JP

WWP Wipo information: published in national office

Ref document number: 2002714888

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWW Wipo information: withdrawn in national office

Ref document number: 2002714888

Country of ref document: EP