WO1998000124A1 - Utilisation du topiramate ou de ses derives pour fabriquer un medicament qui traite les affections neurodegeneratives post-ischemiques - Google Patents

Utilisation du topiramate ou de ses derives pour fabriquer un medicament qui traite les affections neurodegeneratives post-ischemiques Download PDF

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Publication number
WO1998000124A1
WO1998000124A1 PCT/US1997/010977 US9710977W WO9800124A1 WO 1998000124 A1 WO1998000124 A1 WO 1998000124A1 US 9710977 W US9710977 W US 9710977W WO 9800124 A1 WO9800124 A1 WO 9800124A1
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WO
WIPO (PCT)
Prior art keywords
formula
topiramate
compounds
alkyl
neurodegeneration
Prior art date
Application number
PCT/US1997/010977
Other languages
English (en)
Inventor
Richard P. Shank
Bruce E. Maryanoff
Original Assignee
Ortho Pharmaceutical Corporation
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 Ortho Pharmaceutical Corporation filed Critical Ortho Pharmaceutical Corporation
Priority to AU35016/97A priority Critical patent/AU3501697A/en
Publication of WO1998000124A1 publication Critical patent/WO1998000124A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin

Definitions

  • R1 , R2, R3, R4 and R5 are as defined hereinafter are useful in treating acute ischemia-induced neuroprotection.
  • X is CH2 or oxygen
  • R1 is hydrogen or alkyl
  • R2, R3, R4 and R5 are independently hydrogen or lower alkoxyl when X is oxygen, R2 and R3 and/or R4 and R5 together may be a methylenedioxy group of the following formula (II):
  • R ⁇ and R7 are the same or different and are hydrogen, lower alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring.
  • R1 in particular is hydrogen or alkyl of about 1 to 4 carbons, such as methyl, ethyl and iso-propyl.
  • Alkyl throughout this specification includes straight and branched chain alkyl.
  • Alkyl groups for R2, R3, R4, R5, R6 and R7 are of about 1 to 3 carbons and include methyl, ethyl, iso-propyl and n-propyl.
  • a particular group of compounds of formula (I) are those wherein X is oxygen and both R2 and R3 ( and R4 and R5 together are methylenedioxy groups of the formula (II), wherein Re and R7 are both hydrogen, both alkyl, or combine to form a spiro cyclopentyl or cyclohexyl ring, in particular where R6 and R7 are both alkyl such as methyl.
  • a second group of compounds are those wherein X is CH2 and R4 and R5 are joined to form a benzene ring.
  • a third group of compounds of formula (I) are those wherein both R2 and R3 are hydrogen.
  • the compounds of formula (I) may be synthesized by the following methods:
  • the chlorosulfate of the formula RCH2OSO2CI may then be reacted with an amine of the formula R1 NH2 at a temperature of abut 40° to 25° C in a solvent such as methylene chloride or acetonitrile to produce a compound of formula (I).
  • a solvent such as methylene chloride or acetonitrile
  • the starting materials of the formula RCH2OH may be obtained commercially or as known in the art.
  • starting materials of the formula RCH2OH wherein both R2 and R3, and R4 and R5 are identical and are of the formula (II) may be obtained by the method of R. F. Brady in Carbohydrate Research, Vol. 14, p. 35 to 40 (1970) or by reaction of the trimethylsilyl enol ether of a R6COR7 ketone or aldehyde with fructose at a temperature of about 25° C, in a solvent such a halocarbon, e.g. methylene chloride in the presence of a protic acid such as hydrochloric acid or a Lewis Acid such as zinc chloride.
  • the trimethylsilyl enol ether reaction is described by G. L. Larson et al in J. Org. Chem. Vol. 38, No. 22, p. 3935 (1973).
  • carboxylic acids and aldehydes of the formulae RCOOH and RCHO may be reduced to compounds of the formula RCH2OH by standard reduction techniques, e.g. reaction with lithium aluminum hydride, sodium borohydride or borane-THF complex in an inert solvent such a diglyme, THF or toluene at a temperature of about 0° to 100° C, e.g. as described by H.O. House in "Modern Synthetic Reactions", 2nd Ed., pages 45 to 144 (1972).
  • standard reduction techniques e.g. reaction with lithium aluminum hydride, sodium borohydride or borane-THF complex in an inert solvent such a diglyme, THF or toluene at a temperature of about 0° to 100° C, e.g. as described by H.O. House in "Modern Synthetic Reactions", 2nd Ed., pages 45 to 144 (1972).
  • the compounds of formula I may also be made by the process disclosed US Patent: No.4,513,006, which is incorporated by reference herein.
  • the compounds of formula I include the various individual isomers as well as the racemates thereof, e.g., the various alpha and beta attachments, i.e., below and above the plane of the drawing, of R2, R3, R4 and R5 on the 6- membered ring.
  • the oxygenes of the methylenedioxy group (II) are attached on the same side of the 6-membered ring.
  • the activity of the compounds of formula I in treating acute ischemia- induced neurodegeneration was determined from the results of a study in which topiramate (dissolved in 0.1 M KCI at 33 mg/mL and diluted into isotonic saline) was found to exert a dose-related neuroprotective effect in a rat model of global (whole body) ischemia.
  • topiramate dissolved in 0.1 M KCI at 33 mg/mL and diluted into isotonic saline
  • a transient ischemia 11 min
  • was induced in anesthetized rats by applying a precisely controlled pressure to the chest that was sufficient to prevent the heart from pumping blood to the brain.
  • resuscitation was initiated by external cardiac massage and mechanically assisted ventilation with 95% oxygen. Rats in which spontaneous ECG activity did not return within 5 min were sacrificed. Assisted ventilation was continued until persistent spontaneous ventilation occurred.
  • Topiramate, vehicle, or phenytoin (reference compound) was administered intravenously (i.v.), usually 30 min after resuscitation, to rats in groups 5 or 6.
  • the compounds were administered at doses of 2.5, 5, 10, 20 or 40 mg/kg.
  • Five days after the ischemic insult brain damage was assessed based on a neurological examination, the incidence and severity of sound- induced seizures, motor performance on an inclined plane, exploratory behavior, and histoiogical examination of brain tissue.
  • a neurodeficit score in which decrements in cranial and spinal reflexes, postural muscle tone, forepaw placing reactions, motor gait and spontaneous locomotor activity were assessed, was used to quantitate the degree of neurological impairment.
  • Topiramate when administered at 10 mg/kg 30 min after resuscitation, significantly reduced the neurodeficit score and seizure severity as compared to control rats.
  • Administration of topiramate at 20 mg/kg was associated with a significantly lower neurodeficit score and significantly improved motor activity on the inclined plane as compared to control rats.
  • Topiramate also greatly reduced neuronal cell death in the hippocampus at this dose, as determined histologically using cresyl violet-stained 10 micron sections of formalin-fixed brain tissue prepared from rats sacrificed 5 days after the ischemic insult.
  • Phenytoin at 20 mg/kg iv exhibited a similar neuroprotective effect, but was more toxic than topiramate, as judged by a greater degree of neurological impairment in normal rats (e.g., higher neurodeficit score). This indicates that topiramate and phenytoin both have neuroprotective activity, but that topiramate has a greater neuroprotective index; which is similar to the higher neuroprotective index for topiramate when the anticonvulsant effects of these compounds are compared (SHANK, R.P., GARDOCKI, J.F., VAUGHT, J.L, DAVIS, C.B., SCHUPSKY, J.J., RAFFA, R.B., DODGSON, S.J., NORTEY, S.O., and MARYANOFF, B.E., Epilepsia 2 ⁇ 450-460, 1994).
  • a compound of formula (I) may be employed by administering a single i.v. dosage in the range of about 200 to 1600 mg within a period of several hours after the medical condition is identified, for an average adult human.
  • one or more sulfamate compounds of formula (I) are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., i.v. Sterile injectable formulations will be prepared using appropriate solubilizing agents.
  • a unit dose would contain about 50 to 400 mg of the active ingredient.
  • Topiramate is currently available for oral administration in round tablets containing 25 mg, 100 mg or 200 mg of active agent.
  • the tablets contain the following inactive ingredients: lactose hydrous, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, synthetic iron oxide, and polysorbate 80.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés anticonvulsifs utiles pour le traitement des affections neurodégénératives aiguës induites par l'ischémie.
PCT/US1997/010977 1996-06-28 1997-06-24 Utilisation du topiramate ou de ses derives pour fabriquer un medicament qui traite les affections neurodegeneratives post-ischemiques WO1998000124A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU35016/97A AU3501697A (en) 1996-06-28 1997-06-24 Use of topiramate or derivatives thereof for the manufacture of a medicament for the treatment of postischemic neurodegeneration

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2200396P 1996-06-28 1996-06-28
US60/022,003 1996-06-28

Publications (1)

Publication Number Publication Date
WO1998000124A1 true WO1998000124A1 (fr) 1998-01-08

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PCT/US1997/010977 WO1998000124A1 (fr) 1996-06-28 1997-06-24 Utilisation du topiramate ou de ses derives pour fabriquer un medicament qui traite les affections neurodegeneratives post-ischemiques

Country Status (3)

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AU (1) AU3501697A (fr)
WO (1) WO1998000124A1 (fr)
ZA (1) ZA975769B (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000061138A1 (fr) * 1999-04-08 2000-10-19 Ortho-Mcneil Pharmaceutical, Inc. Derives anticonvulsivants utiles pour traiter des etats neurodegeneratifs chroniques
WO2001007453A1 (fr) * 1999-07-26 2001-02-01 Ortho-Mcneil Pharmaceutical, Inc. Derives de monosaccharide tricycliques utiles dans le traitement des maladies neurodegeneratives induites par l'ischemie aigue
WO2002102369A2 (fr) * 2001-06-18 2002-12-27 Ortho-Mcneil Pharmaceutical, Inc. Agent de protection des neurones retiniennes
WO2003020289A1 (fr) * 2001-08-30 2003-03-13 Ortho-Mcneil Pharmaceutical, Inc. Traitement de la demence et des troubles de la memoire par le biais d'anticonvulsifs et d'inhibiteurs de l'acetylcholinesterase
US6908902B2 (en) 2001-02-02 2005-06-21 Ortho-Mcneil Pharmaceutical, Inc. Treatment of neurological dysfunction comprising fructopyranose sulfamates and erythropoietin
US8084490B2 (en) 2004-06-16 2011-12-27 Janssen Pharmaceutica N.V. Sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders
US8283478B2 (en) 2005-05-20 2012-10-09 Janssen Pharmaceutica Nv Process for preparation of sulfamide derivatives
US8492431B2 (en) 2005-12-19 2013-07-23 Janssen Pharmaceutica, N.V. Use of benzo-fused heterocycle sulfamide derivatives for the treatment of obesity
US8497298B2 (en) 2005-12-19 2013-07-30 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
US8691867B2 (en) 2005-12-19 2014-04-08 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction
US8716231B2 (en) 2005-12-19 2014-05-06 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for the treatment of pain
US8809385B2 (en) 2008-06-23 2014-08-19 Janssen Pharmaceutica Nv Crystalline form of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide
US8815939B2 (en) 2008-07-22 2014-08-26 Janssen Pharmaceutica Nv Substituted sulfamide derivatives
US8853263B2 (en) 2006-05-19 2014-10-07 Janssen Pharmaceutica Nv Co-therapy for the treatment of epilepsy and related disorders
US8937096B2 (en) 2005-12-19 2015-01-20 Janssen Pharmaceutica Nv Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4513006A (en) * 1983-09-26 1985-04-23 Mcneil Lab., Inc. Anticonvulsant sulfamate derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4513006A (en) * 1983-09-26 1985-04-23 Mcneil Lab., Inc. Anticonvulsant sulfamate derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HARVEY L. EDMONDS ET AL.: "Topiramate as a neuroprotectant and anticonvulsant in postischemic injury", EPILEPSIA, vol. 33, no. suppl. 3, 1992, pages 118 - 119, XP002042704 *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000061138A1 (fr) * 1999-04-08 2000-10-19 Ortho-Mcneil Pharmaceutical, Inc. Derives anticonvulsivants utiles pour traiter des etats neurodegeneratifs chroniques
US6583172B1 (en) 1999-04-08 2003-06-24 Richard P. Shank Anticonvulsant derivatives useful in treating chronic neurodegenerative disorders
WO2001007453A1 (fr) * 1999-07-26 2001-02-01 Ortho-Mcneil Pharmaceutical, Inc. Derives de monosaccharide tricycliques utiles dans le traitement des maladies neurodegeneratives induites par l'ischemie aigue
US6495523B1 (en) 1999-07-26 2002-12-17 Ortho Mcneil-Pharmaceutical, Inc. Tricyclic monosaccharide derivatives useful in treating acute ischemia-induced neurodegeneration
US6908902B2 (en) 2001-02-02 2005-06-21 Ortho-Mcneil Pharmaceutical, Inc. Treatment of neurological dysfunction comprising fructopyranose sulfamates and erythropoietin
WO2002102369A2 (fr) * 2001-06-18 2002-12-27 Ortho-Mcneil Pharmaceutical, Inc. Agent de protection des neurones retiniennes
WO2002102369A3 (fr) * 2001-06-18 2003-07-24 Ortho Mcneil Pharm Inc Agent de protection des neurones retiniennes
US7153837B2 (en) 2001-06-18 2006-12-26 Ortho-Mcneil Pharmaceutical Inc. Agent for protection of retinal neurons
AU2002309280B2 (en) * 2001-06-18 2007-01-25 Ortho-Mcneil Pharmaceutical, Inc. Agent for protection of retinal neurons
WO2003020289A1 (fr) * 2001-08-30 2003-03-13 Ortho-Mcneil Pharmaceutical, Inc. Traitement de la demence et des troubles de la memoire par le biais d'anticonvulsifs et d'inhibiteurs de l'acetylcholinesterase
US8084490B2 (en) 2004-06-16 2011-12-27 Janssen Pharmaceutica N.V. Sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders
US8283478B2 (en) 2005-05-20 2012-10-09 Janssen Pharmaceutica Nv Process for preparation of sulfamide derivatives
US8492431B2 (en) 2005-12-19 2013-07-23 Janssen Pharmaceutica, N.V. Use of benzo-fused heterocycle sulfamide derivatives for the treatment of obesity
US8497298B2 (en) 2005-12-19 2013-07-30 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels
US8937096B2 (en) 2005-12-19 2015-01-20 Janssen Pharmaceutica Nv Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder
US8691867B2 (en) 2005-12-19 2014-04-08 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction
US8716231B2 (en) 2005-12-19 2014-05-06 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for the treatment of pain
US8853263B2 (en) 2006-05-19 2014-10-07 Janssen Pharmaceutica Nv Co-therapy for the treatment of epilepsy and related disorders
US8809385B2 (en) 2008-06-23 2014-08-19 Janssen Pharmaceutica Nv Crystalline form of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide
US8815939B2 (en) 2008-07-22 2014-08-26 Janssen Pharmaceutica Nv Substituted sulfamide derivatives
US8889190B2 (en) 2013-03-13 2014-11-18 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
US10363224B2 (en) 2013-03-13 2019-07-30 Upsher-Smith Laboratories, Llc Extended-release topiramate capsules
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US9555005B2 (en) 2013-03-15 2017-01-31 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US10172878B2 (en) 2013-03-15 2019-01-08 Upsher-Smith Laboratories, Llc Extended-release topiramate capsules

Also Published As

Publication number Publication date
AU3501697A (en) 1998-01-21
ZA975769B (en) 1998-12-28

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