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• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
• • 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
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
• • 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
• • 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
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • 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
  • A61P25/08—Antiepileptics; Anticonvulsants
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• topiramate should be effective in treating some other neurological disorders.
• One of these is chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathies, retinopathy, peripheral nerve injury and brain and spinal neurodegeneration arising as a result of head trauma or spinal injury.
• Rl, R2, R3, R4 and R5 are as defined hereinafter are useful in treating chronic neurodegenerative conditions, such as occurs in Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathies, retinopathy, peripheral nerve injury and brain and spinal neurodegeneration arising as a result of head trauma or spinal injury.
• X is CH2 or oxygen
• Rl is hydrogen or alkyl
• R2, R3, R4 and R5 are independently hydrogen or alkyl and, when X is CH2, R4 and R5 may be alkene groups joined to form a benzene ring and, when X is oxygen, R2 and R3 and/or R4 and R5 together may be a methylenedioxy group of the following formula (II):
• R6 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.
• Rl 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) is that wherein X is oxygen and both R2 and R3 and R4 and R5 together are methylenedioxy groups of the formula (II), wherein R6 and R7 are both hydrogen both alkyl or combine to form a spiro cyclopentyl or cyclohexyl ring, in particular where R and R7 are both alkyl such as methyl.
• a second group of compounds is that wherein X is CH2 and R4 and R5 are joined to form a benzene ring.
• a third group of compounds of formula (I) is that 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 R1NH2 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. Volaa 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 "Modem 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 "Modem Synthetic Reactions", 2nd Ed., pages 45 to 144 (1972).
• the compounds of formula I may also be made by the process disclosed in US Patents: No.4,513,006, No.5,242,942, and No.5,384,327, which are 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 oxygene of the methylenedioxy group (II) are attached on the same side of the 6-membered ring.
• rat hippocampal and cerebral cortical cells were established from embryonic day 18 pups.
• the cells were grown in culture wells (plates) for seven days in the presence of various concentrations of topiramate (O.lnM-lOOuM), or the neurotrophic factors BDNF (brain-derived neurotrophic, lOng) and ⁇ -MSH (alpha-melanocyte stimulating hormone, 50nM), or vehicle (isotonic saline).
• BDNF brain-derived neurotrophic, lOng
• ⁇ -MSH alpha-melanocyte stimulating hormone, 50nM
• vehicle isotonic saline
• topiramate was evaluated in a rat facial nerve compression model of peripheral nerve injury. Rats were anesthetized, their skin and muscle excised to visualize the facial nerve. The nerve was injured near the stylom by compression with forceps. The wound was sutured and the rat allowed to recover before compound administration.
• the rats were divided into three groups: vehicle-treated, topiramate- treated (p.o., 20mg/kg) and ⁇ -MSH-treated (s.c, lmg/kg). Compounds were administered twice daily for 14 days post-surgery. Facial nerve compression causes paralysis of the whisker muscle ipsilateral to the injury site.
• topiramate or another compound of formula (I) may be employed by administering repeated oral doses in the range of about 16 to 256 mg once or twice daily.
• 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 10 to 100 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, camauba wax, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, synthetic iron oxide, and polysorbate 80.

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• 2000
  • 2000-03-30 WO PCT/US2000/008401 patent/WO2000061138A1/en not_active Ceased
  • 2000-03-30 MX MXPA01010217A patent/MXPA01010217A/es active IP Right Grant
  • 2000-03-30 US US09/538,815 patent/US6583172B1/en not_active Expired - Fee Related
  • 2000-03-30 NZ NZ51481300A patent/NZ514813A/xx unknown
  • 2000-03-30 AU AU40476/00A patent/AU782344C/en not_active Ceased
  • 2000-03-30 JP JP2000610471A patent/JP2003521471A/ja not_active Withdrawn
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