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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals

Definitions

• the present invention relates to new pharmaceutical uses of carbamazepine derivatives.
• Ri represents hydrogen, and R 2 represents hydroxy or C C 3 alkyl carbonyloxy, or
• Ri and R 2 together represent an oxo group, and of their pharmaceutically acceptable salts.
• the carbamazepine derivatives of formula I wherein R ⁇ represents hydrogen, and R 2 represents hydroxy or CrC 3 alkyl carbonyloxy constitute chiral compounds.
• the chiral compounds disclosed herein can be employed in the form of racemates, in mixtures comprising one enantiomer in excess (e.g., more S-10-hydroxy- 10,11-dihydro-carba ⁇ mazepine than R-10-hydroxy-10,11-dihydro-carbamazepine) or in enantiomerically pure form (e.g. pure S-10-hydroxy-10,11-dihydro-carbamazepine or pure S- 10-acetoxy-10,11-dihydro-carbamazepine).
• oxcarbazepine (10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide, marketed e.g. under the brand name Trileptal ® ).
• Oxcarbazepine is a known anticonvulsant drug useful in the treatment of seizures of, for example, epileptic origin. Its preparation is described, e.g., in the German patent 2,011 ,087.
• Tinnitus is the medical term for roaring, buzzing, clicking, whistling, hissing, or high pitched ringing in the ears or inside the head. Tinnitus may be constant or occur intermittently in one or both ears. Although there are many theories about how tinnitus occurs, there is no scientific consensus to its origin. Some causes of tinnitus result from a blow to the head, large doses of aspirin, anemia, noise exposure, stress, impacted wax, hypertension and certain types of medications and tumors.
• other inner ear/cochlear excitability related diseases includes, but is not restricted to neuronal loss, hearing loss, sudden deafness, vertigo or Meniere's disease.
• the present invention relates to the use of a compound of formula I wherein
• Ri represents hydrogen, and R 2 represents hydroxy or C C 3 alkyl carbonyloxy, or
• R and R 2 together represent an oxo group, or pharmaceutically acceptable salts thereof for the treatment of tinnitus or other inner ear/cochlear excitability related diseases.
• Ri represents hydrogen and R 2 represent hydroxy. In another preferred embodiment of the present invention, R represents hydrogen and R 2 represents acetoxy.
• ⁇ and R 2 together represent an oxo group.
• the activity in tinnitus of the compounds can be shown in standard tests, e.g. in the salicylate-induced tinnitus model in rats, or in tinnitus models in cats, and in particular in those models described herein.
• the pharmacological activity of the compounds of formula I may, for example, also be evidenced in clinical studies known as such. Such clinical studies are preferably randomized, double-blind, clinical studies in patients with tinnitus. The beneficial effects on tinnitus can be determined, e.g., directly through the results of these studies.
• tinnitus and the other conditions mentioned herein appropriate dosage will of course vary depending upon, for example, the specific compound of formula I employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 1 to about 300 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 10 to about 3000 mg of a compound of formula I, conveniently administered, for example, in divided doses up to four times a day.
• the compounds of formula I may be administered in any usual manner, e.g. orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injection solutions or suspensions.
• the present invention also provides pharmaceutical compositions comprising a compound of formula I in association with at last one pharmaceutical carrier or diluent for use in the treatment of tinnitus.
• Such compositions may be manufactured in conventional manner.
• Unit dosage forms may contain for example from about 2.5 mg to about 1000 mg of a compound of formula I.
• the invention further provides the use of a compound of formula I for the manufacture of a pharmaceutical composition for the treatment of tinnitus and other inner ear/cochlear excitability related diseases such as neuronal loss, hearing loss, sudden deafness, vertigo or Meniere's disease.
• the invention further provides a method for the treatment of tinnitus and other inner ear/cochlear excitability related diseases such as neuronal loss, hearing loss, sudden deafness, vertigo or Meniere's disease in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of a compound of formula I.
• Racemates of compounds of formula I wherein Ri represents hydrogen and R 2 represents hydroxy or C ⁇ -C 3 aikyl carbonyloxy can, e.g., be obtained by mixing the pure enantiomers of the respective compound of formula I.
• the pure enantiomers of a compound of formula I wherein Ri represents hydrogen and R represents hydroxy or C C 3 alkyl carbonyloxy can be obtained starting from the racemate by procedures known as such.
• the racemate may be separated into its enantiomers through the formation of diastereomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands.
• the pure enantiomers of the compound of formula I wherein Ri represents hydrogen and R 2 represents hydroxy are prepared according to the procedures described in the Examples.
• enantiomerically pure form means that a chiral compound is almost free of its enantiomer, i.e., a sample of the chiral compound comprises less than about 5, preferably less than about 2, more preferably less than about 0.5, weight percent of its enantiomer.
• the present invention relates to the use of a compound of formula I, wherein Ri represents hydrogen and R 2 represents hydroxy or C C 3 alkyl carbonyloxy, especially acetoxy, wherein the compound is employed in enantiomerically pure form, in particular of a compound of formula I having the S configuration.
• Example 1 Procedure for the enantioselective Transfer Hydrogenation of 10-Oxo-10,11- dihydro-dibenzo[b,/]azepine-5-carboxylic acid amide to /?(-)-10,11 -Dihydro-10-hydroxy-5/-/- dibenz[£>, t]azepine-5-carboxamide
• Example 2 Procedure for the enantioselective Transfer Hydrogenation of 10-Oxo-10,11- dihydro-dibenzo[ib,/]azepine-5-carboxylic acid amide to S(+)-10,11 -Dihydro-10-hydroxy-5 -- dibenz[£> , t]azepine-5-carboxamide
• reaction mixture is cooled to RT, diluted with CH 2 CI 2 (20 ml) and neutralised with aqu. NaHCO 3 . After washing with brine the solution is concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel using a 6:1 EtOAc-MeOH mixture as eluent to afford of S(+)-10,11 -dihydro-10-hydroxy-5H-dibenzo[b,/]azepine-5-carboxamide.

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• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
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• Animal Behavior & Ethology (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
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• Bioinformatics & Cheminformatics (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Other In-Based Heterocyclic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 2003
  • 2003-08-05 WO PCT/EP2003/008669 patent/WO2004014391A1/en not_active Ceased
  • 2003-08-05 EP EP03747877A patent/EP1528927A1/en not_active Withdrawn
  • 2003-08-05 CN CNA03818835XA patent/CN1674909A/zh active Pending
  • 2003-08-05 US US10/523,291 patent/US7465723B2/en not_active Expired - Fee Related
  • 2003-08-05 CA CA002494660A patent/CA2494660A1/en not_active Abandoned
  • 2003-08-05 JP JP2004526887A patent/JP2005538126A/ja active Pending
  • 2003-08-05 BR BR0313230-7A patent/BR0313230A/pt not_active IP Right Cessation
  • 2003-08-05 AU AU2003266965A patent/AU2003266965A1/en not_active Abandoned

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