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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • 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
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • 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
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • 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
  • A61P25/00—Drugs for disorders of the nervous system

Definitions

• the present invention provides in general a method for treating a patient suffering from a disorder relating to the serotonergic system by administering to the patient an effective amount of l,7,7-trimethylbicyclo[2.2.1]heptane derivative of Formula I
• R is hydrogen or methyl, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an anxiolytic agent or an antidepressant.
• the present invention provides also a method for providing rapid onset of the treatment of a disorder relating to the serotonergic system by combining an effective amount of l,7,7-trimethylbicyclo[2.2.1]heptane derivative of Formula I or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an anxiolytic agent or an antidepressant.
• GAD Generalized Anxiety Disorder
• OCD obsessive compulsive disorder
• PD panic disorder
• agoraphobia Social Anxiety Disorder
• SAD Social Anxiety Disorder
• PTSD Post- Traumatic Stress Disorder
• ADHD Attention Deficit Hyperactivity Disorder
• l,7,7-trimethylbicyclo[2.2.1]heptane derivatives of Formula I of the present invention are (lR,2S,4R)-(-)- 2-phenyl 2-(dimethylaminoethoxy)-l,7,7-trimethyl- bicyclo[2.2.1]heptane, known as deramciclane, and (lR,2S,4R)-(-)- 2-phenyl-2- (methylaminoethoxy)-l,7,7-trimethyl-bicyclo[2.2.1]heptane, and their pharmaceutically acceptable acid addition salts with inorganic and organic acids generally used for the purpose.
• These compounds are disclosed in U.S. Patent No. 4,342,762 and in International Patent Application No. WO 98/17230, respectively. They are selective serotonin 5HT2A- and/or 5HT2C-receptor antagonists, which have shown anxiolytic-like effects in animal test models.
• Anxiolytic agents of the present invention include, but are not limited to, benzodiazepines, buspirone and its active metabolite 6-hydroxy-buspirone.
• Benzodiazepines which may employed in the present invention include, without limitation, diazepam, alprazolam, oxazepam, and lorazepam.
• Antidepressants of the present invention include, without limitation, tricyclic antidepressants, such as clomipramine, mianserine, amiriptyline and nortriptyline, monoamine oxidase , preferably a MAO-A inhibitor, such as moclobemide, SSRIs, such as fluoxetine, paroxetine, sertraline and citalopram, or a SNRI, such as venlafaxine. Also serotonine precursor, L-tryptophan may be used in the combination of the invention. DESCRIPTION OF THE INVENTION
• the combination of the present invention is effective in the treatment of disorders relating to the serotonergic system.
• the applicant has also discovered that when administering the combination of the present invention to a patient suffering from disorders relating to the serotonergic system, a rapid onset of action is provided/achieved.
• an object of the present invention is a method for treating a patient suffering from a disorder relating to the serotonergic system by administering to the patient an effective amount of l,7,7-trimethylbicyclo[2.2.1]heptane derivative of Formula I or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an anxiolytic agent or an antidepressant.
• an object of the present invention is a method for treating depression or an anxiety disorder, such as GAD, SAD, or OCD or PD, by administering to the mammal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an effective amount of an anxiolytic agent or an antidepressant.
• an object of the present invention is a method for providing rapid onset of the treatment of a disorder relating to the serotonergic system by combining an effective amount of 1 ,7,7- trimethylbicyclo[2.2.1]heptane derivative of Formula I or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an anxiolytic agent or an antidepressant.
• treating is relating to treatment in order to cure or alleviate the disease or the symptoms, and to treatment in order to prevent the development of the disease or the symptoms.
• Pharmaceutically acceptable salts of the drugs of the present invention can be formed with inorganic acids, e.g. hydrohalogenic acid such as hydrochlorid acid or hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid, or organic acids e.g., tartaric acid, succinic acid, malic acid, maleic acid, fumaric acid, citric acid, or lactic acid.
• inorganic acids e.g. hydrohalogenic acid such as hydrochlorid acid or hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid
• organic acids e.g., tartaric acid, succinic acid, malic acid, maleic acid, fumaric acid, citric acid, or lactic acid.
• the fumaric salt of the compounds of Formula (I) acid are preferred.
• Pharmaceutical compositions containing compound of Formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient include the usual oral dosage forms, such as tablets, capsules, and liquid preparations.
• the active ingredient can be mixed with suitable pharmaceutically acceptable excipients, such as starch, lactose, sucrose and magnesium stearate, in accordance with conventional pharmaceutical practice.
• suitable pharmaceutically acceptable excipients such as starch, lactose, sucrose and magnesium stearate
• anxiolytic agents such as benzodiazepines and buspirone, and antidepressants are commonly known.
• the precise amounts of the drugs to be administered to a mammal are dependent on numerous factors known to one skilled in the art, such as the combination to be administered, the general condition of the patient, the condition to be treated etc.
• the usual recommended oral daily dose of deramciclane would be about 5-150 mg, preferably 30-60 mg.
• the usual recommended oral daily doses of benzodiazepines are 0.25 - 6 mg for alprazolam, 2 - 60 mg for diazepam, 7.5 -120 mg for oxazepam, and 1 - 10 mg for lorazepam.
• the usual recommended oral daily dose of buspirone is 5 - 60 mg.
• the usual recommended oral daily doses of the antidepressants are 10 - 225 mg for clomipramine, 30 - 90 mg for mianserine, 10 - 300 mg for amiriptyline, 10 - 225 mg for nortriptyline, 150 - 600 mg for moclobemide, 5 - 80 mg for fluoxetine, 5 - 60 mg for paroxetine, 25 - 200 mg for sertraline, 10 - 60 mg for citalopram, and 37.5 - 375 mg for venlafaxine. These compounds are normally administered orally, however, the oral administration is not the only route.
• the compound of Formula (I) and the anxiolytic agent or the antidepressant may be administered together, in a single dosage form, or may be administered in separate dosage forms, simultaneously or separately.
• the efficacy of deramciclane in the treatment of an anxiety disorder, GAD was studied in a randomised placebo-controlled double-blind study.
• HAM- A Hamilton Anxiety rating scale
• HAM-A score 19 before the treatment received deramciclane 30 mg b.i.d.
• HAM-A score was 17. Then, he started receiving also a benzodiazepine, alprazolam, and at 3 rd treatment week his HAM-A score was declined to 6.

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• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Citations (4)

• 2000
  • 2000-11-28 FI FI20002612A patent/FI20002612A0/fi unknown
• 2001
  • 2001-11-27 WO PCT/FI2001/001029 patent/WO2002043724A1/en not_active Application Discontinuation
  • 2001-11-27 AU AU2002218335A patent/AU2002218335A1/en not_active Abandoned

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