Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems
• • 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
  • A61P25/08—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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
  • A61P25/22—Anxiolytics
• • 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
  • A61P25/24—Antidepressants
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
  • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines

Definitions

• the present invention relates to new benzothiazine and benzothiadiazine derivatives, their preparation process and the pharmaceutical compositions containing them.
• the AMPA receptor (“-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid”) appears to be the most involved in the phenomena of physiological neuronal excitability and in particular in those involved in memorization processes. For example, learning has been shown to be associated with increased binding of AMPA to its receptor in the hippocampus, one of the brain areas essential for mnemocognitive processes. Likewise, nootropic agents such as aniracetam have been described very recently as positively modulating the AMPA receptors of neuronal cells (Journal of Neurochemistry, 1992, 58, 1199-1204).
• patent EP 692 484 describes a benzothiadiazme derivative having a facilitating activity on the AMPA current and patent application WO 99/42456 describes inter alia certain benzothiadiazme derivatives as modulators of AMPA receptors.
• Prior. They are useful as AMPA modulators for the treatment or prevention of mnemocognitive disorders associated with age, anxiety or depressive syndromes, progressive neurogenerative diseases, Alzheimer's disease, Pick's disease, chorea. Huntington's, schizophrenia, sequelae of acute neurodegenerative diseases, sequelae of ischemia and sequelae of epilepsy.
• Ri represents an aryl or heteroaryl group
• R 2 represents a hydrogen atom, a halogen atom or a hydroxy group
• X represents an oxygen or sulfur atom
• Y represents an oxygen or sulfur atom or a group NR in which R represents a hydrogen atom or an alkyl group (C ⁇ -C 6 ) linear or branched, A represents a group CR_jR 5 or a group NR4, R 3 represents a hydrogen atom, a linear or branched alkyl group (C ⁇ -C 6 ) or a cycloalkyl group (C 3 -C), Rj represents a hydrogen atom or a linear or branched alkyl group (C ⁇ -C 6 ) , or A represents a nitrogen atom and forms with the group -CHR 3 - adjacent the ring in which m represents 1, 2 or 3,
• R 5 represents a hydrogen or halogen atom
• alkyl groups C ⁇ -C 6 linear or branched
• alkyl (C ⁇ -C 6 ) sulfonylamino optionally substituted by one or more alkyl groups (C ⁇ -C 6 ) linear or branched
• alkyl (C ⁇ -C 6 ) sulfonylamino optionally substituted by one or more alkyl groups (C ⁇ -C 6 ) linear or branched
• hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methane sulfonic, camphoric acids, etc.
• the preferred aryl group is the phenyl group.
• the preferred group R is the hydrogen atom.
• A preferably represents an NR group or else a nitrogen atom and forms with the group -CHR 3 - adjacent the —N - ring, m preferably representing
• Y preferably represents an oxygen or sulfur atom.
• the invention also extends to the process for the preparation of the compounds of formula (I).
• R'i represents a linear or branched alkoxy group (C ⁇ -C 6 ),
• R ′ 2 represents a hydrogen or halogen atom or a linear or branched alkoxy group (C ⁇ -C 6 ), who is :
• R 3 is such a defined in formula (I),
• R'i represents a linear or branched alkoxy group (C ⁇ -C 6 ),
• R ' 2 represents a hydrogen, halogen atom or an alkoxy group (C ⁇ -C 6 ) linear or branched, which undergoes the action of chloroacetone in the presence of a mineral base in dimethylformamide medium, to lead to the compound of formula (XVI):
• R'i and R ' 2 have the same meaning as above, including, possibly, in the particular case where R 3 is different from the hydrogen atom, we protects the nitrogen atom with a protective group, then, after treatment with a strong base, which is treated with a compound of formula R ' 3 -P, in which R' represents an alkyl group (-C 6 ) linear or branched or a cycloalkyl group (C 3 -C) and P represents a leaving group, to lead after deprotection of the nitrogen atom, to the compound of formula (XlX'a):
• R'i, R ' 2 and R' have the same meaning as above, composed of formula (XIXa) and (XlX'a) represented by the formula (XIX):
• R'i and R ' 2 have the same meaning and R 3 is as defined in formula (I), which:
• R'i and R ' 2 have the same meaning as above, R' 5 represents a halogen atom,
• R 'MgBr represents a linear or branched alkyl group (C ⁇ -C 6 )
• R'i, R ' 2 and R' 4 have the same meaning as above and R ' 5 represents a halogen atom
• Ri in which Ri, X have the same meaning as in formula (I), and Y 'represents an oxygen or sulfur atom or a group ⁇ in which R represents a linear or branched (C ⁇ -C 6 ) alkyl group ,
• the invention also extends to pharmaceutical compositions containing as a principle active a compound of formula (I) with one or more inert, non-toxic and suitable excipients.
• pharmaceutical compositions according to the invention mention may be made more particularly of those which are suitable for oral, parenteral (intravenous or subcutaneous), nasal administration, simple or coated tablets, sublingual tablets, capsules, tablets, suppositories, creams, ointments, dermal gels, injections, oral suspensions, etc.
• the useful dosage is adaptable according to the nature and severity of the disease, the route of administration as well as the age and weight of the patient. This dosage varies from 1 to 500 mg per day in one or more doses.
• the starting materials used are known products or prepared according to known procedures.
• the product obtained in the preceding stage is stirred overnight, at room temperature, in 320 ml of an aqueous solution of IN sodium hydroxide. After adding 50 ml of ethyl acetate and vigorous stirring, the expected product which precipitates is filtered, rinsed and dried.
• the expected product is obtained by replacing, in Stage E, phenyl chloroformate with phenyl thionochloroformate. Melting point: 252-254 ° C Elemental microanalysis: C H N S
• the expected product is obtained by replacing, in stage E, phenyl chloroformate with 4-chlorophenyl thionochloroformate, Melting point: 189-194 ° C. Elemental microanalysis:
• a suspension of 3.0 g of 2-amino-5-methoxybenzenesulfonamide is stirred for 1 night at 80 ° C. in the presence of 1.31 g of formamidine hydrochloride and 2.27 ml of triethylamine in 50 ml of toluene.
• the toluene is evaporated under vacuum, the residue is taken up in water and the precipitate is filtered.
• Stage E O- (4-Ethyl-l, l-dioxido-3,4-dihydro-2-H-l, 2,4-benzothiadiazin-7-ylVO- phenyl thiocarbonate
• the expected product is obtained according to the process described in Stage E of Example 1, replacing the phenyl chloroformate with the phenyl thionochloroformate.
• the expected product is obtained according to the process described in Example 5 by replacing, in Stage E, phenyl thionochloroformate with 4-chlorophenyl thionochloroformate. Melting point: 155-156 ° C
• MRNAs are prepared from the cerebral cortex of a male Wistar rat by the guanidium thiocyanate / phenol / chloroform method.
• Poly (A + ) mRNAs are isolated by chromatography on oligo-dT cellulose and injected at a rate of 50 ng per oocyte. The oocytes are left for 2 to 3 days in incubation at 18 ° C to allow the expression of receptors and then stored at 8-10 ° C.
• the electrophysiological recording is carried out in a plexiglass® chamber at 20-24 ° C in OR2 medium (J. Exp. Zool., 1973, 184, 321-334) by the "voltage clamp" method with 2 electrodes, a third electrode placed in the bath serving as a reference.
• the compounds of the invention very strongly potentiate the excitatory effects of AMPA and their activity is very clearly superior to that of the reference compounds.
• the compound of Example 2 has in particular an EC2X equal to 1.8 ⁇ M and an EC5X equal to 9.6 ⁇ M.

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• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
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• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Psychology (AREA)
• Hospice & Palliative Care (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

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• 2001
  • 2001-12-21 FR FR0116620A patent/FR2833955B1/fr not_active Expired - Fee Related
• 2002
  • 2002-12-19 AR ARP020105011A patent/AR038260A1/es unknown
  • 2002-12-20 EA EA200400757A patent/EA007492B1/ru not_active IP Right Cessation
  • 2002-12-20 CN CNB028256743A patent/CN1289508C/zh not_active Expired - Fee Related
  • 2002-12-20 JP JP2003554694A patent/JP2005518385A/ja active Pending
  • 2002-12-20 WO PCT/FR2002/004483 patent/WO2003053978A1/fr active Application Filing
  • 2002-12-20 UA UA20040706009A patent/UA78742C2/uk unknown
  • 2002-12-20 KR KR1020047009200A patent/KR100586684B1/ko not_active IP Right Cessation
  • 2002-12-20 CA CA002471120A patent/CA2471120A1/fr not_active Abandoned
  • 2002-12-20 MX MXPA04005839A patent/MXPA04005839A/es active IP Right Grant
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  • 2002-12-20 BR BR0214926-5A patent/BR0214926A/pt not_active IP Right Cessation
  • 2002-12-20 AU AU2002364673A patent/AU2002364673B2/en not_active Ceased
  • 2002-12-20 PL PL02370166A patent/PL370166A1/xx not_active Application Discontinuation
  • 2002-12-20 US US10/499,164 patent/US7262189B2/en not_active Expired - Fee Related
  • 2002-12-20 HU HU0402583A patent/HUP0402583A3/hu unknown
  • 2002-12-20 EP EP02805406A patent/EP1472219A1/fr not_active Withdrawn
  • 2002-12-20 GE GE5643A patent/GEP20063757B/en unknown
• 2004
  • 2004-06-01 ZA ZA200404295A patent/ZA200404295B/en unknown
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• 2005
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