EP1620441A1 - Derives de thiadiazine et leur utilisation comme modulateurs positifs des recepteurs ampa - Google Patents

Derives de thiadiazine et leur utilisation comme modulateurs positifs des recepteurs ampa

Info

Publication number
EP1620441A1
EP1620441A1 EP04742632A EP04742632A EP1620441A1 EP 1620441 A1 EP1620441 A1 EP 1620441A1 EP 04742632 A EP04742632 A EP 04742632A EP 04742632 A EP04742632 A EP 04742632A EP 1620441 A1 EP1620441 A1 EP 1620441A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
group
compounds
linear
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP04742632A
Other languages
German (de)
English (en)
French (fr)
Inventor
Emmanuel Graindorge
Pierre Francotte
Stéphane Boverie
Pascal De Tullio
Bernard Pirotte
Pierre Lestage
Laurence Danober
Pierre Renard
Daniel-Henri Caignard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universite de Liege
Original Assignee
Laboratoires Servier SAS
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 Laboratoires Servier SAS filed Critical Laboratoires Servier SAS
Publication of EP1620441A1 publication Critical patent/EP1620441A1/fr
Withdrawn legal-status Critical Current

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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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to new thiadiazine 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 physiological neuronal excitability phenomena and in particular in those involved in the memorization process. 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 to 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 benzothiadiazine derivative having a facilitating activity on the AMPA current and patent application WO 99/42456 describes inter alia certain benzothiadiazine derivatives as modulators of AMPA receptors.
  • the thiadiazine derivatives which are the subject of the present invention, apart from the fact that they are new, have, surprisingly, pharmacological activities on the AMPA current clearly superior to those of compounds of similar structures described in the prior art. They are useful as AMPA modulators for the treatment or prevention of mnemocognitive disorders associated with age, anxiety or depressive syndromes, progressive neurodegenerative diseases, Alzheimer's disease, Pick's disease, chorea. Huntington's, schizophrenia, sequelae of acute neurodegenerative diseases, sequelae of ischemia and sequelae of epilepsy.
  • A forms with the two carbon atoms which carry it a thienyl, furyl or pyrrolyl group chosen from the groups Ai, A 2 , A:
  • X represents respectively a sulfur, oxygen or nitrogen atom and R a , Rb, identical or different, independently of one another, represent a hydrogen atom, an alkyl group (C ⁇ -C 6 ) linear or branched optionally substituted by one or more fluorine atoms, an alkoxy group (Cj-C) linear or branched, a halogen atom, a hydroxy group, a carboxyl group, a linear or branched alkoxycarbonyl group (C ⁇ -C 6 ), or an amino group optionally substituted by an alkylcarbonyl group (C ⁇ -C 6 ) linear or branched, with one or two linear or branched alkyl groups (C ⁇ -C 6 ),
  • an oxathiole group chosen from groups A 4 , A 5 , A 6 , A 7 :
  • a thiazole group chosen from groups A 8 , A 9
  • R a is as defined above, an isothiazole group selected from the groups A ⁇ 0, An
  • Ri represents a hydrogen atom, a linear or branched alkyl group (C ⁇ -C 6 ), optionally substituted by one or more fluorine atoms, or several halogen atoms, other than fluorine, or an alkoxy group (C ⁇ - C 6 ) alkyl (C ⁇ . -C 6 ) in which the alkyl part can be linear or branched,
  • R 2 represents a hydrogen atom or a linear or branched alkyl group (C ⁇ -C 6 ), optionally substituted by one or more fluorine atoms, or more halogen atoms, other than fluorine,
  • R 3 represents a hydrogen atom or a group chosen from linear or branched (C ⁇ -C 6 ) alkyl, CONHR 'or SO 2 NHR in which R' represents a linear or branched (C ⁇ -C 6 ) alkyl group,
  • hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methane sulfonic, camphoric acids, etc.
  • the preferred group A is a thienyl group chosen from the groups Ai, A 2 or A 3 , in which X represents a sulfur atom.
  • the preferred group A is a thienyl group chosen from the groups Aj or A 2 , in which X represents a sulfur atom.
  • R a and R b independently of one another, are the hydrogen atom and the chlorine atom.
  • the preferred Ri group is the hydrogen atom, or a linear or branched (C.-C 6 ) alkyl group, preferably a methyl, ethyl and i-propyl group.
  • the preferred group R 2 is the hydrogen atom.
  • the preferred R 3 group is a hydrogen atom or a CONHR 'group in which
  • R ' is as defined in formula (I).
  • the preferred compounds according to the invention are:
  • the invention also extends to the process for preparing the compounds of formula (I) characterized in that a compound of formula (II) is used as starting material: in which A and • are as defined in formula (I), compound of formula (II) which is cyclized in the presence of a compound of formula (111):
  • the compounds of the present invention in addition to being new, have activating properties of AMPA receptors which make them useful in the treatment of cognitive deficits associated with cerebral aging and neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Pick's disease, Korsakoff's disease, frontal and subcortical dementias, as well as in the treatment of schizophrenia.
  • the invention also extends to pharmaceutical compositions containing as active principle at least one 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 0.01 to 500 mg per day in one or more doses.
  • the starting materials used are known products or prepared according to known preparatory methods.
  • the insoluble material is quickly collected by filtration, washed with water and then dried.
  • This compound is obtained according to the process described in stage A of Example 2 using bromoethane in place of methyl iodide.
  • Stage B ô-chloro ⁇ -éthyl-S ⁇ -dihydro- jfiT-thienop ⁇ -elll ⁇ lthiadiazine 1,1- dioxide
  • This compound is obtained according to the method described in stage B of Example 2 using the compound from preceding stage A.
  • This compound is obtained according to the method described in stage B of Example 2 using the compound from preceding stage A.
  • Stage A 6-chloro-4- (2-fluoroelhyl) -4J3-thieno [3,2-e] [l, 2 5 , 4] tb.iadiasine 1,1- dioxide
  • 500 mg of the compound of preparation 1 are placed in suspension in 15 ml of acetonitrile. 500 mg of potassium carbonate and 1 ml of bromofluoromethane are added to it. The medium is placed in a sealed autoclave and heated at 70 ° C for 8 hours. The insoluble material is then removed by filtration. After evaporation of the solvent, the residue is taken up in 20 ml of water and collected on a filter. The solid thus obtained is recrystallized from methanol.
  • 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 expression of the receptors and then stored at 8-10 ° C.
  • the electrophysiological recording is carried out in a plexiglass® chamber at 20-
  • the compounds of the invention very strongly potentiate the excitatory effects induced by (S) -AMPA.
  • the compounds of Examples 4 and 6 show the EC2X and EC5X mentioned in the table below:
  • PEPS post-synaptic excitatory potentials
  • Cross sections of hippocampus (500 ⁇ M) of male Wistar rat are prepared using a “chopper tissue” then incubated for 45 minutes in a calcium-free medium containing Mg 2+ (10 mM). They are then stabilized in Krebs adjusted to pH 7.35 and oxygenated with O 2 / CO 2 (95% / 5%) at room temperature.
  • the sections are submerged at 30 ° C and the post-synaptic excitatory potentials (PEPS) are recorded in the dendritic field of the granular cells of dentate gyrus during stimulation (50-100 ⁇ A, 50 ⁇ sec) every 30 seconds of the perforating route by tungsten bipolar electrode.
  • PEPS post-synaptic excitatory potentials
  • PEPS are acquired and analyzed using an A-D converter, a TL-1 interface and "pCLAMP" software.
  • the amplitude and the duration of the PEPS are evaluated on the negative wave compared to the basic current.
  • the compounds are applied for 10 minutes in the superfusion bath containing MgSO 4 (1 mM) in order to block the activation of the NMD A receptors.
  • concentration is increased, increasing the amplitude by 50% (A50) or the duration (D50) of the PEPS.
  • the compounds of the invention greatly increase the amplitude and the duration of the potentials of post-synaptic excitatory fields recorded on sections of rat hippocampus.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
EP04742632A 2003-05-05 2004-05-04 Derives de thiadiazine et leur utilisation comme modulateurs positifs des recepteurs ampa Withdrawn EP1620441A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0305448A FR2854634B1 (fr) 2003-05-05 2003-05-05 Nouveaux derives de thiadiazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
PCT/FR2004/001070 WO2004099217A1 (fr) 2003-05-05 2004-05-04 Derives de thiadiazine et leur utilisation comme modulateurs positifs des recepteurs ampa

Publications (1)

Publication Number Publication Date
EP1620441A1 true EP1620441A1 (fr) 2006-02-01

Family

ID=33306157

Family Applications (1)

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EP04742632A Withdrawn EP1620441A1 (fr) 2003-05-05 2004-05-04 Derives de thiadiazine et leur utilisation comme modulateurs positifs des recepteurs ampa

Country Status (21)

Country Link
US (1) US7476668B2 (es)
EP (1) EP1620441A1 (es)
JP (1) JP4461139B2 (es)
KR (1) KR100741235B1 (es)
CN (1) CN100363368C (es)
AR (1) AR044245A1 (es)
AU (1) AU2004236005B2 (es)
BR (1) BRPI0410002A (es)
CA (1) CA2524377C (es)
EA (1) EA009240B1 (es)
FR (1) FR2854634B1 (es)
GE (1) GEP20084318B (es)
HK (1) HK1088327A1 (es)
MA (1) MA27732A1 (es)
MX (1) MXPA05011823A (es)
MY (1) MY136694A (es)
NO (1) NO20055695L (es)
NZ (1) NZ543214A (es)
UA (1) UA80046C2 (es)
WO (1) WO2004099217A1 (es)
ZA (1) ZA200508660B (es)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2005280058B2 (en) 2004-08-25 2010-09-02 Essentialis, Inc. Pharmaceutical formulations of potassium ATP channel openers and uses thereof
US7799777B2 (en) 2006-01-05 2010-09-21 Essentialis, Inc. Salts of potassium ATP channel openers and uses thereof
US20110218190A1 (en) * 2008-11-10 2011-09-08 The Regents Of The University Of California Therapeutic uses of ampa receptor modulators for treatment of motor dysfunction
HUE049460T2 (hu) 2010-08-10 2020-09-28 Takeda Pharmaceuticals Co Heterociklusos vegyület és annak alkalmazása ampa receptor pozitív allosztérikus modulátorként
JP5901365B2 (ja) * 2012-03-12 2016-04-06 株式会社トクヤマ イミダート化合物の製造方法
EP3311842A1 (en) 2013-06-13 2018-04-25 VeroScience LLC Compositions and methods for treating metabolic disorders
CA2991400C (en) 2015-07-06 2020-05-12 Public University Corporation Yokohama City University Phenylsulphonamide derivatives useful as ampa receptor imaging agents
JP6241974B1 (ja) 2017-01-11 2017-12-06 公立大学法人横浜市立大学 霊長類生体の脳内ａｍｐａ受容体のイメージング方法、プログラム、及びスクリーニング方法
US10680583B1 (en) * 2019-02-26 2020-06-09 Xilinx, Inc. Control circuit for and method of controlling an operation of an integrated circuit device

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US3733409A (en) * 1969-05-20 1973-05-15 Schering Corp Method of treating hypertension using thieno (1,2,4) thiadiazines
AU4345297A (en) * 1996-09-17 1998-04-14 Regents Of The University Of California, The Benzothiadiazide derivatives and their use as allosteric up-modulators of the ampa receptor
KR20010021936A (ko) * 1997-07-16 2001-03-15 한센 핀 베네드, 안네 제헤르, 웨이콥 마리안느 융합된 1,2,4-티아디아진 유도체, 그의 제조와 사용
CA2320354A1 (en) * 1998-02-18 1999-08-26 Neurosearch A/S Novel compounds and their use as positive ampa receptor modulators
FR2801587B1 (fr) * 1999-11-30 2002-01-11 Adir Nouveaux derives de benzothiadiazines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

Non-Patent Citations (1)

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Title
See references of WO2004099217A1 *

Also Published As

Publication number Publication date
CN100363368C (zh) 2008-01-23
MXPA05011823A (es) 2006-05-25
JP4461139B2 (ja) 2010-05-12
FR2854634A1 (fr) 2004-11-12
WO2004099217A1 (fr) 2004-11-18
CA2524377C (fr) 2010-08-24
BRPI0410002A (pt) 2006-04-25
CA2524377A1 (fr) 2004-11-18
NZ543214A (en) 2009-02-28
CN1798750A (zh) 2006-07-05
AU2004236005B2 (en) 2010-01-21
UA80046C2 (en) 2007-08-10
US7476668B2 (en) 2009-01-13
MY136694A (en) 2008-11-28
AU2004236005A1 (en) 2004-11-18
JP2006525292A (ja) 2006-11-09
GEP20084318B (en) 2008-03-10
KR20060006830A (ko) 2006-01-19
US20070004709A1 (en) 2007-01-04
ZA200508660B (en) 2007-01-31
EA200501696A1 (ru) 2006-06-30
EA009240B1 (ru) 2007-12-28
MA27732A1 (fr) 2006-01-02
NO20055695L (no) 2005-12-01
KR100741235B1 (ko) 2007-07-19
HK1088327A1 (en) 2006-11-03
AR044245A1 (es) 2005-09-07
FR2854634B1 (fr) 2005-07-08

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