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
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• • 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
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/20—Hypnotics; Sedatives
• • 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
• • 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
  • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• • 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
  • A61P9/08—Vasodilators for multiple indications
• • 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

• the present invention relates to a new therapeutic application of the compounds of formula:
• Rj, R2, R3 and R4 identical or different, represent a hydrogen atom, halogen or an alkyl or alkoxy radical, it being understood that Rj, R2, R3 and R ⁇ do not represent all four a hydrogen atom.
• alkyl and alkoxy radicals contain 1 to 6 carbon atoms in straight or branched chain, and, preferably, from 1 to 4 carbon atoms.
• NMDA N-methyl-D-aspartate receptor
• ligands for the glycine modulator sites of the NMDA receptor are non-competitive antagonists of the N-methyl-D-aspartate receptor (NMDA) and, more particularly, are ligands for the glycine modulator sites of the NMDA receptor.
• the compounds of formula (I) can be prepared by reaction of an aniline of formula:
• R-j, R2, R3 and R4 have the same meanings as in formula (I) with chlorosulfonyl isocyanate.
• This reaction is carried out in an inert solvent such as nitromethane, nitroethane, nitrobenzene, carbon disulfide, tetrachloroethane, in the presence of a FRIEDEL-CRAFTS type catalyst such as aluminum chloride, titanium tetrachloride, zirconium tetrachloride, at a temperature of 40 to 105 ° C.
• an inert solvent such as nitromethane, nitroethane, nitrobenzene, carbon disulfide, tetrachloroethane
• the compounds of formula (I) can optionally be converted into metal salts or into addition salts with nitrogenous bases according to methods known per se. These salts can be obtained by the action of a metal base (alkaline or alkaline earth for example), ammonia, a tetraalkylammonium, an amine or a salt of an organic acid on a compound of formula ( I), in a solvent. The salt formed is separated by the usual methods.
• salts with alkali metals sodium, potassium, lithium
• alkaline earth metals calcium, magnesium
• the ammonium salt the tetraalkylammonium salts (tetrabutylammonium for example)
• salts of nitrogenous bases ethanolamine, trimethylamine, methylamine, benzylamine, N-benzyl- ⁇ -phenethylamine, choline, arginine, leucine, lysine, N-methyl glucamine.
• NMDA N-methyl-D-aspartate receptor
• these compounds are useful for treating or preventing all ischemias (such as focal or global ischemia) following stroke, cardiac arrest, low blood pressure, cardiac or pulmonary surgery or severe hypoglycemia. They are also useful in the treatment of effects due to anoxia, whether perinatal or consecutive to drowning or cerebro-spinal lesions. These compounds can also be used to treat or prevent the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, amyotrophic lateral sclerosis, olivopontocerebellar atrophy, PARKINSON disease .
• These compounds can also be used with respect to epileptogenic and / or convulsive manifestations, for the treatment of cerebral or spinal trauma, of anxiety (KEHNE et al., Eur. J. Pharmacol., 193, 283 (1991 ), depression (TRULLAS et al., Eur. J. Pharmacol., 185, 1 (1990), schizophrenia (REYNOLDS, TIPS, 13, 116 (1992), as analgesics (DICKENSON et al. , Neurosc.
• the affinity of the compounds of formula (I) for the glycine site linked to the NMDA receptor was determined by studying the antagonism of the specific binding of [ 3 H] -DCKA (6,8-dichloro kynurenic acid) on membranes of rat cerebral cortex according to a method derived from that described by BARON et al., Eur. J. Pharm., 206, 149 (1991).
• [ 3 H] -DCKA (20 nM) is incubated in the presence of 0.1 mg of proteins at 4 ° C. for 10 minutes in HEPES buffer (acid (N- [2-hydroxyethyl] piperazine-N'- [ 2-ethanesulfonic]) 50 mM, pH 7.5.
• HEPES buffer acid (N- [2-hydroxyethyl] piperazine-N'- [ 2-ethanesulfonic]) 50 mM, pH 7.5.
• the non-specific binding is determined in the presence of 1 mM glycine
• the compounds of formula (I) have a low toxicity. Their LD50 is greater than 50 mg / kg by the IP route.
• the colored solid (12.47 g) is crystallized from 160 cm3 of isopropanol and recrystallized from 135 cm3 of isopropanol to give 5.5 g of 5-chloro-2H-1, 2,4-benzothiadiazine-3 (4H) -one-1, 1-dioxide melting at 245 ° C.
• Example 2 The procedure is as in Example 1, but starting from 17.7 g of chlorosulfonyl isocyanate, 12.12 g of 3,5-dimethylaniline and 16.67 g of aluminum chloride in nitromethane.
• the crude product (17 g) is treated by beating in 100 cm3 of tert-butyl methyl oxide and provides, after filtration and drying, 11.3 g of 6,8-dimethyl-2H-1, 2,4-benzothiadiazine-3 (4H ) -one- 1, 1-dioxide in the form of a light beige solid melting above 260 ° C (Analysis% calculated C: 47.78, H: 4.45, N: 12.38, 0:21, 21 , S: 14.17,% found C: 47.1; H: 4.5; N: 12.4; 0:21, 1; S: 14.1).
• Example 2 The procedure is as in Example 1, but using 3.5 g of chlorosulfonyl isocyanate, 3.24 g of 3,5-dichloroaniline and 3.29 g of aluminum chloride in nitromethane.
• the crude product (3 g) is recrystallized from boiling 2-butanone to yield 0.8 g of hydrate of 6,8-dichloro-2H-1,2,4-benzothiadiazine-3 (4H) -one-1 , 1-dioxide in the form of a white solid melting above 260 ° C (Analysis% calculated C: 31, 48, H: 1.51, CI: 26.55, N: 10.49, 0: 17.97, S: 12.00,% found C: 31.5; H1.5; Cl: 26.5, N: 10.4; 0: 17.3; S: 12.1).
• the medicaments consist of a compound of formula (I) in free form or in the form of a salt, in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product, which may be inert. or physiologically active.
• These drugs can be used orally, parenterally, rectally or topically.
• compositions for oral administration tablets, pills, powders (gelatin capsules, cachets) or granules can be used.
• the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon.
• inert diluents such as starch, cellulose, sucrose, lactose or silica
• These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.
• compositions for oral administration there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
• inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
• These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
• the sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions.
• solvent or vehicle water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable.
• These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by filtration sanitizer, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
• compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
• compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.
• the compounds according to the invention are particularly useful for the treatment and / or prevention of conditions which require the administration of an NMDA receptor antagonist or an AMPA receptor antagonist.
• These compounds are in particular useful for treating or preventing all ischemias and in particular cerebral ischemia, the effects due to anoxia, the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and PARKINSON's disease, with respect to epileptogenic and / or convulsive manifestations, for the treatment of cerebral or spinal trauma, anxiety, depression, schizophrenia, as analgesics, antianorexics, antiemetics, antimigraine and to treat poisoning by neurotoxins or other substances agonists of the NMDA receptor, as well as the neurological disorders associated with viral diseases such as AIDS, rabies, measles and tetanus.
• These compounds are also useful for the prevention of symptoms of abstinence from drugs and alcohol
• the doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 10 mg and 100 mg per day orally for an adult with unit doses ranging from 5 mg to 50 mg of active substance. In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.
• capsules containing 50 mg of active product having the following composition are prepared:
• Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique:

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• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Psychiatry (AREA)
• Vascular Medicine (AREA)
• Urology & Nephrology (AREA)
• Pain & Pain Management (AREA)
• Hospice & Palliative Care (AREA)
• Anesthesiology (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

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• 1993
  • 1993-03-03 FR FR9302439A patent/FR2702150B1/fr not_active Expired - Fee Related
• 1994
  • 1994-02-25 JP JP6519646A patent/JPH08507303A/ja active Pending
  • 1994-02-25 EP EP94908373A patent/EP0687178A1/fr not_active Withdrawn
  • 1994-02-25 CA CA002153951A patent/CA2153951A1/fr not_active Abandoned
  • 1994-02-25 WO PCT/FR1994/000207 patent/WO1994020109A1/fr not_active Application Discontinuation
  • 1994-02-25 HU HU9502572A patent/HU9502572D0/hu unknown
  • 1994-02-25 AU AU61436/94A patent/AU6143694A/en not_active Abandoned
  • 1994-02-25 PL PL94310439A patent/PL310439A1/xx unknown
  • 1994-02-28 IL IL10878494A patent/IL108784A0/xx unknown
• 1995
  • 1995-08-29 NO NO953387A patent/NO953387L/no unknown

Non-Patent Citations (1)

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