Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
• • 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

• n represents the number 0, 1, 2 or 3
• R represents a hydrogen or halogen atom or a methyl or methoxy group
• R 2 represents a hydrogen atom or a methyl group
• R 3 represents a hydrogen atom or one or two halogen atoms.
• the compounds of the invention may exist in the form of free bases or of addition salts with acids.
• amide at a temperature of 50 to 80 ° C. , and in the presence of a mineral base, for example potassium carbonate.
• a simple or complex reducing agent such as an alkali metal hydride, for example, lithium aluminum hydride, boron hydride, boron hydride-tetrahydro
• a piperidine of general formula (V), in which n and R 3 are as defined above, is reacted with l-bromo-2-chloroethane, under the conventional conditions for such a reaction, it that is to say in a polar solvent, for example N, iV-dimethylformamide, in the presence of a mineral base, for example potassium carbonate, at a temperature of 50 to 80 ° C.
• a polar solvent for example N, iV-dimethylformamide
• a mineral base for example potassium carbonate
• N- (Benzothiazolyl-2-yl) -4- [(4-fluorophenyl) methyl] piperidine-1 -ethanamine, ethanedioate 1.3 g (0.00349 mole) of N- (benzothiazolyl-) are introduced into a 250 ml three-necked flask 2-yl) -4- [(4-fluorophenyl) methyl] piperidme-1-acetamide in solution in 25 ml of dry tetrahydrofuran, 1.09 ml, or 3 equivalents, of borane-methyl sulfide complex is added, and heats the mixture at reflux for 4 hours.
• a suspension of 0.854 g (0.0224 mole) of lithium aluminum hydride in 50 ml of tetrahydrofuran is prepared, it is heated to reflux, a solution of 2 g (0.0112 mole) of intermediate is added. formylated in 100 ml of tetrahydrofuran and heating is continued for 30 mm. The mixture is cooled, 100 ml of ethyl acetate are added and, dropwise, 38 ml of water, the organic phase is separated by decantation, it is evaporated under reduced pressure, the crystallized residue is triturated in petroleum ether, it is filtered and dried in the presence of phosphorus pentoxide. 1.5 g of compound are obtained.
• N- (Benzothiazol-2 -yl) -4- [2- (4-fluorophenyl) ethyl] piperidine-1-ethanamine 0.96 g (0.025 mole) of lithium aluminum hydride and 140 ml of dry tetrahydrofuran are introduced into a 500 ml three-necked flask, under nitrogen atmosphere, the suspension is heated to reflux, drip, 5.0 g (0.01 mole) of N- (benzothiazol -2 -yl) -4- [2- (4-fluorophenyl) - ethyl] piperidine-1-acetamide dissolved in 60 ml of tetrahydrofuran dry and heating continues 30 min.
• the compounds of the invention have been subjected to tests which have demonstrated their interest as therapeutic active substances.
• test compounds are administered after intravenous occlusion. 24 hours after occlusion of the middle cerebral artery, the animals are sacrificed and the brain is removed.
• the volume of the cerebral infarction is evaluated from the measurement of the surface of the necrosis on 6 coronal sections stained with 2, 3, 5-t ⁇ phenyltetrazol ⁇ um chloride.
• compound No. ll of the above table significantly reduces the volume of the infarction by approximately
• the compounds of the invention were also subjected to the test of global cerebral ischemia in mice.
• the ischemia is due to cardiac arrest induced by a rapid intravenous injection of magnesium chloride.
• the "survival time” is measured, that is to say the interval between the moment of injection of magnesium chloride and the last observable respiratory movement of each mouse. This last movement is considered the ultimate index of a function of the central nervous system. Respiratory arrest occurs approximately 19 seconds after the injection of magnesium chloride.
• Male mice (Charles River CD1) are studied in groups of 10. They are fed and watered ad libitum before the tests. The survival time is measured 10 minutes after the intraperitoneal administration of the compounds of the invention.
• the results are given in the form of the difference between the survival time measured in a group of 10 mice having received the compound and the survival time measured in a group of 10 mice having received the carrier liquid.
• the relationships between the modifications in the survival term and the dose of the compound are recorded graphically according to a semilogarithmic curve.
• a 3 second increase in survival time is both statistically significant and reproducible.
• the ED 3 ride of the most active compounds of the invention are less than 5 mg / kg intraperitoneally.
• the compounds according to the invention have also been the subject of an in vitro study as to their affinity for the dopaminergic receptors D 4 obtained by transfection of human receptors D 4 ⁇ 4 into CHO cells, essentially as described by Van Toi . et al., Nature (1991) 350 610-614 and Van Toi. et al., Nature (1992) 358 149-152.
• the membrane suspension (100 ⁇ l, 78 ⁇ g of membrane) is incubated at 25 ° C for 60 min in the presence of 0.5 nM of [ 3 H] spiperone (specific activity 17 to 20 Ci / mmol, New England Nuclear / Du Pont de Nemours, Boston, MA, USA) in a final volume of 1 ml of incubation buffer in the presence or absence of the test compound.
• the filters are dried in an oven at 120 ° C for 5 min.
• the radioactivity retained on the filters is determined by liquid scintigraphy.
• the non-specific binding is determined in the presence of 1 ⁇ M of haloperidol.
• the percentage inhibition of the specific binding of [ 3 H] spiperone is calculated, then the IC 50 , concentration which inhibits 50% of the binding, is determined.
• the IC 50 values of the compounds of the invention are of the order of 3 to 30 nM.
• results of the tests show that, in vivo, the compounds according to the invention have neuroprotective properties and that, in vi tro, they displace the specific binding of [ 3 H] spiperone to human D 4 4 dopaminergic receptors.
• ischemic or hypoxic origin Cerebral infarction, cranial or spinal trauma, cardiac or respiratory arrest, transient ischemic attack, perinatal asphyxia
• glaucoma progressive neurodegenerative diseases
• senile dementia such as Alzheimer's disease, vascular dementias, Parkinson's disease, Huntington's disease, olivo-ponto-cerebellar atrophy, amyotrophic lateral sclerosis, neurodegenerative diseases of viral origin, etc.
• senile dementia such as Alzheimer's disease, vascular dementias, Parkinson's disease, Huntington's disease, olivo-ponto-cerebellar atrophy, amyotrophic lateral sclerosis, neurodegenerative diseases of viral origin, etc.
• psychoses in particular schizophrenia (deficit and productive forms) and acute and chronic extrapyramidal symptoms, induced by neuroleptics or consecutive to Parkinson's disease, for the treatment various forms of anxiety, panic attacks, phobias, obsessive compulsive disorder, for the treatment of various forms of depression, including psychotic depression, for the treatment of drug and alcohol dependence and disorders of the hypothalamic-pituitary function, and for the treatment cognitive impairment related to age or Alzheimer's disease.
• psychoses in particular schizophrenia (deficit and productive forms) and acute and chronic extrapyramidal symptoms, induced by neuroleptics or consecutive to Parkinson's disease
• various forms of anxiety, panic attacks, phobias, obsessive compulsive disorder for the treatment of various forms of depression, including psychotic depression, for the treatment of drug and alcohol dependence and disorders of the hypothalamic-pituitary function, and for the treatment cognitive impairment related to age or Alzheimer's disease.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Hydrogenated Pyridines (AREA)

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Citations (2)

• 1996
  • 1996-10-01 FR FR9611925A patent/FR2753970B1/fr not_active Expired - Fee Related
• 1997
  • 1997-09-26 WO PCT/FR1997/001692 patent/WO1998014444A1/fr not_active Ceased
  • 1997-09-26 CO CO97056315A patent/CO4650030A1/es unknown
  • 1997-09-26 TR TR1999/00634T patent/TR199900634T2/xx unknown
  • 1997-09-26 EP EP97943001A patent/EP0929550A1/fr not_active Ceased
  • 1997-09-26 JP JP10516272A patent/JP2001501217A/ja active Pending
  • 1997-09-26 PL PL97332648A patent/PL332648A1/xx unknown
  • 1997-09-26 BR BR9711842A patent/BR9711842A/pt not_active Application Discontinuation
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  • 1997-09-26 IL IL12890297A patent/IL128902A/en not_active IP Right Cessation
  • 1997-09-26 CZ CZ991126A patent/CZ112699A3/cs unknown
  • 1997-09-26 CN CN97198112A patent/CN1230959A/zh active Pending
  • 1997-09-26 CA CA002266510A patent/CA2266510A1/en not_active Abandoned
  • 1997-09-26 HU HU9904091A patent/HUP9904091A3/hu unknown
  • 1997-09-26 NZ NZ334553A patent/NZ334553A/xx unknown
  • 1997-09-26 AU AU44638/97A patent/AU722147B2/en not_active Ceased
  • 1997-09-26 KR KR1019990702753A patent/KR20000048767A/ko not_active Withdrawn
  • 1997-09-30 ZA ZA9708772A patent/ZA978772B/xx unknown
  • 1997-09-30 TW TW086114229A patent/TW438800B/zh active
  • 1997-09-30 AR ARP970104493A patent/AR009105A1/es not_active Application Discontinuation
• 1999
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