Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • 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
  • A61P25/16—Anti-Parkinson drugs
• • 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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

• the subject of the present invention is compounds derived from oxazolidin-2-one, their preparation process and their use in therapy.
• n 0 or 1
• R 1 represents a cyano group, an alkyl group comprising 1 to 4 carbon atoms or a fluoroalkyl group comprising 1 to 4 carbon atoms,
• R 2 represents a hydrogen atom or a hydroxyl group
• R 3 represents a hydrogen atom or a methyl group
• an alkyl group is an aliphatic group, saturated, linear or branched
• a fluoroalkyl group is an alkyl group as defined above, in which at least one of the carbon atoms is substituted by one or more fluorine atoms.
• a fluoroalkyl group according to the invention comprises 3 fluorine atoms substituted on the terminal carbon atom of the alkyl chain.
• Preferred compounds of formula (I) are those for which (i) R 1 represents a cyano, methyl or
• R 3 represents a methyl group.
• the compounds of formula (I) contain at least two asymmetric carbon atoms, one in position 5 of oxazolidine, the other in position 2 of dihydrobenzofuran or dihydro benzopyran (these positions are indicated by 5 and 2 respectively in the configurations). Iks can therefore exist in the form of enantiomers or diastereoisomers.
• the invention includes these different forms and their mixtures, including racemic mixtures.
• the compounds of formula (I) can be prepared according to the process represented in appendix 1.
• the compounds of formula (I) in which R 3 represents a methyl group can be prepared starting from a compound of formula (II)
• Isomers 5 (R) and 5 (S) of the compounds of formula (I) can be prepared by reaction of a compound of formula (IV) described above, with isomers 4 (S) and 4 (R) respectively 4-methoxymethyl-1,3-dioxolan-2-one.
• the compounds of formula (I) can exist in the form of (R) and (S) enantiomers in position 2 of the group
• reaction medium is then diluted with dichloromethane and washed with water, then the organic phase is dried over sodium sulphate and concentrated under reduced pressure.
• chromatography of the residue on a silica column with cyclohexane containing 0 to 50% of dichloromethane 5.9 g of product are obtained.
• step 6 of Example 1 By a process analogous to that of step 6 of Example 1, starting from 2.4 g (12 mmol) of 2-cyanoethyl-6-amino-3,4-dihydro-2H-1-benzopyran, 1 , 24 ml (13.0 mmol) of ethyl chloroformate and 1.5 g (18 mmol) of sodium hydrogen carbonate, 2.0 g of product are obtained.
• step 7 of Example 1 By a process analogous to that of step 7 of Example 1, starting from 1.9 g (6.9 mmol) of 2-cyanoethyl-6-ethoxy carbonylamino-3,4-dihydro-2H-1- benzopyran, 0.1 g (0.7 mmol) of potassium carbonate and 1.2 g (0.9 mmol) of 4 (S) -methoxy methyl-1,3-dioxolan-2-one, we obtain 0, 6 g of product in the form of an oil.
• Example 1 3.2 g of product were obtained.
• Hydrogenation is carried out for 8 hours under a pressure of 500 kPa, in the presence of 14 g of 10% palladium on carbon.
• the compounds of the invention are collated in the following table with their physical characteristics.
• the compounds of the invention have been the subject of pharmacological tests making it possible to determine their inhibitory power of monoamine oxidase A and of monoamine oxidase B.
• the reaction is
• the inhibitory activities with respect to MAO-A and MAO-B are given respectively by the inhibition constants Ki (MAO-A) and Ki (MAO-B).
• the Ki (MAO-A) vary between 1.5 and 17.7 nM, the Ki (MAO-B) generally being greater than 1000 nM.
• the invention can be used for the preparation of selective MAO-A inhibitor drugs, these
• drugs finding their use in therapy, particularly in the treatment of depressive states, attacks of panic, phobias, anxiety, cognitive deficits related to age, dementia or stroke or trauma, and in the prevention and treatment of neurodegenerative diseases of the central nervous system such as Parkinson's disease and the disease Alzheimer's, the treatment of dependence and withdrawal linked to the consumption of alcohol, tobacco and / or
• the compounds of the invention may be presented, in combination with at least one excipient, in the form of pharmaceutical compositions formulated with a view to
• administration in particular, by oral, parenteral or rectal route, for example in the form of tablets, dragees, capsules, solutions, suspensions or suppositories.
• the dose of active ingredient administered per day can vary between 1 and 100 mg / kg, in one or more doses.

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

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• 1995
  • 1995-11-09 FR FR9513257A patent/FR2741072B1/fr not_active Expired - Fee Related
• 1996
  • 1996-11-05 US US09/066,364 patent/US5925662A/en not_active Expired - Fee Related
  • 1996-11-05 JP JP9517919A patent/JP2000500127A/ja active Pending
  • 1996-11-05 WO PCT/FR1996/001732 patent/WO1997017347A1/fr not_active Application Discontinuation
  • 1996-11-05 EP EP96937392A patent/EP0859776A1/de not_active Withdrawn

Non-Patent Citations (1)

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