WO1998047889A1 - Derives de chromane - Google Patents

Derives de chromane Download PDF

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Publication number
WO1998047889A1
WO1998047889A1 PCT/EP1998/002344 EP9802344W WO9847889A1 WO 1998047889 A1 WO1998047889 A1 WO 1998047889A1 EP 9802344 W EP9802344 W EP 9802344W WO 9847889 A1 WO9847889 A1 WO 9847889A1
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WO
WIPO (PCT)
Prior art keywords
compound
free base
acid addition
addition salt
salt form
Prior art date
Application number
PCT/EP1998/002344
Other languages
English (en)
Inventor
Robert Swoboda
Esteban Pombo Villar
Original Assignee
Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft M.B.H.
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 Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft M.B.H. filed Critical Novartis Ag
Priority to AU75277/98A priority Critical patent/AU7527798A/en
Publication of WO1998047889A1 publication Critical patent/WO1998047889A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4

Definitions

  • the present invention relates to novel chromans, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
  • Ri and R 2 independently, are hydrogen, (C ⁇ - 4 )alkyl, (C ⁇ - 4 )alkoxy, halogen, trifluoromethyl, trifluoromethoxy, cyano, or sulfamoyl, at least one of Ri and R 2 being other than hydrogen, R 3 is hydrogen, hydroxy, (C.- ⁇ alkyl, (C M )alkoxy, (C ⁇ cycloalkyloxy, halogen, cyano, ( .
  • R* and R 5 independently, are hydrogen, (Q- ⁇ alkyl, hydroxy(C 2 - 4 )alkyl or phenyl(C ⁇ - 4 )alkyl, or form together with the nitrogen atom to which they are attached a pyrrolidinyl, piperidino, piperazinyl or morpholino group, in free base or acid addition salt form.
  • Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • alkyl, alkoxy and alkylthio radicals preferably are straight chain radicals. They preferably have 1 to 3 carbon atoms, more preferably they are methyl, methoxy and methylthio groups. The following significances and their combinations are preferred:
  • R, and R independently, are hydrogen, (C ⁇ - 4 )alkyl, (C ⁇ - 4 )alkoxy, halogen or trifluoromethyl, at least one of Rj and R being other than hydrogen,
  • R 3 is hydrogen, hydroxy, (Q ⁇ alkoxy, (Cs ⁇ ) cycloalkyloxy, cyano or caibamoyl,
  • R and R 5 independently, are hydrogen or or form together with the nitrogen to which they are attached a piperidino or moipholino group.
  • the compounds of the invention possess an asymmetrical carbon atom in position 3. They may therefore appear in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures. Individual optical isomers and their mixtures including the racemic mixtures are part of the present invention.
  • the invention provides a process for the production of the compounds of the invention, whereby a compound of formula II
  • the reaction may be effected in known manner, preferably by transition metal-catalysed aryl-aryl coupling, e.g. as described in Example 1.
  • Hal is preferably bromine or iodine, particularly iodine.
  • Acid addition salts may be produced in known manner from the free base forms and vice-versa.
  • Suitable pharmaceutically acceptable acid addition salts for use in accordance with the present invention include for example the hydrochloride, the hydrogen maleate, the hydrogen fumarate and the hydrogen malonate.
  • Racemic compounds of the invention may be obtained from racemic starting materials.
  • Optically active isomers may be obtained form optically active starting materials or from the racemate.
  • the enantiomers may be obtained from the racemate by known methods, for example by fractional crystallization of diastereoisomeric salts, e.g. their salts with (+)-di-0,0'-p-toluoyl-D-tartaric acid or (-)-di-0,0'-p-toluoyl-L- tartaric acid.
  • the starting materials of formula ⁇ may be produced by halogenating compounds of formula IV
  • R 4 and R 5 are as defined above, in accordance to known procedures, e.g. as described in Example 1.
  • the starting materials of formulae III and IV are known or may be produced in analogous manner to known procedures.
  • the compound of formula IV wherein R 3 is methoxy and R4 and R 5 are both hydrogen, for example, which is used as starting material in Example 1, is known from, and can be prepared according to, M. Al Neirabeyeh et al., Eur. J. Med. Chem.26, 497 (1991).
  • agents of the invention exhibit pharmacological activity and are, therefore, useful as pharmaceuticals.
  • the agents of the invention provide long-lasting protection against maximal electroshock-induced convulsions in mice at doses of about 1 to 100 mg/kg p.o. and about 0.32 to 32 mg/kg i.p. [cf. E.A. Swinyard, J. Am.Pharm. Assoc. Scient. Ed.38, 201 (1949) and IPha ⁇ nacol. Exptl. Therap. 106, 319 (1952)].
  • the agents of the invention are therefore useful in the treatment of epilepsy and other convulsive states such as high pressure neurological syndrome.
  • the agents of the invention reduce ischaemia-induced neuronal damage and ensuing symptoms in the middle cerebral artery (MCA) occlusion model in rats at a dosage of 1-50 mg/kg i.p, i.v. and p.o. [cf. A. Tamura et al., J. Cereb. Blood Flow Metabol. 1, 53-60 (1981), A. Sauter, M. Rudin, Stroke 17, 1228-1234 (1986)].
  • the agents of the invention are therefore useful in the treatment of any clinical condition involving a component of cerebral anoxia, hypoxia and/or ischaemia, e.g. ischemic damage to grey and white matter, stroke, reperfusion injury, subarachnoid haemorrhage, brain and spinal cord injury/trauma, high intracranial pressure, multi-inf arct dementia or vascular dementia, and any surgical procedure potentially associated with cerebral anoxia, hypoxia and/or ischemia (e.g. cardiac bypass, operations on extracerebral vessels).
  • ischemic damage to grey and white matter e.g. ischemic damage to grey and white matter
  • stroke reperfusion injury
  • subarachnoid haemorrhage e.g. ischemic damage to grey and white matter
  • stroke reperfusion injury
  • subarachnoid haemorrhage e.g. ischemic damage to grey and white matter
  • brain and spinal cord injury/trauma e.g. ischemic damage to grey and white matter
  • the agents of the invention display binding to the veratridine-sensitive sodium channel with I os of from about 0.1 to about 100 ⁇ M.
  • I os of from about 0.1 to about 100 ⁇ M.
  • They block veratridine-induced glutamate release in rat hippocampal slice preparations at concentrations of about 0.1-1 ⁇ M.
  • the experiment is performed according to a modification of M. J. Leach et al. in Epilepsia 27, 490-497 (1986) and Stroke 24, 1063-1067 (1993), using exogenous glutamate.
  • the agents of the invention are indicated for the treatment of any pathology, disorder or clinical condition involving glutamate release in their etiology, including psychiatric disorders (such as schizophrenia, depression, anxiety, panic attacks, attention deficit and cognitive disorders, social withdrawal), hormonal conditions (excess GH [e.g.
  • LH prostate hypertrophy, menopausal syndrome] secretion, corticosterone secretion in stress
  • metabolic induced brain damage hyperoglycaemia, non-ketotic hypergly
  • the agents of the invention are indicated in the treatment of any pathology involving neuronal damage, for example neurodegenerative disorders such as Alzheimer's, Huntington's or Parkinson's diseases, virus (including Hiy)-induced neurodegeneration, Amyotrophic lateral sclerosis (ALS), supra-nuclear palsy, olivoponto-cerebellar atrophy (OPCA), and the actions of environmental, exogenous neurotoxins.
  • neurodegenerative disorders such as Alzheimer's, Huntington's or Parkinson's diseases, virus (including Hiy)-induced neurodegeneration, Amyotrophic lateral sclerosis (ALS), supra-nuclear palsy, olivoponto-cerebellar atrophy (OPCA), and the actions of environmental, exogenous neurotoxins.
  • the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.1 to about 100, preferably from about 0.5 to about 100 mg/kg animal body weight In larger mammals, for example humans, an indicated daily dosage is in the range from about 1 to about 500, preferably from about 1 to about 300 mg of an agent of the invention, conveniently administered, for example, in divided doses up to four times a day or in sustained release form.
  • the preferred compounds are 3,4-dihydro-3-dimethylamino-5-methoxy-8-[4- (trifluoromethyl)phenyl]-2H-l-benzopyran, which is the compound of example 1 and the corresponding antipodes of examples 2 and 3.
  • the (-)-antipode of example 2 is particularly preferred. It has for example been determined that in the above mentioned electroshock model, this compound provides protection against maximal electroshock-induced convulsions with a threshold dose of 10 mg/kg p.o. and 100% protection at 32 mg/kg p.o. In the MCA occlusion model, the compound given i.v.5 minutes after occlusion has been found to reduce infarct size by 25% at about 4.5 mg/kg.
  • the preferred indications are epilepsy, stroke and brain and spinal trauma.
  • the agent of the invention may be administered by any conventional route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.
  • the present invention also provides an agent of the invention, for use as a pharmaceutical, e.g. for the treatment of epilepsy, stroke and brain or spinal trauma.
  • the present invention furthermore provides a pharmaceutical composition
  • a pharmaceutical composition comprising an agent of the invention in association with at least one pharmaceutical carrier or diluent.
  • Such compositions may be manufactured in conventional manner.
  • Unit dosage forms contain, for example, from about 0.25 to about 150, preferably from 0.25 to about 25 mg of a compound according to the invention.
  • the present invention provides the use of an agent of the invention, for the manufacture of a medicament for the treatment of any condition mentioned above, e.g. epilepsy, stroke and brain or spinal trauma.
  • the present invention provides a method for the treatment of any condition mentioned above, e.g. epilepsy, stroke and brain or spinal trauma, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of an agent of the invention.
  • the organic phases are washed first with aqueous sodium bisulfite, then with water. Drying the organic phase with sodium sulfate, filtering and evaporating yields a brown viscous oil. After flash chromatography over silica gel with hexane/ethanol/ammonia 85/15/1, the title compound is obtained as a bright orange viscous oil.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés représentés par la formule (I) dans laquelle R1, R2, R3, R4 et R5 sont tels qu'ils sont définis dans le descriptif. Ces composés sont utiles en tant qu'agents pharmaceutiques.
PCT/EP1998/002344 1997-04-23 1998-04-21 Derives de chromane WO1998047889A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU75277/98A AU7527798A (en) 1997-04-23 1998-04-21 Chroman derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9708235.8A GB9708235D0 (en) 1997-04-23 1997-04-23 Organic compounds
GB9708235.8 1997-04-23

Publications (1)

Publication Number Publication Date
WO1998047889A1 true WO1998047889A1 (fr) 1998-10-29

Family

ID=10811237

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/002344 WO1998047889A1 (fr) 1997-04-23 1998-04-21 Derives de chromane

Country Status (7)

Country Link
AR (1) AR012487A1 (fr)
AU (1) AU7527798A (fr)
CO (1) CO4940440A1 (fr)
GB (1) GB9708235D0 (fr)
PE (1) PE69599A1 (fr)
WO (1) WO1998047889A1 (fr)
ZA (1) ZA983370B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AP1587A (en) * 1999-12-24 2006-03-02 Aventis Pharma Ltd Azaindoles.

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0452204A1 (fr) * 1990-04-09 1991-10-16 Adir Et Compagnie Nouveaux dérivés du 3-aminochromane, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0452204A1 (fr) * 1990-04-09 1991-10-16 Adir Et Compagnie Nouveaux dérivés du 3-aminochromane, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AP1587A (en) * 1999-12-24 2006-03-02 Aventis Pharma Ltd Azaindoles.
AP1917A (en) * 1999-12-24 2008-11-12 Aventis Pharma Ltd Azaindoles

Also Published As

Publication number Publication date
ZA983370B (en) 1998-10-23
AR012487A1 (es) 2000-10-18
AU7527798A (en) 1998-11-13
CO4940440A1 (es) 2000-07-24
PE69599A1 (es) 1999-08-23
GB9708235D0 (en) 1997-06-11

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