6-sulphanoyl-3-quinolylphosphonic acid compounds

Details 6-sulphanoyl-3-quinolylphosphonic acid compounds 6-sulphanoyl-3-quinolylphosphonic acid compounds

2002-12-09

2003-07-22

Krass, Frederick (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S080000, C514S089000, C514S878000, C514S879000, C514S907000

Reexamination Certificate

active

06596709

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new 6-sulphamoyl-3-quinolylphosphonic acid compounds and to compositions containing them.
DESCRIPTION OF THE PRIOR ART AND BACKGROUND OF THE INVENTION
The present invention constitutes a selection with respect to the patent EP 0 640 612. Patent specification EP 0 640 612 describes compounds that are capable of countering the excitatory and toxic effects of the excitatory amino acids (EAA) by blocking the initial activation of the AMPA (&agr;-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid)/kainate receptor. Their usefulness is accordingly recognised for inhibiting pathological phenomena, especially neurotoxic phenomena associated with hyperactivation of the neurotransmission paths to the excitatory amino acids. The Applicant has, however, found serious problems of nephrotoxicity associated with the use of those compounds, for example in the case of (6,7-dichloro-2-oxo-1,2-dihydro-3-quinolyl)phosphonic acid, as has also been shown to be the case, moreover, for other non-NMDA (N-methyl-D-aspartate) antagonists of reference, for example 6-nitro-7-sulphamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) (Journal of Cerebral Blood Flow and Metabolism, 1994, 14, 251-261).
The Applicant has discovered, surprisingly, that a small group of compounds not described in patent specification EP 0 640 612 not only have powerful non-NMDA antagonist properties but are completely without associated nephrotoxicity. These compounds are therefore new and are potential powerful therapeutic agents for acute, and also chronic, treatment of neurological and psychological disorders involving those amino acids, for example degenerative disorders such as cerebrovascular accident, cerebral or spinal traumatism, epilepsy, chronic neurodegenerative diseases such as Alzheimer's disease, schizophrenia, lateral amyotrophic sclerosis or Huntington's chorea.
DETAILED DESCRIPTION OF THE INVENTION
More specifically, the present invention relates to compounds of formula (I):
wherein:
X represents a chlorine or fluorine atom or a trifluoromethyl group,
R represents a hydrogen atom or a group
wherein R′ represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl or phenyl group, their isomers and addition salts thereof with a pharmaceutically acceptable base.
Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Preferred compounds of the invention are compounds of formula (I) wherein R represents a hydrogen atom.
More particularly, the invention relates to the compounds of formula (I) which are:
(7-chloro-2-oxo-6-sulphamoyl-1,2-dihydro-3-quinolyl)phosphonic acid,
(7-trifluoromethyl-2-oxo-6-sulphamoyl- 1,2-dihydro-3-quinolyl)phosphonic acid,
(7-fluoro-2-oxo-6-sulphamoyl-1,2-dihydro-3-quinolyl)phosphonic acid.
The isomers, as well as the addition salts with a pharmaceutically acceptable base, of the preferred compounds form an integral part of the invention.
The invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (II):
wherein X is as defined for formula (I),
which is condensed, in the presence of a base, such as, for example, pyridine, with a compound of formula (III):
to yield a compound of formula (IV):
wherein X is as defined hereinbefore,
which is cyclised in the presence of a catalytic amount of piperidine to obtain a compound of formula (V):
wherein X is as defined hereinbefore,
which is subjected to a mixture of nitric acid and sulphuric acid to yield a compound of formula (VI):
wherein X is as defined hereinbefore,
which is reduced using palladium-on-carbon in the presence of hydrogen or iron in a dilute alcoholic medium to obtain a compound of formula (VII):
wherein X is as defined hereinbefore,
which is subjected, after conversion into the corresponding diazonium salt, to the action of sulphur dioxide in the presence of CuCl
2
to yield a compound of formula (VIII):
wherein X is as defined hereinbefore,
which is placed in the presence of ammonium hydroxide solution to obtain a compound of formula (IX):
wherein X is as defined hereinbefore,
which is deprotected in the presence of trimethylsilane bromide in an acetonitrile medium
to yield a compound of formula (I/a), a particular case of the compounds of formula (I):
wherein X is as defined hereinbefore,
which may be reacted in a basic medium with a compound of formula (X):
wherein R′ is as defined for formula (I),
to yield a compound of formula (I/b), a particular case of the compounds of formula (I):
wherein X and R′ are as defined hereinbefore,
which compounds of formulae (I/a) and (I/b) constitute the totality of the compounds of formula (I), and can be purified according to a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable base, and separated, where appropriate, into their isomers according to a conventional separation technique.
The compounds of the invention have very valuable pharmacological properties since they are powerful inhibitors of the AMPA receptor, and they are moreover selective since they do not affect the NMDA receptor and therefore do not have any of the side-effects described for NMDA antagonists; above all, they do not have the nephrotoxicity associated with a number of AMPA
on-NMDA antagonists. The use of those compounds as inhibitors of pathological phenomena associated with hyperactivation of the neurotransmission paths to the excitatory amino acids will therefore be particularly appreciated in the acute, and especially chronic, treatment of neurological and psychological disorders involving those amino acids, for example degenerative disorders such as cerebrovascular accident, cerebral or spinal traumatism, epilepsy, chronic neurodegenerative diseases such as Alzheimer's disease, schizophrenia, lateral amyotrophic sclerosis or Huntington's chorea.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) alone or in combination with one or more pharmaceutically acceptable excipients.
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration, and especially tablets or dragées, sublingual tablets, sachets, paquets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels and drinkable or injectable ampoules.
The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or any associated treatments, and ranges from 50 mg to 1 g per 24 hours in 1 or more administrations.


REFERENCES:
patent: 6420386 (2002-07-01), Cordi et al.

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