Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-14
2002-07-16
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S312000, C546S021000, C546S156000, C546S157000
Reexamination Certificate
active
06420386
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new aryl or heteroaryl quinolylphosphonic acid compounds, and to compositions containing them.
DESCRIPTION OF THE PRIOR ART AND BACKGROUND OF THE INVENTION
The prior art 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-isoxazolepropionic acid)/kainate receptor (EP 0 640 612). 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 discovered new compounds of novel structure that have more powerful non-NMDA antagonist properties than do the compounds of the prior art. The compounds are therefore new and are potential powerful therapeutic agents for the 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
The present invention relates more especially to compounds of formula (I):
wherein:
R
1
represents a halogen atom or a trifluoromethyl group,
R
2
represents an aryl or heteroaryl group,
R
3
and R
4
, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, aryl or arylalkyl group or a group
(wherein R
5
and R
6
, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl or aryl group),
it being understood that:
“alkyl” is understood to mean a linear or branched alkyl group containing from 1 to 6 carbon atoms,
“cycloalkyl” is understood to mean a cyclic alkyl group containing from 3 to 8 carbon atoms,
“aryl” is understood to mean the groups phenyl, naphthyl or biphenyl, it being possible for those groups to be unsubstituted or substituted by from 1 to 3 groups selected from alkyl, cycloalkyl, alkoxy, polyhaloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, SO
2
NR
7
R
8
(wherein R
7
and R
8
, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl or aryl group) and halogen atoms,
“heteroaryl” is understood to mean any mono- or bi-cyclic aromatic group containing from 5 to 10 ring atoms and containing from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur, it being possible for the heteroaryl to be attached to the benzene ring that carries it by a carbon atom or by a nitrogen atom when it has one, and for it to be unsubstituted or substituted by from 1 to 3 groups selected from alkyl, cycloalkyl, alkoxy, polyhaloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, SO
2
NR
7
R
8
(wherein R
7
and R
8
are as defined hereinbefore) and halogen atoms,
their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred compounds of the invention are compounds of formula (I) wherein R
1
represents a chlorine atom or a group CF
3
.
The preferred groups R
2
are phenyl, naphthyl or biphenyl, those groups being unsubstituted or substituted, more especially by a halogen atom or by a group CF
3
, NO
2
, alkyl or SO
2
NH
2
, or pyrrole or thiophene groups.
More preferably, the invention relates to compounds of formula (I) wherein R
3
and R
4
simultaneously represent a hydrogen atom.
More especially still, the invention relates to compounds of formula (I) which are:
{7-chloro-2-oxo-6-[4-(trifluoromethyl)phenyl]-1,2-dihydro-3-quinolyl}-phosphonic acid
[7-chloro-6-(4-methylphenyl)-2-oxo-1,2-dihydro-3-quinolyl]phosphonic acid.
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 R
1
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 R
1
is as defined hereinbefore,
which is cyclised in the presence of a catalytic amount of piperidine to obtain a compound of formula (V)
wherein R
1
is as defined hereinbefore,
which is subjected to a mixture of nitric acid and sulphuric acid to yield a compound of formula (VI):
wherein R
1
is as defined hereinbefore,
which is reduced using palladium-on-carbon in the presence of hydrogen or iron in a dilute alcoholic medium to yield a compound of formula (VII):
wherein R
1
is as defined hereinbefore,
which is converted by the action of NaNO
2
and HBF
4
to the corresponding diazonium fluoroborate salt of formula (VIII):
wherein R
1
is as defined hereinbefore,
which is condensed in the presence of palladium with a boronic acid compound of formula (IX):
wherein R′
2
represents an aryl or heteroaryl group as defined for formula (I), the heteroaryl group being attached to the boron atom by a carbon atom,
to yield a compound of formula (I/a), a particular case of the compounds of formula (I):
wherein R
1
and R′
2
are as defined hereinbefore,
or which compound of formula (VII) is subjected to the action of 2,5-dimethoxytetrahydrofuran to yield a compound of formula (I/b), a particular case of the compounds of formula (I):
wherein R
1
is as defined hereinbefore,
which compounds of formulae (I/a) and (I/b) may be partially or totally deprotected in the presence of, for example, trimethylsilane bromide to yield a compound of formula (I/c), a particular case of the compounds of formula (I):
wherein R
1
and R
2
are as defined hereinbefore and R′ represents a hydrogen atom or an ethyl group,
which may be condensed with a compound of formula (X):
R″—Cl (X)
wherein R″ represents an alkyl, aryl or arylalkyl group or a group
(wherein R
5
and R
6
are as defined hereinbefore), to obtain a compound of formula (I/d), a particular case of the compounds of formula (I):
wherein R
1
, R
2
, R
3
and R″ are as defined hereinbefore,
which compounds of formulae (I/a) to (I/d) 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 acid or 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. 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 inventio
Cordi Alex
Desos Patrice
Lestage Pierre
Desai Rita
Hueschen and Sage
Les Laboratories Servier
Rotman Alan L.
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