Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-02-15
2002-11-26
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S312000, C514S313000, C546S021000, C546S154000, C546S157000, C546S172000
Reexamination Certificate
active
06486143
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new 6-amino- or 6-hydrazino-sulphonyl-3-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. Those compounds pose serious problems of nephrotoxicity, however, as has also been shown to be the case for other non-NMDA (N-methyl-D-aspartate) antagonists of reference, such as, 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 new compounds that have more powerful non-NMDA antagonist properties than do the compounds of the prior art, with greatly reduced associated nephrotoxicity. Those 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
More especially, the present invention relates to compounds of formula (I):
wherein:
R
1
represents a halogen atom or a trifluoromethyl group,
R
2
represents a hydrogen atom or an alkyl or cycloalkyl group,
R
3
represents an alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, hydroxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonyl, arylcarbonyl or arylalkylcarbonyl group or an NHR
6
group (wherein R
6
represents a hydrogen atom or an alkyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, arylalkyl or arylalkylcarbonyl group),
or R
2
and R
3
together form with the nitrogen atom carrying them a ring having 5 or 6 carbon atoms, in which one of the carbon atoms can be replaced by an oxygen, nitrogen or sulphur atom or by an SO or SO
2
group or by an NR
a
group (wherein R
a
represents a hydrogen atom or an alkyl, cycloalkyl, aryl or arylalkyl group),
R
4
and R
5
, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, aryl or arylalkyl group or a group
(wherein R
7
and R
8
, 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,
“alkoxy” is understood to mean a linear or branched alkoxy 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 or naphthyl, it being possible for those groups to be unsubstituted or substituted by from 1 to 3 groups selected from alkyl, cycloalkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cyano, nitro, polyhaloalkyl, SO
2
NR
9
R
10
(wherein R
9
and R
10
, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl or aryl group) 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.
The preferred groups R
3
are the alkyl group (such as, for example, methyl or propyl), the dialkylaminoalkyl group (such as, for example, dimethylaminoethyl), the aryl group (such as, for example, phenyl), the arylcarbonyl group (such as, for example, benzoyl) or the group NHCOR wherein R represents an alkyl or aryl group.
An advantageous aspect of the invention relates to compounds of formula (I) wherein R
2
is a hydrogen atom, or an alkyl group.
When R
2
is a hydrogen atom, R
3
advantageously represents the groups cycloalkyl, aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, hydroxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl or NHR
6
.
When R
2
is an alkyl group, R
3
advantageously represents the group alkyl.
The hydrogen atom is the preferred meaning for the substituents R
4
and R
5
.
More especially still, the invention relates to compounds of formula (I) which are:
7-chloro-2-oxo-6-[(n-propylamino)sulphonyl]-1,2-dihydro-3-quinolylphosphonic acid,
7-chloro-6-[(methylamino)sulphonyl]-2-oxo-1,2-dihydro-3-quinolylphosphonic acid,
6-(anilinosulphonyl)-7-chloro-2-oxo-1,2-dihydro-3-quinolylphosphonic acid,
6-[(2-benzoylhydrazino)sulphonyl]-7-chloro-2-oxo-1,2-dihydro-3-quinolylphosphonic acid,
7-chloro-6-[(2-{4-[(di-n-propylamino)sulphonyl]benzoyl}hydrazino)sulphonyl]-2-oxo-1,2-dihydro-3-quinolylphosphonic acid, and
7-chloro-6-({[2-(dimethylamino)ethyl]amino}sulphonyl)-2-oxo-1,2-dihydro-3-quinolylphosphonic acid hydrobromide.
The enantiomers, diastereoisomers and pharmaceutically acceptable addition salts with an acid or a base of the preferred compounds of the invention 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 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 subjected, after conversion to the corresponding diazonium salt, to the action of sulphur dioxide in the presence of CuCl
2
to yield a compound of formula (VIII):
wherein R
1
is as defined hereinbefore,
which is condensed with a compound of formula HNR
2
R
3
wherein R
2
and R
3
are as defined for formula (I) to yield a compound of formula (I/a), a particular case of the compounds of formula (I):
wherein R
1
, R
2
and R
3
are as defined hereinbefore,
which is partially or totally deprotected in the presence of, for example, trimethylsilane bromide to yield a compound of formula (I/b), a particular case of the compounds of formula (I):
wherein R
1
, R
2
and R
3
are as defined hereinbefore and R
1
represents a hydrogen atom or an ethyl group,
which may be condensed with a compound of formula (IX):
wherein R″ represents an alkyl, aryl or arylalkyl group or a group
(wherein R
7
and R
8
are as defined for formula (I)),
to obtain a compound of formula (I/c), a particular case of the compounds o
Cordi Alex
Desos Patrice
Lestage Pierre
Huang Evelyn Mei
Les Laboratoires Servier
LandOfFree
6-amino- or 6-hydrazino-sulphonyl-3-quinolynyl-phosphonic... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 6-amino- or 6-hydrazino-sulphonyl-3-quinolynyl-phosphonic..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 6-amino- or 6-hydrazino-sulphonyl-3-quinolynyl-phosphonic... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2952488