Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-21
2004-02-03
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S461000, C514S469000, C514S227500, C514S337000, C514S451000, C549S200000, C549S356000, C549S435000, C549S425000, C549S426000, C549S427000, C549S456000, C549S462000, C549S469000, C549S471000, C549S497000, C544S059000, C544S060000
Reexamination Certificate
active
06686348
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to new metalloprotease inhibitors, to pharmaceutical compositions containing them.
In the physiological state, the synthesis of connective tissues is in dynamic equilibrium with the degradation of the extracellular matrix. That degradation is due to zinc proteases (metalloproteases) secreted by the cells of the existing matrix: they are, without implying any limitation, collagenases (MMP-1, MMP-8, MMP-13), gelatinases or collagenases of type TV (MMP-2, MMP-9) and stromelysins (MMP-3).
In the normal state, those catabolic enzymes are regulated in terms of their synthesis and their secretion, and in terms of their extracellular enzymatic activity, by natural inhibitors, such as &agr;
2
-macroglobulin or the TIMPs (Tissue Inhibitors of MetalloProteinases), which form inactive complexes with the metalloproteases.
A common factor in pathologies in which those enzymes are implicated is an imbalance between the activity of the activated enzymes and that of their natural inhibitors, the consequence of which is excessive tissue degradation.
Uncontrolled and accelerated membrane degradation by resorption of the extracellular matrix catalysed by the metalloproteases is a parameter common to a number of pathological conditions, such as rheumatoid arthritis, arthrosis, tumour invasion and growth, including malignant spread and the formation of metastases, ulcerations, atherosclerosis, etc.
BB94, a metalloprotease inhibitor, has recently exhibited anti-tumour activity in clinical use, where it has proved to be active against ovarian cancers (Becket et al., DDT 1996, 1 (1), 16).
It may therefore be expected that a metalloprotease inhibitor will restore the equilibrium between protease and inhibitor and thus favourably modify the development of such pathologies.
DESCRIPTION OF THE PRIOR ART
A certain number of metalloprotease inhibitors have been described in the literature. There should be mentioned, more especially, the compounds described in Patent Specifications WO 95/35275, WO 95/35276, EP 606 046, WO 96/00214, EP 803 505, WO 97/20824 and EP 780 386.
The compounds of the present invention are not only new but have also proved to be more powerful metalloprotease inhibitors than those described in the literature, thus making them potentially useful in the treatment of cancer, rheumatic diseases, such as arthrosis and rheumatoid arthritis, atherosclerosis, etc.
DETAILED DESCRIPTION OF THE INVENTION
More specifically, the present invention relates to compounds of formula (I):
wherein:
R
1
represents a hydrogen atom, a halogen atom, a linear or branched (C
1
-C
6
)alkyl group or a linear or branched (C
1
-C
6
)alkoxy group,
X represents an oxygen atom, a sulphur atom or an NR group wherein R represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group,
A represents any one of the following groups:
wherein R
a
represents a hydrogen atom, a halogen atom, a linear or branched (C
1
-C
6
)-alkyl group or a linear or branched (C
1
-C
6
)alkoxy group,
wherein R
b
and R
c,
which may be identical or different, represent a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group, and n is 0, 1 or 2, or
their isomers, N-oxides, 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, phosphoric 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, oxalic acid, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, tert-butylamine, etc.
The preferred compounds of the invention are the compounds of formula (I) wherein X represents an oxygen atom.
R
1
is preferably a hydrogen atom.
When A represents a group
that group is preferably the group
The preferred compounds of the invention are:
N-hydroxy-(5R)-6-{[2-(4-pyridyl)-1-benzofuran-5-yl]sulphonyl}-4,5,6,7-tetrahydro-furo[2,3-c]pyridine-5-carboxamide,
N-hydroxy-(3S)-2,2-dimethyl-4-{[2-(4-pyridyl)-1-benzofuran-5-yl]sulphonyl}-3-thiomorpholinecarboxamide,
N-hydroxy-4-{{[2-(4-pyridyl)-1-benzofuran-5-yl]sulphonyl}methyl}tetrahydro-2H-pyran-4-carboxamide,
and addition salts thereof.
The invention relates also to a process for the preparation of compounds of formula (I).
When the compounds of formula (I) are those wherein A represents any one of the groups:
the process is characterised in that there is used as starting material a compound of formula (II):
wherein R
1
and X are as defined for formula (I) and Hal represents a halogen atom, which is reacted with any one of the compounds (IIIa) and (IIIb), in racemic form or in the form of a specific isomer:
wherein Rb, Rc and n are as defined for formula (I),
to yield the compounds of formulae (IVa) and (IVb), respectively:
wherein X, R
1
, Rb, Rc and n are as defined for formula (I),
which are deprotected to yield the compounds of formulae (Va) and (Vb), respectively,
wherein X, R
1
, Rb, Rc and n are as defined for formula (I),
which are subjected to the action of an O-substituted hydroxylamine, to yield, after deprotection of the hydroxamate function, the compounds of formulae (I/a) and (I/b), respectively:
wherein X, R
1
, Rb, Rc and n are as defined for formula (I),
which compounds of formulae (I/a) and (I/b):
are optionally converted to the corresponding N-oxides,
are purified, if necessary, in accordance with a conventional purification technique,
are separated, where appropriate, into their isomers in accordance with a conventional separation technique, and
converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base.
When the compounds of formula (I) are those wherein A represents the group:
the process is characterised in that there is used as starting material a compound of formula (VI):
wherein R
1
and X are as defined for formula (I), and Hal represents a halogen atom,
which is reacted with a compound of formula (VII):
wherein Alk represents a linear or branched (C
1
-C
6
)alkyl group, to yield, after acid hydrolysis, the compound of formula (VIII):
wherein R
1
and X are as defined for formula (1),
which is reacted with an oxidation reagent, to yield the compound of formula (IX):
wherein X and R
1
are as defined for formula (I),
which is subjected to the action of an O-substituted hydroxylamine, to yield, after deprotection of the hydroxamate function, the compound of formula (I/c), a particular case of the compounds of formula (I):
wherein R
1
and X are as defined for formula (I),
which is optionally converted to the corresponding N-oxide,
which is purified, if necessary, in accordance with a conventional purification technique, separated, where appropriate, into its isomers in accordance with a conventional separation technique, and converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base.
The compounds of formulae (II) and (VI) are obtained using as starting material a compound of formula (X):
wherein Hal represents a halogen atom and X is as defined for formula (I),
which is reacted with triphenylphosphine bromide to yield the compound of formula (XI):
wherein Hal and X are as defined hereinbefore,
which is reacted with an isonicotinoyl chloride of formula (XII):
wherein R
1
is as defined for formula (I),
to yield a compound of formula (VI):
wherein Hal, X and R
1
are as defined hereinbefore,
which is then converted to the compound of formula (XIII) in the presence of sulphur dioxide and of n-butyllithium:
wherein R
1
and X are as defined hereinbefore,
and then to the compound of formula (II) in the presence of sulphuryl halide:
wherein Hal, X and R
1
are as define
Benoist Alain
De Nanteuil Guillaume
Hickman John
Pastoureau Philippe
Pierre Alain
Les Laboratoires Servier
Patel Sudhaker B.
Shah Mukund J.
The Firm of Hueschen and Sage
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