Metalloprotease inhibitors

Details Metalloprotease inhibitors Metalloprotease inhibitors

2000-06-30

2002-01-15

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C540S597000, C544S127000, C544S233000, C546S115000, C546S116000

Reexamination Certificate

active

06339092

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new metalloprotease inhibitors and 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 IV (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 el 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.
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 and EP 803 505.
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 or halogen atom, or a linear or branched (C
1
-C
6
)alkyl or linear or branched (C
1
-C
6
)alkoxy group,
R
2
represents a hydroxy, linear or branched (C
1
-C
6
)alkoxy or —NHOH group,
Ar
1
represents a phenylene or biphenylene group,
X represents an oxygen or sulphur atom, an NR group, a —C≡C— group or a bond,
R represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group,
n is an integer from 0 to 6 inclusive,
Ar
2
represents:
a phenyl group substituted by a heteroaryl group,
a biphenyl group substituted by a heteroaryl group,
a pyridinyl group substituted by a heteroaryl group, or
a heterocyclic group,
their isomers and addition salts thereof with a pharmaceutically acceptable acid or base, it being understood that
“heteroaryl group” is understood to mean a mono-cyclic aromatic group- or bi-cyclic aromatic group wherein at least one cycle is aromatic containing one, two or three identical or different hetero atoms selected from nitrogen, oxygen and sulphur, optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, linear or branched trihalo-(C
1
-C
6
)alkyl, linear or branched trihalo-(C
1
-C
6
)alkoxy, and hydroxy,
“heterocyclic group” is understood to mean a saturated or partially saturated, mono- or bi-cyclic non-aromatic group containing one, two or three identical or different hetero atoms selected from nitrogen, oxygen and sulphur, optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, linear or branched trihalo-(C
1
-C
6
)alkyl, linear or branched trihalo-(C
1
-C
6
)alkoxy, and hydroxy.
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, 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, triethylamine, tert-butylamine, etc.
The preferred heteroaryl groups are the imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidyl, triazolyl, pyrazolyl and benzimidazolyl groups.
The preferred heterocyclic groups are the pyrrolidinyl, morpholino, piperidino, imidazolidinyl, thiazolidinyl, oxazolidinyl, piperazinyl, isoindolyl, 2,3-dihydroisoindolyl and cyclopenta[c]pyrrolidinyl groups.
The preferred compounds of the invention are the compounds of formula (I) wherein X represents an oxygen atom or a sulphur atom.
The preferred R
1
group is the hydrogen atom.
The preferred R
2
group is the —NHOH group.
When Ar
1
represents a phenylene group, n is more especially zero.
When Ar
1
represents a phenylene group, Ar
2
preferably represents a phenyl group substituted by a heteroaryl group, the heteroaryl group preferably being an imidazolyl, triazolyl or pyridinyl group.
More especially, the preferred compounds of the invention are the compounds of formula (I) wherein Ar
1
represents a phenylene group, X represents an oxygen or sulphur atom, n is zero, and Ar
2
represents a phenyl group substituted by a heteroaryl group selected from imidazolyl, triazolyl and pyridinyl.
When Ar
1
represents a biphenylene group, Ar
2
preferably represents a heterocyclic group.
The configuration of the 4,5,6,7-tetrahydrofuro[2,3-c]pyridine ring is preferably (5R).
The preferred compounds of the invention are:
6- {4-[4-(imidazol-1-yl)phenoxy]benzenesulphonyl}-4,5,6,7-tetrahydrofuro[2,3-c]-pyridine-(5R)-(N-hydroxy)carboxamide, and its corresponding addition salts,
6-{4′-[2-(pyrrolidin-1-yl)ethoxy]biphenyl-4-sulphonyl}-4,5,6,7-tetrahydrofuro[2,3-c]-pyridine-(5R)-(N-hydroxy)carboxamide, and its corresponding addition salts,
6-{4-[4-(1,3,4-triazol-1-yl)phenoxy]benzenesulphonyl}-4,5,6,7-tetrahydrofuro[2,3-c]-pyridine-(5R)-(N-hydroxy)carboxamide, and its corresponding addition salts,
6-{4-[4-(pyridin-4-yl)phenoxy]benzenesulphonyl}-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-(5R)-(N-hydroxy)carboxamide, and its corresponding addition salts,
6-{4-[(4-(1,3,4-triazol-1-yl)phenylthio]benzenesulphonyl}-4,5,6,7-tetrahydrofuro[2,3-c]-pyridine-(5R)-(N-hydroxy)carboxamide, and its corresponding addition salts.
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), in racemic form or in the form of a specific isomer:
wherein R
1
is as defined for formula (I), and R′ represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group, the amine function of which is substituted by a halogen compound of formula (III):
ClSO
2
—Ar
1
—X—(CH
2
)
n
—Ar
2
  (III)
wherein Ar
1
, X, n and Ar
2
are as defined for formula (I), to yield:
when R′ represents a hydrogen atom, a compound of formula (I/a), a particular case of the compounds of formula (I):
wherein R
1
, Ar
1
, X, N and Ar
2
are as defined hereinbefore,
or, when R′ represents a linear or branched (C
1
-C
6
)alkyl group (R″), a compound of formula (I/a
1
), a particular case of th

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