Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-12-26
2003-08-12
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S359000, C514S367000, C514S412000, C548S152000, C548S207000, C548S255000, C548S259000, C548S452000
Reexamination Certificate
active
06605604
ABSTRACT:
BACKGROUND OF THE INVENTION
In the physiological state, the synthesis of connective tissue 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: those proteases are, without implying any limitation, collagenases (MMP-1, MMP-8, MMP-13) or gelatinases (MMP-2, MMP-9), Matrilysin (MMP-7) and stromelysins (MMP-3, MMP-10, MMP-11).
In the normal state, those catabolic enzymes are regulated in their synthesis and in their secretion as well as in their extracellular enzymatic activity by natural inhibitors, such as &agr;
2
-macroglobulin or TIMPs (Tissue Inhibitors of MetalloProteinase), which form inactive complexes with the metalloproteases.
A factor common to the pathologies in which those enzymes are implicated is an imbalance between the activity of the activated enzymes and the activity of their natural inhibitors, the consequence of which is excessive tissue degradation.
Uncontrolled and accelerated degradation of tissue by way of 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 dissemination and the formation of metastases, ulceration, atherosclerosis, etc.
More recently, it has been demonstrated that each of those pathologies may be associated with the dominant activity of one or more metalloproteases. Thus, experiments carried out on the Wistar rat have shown a relationship between the development of osteoarthritis and an increase in the production of stromelysin (MMP-3) (Pathol. Res. Pract. 1998, 194, 41). On the other hand, it has been possible to correlate the appearance of rheumatoid arthritis with an increased expression of certain collagenases (MMP-8), which are responsible, alongside polymorphonuclear neutrophils, for cartilage degradation (J. Biol. Chem., 1997, 272, 31504). As for the gelatinases, they seem to play a significant role in tumour invasion. Indeed elevated levels of those enzymes have been demonstrated, in vivo, in several types of tumour, and an activation phenomenon in cancer cells confers invasive properties to non-metastatic tissues (J. of Immunology, 1998, 160, 2967).
Recently, BB94, a metalloprotease inhibitor, has exhibited anti-tumour activity in clinical use, where it has proved to be active in ovarian cancers (Becket et al., DDT 1996, 1, 16).
It may therefore be expected that a metalloprotease inhibitor will restore the equilibrium between protease and inhibitor and, as a result, favourably modify the development of those pathologies. Selectivity in respect of one of the different types of enzyme would allow the efficacy of such a compound to be increased.
Metalloprotease inhibitors are also capable of inhibiting the release of TNF-&agr; (Tumour Necrosis Factor-&agr;) from cells. TNF-&agr; is a powerful inflammation mediator implicated in numerous inflammatory pathologies, such as rheumatoid arthritis, asthma etc.
The concept of compounds capable of opposing the release of TNF-&agr; is hence of interest especially in the treatment of the pathologies mentioned above.
DESCRIPTION OF THE PRIOR ART
A certain number of metalloprotease inhibitors have been described in the literature, especially the compounds described in Patent Specifications WO 97/24117, WO 96/35711 and EP 803 505.
The compounds of the present invention are not only new but have also proved to be more powerful inhibitors of metalloproteases and/or of TNF-&agr; release than the inhibitors described in the literature, thus making them potentially useful in the treatment of cancers, rheumatic diseases, such as arthrosis and rheumatoid arthritis, ulcers, atherosclerosis, asthma etc.
DETAILLED DESCRIPTION OF THE INVENTION
The present invention relates to the compounds of formula (I):
wherein:
n is 0 or 1,
R
1
, R
2
, R
3
and R
4
independently represent a hydrogen atom or an alkyl group, or R
1
and R
3
form together with the carbon atoms carrying them a (C
5
-C
8
)cycloalkyl group and in that case R
2
and R
4
each represents a hydrogen atom,
R
5
represents a hydrogen atom, an alkyl, (C
3
-C
8
)cycloalkyl, cycloalkyl-(C
3
-C
8
)alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkylalkyl group, or a —CO—R
6
group,
R
6
represents a group R
7
, OR
7
or NR
7
R
8
wherein R
7
represents an optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group, and R
8
represents an alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkylalkyl group, or,
R
5
and R
6
form together with the nitrogen atom and the group Z carrying them a saturated, partially unsaturated or unsaturated mono-, bi- or tri-cyclic group having from 5 to 16 ring members and containing from 1 to 7 hetero atoms selected from nitrogen, oxygen and sulphur and/or a sulphoxide or sulphone group, the said cyclic group being optionally substituted by from 1 to 7 identical or different substituents selected from halogen, alkyl, amino, hydroxy, alkoxy, nitro, mercapto, alkylthio, cyano, oxo, imino, thioxo, carboxy, alkoxycarbonyl and aminocarbonyl (optionally substituted on the nitrogen atom by one or two alkyl groups),
R
10
represents a hydrogen atom or a hydroxy group, and in the latter case R
1
, R
2
, R
3
and R
4
are independently selected from hydrogen and alkyl,
Z represents a —CO— group or a —SO
2
— group,
Y represents a hydroxy, alkoxy, alkenyloxy or benzyloxy group or an —NH—OR group wherein R represents a hydrogen atom or an alkyl, alkenyl or benzyl group,
X represents: a sulphur atom or a —SO— or —SO
2
— group and in those cases R
3
and R
4
are other than an alkyl group, or X represents a —COO— group and in that case R
1
and R
3
together form a (C
5
-C
8
)cycloalkyl group, or X represents an oxygen atom,
W represents a W
1
—(A)
p
group or a W
1
—B—W
2
—(A)
p
group wherein W
1
and W
2
independently represent an aryl or heteroaryl group, A, a substituent of the aromatic cyclic group, is attached at any of the positions of that cyclic group and represents a halogen atom or an alkyl, alkoxy, hydroxy, mercapto, cyano, amino, nitro, cyanoalkyl or thioalkyl group, B represents a bond, an oxygen atom or an alkylene, alkenylene or alkynylene group (wherein any one of the carbon atoms of the alkylene, alkenylene or alkynylene groups may be replaced by an oxygen atom), and p represents an integer of from 0 to 5 inclusive,
T
1
and T
2
independently represent a bond or an alkylene, alkenylene or alkynylene group,
wherein when T
2
represents a bond and n is 0 and at the same time R
1
, R
2
, R
3
and R
4
each represents a hydrogen atom, then R
5
and R
6
form together with the nitrogen atom and the group Z carrying them a bicyclic group as defined hereinbefore that is other than a 1,3-dioxo-2,3-dihydro-1H-2-isoindolyl group, a 2,5-pyrrolidinedione group or an optionally substituted 2,5-dioxo-1-imidazolinyl group,
to their enantiomers, diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base.
In the compounds of formula (I)
the term “alkyl” denotes a linear or branched hydrocarbon chain having from 1 to 6 carbon atoms,
the term “alkenyl” denotes a linear or branched hydrocarbon chain having from 1 to 6 carbon atoms and containing from 1 to 3 double bonds,
the term “alkylene” denotes a linear or branched divalent hydrocarbon radical having from 1 to 6 carbon atoms,
the term “alkenylene” denotes a linear or branched divalent hydrocarbon radical having from 1 to 6 carbon atoms and containing from 1 to 3 double bonds,
the term “alkynylene” denotes a linear or
Atassi Ghanem
Bonnet Jacqueline
Casara Patrick
Chollet Anne Marie
Guilbaud Nicolas
Balasubramanian Venkataraman
Les Laboratoires Servier
Raymond Richard L.
The Firm of Hueschen and Sage
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