Oxo-azabicyclic compounds

Details Oxo-azabicyclic compounds Oxo-azabicyclic compounds

2003-04-16

2004-06-08

Rao, Deepak (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen in the nitrogen containing substituent

C544S287000

Reexamination Certificate

active

06747147

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel oxo azabicyclic compounds which are useful for preparing medicinal products for treating complaints involving a therapy with a matrix metalloprotease-13 (MMP-13) inhibitor. These medicinal products are useful in particular for treating certain inflammatory conditions such as rheumatoid arthritis or osteoarthritis, as well as certain proliferative conditions such as cancers, particularly human breast cancer.
TECHNOLOGICAL BACKGROUND OF THE INVENTION
Matrix metalloproteases (MMPs) are enzymes which are involved in the renewal of extracellular matrix tissue, such as cartilage, tendons and joints. MMPs bring about the destruction of the extracellular matrix tissue, which is compensated for, in a non-pathological physiological state, by its simultaneous regeneration.
Under normal physiological conditions, the activity of these extremely aggressive peptidases is controlled by specialized proteins which inhibit MMPs, such as the tissue inhibitors of metalloprotease (TIMPs).
Local equilibrium of the activities of MMPs and of TIMPs is critical for the renewal of the extracellular matrix. Modifications of this equilibrium which result in an excess of active MMPs, relative to their inhibitor, induce a pathological destruction of cartilage, which is observed in particular in rheumatoid arthritis and in osteoarthritis.
In pathological situations, an irreversible degradation of articular cartilage takes place, as is the case in rheumatic diseases such as rheumatoid arthritis or osteoarthritis. In these pathologies, the cartilage degradation process predominates, leading to a destruction of the tissue and resulting in a loss of function.
At least twenty different matrix metalloproteases have been identified to date and are subdivided into four groups, the collagenases, the gelatinases, the stromelysins and the membrane-type MMPs (MT-MMPs), respectively.
Matrix metalloprotease-13 (MMP-13) is a collagenase-type MMP which constitutes the predominant collagenase observed during osteoarthritis, in the course of which pathology the chondrocyte directs the destruction of cartilage.
There is a need for novel MMP inhibitors, more particularly for MMP-13 inhibitors, in order to prevent and/or correct the imbalance in the renewal of extracellular matrix tissue, such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases (COPD), age-related macular degeneration (ARMD) and cancer.
MMP-inhibitor compounds are known. Most of these MMP-inhibitors are not selective for a single MMP, such as those described by Montana and Baxter (2000) or by Clark et al. (2000).
There is also a need in the prior art for novel inhibitors that are active on matrix metalloprotease-13, in order to enrich the therapeutic arsenal that can be used for treating pathologies associated with the destruction of the extracellular matrix and with cancer.
The patent application WO9826664 describes quinazolinone compounds which are used as new antifungic compounds.
The compounds of the present application are novel and represent powerful inhibitors of MMP-13. They are consequently of use in the treatment of rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases (COPDs), age-related degeneration (ARNMD) and cancer.
SUMMARY OF THE INVENTION
The applicant has identified novel oxo azabicyclic compounds that are matrix metalloprotease inhibitors, and more specifically compounds that are selective MMP-13 inhibitors.
More specifically, the present invention relates to compounds of formula (I):
wherein:
X
1
, X
2
, and X
3
, independently of each other, represent a nitrogen atom or a group —CR
3
in which R
3
represents a group selected from hydrogen, (C
1
-C
6
)alkyl, amino, mono(C
1
-C
6
)alkylamino, di(C
1
-C
6
)alkylamino, hydroxy, (C
1
-C
6
)alkoxy, and halogen, with the proviso that not more than two of the groups X
1
, X
2
and X
3
simultaneously represent a nitrogen atom,
G
1
represents a group selected from those of formulae (i/a) and (i/b):
 in which:
the carbon atom with number 2 is attached to the group N—R
1
in the ring,
R
4
and R
5
, identical or different, independently of each other, represent a group selected from hydrogen, (C
1
-C
6
)alkyl, aryl, aryl(C
1
-C
6
)alkyl, cycloalkyl, cycloalkyl(C
1
-C
6
)alkyl, heteroaryl, heteroaryl(C
1
-C
6
)alkyl, heterocycloalkyl, and heterocycloalkyl(C
1
-C
6
)alkyl,
R
6
represents a group selected from:
hydrogen, trifluoromethyl, OR
7
, NR
7
R
8
, in which R
7
and R
8
, identical or different independently of each other, represent hydrogen or (C
1
-C
6
)alkyl,
(C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, aryl, aryl(C
1
-C
6
)alkyl, cycloalkyl(C
1
-C
6
)alkyl, heteroaryl, heteroaryl(C
1
-C
6
)alkyl, heterocycloalkyl, and heterocycloalkyl(C
1
-C
6
)alkyl, these groups being optionally substituted by one or more groups, which may be identical or different independently of each other, selected from halogen, amino, mono(C
1
-C
6
)alkylamino, di(C
1
-C
6
)alkylamino, each alkyl moiety being identical or different independently of each other, cyano, trihalogeno(C
1
-C
6
)alkyl, (C
1
-C
6
)acyl, —C(═O)OR
7
, —OR
7
and —SR
7
, in which R
7
is as defined hereinbefore,
G
2
represents a group selected from carbon-carbon triple bond, —CH═C═CH—, C═O, C═S, S(O)
n1
in which n1 represents an integer from 0 to 2 inclusive, and a group of formula (i/c):
in which the carbon atom with number 1 is attached to the bicycle of the compound of formula (I), Y
1
represents a group selected from oxygen, sulphur, —NH and —N(C
1
-C
6
)alkyl, and Y
2
represents a group selected from oxygen, sulphur, —NH and —N(C
1
-C
6
)alkyl,
n represents an integer from 0 to 6 inclusive,
Z
1
represents —CR
9
R
10
, wherein R
9
, and R
10
, identical or different independently of each other, represent a group selected from hydrogen, (C
1
-C
6
)alkyl, trihalogeno(C
1
-C
6
)alkyl, halogen, —OR
7
, —SR
7
, and —C(═O)OR
7
, in which R
7
is as defined hereinbefore, amino, mono(C
1
-C
6
)alkylamino, di(C
1
-C
6
)alkylamino in which each alkyl moiety is identical or different independently of each other, and
wherein when n is greater than or equal to 2, the hydrocarbon chain Z
1
optionally contains one to two isolated or conjugated multiple bonds,
and/or wherein when n is greater than or equal to 2, one of said —CR
9
R
10
may optionally be replaced with a group selected from oxygen, S(O)
n1
in which n1 is as defined hereinbefore, —NH and —N(C
1
-C
6
)alkyl,
A represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being 5- or 6-membered monocycle or bicycle composed of two 5- or 6-membered monocycle,
R
1
represents a group selected from:
hydrogen,
(C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, these groups may be optionally substituted with one or more groups, which may be identical or different independently of each other, selected from amino, cyano, trihalogeno(C
1
-C
6
)alkyl, cycloalkyl, —C(═O)NR
7
R
8
, —C(═O)OR
8
, OR
8
, SR
8
, in which R
7
and R
8
, which may be identical or different independently of each other, represent hydrogen or (C
1
-C
6
)alkyl,
and the group of formula (i/d):
in which p is an integer from 0 to 8 inclusive,
Z
2
represents —CR
11
R
12
wherein R
11
and R
12
, identical or different independently of each other, represent a group selected from hydrogen, (C
1
-C
6
)alkyl, phenyl, trihalogeno(C
1
-C
6
)alkyl, halogen, amino, OR
7
, SR
7
and —C(═O)OR
7
in which R
7
represents hydrogen or (C
1
-C
6
)alkyl, and
wherein when p is greater than or equal to 2, the hydrocarbon chain Z
2
optionally contains one or two isolated or conjugated multiple bonds,
and/or wherein n is greater than o

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