Metalloproteinase inhibitors

Details Metalloproteinase inhibitors Metalloproteinase inhibitors

1999-10-08

2001-07-10

Huang, Evelyn Mei (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S357000, C514S602000, C514S252120, C514S256000, C514S247000, C514S292000, C514S362000, C514S363000, C514S364000, C514S393000, C514S396000, C514S424000, C544S238000, C544S335000, C544S400000, C546S084000, C546S101000, C546S336000, C548S128000, C548S131000, C548S136000, C548S314700, C548S317100, C548S335100, C549S077000, C549S462000, C549S496000, C564S090000, C564S154000

Reexamination Certificate

active

06258851

ABSTRACT:

This is the national phase of PTC/GB98/60985, filed Mar. 31, 1998.
The present invention relates to therapeutically active N-acyl alpha amino acid amides having a mercapto or acyl mercapto group in the amino acid side chain, to processes for their preparation, to pharmaceutical compositions containing them, and to the use of such compounds in medicine. In particular, the compounds are inhibitors of metalloproteinases involved in tissue degradation.
BACKGROUND TO THE INVENTION
The matrix metalloproteinases (MMPs) are a family of enzymes including interstitial collagenase, neutrophil collagenase, collagenase-3, 72 kDa gelatinase, 92 kDa gelatinase, stromelysin-1, stromelysin-2, stromelysin-3, matrilysin, macrophage metalloelastase, membrane-type metalloproteinase-1 and membrane-type metalloproteinase-2. These enzymes share a common zinc-containing catalytic domain and a pro-sequence which maintains latency. A wide range of cells and tissues can express MMPs in response to activation by inflammatory stimuli such as interleukin-1 or tumour necrosis factor-&agr; (TNF-&agr;). Different stimuli can induce overlapping yet distinct repertoires of MMPs and different cell types can respond to the same stimuli by expression of distinct combinations of MMPs. MMPs can attack the protein components of extracellular matrix such as collagens, vitronectin and elastin, and have recently been shown to process membrane proteins such as pro-TNF-&agr; to release soluble TNF-&agr;. MMPs are thought to play a central role in the pathology of inflammatory diseases such as rheumatoid arthritis as well as in the growth and metastasis of tumours.
Compounds which have the property of inhibiting the action of MMPs are thought to be potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth. MMP inhibitors are also of potential value in the treatment of neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis, as well as in the management of angiogenesis dependent diseases, which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumours, angiofibromas and hemangiomas.
Two known classes of pseudopeptide or peptide mimetic MMP inhibitors have a hydroxamic acid group or a carboxylic group respectively as their zinc binding groups. Many such known MMPs may be represented by the structural formula (IA)
in which X is the zinc binding hydroxamic acid (—CONHOH) or carboxylic acid (—COOH) group and the groups R
1
to R
5
are variable in accordance with the specific prior art disclosures of such compounds.
WO 96/16027 (Syntex/Agouron) discloses a class of MMP inhibitor compounds which can be represented by formula (IA) above. The principal structural characterising feature of the compounds disclosed in WO 96/16027 is the group R
2
which is defined in the publication as being a group R
2
—X— wherein X is —(CH
2
)
m
—Y—(CH
2
)
n
, Y being O, S or a single bond, m and n being 0, 1, 2, 3 or 4 and m+n being 0, 1, 2, 3, or 4, and R
2
being (inter alia) aryl or heteroaryl, the latter terms including biaryl such as biphenyl and heteroaryl-aryl such as 4-pyridylphenyl.
Another known class of collagenase inhibitors is represented by those disclosed in EP-A-0574758 (Roche), EP-A-0684240 (Roche), and WO 95/33731 (Roche). In general, the compounds disclosed in those publications may be represented by the structural formula (IB):
in which R
1
, R
2
and the N-containing ring are variable in accordance with the specific disclosures of the publications.
Foley et. al., Bioorg. Med. Chem Lett. 1996, 6:1905-1910 disclose MMP inhibitors which are C-terminal amido-, N-terminal acyl-dipeptides, wherein the zinc binding group is a mercapto group located in the side chain of the N-terminal amino acid.
BRIEF DESCRIPTION OF THE INVENTION
The present invention makes available a class of compounds which differ in structure from those disclosed by Foley et. al. principally in that they are derivatives of a single amino acid rather than a dipeptide, but also in other respects, for example the identity of the N-acyl group. Despite these structural modification relative to Foley et. al., compounds of the invention have been found to retain MMP inhibitory activity.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, there is provided a compound of formula (I):
wherein:
n is 0 or 1;
A represents an optionally substituted phenyl or heteroaryl group;
B represents a divalent 1,4-phenylene moiety or a divalent C
1
-C
4
alkylene or C
2
-C
4
alkenylene or C
2
-C
4
alkynylene moeity;
x represents —C(═O)— or —S(═O)
2
—,
R
1
and R
2
(i) independently represent
hydrogen,
a C
1
-C
6
alkyl group, or
a group D-(C
1
-C
6
alkyl)- wherein D represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S, SO or SO
2
as an additional ring member, (c) is substituted by oxo on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other C atoms by C
1
-C
6
alkyl, or oxo and/or on any additional N atoms by C
1
-C
6
alkyl, phenyl or heteroaryl; or
(ii) taken together with the carbon atom to which they are attached form a cycloalkyl or cycloalkenyl ring;
R
3
represents:
(a) an optionally substituted cycloalkyl or cycloalkenyl ring or
(b) a group —CHR
x
R
y
wherein (i) R
x
and R
y
each independently represents an optionally substituted phenyl or heteroaryl group which may be linked covalently to each other by a bond or by a divalent C
1
-C
4
alkyl or C
2
-C
4
alkenyl bridge, or (ii) R
x
represents a group D-(C
1
-C
6
alkyl)- wherein D is as defined above in relation to R
1
and R
2
, or is an optionally substituted phenyl or heteroaryl, group, and R
y
represents an optionally substituted phenyl or heteroaryl ring;
(c) a group of formula -(Z′—O)
w
-Z wherein Z′ is straight or branched C
1
-C
6
alkyl optionally interrupted by one or more non-adjacent S and/or N atoms, w is an integer >1, and no continuous linear sequence of atoms in the group R
4
is >12, or
(d) hydrogen, C
1
-C
6
alkyl, C
1
-C
4
perfluoroalkyl, or a group D-(C
1
-C
6
alkyl)- wherein D is as defined above in relation to R
1
and R
2
, or is hydroxy, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio, acylamino, optionally substituted phenyl or heteroaryl, NH
2
, or mono- or di-(C
1
-C
6
alkyl)amino;
 or R
3
and R
4
taken together represent a divalent chain of formula —C(R
a
)(R
b
)-A
1
-Alk- wherein R
a
and R
b
are independently hydrogen or C
1
-C
6
alkyl, A
1
is a bond, —O —, —S —, —S —S —, —NH— or —NR
a
— wherein R
a
is C
1
-C
6
alkyl, and Alk is a divalent C
1
-C
4
alkylene moeity;
R
4
represents hydrogen or a C
1
-C
6
alkyl group;
R
5
represents hydrogen or acyl; and
R
6
represents hydrogen, a C
1
-C
6
alkyl group, or a group D-(C
1
-C
6
alkyl)- wherein wherein D is as defined above in relation to R
1
and R
2
;
or a salt, hydrate or solvate thereof.
As used herein, the term “cycloalkyl” means a saturated alicyclic moiety having from 3-8 carbon atoms and includes, for example, cyclohexyl, cyclooctyl, cycloheptyl, cyclopentyl, cyclobutyl and cyclopropyl.
As used herein the term “cycloalkenyl” means an unsaturated alicyclic moiety having from 4-8 carbon atoms and includes, for example, cyclohexenyl, cyclooctenyl, cycloheptenyl, cyclopentenyl, and cyclobutenyl. In the case of cycloalkenyl rings of from 5-8 carbon atoms, the ring may contain more than one double bond.
As used herein, the term “acyl” means a group R
20
C(O)— where R
20
is C
1
-C
6
alkyl, C
2
-C
6
alkenyl, cycloalkyl, phenyl, heterocyclyt, phenyl(C
1
-C
6
)alkyl, heterocyclyl(C
1
-C
6
)alkyl, cycloalkyl(C
1
-C
6
alkyl), phenyl(C
2
-C
6
alkenyl), heterocyclyl(C

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