Hydroxamic acid derivatives as proteinase inhibitors

Details Hydroxamic acid derivatives as proteinase inhibitors Hydroxamic acid derivatives as proteinase inhibitors

2001-02-21

2002-11-12

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S244000, C546S247000, C546S248000, C546S193000, C546S223000, C546S233000, C546S153000, C546S122000, C546S081000, C546S082000

Reexamination Certificate

active

06479502

ABSTRACT:

This invention relates to novel hydroxamic acid and carboxylic acid derivatives which are inhibitors of matrix metalloproteinases to pharmaceutical compositions comprising such compounds and to their use in the treatment of diseases and conditions responsive to modulation of matrix metalloproteinase activity.
BACKGROUND TO THE INVENTION
The matrix metalloproteinases (MMPs) are a family of enzymes including interstitial collagenase, neutrophil collagenase, collagenase-3, 72kDa gelatinase, 92kDa 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 degrade 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 venous, diabetic or gastric ulceration, ulcerative colitis, Crohn's disease, pressure sores, 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, cardiac and cerebral infarction, and wound healing.
A 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 (IA):
in which R
1
, R
2
and the N-containing ring are variable in accordance with the specific disclosures of the publications.
Another known class of MMP inhibitors is represented by those disclosed in EP-A-0606046 (Ciba-Geigy) WO 96/00214 (Ciba-Geigy), WO 95/35275 (British Biotech) and WO 95/35276 (British Biotech), which in general may be represented by the structural formula (IB):
in which R
1
, R
2
and and R
3
are variable in accordance with the specific disclosures of the publications.
WO 99/24399 (Darwin Discovery Ltd), published May 20, 1999, discloses MMP inhibitors inter alia of structural formula (IC)
wherein X is —SO
2
—or —SO—, and R
1
, R
2
and each B is as defined in the document.
BRIEF DESCRIPTION OF THE INVENTION
The present invention makes available a new class of inhibitors of MMPs which, as a result of that activity, are useful in the management of diseases or disorders associated with over production of or over responsiveness to MMPs. The compounds of the invention differ in structure from those of WO 99/24399 inter alia in that the methylene group equivalent to that marked with an asterisk in formula (IC) is substituted in the present compounds.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention there is provided a compound of formula (I)
wherein
X represents a carboxylic acid group —COOH, or a hydroxamic acid group —CONHOH;
R
2
represents a radical of formula (II)
R
3
—(ALK)
m
—(Q)
p
—(ALK)
n
—  (II)
 wherein
R
3
represents hydrogen or an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclic ring having 5 or 6 ring members,
each ALK independently represents an optionally substituted divalent C
1
-C
3
alkylene radical,
Q represents —O—, —S—, —S(O)—, —S(O
2
)—, —C(O)O—, —OC(O)—or —N(R
9
)—wherein R
9
is hydrogen, C
1
-C
6
alkyl, or C
1
-C
6
alkoxy, and
m, n and p are independently 0 or 1;
R
1
represents a radical of formula (II) as defined for R
2
, except that R
1
is not hydrogen;
W represents a cyclic amino radical of formula (IIIA) or (IIIB):
 wherein
Y represents —O—, —S—, —S(O)—, —S(O
2
)—, —N(R
8
)—, or —(CH(R
8
))—, or —(C═N-R
8
)—wherein R
8
is a radical of formula (II) as defined in relation to R
2
; and
(i) R
4
, R
5
R
6
and R
7
each independently represents a radical of formula (II) as defined in relation to R
2
, and R
4a
and R
7a
each independently represent hydrogen or C
1
-C
3
alkyl, or
(ii) R
4
, R
4a
and R
5
taken together with the carbon atoms to which they are attached form an optionally substituted benzene or pyridine ring fused to the cyclic amine ring, R
7a
represents hydrogen or C
1
-C
3
alkyl, and R
6
and R
7
each independently represents a radical of formula (II) as defined in relation to R
2
, or
(iii) R
4
, R
4a
and R
5
taken together with the carbon atoms to which they are attached form an optionally substituted benzene or pyridine ring fused to the cyclic amine ring, R
6
, R
7
and R
7a
taken together with the carbon atoms to which they are attached also form an optionally substituted benzene or pyridine ring fused to the cyclic amine ring, or
(iv) when W is a cyclic amino radical of formula (IIIA) wherein Y is —(CH(R
8
))—, then R
4
R
4a
and R
8
taken together with the carbon atoms to which they are attached form an optionally substituted benzene or pyridine ring fused to the cyclic amine ring, R
7a
represents hydrogen or C
1
-C
3
alkyl, and R
5
, R
6
and R
7
each independently represents a radical of formula (II) as defined in relation to R
1
and R
2
, or
(v) when W is a cyclic amino radical of formula (IIIB) then R
4
, R
4a
, R
7
and R
7a
taken together with the carbon atoms to which they are attached form an optionally substituted benzene or pyridine ring fused to the cyclic amine ring, and R
5
and R
6
each independently represents a radical of formula (II) as defined in relation to R
1
and R
2
,
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
As used herein the term “C
1
-C
3
alkyl” means a straight or branched chain alkyl moiety having from 1 to 3 carbon atoms, including for example, methyl, ethyl and n-propyl.
As used herein the term “divalent C
1
-C
3
alkylene radical” means a saturated hydrocarbon chain having from 1 to 3 carbon atoms and two unsatisfied valencies.
As used herein the term “cycloalkyl” means a saturated alicyclic moiety having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein the term “cycloalkenyl” means a saturated alicyclic moiety having from 5-8 carbon atoms and at least one double bond, and includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
As used herein the term “aryl” means a mono-, bi- or tri-cyclic carbocyclic aromatic group, and includes groups consisting of two covalently linked monocyclic carbocyclic aromatic groups. Illustrative of such groups are phenyl, biphenyl and napthyl.
As used herein, the term C
3
-C
8
carbocyclic ring means a ring of 3 to 8 carbon atoms, with no heteroatom as part of the ring. The term includes aromatic (aryl) and non aromatic (non aryl) carbocyclic rings, for example the benzene ring and cycloalkyl rings.
As used herein the term “heteroaryl” refers to a 5- or 6- membered aromatic ring containing one or more heteroatoms, and

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