Metalloproteinase inhibitors

Details Metalloproteinase inhibitors Metalloproteinase inhibitors

2000-02-11

2001-10-30

Geist, Gary (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S415000, C514S561000, C514S563000, C514S567000, C548S300100, C549S469000, C562S444000, C562S504000, C562S621000, C562S622000, C562S623000

Reexamination Certificate

active

06310084

ABSTRACT:

The present invention relates to therapeutically active hydroxamic acid and carboxylic acid derivatives, 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 metalloproteases 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.
M. A. Abreo et al. presented a poster entitled “Truncated Succinamide Hydroxamates With Nanomolar Potency against various MMPs” at the 213th ACS Meeting in San Francisco, Apr. 13th-17th 1997. In that poster compounds of formula (IC) were disclosed:
wherein X is —COOH or —CONHOH, P
1
is biphenylpropyl, R is hydroxymethyl and P
2
is the side chain found in one of the following amino acids, namely serine, tert-butylglycine, histidine, O-benzylthreonine, phenylalanine, tyrosine, methionine, threonine, and 3-(3-pyridyl)alanine. Also disclosed were compounds of formula (IC) wherein X and P
1
are as just defined, and P
2
and R together with the carbon atom to which they are attached form a trans-cyclohexane-2-ol or glucosyl ring. The authors stated that the compound (IC), P
2
=the histidine side chain and R=hydroxymethyl, showed good plasma levels after iv and oral dosing to mice. They also stated that the X-ray crystal structure of compound (IC), P
2
=tert-butyl and R=hydroxymethyl, was obtained with stromelysin-1, and that the hydroxyl moiety in R makes an H-bond in the P
3
area of the enzyme, while the tert-butyl group makes good hydrophobic contact in the P
2
area.
BRIEF DESCRIPTION OF THE INVENTION
The present invention makes available a novel class of MMP inhibitors with a hydroxamic acid or carboxylic acid zinc binding group X, differing in structure from compounds (IC) above principally by the presence of a cycloalkyl, cycloalkenyl or non-aromatic heterocyclic substituent on the carbon atom carrying the group X. Compounds (IA) and (IB) known in the art do not include those with R
1
=cycloalkyl, cycloalkenyl or non-aromatic heterocyclic. Compounds of the new class have good inhibitory potencies against various MMP enzymes. The class includes compounds with appropriate aqueous solubility, pKa, log P and molecular weight for good oral absorption.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of general formula (I)
wherein:
X is a —CO
2
H or —CONHOH group;
R
1
is a cycloalkyl, cycloalkenyl or non-aromatic heterocyclic ring containing up to 3 heteroatoms, any of which may be (i) substituted by one or more substituents selected from C
1
-C
6
alkyl, C
2
-C
6
alkenyl, halo, cyano (—CN), —CO
2
H, —CO
2
R, —CONH
2
, —CONHR, —CON(R)
2
, —OH, —OR, oxo-, —SH, —SR, —NHCOR and —NHCO
2
R wherein R is C
1
-C
6
alkyl or benzyl and/or (ii) fused to a cycloalkyl or heterocyclic ring;
R
2
is a C
1
-C
12
alkyl, C
2
-C
12
alkenyl, C
2
-C
12
alkynyl, phenyl(C
1
-C
6
alkyl)-, heteroaryl(C
1
-C
6
alkyl)-, cycloalkyl(C
1
-C
6
alkyl)-, cycloalkenyl(C
1
-C
6
alkyl)-, phenoxy(C
1
-C
6
alkyl)-, heteroaryloxy(C
1
-C
6
alkyl)-, phenyl(C
1
-C
6
alkyl)O(C
1
-C
6
alkyl)-, heteroaryl(C
1
-C
6
alkyl)O(C
1
-C
6
alkyl)-, phenyl(C
1
-C
6
alkyl)S(C
1
-C
6
alkyl)-, or heteroaryl(C
1
-C
6
alkyl)S(C
1
-C
6
alkyl)- group, any one of which may be optionally substituted by C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo, cyano (—CN), phenyl, substituted phenyl or heteroaryl.
R
3
is the characterising group of a natural or non-natural a amino acid in which any functional groups may be protected;
R
4
hydrogen, C
1
-C
6
alkyl, phenyl(C
1
-C
6
alkyl) or heterocyclyl(C
1
-C
6
alkyl);
R
5
is hydrogen or a C
1
-C
6
alkyl group;
or (when R
5
is hydrogen) R
3
and R
4
taken together with the carbon atoms to which they are attached form a 2-hydroxycyclohexyl or C
6
sugar (hexose) ring;
or R
4
and R
5
taken together with the carbon atom to which they are attached form a 5 or 6-membered carbocyclic or heterocyclic ring;
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
The term “cycloalkyl” as used herein means a saturated alicyclic ring having from 3-8 carbon atoms and includes, for example, cyclohexyl, cyclooctyl, cycloheptyl, cyclopentyl, cyclobutyl, and cyclopropyl.
The term “cycloalkenyl” as used herein means an unsaturated alicyclic ring having from 5-8 carbon atoms and includes, for example, cyclohexenyl, cyclooctenyl, cycloheptenyl, and cyclopentenyl. The ring may contain more than one double bond.
The unqualified term “heterocyclic” or “heterocyclyl” as used herein means (i) a 3-8 membered heterocyclic ring containing one or more heteroatoms selected from S, N and O, and optionally fused to a benzene ring, including for example, pyrrolyl, furyl, thienyl, imidazolyl, o

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