Metalloproteinase inhibitors

Details Metalloproteinase inhibitors Metalloproteinase inhibitors

2001-03-05

2002-03-19

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S336100, C546S340000, C514S357000

Reexamination Certificate

active

06358987

ABSTRACT:

The present invention relates to therapeutically active hydroxamic 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 matrix 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.
The following patent publications disclose such MMP inhibitors:
US 4599361
(Searle)
WO 95/04033
(Celltech)
EP-A-2321081
(ICI)
WO 95/04735
(Syntex)
EP-A-0236872
(Roche)
WO 95/04715
(Kanebo)
EP-A-0274453
(Bellon)
WO 95/06031
(Immunex)
WO 90/05716
(British Biotech)
WO 95/09841
(British Biotech)
WO 90/05719
(British Biotech)
WO 95/12603
(Syntex)
WO 91/02716
(British Biotech)
WO 95/19956
(British Biotech)
WO 92/09563
(Glycomed)
WO 95/19957
(British Biotech)
US 5183900
(Glycomed)
WO 95/19961
(British Biotech)
US 5270326
(Glycomed)
WO 95/19965
(Glycomed)
WO 92/17460
(SB)
WO 95/22966
(Sanofi Winthrop)
EP-A-0489577
(Celltech)
WO 95/23790
(SB)
EP-A-0489579
(Celltech)
WO 95/32944
(British Biotech)
EP-A-0497192
(Roche)
WO 95/33709
(Roche)
US 5256657
(Sterling)
WO 96/06074
(British Biotech)
WO 92/13831
(British Biotech)
WO 96/16027
(Syntex/Agouron)
WO 92/22523
(Research Corp)
WO 96/16931
(British Biotech)
WO 93/09090
(Yamanouchi)
WO 96/23791
(Syntex)
WO 93/09097
(Sankyo)
WO 96/29313
(Procter & Gamble)
WO 93/20047
(British Biotech)
WO 96/33161
(British Biotech)
WO 93/24449
(Celltech)
WO 96/33165
(British Biotech)
WO 93/24475
(Celltech)
WO 96/33166
(DuPont Merck)
EP-A-0574758
(Roche)
WO 96/33968
(Fuji YKKK)
EP-A-0575844
(Roche)
WO 96/33991
(Sankyo)
WO 94/02446
(British Biotech)
WO 97/02239
(British Biotech)
WO 94/02447
(British Biotech)
WO 97/03966
(British Biotech)
WO 94/21612
(Otsuka)
WO 97115553
(Sankyo)
WO 94/21625
(British Biotech)
WO 97/19053
(British Biotech)
WO 94/24140
(British Biotech)
WO 94/25434
(Celltech)
WO 94/25435
(Celltech
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 P2 and R together with the carbon atom to which they are attached form a trans-cyclohexan-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
This invention makes available a novel class of compounds which are inhibitors of matrix metalloproteinases. The compounds of the invention conform to general formula (IA), or have structural features similar to those of Abreo et. al., but differ in structure from prior art compounds of formula (IA) or (IC) principally in the identity of the group R
1
. In the compounds of the present invention, the group R
1
is a sulfonamidoalkyl group.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention there is provided a compound of formula (I)
wherein
X is —COOH or —CONHOH
n is 1, 2, 3 or 4;
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)-,
non-aryl heterocyclyl(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, trifluoromethyl, C
1
-C
6
alkoxy, halo, cyano (—CN), phenyl, substituted phenyl or heteroaryl; or
R
3
represents the characterising group of a natural or non-natural a amino acid in which any functional groups may be protected;
R
8
is hydrogen, C
1
-C
6
alkyl, benzyl, acyl, optionally substituted phenyl, optionally substituted heterocyclyl, an amino protecting group, or a group —(CH
2
)
m
COZ where m is an integer from 1 to 6, and Z represents OH, C
1
-C
6
alkoxy or —NR
x
R
y
where R
x
, R
y
each independently represent hydrogen or C
1
-C
6
alkyl; and
R
9
is optionally substituted C
1
-C
6
alkyl, cycloalkyl, cycloalkenyl, di-(C
1
-C
6
alkyl)amino, heterocyclyl, phenyl, naphthyl, or heteroaryl; or
R
8
and R
9
taken together represent a divalent C
3
-C
6
alkylene or alkenylene group which may optionally be (i) substituted by an oxo group, and/or (ii) substituted by (C
1
-C
6
)alkoxy, hydroxy, mercapto, (C
1
-C
6
)alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), cyano, trifluoromethyl, nitro, —COOH, —CONH
2
, —CONHR
A
or —CONR
A
R
A
wherein R
A
is a (C
1
-C
6
)alkyl group, and/or (iii) fused to a phenyl or heteroaryl group which itself may be substituted;
Y Is a group of formula (ID) or (IE)
 wherein:
R
4
represents
(a) an optionally substituted cycloalkyl or cycloalkenyl ring; or
(b) a phenyl or heteroaryl ring which may be fused to a benzene or hetero

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