Matrix metalloproteinase inhibitors

Details Matrix metalloproteinase inhibitors Matrix metalloproteinase inhibitors

1999-07-30

2001-02-27

Lambkin, Deborah C. (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C549S419000

Reexamination Certificate

active

06194451

ABSTRACT:

The present invention relates to new inhibitors of matrix metalloproteinases (hereinafter MMPs), to a process for their preparation, to pharmaceutical compositions containing them, and to the use of such compounds in the prevention, control and treatment of diseases in which the proteolytic action of MMPs is involved. Furthermore, since some of the compounds herein described potently inhibit the release of tumor necrosis factor-alpha (hereinafter TNF) from cells, another object of the present invention is the use of pharmaceutical compositions containing said compounds for the treatment or prophylaxis of inflammatory, immunological or infectious diseases promoted by the release of such cytokine.
Low molecular weight compounds able to inhibit one or more of the matrix metalloproteinases, in particular stromelysin-1 (MMP-3; EC 3.4.24.17), gelatinase A (MMP-2; EC 3.4.24.24), gelatinase B (MMP-9; EC 3.4.24.35), neutrophil collagenase (MMP-8; EC 3.4.24.34), interstitial collagenase (MMP-1; EC 3.4.27.7), matrilysin (MMP-7; EC 3.4.24.23), and collagenase-3 (MMP-13) are currently considered as promising therapeutic agents in degenerative, tumoral and autoimmune pathologies (e.g., P. D. Brown: “Matrix metalloproteinase inhibitors: A new class of anticancer agent”, Curr. Opin. Invest. Drugs, 2:617-626, 1993; A. Krantz: “Proteinases in Inflammation”, Annu. Rep. Med. Chem. 28:187-195, 1993). Many of such compounds described hitherto are peptide derivatives or pseudopeptides, bearing analogies to recognized peptide substrates of these enzymes, and characterized in addition by a functional group capable of binding the Zn (II) atom present in the catalytic site of said enzymes. Known classes of MMP inhibitors include those in which the Zn binding group is a hydroxamic acid, which is part of a (substituted) succinic moiety, in particular a succinic amide represented by the general formula (A)
wherein R
a
, R
b
, R
c
, and R
d
are hydrogen atoms or appropriate substituents (e.g., N. R. A. Beeley et al., “Inhibitors of matrix metalloproteinases (MMP's)”, Curr. Opin. Ther. Patents 4:7-16, 1994; J. R. Porter et al., “Recent developments in matrix metalloproteinase inhibitors”, Exp. Opin. Ther. Patents 5:1287-1296, 1995; J. R. Morphy et al., “Matrix metalloproteinase inhibitors: Current status”, Curr. Med. Chem. 2:743-762, 1995; R. P. Beckett et al., “Recent advances in matrix metalloproteinase research”, DDT 1:16-26, 1996).
Further, it is now recognized that some compounds of the same general formula (A) may be able to inhibit the release of TNF from the cell membrane anchored precursor, pro-TNF (e.g., G. M. McGeehan et al., “Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor”, Nature 370:558-561, 1994).
Although MMPs have been recognized as drug targets for at least 20 years, and MMP inhibitors encompassed by the general formula (A) have been disclosed since 1986 or before (e.g., see J. P. Dickens et al., U.S. Pat. No. 4,599,361), no drug of this type has arrived at the market yet. This is not because of questions about the therapeutic potential of MMP inhibitors, but because of problems of the “first generation” compounds, such as inhibitor potency, aqueous solubility, metabolic stability, and other desirable properties, oral bioavailability in particular (e.g., J. R. Porter, reference above; J. Hodgson, “Remodelling MMPIs”, Biotechnology 13:554-557, 1995). For example, it is well known that most “first generation” hydroxamate MMP inhibitors are rapidly glucuronidated, oxidized to the carboxylic acid, and excreted in the bile (e.g., see J. Singh et al., Bioorg. Med. chem. Lett. 5:337-342, 1995, and reference above). Thus, there is a strong need for better and diversified molecules, especially as far as the properties referred to above are concerned. The present invention relates to a new class of carboxylic or hydroxamic acid derivatives, which are characterised by the presence of a 1,2-glycol, or a derivative thereof, next to the carbonyl group.
In particular, the present invention provides a compound of formula (I)
wherein
W is —NHOH or —OH;
R
1
is hydroxymethyl or a hydroxymethyl derivative which is an ether, an ester, a carbonate or a carbamate; or
R
1
is mercaptomethyl or a mercaptomethyl derivative which is a sulfide (i.e., a thioether), a sulfoxide, a sulfone or a thioester;
R
2
is hydroxy or a protected derivate thereof; or
R
1
and R
2
, taken together with the carbon atom to which they are attached, represent an optionally substituted cyclopropane or oxirane, 1,3-dioxolane or 2-oxo-1,3-dioxolane ring of the following formulae (B1)-(B4):
R
3
is a group —A
I
—X—(CH
2
)
n
—A, wherein A is C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
3
-C
7
cycloalkyl, aryl, or heterocyclyl, the said alkyl, alkenyl, cycloalkyl, aryl and heterocyclyl groups being unsubstituted or substituted; n is either zero or an integer from 1 to 5; —X— is either a direct bond or a group —O—, —S—, —SO—, —SO
2
—, —SO
2
NH—, —CO—, —CONH—, —NHCO—, —OCONH—, NHCONH or —NHSO
2
—, and —A
I
— is C
1
-C
10
alkylene, C
2
-C
6
alkenylene, or phenylene;
R
4
is either a group of formula (C):
wherein R
6
is hydrogen or the side chain of a natural or non-natural alpha-amino acid, and R
7
is amino or a group —NH—A, —NH—CH
2
—A or —NH—CH
2
CH
2
—A wherein A is as defined above; or R
4
is a group A as defined above or a group —A
I
—X—A wherein A, —X— and —A
I
— are as defined above; or
R
4
is a group of formula (D):
wherein R
8
is methyl, ethyl, phenyl, pyridyl, isopropyl, sec-butyl, tert-butyl, adamantyl, cylclopentyl, cyclohexyl, cyclohexylmethyl, phenylmethyl, 3,4-(methylenedioxy)phenyl, piperonyl, pyridylmethyl, thienylmethyl, 3-indolylmethyl, 3-(N-methyl)indolylmethyl, 1,1-diphenylmethyl, naphthyl, naphthylmethyl, quinolylmethyl, isoquinolylmethyl, thiazolyl, thiazolylmethyl, imidazolyl, imidazolylmethyl, or a derivative thereof optionally substituted, or R
8
is —C(CH
3
)
2
SCH
3
or a sulfoxide or sulfone thereof, —C(CH
3
)
2
OCH
3
, —CH
2
CH
2
CH
2
—OCH
3
, or —CH(CH
3
)OH or a tert-butyl ether thereof; R
9
is either hydrogen or a group selected from methyl, ethyl, phenyl, 3,4-(methylenedioxy)phenyl, piperonyl, pyridyl, benzimidazolyl and 4-tetrazolyl, which group is optionally substituted; or R
8
and R
9
, taken together with the nitrogen atom to which they are attached, constitute a dihydrocarbostyril ring (D′):
wherein the nitrogen atom and the phenyl ring may be optionally substituted;
R
5
is hydrogen or methyl; or
R
4
and R
5
, taken together with the nitrogen atom to which they are attached, form an optionally substituted azaheterocyclyl ring; and the solvates, hydrates and pharmaceutically acceptable salts thereof.
As used herein the term “alkyl” refers to a straight or branched chain alkyl moiety having from 1 to 10 carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl and n-octyl. The term “alkylene” refers to an alkyl group as defined above, but connected to the rest of the molecule by two covalent bonds, either at the same or at different carbon atoms, including for example methylene (—CH
2
—), 1,2-ethylene (—CH
2
—CH
2
—) and 1,1-ethylene (—CH(CH
3
)—). The term “alkenyl” as used herein refers to a straight or branched chain alkenyl moiety having from 2 to 10 carbon atoms and having in addition one double bond of either E or Z stereochemistry where applicable. Examples of alkenyl groups include: vinyl, allyl, metallyl, butenyl and crotyl. The term “alkenylene” refers to an alkenyl group as defined above, but connected to the rest of the molecule by two covalent bonds, either at the same or at different carbon atoms, including for example 1,2-ethenylene (—CH═CH—) and 1,1-ethenylene (—C(═CH
2
)—) and 1,3-propenylene (—CH═CH—CH
2
—).
The term “aryl” as used herein refers to a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 carbon atoms, such as phenyl, naphthyl, indanyl; furthermore, “aryl” as used herein may refer to a biphenyl gro

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