Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-09
2004-03-30
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S227500, C514S227800, C514S228200, C514S228500, C514S367000, C514S369000, C544S047000, C544S048000, C544S049000, C544S058200, C548S171000, C548S187000
Reexamination Certificate
active
06713477
ABSTRACT:
TECHNICAL FIELD
The present invention relates to hydroxamic acid derivatives useful as matrix metallo-proteinase inhibitors.
BACKGROUND ART
Extra cellular matrix, composition of connective tissue, is metabolized by a family of proteinases termed matrix metallo-proteinases. It is known that there exist 16 kinds of matrix metallo-proteinases such as collagenase (matrix metallo-proteinase-1: MMP-1), gelatinase A (matrix metallo-proteinase-2: MMP-2), stromelysin (metallo-proteinase-3: MMP-3), gelatinase B (matrix metallo-proteinase-9: MMP-9) and collagenase-3 (matrix metallo-proteinase-13: MMP-13). Extra cellular matrix is under tight control by the expression and secretion of these matrix metallo-proteinases or endogenous inhibitors such as tissue inhibitor of matrix metallo-proteinases in normal. There are many reports about relationships between diseases characterized by excessive tissue disruption and elevated activities of matrix metallo-proteinases derived form the breakdown of these control.
Elevated levels of matrix metallo-proteinases, particularly collagenase and stromelysin, have been detected in joints of osteoarthritic humans or that of rheumatoid arthritis (Arthr. Rheum., 33, 388-97 (1990); S. M. Krane et. al., “Modulation of matrix synthesis and in The Control of degradation in joint inflammation, The Control of Tissue Damage”, A. B. Glauert (ed.), Elsevier Sci. Publ., Amsterdam, 1988, Ch. 14, pp 179-95; Clin. Chim. Acta, 185, 73-80(1989); Arthr. Rheum., 27, 305-312(1984); J. Clin. Invest., 84, 678-685(1989)).
Secreted proteinases such as stromelysin, collagenase and gelatinase play an important role in processes involved in the movement of cells during metastatic tumor invasion. Indeed, there is also evidence that the matrix metallo-proteinases are overexpressed in certain metastatic tumor cell line. In this context, the enzyme functions to penetrate underlying basement membranes and allow the tumor cell to escape from the site of primary tumor formation and enter circulation (FEBS J., 5, 2145-2154(1991); Trends Genet., 6, 121-125(1990); Cancer Res., 46, 1-7(1986); Cell, 64, 327-336(1990); Cancer and Metastasis Rev., 9, 305-319(1990)).
Both collagenase and stromelysin activities are observed in fibroblasts isolated from inflamed gingiva (J. Periodontal Res., 16, 417-424(1981)). Enzyme levels have been correlated to the severity of gum disease (J. Periodontal Res., 22, 81-88 (1987)).
Collagenase-3 (matrix metalloproteinase-13: MMP-13) is expressed in synovia of rheumatoid arthritis and chondrocyte of human osteoarthritis (J. Clin. Invest., 97, 2011-2019(1996); J. Rheumatol., 23, 509-595(1996); J. Biol. Chem., 271, 23577-23581(1996); J. Clin. Invest., 97, 761-768(1996)). MMP-13 has a strong enzyme activity against type II collagen and aggrecan. Thus, it is suggested that MMP-13 plays an important role in osteoarthritis and rheumatoid arthritis (J. Biol. Chem., 271, 1544-1550(1996); FEBS Lett., 380, 17-20(1996)). Therefore, inhibitors to matrix metallo-proteinase are useful as therapeutic agents or prophylactic drugs for joint diseases such as osteoarthritis, rheumatoid arthritis, metastasis of tumor cell and gingivitis.
Matrix metallo-proteinases are also concerned with conversion from the latent form of tumor necrosis factor-a to the mature form (Nature, 370, 555-557(1994)), degradation of &agr; 1-antitrypsin (FEBS Lett., 279, 191-194(1991)) and processing of other matrix metallo-proteinases (Biochemistry, 29, 10261-10670(1990); J. Biol. Chem., 267, 21712-21719(1992)). Therefore, inhibitors to matrix metalloproteinase are useful as anti-inflammatory agents.
WO 96/20936 disclose novel thiazolidin-4-one derivatives which inhibit platelet-activating factor and/or 5-lipoxygenase. But, it does not disclose the compounds can inhibit matrix metallo-proteinases.
DESCRIPTION OF THE INVENTION
The present invention is intended to provide novel compounds useful as matrix metallo-proteinase inhibitors.
The present inventors have earnestly examined and found that hydroxamic acid derivatives have excellent inhibition activity against matrix metallo-proteinases such as MMP-3, MMP-13 and the like. Thus, the present invention has been accomplished.
That is, the present invention is as follows:
(1) A hydroxamic acid derivative represented by the formula [1] or a prodrug thereof, or a pharmaceutically acceptable salt thereof:
wherein
X is C
1
-C
2
alkylene which is substituted by optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; optionally substituted ortho-arylene; or optionally substituted ortho-heteroarylene;
Y
1
is —O—, —S—, —S(O)— or —S(O)
2
—;
Y
2
is O, or S;
One of R
1
and R
3
is —(CHR
4
)
n
—(CR
5
R
6
)—CO—NHOH;
The other of R
1
and R
3
is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
R
2
is hydrogen, optionally substituted alkyl, optionally substituted alkenyl , optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted hetero-cycloalkyl; or R
2
and R
3
may be taken together to be optionally substituted C
1
-C
10
alkylidene;
R
4
, R
5
and R
6
are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteraryl; or R
5
may be joined with R
4
or R
6
to form, with the carbon atom which they attach, optionally substituted cycloalkane or optionally substituted heterocycloalkane;
n is an integer of 0 to 4;
provided that when R
2
and R
3
are taken together to be optionally substituted C
1
-C
10
alkylidene, X is not methylene substituted by a phenyl or a pyridyl wherein the phenyl and the pyridyl are optionally substituted by methyl or methoxy.
(2) A hydroxamic acid derivative according to (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein
X is C
1
-C
2
alkylene substituted by —Z—Ar; optionally substituted ortho-arylene; or optionally substituted ortho-heteroarylene;
Z is single bond or alkylene;
Ar is optionally substituted aryl or optionally substituted heteroaryl.
(3) A hydrozamic acid derivative according to (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein
X is one of the groups represented by the formulae:
Ar
1
is optionally substituted aryl or optionally substituted heteroaryl;
A
1
is ortho-phenylene or monocyclic ortho-heteroarylene;
R
8
and R
9
are independently hydrogen or substituent.
(4) A hydroxamic acid derivative according to any one of (1)-(3) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein Y
1
is —S—, —S(O)— or —S(O)
2
—.
(5) A hydroxamic acid derivative according to any one of (1)-(4) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2.
(6) A hydroxamic acid derivative according to any one of (1)-(5) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0.
(7) A hydroxamic acid derivative according to (1) represented by the formula [2] or a prodrug thereof, or a pharmaceutically acceptable salt thereof:
wherein
Y
2
, R
4
, R
5
and R
6
are as defined in (1);
Ar
2
is optionally substituted phenyl; optionally substituted naphthyl; or optionally substituted mono or bicyclic heteroaryl;
Y
3
is —S—, —S(O)— or —S(O)
2
—;
R
10
and R
11
are independently hydrogen or optionally substituted alkyl;
n1 is an integer of 0, 1 or 2.
(8) A hydroxamic acid derivative according to (7) or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
wherein n1 is 0.
(9) A hydroxamic acid derivative according to (1) represented by the formula [3] or a prodrug thereof, or a pharmaceutically acceptable salt thereof:
wherein
Y
2
, R
4
, R
5
and R
6
are as defined in (1);
A
1
, R
8
, and R
9
are defined in (3);
R
12
and R
13
Hadida Ruah Sara Sabina
Houtigai Hitoshi
Kamikawa Yumiko
Nakatsuka Masashi
Nishimura Tamiki
Kifle Bruck
Sumitomo Pharmaceuticals Company Limited
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