Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-23
2003-03-11
Wessendorf, T. D. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S391000, C514S595000, C514S596000, C514S597000, C562S575000, C564S047000, C564S048000, C564S052000, C564S057000, C564S058000, C564S059000, C564S060000, C564S117000, C564S118000
Reexamination Certificate
active
06531499
ABSTRACT:
FIELD OF THE INVENTION
The invention is directed to novel matrix metalloproteinase inhibitors and their use in the treatment of matrix metalloproteinase-mediated disease states. The invention is further directed to combinatorial libraries of the compounds and methods to generate these libraries.
DESCRIPTION OF THE PRIOR ART
Matrix metalloproteinases, hereinafter referred to as “MMP's,” are a class of proteases which are capable of degrading basement membranes and/or collagen. MMP's are often also referred to using more specific names, such as collagenases or gelatinases. Unless designated otherwise, the term MMP shall refer to all enzymes which can be classified as matrix metalloproteinases.
The presence of circulating MMP's is associated with a host of disease states, including endotoxic shock, systemic inflammatory response syndrome (SIRS), metastatic and/or invasive cancer, malaria, as well as the presence of other pathogenic organisms. Elevated MMP levels have also been associated with autoimmune diseases such as arthritis. The appearance of elevated MMP concentrations in a mammal is frequently followed by death of the subject due to vascular leakage (i.e., the leakage of plasma proteins into the tissues) and/or SIRS leading to multiple organ failure. SIRS, as befitting its designation as a “syndrome,” is etiologically linked to a host of conditions often leading to fatal consequences, including sepsis syndrome, non-responsive septic shock, multiple organ failure syndrome, immuno-mediated organ injury, pancreatitis, hemorrhage, ischemia, or multiple trauma. Where the precipitating condition is an acute occurence, such as ischemia or multiple trauma, the rise in MMP levels can be extremely rapid and if not quickly stabilized and lowered will cause death. Where the precipitating condition tends toward a more chronic ailment, such as a slowly invading malignancy, the rise in MMP levels tends to mirror the growth pattern of the tumor.
Individual matrix metalloproteinases within the larger class of MMP enzymes are designated numerically. Of particular interest are MMP-2 and MMP-9. These two MMP's have been clearly and positively correlated to the presence of invasive and/or metastatic cancer, as well as to certain immune system dysfunctions, as noted hereinabove. MMP-2 and MMP-9 fall within a sub-class of MMPs designated “Type IV” collagenases. Type IV collagenases like MMP-2 and MMP-9 are known to be involved in the breakdown of Type IV collagen, a major component of basement membrane (20 to 70% by total mass). See U.S. Pat. No. 5,866,570, to Liang et al. In mammals, Type IV collagen defines a supramolecular network which maintains the integrity of the basement membrane. Consequently, degradation of Type IV collagen by MMP-2 and MMP-9 is believed to be a critical step in basement membrane degradation. The complete amino acid sequences for both MMP-2 and MMP-9 are known, as are the sequences for the their respective and inactive pre-pro and pro-forms. See U.S. Pat. No. 4,992,537 to Goldberg et al. MMP-2 and MMP-9 can be purchased from several international suppliers, including Sigma, St. Louis, Mo.
Several synthetic MMP inhibitors have been described in the patent literature. For instance, U.S. Pat. No. 5,866,570, to Liang et al., noted above, describes bis(dioxopiperazine) compounds which are potent MMP inhibitors. For descriptions of others compounds and treatments which have been reported as having MMP-inhibitory activity, see U.S. Pat. Nos. 4,235,885; 4,263,293; 4,276,284; 4,297,275; 4,367,233; 4,371,465; 4,371,466; 4,374,765; 4,382,081; 4,558,034; 4,704,383; 4,950,755; and 5,270,447. All of these compounds suffer from certain intractable drawbacks, such as cytoxicity or difficult syntheses, which have limited their in vivo application as MMP inhibitors.
There are also known at least two endogenous MMP inhibitors known as tissue inhibitors of metalloproteinase (TIMP's): TIMP-1 and TIMP-2. The complete amino acid sequences for these proteinaceous MMP inhibitors are known. See DeClerk et al. (1989)
J. Biol. Chem.
264:17445; Boone et al. (1990)
Proc. Natl. Acad. Sci. USA
87:2800; Docherty et al. (1985)
Nature
318:65; and Carmichael et al. (1986)
Proc. Natl. Acad. Sci. USA
83:2407.
The expression of MMP's in general and collagenases in particular has been studied by several research groups. For instance, Wegus and co-workers have shown that mononuclear phagocytes secrete several different MMP's, including a 57 kD interstitial collagenase (MMP-1), a 72 kD Type IV collagenase (MMP-2), a 60 kD stromelysin (MMP-3), and a 92 kD Type IV collagenase (MMP-9). This same group has also shown that endotoxin stimulates the secretion of MMP-1, MMP-2, MMP-3, and MMP4 from mononuclear phagocytes in vitro. See Wegus et al. (1990)
J. Clin. Invest.
86:1496.
Mononuclear phagocytes are also known to secrete interleukin-1 and tumor necrosis factor, compounds which induce MMP gene expression. See Dayer et al.
J. Clin. Invest.
(1986) 77:645 and Dayer et al. (1985)
J. Exp. Med.
162:2163.
Currently, sepsis, septic shock, and the like are treated symptomatically by supporting respiration, replacing lost blood volume, and administering vasoactive drugs to increase renal and/or cardiac function. Surgery and/or antibiotics are used to remove or kill infectious or malignant agents underlying the condition. However, there remains a long-felt need for effective, non-toxic medicinal compounds which are specific and potent inhibitors of MMP's.
SUMMARY OF THE INVENTION
A first embodiment of the invention is directed to compounds of Formula I or II:
wherein R
1
is selected from the group consisting of H, C
1-12
-alkyl, C
3-8
-cycloalkyl, C
3-8
-cycloalkyl-C
1-12
-alkyl, amino-C
1-12
-alkyl, N—C
1-6
-alkylamino-C
1-12
-alkyl, N,N-di-C
1-6
-alkylamino-C
1-12
-alkyl,
and
wherein R
5
and R
6
are independently selected from the group consisting of H, C
1-6
-alkyl, C
1-6
-alylthio, C
1-6
-alkoxy, fluoro, chloro, bromo, iodo, and nitro; and X is halo;
wherein R
4
is selected from the group recited above for R
1
, and R
7
is selected from the group consisting of
R
2
and R
3
are selected from the group consisting of
wherein R
5
and R
6
are as described above; and pharmaceutically-suitable salts thereof.
A second embodiment of the invention is directed to solution-phase or resin-bound combinatorial libraries containing any combination of the above-described compounds.
A third embodiment of the present invention is drawn to pharmaceutical compositions for the treatment of MMP-mediated diseases in mammals. The composition includes an amount of one or more of the above-described compounds in an amount effective to inhibit MMP activity, optionally in combination with a pharmaceutically-acceptable carrier. The pharmaceutical composition is effective to inhibit and to treat disorders in which MMP activity plays a role, including endotoxic shock, SIRS, invasive cancers, and metastatic cancers.
A fourth embodiment of the invention is directed to a method of inhibiting or treating MMP-mediated diseases in mammals, including human. The invention thus provides a method of treating a host mammal afflicted with an MMP-mediated disorder, the method comprising administering to the mammal an effective MMP-inhibitory amount of a compound of Formula I or II or a pharmaceutically-acceptable salt thereof, optionally in combination with a pharmaceutically-acceptable carrier. The invention further provides a method of inhibiting and/or preventing MMP-mediated disorders, including invasive and metastatic carcinomas, endotoxic shock, and SIRS, the method comprising administering to a mammal susceptible of developing an MMP-mediated disorder an effective MMP-inhibitory amount of a compound of Formula I or II or a pharmaceutically-acceptable salt thereof, optionally in combination with a pharmaceutically-acceptable carrier.
It has now been found that the subject compounds, including pharmacologically-active isomers and pharmaceutically-acceptable salts thereof, possess potent MMP
Bertics Paul J.
Witiak Deanne B.
Witiak Donald T.
Zhang Yingsheng
DeWitt Ross & Stevens S.C.
Leone, Esq. Joseph T.
Wessendorf T. D.
Wisconsin Alumni Research Foundation
Witiak Deanne B.
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