Method of inhibiting connective tissue degradation

Details Method of inhibiting connective tissue degradation Method of inhibiting connective tissue degradation

1998-08-06

2001-04-03

Reamer, James H. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S363000, C514S364000, C514S384000

Reexamination Certificate

active

06211209

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a method of inhibiting connective tissue degradation. This invention also relates to a method of inhibiting the production of matrix metalloproteinases.
BACKGROUND OF THE INVENTION
In certain conditions, connective tissues in a patient are detrimentally degraded. For example, cartilage can be degraded as a result of a disease, or injury from a mechanical trauma, such as a sports accident; the bones or intervertebral disks of a patient can be degraded due to various environmental conditions or diseases; dermis of the skin can be degraded in the elderly causing chronic ulcers; and degradation of the connective tissue of blood vessels can lead to aneurysm formation or atherosclerosis. The term “connective tissue” means the structural framework of organs containing supporting matrix molecules such as collagens, elastins, and proteoglycans (glycosaminogylcans).
In conditions in which connective tissue degradation occurs, matrix metalloproteinases are known to play an important role in the degradation of the tissues. A good review of the matrix metalloproteinases and their role in tissue degradation can be found in the article “Matrix Metalloproteinases and Their Inhibitors In Connective Tissue Remodelling” by J. Frederick Woessner, Jr.,
The FASEB Journal
, 1991;5:2145-2154.
Presently, there is no way of inhibiting the tissue degradation that results from such conditions, and physicians have, instead, prescribed compounds that act to mask the symptoms, i.e., ameliorate the pain associated with such conditions, but these compounds have not inhibited the tissue degradation. That is, destruction of the tissues continues unabated despite symptomatic relief. Eventually, the tissues are destroyed by the disease process and dysfunction occurs.
Thus, it would be beneficial to have a method to inhibit connective tissue degradation in a patient.
SUMMARY OF THE INVENTION
The present invention provides a method of inhibiting connective tissue degradation that comprises administering to a patient having a condition in which connective tissue is degraded a therapeutically effective amount of a compound having the formula
where R
1
, R
2
, R
3
, and R
4
are independently hydrogen, hydroxy, halo, amino, nitro, C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, C
1
-C
6
alkoxy, CF
3
, CN, S(O)
n
—[C
1
-C
6
alkyl],
R
6
and R
7
are independently hydrogen, C
1
-C
6
alkyl or acyl;
n is 0 to 2;
R
8
is hydrogen or C
1
-C
6
alkyl;
W is S or O;
Z is C
1
-C
6
alkyl, C
1
-C
6
alkoxy or NR
9
R
10
;
R
9
and R
10
are independently hydrogen or C
1
-C
6
alkyl; and R
5
is
where Y is hydroxy, thiol, amino or NHCN;
X is sulfur or oxygen; and Q is sulfur, oxygen, NH or NCN, and the pharmaceutically acceptable salts and prodrugs thereof.
In one embodiment of the invention, R
5
is
In another embodiment of the invention, R
5
is
In a third embodiment of the invention, R
5
is
In another embodiment of the invention, R
5
is
Also provided is a method of inhibiting the production of matrix metalloproteinases comprising administering to a patient having a condition associated with matrix metalloproteinase-mediated tissue degradation a therapeutically effective amount of a compound having the formula
where R
1
, R
2
, R
3
, and R
4
are independently hydrogen, hydroxy, halo, amino, nitro, C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, C
1
-C
6
alkoxy, CF
3
, CN, S(O)
n
—[C
1
-C
6
alkyl],
R
6
and R
7
are independently hydrogen, C
1
-C
6
alkyl or acyl;
n is 0 to 2;
R
8
is hydrogen or C
1
-C
6
alkyl;
W is S or O;
Z is C
1
-C
6
alkyl, C
1
-C
6
alkoxy or NR
9
R
10
;
R
9
and R
10
are independently hydrogen or C
1
-C
6
alkyl; and
R
5
is
where Y is hydroxy, thiol, amino or NHCN; X is sulfur or oxygen; and Q is sulfur, oxygen, NH or NCN, and the pharmaceutically acceptable salts and prodrugs thereof.


REFERENCES:
patent: 3531493 (1970-09-01), Gittos et al.
patent: 4962119 (1990-10-01), Boschelli et al.
patent: 5066668 (1991-11-01), Boschelli et al.
patent: 5114958 (1992-05-01), Boschelli et al.
patent: 5143929 (1992-09-01), Belliotti et al.
patent: 5212189 (1993-05-01), Belliotti et al.
patent: 5358964 (1994-10-01), Baragi et al.
patent: 5677282 (1997-10-01), Oleksyszyn et al.
patent: 5847148 (1998-12-01), Jacobsen et al.
patent: 5902791 (1999-05-01), Beckett et al.
Woessner, Jr., “Matrix metalloprotieinases and their inhibitors in connective tissue remodeling”, The FASEB Journal, 1991, vol. 5, pp. 2145-2154.
Ranst, et al., “The Cytokine-Protease Connection: Identification of a 96-kD THP-1 Gelatinase and Regulation by Interkeukin-1 and Cytokine Inducers”, Cytokine, 1991, vol. 3, No. 3, pp. 231-239.
Unemori, et al., “Constitutive Expression of a 92-kD Gelatinase (Type V Collagenase) by Rheumatoid Synovial Fibroblasts and Its Induction in Normal Human Fibroblasts by Inflammatory Cytokines”, J. Clin. Invest., 1991, vol. 88, pp. 1656-1662.
K.D. Rainsford, “Effects of Meloxicam, Compared with other NS AIDs, on Cartilage Proteoglycan Metabolism, Synovial Prostaglandin E2, and Production of Interleukins 1, 6 and 8, in Human and Porcine Explants in Organ Culture,” J. Pharm. Pharmacol., 1997, pp. 991-998.
E.C. Arner et al., “Independent Effects of Interleukin-1 on Proteoglycan Breakdown, Proteoglycan Synthesis, and Prostaglandin E2Release From Cartilage in Organ Culture,” Arthritis and Rheumatism, vol. 32, No. 3, Mar. 1989, pp. 288-297.
E.C. Arner et al., “Effect of Antiinflammatory Drugs on Human Interleukin-1-Induced Cartilage Degradation,” Agents and Actions, vol. 21, 3/4, 1987, pp. 334-336.
J. Steinmeyer et al., “Pharmacological Influence of Antirheumatic Drugs on Proteoglycanases from Interleukin-1 Treated Articular Cartilage,” Bichemical Pharmacology, vol. 53, 1997, pp. 1627-1635.
M.J. Palmoski et al., “Effects of Some Nonsteroidal Antiinflammatory Drugs on Proteoglycan Metabolism and Organization in Canine Articular Cartilage,” Arthritis and Rheumatism, vol. 23, No. 9, Sep. 1980, pp. 1010-1020.
M. Doherty et al., Editorial, “Indomethacin Hastens Large Joint Osteoarthritis in Humans—How Strong is the Evidence,” The Journal of Rheumatology, 1995, pp. 2013-2015.
J.H. Herman et al., “The In vitro Effect of Select Classes of Nonsteroidal Antiinflammatory Drugs on Normal Cartilage Metabolism,” The Journal of Rheumatology, 1986, pp. 1014-1018.

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