Treatment of hepatic cirrhosis

Details Treatment of hepatic cirrhosis Treatment of hepatic cirrhosis

1999-10-13

2003-05-13

Goldberg, Jerome D. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

Reexamination Certificate

active

06562829

ABSTRACT:

FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to the treatment of hepatic cirrhosis and, in particular, to the treatment of hepatic cirrhosis with quinazolinone derivatives such as Halofuginone.
Hepatic cirrhosis has a number of causes, including hepatic fibrosis caused by chronic alcoholism, malnutrition, hemochromatosis, passive congestion, hypercholesterolemia, exposure to hepatotoxic chemical substances, exposure to drugs, immune reactions, genetically determined sensitivities to certain substances as seen with copper in Wilson's disease and infections such as viral hepatitis, syphilis and various parasitic infections including, but not limited to,
Schistosomiasis mansoni
and
S. japonica.
For reasons given in greater detail below, the disease is currently incurable and frequently fatal.
The pathogenesis of hepatic cirrhosis progresses in a number of stages. First, an enlarged liver is seen with various fatty changes. Next, overt fibrosis is evident with a concomitant decrease in liver function. Finally, atrophy of the liver begins, with a corresponding reduction in the size and functionality of the liver. Necrosis of the liver can be seen at any stage, but is particularly pronounced by late stage cirrhosis. Microscopically, a complete disruption of the normal architecture of the liver is evident.
Outside of the liver, other pathological changes become evident as cirrhosis progresses. Portal circulation is reduced as fibrotic tissue is formed in the liver, further reducing liver functionality. This reduced circulation causes an increase in collateral venous circulation, particularly in the esophagus. These esophageal blood vessels can rupture, causing fatal hemorrhage. Thus, cirrhosis is an entire pathological process with effects that are not limited to the liver, although the root causes can be found in specific pathological changes to the liver itself.
One necessary step in the pathogenesis of hepatic cirrhosis is the formation of fibrotic tissue in the liver. Hepatic fibrosis is a feature of most chronic liver diseases, not just cirrhosis [S. L. Friedman,
New Eng. J. Med.,
328:1828-35, 1993]. In hepatic fibrosis, connective tissue accumulates in the liver, replacing normal hepatic parenchymal tissue, and reducing liver functionality. The fibrotic tissue replaces more complex normal liver tissue in a pathological process which reduces the amount of liver tissue available for normal functions, such as the removal of toxic substances from the blood, and which progressively disrupts intrahepatic blood flow. The formation of fibrotic tissue in the liver is characterized by the deposition of abnormally large amounts of extracellular matrix components, including at least five types of collagen, in particular collagen types I, III, and IV, as well as other matrix proteins [L. Ala-Kokko,
Biochem. J,
244:75-9, 1987].
The synthesis of collagen is also involved in a number of other pathological conditions. For example, clinical conditions and disorders associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), lung fibrosis and a large variety of autoimmune disorders, are distinguished by excessive production of connective tissue, which results in the destruction of normal tissue architecture and function. These diseases can best be interpreted in terms of perturbations in cellular functions, a major manifestation of which is excessive collagen synthesis and deposition. The crucial role of collagen in fibrosis has prompted attempts to develop drugs that inhibit its accumulation [K. I. Kivirikko,
Annals of Medicine,
Vol. 25, pp. 113-126 (1993)].
Such drugs can act by modulating the synthesis of the procollagen polypeptide chains, or by inhibiting specific post-translational events, which will lead either to reduced formation of extra-cellular collagen fibers or to an accumulation of fibers with altered properties. Unfortunately, only a few inhibitors of collagen synthesis are available, despite the importance of this protein in sustaining tissue integrity and its involvement in various disorders.
For example, cytotoxic drugs have been used in an attempt to slow the proliferation of collagen-producing fibroblasts [J. A. Casas, et al.,
Ann. Rhem. Dis.,
46: 763, 1987], such as colchicine, which slows collagen secretion into the extracellular matrix [D. Kershenobich, et al.,
N. Engl. J. Med.,
318:1709, 1988], as well as inhibitors of key collagen metabolism enzymes [K. Karvonen, et al.,
J. Biol Chem.,
265: 8414, 1990; C. J. Cunliffe, et al.,
J. Med. Chem.,
35:2652, 1992].
Unfortunately, none of these inhibitors are collagen-type specific. Also, there are serious concerns about the toxic consequences of interfering with biosynthesis of other vital collagenous molecules, such as Clq in the classical complement pathway, acetylcholine esterase of the neuro-muscular junction endplate, conglutinin and liver surfactant apoprotein.
Other drugs which can inhibit collagen synthesis, such as nifedipine and phenytoin, inhibit synthesis of other proteins as well, thereby non-specifically blocking the collagen biosynthetic pathway [T. Salo, et al.,
J. Oral Pathol. Med.,
19: 404,1990].
Collagen cross-linking inhibitors, such as &bgr;-amino- propionitrile, are also non-specific, although they can serve as useful anti-fibrotic agents. Their prolonged use causes lathritic syndrome and interferes with elastogenesis, since elastin, another fibrous connective tissue protein, is also cross-linked. In addition, the collagen cross-linking inhibitory effect is secondary, and collagen overproduction has to precede its degradation by collagenase. Thus, a type-specific inhibitor of the synthesis of collagen itself is clearly required as an anti-fibrotic agent.
Such a type-specific collagen synthesis inhibitor is disclosed in U.S. Pat. No. 5,449,678 for the treatment of a fibrotic condition. This specific inhibitor is a composition with a pharmaceutically effective amount of a pharmaceutically active compound of a formula:
wherein:
R
1
is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl and lower alkoxy; R
2
is a member of the group consisting of hydroxy, acetoxy and lower alkoxy; and R
3
is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl; wherein n is 1 or 2. Pharmaceutically acceptable salts thereof are also included. Of this group of compounds, Halofuginone has been found to be particularly effective for such treatment.
U.S. Pat. No. 5,449,678 discloses that these compounds are effective in the treatment of fibrotic conditions such as scleroderma and GVHD. PCT Application No. WO 96/06616 further discloses that these compounds are effective in treating restenosis. The two former conditions are associated with excessive collagen deposition, which can be inhibited by Halofuginone. Restenosis is characterized by smooth muscle cell proliferation and extracellular matrix accumulation within the lumen of affected blood vessels in response to a vascular injury [Choi et al.,
Arch. Surg.,
130:257-261, 1995]. One hallmark of such smooth muscle cell proliferation is a phenotypic alteration, from the normal contractile phenotype to a synthetic one. Type I collagen has been shown to support such a phenotypic alteration, which can be blocked by Halofuginone [Choi et al.,
Arch. Surg.,
130: 257-261, 1995; U.S. Pat. No. 5,449,678].
However, the in vitro action of Halofuginone does not always predict its in vivo effects. For example, Halofuginone inhibits the synthesis of collagen type I in bone chrondrocytes in vitro, as demonstrated in U.S. Pat. No. 5,449,678. However, chickens treated with Halofuginone were not reported to have an increased rate of bone breakage, indicating that the effect is not seen in vivo. Thus, the exact behavior of Halofuginone in vivo cannot always be accurately predicted from in vitro studies.
Furthermore, the ability of Halofuginone or other rela

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