Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-10
2002-07-16
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
06420371
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to compositions containing quniazolinones. More particularly, the present invention relates to a composition, containing a quinazolinone derivative, useful for the treatment of angiogenic-associated diseases, as well as for the treatment of malignancies, including inhibition of primary tumor growth, tumor progression and metastasis.
Malignancies are characterized by the growth and spread of tumors. A number of factors are important in the progression of this disease. One crucial factor is angiogenesis, a complex process in which capillary blood vessels grow in an ordered sequence of events [J. Folkman and M. Klagsbrun,
Science,
Vol. 235, pp 442-447 (1987); J. Folkman and Y. Shing,
J. Biol. Chem.,
Vol. 267, pp. 19031-10934 (1992)]. Once a tumor has started, every increase in tumor cell population must be preceded by an increase in new capillarities that converge on the tumor and supply the cells with oxygen and nutrients [J. Folkman,
Perspect, in Biol, and Med.,
Vol 29, p. 10-36 (1985); J. Folkman,
J. Natl. Cancer Inst.
Vol. 82, pp. 4-6 (1989); M. Weidner, et al.,
Amer. J. Pathol.
Vol. 143, pp. 401-409 (1993)]. Tumors may thus remain harmless and confined to their tissue of origin, as long as an accompanying angiogenic program is prevented from being activated. Since the angiogenesis-dependent step in tumor progression is shared by solid tumors of all edologies, the ability to inhibit tumor-associated angiogenesis is a most promising approach in combating cancer [M. S. O'Reilly, et al.,
Cell.
Vol. 79, pp. 316-328 (1994)].
A substantial body of experimental evidence supports the hypothesis that tumor angiogenesis is fundamental for the growth and metastasis of solid tumors [J. Folkman, ibid. (1989); N. Weidner, et al., ibid, (1993); M. S. O'Reilly, et al., ibid. (1994); N. Weidner, et al.,
N. Eng. J. Med.,
Vol. 324, pp. 1-8 (1991)]. Indeed, the majority of solid tumors are not even clinically detectable until after the occurrence of neovascularizartion, whose induction in solid tumors is mediated by one or more angiogenic factors [J. Folkman, ibid. (1987); J. Folkman and Y. Shin, ibid, (1992)].
Furthermore, angiogenesis is also important in a number of other pathological processes, including arthritis, psoriasis, diabetic retinopath, chronic inflammation, scleroderma, hemangioma, retrolental fibroplasia and abnormal capillary proliferation in homophiliac joints, prolonged menstruation and bleeding, and other disorders of the female reproductive system [J. Folkman,
Nature Medicine,
Vol. 1, pp. 27-31, (1995); J. W. Miller, et al.,
J. Pathol,
Vol. 145, pp. 574-584(1994), A. P. Adamid, et al.,
Amer J. Ophthal.,
Vol. 118, pp. 445-450 (1994), K. Takahashi, et al.,
J. Clin. Invest.,
Vol. 93, pp. 2357-2364 (1994); D. J. Peacock, et al.,
J. Exp. Med.,
Vol. 175, pp. 1135-1138 (1992); B. J. Nickoloff, et al.,
Amer. J. Pathol.,
Vol. 44, pp. 820-828 (1994); J. Folkman,
Steroid Hormones and Uterine Bleeding,
N. J. Alexander and C. d'Arcangues, Eds., American Association for the Advancement of Science Press, Washington, D.C. U.S.A., pp. 144-158 (1992)].
Thus, clearly methods of blocking the mechanism of angiogenesis are necessary. The basic mechanism of angiogenesis is as follows. Briefly, when a new capillary sprout grows from the side of the venule, endothelial cells degrade basement membrane, migrate inward an angiogenic source, proliferate, form a lumen, join the tips of two sprouts to generate a capillary loop, and manufacture new basement membrane [J. Folkman.,
Perspective in Biology and Medicine,
Vol. 29, pp. 1-36 (1985)].
Degradation and remodeling of the ECM are essential processes for the mechanism of angiogenesis. In addition, ECM components synthesized by endothelial cells (i.e. collagens, laminin, thrombospondin, fibronectin and SPARC) function to regulate endothelial cell growth, migration and shape [J. Bischoff,
Trends Cell Biol.,
No. 5, pp. 69-74 (1995)]. Bovine aortic endothelial cells (BAE) undergoing sprouting and tube formation synthesize type I collagen and SPARC. It was proposed that type I collagen may be involved in directing migration and assembly of the BASE cells [M. L. Iruela-Arispe, et al.,
Lab. Invest,
No. 64, pp. 174-186 (1991). It was also found that exogenous type I collagen promoted rapid tube formation by confluent human dermal microvascular endothelial cells [C. J. Jackson and K. L. Jenkins,
Exp. Cell. Res.,
No. 192, pp. 319-323 (1991)]. the tubes contained collagen fibrils in the luminal spaces, suggesting that the endothelial cells use the fibrils to fold and align into tube structures.
Furthermore, in order to extend a capillary blood vessel, interactions must occur between ECM components and the surrounding matrix molecules, which provide a scaffold for the ECM components of the new vessel [Brooks, P. C. et al., Cell, Vol. 79, p. 1157-1164, (1994)]. Disruption of cell-matrix interactions induced apoptosis in human endothelial cells. It has been demonstrated that integrin &agr;
2
&bgr;
3
, which has an enhanced expression in angiogenic vascular cells, promotes a survival signal, since inhibitors of this integrin cause unscheduled apoptosis and disintegration of newly formed blood vessels.
In order to treat angiogenesis-related diseases, several inhibitors of the above mechanism of angiogenesis are being studied, including platelet factor 4, the fumagillin derivative AGM 1470, Interferon &agr;
2
a, thrombospondin, angiostatic steroids, and angiostatin [J. Folkman, ibid, (1995); M. S. O'Reilly, et al., ibid, (1994); V. Castle, et al.,
J. Clin. Invest.,
Vol. 87, pp. 1883-1888; D. Ingber, et al.,
Nature,
Vol. 348, pp. 555-557]. All of these compounds have disadvantages. For example, endostatin and angiostatin are proteins, so that they have all of the disadvantages of proteins, including the requirement for being administered parenterally. Therefore, a non-protein inhibitor which would selectively block the underlying mechanism of angiogenesis without adversely affecting other physiological functions, and which could be administered by many different routes, would be extremely useful.
In addition, many of the compounds that are now being evaluated as antiangiogenic agents are proteins, e.g., antibodies, thrombospondin, angiostatin, platelet factor IV [J. Folkman, ibid, (1995); M. S. O'Reilly, et al., ibid, (1994); V. Castle, et al., ibid., P. C. Brooks, et al., ibid. (1994)], which suffer from poor bioavailability and are readily degraded in the body. Hence, these substances should be administered in high doses and frequencies.
Other approaches for cancer treatment focus on cytotoxic therapies, such as chemotherapy or radiation treatments, in order to kill actively proliferating cells. Unfortunately, these therapies are highly toxic to non-cancer cells and cause severe side effects, such as bone marrow suppression, hair loss and gastrointestinal disturbances.
As noted above, degradation and remodeling of the ECM are essential processes for the mechanisms of angiogenesis. Such processes involve the synthesis of a number of components of the ECM, such as collagen. The synthesis of collagen is also involved in a number of other pathological condition. For example, clinical conditions and disorders associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary and hepatic 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. Kivirikk
Nagler Arnon
Pines Mark
Vlodavsky Israel
Goldberg Jerome D.
Madasit Medical Research Services & Development Co., Ltd.
Webb & Associates
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