Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-30
2001-04-10
Jarvis, William R. A. (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
06214860
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates in general in the field of cancer and, more particularly, provides an antitumor composition comprising a cytostatic agent and a biologically active ureido compound, having a synergistic antineoplastic effect.
BACKGROUND OF THE INVENTION
Neoplastic diseases in humans are recognized throughout the world as being serious and oftentimes life-threatening conditions. These neoplastic diseases, which are characterized by rapidly-proliferating cell growth, have been and continue to be the subject of worldwide research efforts directed toward the identification of therapeutic agents which are effective in the treatment of patients suffering therefrom. Effective therapeutic agents can be characterized as those which prolong the survival of the patients, which inhibit the rapidly-proliferating cell growth associated with the neoplasm, or which effect a regression of the neoplasm. Research in this area is primarily focused toward identifying agents which would be therapeutically effective in humans. Typically, compounds are tested for antineoplastic activity in small mammals, such as mice, in experiments designed to be predictive of antineoplastic activity not only in those animals but also in humans against specific neoplastic disease states. The present invention concerns a method for treating tumors utilizing a combination of known antitumor agents which exert their efficacy through inhibition of tumor cells proliferation (cytotoxic agents) with known not-cytotoxic ureido compounds which exert their efficacy through inhibition of blood vessel formation (angiogenesis).
It is a recognized phenomenon that angiogenesis is a fundamental requisite for solid tumor growth and metastatic spread. Angiogenesis is started when tumor cells produce angiogenic factors which stimulate quiescent endothelial cells to proliferate, destroy the basal membrane, migrate, adhere and proliferate to form new capillaries. As a consequence, inhibitors of angiogenesis will block tumor growth; although no definitive clinical response is presently available on the activity of the angiogenesis inhibitors undergoing clinical trials, experimental evidence indicates that modulation of angiogenesis alone may be insufficient to efficiently control tumor growth and metastatic spread. It is thus conceivable that combined therapy with non toxic inhibitors of angiogenesis and cytotoxic agents can represent a new effective clinical regimen.
Biologically active compounds known from WO 91/10649 inhibit angiogenesis through making a complex with growth factors and angiogenic polypeptides such as basic fibroblast growth factor, insulin growth factor-1 and hepatocyte growth factor. They do not inhibit tumor cells proliferation, and administered by intravenous (iv), intraperitoneal (ip), subcutaneous (sc) and oral route inhibit in mice angiogenesis induced by growth/angiogenic factors and the growth of transplanted human and murine tumors.
It has now been found that in treating a patient affected with certain neoplastic disease states, conjunctive therapy with a biologically active compound known from WO 91/10649 and a cytotoxic agent, will provide a synergistic antineoplastic effect.
A synergistic effect is achieved when a greater antineoplastic effect results with a conjunctive therapy than use of either drug alone, thus giving a superadditive antineoplastic effect. One advantage of conjunctive therapy with a synergistic effect is that lower dosages of the antineoplastic agent may be used so that the therapeutic index is increased and toxic side effects are reduced.
DESCRIPTION OF THE INVENTION
The present invention provides, in a first aspect, a pharmaceutical composition for use in antineoplastic therapy in mammals, including humans, comprising a biologically active ureido compound of formula (I)
wherein
each of m and n, being the same, is an integer of 1 to 3; and each of the R groups, which are the same, is a naphthyl group substituted by 1 to 3 sulfonic groups, or a pharmaceutically acceptable salt thereof, and an antineoplastic agent selected from the group consisting of an antineoplastic vinca alkaloid, an antineoplastic antibiotic, an antineoplastic antimetabolite, an antineoplastic platinum coordination complex, an antineoplastic taxane compound, an antineoplastic ceramide compound, an antineoplastic distamycin compound, an antineoplastic epidophyllotoxin compound and an antineoplastic topoisomerase I inhibitor, and a pharmaceutically acceptable carrier or excipient, in amounts effective to produce a synergistic antineoplastic effect.
The present invention also provides a product comprising synergistic amounts of a biologically active ureido compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, and an antineoplastic agent selected from the group consisting of an antineoplastic vinca alkaloid, an antineoplastic antibiotic, an antineoplastic antimetabolite, an antineoplastic platinum coordination complex, an antineoplastic taxane compound, an antineoplastic ceramide compound, an antineoplastic distamycin compound, an antineoplastic epidophyllotoxin compound and an antineoplastic topoisomerase I inhibitor, as a combined preparation for simultaneous, separate or sequential use in antitumor therapy.
A further aspect of the present invention is to provide a method of treating a mammal including humans, suffering from a neoplastic disease state comprising administering to said mammal a biologically active ureido compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, and an antineoplastic agent selected from the group consisting of an antineoplastic vinca alkaloid, an antineoplastic antibiotic, an antineoplastic antimetabolite, an antineoplastic platinum coordination complex, an antineoplastic taxane compound, an antineoplastic ceramide compound, an antineoplastic distamycin compound, an antineoplastic epidophyllotoxin compound and an antineoplastic topoisomerase I inhibitor, in amounts effective to produce a synergistic antineoplastic effect.
The present invention also provides a method for lowering the side effects caused by antineoplastic therapy with an antineoplastic agent in mammals, including humans, in need thereof, the method comprising administering to said mammal a combination preparation comprising an antineoplastic agent selected from the group consisting of an antineoplastic vinca alkaloid, an antineoplastic antibiotic, an antineoplastic antimetabolite, an antineoplastic platinum coordination complex, an antineoplastic taxane compound, an antineoplastic ceramide compound, an antineoplastic distamycin compound, an antineoplastic epidophyllotoxin compound and an antineoplastic topoisomerase I inhibitor, and a biologically active ureido compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, in amounts producing a synergistic antineoplastic effect.
Preferred compounds of formula (I) are the compounds wherein m and n are each 2 and each of the R groups are as defined above, and the pharmaceutically acceptable salts thereof.
Examples of specific preferred compounds of formula (I) are:
7,7′-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl-imino(N-methyl-4,2-pyrrole)carbonylimino))bis(3,5-naphthalendisulfonic acid);
7′-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl-imino(N-methyl-4,2-pyrrole)carbonylimino))bis(3,6-naphthalendisulfonic acid);
7,7′-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl-imino(N-methyl-4,2-pyrrole) carbonylimino))bis (1,3,5-naphthalentrisulfonic acid);
8,8′-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl-imino(N-methyl-4,2-pyrrole) carbonylimino))bis (1,3,6-naphthalentrisultonic acid);
7,7′-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl-imino(N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3-naphthalendisulfonic acid);
7,7′-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl-imino(N-methyl-4,2-pyrrole) carbonylimino))bis (2,4-naphthalendisulfonic acid);
8,8′-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarb
Grandi Maria
Sola Francesco
Jarvis William R. A.
Kim Vickie
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Pharmacia & Upjohn S.p.A.
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