Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-17
2002-11-12
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S158000
Reexamination Certificate
active
06479513
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a compound that can be used in the treatment of hyperproliferative disease, such as cancer, in mammals. This invention also relates to a method of using this compound, namely (+)-6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one, in the treatment of hyperproliferative disease in mammals, especially humans, and to pharmaceutical compositions containing these enantiomers. This invention further relates to a method of separating enantiomers in a racemic mixture from one another, which method can be utilized to obtain the aforementioned compound of the invention.
Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer.
To acquire transforming potential, the precursor of the Ras oncoprotein must undergo famesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, have therefore been suggested as agents to combat tumors in which Ras contributes to transformation. Mutated, oncogenic forms of Ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al.,
Science
, Vol. 260, 1834 to 1837, 1993, incorporated herein in its entirety by reference). The compound of the present invention exhibits activity as an inhibitor of the enzyme farnesyl protein transferase and therefore is believed to be useful as an anti-cancer and anti-tumor agent. Further, the compound of the present invention may be active against any tumors that proliferate by virtue of farnesyl protein transferase.
The racemate 6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl )-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one and other compounds that can inhibit farnesyl protein transferase are disclosed in U.S. patent application Ser. No. 09/501,163, filed Feb. 9, 2000, and in International Publication No. WO 00/47574, both of which are hereby incorporated by reference in their entireties.
Other compounds that are indicated as having activity inhibiting farnesyl protein transferase are referred to in International Publication Number WO 97/21701, entitled “Farnesyl Protein Transferase Inhibiting (Imidazol-5-yl)methyl-2-quinolinone Derivatives”, which has an International Publication Date of Jun. 19, 1997; in International Publication Number WO 971/6443, entitled “Farnesyl Transferase Inhibiting 2-Quinolone Derivatives”, which has an International Publication Date of May 9, 1997; PCT/IB99/01393, filed Aug. 5, 1999, entitled “2-Quinolone derivatives Useful as Anticancer Agents”; and PCT/IB99/01398, filed Aug. 6, 1999, entitled “Alkynyl-Substituted Quinolin-2-one Derivatives Useful as Anticancer Agents”; all of which are incorporated herein by reference in their entireties.
SUMMARY OF THE INVENTION
The present invention relates to the compound (+)-6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one and to pharmaceutically acceptable salts and solvates thereof, and to prodrugs thereof.
“(+)-6-[Amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chlorophenyl)-1-cyclopropylmethyl-1H-quinolin-2-one” refers to the dextrorotatory isomer of 6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one. The dextrorotatory isomer of 6-[amino-(6-chloropyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one has been found to have greater activity in inhibiting the enzyme farnesyl protein transferase than the levorotatory isomer. The term “(+)-6-[amino-(6-chloro-pyridin-3-yl)(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one” for purposes of the present invention and unless otherwise indicated herein, however, also refers to compositions consisting essentially of (+)-6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one substantially free of (−)-6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one, the levorotatory isomer of 6-[amino -(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one. The term “substantially free” means that the amount of the dextrorotatory isomer predominates the composition relative to the levorotatory isomer of 6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one. More specifically, this means that the amount of the dextrorotatory isomer relative to the levorotatory isomer by weight is at least about 90%, preferably greater than about 95%, more preferably greater than about 99%.
The phrases “racemate”, “racemic mixture”, and other like phrases refer to generally equimolar proportions of a levorotatory isomer and a dextrorotatory isomer of a compound in a composition.
This invention also relates to a method of inhibiting abnormal cell growth in a mammal comprising administering to said mammal an amount of the aforementioned compound of the invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, that is effective in inhibiting farnesyl protein transferase.
This invention also relates to a method of inhibiting abnormal cell growth in a mammal comprising administering to said mammal an amount of the aforementioned compound of the invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, that is effective in inhibiting abnormal cell growth.
This invention further relates to a method of inhibiting abnormal cell growth in a mammal which comprises administering to said mammal an amount of the aforementioned compound of the invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with an amount of a chemotherapeutic, wherein the amounts of the compound, salt, solvate, or prodrug, and the chemotherapeutic are together effective in inhibiting abnormal cell growth. Several chemotherapeutics are known in the art, and these can be used in the present invention. In one embodiment, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, e.g. anti-androgens.
This invention further relates to a method for inhibiting abnormal cell growth in a mammal which method comprises administering to the mammal an amount of the aformentioned compound of the invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with radiation therapy, wherein the amount of the compound, salt, solvate or prodrug is in combination with the radiation therapy effective in inhibiting abnormal cell growth in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of the invention in this combination therapy can be determined as described herein.
It is believed that the compound of the invention can render abnormal cells more sensitive to treatment with radiation for purposes of killing and/or inhibiti
Ginsburg Paul H.
Myers Jeffrey N.
Pfizer Inc.
Richardson Peter C.
Seaman D. Margaret
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