Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-27
2001-05-08
Aulakh, C. S. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C544S180000, C544S282000, C544S333000
Reexamination Certificate
active
06229016
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new compounds within the general class of 2-aryl-1,8-naphthyridin-4-ones. The present invention also relates to methods of inhibiting cellular mitosis and/or tumor growth.
BACKGROUND OF THE INVENTION
The microtubule system of eukaryotic cells is an attractive target for the development of compounds useful in anticancer chemotherapeutics. Microtubules show highly dynamic instability and play an important role in cellular mitosis. Chemicals that attack microtubules through their major structural component, tubulin, disrupt or suppress both microtubule structure and normal functions by inhibition or promotion of microtubule assembly. Inihibition or arrest of cellular mitosis is the result.
One example of conventional antimitotic agents includes the vinca alkaloids, which inhibit microtubule polymerization. Another example of conventional antimitotic agents includes the taxoids, which promote microtubule assembly.
Colchicine is another conventional antimitotic agent. Although colchicine has limited medicinal application due to its high toxicity, it has played a fundamental role in elucidation of the properties and fictions of tubulin and microtubules.
Many natural products, such as comigerine, podophyllotoxin, steganacin, and combretastatins, bind to the colchicine site of tubulin. Structurally, the compounds binding to this site are much simpler than those binding to vinca alkaloid or taxol domains. These compounds generally possess a “biaryl” system connected by a hydrocarbon bridge of variable length.
In the course of this groups search for novel plant-derived potent cytotoxic agents that are active against slow-growing solid tumors, we have isolated several flavonols as antitumor principles from a phytochemically and biologically heretofore uninvestigated plant,
Polanisia dodecandra
. Among these flavonols, 5,3′-dihydroxy-3,6,7,8,4′-pentamethoxyflavone showed remarkable cytotoxicity in vitro against panels of central nervous system, lung, ovarian, colon, and renal cancers and against melanoma and leukemia cell lines with GI
50
values in the low micromolar to nanomolar concentration range. Flavonoids also possess the biaryl structural pattern of compounds binding to the colchicine site. We found that this compound is a strong inhibitor of tubulin polymerization with an IC
50
value of 0.83±0.2 &mgr;M and to be a potent inhibitor of radiolabeled colchicine binding to tubulin, showing 59% inhibition when present in an equimolar concentration with colchicine.
Paralleled with our studies of plant antitumor agents, we synthesized a large series of 2-aryl-1,8-naphthyridiones, which are the amino analogs of cytotoxic antimitotic flavonoids, and found that many of these compounds were cytotoxic and possess activitity against tubulin polymerization and colchicine binding;
There remains a need in the art for cytotoxic agents for use in cancer therapy. There remains a need in the art for agents capable of inhibiting cellular mitosis for use in cancer therapy. Further there remains a need in the art for methods of treating cancer and methods of providing cancer therapy.
SUMMARY OF THE INVENTION
As a first aspect, the present invention provides a compound of Formula the general Formula I:
wherein A is an aromatic moeity selected from the the group consisting of
wherein X
1
, X
2
, and X
3
are each individually selected from the group consisting of C, or N; X
4
and X
5
are each individually selected from the group consisting of C, N, O, and S wherein at least one of X
4
and X
5
is N, O, or S; R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, and R
8
are each independently selected from the group consisting of H, alkyl, hydroxyl, alkoxyl, aryloxyl, halo, amino, alkylamino, dialkylamino, or nitro, or alterantively, two adjacent R groups together may form a bridging group selected from the group consisting of alkyldienyl, alkyleneoxy, alkylenedioxy, alkyleneimine, and alkylenediimine; and the dashed line indicates that the bond may be a double bond or a single bond, with the provisos that when any of X
1
, X
2
, X
3
, X
4
or X
5
is C, the dashed lines connected thereto are double bonds; when any of XI, X
2
, or X
3
is N, the dashed lines connected thereto are double bonds and the R group attached at that position is absent; when either X
4
or X
5
is N, the dashed lines connected thereto may be single bonds or double bonds, and when the dashed line is a double bond, the R group attached at that position is absent; and when either X
4
or X
5
is O or S, the dashed lines connected thereto are single bonds and the R group attached at that position is absent.
As a second aspect, the present invention provides a process for making compounds of Formula I. The process comprises (a) reacting a compound of Formula II:
with a compound of Formula IV:
A—CHO IV
to produce a Schiff base intermediate of Formula VI:
(b) cyclizing the Schiff base intermediate to give a pyridopyrimidinone intermediate of Formula V:
and (c) thermally converting the pyridopyrimidinone intermediate to a compound of Formula I.
As a third aspect, the present invention provides another process for making compounds of Formula I wherein A is a six-member aromatic hydrocarbon ring. The process comprises the steps of (a) condensing a compound of Formula II with a compound of Formula III:
in the presence of polyphosphoric acid to produce a pyridopyrimidinone intermediate of Formula V-A:
and (b) thermally converting the pyridopyrimidinone intermediate of Formula V-A to a compound of Formula I wherein A is a six-member aromatic hydrocarbon ring.
As a fourth aspect, the present invention provides a compound of Formula V.
As a fifth aspect, the present invention provides a compound of Formula VI.
As a sixth aspect, the present invention provides a method for treating a tumor. The method comprises administering to a subject in need of treatment, a compound of Formula I in an amount effective to treat a tumor.
As a seventh aspect, the present invention provides a method of inhibiting cellular mitosis. The method comprises contacting a cell with a compound of Formula I in an amount effective to inhibit cellular mitosis.
The foregoing and other aspects of the present invention are explained in detail in the detailed description and examples set forth hereinbelow.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term “alkyl” refers to C
1-20
inclusive, linear, branched, or cyclic, saturated or unsaturated hydrocarbon chains, including for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, and allenyl groups. Thus, the term “alkyl” refers to C
1-20
inclusive alkyls unless otherwise specified. The term “alkoxy” as used herein refers to C
1-20
inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, and pentoxy. The term “aryloxyl” as used herein refers to phenyloxyl and alkyl, halo, or alkoxyl substituted phenyloxyl. The terms “halo,” “halide,” or “halogen” as used herein refer to fluorine, chlorine, bromine, and iodine. The term “alkylamino” refers to a group of the general formula —NHR′, wherein R′ is alkyl. The term “dialkylamino” refers to a group of the general formula —NR′R″, wherein R′ and R″ are each the same of different alkyl groups. The term “heteroatom” as used herein refers to N, O, or S. The term “alkydienyl” refers to a group of the general formula —R′— where R′ is alkyl. The term “alkyleneoxy” refers to a group having the general formula —OR′— or —R′OR′— where each R′ is independently alkyl. The term “alkylenedioxy” refers to a group of the general formula —OR′O—, —OR′OR′—, or —R′OR′OR′— where each R′ is independently alkyl. The term “alkyleneimine” refers to a group having the general formula —NR&
Chen Ke
Kuo Sheng-Chu
Lee Kuo-Hsiung
Aulakh C. S.
Myers Bigel & Sibley & Sajovec
The University of North Carolina at Chapel Hill
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