Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-09-12
2003-12-02
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S089000
Reexamination Certificate
active
06656949
ABSTRACT:
BACKGROUND OF THE INVENTION
1) Field of the Invention
The present invention relates to novel 4-anilino[3,2-c]quinoline derivatives, which are found to have the ability to inhibit the growth of a variety of tumor/cancer cells (particularly melanoma cell lines UACC-62 and UACC-257, and one of the renal cancer cell lines, i.e. UO-31), the preparation processes of these derivatives, and their uses in the manufacture of pharmaceutical compositions.
2) Description of the Related Art
Acridine derivatives, especially 9-anilinoacridines, have been extensively studied as potential chemotherapeutic agents due to their capability of intercalating DNA leading to the inhibition of mammalian topoisomerase II (Atwell, G. J. et. al.,
J. Med. Chem
. 1972, 15, 611-615; Denny, W. A. et. al.,
J. Med. Chem
. 1978, 21, 5-10; Denny, W. A. et. al.,
J. Med. Chem
. 1982, 25, 276-315; Gamage, S. A. et. al.,
J. Med. Chem
. 1994, 37, 1486-1494; Gamage, S. A. et. al.,
J. Med. Chem
. 1997, 40, 2634-2642). In these published articles, 4′-(9-acridinylamino) methanesulfonyl-m-anisidine (amsacrine, m-AMSA) is reported to be specifically relevant and has become a useful clinical drug for the treatment of leukemia and lymphoma (Atwell, G. J. et. al.,
J. Med. Chem
. 1972, 15, 611-615).
A tremendous amount of effort has been directed toward the design and preparation of new amsacrine analogues with the aim of developing new drug candidates with an improved broad spectrum of antitumor activity (Baguley, B. C. et. al.,
J. Med. Chem
. 1981, 24, 520-525; Rewcastle, G. W. et. al.,
J. Med. Chem
. 1986, 29, 472-477; Denny, W. A. et. al.,
J Med. Chem
. 1987, 30, 658-663; Su, T. L. et. al.,
J. Med. Chem
. 1995, 38, 3226; Stanslas, J. et. al.,
J. Med. Chem
. 2000, 43, 1563-1572).
However, the above-mentioned studies focused only on the 9-anilinoacridine skeleton, with a wide variety of substituents on anilino- and/or acridine chromophore. No attempt has been carried out concerning the replacement of acridine with its isosteric 4-anilinofuro[3,2-c]quinoline ring which constitutes an important group of natural products (Moulis, C. et. al.,
Phytochemistry
1983, 22, 2095 Reisch, J. and Iding, M.,
Montash. Chem
. 1989, 120, 363).
SUMMARY OF THE INVENTION
Therefore, in the first aspect of this invention, the present invention provides novel 4-anilino[3,2-c]quinoline derivatives of formula (I):
wherein
R
1
represents: H, halogen, OH, NO
2
, NH
2
, a C
1
-C
4
alkyl group, or a C
1
-C
4
alkoxy group;
R
2
represents a group of the following formula:
wherein
two of R
3
, R
4
, and R
5
are H, and the other is
wherein
X represents O, S, NH, or NOR, R in NOR being H or a C
1
-C
4
alkyl group; and
R
6
represents H or a C
1
-C
4
alkyl group.
In the second aspect, the present invention provides a pharmaceutical composition which comprises the above-described derivative, in its free type or a pharmaceutically acceptable salt thereof, as an active ingredient in inhibiting the growth of tumor/cancer cells, especially melanoma and renal cancer cells.
In the third aspect, the present invention provides processes for preparing the above-described derivatives of formula (I), as well as their intermediate compounds.
In particular, the present invention provides processes for preparing a compound of formula (I′):
wherein
R
1
represents: H, halogen, OH, NO
2
, NH
2
, a C
1
-C
4
alkyl group, or a C
1
-C
4
alkoxy group;
R
2
′ represents a group of the following formula:
wherein
two of R
3
′, R
4
′ and R
5
′ are H, and the other is
wherein R
6
represents H or a C
1
-C
4
alkyl group;
the process comprising the step of reacting a compound of formula (A):
wherein
R
1
is the same as that defined for formula (I′); and
Y represents: Cl, Br, or I;
with a compound of formula (B):
wherein
R
3
′, R
4
′ and R
5
′ are the same as those defined for formula (I′).
The above and other objects, features and advantages of the present invention will become apparent with reference to the following detailed description of the preferred examples.
DETAILED DESCRIPTION OF THE INVENTION
After a variety of studies, the Applicant discovered a novel 4-anilino [3,2-c]quinoline derivative:
wherein
R
1
represents: H, halogen, OH, NO
2
, NH
2
, a C
1
-C
4
alkyl group, or a C
1
-C
4
alkoxy group;
R
2
represents a group of formula:
wherein
two of R
3
, R
4
, and R
5
are H, and the other is
wherein
X represents O, S, NH, or NOR, R in NOR being H or a C
1
-C
4
alkyl group; and
R
6
represents H or a C
1
-C
4
alkyl group.
Preferably, R
1
is H.
Preferably, R
6
is CH
3
.
In a preferred embodiment, R
3
and R
5
are H, and R
4
is
In a more preferred embodiment, R
3
and R
5
are H, and R
4
is
In still another preferred embodiment, R
3
and R
5
are H, and R
4
is
In yet another preferred embodiment, R
3
and R
5
are H, and R
4
is
In a further preferred embodiment, R
3
and R
5
are H, and R
4
is
wherein R is H or a C
1
-C
4
alkyl group, and, more preferably, R is CH
3
.
In a preferred embodiment, R
4
and R
5
are H, and R
3
is
In a more preferred embodiment, R
4
and R
5
are H, and R
3
is
In still another preferred embodiment, R
4
and R
5
are H, and R
3
is
In yet another preferred embodiment, R
4
and R
5
are H, and R
3
is
In a further preferred embodiment, R
4
and R
5
are H, and R
3
is
wherein R is H or a C
1
-C
4
alkyl group, and, more preferably, R is CH
3
.
In a preferred embodiment, R
1
, R
2
and R
3
are all H, and R
4
is selected from the group consisting of:
wherein R is H or a C
1
-C
4
alkyl group.
Through in vitro antitumor activity assay, the compound of formula (I) according to the present invention has been found to exhibit inhibitory activities against the growth of a variety of tumor/cancer cells, especially melanoma and renal cancer cells. Therefore, the present invention also envisions the application of the compounds of formula (I) of this invention or the pharmaceutically acceptable salts thereof in the manufacture of antitumor or anticancer compositions.
Therefore, a pharmaceutical composition according to the present invention comprises a compound of formula (I) as described above or the pharmaceutically acceptable salts thereof, and optionally, a pharmaceutically acceptable carrier.
As used herein, the pharmaceutically acceptable salts include salts with inorganic acids, such as hydrochloride, hydrobromide, sulfate, and phosphate; those with organic acids, such as acetate, maleate, tartrate, methanesulfonate; and those with amino acids, such as arginine, aspartic acid and glutamic acid.
The compounds of the present invention may also be present as a hydrate or as a stereoisomer. Therefore, it is contemplated that these hydrates and stereoisomers fall within the technical concept of the present invention.
As stated above, the pharmaceutical composition according to this invention may additionally comprise a pharmaceutically acceptable carrier widely employed in the art for the manufacture of medicaments. For example, the pharmaceutically acceptable carrier can include one or more of the following reagents: solvents, disintegrating agents, binders, excipients, lubricants, absorption delaying agents and the like.
The pharmaceutical composition according to this invention may be administered parenterally or orally in a suitable pharmaceutical form. Suitable pharmaceutical forms include sterile aqueous solutions or dispersions, sterile powders, tablets, troches, pills, capsules, and the like. In addition, the active compounds of the present invention may be incorporated into sustained-release preparations and formulations. Optionally, the pharmaceutical composition according to this invention may be administered alone or in conjunction with an additional anticancer agent, such as Mitomycin, Adriamycin, Actinomycin, cis-platin and the like.
The novel compound of the present invention may be prepared according to the following reaction schemes and protocols.
A
Baker & Botts L.L.P.
Huang Evelyn Mei
Kaohsiung Medical University
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