4-Anilino[2,3-b]quinoline derivatives, their...

Details 4-Anilino[2,3-b]quinoline derivatives, their... 4-Anilino[2,3-b]quinoline derivatives, their...

2002-09-12

2004-06-15

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...

C514S292000, C546S084000, C546S089000, C546S092000

Reexamination Certificate

active

06750223

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel 4-anilino[2,3-b]quinoline derivatives, which are found to have the ability to inhibit the growth of a variety of tumor/cancer cells, especially leukemia, colon, melanoma, and breast cancer cells, and 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). 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).
For example. 3-(acridin-9-ylamino)-5-(hydroxymethyl) aniline (AHMA) was reported to be superior to m-AMSA against the growth of certain solid tumors, such as mammary adenocarcinoma, melanoma, and Lewis lung carcinoma in mice. Unlike m-AMSA, AHMA, which has a 3,5-disubstituted anilino moiety, was resistant to the oxidative metabolism and, therefore, was expected to have longer half-life in plasma. (T. L. Su, T. C Chou, J. Y. Kim, J. T. Huang, G. Ciszewska, W. Y. Ren, G. M. Otter, F. M. Sirotnak, K. A. Watanabe,
J. Med. Chem.
1995, 38, 3226).
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 furo[2,3-b]quinoline ring which constitutes an important group of bioactive natural products, such as dictamnine, robustine, and haplopine (Chen, I. S. et. al.,
Phytochemistry
1994, 36, 237-239; Zhao, W. et. al.,
Phytochemistry
1998, 47, 7-11).
SUMMARY OF THE INVENTION
Therefore, in the first aspect of this invention, the present invention provides novel 4-anilino[2,3-b]quinoline derivatives of formula (I):
wherein
Y represents: S, O or NH
R
1
represents a group selected from the group consisting of:
 wherein
R
4
represents: H or
 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;
R
5
is selected from the group consisting of H,
 and
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;
with the proviso that one of R
4
and R
5
is H;
R
2
represents: H, halogen, a C
1
-C
4
alkyl group, hydroxyl, a C
1
-C
4
alkoxy group, nitro or amino; and
R
3
represents: H, halogen, a C
1
-C
4
alkyl group, hydroxyl, a C
1
-C
4
alkoxy group, nitro or amino.
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 leukemia, colon, melanoma, and breast 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
Y represents: S, O or NH;
R
1
represents a group selected from the group consisting of:
 wherein one of R
4
′ and R
5
′ is H, and the other is
 wherein R
6
represents H or a C
1
-C
4
alkyl group;
R
2
represents: H, halogen, a C
1
-C
4
alkyl group, hydroxyl, a C
1
-C
4
alkoxy group, nitro or amino; and
R
3
represents: H, halogen, a C
1
-C
4
alkyl group, hydroxyl, a C
1
-C
4
alkoxy group, nitro or amino;
the process comprising the step of reacting a compound of formula (A):
 wherein
R
2
, R
3
and Y are the same as those defined for formula (I′); and
X′ represents Cl, Br or I;
with a compound selected from the group consisting of a compound of formula
 and a compound of formula
 wherein 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
The applicant noted that furo[2,3-b]quinoline system possesses a higher electron density than that of acridine systems and, therefore, is advantageous, since the major route of breakdown for m-AMSA in vivo is a non-enzymatically mediated attack of thiol at C(9), which would eventually result in loss of the side chain and the formation of inactive products (B. F. Cain, W. R. Wilson, B. C. Baguley,
Mol. Pharmacol.
1976, 12, 1027; W. R. Wilson, B. F. Cain, B. C. Baguley,
Chem.
-
Biol. Interact.,
977, 18, 163; and R. L. Cysyk, D. Shoemaker, R. H. Adarnson,
Drug Metab. Dispos.
1977, 5, 579).
In earlier researches, the applicant synthesized certain &agr;-methylindene-&ggr;-butyrolactone-bearing quinolones and evaluated their cytotoxicities on the ground that, through the intercalation of quinolone, the &agr;-methylidene-&ggr;-butyrolactone can specifically alkylate DNA molecule (K. C. Fang, Y. L. Chen, J. Y. Sheu, T. C. Wang, C C. Tzeng,
J. Med. Chem.
2000, 43, 3809; C. C. Tzeng, K. H. Lee, T. C. Wang, C. H. Han, Y. L. Chen,
Pharmaceut. Res.
2000. 17, 715; and S. L. Hsu, Y. L. Chen, K. C. Fang, J. Y. Sheu, C. C. Tzeng,
Helv. Chim. Acta
2001, 84, 874). This versatile &agr;-methylidene-&ggr;-butyrolactone moiety is appended on the 9-anilino group (see compound 6 shown in the following synthesis scheme I) in an attempt to prepare a bifunctional compound in which the furo[2,3-b]quinoline moiety acts as an intercalator while the lactone ring plays the role of an alkylating unit.
Based on the above, the applicant further developed new bioisosteric isomers of AHMA, i.e. compounds of formula (I) or pharmaceutically acceptable salts thereof:
wherein
Y represents: S, O or NH;
R
1
represents a group selected from the group consisting of:
wherein
R
4
represents: H or
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;
R
5
is selected from the group consisting of H,
and
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;
with the proviso that one of R
4
and R
5
is H;
R
2
represents: H, halogen, a C
1
-C
4
alkyl group, hydroxyl, a C
1
-C
4
alkoxy group, nitro or amino; and
R
3
represents: H, halogen, a C
1
-C
4
alkyl group, hydroxyl, a C
1
-C
4
alkoxy group, nitro or amino.
Preferably, Y is O.
Preferably, R
2
is H.
Preferably, R
3
is H.
Preferably, R
1
is selected from the group consisting of
In a preferred embodiment, R
1
is
wherein R is H or methyl.
In another preferred embodiment, R
1
is
wherein R is H or methyl.
Specifically, the applicant synthesized certain mono-substituted 4-anilinofuro[2,3-b]quinoline derivatives, in wh

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