2-phenyl-4-quinazolinone compounds,...

Details 2-phenyl-4-quinazolinone compounds,... 2-phenyl-4-quinazolinone compounds,...

2000-06-28

2002-11-12

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S232500, C514S234500, C544S080000, C544S116000, C544S062000

Reexamination Certificate

active

06479499

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a series of substituted 2-phenyl-4-quinazolinones compounds and substituted 2-phenyl4-alkoxy-quinazoline compounds; and in particular to their uses in treating human cancers and in inhibiting platelet aggregation.
BACKGROUND OF THE INVENTION
Microtubules provide an important framework defining cellular morphology and are essential in the division and transport of cellular chromosomes. Consequently, the microtubule has become an important target for the design of new antimitotic anticancer agents. The antimitotic agents currently in clinical use include vinca alkaloids [Rowinsky, E. K.; Donehower, R. C. The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapeutics.
Pharmacol. Ther
. 1992, 52, 35-84], which inhibit microtubule polymerization, and taxoids, which promote microtubule assembly [Verweij, J.; Clavel, M.; Chevalier, B. Paclitaxel (Taxol) and docetaxel (Taxotere): not simply two of a kind.
Ann. Oncol
. 1994, 5, 495-505]. Colchicine is another well-known antimitotic agent; however, being too toxic to be used as anticancer agent, it is used clinically only as an antigout agent [Hastie, S. B. Interactions of colchicine with tubulin.
Pharmacol. Ther
. 1991, 51, 377-401; Brossi,A; Yeh, H. J.; Chrzanowska, M.; Wolff, J.; Hamel, E.; Lin, C. M.; Quinn, F.; Suffness, M.; Silverton, J. Colchicine and its analogues: recent findings. Med. Res. Rev 1988, 8, 77-94].
In recent years, some of the inventors of the present application and their co-workers have designed and synthesized three type of heterocyclic ketones, the 2-phenyl4-qinolones (PQ), 2,3-dihydro-2-phenyl-4-quinolones (DHPQ) and 2-phenyl-1,8-naphthyridin4-ones (PN) as novel antimitotic agents and have established a preliminary structure-activity relationships [Brossi, A.; Yeh, H. J.; Chrzanowska, M.; Wolff, J.; Hamel, E.; Lin, C. M.; Quinn, F.; Suffness, M.; Silverton, J. Colchicine and its analogues: recent findings.
Med. Res. Rev
. 1988, 8, 77-94; Kuo, S. C.; Lee, H. Z.; Juang, J. P.; Lin, Y. T.; Wu, T. S.; Chang, J. J.; Ledniced, D.; Paull, K. D.; Lin, C. M.; Hamel, E.; Lee, K. H. Synthesis and cytotoxicity of 1,6,7,8 and 4′-substituted 2-phenyl-4-quinolones and related compounds: identification as antimitotic agents interacting with tubulin.
J. Med. Chem
. 1993, 36, 1146-1156; Li, L.; Eang, H. K.; Kuo, S. C.; Lednicer, D.; Lin, C. M.; Hamel, E.; Lee, K. H. 2′,3′,4′,5′,5,6,7-Substituted 2-phenyl-4-quinolones and related compounds: their synthesis, cytotoxicity, and inhibition of tubulin polymerization.
J. Med. Chem
. 1994, 37 (8),1126-1135; Li, L.; Wang, H. K.; Kuo, S. C.; Wu, T. S.; Mauger, A.; Lin, C. M.; Hamel, E.; Lee, K. H. Synthesis and biological evaluation of 3′,6′,7-substituted 2-phenyl4-quinolones as antimitotic antitumor agents.
J. Med. Chem
. 1994, 37 (20), 3400-3407;Xia, Y.; Yang, Z. Y.; Xia, P.; Bastow, K. F.; Tachibana, Y.; Kuo, S. C.; Hamel, E.; Hackl, T.; Lee, K. H. Synthesis and biological evaluation of 6,7,2′,3′,4′-substituted-1,2,3,4-tetrahydro-2-phenyl-4-quinolones as a new class of antimitotic agents.
J. Med. Chem
. 1998, 41 (7), 1155-1162; Xia, Y; Yang, Z. Y.; Xia, P.; Bastow, K. F.; Tachibana, Y.; Kuo, S. C.; Hamel, E.; Hackl, T.; Lee, K. H. Synthesis and biological evaluation of 6,7,2′,3′,4′-substituted-1,2,3,4-tetrahydro-2-phenyl-4-quinolones as a new class of antimitotic agents.
J. Med. Chem
. 1998, 41 (7), 1155-1162; Chen, K.; Kuo, S. C.; Hsih, M. C.; Mauger, A.; Lin, C. M.; Hamel, E.; Lee, K. H. 2′,3′,4′,5,6,7-Substituted 2-phenyl-1,8-naphthyridin-4-ones: their synthesis, cytotoxicity, and inhibition of tubulin polymerization.
J. Med. Chem
. 1996, 40 (14), 2266-2275; Chen, K.; Kuo, S. C.; Hsih, M. C.; Mauger, A.; Lin, C. M.; Hamel, E.; Lee, K. H. Synthesis and biological evaluation of substituted 2-aryl-1,8-naphthyridin-4(1H)-ones as antimitotic antitumor agents that inhibit tubulin polymerization.
J. Med. Chem
. 1997, 40 (19), 3049-3056.]. The structures of PQ, DHPQ and PN are shown as follows:
Among these three types of heterocyclic ketones, the common structural feature is a biaryl system composed of A- and C-rings that are linked by an interposed B-ring or sometimes by a hydrocarbon bridge. However, some minor structural differences also exist.
In the PQ system, when functional groups with nonbonding electrons, e.g. —OCH
3
, —O—CH
2
—O—, —NRR′, Cl and F (PQ
1-6
), were placed at the 6-position of the A-ring and the 3′-position of the C-ring, activity was very potent. These two functional groups are about 10 to 11 Å apart, and these two groups possibly may interact with the tubulin binding domain by acting as H-receptors. Thus, they might contribute significantly to the potency of PQ compounds. In the DHPQ system, the 6- and 3′-substituents (DHPQ
1
) also plays a decisive role in activity. However, in the PN system, when the 3′-substituent is fixed (e.g. OCH
3
), the identity of the 6-substituent e.g. H (PN-1), CH
3
(PN-2) or Cl (PN-3), does not noticeably affect activity. This finding is unique to the PN system and differentiates it from the PQ and DHPQ systems. The structures of PQI to PQ6, PN-1 to PN-3 and DHPQ
1
are shown in the followings:
The antitumor activities of 2,3-dihydro-2-aryl-4-quinazolinones (DHPQZ) were reported around 1970 [Yale, H. J.; Kalkstein, M. Substituted 2,3-dihydro-4(1H)-quinazolinones. A new class of inhibitors of cell multiplication.
J. Med. Chem
. 1967, 10, 334-336; Neil, G. L.; Li, L. H.; Buskirk, H. H.; Moxicy, T. E. Antitumor effects of the antisperrnatogenic agent, 2,3-dihydro-2-(1-naphthyl)-4(1H)-quinazolinones.
Cancer Chemother
. 1972,56,163-173]. Amore recent reevaluation of this type of compounds by NCl against human tumor cell lines reconfirmed that, like colchicine, they are effective inhibitors of tubulin polymerization [Hamel, E.; Lin, C. M.; Plowman, J.; Wang, H. K.; Lee, K. H.; Paull, K. D. Antitumor 2,3-dihydro-2-(aryl)-4(1H)-quinazolinone derivatives. Interactions with tubulin.
Biochem. Pharmacol
. 1996, 51, 53-59]. At the same time, 2-styrylquinazolin-4-ones (SQZ) were also identified as potent inhibitors of tubulin polymerization [Jiang, J. B.; Hesson, D. P.; Dusak, B. A.; Dexter, D. L.; Kang, G. J.; Hamel, E. Synthesis and biological evaluation of 2-styryl-quinazolin-4(3H)-ones, a new class of antimitotic anticancer agents which inhibit tubulin polymerization.
J. Med. Chem
. 1990, 33, 1721-1728; Lin, C. M.; Kang, G. J.; Roach, M. C.; Jiang, J. B.; Hesson, D. P.; Luduena, R. F.; Hamel, E. Investigation of the mechanism of the interaction of tubulin with derivatives of 2-styrylquinazolin-4(3H)-one.
Mol. Pharmacol
. 1991, 40, 827-832.]. DHPQZ and SQZ compounds have the following structures:
SUMMARY OF THE INVENTION
The present invention synthesizes compounds having the structures of the following formulas (I) to (IV):
wherein
R
2′
, R
3′
, R
4′
, and R
5′
independently are H, (CH
2
)
n
CH
3
, OH, O(CH
2
)
n
CH
3
, X, or NR
8
R
9
, wherein n is an integer of 0~4, X is F, Cl, or Br, and R
8
and R
9
independently are H or (CH
2
)
n
CH
3
, wherein n is defined as above;
R is (CH
2
)
n
CH
3
or (CH
2
)
n
COO(CH
2
)
n
CH
3
, wherein n is defined as above; and
R
6
and R
7
independently are H, (CH
2
)
n
CH
3
, OH, O(CH
2
)
n
CH
3
, X, NR
8
R
9
,
or R
6
and R
7
together is —OCH
2
O—, wherein n, X, R
8
and R
9
are defined as above.
The compounds (I) and (II) were evaluated for cytotoxicity and as inhibitors of tubulin polymerization in the present invention. Some of them show potent cytotoxicity against a panel of human tumor cell lines and show potent inhibition of tubulin polymerization, and thus have great potential to be used as a therapeutically effective component in a pharmaceutical composition for treating cancer.
The compounds (III) and (IV) were found potent in inhibiting aggregation of platelet in the present inve

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