Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-30
2002-01-08
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S043000, C549S044000, C549S045000, C549S048000
Reexamination Certificate
active
06337346
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns naphtho and dihydrobenzo-thiophene derivatives, which are active as antitumor agents and in inhibiting cellular mitosis, along with pharmaceutical formulations containing the same.
BACKGROUND OF THE INVENTION
Many naturally occurring substituted anthraquinone and naphthoquinones possess cytotoxic antileukemic activities (Zee-Cheng P. et al.,
J. Med. Chem
. 1979, 22, 501-505; Chang, P., Lee, K. H.
Phytochemistry
. 1984, 23, 1733-1736; T. Hayashi, F. Smith, and K. H. Lee, K. H.
J. Med. Chem
. 1987, 30, 2005-2008). In addition, the natural furanonaphthoquinones 1 and 2 and their synthetic analog 3 (see figures below) show potent cytotoxicity against KB cells with ED
50
values of 1.0, 2.0, and 0.3 &mgr;g/mL, respectively (Rao, M. M.; Kingston, D. G. I.
J. Nat. Prod
. 1982, 45, 600-604).
The unsubstituted thiophene derivative naphtho[2,3-b]thiophene-4,9-dione (4) also was found to be cytotoxic against KB cells with an ED
50
value of 1.4 &mgr;g/mL (Goncalves, R.; Brown, E. V. J.
Org. Chem
. 1952, 17, 698-704; Weinmayr, V. U.S. Pat. No. 2,497,334 1950; Weinmayr, V.
J. Am. Chem. Soc
. 1952, 74, 4353-4357; Carruthers, W.; Douglas, A. G.; Hill, J.
J. Chem. Soc
. 1962, 704-708; Carruthers, W.
J. Chem. Soc
. 1963, 4477-4483; Tagawa, H.; Ueno, K.
Chem. Pharm. Bull
. 1978, 26, 1384-1393; Huang, L. J.; Kuo, S. C.; Perng, C. Y.; Chao, Y. H.; Wu, T. S.; McPhail, A. T.; Cheng, H. H.; Lee, K. H. Bioorg & Med. Chem. Letters, submitted.) Introduction of a lipophilic acetyl group gave 2-acetyl naphtho[2,3-b]thiophene-4,9-dione (5) with enhanced cytotoxicity (ED
50
=0.4 &mgr;g/mL)(Huang, L. J.; Kuo, S. C.; Perng, C. Y.; Chao, Y. H.; Wu, T. S.; McPhail, A. T.; Cheng, H. H.; Lee, K. H. Bioorg & Med. Chem. Letters, submitted).
SUMMARY OF THE INVENTION
A first aspect of the present invention is a compound selected from the group consisting of compounds of Formula I and compounds of Formula II:
wherein:
R
1
, R
2
, R
3
and R
4
are each independently selected from the group consisting of:
hydrogen, alkyl, carboxy, alkoxy, hydroxyalkyl, alkylcarbonyl; alkylcarbonyloxy; alkyl substituted with alkylcarbonyloxy, thiophenylcarbonyl; nitro and cyano;
thiophenyl and thiophenylthiophenyl, each of which may be unsubstituted or substituted with alkyl, carboxy, alkoxy, hydroxyalkyl, alkylcarbonyl; alkylcarbonyloxy; alkyl substituted with alkylcarbonyloxy, nitro or cyano;
subject to the proviso that at least one of R
1
, R
2
, R
3
and R
4
is not hydrogen;
A
1
and A
2
are each selected from the group consisting of: ═O, alkyl, alkoxy, and alkylcarbonyloxy;
and the pharmaceutically acceptable salts thereof.
Note that, When A
1
and A
2
are ═O, the center ring has only two, and not three, double bonds, as shown in Formula Ia and IIa below.
In a preferred embodiment of the foregoing, at two or (most preferably) three of R
1
, R
2
, R
3
and R
4
are hydrogen.
A second aspect of the present invention is a compound according to Formula III:
wherein:
R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are each independently selected from the group consisting of:
hydrogen, alkyl, carboxy, alkoxy, hydroxyalkyl, alkylcarbonyl, alkylcarbonyloxy, alkyl substituted with alkylcarbonyloxy, thiophenylcarbonyl; nitro and cyano;
thiophenyl and thiophenylthiophenyl, each of which may be unsubstituted or substituted with alkyl, carboxy, alkoxy, hydroxyalkyl, alkylcarbonyl, alkylcarbonyloxy, alkyl substituted with alkylcarbonyloxy, nitro or cyano;
subject to the proviso that at least one of R
1
, R
2
, R
3
and R
4
is not hydrogen;
and the pharmaceutically acceptable salts thereof.
A further aspect of the present invention is a composition comprising an effective antitumor amount of a compound of Formula I, II or III above, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
A further aspect of the present invention is a method for treating a tumor, the method comprising administering to a subject in need of treatment a compound of Formula I, II or III above, or a pharmaceutically acceptable salt thereof, in an amount effective to treat said tumor.
A still further aspect of the present invention is a method for inhibiting cellular mitosis, said method comprising contacting a cell with a compound of Formula I, II or III above, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cellular mitosis.
A still further aspect of the present invention is the use of a compound of Formula I, II or III above, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for carrying out the methods described above.
DETAILED DESCRIPTION OF THE INVENTION
The term “alkyl” as used herein, inidividually or as a portion of another substituent term such as “alkoxy”, refers to C1 to C4 alkyl, which may be linear or branched, and saturated or unsaturated. Preferably, the alkyl is saturated, and preferably the alkyl is linear.
The term “halogen” or “halo” as used herein refers to fluorine, chlorine, bromine, iodine, etc., or fluoro, chloro, bromo, iodo, etc., respectively.
Compounds of the present invention can be made in accordance with known techniques, or variations thereof which will be apparent to those skilled in the art in given the Examples set forth below.
Specific examples of compounds of Formula I and II are compounds of Formula Ia and compounds of Formula IIa:
wherein:
R
1
, R
2
, R
3
and R
4
are each independently selected from the group consisting of:
hydrogen, alkyl, carboxy, alkoxy, hydroxyalkyl, alkylcarbonyl, alkylcarbonyloxy, alkyl substituted with alkylcarbonyloxy, thiophenylcarbonyl; nitro and cyano;
thiophenyl and thiophenylthiophenyl, each of which may be unsubstituted or substituted with alkyl, carboxy, alkoxy, hydroxyalkyl, alkylcarbonyl, alkylcarbonyloxy, alkyl substituted with alkylcarbonyloxy, nitro or cyano;
subject to the proviso that at least one of R
1
, R
2
, R
3
and R
4
is not hydrogen;
and the pharmaceutically acceptable salts thereof.
Additional examples of compounds of Formulas I and II are compounds of Formula Ib and compounds of Formula IIb:
wherein:
R
1
, R
2
, R
3
and R
4
are each independently selected from the group consisting of:
hydrogen, alkyl, carboxy, alkoxy, hydroxyalkyl, alkylcarbonyl, alkylcarbonyloxy; alkyl substituted with alkylcarbonyloxy, thiophenylcarbonyl, nitro and cyano;
thiophenyl and thiophenylthiophenyl, each of which may be unsubstituted or substituted with alkyl, carboxy, alkoxy, hydroxyalkyl, alkylcarbonyl, alkylcarbonyloxy, alkyl substituted with alkylcarbonyloxy, nitro or cyano;
subject to the proviso that at least one of R
1
, R
2
, R
3
and R
4
is not hydrogen;
A
1
and A
2
are each selected from the group consisting of alkyl, alkoxy, and alkylcarbonyloxy;
and the pharmaceutically acceptable salts thereof.
Thiophenyl and thiophenylthiophenyl substituents that may be used to carry out the present invention include those having the structures:
where R
7
is the same as given in connection with R
1
through R
4
above.
Compounds illustrative of Formulas I and II above (along with the reference numbers assigned to these compounds in Examples 1-13 below), are:
2-Acetyl-4,8-dihydrobenzo[1,2-b:4,5-b′]dithiophene-4,8-dione (9);
2-(1′-Hydroxyethyl)-4,8-dihydrobenzo[1,2-b:4,5-b′]dithiophene-4,8-dione (10);
2-(1′-Acetoxyethyl)-4,8-dihydrobenzo[1,2-b:4,5-b′]dithiophene-4,8-dione (11);
2,7-Diacetyl-4,8-dihydrobenzo[1,2-b:4,5-b′]dithiophene-4,8-dione (13);
2,7-Bis(1′-hydroxyethyl)-4,8-dihydrobenzo[1,2-b:4,5-b′]dithiophene-4,8-dione (14);
2,7-Bis(1′-acetoxyethyl)-4,8-dihydrobenzo[1,2-b:4,5-b′]dithiophene-4,8-dione (15);
2-Acetyl-4,8-dihydrobenzo[1,2-b:5,4-b′]dithiophene-4,8-dione(19);
2-(1′-Hydroxyethyl)-4,8-dihydrobenzo[1,2-b:5,4-b′]dithiophene-4,8-dione (20);
2-(1′-Acetoxyethyl)-4,8-dihydrobenzo[1,2-b:5,4-b′]dithiophene-4,8-dione (21);
Kuo Sheng-Chu
Lee Kuo-Hsiung
Lambkin Deborah C.
Myers Bigel & Sibley & Sajovec
University of North Carolina at Chapel Hill
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