Aza-benzothiopyranoindazoles with antitumor activity

Details Aza-benzothiopyranoindazoles with antitumor activity Aza-benzothiopyranoindazoles with antitumor activity

2002-03-12

2004-06-08

Barts, Samuel (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S248000, C514S224200, C546S064000, C546S063000, C544S233000, C544S247000, C548S358500

Reexamination Certificate

active

06747039

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a group of aza-benzothiopyranoindazole compounds having antitumor activity, and processes for their preparation.
BACKGROUND OF THE INVENTION
Cellular Proliferation and Cancer.
The disruption of external or internal regulation of cellular growth can lead to uncontrolled proliferation and in cancer, tumor formation. This loss of control can occur at many levels and, indeed, does occur at multiple levels in most tumors. Further, although tumor cells can no longer control their own proliferation, they still must use the same basic cellular machinery employed by normal cells to drive their growth and replication.
Aza-Benzothiopyranoindazoles Antitumor Agents.
Certain 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones have been reported which show antitumor activity in clinical trials. Of particular interest has been ametantrone, 1,4-bis[(2-(2-hydroxyethylamino)ethyl)amino]anthracene-9,10-dione and mitoxantrone, 5,8-dihydroxy-1,4-bis[(2-(2-hydroxyethylamino)ethyl)amino]anthracene-9,10-dione (Zee-Cheng et al., “Antineoplastic Agents. Structure-Activity Relationship Study of Bis(substituted aminoalkylamino)anthraquinones,”
J. Med. Chem.
21:291-294 (1978); and Cheng et al., “Progress in Medicinal Chemistry”, Ellis, G. P. and West, G. B., Elsevier: Amsterdam, vol. 202, p. 83 (1983)).
Mitoxantrone is a broad-spectrum oncolytic agent, whose activity is similar to that of the anthracyclines antibiotic doxorubicin. Clinical trials have demonstrated a diminish cardiotoxicity in comparison to doxorubicin. Both mitoxantrone and ametantrone have remarkable myelodepressive toxicity and both compounds show cross-resistance to cell histotypes developing resistance against doxorubicin mediated by overexpression of glycoprotein P (also known as multidrug resistance).
In an attempt to overcome the above-mentioned drawbacks, some chromophore modified anthracendiones have been reported.
Blanz et al.,
J. Med. Chem.
6:185-191 (1963) discloses the synthesis of a series of thioxanthenones related to lucanthones and the results of the testing of the compounds against leukemia and two solid tumors. Among the compounds disclosed are:
where R is methyl, methoxyl, and ethoxyl.
Yarinsky et al.,
J. Trop. Med.
&
Hyg.
73:23-27 (1970) discloses
as an antischistosomal agent.
Palmer et al., “Potential Antitumor Agents. 54. Chromophore Requirements for in vivo Antitumor Activity Among the General Class of Linear Tricyclic Carboxamides,”
J. Med. Chem.
31(4):707-712 (1988) discloses N-[2-(dimethylamino)ethyl-]-9-oxo-9H-thioxanthene-4-carboxamide monohydrochloride which was tested in vitro versus murine leukemia (L1210) and in vivo versus P388 leukemia cells and was found to be “unlikely to worth pursuing” as a potential antitumor agent.
U.S. Pat. No. 4,539,412 to Archer discloses compounds of the formula:
where for X═S: R
1
and R
2
are individually selected from one of lower-alkyls, and jointly selected from one of pyrolidinyl, piperidinyl, morpholinyl, piperazinyl and N-substituted piperazinyl; and R
3
is hydroxy. The compounds are said to be useful as antitumor agents.
However, the search for newer active analogues is still highly desirable. WO 94/06795 describes aza-thiopyranopyridine derivatives which are endowed with antitumor activity. WO 98/49172 to Krapcho discloses compounds of the formula:
where one of X, Y, or T is nitrogen (═N—) and the others are ═CH—; D is selected from the group consisting of C
1
-C
4
alkyl, nitro or —NH—A, where A is on its turn is selected from the group consisting of hydrogen, —CO—, CH
2
—NR
2
R
3
and alkyl. B is selected in the group consisting of C
1
-C
10
alkyl having one or two substituents selected from the group consisting of OR
1
and —NR
2
R
3
. These compounds have antitumor activity against human leukemias and solid tumors sensitive to treatment with mitoxantrone and antitumor antibiotics, such as doxorubicin.
Aza-derivatives of lucanthone have also been described. For example, M. Croisy-Delcey et al., “Aza Analogues of Lucanthone: Synthesis and Antitumor and Bactericidal Properties,”
J. Med. Chem.
26(9):1329-1333 (1983) and Blanz et al.,
J. Med. Chem.
6:185-191 (1963) describe the following compounds, respectively:
where R is an aminoalkyl chain and, in (2), one of X or Y is nitrogen and the other is carbon. In both the cases these compounds showed little, if any, antitumor activity.
U.S. Pat. No. 5,346,917 to Miller et al. discloses compounds of the formula:
where n is 2 or 3; R is hydrogen, C(O)H, C(O)R
3
, SO
2
R
3
and C(O)OR
3
; R
1
and R
2
are independently hydrogen or lower alkyl; and R
9
is hydrogen, lower-alkyl; lower-alkoxy, or hydroxy.
In addition, European Patent Application No. 127,389 to Elslager et al. discloses N,N, diethyl-5-methyl-2H-[1]-benzothiopyrano[4,3,2-cd]indazole-2-ethanamine which is stated to be useful as an antitumor agent.
European Patent Application No. 284,966 to Beylin et al. discloses a process for preparing compounds of the formula:
where X is oxygen, sulfur or selenium; D and D′ may be the same or different and are a straight or branched alkylene group of from two to five carbon atoms; R
1
and R
2
may be the same or different and are hydrogen or an alkyl group of from two to eight carbon atoms which may be substituted by hydroxy; R
3
, R
4
, R
5
and R
6
may be the same or different and are hydrogen or hydroxy; or a pharmaceutically acceptable salt thereof. The compounds are stated to possess antibacterial, antifungal and antineoplastic activity. A similar disclosure is found in Beylin et al.,
J. Heterocyclic Chem.
28:517-527 (1991).
U.S. Pat. No. 3,505,341 to Elslager et al. discloses compounds of the formula:
where A is an alkylene radical containing 2 to 4 carbon atoms; Q is a hydrogen or halogen atom; R
1
and R
2
are the same or different and represent C
1
-C
4
alkyl or together with the nitrogen atom [—N(R
1
)R
2
] a lower alkylene radical containing 4 to 8 carbon atoms, 4 to 6 of which are joined in a ring with the nitrogen atom; and W is the aldehyde group —CHO or a methyl or hydroxymethyl group. The compounds are stated to possess antiparasitic and antibacterial activity.
U.S. Pat. No. 3,963,740 to Elslager discloses compounds of the formula:
where A is an alkylene radical containing 2 to 4 carbon atoms. R
1
and R
2
are the same or different and represent C
1
-C
4
alkyl or together a lower-alkylene radical containing 4 to 8 carbon atoms, 4 to 6 of which are joined in ring with the nitrogen atom; and W is methyl, hydroxymethyl, or acyloxymethyl where said acyl fragment contains from one to eight carbon atoms; Y is S or O; and one of Q and R is hydrogen and the other is selected from hydrogen and a substituted halo or alkoxy group having one to four carbon atoms. The compounds are stated to be intermediates in the preparation of the corresponding N-oxide derivative which are stated to be useful as parasiticidal agents. A similar disclosure is found in U.S. Pat. No. 4,026,899 to Elslager.
Blanz et al.,
J. Med. Chem.
6:185-191 (1963) discloses 5-methyl-2H-[1]benzothiopyrano[4,3,2-cd]indazole (example 39) which was tested and found to be inactive as an antitumor agent.
Showalter et al., “Benzothiopyranoindazoles, A New Class of Chromophore Modified Anthracenedione Anticancer Agents. Synthesis and Activity Against Murine Leukemias,”
J. Med. Chem.
31(8):1527-1538 (1988) discloses the synthesis and anticancer activity of a series of substituted 5-amino-2H-[1]benzothiopyrano[4,3,2-cd]indazol2-2-ethanamine.
Baily et al.,
Biochem.
32:5985-5993 (1993) discloses compounds of the formula:
where R
1
═Cl and R
2
═CH
3
; R
1
═Cl and R
2
═CH
2
OH. The compounds are stated to exhibit antitumor activity.
Gordon et al., “Antimuscarinic Activities of Hycanthone Analogs: Possible Relationship with Animal Toxicity,”
J. Pharm. & Exp. Ther.
236(1):85-89 (1986) discloses N,N-diethyl-5-methyl-8-chloro-2H-&l

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