Topoisomerase inhibitors

Details Topoisomerase inhibitors Topoisomerase inhibitors

2001-09-27

2004-01-13

Kifle, Bruck (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

Reexamination Certificate

active

06677450

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to sugar derivatives of indolopyrrolocarbazoles which exhibit topoisomerase I activity and are useful in inhibiting the proliferation of tumor cells.
BACKGROUND
Topoisomerases are vital nuclear enzymes which function to resolve topological dilemmas in DNA, such as overwinding, underwinding and catenation, which normally arise during replication, transcription and perhaps other DNA processes. These enzymes allow DNA to relax by forming enzyme-bridged strand breaks that act as transient gates or pivotal points for the passage of other DNA strands. Topoisomerase-targeting drugs appear to interfere with this breakage-reunion reaction of DNA topoisomerases. In the presence of topoisomerase active agents, an aborted reaction intermediate, termed a ‘cleavable complex’, accumulates and results in replication/transcription arrest, which ultimately leads to cell death.
The development of topoisomerase I active agents therefore offers a new approach to the multi-regimental arsenal of therapies currently used in the clinic for the treatment of cancer. An article in
Cancer Chemother. Pharmacol
[1994, 34 (suppl): S 41-S 45] discusses topoisomerase I active compounds that are in clinical studies and these have been found to be effective clinical anti-tumor agents. Structurally these clinical candidates are related to the alkaloid camptothecin.
Indolo[2,3-a]carbazole derivatives related to the Rebeccamycin class are disclosed (EP Appl. 0 545 195 B1 and 0,602,597 A2
; Cancer Research
1993, 53, 490-494; ibid 1995, 55, 1310-1315) and claimed to exhibit anti-tumor activity; however the major mechanism of action of these derivatives may not be like camptothecin, which acts as a topoisomerase I poison.
Indolo[2,3-a]carbazole alkaloids such as rebeccamycin (U.S. Pat. Nos. 4,487,925 and 4,552,842) and its water-soluble, clinically-active analog, 6-(2-diethylaminoethyl)rebeccamycin (U.S. Pat. No. 4,785,085), are useful antitumor agents which target DNA. Furthermore, fluoroindolocarbazoles such as described in WO 98/07433 are antineoplastic agents with topoisomerase I inhibitory activity. Indolocarbazoles are also disclosed (WO 9530682) and claimed to exhibit anti-tumor activity. Hudkins, et al. have disclosed a series of fused pyrrolocarbazoles (WO 96/11933 and U.S. Pat. No. 5,475,110) and showed in vitro biological data such as inhibition of neuronal choline acetyltransferase (ChAT) and protein kinase C (PKC) inhibition for some compounds. U.S. Pat. No. 5,468,849 discloses certain fluororebeccamycin analogs as useful antitumor agents, along with a process for their production by fluorotryptophan analog feeding of a rebeccamycin-producing strain of
Saccharothrix aerocolonigenes
, preferably
Saccharothrix aerocolonigenes
C38,383-RK2 (ATCC 39243). Glicksman, et al. disclose indolocarbazole alkaloids (U.S. Pat. No. 5,468,872) which are different in structure from those of the present invention. Kojiri, et al. disclose indolopyrrolocarbazoles having a dissacharide substituent (WO 96/04293). Weinreb, et al. (
Heterocycles
1984, 21, 309) and Kleinschroth, et al. (U.S. Pat. No. 5,043,335) have disclosed indolopyrrolocarbazole derivatives with a bridging furan moiety and McCombie, et al. (
Bioorg. Med. Chem. Lett
. 1993, 3, 1537) have reported a more functionalized bridged furan. Wood, et al. have reported the total synthesis of (+)−K252a (
J. Am. Chem. Soc
. 1995, 117, 10413), a related, naturally-occurring indolocarbazole alkaloid which has demonstrated PKC inhibitory activity. During the course of their total synthesis of (+)−K252a, Fukuyama, et al. (
J. Am. Chem. Soc
. 1999, 121, 6501) have also described the isolation of a cycloglycoside as an undesired product.
Danishefsky, et al., during the course of their first total synthesis of staurosporine (
J. Am. Chem. Soc
. 1996, 118, 2825), describe the synthesis of an intermediate N12, N13-bridged indolopyrrolocarbazole. Indolocarbazole derivatives with the nitrogens linked by a three-atom bridge have been reported to be potent PKC inhibitors (S. F. Vice, et al.
Bioorg. Med. Chem. Lett
. 1994, 4, 1333). The synthesis of simple indolocarbazole derivatives with C1′, C-5′-bridging or C1′, C3′-bridging glycosides have also been reported in the literature (B. M. Stolz, J. L. Wood
Tetrahedron Lett
. 1995, 36, 8543 and B. B. Shankar, S. W. McCombie
Tetrahedron Lett
. 1994, 35, 3005, respectively). Prudhomme, et al. disclose a series of antitumor indolocarbazoles derived from rebeccamycin which exhibit a carbohydrate attached to the two indole nitrogens, and reported their cytotoxicity and their topoisomerase I and PKC inhibitory activities to be in the millimolar to micromolar range (
Bioorg. Med. Chem
. 1998, 6, 1597). Despite these examples, there remains a need for novel and potent cytotoxic compounds useful for inhibiting topoisomerase I activity.
SUMMARY OF THE INVENTION
Thus according to a first embodiment of the first aspect of the present invention are provided compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof, useful for inhibiting topoisomerase I and the proliferation of tumor cells
wherein
Z is selected from the group consisting of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E), Formula (F) and Formula (G)
R is hydrogen, OH, OC
1-7
alkyl, NH
2
, N(C
1-3
alkyl)
2
, or C
1-7
alkyl, wherein said C
1-7
alkyl or C
1-3
alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, SR
9
, OR
9
and NR
9
R
10
;
R
1
, R
2
, R
3
, R
4
and R
5
are each independently selected from the group consisting of hydrogen, C
1-7
alkyl, C
3-7
cycloalkyl, halogen, azido, NR
9
R
10
, NHC(O)NR
9
R
10
, NHC(O)OR
9
, C(O)OR
9
, SR
9
and OR
9
, wherein said C
1-7
alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, SR
9
, OR
9
and NR
9
R
10
;
provided that no more than two of the variables selected from the group consisting of R
1
, R
2
, R
3
, R
4
and R
5
may be C
3-7
cycloalkyl, azido, NHC(O)NR
9
R
10
or NHC(O)OR
9
;
R
7
and R
8
are independently OH or H or R
7
and R
8
together form ═O;
R
9
and R
10
are independently selected from the group consisting of hydrogen, C
1-7
alkyl and C
3-7
cycloalkyl, wherein said C
1-7
alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, O—C
1-7
alkyl, NH
2
and N(C
1-3
alkyl)
2
; or
R
9
and R
10
together with the nitrogen atom to which they are attached form a non-aromatic 5-8 membered heterocycle containing one or two of the same or different heteroatoms selected from the group consisting of O, N and S;
m is 0 or 1; and
X
1
, X
1′
, X
2
and X
2′
are independently selected from the group consisting of hydrogen, halogen, cyano, OR
9
, —CF
3
, alkylcarbonyl, C-
1-7
alkyl, nitro, alkoxyaminoalkyl, NR
9
R
10
, SR
9
and C(O)OR
9
; wherein said C
1-7
alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR
9
, SR
9
and NR
9
R
10
.
According to a first embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein Z is selected from the group consisting of Formula (A), Formula (C) and Formula (D).
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein Z is formula (A).
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein Z is formula (B).
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein Z is formula (C).
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein Z is formula (D).
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I)

Affiliated with

Also associated with

Rating

Topoisomerase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Topoisomerase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Topoisomerase inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3265182