Anhydro sugar derivatives of indolocarbazoles

Details Anhydro sugar derivatives of indolocarbazoles Anhydro sugar derivatives of indolocarbazoles

2003-05-07

2004-02-03

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S416000

Reexamination Certificate

active

06686385

ABSTRACT:

FIELD OF THE INVENTION
The present invention describes sugar derivatives of indolocarbazoles 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, undewinding 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 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 alkaloids such as rebeccamycin (U.S. Pat. No. 4,487,925 and U.S. Pat. No. 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 have been disclosed in WO 98/07433 to act as antineoplastic agents with topoisomerase I inhibitory activity.
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. Other indolocarbazoles related to those mentioned above are disclosed in WO 95/30682 and are claimed to exhibit anti-tumor activity.
Hudkins, et al. 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 rebeccamiycin-producing strain of
Saccharothrix aerocolonigenes
, particularly
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) which are not related to the anhydrosugar indolocarbazoles. 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. Similarly, Wood, et al. have reported the total synthesis of (+)-K252a (
J. Am. Chem. Soc
. 1995, 117, 10413), a related, naturally-occuring indolocarbazole alkaloid which has demonstrated PKC inhibitory activity.
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, 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). There is yet 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:
R is hydrogen, OH, OC
1-7
alkyl, NH
2
, N(C
1-3
alky1)
2
or C
1-7
alkyl, wherein said C
1-7
alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR
9
and NR
9
R
10
;
Q is O, S, CH
2
or NR
5a
;
R
5
and R
5a
are each independently selected from the group consisting of hydrogen, Formula (A), Formula (B), Formula (C) and Formula (D):
 provided that
if Q is NR
5a
, then either R
5
or R
5a
must be hydrogen;
R
1
, R
2
, R
3
and R
4
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, OR
9
, SR
9
and NR
9
R
10
;
or R
1
and R
2
together form ═N—OH, ═O or —NR
9
R
10
;
or R
3
and R
4
together form ═N—OH, ═O or —NR
9
R
10
;
W is 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
, N—OH, O 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, OR
9
and NR
9
R
10
;
R
7
and R
8
are independently OH or H or 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; 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, 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 another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein R
5a
is not H.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein R
5a
is formula (C ) or (A).
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein R
5
is formula (A).
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein R
5
is formula (B).
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein R
5
is formula (C).
Accord

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