Tumor proliferation inhibitors

Details Tumor proliferation inhibitors Tumor proliferation inhibitors

2001-09-25

2003-11-25

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S042000, C436S018000, C436S022000, C436S027000, C436S028000

Reexamination Certificate

active

06653290

ABSTRACT:

FIELD OF THE INVENTION
The present invention describes substituted 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 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 (WO 98/07433) have been disclosed 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. Related indolocarbazoles are also disclosed (WO 95/30682) 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 reported in vitro biological activity 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), while Kojiri, et al. disclose indolopyrrolocarbazoles having a dissacharide substituent (WO 96/04293). Mazur and Hiller report the synthesis of simple 5-hydroxymethyl glycosides (
J. Org. Chem.
1997, 62, 4471), while Danishefsky, et al (
J. Am. Chem. Soc.
1996, 118, 2825) describe the synthesis of 5-methoxy substituted sugar derivatives. Despite these reports, there remains the 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,
X
1
, X
1′
, X
2
and X
2′
are independently selected from the group consisting of hydrogen, halogen, cyano, OR
6
, —CF
3
, alkylcarbonyl, C-
1-7
alkyl, nitro, NR
6
R
7
, SR
6
and C(O)OR
6
; wherein said C
1-7
alkyl is optionally substituted with one or more sub stituents selected from the group consisting of halogen, CN, SR
6
, OR
6
and NR
6
R
7
;
Z is selected from the group consisting of NH, O and S;
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 is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, SR
6
, OR
6
and NR
6
R
7
;
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
6
R
7
, NHC(O)NR
6
R
7
, NHC(O)OR
6
, C(O)OR
6
, SR
6
and OR
6
, wherein said C
1-7
alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, SR
6
, OR
6
and NR
6
R
7
; and
R
5
is selected from the group consisting of C
1-7
alkyl, C
3-7
cycloalkyl, halogen, azido, NR
6
R
7
, NHC(O)NR
6
R
7
, NHC(O)OR
6
, C(O)OR
6
, SR
6
and OR
6
, wherein said C
1-7
alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, SR
6
, OR
6
and NR
6
R
7
; and
R
6
and R
7
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, OC
1-3
alkyl, NH
2
or N(C
1-3
alkyl)
2
; or
R
6
and R
7
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.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein R is hydrogen.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein Z is NH.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein X
1
, X
1′
, X
2
and X
2′
are each F.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein X
2′
and X
2
are each F and X
1
and X
1′
are each H.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein X
2
is F and X
2′
, X
1
and X
1′
are each H.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein X
2′
is F and X
2
, X
1
and X
1′
are each H.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) wherein R
1
, R
2
, R
3
, R
4
and R
5
are independently selected from the group consisting of H, OH, F, azido and amino.
Other embodiments of the first aspect of the present invention provide compounds of Formula (I) comprising two or more of the above embodiments of the first aspect suitably combined.
Embodiments of a second aspect of the present invention provide a method for inhibiting tumor growth in a mammalian host which comprises the administration to said host of a tumor-growth inhibiting amount of a compound of the present invention as defined in the embodiments of the first aspect of the invention.
Embodiments of a third aspect of the present invention provide a method for inhibiting tumor growth in a mammalian host which comprises the administration to said host of a tumor-growth inhibiting amount of a pharmaceutical formulation of a compound of the present invention as defined in the embodiments of the first aspect of the invention.
Other embodiments and aspects of the invention will be apparent according to the description provided below.
DETAILED DESCRIPTION OF THE INVENTION
The description of the invention herein should be construed in congruity with the laws and principals of chemical bonding. An embodiment or aspect which depends from another embodiment or aspect, will describe only the variables having values and provisos that differ from the embodiment

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