Indolopyrrolocarbazole derivatives and antitumor agents

Details Indolopyrrolocarbazole derivatives and antitumor agents Indolopyrrolocarbazole derivatives and antitumor agents

2002-03-11

2004-03-09

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S027000, C536S017700, C536S018700, C536S027100, C536S028100

Reexamination Certificate

active

06703373

ABSTRACT:

TECHNICAL FIELD
This invention is useful in the pharmaceutical field, and, more detailedly, relates to novel indolopyrrolocarbazole derivatives inhibiting growth of tumor cells and exerting antitumor effect, and their use as antitumor agents.
BACKGROUND ART
Many compounds are already put to practical use as pharmaceuticals in the field of tumor chemotherapy. However, their effects are not always sufficient against various kinds of tumors, and the problem of resistance of tumor cells to these drugs also makes the methods of clinical use complicate (see, Proceedings of the 47th Annual Meeting of Japan Cancer Society, pages 12-15, 1988).
Under the circumstances, development of novel anticancer substances is always desired in the field of cancer treatment. Particularly, there is need for substances overcoming resistance to existing carcinostatic substances and showing effectiveness against cancers on which existing carcinostatic substances cannot exert sufficient effect.
Under these present circumstances, the present inventors have widely screened metabolites of microorganisms, and as a result, they found a novel compound BE-13793C (12,13-dihydro-1,11-dihydroxy-5H-indolo[2.3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione) having antitumor activity (see, EP-A2-0388956).
Thereafter, they have tried to create compounds having further excellent antitumor activity by chemically modifying BE-13793C, and disclosed such compounds in prior patent applications and patents (EP-A1-0528030, U.S. Pat. Nos. 5,591,842, 5,668,271 and 5,804,564, WO95/30682 and WO96/04293).
U.S. Pat. No. 5,668,271 discloses a wide range of compounds having antitumor activity, including compounds wherein R
1
(or R
2
) is 1) a C
1
-C
6
alkyl group substituted by a C
6
-C
12
aromatic hydrocarbon group; or 2) a 5- or 6-membered nonaromatic or aromatic heterocyclic group. The compounds of the present invention have a —(CH
2
)m-R group (wherein R represents a substituted or unsubstituted group selected from pyridyl, furyl or thienyl) bound to the exocyclic nitrogen instead of R
1
(or R
2
). Furthermore, as disclosed in the instance application, the compounds of the invention have much better antitumor effects than the analogous compounds generically and specifically disclosed in U.S. Pat. No. 5,668,271.
Although, in the structural formula shown in Example 35 of the above U.S. Pat. No. 5,668,271, a group corresponding to —(CH
2
)
m
—R in the compounds of the present invention is shown as a 2-pyridylmethyl group, this group should be read a 2-pyridylcarbonyl group. This is apparent from that &agr;-picolinohydrazide is used as a reactant.
Compounds disclosed in the above-mentioned other prior applications and patents are further remoter in structure from the compounds of the present invention. Namely, EP-A1-0528030 solely discloses compounds wherein a group correspoding to —NH—(CH
2
)
m
—R in the compounds of the present invention is H. U.S. Pat. No. 5,591,842 discloses compounds wherein groups corresponding to —(CH
2
)
m
—R and H bound to N in the compounds of the present invention are R
1
and R
2
and the R
1
and R
2
include comprehensive groups, but as compounds closest to the compounds of the present invention, only compounds wherein R
1
and R
2
are C
1
-C
6
alkyl groups substituted with a C
6
-C
12
aromatic hydrcarbonic group, or furyl, thienyl or pyridyl groups (one of R
1
and R
2
can be H) are disclosed. U.S. Pat. No. 5,804,564 and WO95/30682 solely disclose compounds wherein a group corresponding to —(CH
2
)
m
—R in the compounds of the present invention is a bis(hydroxymethyl)methyl group. WO96/04293 discloses compounds wherein a group corresponding to —NH(CH
2
)
m
—R in the compounds of the present invention is R
1
and this R
1
includes comprehensive groups, but compounds close to the compounds of the present invention are not found and, further, a group corresponding to G in the compounds of the present invention is a disaccharide group.
Some of the compounds of the present invention, namely compounds wherein R is a pyridyl, furyl or thienyl group each having a substituent are disclosed in JP-A-10-245390 (published on Sep. 14, 1998), the inventors of which are the applicants of the present application. The JP-A application has not yet been examined and applications to other countries corresponding thereto have not been made except the present application.
From the above, in relation with the above-mentioned background art, the invention of the present application are believed not to be considered at least as an object of rejection under 35 U.S.C. §102 (B) and (D).
DISCLOSURE OF INVENTION
It is a problem to be solved in the present invention to create compounds having further excellent antitumor activity by chemically modifying indolopyrrolocarbazole antitumor substances disclosed in the prior patent applications.
For solving the above problem, the present inventors have synthesized a wide range of indolopyrrolocarbazole derivatives and examined their antitumor or activity, and found that compounds represented by the later-described formula [I] show further excellent antitumor activity than the indolopyrrolocarbazole compounds disclosed in the prior applications, and completed the present invention.
Namely, the invention relates to a compound represented by the formula or a pharmaceutically acceptable salt thereof
wherein R represents an unsubstituted pyridyl, furyl or thienyl group, or a pyridyl, furyl or thienyl group each of which has one or more substituents selected from the group consisting of a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group and a hydroxy lower alkenyl group except that when the pyridyl, furyl or thienyl group has a lower alkoxy group as a substituent, each of which simultaneously has another substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group and a hydroxy lower alkenyl group, m represents an integer of 1 to 3, and G represents a &bgr;-D-glucopyranosyl group, and the positions of substitution of the hydroxyl groups on the indolopyrrolocarbazole ring are the 1- and 11-positions, or the 2- and 10-positions, and a use thereof as an antitumor agent.
BEST MODE FOR CARRYING OUT THE INVENTION
In the definition of the substituents in the compounds of the invention represented by the formula [I], lower alkoxy groups represent straight-chain or branched alkoxy groups having 1 to 6, preferably 1 to 4, further preferably 1 or 2, most preferably 1 carbon atoms, and there can for example be mentioned a methoxy group, an ethoxy group, a propoxy group, n-butoxy group, s-butoxy group, n-hexyl group, etc.
Hydroxy lower alkyl groups represent straight-chain or branched hydroxyalkyl groups having 1 to 6, preferably 1 to 4, further preferably 1 or 2, most preferably 1 carbon atoms, and there can for example be mentioned a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, a hydroxyhexyl group, etc.
Hydroxy lower alkenyl groups represent straight-chain or branched hydroxyalkenyl groups having 2 to 6, preferably 3 or 4, further preferably 3 carbon atoms, and there can for example be mentioned a 3-hydroxy-1-propenyl group, etc. m represents an integer of 1 to 3, preferably 1.
The positions of substitution of the hydroxyl groups on the indolopyrrolocarbazole ring may be the 1- and 11-positions, or the 2- and 10-positions, but the 2- and 10-positions are preferred.
Description is made below on processes for preparing the compounds of the invention.
An indolopyrrolocarbazole derivative of the invention can be prepared by reacting a compound represented by the formula
wherein, A represents NH or H, and G is as defined above, the compound being a known compound disclosed in EP-A1-0528030, EP-A1-0545195, WO95/30682 and WO96/04293, with a compound represented by the formula
H
2
N—NH(CH
2
)
m
R  [III]
wherein, R and m are as defined above, or by condensing a compound represented by the formula
wherein, G is as defined above, with a

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