Tricyclic derivatives and their use as anti-cancer agents

Details Tricyclic derivatives and their use as anti-cancer agents Tricyclic derivatives and their use as anti-cancer agents

1997-08-01

2001-03-13

Qazi, Sabiha (Department: 1616)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S441000, C514S454000

Reexamination Certificate

active

06201129

ABSTRACT:

This application is a 371 of PCT/GB95/00203 filed on Aug. 1, 1997 (Priority (Feb. 1, 1995).
The present invention relates to heterocyclic compounds which have been found to have anti-tumour activity. More specifically, the invention concerns benzo[1,2-b:4,5-b′]dipyrroles, benzo[1,2-b:5,4-b′]dipyrroles, cyclopent[f]indoles, benzo[1,2-b:4,5-b′]difurans, benzo[1,2-b:5,4-b′]difurans, 2H-indeno[5,6-b]furans, benzo[1,2-b:4,5-b′]dithiophenes, benzo[1,2-b:5,4-b′]dithiophenes, cyclopent[f]indenes and 5H-furo[2,3-f]indoles methods for their preparation, pharmaceutical formulations containing them and their use as anti-tumour agents.
Research in the area of cancer chemotherapy has produced a variety of anti-tumour agents, which have differing degrees of efficacy. Standard clinically used agents include adriamycin, actinomycin D, methotrexate, 5-fluorouracil, cis-platinum, vincristine and vinblastine. However, these presently available anti-tumour agents are known to have various disadvantages, such toxicity to healthy cells and resistance to certain tumour types.
There thus exists a continuing need to develop new and improved anti-tumour agents.
Khoshtariya et al, khim. Geterotsikl. Soedin (1982), (4) 304-7, disclose the synthesis of certain pyrroloindoles.
Gruenhaus H., J.Heterocyclic Chem. 13(6), 1161-3 discloses the synthesis of certain indenothiophenes.
There have now been discovered novel compounds which exhibit anti-tumour cell activity including a group of novel compounds which exhibit anti-tumour cell activity with low toxicity against normal cell lines.
Thus, in a first aspect the present invention provides a compound of the general formula (1)
or a salt or physiologically functional derivative thereof,
wherein A is
X is O, S, SO, SO
2
, CH
2
, CO or NR
7
, wherein R
7
is H, alkyl, aralkyl, aryl, alkenyl, acyl, alkynyl, sulphonyl, substituted sulphonyl, or COOMe;
Y is O, S, SO, SO
2
, CH
2
, CO or NR
7
;
R
1
is COR
8
, CHO, CH
2
OH, CH
2
OR
8
, CONH
2
, COOR
8
, CONHR
8
, CONR
8
R
9
, CSOR
8
, CSSR
8
, COSR
8
, CSNHR
8
, CSNR
8
R
9
, CNHOR
8
wherein R
8
and
R
9
are independently hydrogen, alkoxyalkyl, heterocycloalkyl, heteroaralkyl, or C
1-10
optionally substituted hydrocarbyl group which may optionally contain one or two oxygen atoms in the chain;
or R
8
and R
9
are a sugar group.
R
2
is H, halo, cyano, COOR
8
, alkyl, aryl, alkenyl, alkynyl, alkoxy, (wherein alkyl, aryl, alkenyl, alkynyl and alkoxy can be substituted) or CH
2
CH
2
CO
2
R
12
wherein R
12
is alkyl or aryl;
R
3
is H, alkyl, halogen, cyano, amino, COOR
8
, CONHR
8
, COR
8
, CH
2
OH, CH
2
OR
8
, CONH
2
, CONR
8
R
9
, CSOR
8
, CSSR
8
, COSR
8
, CSNHR
8
, CSNR
8
R
9
or CNHOR
8
;
R
4
is H, halogen, cyano, amino, alkyl, COOR
8
, CONHR
8
, COR
8
, CH
2
OH, CH
2
OR
8
, CONH
2
, CONR
8
R
9
, CSOR
8
, CSSR
8
, COSR
8
, CSNHR
8
, CSNR
8
R
9
or CNHOR
8
;
R
5
is H, hydroxy, aryloxy, aralkyloxy, alkyl, substituted alkyl, aralkyl, nitro, amino, halo, cyano, COOR
8
or CHO;
R
6
is H, aryl, alkyl, aralkyl, nitro, halogen, CHO or COR
13
wherein R
13
is alkyl or aryl; wherein R
8
is not H when R
2
is H and R
3
is not H or Me when A is
Alkyl groups present in general formula (I) may be straight or branched chain alkyl groups, and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, t-butyl and the like.
Acyl groups may be straight or branched and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of such acyl groups include ethanoyl and propanoyl groups.
Alkoxy may be straight or branched and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of such alkoxy groups include methoxy, ethoxy, and the like.
Aryl includes both carbocyclic aryl groups and heterocyclic aryl groups normally containing a maximum of 10 ring atoms. Carbocyclic aryl groups include, for example, phenyl and naphthyl and contain at least one aromatic ring. Heterocyclic aryl groups include, for example, thienyl, furyl, pyridyl, indole and quinoline rings.
An aralkyl group may contain from 1 to 4 atoms in the alkyl portion and the aryl portion may be a carbocyclic or heterocyclic aryl group.
Cycloalkyl includes both cycloalkyl groups and heterocyclo alkyl groups normally containing between 3 and 6 ring atoms. Heterocycloalkyl groups include e.g. morpholino, thiomorpholino, piperidino, imidazolino, pyrrolidino, pyrazolidino, piperazino, tetrahydrofuranyl, tetrahydropyranyl.
When R
8
and R
9
are independently optionally substituted C
1-10
hydrocarbyl which may optionally contain one or two oxygen atoms in the chain this includes optionally substituted alkyl, hydroxyalkyl, alkenyl, alkynyl, carbamoylalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, aralkyl, aryloxyalkyl.
Substituents which may be present on the C
1-10
hydrocarbyl group which may optionally contain one or two oxygen atoms in the chain include hydroxy, azido, alkenyl, halo, nitro (NO
2
), amino, (optionally substituted by one or 2 alkyl groups), cyano, carboxylate, alkyl ester, aralkyl esters or aryl esters, (wherein the alkyl ester, aralkyl ester and aryl ester can be substituted) alkyl, aryl, aralkyl, aryloxy, aryalkoxy, substituted arylalkoxy, sulphinyl, sulphonyl, thio, alkylthio, alkoxy, hydroxyalkyl, halo alkyl, phosphate, phsophonate, silyl, silyloxy, (wherein silyl and silyloxy may be substituted by one or more C
1-6
alkyl or aryl) keto, and formyl. Substituents which may be present on alkyl esters, aralkyl esters and aryl esters include nitro, amino, hydroxy, alkoxy, halogen, cyano and alkyl.
Where R
8
is a sugar this group may be present in a protected or unprotected form. Preferred sugar-protecting groups include isopropylidene, benzylidene acetate, benzoyl, paranitrobenzyl, paranitrobenzoyl, benzyl, substituted silyl and tetrahydropyranyl.
When R
8
is a sugar such as a tetrose, pentose, hexose (including furanose and pyranose) or heptose, preferred sugars include glucose, fructose, mannose, ribose, arabinose.
Substituents which may be present on the sulphonyl and sulphinyl include alkyl, aryl and aralkyl.
Halogen represents fluoro, chloro, bromo or iodo.
X preferably represents NH, A is preferably
and Y preferably represents NH.
R
1
is preferably COOR
8
, with R
8
preferably being alkyl or aralkyl.
R
2
is preferably H, alkyl, or COOR
8
wherein R
8
is preferably alkyl,
R
3
is preferably alkyl,
R
4
is preferably alkyl or COOR
8
,
R
5
is preferably hydrogen, and
R
6
is preferably hydrogen or methyl,
and salts and physiologically functional derivatives thereof.
One group of preferred compounds according to the present invention includes:
Ethyl 1,7-dihydro-3,4,6-trimethylpyrrolo[3,2-f]indole-2-carboxylate;
Diethyl 1,7-dihydro-3,4,6-trimethylpyrrolo[3,2-f]indole-2,5-dicarboxylate; and
Ethyl 6-methoxycarbonyl-3,4-dimethylpyrrolo[3,2-f]indole-2-carboxylate
and physiologically functional derivatives thereof.
A second group of preferred compounds according to the invention include:
Ethyl 6-Benzyloxycarbonyl-3,4-dimethylpyrrolo[3,2-f]indole-2-carboxylate;
Dibenzyl 3,4-dimethylpyrrolo[3,2-f]indole-2,6-dicarboxylate;
Ethyl 7-methoxycarbonyl-3,4-dimethylpyrrolo[3,2-f]indole-2-carboxylate; and
Ethyl 3,4-dimethylpyrrolo[3,2-f]indole-2-carboxylate
and physiologically functional derivatives thereof.
Compounds of the general formula (I) have been tested against two specially developed cell lines which are clones of the human fibrosarcoma cell-line HT1080. One clone HT1080scc2, retains the transformed phenotype of the parental line, whilst the other, HT10801c, is a morphologically flat, non-tumourigenic, revertant.
According to a further aspect, the present invention also provides a process for preparing compounds of general formula (I), which process comprises the catalysed reaction of a compound of formula (II) with a compound of formula (III) in an inert solvent at a temp

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