Tetracyclic analogues of camptothecins, their preparation...

Details Tetracyclic analogues of camptothecins, their preparation... Tetracyclic analogues of camptothecins, their preparation...

2000-12-12

2003-10-14

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06632946

ABSTRACT:

Camptothecin is a natural compound which was isolated for the first time from the leaves and bark of the Chinese plant called
camptotheca acuminata
(seer Wall et al., J. Amer. Chem. Soc. 88:3888 (1966)). Camptothecin is a pentacyclic compound, constituted by a an indolizino[1,2-b]quinoline fragment fused with an &agr;-hydroxylactone with six links, and corresponding to the following formula:
Camptothecin has an anti-proliferative activity in several cancerous cell lines, including the cell lines of human colon, lung and breast tumours (Suffness, M. et al.: The Alkaloids Chemistry and Pharmacology, Bross, A., ed., Vol. 25, p. 73 (Academic Press, 1985)). It has been established that the anti-proliferative activity of camptothecin is related to its inhibitor activity on DNA topoisomerase I.
It had been indicated that &agr;-hydroxylactone was an absolute requirement both for in vivo and in vitro activity of camptothecin (Camptothecins: New Anticancer Agents, Putmesil, M., et al., ed., p. 27 (CRC Press, 1995); Wall, M. et al., Cancer Res. 55:753 (1995); Hertzberg et al., J. Med. Chem. 32:715 (1982) and Crow et al., J. Med. Chem. 35:4160 (1992)). Unexpectedly, the Applicant had discovered that &bgr;-hydroxylactones with 7 links have a biological activity which is comparable to or greater than that of &agr;-hydroxylactones (PCT Application No. FR 96/00980). Now, the Applicant has just discovered unexpectedly that certain camptothecin analogues comprising neither &agr;-hydroxylactone nor &bgr;-hydroxylactone also present an inhibitory activity on topoisomerases. The present invention therefore relates to a new class of tetracyclic analogues of camptothecin, in which the natural &agr;-hydroxylactone of camptothecin or the &bgr;-hydroxylactone of the analogues previously described by the Applicant is absent. The compounds according to the present invention have a powerful biological activity inhibiting topoisomerase I and/or topoisomerase II, which is unexpected with respect to the prior state of the art.
A subject of the invention is therefore compounds of formula (I),
in racemic or enantiomeric form or any combination of these forms, in which
R
1
represents a lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, lower alkoxyalkyl or lower alkylthioalkyl radical;
R
2
, R
3
and R
4
represent, independently, an H, hydroxy, lower alkoxy, arylalkoxy, halo, lower haloalkyl, lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl, amido, lower amidoalkyl, (CH
2
)
m
NR
6
R
7
, (CH
2
)
m
OR
6
, (CH
2
)
m
SR
6
, (CH
2
)
m
CO
2
R
6
, (CH
2
)
m
NR
6
C(O)R
8
, (CH
2
)
m
C(O)R
8
, (CH
2
)
m
OC(O)R
8
, O(CH
2
)
m
NR
6
R
7
, OC(O)NR
6
R
7
, OC(O)(CH
2
)
m
CO
2
R
6
, aryl or lower arylalkyl radical substituted (i.e., substituted one to four times on the aryl group) or non-substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl) or R
2
and R
3
, or R
3
and R
4
, or R
4
and R
5
, independently form together a chain with 3 or 4 links, in which the elements of the chain are selected from the group consituted by CH, CH
2
, O, S, N or NR
9
;
R
5
represents an H, halo, lower haloalkyl, lower alkyl, lower alkoxy, lower alkoxyalkyl, lower alkylthioalkyl, cycloalkyl, lower cycloalkylalkyl, cyano, cyanoalkyl, lower alkanesulphonylalkyl, lower hydroxyalkyl, nitro, (CH
2
)
m
C(O)R
8
, (CH
2
)
m
NR
6
C(O)R
8
, (CH
2
)
m
NR
6
R
7
, (CH
2
)
m
N(CH
3
)(CH
2
)
n
NR
6
R
7
, (CH
2
)
m
OC(O)R
8
, (CH
2
)
m
OC(O)NR
6
R
7
, aryl or lower arylalkyl radical substituted (i.e. one to four times on the aryl group) or non-substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxyalkyl;
R
6
and R
7
represent, independently, H, a lower alkyl, lower hydroxyalkyl, lower alkylaminoalkyl, lower aminoalkyl, cycloalkyl, lower cycloalkylalkyl, lower alkenyl, lower alkoxyalkyl, lower haloalkyl, or aryl or lower arylalkyl radical substituted (i.e., one to four times on the aryl group) or non-substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl, or, when the chains R
6
and R
7
are attached to the same nitrogen atom, R
6
and R
7
optionally together form an aromatic or non-aromatic heterocycle, for example a heterocycle of morpholine, piperazine or piperidine type, said heterocycle being optionally substituted by one or more groups chosen from the lower alkyl, substituted or non-substituted aryl, substituted or non-substituted arylalkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxyalkyl radicals;
R
8
represents an H, lower alkyl, lower hydroxyalkyl, amino, lower alkylamino, lower alkylaminoalkyl, lower aminoalkyl, cycloalkyl, lower cycloalkylalkyl, lower alkenyl, lower alkoxy, lower alkoxyalkyl, lower haloalkyl, or aryl or lower arylalkyl radical substituted (i.e., one to four times on the aryl group) or non-substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl radical;
R
9
represents an H, lower alkyl, lower haloalkyl, aryl or arylalkyl radical, the aryl or arylalkyl group optionally being able to be substituted on the aromatic cycle by one or more groups chosen from the lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl radicals;
R
10
represents a cyano, C(O)OR
11
, 1H-1,2,3,4-tÈtrazo-5-yl or 1-alkyl-1,2,3,4-tÈtrazo-5-yl radical;
R
11
represents an H, lower alkyl, lower haloalkyl, lower hydroxyalkyl, alkylcarbonyloxyalkyl, (CH
2
)
p
NR
6
R
7
, aryl, arylalkyl or aryl radical, the aryl or arylalkyl group optionally being able to be substituted on the aromatic cycle by one or more groups chosen from the lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl radical;
m
is an integer comprised between 0 and 6;
n
is an integer comprised between 1 and 4;
p
is an integer comprised between 2 and 6;
or a pharmaceutically acceptable salt of the latter.
When it is used without further precision, the term alkyl refers to a lower alkyl radical. As used in this text, the term lower with reference to the alkyl, alkylthio and alkoxy groups designates saturated aliphatic hydrocarbon groups, linear or branched, comprising 1 to 6 carbon atoms, such as for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methylthio, ethylthio, methoxy and ethoxy. With reference to the alkenyl or alkynyl groups, the term lower designates groups comprising 2 to 6 carbon atoms and one or more double or triple bonds, such as for example the vinyl, allyl, isopropenyl, pentenyl, hexanyl, propenyl ethynyl, propynyl and butynyl groups. The term cycloalkyl designates a cycle of 3 to 7 carbons, such as for example the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. The term aryl designates a mono-, di- or tricyclic hydrocarbon compound with at least one aromatic cycle, each cycle containing at most 7 links, such as for example phenyl, naphthyl, anthracyl, biphenyl or indenyl. The term halo means chloro, bromo, iodo or fluoro. The radicals corresponding to the expressions lower haloalkyl, lower cyanoalkyl, lower nitroalkyl, lower amidoalkyl, lower hydrazinoalkyl, lower azidoalkyl, lower arylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkylthioalkyl, and lower alkanesulphonylalkyl are substituted, respectively, by one to three halo, cyano, nitro, amido, hydrazino, azido, aryl, hydroxy, lower alkoxy, lower alkylthio or lower sulphonyl groups. The lower alkylamino radical can contain one or two lower alkyl groups, and represent for example NHCH
3
, NHCH
2
CH
3
, N(CH
3
)
2
, or N(CH
3
)(CH
2
CH
3
).
The compounds according to the present invention carry an asymetric carbon. As a resu

Affiliated with

Also associated with

Rating

Tetracyclic analogues of camptothecins, their preparation... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Tetracyclic analogues of camptothecins, their preparation..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Tetracyclic analogues of camptothecins, their preparation... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3147016