Analogues of camptothecin, their use as medicaments and the...

Details Analogues of camptothecin, their use as medicaments and the... Analogues of camptothecin, their use as medicaments and the...

2002-01-30

2004-07-13

Kifle, Bruck (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S116000

Reexamination Certificate

active

06762301

ABSTRACT:

Camptothecin is a natural compound which has been isolated for the first time from the leaves and the bark of the Chinese plant called
camptotheca acuminata
(see Wall et al. J. Amer. Chem. Soc. 88:3888 (1966)). Camptothecin is a pentacyclic compound constituted by an indolizino[1,2-b]quinoline fragment fused with an (&agr;-hydroxylactone with six members. The carbon in position 20 which carries the &agr;-hydroxy group is asymmetrical and confers a rotatory power on the molecule. The natural form of camptothecin has an absolute “S” configuration as regards the carbon 20 and corresponds to the following formula:
Camptothecin has an anti-proliferative activity in several cancerous cell lines, including the cell lines of human tumors of the colon, lung and breast (Suffness, M et al: The Alkaloids Chemistry and Pharmacology, Bross A., ed., Vol. 25, p. 73 (Acedemic Press, 1985)). It is suggested that the anti-proliferative activity of camptothecin is related to its inhibitory activity on DNA topoisomerase I.
It has been indicated that &agr;-hydroxylactone was an absolute requirement both for the in vivo and in vitro activity of campotothecin (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)). The present invention relates to a new class of compounds of camptothecin, in which a &bgr;-hydroxylactone replaces the natural &agr;-hydroxylactone of camptothecin. The compounds according to the present invention present a powerful biological activity which is unexpected with regard to the state of the prior art.
Therefore a subject of the invention is new analogues of camptothecin which differ from all known derivatives of camptothecin in the sense that they contain &bgr;-hydroxylactone (or its open hydroxycarboxylic form) instead of an &agr;-hydroxylactone (or its open hydroxycarboxylic form); or a pharmaceutically acceptable salt of one of the latter. By derivative of camptothecin is meant a compound having the same structural skeleton as that of camptothecin (i.e. an indolizino[1,2-b]quinoline fragment fused with an &agr;-hydroxylactone with six members), with or without other chemical substitutions on the skeletal structure. Different derivatives of camptothecin are well known by specialists, as described hereafter. By &bgr;-hydroxylactone is meant a lactone which contains an additional carbon atom between the carbon of the carboxyl and the &agr;-carbon carrying the hydroxyl group in the &agr;-hydroxylactone.
An analogue of camptothecin according to the invention can therefore contain substitutions on the indolizino[1,2-b]quinoline fragment (for example in order to improve the solubility of the compound), or on the open or closed &bgr;-hydroxylactone (for example in order to improve the stability of the compound). Examples of substitutions on the closed &bgr;-hydroxylactone include an alkyl substitution (for example ethyl) on the &bgr;-carbon. Examples of substitutions on the open &bgr;-hydroxylactone include alkyl substitutions on the &bgr;-carbon, substitutions (for example an amidation) on the resultant carboxylic acid and substitutions (for example an esterification) or suppressions of the resultant hydroxyl group.
Preferred &bgr;-hydroxylactone camptothecin analogues are notably those in which the pentacyclic skeletton is substituted at least once by an halogen atom in any of positions 9, 10, 11 or 12.
The invention first relates to compounds of general formula (B1) and (B2)
in racemic or enantiomeric form or any combinations of these forms, in which
R
1
represents a lower alkyl; a lower alkenyl, a lower alkynyl, a lower haloalkyl, a lower alkoxy lower alkyl or lower alkylthio lower alkyl;
R
2
, R
3
and R
4
represent, independently, H, halo, lower haloalkyl, lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl, (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
or (CH
2
)
n
[N═X], OC(O)[N═X], (CH
2
)
m
OC(O)[N═X] (in which [N═X], in this invention, represents a heterocyclic group with 4 to 7 members with the nitrogen atom N, which is a member of the heterocyclic group, and X represents the remaining members, which are necessary to complete the heterocylic group; selected from the group constituted by O, S, CH
2
, CH, N, NR
9
and COR
10
), substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl group or the heterocycle), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl) or R
2
and R
3
form together a chain with 3 or 4 members in which the elements of the chain are selected from the group constituted by CH, CH
2
, O, S, N or NR
9
;
R
5
represents H, halo, lower haloalkyl, lower alkyl, lower alkoxy, lower alkoxy lower alkyl, lower alkylthio lower alkyl, cycloalkyl, cycloalkyl lower alkyl, cyano, cyanoalkyl, lower alkyl lower sulphonylalkyl, 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
, (CH
2
)
m
S(O)
q
R
11
, (CH
2
)
m
P(O)R
12
R
13
, (CH
2
)
2
P(S)R
12
R
13
or (CH
2
)
n
[N═X], OC(O)[N═X], (CH
2
)
m
OC(O)[N═X], substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl or heteroaryl group), in which the substituent is a lower alkyl, halo, hydroxy, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R
6
and R
7
represent, independently, H, a lower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy lower alkyl, lower haloalkyl, or substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl group), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R
8
represents H, a lower alkyl, lower hydroxyalkyl, amino, lower alkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy lower alkyl, lower haloalkyl, or substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl group), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R
9
represents H, a lower alkyl, lower haloalkyl, aryl, lower arylalkyl, or aryl or lower arylalkyl in which the aryl group is substituted by one or more groups chosen from the following radicals: lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R
10
represents H, a lower alkyl, lower haloalkyl, lower alkoxy, aryl or aryl substituted (i.e. having one to four substituents on the aryl group) by one or more groups chosen from the following radicals: lower alkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy lower alkyl;
R
11
represents a lower alkyl, aryl, (CH
2
)
m
OR
14
, (CH
2
)
m
SR
14
, (CH
2
)
2
NR
14
R
15
or (CH
2
)
m
[N═X];
R
12
and R
13
represent, independently, a lower alkyl, aryl, lower alkoxy, aryloxy or amino;
R
14
and R
15
represent, independently, H, lower alkyl or aryl;
R
16
represents H or OR
21
;
R
17
represents OR
6
or NR
6
R
7
;
R
18
and R
19
represent, independently, H, halo, lower alk

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