Analogues of camptothecin, preparation procedures, their...

Details Analogues of camptothecin, preparation procedures, their... Analogues of camptothecin, preparation procedures, their...

1999-06-04

2001-11-06

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S070000

Reexamination Certificate

active

06313135

ABSTRACT:

Camptothecin is a natural compound that was 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 comprised of an indolizino [1,2-b]quinoline fragment fused with a six chained &agr;-hydroxylactone. The carbon in position 20, which carries the &agr;-hydroxy, is asymmetric and confers a rotational capacity to the molecule. The natural form of camptothecin possesses the absolute “S” configuration to the carbon 20 and complies with the following formula:
Camptothecin presents an anti-proliferating activity in several cancerous cellular lines, comprising the cellular lines of human tumors of the colon, of the lung and of the breast (Suffness, M. et al., The Alkaloids Chemistry and Pharmacology, Bross, A., ed., Vol. 25, p. 73 (Academic Press, 1985)). It is suggested that the anti-proliferating activity of camptothecin is in relation to its inhibiting activity of topoisomerase I of DNA.
It was indicated that the &agr;-hydroxylactone was an absolute necessity both for in vivo and in vitro activity of the 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: 160 (1992)). The present invention concerns a new class of camptothecin compounds, in which a &bgr;-hydroxylactone replaces the natural &agr;-hydroxylactone of the camptothecin. The compounds according to the present invention exhibit powerful biological activity which is unexpected with respect to prior art.
Thus the invention has as its object new compounds of camptothecin which differ from all known compounds of camptothecin, in the sense that they contain a &bgr;-hydroxylactone (or its open hydroxycarboxylic form) in place of an &agr;-hydroxylactone (or its open hydroxycarboxylic form); or a pharmaceutically acceptable salt of the latter. By compound of camptothecin it is understood a compound presenting the same structural skeleton as that of camptothecin (that is to say an indolizino [1,2-b]quinoline fragment that is fused to a six chained &agr;-hydroxylactone), with or without other chemical substitutions on the skeletal structure (for example the camptothecin compounds). Different camptothecin compounds are well known by specialists, as described below. By &bgr;-hydroxylactone is meant a lactone that is comprised of a supplementary carbon atom between the carbon of the carboxyl and the &agr;-carbon carrying the hydroxy group on the &agr;-hydroxylactone. The &bgr;-hydroxylactone of seven “closed” or “open” chains, in which the ester bond between the carbonyl group and the adjacent oxygen atom is hydrolized, which shows by the formation of a carboxylic acid group and a hydroxyl group, which groups may or may not be substituted.
A compound of camptothecin according to the invention may then comprise substitutions on the indolizino [1,2-5]quinoline fragment (for example to improve the solubility of the compound) or on the open or closed &bgr;hydroxylactone (for example to improve the stability of the compound). The examples of substitutions on closed &bgr;-hydroxylactone are comprised of an alkyl substitution (for example ethyl) on the &bgr;-carbon. The examples of substitution on the open &bgr;-hydroxylactone are comprised of an alkyl substitution on the &bgr;-carbon, substitutions (for example an amidation) on the carboxylic acid result, and the substitutions (for example an esterification) or suppressions of a hydroxyl group result.
The invention has more particularly for subject matter compounds of formula (I) and of formula (II),
in racemic form, enantiomer or any combination of these forms, in which
R
1
represents a lower alkyl, a lower alkenyl, a lower alkynyl, a lower haloalkyl, and lower alkoxy lower alkyl or a lower alkylthio lower alkyl;
R
2
, R
3
, and R
4
represent, independently, H, halo, lower halo alkyl, lower alkyl, lower alkenyl, cyano, lower cyano alkyl, nitro, lower nitro alkyl, amido, lower amido alkyl, hydrazino, lower hydrazino alkyl, azido, lower azido alkyl, (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)(CH2)
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 of 4 to 7 chains with the nitrogen atom N, which is a member of the heterocyclic group, and X represents the resulting members, necessary to complete the heterocyclic group, selected from among the group comprised of O, S, CH
2
, CH, N, NR
9
and COR
10
), aryl or lower aryl alkyl substituted (that is to say, substituted one to four times on the heterocyclic or aryl group) or not substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxy alkyl, lower alkoxy, or lower alkoxy lower alkyl) or R
2
and R
3
form together a chain of 3 or 4 links, in which the elements of the chain are selected from among the group comprised of CH, CH
2
, O, S, N or NR
9
;
R
5
represents H, halo, lower halo alkyl, lower alkyl, lower alkoxy, lower alkoxy lower alkyl, lower alkylthio lower alkyl, cycloalkyl, lower cycloalkyl alkyl, cyano, cyano alkyl, lower alkyl lower sulphonyl alkyl, lower hydroxy alkyl, 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
, CH2)
m
OC(O)R
8
, (CH
2
)
m
OC(O)NR
6
R
7
, (CH2)
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], aryl or substituted lower aryl alkyl (that is to say one to four times on the aryl group or heteroaryl) or not substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkyl amino, lower halo alkyl, lower hydroxy alkyl, lower alkoxy or lower alkoxy lower alkyl;
R
6
and R
7
represent, independently, H, and lower alkyl, lower hydroxy alkyl, lower alkyl lower amino alkyl, lower amino alkyl, cycloalkyl, lower cycloalkyl alkyl, lower alkenyl, lower alkoxy lower alkyl, lower halo alkyl, or aryl or substituted lower aryl alkyl (that is to say one to four times on the aryl group) or non-substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkyl amino, lower halo alkyl, lower hydroxy alkyl, lower alkoxy, or lower alkoxy lower alkyl;
R
8
represents H, and lower alkyl, lower hydroxy alkyl, amino, lower alkyl amino, lower alkyl lower amino alkyl, lower amino alkyl, cycloalkyl, lower cycloalkyl alkyl, lower alkenyl, lower alkoxy, lower alkoxy lower alkyl, lower halo alkyl, or aryl or substituted lower aryl alkyl (that is to say, one to four times on the aryl group) or non-substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkyl amino, lower halo alkyl, lower hydroxy alkyl, lower alkoxy, or lower alkoxy lower alkyl;
R
9
represents H, a lower alkyl, lower halo alkyl, aryl, or substituted aryl by one or more groups chosen from among the lower radical alkyl, halo, nitro amino, lower alkyl amino, lower halo alkyl, lower hydroxy alkyl, lower alkoxy, or lower alkoxy lower alkyl;
R
10
represents H, a lower alkyl, lower halo alkyl, lower alkoxy, aryl or substituted aryl (that is to say, presenting one to four substituents on the aryl group) by one or more groups chosen from among the lower radical alkyl, lower halo alkyl, lower hydroxy alkyl, 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, and lower alkyl or aryl;
R
16
represents H or OR
2

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