Camptothecin analogue compounds

Details Camptothecin analogue compounds Camptothecin analogue compounds

2001-11-05

2003-01-21

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...

C546S051000

Reexamination Certificate

active

06509345

ABSTRACT:

DESCRIPTION OF THE PRIOR ART
Camptothecin, an alkaloid isolated from
Camptotheca accuminata
, is an anti-cancer agent having a broad spectrum of activity. Its insoluble nature has for a long time directed research towards the insoluble salts of the compound, the toxicity of which has proved to be a major handicap. Several other studies have been carried out with a view to obtaining structural analogues and to overcoming the lack of solubility of the natural molecule (J. Med. Chem. 1991. 34, 98; Chem. Pharm. Bull., 1991, 39, 3183). The modifications made relate principally to the A and B rings. The conclusions of different studies also show the importance of the E ring and more especially of the lactone function. In fact, the latter, in equilibrium with the open hydroxy-acid form, appears to be the most active form having reduced undesirable effects (Cancer Res., 1989, 49, 1465; ibid, 1989, 49, 5077). Attempts at modifying this ring have been carried out, in particular the cyclic oxygen atom has been replaced by a nitrogen or sulphur atom, but in each case there is a loss of pharmacological activity, so confirming the importance of the lactone (J. Med. Chem., 1989. 32, 715).
BACKGROUND OF THE INVENTION
The present invention relates to camptothecin structural analogue compounds, the E ring of which has been modified. They are characterised by the replacement of the lactone function of that ring by a cyclic ketone function, the cyclic oxygen having been replaced by a carbon atom. The compounds so obtained have a novel structure and, surprisingly, have a significant cytotoxic character. It will therefore be possible to use them in the manufacture of medicaments for use in the treatment of cancerous diseases.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to the compounds of formula (I):
wherein:
n is 0, or 2,
R
1
, R
2
, R
3
, R
4
and R
5
are selected each independently of the others from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a perhaloalkyl group, a (C
3
-C
11
)cycloalkyl group, a (C
3
-C
11
)cycloalkyl-alkyl group, a hydroxy group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, an alkoxycarbonyl group, an acyloxy group, a carboxy group, a nitro group, a cyano group, an aminocarbonyl group (optionally substituted on the nitrogen atom by one or two alkyl groups), and the groups (CH
2
)
p
—NR
a
R
b
and —O—C(O)—N—R
a
R
b
, wherein p is an integer from 0 to 6, and R
a
and R
b
each independently of the other represents a hydrogen atom, an alkyl group, a (C
3
-C
11
)cycloalkyl group, a (C
3
-C
11
)cycloalkyl-alkyl group, an acyl group, an optionally substituted aryl group or an optionally substituted arylalkyl group, or R
a
and R
b
form together with the nitrogen atom carrying them a pyrrolyl, piperidinyl or piperazinyl group, it being possible for each of those cyclic groups to be optionally substituted, or two adjacent groups R
2
, R
3
, R
4
and R
5
form together with the carbon atoms carrying them a group —O—(CH
2)
t
—O, t being an integer from 1 to 3 inclusive,
R
60
, R
70n
, R
80
and R
90
each independently of the others represents a hydrogen atom, a hydroxy group, an alkoxy group, or a group O—(CO)—X or O—(CO)—NXW wherein X and W each independently of the other represents an alkyl group, an alkenyl group, an alkynyl group, a (C
3
-C
11
)cycloalkyl group, a (C
3
-C
11
)cycloalkyl-alkyl group, an optionally substituted aryl group or an optionally substituted arylalkyl group,
R
61
, R
71n
, R
81
, and R
91
, each independently of the others represents a hydrogen atom, an alkyl group, an alkenyl group or an alkynyl group, or, taken in pairs on adjacent carbon atoms, together form a bond or an oxirane group, or two germinal groups (R
60
and R
61
) and/or (R
70n
and R
71n
) and/or (R
80
and R
81
) and/or (R
90
and R
91
) together form an oxo group or a group —O—(CH
2
)
t1
—O, t
1
being an integer from 1 to 3 inclusive,
with the proviso that R
60
, R
61
, R
70n
, R
71n
, R
80
, R
81
, R
90
and R
91
do not all represent a hydrogen atom.
their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
it being understood that
the term “alkyl” denotes a linear or branched chain having from 1 to 6 carbon atoms,
the term “alkenyl” denotes a linear or branched chain having from 2 to 6 carbon atoms and containing from 1 to 3 double bonds.
the term “alkynyl” denotes a linear or branched chain having from 2 to 6 carbon atoms and containing from 1 to 3 triple bonds,
the term “alkoxy” denotes a linear or branched alkyl-oxy radical containing from 1 to 6 carbon atoms.
the term “acyl” denotes a linear or branched alkyl-carbonyl radical containing from I to 6 carbon atoms.
the term “aryl” represents a phenyl or naphthyl group,
the expression “substituted” when used in relation to aryl or arylalkyl groups means that the groups in question are substituted by one or more halogen atoms, and/or groups alkyl, alkoxy, hydroxy, cyano, nitro, and/or amino (optionally substituted by one or two alkyl groups),
the expression “substituted” when used in relation to pyrrolyl, piperidinyl or piperazinyl groups means that the groups in question are substituted by one or more alkyl, alkoxy, aryl, arylalkyl, aryloxy and/or aryloxyalkyl groups.
An advantageous aspect of the invention relates to compounds of formula (I) wherein R
60
represents a hydroxy group and R
61
represents an alkyl group (for example ethyl).
Another advantageous aspect of the invention relates to compounds of formula (I) wherein R
80
and R
81
, together form an oxo group, or R
90
and R
91
together form an oxo group, or R
80
with R
81
and R
90
with R
91
form two oxo groups. Preferred compounds of formula (I) are those wherein R
1
represents a hydrogen atom.
Other preferred compounds of formula (I) are those wherein R
2
, R
3
, R
4
and R
5
are selected from a hydrogen atom, a halogen atom, an alkyl group and an alkoxy group, or two of those groups, when bonded to two adjacent carbon atoms, together form a methylenedioxy or ethylenedioxy group (preferably methylenedioxy). Among those compounds, preference is given to those wherein each of R
2
and R
5
represents a hydrogen atom.
An especially advantageous aspect of the invention relates to compounds of formula (I) wherein each of R
1
, R
2
and R
5
represents a hydrogen atom, R
3
and R
4
are selected from a hydrogen atom, a halogen atom, an alkyl group and an alkoxy group, or together form a methylenedioxy group, R
60
, R
70n
, R
80
and R
90
each independently of the others represents a hydrogen atom, a hydroxy group or an alkoxy group, and R
61
, R
71n
, R
81
, and R
91
each independently of the others represents a hydrogen atom or an alkyl group, or, taken in pairs on adjacent carbon atoms, together form a bond or an oxirane group, or two germinal groups (R
60
and R
61
) and/or (R
70n
and R
71n
) and/or (R
80
and R
81
) and/or (R
90
and R
91
) together form an oxo group.
The present invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (II):
wherein n, R
60
, R
61
, R
70n
, R
71n
, R
80
, R
81
, R
90
and R
91
are as defined for formula (I), which is condensed, in a basic medium, with a compound of formula (III):
wherein R
1
, R
2
, R
3
, R
4
and R
5
are as defined for formula (I), and Hal and Hal′ each independently of the other represents a halogen atom,
or, in accordance with the conditions of a Mitsunobu reaction, with a compound of formula (III′):
wherein R
1
, R
2
, R
3
, R
4
, R
5
and Hal are as defined hereinbefore,
to yield a compound of formula (IV):
wherein R
1
, R
2
, R
3
, R
4
, R
5
, n, R
60
, R
61
, R
70n
, R
71n
, R
80
, R
81
, R
90
, R
91
and Hal are as defined hereinbefore,
which compound (IV) is subjected to an intramolecular cyclisation reaction of the “Heck” type catalysed by a palladium compound, to yield a compound of formula (I), it being understood, for the purpose of simplifying the

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