Preparation of camptothecin and of its derivatives

Details Preparation of camptothecin and of its derivatives Preparation of camptothecin and of its derivatives

2001-09-14

2002-11-26

Dentz, Bernard (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C084S157000, C084S175000

Reexamination Certificate

active

06486320

ABSTRACT:

The present invention relates to the preparation of camptothecin and of its derivatives. It relates more particularly to the preparation of camptothecin, of topotecan and of irinotecan.
Camptothecin derivatives of general formula:
in which in particular R
1
is hydrogen, halogen or alkyl and X is a chlorine atom or NR
2
R
3
for which R
2
and R
3
, which are identical or different, can represent a hydrogen atom, an optionally substituted alkyl radical, an optionally substituted carbocyclyl, an optionally substituted heterocycle or alkyl radicals (optionally substituted) which form, with the nitrogen atom to which they are attached, a heterocycle optionally comprising another heteroatom chosen from O, S and/or NR
4
, R
4
being a hydrogen atom or an alkyl radical, and in which the X—CO—O— group is situated at the 9-, 10- or 11-position of the A ring are known according to European Patent EP 137 145, cited here by way of reference. These camptothecin derivatives are anticancer agents which are topoisomerase I inhibitors, among which irinotecan, for which X—CO—O— is [4-(1-piperidino)-1-piperidino]carbonyloxy, is an active principle which is particularly effective with respect to solid tumours and in particular colorectal cancer.
Other camptothecin derivatives which are mentioned as anticancer agents, in particular derivatives with a structure analogous to the structure given above, in which structure X—CO—O— is replaced by an —X′R′ radical for which X′ is O or S and R′ is a hydrogen atom or an alkyl or acyl radical, are also known according to Patent Application EP 74 256, cited here by way of reference.
Other camptothecin derivatives have also been disclosed, for example in the patents or patent applications, cited here by way of reference, EP 56 692, EP 88 642, EP 296 612, EP 321 122, EP 325 247, EP 540 099, EP 737 686, WO 9003169, WO 9637496, WO 9638146, WO 9638449, WO 9700876, U.S. Pat. No. 7,104,894, JP 57 116015, JP 57 116074, JP 59 005188, JP 60 019790, JP 01 249777, JP 01246287 or JP 91 012070, or in Canc. Res., 38 (1997) Abst. 1526 or 95 (San Diego, April 12-16), Canc. Res., 55(3), 603-609 (1995) or AFMC Int. Med. Chem. Symp. (1997) Abst. PB-55 (Seoul, July 27-August 1).
Irinotecan (CPT-11) and its derivatives are usually prepared from natural camptothecin (U.S. Pat. No. 4,604,463; S. Sawada et al., Chem. Pharm. Bull., 39, 2574-80 (1991), Chem. Pharm. Bull., 39, 1446-54 (1991), Chem. Pharm. Bull., 39, 3183-88 (1991) and Ann. N.Y. Acad. Sci., 803, 13-28 (1996). The stages comprise the introduction of a hydroxyl functional group at the 9-position, an alkylation at the 11-position and the introduction of a radical at the 9-position.
International Patent Application WO 96/31513 has disclosed the preparation of mappicine and camptothecin derivatives by total synthesis by firstly preparing the C-D or C-D-E ring sequence.
Tetrahedron, 53(32), 11049-60 (1997), also describes total syntheses of camptothecin derivatives in which the A-B and D-E rings are prepared beforehand or, according to another aspect, the C-D-E or A-B-C sequences.
It has now been found, and it this which forms the subject matter of the present invention, that camptothecin or camptothecin derivatives of following formula (I):
in which R
1
, R
2
and R
3
each represent an identical or different group chosen from:
hydrogen,
a hydroxyl group,
a halogen atom chosen from fluorine, chlorine, bromine or iodine,
linear or branched alkoxy groups comprising 1 to 4 carbon atoms,
linear or branched alkylthio groups comprising 1 to 4 carbon atoms,
(C
1
-C
4
)alkylamino groups optionally substituted by one or more C
1
-C
4
alkyl groups,
aralkyl groups optionally substituted by a C
1
-C
4
alkyl group, said aryl groups also optionally being heterocycles comprising 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen,
arylcarbonyloxy groups, said aryl groups also optionally being mono- or polycyclic heterocycles comprising 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, can be obtained by a convergent synthesis starting from a 3-(aminomethyl)quinoline derivative and 5-hydroxy-5-ethyl-6-oxo-5,6-dihydropyrancarboxylic acid with particularly advantageous results.
The preferred and commercial compounds synthesized by the process of the invention are:
camptothecin, for which R
1
, R
2
and R
3
represent hydrogen,
topotecan or Hycamtin®, for which R
1
is hydrogen, R
2
represents a dimethylamino-methyl group and R
3
represents a hydroxyl group,
irinotecan or Campto®, for which R
1
represents an ethyl group, R
2
represents a piperidinopiperidinocarbonyloxy group and R
3
represents hydrogen.
The process according to the invention consists in condensing a 3-(aminomethyl)quinoline derivative and 5-hydroxy-5-ethyl-6-oxo-5,6-dihydro-pyrancarboxylic acid, followed by an ethynylation stage, optionally by a hydrolysis stage, by a double cyclization stage, by a dehydrogenation and by a deprotection/dealkoxycarbonylation stage.
According to the invention, 5-hydroxy-5-ethyl-6-oxo-5,6-dihydropyrancarboxylic acid with the structure:
in which G
1
, represents hydrogen or a protective group for the hydroxyl functional group chosen in particular from the benzyl, para-methoxybenzyl, methoxymethyl, tert-butyl and trialkylsilyl groups, at least one alkyl group in the trialkylsilyl having more than two carbon atoms, is condensed with a 3-(aminomethyl)quinoline derivative of general formula:
in which R
1
, R
2
and R
3
have the same meaning as in the formula (I) or represent protected radicals or radicals which can be easily converted to R
1
, R
2
and R
3
radicals mentioned above and Y represents a leaving group chosen in particular from halogen atoms or an OSO
2
R radical where R represents an alkyl, tolyl, naphthyl or trifluoromethyl group, in order to obtain the quinoline derivative of general formula:
in which G
1
, R
1
, R
2
, R
3
and Y are defined as above.
The benzyl group is preferred among the G
1
groups. Preference is given, among the Y groups, to halogens chosen from bromine or iodine and, among the OSO
2
R groups, to trifluoromethylsulfonate.
The reaction is generally carried out according to the usual methods for condensing acids with amines, in particular by reaction with the acid or a reactive or activated derivative of the acid.
When the condensation of a reactive derivative of the acid of general formula (II) is carried out, the reaction is advantageously carried out by means of the acid chloride, of the anhydride, of a mixed anhydride or of a reactive ester, or of an ammonium or pyridinium acyl intermediate.
It is preferable, among the reaction conditions, to use a temperature of between −40 and +40° C. It is preferable, among the inert solvents which can be used, to use an organic solvent such as in particular a chlorinated solvent (dichloromethane, dichloroethane or chloroform, for example). The reaction can optionally be carried out in the presence of an acid acceptor, such as a nitrogenous organic base, such as, for example, pyridine, dimethyl-aminopyridine, N-methylmorpholine or a trialkylamine (in particular triethylamine or diisopropylethylamine). It is also preferable to carry out the reaction in the presence of a coupling agent, such as a carbodiimide [for example dicyclohexylcarbodiimide or 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide], N,N′-carbonyldiimidazole or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. The reaction is preferably carried out under argon or nitrogen.
It is understood that the amino, alkylamino or carboxyl radicals present in R
1
, R
2
and R
3
, like the hydroxyl functional group carried by the pyran ring, are preferably protected beforehand. Protection is carried out in particular according to the methods described by T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (3
rd
ed.), A. Wiley-Interscience Publication (1999).
Subsequently, the quinoline derivative of general formula (IV) and trialkyl (optionally substituted C
1
-C
4
) orthopropiolate or alkyl (optionally substituted C

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