Preparation of camptothecin and nothapodytine derivatives

Details Preparation of camptothecin and nothapodytine derivatives Preparation of camptothecin and nothapodytine derivatives

2001-01-26

2002-12-31

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S062000, C546S070000

Reexamination Certificate

active

06500953

ABSTRACT:

The present invention relates to the preparation of camptothecin derivatives. The present invention also relates to the preparation of nothapodytine, mappicine or its derivatives.
In European patent EP 137145, cited here by way of reference, there have been described camptothecin derivatives of general formula:
in which in particular R
1
is hydrogen, halogen or alkyl, X is a chlorine atom or NR
2
R
3
for which R
2
and R
3
, which are identical or different, may represent a hydrogen atom, an optionally substituted alkyl radical, an optionally substituted carbocycle or heterocycle, or alkyl derivatives (optionally substituted) forming with the nitrogen atom to which they are attached, a heterocycle optionally containing another heteroatom chosen from O, S and/or NR
4
, R
4
being a hydrogen atom or an alkyl radical and in which the group X—CO—O—is situated at the 9-, 10- or 11-position of the A ring. These camptothecin derivatives are anticancer agents, inhibitors of topoisomerase I, among which irinotecan, for which X—CO—O—is [4-(1-piperidino)-1-piperidino]-carbonyloxy, is an active ingredient which is particularly effective on solid tumors and in particular colorectal cancer.
In patent application EP 74256, cited here by way of reference, there have also been described other camptothecin derivatives which are mentioned as anticancer agents, in particular derivatives having a structure analogous to the structure given above and in which X—CO—O— is replaced by a radical —X′R′ for which X′ is O or S and R′ is a hydrogen atom, an alkyl or acyl radical.
Other camptothecin derivatives have also been described, for example, in patents or patent applications, cited here by way of reference, EP 56692, EP 88642, EP 296612, EP 321122, EP 325247, EP 540099, EP 737686, 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, JP 91 012070 or in Canc. Res., 38 (1997) Abst. 1526 or 95 (San Diego—12-16 April), Canc. Res., 55(3), 603-609 (1995) or AFMC Int. Med. Chem. Symp. (1997) Abst. PB-55 (Seoul—27 July-1 August).
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 steps comprise the introduction of a hydroxyl functional group at the 9-position, and an alkylation at the 11-position and the introduction of the radical at the 9-position.
Mappicine and nothapodytine are known products; nothapodytine is a natural alkaloid possessing an antiviral activity on the HSV-1, HSV-2 and HCMV viruses.
In international patent application WO 96/31513, there has been described the preparation of camptothecin and mappicine derivatives by total synthesis by preparing, in the first place, the cyclic linkage C-D or C-D-E.
Tetrahedron, 53(32), 11049-60 (1997) also describes the total syntheses of camptothecin derivatives in which the A-B and D-E rings are prepared beforehand, or according to another aspect, the linkages C-D-E or A-B-C.
J. Amer. Chem. Soc., 120, 1218-1222 (1998) and J. Org. Chem., 61, 9623-24 (1996) describe syntheses of nothapodytine from the A-B rings with yields of 17 and 30%, respectively; however, these synthesis routes were not easy to carry out given the preparation of the raw materials involving low temperatures and problems of industrial hygiene.
It has now been found, and it is what constitutes the subject of the present invention, that the camptothecin derivatives, as well as mappicine and nothapodytine, could be obtained by a convergent synthesis from a derivative of 3-aminomethyl-2-bromoquinoline and of 4-ethyl-2-methylhepta-2,4-dienoic acid with particularly advantageous results.
According to the invention, 4-ethyl-2-methyl-hepta-2,4-dienoic acid having the structure:
is condensed with a 3-aminomethyl-2-bromoquinoline derivative of general formula:
in which R
1
and R
2
may be hydrogen atoms or R
1
represents a halogen atom or an alkyl radical, R
2
is a radical having the structure —O—CO—X as cited above or R
1
and R
2
are as defined in the references cited above or represent radicals which are protected or which can be easily converted to the radicals R
1
and R
2
cited above, to give the quinoline derivative of general formula:
in which R
1
and R
2
are as defined above.
The reaction is generally carried out according to the usual methods for condensing acids with amines, in particular by the action of the acid or of a reactive derivative of the acid.
When the condensation of a reactive derivative of the acid of general formula (II) is carried out, the procedure is advantageously carried out by means of acid chloride, anhydride, a mixed anhydride or a reactive ester in which the ester residue is a succinimido, optionally substituted 1-benzotriazolyl, 4-nitrophenyl, 2,4-dinitrophenyl, pentachlorophenyl or phthalimido.
The reaction is generally carried out at a temperature of between −40 and +40° C., in an organic solvent such as in particular a chlorinated solvent (for example dichloromethane, dichloroethane or chloroform), in the presence of an acid acceptor such as a nitrogen-containing organic base such as for example pyridine, dimethylaminopyridine, N-methylmorpholine or a trialkylamine (in particular triethylamine, diisopropylethylamine) or such as an epoxide (for example propylene oxide). It is also possible to carry out the procedure in the presence of a condensing agent such as a carbodiimide [for example dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide], N,N′-carbonyldiimidazole or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. Preferably, the procedure is carried out under argon or nitrogen.
It is understood that the amino, alkylamino or carboxyl radicals contained in R
1
and/or R
2
are preferably protected beforehand. In particular, the protection is performed according to the methods described by T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (2nd Ed.), A. Wiley-Interscience Publication (1991), or by Mc Omie, Protective Groups in Organic Chemistry, Plenum Press (1973).
(2-Methoxycarbonylvinyl)tributyltin is added to the quinoline derivative of general formula (IV), in the presence of a complex of palladium [such as for example tris(dibenzylidene acetone)dipalladium] and triphenylarsine, to give the quinoline derivative of general formula:
in which R
1
and R
2
are as defined above.
The reaction is generally carried out in an organic solvent such as an ether (for example dioxane) at a temperature of between 50 and 110° C. Preferably, the procedure is carried out under argon or nitrogen.
The quinoline derivative of general formula (V), in the presence of triethylamine, is cyclized by addition of t-butyldimethylsilyl triflate to give the tetracyclic derivative of general formula:
in which R
1
and R
2
are as defined above.
The reaction is carried out in an anhydrous medium, in a chlorinated organic solvent (for example dichloromethane), at a temperature of between −30 and +30° C. Preferably, the procedure is carried out under argon or under nitrogen.
This derivative is subjected to ozonolysis, followed by treatment with dimethyl sulfide to give the ketone derived from the tetracyclic compound of general formula:
in which R
1
and R
2
are as defined above.
The ozonolysis is carried out in a mixture of chlorinated solvent and alcohol (for example dichloromethane/methanol), at a temperature in the region of −78° C. The product obtained is treated with dimethyl sulfide at a temperature of between −78 and 20° C.
The tetracyclic derivative of general formula (VII) is saponified and then decarboxylated under oxidizing conditions to give the nothapodytine derivative of general formula:
in which R
1
and R
2
are as defined above.
The reaction is advantageously car

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