Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1994-08-02
2002-06-11
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...
C546S048000
Reexamination Certificate
active
06403603
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a new process for the preparation of 9-amino-20 (S)-camptothecin of formula (I)
which is a known antitumor agent: Wani et al., J. Med. Chem. 1987, 30, 1774-1779; Hsiang et al., Cancer Res. 49, 4385-4389, Aug. 15, 1989; Cancer Res. 49, 1465-1469, Mar. 15, 1989.
BACKGROUND OF THE INVENTION
Totally synthetic approaches to 9-amino camptothecin have been widely described (U.S. Pat. No. 4,894,456 and U.S. Pat. No. 5,053,512). Total synthesis of the product, however, is neither desirable nor suitable for large scale production because it involves too many process steps that make the synthesis too long and, especially, too expensive.
A semisynthetic approach to 9-amino camptothecin is described, e.g., in JP-A-59-51289, published in 1984, starting from the known natural product camptothecin: Cancer Chemotherapy Reports, part I, vol. 54, No. 6, December 1970, 461-470; J. Med. Chem., 1980, 23, 554-560; Science, vol. 246, November 1989, 1046-1048. The said semisynthetic approach involves the nitration of the naturally occurring camptothecin, followed by reduction of the 9-nitro derivative. That nitration, however, initially produces a 70/30 mixture of the undesired 12-nitro camptothecin derivative (70%) and of the desired 9-nitro camptothecin derivative (30%). The 9-nitro derivative is therefore formed only in a minor amount.
After the separation of the two nitration products, the 12-nitro derivative, which is itself biologically inactive (see, for instance, Wani C., Nicholas A. W., Wall M. E., J. Med. Chem., 1986, 29, 2358), must then be discharged, giving rise to waste treatment problems. The considerable drawback concerning the removal of the undesired 12-nitro derivative byproduct is particularly relevant for large scale production since large amounts of unuseful 12-nitro derivative are collected and need to be eliminated.
Moreover, following this semisynthetic approach, large quantities of natural camptothecin, which is highly expensive, are needed to produce small quantities of the desired antitumor agent 9-amino camptothecin. The low overall productivity and yields of this approach make the production of substantial amounts of the desired compound difficult. There is therefore a need for a process permitting increased productivity and yields compared to the above outlined semisynthetic approach to 9-amino camptothecin.
We have developed a new process which fulfils this purpose and, at the same time, resolves the waste product problems deriving from the production of consistent amounts of the undesired 12-nitro derivative. According to the invention, this 12-nitro derivative is recycled into the process through conversion into 9-amino camptothecin by easy and mild reaction conditions ensuring high yields and clean reaction products.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a new process for preparing 9-amino camptothecin of formula (I) starting from 12-nitro camptothecin of formula (II), according to the steps illustrated in Scheme I below:
wherein X is a group which can be removed reductively.
The process includes the reductive transformation of the 12-nitro derivative of formula (II), into the 12-amino derivative of formula (III). This intermediate is in turn transformed into the corresponding diazo derivative, which is “in situ” transformed into a compound of formula (IV), wherein X is a group which can be reductively removed, e.g. a halogen.
Nitration of the 12-substituted derivative of formula (IV) affords with high selectivity and yields the corresponding 9-nitro-12-substituted derivative of formula (V). The subsequent reduction of the compound of formula (V) to give the 9-amino camptothecin compound of formula (I) may be performed either in a single step leading directly the compound of formula (I) or, alternatively, in two steps reducing first a compound of formula (V) to a compound of formula (VI) and, further, reducing a compound of formula (VI) to the compound of formula (I). The compound of formula (VI) may not be necessarily isolated.
In JP-A-59-51289 cited above and in published literature articles (see for instance Chem. Pharm. Bull. 1991, 39, 3183) much chemistry has been disclosed about the camptothecin molecule, including conversion of the 12-amino group into a corresponding 12-halo derivative, but it was used only for the purpose of synthesizing compounds for biological evaluation. The biological uselessness of the 12 substituted compounds (see, for instance Crow, R. T.; Crothers, D. M. J. Med. Chem. 1992, 35, 4160), and the chemical difficulties have then prevented any effort toward possible further modifications of the 12-substituted camptothecin derivatives.
In particular, the introduction of a nitro group on a 12-substituted derivative of this molecule is not known and looks problematic as it could give rise to mixtures of derivatives: different positions of the ring system, in fact, could undergo to reaction.
Furthermore, with reference to the removal of the X group from the compound (V) or (VI) it must be emphasized that, while the reductive removal of halogen atoms from quinolines is well known (see for instance Jones, G. The Chemistry of heterocyclic compounds, 32, I. p. 604-611) where, generally, the presence of bases is regarded as beneficial in order to achieve mild reaction conditions, on the contrary, in spite of the several years effort on the chemistry of camptothecin, nothing is known about group removal (e.g. removal of halogen groups) from camptothecin derivatives, and, more, camptothecin derivatives are known to be extremely base sensitive so that the recourse to a base would appear problematic.
Surprisingly we have now found that it Is possible to remove, e.g., a halogen atom from camptothecin in the presence of an organic or inorganic non-nucleophilic base. The present invention includes this aspect and is also based on the observation of the very weak basic and nucleophilic nature of the 9-amino group in camptothecin molecule. Indeed, the reduction of the 9-nitro group in 9-nitro-12-substituted derivatives of formula (V) would afford the 9-amino functionality and the so formed 9-amino group could then act as an in situ generated weak non-nucleophilic base, and, in principle, promote the reductive removal of group X, without decomposition.
On the other hand, the presence of the two substituents in the p-position to each other in a compound of formula (V) could be expected to have an undesired influence, and impede or render very difficult the double reduction step; low yields or decomposition of the desired product could be expected. In any case, the overall synthetic scheme illustrated above combining such a sequence of reactions, has never been reported, nor has its potential utility been recognized or exploited before.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparing 9-amino camptothecin of formula (I)
said process comprising:
(1) reducing the compound of formula (II)
so obtaining the compound of formula (III)
(2) converting the compound of formula (III) into a compound of formula (IV)
wherein
X is a group which can be reductively removed;
(3) reacting a compound of formula (IV) with a nitrating agent so obtaining a compound of formula (V)
wherein X is as defined above, and
(4) reducing in a single step a compound of formula (V)
so obtaining the 9-amino camptothecin of formula (I) or, alternatively,
(5) reducing a compound of formula (V) so obtaining a compound of formula (VI)
wherein X is as defined above, and
(6) reductively removing the X group from a compound of formula (VI) so obtaining the 9-amino camptothecin of formula (I).
Preferably the X group is a halogen, such as, e.g., Cl, I, Br or F, more preferably Cl or Br.
The reduction of the compound of formula (II) into the compound of formula (III) may be carried out, for example, with suitable reducing agents, or by catalytic reduction with suitable catalysts, in the presence of suitable reducing agents. For example, it may be perfo
Bedeschi Angelo
Cabri Walter
Candiani Ilaria
Zarini Franco
Kifle Bruck
Oblon, Spivak, McClelland, Maier & Neustandt P.C.
Pharmacia & Upjohn S.p.A.
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