Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-15
2003-11-18
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S348000, C514S451000, C514S452000, C424S009200
Reexamination Certificate
active
06649647
ABSTRACT:
This invention relates to certain compounds containing a trioxane moiety which have cytotoxic and antitumour activity and their use in the treatment of cancer, processes for preparing such compounds and pharmaceutical compositions containing such compounds.
The compound artemisinin, also known as ginghaosu (1), is a tetracyclic 1,2,4-trioxane occurring in
Artemisia annua
. Artemisinin and its derivatives dihydroartemisinin (2), artemether (3) and sodium artesunate (4) are routinely used for the treatment of malaria and are particularly effective against cerebral malaria.
Different modes of action have been proposed by various groups to account for the action of artemisinin and its derivatives in treating malaria (Posner et al.,
J.Am.Chem.Soc.
1996,118,3537; Posner at al.,
J.Am.Chem.Soc.
1995,117,5885; Posner at al.,
J. Med.Chem.
1995,38,2273). Whilst the mode of action of artemisinin as an antimalarial has not been unequivocally established, it has been demonstrated that the peroxide linkage is essential for expression of activity. One proposal embodies cleavage of the endoperoxide bridge by intraparasitic heme iron (II) to generate unstable free radical intermediates which alkylate malaria proteins (see Scheme 1 below).
Recently, the isolation of a covalent adduct formed between artemisinin and a heme model Mn
II
TPP tends to support this proposal (Robert et al,
J.Am.Chem.Soc.
1997,119,5968). Formation of artemisinin-heme and artemisinin-protein adducts have also been reported when
P. falciparum
infected erythrocytes have been incubated in vitro with radiolabelled artemisinin (Hong et. al.,
Mol.Biochem.Parasitol.
,1994,63,121; Asawamahasakda et al.,
Antimicrob.Agents Chemother.
, 1994,38,1854). However, attention has also focused on perferryl iron as the active species as this has been unambiguously detected when artemisinin analogues have been incubated with iron(II). Its postulated mode of formation is rather curious in that it is presumed to arise via a reductive scission of the peroxide bond by iron(II) (see Scheme I).
Based on a careful analysis of products obtained from artemisinin on treatment both with iron (II) and iron (III), it has been shown that the trioxane unit acts as a source of free hydroperoxide or equivalent, which is then capable of generating hydroxyl or alkoxy radicals, or of perferryl iron by direct coordination to the iron(II) site in ferroheme according to well-established models (Haynes et al.,
Today's Life Science
,1993,14;
Tetrahedron Lett.
1996,37,253;1996,37, 257). These are set out in Scheme 2 below.
Peroxides in general are biologically active. Tert-butylhydroperoxide is used as a potent inhibitor of bacterial growth on fish, although it is quite toxic towards many living organisms. The root growth inhibitor of Formula A below also has a peroxide bridge in the ring and the inhibitory action on the plant root is correlated with the peroxide bridge. Recently, the simple cyclic peroxide of Formula B below has been studied as a candidate for radical releasing drugs, because these compounds are known to generate hydroxyl radicals by heat stimuli.
Certain artemisinin derivatives which contain a peroxide moiety have also been tested for biological activity other than antimalarial activity. For instance, the cytotoxicity of artemisinin, dehydroartemisinin, artemisitene, arteether, ethylperoxyartemisitene and an ether dimer of artemisinin to Ehrlich ascites tumor cells has been reported (Beekman et al.,
Phytother.Res.
,1996,10,140; Woerdenberg et al.,
J.Nat.Prod.
,1993,56,849). Selective cancer cell cytotoxicity from exposure to dehydroartemisinin and holotransferrin, a non-heme iron-transport protein saturated with iron, has also been disclosed (Lai et al.,
Cancer Lett.
,1995,91,41 and U.S. Pat. No. 5,578,637) with the drug combination being approximately 100 times more effective on molt-4 cells than lymphocytes.
It is known that some biologically active molecules contain chemical groups which enable the molecule to bind to DNA. The method by which DNA-binding occurs will depend upon the overall structure of the molecule and the nature of the chemical groups contained within the molecule.
For instance, the major and minor grooves of double helical DNA are occupied by water under physiological conditions. However, certain oligopeptidic compounds, such as netropsin and distamycin can displace water molecules and form strong hydrogen bonds with hydrophilic groups along the DNA strands. The crescent-shaped structures of netropsin and distamycin can make them fit tightly into the helical structure of DNA.
Alternatively, some compounds contain groups which are capable of intercalating with DNA. Intercalators are flat aromatic compounds which insert between the bases of DNA, the ensemble being held together by hydrophilic and &pgr;—&pgr; interactions. Well characterised examples of intercalators are provided by anthracyclines, such as adriamycin and daunomycin, which are used for treatment of cancer, and acridines, such as amascrine, which is used for treating acute leukaemia and malignant lymphomas, the antitumour activity is associated with the intercalating property of these compounds.
The technique of incorporating minor groove binding agents related to netropsin or distamycin, or intercalating agents to free-radical generators or electrophilic alkylating agents as a means of inducing DNA strand cleavage is well known. For instance, Toshima and co-workers (
J.Am.Chem.Soc.
, 1995,117,4822;
J.Chem.Soc.,Chem.Commun.
,1993,1525;
J.Chem.Soc., Chem.Commun.
,1992,1306;
Heterocycles
, 1997,45,851) have synthesised DNA-cleaving hybrid molecules of Formula C below containing enediyne and DNA intercalators.
DNA cleavage takes place via collapse of the enediyne moiety to a highly reactive diradical which abstracts hydrogen atoms from C4′ of the deoxyribose in the DNA.
The best known anti-cancer agent, which acts by cleaving DNA through generation of active oxygen species, is bleomycin (BLM). It is a glycopeptide which binds to DNA via intercalation of the bis-thiazole group. The compound sequesters iron to form a planar BLM-iron(II) complex and activation by oxygen then provides perferryl capable of abstracting hydrogen atoms from C4′ of deoxyribose. DNA cleavage takes place mainly at the C or T position in GC or GT array.
Examples of hydroxyl radical participation in DNA cleavage are also observed in many other anticancer drugs.
It has how been discovered that artemisinin and synthetic trioxane derivatives can be chemically modified by the attachment of a DNA-binding group to form analogues of artemisinin and synthetic trioxane derivatives which are capable of targeting DNA in pathogenic organisms. Moreover, in the course of synthesising such compounds, other artemisinin and synthetic trioxane derivatives were prepared which do not contain a DNA-binding group but which were found to exhibit cytotoxic and antitumour activity. According to a first aspect of the present invention there is therefore provided a compound of the general formula I
or a salt thereof,
in which
X represents a hydrogen atom or a group —NR
1
R
2
, —CHR
8
R
9
or Ar;
Y represents a hydrogen or halogen atom, an or hydroxyl oxo group, an optionally substituted cycloalkyl, aryl, C-linked heteroaryl or heterocyclylalkyl group or a group —NR
3
R
4
, —O—CO—R
5
or —OR
6
; and
Z represents an oxygen atom or a group =NR
7
; where
R
1
and R
2
independently represent an optionally substituted alkyl, cycloalkyl, aryl or aralkyl group;
or R
1
and R
2
together with the interjacent nitrogen atom represent an optionally substituted heterocyclic group or an amino group derived from an optionally substituted amino acid ester;
R
3
represents a hydrogen atom or an optionally substituted alkyl, alkenyl or alkynyl group;
R
4
represents an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group;
or R
3
and R
4
together with the interjacent nitrogen atom represent an optionally substituted heterocyclic group or an amino group derived fro
Baumgarten Jörg
Chan Ho-Wai
Haynes Richard
Hsiao Wen-Luan
Lam Wai-Lun
Aulakh Charanjit S.
Gioeni, Esq. Mary Louise
Heslin Rothenberg Farley & & Mesiti P.C.
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