Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-27
2003-10-14
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...
C546S049000, C546S056000
Reexamination Certificate
active
06632822
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to compounds containing a indolo[3,2-j]phenanthridine ring system. In particular, the present invention relates to compounds which are useful in the treatment of cancer and other diseases of humans and animals, particularly parasitic diseases, such as those of apicomplexan origin, compositions containing said compounds and methods of treatment using them.
BACKGROUND ART
Despite the significant advances made by the medical and scientific community over the last fifty years, a number of potentially mortal and debilitating mammalian, particularly humanp diseases are yet to be conquered by effective and adequate prophylaxis, treatment or cure. Two examples of such diseases are cancer and malaria.
Malaria is a disease which has been estimated to affect approximately 5% of the World's population at any time, accounts for 25-50% of all hospital admissions in Africa, and is responsible for the death of between 1 to 2 million children each year.
The disease is caused by the entry of an apicomplexan parasite, Plasmodium, particularly
P. falciparum
or
P. vivax
into the bloodstream, through the bites of females of certain mosquito species which transmit the disease from one host to another. The parasite invades the liver and the red blood cells of the host and manifests its presence in the well recognised symptoms of chills, shivering, fever and profuse sweating. If left untreated, the disease chronically manifests itself through regularly recurring bouts of fever and prostration. Repeated attacks may result in the development of anaemia and enlargement of the liver and spleen. In the very young or old, the disease can be fatal.
Chloroquine has become the standard antimalarial for the treatment and prophylaxis of human malarial diseases and has become one of the most widely used drugs in the world. Increasingly, however, the parasites have developed resistance to the drug and
P. falciparum
is now almost untreatable with chloroquine and many strains of
P. vivax
are also resistant. Although quinine is often used against chloroquinine resistant strains of Plasmodium it is poorly tolerated and compliance is low. (White, N. J. (1992),
J. Antimicrob. Chemother.
30, 571-85; Krishna, S. (1997),
Br. Med. J.,
315, 730-32). Other drugs such as mefloquine produce undesirable side effects.
Accordingly, there exists a need for new anti-malarial drugs which are effective against Plasmodium.
Another disease which has long been the subject of intense research by the medical and scientific communities is cancer. The growth, development and death of normal cells are highly regulated by mechanisms which are not yet fully understood. When these regulatory controls cease or malfunction, due to either external or genetic factors, the aberrant cells multiply at a greater rate than normal. Malignant tumours can metastasise throughout the body and invade other tissues and organs. The aetiology of cancer remains incompletely understood and despite advances in the detection and treatment of cancerous conditions over the last several decades, there remains a continued need for the development of new anticancer agents.
DISCLOSURE OF THE INVENTION
The present inventors have now isolated for the first time, specific compounds from extracts of certain Calothrix strains of cyanobacteria which have bioactivity against Plasmodium and cancer cells and may provide new treatments for mammalian diseases, including parasitic diseases such as malaria, or cancerous conditions. Without intending to limit the invention in any way, it has also been found that one mode of biochemical action of these compounds involves inhibition of DNA transcription or replication, and therefore, the present invention may also provide therapeutic and/or prophylactic methods for other conditions or infections.
Accordingly, in a first aspect, the present invention provides compounds of Formula (I):
wherein
R is selected from hydrogen, alkyl, acyl, carboxyalkyl, carboalkoxyalkyl;
m and n are independently selected from 0, 1, 2;
each Y and each Z are independently selected from halo, acyl, nitro, amino, alkylamino, acylamino, hydroxy, acyloxy, alkoxy, alkyl, CO
2
H, CO
2
alkyl, CONX
2
(where each X is independently H or alkyl), SO
3
H, SO
2
NX
2
(wherein each X is independently H or alkyl), nitrile, formyl, carboxyalkyl, carboalkoxyalkyl;
a, b, c and d are independently selected from hydrogen, hydroxy, alkoxy, acyloxy, alkyl; or,
a and b together and/or c and d together independently form a carbonyl group (C═O), an imine group (C═N—R
1
, where R
1
is alkyl, hydroxy, alkoxy or amino NR
2
R
3
), or an alkene group (C═CR
2
R
3
, where R
2
and R
3
are independently hydrogen or alkyl);
or salt, derivative or prodrug thereof.
Compounds of Formula I can exist in their N-oxide form or as the free (unoxidized) base.
As used herein, the term “alkyl” denotes a straight, branched or cyclic fully saturated hydrocarbon residue of 1-6 carbon atoms including methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 3-methylpentyl, 2,3-dimethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Particularly preferred alkyl are methyl, ethyl, n- and iso-propyl, n-, sec and t- butyl. Optionally the alkyl group may be substituted by one or more halo, hydroxy, phenyl, amino, alkoxy, acyl, nitro, carboxylic acid, or carboxylic ester groups, for example halomethyl groups (eg CF
3
, CBr
3
) hydroxy alkyl groups (eg hydroxymethyl, hydroxyethyl), benzyl, aminoalkyl and alkoxyalkyl.
The term “acyl” is intended to refer to a group of the group of the formula —C(O)R′, where R′ is alkyl as defined above.
“Acyloxy” and “alkoxy” are taken to refer to acyl and alkyl groups when linked by an oxygen atom.
The term “halogen” denotes fluorine, chlorine, bromine or iodine.
Suitable alkoxy groups include methoxy, ethoxy, propoxy (n- and iso-) butoxy (n-, sec- and t-). Sitable carboxyalkyl groups include carboxymethyl, carboxyethyl, carboxybutyl, carboxypropyl. Suitable carboalkoxyalkyl include carbomethoxymethyl, carboethoxymethyl, carbopropoxymethyl, carbobutoxymethyl, carbomethoxyethyl, carboethoxyethyl, carbopropoxyethyl, carbobutoxyethyl, carbomethoxypropyl, carboethoxypropyl, carbopropoxypropyl, carbobutoxypropyl, carbomethoxybutyl, carboethoxybutyl, carbopropoxybutyl, carbobutoxybutyl. Suitable acyloxy include C(O)methyl, C(O)ethyl, C(O)propyl, C(O)butyl. Suitable CO
2
alkyl includes CO
2
methyl, CO
2
ethyl, CO
2
propyl, CO
2
butyl. Suitable amides include CONH
2
, CONHMe, CONHEt, CONHPr, CONMe
2
, CONEt
2
, CONPr
2
. Suitable amino groups include NH
2
, NHMe, NHEt, NHPr, NMe
2
, NEt
2
, NPr
2
.
The term “salt, derivative or prodrug” refers to any pharmaceutically acceptable salt, ester, solvate, hydrate or any other compound which, upon administration to the recipient is capable of providing (directly or indirectly) a compound as described herein. However, it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the invention since these may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts and prodrugs and derivatives can be carried out by methods known in the art.
Suitable pharmaceutically acceptable salts include salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lit
Kirk Kiaran
Rickards Rodney W.
Smith Geoffrey D.
Aulakh Charanjit S.
Greenlee Winner and Sullivan P.C.
The Australian National University
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