Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-09
2003-12-16
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06664285
ABSTRACT:
This application is a 371 of PCT/EP00/03210 filed Apr. 11, 2000.
The present invention relates to the use of cell membrane penetrating indigoid bisindole derivatives for the manufacture of a medicament for the treatment of human solid cancers.
Indigoid bisindoles comprise a spectrum of natural dye stuffs. Many of these can be obtained from plants. Accordingly, indirubin, indigo and isoindigo are natural products which can be obtained from different plants: namely,
Baphicacanthus cusia
(Acanthaceae),
Indigofera suffruticosa
(Fabaceae),
Isatis indigotica
(Brassicaceae) and others. Indican, a glycoside which is found in plants, gives glucose and 3-hydroxyindole due to acidic or enzymatic hydrolysis. 3-Hydroxy-indole is converted by air-oxidation into indigo and its isomers. Indigo naturalis (Chinese: quingdai) is the natural blue dye obtained from plant material, e.g.
Isatis indigotica
(Brassicaceae). Indirubin, an isomer of indigo, can be found in Indigo naturalis in an amount of up to 60% (Falbe J. & Regitz M., Römpp Chemie Lexikon (1992), 9. Aufl., Stuttgart, Georg Thieme Verlag). It occurs also in
Isatis tinctoria
in an amount of up to 5% which is indigenous to Central Europe (Gelius R., Z. Chem., 20, (1980), 340-341). Derivatives of indirubin are known for a long time as dyes of low persistence.
Indigo naturalis is reported to be used in traditional Chinese medicine as a haemostatic, anti-pyretic, anti-inflammatory and sedative agent in the treatment of bacterial and viral infections. Antileukemic effects of Indigo naturalis have also been reported, with indirubin being the effective principle (Ji X. et al., Acta Pharm. Sin., 16, (1981), 146-148; Gan W. J. et al., J. Hematol., 6, (1985), 611-613). In spite of its anti-leukaemic activity, however, indirubin dissolves only poorly in water and is therefore not readily resorbed. Recently, the antileukemic activity of some better soluble indirubin derivatives has been reported (Ch. Li et a., Bull. Chem. Soc. Jpn. 69, 1621-1627 (1996)).
However, indigoid bisindole or its derivatives have never been investigated with respect to solid tumors, in particular human solid tumors, and furthermore, the problem of the poor solubility resulting in a poor resorption has not been sufficiently solved yet.
Thus, the technical problem underlying the present invention is to provide new active substances which can be used in the treatment of human solid tumors and metastasis thereof. Furthermore, the resorption of said substances should be improved in order to improve their in vivo anti-tumor activity.
The solution to the above technical problem is achieved by the embodiments characterized in the claims.
In particular, the present invention relates to the use of cell membrane penetrating indigoid bisindole derivatives for the manufacture of a medicament for the treatment of human solid tumors and metastasis thereof wherein the indigoid derivatives are selected from indigo, bis(3-phenylindol-2-yl), isoindigo and indirubin derivatives, the latter represented by the following formula (I):
wherein, when X represents an oxygen atom, R
1
represents a hydrogen atom, a halogen atom, a —NO
2
group, a methyl group, a sulfonamide group or SO
2
—NH—CH
2
CH
2
—OH; and
wherein, when X represents NOH, R
1
represents a hydrogen atom or an iodine atom.
The above indigoid bisindole derivatives can also be employed in the form of their physiologically acceptable salts. Furthermore, the indigoid bisindole derivatives according to the present invention may also be chemically coupled to masking agents as described e.g. in German patent application DE-A-38 27 488 which function to carry the anti-tumor active substances to the tumor.
In the following, the indigoid derivatives selected from indigo, isoindigo and indirubin derivatives according to the present invention are also addressed to as “anti-tumor active compounds according to the present invention”.
According to the present invention the terms “cell membrane penetrating” and “cell resorbable” mean the ability of the indigoid bisindole derivatives to be taken up by the tumor cell through the cellular membrane.
The term “human solid tumors” according to the present invention preferably includes carcinomas, melanomas, adenomas, sarcomas, lymphomas, neuroblastomas, teratomas, astrocytomas, glioblastomas and mesotheliomas. Specific examples are mammary carcinoma, large-cell lung carcinoma, small-cell lung carcinoma, lung epidermoid and adenocarcinoma, colorectal carcinoma, bladder carcinoma, ovarian carcinoma, pancreatic carcinoma, renal carcinoma, prostatic carcinoma, head and neck carcinomas, melanomas, cervical carcinomas, osteosarcoma and the like.
The above identified indigoid bisindole derivatives of the present invention can be formulated into pharmaceutical compositions which contain optionally a pharmaceutically acceptable carrier and/or diluent. Said pharmaceutical compositions can be applied e.g. orally, topically, intravenously, intraperitoneally, subcutaneously and rectally in pharmaceutically effective amounts.
One general problem in the field of pharmacology is the formulation of pharmaceutically active substances in pharmaceutical compositions which can be applied to a human body. Since most physiological fluids are waterbased, the pharmaceutically active substances should be soluble in water and/or a water mixable solvent wherein the latter of course has to be physiologically acceptable in small concentrations, such as ethanol. Furthermore, pharmaceutically active substances which are taken orally have to be resorbed into surface of the human body—including the gastrointestinal mucous membrane—or, in case of an application via syringe, e.g. intraperitoneal or intravasal, have to be resorbed through the cellular membranes of the of destination cells, specifically into the tumor cells.
According to the present invention it has been found that in case of the indigoid bisindole derivatives according to the present invention, a good solubility is not the only prerequisite guaranteeing a good anti-tumor activity in viva as it will become apparent by the Examples and Comparative Examples shown below. An important factor for the anti-tumor activity of indigoid bisindole derivatives is their ability to penetrate the cellular membranes of the tumor cells. Cellular membranes are composed of lipids and compose a rather non-polar medium. Therefore, substitution with extremely polar groups such as the sulfonate group on the one hand improves the water solubility of a compound but on the other hand hinders or even prohibits the resorption of anti-tumor active substances into a tumor cell. Thus, anti-tumor active substances which show good anti-tumor activities under certain in vitro conditions, have to be rejected because of not showing any activity when tested using intact cells or in vivo.
Therefore, in the following Examples the testing of the anti-tumor active substances are tested by in vitro tests using intact tumor cells and, additionally, in vivo tests. Furthermore, a comparison of the activity test results and the tests evaluating the ability to penetrate cellular membranes shows that indigoid bisindole compounds which exhibit a good cell-penetrating ability also show good to excellent anti-tumor activity.
REFERENCES:
patent: 5935581 (1999-08-01), Kapadia et al.
patent: WO 99/62503 (1999-12-01), None
patent: WO 00/61555 (2000-10-01), None
Li et al., Chung Hua I Hsueh Tsa Chih, (1979), 59, (3), 129-132 Abstract .*
Dyer, AN index of Tumor chemotherapy, NIH, Mar. 1949, pp. 10-12 and 131.*
International Search Report (For PCT/ISA/210), PCT/EP00/03210.
Derwent, database WPI, XP 002164029 abstract for JP 61 007254 A, Jan. 13, 1986.
Derwent, database WPI, XP 002164030 abstract for JP 57 209271 A, Dec. 22, 1982.
Derwent, database WPI, XP 002164031 abstract for 57 209272 A, Dec. 22, 1982.
Derwent, database WPI, XP 002164032 abstract for CN 1 207 924 A, Feb. 17, 1999.
K.C. Tsou et al., “Indigogenic Phosphodiesters as Potential Chromogenic Cancer Chemotherapeutic Agents,” J. Med. Chem. 1972, vol. 15, N
Eisenbrand Gerhard
Fiebig Heinz Herbert
Hössel Ralf
Marko Doris
Tang Weici
Burns Doane Swecker & Mathis L.L.P.
Goldberg Jerome D.
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