Xanthone compounds, their preparation and use as medicament

Details Xanthone compounds, their preparation and use as medicament Xanthone compounds, their preparation and use as medicament

2000-06-28

2002-06-11

Higel, Floyd D. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S381000, C549S414000

Reexamination Certificate

active

06403636

ABSTRACT:

INTRODUCTION
This invention relates to novel xanthone compounds, their preparation and use as a medicament. More particularly this invention is directed to the isolation of the novel xanthone natural product sootepenseone from
Dasymaschalon sootepense
Craib, Annonaceae, its identification and derivatization, and the use of sootepenseone and its derivatives as anticancer agents.
FIELD OF INVENTION
Cancer is perhaps one of the most active anti-human factor operating in the world today, and efforts are being made all over the scientific world to prevent and eradicate it.
New agents with chemotherapeutic value in the fight against cancer is obviously a medical problem of high importance. But the development of new drugs in the cancer field is a difficult task given that anticancer agents must be lethal to, or incapacitate tumor cells, but they should not cause excessive damage to normal cells. At present the state of knowledge in cancer biology and in medical chemistry does not warrant the designing of new classes of molecules which may be effective antitumor agents. Despite the great progress made in cancer biology, molecular pharmacology, pharmacokinetics, medical chemistry and allied fields, the knowledge sought after, is still elusive.
Since the concept of chemotherapeutic treatment of malignant diseases had come to the forefront during the last decades, plant principles and their derivatives have been intensively investigated by scientists all over the world as new antitumor inhibitors. Examples for important anticancer agents of plant origins are the alkaloids vincaleukoblastine (vinblastine) and leurocristine (vincristine), both isolated from
Catharanthus roseus
. A comprehensive review on natural products as anticancer agents is given by Shradha Sinha and Audha Jain, in: Progess in Drug Research, Vol. 42, pages 53-132 (1994) Basel (Switzerland).
SUMMARY OF INVENTION
In accordance with the present invention there are provided novel cytotoxic xanthone compounds of the general formula (I)
wherein
R
1
is a hydrogen atom; a methyl group (—CH
3
), a C
2
-C
6
alkyl residue, a formyl group (—CHO); an acetyl residue (—COCH
3
), —CO—C
2-6
-alkyl, CO—C
3-8
-cycloalkyl, —CO—C
6-18
-aryl or —CO—C
7-24
-aralkyl residue each having optionally one or more substituents selected from the group consisting of —OH, —SH, —NH
2
, —NHC
1-6
-alkyl, —N(C
1-6
-alkyl)
2
, —NHC
6-14
-aryl, —N(C
6-14
-aryl)
2
, —N(C
1-6
-alkyl)(C
6-14
-aryl), —NHCOR
2
, —NO
2
, —CN, —(CO)R
3
, —(CS)R
4
, —F, —CI, —Br, —I, —O—C
1-6
-alkyl, —O—C
6-14
-aryl, —O—(CO)R
5
, —S—C
1-6
-alkyl, —S—C
6-14
-aryl, —SOR
6
, and —SO2R
7
, wherein R
2
to R
7
stands independently of each other for a hydrogen atom, —C
1-6
-alkyl, —O—C
1-6
-alkyl, —O—C
6-14
-aryl, —NH
2
, —NHC
1-6
-alkyl, —N(C
1-6
-alkyl)
2
, —NHC
6-14
-aryl, —N(C
6-14
-aryl)
2
, —N(C
1-6
-alkyl)(C
6-14
-aryl), —S—C
1-6
-alkyl, —S—C
6-14
-aryl residue;
a —COO—C
1-6
-alkyl residue having optionally one or more substituents selected from the group consisting of —OH, —SH, —NH
2
, —NHC
1-6
-alkyl, —N(C
1-6
-alkyl)
2
, —NHC
6-14
-aryl, —N(C
6-14
-aryl)
2
, —N(C
1-6
-alkyl)(C
6-14
-aryl), —NHCOR
8
, —NO
2
, —CN, —(CO)R
9
, —(CS)R
10
, —F, —CI, —Br, —I, —O—C
1-6
-alkyl, —O—C
6-14
-aryl, —O—(CO)R
11
, —S—C
1-6
-alkyl, —S—C
6-14
-aryl, —SOR
12
, and —SO2R
13
, wherein R
8
to R
13
stands independently of each other for a hydrogen atom, —C
1-6
-alkyl, —O—C
1-6
-alkyl, —O—C
6-14
-aryl, —NH2, —NHC
1-6
-alkyl, —N(C
1-6
-alkyl)
2
, —NHC
6-14
-aryl, —N(C
6-14
-aryl)
2
, —N(C
1-6
-alkyl)(C
6-14
-aryl) —S—C
1-6
-alkyl, —S—C
6-14
-aryl residue;
a —CONR
14
R
15
residue wherein R
14
and R
15
stand independently of each other for a hydrogen atom, —C
1-6
-alkyl, —O—C
1-6
-alkyl, —O—C
6-14
-aryl, —NH2, —NHC
1-6
-alkyl, N(C
1-6
-alkyl)
2
, —NHC
6-14
-aryl, —N(C
6-14
-aryl)
2
, —N(C
1-6
-alkyl)(C
6-14
-aryl), —S—C
6-14
-aryl residue;
or a counter cation selected from the group consisting of an alkali or earth alkali metal such as Li, Na, K, Ca, Mg, NR
16
R
17
R
18
R
19
(+) wherein R
16
to R
19
stands independently of each other for a hydrogen atom or a C
1
-C
6
-alkyl residue;
R
2
and R
3
either form part of the C
17
═C
18
-double bond or are each hydrogen, or a tautomer, an enantiomer, an stereoisomer or a physiologically acceptable salt or a solvate thereof or mixtures thereof.
In the case of a compound according to formula 1 above in the form of a phenolate with a di- or multivalent counter cation, the remaining positive charge can be compensated by association with a physiologically acceptable anion such as CI- or OH-.
The novel compound according to formula I, wherein R
1
is a hydrogen atom and R
2
and R3 form part of the C
17
-C
18
-double bound, has been given the name sootepenseone (1).
According to another aspect of the invention there is provided a process for manufacturing a compound according to formula I by isolation of sootepenseone (1) from the leaves of
Dasymaschalon sootepenseone
Craib, Annonaceae and its subsequent derivatization.
The present invention further provides the use of the compounds according to formula (I) as medicament, in particular for the treatment of cancer diseases.
The present invention further provides pharmaceutical formulations, comprising an effective amount of a compound according to formula (I) for treating a patient in need thereof. As used herein, an effective amount of a compound according to formula (I) is defined as the amount of the compound which, upon administration to a patient, inhibits growth of tumor cells, kills malignant cells, reduces the volume or size of the tumors or eliminates the tumor entirely in the treated patient.
Thus, the substantially pure compounds in accordance with the invention can be formulated into dosage forms using pharmaceutically acceptable carriers for oral, topical or parenteral administration to patients in need of oncolytic therapy.
In a preferred embodiment, the patient is a mammal, in particular a human.
The effective amount to be administered to a patient is typically based on body surface area, patient weight, and patient condition. The interrelationship of dosages for animals or humans (based on milligrams per meter squared of body surface) is described by Freireich, E. J. et al., Cancer Chemother. Rep., 50 (4) 219 (1966). Body surface area may be approximately determined from patient height and weight (see e.g. Scientific Tables, Geigy Pharmaceuticals, Ardly, N.Y., pages 537-538 (1970)). Preferred dose levels will also depend on the attending physicians assessment of both the nature of the patient's particular cancerous condition and the overall physical condition of the patient. Effective antitumor doses of the present xanthone compounds range from 1 microgram per kilogram to about 5000 micrograms per kilogram of patient body weightmilligram, more preferably between 2 micrograms to about 1000 micrograms per kilogram of patient body weight.
Effective doses will also vary, as recognized by those skilled in the art, dependent on route of administration, excipient usage and the posibility of co-usage with other therapeutic treatments including other anti-tumor agents, and radiation therapy.
The present pharmaceutical formulation may be administered intravenous, intramuscular, intradermal, subcutaneous, intraperitoneally, topical, or intravenous in the form of a liposome.
Examples of dosage forms include aqueous solutions of the active agent, in an isotonic saline, 5% glucose or other well-known pharmaceutically acceptable liquid carrier. Additional solubilizing agents well-known to those familiar with the art can be utilized as pharmaceutical excipients for delivery of the active agent. Alternatively, the present compounds can be chemically modified to enhance water solubility, for example, by formation of pharmaceutically acceptable phenolate salts.
The present compounds can also be formulated into dosage forms for other routes of administration utilizing well-known methods. The pharmaceutical compositions can be formulated, for example, in dosage forms for oral administ

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