Spisulosine compounds

Details Spisulosine compounds Spisulosine compounds

1999-08-31

2004-10-05

Cook, Rebecca (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S669000

Reexamination Certificate

active

06800661

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions of spisulosine compounds. It further relates to the treatment of tumors, and provides new cytotoxic compounds and pharmaceutical compositions for use against tumors. In one aspect, the invention relates to antitumor compounds from marine organisms.
BACKGROUND OF THE INVENTION
There has been considerable interest in isolating bioactive compounds from marine organisms. Typical procedures involve in vitro screening programs to test crude extracts for antimicrobial, antiviral, and cytotoxic activities. Illustrative examples of known bioactive compounds from marine sources include bryostatins, ecteinascidins and furthermore didemnins where didemnin B, also now known as aplidine, is the first marine natural product in clinical testing.
SUMMARY OF THE INVENTION
The present invention provides new pharmaceutical compositions containing a long-chain, straight-chain alkane or alkene compound which has a 2-amino group and a 3-hydroxy group, together with a pharmaceutically acceptable carrier. Typically the compound is a 2-amino-3-hydroxyalkane or a 2-amino-1,3-dihydroxyalkene. Preferably the compound is a substituted C
10
-C
24
alkane or alkene. The compound is preferably a substituted alkane, more preferably a substituted C
18
-C
20
alkane, and most preferably a 2-amino-3-hydroxy C
18
alkane. The substituted alkene is preferably a substituted mono- or di-alkene, more preferably a substituted C
18
-C
20
alkene. In one embodiment, the compounds have the partial stereochemistry:
In particular, the present invention provides compositions which contain bioactive sphingoid-type bases, spisulosines 285, 299 and 313 (1-3), sphingosine (also referred to as 4-sphingenine or octadeca-4-sphingenine, 4) and two related compounds, nonadeca-4-sphingenine (a one carbon longer homologue, 5) and sphinga-4,10-diene (a dehydrosphingosine derivative, 6).
Thus, the preferred compositions contain one or more of the following preferred compounds:
spisulosine 285 (1), n=12; spisulosine 299 (2), n=13; spisulosine 313 (3), n=14
as well as sphingosine (4), n=12 and nonadeca-4-sphingenine (5), n=13; and
sphinga-4,10-diene (6).
The preferred compound, spisulosine 285, is known in the literature. Compound 1 and the syn diastereoisomer, were first synthesized by Croatian researchers in the determination of absolute configurations of lipid bases with two or more asymmetric carbon atoms, see Prostenik, M., Alaupovic, P.
Croat. Chem. Acta.
1957, 29, 393.
It is believed that the other compounds in the compositions of this invention are new compounds.
Compounds 1-3 show unique cytotoxicity against L1210 murine lymphocytic leukemia cells. In a number of the L1210 assays, a distinct morphological alteration was observed. This effect was also described in our earlier U.S. Provisional Patent Application Serial No. 60/043,326. We make no patent claim in this patent application to the effect itself on L1210, and indeed there is now some preliminary data that suggests that the compounds such as spisulosine 285 might lack activity against leukemia tumors.
A synthetic sample of 1 was assayed against L1210 leukemia cells and showed both cytotoxicity and morphological alteration, pointed cell activity.
L1210 Inhibition and pointed cell activity
Concentration
% cytotoxicity
% pointed cells
a
 0.5 &mgr;g/ml
100
97
0.25 &mgr;g/ml
99
100
 0.1 &mgr;g/ml
99
62
0.05 &mgr;g/ml
96
71
0.025 &mgr;g/ml 
90
21
0.01 &mgr;g/ml
45
1
a
Percent pointed cells are a percent of the living cells.
Spisulosine 285 (1) is also active against other tumor cell lines in vitro, including P-388 (0.01 mg/ml); A-549 (0.05 mg/ml); HT-29 (0.05 mg/ml) and MEL-28 (0.05 mg/ml) .
In a particularly preferred embodiment, the present invention relates to use of spisulosine 285, and related compounds, in the treatment of all types of cancer, such as breast cancers, prostate, bladder, pancreas, lung, esophagus, larynx, liver, colon, thyroid, melanoma, kidney, testicular, leukemia, ovarian, gastro-intestinal, hepatocellular carcinoma and vascular endothelial cancer. Other forms of cancer are well known to the person skilled in the art. It is preferred that the use of spisulosine 285, and related compounds is against solid tumors, with use against slow proliferating tumors such as prostate, lung, liver, kidney, endocrine gland and vascular endothelial cancer particularly preferred. In one aspect, the compositions are for use in therapy directed at the vascular endothelium for control of tissue and tumor vascularisation.
The present invention is directed to bioactive compounds that have been found to possess specific antitumor activities and as such they will be useful as medicinal agents in mammals, particularly in humans. Thus, another aspect of the present invention concerns pharmaceutical compositions containing the active compounds identified herein and methods of treatment employing such pharmaceutical compositions.
The active compounds of the present invention exhibit antitumor activity. Thus, the present invention also provides a method of treating any mammal affected by a malignant tumor sensitive to these compounds, which comprises administering to the affected individual a therapeutically effective amount of an active compound or mixture of compounds, or pharmaceutical compositions thereof. The present invention also relates to pharmaceutical preparations, which contain as active ingredient one or more of the compounds of this invention, as well as the processes for its preparation.
Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) with suitable composition or oral, topical or parenteral administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. These compositions may need to be sterile when administered parenterally.
Administration of the composition of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, intraperitoneal and intravenous administration. Intravenous delivery may be carried out over any suitable time period, such as 1 to 4 hours or even longer if required, at suitable intervals of say 2 to 4 weeks. Pharmaceutical compositions containing spisulosine may be delivered by liposome or nanosphere encapsulation, in sustained release formulations or by other standard delivery means.
The correct dosage of a pharmaceutical composition comprising the compounds of this invention will vary according to the particular formulation, the mode of application, and the particular situs, host and bacteria or tumor being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.
The compounds may be provided in the pharmaceutical compositions of this invention in the form of a prodrug or precursor, which upon administration converts or is metabolized to the active compound.
The compositions of this invention may be used with other drugs to provide a combination therapy. The other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or a different time. The identity of the other drug is not particularly limited, and suitable candidates include:
a) drugs with antimitotic effects, especially those which target cytoskeletal elements, including microtubule modulators such as taxane drugs (such as taxol, paclitaxel, taxotere, docetaxel), podophylotoxins or vinca alkaloids (vincristine, vinblastine);
b) antimetabolite drugs such as 5-fluorouracil, cytarabine, gemcitabine, purine analogues such as pentostatin, methotrexate);
c) alkylating agents such as nitrogen mustards (such as cyclophosphamide

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