Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2002-06-03
2004-11-09
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S529000
Reexamination Certificate
active
06815465
ABSTRACT:
This invention relates to novel borrelidin derivatives, more specifically to novel borrelidin derivatives prepared by transforming the carboxyl group on the cyclopentane ring of borrelidin. Furthermore, the invention relates to pharmaceutical compositions containing such compounds and to the use of these compounds for preparing pharmaceutical compositions.
The novel compounds according to the invention show valuable biological efficiency, namely they have remarkable angiogenesis-inhibiting effect and antimetastatic action.
It is known that the angiogenesis is a phenomenon where blood-vessels are formed in the organism and a new vascular system is formed. The angiogenesis has very different forms depending on the growth and function of the endothelial cells, by all means it can be considered as a certain kind of cascade reactions. The angiogenesis takes place under normal physiological circumstances like a part of the evolution and reproduction processes in the case of the embryo, foetus, placenta, uterus and similar organs. It may be, however, a part even of a pathological process which accompanies the wound healing, infection as well as tumour growth, furthermore promote the formation of tumour metastases.
From the literature the clinical observation is known for a long time that the majority of cancer tumorous patients die due to metastases. This situation has been improved in the recent years by the radiation therapy and chemotherapy but the results attained are by no means reassuring.
Owing to the results attained while studying the pathobiological features of the malignant diseases, in the last years a new trend of antitumour drug research has developed. It can be attributed to this new tendency that nowadays the planning of novel active agents is directed, besides the research of active agents inhibiting the growth of tumorous tissues, even towards other pathobiological events (immortalisation, metastases, apoptosis, angiogenesis) responsible for maintaining the malignity. From these events special attention deserves the neovascularisation (formation of novel blood-vessels) which ensures continuous blood supply for the growing tumours, since in lack of same the tumorous cells are killed. According to the conclusions of tumour-biological examinations the progression of malignant diseases can be considered to be a function of angiogenesis, and the transition of the premalignant period into the invasive period, further the induction of the dormant state of the tumorous cell population in direction of proliferation can be brought into close connection with the formation of blood vessels.
Thus, the drug research of antitumorous agents is aimed today at planning and developing molecules having novel points of attack, by the aid of which the healing of cancer can be rendered more efficient than before.
Among these novel molecules priority is given to the group of antiangiogenetic agents which, by inhibiting the neovascularization and consequently the formation of metastases, may open a new period in the therapy of tumorous diseases.
Several compounds are known for having angiogenesis-inhibiting effect. From these compounds the following are enumerated as examples, without being exhaustive: angiostatic steroids [Folkman, J. et al., Science 221, 719 (1993)] like the cortisone which inhibits the function of the endothelial cells; the medroxyprogesterone acetate which inhibits the production of plasminogen-activator by the endothelial cells [Nicosia, R. F. and Ottinetti, A., Lab. Invest. 63, 115 (1990)]; the fumagillin which inhibits the formation of tubules [Ingber, D. et al., Nature 348, 555 (1990)]; a polysaccharide sulfate (SD-4152) which inhibits the migration and multiplication of the endothelial cells; and the retinoic acid responsible for the differentiation and transformation of the endothelial cells [Tsutomu Oikawa, Kekkan to Naihi 2, 470 (1992)]. However, these substances did not work as angiogenesis-inhibitors in the clinical practice: some of them due to a strong side-effect and others due to an insufficient target effect.
The first, even clinically effective angiogenesis-inhibitor was the &agr;-interferon [Bronty-Boye, D. and Zetter, B. E., Science 208, 516 (1980); Sidky, Y. A. and Borden, E. C., Cancer Res., 47, 5155 (1987)]. At present the clinical trials of several angiogenesis-inhibiting compounds with different chemical structures are under investigation; such compounds are for example the derivatives of fumagillin, e.g. the AGM-1470 [Kusaka, M. et al., Biophys. Res. Comm. 174, 1070 (1991)]; the 3-(2,4-dimethylpyrrol-5-yl)-indolin-2-one (SU-5416), U.S. Pat. No. 5,792,783; the 5-methylisoxazole-4-carboxylic-N-[4-(trifluoromethyl)-phenyl]-amide (leflunomide, SU-101), U.S. Pat. No. 5,610,173; the 2(R)-isobutyl-3(S)-dihydroxy-N-[2,2-dimethyl-1(S)—(N-methylcarbamoyl)-propyl]-succinamide (marimastat); the 3&bgr;-[{3-[(4-aminobutyl)-amino]-propyl}-amino]-5&agr;-cholestane-7,24-diol-24-hydrogen sulfate (squalamine), U.S. Pat. No. 5,192,756; the ZD4190, an inhibitor of vascular endothelial growth factor etc.
Recently Japanese authors have described that the known borrelidin [chemically: 2′-(7-cyano-8,16-dihydroxy-9,11,13,15-tetramethyl-18-oxo-oxacyclooctadeca-4,6-dien-2-yl)-cyclopentane-1′-carboxylic acid], which is a macrolid antibiotic comprising a 18-membered ring [Keller-Schierlein, W., Experientia 22, 476 (1966); Helvetica Chim. Acta 50, 731 (1967); Anderson, B. F. et al., Aust. J. Chem. 42, 717 (1989)] has angiogenesis-inhibiting effect due to the property that it induces the apoptosis of the cells forming capillary tubules [Wakabayashi, T. et al., J. Antibiot. 50, 671 (1997)]. Furthermore, it has been proved that it is effective against cell lines WiDr of human colon cancer and PC-3 of human prostate cancer (published Japanese patent applications Nos. 8-173,167 and 9-227,549).
Furthermore, it is known that the borrelidin exerts antibacterial, antiviral, herbicidal and insecticidal effects and has a medium LD
50
value (Glasby, J. S., Encyclopedia of Antibiotics, p. 145, J. Wiley (editor), 1979).
It is known from the literature and it is supported even by our own investigations that the efficiency of borrelidin is directed towards two tumourbiological events: the proliferation on the one hand and the capillary formation by the endothelial cells, that is the angiogenesis, on the other hand. Although there is a difference in respect of the sensitivity of the two cellular functions (about a five fold difference exists in favour of capillary formation), this selectivity is yet of smaller degree when we consider the inhibition of cell proliferation aimed at other cell kinds.
The invention aims at separating the two cell-biological effects by modifying the structure of borrelidin. More specifically, the invention aims at preparing, by transforming the carboxyl group on the cyclopentane ring of the borrelidin molecule, novel borrelidin derivatives which exert a much stronger effect on the capillary formation by the endothelial cells than on the cell proliferation. Namely, according to our hypothesis, in the clinical practice an angiogenesis-inhibiting active agent is needed which inhibits the cell proliferation only in higher doses. (Here it is mentioned that the selectivity of the known angiogenesis-inhibiting compounds prevails in the fact that they inhibit the proliferation of endothelial cells more definitely than the division of the other cells of the organism.)
During our investigations it has been surprisingly observed that the novel borrelidin derivatives of general formula (I)
fully satisfy the above aims.
This recognition is surprising for a person skilled in the art because only a few borrelidin derivatives are known in the literature, i.e. its methyl ester and the diacetate of the methyl ester were prepared by Anderson, K. and Rickards, R. W. [Nature 206, 269 (1965)], further its benzyl ester and the
Ambrus Gábor
Jeney András
Makk Nándor
Tegdes Anikó
Timár Ferenc
IVAX International GmbH
Seaman D. Margaret
LandOfFree
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