Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-26
2004-11-16
Owens, Amelia A. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S268000
Reexamination Certificate
active
06818667
ABSTRACT:
The present invention relates to novel compounds of the formula I
in which R(1), R(2), R(3) and R(4) are, independently of each other, hydrogen or an alkyl radical. The compounds of formula I are inhibitors of the KDR kinase and are suitable, on account of their antiangiogenic effect, for preventing and/or treating malignant diseases. The compounds of the formula I can be obtained by fermenting the microorganism
Eurotium echinulatum Delacroix
(DSM 13872) or by chemically derivatizing the compounds which are obtained after fermenting said microorganism. The invention consequently also relates to a process for preparing the compounds of the formula I, to the use of the compounds of the formula I for producing a pharmaceutical for treating malignant diseases and diseases which can be treated by inhibiting KDR kinase, and to pharmaceutical preparations which comprise a content of at least one compound of the formula I.
Cancer is a disease of humans and animals which often has a fatal outcome and which is caused by the uncontrolled growth of the body's own cells. Cancer is the term for the formation of malignant growths (malignomas) and neoplasms (tumors or carcinomas) or for malignant degeneration and maturation disturbance in white blood cells (leukemia, blood cancer). Cancer cells or tumor cells arise due to the transformation of the body's own cells. malignancy of the cancer cells is expressed in the autonomy of its growth, that is in the ability of the cell to grow in an infiltrating manner, without being inhibited, without being correctly incorporated into the structural plan of the organ, and with the tissue being destroyed. A reliable sign of malignancy is the formation of metastases at a distance from a tumor, following the hematogenic or lymphogenic dispersal of tumor cells. Cancer is one of the most frequent causes of death in humans and there is therefore a great need for methods and means for curing or treating malignant degeneration.
Aside from the operative removal of the tumor, the possibilities of treating malignant tumors include radiological therapy using X-rays, &agr;-rays, &bgr;-rays or &ggr;-rays, immunotherapy, and chemotherapy. At present, immunotherapy can only be used to a limited extent. The chemotherapy of tumors is understood as being the administration of cell poisons (cytostatic agents) for treating tumors and tumor cells which have remained following local surgical treatment or irradiation. These substances intervene specifically in particular events in cell division such that tissues which contain a high proportion of dividing cells, such as rapidly growing tumor tissue, react with more sensitivity. Among the compounds used are alkylating compounds, such as cyclophosphamide (The Merck Index, 12th ed. page 463), antimetabolites, such as methotrexate (The Merck Index, 12th ed. page 1025), alkaloids, such as vincristine (The Merck Index, 12th ed. page 1704) and antibiotics, such as daunomycin (The Merck Index, 12th ed. page 479) and adriamycin (The Merck Index, 12th ed. page 581-582). Due to massive side-effects, all these agents suffer from severe disadvantages such that the death of the affected patient is only delayed but not averted. Furthermore, resistances to the cytostatic agents employed can develop in the degenerate (cancer) cells with the result that the medicaments being used no longer have a cytostatic effect but, instead, have a toxic effect as a consequence of the side-effects. In addition, it has been found that the combined or sequential use of cytostatic agents exceeds the activity of a single cytostatic agent (monotherapy) and, as a result, it is possible that the substantial side-effects associated with polychemotherapy are not simply additive. For all these reasons, novel chemotherapeutic agents are urgently required and are therefore being sought world-wide.
The growth of a tumor presupposes that the tumor is being adequately supplied with oxygen, something which is only guaranteed by the tumor being provided with an adequate blood supply (vascularization). Tumors are unable to form new blood vessels (=angiogenesis); instead, they have to induce the surrounding connective tissue to perform this angiogenesis.
The formation of new blood vessels using an already existing vascular system as the starting point is of central importance for embryonic development and organ development. Abnormally increased angiogenesis is observed, inter alia, in rheumatoid arthritis, diabetic retinopathy, and tumor growth (Folkman, 1995, Nat. Med., 1:27-31). Angiogenesis is a complex, multistep process which includes the activation, migration, proliferation and survival of endothelial cells.
In combination with other endothelium-specific signal systems, what are termed the vascular endothelial growth factors (VEGFRs) transmit signals for the migration, proliferation and survival of the endothelial cells. The VEGFR family includes the subtypes VEGFR-1 (Flt-1), VEGFR-2 (KDR) and VEGFR-3 (Flt-4). Whereas VEGFR-1 and VEGFR-2 function as universal regulators of endothelial cells, VEGFR-3 principally controls the growth of the lymphatic vascular system. VEGFRs play a key role in all the stages of the angiogenic process.
Extensive studies carried out in the field of tumor angiogenesis during the last 20 years have described a large number of potential therapeutic targets, e.g. kinases, proteases and integrins. This has led to the discovery of a large number of novel antiangiogenic agents, some of which are already being tested clinically (Jekunen et al., 1997, Cancer Treatment Rev., 23:263-286). Within the context of a chemotherapeutic treatment of tumors, angiogenesis inhibitors could be used both for monotherapy and in a combination therapy together with other cytostatic agents. In addition to this, it is possible to conceive of using them for preventing a tumor from growing once again after a therapy has been completed.
The inhibition or regulation of VEGFR-2 (KDR) is a reaction mechanism which offers a novel approach for treating a large number of solid tumors. Thus, the activation of this tyrosine kinase receptor is crucial for endothelial cell growth and the formation of new blood vessels in association with angiogenesis and consequently has an influence on tumor growth and the formation of metastases. In addition to this, there is new evidence to suggest that the expression of VEGF contributes to survival of tumor cells following radiation therapy or chemotherapy (Lee C. G., Heijn M. et al., 2000, Cancer Research, 60 (19):5565-70). This underlines the importance of KDR inhibitors and the previously known cytostatic agents possibly acting synergistically.
It has been found, surprisingly, that the microorganism
Eurotium echinulatum Delacroix
(DSM 13872) is able to form an active compound which exhibits a pronounced inhibitory effect on KDR kinase and consequently constitutes an effective inhibitor of angiogenesis. The novel compound is termed eurotinone below and is, together with eurotinone derivatives, part of the subjectmatter of the invention.
The present invention therefore relates to compounds of the formula I
in which
R(1), R(2), R(3) and R(4) are, independently of each other, in each case hydrogen or an alkyl radical, in all the stereochemical forms thereof, and mixtures of these forms in any ratio, and to the physiologically tolerated salts thereof.
An alkyl radical in formula I can, for example, be (C
1
-C
6
)-alkyl, (C
2
-C
6
)-alkenyl, (C
2
-C
6
)-alkynyl, C
3
-C
6
-cycloalkyl, or (C
1
-C
3
)-alkyl-(C
3
-C
6
)-cycloalkyl.
(C
1
-C
6
)-alkyl can be a straight-chain or branched alkyl having from 1 to 6 C atoms, such as methyl, ethyl, i-propyl, tert-butyl and hexyl;
(C
2
-C
6
)-alkenyl can be a straight-chain or branched alkenyl having from 2 to 6 C atoms, such as allyl, crotyl and pentenyl;
(C
2
-C
6
)-alkynyl can be a straight-chain or branched alkynyl having from 2 to 6 C atoms, such as propynyl, butynyl and pentynyl.
Examples of (C
3
-C
6
)-cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The abovementi
Eder Claudia
Kogler Herbert
Toti Luigi
Aventis Pharma Deutschland GmbH
Dubberley F. Aaron
Owens Amelia A.
LandOfFree
Eurotinones, and derivatives thereof, processes for... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Eurotinones, and derivatives thereof, processes for..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Eurotinones, and derivatives thereof, processes for... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3353655