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  Novel cytostatic conjugates with integrin ligandsUSPTO Application #: 20080108576Title: Novel cytostatic conjugates with integrin ligands Abstract: The present invention relates to cytostatics which have a tumour-specific action as a result of linkage to αvβ3 integrin antagonists via preferred linking units which can be selectively cleaved by elastase, i.e. by an enzyme which can especially be found in tumour tissue. The preferred linking units provide sufficient stability of the conjugate of cytostatic and αvβ3 integrin antagonist in biological fluids and, at the same time, the desired intracellular action within tumour cells as a result of its specific enzymatic or hydrolytic cleavability with release of the cytostatic. (end of abstract) Agent: Bayer Health Care Llc - West Haven, CT, US Inventors: Hans-Georg Lerchen, Jorg Baumgarten, Andreas Schoop, Markus Albers USPTO Applicaton #: 20080108576 - Class: 514018000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 3 Or 4 Peptide Repeating Units In Known Peptide Chain The Patent Description & Claims data below is from USPTO Patent Application 20080108576. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to cytostatics which have a tumour-specific action as a result of linkage to .alpha..sub.v.beta..sub.3 integrin antagonists via preferred linking units which can be selectively cleaved by elastase, i.e. by an enzyme which can especially be found in tumour tissue. The preferred linking units provide sufficient stability of the conjugate of cytostatic and .alpha..sub.v.beta..sub.3 integrin antagonist in biological media, e.g. culture medium or serum and, at the same time, the desired intracellular action within tumour tissue as a result of its specific enzymatic or hydrolytic cleavability with release of the cytostatic. [0002] Chemotherapy in cancer is accompanied by usually serious side effects which are to be attributed to the toxic action of chemotherapeutics on proliferating cells of other tissue types than tumour tissue. For many years, scientists have occupied themselves with the problem of improving the selectivity of active compounds employed. A frequently followed approach is the synthesis of prodrugs which are released more or less selectively in the target tissue, for example, by change of the pH (DE-A 42 29 903), by enzymes (e.g. glucuronidases; EP-A 511 917 and 595 133) or by antibody-enzyme conjugates (WO 88/07378; U.S. Pat. No. 4,975,278; EP-A 595 133). A problem in these approaches is, inter alia, the lack of stability of the conjugates in other tissues and organs, and in particular the ubiquitous active compound distribution which follows the extracellular release of active compound in the tumour tissue. [0003] The marked lectin pattern on tumour cell surfaces (Gabius, Onkologie 12, 175 (1989)) opens up the fundamental possibility of addressing these specifically on tumour cells by linkage of appropriate carbohydrate units to cytostatics. This prospect is restricted by the fact that, even in other tissues, in particular in the liver, lectins having similar carbohydrate specificities (galactose, lactose, mannose, N-acetyl glucosamine, fucose etc.) occur (Ashwell et al., Annu. Rev. Biochem. 46, 531 (1982); Stahl et al., Proc. Natl. Acad. Sci. USA 74, 1521 (1977); Haltiwanger et al., J. Biol. Chem. 261, 7433-7439 (1986); Jansen et al., J. Biol. Chem. 266, 3343 (1991)). Accordingly, a marked concentration of active compound-containing glycoconjugates in the liver and other lectin-rich organs must be expected if, in this approach, carbohydrates are used without particular modification establishing a selectivity to tumour tissue. [0004] The heterocyclic amine batracylin (1) shows a good antitumour action in various stomach cancer models (U.S. Pat. No. 4,757,072). [0005] Peptide conjugates of (1) having good in-vitro action and more favourable solubility properties (U.S. Pat. No. 4,980,343) are more poorly tolerable in animal experiments than free batracylin. The fucose conjugates of batracylin (1) described in EP-A 501 250 disadvantageously concentrate very strongly in the liver. [0006] Quinolone-a (2), 7-[(3a-R,S, 4-R,S, 7a-S,R)-4-amino-1,3,3a,4,7,7a-hexahydro-isoindol-2-yl]-8-chloro-1-cyclopr- opyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, also shows, in addition to its outstanding antibacterial activity, a very good activity against various tumour cell lines (EP-A 520 240, JP-A 04 253 973). However, considerable toxicological problems face it (e.g. genotoxicity, bone marrow toxicity, high acute toxicity in-vivo etc.). [0007] 20(S)-Camptothecin is a pentacyclic alkaloid which was isolated in 1966 by Wall et al. (J. Am. Chem. Soc. 88, 3888 (1966)). It has a high active antitumour potential in numerous in-vitro and in-vivo tests. Unfortunately, however, the realization of the promising potential in the clinical investigation phase failed because of toxicity and solubility problems. [0008] By opening of the E ring lactone and formation of the sodium salt, a water-soluble compound was obtained which is in a pH-dependent equilibrium with the ring-closed form. Here too, clinical studies have not led to success as yet. [0009] About 20 years later, it was found that the biological activity is to be attributed to enzyme inhibition of topoisomerase I. Since then, the research activities have again been increased in order to find a camptothecin derivative which is more soluble and more tolerable and which is active in-vivo. [0010] For improvement of the water solubility, salts of A-ring- and B-ring-modified camptothecin derivatives and of 20-O-acyl derivatives with ionizable groups have been described (U.S. Pat. No. 4,943,579). The latter prodrug concept was later also transferred to modified camptothecin derivatives (WO 96/02546). The described 20-O-acyl prodrugs, however, have a very short half-life in vivo and are very rapidly cleaved to give the parent structure. [0011] WO 96/31532 describes carbohydrate-modified cytostatics in which both serum stability and release of the cytostatic within the tumour cells and a specific concentration of the cytostatic in tumour tissue is achieved by a novel linkage of selectively modified carbohydrates to cytostatics (for example batracylin, quinolone-a, camptothecin) via preferred spacer and linker groups. [0012] Integrins are heterodimeric transmembrane proteins found on the surface of cells, which play an important part in the adhesion of the cells to an extracellular matrix. They recognize extracellular glycoproteins such as fibronectin or vitronectin on the extracellular matrix via the RGD sequence occurring in these proteins (RGD is the single-letter code for the amino acid sequence arginine-glycine-aspartate). [0013] In general, integrins such as, for example, the vitronectin receptor, which is also called the .alpha..sub.v.beta..sub.3 receptor, or alternatively the .alpha..sub.v.beta..sub.5 receptor or the GpIIb/IIIa receptor play an important part in biological processes such as cell migration, angiogenesis and cell-matrix adhesion and thus for diseases in which these processes are crucial steps. Cancer, osteoporosis, arteriosclerosis, restenosis and ophthalmia may be mentioned by way of example. [0014] The .alpha..sub.v.beta..sub.3 receptor occurs, for example, in large amounts on growing endothelial cells and makes possible their adhesion to an extracellular matrix. The .alpha..sub.v.beta..sub.3 receptor thus plays an important part in angiogenesis, i.e. the formation of new blood vessels, which is a crucial prerequisite for tumour growth and metastasis formation in carcinomatous disorders. [0015] It was possible to show that the blockade of the above-mentioned receptors is an important starting point for the treatment of disorders of this type. If the adhesion of growing endothelial cells to an extracellular matrix is suppressed by blocking their corresponding integrin receptors, for example, by a cyclic peptide or a monoclonal antibody, angiogenesis does not occur, which leads to a stoppage or regression of tumour growth (cf., for example, Brooks et al. in Cell 79, 1157-1164 (1994)). [0016] Moreover, the invasive properties of tumour cells and thus their capability to form metastases markedly decrease when their .alpha..sub.v.beta..sub.3 receptor is blocked by an antibody (Brooks et al. in J. Clin. Invest. 96, 1815 (1995)). [0017] WO 98/10795 describes conjugates in which a molecule adding to tumours is linked to a functional unit such as, for example, a cytostatic or a detectable label such as, for example, a radioactive nuclide. Inter alia, integrin antagonists such as, for example, peptides having the RGD sequence described above are described as molecules adding to tumours. Doxorubicin is described as an example of a cytostatic which is linked to a molecule of this type addressing tumours. [0018] In the case of the compounds of WO 98/10795, the linkage is carried out such that the molecule addressing a tumour and the functional unit are directly bonded to one another with retention of their respective properties (cf., for example, p. 56, 1. 17, to p. 58, 1. 10, and Ex. 6). This has the result that these compounds are indeed selectively concentrated in the immediate vicinity of tumour cells by binding of the entity addressing a tumour (in the case of a radical having .alpha..sub.v.beta..sub.3 integrin-antagonistic action by binding to the .alpha..sub.v.beta..sub.3 integrin receptor which, in particular, is expressed on endothelial cells newly formed by angiogenesis), but on account of the direct combination the functional unit such as, for example, a cytostatic cannot be released into the intracellular space of the tumour tissue. [0019] Fundamentally, the conjugate which on the one hand is selectively concentrated in tumour tissue by the effect of a part addressing .alpha..sub.v.beta..sub.3 or .alpha..sub.v.beta..sub.5 integrin receptors found in the conjugate, but on the other hand comprises a cytostatic which can be released from the conjugate, should have an increased toxophoric effect on tumour tissue due to the possibility of the more direct action of the cytostatic on the tumour cells compared with the conjugates described in WO 98/10795. In particular, such a toxophoric effect and tumour selectivity should even be higher, if the release of the cytostatic takes place in the immediate vicinity of the tumour tissue or even in the tumour cells. [0020] In principle, medicament-containing conjugates are complex, difficult-to-prepare compounds, as is explained, for example, in Anti-Cancer Drug Design 10, 1-9 (1995), in particular p. 1. This article describes conjugates of the cytostatic methotrexate, an oligopeptide spacer, and a protein (human serum albumin). However, it is also pointed out (cf: p. 7, first paragraph) that the nature of the linking unit and the type of linkage of this unit to the toxophore and the carrier (for example an antibody) can affect the cleavage of the linking unit. This article therefore teaches that the linkage presented there cannot be transferred to other conjugate systems without difficulty. In particular, nothing is said about whether moieties addressed also to .alpha..sub.v.beta..sub.3 integrin receptors in this manner can be linked to toxophores without the moiety addressing .alpha..sub.v.beta..sub.3 integrin receptors by this means losing its ability to bind to .alpha..sub.v.beta..sub.3 integrin receptors. [0021] The linking units disclosed in WO 96/31532 are used specifically for the linkage of a toxophore to a mono- or oligosaccharide radical. Nothing is said about whether moieties addressed also to .alpha..sub.v.beta..sub.3 integrin receptors can be linked to toxophores in this manner, without, by this means, the moiety addressing .alpha..sub.v.beta..sub.3 integrin receptors losing its ability to bind to .alpha..sub.v.beta..sub.3 integrin receptors. [0022] In WO 00/69472 enzyme-activated anti-tumour prodrug compounds are disclosed which can be specifically cleaved by collagenase (IV) and elastase. With respect to linking units cleavable by elastase this application describes that the specific tetrapeptide sequences Ala-Ala-Pro-Val and Ala-Ala-Pro-Nva are suitable therefore. Furthermore, in this reference, no conjugates which comprise a moiety addressing .alpha..sub.v.beta..sub.3 integrin receptors and a cytostatic are mentioned. [0023] It was therefore one object of the present invention to develop conjugates which comprise a moiety addressing .alpha..sub.v.beta..sub.3 integrin receptors and a cytostatic which can be released from the conjugate preferably at least in the vicinity of tumour tissue, where the moiety in the conjugate addressing .alpha..sub.v.beta..sub.3 integrin receptors retains its ability to bind to the .alpha..sub.v.beta..sub.3 integrin receptor and therefore provides tissue selectivity to such compounds. [0024] The above object is achieved by conjugates which comprise a non-peptide moiety addressing .alpha..sub.v.beta..sub.3 integrin receptors, a cytostatic and a linking unit which is selectively enzymatically cleavable with release of the cytostatic by elastase, i.e. by an enzyme which can especially be found in tumour tissue. Continue reading... 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