Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1998-01-28
2000-10-03
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
A01N 5700
Patent
active
061273503
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to antineoplastic agents, and in particular to the use of phenol substituted gem-diphosphonate derivatives in the treatment of neoplastic diseases. More specifically, the present invention provides the use of certain phenol substituted gem-diphosphonate derivatives for the preparation of pharmaceutical compositions useful in the treatment and prevention of cancers and metastasis and in particular useful in the treatment and prevention of ras oncogene dependent cancers and metastatic invasions.
The majority of existing anticancer drugs are cytotoxic compounds which lack specificity for killing tumor cells and therefore also affect normal cells, resulting in toxic side effects. There remains therefore a need for the development of more specific agents acting on the cell signalling pathways leading to the inhibition of cancer cell proliferation without affecting normal cell proliferation (Oncolytic Drugs, J. R. Prous, The Year's Drug News, 1994 edition, p.459 and Ras Oncogene Directed Approaches in Cancer Chemotherapy, G. Bolton et. al., Annual Reports in Medicinal Chemistry 1994; 29: 165-174).
Mutations of the ras oncogene have been shown to be present in a wide variety of human tumors and may contribute to as many as one-fifth of all human cancers. Specifically, it is found in more than fifty percent of colon and ninety percent of pancreatic carcinomas. Ras mutations are therefore considered to play a key role in triggering cancer formation and development (J. L. Bos, Cancer Res. 1989;49:4682-4689). It has also been established that the mutated forms of ras protein are present only in tumors and not in normal tissues of cancer patients. Blocking the activity of ras mutations to transform normal cells into cancer cells as well as to further promote the development of cancer cells and tumors is therefore an attractive therapeutic target.
The U.S. Pat. No. 5,043,330 (1991) corresponding to the European Patent No. 0,339,237 discloses the synthesis of a class of phenol substituted gem-diphosphonate derivatives and their utility as lipid lowering agents, for example in the treatment of cardiovascular diseases.
The present applicants have now found that diphosphonates of the type disclosed in U.S. Pat. No. 5,043,330 are surprisingly effective for inhibiting specifically the proliferation as well as inducing apoptosis in cancer cells without being cytotoxic to normal cells.
Accordingly, in one aspect, the invention provides the use of a compound for the manufacture of a medicament for the treatment of neoplastic diseases, said compound having the following formula (I): ##STR2## where: Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 are identical or different and are 1 to 8 carbon atoms, comprising 2 to 8 carbon atoms, straight, branched or cyclic alkyl or alkoxy group from 1 to 8 carbon atoms, group C(O)R.sup.1, a carbamyl group C(O)NHR.sup.1 where R.sup.1 is described as above, X.sup.3 O and one of the two other substituents X.sup.1 or X.sup.2 may form an alkylidenedioxy ring comprising from 1 to 4 carbon atoms, --, --S--, --SO.sub.2 --, --S(CH.sub.2).sub.n --, --SO.sub.2 (CH.sub.2).sub.n, where n is an integer from 1 to 7, or together with B forms an alkylidene group of the formula (CH.dbd.CH).sub.k --(CH.sub.2).sub.d --CH.dbd. where k is zero or 1 and d is an integer from zero to 4, (CH.dbd.CH).sub.k --(CH.sub.2).sub.d --CH.dbd. where k and d are as described above.
The compounds of formula (I) can exist as salts and references to the compounds of formula (I) hereinafter include the salt forms of the compounds, unless the context indicates otherwise. Examples of salts are compounds of formula (I) wherein one or more of the groups Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 are constituted by the group OM where M is an alkaline or alkaline earth metal ion or an ammonium group NR.sub.4 where R has the same meaning as defined above.
In another aspect the invention provides the use of a compound of the formula (I) as hereinbefore defined for the manufacture of a medicament for treating solid tumors, fo
REFERENCES:
patent: 5043330 (1991-08-01), Nguygen et al.
patent: 5128331 (1992-07-01), Nguygen et al.
"Gene-based Therapy", The Year's Drug News, 459-462, 1994.
Bolton et al., "Ras Oncogene Directed Approaches in Cancer Chemotherapy", Annual Reports in Medicinal Chemistry-29, 17, 165-174, 1994.
Bentzen Craig Leigh
Flach Jean
Nguyen Lan Mong
Niesor Eric
Phan Hieu Trung
Goldberg Jerome D.
Symphar S.A.
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