Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-12-20
2001-11-20
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S604000, C564S082000, C564S512000
Reexamination Certificate
active
06319956
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel polyamine compounds and polyamine compounds having carcinostatic action.
2. Description of Related Art
Cancer accounts for the largest statistical portion of causes of death. It is one of the most difficult diseases to be cured, for which an establishment of an effective therapy is required. Currently, treatment is performed by using surgical therapy, immunological therapy, physiotherapy, chemotherapy and gene therapy individually or in a combination thereof. Cancer, which develops in any body tissues, is extremely diverse in appearance due to functions unique to each tissue, and can never be completely cured only by symptomatic therapies. Furthermore, drug resistance acquired by cancer cells after multiple uses of agents is a serious problem in chemotherapy. Therefore, development of anticancer agents that act with a novel mechanism has been strongly required.
One of the studies that can be a basis for new therapies in the development of anticancer agents is the study of the carcinostatic action of polyamine compounds. Polyamines are low molecular-weight compounds that can be found in cells of all species. Since polyamines considerably increase in concentration during proliferation and division of cells (C. W. Tabor and H. Tabor, Ann. Rev. Biochem., 53, pp.749-790 (1984) and L. J. Marton and D. R. Morris, “Inhibition of Polyamine Metabolism” (P. P. McCann, A. E. Pegg and A. Sjoerdsma eds.)), their relationship with these biochemical processes has long been noted. As studies progress, many aspects such as expression stages and roles of polyamines in the cell cycle, biosynthesis processes, types and functions of related enzymes and polyamine-decomposing enzymes and their metabolites have come to light. In recent years, existing sites and nucleotide sequences on DNA involved in the production of these enzymes have been elucidated, which continues to attract the attention of researchers engaged in molecular biology.
These studies have revealed that polyamines are involved in proliferation and division of cells. Since cancer is a type of abnormal cell proliferation, there is suggested a possibility that polyamines can control cancer. Therefore, from the viewpoint that if it is possible to block biosynthesis pathways of polyamines or accelerate metabolism of reserved polyamines, cell proliferation can be inhibited, which may result in carcinostatic effect. Therefore, many enzyme inhibitors have been developed as anticancer agents. The first report of polyamine anticancer agents was made by R. J. Bergeron et al. (J. Med. Chem. 31:1183-1190 (1988)). Since then, they have pursued the investigation of the action mechanism and the correlation between structure and activity of polyamines, thereby contributing to the orientation of molecular design of polyamine anticancer agents. They have also provided a major driving force for many researchers stimulated by their study to turn to the development of polyamine anticancer agents.
With the success of these studies, clinical studies of BE333 as an anticancer agent began a few years ago. Since then, steady steps have been taken towards development of chemotherapeutic agents. Polyamines having an extremely low molecular weight and a simple structure are involved in the cell proliferation process, where macromolecules such as nucleic acid and protein are fully operating, and play a major role of functional regulation. From this fact, it can be considered to be highly possible that more useful polyamine anticancer agents can be developed. Therefore, there are expected further development of polyamine compounds, study of structures and actions of existing and novel polyamine compounds, investigation of action mechanisms and study of the correlation between structure and activity and so forth, and how to apply results of these studies to development of anticancer agents is considered a problem.
An object of the present invention is to provide novel polyamine compounds having much potential for the development of anticancer agents, in particular, to provide novel polyamine compounds by using a method of systematically synthesizing linear polyamine derivatives in order to facilitate detection of structural factors and specificity influencing on physiological activity of polyamines to be produced. Another object of the present invention is to provide polyamine compounds having carcinostatic action.
SUMMARY OF THE INVENTION
The present invention relates to polyamine compounds represented by the following Formula (I) and pharmaceutically acceptable salts thereof.
In Formula (I), n is an integer of 1-8,
R
1
represents a hydrogen atom or a p-toluenesulfonyl group,
R
2
represents an ethyl group or a group represented by the following Formula (II),
R
3
represents a hydrogen atom or a p-toluenesulfonyl group, and
R
4
represents an ethyl group or a group represented by the following Formula (II).
In Formula (II), m is 1 or 2,
R
5
represents a hydrogen atom or a p-toluenesulfonyl group,
R
6
represents a hydrogen atom, an ethyl group, an aldehyde group, or a cyclopropylmethyl group, or
R
5
and R
6
form a phthaloyl group.
The present invention further relates to polyamine compounds represented by the following Formula (III) and pharmaceutically acceptable salts thereof.
In Formula (III), p is 1,
q is 1 or 2,
R
7
represents a hydrogen atom or a p-toluenesulfonyl group,
R
8
representsahydrogenatom, anethylgroup, analdehydegroup,
a cyclopropylmethyl group or a group represented by the following Formula (IV), or
R
7
and R
8
form a phthaloyl group.
R
9
represents a hydrogen atom, a p-toluenesulfonyl group or a benzyl group,
R
10
represents a hydrogen atom or a p-toluenesulfonyl group,
R
11
represents a hydrogen atom, anethyl group, an aldehyde group,
a cyclopropylmethyl group or a group represented by the following Formula (IV), or
R
10
and R
11
form a phthaloyl group.
In Formula (IV), u is 1 or 2,
R
12
represents a hydrogen atom or a p-toluenesulfonyl group,
R
13
represents a hydrogen atom, an ethyl group, or a cyclopropylmethyl group.
The present invention also relates to anticancer agents containing, as an active ingredient, at least one of the compounds represented by the above Formula (I) or (III) and/or pharmaceutically acceptable salts thereof. More specifically, the present invention relates to anticancer agents containing, as an active ingredient, at least one of
1,18-bis(ethylamino)-5,14-diazaoctadecane (Formula (V)),
1,16-bis(cyclopropylmethylamino)-5,12-diazahexadecane (Formula (VI)),
1,17-bis(cyclopropylmethylamino)-5,13-diazaheptadecane (Formula (VII)) and/or pharmaceutically acceptable salts thereof.
REFERENCES:
patent: 5109024 (1992-04-01), Prakash et al.
patent: 5719193 (1998-02-01), Bowlin et al.
Burns Doane Swecker & Mathis L.L.P.
O'Sullivan Peter
Riken
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