Melamine derivatives as potent anti-cancer agents

Details Melamine derivatives as potent anti-cancer agents Melamine derivatives as potent anti-cancer agents

1999-06-23

2001-07-17

Raymond, Richard L. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S197000

Reexamination Certificate

active

06262053

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to melamine derivatives effective for treating tumor cells and particularly effective to induce apoptosis in leukemia and breast tumor cells.
BACKGROUND OF THE INVENTION
Cancer is a major disease that continues as one of the leading causes of death at any age. In the United States alone, it is anticipated that more than a half a million Americans will die of cancer in 1999. Currently, radiotherapy and chemotherapy are two important methods used in the treatment of cancer.
Considerable efforts are underway to develop new chemotherapeutic agents for more potent and specific anti-cancer therapy, presenting effective and efficient cytotoxicity against tumor cells, with minimal interference with normal cell function. Accordingly, there is an urgent need for the development and analysis of novel, effective anti-cancer agents.
SUMMARY OF THE INVENTION
Novel derivatives of melamine have been found to be potent cytotoxic agents with potent activity against cancer cells. For example, certain melamine derivatives were found to exhibit potent cytotoxic activity, particularly against human breast cancer and leukemic cell lines, at micromolar concentrations.
Accordingly, the present invention includes novel compounds and compositions as cytotoxic therapeutic agents, and particularly as anti-tumor agents. The present invention also includes methods for killing tumor cells and/or inhibiting the growth of tumors by administering to a subject an effective antitumor amount of a compound of the invention. Compositions of the invention contain an effective cytotoxic or inhibitory amount of a melamine derivative.
The melamine compounds of the invention have following formula:
wherein each R is independently selected from the substituents described more fully below, and each n is independently in the range of 1 to 5, preferably 1-3.
Preferred compounds of the invention are those where each R independently comprises one or more halo or hydroxy group, such as those in compounds shown in Table 2 below. Most preferred is 2,4,6-tri(3′,5′-dichloro-4′-hydroxy phenyl) amino-1,3,5-triazine (WHI-P239).
DETAILED DESCRIPTION OF THE INVENTION
The present invention includes novel melamine derivatives having potent activity as cytotoxic agents. The compounds of the invention are useful agents in the treatment of cancer for example to inhibit tumor growth or to kill tumor cells, for example, leukemia and breast tumor cells.
Definitions
All scientific and technical terms used in this application have meanings commonly used in the art unless otherwise specified. As used in this application, the following words or phrases have the meanings specified.
As used herein, “alkyl”, which includes the alkyl group of “alkoxy” substituents, includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. As a preferred embodiment, chains of 1 to 4 carbon atoms are included, for example methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, t-butyl, and the like.
As used herein “halogen” or “halo” substituent includes fluoro, chloro, bromo, and iodo.
As used herein, “pharmaceutically acceptable salt thereof” includes an acid addition salt or a base salt.
As used herein, “pharmaceutically acceptable carrier” includes any material which, when combined with a compound of the invention, allows the compound to retain biological activity, such as the ability to induce apoptosis of leukemia or breast tumor cells, and is non-reactive with the subject's immune system. Examples include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsions, and various types of wetting agents. Compositions comprising such carriers are formulated by well known conventional methods (see, for example, Remington's Pharmaceutical Sciences, Chapter 43, 14th Ed., Mack Publishing Co., Easton, Pa.).
“Treating” or “Treatment” in the context of this invention means the prevention or reduction of severity symptoms or effect of a pathological condition, including prolonging life expectancy. In the context of cancer therapy, treatment includes prevention, of tumor growth, reduction of tumor size, enhanced tumor cell death, and increased apoptosis.
Compounds of the Invention
The novel melamine derivatives of the invention have the general structure represented by the following formula I:
Where each n is independently an integer ranging from 1 to 5 (inclusive), and preferably is 1 to 3.
Each R is independently halo, hydroxy, mercapto, alkyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms, thioalkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, NR
1
R
2
, nitro, cyano, CF
3
, COOH, SO
3
H, SO
2
NR
1
R
2
, or SO
2
F, where R
1
and R
2
are each independently hydrogen or a C
1
-C
4
alkyl group.
Preferably, each R is independently hydroxy, alkoxy having 1 to 4 carbon atoms, fluoromethyl, or halogen. More preferably, each R is independently hydroxy or halo. Preferred halo is bromo or chloro. A particularly useful compound of the invention is 2,4,6-tri(3′75′-dichloro-4′-hydroxyphenyl)-amino-1,3,5-triazine.
Preferred compounds include those where phenyl groups of formula I are substituted with one or more halogen or hydroxy groups. For example, useful compounds of the invention include those having the following structures:
Although the triazine compounds of invention has been exemplified above where each of the three substituted phenyl groups
are identical, it is understood that each substituted phenyl group can be the same or different. Synthesis of compounds where the substituted phenyl groups are identical is more easily accomplished, however synthetic schemes for the production of compounds having different substituted phenyl groups are known.
The compounds of the invention are capable of forming both pharmaceutically acceptable acid addition and/or base salts. Base salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Also included are heavy metal salts such as for example silver, zinc, cobalt, and cerium. Examples of suitable amines are N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamene, N-methylglucamine, and procaine.
Pharmaceutically acceptable acid addition salts are formed with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, gluconic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and the like. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce either a mono or di, etc. salt in the conventional manner. The free base forms may be regenerated by treating the salt form with a base. For example, dilute solutions of aqueous base may be utilized. Dilute aqueous sodium hydroxide, potassium carbonate, ammonia, and sodium bicarbonate solutions are suitable for this purpose. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for the purposes of the invention.
Melamine compounds of the present invention, such as the exemplary melamine derivative, 2,4,6-tri(3′,5′-dichloro-4′-hydroxyphenyl)-amino-1,3,5-triazine (WHI-P239), can be prepared by the condensation of cyanuric chloride with 3,5-dichloro-4-hydroxyaniline as shown in Scheme 1. This synthesis scheme serves to illustrate the general scheme that can be used for the synthesis of other melamine derivatives of the invention. Reactants for the synthesis of WHI-P239 and other melamine derivatives of the invention are commercially available and/or prepared by known methods.
Synthesis procedure of Melamine derivativ

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