Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Acyclic nitrogen double bonded to acyclic nitrogen – acyclic...
Reexamination Certificate
2003-01-30
2004-02-03
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Acyclic nitrogen double bonded to acyclic nitrogen, acyclic...
C514S184000, C514S186000, C534S694000, C544S226000
Reexamination Certificate
active
06686344
ABSTRACT:
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
The invention provides compounds of formula (I)
where R is
R
2
is H, NR
3
R
4
, SR
3
, OR
3
, or a group capable of bonding with X, when X is C, to form a fused aromatic or 5- or 6-membered heteroaromatic ring, wherein R
3
and R
4
are each independently hydrogen or a C
1
-C
4
alkyl group;
or a pharmaceutically acceptable salt thereof.
The invention also provides a compound having the formula (II)
The invention also provides a method of inhibiting the growth of tumor cells in a subject that includes administering to the subject a compound of formula I.
The invention also provides a method of treating cancer that includes administering to a subject a compound of formula I.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel organic arsonic acid substituted compounds having potent activity as cytotoxic agents. The compounds of the invention are useful agents in treating tumor cells, and treating cancer, for example leukemia.
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, the term “about” applies to all numeric values, whether or not explicitly indicated. The term “about” generally refers to a range of numbers that one of skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many instances, the term “about” may include numbers that are rounded to the nearest significant figure.
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.).
The term “halo” or “halogen” is used to describe an atom selected from the group of Bromine (Br), Chlorine (Cl), Fluorine (F) and Iodine (I).
The term “haloalkyl” is used to describe a functional group having an alkyl group that has at least one hydrogen substituted with a halogen.
Compounds of the Invention
The organic arsonic acid substituted compounds of the invention have the general structure represented by formula (I):
where R is
R
1
is halo, or haloalkyl. In one embodiment of the invention, R
1
is F, Cl, Br, or I. In another embodiment of the invention, R
1
is CH
2
X, CHX
2
, or CX
3
, where X is F, Cl, Br, or I. In yet another embodiment of the invention, R
1
is CX
3
, where X is F, Cl, Br, or I. In a further embodiment, R
1
is CCl
3
.
R
2
is H, NR
3
R
4
, SR
3
, OR
3
, or a group capable of bonding with X, when X is C, to form a fused aromatic or 5- or 6-membered heteroaromatic ring, wherein R
3
and R
4
are each independently hydrogen or a C
1
-C
4
alkyl group; or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, R
2
is a fused aromatic ring. In yet another embodiment of the invention, R
2
is a benzene or naphthalene ring, which can be unsubstituted or substituted by one or more groups selected from halo, hydroxy, mercapto, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, thioalkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, NR
3
R
4
, nitro, cyano, CF
3
, COOH, SO
3
H, SO
2
NR
3
R
4
in which R
3
and R
4
are as defined above, and SO
2
F. In a further embodiment, R
2
is a benzene ring unsubstituted or substituted by one or more groups selected from halo, hydroxy, C
1
-C
4
alkoxy or trifluoromethyl. In yet a further embodiment, R
2
is benzene.
One embodiment of the invention is a compound of the formula (II) below.
Salts
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 can be regenerated by treating the salt form with a base. For example, dilute solutions of aqueous base can 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.
Synthesis of Compounds of the Invention
The organic arsonic acid substituted compounds of the present invention can be prepared by the condensation of, for example, quinazoline, pyrimidine, triazine or purine derivatives and a organic arsonic acid derivative as shown in Scheme 1. R, R
1
and is R
2
in Scheme 1 represent the groups previously defined. The reactants, which are either commercially available or prepared by known methods, are heated to reflux in an appropriate solvent for a period of time up to 24 hours. An excess amount of triethylamine is added and the solvent evaporated to afford the crude product which is purified by recrystallization.
Tumor Treatment
For purposes of this invention, a method of inhibiting the growth of tumor cells includes administering to a subject a compound of the invention in order to achieve an inhibition of tumor cell growth, a killing of tumor cells, reduction of tumor size, induction of cellular apoptosis, and/or increased patient survival time.
The cytotoxic compounds of the invention are suitable for use in mammals. As used herein, “mammals” means any class of higher vertebrates that nourish their young with milk secreted by mammary glands, including, for example, humans, rabbits, and monkeys.
Cancer Treatment
For purposes of this invention, a method of treating cancer includes administering to a subject a compound of the invention in order to inhibit the growth of a cancer cell, kill a cancer cell, reduce the life expectancy of a cancer cell, and/or increase patient survival time.
The compounds of the invention are useful in treating
Paker Hughes Institute
Powers Fiona T.
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