Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1997-02-27
2004-03-30
Ponnaluri, Padmashri (Department: 1627)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S619000, C564S163000
Reexamination Certificate
active
06713517
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to methods of inhibiting or killing tumor and cancer cells in human patients using aryl N-substituted carboxamides such as N-substituted benzamides and nicotinamides as direct chemotherapeutic agents or as sensitizers for radiation and/or other chemotherapeutic agents, and to novel aryl N-substituted benzamides and nicotinamides for such use.
A variety of chemical structures including the nitroimidazoles, phenothiazines, butyrophenones, halopyrimidines, benzamides and nicotinamides are known to possess radio- and chemosensitizing properties (Horsman, M. R. et al., Acta Oncologica 34:571, 1995; Brown, J. M. et al., Cancer Treatment Symposia 1, 85-101, 1984; Pu, A. T. et al., Oncology 9(8):707-21, 1995; George, K. C. and Singh, B. B., Indian J. Expt. Biol. 22:305-07, 1984; Kennedy, K. A. et al., Int. J. Radiat. Oncol. Biol. Phys. 12:1367-70, 1986; U.S. Pat. No. 5,340,565; Charp, P. A. and Regan, J. D., Biochim. Biophys. Acta 824:34-39, 1985, Ganapthi, R. et al., Biochem. Biophys. Res. Commun. 131:912-19, 1985; Lazo, J. S. et al., Cancer Res. 45:2103-09, 1985; Lazo, J. S. et al., Cancer Res. 46:2236-40, 1986). Common chemical structural features linking these diverse agents as radio- and chemosensitizers are not known in the prior art. U.S. Pat. Nos. 5,340,565, 5,215,738, 5,032,617 and 5,041,653 teach that benzamides and nicotinamides can radio- and chemosensitize by several mechanisms of action including by inhibiting DNA repair, by directly damaging DNA and by increasing tumor blood flow thus decreasing hypoxic resistance to tumor cell killing. The chemical features previously identified giving these classes of drugs radio- and chemosensitizing properties were di, mono- or un-N-substituted (—CONH
2
) or (—CSNH
2
) substitutions of the pyridine and benzene rings along with other aryl substitutions in structures I, II and III described below.
Structure I (from U.S. Pat. No. 5,340,565) has the formula
wherein
X is any compatible aliphatic or aryl mono (—NHX) or di-substitutions (—NX
2
); and
Y can be from 0 to 5 substitutions of a compatible chemical structure, for example (but not limited to) a group consisting of: H, OR, SR or NHR in which R is H, hydrocarbyl (1-6 C) including cyclic and unsaturated hydrocarbyl, optionally substituted with 1 or 2 substituents selected from the group consisting of halo, hydroxy, epoxy, alkoxy, alkylthio, amino including morpholino, acyloxy and acylamido and their thio analogs, alkylsulfonyl or alkylphosphonyl, carboxy or alkoxycarbonyl, or carbamyl or alkylcarbamyl, and in which R can optionally be interrupted by a single ether (—O—) linkage; or Y is O(CO)R, NH(CO)R, O(SO)R, or O(POR)R in which R is as above defined.
Structure II (from U.S. Pat. No. 5,215,738) has the formula
wherein
X is O or S; and
Z is H, OR, SR or NHR in which R is H, hydrocarbyl (1-6 C) including cyclic and unsaturated hydrocarbyl, optionally substituted with 1 or 2 substituents selected from the group consisting of halo, hydroxy, epoxy, alkoxy, alkylthio, amino including morpholino, acyloxy and acylamido and their thio analogs, alkylsulfonyl or alkylphosphonyl, carboxy or alkoxycarbonyl, or carbamyl or alkylcarbamyl, and in which R can optionally be interrupted by a single ether (—O—) linkage; or Z is O(CO) R, NH(CO)R, O(SO) R, or O(POR) R in which R is as above defined.
Structure III (from U.S. Pat. No. 5,041,653) has the formula
wherein
x is O or S;
Y is H, Me, OMe, OEt acetoxy or acetamido; and
Z is OR or NHR in which R is H, straight chain alkyl (1-6 C) optionally substituted with 1 or 2 substituents selected from the group consisting of halo, hydroxy, epoxy, alkoxy, amino, acyloxy and acylamido, and in which R can optionally be interrupted by a single ether (—O—) linkage; or O(CO)R or NH(CO)R in which R is as above defined.
In addition, prior art teaches that some analogs of the benzamides (Lybak, S. and Pero, R. W., Carcinogenesis 12:1613-17, 1991; Olsson, A. et al., Carcinogenesis 16:1029-35, 1995; George, A. M. et al., Int. J. Radiat. Biol. 49:783-98, 1986; Horsman et al., Int. J. Radiat. Oncol. Biol. Phys. 12:1307-10, 1986), nicotinamides (Horsman, M. R. et al., Radiat. Res. 118:139-50, 1989; Ben Hur, E. et al., Radiat. Res. 97:546, 1984; Horsman, M. R., Acta Oncologica 34:571, 1995), phenothiazines (Rosenthal, S. A. and Hart, W. N., Yale J. Biol. Med. 61:39-49, 1988), butyrophenones (U.S. Pat. No. 5,340,565) and halopyrimidines (Pu, A. T. et al., Oncology 9(8):707-21, 1995) can either directly by reacting with DNA, or directly by reacting with some chemical intermediate that in turn is converted to a DNA reactive intermediate, or indirectly by causing an increase in oxygen uptake by tumors which in turn can form DNA binding radicals, or indirectly by inhibiting DNA repair, cause DNA and other cell constituents to become damaged resulting in antitumor or radio- and chemosensitization. However, there is no prior knowledge in the literature that there are common chemical structural features which can give this diverse group of agents properties of antitumor or radio- and chemosensitization by a variety of mechanisms that amplify the levels of cellular DNA damage.
Among the specific compounds thus considered in the prior art are nicotinamide (hereinafter sometimes referred to as NAM), 4-amino-5-chloro-N-(2-diethylamino-ethyl)-2-methoxybenzamide (hereinafter sometimes referred to as metoclopramide or MCA), and their acid addition salts, e.g. metoclopramide hydrochloride (metoclopramide HCl).
SUMMARY OF THE INVENTION
The present invention, in a first aspect, broadly contemplates the provision of a method of inhibiting or killing tumor or cancer cells in a human patient, consisting essentially of treating the patient with a composition selected from the group consisting of aryl N-substituted carboxamides having one or more aryl halo or one or, more aromatic nitrogens, acid addition salts of these carboxamides, and mixtures thereof. In this method, the defined carboxamides act directly as chemotherapeutic agents, not merely as sensitizers for radiation and other chemotherapeutic agents. The term “consisting essentially,” as used in the definition of the above-described method, excludes the use or presence of radiation or chemotherapeutic agents (other than the stated carboxamides and/or acid addition salts thereof) in the practice of the method.
The invention in a second aspect contemplates the provision of a method of inhibiting or killing tumor or cancer cells in a human patient, consisting essentially of treating the patient with radiation or a chemotherapeutic agent together with a composition selected from the group consisting of N-substituted nicotinamides, N-(2-diethylamino-ethyl)-4-amino-3-chlorobenzamide (hereinafter sometimes referred to as 3-chloro-procainamide or 3-CPA), their acid addition salts, and mixtures thereof, in an amount effective to enhance the cytotoxicity of the radiation or chemotherapeutic agent employed. The selected composition, in the latter method, acts as a sensitizer for the radiation or chemotherapeutic agent. The compositions used as such sensitizers, in accordance with the invention in this aspect, are novel in themselves or have at least not heretofore been recognized as capable of acting as sensitizers in radiation or chemotherapeutic treatments. They are within the broadly defined class of aryl N-substituted carboxamides having one or more aryl halo or one or more aromatic nitrogens.
In further important specific aspects, the invention contemplates the provision of certain novel compositions within the last-mentioned class and suitable for use in the practice of one or more of the above-stated methods of the invention; and the use of such compositions in the same methods. These compositions are the compounds N-(2-diethylamino-ethyl)nicotinamide (which is an N-substituted nicotinamide, and is hereinafter sometimes referred to as N-NAM), N-(2-diethylamino-ethyl)-4-amino-3-chlorobenzamide (i.e., 3-chloro-prcainamide, mentioned above), their acid addition salts, and mixtures thereof
Chaplin David
Ekberg Tomas
Olsson Anders
Pero Ronald W.
Schwartz Alan
Cooper & Dunham LLP
OXiGENE, Inc.
Ponnaluri Padmashri
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