Antivesicant compounds and methods of making and using thereof

Details Antivesicant compounds and methods of making and using thereof Antivesicant compounds and methods of making and using thereof

2002-06-17

2003-12-16

Desai, Rita (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S347000

Reexamination Certificate

active

06664280

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to antivesicant compounds and methods of making and using thereof. In particular, the present invention relates to antivesicant compounds comprising 2-mercaptopyridine-N-oxide as a backbone structure.
2. Description of the Related Art
Vesicants are chemical warfare agents which cause blisters and include sulfur mustard, nitrogen mustard, Lewisite, and phosgene oxime. Bis-2-chloroethylsulfide (HD) is a radiomimetic alkylating agent that has mutagenic, cytotoxic, and carcinogenic properties. See Auerbach, C, et al. (1946) Nature 157:302; Wheller, G. P. (1962) Cancer Res. 22:651-688; and Heston, W. E. (1950) J. Natl. Cancer. Inst. 11:415-423. In the battlefield, HD has been used as a chemical weapon which produces incapacitating blistering injuries at the site of exposure. See Collumbine, H. (1947) Nature 159:151-153; Papirmeister, B., et al. (1984) J. Cut. and Ocular Toxicol. 3:371-393; and Vogt, R. F. et al. (1984) Fundam. Appl. Toxicol. 4(2):571-583.
Biochemical studies on cells exposed to HD indicate that DNA alkylation is the primary lesion which leads to a series of biochemical changes, including depurination of DNA strands, DNA break, activation of chromosomal enzyme poly(ADP-ribose)polymerase, depletion of cofactor NAD
+
, inhibition of glycolysis, elevation of protease activity and finally blister formation. See Papirmeister, B., et al. (1985) Fundam. Appl. Toxicol. 5:S134. Chemically, HD first forms a reactive sulfonium intermediate which then reacts randomly with macromolecules, such as DNA, RNA and protein. See Walker, I. G., et al. (1969) Canadian J. Physiol. Pharmacol. 47(2):143-151; and Ogston, A. G., et al. (1948) Trans. Fara. Soc. 44:45. The alkylation of DNA is what causes the drastic biochemical changes and blister formation. The site of alkylation on DNA is found to be the N
7
of purine bases, particularly guanidine.
Various approaches have been attempted in order to find therapeutic compounds which prevent blister formation caused by HD exposure. For example, the examination of poly(ADP-ribose)polymerase or protease as potential target enzymes have been emphasized in recent years. See Purnell, M. R., et al. (1980) Biochem. J. 185:775; Sestili, P., et al. (1988) Pharm. Res. Comm. 20:613; Rankin, P. W., et al. (1989) J. Biol. Chem. 264:4312; Powers, J. C., et al. (1991) Proceed. 1991 Med. Defense Biosci. Rev. 41-48; and Cowan, F. M., et al. (1991) Proceed. 1991 Med. Defense Biosci. Rev. 155-158. Inhibitors of these two enzymes have been shown to decrease the toxicity of HD. See Clayson, E. T., et al. (1991) Proceed. 1991 Med. Defense Biosci. Rev. 127-130; Meiers, H. L. Proceed. 1991 Med. Defense Biosci. Rev. 135-142; and Dannenberg, Jr., A. M. et al. (1991) Proceed. 1991 Med. Defense Biosci. Rev. 147-150.
Other approaches are based on compounds which possess strong nucleophilicity and react rapidly with HD to produce non-invasive products. See Ogston, A. G., et al. (1948) Trans. Fara. Soc. 44:45. For example, sulfur containing chemicals, such as cysteine, glutathione and 2-mercaptoethylamines have been shown to protect cells from HD toxicity in experimental animals. See Walker, I. G., et al. (1969) Canadian J. Physiol. Pharmacol. 47(2):143-51. These mercapto compounds protect the cell by interacting with HD to form non-reactive sulfides. The practical values of the above mentioned sulfur compounds, however, are impaired by either poor passage of the drugs across the cell membrane, easy oxidation to form inactive disulfide or their poor nucleophilicity. It has been shown that sulfide anions (RS
−
) are much stronger nucleophiles than the free thiols (RSH). See Reid, E. E.: ORGANIC CHEMISTRY OF BIVALENT SULFUR, Vol. II. Chapt. 5, 237-288, Chemical Publishing Co., Inc., New York, N.Y. (1960); and Quayle, O. R. et al. (1942) J. Amer. Chem. Soc. 64:226-230. For example, sodium thiophenol (PhSNa) reacts with n-butylbromide one thousand times faster than thiophenol (PhSH). Since the aliphatic thiols, such as cysteine and glutathione, do not ionize in physiological pH, their nucleophilicity are weak under physiological conditions and thus have limited potential as a scavenger of HD.
Despite all the research and various approaches, the biochemical mechanism of HD-induced injury is still not fully understood and no effective treatment for HD-induced injury is available. Thus, a need still exists for effective treatments for HD-induced injuries.
SUMMARY OF THE INVENTION
The present invention generally relates to a compound having the structural formula
wherein R
1
, R
2
, R
3
, and R
4
are each independently H, or a methyl, halo, trifluoromethyl, nitro, alkyloxy, or acyloxy group, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, two adjacent R substituents may form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group. In some preferred embodiments, R
1
, R
2
, R
3
and R
4
are each independently H, methyl, methoxy, chloro, fluoro, or bromo. In some preferred embodiments, the compound is 2-mercaptopyridine-N-oxide, 4-methyl-2-mercaptopyridine-N-oxide, 6-methyl-2-mercaptopyridine-N-oxide, 4,6-dimethyl-2-mercaptopyridine-N-oxide, 5-bromo-2-mercaptopyridine-N-oxide, 5-methyl-2-mercaptopyridine-N-oxide, 3-chloro-2-mercaptopyridine-N-oxide, 5-chloro-2-mercaptopyridine-N-oxide, 4-chloro-2-mercaptopyridine-N-oxide, 3,4,5, or 6-methoxy-2-mercaptopyridine-N-oxide, 5-trifluoromethyl-2-mercaptopyridine-N-oxide, 2-mercaptoquinoline-N-oxide, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the compound is an antivesicant.
In some embodiments, the present invention provides a pharmaceutical composition comprising a compound having the structural formula
wherein R
1
, R
2
, R
3
, and R
4
are each independently H, or a methyl, halo, trifluoromethyl, nitro, alkyloxy, or acyloxy group, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient. In some embodiments, two adjacent R substituents may form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group. In some preferred embodiments, R
1
, R
2
, R
3
, and R
4
are each independently H, methyl, methoxy, chloro, fluoro, or bromo. In some embodiments, the compound is 2-mercaptopyridine-N-oxide, 4-methyl-2-mercaptopyridine-N-oxide, 6-methyl-2-mercaptopyridine-N-oxide, 4,6-dimethyl-2-mercaptopyridine-N-oxide, 5-bromo-2-mercaptopyridine-N-oxide, 5-methyl-2-mercaptopyridine-N-oxide, 3-chloro-2-mercaptopyridine-N-oxide, 5-chloro-2-mercaptopyridine-N-oxide, 4-chloro-2-mercaptopyridine-N-oxide, 3,4,5, or 6-methoxy-2-mercaptopyridine-N-oxide, 5-trifluoromethyl-2-mercaptopyridine-N-oxide, 2-mercaptoquinoline-N-oxide, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical composition further comprises a second antivesicant compound. In some embodiments, the pharmaceutical composition further comprises a supplementary active compound such as an anti-inflammatory or an anti-protease drug or compounds.
In some embodiments, the present invention is directed to protectant or decontaminant comprising a compound having the structural formula
wherein R
1
, R
2
, R
3
, and R
4
are each independently H, or a methyl, halo, trifluoromethyl, nitro, alkyloxy, or acyloxy group. In some embodiments, two adjacent R substituents of the compound form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group. In preferred embodiments, R
1
, R
2
, R
3
, and R
4
are each independently H, methyl, methoxy, chloro, fluoro, or bromo. In some preferred embodiments, the compound is 2-mercaptopyridine-N-oxide, 4-methyl-2-mercaptopyridine-N-oxide, 6-methyl-2-mercaptopyridine-N-oxide, 4,6-dimethyl-2-mercaptopyridine-N-oxide, 5-bromo-2-mercaptopyridine-N-oxide, 5-methyl-2-mercaptopyridine-N-oxide, 3-chloro-2-mercaptopyridine-N-oxide, 5-chloro-2-mercaptopyridine-N-oxide, 4-chloro-2-mercaptopyridine-N-oxide, 3,4,5, or 6-methoxy-2-mercaptopyridine-N-oxide, 5-trifluoromethyl-2-mercaptopyridine-N-oxide, or 2-mercaptoquinoline-N-o

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