AU2002360747B2

AU2002360747B2 - Method of treating patients exposed to toxic chemical agents

Info

Publication number: AU2002360747B2
Application number: AU2002360747A
Authority: AU
Inventors: Thomas J. Dodd; Frederick H. Hausheer; Seetharamulu Peddaiaghari
Original assignee: BioNumerik Pharmaceuticals Inc
Current assignee: BioNumerik Pharmaceuticals Inc
Priority date: 2002-12-21
Filing date: 2002-12-21
Publication date: 2008-07-03
Anticipated expiration: 2022-12-21
Also published as: JP2006513190A; EP1583540A1; WO2004058274A1; EP1583540A4; MXPA05006721A; AU2002360747A1; CN1735417A; CA2511778A1

Description

WO 2004/058274 PCT/US2002/041238 METHOD OF TREATING PATIENTS EXPOSED TO TOXIC CHEMICAL AGENTS FIELD OF THE INVENTION This invention relates to a method for treating patients who have been exposed to toxic chemical agents. The method involves administering an effective amount of a disulfide or thiol-containing compound to a patient who has been exposed to a toxic chemical, or to prophylax persons who are regularly exposed to such agents.

BACKGROUND OF THE INVENTION Human beings may be exposed to toxic chemical agents in a variety of ways. Accidental exposure to toxic agents can occur at home both indoors and outdoors, or in any place where such agents may be utilized or may persist in the ground, water or air. Public parks and gardens, rural areas where crop dusting is commonly practiced, as well as golf courses and other areas where pesticides, herbicides, fungicides and other chemicals are used on a regular basis, all present potential risks of toxic chemical agent exposure.

Exposure may also come about in the event of intentional dispersing of toxic chemicals during war, or by terrorist organizations on either military personnel, or on a civilian population.

Toxic chemical agents may be grouped in any of a number of classifications. The most well known are the organophosphates, which include both pesticides and certain chemical agents classified as chemical warfare agents, and which include mustards and Lewisites.

Sulfur and nitrogen mustards include many well-known chemical agents, for military purposes as well as for 1 SUBSTITUTE SHEET (RULE 26) WO 2004/058274 PCT/US2002/041238 medicinal use. Lewisites, which are chlorinated arsenic complexes, are particularly toxic agents.

Lists of some chemical agents that pose potential health threats upon exposure are listed in Tables 1 and 2, below.

Regardless of the type of exposure, rapid treatment is necessary to prevent serious, permanent injury or death by chemical agents. Exposure to chemical agents is usually through the skin, the eyes or mucous membranes or through inhalation of aerosolized compounds, occasionally through ingestion of the toxic agent. It would be highly desirable to neutralize chemical agents when released into the environment deliberately or accidentally and this is yet another useful purpose of this invention.

Current treatments of patients exposed to toxic chemicals include both symptomatic and supportive care, and in some cases the administration of drugs. Drugs may be used to treat either the symptoms of exposure, or may be antidotal in nature. Currently, none of the present treatments for chemical agents is safe and effective in terms of preventing or treating serious toxicities arising from the exposure of patients to toxic chemical agents including organophosphates, mustards or Lewisites.

Some examples of recognized treatments include the administration of anticholinergic and/or antimuscarinic agents to exposed patients. Atropine is a well-known natural product of the deadly nightshade plant family and may be administered topically to the skin or eyes, or parenterally in the event of a systematic exposure to cholinesterase inhibiting agents.

Pralidoxime is a quaternary ammonium oxime that is classed as a cholinesterase re-activator, and is often administered to patients exposed to organophosphate based chemicals.

2 SUBSTITUTE SHEET (RULE 26) WO 2004/058274 PCT/US2002/041238 Other treatment methods and agents for chemical exposure .are also available.

Mesna (sodium 2-mercaptoethene sulfonate) and dimesna (disodium 2,2'-dithiobis ethane sulfonate) are known therapeutic compounds that have heretofore demonstrated a wide variety of therapeutic uses. Both mesna and dimesna have been shown to be effective protective agents against.

certain specific types of toxicity associated with the administration of cytotoxic drugs used to treat patients for various types of cancer.

In particular, mesna has been used with some success in mitigating the toxic effects of cytotoxic agents such as ifosfamide, oxazaphosphorine, melphalane, cyclophosphamide, trofosfamide, sulfosfamide, chlorambucil, busulfan, triethylene thiophosphamide, triaziquone, and others, as disclosed in U.S. Patent 4,220,660, issued September 2, 1980.

The near absence of toxicity of dimesna further underscores the usefulness of this compound, as large doses can be given to a patient without increasing the risk of adverse effects from the protective agent itself.

Further, pharmacological profiles of each compound indicate that, if proper conditions are maintained, mesna and dimesna do not prematurely inactivate primary therapeutic drugs to a significant degree. Thus, neither compound will significantly reduce activity of the chemotherapeutic agent, and in many cases, act to potentiate the effect of the main drug on targeted cancer cells.

The molecular structures of both mesna and dimesna are shown below as Structure I and Structure II respectively.

HS-CH

2

-CH

2

-SO

3 Na (II) NaS03-CH 2

-CH

2

-S-S-CH

2

-CH

2

-SO

3 Na As shown, dimesna is a dimer of mesna, with the optimum conditions for oxidation occurring in the slightly basic (pH oxygen rich environment found in blood plasma. In 3 SUBSTITUTE SHEET (RULE 26) WO 2004/058274 PCT/US2002/041238 mildly acidic, low oxygen conditions, in the presence of a reducing agent such as glutathione reductase, conditions prevalent in the kidneys, the primary constituent is mesna.

Mesna acts as a protective agent for a number of cytotoxic agents by substituting a nontoxic sulfhydryl moiety for a toxic hydroxy (or aquo) moiety. This action is particularly evidenced in the coadministration of mesna and oxazaphosphorine, and in the administration of dimesna along with certain platinum agents and/or taxanes.

Dimesna, as well as some analogues, have excellent toxicity profiles in mammalian species. In fact, dimesna has been administered intravenously to mice and dogs in doses higher than the accepted oral LDso for common table salt (3750 mg/kg), with no adverse effects. Dimesna has also been administered to humans in doses exceeding 40 g/m 2 with no adverse effects.

Mesna, and other analogues with free thiol moieties, constitute the more physiologically active form of the two types of compounds described in this specification. These compounds manifest their activity by providing free thiol moieties for terminal substitution at locations where a terminal leaving group of appropriate configuration, usually a hydroxy, aquo or superoxide is located. Mesna also tends to form conjugates with naturally occurring biochemicals that contain a free thiol moiety, such as cysteine, glutathione, homocysteine, and others.

Dimesna and other disulfides can be activated intracellularly by glutathione reductase, a ubiquitous enzyme, thereby generating high concentrations of intracellular free thiols. These free thiols act to scavenge the free radicals and other nucleophilic compounds often responsible for causing cell damage.

This profile is especially significant in explaining the success of dimesna in controlling and mitigating the toxic 4 SUBSTITUTE SHEET (RULE 26) WO 2004/058274 PCT/US2002/041238 effects of platinum complex antitumor drugs. The mechanism for action in the case of cisplatin (cis-diammine dichloro platinum) is explained in United States Patent 5,789,000, which is incorporated herein by reference.

Mesna, dimesna, and analogues of these compounds have been the subject of several prior pharmaceutical uses described in the literature and in prior patents, both in the United States and around the world. In addition to the cytotoxic agent protection uses, one or more of these compounds have proven effective, in vitro, against a multiplicity of biological targets, and have been effective, in vivo, in the treatment of sickle cell disease, radiation exposure, chemical agent exposure, and other uses.

Mesna, dimesna, and analogues thereof are synthesized from commonly available starting materials, using acceptable routes well known in the art. One such method involves the two-step, single pot synthetic process for making dimesna and like compounds of the following formula:

RI-S-R

2 wherein: RI is hydrogen, X-lower alkyl, or X-lower alkyl-R 3

R

2 is -lower alkyl-R 4

R

3 and R 4 are each individually S0 3 M or P0 3

M

2 X is absent or X is sulfur; and M is an alkali metal.

The process essentially involves a two-step single pot synthetic process, which results in the conversion of an alkenyl sulfonate salt or acid to the desired formula I compound. The process in the case of mesna is a single step process that converts the alkenyl sulfonate salt to mesna or SUBSTITUTE SHEET (RULE 26) WO 2004/058274 PCT/US2002/041238 a mesna derivative by reacting with an alkali metal sulfide or with hydrogen sulfide.

If the desired end product is dimesna or a dimesna analogue, a two-step single pot process is involved. Step 1 is as described above. Step 2 of the process is performed in the same reaction vessel as Step 1 without the need to purify or isolate the mesna formed during that step. Step 2 includes the introduction of oxygen gas into the vessel, along with an increase in pressure and temperature above ambient values, at least 20 pounds per square inch (psi) and at least 60° C. Dimesna or a derivative thereof is formed in essentially quantitative yield.

Other processes, well known and documented in the prior art, may be employed to make either mesna or dimesna, or derivatives and analogues thereof.

SUMMARY OF THE INVENTION This invention involves the administration of an effective amount of a compound of formula I, below, for treating or mitigating the toxic adverse effects of toxic chemical-exposure:

(I)

R

3 Ri-S-(alkyl),-

R

2 wherein: Rj RI is hydrogen, lower alkyl or -S-(alkyl)m-R 4

R

2 and R 4 are each individually SO3-M, PO 3 2

-M

2 or PO2S 2 M22+;

R

3 and Rs are each individually hydrogen, hydroxy, amino, nitro or sulfhydryl; Each m is individually 1, 2, 3, 4, 5 or 6 with the proviso that if m is 1, then R 3 is hydrogen; and 6 SUBSTITUTE SHEET (RULE 26) WO 2004/058274 PCT/US2002/041238 M is hydrogen or an alkali metal ion; or a pharmaceutically acceptable salt thereof.

Effective amounts of the formula I compound to be administered according to the method of this invention are variable, and depend upon the severity of exposure and on the patient's response. Due to the excellent toxicity profile of the formula I compounds, large amounts of drug may be administered without risk of untoward side effects commonly associated with other drugs used to treat this condition.

The formula I compound may be administered by oral route, allowing the patient to self-administer the agent, adding to convenience of use.

The method also contemplates the possible administration of the formula I compound in combination with other agents to provide effective and safe treatment for toxic chemical exposure.

Accordingly, it is an object of this invention to provide for a method of safely and effectively treating a patient to neutralize, reverse or mitigate the adverse effects of exposure to toxic chemicals.

Another object is to provide a method of treating a patient for toxic chemical exposure by administration of a thiol or reducible disulfide to the patient desirous of treatment.

Another object is to provide for a safe and effective method of providing prophylaxis to a person at risk for toxic chemical exposure.

Other objects will become apparent upon a reading of the following description.

7 SUBSTITUTE SHEET (RULE 26) WO 2004/058274 PCT/US2002/041238 DESCRIPTION OF THE PREFERRED EMBODIMENTS The preferred embodiments herein described are not intended to be exhaustive or to limit the invention to the precise form disclosed. They are chosen and described to explain the principles of the invention, and its application and practical use to best enable others skilled in the art to follow its teachings.

The method of this invention involves the administration of an effective amount of a formula I compound to a patient suffering from complications of toxic chemical exposure. The effective amount of the formula I compound will depend upon the severity of the exposure and on the individual patient's response to treatment. Since the formula I compounds are essentially nontoxic, large amounts can be safely administered. The preferred initial dosage to treat toxic chemical exposure will depend upon the level of exposure of each individual patient. Dosage may initially be as low as 0.1 mg/kg up to 3,000 mg/kg.

The formula I compounds may be used to treat exposure to one or more of the toxic chemicals listed below in Tables 1 and 2.

TABLE 1 COMMERCIAL PRODUCTS (Agricultural, Home use, etc.) Chemical Name Brand(s) Chemical Class Acetic acid Shotgun Herbicide Acetochlor Harness Herbicide Acrolein Magnacide H Herbicide Alachlor Lasso Herbicide Aldicarb Temik Insecticide Aluminum Phosphide Fumex Fumigant 8 SUBSTITUTE SHEET (RULE 26) WO 2004/058274 WO 204/08274PCTUS2002/041238 Amitraz Mitac Insecticide Aitrole Amizol Herbicide Arsenic acid Chernonite Herbicide Ar-senic pentoxide Wolmanac Wood Preservative Atrazine Surpass Herbicide Avermectin Zephyr Insecticide Avitro. Avitrol Bird control Azinphos-methyl Guthion Insecticide Bendiocarb Turcam Insecticide Bifenthrin Taistar Insecticide Bis (tributyltin) oxide Navicote2000 Antifouling paint Carbofuran Furadan Insecticide Chiorophacinone Rozol Rodenticide Chioropicrin Metabroa Fungicide Chiorothoxyfos Fortress Insecticide Chiorpyrifos Dursban Insecticide Chromic acid CCA Wood preservative Clofentezine Apollo SC Miticide Coumaphos CO-PAL Insecticide Cyanazine Bladex Herbicide Cyfluthrin Aztec Insecticide Cyhalothrin Karate 50 Insecticide Cypermethrin Cynoff Insecticide Deltarnethrin Striker Insecticide Diazinon Diazinon Insecticide Dichloenil Vaporooter Herbicide Dichioropropene Telone Soil fumigant Diclofop methyl Brestan H Herbicide Dicrotophos Chiles' Go-Better Insecticide Diflubenzuron Dimilin Insecticide Dioxathion Cooper Del-Tox Insecticide Disulfoton Stand-aid Insecticide Fenarniphos Nemacur Nematicide SUBSTITUTE SHEET (RULE 26) WO 2004/058274 WO 204/08274PCTUS2002/041238 Fenbutat in-oxide Venclex 50 Miticide Feriltrothion Surnithion Insecticide Fenpropathrin Danitol Insecticide FetinBaytex Insecticide Fenvalerate Asana XL Insecticide FirnlRegent Insecticide Hydrogen cyanamide Dormex Herbicide Tsoxaflutole [soxaflutole Lindane Lindane Insecticide Magnesium phosphide Phostoxii Insecticide Methamidophos Monitor-4 Insecticide Methiocarb Mesurol Insecticide MehmlLannate Insecticide Methylisothiocyanate Mitc-fume Wood Preservative Mevinphos Duraphos Insecticide Nicotine Insecticide Oxamyl Vydate Insecticide Oxydemeton methyl Harpoon Insecticide Paraquat Cyclone Herbicide Parathion Parathion Insecticide Pentachiorophenol Dura-Treet Wood Preservative Permethrin Pounce Insecticide Phorate Rampart Insecticide Phostebupirim Aztec Insecticide Picloram Grazon Herbicide Piperonyl Butoxide Vex Insecticide Profenophos Curacron Insecticide Pronaraide Kerb Herbicide Propanoic Acid Silverado Herbicide Propetamphos Zoecon Insecticide Resmethrin Oblique Insecticide Rotenone Rotenone Fish Toxicant Simazine Printrex Herbicide SUBSTITUTE SHEET (RULE 26) WO 2004/058274 WO 204/08274PCTIUS2002/041238 Sodium Cyanide DRC-1339 Rodenticide Sodium dichromate Osmopiastic SD Wood Preservative Sodium Fluoroacetate Compound 1080 L2C Rodenticide Sodium Hydroxide Angus Hot Rod Herbicide Starlicide Compound DRC Bird Repellant Strychnine Rodenticide Sulfotep Dithio Ins. Smoke Insecticide Sulprofos Boistar 6 Insecticide Tefluthrin Force Insecticide Terbufos Counter Insecticide TEM Aquatic Pest Control Traiomethrin Scout Insecticide Triisopropanolamine Toram 101 Herbicide Triphenyltin Agritin Fungicide hydroxide Zinc Phosphide ZP Rodent Bait Rodent icide--- Azoxystrobin Abound Fungicide Triademifon Accost Fungicide Dimethomorph Acrobat Fungicide Propiconazole Alamo Fungicide Fosetyl-aluminun Aliette Fungicide Metailaxyl Apron Fungicide Thirant Arasan Fungicide Thiabendazole Arbotect Fungicide Propamnocarb HC1 Banol Insecticide Etridiazcle Banrot Fungicide Tbhiophanate methyl Cleary's 3336 Fungicide Benomyl Berilate Fungicide Copper sulfate Bordeaux Mix Fungicide Chiorothalonil Bravo, Daconil Fungicide Captan Captan Fungicide Carboxin Carbcxin Fungicide SUBSTITUTE SHEET (RULE 26) WO 2004/058274 WO 204108274PCTiUS2002/041238 ]Iprodione Chipco 26019 Fungicide Vinclozolin Curalan Fungicide Cyrnoxanil Curzate 6ODF Fungicide Dodine Cyprex Fungicide Fenhexamid Decree Fungicide PCNB Defend Fungicide Chioroneb Demaosan Fungicide Mancozeb Dithane, M45 Fungicide Anilazene Dyrene Fungicide Tebuconazole Elite Fungicide Fenbuconazole Enable Fungicide Triforine Funginex Fungicide Bacticin Gallex Fungicide Maneb Manzate Fungicide Piperalin Pipron Fungicide Flutolanil ProStar Fungicide Fenarimol Rubigan Fungicide Mefenoxam Subdue Maxx Fungicide Strobilurin Compass Fungicide Acephate Orthene, Insecticide 12 SUBSTITUTE SHEET (RULE 26) WO 2004/058274 PCT/US2002/041238 Table 2 TOXIC NON-COMMERCIAL CHEMICALS B. SCHEDULES OF CHEMICALS The following Schedules list toxic chemicals and their precursors. For the purpose of implementing this Convention, These Schedules identify chemicals for the application of verification measures according to the provisions of the Verification Annex. Pursuant to Article II, subparagraph these Schedules do not constitute a definition of chemical weapons.

(Whenever reference is made to groups of dialkylated chemicals, followed by a list of alkyl groups in parentheses, all chemicals possible by all possible combinations of alkyl groups listed in the parentheses are considered as listed in the respective Schedule as long as they are not explicitly exempted. A chemical marked on Schedule 2, part A, is subject to special thresholds for declaration and verification, as specified in Part VII of the Verification Annex.) Schedule 1 A. Toxic Chemicals (CAS registry number} O-alkyl (<Clo, incl. cycloalkyl)alkyl (Me, Et, n- Pr or i-Pr)-phosphonofluoridates e.g. Sarin: O-isopropyl) methylphosphonofluoridate 107-44-8 Soman: O-pinacolyl methylphosphonofluoridate 96-64-0 13 SUBSTITUTE SHEET (RULE 26) WO 2004/058274 WO 204108274PCTiUS2002/041238 0-alkyl (<Cio, incl. Cycloalkyl)N,N-dialkyl (Me, Et, n-Pr, i-Pr) phosphoroamiclocyanidates e.g. Tabun: 0-ethyl N,N-dimethyl phos phoroarnidocyanidate 77-81-6 0-alkyl (<C 1 0 incl. Cycloalkyl)S-2 dialkyl (Me,1 Et, n-Pr or i-Pr)aminoethyl alkyl (Me, Et, n-Pr or i-Pr) phosphonothiolates and corresponding alkylated and protonated salts e.g. VX: 0-ethyl S-2-diisopropylaminoethyl methyl phosphonothiolate 50782-69-9 4- Sulfur Mustards 2 -Chloroethylchloromethylsulfide Mustard gas: Bis (2-chioroethyl) sulfide Bis (2-chloroethyithio) methane Sesquimustard: 1,2-Bis (2-chloroethylthio)ethane 1, 3-Bis (2-chloroethylthio)-n-propane 1, 4-Bis (2-chloroethylthio)-n-butane 1, 5-Bis (2-chloroethylthio)-n--pentane Bis (2-chloroethylthiomethyl) ether 0-mustard: Bis (2-chloroethylthioethyl) ether 2625-76-5 505-60-2 63869-13-6 3563-36-8 63905-10-2 142868-93-7 1428 6B-9 4-8 63918-90-1 63 918-8 9-a Lewisites Lewisite 1: 2-Chlorovinyldichlorcarsine 512- L e w i s i t e 2 1 -2-h l r v n y h o r a n 503 3 9 Lewisite 2: Bis(2-chorovinyl)achirarin 40334-70-8 Nitrogen Mustards SUBSTITUTE SHEET (RULE 26) WO 2004/058274 WO 204108274PCTiUS2002/041238 HN1: Bi s (2 -chioroethyl) ethyl amine 538-C7-8 HN2: Bis (2-chloroethyl)methylamine 51-75-2 555-71-1 H'N3: Tris (2-chloroethyl)anine Saxi 'oxin 35523-89-8 Ricin 9009-86-3 B. Precursors: Alkyl (Me, Et, n-Pr, i-Pr)phosphonyldifluorides e.g. DF: Nethyiphosphonyldifluoride 676-99-3 0-alkyl (H or <CIO, incl. Cycloalkyi)0-2 dialkyl (Me, Et, n-Pr or i-Pr)aminoethyl alkyl (Me, Et, n- Pr or i-Pr)phosphonites and corresponding alkylated and protonated salts e.g. QL: 0-ethyl 0-2-diisopropylaminoethyl 5861methyl phosphonite Chiorosarin: 0-isopropyl methyiphosphonochior idate 1445-76-7 Chiorsoman: O-Pinacolyl methyiphosphonochioridate 7040-57-5 Schedule 2 A. Toxic Chemicals Amiton: 0,0-Diethyl S-[2-2(diethylamino) ethyl) 78-53-5 phosphorothiolate and corresponding alkylated and SUBSTITUTE SHEET (RULE 26) WO 2004/058274 WO 204/08274PCTUS2002/041238 protonated salts PEIB: l,l, 3 3 3 -Plentafluoro-2-(trifluoromethyl)-l- 382-21-8 propene BZ: 3-Quinuclidiny. benzilate 6T58 1 -0 6-2 B. Precursors: Chemicals, except for those listed in Schedule 1, containing a phosphorous atom to which is bonded one methyl, ethyl or propyl (normal or iso) group but not further carbon atoms e.g. Methyiphosphonyl dichloride .B76-97-1 Dimethyl methylphosphonate 756-79-6 N,N-Dialkyl(Me, Et, n-Pr, i-Pr)phosphoramidic dihalide3 Diaikyl(Me, Et, n-Pr, i-Pr)N,N-dialkyl (Me, Et, n- Pr, i-Pr) -phosphoroamidates Arsenic trichioride 77B4-34-1 2, 2-Diphenyl-2-hydroxyacetic acid 76-93-7 Quinuclidin-3-ol 1619-34-7 N,N-Dialkyl(Me, Et, n-Pr, i-Pr)aminoethyl-2chlorides and corresponding protonated salts N,N-Dialkyl(Me, Et, n-Pr, i-Pr)aminoethane-2-ols and corresponding protonated salts SUBSTITUTE SHEET (RULE 26) WO 2004/058274 WO 204108274PCTiUS2002/041238 and corresponding protonated salts Exemptions: N, N- Dime thyl aminoe thanol and corresponding protonated salts N,N-Diethyilaminoethanol and 100-37-8 corresponding protonated salts N,N-Dialkyl(Me, Et, n-Pr, i-Pr)amninoethane-2thiols and corresponding protonated salts Thiodiglycol: Bis (2-hydroxyethyl) sulfide 111-48-8 Pinacolyl alcohol: 3,3-Dirnethylbutan--2-ol 464-07-3 Schedule 3 A. Toxic Chemicals: Phosgene: Carbonyl dichloride 75-44-5 Cyanogen chloride 506-77-4 Hydrogen cyanide7-9- Chioropicrin: Trichloronitromethane -/6-05-2 B. Precursors: Phosphorous oxychloride 10025-87-3 Phosphorous Lrichlotide 7719-12-2 Phosphorous pentachioride 10025-13-8 17 SUBSTITUTE SHEET (RULE 26) WO 2004/058274 PCT/US2002/041238 Trimethyl phosphite 121-45-9 Triethyl phosphite 122-52-1 Dimethyl phosphite 868-85-9 Diethyl phosphite 762-04-9 Sulfur monochloride 10025-67-9 Sulfur dichloride 10545-99-0 Thionyl chloride 7719-09-7 Ethyldiethanolamine 139-87-7 Methyldiethanolamine 105-59-9 Triethanolamine 102-71-6 For parenteral administration, the formula I compound is dissolved in a suitable solvent, most preferably water, to produce a solution. One or more pharmaceutically acceptable excipients may also be added to provide for an elegant formulation. The formulation may also be incorporated into a continuous delivery device, such as an implanted parenteral infusional pump or similar device.

The formula I compound may also be administered as a prophylactic measure to persons at risk for exposure to toxic chemicals. A person at risk is generally defined as one likely to come into contact with toxic chemicals in the near future, more specifically soldiers fighting an enemy known to possess chemical weapons, sportsmen and women.during periods immediately following application of pesticides, even civilians against whom a terrorist attack has been imminently threatened.

Prophylactic administration according to this invention would preferably be through oral, topical or subdermal 18 SUBSTITUTE SHEET (RULE 26) WO 2004/058274 PCT/US2002/041238 routes, most preferably in some form of time-release medicament. The formula I compound may be delivered subdermally, as by a skin patch. Skin patches and pumps have the advantage of continuous drug delivery without the need to take a pill every so often. Another means of administration is by aerosol spray, which can be sprayed on potential areas of skin exposure.

For oral administration the formula I compound is preferably combined with one or more pharmaceutically acceptable excipients, fillers and/or diluents. Oral dosage forms may include pills, caplets, tablets, a pleasantly flavored liquid solution or suspension, and others.

Alternatively, the formula I compound may be contained in a deglutable container such as a gelatin capsule or the like.

Since the half-life of the formula I compound is usually short, slow-release oral dosage forms are most preferred.

The formula I compounds are believed to alleviate toxic chemical exposure by binding to the active, toxic species of the molecule and/or to its toxic metabolites. In so binding, the resultant compound is rendered relatively nontoxic and highly water soluble, which aids in its rapid elimination from the body.

Administration of the formula I compound should preferably be started as soon as possible based on the clinical suspicion that a patient has been exposed to a toxic chemical, and may be administered to a patient who risks exposure, such as farmers, gardeners, pet groomers, veterinarians, soldiers or anyone else who risks exposure to such chemicals. The preferred initial dose is between mg/kg and 1000 mg/kg. High doses may be repeated ad libitum until positive results are achieved.

Careful observation and analysis may be performed regularly throughout treatment, especially in acute, potentially life-threatening cases. Dose rate may be altered 19 SUBSTITUTE SHEET (RULE 26) WO 2004/058274 PCTiUS2002/041238 depending upon the patient's response. If any adverse effects appear, the dose may be lowered or the timing changed. Dose alteration is well within the purview of one skilled in the medical arts. Slow release formulations of oral dosage forms are preferred in prophylaxis to provide for longer protection. In cases of continual exposure to pesticides, long-term affects may be controlled through administration of periodic amounts of the formula I compounds.

Also, due to the excellent safety profile, additional doses of the formula I compound may be administered safely if the initial dose does not produce a positive response.

Treatment may be repeated as often as necessary.

It is understood that the above description is in no way limiting of the invention, which may be modified within the scope of the following claims.

SUBSTITUTE SHEET (RULE 26)

Claims

1. A method of treating a patient to alleviate the adverse effects of toxic chemical exposure, said method comprising administering to the patient an effective amount of a compound of formula I: (I) R 3 R 1 -S-(alky)m-- R 2 wherein: R- -s-(alkyvm -R4. RI is hydrogen, lower alkyl or (alk)m Rz and R 4 are each individually SO 3 -M PO 3 -M 2 or P0 2 S 2 M22+; R 3 and R 5 are each individually hydrogen, hydroxy, amino, nitro or sulfhydryl; Each m is individually 1, 2, 3, 4, 5 or 6 with the proviso that if m is 1, then R 3 is hydrogen; and M is hydrogen or an alkali metal ion; or a pharmaceutically acceptable salt thereof.

2. The method of Claim 1 wherein the effective amount of the formula I compound administered is from 0.1 ng/kg of body weight to 3,000 mg/kg of body weight.

3. The method of Claim 1 wherein the compound is administered orally.

4. The method of Claim 1 wherein the compound is administered subdermally or parenterally.

5. The method of Claim 1 wherein the toxic chemical to which the patient has been exposed is organophosphate based.

6. The method of Claim 1 wherein the toxic chemical to which the patient has been exposed is a Lewisite.

7. The method of Claim 1 wherein the toxic chemical to which the patient has been exposed is a sulfur mustard derivative.

8. The method of one of Claims 5, 6 or 7 wherein the 21 SUBSTITUTE SHEET (RULE 26) WO 2004/058274 PCT/US2002/041238 toxic chemical to which the patient has been exposed is a precursor compound to an organophosphate, a Lewisite, or a sulfur mustard.

9. The method of Claim 1 wherein the toxic chemical to which the patient has been exposed is Saxitoxin or Ricin.

The method of Claim 1 wherein said toxic chemical to which the patient has been exposed is a copper-based fungicide.

11. The method of Claim 1 wherein which the patient has been exposed is a fungicide.

12. The method of Claim 1 wherein a carbamate based pesticide.

13. The method of Claim 1 wherein a strobilurin based fungicide.

14. The method of Claim 1 wherein a topical plant fungicide.

The method of Claim 1 wherein a systemic plant fungicide.

16. A method for prophylactically the toxic chemical to chlorinated aromatic the toxic chemical is the toxic chemical is the toxic chemical is the toxic chemical is treating a person at risk for exposure to toxic chemical agents, said method comprising administering to said person a compound of formula I: (I) R 3 Ri-S-(alkyl)m-R 2 wherein: R R1 is hydrogen, lower alkyl or -S(a l kyl)--R4 R 2 and Rq are each individually SO 3 -M 1 PO 3 2-M 2 2 or POzS 2 M22+; R 3 and Rs are each individually hydrogen, hydroxy, amino, nitro or sulfhydryl; 22 SUBSTITUTE SHEET (RULE 26) WO 2004/058274 PCT/US2002/041238 Each m is individually 1, 2, 3, 4, 5 or 6 with the proviso that if m is 1, then R 3 is hydrogen; and M is hydrogen or an alkali metal ion; or a pharmaceutically acceptable salt thereof.

17. The method of Claim 16 wherein the formula I compound is administered orally.

18. The method of Claim 1 wherein the formula I compound is administered by continuous flow subdermal patches. 23 SUBSTITUTE SHEET (RULE 26)