WO2004058274A1

WO2004058274A1 - Method of treating patients exposed to toxic chemical agents

Info

Publication number: WO2004058274A1
Application number: PCT/US2002/041238
Authority: WO
Inventors: Frederick H. Hausheer; Seetharamulu Peddaiaghari; Thomas J. Dodd
Original assignee: Bionumerik Pharmaceuticals, Inc.
Priority date: 2002-12-21
Filing date: 2002-12-21
Publication date: 2004-07-15
Also published as: CN1735417A; EP1583540A1; MXPA05006721A; CA2511778A1; JP2006513190A; EP1583540A4; AU2002360747B2; AU2002360747A1

Abstract

This invention relates to a method of treating patients suffering from the adverse effects of exposure to pesticides. The method includes administering to a patient in need of treatment an effective amount of a thiol or reducible disulfide compound according to the formula set forth in the specification.

Description

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 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 . 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, cyclophospha-mide, 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. (I) HS-CH₂-CH₂-S0₃Na

(II ) NaS0₃-CH₂-CH₂-S-S-CH₂-CH₂-SO₃Na As shown, dimesna is a di er of mesna, with the optimum conditions for oxidation occurring in the slightly basic (pH -7.3), oxygen rich environment found in blood plasma. In 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 LD₅o for common table salt (3750 g/kg) , with no adverse effects. Dimesna has also been administered to humans in doses exceeding 40 g/m², 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 thic^ls . 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 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 vi tro, 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-Rz;

wherein :

Ri is hydrogen, X-lower alkyl, or X-lower alkyl-R₃; R₂ is -lower alkyl-R₄; R₃ and R₄ are each individually S0₃M or P0₃M₂;

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 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)

Rl—S—(alky rn—R₂ wherein:

Ri is hydrogen, lower alkyl or -(alkyl)m— R4 .

R₂ and R₄ are each individually S0₃ ^~M⁺, P0₃ ² M₂ ²⁺, or P0₂S ^~

M₂ ²⁺;

R₃ and R₅ 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 R₃ is hydrogen; and 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. 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.)

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 1 (a) , 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 (<C₁₀, incl. cycloalkyl) alkyl (Me, Et, n- Pr or i-Pr) -phosphonofluoridates

e.g. Sarin: O-isopropyl) methylphosphonofluoridate 107-44-, So an: O-pinacolyl methylphosphonofluoridate 96-64-0

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 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. I

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 10 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 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 compoun s . 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.

Claims

What Is Claimed Is:

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)

wherein:

Ri is hydrogen, lower alkyl or

R₂ and R₄ are each individually S0₃ ^"M⁺, P0₃ ^2"M₂ ²⁺, or P0₂S^2~ M₂ ²⁺;

2. The method of Claim 1 wherein the effective amount of the formula I compound administered is from 0.1 mg/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 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.

10. 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 the toxic chemical to which the patient has been exposed is a chlorinated aromatic fungicide .

12. The method of Claim 1 wherein the toxic chemical is a carba ate based pesticide.

13. The method of Claim 1 wherein the toxic chemical is a strobilurin based fungicide.

14. The method of Claim 1 wherein the toxic chemical is a topical plant fungicide.

15. The method of Claim 1 wherein the toxic chemical is a systemic plant fungicide.

16. A method for prophylactically treating a person at risk for exposure to toxic chemical agents, said method comprising administering to said person a compound of formula I:

(I)

wherein:

Ri is hydrogen, lower alkyl or

R₂ and R₄ are each individually S0₃ ^~M⁺, P0₃ ^2~M₂ ²⁺, or P0₂S^2" M₂ ²⁺; R₃ 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 R₃ 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 .