Useful tetraalkyl diamides in the treatment of poison ivy

Abstract

The relief from poison ivy on warm-blooded animals is obtained by applying to the surface of the affected area, a tetraalkyl diamide of the formula: ##SPC1## Wherein each R represents a member selected from the group consisting of a saturated aliphatic hydrocarbon group of from 1 to 6 carbon atoms and an unsaturated aliphatic hydrocarbon group of from 1 to 6 carbon atoms, and wherein R.sub.1 represents a member selected from the group consisting of a saturated aliphatic hydrocarbon group of from 0 to 22 carbon atoms and an unsaturated aliphatic hydrocarbon group of from 0 to 22 carbon atoms.

Description

BACKGROUND OF THE INVENTION

1. FIELD OF THE INVENTION

The present invention relates to a method for alleviating the itching and clearing the rash on warm-blooded animals, e.g., humans, exposed to poison ivy. More particularly, the present invention is directed to a method for treating poison ivy through the use of certain tetraalkyl diamides.

2. DESCRIPTION OF THE PRIOR ART

It is well known to those versed in the art and science of medicine that subsequent to exposure, either by direct contact or from the volatile oils of the plant Rhus (Toxicodendron L.) and other plants of the Rhus species (Anacardiaceae) an annoying dermatitis appears. This dermatitis takes the form of an itching rash which subsequently develops into a running itching area. It appears that the reaction is an allergic response to an irritant catechol compound known as "urushiol," a volatile oil found in the above-identified plants. The chemical structure for urushiol can be found in Merck Index, p. 1098 (Eighth Ed.).

To date, numerous therapeutic formulations have evolved for the treatment of poison ivy, such as treatment with strong alkaline soaps, the use of astringents and drying agents, such as calamine, the use of topical application of anti-histamines, and the use of zirconium salts. However, none of the above therapeutic measures have been truly found to be effective in treating the patient either prior to or following exposure to the poison ivy irritant. Moreover, none of the above measures are directed at the causative agent of the dermatitis associated with poison ivy.

U.S. Pat. No. 3,632,783 discloses the use of tetraalkyl diamides of this invention for obtaining relief from mosquito bites on humans. However, there is no disclosure or suggestion by the patentee to the effect that these tetraalkyl diamides could be used in alleviating the dermatitis associated with poison ivy. Moreover, the irritant which causes the itching following a mosquito bite is not the irritant which causes the dermatitis following contact with the above-identified plants, responsible for poison ivy.

The compound dimethylacetamide has been used in the treatment of the inflammation associated with arthritis. However, this inflammation is not even remotely related to that observed in individuals suffering from "poison ivy." Obviously, the origin of inflammation in each case is totally unrelated. In fact, to date, it is questionable as to the origin of arthritis.

SUMMARY OF THE INVENTION

It is the primary object of this invention to provide a new and novel approach to the treatment of the poison ivy dermatitis found on warm-blooded animals, e.g. humans by actually cancelling out the irritant effect produced by the compound known as urushiol.

The above object is obtained by applying to the dermatitic area of a patient afflicted with poison ivy, a tetraalkyl diamide of the formula: ##SPC2##

wherein each R represents a member selected from the group consisting of a saturated aliphatic hydrocarbon group of from 1 to 6 carbon atoms and an unsaturated aliphatic hydrocarbon group of from 1 to 6 carbon atoms, and wherein R.sub.1 represents a member selected from the group consisting of a saturated aliphatic hydrocarbon group of from 0 to 22 carbon atoms and an unsaturated aliphatic hydrocarbon group of from 0 to 22 carbon atoms.

Specifically, it has now been found that the use of any one of the above-identified compounds significantly reduces the dermatitis associated with poison ivy. The reduction in the dermatitis is due to the interaction of the tetraalkyl diamide with urushiol to alter the physiological activity of the latter.

The approach is novel from the standpoint that the therapeutic agent does not at all attempt to degrade urushiol but rather, it forms a molecular complex having properties which are different than the parent structure, and consequently, reduces its ability to illicit the typical dermatitis response noted after poison ivy contact.

With respect to the above-identified generic formula, the following remarks for purposes of clarification are deemed pertinent. The substituent "R" includes any straight or branched chain or cyclo derivative within the definition of the same. The substituent "R.sub.1 " is essentially a straight-chain moiety, though chains with a hydroxy substituent are also equivalent.

Consequently, one may use a diamide of oxalic, malonic, succinic, glutaric, maleic, adipic, pimelic, suberic, azelaic, sebacic, undecanoic, dodecanoic, octadecylic, or eicosanoic acid, etc., provided the total number of carbon atoms in the diamide do not exceed about 20. In addition, isomers of these acids can also be employed, for instance, iso-sebacic acid, iso-glutaric, iso-adipic, etc. Moreover, tricarboxylic acids, such as tricarballic acid are equivalent, as are acids which include a hydroxy group, such as ricinoleic acid.

PREFERRED EMBODIMENTS OF THE INVENTION

While all the compounds encompassed within the above generic formula are suitable for the purposes of this invention, the following are preferred:

N,n,n',n'-tetramethyl adipamide

N,n,n',n'-tetramethyl glutaramide

N,n,n',n'-tetramethyl sebacamide

N,n,n',n'-tetramethyl succinamide

Other diamides which may also be used include:

N,n,n',n'-tetrabutyldiamide of oxalic acid

N,n,n',n'-tetra-n-butyldiamide of malonic acid

N,n-dibutynylamide-N',N'-diallylamide of malonic acid

N,n-di-n-butylamide-N',N'-diethylamide of succinic acid

N,n-dimethylamide-N',N'-dibutylamide of succinic acid

N,n,n',n'-tetramethyldiamides of iso-glutaric acid

N,n,n',n'-tetraallyldiamide of glutaric acid

N,n-dimethylamide-N',N'-dibutylamide of glutaric acid

N,n-di(methylethyl)-N',N'-dimethylamide of adipic acid

N,n,n',n'-tetramethyldiamides of iso-adipic acid

N,n-dimethylamide-N',N'-dibutylamide of adipic acid

N,n-dimethyl-N',N'-dihexyldiamide of pimelic acid

N,n,n',n'-tetraisopropyldiamide of azelaic acid

N,n-dimethyl-N',N'-dihexyldiamide of azelaic acid

N,n,n',n'-tetraallyldiamide of azelaic acid

N,n-di-n-butyl-N',N'-dihexylamide of sebacic acid

N,n,n',n'-tetramethyldiamide of iso-sebacic acid

N,n,n',n'-tetraisopropyldiamide of brassylic acid

The compounds of this invention may be prepared according to the established synthesis procedure set forth in U.S. Pat. No. 3,417,114 and/or U.S. Pat. No. 3,288,794, the subject matter of which, insofar as it pertains to the preparation of such compounds, is incorporated herein by reference.

The tetraalkyl diamides of this invention are preferably applied as a solution (normally, 1-95%, but preferably 5-25%) in water. The term "solution" is meant to include a water-miscible alcohol solution, such as isopropyl alcohol or ethyl alcohol, or the alcohol may be used undiluted. The solution is applied in any suitable manner, e.g., by spraying or swabbing the dermatitic area. Alternatively, the tetraalkyl diamides of this invention may be applied in the form of any other topical pharmaceutical form, such as a powder, paste, salve, ointment, aerosol spray, etc. These compounds can also be dissolved in a cosmetic base, a cream or oil, and added to other solutions or sprays normally applied to the skin, such as insect repellants, sun screen lotions, and ointments and creams normally used in the treatment of skin rashes and allergies, and in topical anesthetics used for the relief of pain and itching of sunburn. The skilled artisan concerned with the subject matter of this invention can easily prepare any of the above-mentioned conventional pharmaceutical dosage forms for topical application by simply referring to "REMINGTON'S PHARMACEUTICAL SCIENCES" (Fourteenth Edition), 1970, pp. 1461-1762.

Normally, a single application brings immediate relief to the area treated; however, for stubborn cases, repeated application may be necessary.

Without further elaboration, it is believed that one of ordinary skill in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the specification and claims in any way whatsoever.

EXAMPLE I

Set forth below are some illustrative topical formulations containing a selected tetraalkyldiamide compound of the instant invention.

Formulation Number 1 -- Solution

N,n,n',n'-tetramethyl succinamide 1 - 25%

Distilled water qs to 100%

Procedure: Dissolve the tetramethyl succinamide in enough water to make 100%. Filter the solution. Apply to the effected area.

Formulation Number 2 -- Tincture N,N,N',N'-tetramethyl succinamide 1 25% Alcohol USP 50% Water qs 100%

Procedure: Dissolve the tetramethyl succinamide in the alcohol. Add sufficient water to make 100%. Filter and apply to affected area.

Formulation Number 3 -- Topical Aerosol

N,N,N',N'-tetramethyl succinamide 1 25% Alcohol USP 5% Isopropylmyristate 5% *Conventional halogenated hydrocarbon propellant qs 100% *e.g. - Freon 11 (trichlorofuluromethane), Freon 12 (dichlorodifluromethane), Freon 14 (carbon tetrafluoride), Freon C 318 (Octaflurocyclobutane), Freon 114 (Cryofluorane), etc.

Procedure: Dissolve the tetramethyl succinamide in the alcohol and isopropylmyristate. Add sufficient halogenated propellant and introduce into conventional aerosol containers either by pressure or by cold filling. Apply to affected area.

Formulation Number 4 -- Ointment

N,N,N',N'-tetramethyl succinamide 1 25% Petrolatum USP qs 100%

Procedure: Heat the petrolatum to 60.degree. C. Add the tetramethyl succinamide and stirr until thoroughly dispersed. Cool to room temperature. Apply to affected area.

The concentrations implied in the above exemplary formulations are typical of those used medicinally but in no way should they be construed as limiting the scope of this invention.

EXAMPLE II

(In Vivo Studies)

A topical aerosol formulation, in accordance with Formulation Number 3 of Example I above was prepared. The concentration of tetramethylsuccinamide in the formulation was 5 percent. The halogenated hydrocarbon propellant employed was a conventional propellant, *Freon 11-12 (50/50). *A 50/50 mixture of Freon 11 and Freon 12.

At 24 hour intervals, the aerosol was applied to dermatitic areas resulting from poison ivy contact on human volunteers of both sexes. Within 24 to 36 hours following application, dramatic reduction in the dermatitis of each individual treated was observed.

The tetraalkyl diamide compounds of this invention are highly water soluble and a finite affinity for the organic phase. These characteristics permit dermal penetration without significant systemic absorption. In addition, the topical LD.sub.50 of these compounds is relatively high. For instance, the compound, N,N,N',N'-tetramethyl succinamide gave a topical LD.sub.50 of 2000 mg./Kg. when applied to denuded rabbits.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, such changes and modifications are properly, equitably and intended to be, within the full range of equivalence for the following claims.

Claims

What I claim is:

1. A method of reducing poison ivy dermatitis on a warm-blooded animal, which comprises applying to the dermatitic area, an effective amount of a compound of the formula: ##SPC3##

wherein each R represents a member selected from the group consisting of a saturated aliphatic hydrocarbon group of from 1 to 6 carbon atoms and an unsaturated aliphatic hydrocarbon group of from 1 to 6 carbon atoms, and wherein R.sub.1 represents a member selected from the group consisting of a saturated aliphatic hydrocarbon group of from 0 to 22 carbon atoms and an unsaturated aliphatic hydrocarbon group of from 0 to 22 carbon atoms,

whereby said compound forms a molecular complex with urushiol, the causative agent of said dermatitis.

2. The method of claim 1, wherein said compound is:

N,n,n',n'-tetramethyl adipamide.

3. The method of claim 1, wherein said compound is:

N,n,n',n'-tetramethylglutaramide.

4. The method of claim 1, wherein said compound is:

N,n,n',n'-tetramethylsebacamide.

5. The method of claim 1, wherein said compound is:

N,n,n',n'-tetramethylsuccinamide.

6. The method of claim 1, in which said compound is applied as a pharmaceutically acceptable topical preparation.

7. The method of claim 2, wherein said compound is applied as a water solution.

8. The method of claim 2, wherein said compound is applied as an alcohol solution.

9. The method of claim 2, wherein said compound is applied as an aqueous-alcoholic solution.

10. The method of claim 2, wherein said compound is applied as a halogenated hydrocarbon propellant solution.

11. The method of claim 10, wherein said propellant is a 50/50 mixture of trichlorofluoromethane and dichlorodifluoromethane.