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Publication numberUS3875301 A
Publication typeGrant
Publication dateApr 1, 1975
Filing dateApr 30, 1974
Priority dateApr 30, 1974
Publication numberUS 3875301 A, US 3875301A, US-A-3875301, US3875301 A, US3875301A
InventorsWindheuser John J
Original AssigneeInterx Research Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Useful tetraalkyl diamides in the treatment of poison ivy
US 3875301 A
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:
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Description  (OCR text may contain errors)

United States Patent [1 1 [111 3,875,301 Windheuser Apr. 1, 1975 USEFUL TETRAALKYL DIAMINES IN THE Primary Examiner-Albert T. Meyers TREATMENT OF POISON IVY [75] Inventor: John J. Windheuser, Lawrence,

Kans.

[73] Assignee: Interx Research Corporation,

Lawrence, Kans.

[22] Filed: Apr. 30, 1974 [21] Appl. No.: 465,527

[52] U.S. Cl 424/45, 424/320 [51] Int. Cl. A6lk 27/00, A611 23/00 [58] Field of Search 424/320, 45

[56] References Cited UNITED STATES PATENTS 3,288,794 11/1966 Kuceski 260/56] R 3,312,620 4/1967 Low et al..... 260/561 R 3,417,114 12/1968 Kuceski 260/557 3.632.783 1/1972 Stonis 424/320 Assistant ExaminerNorman A. Drezin' Attorney, Agent, or Firm-Charles N. Blitzer [57] 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:

0 0 'R 11 11 /R R N-C-R -C-N R 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 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.

11 Claims, No Drawings USEFUL TETRAALKYI. DIAMINES IN THE TREATMENT OF POISON IVY 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 warmblooded 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. I I

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.

US. 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 dimethylacetamidc 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 eancelling 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:

wherein each R represents a member selected from the group consisting of a saturated aliphatic hydrocarbon group of from I to 6 carbon atoms and an unsaturated aliphatic hydrocarbon group of from 1 to 6 carbon atoms, and wherein R, represents a member selected from the group consisting of a saturated aliphatic hydrocarbon group of from O to 22 carbon atoms and an unsaturated aliphatic hydrocarbon group of from O 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, 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. glutarie. maleic. adipie. pimclic. suberic. azelaie. 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. isoglutaric. iso-adipic. etc. Moreover. tricarboxylic acids, such as tricarballie 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 malonie acid N.N-dibutynylamidc-N.N-diallylamide of malonic acid N.N-din-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-dimcthylamide-N.N-dibutylamide of glutaric acid N.N-di(methylethyl)-N.N'-dimethylamide of adipic acid N.N.N.N'-tetramethyldiamides of iso-adipie acid N,N-dimethylamide-N,N'-dibutylamide acid N,N-dimethyl-N,N'-dihcxyldiamide 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 azclaic 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'-tetraisopropyldiamidc of brassylic acid The compounds of this invention may be prepared according to the established synthesis procedure set forth in US. Pat, No. 3,417,114 and/or US. Pat. No. 3,288,794, the subject matter of which, insofar as it pertains to the preparation of such compounds, is ineorporated herein by reference.

The tetraalkyl diamides of this invention are preferably applied as a solution (normally, l95'/(, but preferably 25/( in water, The term solution" is meant to include a water-miscible alcohol solution, such as isoof adipic propyl 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 REMINGTONS PHARMACEUTICAL SCIENCES" (Fourteenth Edition), I970, pp, l46l-l762.

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 coinpound of the instant invention.

Formulation Number I Solution N,N,N',N'-tetramethyl succinamide l 2571 Distilled water qs to 100% Procedure: Dissolve the tetramcthyl succinamidc in enough water to make 100%, Filter the solution. Apply to the effected area.

Formulation Number 2 Tincture N,N.N',N'-tetramethyl succinamide l Alcohol USP 5071 Water qs 10071 Procedure: Dissolve the tetramcthyl succinamide in the alcohol. Add sufficient water to make Filter and apply to affected area.

Formulation Number 3 Topical Aerosol N,N,N',N'-tetramethyl succinamide l 2571 Alcohol USP 5% lsopropylmyristate 57 *(onvenlional halogenated hydrocarbon propellant us (00% 0.2g. Freon ll ltrichlorol'uluromethane). Freon l2 Idichlorodil'luromelhane),

Freon l4 (carbon lctral'luoride lreon 3 l X (()etaflurocyelobutancl. Freon 1 l4 ((ryofluoraneJ. etc.

Procedure: Dissolve the tetramcthyl 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-tetrameth)'l succinamide l Petrolatum USP t s 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 ll-l2 (50/50). *A 50/50 mixture of Freon I1 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 of these compounds is relatively high. For instance, the compound, N,N,N.N- tetramcthyl succinamide gave a topical LD 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.

What I claim is:

l. 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:

wherein each R represents a member selected from the group consisting of a saturated aliphatic hydrocarbon group olfrom I to 6 carbon atoms and an unsaturated aliphatic hydrocarbon group of from I to (a carbon atoms. and wherein R 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 l'r'om to 22 carbon atoms.

whereby said compound forms a molecular complex with urushiol, the causative agent of said dermatitis. 2. The method of claim I, wherein said compound is: N.N.N.N '-tetramethyl adipamide. 3. The method ol claim I, wherein said compound is:

N.N.N',N'-tetramethylg|utaramide.

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

N.N,N.N-tetramethylsebacamide.

5. The method ol'claim I, wherein said compound is:

N N,N,N'-tetramethylsuccinamide.

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

7. The method ol'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 triehlorotluoromethane and dichlorodil'luoromethane.

* a: q: a: :k

TINTTED STATES PATENT OFFICE QETTFTQATE ECTION Q Patent No. 3,875,301 Dated April 1, 1975 Invent (s) John J. Windheuser It is certified that error appears in the aboveidentified patent and that said Letters Patent are hereby corrected as shown below:

IN THE TITLE:

Delete "DIAMINES" and insert --DIAMIDES-.

" IN THE SPECIFICATION:

Column 3, the first line following the heading "Formulation Number 2 Tincture" delete "l"; delete "25%" and insert l 25% 0 Column 4, the first line following the heading "Formulation Number 3 Ibpical Aerosol" delete "l"; delete "25%" and insert l 25% ColuIm 4, the first line following the heading "Formulation Q Number 4 Ointment" delete "l"; delete "25%" and insert l 25% this itd an 0 fifth ay of August 1975 [SEAL] Arrest:

0 RUTH C. MASQN C. MARSHALL DANN Arresting Off 11'" (umml'ssium'r nt'lurcnls and Trudvmurks

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3288794 *Sep 9, 1963Nov 29, 1966C P Hall Company Of IllinoisMethod of making amides of dimethylamine and piperazine
US3312620 *Dec 21, 1964Apr 4, 1967Shell Oil CoAmide lubricants
US3417114 *Jul 20, 1965Dec 17, 1968C P Hall Company Of IllinoisMethod of making amides from moisture and acid-gas containing esters
US3632783 *May 27, 1969Jan 4, 1972Hall Co C PTreatment of mosquito bites employing certain tetraalkyl diamides
Referenced by
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US5369108 *Oct 4, 1991Nov 29, 1994Sloan-Kettering Institute For Cancer ResearchPotent inducers of terminal differentiation and methods of use thereof
US5409908 *Oct 20, 1993Apr 25, 1995Vyrex CorporationComplexing urushiols
US5443847 *Jul 15, 1993Aug 22, 1995West; Philip W.Specific detoxification of urushiol with manganese salts
US5700811 *May 19, 1994Dec 23, 1997Sloan-Kettering Institute For Cancer ResearchPotent inducers of terminal differentiation and method of use thereof
US5767109 *Apr 17, 1995Jun 16, 1998Sanchez; Robert A.Complexing urushiols
US5932616 *Apr 4, 1994Aug 3, 1999Sloan-Kettering Institute For Cancer ResearchPotent inducers of terminal differentiation and methods of use thereof
US6087367 *May 18, 1999Jul 11, 2000Sloan-Kettering Institute For Cancer ResearchPotent inducers of terminal differentiation and methods of use thereof
US6423746Jul 3, 1999Jul 23, 2002The William M. Yarbrough FoundationTopical mixture of nonylphenol ethoxylate and sodium lauryl sarcosinate
US6511990Aug 24, 2000Jan 28, 2003Sloan-Kettering Institute For Cancer ResearchClass of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof
US7126001Oct 25, 2002Oct 24, 2006Sloan-Kettering Institute For Cancer ResearchAntiproliferative agents; antitumor agents
US7199134Apr 1, 2004Apr 3, 2007Sloan-Kettering Institute For Cancer ResearchHydroxamic acid compounds and methods of use thereof
US7345174Jun 22, 2006Mar 18, 2008Sloan-Kettering Institute For Cancer ResearchSelectively inducing terminal differentiation of neoplastic cells; antiproliferative agents; antineoplastic agents; antitumor agents; melanomes; acute leukemia, multiple myeloma; carcinomas; neuroblastoma; N-t-butoxycarbonyl- omega -methyl - alpha -aminosuberateanilide
US7351747Jan 6, 2003Apr 1, 2008Gilbert BuchalterSkin treatment for relief of itch
US7799803Feb 22, 2007Sep 21, 2010The Trustees Of Columbia University In The City Of New YorkHydroxamic acid compounds and methods of use thereof
US7988827 *Jan 29, 2008Aug 2, 2011Cognis Ip Management GmbhMixture of dialkylamide and nonionic surfactants in aqueous solution; reducing pitch during papermaking
USRE38506Nov 2, 2001Apr 20, 2004Sloan-Kettering Institute For Cancer ResearchPotent inducers of terminal differentiation and methods of use thereof
EP0642509A1 *Oct 5, 1992Mar 15, 1995Sloan-Kettering Institute For Cancer ResearchNovel potent inducers of terminal differentiation and methods of use thereof
WO1996032950A1 *Apr 17, 1995Oct 24, 1996Sheldon HendlerComplexing urushiols
WO2001010402A1 *Aug 6, 1999Feb 15, 2001Innovet Italia S R LUse of n,n1-bis(2-hydroxyethyl)nonandiamide as a cosmetic agent
WO2004052358A1 *Dec 4, 2002Jun 24, 2004William Yarbrough FoundationUrushiol induced contact dermatitis treatment and method of use
Classifications
U.S. Classification424/45, 514/616
International ClassificationA61K8/42, A61K31/16, A61Q17/00, A61K8/30
Cooperative ClassificationA61K8/42, A61Q17/00
European ClassificationA61K8/42, A61Q17/00