AU3561689A - N-dodecyl-pyrrolidone penetration enhancers - Google Patents

N-dodecyl-pyrrolidone penetration enhancers

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Publication number
AU3561689A
AU3561689A AU35616/89A AU3561689A AU3561689A AU 3561689 A AU3561689 A AU 3561689A AU 35616/89 A AU35616/89 A AU 35616/89A AU 3561689 A AU3561689 A AU 3561689A AU 3561689 A AU3561689 A AU 3561689A
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AU
Australia
Prior art keywords
hydrogen
coor
zero
alkyl
sulfur
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Granted
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AU35616/89A
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AU628344B2 (en
Inventor
Gevork Minaskanian
James V. Peck
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Whitby Research Inc
Original Assignee
Nelson Research and Development Co
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Publication of AU3561689A publication Critical patent/AU3561689A/en
Assigned to WHITBY RESEARCH, INC. reassignment WHITBY RESEARCH, INC. Amend patent request/document other than specification (104) Assignors: NELSON RESEARCH & DEVELOPMENT COMPANY
Application granted granted Critical
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Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/46—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom rings with more than six members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C05—FERTILISERS; MANUFACTURE THEREOF
    • C05G—MIXTURES OF FERTILISERS COVERED INDIVIDUALLY BY DIFFERENT SUBCLASSES OF CLASS C05; MIXTURES OF ONE OR MORE FERTILISERS WITH MATERIALS NOT HAVING A SPECIFIC FERTILISING ACTIVITY, e.g. PESTICIDES, SOIL-CONDITIONERS, WETTING AGENTS; FERTILISERS CHARACTERISED BY THEIR FORM
    • C05G3/00—Mixtures of one or more fertilisers with additives not having a specially fertilising activity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/08—Oxygen atoms
    • C07D223/10—Oxygen atoms attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06P—DYEING OR PRINTING TEXTILES; DYEING LEATHER, FURS OR SOLID MACROMOLECULAR SUBSTANCES IN ANY FORM
    • D06P1/00—General processes of dyeing or printing textiles, or general processes of dyeing leather, furs, or solid macromolecular substances in any form, classified according to the dyes, pigments, or auxiliary substances employed
    • D06P1/44—General processes of dyeing or printing textiles, or general processes of dyeing leather, furs, or solid macromolecular substances in any form, classified according to the dyes, pigments, or auxiliary substances employed using insoluble pigments or auxiliary substances, e.g. binders
    • D06P1/64—General processes of dyeing or printing textiles, or general processes of dyeing leather, furs, or solid macromolecular substances in any form, classified according to the dyes, pigments, or auxiliary substances employed using insoluble pigments or auxiliary substances, e.g. binders using compositions containing low-molecular-weight organic compounds without sulfate or sulfonate groups
    • D06P1/642—Compounds containing nitrogen
    • D06P1/6426—Heterocyclic compounds

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Dermatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Medicinal Preparation (AREA)
  • Indole Compounds (AREA)
  • Treatments For Attaching Organic Compounds To Fibrous Goods (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyrrole Compounds (AREA)
  • Cosmetics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Description

per WORLD INTELLECTUAL PROPERTY ORGANIZATION International Bureau
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PC
(51) International Patent Classification 4 (11) International Publication Number: WO 89/0
C09B 67/00, A01N 25/00 Al A61K 31/70, 31/505, 31/56 (43) International Publication Date: 19 October 1989 (19.
(21) International Application Number: PCT/US89/01381 (74) Agent: BOSTICH, June, M. ; Nelson Research & De ment Co., 1001 Health Sciences Road West, Irvin
(22) International Filing Date : 5 April 1989 (05.04.89) 92715 (US).
(30) Priority data: (81) Designated States: AT (European patent), AU, BE (
179,144 8 April 1988 (08.04.88) US pean patent), CH (European patent), DE (Europea tent), DK, FR (European patent), GB (Europea tent), IT (European patent), JP, KR, LU (Europea
(60) Parent Application or Grant tent), NL (European patent), NO, SE (European pa
(63) Related by Continuation US. US 179,144 (CIP) Filed on 8 April 1988 (08.04.88)
Published
With international search report.
(71) Applicant (for all designated States except US): NELSON
RESEARCH & DEVELOPMENT CO. [US/US]; 1001 Health Sciences Road West, Irvine, CA 92715 (US).
(72) Inventors; and
(75) Inventors/ Applicants (for US only) : PECK, James, V. [US/ US]; 2524 Bowdoin Place, Costa Mesa, CA 92626 (US). MINASKANIAN, Gevork [US/US]; 8 Havenwood, Irvine, CA 92714 (US).
(54) Title: NOVEL TRANSDERMAL PENETRATION ENHANCERS
( I )
(57) Abstract
This invention relates to compounds and a method for their use in carrying physiologically active agents through b membranes such as skin and for retaining these agents in body tissues. More specifically, the invention relates to carboxylic derivatives and salts thereof, which compounds are useful in topically administering a physiologically active agent to a huma animal via a composition comprising the agent and an effective amount of a compound represented in one embodiment by eral formula (I), wherein W represents oxygen, sulfur, or two hydrogen radicals ; wherein Z represents oxygen, sulfur, or -C wherein R represents alkyl optionally substituted with one to three double or triple bonds, -SR'", -OR'", -NHR'", -CH3 COORj, and wherein R] represents hydrogen or lower alkyl; wherein R'" represents alkyl, alkylthioalkyl, alkoxyalkyl, s stituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group ; wherein R' represents hydrogen, kyl, alkoxy, acyloxy, alkylthio, hydroxy, -(CH2)yCOORι and with y being between zero and 3, inclusive; and wherein R" presents hydrogen or -(CH2)yCOORι such that when R" is hydrogen, then W is two hydrogen radicals and R' is hydrogen ; and when R' is hydrogen, then R" is not hydrogen ; and wherein m is between 1 and 5, preferably 2, 3, or 4, w n is between 1 and 24, preferably between 5 and 12, and x is zero or 1, inclusive. It has been found that physiologically tive agents are carried through body membranes by the above penetration-enhancing agents and are retained in body tiss The invention further relates to the penetration-enhancing agents themselves and the method of making such penetrati enhancing agents.
FOR THE PURPOSES OFINFORMAπON ONLY
Codes used to identify States party to the PCT on the front ages ofpamphlets publishing international appli- cations under the PCT.
AT Austria FR France ML Mali
AU Australia GA Gabon MR Mauritania
BB Barbados GB United Kingdom MW Malawi-
BE. Belgium HU Hungary NL Netherlands
BG Bulgaria rr Italy NO Norway
BJ Benin JP Japan RO Romania
BR Brazil KP Democratic People's Republic SD Sudan
CF Central African Republic ofKorea SE Sweden
CG Congo KR Republic ofKorea SN Senegal
CH Switzerland LI Liechtenstein SU Soviet Union
CM Cameroon LK Sri Lanka TD Chad
DE Germany, Federal Republic of LU Luxembourg TG Togo
DK Denmark MC Monaco US United States of America
NOVEL TRANSDERMAL PENETRATION ENHANCERS
1. Field of the Invention
This invention relates to compositions comprising a physiologically active agent and a novel transdermal penetration enhancer in an amount effective to enhance the penetration of the physiologically-active agent through the skin or other membrane of the body of an animal.
Other such compositions and their uses relate to an improved method of dyeing fibers, improved delivery of plant nutrients, improved plant pest control, improved delivery of plant growth regulations, improved acid-catalyzed conversion of a reactant into a reaciton product and an improved insect repellant.
2. Background of the Art
As hereinabove indicated, the present invention includes a number of uses in which it provides an advantage. Each of these uses will be hereinafter addressed in the order of their recital beginning with the use of the ocmposiion of the present invention in the enhancement of the penetration of a physiologically-active agent through the skin or other membranes of body.
It is well known that in many physiologically active agents are best applied topically to obtain desirable results. Topical application, as contrasted to systemic application, can avoid metabolic degradation of the agents, largely avoids side effects of the agents, and permits high local concentrations of the agents. The greatest problem in applying physiologically active agents topically is that the skin is a very effective barrier to penetration. The epidermis of the skin has an exterior layer of dead cells called the stratum corneum, which is tigh'tly compacted and oily and which provides an effective barrier against gaseous, solid or liquid chemical agents, whether used alone or in water or oil solutions. If a physiologically active agent penetrates the stratum corneum, it can readily pass through the basal layer of the epidermis and into the dermis.
Although the effectiveness of the stratum corneum as a barrier provides great protection, it also frustrates efforts to apply beneficial agents directly to local areas of the body. The inability of physiologically active agents to penetrate the stratum corneum prevents their effective use to treat such conditions as inflammation, acne, psoriasis, herpes simplex, eczema, infections due to fungus, virus or other microorganisms, or other disorders and conditions of the skin or mucous membranes, or of conditions beneath the exterior surface of the skin or mucous membranes. The stratum corneum also prevents the skin from absorbing and retaining cosmetic-type materials such as sunscreens, perfumes, mosquito repellents and the like.
Physiologically active agents may be applied to locally affected parts of the body through the vehicles system described herein. Vehicles such as TJSP cold cream, ethanol and various ointments, oils, solvents, and emulsions have been used heretofore to apply physiologically active ingredients locally. Most such vehicles are not effective to carry significant amounts of physiologically active agents through the skin. One such vehicle is dimethyl sulfoxide.
The 1-lower alkyl substituted azacyclopentan-2-ones having 1-4 carbon atoms in the alkyl group are known to moderately enhance percutaneous absorption of chemicals, e.g. drugs. It was earlier recognized that it would be desirable to obtain the same or higher level of percutaneous absorption with substantially lower concentrations of the penetration-enhancing compound. Therefore, various N-substituted azacycloalkan-2-ones were invented having the desired properties. These new penetration-enhancing agents are described in U.S. Patents 3,989,815; 3,989,816; 3,991,203; 4,122,170; 4,316,893; 4,405,616; 4,415,563; 4,423,040; 4,424,210; and 4,444,762, which are hereby incorporated by reference.
It is an object of this invention to provide new penetration-enhancing agents having the desirable property of enhancing the percutaneous absorption of physiologically-active agents at concentrations lower than the 1-lower alkyl substituted azacyclopentan-2-ones.
It is also an object of this invention to provide penetration-enhancing agents that are equivalent to the aforesaid new penetration-enhancing agents described in the above U.S. patents.
Other objects and advantages of the instant invention will be apparent from a careful reading of the specification below.
In this description, the term "animal" includes human beings as well as other forms of animal life, and especially domesticated animals and pets.
SUMMARY OF THE INVENTION This invention relates to compounds and a method for their use in carrying physiologically active agents through body membranes such as skin and for retaining these agents in body tissues. More specifically, the invention relates to carboxylic acid derivatives and salts thereof, which compounds are useful in topically administering a physiologically active agent to a human or animal via a composition comprising the agent and an effective amount of a compound represented by the general formulae.
wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur, or -CH2-; wherein R represents alkyl optionally substituted with one to three double or triple bonds, -SR''', -OR''', -NHR''', -CH3, or COOR1, and wherein R1 represents hydrogen or lower alkyl; wherein R''' represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, -(CH2)yCOOR1 and with y being between zero and 3, inclusive; and wherein R' ' represents hydrogen or -(CH2)yCOOR1 such that when R' ' is hydrogen, then W is two hydrogen radicals and R' is not hydrogen; and when R' is hydrogen, then R'' is not hydrogen; and wherein m is between one and 5 , preferably 2, 3, or 4, while n is between 1 and 24, preferably between 5 and 12, and x is zero or 1, inclusive.
In an alternative embodiment, the novel penetration enhancers include compounds represented by the general formula: wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur, or -(CH2)-; wherein R, R2 and R3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds, - SR''', -OR''', -NHR''', -CH3, or COOR1; wherein R''' represents hydrogen, alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl, or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or - (CH2)yCOOR1 ; wherein R'' represents hydrogen, or -(CH2)yCOOR1; wherein R1 represents a hydrogen or lower alkyl radical and y is between zero and 3, inclusive. wherein m is between zero and 5, preferably 1 or 2; while n is between l and 24, preferably between 5 and 12, inclusive;
And in yet another embodiment the compound is represented by the formula:
wherein R2 is COOR1 or an alkyl radical, optionally substituted with between 1 and 3 double or triple bonds; wherein R' is a hydrogen radical, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1; wherein B' represents oxygen, sulfur, or two hydrogen, radicals; wherein B' ' represents oxygen, sulfur, or two hydrogen radicals such that when B'' is not hydrogen, B' is two hydrogen radicals, and R2 is alkyl, then R' is -(CH2)yCOOR1 where y cannot be zero; wherein y is between zero and three, inclusive, and R1 represents a lower alkyl or hydrogen radical. and wherein m is between 3 and 6 , preferably 3 , 4 or 5 while n is between 1 and 24, preferably between 5 and 12, inclusive; and wherein y is between zero and three, inclusive, and R1 represents a lower alkyl or hydrogen radical.
It has been found that physiologically active agents are carried through body membranes by the above penetration-enhancing agents and are retained in body tissue.
The invention further relates to the penetration-enhancing agents themselves and the method of making such penetration-enhancing agents.
It has been found that the hereinabove described 1- substituted azacycloalkanes are also useful in the enhancement of dye penetration in fibers by utilizing in a dyeing process an effective amount of the 1-substituted azacyloalkane. The invention also includes a compound comprising an effective amount of dye and an effective amount of the 1-substituted azacyloalkane.
When combined with a plant nutrient, 1-substituted azacycloaklane provides an improved method of delivery of such plant nutrients by enhancing the uptake and assimilation of the plant nutrients in the plant. The invention also includes a compound comprising an effective amount of a plant nutrient and an effective, delivery-enhancing amount of a novel penetration enhancer.
It has been found that the hereinablve described novel penetration enhancers are also useful in an improved method of plant pest control by enhancing the delivery of pesticides to plant pests and the present invention includes a compound comprising an effective amount of a plant pesticide and an effective, delivery-enhancing amount of a novel penetration enhancer.
The compound containing the delivery-enhancing compound and pesticide may be applied directly to the plant pest by topical applicaiton or indirectly by topical application to the plant to be protected. The latter indirect method of application enables the pesticide to reach its ultimate site of action, namely, the plant pest, after the plant pest has come into contact with the treated plant.
It has been found that the hereinabove described novel penetration enhancers are also useful in an improved method of delivery of plant growth regulators and the present invention includes a compound comprising an effective amount of a plant growth reglator and an effective delivery-enhancing amount of the novel penetration enhancers. The plant gorwth regulators and penetration enhancer may be applied to the plant in a conventional manner.
It has been found that the hereinabove described novel penetration enhancers are also useful as insepct repellants, the application and/or delivery of penetratioOn enhancers for such use being by conventional means.
The present invention also provides a process fo rht econversion of a reactant into a reaction product in the presence of an acid catalyst which comprises contacting said reactant with an acid catalyst comprising a salt of the hereinabove described novel penetration enhancers.
DETAILED DESCRIPTION OF THE INVENTION Novel transdermal penetration enhancers useful in the method of the present invention include carboxylic acid derivatives and their salts, which are compounds represented by the general formulaes
wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur, or -CH2-; wherein R represents alkyl optionally substituted with one to three double or triple bonds, -SR''', -OR''', -NHR''', -CH3, or COOR1, and wherein R1 represents hydrogen or lower alkyl; and wherein R''' represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, -(CH2)yCOOR1 and with y being between zero and 3, inclusive; wherein R'' represents hydrogen or -(CH2)yCOOR1 such that when R'' is hydrogen, then W is two hydrogen radicals and R' is not hydrogen; and when R' is hydrogen, then R' ' is not hydrogen; and wherein m is between one and 5, preferably 2, 3, or 4 while n is between 1 and 24, preferably between 5 and 12, inclusive, and x is zero or 1, inclusive.
In an alternative embodiment, the compounds useful as penetration enhancers include those represented by the general formula:
wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur or -(CH2)-; wherein R, R2 and R3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds, - SR''', -OR''', -NHR''', -CH3, or COOR1; wherein R''' represents hydrogen, alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl, or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or - (CH2)yCOOR1; wherein R'' represents hydrogen or -(CH2)yCOOR1; wherein m is between zero and 5, preferably 1 or 2; while n is between 1 and 24, preferably between 5 and 12, inclusive; and wherein R1 represents a hydrogen or lower alkyl radical and y is between zero and 3, inclusive.
And in yet another embodiment the compound is represented by the formula:
wherein R2 is COOR1 or an alkyl radical, optionally substituted with between 1 and 3 double or triple bonds; wherein R' is a hydrogen radical, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1; wherein B' represents oxygen, sulfur, or two hydrogen radicals; wherein B'' represents oxygen, sulfur, or two hydrogen radicals such that when B'' is not hydrogen, B' is two hydrogen radicals, and R2 is alkyl, then R' is -(CH2)yCOOR1 where y is not zero; wherein y is between zero and three, inclusive, and R1 represents a lower alkyl or hydrogen radical. and wherein m is between 3 and 6, preferably 3,4,or 5, while n is between 1 and 24, preferably between 5 and 12, inclusive;
These novel transdermal penetration-enhancing additives may be made by the methods illustrated in the Examples below. Typical examples of compounds represented by the above general formulae include:
1-N-dodecyl-2-pyrrolidone-5-carboxylic acid 1-N-butyl-2-pyrrolidone-5-carboxylic ac d
1-N-pentyl-2-pyrrolidone-5-carboxylic acid 1-N-hexyl-2-pyrrolidone-5-carboxylic acid 1-N-octyl-2-pyrrolidone-5-carboxylic acid 1-N-nonyl-2-pyrrolidone-5-carboxylic acid 1-N-decyl-2-pyrrolidone-5-carboxylic acid 1-N-tetradecyl-2-pyrrolidone-5-carboxylic acid 1-N-hexadecyl-2-pyrrolidone-5-carboxylic acid 1-N-heptyl-2-pyrrolidone-5-carboxylic acid
1-N-dodecyl-2-piperidone-6-carboxylic acid l-N-butyl-2-piperidone-6-carboxylic acid l-N-pentyl-2-piperidone-6-carboxylic acid
1-N-hexyl-2-piperidone-6-carboxylic acid
1-N-octyl-2-piperidone-6-carboxylic acid
1-N-nonyl-2-piperidone-6-carboxylic acid
1-N-decyl-2-piperidone-6-carboxylic acid 1-N-tetradecyl-2-piperidone-6-carboxylic acid
1-N-hexadecyl-2-piperidone-6-carboxylic acid
1-N-heptyl-2-piperidone-6-carboxylic acid 1-(2-(n-dodecylthio)ethyl)-2-pyrrolidone-5-carboxylic acid
1-(2-(n-butylthio)ethyl)-2-pyrrolidone-5-carboxylic acid
1-(2-(n-pentylthio)ethyl)-2-pyrrolidone-5-carboxylic acid
1-(2-(n-hexylthio)ethyl)-2-pyrrolidone-5-carboxylic acid
1-(2-(n-octylthio)ethyl)-2-pyrrolidone-5-carboxylic acid
1-(2-(n-nonylthio)ethyl)-2-pyrrolidone-5-carboxylic acid
1-(2-(n-decylthio)ethyl)-2-pyrrolidone-5-carboxylic acid
1-(2-(n-tetradecyIthio)ethyl)-2-pyrrolidone-5-carboxylic acid
1-(2-(n-hexadecylthio)ethyl)-2-pyrrolidone-5-carboxylic acid
1-(2-(n-heptylthio)ethyl)-2-pyrrolidone-5-carboxylic acid
1-(2-(n-dodecylthio)ethyl)-piperidine-3-carboxylic acid 1-(2-(n-butylthio)ethyl)-piperidine-3-carboxylic acid
1-(2-(n-pentylthio)ethyl)-piperidine-3-carboxylic acid
1-(2-(n-hexylthio)ethyl)-piperidine-3-carboxylic acid
1-(2-(n-octylthio)ethyl)-piperidine-3-carboxylic acid
1-(2-(n-nonylthio)ethyl)-piperidine-3-carboxylic acid
1-(2-(n-decylthio)ethyl)-piperidine-3-carboxylic acid
1-(2-(n-tetradecylthio)ethyl)-piperidine-3carboxylic acid
1-(2-(n-hexadecylthio)ethyl)-piperidine-3-carboxylic acid
1-(2-(n-heptyllthio)ethyl)-piperidine-3-carboxylic acid
2-dodecyl,2-N-(2-pyrrolidone)-acetic acid 2-butyl,2-N-(2-pyrrolidone)-acetic acid 2-pentyl,2-N-(2-pyrrolidone)-acetic acid 2-hexyl,2-N-(2-pyrrolidone)-acetic acid 2-octyl,2-N-(2-pyrrolidone)-acetic acid 2-nonyl,2-N-(2-pyrrolidone)-acetic acid 2-decyl,2-N-(2-pyrrolidone)-acetic acid 2-tetradecyl,2-N-(2-pyrrolidone)-acetic acid 2-hexadecyl,2-N-(2-pyrrolidone)-acetic acid 2-heptyl,2-N-(2-pyrrolidone)-acetic acid 2-dodecyl,2-N-(2-piperidone)-acetic acid 2-dodecyl,2-N-(azacycloheptane-2-one)-acetic acid 2-butyl,2-N-(azacycloheptane-2-one)-acetic acid 2-pentyl,2-N-(azacycloheptane-2-one)-acetic acid 2-hexyl,2-N-(azacycloheptane-2-one)-acetic acid 2-octyl,2-N-(azacycloheptane-2-one)-acetic acid 2-nonyl,2-N-(azacycloheptane-2-one)-acetic acid
2-decyl,2-N-(azacycloheptane-2-one)-acetic acid
2-tetradecyl,2-N-(azacycloheptane-2-one)-acetic acid
2-hexadecyl,2-N-(azacycloheptane-2-one)-acetic acid
2-heptyl,2-N-(azacycloheptane-2-one)-acetic acid 6-(N-pyrrolidine)-hexanoic acid
8-(N-pyrrolidine)-octanoic acid
10-(N-pyrrolidine)-decanoic acid
12-(N-pyrrolidine)-dodecanoic acid
12-diethylaminododecanoic acid
10-diethylaminodecanoic acid
6-diethylaminohexanoic acid
8-diethylaminooctanoic acid
2-(N-morpholine)-2-dodecylacetic acid
2-(N-morpholine)-2-decylacetic acid 2-(N-morpholine)-2-octylacetic acid
2-(N-morpholine)-2-hexylacetic acid
2-(N-morpholine)-2-butylacetic acid
It has also been found that the penetration enhancers herein also themselves possess antiviral activity and can be used alone to combat viral infections.
When used in compositions comprising a second physiologically active agent, the amount of the novel transdermal penetration enhancers used in the present invention is an effective amount for enhancing percutaneous absorption. Generally, this amount ranges between about 0.01 to about 5 and preferably about 0.1 to 2 percent by weight of the composition.
The subject compositions may find use with many physiologically active agents which are soluble in the vehicles disclosed. The penetration enhancer can be applied before, after, or in combination with the physiologically active agent. The order of application is immaterial. Fungistatic and fungicidal agents such as, for example, thiabendazole, chloroxine, amphotericin B, candicidin, fungimycin, nystatin, chlordantoin, clotrimazole, miconazole nitrate, pyrrolnitrin, salicyclic acid, fezatione, tolnaftate, triacetin and zinc and sodium pyrithione may be dissolved in the penetration-enhancing agents described herein and topically applied to affected areas of the skin. For example, fungistatic or fungicidal agents so applied are carried through the stratum corneum, and thereby successfully treat fungus-caused skin problems. These agents, thus applied, not only penetrate more quickly than when applied in the vehicles of the prior art, but additionally enter the animal tissue in high concentrations and are retained for substantially longer time periods whereby a far more successful treatment is effected.
For example, the subject compositions may also be employed in the treatment of fungus infections on the skin caused by Candida and dermatophytes which cause athletes foot or ringworm, by dissolving thiabendazole or similar antifungal agents in one of the above-described penetration-enhancing agents and applying it to the affected area.
The subject compositions are also useful in treating skin problems, for example, herpes simplex, which may be treated by a solution of iododeoxyuridine dissolved in one of the penetration-enhancing agents or such problems as warts which may be treated with agents such as podophylline dissolved in one of the penetration-enhancing agents. Skin problems such as psoriasis may be treated by topical application of a solution of a conventional topical steroid in one of the penetration-enhancing agents or by treatment with theophylline or antagonists of β-adrenergic blockers such as isoproterenol in one of the penetration-enhancing agents. Scalp conditions such as alopecia areata may be treated more effectively by applying steroids such as triamcinolone acetonide dissolved in one of the penetration-enhancing agents of this invention directly to the scalp.
The subject compositions are also useful for treating mild eczema, for example, by applying a solution of fluocinolone acetonide or its derivatives; hydrocortisone, triamcinolone acetonide, indomethacin, or phenylbutazone dissolved in one of the penetration-enhancing agents to the affected area.
Examples of other physiologically active steroids which may be used with the vehicles include corticosteroids such as, for example, cortisone, cortodoxone, flucetonide, fluorocortisone, diflursone diacetate, flurandrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and its esters, chloroprednisone, clocortelone, descinolone, desonide, dexamethasone, dichlorisone, defluprednate, flucloronide, flumethasone, flunisolide, fluocinonide, flucortolone, fluoromethalone, fluperolone, fluprednisolone, meprednisone, methylmeprednisolone, paramethasone, predisolone and prednisone.
The subject compositions are also useful in antibacterial chemotherapy, e.g. in the treatment of skin conditions involving pathogenic bacteria. Typical antibacterial agents which may be used in this invention include sulfonamides, penicillins, cephalosporins, penicillinase, erythromycins, lincomycins, vancomycins, tetracyclines, chloramphenicols, streptomycins, etc. Typical examples of the foregoing include erythromycin, erythromycin ethyl carbonate, erythromycin estolate, erythromycin glucepate, erythromycin ethylsuccinate, erythromycin lactobionate, lincomycin, clindamycin, tetracycline, chlortetracycline, demeclocycline, doxycycline, methacycline, oxytetracycline, minocycline, etc.
The subject compositions are also useful in protecting ultra-sensitive skin or even normally sensitive skin from damage or discomfort due to sunburn. Thus, dermatitis actinica may be avoided by application to the skin surfaces that are to be exposed to the sun of a sunscreen, such as para-aminobenzoic acid or its well-known derivatives in combination with one of the above-described penetration-enhancing agents. The protective para-aminobenzoic acid or its derivatives will thereby be carried into the stratum corneum more successfully and will therefore be retained even when exposed to water or washing for a substantially longer period of time than when applied to the skin in conventional vehicles. This invention is particularly useful for ordinary suntan lotions used in activities involving swimming because the ultraviolet screening ingredients in the carriers of the prior art are washed off the skin when it is immersed in water.
The subject compositions may also find use in treating scar tissue by applying topically to the scar tissue agents which soften collagen, such as aminopropionitrile or penicillamine dissolved in one of the penetration-enhancing agents of this invention.
Agents normally applied as eye drops, ear drops, or nose drops are more effective when dissolved in the penetration-enhancing agents of this invention.
Agents used in diagnosis may be used more effectively when applied dissolved in one of the penetration-enhancing agents of this invention. Patch tests to diagnose allergies may be effected promptly without scratching the skin or covering the area subjected to an allergen when the allergens are applied in one of the penetration-enhancing agents of this invention.
The subject compositions are also useful for topical application of cosmetic or esthetic agents. For example, compounds such as melanin-stimulating hormone (MSH) or dihydroxyacetone and the like are more effectively applied to skin to stimulate a suntan when they are dissolved in one of the penetration-enhancing agents of this invention. The agent is carried into the skin more quickly and in greater quantity when applied in accordance with this invention. Hair dyes also penetrate more completely and effectively when dissolved in one of the penetration-enhancing agents of this invention.
The effectiveness of such topically applied materials as insect repellents or fragrances, such as perfumes and colognes, can be prolonged when such agents are applied in combination with one of the penetration-enhancing agents of this invention.
It is to be emphasized that the foregoing are simply examples of physiologically active agents including therapeutic and cosmetic agents having known effects for known conditions, which may be used more effectively for their known properties in accordance with this invention.
In addition, the penetration-enhancing agents of the present invention may also be used to produce therapeutic effects which were not previously known. That is, by use of the penetration-enhancing agents described herein, therapeutic effects heretofore not known can be achieved.
As an example of the foregoing, griseofulvin is known as the treatment of choice for fungus infections of the skin and nails. Heretofore, the manner of delivery of griseofulvin has been oral. However, it has long been known that oral treatment is not preferred because of side effects resulting from exposure of the entire body to griseofulvin and the fact that only the outer layers of affected skin need to be treated. Therefore, because fungal infections are generally infections of the skin and nails, it would be advantageous to utilize griseofulvin topically. However, despite a long-felt need for a topical griseofulvin, griseofulvin has been used orally to treat topical fungus conditions because there was not heretofore known any formulation which could be delivered topically which would cause sufficient retention of griseofulvin in the skin to be useful therapeutically.
However, it has now been discovered that griseofulvin, in a range of therapeutic concentrations between about 0.1% and about 10% may be used effectively topically if combined with one of the penetration-enhancing agents described herein.
As a further example, acne is the name commonly applied to any inflammatory disease of the sebaceous glands; also acne vulgaris. The microorganism typically responsible for the acne infection is Corynebacterium acnes. Various therapeutic methods for treating acne have been attempted including topical antibacterials, e.g. hexachlorophene, and systemic antibiotics such as tetracycline. While systemic antibiotic treatments are known to be partially effective, topical treatments are generally not effective.
However, it has long been known that systemic treatment of acne is not preferred because of side effects resulting from exposure of the entire body to antibiotics and the fact that only the affected skin need be treated. Heretofore, despite a long-felt need for a topical treatment for acne, antibiotics generally have been used only systemically to treat acne because an antibacterial formulation which could be used topically as an effective therapeutic in the treatment of acne was not known. However, it has now been discovered that antibiotics, especially those of the lincomycin and erythromycin families of antibiotics, may be used topically in the treatment of acne if combined with one of the penetration-enhancing agents described herein.
The antibiotic compositions so applied are carried into and through the epidermis and deeper layers of the skin as well as into follicles, (which contain C. acnes) in therapeutically effective amounts and thereby successfully may be used to temporarily eliminate the signs and symptoms of acne.
The term "physiologically active agent" is used herein to refer to a broad class of useful chemical and therapeutic agents including physiologically active steroids, antibiotics, antifungal agents, antibacterial agents, antineoplastic agents, allergens, antihistaminic agents, anti-inflammatory agents, ultraviolet screening agents, diagnostic agents, perfumes, insect repellents, hair dyes, etc.
Dosage forms for topical application may include solution nasal sprays, lotions, ointments, creams, gels, suppositories, sprays, aerosols and the like. Typical inert carriers which make up the foregoing dosage forms include water, acetone, isopropyl alcohol, freons, ethyl alcohol, polyvinylpyrrolidone, propylene glycol, fragrances, gel-producing materials, mineral oil, stearyl alcohol, stearic acid, spermaceti, sorbitan monooleate, "Polysorbates", "Tweens", sorbital, methyl cellulose, etc.
The amount of the composition and/or of the physiologically active agent to be administered will obviously be an effective amount for the desired result expected therefrom. This, of course, will be ascertained by the ordinary skill of the practitioner. Due to enhanced activity which is achieved, the dosage of physiologically active agent may often be decreased from that generally applicable. In accordance with usual prudent formulating practices, a dosage near the lower end of the useful range of the particular physiologically active agent may be employed initially and the dosage increased as indicated from the observed response, as in the routine procedure of the physician. The invention is further illustrated by the following examples which are illustrative of various aspects of the invention, and are not intended as limiting the scope of the invention as defined by the appended claims.
EXAMPLE 1 Preparation of 1-N-dodecyl-2-pyrrolidone-5-carboxylic acid
A. To a stirred solution of 1.92 g NaH (60%, washed with pet ether) in dry THF at room temperature under N2 was added dropwise a solution of 7.06 g of ethyl 2-pyrrolidone-5- carboxylate in 20 mL of THF. The mixture was refluxed for 1 h, cooled to room temperature, followed by dropwise addition of 1.3 equivalents of 1-bromododecane. After additional reflux overnight and workup, the crude oil was subjected to flash chromatography (silica, 8:2 pet ether/EtOAC) to give 3.14 g of ethyl 1-N-dodecyl-2- pyrrolidone-5-carboxylate as a clear oil: KMR (CDCl3) δ 4.2(m), 3.68(m), 2.9(m), 2.6-2.2 (m), 2.1(m), 1.6-1.0(m), 0.9(t).
Basic hydrolysis of the product of example 1A at room temperature, followed by acidic workup resulted in 1.73 g of 1-dodecyl-2-pyrrolidone-5-carboxylic acid as a white solid: NMR (CDCl3) 5 4.29(m), 3.75(m), 3.00(m), 2.7-2.3(m), 2.2(m), 1.5(m), 1.3(s), 0.9(t).
B. Example 1A was repeated using Ethyl 12-Bromododecanoate, followed by hydrolysis to give 12-(N-pyrrolidin-2-one-5- carboxy)dodecanoic acid.
C. Example 1A was repeated using Ethyl 2-Bromotetradecanoate, followed by hydrolysis to give 2-(N-pyrrolidin- 2-one-5-carboxy)-2-dodecylacetic acid. D. Example 1A was repeated replacing ethyl 2-pyrrolidone-5- carboxylic acid with proline ethyl ester, followed by hydrolysis to give N-dodecylproline.
E. Example 1A was repeated replacing ethyl-2-pyrrolidone-5- carboxylic acid with N-Acetyl alanine ethyl ester, followed by hydrolysis to give N-Acetyl-N-dodecylalanine.
F. Example 1A was repeated, replacing starting materials with N-ethyl alanine ethyl ester and dodecanoyl chloride and followed by hydrolysis to give N-Ethyl-N-(1- oxododecyl)alanine.
EXAMPLE 2 Preparation of 2-pentyl-2-oxo-1-pyrrolidineacetic acid
A. Alkylation of 2.0 g 2-pyrrolidone, under the same procedure described in Example 1A, with 7.23 g ethyl-2- bromoheptanoate resulted in 1.6 g of 2-pentyl-2-oxo-1- pyrrolidineacetic acid ethyl ester as a light yellow oil: NMR (CDCl3) δ 4.75 (dd), 4.15 (q), 3.55(m), 3.35(m), 2.45(t), 2.2-1.6(m), 1.4-1.2(m), 0.9(m).
Basic hydrolysis of the product in Example 2A at room temperature, followed by acidic workup resulted in 0.89 g of 2-pentyl-2-oxo-1-pyrrolidineacetic acid as a white solid: NMR (CDCl3) δ 4.8(dd), 3.6(m), 3.4 (m), 2.5(t), 2.2-2.05(m), 1.75(m), 1.4-1.2(s), 0.9(t).
B. Example 2A was repeated using 2-Oxazolidine, followed by hydrolysis to give 2-dodecyl-2-oxa-3-oxazolidineacetic acid. C. Example 2A was repeated using ε-Caprolactam and ethyl 2- bromotetra-decanoate, followed by hydrolysis to give 2- (1-azacycloheptan-2-one)-2-dodecylacetic acid.
D. Example 2A was repeated using Morpholine, followed by hydrolysis to give 2-dodecyl-4-morpholineacetic acid.
E. Example 2A was repeated using Pyrrolidine, followed by hydrolysis to give 2-dodecyl-1-pyrrolidineacetic acid.
F. Example 2A was repeated using Proline ethyl ester, followed by hydrolysis to give 2-(N-pyrrolidino-2- carboxy)-2-dodecylacetic acid.
G. Example 2A was repeated using N-Ethyl acetamide, followed by hydrolysis to give 2-(N-ethylacetamido)-2- dodecylacetic acid.
H. Example 2A was repeated using Diethylamine, followed by hydrolysis to give 2-(N,N-diethylamino)-2-dodecylacetic acid.
I. Example 2A was repeated using ethyl 2-bromotetradecanoate, followed by hydrolysis to give 2-dodecyl-2- oxo-1-pyrrolidineacetic acid.
EXAMPLE 3 Preparation of 11-(diethylamino)-undecanoic acid A. According to the previously described basic hydrolysis procedure of Example 1B, 0.47 g of ethyl 11- (diethylamino)-undecanoate resulted in the desired product as a white solid: NMR (CDCl3) δ 3.1 (q), 2.95(m), 2.25(t), 1.7-1.6(m), 1.4-1.1(m). B. Example 3A was repeated using Pyrrolidine, followed by hydrolysis, to give 11-(1-pyrrolidino)undecanoic acid.
C. Example 3A was repeated using Morpholine, followed by hydrolysis, to give 11-(4-Morpholino)undecanoic acid.
D. Example 3A was repeated using Piperazine, followed by hydrolysis, to give 11-(1-Piperazino)undecanoic acid.
E. Example 3A was repeated using 2-Pyrrolidinone, followed by hydrolysis, to give 11-(N-Pyrrolidino-2-one) undecanoic acid.
F. Example 3A was repeated using 2-Oxazolidone, followed by hydrolysis, to give 11-(3-Oxazolidin-2-one)undecanoic acid.
G. Example 3A was repeated using ε-Caprolactam, followed by hydrolysis, to give 11-(1-hexamethylineimin-2-one) undecanoic acid.
H. Example 3A was repeated using Proline ethyl ester, followed by hydrolysis, to give 11-(1-pyrrolidin-2- carboxy)undecanoic acid.
I. Example 3A was repeated using N-Ethyl acetamide, followed by hydrolysis, to give 11-(N-Ethyl acetamido)-undecanoic acid.
J. Example 3A was repeated using N-Acetyl alanine ethyl ester, followed by hydrolysis, to give N-acetyl-N-(10- carboxy-1-decyl)alanine. EXAMPLE 4 To model the capacity of the carboxylic acid derivatives of 1-substituted azacycloalkanes for enhancing permeability of physiologically active agents through skin and mucous membranes, a series of experiments were conducted using either ethanol-C14 or butanol-C14 as a control. The amount penetrating was calculated as percent of penetration of the control. For comparison with each control, parallel tests were also conducted using a known penetration enhancer, 1-n-dodecylazacyclo-heptane-2-one.
Ethanol and butanol have known permeability coefficients for passage through hairless mouse skin via a diffusion cell. The permeability coefficient is expressed by the formula:
wherein D is the diffusivity (diffusion coefficient), Km/v is the partition coefficient between the membrane (m) and medium (v, vehicle), and h is the membrane thickness, respectively. See Kurihara-Bergstrom, T, et al., "Physiochemical Study of Percutaneous Absorption Enhancement by Dimethyl Sulfoxide: Kinetic and Thermodynamic Determinants of Dimethyl Sulfoxide Mediated Mass Transfer of Alkanols" in Journal of Pharmaceutical Sciences. Vol. 75, No. 5, May 1986, pp. 479-86. Full thickness abdominal and dorsal sections of mouse skin membranes were obtained from the hairless mouse strain (Skin Cancer Hospital, Temple University, Philadelphia, PA).
Formulations to be tested contained either one or five weight percent of a penetration enhancer, three weight percent Tween 20, and the balance of nanopure water. A trace amount of radio labelled ethanol C14 or butanol C14 was added to each formulation prior to assay and then 10ml of the labelled formulation was counted in a liquid scintillation counter to determine the number of disintegrations per minute (DPM).
The receptor cells of nine finite dose Franz diffusion cells were filled with isotonic saline and maintained at 37°C by submersion into a thermostatically controlled water jacket. The saline was stirred for 30 minutes with a magnetic stir bar to achieve equilibrium.
Freshly excised full thickness mouse skin was then mounted with an O ring between the donor and the receptor cells. After one hour of equilibration the saline was removed from the receptor cells and replaced by 4-5 ml of fresh saline solution at 37°C.
Three of the nine donor cells were charged with 100 μl of radio-labelled saline containing no penetration enhancer as the control, three were charged with 100 μl of the one weight percent penetration enhancer formulation in labelled saline, and three cells were charged with equal amounts of the five weight percent penetration enhancer formulation in labelled saline.
At 45 minute intervals, 50 μl samples were taken from each receptor cell port with a micropipettor. The volume removed was replaced with a 50 μl sample of fresh 37°C saline formulation. Each sample was then placed into a liquid scintillation counting vial along with 4.0 μl of scintillation cocktail (Aquasol, New England Nuclear, Boston, MA) .
Based upon the predetermined DPM for each formulation, the amount of alkanol carried through the mouse skin by each formulation was calculated using known methods.
Tables II and III below summarize the increase in permeation of radio labelled alkanol achieved by addition of the penetration enhancer. It will be noted that in every test the penetration of ethanol was increased by at least 76 per cent over that achieved without aid of the penetration enhancers of this invention. The best results in these tests were achieved using a 1 weight percent concentration of N-0917 penetration enhancer, which yielded a penetration of ethanol through hairless mouse skin of 616% of that achieved without the penetration enhancer.
As shown in Table II, all of the penetration enhancers of this invention yielded penetration of butanol at least 119 percent of that achieved by the control.
TABLE I
ETHANOL - C14 AS PERMEANT
PENETRATION COEFFICIENT
COMPOUND CONC'N (X10-3CM/NR) % OF CONTROL
1% 19.42 616
1A 5% 17.20 546
1% 8.21 155
2A 5% 25.62 484
1% 11.28 341
2I 5% 6.89 208
1% 2.38 76
2C 5% 4.82 155
1% 10.69 269
AZONE 5% 18.58 466 TABLE II
BUTANOL - C14 AS PERMEANT
PENETRATION
COEFFICIENT
COMPOUND CONC'N (X10-3CM/NR) % OF CONTROL
1% 37.39 297
1A 5% 40.74 324
1% 14.69 135 2A 5% 22.23 204
1% 18.91 204
2I 5% 23.68 255
1% 10.80 119
2C 5% 11.65 128
1% 24.83 340
AZONE 5% 23.29 319
EXAMPLE 5 The following formulation is prepared:
Solution (%)
Griseofulvin 1
N-dodecyl-2-pyrrolidone-5-carboxylic acid 1 Isopropyl myristate 5
Fragrance 0.1
Ethanol 92.9
This formulation is effective in the treatment of fungus infections. EXAMPLE 6 An aerosol form of the formulation of Example 7 is prepared by preparing the following mixture:
Formulation 25%
Freon1 75% 1Freon is 75/25 Freon 114/12.
EXAMPLE 7 The following cream formulation is prepared: %
Clindamycin base 1.0 Stearyl alcohol, U.S.P. 12.0 Ethoxylated cholesterol 0.4 Synthetic spermaceti 7.5 Sorbitan monooleate 1.0 Polysorbate 80, U.S.P. 3.0 N-dodecyl-2-pyrrolidone-5-carboxylic acid 0.5 Sorbitol solution, U.S.P. 5.5 Sodium citrate 0.5 Chemoderm #844 Fragrance 0.2 Purified water 68.4
This formulation is effective in the treatment of acne. EXAMPLE 8 The following solution formulations are prepared: A (%) B (%)
Clindamycin base - - 1.0
Clindamycin phosphate acid 1. 3 - -
Sodium hydroxide 0.077 - -
1.0 M Hydrochloric acid - - 2.27
Disodium edetate-2H2O 0.003 0.003
Fragrances 0.5 0.5
N-dodecyl-2-pyrrolidone-5- carboxylic acid .0 1.0 Purified water 20.0 17.73 Isopropanol 77.12 77.497
These solutions are effective for the treatment of acne in humans.
EXAMPLE 9 The following solution formulation is prepared: %
Neomycin sulfate 0.5
Lidocaine 0.5
Hydrocortisone 0.25
N-dodecyl-2-pyrrolidone-5-carboxylic acid 0.5 Propylene glycol 98.25
This solution is effective for the treatment of otitis in domestic animals. EXAMPLE 10 The following sunscreen emulsion is prepared: % p-Aminobenzoic acid 2.0 Benzyl alcohol 0.5
N-dodecyl-2-pyrrolidone-5-carboxylic acid 1.0
Polyethylene glycol 500-MS 10.0 Isopropyl lanolate 3.0
Lantrol 1.0
Acetylated lanolin 0.5
Isopropyl myristate 5.0
Light mineral oil 8.0
Cetyl alcohol 1.0
Veegum 1.0
Propylene glycol 3.0
Purified water 64.0
EXAMPLE 11 The following antineoplastic solution is prepared: %
5-Fluorouracil 5.0 N-dodecyl-2-pyrrolidone-5-carboxylic acid 0.1 Polyethylene glycol 5.0 Purified water 89.9 EXAMPLE 12
The following insect repellant atomizing spray is prepared: %
Diethyltoluamide 0.1 N-dodecyl-2-pyrrolidone-5-carboxylic acid 0.1 Ethanol 99.8
EXAMPLE 13 The following lotion formulation may be prepared containing about 0.001 to 1 percent, with preferably 0.1 percent fluocinolone acetonide: %
Fluocinolone acetonide 0.001-1
Cetyl alcohol 15.0
Propylene glycol 10.0
Sodium lauryl sulfate 15.0
N-dodecyl-2-pyrrolidone-5-carboxylic acid 1.0
Water (to make 100%)
The steroid is dissolved in the vehicle and added to a stirred, cooling melt of the other ingredients. The preparation is particularly useful for the treatment of inflamed dermatoses by topical application to the affected skin area. The amount and frequency of application is in accordance with standard practice for topical application of this steroid. Penetration of the steroid into the inflamed tissue is enhanced and a therapeutic level is achieved more rapidly and sustained for longer duration than when the steroid is applied in conventional formulations.
The pentration enhancers of the present invention can also be used in combination with fabric dyes for the dyeing of fibers, additives, or textile auxiliaries, useful in improving or enhancing the dyeing process by enabling the dyeing of fibers at lower temperatures and in shorter times than without the use of the composition. Dyeable fibers include both natural and man-made fibers.
Natural fibers suitable for use in the method of the present invention include cotton, linen, wood, and silk and others such as kapok, hemp, jute and ramie. Man-made fibers include rayon (fibers composed of regenerated cellulose), acetate (fibers composed of cellulose approximately di- or tri-acetate) and synthetic fibers which are composed of non-natural fiber-forming substances manufactured by chemical methods, such as polyamide, acrylic, polyester and polyolefin.
Typical polyamide fibers include nylons, such as, for example, poly (hexamethylene-adipamide), poly (mxylylene adipamide), poly (xylylene sebacamide), polycaprolactam and the like. Typical acrylic fibers are synthetic consisting wholly of polyacrylonitrile or a copolymer of a mixture of acrylonitrile and another vinyl compound, such as Orion, Dynel, Verel, Creslan, Acrilan, Courtelle and Vinyon. Typical polyester fibers include Terylene, Dacron and Kodel. Typical polyolefin fibers include polyethylene, polypropylene, Vinylon, Rhouyl, Zefran and Darvan.
Various dyestuffs are available and may be classified as substantive or direct dyes, asoic or naphthol dyes, vat dyes and sulfur dyes, acid dyes and mordant or metalized dyes, basic or cationic dyes, disperse dyes and fiber reactive dyes.
Direct dyes are soluble in water and are applied primarily to cellulosic fibers and occasionally to protein fibers and polyamides, azoic or naphthol dyes are somewhat similar to developed direct dyes and are used on the same fiber group. Acid dyes and mordant or metalized dyes are used in protein fibers, acrylic fibers, nylon fibers and some modified polyester fibers. Cationic or basic dyes are used especially for coloring acrylic fibers and may be useful with nylon and polyester fibers. Disperse dyes were originally developed for use on acetate fibers and are now used for coloring acetate, polyester, acrylic and polyamide fibers. Reactive dyes are used primarily on cotton, cellulosis, wool, silk and acrylics.
While it is usual to dye most natural fibers in dye liquors at temperatures up to 100°C, these conditions are generally not sufficient to allow the production of deep shades on synthetic fiber materials. Furthermore, while some natural fibers, such as wool, can be satisfactorily dyed in boiling aqueous dye liquors, it usually takes 1-1/2 to 2 hours for the dye to be fully absorbed to produce a deep shade. Wool dyes more slowly than cotton and viscose rayon. For this reason, it is generally not practical to dye wool fabrics by conventional continuous dyeing methods. However, at temperatures above 100°C., wool and synthetic fibers absorb dyes more quickly and thus the continuous dyeing of wool would be possible, except that such high temperature dyeing conditions can result in deterioration of the fiber.
With the use of the compounds described herein, the dyeing process can often be carried out at lower temperatures and completed in a shorter time than without the use of such compounds. Furthermore, use of the compounds described herein enhances the penetration of the dyes into the fiber being dyed and improves fastness. The compounds described herein are especially useful in the dyeing of synthetic fibers for carpet.
The amount of the compounds described herein which may be used in the present invention varies with the desired fiber and dye, the desired time and temperature of dyeing, and the dyeing process that is used. Generally, the compounds described herein may be used in amounts of about 0.1 to about 50% by weight and preferably about 1 to about 10% by weight of the dye liquor.
The textile materials with which the compounds of the present invention may be used may be of any type including, but not limited to, a yarn or fabric of any of the known fabric types including woven, knitted, or non-woven. An especially suitable fabric is a tufted or looped pile carpet.
As used herein, the term "effective amount" in reference to the textile auxiliary disclosed herein has reference to that amount of the disclosed compound sufficient to improve dye penetration by swelling the fibers to be dyed or dispersing the dye being used in the dyeing process into smaller particles for improving dye fastness, or facilitating the use of lower temperatures and shorter times in the dyeing process.
The subject composition is useful in the treatment of plants, in particular for an improved method of the delivery of plant nutrients.
The supply and absorption of chemical compounds needed for growth and metabolism may be defined as nutrition and the chemical compounds required by an organism termed nutrients. The mechanisms by which nutrients are converted to cellular material or used for energetic purposes are metabolic processes. The term 'metabolism' encompasses the various reactions occurring in a living cell in order to maintain life and growth. Nutrition and metabolism are thus very closely interrelated.
The essential nutrients required by green plants are exclusively of inorganic nature. In this respect, green plants differ fundamentally from man, animals and a number of microorganisms, which additionally need organic compounds as foodstuffs. An essential element may be defined as one which is required for the normal life cycle of an organism and whose functions cannot be substituted by other chemical compounds. In addition, the element must be shown to be directly involved in nutrition, as for example as a constituent of an essential enzyme system. Based on this definition, the following chemical elements are now known to be essential for higher plants:
Carbon C Potassium K Zinc Zn
Hydrogen H Calcium Ca Molybdenum Mo
Oxygen 0 Magnesium Mg Boron B
Nitrogen N Iron Fe Chlorine Cl
Phosphorus P Manganese Mn Sodium Na
Sulfur S Copper Cu Silicon Si
Cobalt Co
The list of essential elements shown above may well not be complete and other elements, in very low concentrations, may yet be shown to be essential for higher plants. For some microorganisms, for example, vanadium (V) has now been established as an essential element.
The plant nutrients may be divided into macronutrients and micronutrients. Macronutrients are found and needed in plants in relatively higher amounts than micronutrients. The plant tissue content of the macronutrient N, for example, is over a thousand times greater than the content of the micronutrient Zn. Following the classification based on the element content in plant material, the following elements may be defined as macronutrients: C, H, O, N, P, S, K, Ca, Mg, Na and Si. The micronutrients are: Fe, Mn, Cu, Zn, Mo, B and Cl. This division of the plant nutrients into macro and micronutrients is somewhat arbitrary and in many cases differences between the contents of macronutrients and micronutrients are considerably lower than the example cited above.
The process of nutrient uptake and assimilation by plants is not fully understood, although a number of theories of ion uptake and transport are known, see for example, Mengel, et al. Principles of Plant Nutrition, Chapter 3, "Nutrient Uptake and Assimilation", International Potash Institute, Bern (1978).
The amount of the subject composition which may be used in the present invention is an amount effective for enhancing the delivery of a plant nutrient to a plant. Generally, an effective amount ranges between about 0.01 to about 99.9 and preferably about 0.1 to 10 percent by weight of the composition.
Plant nutrients which may be used in this invention include conventional macronutrients and micronutrients previously described including essential as well as non-essential plant nutrients. Examples of nutrients include, but are not limited to, the primary plant foods: nitrogen including ammonia and nitrate ions, phosphorous (phosphoric acid), potassium (potash); the secondary plant-food elements: calcium, magnesium and sulfur; and the trace elements: manganese, boron, copper, zinc, iron molybdenum and chlorine. The form of the foregoing nutrients may be in any conventional form, see, for example, McVickar, et al., Using Commercial Fertilizer, The Interstate Publishers, Danville, Illinois (1978).
The method of application of the plant nutrient compositions described herein is conventional. See, for example, McVickar, et al., Using Commercial Fertilizers. Chapter XIV, "Methods of Applying Fertilizers".
The precise amount of the plant nutrient composition to be delivered to the plant will obviously be an effective amount for the desired result expected therefrom. This, of course, will be ascertained by the ordinary skill of the practitioner. Due to enhanced activity which is achieved, the amount of plant nutrients may often be decreased from that generally applicable. In accordance with the usual prudent formulating practices, a dosage near the lower end of the useful range of the particular agent may be employed initially and the dosage increased as indicated from the observed response.
The subject composition as hereinabove described in combination with a pesticide, provides a method and composition for plant pest control.
Pesticides are chemicals designed to combat the attacks of various pests on agricultural and horticultural crops. They fall into three major classes: insecticides, fungicides and herbicides (or weed killers). There are also rodenticides (for control of vertebrate pests), nematicides (to kill microscopic eelworms), mollusicides (to kill slugs and snails) and acaricides (to kill mites).
Pesticides may also be divided into two main types, namely contact or nonsystemic pesticides and systemic pesticides. Contact or surface pesticides do not appreciably penetrate plant tissues and are consequently not transported or translocated, within the plant vascular system. The earlier insecticides, fungicides and herbicides were of this type; their disadvantages are that they are susceptible to the effects of weathering (wind, rain and sunlight) over long periods and new plant growth will be left unprotected and hence open to attack by insect and fungal pests. The early agricultural fungicides were, therefore, protectant fungicides--in other words, they are designed ot prevent the development of the fungal spores, but once the fungus has become established and infection starts to ramify through the plant tissues, such nonsystemic fungicides possess little eradicant action and usually cannot halt the infection.
In contrast, many of the more recent pesticides are systemic in character - - these can effectively penetrate the plant cuticle and move through the plant vascular system. Examples are provided by the phenoxyacetic acid selective herbicides, certain organophosphorus insecticides and the more recently discovered systemic fungicides like benomyl.
Systemic fungicides are also sometimes termed plant chemotherapeutants and can not only protect the plant from fungal attack, but also cure or inhibit an established infection. They are little affected by weathering and will also confer immunity on all new plant growth.
Pests can be divided into various groups. In the plant kingdom, characterized by the ability of the organism to photosynthesize carbohydrates from air and water with the aid of the green pigment chlorophyll, higher plants growing where man does not want them are termed weeds and are important pests. Of the lower plants, algae are not generally of as great importance as pests, although in some circumstances, e.g., in lakes and other slow-moving water, excessive algal growth of "bloom" may cause considerable damage and require treatment with chemicals (algicides).
Fungi or nonphotosynthetic plants cannot obtain their nutrients from air and water since they do not have chlorophyll; consequently, they feed directly on decaying plant or animal matter (saprophytic fungi) or on living plants or animals (parasitic fungi). There are thousands of different species of fungi mainly found in soil - - some, like yeasts, are unicellular while others are composed of a network of branched filaments (hyphae). A number of fungi are serious pests attacking both living crop plants and also crops in storage.
Several bacteria are causal agents of plant diseases, although they are not nearly as important as the phytopathogenic fungi. Bacteria can be observed under the microscope and can be classified according to their shape; thus a spherical bacterium is termed a coccus while a rodshaped one is a bacillus. Viruses, like bacteria and fungi, attack plants and animals and some species cause significant plant diseases. Viruses form a distinct category of living organism because they are not true cells. Unlike bacteria, they are too small (100-300 A) in diameter to be observed with an ordinary microscope, but they can be revealed under the electron microscope - - each virus consists of a single strand of DNA or RNA surrounded by a protective coat of protein.
Several higher animals (vertebrates) are important pests, e.g., mice, rats and rabbits; another group of pests is represented by the true insects (arthropods) which are invertebrates. The latter possess three pairs of legs and the adult body has three parts; the arachnids (mites and ticks) differ from true insects in having no distinct division of the body into three parts; also they usually have four pairs of legs. In the lower orders of animals, certain nematodes, parasitic worms often with unsegmented bodies, are important crop pests.
If pesticides are to be active, they must reach the ultimate site of action within the target organism. Thus, even surface fungicides, like Bordeaux mixture, must be able to penetrate the fungal spore; similarly, contact insecticides have to penetrate the insect cuticle, and contact herbicides penetrate the plant cuticle when they impinge on it. The requirements if the pesticides are to be systemic in action are much more stringent because, in addition, they must have the capacity to be absorbed by the roots or leaves or seeds of plants and be delivered to other parts of the plant. In this way, the whole plant, including new growth, is protected from fungal attack, or rendered poisonous to any insect that eats or sucks it. The amount of the subject composition which may be used in the present invention is an amount effective for enhancing the delivery of a pesticide to a plant pest. In the case of indirect application of the active materials to a plant, the enhanced delivery achieved through the use of 1-substituted azacycloalkane includes improved substantivity and systemic effects of the pesticide. Generally, an effective amount ranges between about 0.01 to about 99.9 and preferably about 0.1 to 10 percent by weight of the pesticide composition.
Suitable pesticides include botanical insecticides such as, for example, nicotine, derris (rotenone) and pyrethrum; synthetic insecticides including dinitrophenols, such as, for example, DNOC; organic thiocyanates such as, for example, lethane and thanite, organochlorine insecticides including DDT and related compounds; containing the cyclodiene group such as, for example, aldrin and dieldren, organosphosphorous insecticides; hexachlorocyclohexane; insecticides including malathion, mevinphos, rogar, dimethtoate, nenozan, miral, diazinon, dursbon, bay-rusil; organocarbonate insecticides including pirimicarb, carbaryl, baygon, propoxur, zectron, carbofuran, aldicarb (Temik), methomul (Lonnate); fungicides including phenylmercury compounds, naban, metham, sodium, thiron; compounds containing the n-trichloromethylthio group, such as, for example, captan, folpet and oifolatan; dinitrophenols, including dinocap (Karathane); chlorobenzynes and related compounds, quinones such as, for example, dodine and roural, sulphonamides, benzimidazoles; thiophonates; oxathinns; pyrimadines; piperozine, morpholine and azepine derivatives; organophosphorous compounds including wepsyn, kitazin and conen, herbicides including carboxylic acid herbicides, such as, for example, 2, 4-D MCPA, 2, 3, 6-TBA, IAA, picloram and dichlobenil; chloroaliphatic acids such as dalapan and TCA, and heterocyclic compounds such as atrozine (Gesaprim); triazales such as amitrole, pyrazon, bromacil, endothal; bipyridinum herbicides including paraquat and diquat; benzonitriles; diphenyl ethers; organosphosphorous compounds such as, for example, phosphorothiolates such as bensullide; phosphoramidates such as DMPA (Zyron); phosphonates such as glyphosate; plant growth regulators; fumigants; rodenticides including anticoagulants such as warfarin, pidone and norbormide (Raticote); sleep-inducing narcotic drugs such as chloralose; gophacide, silatrane and crimidine, nematicides such as dazomet and nellite; molusicides such as metaldehyde, methiocasb and frescon; repellants, antifeeding compounds such as ZIP; chemosterilants, hormones and growth inhibitors. Further examples of pesticides suitable for use in the present invention are known in the art (see, for example, R. Cremyln, Pesticides. Preparation and Mode of Action, John Wiley and Sons, 1979; F. McEwan, et al., The Use of Significance of Pesticides in the Environment. John Wiley and Sons, 1979; D. Roberts, Fundamentals of Plant Pest Control. E. H. Freeman and Company, 1978.
The method of application of the pesticide composition described herein is conventional. See, for example, G. Hartley, et al., Chemicals for Pest Control, Chapter 15, "Application of Pesticides," Pergamon Press, 1969.
The precise amount of the pesticide composition to be delivered to the plant or pest will obviously be an effective amount for the desired result expected therefrom. Most modern pesticides are used in agriculture at a dosage of less than one pound per acre. This, of course, will be ascertained by the ordinary skill of the practitioner. Due to enhanced activity which is achieved, the dosage of agent may often be decreased from that generally applicable. In accordance with the usual prudent formulating practices, a dosage near the lower end of the useful range of the particular agent may be employed initially and the dosage increased as indicated from the observed response.
The subject composition as hereinabove described, in combination with a plant growth regulator, is a method and composition for plant growth.
Plant growth regulators are organic compounds, other than nutrients, that, in low concentrations, affect the morphological structure and/or physiological processes of plants. Plant hormones or phytohormones, are naturally occurring growth regulators that in low concentrations control physiological processes in plants. The synthetic growth regulators are used by Man to control such processes as fruit development, fruit thinning, defoliation, growth stimulation and retardation, rooting of cuttings and many other processes. Over the past 30 years, the investigation and development of plant growth regulators has been one of the most active areas of fundamental and applied botanical research. The PANS Plant Growth Regulator Index (P.J. Kempt, 25 (2), 211 and 213) under the list of Common and Trade Names and Code Numbers has 492 entries (excluding herbicides except where these are used specifically for some growth regulatory purpose other than weed killing).
Plant growth regulators that are currently in use at the present time affect a great variety of plant growth processes, including the following (some of the growth regulators in common use are in brackets): rooting of cuttings (indole-butyric acid); promotion of flowering in pineapples (1-naphtlιaleneacetic acid; B-hydroxyethylhydrazine; ethephon); prevention of preharvest drop of apples (NAA; daminozide); inhibition of turf growth (maleic hydrazide; mefluididediethanolamine); prevention of sprouting of potatoes (maleic hydrazide); floral induction in apple, pear, peach (succinic acid-2, 2-dimethylhydrazine; 2, 3, 5-triodobenzoic acid); early flowering of 'long day' plants, e.g., lettuce radish, mustard, dill (gibberellins); flowering of many biennials which normally require low temperatures to flower (gibberellins); improvement of yield of sugar-cane and prevention of flowering (diuron; diquat); delay in flowering in almond and peach to avoid adverse weather conditions (diaminozide); induction of abscission of mature citrus fruits (cyclohexim; 5-chloro-3-methyl-4-nitro-1-H-pyrazole); defoliation of cotton leaves to aid harvesting of bolls (ethephon); thinning of fruit, e.g., grapes, peaches, (gibberellic acid; ethephon, 3-chlorophenoxy-α-propionamide); prevention of pre-harvest drop of citrus (2, 4-dichlorophenoxyacetic acid); induction of fruit set, e.g., in tomato, squash, eggplant, fig (4-chloro-phenoxyacetic acid; 2-naphthyloxyacetic acid); increase in size and quality of grapes (gibberellins); induction of amylase in barley for malting (gibberellins); stimulation of growth of sugar-cane (gibberellins); reduction of stem length in cereals (2-chloroethyl trimethyl-ammonium chloride); development of female flowers, e.g., in pumpkins (NAA; ethephon; daminozide); promotion of male flowers, e.g., in hops (gibberellins); bioregulation of plant composition, e.g., colour in citrus, sugar in sugarcane, vitamin content in vegetables, increase in dry weight, timing of crop development, increased latex from rubber trees (various growth regulators).
The amount of the subject composition which may be used in the present invention is an amount effective for enhancing the delivery of a plant growth regulator to a plant. Generally, an effective amount ranges between about 0.01 to about 99.9 and preferably about 0.1 to 10 percent by weight of the composition. Suitable plant growth regulators include both natural and synthetic auxins, such as IAA (indolyl-3-acetic acid), IBA (4-(indol-3 yl) butyric acid), NAO (alphanaphthylacetic acid), NOA (2-naphthyloxy-acetic acid) and NAD (1-naphthylacetamide); phenoxyalkanoic acids, gibberellins, cytokinins, abscisic acid, maleic hydrazide, propham and cloropopham, S,S,S-tributyl phosphorotrithioate, S,S,S,- Tributyl phosphorotrithioite, chloromequat, daminozide, glyphosine, ancymidol, chlorphonium chloride, dikegulac sodium, morpholinium chloride, fosamine, mefulidide, 4-methoxybenzophenones, PP 528 (ethyl-5-(4-chlorophenyl)-2H-tetrazol-2-yl acetate), piproctanyl bromide, 2-(3-aryl-5-pyrazoyl) benzoic acids, BTS 34723 (1-(N-2-phenoxyethyl)-N-propylcarbamoy)-N-imidazole), BTS 34442 (1-(N-2,4-dichlorobenzyl)-N-isopropyl-carbamoyl)-1N-imidazole), UBI
P293 (2,3,-dihydro-5, 6-diphenyl-1, 4-oxathiin), MSB 25, 105
(propyl 3-t-butyl phenoxyacetate), thidaizuron (N-phenyl-N'- (1,2,3-thiadiazol-5-yl) urea) , mepiquat (1,1-dimethylpiperidinium chloride), BAS 09800W (mepiquat chloride plus ethephan), IZAA (5-chloroindazole-8-acetic ethyl ester), MON 8000, DOWCO 242 (tetraisopentyl-ammonium bromide), quarternary ammonium iodides; morphactins including chloroflurecol-methyl, flurecol-butyl, TIBA
(2,3,5-tri-iodobenzoic acid; gametocides including RH 531
(sodium 1-(4-chlorphenyl)-1,2-dihydro-4, 6-dimethyl-2-oxonicotinate), DPX-3778 (3-(4-chlorophenyl)-6-methoxy- 1,3,5-triazine-2, 4-dione triethanolamine) and allelopathins. Additional plant growth regulators are known in the literature, see, for example, Fletcher, et al.,
Herbicides and Plant Growth Regulators, Chapter 2.
Opportunities for use of plant growth regulators include treatments for seed or seedlings for transplanting which will promote early growth and root development; substances to improve quality (usually protein levels and amino acid balance) of grain crops; substances to improve yield and quality of forages; opportunities in forestry, such as seeling survival and growth, early seed production and accelerated growth rates; systems to reduce energy costs by maximizing response to cultivation, fertilizers (i.e., uptake, mobilization, etc.) and irrigation water; compounds to inhibit ethylene action or production and thus reduce young fruit abscission in indeterminately fruiting crops; new gibberellins with species- or function specific effects, new applications of known substances based on understanding hormone interactions and storage/inactivation systems ('slow release' compounds) and substances to manipulate natural conjugation reactions; substances to alleviate or minimize effects of plant diseases and insects, or to facilitate systems of integrated pest management; substances to modify productivity by reducing photorespiration, dark respiration, or by promoting nitrogen metabolism/fixation, photosynthesis, translocation; substances that intensify synthesis of specific highly desired end-products (oil, protein, cellulose); substance to increase productivity by shifting developmental patterns, such as extending the period of inflorescence differentiation or seed development. The foregoing serves to illustrate the wide range of opportunities available to agricultural chemists.
Plant tissue culture pioneered by White, Steward, Skoog and others, beginning almost as a botanical curiosity, has with the help of growth-regulatory chemicals become a powerful tool in the hands of the plant breeder. It is now possible to tissue culture almost any plant and to develop uniform plantlets from such cultures. Even pollen grains can be used and the subsequent haploid plants made polyploid by the use of suitable chemical agents. Together with apical meristem culture, there is an unending supply of material. The method of application of the plant growth regulator composition described herein is conventional. See, for example, W.W. Fletcher and R.C. Kirkwood, Herbicides and Plant Growth Regulators, Granada Publishing Limited, New York, 1982.
The precise amount of the plant growth regulator composition to be delivered to the plant will obviously be an effective amount for the desired result expected therefrom. This, of course, will be ascertained by the ordinary skill of the practicioner. Due to enhanced activity which is achieved, the amount of plant growth regular may often be decreased from that generally applicable. In accordance with the usual prudent formulating practices, a dosage near the lower end of the useful range of the particular agent may be employed initially and the dosage increased as indicated from the observed response.
While particular embodiments of the invention have been described, it will be understood, of course, that the invention is not limited thereto since many obvious modifications can be made and it is intended to include with this invention any such modifications as will fall within the scope of the appended claims.

Claims (101)

Having now described the invention, we claim:
1. A composition comprising an effective amount of a physiologically active agent and an effective penetrating amount of a compound represented by the general formula
and salts thereof wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur, or -CH2-; wherein R represents alkyl optionally substituted with one to three double or triple bonds -SR''', -OR''',- NHR''', -CH3, or -COOR1; wherein R''' represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or - (CH2)yCOOR1; wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive. wherein R'' represents hydrogen, or -(CH2)yCOOR1 such that when R'' is hydrogen, then W is two hydrogen radicals and R' is not hydrogen; and when R' is hydrogen, then R'' is not hydrogen; and wherein m is between one and 5, n is between 1 and 24, and x is zero or 1, inclusive; and wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive.
2. The composition of claim 1 wherein R is -CH3, n is 4, R'' is -(CH2)yCOOR1 with y being zero and R1 being hydrogen; W is oxygen, Z is -CH2-, m is one, x is one and R' is hydrogen.
3. The composition of claim 2 wherein R1 is ethyl.
4. The composition of claim 2 wherein R1 is methyl.
5. The composition of claim 2 wherein n is eleven.
6. The composition of claim 2 wherein n is eleven, and m is three.
7. The composition of claim 2 wherein n is ten, W is two hydrogen radicals, R'' is hydrogen, and R' is -(CH2)yCOOR, with y being zero and R1 being hydrogen.
8. The composition of claim 5 wherein W is oxygen, m is three and y is one.
9. The composition of claim 1 wherein Z is -CH2-, m is three, R'' is hydrogen, x is one, n is ten, W is two hydrogen radicals and R is -COOR1 with R1 being hydrogen.
10. The composition of claim 1 wherein W is two hydrogen radicals, m is one, R' ' is -(CH2)yCOOR1 with y being zero and R1 being hydrogen, R is -CH3, Z is -CH2-, R' is hydrogen and n is ten.
11. The composition of claim 1 wherein m is 1 or 2 and n is between 5 and 12, inclusive.
12. The composition of claim 1 wherein n is ten, R is -CH3, R'' is hydrogen, R' is -(CH2)yCOOR1 with y being zero and R1 being hydrogen; W is oxygen, x is one, m is one and Z is -CH2-.
13. The composition of claim 1 wherein Z is oxygen, R'' is - (CH2)yCOOR1 where y is zero and R1 is hydrogen, W is oxygen, x is zero, R is -CH3, n is eleven and, m is two.
14. The composition of claim 13 wherein W is two hydrogen radicals, x is one.
15. The composition of claim 1 wherein W is oxygen, Z is -CH2-, R' is hydrogen, R is -CH3, R'' is -(CH2)yCOOR1 where y is zero and R1 is hydrogen, n is eleven, x is one and m is three.
16. The composition of claim 1 wherein Z is oxygen, R' ' is -(CH2)yCOOR1 where y is zero and R1 is hydrogen, W is oxygen, x is zero, R is -CH3, n is eleven, m is two.
17. The composition of claim 16 wherein W is two hydrogen radicals, x is one.
18. The composition of claim 1 wherein W is oxygen, Z is -CH2-, R' is hydrogen, R is -CH3, R'' is -(CH2)yCOOR1 where y is zero and R1 is hydrogen, n is eleven, x is one and m is three.
19. The composition of claim 1 wherein the physiologically active agent is an antibacterial agent.
20. The composition of claim 11 wherein the antibacterial agent is an antibiotic.
21. The composition of claim 12 wherein the antibiotic is selected from the group consisting of lincomycin, clindamycin, erythromycin and pharmaceutically useful salts thereof.
22. The composition of claim 1 wherein the physiologically active agent is a physiologically active steroid.
23. The composition of claim 1 wherein the physiologically active agent is an antifungal agent.
24. The composition of claim 1 wherein the physiologically active agent is iododeoxyuridine.
25. the composition of claim 1 wherein the physiologically active agent is 5-fluorouracil.
26. A method for enhancing penetration of physiologically active agents through the skin or mucosal membranes of humans and animals comprises the topical administration to the skin or mucosal membrane of humans and animals of effective amounts of a physiologically active agent and a membrane penetration enhancer having the structural formula
and salts thereof wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur, or two hydrogen radicals; wherein R represents alkyl substituted with 1 to 3 double or triple bonds, -SR''', -OR''', -NHR''', -CH3, or -COOR1; wherein R'''' represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, -(CH2)yCOOR1; wherein R'' represents hydrogen, -(CH2)yCOOR1 such that when R'' is hydrogen, then W is two hydrogen radicals; and when R' is hydrogen, then R'' is not hydrogen; and when R'' is hydrogen, then R' is not hydrogen; wherein m is between one and 5 and n is between 1 and 24, inclusive and x is zero or 1; and wherein R1 represents hydrogen or lower alkyl radical and y is between zero and three, inclusive.
27. The method of claim 26 wherein the physiologically active agent is an antibacterial agent.
28. The method of claim 27 wherein the antibacterial agent is an antibiotic.
29. The method of claim 28 wherein the physiologically active agent is a physiologically active steroid.
30. The method of claim 26 wherein the physiologically active agent is an antifungal agent.
31. The method of claim 26 wherein the physiologically active agent is iododeoxyuridine.
32. The method of claim 26 wherein the physiologically active agent is 5-fluorouracil.
33. A composition comprising an effective amount of a physiologically active agent and an effective penetrating amount of a compound represented by the general formula
and salts thereof wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur, or -CH2-; wherein R, R2 and R3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds -SR''', -OR''', -HNR''', -CH3, or -COOR1; wherein R1 represents hydrogen or a lower alkyl radical; wherein R2 represents -SR''', -OR''', -NHR''', -CH3, or -COOR1; wherein R' ' ' represents hydrogen alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1, and further wherein y is between zero and 3, inclusive; wherein R' ' represents hydrogen, or - (CH2)yCOOR1 and wherein m is between zero and 5, while n is between 1 and 24, inclusive.
34. The composition of claim 33 where A is -CH2-, R2 is -CH3, R3 is -CH3, m is zero, R' is hydrogen, B is two hydrogen radicals, R is -COOR1 where R1 is hydrogen, R'' is hydrogen, and n is nine.
35. The composition of claim 34 where R1 is ethyl.
36. The composition of claim 34 where R1 is methyl.
37. The composition of claim 33 where A is -CH2-, R2 is -CH3, R3 is -CH3, m is zero, R' is hydrogen, B is two hydrogen radicals, R is -COOR1 where R1 is hydrogen, R'' is hydrogen, and n is nine.
38. The composition of claim 37 where R1 is ethyl.
39. The composition of claim 37 where R1 is methyl.
40. The composition of claim 33 wherein the antibacterial agent is an antibiotic.
41. The composition of claim 40 wherein the antibiotic is selected from the group consisting of lincomycin, clindamycin, erythromycin and pharmaceutically useful salts thereof.
42. The composition of claim 33 wherein the physiologically active agent is a physiologically active steroid.
43. The composition of claim 33 wherein the physiologically active agent is an antifungal agent.
44. The composition of claim 33 wherein the physiologically active agent is iodcdeoxyuridine.
45. The composition of claim 33 wherein the physiologically active agent is 5-fluorouracil.
46. A method for enhancing penetration of topically administered active agents through the skin or mucosal membranes of humans and animals comprises the topical administration to the skin or mucosal membrane of humans and animals of effective amounts of a physiologically active agent and a membrane penetration enhancer having the structural formula
and salts thereof
wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur, or -CH2-; wherein R, R2 and R3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds -SR''', -OR''', -HNR''', -CH3, or -COOR1; and wherein m is between zero and 5 while n is between 1 and 24, inclusive; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1; wherein R' ' represents hydrogen, or -(CH2)yCOOR1; wherein R''' represents hydrogen alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; and wherein R1 represents hydrogen or a lower alkyl radical and y is between zero and 3, inclusive.
47. The method of claim 46 wherein the physiologically active agent is an antibacterial agent.
48. The method of claim 47 wherein the antibacterial agent is an antibiotic.
49. The method of claim 47 wherein the antibiotic is selected from the group consisting of lincomycin, clindamycin, erythromycin and pharmaceutically useful salts thereof.
50. The method of claim 46 wherein the physiologically active agent is a physiologically active steroid.
51. The method of claim 46 wherein the physiologically active agent is an antifungal agent.
52. The method of claim 46 wherein the physiologically active agent is iododeoxyuridine.
53. The method of claim 46 wherein the physiologically active agent is 5-fluorouracil.
54. A composition comprising an effective amount of a physiologically active agent and an effective penetrating amount of a compound represented by the general formula
and salts thereof wherein R' is hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy or -(CH2)yCOOR1; wherein R2 is COOR-j_ or an alkyl, optionally substituted with between 1 and 3 double or two triple bonds; wherein B' represents oxygen, sulfur or hydrogen radicals; wherein B'' represents oxygen, sulfur, or two hydrogen radicals; wherein m is between zero and 5 and n is between 1 and 24, inclusive; and wherein y is between zero and three and R1 represents hydrogen or a lower alkyl radical; such that when B'' is oxygen or sulfur, the R' is not alkyl or hydrogen and y is not zero and when B'' is oxygen and B' is two hydrogen radicals, then R' is -(CH2)yCOOR1.
55. The composition of claim 54 wherein B' is oxygen, B' ' is two hydrogen radicals, R2 is -CH3, n is ten, m is three, and R' is -(CH2)yCOOR1 where y is zero and R1 is hydrogen.
56. The composition of claim 54 wherein B' is two hydrogen radicals, B'' is two hydrogen radicals, R' is -(CH2)yCOOR1 with y being zero and R1 being -CH3; R2 is -CH3, n is ten, and m is three.
57. The composition of claim 54 wherein the physiologically active agent is an antibiotic.
58. The composition of claim 57 wherein the antibiotic is selected from the group consisting of lincomycin, clindamycin, erythromycin and pharmaceutically useful salts thereof.
59. The composition of claim 54 wherein the physiologically active agent is a physiologically active steroid.
60. The composition of claim 54 wherein the physiologically active agent is an antifungal agent.
61. The composition of claim 54 wherein the physiologically active agent is iododeoxyuridine.
62. The composition of claim 54 wherein the physiologically active agent is 5-fluorouracil.
63. A method for enhancing penetration of physiologically active agents through the skin or mucosal membranes of humans and animals comprises the topical administration of effective amounts of a physiologically active agent and a membrane penetration enhancer having the structural formula
and salts thereof wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy or - (CH2)yCOOR1; wherein R2 represents COOR1 or an alkyl, optionally substituted with between 1 and 3 double or triple bonds; wherein B' represents oxygen, sulfur, or two hydrogen radicals; wherein B' ' represents oxygen, sulfur, or two hydrogen radicals wherein m is between zero and 5 and n is between 1 and 24, inclusive; and wherein y is between zero and three and R1 represents hydrogen or a lower alkyl radical; such that when B'' is oxygen or sulfur, then R' is not alkyl or hydrogen and y is not zero; and when B'' is oxygen and B' is two hydrogen radicals, then R' is- (CH2)yCOOR1.
64. The method of claim 63 wherein the physiologically active agent is an antibacterial agent.
65. The method of claim 64 wherein the antibacterial agent is an antibiotic.
66. The method of claim 65 wherein the antibiotic is selected from the group consisting of lincomycin, clindamycin, erythromycin and pharmaceutically useful salts thereof.
67. The method of claim 63 wherein the physiologically active agent is a physiologically active steroid.
68. The method of claim 63 wherein the physiologically active agent is an antifungal agent.
69. The method of claim 63 wherein the physiologically active agent is iododeoxyuridine.
70. The method of claim 63 wherein the physiologically active agent is 5-fluorouracil.
71. The method of claim 63 wherein m is between 1 and 2 and n is between 5 and 12, inclusive.
72. A method of enhancing dye penetration of fibers by utilizing in the dyeing process, an effective, dye-enhancing amount of a compound having the structural formula
and salts thereof wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur, or -CH2-;
wherein R represents alkyl optionally substituted with one to three double or triple bonds -SR''', -OR''',- NHR''', -CH3, or -COOR1; wherein R''' represents alkyl, alkyIthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1; wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive. wherein R'' represents hydrogen, or -(CH2)yCOOR1 such that when R'' is hydrogen, then W is two hydrogen radicals and R' is not hydrogen; and when R' is hydrogen, then R'' is not hydrogen; and wherein m is between one and 5, n is between 1 and 24, and x is zero or 1, inclusive; and wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive.
73. The method of Claim 72 wherein the fibers are selected from the group of natural and synthetic fibers.
74. The method of Claim 72 wherein the fibers are synthetic fibers selected from the group consisting of rayon, acetate, polyamide, acrylic, polyester and polyolefin fibers.
75. A composition comprising an effective amount of dye and an effective dye-enhancing amount of a compound having the structural formula
and salts thereof wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur, or -CH2-; wherein R represents alkyl optionally substituted with one to three double or triple bonds -SR''', -OR''',- NHR''', -CH3, or -COOR1; wherein R''' represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or - (CH2)yCOOR1; wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive. wherein R'' represents hydrogen, or -(CH2)yCOOR1 such that when R'' is hydrogen, then W is two hydrogen radicals and R' is not hydrogen; and when R' is hydrogen, then R'' is not hydrogen; and wherein m is between one and 5, n is between 1 and 24, and x is zero or 1, inclusive; and wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive.
76. A method for improved delivery of plant nutrients comprising contacting a plant with a composition comprising an effective amount of a plant nutrient and an effective delivery-enhancing amount of compound having the structural formula
and salts thereof wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur, or -CH2-; wherein R represents alkyl optionally substituted with one to three double or triple bonds -SR''', -OR''',- NHR''', -CH3, or -COOR1; wherein R''' represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or - (CH2)yCOOR1; wherein R1 represents hydrogen αr lower alkyl and y is between zero and 3, inclusive. wherein R'' represents hydrogen, or -(CH2)yCOOR1 such that when R'' is hydrogen, then W is two hydrogen radicals and R' is not hydrogen; and when R' is hydrogen, then R'' is not hydrogen; and wherein m is between one and 5, n is between 1 and 24, and x is zero or 1, inclusive; and wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive.
77. A composition comprising an effective amount of a plant nutrient and an effective delivery enhancing amount of a compound having the structural formula
and salts thereof wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur, or -CH2-; wherein R represents alkyl optionally substituted with one to three double or triple bonds -SR''', -OR''',- NHR'", -CH3 , or -COOR1; wherein R''' represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or - (CH2)yCOOR1; wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive. wherein R'' represents hydrogen, or -(CH2)yCOOR1 such that when R'' is hydrogen, then W is two hydrogen radicals and R' is not hydrogen; and when R' is hydrogen, then R' ' is not hydrogen; and wherein m is between one and 5, n is between 1 and 24, and x is zero or 1, inclusive; and wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive.
78. A method for improved pest control comprising contacting a plant or plant pest with a composition comprising an effective amount of a plant pesticide and an effective delivery-enhancing amount of compound having the structural formula
and salts thereof wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur, or -CH2-; wherein R represents alkyl optionally substituted with one to three double or triple bonds -SR''', -OR''',- NHR''', -CH3, or -COOR1; wherein R''' represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1; wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive. wherein R' ' represents hydrogen, or -(CH2)yCOOR1 such that when R' ' is hydrogen, then W is two hydrogen radicals and R' is not hydrogen; and when R' is hydrogen, then R' ' is not hydrogen; and wherein m is between one and 5, n is between 1 and 24, and x is zero or 1, inclusive; and wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive.
79. A composition comprising an effective amount of a plant pesticide and an effective delivery-enhancing amount of a compound having the structural formula
and salts thereof wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur, or -CH2-; wherein R represents alkyl optionally substituted with one to three double or triple bonds -SR''', -OR''',- NHR''', -CH3, or -COOR1; wherein R''' represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1; wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive. wherein R' ' represents hydrogen, or -(CH2)yCOOR1 such that when R' ' is hydrogen, then W is two hydrogen radicals and R' is not hydrogen; and when R' is hydrogen, then R' ' is not hydrogen; and wherein m is between one and 5, n is between 1 and 24, and x is zero or 1, inclusive; and wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive.
80. A method for improved delivery of plant growth regulators comprising contacting a plant with a composition comprising an effective amount of a plant growth regulator and an effective delivery-enhancing amount of compound having the structural formula
and salts thereof wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur, or -CH2-; wherein R represents alkyl optionally substituted with one to three double or triple bonds -SR''', -OR''',- NHR''', -CH3, or -COOR1; wherein R' '' represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1; wherein R1 represents hydrogen or lower alkyl and y is between zero and 3 , inclusive. wherein R'' represents hydrogen, or -(CH2)yCOOR1 such that when R'' is hydrogen, then W is two hydrogen radicals and R' is not hydrogen; and when R' is hydrogen, then R'' is not hydrogen; and wherein m is between one and 5, n is between 1 and 24, and x is zero or 1, inclusive; and wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive.
81. A composition comprising an effective amount of plant growth regulator and an effective delivery-enhancing amount of a compound having the structural formula
wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur, or -CH2-; wherein R represents alkyl optionally substituted with one to three double or triple bonds -SR''', -OR''',- NHR''', -CH3, or -COOR1; wherein R''' represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1; wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive. wherein R'' represents hydrogen, or -(CH2)yCOOR1 such that when R' ' is hydrogen, then W is two hydrogen radicals and R' is not hydrogen; and when R' is hydrogen, then R' ' is not hydrogen; and wherein m is between one and 5, n is between 1 and 24, and x is zero or 1, inclusive; and wherein R1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive.
82. A method of enhancing dye penetration of fibers by utilizing in the dyeing process, an effective, dye-enhancing amount of a compound having the structural formula
and salts thereof wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur, or -CH2-; wherein R, R2 and R3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds -SR'", -OR''', -HNR''', -CH3, or -COOR1; wherein R1 represents hydrogen or a lower alkyl radical; wherein R2 represents -SR''', -OR''', -NHR''', -CH3, or -COOR1; wherein R''' represents hydrogen alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1, and further wherein y is between zero and 3, inclusive; wherein R' ' represents hydrogen, or -(CH2)yCOOR1 and wherein m is between zero and 5, while n is between 1 and 24, inclusive.
83. The method of Claim 82 wherein the fibers are selected from the group of natural and synthetic fibers.
84. The method of Claim 82 wherein the fibers are synthetic fibers selected from the group consisting of rayon, acetate, polyamide, acrylic, polyester and polyolefin fibers.
85. A composition comprising an effective amount of dye and an effective dye-enhancing amount of a compound having the structural formula and salts thereof wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur, or -CH2-; wherein R, R2 and R3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds -SR''', -OR''', -HNR''', -CH3, or -COOR1; wherein R1 represents hydrogen or a lower alkyl radical; wherein R2 represents -SR''', -OR''', -NHR''', -CH3, or -COOR1; wherein R' ' ' represents hydrogen alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1, and further wherein y is between zero and 3, inclusive; wherein R'' represents hydrogen, or -(CH2)yCOOR1 and wherein m is between zero and 5, while n is between 1 and 24, inclusive.
86. A method for improved delivery of plant nutrients comprising contacting a plant with a composition comprising an effective amount of a plant nutrient and an effective delivery-enhancing amount of compound having the structural formula
and salts thereof wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur, or -CH2-; wherein R, R2 and R3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds -SR''', -OR''', -HNR''', -CH3, or -COOR1; wherein R1 represents hydrogen or a lower alkyl radical; wherein R2 represents -SR''', -OR''', -NHR''', -CH3, or -COOR1; wherein R' ' ' represents hydrogen alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1, and further wherein y is between zero and 3, inclusive; wherein R'' represents hydrogen, or -(CH2)yCOOR1 and wherein m is between zero and 5, while n is between 1 and 24, inclusive.
87. A composition comprising an effective amount of a plant nutrient and an effective delivery enhancing amount of a compound having the structural formula and salts thereof wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur, or -CH2-; wherein R, R2 and R3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds -SR''', -OR''', -HNR''', -CH3, or -COOR1; wherein R1 represents hydrogen or a lower alkyl radical; wherein R2 represents -SR''', -OR''', -NHR''', -CH3, or -COOR1; wherein R' ' ' represents hydrogen alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1, and further wherein y is between zero and 3, inclusive; wherein R' ' represents hydrogen, or -(CH2)yCOOR1 and wherein m is between zero and 5, while n is between 1 and 24, inclusive.
88. A method for improved pest control comprising contacting a plant or plant pest with a composition comprising an effective amount of a plant pesticide and an effective delivery-enhancing amount of compound having the structural formula
and salts thereof wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur, or -CH2-; wherein R, R2 and R3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds -SR''', -OR''', -HNR''', -CH3, or -COOR1; wherein R1 represents hydrogen or a lower alkyl radical; wherein R2 represents -SR''', -OR''', -NHR''', -CH3, or -COOR1; wherein R''' represents hydrogen alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or - (CH2)yCOOR1, and further wherein y is between zero and 3, inclusive; wherein R'' represents hydrogen, or -(CH2)yCOOR1 and wherein m is between zero and 5, while n is between 1 and 24, inclusive.
89. A composition comprising an effective amount of a plant pesticide and an effective delivery-enhancing amount of a compound having the structural formula and salts thereof wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur, or -CH2-; wherein R, R2 and R3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds -SR''', -OR''', -HNR''', -CH3 , or -COOR1; wherein R1 represents hydrogen or a lower alkyl radical; wherein R2 represents -SR''', -OR''', -NHR''', -CH3, or -COOR1; wherein R' ' ' represents hydrogen alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or - (CH2)yCOOR1, and further wherein y is between zero and 3, inclusive; wherein R' ' represents hydrogen, or -(CH2)yCOOR1 and wherein m is between zero and 5, while n is between 1 and 24, inclusive.
90. A method for improved delivery of plant growth regulators comprising contacting a plant with a composition comprising an effective amount of a plant growth regulator and an effective delivery-enhancing amount of compound having the structural formula
and salts thereof wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur, or -CH2-; wherein R, R2 and R3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds -SR''', -OR''', -HNR''', -CH3 , or -COOR1; wherein R1 represents hydrogen or a lower alkyl radical; wherein R2 represents -SR''', -OR''', -NHR''', -CH3,or -COOR1; wherein R' ' ' represents hydrogen alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1, and further wherein y is between zero and 3, inclusive; wherein R' ' represents hydrogen, or -(CH2)yCOOR1 and wherein m is between zero and 5, while n is between 1 and 24, inclusive.
91. A composition comprising an effective amount of plant growth regulator and an effective delivery-enhancing amount of a compound having the structural formula
and salts thereof wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur, or -CH2-; wherein R, R2 and R3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds -SR' '', -OR''', -HNR''', -CH3, or -COOR1; wherein R1 represents hydrogen or a lower alkyl radical; wherein R2 represents -SR''', -OR''' -NHR''', -CH3, or -COOR1; wherein R' ' ' represents hydrogen alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1, and further wherein y is between zero and 3, inclusive; wherein R'' represents hydrogen, or - (CH2)yCOOR1 and wherein m is between zero and 5, while n is between 1 and 24, inclusive.
92. A method of enhancing dye penetration of fibers by utilizing in the dyeing process, an effective, dye-enhancing amount of a compound having the structural formula
and salts thereof wherein R' is hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy or -(CH2)yCOOR1; wherein R2 is COOR1 or an alkyl, optionally substituted with between 1 and 3 double or two triple bonds; wherein B' represents oxygen, sulfur or hydrogen radicals; wherein B'' represents oxygen, sulfur, or two hydrogen radicals; wherein m is between zero and 5 and n is between 1 and 24, inclusive; and wherein y is between zero and three and R1 represents hydrogen or a lower alkyl radical; such that when B'' is oxygen or sulfur, the R' is not alkyl or hydrogen and y is not zero and when B'' is oxygen and B' is two hydrogen radicals, then R' is -(CH2)yCOOR1.
93. The method of Claim 92 wherein the fibers are selected from the group of natural and synthetic fibers.
94. The method of Claim 92 wherein the fibers are synthetic fibers selected from the group consisting of rayon, acetate, polyamide, acrylic, polyester and polyolefin fibers.
95. A composition comprising an effective amount of dye and an effective dye-enhancing amount of a compound having the structural formula
and salts thereof wherein R' is hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy or -(CH2)yCOOR1; wherein R2 is COOR1 or an alkyl, optionally substituted with between 1 and 3 double or two triple bonds; wherein B' represents oxygen, sulfur or hydrogen radicals; wherein B'' represents oxygen, sulfur, or two hydrogen radicals; wherein m is between zero and 5 and n is between 1 and 24, inclusive; and wherein y is between zero and three and R1 represents hydrogen or a lower alkyl radical; such that when B' ' is oxygen or sulfur, the R' is not alkyl or hydrogen and y is not zero and when B ' ' is oxygen and B' is two hydrogen radicals, then R' is -(CH2)yCOOR1.
96. A method for improved delivery of plant nutrients comprising contacting a plant with a composition comprising an effective amount of a plant nutrient and an effective delivery-enhancing amount of compound having the structural formula and salts thereof wherein R' is hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy or -(CH2)yCOOR1; wherein R2 is COOR1 or an alkyl, optionally substituted with between 1 and 3 double or two triple bonds; wherein B' represents oxygen, sulfur or hydrogen radicals; wherein B'' represents oxygen, sulfur, or two hydrogen radicals; wherein m is between zero and 5 and n is between 1 and 24, inclusive; and wherein y is between zero and three and R1 represents hydrogen or a lower alkyl radical; such that when B' ' is oxygen or sulfur, the R' is not alkyl or hydrogen and y is not zero and when B' ' is oxygen and B' is two hydrogen radicals, then R' is -(CH2)yCOOR1.
97. A composition comprising an effective amount of a plant nutrient and an effective delivery enhancing amount of a compound having the structural formula
and salts thereof wherein R' is hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy or -(CH2)yCOOR1; wherein R2 is COOR1 or an alkyl, optionally substituted with between 1 and 3 double or two triple bonds; wherein B' represents oxygen, sulfur or hydrogen radicals; wherein B'' represents oxygen, sulfur, or two hydrogen radicals; wherein m is between zero and 5 and n is between 1 and 24, inclusive; and wherein y is between zero and three and R1 represents hydrogen or a lower alkyl radical; such that when B'' is oxygen or sulfur, the R' is not alkyl or hydrogen and y is not zero and when B' ' is oxygen and B' is two hydrogen radicals, then R' is -(CH2)yCOOR1.
98. A method for improved pest control comprising contacting a plant or plant pest with a composition comprising an effective amount of a plant pesticide and an effective delivery-enhancing amount of compound having the structural formula
and salts thereof wherein R' is hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy or -(CH2)yCOOR1; wherein R2 is COOR1 or an alkyl, optionally substituted with between 1 and 3 double or two triple bonds; wherein B' represents oxygen, sulfur or hydrogen radicals; wherein B'' represents oxygen, sulfur, or two hydrogen radicals; wherein m is between zero and 5 and n is between 1 and 24, inclusive; and wherein y is between zero and three and R1 represents hydrogen or a lower alkyl radical; such that when B'' is oxygen or sulfur, the R' is not alkyl or hydrogen and y is not zero and when B ' ' is oxygen and B' is two hydrogen radicals, then R' is -(CH2)yCOOR1.
99. A composition comprising an effective amount of a plant pesticide and an effective delivery-enhancing amount of a compound having the structural formula
and salts thereof wherein R' is hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy or -(CH2)yCOOR1; wherein R2 is COOR1 or an alkyl, optionally substituted with between 1 and 3 double or two triple bonds; wherein B' represents oxygen, sulfur or hydrogen radicals; wherein B'' represents oxygen, sulfur, or two hydrogen radicals; wherein m is between zero and 5 and n is between 1 and 24, inclusive; and wherein y is between zero and three and R1 represents hydrogen or a lower alkyl radical; such that when B'' is oxygen or sulfur, the R' is not alkyl or hydrogen and y is not zero and when B'' is oxygen and B' is two hydrogen radicals, then R' is - (CH2)yCOOR1.
100. A method for improved delivery of plant growth regulators comprising contacting a plant with a composition comprising an effective amount of a plant growth regulator and an effective delivery-enhancing amount of compound having the structural formula
and salts thereof wherein R' is hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy or -(CH2)yCOOR1; wherein R2 is COOR1 or an alkyl, optionally substituted with between 1 and 3 double or two triple bonds; wherein B' represents oxygen, sulfur or hydrogen radicals; wherein B' ' represents oxygen, sulfur, or two hydrogen radicals; wherein m is between zero and 5 and n is between 1 and 24, inclusive; and wherein y is between zero and three and R1 represents hydrogen or a lower alkyl radical; such that when B' ' is oxygen or sulfur, the R' is not alkyl or hydrogen and y is not zero and when B'' is oxygen and B' is two hydrogen radicals, then R' is -(CH2)yCOOR1.
101. A composition comprising an effective amount of plant growth regulator and an effective delivery-enhancing amount of a compound having the structural formula
and salts thereof wherein R' is hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy or -(CH2)yCOOR1; wherein R2 is COOR1 or an alkyl, optionally substituted with between 1 and 3 double or two triple bonds; wherein B' represents oxygen, sulfur or hydrogen radicals; wherein B'' represents oxygen, sulfur, or two hydrogen radicals; wherein m is between zero and 5 and n is between 1 and 24, inclusive; and wherein y is between zero and three and R1 represents hydrogen or a lower alkyl radical; such that when B'' is oxygen or sulfur, the R' is not alkyl or hydrogen and y is not zero and when B'' is oxygen and B' is two hydrogen radicals, then R' is -(CH2)yCOOR1.
AU35616/89A 1988-04-08 1989-04-05 N-dodecyl-pyrrolidone penetration enhancers Ceased AU628344B2 (en)

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JPH11171795A (en) 1999-06-29
JP2965303B2 (en) 1999-10-18
KR900700112A (en) 1990-08-11
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EP0374218A1 (en) 1990-06-27
JPH03500543A (en) 1991-02-07

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