CA1076028A - Vehicle compositions containing 1-n-dodecylazacycloheptan-2-one - Google Patents
Vehicle compositions containing 1-n-dodecylazacycloheptan-2-oneInfo
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- CA1076028A CA1076028A CA255,236A CA255236A CA1076028A CA 1076028 A CA1076028 A CA 1076028A CA 255236 A CA255236 A CA 255236A CA 1076028 A CA1076028 A CA 1076028A
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- physiologically active
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- 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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F5/00—Orthopaedic methods or devices for non-surgical treatment of bones or joints; Nursing devices; Anti-rape devices
- A61F5/41—Devices for promoting penis erection
- A61F2005/415—Devices for promoting penis erection by inflatable means
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- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Communicable Diseases (AREA)
- Rheumatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pain & Pain Management (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
- Cosmetics (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
This invention relates to compositions for carrying physiologi-cally active agents through body membranes. Many physiologically active agents are best applied topically to obtain desirable results. The greatest problem in applying physiologically active agents topically is that the skin is such an effective barrier to penetration. Vehicles such as USP 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 physiologi-cally active agents through the skin. The present invention relates to compositions useful in topically administering a physiologically active agent to a human or animal comprising the agent and an effective, non-toxic amount of a compound having the structural formula Where R' is H or a lower alkyl group having 1-4 carbon atoms, m is 3-7,n is 0-17, and R is -CH3 , or
This invention relates to compositions for carrying physiologi-cally active agents through body membranes. Many physiologically active agents are best applied topically to obtain desirable results. The greatest problem in applying physiologically active agents topically is that the skin is such an effective barrier to penetration. Vehicles such as USP 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 physiologi-cally active agents through the skin. The present invention relates to compositions useful in topically administering a physiologically active agent to a human or animal comprising the agent and an effective, non-toxic amount of a compound having the structural formula Where R' is H or a lower alkyl group having 1-4 carbon atoms, m is 3-7,n is 0-17, and R is -CH3 , or
Description
:~076~Z8 BACKGROUI~D OF THE INVENT ION
Many physiologically active agents are best applied topically to obtain desirable result~. Topical application, as contrasted to sy9temic application, largely avoids side effect~
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 such an effective barrier to penetration. The epidermis of the skin has an exterior layer of dead cells called the stratum corneum which is tightly 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 inflamation, acne, psoriasis, herpes simplex, eczema, infections due to fungus, virus or other microorganisms, or other disorders or 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 repellants and the like.
Physiologically active agents may be applied to locally affected parts of the body through the vehicle system described herein. Vehicles such as USP 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 1076()28 physiologically active agents through the skin. One such vehicle is dimethyl sulfoxide, which is described in United States Patent No. 3,551,554. In this description, the term "animal" includes human beings as well as other forms of animal life, and especially domesticated animals and pets.
The l-lower alkyl substituted azacyclopentan-2-ones having 1-4 carbon atoms are known to moderately enhance percu-taneous absorption of chemicals, e.g. drugs. It would be desirable to obtain the same or higher level of percutaneous absorption with substantially lower concentrations of the -penetration-enhancing compound.
SUMMARY OF THE INVENTION
This invention relates to compositions for carrying physiologically active agents through body membranes such as skin and for retaining these agents in body tissues. More specifically, the invention relates to compositions useful in - topically administering a physiologically active agent to a human or animal, comprising an effective amount of a physiologically active agent and a non-toxic, penetrating amount of 1-n-dodecylazacycloheptan-2-one. This has the structural formula 1~ (CH2 ) 11--CH3 ~076~)Z8 It has been found that the physiologically active agents are carried through body membranes by the claimed vehicles and are retained in body tissue.
The invention further relates to vehicles themselves and their method of making.
DETAILED DESCRIPTIO~ OF THE INVENTION
The claimed l-substituted azacycloalkan-2-ones are made by methods described below and as further described in the Examples. Typical examples of compound included in the foregoing formula are the ~ollowing:
l-n-hexylazacyclopentan-2-one l-n-heptylazacyclopentan-2-one l-n-octylazacyclopentan-2-one l-n-nonylazacyclopentan-2-one l-n-decylazacyclopentan-2-one l-n-dodecylazacyclopentan-2-one l-methylazacycloheptan-2-one l-n-propylazacycloheptan-2-one l-n-butylazacycloheptan-2-one 1-n-pentylazacycloheptan-2-one l-n-h~xylazacycloheptan-2-one l-n-heptylazacycloheptan-2-one l-n-octylazacycloheptan-2-one l-n-nonylazacycloheptan-2-one l-n-decylazacycloheptan-2-one l-n-butylazacyclononan-2-one l-n-octylazacyclononan-2-one l-phenylazacyclopentan-2-one l-benzylazacyclopentan-2-one 1-(2-chlorophenyl)azacyclopentan-2-one 1,3-Bis-(l-azacyclopentan-2-onyl)propane 1,6-Bis-(l-azacyclopentan-2-onyl)hexane The compounds covered by the general formula may be prepared by treating azacycloalkan-2-one with an alkyl or aralkyl halide or mesylate in the presence of a base, e.g. sodium hydride.
The reaction is carried out under anhydrous conditions in a hydrocarbon solvent, for example, dry toluene at reflux temperature - ~0761)28 for about 10 to 72 hours in an inert atmosphere, for example, nitrogen. This method is outlined below:
(CH2 ~ N-H NaH ~ (CH m~ N: ~ Na ~ R-halide~
R-mesylate ~ - .
(cH2)m _~N R
In the above method, substitution of an equimolar ratio of a dibromoalkane in place of an alkyl halide gives Bis-~-azacyclo-alkan-2-onyl alkane.
Alternatively, a lactone of an alkanoic acid may be heated with an alkyl, aryl or aralkyl amine (with or without solvent) for about 20 to 72 hours at about 180-250C with removal of water to obtain the corresponding l-substituted azacycloalkan-2-one as shown below:
R;~ Z) (CH ~ R
Similarly, heating a lactone of an alkanoic acid with a diaminoalkane in a 2.5 to 1 molar ratio gives the bis-N-azacyclo-alkan-2-onyl alkane.
In another method gamma-dialkylaminobutyric acid may be treated with phosphorous trihalide and the resulting acid halide (which need not be isolated) is heated, resulting specifically in the formation of N-alkylazacyclopentan-2-one. Suitable acid halide forming agents include phosphorous trichloride, phosphorous tribromide, thionyl chloride, etc. The acid halide is ormed at room temperature and then the reaction temperature is raised to 70 - 90C. One of the alkyl groups on the amino nitrogen of the parent acid is eliminated as alkyl halide. If the alkyl groups on the amino nitrogen are different, the smaller of the two alkyl groups is eliminated preferentially. This methOd is described below.
~OOH COCl ~H2~3 PC13 ~H2~3 ~ ~ N-Alkyl ~
~-(Alkyl)2 ~-(Alkyl)2 ~ /Alkyl halide The amount of l-substituted azacycloalkan-2-one which may be used in the present invention is an effective, non-toxic amount for enhancing percutaneous absorption. Generally, this amount ranges between about O.Ol to about 5 and preferably about 0.1 to 2 percent by weight of the composition.
The subject compositions may find use with many physio- .
logically active agents which are soluble in the vehicles disclosed.
Fungistatic and fungicidal agents such as, for example, thiabendazole, chloroxine, amphotericin, candicidin, fungimycin, nystatin, chlordantoin, clotrimazole, ethonam nitrate, miconazole nitrate, pyrrolnitrin, salicylic acid, fezatione, ticlatone, tolnaf-tate, triacetin and zinc and sodium pyrithione may be dissolved in the vehicles 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 lor.ger time periods whereby a far more successful treatment is effected.
For example, the subject composition 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 vehicles and applying it to the affected area.
The subject compositions are also useful in treating skin problems, such as for example, herpes simplex, which may be treated by a solution of iododeoxyuridine dissolved in one of the vehicles, or such problems as warts which may be treated with agents such as podophylline dissolved in one of the vehicles. Skin problems such ~076~128 as psoriasis may be treated by topical application of a solution of a conventional topical steroid in one of the vehicles or by treatment with theophylline or antagonists of ~ -adrenergic blockers such as isoprotereno1~ in one of the vehicles. Scalp conditions such as alopecia?areata may be treated more effectively by applying steroids such as triamcinolone acetonide dissolved in one of the vehicles 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; hydrocortisonç, triamcinolone acetonide, indomethacin, or phenylbutazone dissolved in one of the vehicles to the affected area.
Examples of other physiologically active steroids which may be used with ~he vehicles include corticosteroids such as, for example, cortisone, cortodoxonel flucetonide, fludrocortisone, difluorsone diacetate, flurandrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and its esters, chloro-prednisone, clocortelone, descinolone, desonide, dexamethasone, dichlorisone, difluprednate, flucloronide, flumethasone, flunisolide, fluocinonide, flucortolone, fluoromethalone, fluperolone, flupred-nisolone, meprednisone, methylmeprdnisolone, paramethasone, prednisolone 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 sulfonomides, 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.
`" ~0761~28 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 of a sunscreen, such as para-aminobenzoic acid or its well-known derivatives dissolved in one of the vehicles, to skin surfaces that are to be exposed to the sun; and the protective para-aminobenzoic acid or its derivatives will 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 agents which soften collagen, such as amino-proprionitrile or penecillamine dissolved in one of the vehicles of this invention topically to the scar tissue.
Agents normally applied as eye drops, ear drops,or nose drops are more effective when dissolved in the vehicles of this invention.
Agents used in diagnosis may be used more effectively when applied dissolved in one of the vehicles 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 vehicles 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 dihydroxy acetone and the like are more effectively applied to skin to simulate a suntan when they are dissolved in one of the vehicles of this 1076~28 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 vehicles of this invention.
The effectiveness of such topically applied materials as insect repellants or fragrances, such as perfumes and colognes, can be prolonged when such agents are applied dissolved in one of the vehicles 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 vehicles of the present invention may also be used to produce therapeutic effects which were not previously known. That is, by use of the vehicles 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 saturation of the entire body with 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 Xnown any formulation which could be delivered topically which would cause sufficient retention of griseofulvin in the skin to be useful therapeutically.
~0760Z~
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 vehicles described herein.
As a further example, acne ~s 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. hexachloro-phene, and systemic antibiotics such as tetracycline. While thesystemic antibiotic treatment are known to be partially effective, the topical treatments are generally not effective.
5.- It has long been known that systemic treatment of acne is not preferred because of side effects resulting from saturation of the entire body with antibiotics and the fact that only the affected skin ne~d by treated. However, despite a long-fe~;t need for a topical treatment for acne, antibiotics generally have been used only systemi-cally to treat acne because there was not heretofore known an anti-- bacterial formulation which could be used topically which would be effective therapeutically in the treatment of acne. However, it has now been discovered that antibiotics, especially those of the linco-mycin and erythryomycin families of antibiotics, may be used in t~e treatment of acne topically if combined with one of the vehicles described herein.
The antibiotics composition so applied is carried into and through the epidermis and deeper layers of the skin as well as into follicles and comedones (sebum-plugged follicles which contain C. acnes) in therapeutically effective amounts and thereby success-fully 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 ~0760Z~
including physiologically active steroids, antibiotics, anti-fungal agents, antibacterial agents, antineoplastic agents, allergens, antihistaminic agents, anti-inflammatory agents, ultraviolet screening agents, diagnostic agents, perfumes, insect repellants, 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 wich make up the foregoing dosage forms include water, acetone, isopropyl alcohol, freons, ethyl alcohol, polyvinyl pyrrolidone, propylene glycol, fragrances, gel_producing mater~ls, mineral oil, stearyl alcohol, stearic acid, spermaceti, sorbitan monooleate, "Polysorbates", "Tweens", sorbital, methylcellulose, etc.
The amount of the composition, and thus of the physiologically active agent therein, 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 practioner. 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, as in the routine procedure of the physician.
The examples which follow illustrate the vehicles and the compositions of the present invention. Temperatures are given in degrees Centigrade. All reactions involving sodium hydride were carried out in an inert nitrogen atmosphere.
E ~ : Preparation of l_n_Hexylazacyclopentan-2_one having the following structure:
O
~ N- (CH2)5cH3 13.7 g of 50% sodium hydride-mineral oil dispersion (6.85 g NaH, 0.285 M) was placed in a 1 liter flask equipped with an _10-:1076~28 addition funnel, condenser and a mechanical stirrer. This was washed with 2 x 100 ml of petroleum ether and the petroleum ether was decanted. About 250 ml of dry toluene was then added and to this stirred mixture was added dropwise a solution of 20.35 g (0.239 M) of azacyclopentan-2-one in 100 ml of dry toluene. Upon completion of addition the mixture was heated to reflux for 1 hour and then cooled to room temperature. A
solution of 43.6 g (0.264 M) of l-bromohexane in 100 ml of dry toluene was added dropwise for a period of one-half hour and thereafter the mixture was refluxed for 48 hours. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with dry toluene. The combined filtrate was concentrated to a yellow oil. Distillation gave 25.7 g (63.5%) of colorless 1-n-Hexylazacyclopentan-2-one, boiling point 98-102/0.5 mm.
EXAMPLE 2: Preparation of l-n-Heptylazacyclopentan-2-one havina the formula:
o ~ ( 2)6 3 Following example 1, on refluxing 13 g of 50% oil dispersion 20 of sodium hydride (6.5 g ~aH, 0.271 M), 20.35 g (0.239 M) of azacyclopentan-2-one and 47.28 g (0.264 M) of l-bromoheptane in dry toluene for 21 hours was obtained 13.6 g (31%) of colorless oil; boiling point 115-120/0.6 mm.
EXAMPLE 3: Preparation of l-n-Octylazacyclopentan-2-one ~N - (CH2)7-CH3 Following example 1, from 5.44 g of 57% oil dispersion of sodium hydride (3.10 g NaH, 0.13 M), 10 g (0.1174 M) of azacyclopentan-2-one and 25.1 g (0.13 M) of l-bromooctane was obtained 13.6 g (59%) of colorless 1-n-Nonylazacyclopentan-2-one.
30 B.P. 123-132/0.3 mm. -11-~0760Z8 EXAMPLE 4: Preparation of l-n-Nonylazacyclopentan-2-one having the formula:
o ~ N-(CH2)8-CH3 Following example 1, from 5.44 g of 57% sodium hydride-mineral oil dispersion (3.10 g NaH, 0.13 M), 10 g (0.1174 M) of azacyclopentan-2-one and 27 g (0.13 M) of l-bromononane was obtained 13.4 g (56%) of 1-n-Nonylazacyclopentan-2-one, b.p. 139-143/0.5 mm.
EXAMPLE 5: Preparation of l-n-Decylazacyclopentan-2-one having the formula ~ -(CH2)9-CH3 18.8 g (0.22 M) of ~-butyrolactone and 34.6 g (0.22 M) of n-decylamine were mixed and heated to 180 in a round bottom flask equipped with a condenser and a Dean-Stark trap for 22 hours. The dark brown reaction mixture was distilled at reduced pressure to yield 40.9 g (82.5%) of colorless product;
b.p. 150-155/0.5-1 mm.
EXAMPLE 6: Preparation of n-Dodecylazacyclopentan-2-one having the formula ~ N-(CH2)ll CH3 Following example 5, 18.8 g (0.22 M) of v-butyrolactone and 37 g (0.2 M) of n-dodecylamine was heated for 24 hours.
Distillation of the residue gave 40.7 g (80.3%) of l-n-Dodecyl-azacyclopentan-2-one; b.p. 165-170/0.5 mm.
EXAMPLE 7: Preparation of l-Methylazacycloheptan-2-one having the formu ~
~ -CH3 V
~0t76~28 A suspension of 8.42 g of 57% sodium hydride-mineral oil suspension (4.8 g NaH, 0.2 M) was washed with 2 x 400 ml portions of dry toluene and the toluene washings were decanted.
350 ml of dry toluene was added and the suspension was mechanically stirred while a solution of 20 g (0.177 M) of azacycloheptan-2-one in 50 ml of dry toluene was added dropwise over 1 hour. After the addition was over, the mixture was refluxed for 1 hour and then cooled to room temperature.
22.0 g (0.2 M) of methyl mesylate was added dropwise over 1 hour and the reaction mixture was then warmed to 50 for 1 hour. The mixture was cooled,filtered and the filter cake was resuspended in 100 ml of dry toluene and filtered. The combined filtrate was concentrated and the residue was distilled to yield 20 g (88.85%) of 1-Methylazacycloheptan-2-one; b.p. 85-87/0.1 mm.
EXAMPLE 8: Preparation of l-n-propylazacycloheptan-2-one having the formula ~ N (CH2)2 3 In a 1 liter 3-neck flask equipped with a dry ice-isopropanol condenser, an addition funnel and a mechanical stirrer was placed 10.2 g of 50% sodium hydride-mineral oil disperson (5.1 g ~aH, 0.2125 M) and 150 ml of petroleum ether.
The suspension was momentarily stirred and then sodium hydride was allowed to settle. Most of the petroleum ether was pipetted out and 200 ml of dry toluene was added. To this was added dropwise a solution of 20 g (0.177 M) of azacycloheptan-2-one in 100 ml of dry toluene. The mixture was refluxed for 1 hour and then cooled to room temperature. A solution of 30.75 g (0.25 M) of l-bromopropane in 100 ml of dry toluene was added dropwise under stirring. Upon completion of the addition, tlle 10760Z~
mixture was warmed to 80-100 and the temperature was maintained there for 4 hours. Then the isopropanol-dry ice condenser was replaced with a water condenser and the reaction mixture was heated to reflux for 15 hours. The reaction mixture was cooled, filtered and the filtrate was concentrated to a yellow oil. Distillation affprded 22.2 g t81%) of colorless product;
b.p. 83-86~0.25 mm.
EXAMPLE 9: Preparation of l-n-Butylazacycloheptan-2-one having the formula _(CH2)3-CH3 Following example 8, from 12.75 g of 50% sodium hydride-mineral oil dispersion ~6.375 g NaH, 0.266 M), 25 g tO.221 M) of 1 azacycloheptan-2-one and 34.25 g tO.25 M) of l-bromobutane was obtained o-.~ 18 hr. reflux 26.8 g (72~) of colorless product .p. 95-100/0.3 mm.
I
EXAMPLE 10: Prèparation of l_n-Pentylazacycloheptan-2-one having the formula C~N-C~2)4-CH3 Following e~am~le 8 and using water condenser frG-; th~
start of the reaction, 10 g of 50% sodium hydride-mineral oil dispersion tS g NaH, 0.2~ M), 20 g tO.177 M) of azacycloheptan-2-one and 30.2 g (0.2 M) of l-bromopentane on 18 hr. reflux gave 23.3 g t87%) of colorless product; b.p. 110-115/0.3 mm.
EXAMPLE 11: Preparation of l_n-Hexylazacycloheptan_2_one having the formula ~_~< 11 , ~ N-tCH2)5-CH3 i ~ ~, " 1076~)28 Following example 10, from 10.2 g of 50/O sodium hydride-mineral oil dispersion (5.1 g NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 33 g (0.2 M) of 1-bromohexane on 19 hr. reflux was obtained 29.8 g (85.3%) of colorless product;
b.p. 122-128/0.4 mm.
EXAMPLE 12: Preparation of l-n-Heptylazacycloheptan-2-one having the formula ~P
~ N-(CH2)6-CH3 Following example 10, 10.2 g of 50/O sodium hydride-mineral 10 oil dispersion (5.1 g of NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 35.8 g (0.2 M) of l-bromoheptane on 18 hr. reflux gave 33.5 g (90%) of colorless product b.p. 155-158/0.5 mm.
EXAMPLE 13: Preparation of l-n-Octylazacycloheptan-2-one having the formula ~ ` .
-(CH2)7-CH3 Following example 5, heating 17.5 g (0.153 M) of 6-hexanolactone and 22 g (0.17 M) of l-aminooctane at 180 for 29 hr. gave 8.8 g (27%) of product; b.p. 155-160/0.5 mm.
0 EXAMPLE 14: Preparation of l-n-Nonylazacycloheptan-2-one having the formula ~ N-(CH2)8-CH3 Following example 5, heating 22.83 g (0.2 M) of 6-he~ano-lactone and 28.65 g (0.2 M) of l-aminononane at 180 for 20 hours 10~76~Z8 gave 11.5 g (26% ) of product; b.p. 155-165/0.6 mm.
(Higher yields of l-n-Octyl- and l-n-Nonylazacyclo-heptan-2-one may be obtained by use of the sodium hydride method).
EXAMPLE 15: Preparation of l-n-Decylazacycloheptan-2-one having the formula ~ N-(CH2)9-CH3 Following example 10, 10.2 g of 50/O sodium hydride-mineral oil dispersion (5.1 g NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 44.2 g (0.2 M) of l-bromodecane on 19 hr. reflux gave 38 g (84.7%) of product; b.p. 158-163 /0.25-0.3 mm.
EXAMPLE 16: Preparation of l-n-Dodecylazacycloheptan-2-One having the formula ~ -(CH2)11-CH3 Following example 10, 15.3 g of 50% sodium hydride-mineral oil dispersion (7.65 g NaH, 0.319 M), 30 g (0.266 M) of azacyclo-heptan-2-one and 66.1 g (0.265 M) of l-bromododecane on 20 hr.
reflux gave 60 g (80%) of colorless product; b.p. 175-180/0.3 mm.
EXAMPLE 17: Preparation of l-n-Butylazacyclononan-2-one having the formula ~ N
(CH2)7 -(CH2)3-CH3 Following example 10, 16.32 g of 50% sodium hydride-mineral oil dispersion (8.16 g NaH, 0.34 M), 40 g (0.283M) of azacyclononan-2-one and 43 g (0.311M) of l-bromobutane was refluxed for 22 hours. The reaction mixture was diluted with benzene-tolune and was extracted with water. The organic phase was separated, dried and corcentrated to a yellow oil.
Distillation afforded 41.4 g (74%) of product; b.p. 166-170/0.2 mm.
1076~28 EXAMPLE 18: Preparation of l-n-Octylazacyclononan-2-one having the formula (CH2) 7 ~- (CH2) 7 CH3 Following example 17, 4.2 g of 50% sodium hydride-mineral oil dispersion (2.1 g NaH, 0.0875M), 10 g (0.0708M) of azacyclo-nonan-2-one and 15 g (0.0777M) of l-bromooctane gave 12.5 g (70%) of product; b.p. 150-160/0.5 mm.
EXAMPLE 19: Preparation of l-Phenylazacyclopentan-2-one having the formula ~3 !
9.3 g (O.lM) of aniline and 9.5 g (O.llM) of Y-butyro-lactone were mixed and heated to 200 for 48 hours. At the end of the reaction, unreacted starting materials and water were removed at reduced pressure. Distillation of the residue gave 6.3 g (39%) of the product (89% yield based on reclaimed aniline), b.p. 138-140/0.3 mm. Yield in this reaction can be improved if the water formed during the reaction is separated out with or without the use of a solvent (benzene or toluene).
EXAMPLE 20: Preparation of l-Benzylazacyclopentan-2-one having the formula ~ N-CH2 ~
6.97 g (0.06M) of Y-butyrolactone is mixed with 6.97 g (0.065 M) of benzylamine and heated at 190 for 24 hours. Excess benzyl amine and water was distilled off and the residue was distilled to obtain 7.4 g (70%); b.p. 125-130/1 mm.
10~60Z8 EXAMPLE 21: Preparation of 1-(2-chlorophenyl)azacyclopentan-
Many physiologically active agents are best applied topically to obtain desirable result~. Topical application, as contrasted to sy9temic application, largely avoids side effect~
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 such an effective barrier to penetration. The epidermis of the skin has an exterior layer of dead cells called the stratum corneum which is tightly 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 inflamation, acne, psoriasis, herpes simplex, eczema, infections due to fungus, virus or other microorganisms, or other disorders or 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 repellants and the like.
Physiologically active agents may be applied to locally affected parts of the body through the vehicle system described herein. Vehicles such as USP 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 1076()28 physiologically active agents through the skin. One such vehicle is dimethyl sulfoxide, which is described in United States Patent No. 3,551,554. In this description, the term "animal" includes human beings as well as other forms of animal life, and especially domesticated animals and pets.
The l-lower alkyl substituted azacyclopentan-2-ones having 1-4 carbon atoms are known to moderately enhance percu-taneous absorption of chemicals, e.g. drugs. It would be desirable to obtain the same or higher level of percutaneous absorption with substantially lower concentrations of the -penetration-enhancing compound.
SUMMARY OF THE INVENTION
This invention relates to compositions for carrying physiologically active agents through body membranes such as skin and for retaining these agents in body tissues. More specifically, the invention relates to compositions useful in - topically administering a physiologically active agent to a human or animal, comprising an effective amount of a physiologically active agent and a non-toxic, penetrating amount of 1-n-dodecylazacycloheptan-2-one. This has the structural formula 1~ (CH2 ) 11--CH3 ~076~)Z8 It has been found that the physiologically active agents are carried through body membranes by the claimed vehicles and are retained in body tissue.
The invention further relates to vehicles themselves and their method of making.
DETAILED DESCRIPTIO~ OF THE INVENTION
The claimed l-substituted azacycloalkan-2-ones are made by methods described below and as further described in the Examples. Typical examples of compound included in the foregoing formula are the ~ollowing:
l-n-hexylazacyclopentan-2-one l-n-heptylazacyclopentan-2-one l-n-octylazacyclopentan-2-one l-n-nonylazacyclopentan-2-one l-n-decylazacyclopentan-2-one l-n-dodecylazacyclopentan-2-one l-methylazacycloheptan-2-one l-n-propylazacycloheptan-2-one l-n-butylazacycloheptan-2-one 1-n-pentylazacycloheptan-2-one l-n-h~xylazacycloheptan-2-one l-n-heptylazacycloheptan-2-one l-n-octylazacycloheptan-2-one l-n-nonylazacycloheptan-2-one l-n-decylazacycloheptan-2-one l-n-butylazacyclononan-2-one l-n-octylazacyclononan-2-one l-phenylazacyclopentan-2-one l-benzylazacyclopentan-2-one 1-(2-chlorophenyl)azacyclopentan-2-one 1,3-Bis-(l-azacyclopentan-2-onyl)propane 1,6-Bis-(l-azacyclopentan-2-onyl)hexane The compounds covered by the general formula may be prepared by treating azacycloalkan-2-one with an alkyl or aralkyl halide or mesylate in the presence of a base, e.g. sodium hydride.
The reaction is carried out under anhydrous conditions in a hydrocarbon solvent, for example, dry toluene at reflux temperature - ~0761)28 for about 10 to 72 hours in an inert atmosphere, for example, nitrogen. This method is outlined below:
(CH2 ~ N-H NaH ~ (CH m~ N: ~ Na ~ R-halide~
R-mesylate ~ - .
(cH2)m _~N R
In the above method, substitution of an equimolar ratio of a dibromoalkane in place of an alkyl halide gives Bis-~-azacyclo-alkan-2-onyl alkane.
Alternatively, a lactone of an alkanoic acid may be heated with an alkyl, aryl or aralkyl amine (with or without solvent) for about 20 to 72 hours at about 180-250C with removal of water to obtain the corresponding l-substituted azacycloalkan-2-one as shown below:
R;~ Z) (CH ~ R
Similarly, heating a lactone of an alkanoic acid with a diaminoalkane in a 2.5 to 1 molar ratio gives the bis-N-azacyclo-alkan-2-onyl alkane.
In another method gamma-dialkylaminobutyric acid may be treated with phosphorous trihalide and the resulting acid halide (which need not be isolated) is heated, resulting specifically in the formation of N-alkylazacyclopentan-2-one. Suitable acid halide forming agents include phosphorous trichloride, phosphorous tribromide, thionyl chloride, etc. The acid halide is ormed at room temperature and then the reaction temperature is raised to 70 - 90C. One of the alkyl groups on the amino nitrogen of the parent acid is eliminated as alkyl halide. If the alkyl groups on the amino nitrogen are different, the smaller of the two alkyl groups is eliminated preferentially. This methOd is described below.
~OOH COCl ~H2~3 PC13 ~H2~3 ~ ~ N-Alkyl ~
~-(Alkyl)2 ~-(Alkyl)2 ~ /Alkyl halide The amount of l-substituted azacycloalkan-2-one which may be used in the present invention is an effective, non-toxic amount for enhancing percutaneous absorption. Generally, this amount ranges between about O.Ol to about 5 and preferably about 0.1 to 2 percent by weight of the composition.
The subject compositions may find use with many physio- .
logically active agents which are soluble in the vehicles disclosed.
Fungistatic and fungicidal agents such as, for example, thiabendazole, chloroxine, amphotericin, candicidin, fungimycin, nystatin, chlordantoin, clotrimazole, ethonam nitrate, miconazole nitrate, pyrrolnitrin, salicylic acid, fezatione, ticlatone, tolnaf-tate, triacetin and zinc and sodium pyrithione may be dissolved in the vehicles 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 lor.ger time periods whereby a far more successful treatment is effected.
For example, the subject composition 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 vehicles and applying it to the affected area.
The subject compositions are also useful in treating skin problems, such as for example, herpes simplex, which may be treated by a solution of iododeoxyuridine dissolved in one of the vehicles, or such problems as warts which may be treated with agents such as podophylline dissolved in one of the vehicles. Skin problems such ~076~128 as psoriasis may be treated by topical application of a solution of a conventional topical steroid in one of the vehicles or by treatment with theophylline or antagonists of ~ -adrenergic blockers such as isoprotereno1~ in one of the vehicles. Scalp conditions such as alopecia?areata may be treated more effectively by applying steroids such as triamcinolone acetonide dissolved in one of the vehicles 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; hydrocortisonç, triamcinolone acetonide, indomethacin, or phenylbutazone dissolved in one of the vehicles to the affected area.
Examples of other physiologically active steroids which may be used with ~he vehicles include corticosteroids such as, for example, cortisone, cortodoxonel flucetonide, fludrocortisone, difluorsone diacetate, flurandrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and its esters, chloro-prednisone, clocortelone, descinolone, desonide, dexamethasone, dichlorisone, difluprednate, flucloronide, flumethasone, flunisolide, fluocinonide, flucortolone, fluoromethalone, fluperolone, flupred-nisolone, meprednisone, methylmeprdnisolone, paramethasone, prednisolone 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 sulfonomides, 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.
`" ~0761~28 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 of a sunscreen, such as para-aminobenzoic acid or its well-known derivatives dissolved in one of the vehicles, to skin surfaces that are to be exposed to the sun; and the protective para-aminobenzoic acid or its derivatives will 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 agents which soften collagen, such as amino-proprionitrile or penecillamine dissolved in one of the vehicles of this invention topically to the scar tissue.
Agents normally applied as eye drops, ear drops,or nose drops are more effective when dissolved in the vehicles of this invention.
Agents used in diagnosis may be used more effectively when applied dissolved in one of the vehicles 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 vehicles 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 dihydroxy acetone and the like are more effectively applied to skin to simulate a suntan when they are dissolved in one of the vehicles of this 1076~28 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 vehicles of this invention.
The effectiveness of such topically applied materials as insect repellants or fragrances, such as perfumes and colognes, can be prolonged when such agents are applied dissolved in one of the vehicles 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 vehicles of the present invention may also be used to produce therapeutic effects which were not previously known. That is, by use of the vehicles 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 saturation of the entire body with 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 Xnown any formulation which could be delivered topically which would cause sufficient retention of griseofulvin in the skin to be useful therapeutically.
~0760Z~
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 vehicles described herein.
As a further example, acne ~s 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. hexachloro-phene, and systemic antibiotics such as tetracycline. While thesystemic antibiotic treatment are known to be partially effective, the topical treatments are generally not effective.
5.- It has long been known that systemic treatment of acne is not preferred because of side effects resulting from saturation of the entire body with antibiotics and the fact that only the affected skin ne~d by treated. However, despite a long-fe~;t need for a topical treatment for acne, antibiotics generally have been used only systemi-cally to treat acne because there was not heretofore known an anti-- bacterial formulation which could be used topically which would be effective therapeutically in the treatment of acne. However, it has now been discovered that antibiotics, especially those of the linco-mycin and erythryomycin families of antibiotics, may be used in t~e treatment of acne topically if combined with one of the vehicles described herein.
The antibiotics composition so applied is carried into and through the epidermis and deeper layers of the skin as well as into follicles and comedones (sebum-plugged follicles which contain C. acnes) in therapeutically effective amounts and thereby success-fully 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 ~0760Z~
including physiologically active steroids, antibiotics, anti-fungal agents, antibacterial agents, antineoplastic agents, allergens, antihistaminic agents, anti-inflammatory agents, ultraviolet screening agents, diagnostic agents, perfumes, insect repellants, 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 wich make up the foregoing dosage forms include water, acetone, isopropyl alcohol, freons, ethyl alcohol, polyvinyl pyrrolidone, propylene glycol, fragrances, gel_producing mater~ls, mineral oil, stearyl alcohol, stearic acid, spermaceti, sorbitan monooleate, "Polysorbates", "Tweens", sorbital, methylcellulose, etc.
The amount of the composition, and thus of the physiologically active agent therein, 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 practioner. 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, as in the routine procedure of the physician.
The examples which follow illustrate the vehicles and the compositions of the present invention. Temperatures are given in degrees Centigrade. All reactions involving sodium hydride were carried out in an inert nitrogen atmosphere.
E ~ : Preparation of l_n_Hexylazacyclopentan-2_one having the following structure:
O
~ N- (CH2)5cH3 13.7 g of 50% sodium hydride-mineral oil dispersion (6.85 g NaH, 0.285 M) was placed in a 1 liter flask equipped with an _10-:1076~28 addition funnel, condenser and a mechanical stirrer. This was washed with 2 x 100 ml of petroleum ether and the petroleum ether was decanted. About 250 ml of dry toluene was then added and to this stirred mixture was added dropwise a solution of 20.35 g (0.239 M) of azacyclopentan-2-one in 100 ml of dry toluene. Upon completion of addition the mixture was heated to reflux for 1 hour and then cooled to room temperature. A
solution of 43.6 g (0.264 M) of l-bromohexane in 100 ml of dry toluene was added dropwise for a period of one-half hour and thereafter the mixture was refluxed for 48 hours. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with dry toluene. The combined filtrate was concentrated to a yellow oil. Distillation gave 25.7 g (63.5%) of colorless 1-n-Hexylazacyclopentan-2-one, boiling point 98-102/0.5 mm.
EXAMPLE 2: Preparation of l-n-Heptylazacyclopentan-2-one havina the formula:
o ~ ( 2)6 3 Following example 1, on refluxing 13 g of 50% oil dispersion 20 of sodium hydride (6.5 g ~aH, 0.271 M), 20.35 g (0.239 M) of azacyclopentan-2-one and 47.28 g (0.264 M) of l-bromoheptane in dry toluene for 21 hours was obtained 13.6 g (31%) of colorless oil; boiling point 115-120/0.6 mm.
EXAMPLE 3: Preparation of l-n-Octylazacyclopentan-2-one ~N - (CH2)7-CH3 Following example 1, from 5.44 g of 57% oil dispersion of sodium hydride (3.10 g NaH, 0.13 M), 10 g (0.1174 M) of azacyclopentan-2-one and 25.1 g (0.13 M) of l-bromooctane was obtained 13.6 g (59%) of colorless 1-n-Nonylazacyclopentan-2-one.
30 B.P. 123-132/0.3 mm. -11-~0760Z8 EXAMPLE 4: Preparation of l-n-Nonylazacyclopentan-2-one having the formula:
o ~ N-(CH2)8-CH3 Following example 1, from 5.44 g of 57% sodium hydride-mineral oil dispersion (3.10 g NaH, 0.13 M), 10 g (0.1174 M) of azacyclopentan-2-one and 27 g (0.13 M) of l-bromononane was obtained 13.4 g (56%) of 1-n-Nonylazacyclopentan-2-one, b.p. 139-143/0.5 mm.
EXAMPLE 5: Preparation of l-n-Decylazacyclopentan-2-one having the formula ~ -(CH2)9-CH3 18.8 g (0.22 M) of ~-butyrolactone and 34.6 g (0.22 M) of n-decylamine were mixed and heated to 180 in a round bottom flask equipped with a condenser and a Dean-Stark trap for 22 hours. The dark brown reaction mixture was distilled at reduced pressure to yield 40.9 g (82.5%) of colorless product;
b.p. 150-155/0.5-1 mm.
EXAMPLE 6: Preparation of n-Dodecylazacyclopentan-2-one having the formula ~ N-(CH2)ll CH3 Following example 5, 18.8 g (0.22 M) of v-butyrolactone and 37 g (0.2 M) of n-dodecylamine was heated for 24 hours.
Distillation of the residue gave 40.7 g (80.3%) of l-n-Dodecyl-azacyclopentan-2-one; b.p. 165-170/0.5 mm.
EXAMPLE 7: Preparation of l-Methylazacycloheptan-2-one having the formu ~
~ -CH3 V
~0t76~28 A suspension of 8.42 g of 57% sodium hydride-mineral oil suspension (4.8 g NaH, 0.2 M) was washed with 2 x 400 ml portions of dry toluene and the toluene washings were decanted.
350 ml of dry toluene was added and the suspension was mechanically stirred while a solution of 20 g (0.177 M) of azacycloheptan-2-one in 50 ml of dry toluene was added dropwise over 1 hour. After the addition was over, the mixture was refluxed for 1 hour and then cooled to room temperature.
22.0 g (0.2 M) of methyl mesylate was added dropwise over 1 hour and the reaction mixture was then warmed to 50 for 1 hour. The mixture was cooled,filtered and the filter cake was resuspended in 100 ml of dry toluene and filtered. The combined filtrate was concentrated and the residue was distilled to yield 20 g (88.85%) of 1-Methylazacycloheptan-2-one; b.p. 85-87/0.1 mm.
EXAMPLE 8: Preparation of l-n-propylazacycloheptan-2-one having the formula ~ N (CH2)2 3 In a 1 liter 3-neck flask equipped with a dry ice-isopropanol condenser, an addition funnel and a mechanical stirrer was placed 10.2 g of 50% sodium hydride-mineral oil disperson (5.1 g ~aH, 0.2125 M) and 150 ml of petroleum ether.
The suspension was momentarily stirred and then sodium hydride was allowed to settle. Most of the petroleum ether was pipetted out and 200 ml of dry toluene was added. To this was added dropwise a solution of 20 g (0.177 M) of azacycloheptan-2-one in 100 ml of dry toluene. The mixture was refluxed for 1 hour and then cooled to room temperature. A solution of 30.75 g (0.25 M) of l-bromopropane in 100 ml of dry toluene was added dropwise under stirring. Upon completion of the addition, tlle 10760Z~
mixture was warmed to 80-100 and the temperature was maintained there for 4 hours. Then the isopropanol-dry ice condenser was replaced with a water condenser and the reaction mixture was heated to reflux for 15 hours. The reaction mixture was cooled, filtered and the filtrate was concentrated to a yellow oil. Distillation affprded 22.2 g t81%) of colorless product;
b.p. 83-86~0.25 mm.
EXAMPLE 9: Preparation of l-n-Butylazacycloheptan-2-one having the formula _(CH2)3-CH3 Following example 8, from 12.75 g of 50% sodium hydride-mineral oil dispersion ~6.375 g NaH, 0.266 M), 25 g tO.221 M) of 1 azacycloheptan-2-one and 34.25 g tO.25 M) of l-bromobutane was obtained o-.~ 18 hr. reflux 26.8 g (72~) of colorless product .p. 95-100/0.3 mm.
I
EXAMPLE 10: Prèparation of l_n-Pentylazacycloheptan-2-one having the formula C~N-C~2)4-CH3 Following e~am~le 8 and using water condenser frG-; th~
start of the reaction, 10 g of 50% sodium hydride-mineral oil dispersion tS g NaH, 0.2~ M), 20 g tO.177 M) of azacycloheptan-2-one and 30.2 g (0.2 M) of l-bromopentane on 18 hr. reflux gave 23.3 g t87%) of colorless product; b.p. 110-115/0.3 mm.
EXAMPLE 11: Preparation of l_n-Hexylazacycloheptan_2_one having the formula ~_~< 11 , ~ N-tCH2)5-CH3 i ~ ~, " 1076~)28 Following example 10, from 10.2 g of 50/O sodium hydride-mineral oil dispersion (5.1 g NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 33 g (0.2 M) of 1-bromohexane on 19 hr. reflux was obtained 29.8 g (85.3%) of colorless product;
b.p. 122-128/0.4 mm.
EXAMPLE 12: Preparation of l-n-Heptylazacycloheptan-2-one having the formula ~P
~ N-(CH2)6-CH3 Following example 10, 10.2 g of 50/O sodium hydride-mineral 10 oil dispersion (5.1 g of NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 35.8 g (0.2 M) of l-bromoheptane on 18 hr. reflux gave 33.5 g (90%) of colorless product b.p. 155-158/0.5 mm.
EXAMPLE 13: Preparation of l-n-Octylazacycloheptan-2-one having the formula ~ ` .
-(CH2)7-CH3 Following example 5, heating 17.5 g (0.153 M) of 6-hexanolactone and 22 g (0.17 M) of l-aminooctane at 180 for 29 hr. gave 8.8 g (27%) of product; b.p. 155-160/0.5 mm.
0 EXAMPLE 14: Preparation of l-n-Nonylazacycloheptan-2-one having the formula ~ N-(CH2)8-CH3 Following example 5, heating 22.83 g (0.2 M) of 6-he~ano-lactone and 28.65 g (0.2 M) of l-aminononane at 180 for 20 hours 10~76~Z8 gave 11.5 g (26% ) of product; b.p. 155-165/0.6 mm.
(Higher yields of l-n-Octyl- and l-n-Nonylazacyclo-heptan-2-one may be obtained by use of the sodium hydride method).
EXAMPLE 15: Preparation of l-n-Decylazacycloheptan-2-one having the formula ~ N-(CH2)9-CH3 Following example 10, 10.2 g of 50/O sodium hydride-mineral oil dispersion (5.1 g NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 44.2 g (0.2 M) of l-bromodecane on 19 hr. reflux gave 38 g (84.7%) of product; b.p. 158-163 /0.25-0.3 mm.
EXAMPLE 16: Preparation of l-n-Dodecylazacycloheptan-2-One having the formula ~ -(CH2)11-CH3 Following example 10, 15.3 g of 50% sodium hydride-mineral oil dispersion (7.65 g NaH, 0.319 M), 30 g (0.266 M) of azacyclo-heptan-2-one and 66.1 g (0.265 M) of l-bromododecane on 20 hr.
reflux gave 60 g (80%) of colorless product; b.p. 175-180/0.3 mm.
EXAMPLE 17: Preparation of l-n-Butylazacyclononan-2-one having the formula ~ N
(CH2)7 -(CH2)3-CH3 Following example 10, 16.32 g of 50% sodium hydride-mineral oil dispersion (8.16 g NaH, 0.34 M), 40 g (0.283M) of azacyclononan-2-one and 43 g (0.311M) of l-bromobutane was refluxed for 22 hours. The reaction mixture was diluted with benzene-tolune and was extracted with water. The organic phase was separated, dried and corcentrated to a yellow oil.
Distillation afforded 41.4 g (74%) of product; b.p. 166-170/0.2 mm.
1076~28 EXAMPLE 18: Preparation of l-n-Octylazacyclononan-2-one having the formula (CH2) 7 ~- (CH2) 7 CH3 Following example 17, 4.2 g of 50% sodium hydride-mineral oil dispersion (2.1 g NaH, 0.0875M), 10 g (0.0708M) of azacyclo-nonan-2-one and 15 g (0.0777M) of l-bromooctane gave 12.5 g (70%) of product; b.p. 150-160/0.5 mm.
EXAMPLE 19: Preparation of l-Phenylazacyclopentan-2-one having the formula ~3 !
9.3 g (O.lM) of aniline and 9.5 g (O.llM) of Y-butyro-lactone were mixed and heated to 200 for 48 hours. At the end of the reaction, unreacted starting materials and water were removed at reduced pressure. Distillation of the residue gave 6.3 g (39%) of the product (89% yield based on reclaimed aniline), b.p. 138-140/0.3 mm. Yield in this reaction can be improved if the water formed during the reaction is separated out with or without the use of a solvent (benzene or toluene).
EXAMPLE 20: Preparation of l-Benzylazacyclopentan-2-one having the formula ~ N-CH2 ~
6.97 g (0.06M) of Y-butyrolactone is mixed with 6.97 g (0.065 M) of benzylamine and heated at 190 for 24 hours. Excess benzyl amine and water was distilled off and the residue was distilled to obtain 7.4 g (70%); b.p. 125-130/1 mm.
10~60Z8 EXAMPLE 21: Preparation of 1-(2-chlorophenyl)azacyclopentan-
2-one having the formula ~ N ~
Following example 19, 12.57 g (O.lM) of 2_chloroaniline and 9.5 g (O.llM) of y-butyrolactone were heated for 48lhours.
The excess starging materials were removed at 50-80/0.3 mm.
Distillation of the residue gave 4.9 g.(25%) of proruct (45%
based on recovered 2?chloroaniline); b.p. 150-155/0.3-0.4 mm.
EXAMPLE 22: Preparation of 1,3-Bis(l-azacycl~pentan-2_onyl) propane having the f*~mula ~0 ~
~N-CH2-CH2 -CH2-~
To 11.0 g of 57% sodium hydride_mineral oil suspension (6.27 g NaH, 0.261M) was added 150 ml of dry toluene and this was stirred for a few m~nutes. Toluene was decanted and 150 ml of fresh dry toluene was added. 20 g (0.235M) of azacyclopentan-2-one was added dropwise over 1 hour and after the addition was over the mixture was refluxed for 1 hour. 22~3 g (O.liM) of 1,3-dibromopropane was added ~r~pwise over three hours. The refluxing was continued for 72 hours and then the reaction mixture was cooled and filtered twice, the second time through celite. The filtrate was concentrated and the residue was dist~iled to obtain 8.2 g (35.4~) of product; b.p. 179-180/0.03 mm.
EXAMPLE 23: Preparation of 1,6_Bis-tl-azacyclopentan_2-onyl) hexane having the formula 0 ~ ~
4N-(CH2)fi \J
11.62 g (O.lM) of 1,6-diaminohexane and 21.66 g (0.25M) of ~-butyrolactone were mixed and he~ted to 150-165 for 22 hours.
Excess ~-butyrolactone was then distilled off at reduced pressure _18-l ~y: ~
iO76C~28 (80/2 mm). The light brown residue was poured into a crystallization dish where it immediately solidified. The solid was taken in chloroform, powdered, filtered and the tan powder was washed with chloroform. Yield 22.0 g (87%);
melting point 101-103.
EXAMPLE 24: The following solution formulation is prepared:
Solution (%) Griseofulvin l-n-dodecylazacycloheptan-2-one Isopropyl myristate 5 Fragrance 0.1 ` Ethanol 92.9 This formulation is effective in the treatment of fungus infections.
EXAMPLE 25: An aerosol form of the formulation of Example 24 is ` prepared by preparing the following mixture:
Formulation 25%
Freonl(Trade Mhrk) 75%
i8 75/25 Freon 114/12. ~Trade Mark) r . ~
EXAMPLE 26: The following cream formulation s prepared:
~' Clindamycin (base 1.0 Stearyl alcohol, U.S.P.12.0 Ethoxylated cholestrol0.4 Synthetic spermaceti 7.5 Sorbitan monooleate 1.0 Polysorbate 80, U.S.P.3.0 l-n-dodecylazacycloheptan-2-one 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.
1~76~Z8 EXAMPLE 27: The following solution formulations are prepared:
A(%) B(%) Clindamycin base - 1.0 Clindamycin phosphate acid 1.3 Sodium hydroxide 0.077 1.0 Molar hydrochloric acid - 2.27 Disodium edetate.2H2O 0.003 0.003 Fragrances 0.5 0.5 l-n~dodecylazacycloheptan-2-one 1.0 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 28: The following solution formulation is prepared:
%
~eomycin sulfate 0.5 ~\ Lidocaine 0.5 Hydrocortisone 0.25 ;
l-n-dodecylazacycloheptan-2-one 0.5 Propylene glycol 98.25 This solution is effective for the treatment of otitis in domestic animals.
EXAMPLE 29: The following sunscreen emulsion is prepared:
:` %
p-amino benzoic acid 2.0 Benzyl alcohol 0.5 l-n-dodecylazacycloheptan-2-one 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 1076~28 EXAMPLE 30: The following antineoplastic solution is prepared:
%
5-Fluorouracil 5 l-n-dodecylazacycloheptan-2-one 0.1 Polyethylene glycol 5 Purified water 89.9 EXAMPLE 31: The following insect repellant atomizing spray is prepared:
: %
Diethyltoluamide 0.1 ~ l-n-dodecylazacycloheptan-2-one 0.1 Ethanol 99.8 EXAMPLE 32: 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 Propylene glycol 10 Sodium lauryl sulfate 15 l-n-dodecylazacycloheptan-2-one 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 inflammed 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 inflammed 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.
~076~28 EXAMPLE 33: Examples 24-32 are repeated, except the l-n-dodecylazacycloheptan-2-one is replaced with an equal amount of each of the following compounds:
l-n-hexylazacyclopentan-2-one l-n-heptylazacyclopentan-2-one l-n-octylazacyclopentan-2-one l-n-nonylazacyclopentan-2-one l-n-decylazacyclopentan-2-one l-n-dodecylazacyclopentan-2-one 1-methylazacycloheptan-2-one 1-n-propylazacycloheptan-2-one 1-n-butylazacycloheptan-2-one l-n-pentylazacycloheptan-2-one l-n-hexylazacycloheptan-2-one ;~
l-n-heptylazacycloheptan-2-one 1-n-octylazacycloheptan-2-one l-n-nonylazacycloheptan-2-one l-n-decylazacycloheptan-2-one l-n-butylazacyclononan-2-one 1-n-octylazacyclononan-2-one l-phenylazacyclopentan-2-one l-benzylazacyclopentan-2-one 1-(2-chlorophenyl)azacyclopentan-2-one 1,3-Bis-(l-azacyclopentan-2-onyl)propane 1,6-Bis-(l-azacyclopentan-2-onyl)hexane ~i Comparable results are obtained.
:
~\
Following example 19, 12.57 g (O.lM) of 2_chloroaniline and 9.5 g (O.llM) of y-butyrolactone were heated for 48lhours.
The excess starging materials were removed at 50-80/0.3 mm.
Distillation of the residue gave 4.9 g.(25%) of proruct (45%
based on recovered 2?chloroaniline); b.p. 150-155/0.3-0.4 mm.
EXAMPLE 22: Preparation of 1,3-Bis(l-azacycl~pentan-2_onyl) propane having the f*~mula ~0 ~
~N-CH2-CH2 -CH2-~
To 11.0 g of 57% sodium hydride_mineral oil suspension (6.27 g NaH, 0.261M) was added 150 ml of dry toluene and this was stirred for a few m~nutes. Toluene was decanted and 150 ml of fresh dry toluene was added. 20 g (0.235M) of azacyclopentan-2-one was added dropwise over 1 hour and after the addition was over the mixture was refluxed for 1 hour. 22~3 g (O.liM) of 1,3-dibromopropane was added ~r~pwise over three hours. The refluxing was continued for 72 hours and then the reaction mixture was cooled and filtered twice, the second time through celite. The filtrate was concentrated and the residue was dist~iled to obtain 8.2 g (35.4~) of product; b.p. 179-180/0.03 mm.
EXAMPLE 23: Preparation of 1,6_Bis-tl-azacyclopentan_2-onyl) hexane having the formula 0 ~ ~
4N-(CH2)fi \J
11.62 g (O.lM) of 1,6-diaminohexane and 21.66 g (0.25M) of ~-butyrolactone were mixed and he~ted to 150-165 for 22 hours.
Excess ~-butyrolactone was then distilled off at reduced pressure _18-l ~y: ~
iO76C~28 (80/2 mm). The light brown residue was poured into a crystallization dish where it immediately solidified. The solid was taken in chloroform, powdered, filtered and the tan powder was washed with chloroform. Yield 22.0 g (87%);
melting point 101-103.
EXAMPLE 24: The following solution formulation is prepared:
Solution (%) Griseofulvin l-n-dodecylazacycloheptan-2-one Isopropyl myristate 5 Fragrance 0.1 ` Ethanol 92.9 This formulation is effective in the treatment of fungus infections.
EXAMPLE 25: An aerosol form of the formulation of Example 24 is ` prepared by preparing the following mixture:
Formulation 25%
Freonl(Trade Mhrk) 75%
i8 75/25 Freon 114/12. ~Trade Mark) r . ~
EXAMPLE 26: The following cream formulation s prepared:
~' Clindamycin (base 1.0 Stearyl alcohol, U.S.P.12.0 Ethoxylated cholestrol0.4 Synthetic spermaceti 7.5 Sorbitan monooleate 1.0 Polysorbate 80, U.S.P.3.0 l-n-dodecylazacycloheptan-2-one 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.
1~76~Z8 EXAMPLE 27: The following solution formulations are prepared:
A(%) B(%) Clindamycin base - 1.0 Clindamycin phosphate acid 1.3 Sodium hydroxide 0.077 1.0 Molar hydrochloric acid - 2.27 Disodium edetate.2H2O 0.003 0.003 Fragrances 0.5 0.5 l-n~dodecylazacycloheptan-2-one 1.0 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 28: The following solution formulation is prepared:
%
~eomycin sulfate 0.5 ~\ Lidocaine 0.5 Hydrocortisone 0.25 ;
l-n-dodecylazacycloheptan-2-one 0.5 Propylene glycol 98.25 This solution is effective for the treatment of otitis in domestic animals.
EXAMPLE 29: The following sunscreen emulsion is prepared:
:` %
p-amino benzoic acid 2.0 Benzyl alcohol 0.5 l-n-dodecylazacycloheptan-2-one 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 1076~28 EXAMPLE 30: The following antineoplastic solution is prepared:
%
5-Fluorouracil 5 l-n-dodecylazacycloheptan-2-one 0.1 Polyethylene glycol 5 Purified water 89.9 EXAMPLE 31: The following insect repellant atomizing spray is prepared:
: %
Diethyltoluamide 0.1 ~ l-n-dodecylazacycloheptan-2-one 0.1 Ethanol 99.8 EXAMPLE 32: 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 Propylene glycol 10 Sodium lauryl sulfate 15 l-n-dodecylazacycloheptan-2-one 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 inflammed 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 inflammed 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.
~076~28 EXAMPLE 33: Examples 24-32 are repeated, except the l-n-dodecylazacycloheptan-2-one is replaced with an equal amount of each of the following compounds:
l-n-hexylazacyclopentan-2-one l-n-heptylazacyclopentan-2-one l-n-octylazacyclopentan-2-one l-n-nonylazacyclopentan-2-one l-n-decylazacyclopentan-2-one l-n-dodecylazacyclopentan-2-one 1-methylazacycloheptan-2-one 1-n-propylazacycloheptan-2-one 1-n-butylazacycloheptan-2-one l-n-pentylazacycloheptan-2-one l-n-hexylazacycloheptan-2-one ;~
l-n-heptylazacycloheptan-2-one 1-n-octylazacycloheptan-2-one l-n-nonylazacycloheptan-2-one l-n-decylazacycloheptan-2-one l-n-butylazacyclononan-2-one 1-n-octylazacyclononan-2-one l-phenylazacyclopentan-2-one l-benzylazacyclopentan-2-one 1-(2-chlorophenyl)azacyclopentan-2-one 1,3-Bis-(l-azacyclopentan-2-onyl)propane 1,6-Bis-(l-azacyclopentan-2-onyl)hexane ~i Comparable results are obtained.
:
~\
Claims (8)
1. A composition useful for topically administering a physio-logical agent to a human or animal, comprising an effective amount of a physiologically active agent and a non-toxic, penetrating amount of l-n-dodecylazacycloheptan-2-one .
2. The composition of Claim 1, wherein the physiologically active agent is an antibacterial agent.
3. The composition of Claim 2, wherein the antibacterial agent is an antibiotic.
4. The composition of Claim 3, wherein the antibiotic is selected from the group consisting of lincomycin, clindamycin, erthromycin and pharmaceutically useful salts thereof.
5. The composition of Claim 1, wherein the physiologically active agent is a physiologically active steroid.
6. The composition of Claim 1, wherein the physiologically active agent is an antigungal agent.
7. The composition of Claim 1, wherein the physiologically active agent is iododeoxyuridine.
8. The composition of Claim 1, wherein the physiologically active agent is 5-fluorouracil.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US58823475A | 1975-06-19 | 1975-06-19 | |
| US05/588,248 US3989815A (en) | 1975-06-19 | 1975-06-19 | Novel N-bis-azacyclopentan-2-onyl alkanes |
| US05/588,247 US3989816A (en) | 1975-06-19 | 1975-06-19 | Vehicle composition containing 1-substituted azacycloheptan-2-ones |
| US05/588,235 US3991203A (en) | 1975-06-19 | 1975-06-19 | Vehicle composition containing 1-substituted azacyclopentan-2-ones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1076028A true CA1076028A (en) | 1980-04-22 |
Family
ID=27504982
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA255,236A Expired CA1076028A (en) | 1975-06-19 | 1976-06-18 | Vehicle compositions containing 1-n-dodecylazacycloheptan-2-one |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS6037092B2 (en) |
| AU (1) | AU504943B2 (en) |
| CA (1) | CA1076028A (en) |
| DE (1) | DE2627772A1 (en) |
| FR (1) | FR2314731A1 (en) |
| GB (1) | GB1553309A (en) |
| IE (1) | IE43241B1 (en) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4525199A (en) * | 1981-05-04 | 1985-06-25 | Nelson Research & Development Co. | Method of improved pest control |
| US4405616A (en) * | 1975-06-19 | 1983-09-20 | Nelson Research & Development Company | Penetration enhancers for transdermal drug delivery of systemic agents |
| JPS536327A (en) * | 1976-07-08 | 1978-01-20 | Mizusawa Industrial Chem | Waterrresistant gypsum cureemolding structure |
| JPS5995212A (en) * | 1982-11-23 | 1984-06-01 | Nitto Electric Ind Co Ltd | Base composition and pharmaceutical composition for external use |
| LU84514A1 (en) * | 1982-12-09 | 1984-10-22 | Oreal | STABLE COMPOSITION FOR LOCAL CORTICOTHERAPY CONTAINING HYDROCORTISONE IN SOLUBILIZED CONDITIONS |
| US4557934A (en) * | 1983-06-21 | 1985-12-10 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions containing 1-dodecyl-azacycloheptan-2-one |
| US4537776A (en) * | 1983-06-21 | 1985-08-27 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions containing N-(2-hydroxyethyl) pyrrolidone |
| JPH0627074B2 (en) * | 1984-07-25 | 1994-04-13 | 日東電工株式会社 | Pharmaceutical composition |
| JPS61130207A (en) * | 1984-11-30 | 1986-06-18 | Sunstar Inc | Hair tonic agent |
| CA1331137C (en) * | 1988-02-29 | 1994-08-02 | Pfizer, Inc. | Transdermal flux enhancing compositions |
| JPH0742214B2 (en) * | 1990-07-04 | 1995-05-10 | 花王株式会社 | Hair treatment composition |
| JPH0742213B2 (en) * | 1990-07-04 | 1995-05-10 | 花王株式会社 | Hair treatment composition |
| JPH0742215B2 (en) * | 1990-07-04 | 1995-05-10 | 花王株式会社 | Hair treatment composition |
| US6284754B1 (en) | 1992-01-20 | 2001-09-04 | Schwarz Pharma Ag | Pharmaceutical compositions containing 1-oleylazacycloheptan-2-one as enhancing agent of transport across biological membranes |
| DE69330388T2 (en) * | 1992-12-31 | 2002-01-03 | Sunkyong Ind Ltd | PHARMACEUTICAL COMPOSITIONS WITH IMPROVED PERCUTANEOUS ABSORPTION FOR PIROXICAM |
| DE4341572C1 (en) * | 1993-12-07 | 1995-06-22 | Univ Dresden Tech | Timing belt transmission |
| DE19641437A1 (en) * | 1996-10-08 | 1998-04-09 | Basf Ag | 1,3-bis (N-lactamyl) propanes and their pharmaceutical and cosmetic use |
| WO2005115990A1 (en) | 2004-05-26 | 2005-12-08 | Eisai R & D Management Co., Ltd. | Cinnamide compound |
| CN100577657C (en) | 2004-10-26 | 2010-01-06 | 卫材R&D管理有限公司 | Amorphous object of cinnamide compound |
| JP4504210B2 (en) * | 2005-01-25 | 2010-07-14 | 花王株式会社 | Hair dye composition |
| US20090270623A1 (en) * | 2005-11-18 | 2009-10-29 | Naoyuki Shimomura | Process for production of cinnamide derivative |
| TWI378091B (en) | 2006-03-09 | 2012-12-01 | Eisai R&D Man Co Ltd | Multi-cyclic cinnamide derivatives |
| TW200848054A (en) | 2007-02-28 | 2008-12-16 | Eisai R&D Man Co Ltd | Two cyclic oxomorpholine derivatives |
| EP2116266A1 (en) | 2007-03-01 | 2009-11-11 | Cosmed Pharmaceutical Co., Ltd. | Percutaneously absorbable preparation, process for production thereof and method for percutaneous absorption |
| KR20100055456A (en) | 2007-08-31 | 2010-05-26 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | Polycyclic compound |
| US7935815B2 (en) | 2007-08-31 | 2011-05-03 | Eisai R&D Management Co., Ltd. | Imidazoyl pyridine compounds and salts thereof |
| JP2012020991A (en) | 2010-06-16 | 2012-02-02 | Takasago Internatl Corp | Transdermal absorption promoter, and external skin formulation thereof |
| EP3395368A1 (en) | 2014-10-30 | 2018-10-31 | Asahi Kasei Kabushiki Kaisha | Transdermal absorption enhancer and transdermal absorption enhancement aid |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE859016C (en) * | 1944-07-06 | 1952-12-11 | Basf Ag | Process for the preparation of N-substituted lactams |
| DE1053736B (en) * | 1956-03-02 | 1959-03-26 | Konink Nl Gist & Spiritusfabri | Process to increase the solubility of therapeutically active substances in water |
| DE1192208B (en) * | 1960-05-13 | 1965-05-06 | Basf Ag | Process for the production of lactams |
| US3268397A (en) * | 1963-10-04 | 1966-08-23 | Gen Aniline & Film Corp | Method of controlling nematodes with nu-(branched-chained-alkyl) lactams |
| FR2001768A1 (en) * | 1968-02-12 | 1969-10-03 | Gillette Co | N-Alkyl-2-pyrrolidone to improve cutaneous absorption - methyl, ethyl and n-butyl pyrrolidone(s), opt. with water and/or ethanol give improved skin penetration |
| CA1003847A (en) * | 1971-10-29 | 1977-01-18 | G A F Corporation | Low molecular weight complexes of lactams and phenolic compounds |
| CH573404A5 (en) * | 1972-07-28 | 1976-03-15 | Inventa Ag |
-
1976
- 1976-06-16 FR FR7618273A patent/FR2314731A1/en active Granted
- 1976-06-17 GB GB25035/76A patent/GB1553309A/en not_active Expired
- 1976-06-18 CA CA255,236A patent/CA1076028A/en not_active Expired
- 1976-06-18 IE IE1330/76A patent/IE43241B1/en not_active IP Right Cessation
- 1976-06-18 AU AU15063/76A patent/AU504943B2/en not_active Expired
- 1976-06-18 DE DE19762627772 patent/DE2627772A1/en active Granted
- 1976-06-19 JP JP51072683A patent/JPS6037092B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2314731A1 (en) | 1977-01-14 |
| JPS6037092B2 (en) | 1985-08-24 |
| IE43241L (en) | 1976-12-19 |
| IE43241B1 (en) | 1981-01-14 |
| AU504943B2 (en) | 1979-11-01 |
| FR2314731B1 (en) | 1978-11-03 |
| DE2627772A1 (en) | 1976-12-30 |
| JPS521035A (en) | 1977-01-06 |
| GB1553309A (en) | 1979-09-26 |
| DE2627772C2 (en) | 1991-04-25 |
| AU1506376A (en) | 1977-12-22 |
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