Note: Descriptions are shown in the official language in which they were submitted.
:~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.
1076028
~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
--5--
~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
--7--
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
~ ~,
-14--
" 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
-15-
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.
-16-
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.
7 --19--
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
-20-
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.
-21-
~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.
:
~\
