Compositions and method comprising heterocyclic compounds containing two heteroatoms as membrane penetration enhancers

A method and compositions for enhancing absorption of topically administered physiologically active agents through the skin and mucous membranes of humans and animals in a transdermal device or formulation for local or systemic use, comprising a therapeutically effective amount of a pharmaceutically active agent and a non-toxic, effective amount of penetration enhancing agent of the formula I: ##STR1## wherein R is a saturated or unsaturated, straight or branched, cyclic or acyclic hydrocarbon group with from 1 to 19 carbon atoms, alkoxyalkyl, haloalkyl, specifically trifluoromethyl, alkoxy, amino, alkylamino and acylamino; R' and R" are hydrogen, alkyl, trifluoromethyl, alkoxyalkyl, aminoalkyl, alkyl- and acylaminoalkyl, carboxy, carbalkoxy, hydroxyalkyl or lower alkyl ester thereof; X is O or NR.sub.1 wherein R.sub.1 is hydrogen, alkyl, alkenyl, alkoxyalkyl, carbalkoxyalkyl, aminoalkyl, alkyl- and acylaminoalkyl, hydroxyalkyl or hydroxyalkyloxyalkyl and lower alkyl ester thereof; and n is 2 or 3 are disclosed.

FIELD OF THE INVENTION 
This invention relates to substituted oxazolines and imidazolines as 
permeation enhancers for pharmaceutical, agricultural and cosmetic agents. 
BACKGROUND OF THE INVENTION 
Many physiologically active agents are best applied topically to obtain 
desirable results. Topical application, in the form of creams, lotions, 
gels, solutions, etc., largely avoids side effects of the agents and 
permits high level concentrations of the agents. 
Some therapeutic drugs may also be administered for systemic use through 
the skin or other body membranes including intransal and intravaginal 
application of humans and other animals, utilizing a transdermal device or 
formulated in a suppository or aerosol spray. For some years, 
pharmaceutical researchers have sought an effective means of introducing 
drugs into the bloodstream by applying them to the unbroken skin. Among 
other advantages, such administration can provide a comfortable, 
convenient and safe way of giving many drugs now taken orally or infused 
into veins or injected intramuscularly. 
Using skin as the portal for drug entry offers unique potential, because 
transdermal delivery permits close control over drug absorption. For 
example, it avoids factors that can cause unpredictable absorption from 
gastrointestinal tract, including changes in acidity, motility, and food 
content. It also avoids initial metabolism of the drug by the liver known 
as the first pass effect. Thus, controlled drug entry through skin can 
achieve a high degree of of control over blood concentrations of drug. 
Close control over drug concentration in blood can translate readily into 
safer and more comfortable treatment. When a drug's adverse effects occur 
at higher concentrations than its beneficial ones, rate control can 
maintain the concentration that evoke only-or principally the drug's 
desired actions. This ability to lessen undesired drug actions can greatly 
reduce the toxicity hazards that now restrict or prevent the use of many 
valuable agents. 
Transdermal delivery particularly benefits patients with chronic disease. 
Many such patients have difficulty following regimens requiring several 
doses daily of medications that repeatedly cause unpleasant symptoms. They 
find the same drugs much more acceptable when administered in transdermal 
system that require application infrequently-in some cases, only once or 
twice weekly-and reduce adverse effects. 
Transdermal delivery is feasible for drugs effective in amounts that can 
pass through the skin area and that are substantially free of localized 
irritating or allergic effects. While these limitations may exclude some 
agents, many others remain eligible for transdermal delivery. Moreover, 
their numbers will expand as pharmaceutical agents of greater potency are 
developed. Particularly suitable for transdermal delivery are potent drugs 
with only a narrow spread between their toxic and safe blood 
concentrations, those having gastrointestinal absorption problems, those 
susceptible to a higher first pass liver metabolism or those requiring 
frequent dosing in oral or injectable form. 
Transdermal therapy permits much wider use of natural substances such as 
hormones. Often the survival times of these substances in the body are so 
short that they would have to be taken many times daily in ordinary dosage 
forms. Continuous transdermal delivery provides a practical way of giving 
them, and one that can mimic the body's own patterns of secretion. 
At present, controlled transdermal therapy appears feasible for many drugs 
used for a wide variety of ailments including, but not limited to, 
circulatory problems, hormone deficiency, respiratory ailments, and pain 
relief. 
Percutaneous administration can have the advantage of permitting continuous 
administration of drug to the circulation over prolonged periods of time 
to obtain a uniform delivery rate and blood level of drug. Commencement 
and termination of drug therapy are initiated by the application and 
removal of the dosing devices from the skin. Uncertainties of 
administration through the gastrointestinal tract and the inconvenience of 
administration by injection are eliminated. Since a high concentration of 
drug never enters the body, problems of pulse entry are overcome and 
metabolic half-life is not a factor of controlling importance. 
The greatest problems in applying physiologically active agents topically 
or transdermally is that the skin is 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 in 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 of treating such conditions as inflammation, acne, psoriasis, herpes 
labialis, herpes genitalis, eczema, infections caused by fungi, viruses 
and 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 repellents and the like. 
Physiologically active agents may be applied to the locally affected parts 
of the body in the form of a solution, cream, lotion or gel utilizing the 
vehicle system described herein. These agents may also be delivered for 
systemic use utilizing the vehicle system in a transdermal patch. 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 physiologically active agents into and through the 
skin. One such vehicle is dimethyl sulfoxide, which is described in U.S. 
Pat. No. 3,551,554. 
My previous inventions disclosed in U.S. Pat. Nos. 3,989,816; 3,991,203; 
4,122,170; 4,316,893; 4,415,563; 4,423,040; 4,424,210; 4,444,762 describe 
a method for enhancing the topical administration of physiologically 
active agents by combining such an agent with an effective amount of a 
penetration enhancer and applying the combination topically to humans or 
animals, in the form of solution, cream, gel, lotion etc. This prior art 
discloses N-alkyl substituted cyclic lactams as penetration enhancers. 
My related U.S. Pat. No. 4,405,616 describes a method for administering 
systemically active agents through the skin or other body membranes of 
humans and animals, utilizing a transdermal device or formulation 
containing an effective amount of a suitable membrane penetration enhancer 
selected from the disclosed N-alkyl substituted cyclic lactams. 
My related U.S. Pat. Nos. 4,461,638 and 4,762,549 describe a method for 
enhancing delivery of plant nutrients and plant growth regulators, and my 
U.S. Pat. No. 4,525,199 describes an improved method of pest control by 
enhancing pesticide permeation. 
My related U.S. application, Ser. No. 783,621, now U.S. Pat. No. 4,837,026, 
filed on Sept. 30, 1985, describes a method for enhancing topical and 
transdermal administration of physiologically active agents with membrane 
penetration enhancers selected from the alkanoic acid cyclic amides 
disclosed therein. 
My related U.S. application, Ser. No. 002,387, filed on Jan. 12, 1987, 
describes a method for enhancing topical and transdermal administration of 
physiologically active agents with membrane penetration enhancers selected 
from heterocyclic compounds containing two heteroatoms. 
My related U.S. application, Ser. No. 218,316, filed on Jul. 12, 1988, 
describes a method for enhancing topical and transdermal administration of 
physiologically active agents with membrane penetration enhancers selected 
from oxazolidone and related heterocyclic compounds. 
My related U.S. application Ser. No. 07/345,457, filed on May 1, 1989, 
describes a method for enhancing topical and transdermal administration of 
physiologically active agents with membrane penetration enhancers selected 
from substituted imidazolines. 
My related U.S. application Ser. No. 07/348,387, filed on May 8, 1989 
describes a method for enhancing topical and transdermal administration of 
physiologically active agents with yet another series of membrane 
penetration enhancers. 
Penetration enhancers for enhancing systemic administration of therapeutic 
agents transdermally disclosed in the art include dodecyl pyrrolidone, 
dimethyl lauramide and dimethyl sulfoxide. These agents may be used prior 
to or concurrently with administration of the active agent, see, e.g., 
U.S. Pat. Nos. 4,031,894; 3,996,934 and 3,921,636. 
SUMMARY OF THE INVENTION 
The invention relates to compositions for carrying physiologically active 
agents through body membranes such as skin and for retaining these agents 
in the body tissues and further relates to a method of administering 
systemically active agents through the skin or other body membranes of 
humans and animals, utilizing a transdermal device or formulation, 
containing an effective, non-toxic amount of a membrane penetration 
enhancer having the structural formula I: 
##STR2## 
wherein: R is a saturated or unsaturated, straight or branched, cyclic or 
acyclic hydrocarbon group with from 1 to 19 carbon atoms, alkoxyalkyl, 
haloalkyl, specifically trifluoromethyl, alkoxy, amino, alkylamino and 
acylamino. 
R' and R" are hydrogen, alkyl, trifluoromethyl, alkoxyalkyl, aminoalkyl, 
alkyl- and acylaminoalkyl, carboxy, carbalkoxy, hydroxyalkyl or lower 
alkyl ester thereof. 
X is O or NR.sub.1, wherein R.sub.1 is Hydrogen, alkyl, alkenyl, 
alkoxyalkyl, aminoalkyl, alkyl- and acylaminoalkyl, hydroxyalkyl and 
hydroxyalkyloxyalkyl or lower alkyl ester thereof; and n is 2 or 3. 
In one preferred embodiment of I, R' and R" are H; X is O; R and n being as 
defined. The preferred compounds of this embodiment are: 
2-(2-dodecyl)-2-oxazoline, 
2(2-methyl-2-decyl)-2-oxazoline, 
2[1-(3-oxaundecyl)]-2-oxazoline 
In another preferred embodiment of the composition I, R' is Hydrogen, R" is 
alkyl, alkoxyalkyl, trifluoromethyl, carboxy, carbalkoxy, hydroxyalkyl or 
alkyl esters thereof, X is O and R and n being as defined. The preferred 
compounds of this embodiment are: 
4-Methyl-2-(2-dodecyl)-2-oxazoline, 
4-Isopropyl-2-(2-dodecyl)-2-oxazoline, 
4-Trifluoromethyl-2-(2-dodecyl)-2-oxazoline, 
4-Isopropyl-2-(2-methyl-2-decyl)-2-oxazoline, 
4-Decyl-2-trifluoromethyl-2-oxazoline, 
4-[1-(2-Oxadodecyl)]-2-methyl -2-oxazoline, 
4-[1-(2-Oxadodecyl)]-2-trifluoromethyl-2-oxazoline, 
5-[1-(2-Oxadodecyl)]-2-trifluoromethyl-2-oxazoline, 
4-Hydroxymethyl-2-undecyl-2-oxazoline, 
4-Trimethylacetoxymethyl-2-undecyl-2-oxazoline, 
4-Carbethoxy-2-undecyl-2-oxazoline, 
4-Dodecyl-2-ethoxy-2-oxazoline. 
In yet another preferred embodiment of I, R' and R" are selected from 
alkyl, alkoxyalkyl, trifluoromethyl, carboxy, carbalkoxy, hydroxyalkyl and 
alkyl esters thereof; X is O; R and n being as defined. The preferred 
compounds of this embodiment are: 
4,4-Dimethyl-2-undecyl-2-oxazoline, 
4-Methyl-4-trifluoromethyl-2-undecyl-2-oxazoline, 
4,4-Dimethyl-2-(1-dodecen-2-yl)-2-oxazoline, 
4-Methyl-4-trifluoromethyl-2-(1-dodecen-2-yl)2-oxazoline, 
4,4-Dimethyl-2-(2-dodecyl)-2-oxazoline, 
4,4-Dimethyl-2-(2-methyl-2-decyl)-2-oxazoline, 
4,4-Dimethyl-2-[1-(3-oxaundecyl)]-2-oxazoline, 
4-Hydroxymethyl-4-methyl-2-undecyl-2-oxazoline, 
4-Hydroxymethyl-4-trifluoromethyl-2-undecyl-2-oxazoline, 
4-Trimethylacetoxymethyl-4-methyl-2-undecyl-2-oxazoline, 
4-Hydroxymethyl-4-methyl-2-(2-dodecyl)-2-oxazoline, 
4-Hydroxymethyl-4-methyl-2-(2-methyl-2-decyl)-2-oxazoline, 
4-Trimethylacetoxymethyl-4-methyl-2-(2-dodecyl)-2-oxazoline, 
4-Trimethylacetoxymethyl-4-methyl-2-(2-methyl-2-decyl)-2-oxazoline, 
4-Carboxy-4-methyl-2-undecyl-2-oxazoline, 
4-Carbethoxy-4-methyl-2-undecyl-2-oxazoline, 
4-Methyl-4-[1-(2-oxadodecyl)]-2-trifluoromethyl-2-oxazoline, and 
4-Methyl-4-dodecanoyloxymethyl-2-trifluoromethyl-2-oxazoline. 
In another preferred embodiment of I, R' and R" are H; X is NR.sub.1, n, R 
and R.sub.1 being as defined. The preferred compounds of this embodiment 
are: 
2-Undecyl-2-imidazoline, 
1-Methyl-2-heptyl-2-imidazoline, 
1-Isopropyl-2-undecyl-2-imidazoline, 
1-(2-Hydroxyethyl)-2-undecyl-2-imidazoline, 
1-(2-Hydroxyethyl)-2-(heptadec-8-enyl)-2-imidazoline, 
1-[2-(Trimethylacetoxy)ethyl]-2-undecyl-2-imidazoline, and 
1-(2-ethoxyethyl)-2-undecyl-2-imidazoline, 
1-[2-(2-Hydroxyethoxy)ethyl]-2-undecyl-2-imidazoline, 
1-(2-Carbethoxyethyl)-2-undecyl-2-imidazoline and 
1-Dodecyl-2-trifluoromethyl-2-imidazoline. 
In another preferred embodiment of the composition I, R' is Hydrogen, R" is 
alkyl or trifluoromethyl; X is NR.sub.1 ; n, R and R.sub.1 being as 
defined. The preferred compounds of this embodiment are: 
4-Methyl-2-undecyl-2-imidazoline, 
4-Isopropyl-2-undecyl-2-imidazoline, 
4-t-Butyl-2-undecyl-2-imidazoline, 
4-Trifluoromethyl-2-undecyl-2-imidazoline, 
1,4-Diisopropyl-2-undecyl-2-imidazoline, 
4-Methyl-1-isopropyl-2-undecyl-2-imidazoline, 
4-Methyl-2-(2-dodecyl)-2-imidazoline, 
4-Methyl-2-(2-methyl-2-decyl)-2-imidazoline, 
4-Decyl-2-trifluoromethyl-2-imidazoline and 
4-Decyl-2-ethoxy-2-imidazoline. 
In yet another preferred embodiment of I, R' and R" are alkyl or 
trifluoromethyl; X is NR.sub.1 ; n, R and R.sub.1 being as defined. The 
preferred compounds of this embodiment are: 
4,4-Dimethyl-2-undecyl-2-imidazoline, 
4-Methyl-4-t-butyl-2-undecyl-2-imidazoline, 
4,4-Dimethyl-1-isopropyl-2-undecyl-2-imidazoline, 
4-Methyl-1,4-diisopropyl-2-undecyl-2-imidazoline, 
4,4-Dimethyl-2-(2-dodecyl)-2-imidazoline, 
4,4-Dimethyl-1-isopropyl-2-(2-dodecyl)-2-imidazoline, 
4,4-Dimethyl-2-(2-methyl-2-decyl)-2-imidazoline, 
4,4-Dimethyl-1-isopropyl-2-(2-methyl-2-decyl)-2-imidazoline. 
It has been found that the physiologically active agents are carried 
through body membranes by the claimed penetration enhancers and are 
retained in the body tissue when applied topically in form of a cream, 
gel, or lotion or absorbed systemically when applied in the form of a 
transdermal device or formulation, for example, as a transdermal patch, a 
rectal or vagina suppository, as a nasal spray or when incorporated in a 
vaginal sponge or tampon. 
DETAILED DESCRIPTION OF THE INVENTION 
Typical examples of compounds included in the foregoing formula I of this 
invention are the following: 
1. 4-Trifluoromethyl-2-undecyl-2-oxazoline; 
2. 4-Isopropyl-2-nonyl-2-oxazoline; 
3. 4-Isopropyl-2-undecyl-2-oxazoline; 
4. 4-t-Butyl-2-undecyl-2-oxazoline; 
5. 4-Methyl-4-trifluoromethyl-2-undecyl-2-oxazoline; 
6. 4-Methyl-4-isopropyl-2-undecyl-2-oxazoline; 
7. 4-Methyl-4-t-butyl-2-undecyl-2-oxazoline; 
8. 4-Trifluoromethyl-2-(1-dodecen-2-yl)-2-oxazoline; 
9. 4,4-Dimethyl-2-(1-dodecen-2-yl)-2-oxazoline; 
10. 4-methyl-4-trifluoromethyl-2-(1-dodecen-2-yl)-2-oxazoline; 
11. 4-Hydroxymethyl-4-trifluoromethyl-2-undecyl-2-oxazoline; 
12. 4-Trimethylacetoxymethyl-4-methyl-2undecyl-2-oxazoline; 
13. 2-(2-decyl)-2-oxazoline; 
14. 2-(2-dodecyl)-2-oxazoline; 
15. 4-Methyl-2-(2-dodecyl)-2-oxazoline; 
16. 4-Isopropyl-2-(2-dodecyl)-2-oxazoline; 
17. 4-t-Butyl-2-(2-dodecyl)-2-oxazoline; 
18. 4-Trifluoromethyl-2-(2-dodecyl)-2-oxazoline; 
19. 4,4-Dimethyl-2-(2-dodecyl)-2-oxazoline; 
20. 4-Methyl-4-isopropyl-2-(2-dodecyl)-2-oxazoline; 
21. 4-Methyl-4-t-butyl-2-(2-dodecyl)-2-oxazoline; 
22. 4-Methyl-4-trifluoromethyl-2-(2-dodecyl)-2-oxazoline; 
23. 4-Hydroxymethyl-4-methyl-2-(2-dodecyl)-2-oxazoline; 
24. 4-[2-(Trimethylacetoxy)ethyl]-4-methyl-2-(2-dodecyl)-2-oxazoline; 
25. 2-(2-methyl-2-decyl)-2-oxazoline; 
26. 2-(2-methyl-2-dodecyl)-2-oxazoline; 
27. 4-Trifluoromethyl-2-(2-methyl-2-decyl)-2-oxazoline; 
28. 4,4-Dimethyl-2-(2-methyl-2-decyl)-2-oxazoline; 
29. 4,4-Dimethyl-2-(2-methyl-3-tridecyl)-2-oxazoline; 
30. 2-[1-(3-Oxaundecyl)]-2-oxazoline; 
31. 4-Decyl-2-trifluoromethyl-2-oxazoline; 
32. 4-[1-(2-Oxadodecyl)]-2-methyl-2-oxazoline; 
33. 4-[1-(2-Oxadodecyl)]-2-trifluoromethyl-2-oxazoline; 
34. 5-[1-(2-Oxadodecyl)]-2-trifluoromethyl-2-oxazoline; 
35. 4-Hydroxymethyl-2-undecyl-2-oxazoline; 
36. 4-Trimethylacetoxymethyl-2-undecyl-2-oxazoline; 
37. 4-Carbethoxy-2-undecyl-2-oxazoline; 
38. 4,4-Dimethyl-2-[1-(3-oxaundecyl)]-2-oxazoline; 
39. 4-Carboxy-4-methyl-2-undecyl-2-oxazoline; 
40. 4-Carbethoxy-4-methyl-2-undecyl-2-oxazoline; 
41. 4-Methyl-4-[1-(2-oxadodecyl)]-2-trifluoromethyl-2-oxazoline; 
42. 4-Methyl-4-dodecanoyloxymethyl-2-trifluoromethyl-2-oxazoline; 
43. 4-Methyl-2-nonyl-2-oxazoline; 
44. 4-Methyl-2-undecyl-2-oxazoline; 
45. 4,4-Dimethyl-2-nonyl-2-oxazoline; 
46. 4,4-Dimethyl-2-undecyl-2-oxazoline; 
47. 4,4-Dimethyl-2-tridecyl-2-oxazoline; 
48. 4-Hydroxymethyl-4-methyl-2-nonyl-2-oxazoline; 
49. 4-Hydroxymethyl-4-methyl-2-undecyl-2-oxazoline; 
50. 4-Hydroxymethyl-4-ethyl-2-undecyl-2-oxazoline; 
51. 2-Pentyl-2-oxazoline; 
52. 2-Heptyl-2-oxazoline; 
53. 2-Nonyl-2-oxazoline; 
54. 2-Undecyl-2-oxazoline; 
54. 2-Tridecyl-2-oxazoline; 
55. 2-Pentadecyl-2-oxazoline; 
56. 2-Heptadecyl-2-oxazoline; 
57. 2-Undecyl-2-imidazoline; 
58. 1-Isopropyl-2-pentyl-2-imidazoline; 
59. 1-Methyl-2-heptyl-2-imidazoline; 
60. 1-Methyl-2-undecyl-2-imidazoline; 
61. 1-(2-Hydroxyethyl)-2-undeyl-2-imidazoline; 
62. 1-[2-(Trimethylacetoxy)ethyl]-2-undeyl-2-imidazoline; 
63. 1-Isopropyl-2-undecyl-2-imidazoline; 
64. 4-Methyl-2-undecyl-2-imidazoline; 
65. 4-Isopropyl-2-undecyl-2-imidazoline; 
66. 4-Trifluoromethyl-2-undecyl-imidazoline; 
67. 1,4-Diisopropyl-2-undecyl-2-imidazoline; 
68. 4-t-Butyl-1-isopropyl-2-undecyl-2-imidazoline; 
69. 4,4-Dimethyl-2-undecyl-2-imidazoline; 
70. 4-Methyl-4-isopropyl-2-undecyl-2-imidazoline; 
71. 4-Methyl-4-t-butyl-2-undecyl-2-imidazoline; 
72. 4,4-Diisopropyl-2-undecyl-2-imidazoline; 
73. 4-Methyl-4-trifluoromethyl-2-undecyl-2-imidazoline; 
74. 4,4-Dimethyl-1-isopropyl-2-pentyl-2-imidazoline; 
75. 4,4-Dimethyl-1-isopropyl-2-undecyl-2-imidazoline; 
76. 4,4-Dimethyl-1-(2-hydroxyethyl)-2-undecyl-2-imidazoline; 
77. 4,4-Dimethyl-1-[2-(Trimethylacetoxy)ethyl]-2-undecyl -2-imidazoline; 
78. 4,4-Dimethyl-1-(1-hydroxy-2-methyl-2-propyl)-2-undecyl-2-imidazoline; 
79. 4,4-Dimethyl-1-(1acetoxy-2-methyl-2-propyl)-2-undecyl-2-imidazoline; 
80. 2-(2-dodecyl)-2-imidazoline; 
81. 1-(2-Hydroxyethyl)-2-(2dodecyl)-2-imidazoline; 
82. 1-[2-(Trimethylacetoxy)ethyl]-2-(2-dodecyl)-2-imidazoline; 
83. 1-Isopropyl-2-(2-dodecyl)-2-imidazoline; 
84. 4,4-Dimethyl-2-(2-dodecyl)-2-imidazoline; 
85. 4,4-Dimethyl-1-isopropyl-2-(2-dodecyl)-2-imidazoline; 
86. 2-(1-Dodecen-2-yl)-2-imidazoline; 
87. 1-Isopropyl-2-(1-dodecen-2-yl)-2-imidazoline; 
88. 4,4-Dimethyl-2-(1-dodecen-2-yl)-2-imidazoline; 
89. 4,4-Dimethyl-1-isopropyl-2-(1-dodecen-2-yl)-2-imidazoline; 
90. 2-(2-methyl-2-decyl)-2-imidazoline; 
91. 1-(2-Hydroxyethyl)-2-(2-methyl-2-decyl)-2-imidazoline; 
92. 4,4-Dimethyl-2-(2-methyl-2-decyl)-2-imidazoline; 
93. 1-(2-Ethoxyethyl)-2-undecyl-2-imidazoline; 
94. 4,4-Dimethyl-1-(2-ethoxyethyl)-2-undecyl-2-imidazoline; 
95. 1-(2-Diethylaminoethyl)-2-undecyl-2-imidazoline; 
96. 1-(2-Hydroxyethyl)-2-(heptadec-8-enyl)-2-imidazoline; 
97. 1-(2-Carbethoxyethyl)-2-undecyl-2-imidazoline; 
98. 1-[2-(2-Hydroxyethoxy)ethyl]-2-undecyl-2-imidazoline; 
99. 1-Dodecyl-2-trifluoromethyl-2-imidazoline; 
100. 4-Decyl-2-trifluoromethyl-2-imidazoline; 
101. 4-Dodecyl-2-ethoxy-2-imidazoline; 
102. 4-Dodecyl-2-ethoxy-2-oxazoline; 
and esters of the hydroxy substituted compounds listed. 
The following 2-oxazolines, encompassed by general formula I of this 
invention are known in the literature. Compounds 46, 48 and 49 were 
evaluated for phytotoxicity [Allen and Skoog, Plant Physiol. 26, 611 
(1951); C.A. 45: 9790f (1951)]; Compounds 52-57 were evaluated for surface 
activity [Ishii et. al., Yukagaku 7, 70-74 (1958); C.A. 55:5993d (1961)]; 
Compounds 52 and 54 were used to prepare nitrogen containing polymers 
useful as adhesive and thickeners for water base paints [Litt et. al., 
U.S. Pat. No. 3,483,141, Dec. 9, 1969]; Method of preparation for 
compounds 51, 52, 54 and 57 is disclosed by Litt et. al., U.S. Pat. No. 
3,562,263, Feb. 9, 1971; by Bassiri et. al., Polymer Lett. 5,871-9 (1967) 
and by Levy and Litt, Polymer Lett. 5,881-6 (1967) and for compound 54 by 
Seeliger and Thier, Justus Liebigs Ann. Chem 698, 158- 66 (1966); C.A. 66: 
37856x (1967) and by Seeliger et. al., Angew. Chem., Int. Ed. Engl.5, 
875-88 (1966); Lactate, citrate and tartrate salts of compounds 45-47 were 
evaluated for their emulsifying and foaming properties [Kimura et. al., 
Yukagaku, 21, 197-200 (1972); C.A. 77: 50538s (1972)] and same salts of 
compounds 48, 49 and their C.sub.13, C.sub.15, and C.sub.17 homologs were 
evaluated for surface activity [Kimura et. al., Kogyo Kagaku Zasshi, 
63,582-5 (1960); C.A.: 58, 11583b (1963); Method of preparation for 
compound 56 disclosed by Litt et. al. in U.S. Pat. No. 3,681,333, 01 Aug 
1972 and compound 56 in a related U.S. Pat. No. 3,681,329 01 Aug 1972; 
Method of preparation for compounds 51, 54 and 57 is disclosed by Witte 
and Seeliger, Angew. Chem., Int. Ed. Engl. 11,287-8 (1972) and Liebigs 
Ann. Chem. 996-1009 (1974); Compounds 45-47 and their C.sub.5, C.sub.7, 
C.sub.15 and C.sub.17 analogs are disclosed as emulsifiers in 
polymerization of styrene and butadiene [Frump, U.S. Pat. No. 3,886,128; 
27 May 1975; C.A. 83: 180219y (1975)]; Organic acid salts of compounds 
53-55 were evaluated for their emulsifying and foaming properties [Kimura 
et. al., Yukagaku, 24,869-73 (1975); C.A. 84: 137589c (1976)]; compounds 
45-47 and their C.sub.5, C.sub.7, and C.sub.15 analogs were disclosed and 
compound 45 was evaluated for antimicrobial activity [Hunsucker, U.S. Pat. 
No. 4,049,819, 20 Sept. 1977; C.A. 87: 195540c (1977)]; Compound 46 and 
its C.sub.5 and C.sub.17 analogs are disclosed as intermediates in the 
synthesis of monoacyl glycerols [Hersloef and Gronowitz, Chem. Scr. 22, 
230-5 (1983); C.A. 100: 156203n (1984)]; Erskine and Lydon disclose 
oxazolines with alkyl groups of 7-19 carbon atoms in 2-position and 
additionally substituted with alkyl or hydroxyalky groups with 1-3 carbon 
atoms in 4 and/or 5 position as surfactants in Iron Blue Pigment 
Composition suitable for incorporating in transfer or carbon paper inks 
(U.S. Pat. No. 2,893,886, July 7, 1959); Thompson et. al. disclose 
2-alkyl-4,4-dimethyl-2-oxazoline salts of lauryl or oleyl phosphoric acid 
partial esters as antistatic agents in lubricating compositions for 
textiles (U.S. Pat. No. 2,976,186, Mar 21, 1961); Johnson discloses 
2-alkyl substituted oxazolines (7-17 carbon atoms), additionally 
substituted with alkyl or hydroxymethyl groups in 4 position as 
antifoaming and emulsifying agents in fermentation processes (U.S. Pat. 
No. 2,443,825, June 22, 1948) and finally compounds 45-47, 9 and analogs 
are mentioned as intermediates in the synthesis of alpha-substituted 
acrylic acids [Serota et. al., J. Org. Chem 46, 4147-4151 (1981)]. 
The following 2-imidazoline derivatives, encompassed by general formula I 
of this invention, are known in the literature. Synthesis of compound 57 
and other alkyl analogs is reported by Morill (U.S. Pat. No. 2,508,415, 
May 23, 1950); Compound 57 and nonyl analog were prepared in low yield by 
Clintwood and Emmet-Ried, J. Amer. Chem. Soc. 57,2424, (1953); Compound 57 
and its C.sub.17 homolog were synthesized by Waldmann and Chwala, Chem. 
Ber. 74,1763 (1941); French Patent No. 811,423, Apr. 14, 1937; U.S. Pat. 
No. 2,155,877, Apr. 25, 1939; Compound 57 was prepared by Piskov et al; 
Khim. Geterotsikl, Soedin., 1112 (1976); C.A. 86,5372h (1977); Bockmuhl 
and Knoll reported the synthesis of C.sub.15 and C.sub.17 substituted 
2-imidazolines intended to be useful for therapeutic or technical 
purposes, U.S. Pat. No. 1,958,529, May 15, 1934; C.A. 28,4539 (1934); 
Wellman and McCallan have reported 2-heptadecyl-2-imidazoline useful as 
foliage fungicide; C.A. 40,4470 (1946); Kyrides et. al., J. Org. Chem. 
12,577 (1947) and Shepard and Shonle, J. Amer. Chem. Soc. 69,2269 (1947) 
have reported synthesis of compounds 57, 59, 60 and 1-ethyl and 
1-pentyl-2-undecyl-2-imidazolines in low to moderate yields and their 
bacteriostatic and local anesthetic activity; Mikeska in U.S. Pat. No. 
2,361,488; C.A. 39,2190 (1945) discloses 2-imidazolines substituted in 
2-position with saturated or unsaturated alkyl group with 10-23 carbon 
atoms in paving composition; Russell describes the use of 2-imidazolines 
and specifically claims 2-heptadecyl-2-imidazoline in herbicidal 
composition, U.S. Pat. No. 2,514,341, July 4, 1950; Compound 74 was 
prepared by Harnsberger and Riebsomer, J. Hetero. Chem. 1,188 (1964) and 
Compounds 74, 75 and related alkyl analogs were reported in very low yield 
by Riebsomer, J. Amer. Chem. Soc. 70,1629 (1948); Compound 57 and its 
C.sub.5, C.sub.10, C.sub.12 and C.sub.17 analogs as well as compound 64 
and its C.sub.17 analog were prepared by Sawa, Nippon Kagaku Zasshi, 
89,780 (1968; C.A. 70 19983q (1969). Wilson discloses 
1-hydroxyalkyl-2-imidazolines and specifically, 
1-hydroxyethyl-2-heptadecyl-2-imidazoline, as surface active agents, U.S. 
Pat. No. 2,267,965 (Dec. 30, 1941) and U.S. Pat. No. 2,268,273 (Dec. 30, 
1941). Tryon reported the preparation of compounds 58, 63 and two higher 
homologs in very low yield, U.S. Pat. No. 2,520,102 (Aug. 22, 1950). 
Compounds 61, 96 and the corresponding 2-stearyl and 2-isosterayl analogs 
are commercially known cationic surface active agents useful as themselves 
or in the form of their salts in textile auxiliaries, such as softeners, 
dye assistants, finishing aids and antistatics, in emulsifiable 
concentrates such as wool oils, paper softeners, cutting oils, metal 
lubricants, in oil and wax emulsions for polishes and cosmetic creams, in 
agricultural products such as antifungal sprays, in corrosion inhibitors, 
where they are used by themselves or in combination with fatty acids, oils 
and waxes, in organic coatings for improving bonding properties, 
preventing water sealers, in certain hydrophilic pigments to render them 
hydrophobic before subsequent milling with oils and esters, in building 
materials such as concrete, cement and bricks, to make these water 
repellent, and asphalt to improve its binding properties to gravel, p. 230 
in McCutcheon's Emulsifiers and Detergents, 1987 North American Edition, 
MuCutcheon Division, McCutcheon Publishing Co., 175 Rock Road, Glen Rock, 
N.J. 07452. 
To my knowledge the other compounds are novel. 
The use of the compounds of the present invention as penetration enhancers 
is, however, novel and not predictable from the prior art. 
The heterocyclic compounds covered by the general formula I may be prepared 
by any of the processes known for the preparation of 2-oxazoline 
derivatives, for example: 
1) Heating a nitrile of formula R--CN with an aminoalcohol of the following 
formula II in presence of cadmium acetate dihydrate or zinc acetate 
dihydrate at 100.degree.-130.degree. C. with or without a solvent affords 
the compounds of this invention: 
##STR3## 
(wherein R,R' and R are as defined above) [Witte and Seeliger, Angew. 
Chem., Int. Ed. Eng., 11, 287-8 (1972); Liebigs Ann. Chem 996-1009 
(1974)]. Alternately, an allenic or acetylenic nitrile with an 
aminoalcohol of formula II on heating gives the compounds of this 
invention [Fomum et. al., Tet. Lett. 1101-4(1975)]. 
2) A carboxylic acid, R--COOH, is made to react with an aminoalcohol of the 
formula II with or without solvent at a temperature of from 150.degree. to 
250.degree. C. with elimination of water [Serota et. al., J. Org. Chem. 
46, 4147-51 (1981); Hersloef and Gronowitz, Chem. Scr. 22,230-5 (1983); 
Frump, Chem. Rev. 71, 483-505 (1971); Meyers and Mihelich, Angew. Chem., 
Int. Ed. Eng. 15, 270-281(1976)]. In addition compounds, which possess an 
exocyclic doublebond on hydrocarbon group R, for example, compounds 8-10, 
can be prepared according to Serota et. al., J. Org. Chem., 46,4147-51 
(1981) from the reaction of 2-alkyl oxazolines with formaldehyde, followed 
by dehydration. Alternately, aminoalcohol of the formula II may be reacted 
with an acrylate ester in presence of a catalyst and a polymerization 
inhibitor, De Benneville and Luskin, U.S. Pat. No. 2,831,858 (Apr. 22, 
1958); C.A. 52, 16379h (1958); U.S. Pat. No. 2,897,192 (July 28, 1959); 
C.A. 54, 585f (1960); Luskin and De Benneville, Ger. Patent No. 1,067,437 
(Oct. 22, 1959); C.A. 55, 19960a (1961). In case of unsubstituted 
aminoalcohols, the resulting amidoalcohols can be cyclodehydrated as under 
3. 
3) Cyclodehydration of an amidoalcohol of formula III: 
##STR4## 
(wherein R, R' and R" are as defined above) to 2-oxazoline derivative is 
catalyzed by WO.sub.3.H.sub.2 O, NaWO.sub.4.2H.sub.2 O, MoO.sub.2 and 
SrWO.sub.4 (Litt et. al., U.S. Pat. No. 3,681,333 and U.S. Pat. No. 
3,681,329, 01 Aug 1972) or by silica, alumina, silica-alumina or 
silica-magnesia at 200.degree.-400.degree. C. under reduced pressure [Litt 
and Levy, U.S. Pat. No. 3,562,263, Feb 9, 1971; Seeliger and Thier, Justus 
Liebigs Ann. Chem. 698, 158-66 (1966); Seeliger et. al., Angew. Chem., 
Int. Ed. Eng. 5, 875-88 (1966)] or by treatment with SOCl.sub.2, RSO.sub.2 
Cl, COCl.sub.2 or PO(OR).sub.2 Cl in order to replace the hydroxy group by 
an efficient leaving group that can be eliminated more readily during 
cyclization [Ishii et. al., Yukagaku, 7, 70-4 (1958); C.A. 55,5993 (1961) 
and Zioudrou and Schmir, J. Amer. Chem. Soc. 85,3258 (1963)] or simply on 
heating at high temperature with or without a catalytic amount of a strong 
mineral acid, De Benneville et al, J. Org. Chem., 23, 1355 (1958). 
The amidoalcohol of formula III mentioned above may be prepared from 
carboxylic acid of formula, R--COOH; from carboxylic acid chloride of 
formula, R--COCl or from carboxylic acid ester of the formula, 
R--COOR'"(where R'" is an alkyl group) with an aminoalcohol of formula II 
mentioned above with or without solvent at a temperature from 0.degree. C. 
to 150.degree. C. [Wenker, J. Amer. Chem. Soc. 57,1079 (1935); D'Alelio 
and Emmet-Reid, J. Amer. Chem. Soc. 59,111 (1937); Bassiri et. al., 
Polymer Lett 5, 871-9 (1967)]. 
4) Cyclization of the haloamide of the formula IV: 
##STR5## 
(wherein R, R' and R" are as defined above) with a base such as sodium or 
potassium hydroxide in aqueous or aqueous alcohol solution or better yet 
with anhydrous sodium carbonate at an elevated temperature (50.degree. 
C.-250.degree. C.) under reduced pressure (0.1 mm -30 mm), [Frump, Chem. 
Rev. 71,483 (1971) and references cited therein; Bassiri, French Pat. 
1,477,049, 14 Apr. 1967; Bassiri et.al., Polymer Lett. 5, 871-9 (1967); 
5) Addition of an epoxide to a nitrile of the formula, R--CN, in 
concentrated sulfuric acid gives oxazolines of this invention [Oda et. 
al., Bull. Soc. Chem. Japan, 35, 1219 (1962)]. 
6) Reaction of an iminoester with an aminoalcohol of formula II mentioned 
above affords the penetration enhancers of this invention [McCasland and 
Horswill, J. Amer. Chem. Soc., 73, 3744 (1951); Dornow and Theidel, Chem. 
Ber. 88, 1267 (1955); and British Patent 704,946 (1954); C.A. 49, 10370 
(1956)]. 
7) Reaction of an epoxide with an amidine yields oxazolines of this 
invention [Lambert and Kristofferson, J. Org. Chem., 30,3938 (1965)]. 
8) Treatment of a carboxylic acid of the formula, R--COOH or a carboxylic 
acid chloride of the formula, R--COCl with ethyleneimine, followed by 
catalytic isomerization of the carboxylic acid amide gives the oxazolines 
of this invention [Kagiya et. al., Polymer Lett., 4, 441-5 (1966); Heine 
et. al., J. Amer. Chem. Soc., 81 2202 (1959); Fanta and Deutsch, J. Org. 
Chem., 23,72 (1958); Meyers et. al., J. Org. Chem., 39,2787 (1974); Fukui 
et. al., Japan 69 22,285 (Sept. 24, 1969); C.A. 71, 12449p (1969)]. 
2-Amino substituted derivatives may be prepared according to the method of 
Meschino and Bond, J. Org. Chem. 28, 3129 (1963) or Najer et. al., Bull. 
Soc. Chim. Fr. 1609 (1959) and references cited therein. 
The heterocyclic compounds covered by the general formula I, where X is 
NR.sub.1, may be prepared by any one of the classical processes known for 
the preparation of 2-imidazolines; Ferm and Riebsomer, Chem. Rev. 593 
(1954). 
For example, treating a diamine of the formula V or its salt 1) with a 
carboxylic acid of the formula R--COOH, its ester, acid chloride, 
anhydride, amide, thioamide or nitrile derivative followed by ring 
closure. 
##STR6## 
(wherein R, R', R", R1 and n are as defined above) 
The reaction may be carried out in a solvent such as benzene at 
130.degree.-230.degree. C. with azeotropic removal of water, Riebsomer, J. 
Amer. Chem. Soc. 70, 1629 (1948); Harnsberger and Riebsomer, J. Hetero. 
Chem. 1,188 (1964). The monoacyl or diacyl derivatives formed may or may 
not be isolated and ring closed, for example, in presence of oxides of 
calcium or magnesium or other dehydrating agents, Chitwood and Ried, J. 
Amer. Chem. Soc. 57,2424 (1935); Waldman and Chwala, Chem. Ber. 74,1763 
(1941); Fr. Patent No. 811,423 (Apr. 14, 1937); C.A. 31,8550 (1937); Br. 
Patent No. 479,491 (Feb. 7, 1938); C.A. 32,5002 (1938); U.S. Pat. No. 
2,155,877, (Apr. 23, 1939); and 2,155,878 (Apr. 25, 1939); C.A. 33,5878 
(1939), Kyrides and Zienty, U.S. Pat. No. 2,404,300 (July 16, 1946); C.A. 
40,6101 (1946); Kyrides, U.S. Pat. No. 2,404,299 (July 16, 1946); C.A. 
41,160 (1946); Kyrides and Zienty, U.S. Pat. No. 2,399,601 (Apr. 30, 
1946); C.A. 40,4180 (1946); Kyrides, U.S. Pat. No. 2,392,326 (Jan. 8, 
1946); C.A. 40,1972 (1946); Aspinall, J. Amer. Chem. Soc. 61,3195 (1939); 
Hill and Aspinall, J. Amer. Chem. Soc. 61,822 (1939); Kyrides, J. Org. 
Chem. 12,577 (1947); Morill, U.S. Pat. No. 2,508,415 (May 23, 1950); C.A. 
45,668 (1951); Piskov et. al., Khim. Geterotsikl. Soedin, 1112 (1976); 
C.A. 86,537h (1977). The nitrile derivative, R--CN, may be reacted with 
p-toluene sulfonate salt of diamine of formula V, Oxley and Short, J. 
Chem. Soc. 497 (1947), Savignac et. al., J. Hetero. Chem. 15,897 (1978) or 
with diamine of formula V in presence of catalytic amount of sulfur, Sawa, 
Nippon Kagaku Zasshi, 89,780 (1968); C.A. 70,19983q (1969) or in presence 
of catalytic amount of carbon disulfide at 80.degree.-190.degree. C. for 1 
to 48 hours, Hueni, U.S. Pat. No. 2,868,802 (Jan. 13, 1959); Fruhstorfer 
and Muller-Calagan, Ger. Pat. 1,117,588 (Nov. 23, 1961); Hansen, Ger. Pat. 
1,670,143 (May 30, 1974); 
2) with the imidates of the formula 
##STR7## 
or amidines of the formula 
##STR8## 
Bockmuhl and Knoll, U.S. Pat. No. 1,958,529 (May 15, 1934); C.A. 28,4539 
(1934); Oxley and Short, J. Chem. Soc. 497 (1947); Short and Oxley, Brit. 
Patent, 614,032 (Dec. 8, 1948); C.A. 43,5049 (1949); I. G. Farbenindustrie 
A.G., Fr. Pat. 671,362 (Mar. 12, 1929). 
The imidazolines may be prepared by treating the imidates mentioned above 
with an aminoalcohol, Drozdov and Bekhli, J. Gen. Chem. U.S.S.R. 14,480 
(1944); C.A. 39,4590 (1945) or by heating a mixture of a carboxylic acid 
of the formula R--COOH and a 2-imidazolidone at 250.degree.-300.degree. 
C., I. G. Farbenindustrie A.G., Brit. Pat. 492,812 (Sept. 28, 1938); C.A. 
33,1761 (1939). 
2-Alkoxy-2-imidazolines may be prepared by the method of Kohn and Jung, J. 
Amer. Chem. Soc. 107, 2931 (1985) and 2-amino-2-imidazolines may be 
prepared, for example, by the method of Meschino and Bond, J. Org. Chem. 
28, 3129 (1963). 
Finally, 2-imidazolines may be prepared by reducing monoacyl derivatives of 
alpha aminonitriles in presence of a reducing agent, for example, Raney 
nickel, Hawkins and Biggs, J. Amer. Chem. Soc. 71,2530 (1949); Hawkins, 
U.S. Pat. No. 2,587,043 (Feb. 26, 1952); C.A. 46,9122 (1952). 
N-substituted 2-imidazolines my be alternately prepared by alkylation of 
2-substituted 2-imidazolines with an alkyl halide in presence of a strong 
base such as sodium hydride in hexamethylphosphotriamide (HMPT) or an 
organolithium compound, for example, butyllithium in an inert solvent 
according to Cognacq, British Patent No. 1,417,174 (Dec. 10, 1975). 
The compounds of the present invention may be used as penetration enhancers 
in the same manner as described in my U.S. Pat. Nos. 3,989,816; 3,991,203; 
4,415,563; 4,122,170; 4,316,893; 4,423,040; 4,424,210; 4,444,762 and U.S. 
application Ser. No. 783,621, and now U.S. Pat. No. 4,837,026 filed Sept. 
30, 1985, and pending U.S. applications. Ser. No. 002,387, filed Jan. 12, 
1987, Ser. No. 218,316, filed July 12, 1988, Ser. No. 07/345,457 filed May 
1, 1989 and Ser. No. 07/348,387 filed May 8, 1989, which are hereby 
incorporated by reference. 
The compounds of the present invention are useful as penetration enhancers 
for a wide range of physiologically active agents and the compositions 
disclosed herein are useful for topical and transdermal therapeutic effect 
of these agents. Typically systemically active agents which may be 
delivered transdermally are therapeutic agents which are sufficiently 
potent such that they can be delivered through the skin or other membranes 
to the bloodstream in sufficient quantities to produce the desired 
therapeutic effect. In general this includes agents in all of the major 
therapeutic areas including, but not limited to, anti-infectives, such as 
antibiotics and antiviral agents, analgesics, anorexics, anthelmintics, 
antiarthritics, antiasthma agents, anticonvulsants, antidepressants, 
antidiabetic agents, antimigraine preparations, antimotion sickness, 
antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics, 
antipsychotics, antipyretics, antispasmodics, including gastrointestinal 
and urinary; anticholinergics, sympathomimetics, xanthine derivatives, 
cardiovascular preparations including calcium channel blockers, 
beta-blockers, antiarryhthmics, antihypertensives, diuretics, vasodilators 
including general, coronary, peripheral and cerebral; central nervous 
system stimulants, cough and cold preparations, decongestants, 
diagnostics, hormones, hypnotics, immunosuppressives, muscle relaxants, 
parasympatholytics, parasympathomimetics, sedatives, tranquilizers and 
antiosteoporosis agents. 
For topical applications the agents include antibiotics, fungistatic and 
fungicidal agents, corticosteroids, antiinflammatory agents, antiemetics, 
antipruritic agents, vasodilators, bronchodilators, expectorants, 
analgesics, antiosteoporosis agents, sunscreen compounds, antiacne agents, 
collagen softening agents and other similar compounds. Cosmetic agents, 
hair and skin dyes, natural and synthetic hormones, perfumes, insect 
repellents, diagnostic agents and other such compounds may also be 
advantageously formulated with these penetration enhancers. 
Moreover, these penetration enhancers are useful in agriculture in the 
application of fertilizers, hormones, growth factors including 
micronutrients, insecticides, molluscicides, arachides, nematocides, 
rodenticides, herbicides, and other pesticides to plants, animals and 
pests. These penetration enhancers are also useful for penetration of 
micronutrients and chemical hybridization agents in seeds for enhanced 
plant growth. Of course, the appropriate dosage levels of all the 
physiologically active agents, without conjoint use of the penetration 
enhancing compounds of formula I, are known to those of ordinary skill in 
the art. These conventional dosage levels correspond to the upper range of 
dosage levels for compositions including a physiologically active agent 
and a compound of formula I as a penetration enhancer. However, because 
the delivery of the active agent is enhanced by compounds of the present 
invention, dosage levels significantly lower than conventional dosage 
levels may be used with success. Systemically active agents are used in 
amounts calculated to achieve and maintain therapeutic blood levels in a 
human or other animal over the period of time desired. (The term "Animal" 
as used here encompasses humans as well as other animals, including 
particularly pets and other domestic animals.) These amounts vary with the 
potency of each systemically active substance, the amount required for the 
desired therapeutic or other effect, the rate of elimination or breakdown 
of the substance by the body once it has entered the bloodstream and the 
amount of penetration enhancer in the formulation. In accordance with 
conventional prudent formulating practices, a dosage near the lower end of 
the useful range of a particular agent is usually employed initially and 
the dosage increased or decreased as indicated from the observed response, 
as in the routine procedure of the physician. 
The present invention contemplates compositions of compounds of formula I, 
together with physiologically active agents from 0.05% to 100% of 
conventional dosage levels. The amount of compound of Formula I which may 
be used in the present invention is an effective, non-toxic amount for 
enhancing percutaneous absorption. Generally, for topical use the amount 
ranges between 0.01 to about 10 and preferably about 0.1 to 5 percent by 
weight of the composition. For transdermal enhancement of systemic agents, 
the amount of penetration enhancer which may be used in the invention 
varies from about 1 to 100 percent although adequate enhancement of 
penetration is generally found to occur in the range of about 1 to 30 
percent by weight of the formulation to be delivered. For transdermal use, 
the penetration enhancers disclosed herein may be used in combination with 
the active agent or may be used separately as a pre-treatment of the skin 
or other body membranes through which the active agent is intended to be 
delivered. 
Dosage forms for application to the skin or other membranes of humans and 
animals include creams, lotions, gels, ointments, suppositories, sprays, 
aerosols, buccal and sublingual tablets and any one of a variety of 
transdermal devices for use in the continuous administration of 
systemically active drugs by absorption through the skin, oral mucosa or 
other membranes, see for example, one or more of U.S. Pat. Nos. 3,598,122; 
3,598,123; 3,731,683; 3,742,951; 3,814,097; 3,921,636; 3,972,995; 
3,993,072; 3,993,073; 3,996,934; 4,031,894; 4,060,084; 4,069,307; 
r,201,211; 4,230,105; 4,292,299 and 4,292,303. U.S. Pat. No. 4,077,407 and 
the foregoing patents also disclose a variety of specific systemically 
active agents which may also be useful as in transdermal delivery, which 
disclosures are hereby incorporated herein by this reference. 
The penetration enhancers of this invention may also be used in admixture 
with other penetration enhancers disclosed earlier and incorporated herein 
by reference. 
Typical inert carriers which may be included in the foregoing dosage forms 
include conventional formulating materials, such as, for example, water, 
ethanol, 2-propanol, 1,2-propanediol, 1,3-butanediol, 1,2,3,-propanetriol, 
propanone, butanone, carboxylic acid esters such as isopropyl myristate, 
diisopropyl adipate and diisopropyl sebacate, acyclic and cyclic amides 
including N-methyl pyrrolidone, urea, freons, PEG-200, PEG-400, Polyvinyl 
pyrrolidone, fragrances, gel producing materials such as "Carbopol", 
stearyl alcohol, stearic acid, spermaceti, sorbitan monooleate, sorbital, 
"polysorbates", "Tweens", methyl cellulose etc. 
It will be readily appreciated by those skilled in the art that certain 
compounds represented by formula I exhibit chirality. However, where no 
designation of isomers is specified with respect to the compounds of this 
invention, it is to be understood that all possible stereoisomers are 
included. 
It will also be readily appreciated by those skilled in the art that 
certain of the compounds described in the disclosure may form salts with 
carboxylic and mineral acids and it is understood that all such salts are 
included in the invention.

The examples which follow illustrate the penetration enhancers and the 
compositions of the present invention. However, it is understood that the 
examples are intended only as illustrative and are not to be construed as 
in any way limiting to scope of this invention. 
EXAMPLE 1 
Preparation of 2-undecyl-2-oxazoline 
The reaction was carried out under nitrogen atmosphere in a three neck 
flask equipped with a magnetic stirring bar, reflux condenser, addition 
funnel and thermometer. 50 ml of 1-butanol and 667 mg (2.5 mmoles) of 
cadmium acetate dihydrate was introduced and the catalyst was dissolved by 
slight warming. 18.13 g (100 mmoles) of undecyl cyanide was added and the 
solution was heated to 125.degree. C. 7.33 g (120 mmoles) of 
2-aminoethanol was then added dropwise controlling the evolution of 
ammonia. At the end of the reaction (ca. 48 hrs.) the solvent was removed 
under vacuo. The residue was treated with 100 ml of petroleum ether and 
filtered after keeping for several hours. The filtrate was washed with 
water, dried over anhydrous magnesium sulfate, concentrated and the 
residue was distilled 114.degree. C./0.5 mm to give 19.83 g (88%) of 
2-undecyl-2-oxazoline. 
EXAMPLE 2 
Preparation of 2-decyl-2-oxazoline 
Undecyl cyanide in Example 1 was substituted with 18.13 g (108.4 mmoles) of 
undecanenitrile and allowed to react with 7.5 ml (121.3) mmoles of 
aminoethanol in presence of cadmium acetate dihydrate (667 mg; 2.5 mmoles) 
in 1-butanol under identical reaction conditions. The reaction mixture was 
worked up following Example 1 and the residue was distilled at 
118.degree.-120.degree. C./1.2 mm to give 14.72 g (64.3%) of 
2-decyl-2-oxazoline. 
EXAMPLE 3 
Preparation of 2-heptadecyl-2-oxazoline 
Undecyl cyanide in Example 1 was substituted with 26.55 g (100 mmoles) of 
heptadecyl cyanide and the reaction was repeated under identical 
conditions. The residue, after removal of 1-butanol under vacuo, was 
extracted with 150 ml of toluene at 70.degree. C. and filtered. The 
filtrate was washed with water, dried, concentrated and the residue on 
slight wash with acetonitrile gave 23.79 g (77%) of 
2-heptadecyl-2-oxazoline, m.p. 52.degree.-53.degree. C. 
EXAMPLE 4 
Preparation of 2-pentyl-2-oxazoline 
9.72 g (100 mmoles) of hexanenitrile was substituted for undecyl cyanide in 
Example 1 and the reaction was repeated with 6.11 g (100 mmoles) of 
ethanolamine and 549 mg (2.5 mmoles) of zinc acetate dihydrate under 
identical conditions. At the end of the reaction the product was worked up 
as before and distilled at 73.degree. C./10 mm to give 8.2 g (60%) of 
2-pentyl-2-oxazoline. 
EXAMPLE 5 
Preparation of 4-methyl-2-undecyl-2-oxazoline 
10.9 g (60 mmoles) of undecyl cyanide was treated with 5 g (66.6 mmoles) of 
DL-2-amino-1-propanol in presence of 400 mg (1.5 mmoles) of cadmium 
acetate dihydrate in 1-butanol as outlined under Example 1. 13.2 g (92%) 
of product was obtained on distillation at 115.degree.-117.degree. 
C./1-1.5 mm Hg. 
EXAMPLE 6 
The following compounds are prepared analogously following Example 5 and 
substituting DL-2-amino-1-propanol by 66.6 mmoles of the appropriate 
aminoalcohol. 
4-Trifluoromethyl-2-undecyl-2-oxazoline 
4-Isopropyl-2-undecyl-2-oxazoline 
4-t-Butyl-2-undecyl-2-oxazoline 
EXAMPLE 7 
Preparation of 4-ethyl-2-undecyl-2-oxazoline 
25 g (137.9 mmoles) of undecyl cyanide was treated with 15.2 ml (165 
mmoles) of DL-2-amino-1-butanol in presence of 919 mg (3.54 mmoles) of 
cadmium acetate dihydrate in 1-butanol as outlined under Example 1. 31.31 
g (89.6%) of product was obtained on distillation at 
124.degree.-125.degree. C./1.2-1.4 mm Hg. 
EXAMPLE 8 
Preparation of 4,4-dimethyl-2-undecyl-2-oxazoline 
64 g (320 mmoles) of dodecanoic acid and 61.1 ml (640 mmoles) of 
2-amino-2-methylpropanol was placed in a two neck flask equipped with a 
vigreux column, distillation condenser and a thermometer. The temperature 
of the reaction mixture was slowly brought to 180.degree. C. and 
maintained there for 9 hours. After cooling, a 10% alcoholic KOH solution 
(2 g, 3.6 mmoles) was added and the reflux was continued at 180.degree. C. 
for 4 hours. The excess 2-amino-2-methylpropanol was distilled at 
aspirator pressure (86.degree. C./18 mm). When the vapor temperature 
reached 103.degree. C., the distillation was discontinued and the residue 
was taken in petroleum ether and filtered. The filtrate was washed with 
dilute KOH, water, dried and concentrated. The oil was distilled at 
120.degree. C./1.2 mm Hg to give 70.5 g (87%) of product. 
EXAMPLE 9 
Preparation of 4,4-dimethyl-2-pentyl-2-oxazoline 
Following the procedure under Example 8, 6.085 g (52.4 mmoles) of hexanoic 
acid and 10 ml (9.34 g, 104.8 mmoles) of 2-amino-2-methylpropanol were 
heated to 185.degree. C. Work up and fractional distillation gave 7.2 g 
(81%) of product, b.p. 90.degree.-92.degree. C./25 mm Hg. 
EXAMPLE 10 
Preparation of 4,4-dimethyl-2-heptadecyl-2-oxazoline 
Following example 8, 14.9 g (52.4 mmoles) of octadecanoic acid and 9.34 g 
(104.8 mmoles) of 2-amino-2-methylpropanol gave 14.1 g (79.7%) of product, 
b.p. 140.degree.-143.degree. C./0.01 mm Hg. 
EXAMPLE 11 
Preparation of 4,4-Dimethyl-2-(1-dodecen-2-yl)2-oxazoline 
4.2 g (141 mmoles) of paraformaldehyde was added to 22.5 g (88.8 mmoles) of 
4,4-dimethyl-2-undecyl-2-oxazoline (obtained in Example 8) at 90.degree. 
C. The mixture was stirred at 90.degree. C. for 30 minutes and the 
temperature was raised by 5.degree. C. increment every half hour up to 
115.degree. C. 20 ml of cumene was added and the mixture was refluxed for 
2.5 hours at 180.degree. C. with removal of water using a Dean-Stark trap. 
The solution was distilled at 126.degree.-129.degree. C./1 mm to give 18.2 
g of product. This contained 5-10% of starting oxazoline. LPLC 
purification on 40-60 micron silica gel (petroleum ether to 90% petroleum 
ether-ethyl acetate gradient) gave 16.5 g (70%) of pure product. 
EXAMPLE 12 
The following compounds are prepared analogously following Example 11 and 
substituting the 4,4-dimethyl-2-undecyl-2-oxazoline by equimolar amounts 
of the corresponding 4-trifluoromethyl and 4-methyl-4-trifluoromethyl 
derivatives. 
4-Trifluoromethyl-2-(1-dodecen-2-yl)-2-oxazoline 
4-Methyl-4-trifluoromethyl-2-(1-dodecen-2-yl-2-oxazoline 
EXAMPLE 13 
Preparation of 4-hydroxymethyl-4-methyl-2-undecyl-2-oxazoline 
A mixture of 20.03 g (100 mmoles) of dodecanoic acid and 11.57 g (110) 
mmoles) of 2-amino-2-methyl-1,3-propanediol in 10 ml of xylene was heated 
for 30 hours at 185.degree.-190.degree. C. with azeotropic removal of 
water. The reaction mixture was taken up in ethyl acetate and was washed 
with water to remove excess amino alcohol. The organic layer was dried, 
concentrated and the residue was distilled at 152.degree.-155.degree. C./1 
mm Hg to give 22.8 g (84.6%) of 
4-hydroxymethyl-4-methyl-2-undecyl-2-oxazoline. 
EXAMPLE 14 
Preparation of 4-hydroxymethyl-4-ethyl-2-undecyl-2-oxazoline 
26 g (130 mmoles) of dodecanoic acid and 31 g (260 mmoles) of 
2-amino-2-ethyl-1,3-propanediol were condensed together by heating at 
185.degree.-190.degree. C. for 30 hours. Work up and distillation of the 
residue at 160.degree.-162.degree. C./1 mm Hg gave 33.19 g (90%) of the 
product. 
EXAMPLE 15 
Preparation of 2-(2-dodecyl)-2-oxazoline 
100 mmoles of 2-cyanododecane is treated with 120 mmoles of 2-aminoethanol 
in 50 ml of 1-butanol in presence of 2.5 mmoles of cadmium acetate 
dihydrate as outlined under Example 1 to give 2-(2-dodecyl)-2-oxazoline. 
EXAMPLE 16 
The following compounds are prepared analogously following Example 15 and 
substituting 2-aminoethanol by 120 mmoles of the appropriate 
2-aminoalkanol derivative. 
4-Methyl-2-(2-dodecyl)-2-oxazoline 
4-Isopropyl-2-(2-dodecyl)-2-oxazoline 
4-t-Butyl-2-(2-dodecyl)-2-oxazoline 
4-Trifluoromethyl-2-(2-dodecyl)-2-oxazoline 
EXAMPLE 17 
Preparation of 2-(2-Methyl-2-decyl)-2-oxazoline 
100 mmoles of 2-cyano-2-methyldodecane is reacted with 120 mmoles of 
2-aminoethanol in 50 ml of 1-butanol in presence of 2.5 mmoles of cadmium 
acetate dihydrate as outlined under Example 1 to give 
2-(2-methyl-2-decyl)-2-oxazoline. 
EXAMPLE 18 
The following compounds are prepared analogously following Example 17 and 
substituting 2-aminoethanol by 120 mmoles of the appropriate 
2-aminoalkanol derivative. 
4-Methyl-2-(2-methyl-2-decyl)-2-oxazoline 
4-Isopropyl-2-(2-methyl-2-decyl)-2-oxazoline 
4-Trifluormethyl-2-(2-methyl-2-decyl)-2-oxazoline 
EXAMPLE 19 
Preparation of 4,4-Dimethyl-2-(2-dodecyl)-2-oxazoline 
10 g of 4,4-Dimethyl-2-(1-dodecen-2-yl)-2-oxazoline, obtained in Example 
11, was dissolved in 200 ml ethanol and hydrogenated in a Parr apparatus 
over 1 g of 10% Pd/C at 50 p.s.i. The catalyst was removed and the 
filtrate was concentrated to give the product. This was distilled at 
120.degree.-122.degree. C./0.8 mm to give 9.68 g (96.5%) of colorless 
product. 
EXAMPLE 20 
Preparation of 4,4-Dimethyl-2-(2-methyl-3-tridecyl)-2-oxazoline 
A solution of 25.34 g (100 mmoles) of 4,4-dimethyl-2-undecyl-2-oxazoline in 
250 ml of dry THF under nitrogen atmosphere was cooled to -78.degree. C. 
To this was added 62.5 ml (100 mmoles) of 1.6M solution of n-butyl lithium 
in hexane over a period of 15 minutes and the solution was further stirred 
for 2 hours. 18.45 g (150 mmoles) of 2-bromopropane was added at 
-78.degree. C. over a period of 30 minutes and the resulting solution was 
allowed to warm to room temperature overnight. The solution was poured 
into 250 ml of saturated ammonium chloride solution and the organic phase 
was separated. The aqueous phase was extracted with 2.times.100 ml of 
ether, the organic phases were combined and extracted with 2.times.200 ml 
of brine. After drying over anhydrous magnesium sulphate, the solution was 
concentrated and the residue was distilled at reduced pressure. 10.2 g of 
starting material was recovered. 8.82 g (50% based on recovered starting 
material) of product distilled at 131.degree.-134.degree. C./0.8 mm Hg. 
2.98 g (14.8%) of disubstituted product was obtained as a higher boiling 
fraction. 
EXAMPLE 21 
Preparation of 4-Decyl-2-trifluoromethyl-2-oxazoline 
To a cooled solution of 10.2 g of 2-amino-1-dodecanol and 15 ml of 
triethylamine in 100 ml of dichloromethane was slowly added a solution of 
7.1 ml of trifluoroacetic anhydride in 30 ml of dichloromethane. After 3 
hours at room temperature the reaction mixture was poured into sodium 
bicarbonate solution and then extracted with ether. The organic phase was 
dried, concentrated and the residual oil was heated at 
160.degree.-180.degree. C. for 12 hours. The dark oil was dissolved in 
hexane and was washed with sodium bicarbonate solution and water. The 
hexane phase was dried, concentrated and the residual oil was distilled at 
100.degree.-110.degree. C. at 0.1 mm to give 10.4 g (73.6%) of a clear 
oil. 
EXAMPLE 22 
Preparation of 2-Undecyl-2-imidazoline 
18.32 g (100 mmoles) of undecyl cyanide, 8.5 ml (127 mmole) of 
ethylenediamine and 0.5 ml of carbon disulfide were mixed and heated in an 
oil bath at 125.degree. C. for 24 hours. The reaction mixture was cooled, 
treated with dilute hydrochloric acid and treated with charcoal. The light 
yellow filtrate was basified and extracted with ethyl acetate, the organic 
extracts dried over magnesium sulfate and concentrated. The residue was 
Kugelrohr distilled and then recrystallized from toluene. Yield 13.7 g 
(61.1%), m.p. 82.degree. C. 
EXAMPLE 23 
Preparation of 1-Methyl-2-heptyl-2-imidazoline 
14.207 g (113.46 mmoles) of heptyl cyanide, 10.726 g (144.69 mmoles) of 
N-methylethylenediamine and 0.5 ml of carbon disulfide were mixed and 
heated at 125.degree. C. for 24 hours. The solution was cooled, diluted 
with ethyl acetate and extracted with dilute hydrochloric acid. The acidic 
solution was basified with sodium hydroxide and extracted with ethyl 
acetate. The organic extracts were treated with charcoal, filtered, 
concentrated and Kugelrohr distilled at 105.degree. C./1.2 mm to give 
19.73 g (77.3%) of the product. 
EXAMPLE 24 
Preparation of 1-(2-Hydroxyethyl)-2-octyl-2-imidazoline 
13.02 g (93.51 mmoles) of octyl cyanide was treated with 12.327 g (118.36 
mmoles) of 2-(2-aminoethylamino)ethanol in presence of 0.5 ml of carbon 
disulfide at 125.degree. C. for 24 hrs. and worked up as outlined under 
Example 23. Distillation of the residue at 167.degree.-169.degree. C./0.5 
mm gave 12.332 g (62.7%) of product. 
EXAMPLE 25 
Preparation of 1-(2-Hydroxyethyl)-2-undecyl-2-imidazoline 
58.7 g (564.4 mmoles) of 2-(2-aminoethylamino)ethanol and 122.8 g (538.6 
mmoles) of ethyl dodecanoate were heated at 125.degree. C. and ethanol was 
removed by distillation. 100 ml of toluene was cautiously added and water 
was removed azeotropically on further reflux. The reaction mixture was 
fractionally distilled to give 100.2 g (69.5%) of pure product, m.p. 
40.degree.-42.degree. C. 
EXAMPLE 26 
Preparation of 1-(4-Hydroxybutyl)-2-undecyl-2-imidazoline 
8 g (60.6 mmoles) of 4-(2-aminoethylamino)butanol and 12.5 g of ethyl 
dodecanoate were treated as under Example 25. The resulting 10.8 g of an 
oil (66.7%) was dissolved in 100 ml of hexane and kept in the freezer to 
give 8.8 g of pure product, m.p. 58.degree.-60.degree. C. 
EXAMPLE 27 
Preparation of 1-(2-Ethoxyethyl)-2-undecyl-2-imidazoline 
2.54 g (19.2 mmoles) of N-(2-ethoxyethyl)ethylenedimine and 4.3 g of ethyl 
dodecanoate were treated as under Example 25. Distillation of the crude 
product at 128.degree.-130.degree. C./0.2 mm gave 2.9 g (52%) of product. 
1-(2-methoxyethyl)-2-undecyl-2-imidazoline was similarly prepared from 30.8 
g of ethyl dodecanoate and 16 g of N-(2-methoxyethyl)ethylenediamine. 
Distillation of the crude product at 150.degree. C./0.1 mm gave 9.3 g of 
pure product. 
EXAMPLE 28 
Preparation of 1-Isopropyl-2-undecyl-2-imidazoline 
18.324 g of Undecyl cyanide, 15.12 g of N-isopropylethylenediamine and 0.5 
ml of carbon disulfide were heated at 125.degree. C. for 24 hrs. and 
worked up as mentioned under Example 23, followed by distillation at 
150.degree. C./1.2 mm gave 21.93 g (82.3%) of the product. 
EXAMPLE 29 
Preparation of 4-Methyl-2-undecyl-2-imidazoline 
18.13 g (100 mmoles) of undecyl cyanide, 9.3 g (125 mmoles) of 
1,2-diaminopropane and 0.5 ml of carbon disulfide were heated to 
125.degree. C. for 24 hrs. and then worked up as mentioned under Example 
23. Kugelrohr distillation at 163.degree.-165.degree. C./1.2-1.4 mm Hg 
gave 17.85 g (75%) of product. 
EXAMPLE 30 
Preparation of 4,4-Dimethyl-2-undecyl-2-imidazoline 
18.31 g (100 mmoles) of undecyl cyanide, 11 g (125 mmoles) of 
1,2-diamino-2-methylpropane and 0.5 ml of carbon disulfide were heated at 
125.degree. C. for 24 hrs. and then worked up as under Example 23. 
Distillation at reduced pressure gave 19.66 g (78%) of the product. 
EXAMPLE 31 
Preparation of 4,4-Dimethyl-2-pentyl-2-imidazoline 
8.41 g (95.4 mmoles) of 1,2-diamino-2-methylpropane, 7.4 g (76.16 mmoles) 
of hexanenitrile and 0.4 ml of carbon disulfide were heated at 125.degree. 
C. for 24 hours and then worked up as under Example 23. Distillation at 
105.degree.-107.degree. C./0.5 mm gave 9.4 g (73.4%) of product. 
EXAMPLE 32 
Preparation of 4-Methyl-4-t-butyl-2-undecyl-2-imidazoline 
15 g of 2-cyano-2-decanoylamino-3,3-dimethylbutane (prepared from acylation 
of aminonitrile obtained from treatment of pinacolone with sodium cyanide 
and ammonium chloride) in 250 ml of 95% ethanol and 70 ml of ammonium 
hydroxide was hydrogenated with T-1 Raney Nickel. The catalyst was 
filtered off. The filtrate was concentrated and the residue was distilled 
at reduced pressure to give 7.5 g (52%) of the product. 
EXAMPLE 33 
Preparation of 4,4-Dimethyl-1-isopropyl-2-undecyl-2-imidazoline 
22.84 g. (100 mmoles) of ethyl dodecanoate and 15.34 g. (118 mmoles) of 
N.sub.1 -isopropyl-2-methyl-1,2-propanediamine was heated at 
130.degree.-230.degree. C. until approximately 100 mmoles of ethanol was 
collected. Toluene was then cautiously added and the heating was continued 
until no more water separated. The solution was acidified, the aqueous 
layer was separated and basified with NaOH. This was extracted with ethyl 
acetate, the organic extract was dried and concentrated. The oil was 
distilled at 150.degree.-152.degree. C./1.2 mm to give 16.74 g (58%) of 
product. 
EXAMPLE 34 
The following compounds were prepared following the procedure in Example 33 
and substituting the N.sub.1 -isopropyl-2-methyl-1,2-propanediamine by 
equimolar amount of the appropriately N.sub.1 -substituted 
ethylenediamine. 
A) 1-Methyl-2-undecyl-2-imidazoline 131.degree.-133.degree. C./1 mm 79% 
yield 
B) 1-Propyl-2-undecyl-2-imidazoline 160.degree. C./36 1 mm 76.36% yield 
EXAMPLE 35 
Preparation of 1-(2-Carbmethoxyethyl)-2-undecyl-2-imidazoline 
2.2 g (9.82 mmoles) of 2-undecyl-2-imidazoline and 1.4 g (16.3 mmoles) of 
methyl acrylate were dissolved in 50 ml of methylene chloride and the 
solution was heated to reflux. The reaction was followed by glc. The 
solution was concentrated and the residue was distilled at 
160.degree.-170.degree. C./0.1 mm to give 2.2 g (72.4%) of product. 
EXAMPLE 36 
Preparation of 1-[2-(2-Hydroxyethoxy)ethyl]-2-undecyl-2-imidazoline 
13.7 g (92.6 mmoles) N-[2-(2-Hydroxyethoxy)ethyl]ethylenediamine and 19.6 g 
(86 mmoles) of ethyl dodecanoate were mixed and heated in a flask equipped 
with a Dean-Stark trap. After the separated ethanol and water were 
distilled off, the residue was kugelrohr distilled at 
160.degree.-170.degree. C./0.1 mm to give 13.6 g (50.7%) of crude product. 
Recrystallization from ethyl acetate/hexane gave white crystalline 
material, m.p. 58.degree.-60.degree. C. 
EXAMPLE 37 
Preparation of 1-(2-Hyrdoxyethyl)-2-undecyl-2-imidazoline acetate 
34 g (127 mmoles) 1-(2-Hyrdoxyethyl)-2-undecyl-2-imidazoline was dissolved 
in 300 ml of hexane and 8.5 g (14.2 mmoles) of acetic acid in 50 ml of 
hexane were reacted. The precipitate was filtered and then dried at 
40.degree.-50.degree. C. under high vacuum for 5 hours. Yield 40.7 g 
(97.8%). The compound was hydroscopic and was hydrated to a gel upon 
absorbing moisture. 
EXAMPLE 38 
Preparation of 4,4-Dimethyl-1-n-butyl-2-undecyl-2-imidazoline 
22 ml (55 mmoles) of a 2.5M solution of butyl lithium in hexane are added 
to 12.62 g (50 mmoles) of 4,4-dimethyl-2-undecyl-2-imidazoline in 50 ml of 
anhydrous benzene at a temperature kept at around 20.degree. C. The 
mixture is then stirred for 2 hours at ambient temperature (15.degree. to 
20.degree. C.). 8.22 g (60 mmoles) of 1-bromobutane is then added dropwise 
to the reaction mixture, keeping the temperature at around 20.degree. C. 
The reaction mixture is then stirred at ambient temperature until it is 
homogenous, after which it is refluxed for 3 hours. After cooling, 50 ml 
of water is added, the mixture is stirred for half hour, decanted and 
extracted with 100 ml of ether. After drying over magnesium sulfate the 
solvent is removed in vacuo and the oil is distilled at reduced pressure 
to give 10.34 g (67%) of the product. 
The compounds of the present invention were tested in vitro as penetration 
enhancers according to the procedure outlined below. The penetration 
enhancers were formulated with pharmacologically active agents in creams 
and patches. Permeation of the active agent through human stratum corneum 
in vitro over a specific study period was compared to control formulation 
without enhancer. Higher permeation of the active agent in the presence of 
an enhancer exemplified the invention. 
EXAMPLE 39 
Human stratum corneum was isolated from full thickness human skin as 
described by Bronaugh et. al., J. Pharm. Sci. 75, 1094 (1986). The skin 
was placed between the donor and the receptor compartments of diffusion 
cells in such a way that the dermal side of the skin faced the receptor 
compartment which was filled with normal saline (pH 7.2-7.4) or 
appropriate releasing media. The stratum corneum was equilibrated at 
37.degree. C. overnight prior to the application of a topical formulation 
or a transdermal patch. All formulations were studied in triplicate. 
About 500 mg of the following four isosobide dinitrate (ISDN) cream 
formulations (40% ISDN & 60% Lactose) were applied to cover the stratum 
corneum surface within the donor compartment. The entire contents of the 
receptor compartment were removed at specific time intervals for duration 
of the study period and replenished with fresh saline. The aliquots were 
analyzed by HPLC and the average cumulative amount of ISDN in micrograms 
permeating over the study period was calculated. The results are shown 
below. 
______________________________________ 
Average Cumulative Amount 
of ISDN in Micrograms 
Cream Formulation Permeating over 24 hours 
______________________________________ 
(1) 0.7% ISDN (Control) 
442.5 .+-. 27.7 
(2) 0.7% ISDN + 1% Enhancer 
566.1 .+-. 119 
of Example 30 
(3) 0.7% ISDN + 1% Enhancer 
861.8 .+-. 158.3 
of Example 34 A 
(4) 0.7% ISDN + 1% Enhancer 
747.8 .+-. 135.8 
of Example 34 B 
______________________________________ 
The results clearly indicated that the formulations containing Enhancers of 
Examples 30, 34 A and 34 B showed superior permeation for Isosorbide 
Dinitrate as compared to control. 
EXAMPLE 40 
Procedure of Example 39 was repeated with the following Isosorbide 
Dinitrate (ISDN) cream formulations. 
______________________________________ 
Average Cumulative Amount 
of ISDN in Micrograms 
Cream Formulation Permeating over 48 Hours 
______________________________________ 
(1) 0.7% ISDN (Control) 
535.0 .+-. 25.0 
(2) 0.7% ISDN + 2% Enhancer 
872.3 .+-. 85.0 
of Example 25 
______________________________________ 
The results indicated that the formulation containing the Enhancer of 
Example 25 showed superior permeation for Isosorbide Dinitrate as compared 
to control. 
EXAMPLE 41 
Procedure of Example 39 was repeated with the following Isosorbide 
Dinitrate (ISDN) cream formulations. 
______________________________________ 
Average Cumulative Amount 
of ISDN in Micrograms 
Cream Formulation Permeating over 51 Hours 
______________________________________ 
(1) 1% ISDN (Control) 678.5 .+-. 84.0 
(2) 1% ISDN + 2% Enhancer 
1255.3 .+-. 96.0 
of Example 27 
______________________________________ 
The results clearly indicated that the formulation containing the Enhancer 
of Example 27 shows superior permeation for Isosorbide Dinitrate as 
compared to control. 
EXAMPLE 42 
Procedure of Example 39 was repeated with the following Haloperidol 
Decanoate (HD) cream formulations. Normal saline in the receptor 
compartment was replaced by 2-propanol/saline (1:1). 
______________________________________ 
Average Cumulative Amount of 
HD in Micrograms Permeating 
Cream Formulation 
over 51 Hours 
______________________________________ 
(1) 5% HD (Control) 617.68 .+-. 17.68 
(2) 5% HD + 3% Enhancer 
1209.00 .+-. 131.36 
of Example 25 
(3) 5% HD + 3% Enhancer 
1829.20 .+-. 15.55 
of Example 27 
______________________________________ 
The results clearly indicated that the formulations containing Enhancers of 
Examples 25 and 27 showed superior permeation for Haloperidol Decanoate as 
compared to control. 
EXAMPLE 43 
Procedure of Example 39 was repeated with the following Nifedipine (NIF) 
cream and patch formulations. Normal saline in the receptor compartment 
was replaced by ethanol/saline (3:7). 
______________________________________ 
Average Cumulative Amount of 
NIF in Micrograms Permeating 
Cream Formulation 
over 51 Hours 
______________________________________ 
(1) 5% NIF (Control) 157.9 .+-. 14.8 
(2) 5% NIF + 5% Enhancer 
545.5 .+-. 33.3 
of Example 25 
Patch Formulation 
(1) 5% NIF (Control) 3.0 .+-. 0.0 
(2) 5% NIF + Enhancer 
4.73 .+-. 1.2 
of Example 25 
______________________________________ 
The results clearly indicated that the cream and patch formulations 
containing the Enhancer of Example 25 showed superior permeation for 
Nifedipine as compared to control. 
EXAMPLE 44 
Procedure of Example 39 was repeated with the following Nicotine (NI) cream 
and patch formulations. 
______________________________________ 
Average Cumulative Amount of 
NI in Micrograms Permeating 
over 51 Hours 
______________________________________ 
Cream Formulation 
(1) 1% NI (Control) 858.3 .+-. 73.0 
(2) 1% NI + 3% Enhancer 
1733.4 .+-. 76.0 
of Example 25 
Patch Formulation 
(1) 5% NI (Control) 151.7 .+-. 28.2 
(2) 5% NI + 1% Enhancer 
284.2 .+-. 20.5 
of Example 25 
(3) 5% NI + 3% Enhancer 
302.3 .+-. 92.4 
of Example 25 
(4) 5% NI + 5% Enhancer 
296.8 .+-. 25.1 
of Example 25 
______________________________________ 
The results clearly indicated that the cream and patch formulations 
containing the Enhancer of Example 25 showed superior permeation for 
Nicotine as compared to control. 
EXAMPLE 45 
Procedure of Example 39 was repeated with the following 17B-Estradiol (ES) 
patch formulations. Normal saline in the receptor compartment was replaced 
by ethanol/saline (3:7). 
______________________________________ 
Average Cumulative Amount of 
ES in Micrograms Permeating 
Patch Formulation 
over 51 Hours 
______________________________________ 
(1) 5% ES (Control) 30.90 .+-. 1.00 
(2) 5% ES + 9% Enhancer 
151.00 .+-. 5.80 
of Example 27 
______________________________________ 
The results clearly indicated that the patch formulation containing the 
Enhancer of Example 27 showed superior permeation for 17B-Estradiol as 
compared to control. 
EXAMPLE 46 
Procedure of Example 39 was repeated with the following two sets of 
Progesterone (PG) patch formulations. Normal saline in the receptor 
compartment was replaced with ethanol/saline (3:7). 
______________________________________ 
Average Cumulative Amount of 
PG in Micrograms Permeating 
Patch Formulation 
over 51 Hours 
______________________________________ 
SET A 
(1) 3% PG (Control) 176.3 .+-. 92.0 
(2) 3% PG + 5% Enhancer 
562.9 .+-. 25.0 
of Example 25 
(3) 3% PG + 5% Enhancer 
552.0 .+-. 31.0 
1-(2-Hydroxyethyl)- 
2-(heptadec-8-enyl)- 
2-imidazoline 
SET B 
(1) 3% PG (Control) 25 .+-. 17 
(2) 3% PG + 1% Enhancer 
238 .+-. 44 
of Example 30 
______________________________________ 
The results clearly indicated that the patch formulations containing the 
Enhancers of Examples 25 and 30 and the Enhancer 
1-(2-Hydroxyethyl)-2-(heptadec-8-enyl)-2-imidazolineshowedsuperiorpermeati 
on for Progesterone as compared to control. 
EXAMPLE 47 
Procedure of Example 39 was repeated with four different sets of 
Hydrocortisone (HC) cream formulations. 
______________________________________ 
Average Cumulative 
Amount of HC in 
Cream Formulation Micrograms permeating 
______________________________________ 
SET A over 24 Hours 
(1) 0.5% HC (Control) 1.657 .+-. 0.205 
(2) 0.5% HC + 1% Enhancer 
6.364 .+-. 0.55 
of Example 24 
(3) 0.5% HC + 1% Enhancer 
13.634 .+-. 7.68 
of Example 30 
(4) 0.5% HC + 1% Enhancer 
13.78 .+-. 2.91 
of Example 34 A 
(5) 0.5% HC + 1% Enhancer 
9.82 .+-. 3.18 
of Example 34 B 
SET B 
(1) 0.5% HC, Commercial OTC 
5.02 .+-. 0.30 
(Control) 
(2) 0.5% HC, Commercial OTC + 
13.63 .+-. 7.68 
1% Enhancer of Example 30 
(3) 1% HC, Commercial Rx (Control) 
4.94 .+-. 0.10 
(4) 1% HC, Commercial Rx + 
26.10 .+-. 14.92 
1% Enhancer of Example 30 
SET C 
(1) 1% HC, Commercial Rx (Control) 
3.38 .+-. 1.39 
(2) 1% HC, Commercial Rx + 
8.45 .+-. 2.41 
1% Enhancer of Example 30 
(3) 2.5% HC, Commercial Rx 
3.22 .+-. 0.30 
SET D Over 48 Hours 
(1) 0.5% HC (Control) 27.71 .+-. 1.84 
(2) 0.5% HC + 2% Enhancer 
67.53 .+-. 3.34 
of Example 25 
______________________________________ 
All four sets of studies indicated that the formulations containing 
Enhancers of Examples 24, 25, 30, 34 A and 34 B showed superior permeation 
for Hydrocortisone as compared to control. 
EXAMPLE 48 
Example 39 was repeated with 1% Diclofenac gel, with and without compound 
of Example 21, was evaluated. The aliquots were analyzed by U.V. 
Spectrophotometry and average cumulative amount of drug permeating over 24 
hours was calculated. The results shown below demonstrate that the 
Compound of Example 21 increases the permeation of Diclofenac through 
human skin when compared to control. 
______________________________________ 
Average Cumulative Amount 
of Diclofenac in Micrograms 
Gel Formulation permeating over 24 hours. 
______________________________________ 
1% Diclofenac (control) 
106.7 .+-. 33.5 
1% Diclofenac + 1% Compound 
154.13 .+-. 0.01 
of Example 21 
______________________________________ 
EXAMPLE 49 
The compounds of Examples 8 and 13 were tested as penetration enhancing 
agents according to the procedure below: 
Skin from female hairless mice, 8-12 weeks old, was removed from the 
animals and placed between the donor and the receptor compartments of 
diffusion cells, with normal saline (pH 7.2-7.4) bathing corium. The skin 
was incubated at 37.degree. C. and the ambient humidity. 
100 microliters of the solution containing 1 mg of test drug was applied to 
the epidermal surface within the donor compartment. The entire contents 
from the 4.2 ml receptor compartment bathing the corium were removed for 
analysis at 5 or 6, 12 and 24 hours intervals. In each case, the receptor 
compartment was refilled with 4.2 ml of fresh normal saline. 
The aliquots removed after 5 or 6, 12 and 24 hours were analyzed by HPLC 
using a C-18 reverse phase column. The test solutions used in this 
experiment contained 1% Hydrocortisone, 2% 1,2-propanediol and 2% 
penetration enhancer. The control solution did not have penetration 
enhancer. 
The results, as reported in Table 1 below, are average for two cells and 
clearly show that the compounds of Examples 8 and 13 have far superior 
penetration enhancing properties as compared to the control. 
TABLE 1 
______________________________________ 
% Penetration 
Penetration Enhancer 
hrs. 5 6 12 24 
______________________________________ 
(1) Compound of Example 8 
-- 16.1 28.2 49.1 
(2) Compound of Example 13 
-- 8.8 17.3 34.9 
(3) Control -- 1.3 1.8 2.4 
______________________________________ 
EXAMPLE 50 
The compounds of Examples 8 was tested as penetration enhancers according 
to the procedure outlined under Example 49. 1% hydrocortisone in the 
formulations of Example 49 was substituted by 1% 5-Fluorouracil. The 
results are outlined in Table 2 and clearly show that the compound of 
Example 8 is superior to the control. 
TABLE 2 
______________________________________ 
% Penetration 
Penetration enhancer 
hrs 6 12 24 
______________________________________ 
(1) Compound of Example 8 
59.2 60.3 60.5 
(2) Control 8.7 10.4 10.9 
______________________________________ 
EXAMPLE 51 
The following formulation is prepared. 
______________________________________ 
Solution % 
______________________________________ 
Griseofulvin 1 
4-Decyl-2-trifluoromethyl- 
1 
2-oxazoline 
C12-C15 benzoate 5 
Fragrance 0.1 
Ethanol 92.9 
______________________________________ 
This formulation is effective in the treatment of fungus infection. 
EXAMPLE 52 
An aerosol form of the formulation of Example 51 is prepared by preparing 
the following mixture: 
______________________________________ 
Formulation 
25% 
Freon* 75% 
______________________________________ 
*Freon is 75/25 Freon 114/12 
EXAMPLE 53 
The following cream formulation is prepared: 
______________________________________ 
% 
______________________________________ 
Clindamycin Base 1.0 
Stearyl alcohol, U.S.P. 
12.0 
Ethoxylated cholesterol 
0.4 
Synthetic spermaceti 
7.5 
Sorbitan monooleate 1.0 
Polysorbate 80, U.S.P. 
3.0 
4-Decyl-2-trifluoromethyl- 
0.9 
2-oxazoline 
Sorbitol solution, U.S.P. 
5.5 
Sodium citrate 0.5 
Chemoderm #844 0.2 
Purified water 68.0 
______________________________________ 
This formulation is effective in the treatment of acne. 
EXAMPLE 54 
The following solution formulations are prepared: 
______________________________________ 
A (%) B (%) 
______________________________________ 
Clindamycin base -- 1.0 
Clindamycin phosphate acid 
1.3 -- 
Sodium hydroxide 0.077 -- 
1 M Hydrochloric acid 
-- 2.27 
Disodium edentate.2H2O 
0.003 0.003 
Fragrances 0.5 0.5 
4-Decyl-2-trifluoromethyl 
1.0 1.0 
2-oxazoline 
Purified water 20.0 17.73 
Isopropanol 77.12 77.497 
______________________________________ 
These solutions are effective for the treatment of acne in humans. 
EXAMPLE 55 
The following solution formulation is prepared: 
______________________________________ 
% 
______________________________________ 
Neomycin sulfate 0.5 
Lidocaine 0.5 
Hydrocortisone 0.25 
4-Decyl-2-trifluoromethyl- 
1.0 
2-oxazoline 
Propylene glycol 97.75 
______________________________________ 
This solution is effective for the treatment of otitis in domestic animals. 
EXAMPLE 56 
The following sunscreen emulsion is prepared: 
______________________________________ 
% 
______________________________________ 
PABA 2.0 
Benzyl alcohol 0.5 
4-Decyl-2-trifluoromethyl- 
1.0 
2-oxazoline 
Polyethylene glycol 10.0 
Isopropyl lanolate 3.0 
Lantrol 1.0 
Acetylated lanolin 0.5 
C12-C15 benzoate 5.0 
Diisopropyl adipate 2.0 
Cetyl alcohol 1.0 
Veegum 1.0 
Propylene glycol 3.0 
Purified water 70.0 
______________________________________ 
EXAMPLE 57 
The following antineoplastic solution is prepared: 
______________________________________ 
% 
______________________________________ 
5-Fluorouracil 5 
4-Decyl-2-trifluoromethyl- 
1.5 
2-oxazoline 
Polyethylene glycol 5 
Purified water 88.5 
______________________________________ 
EXAMPLE 58 
The following insect repellant atomizing spray is prepared: 
______________________________________ 
% 
______________________________________ 
N,N-diethyltoluamide 
0.5 
4-Decyl-2-trifluoromethyl- 
0.5 
2-oxazoline 
Ethanol 99 
______________________________________ 
EXAMPLE 59 
The following cream formulation may be prepared containing about 0.001 to 1 
percent, with preferably 0.1% fluocinolone acetonide: 
______________________________________ 
% 
______________________________________ 
Oil Phase 
Fluocinolone acetonide 
0.1 
4-Decyl-2-trifluoromethyl 
1.6 
2-oxazoline 
Cetyl alcohol 9.3 
Stearyl alcohol 1.3 
Glyceryl monostearate 
3.8 
Water Phase 
Propylene glycol 10 
Sodium dodecyl sulfate 
0.1 
Deionized water q.s. 
100 
______________________________________ 
The steriod is dissolved in the vehicle and added to a stirred, cooling 
melt of the ingredients. The preparation is particularly useful for the 
treatment of inflamed dermatoses by topical application to the affected 
skin area. The amount and frequency of application is in accordance with 
standard practice for topical application of this steroid. Penetration of 
this steroid in the inflamed tissue is enhanced and a therapeutic level is 
achieved more rapidly and sustained for longer duration than when the 
steroid is applied in the conventional formulation. 
EXAMPLE 60 
The following analgesic gel is prepared: 
______________________________________ 
% 
______________________________________ 
Carbopol 941 1.5 
Diclofenac 1 
Ethanol 35 
Diisopropanolamine 1.8 
Diisopropyl adipate 5 
4-Decyl-2-trifluoromethyl-2-oxazoline 
2 
Water 53.7 
______________________________________ 
EXAMPLE 61 
The following cream formulation is prepared: 
______________________________________ 
% 
______________________________________ 
Isosorbide dinitrate 10.0 
Glycerol monostearate 5.5 
Polyoxyethylene stearate 
4.5 
C8-C18 fatty acid esters of a 
8 
glycerol ethoxylated with about 
7 moles of ethylene oxide 
4-Decyl-2-trifluoromethyl-2-oxazoline 
2 
Sorbic acid 0.165 
Ascorbyl palmitate 0.055 
Citric acid 0.1 
Na EDTA 0.014 
Fragrance 0.05 
Water 69.616 
______________________________________ 
This formulation is effective in the treatment of angina. 
EXAMPLE 62 
The following skin moisturizing formulation is prepared: 
______________________________________ 
% 
______________________________________ 
Pyrrolidonecarboxylic acid Na 
1 
Glycerine 4 
Citric acid 0.03 
Sodium citrate 0.05 
Allantoin 0.1 
Ethanol, 95% 9 
Oleth-15 1 
Linoleic acid 1 
4-Decyl-2-trifluoromethyl-2-oxazoline 
2 
Sunscreen agent 0.1 
Water 81.72 
______________________________________ 
EXAMPLE 63 
Example 39 is repeated, except the Isosorbide Dinitrate is substituted by 
0.5-10% amount by weight of each of the following therapeutically active 
agents. 
______________________________________ 
______________________________________ 
1-10 Indomethacin 
1-10 Diclofenac 
1-10 Piroxicam 
1-10 Propranolol 
0.5-5 Fentanyl 
0.5-5 Naloxone 
0.5-5 Hydromorphone 
1-10 Diltiazem 
1-10 Nicardipine 
1-10 Albuterol 
1-10 Metaproterenol 
0.1-3 Clonidine 
0.1-3 5-Fluorouracil 
0.5-5 Acyclovir 
0.1-3 Alprazolam 
0.5-5 Lisinopril 
0.5.5 Clindamycin 
1-10 Clotrimazole 
1-10 Miconazole 
1-10 Griseofulvin 
______________________________________ 
Comparable results are obtained. 
EXAMPLE 64 
Examples 51-62 are repeated, except the 
4-Decyl-2-trifluoromethyl-2-oxazoline is replaced with an equal amount of 
each of the following listed compounds, and comparable results are 
obtained. 
4-trifluoromethyl-2-undecyl-2-oxazoline 
4-Methyl-4-trifluoromethyl-2-undecyl-2-oxazoline 
4,4-Dimethyl-2-(1-dodecen-2-yl)-2-oxazoline 
4-t-Butyl-2-(dodecyl)-2-oxazoline 
4,4-Dimethyl-2-(2-dodecyl)-2-oxazoline 
2-(Methyl-2-decyl)-2-oxazoline 
4,4-Dimethyl-2-(2-methyl-2-decyl)-2-oxazoline 
4-Methyl-4-[1-(2-oxadodecyl)]-2-trifluoromethyl-2-oxazoline 
4,4-Dimethyl-2-[1-(3-oxaundecyl)]-2-oxazoline 
1-(2-Hydroxyethyl)-2-undecyl-2-imidazoline 
1-(2-Ethoxyethyl)-2-undecyl-2-imidazoline 
1-(2-Carbethoxyethyl)-2-undecyl-2-imidazoline 
1-(2-Hydroxyethyl)-2-undecyl-2-imidazoline acetate 
4-Decyl-2-trifluoromethyl-2-imidazoline 
1-Dodecyl-2-trifluoromethyl-2-imidazoline 
4-Dodecyl-2-ethoxy-2-imidazoline 
4-Dodecyl-2-ethoxy-2-oxazoline 
The next preceeding list of compounds, along with 
4-Decyl-2-trifluoromethyl-2-oxazoline have been found to be significantly 
superior penetration enhancing agents, both as compared with the prior art 
and as compared with the other examples given herein. 
While particular embodiments of the invention have been described it will 
be understood of course that the invention is not limited thereto since 
many obvious modifications can be made and it is intended to include 
within this invention any such modifications as will fall within the scope 
of appended claims. 
Industrial Application 
This invention is useful in the pharmaceutical and agricultural industries 
and in the preparation of compositions for cosmetic, diagnostic and 
therapeutic use.