Retinoic acid derivatives

Esters and amides of all-trans-retinoic acid are disclosed which are useful for their ultraviolet (UV) absorption properties.

BACKGROUND OF THE INVENTION 
Retinoic acid is known to be useful for the treatment of acne. See, for 
example, U.S. Pat. No. 3,729,568, which discloses the use of retinoic acid 
compositions for the treatment of acne. While retinoic acid is also known 
to have ultraviolet (UV) absorption properties, it is not useful as a 
sunscreen agent for skin application because of its irritating effects on 
human skin in effective sunscreening amounts, as well as other metabolic 
effects. Although these effects are useful in the treatment of acne, they 
negate the usefulness of retinoic acid as a human sunscreening agent. 
Surprisingly, of the forty-eight novel esters and amides of 
all-trans-retinoic acid which we have prepared, forty-one have been found 
to be non-irritating to human skin and to be substantially free of the 
metabolic effects characteristic of retinoic acid. The other seven 
compounds, which are useful for the treatment of acne, are the subject of 
our United States Patent 4,055,659 entitled "Retinoic Acid Derivatives." 
SUMMARY OF THE INVENTION 
This invention relates to novel esters and amides of all-trans-retinoic 
acid which are non-irritating to human skin and are substantially free of 
the metabolic effects characteristic of retinoic acid. More particularly, 
the present invention relates to: 
(A) novel esters of all-trans-retinoic acid having the following formula: 
##STR1## 
wherein X is a member selected from the group consisting of: 
##STR2## 
2-cyclohexylethyl; 10-carbomethoxydecyl; 4-hydroxybutyl; cholesteryl; 
mixed m- and p-vinylbenzyl; and 4-bromobenzyl; 
(B) novel esters of all-trans-retinoic acid having the following formula: 
##STR3## 
wherein Y is a member selected from the group consisting of: 
cholesteryloxy; phenyl; 4-bromophenyl; 4-methoxyphenyl; 4-nitrophenyl; 
4-hydroxyphenyl; 4-methylphenyl; 4-cyanophenyl; 4-ethoxyphenyl; 
4-acetoxyphenyl; 2-naphthyl; 4-biphenyl; 2,5-dimethoxyphenyl; 
2,4-dichlorophenyl; 2,4-dimethylphenyl; 3,4-diacetoxyphenyl; 
3,4,5-trimethoxyphenyl; and 2,4,6-trimethylphenyl; and 
(C) novel amides of all-trans-retinoic acid having the following formula: 
##STR4## 
wherein Z is a member selected from the group consisting of: 
n-propylamino; tert-butylamino; 1,1,3,3-tetramethylbutylamino; 
1-morpholino; 4-hydroxyphenylamino; 4-carbomethoxy-2-hydroxyphenylamino; 
.beta.-(3,4-dimethoxyphenyl)-ethylamino; 2-benzothiazolylamino; 
1-imidazolyl; 1-(2-nicotinoylhydrazolyl): 
##STR5## 
1-benzotriazolyl; 1-(1,2,4-triazolyl); 
##STR6## 
It has surprisingly been discovered that the retinoic acid derivatives of 
the invention, while possessing very good ultraviolet light absorption 
properties, do not have irritating effects on the skin and are 
substantially free of the metabolic effects which are characteristic of 
retinoic acid and, therefore, are useful as human sunscreen agents. That 
the compounds of the invention are substantially free of the metabolic 
effects characteristics of retinoic acid is demonstrated by their 
inactivity in the following test measuring DNA synthesis in which retinoic 
acid is significantly active at greater than 95% confidence level. 
Further, the present compounds generally do not produce the excessive 
erythema characteristic of retinoic acid. 
Ten male guinea pigs (Hartley strain) weighing ca. 400 g. each were used 
for each compound to be tested. The animals were housed singly in wire 
cages, handled daily during experimentation, provided chow and water ad 
libitum, and maintained on 12/12 hour light/dark cycles. Prior to the 
experimental procedure, the animals were maintained as just described for 
three days. 
On the first day of the test, one ear (dorsal skin) of each animal was 
randomly selected and treated with 0.025 ml. of the experimental solution, 
and the other ear was treated with an equal volume of the placebo vehicle 
(control). Ten animals for each compound were so treated. These topical 
applications were made at 9:00 a.m. on the first 4 days of the experiment. 
All the animals received chronic administration of tritiated thymidine 
(.sup.3 H-TdR) for these first four days. The .sup.3 H-TdR was given 
intraperitoneally at about 9:30 a.m., 1:30 p.m., and 5:00 p.m. of each day 
(10 micro Curie in 0.1 ml. H.sub.2 O/injection; specific activity=2.0 
Curie/millimole). On the fifth day (9:00 a.m.), the animals were killed, 
and 6 mm. diameter punches of ear skin from the central portion of the 
treated sites were harvested. 
Each of these tissue samples was solubilized at 37.degree.-50.degree. C. 
for 13 days in 1 ml. of an alkali solubilizer sold by Amersham-Searle Co. 
under the registered trademark "NCS" Solubilizer. The dissolved tissues 
kept in nylon scintillation vials were acidified with 0.025-0.050 ml. of 
acetic acid, and diphenyloxazole in toluene was added as a flour to detect 
the beta particles emitted by absorbed tritiated thymidine. The 
radioactivity of the samples was determined by multiple counting on a 
Beckman LS Counter. All count per minute values were quench corrected by 
external standardization to yield disintegrations per minute (dpm)/6 mm. 
punch of skin. Quench correction is especially important as some of the 
samples show faint yellow coloration due to presence of the retinyl 
derivatives, and therefore present considerable color quench. 
The test compounds were found to be inactive (confidence level less than 
90%) in the above test at up to 0.2% concentration by weight when applied 
in 50:50 parts by weight propylene glycol-ethanol or 35:35:30 parts by 
weight propylene glycol-ethanol-chloroform. 
The subject compounds strongly absorb ultraviolet (UV) light, generally 
above 280 nm., and are useful as UV-screening materials, for example, in 
plastic products and sunburn preventive formulations. They may be used as 
UV-absorbers in plastics and resins such as, for example, polystyrene, 
polyethylene, polypropylene, polyacrylics (e.g., methacrylate resins, 
polyacrylamides, polyacrylonitrile fibers, etc.), polyamide (e.g., nylon) 
fibers, and polyester fibers. The inclusion of about 0.01-5.0 percent of 
the absorber, based on the polymer weight, is usually sufficient to render 
protection against UV light, such as in plastic films, light filters, etc. 
The absorber may be incorporated into the mixture of monomers before 
polymerization to form the polymer or it may be incorporated into the 
polymer at other stages during its handling, as by milling into the 
polymer together with other compounding ingredients, or during the 
spinning of the polymer into fibers, etc. The compounds are preferably 
employed as sunscreening agents in typical anti-sunburn formulations in 
amounts of about 0.5-10 percent by weight (see G. W. van Ham & W. P. 
Herzog, Chapter 6, "The Design of Sunscreen Preparations," in "Drug Design 
IV," E. J. Ariens, Ed., Academic Press, N.Y. and London 1973). 
The compounds of the invention may be prepared by one of the following 
methods: 
(A) In the first method of preparation, all-trans-retinoic acid or an 
alkali metal salt of all-trans-retinoic acid is reacted with an 
appropriate alkyl halide. This reaction is conducted in an appropriate 
inert organic solvent, such as for example an ether (e.g., diethylether, 
tetrahydrofuran, and the like), an ester such as ethyl acetate, or the 
like. The desired product may be isolated and purified by methods known in 
the art. 
(B) In the second method, all-trans-retinoyl chloride is reacted with an 
appropriate amine or alcohol to form the desired ester or amide. The 
alcohol or amine is preferably present in a slight molar excess, and the 
reaction may be conducted in an appropriate inert organic solvent such as 
for example an aromatic hydrocarbon (e.g., benzene, toluene, xylene, and 
the like), a halogenated hydrocarbon (e.g., chloroform, carbon 
tetrachloride and the like), and the like. 
(C) The hydrazone compounds of the invention are prepared by refluxing 
all-trans-retinoyl hydrazide with the appropriate ketone in a lower 
alkanol solution. The solution preferably also can contain a trace of 
pyridine. 
(D) The imide compounds of the invention may be prepared by reacting 
all-trans-retinoyl chloride with the appropriate N-hydroxyimide in an 
appropriate inert organic solvent such as for example an aromatic 
hydrocarbon (e.g., benzene, toluene, xylene, or the like), a tertiary 
amide such as N,N-dimethylformamide, and the like.

The desired products may be isolated and purified by methods known in the 
art. The preparation of the compounds of this invention is illustrated by 
the following examples. 
EXAMPLE I 
10-Carbomethoxydecyl all-trans-Retinoate 
The following were stirred together at 65.degree. C. in a nitrogen 
atmosphere for 24 hours: powdered potassium all-trans-retinoate (3.38 g.; 
0.010 mole); powdered potassium iodide (1.66 g.; 0.010 mole); methyl 
11-bromoundecanoate (4.20 g.; 0.0150 mole); dry tetrahydrofuran, 30 ml. 
The reaction mixture was filtered with suction through sintered glass, and 
the filtrate was evaporated to give a thick red liquid. The liquid was 
dissolved in 100 ml. of 95:5 petroleum ether-benzene and put on a 
chromatographic column of 40-140 mesh silica gel. The column was eluted 
with 50:50 petroleum ether-benzene. Fractions containing a mixture of 
retinoate ester and unreacted bromoester were collected and evaporated to 
give a yellow oil from which the retinoate crystallized when cooled and 
seeded. The crude crystals were suction filtered from unreacted 
bromoester. One recrystallization from 12.5 ml. of methanol yielded the 
retinoate ester, melting point 53.degree.-55.degree. C.; which showed the 
correct proton magnetic resonance spectrum and elemental analysis. Anal. 
Calcd. for C.sub.32 H.sub.50 O.sub.4 : C, 77.1; H, 10.1. Found: C, 76.7; 
H, 10.1. 
EXAMPLE II 
Cholesteryl all-trans-Retinoate 
A solution of retinoyl chloride was prepared from 3.0 g of 
all-trans-retinoic acid and 0.92 g. of phosphorous trichloride in 20 ml. 
of benzene. This solution was added during 18 minutes to 3.48 g. of 
cholesterol and 28 ml. of N,N-dimethylaniline with stirring and heating to 
90.degree. C. in an open-neck flask. Stirring was continued for an 
additional 40 minutes, during which most of the benzene evaporated. The 
reaction mix was dissolved in 300 ml. of ethyl ether, and the ether 
solution was successively extracted with three 50-ml. portions of cold 2 N 
sulfuric acid, two 50-ml. portions of cold saturated sodium bicarbonate 
solution, and four 50-ml. portions of cold water. Crystals formed in the 
ether solution as it stood in the refrigerator overnight. They were twice 
recrystallized from 50:50 chloroform-ethanol (20 ml. per gram), giving 
pure product, melting point 162.degree.-163.degree. C. The proton magnetic 
resonance spectrum was consistent with the structure. Anal. Calcd. for 
C.sub.47 H.sub.72 O.sub.2 : C, 84.4; H, 10.8. Found: C, 84.5; H, 10.8. 
EXAMPLE III 
N,N'-Dicyclohexyl-N-(all trans-Retinoyl)-Urea 
The following were magnetically stirred in a 50-ml. flask at room 
temperature for 48 hours: 3.00 g. of all-trans-retinoic acid, 2.06 g. of 
N,N'-dicyclohexylcarbodiimide, 1.01 g. of triethylamine, 15 ml. of dry 
tetrahydrofuran. The solid in the reaction mixture was filtered off and 
washed with 20 ml. of tetrahydrofuran. Evaporation of the tetrahydrofuran 
filtrate plus washings left a yellow, pasty solid which was then diluted 
with 150 ml. of ethyl ether. The ether was washed with 25 ml. of cold 5% 
hydrochloric acid, with 25 ml. of cold saturated potassium bicarbonate, 
and finally with four successive 25-ml. portions of ice water. During the 
washing procedure, a finely-divided solid separated from the ether. It was 
crystallized from 112 ml. of acetone. The crystals melted at 
171.degree.-172.degree. C. The proton magnetic resonance spectrum 
confirmed the structure of the compound. Anal. Calcd. for C.sub.33 
H.sub.50 N.sub.2 O.sub.2 : C, 78.2; H, 9.94; N, 5.53. Found: C, 78.2; H, 
10.2; N, 5.43. 
EXAMPLE IV 
Trans-.beta.-Ionone (All-trans-Retinoyl)-Hydrazone 
A solution of retinoyl chloride was prepared from 3.0 g. of 
all-trans-retinoic acid and 0.92 g. of phosphorous trichloride in 50 ml. 
of benzene by stirring at room temperature for 2.2 hours. This solution 
was added dropwise to a stirred solution of 4.80 g. of dry hydrazine in 20 
ml. of anhydrous ethyl ether during 30 minutes while cooling in an ice 
bath. Stirring was continued for three hours at room temperature, then for 
an additional hour at 50.degree.-60.degree. C. The reaction mixture was 
diluted with 150 ml. of ethyl ether, then extracted with four 25-ml. 
portions of ice water. After drying over sodium sulfate, the ether 
solution was evaporated leaving crude all-trans-retinoyl hydrazide. 
The hydrazide was dissolved in 15 ml. of 95% ethanol, and to the solution 
was added 7.68 g. of trans-.beta.-ionone in 15 ml. of 95% ethanol and one 
drop of pyridine. The solution was refluxed for 15 minutes, filtered, and 
cooled in ice, causing precipitation of yellow crystals. These crystals 
were recrystallized from 1:8 chloroform-ethanol (22.5 ml. per gram), 
giving pure product, melting point 183.degree.-185.degree. C., which 
exhibited the correct proton magnetic resonance spectrum. Anal. Calcd. for 
C.sub.33 H.sub.48 N.sub.2 O: C, 81.1; H, 9.90; N, 5.73. Found: C, 81.1; H, 
10.0; N, 5.51. 
EXAMPLE V 
N-(All-trans-Retinoyloxy)-Succinimide 
A solution of retinoyl chloride was prepared by magnetically stirring 3.00 
g. of all-trans-retinoic acid and 0.92 g. of phosphorous trichloride for 
two hours in 50 ml. of dry benzene at room temperature. This solution was 
added dropwise during 30 minutes at room temperature to a stirred solution 
of 5.75 g. of N-hydroxysuccinimide dissolved in 10 ml. of dry, 
N,N-dimethylformamide. The reaction mixture was stirred for 1.5 hours 
longer, then immersed in an 80.degree. C. oil bath for 15 minutes. The 
reaction mixture was diluted with 150 ml. ethyl ether, and the thick red 
oil which did not dissolve was discarded. The ether solution was washed 
with five 30-ml. portions of ice water and dried over sodium sulfate. 
Evaporation of the solvents left a yellow powder which was recrystallized 
twice from 1:2 chloroform-n-hexane (7.5 ml. per gram) and once from 
isopropanol (25 ml. per gram). Product melting point was 
177.degree.-179.degree. C. The proton magnetic resonance spectrum was 
consistent with the structure. Anal. Calcd. for C.sub. 24 H.sub.31 
NO.sub.4 : C, 72.5; H, 7.86; N, 3.52. Found: C, 72.5; H, 7.91; N, 3.50. 
EXAMPLE VI 
2-Cyclohexylethyl all-trans-Retinoate 
The following were refluxed in an aluminum foil-covered flask under 
nitrogen for 28 hours: 5.0 g. of all-trans-retinoic acid; 3.5 g. of 
cyclohexylethyl bromide; 15.0 g. of anhydrous potassium carbonate; 0.05 g. 
of potassium iodide; 0.05 g. of p-methoxyphenol; and 50 ml. of 
tetrahydrofuran. The reaction mixture was then diluted with 200 ml. of 
n-hexane and filtered through a one-half-inch-thick pad of alumina. The 
pad was eluted with 100 ml. of 1:1 benzene-n-hexane and the washings were 
combined with the original filtrate. The solvents were removed on a rotary 
evaporater, and the residual yellow oil was placed on a silica gel column 
(100 g.) with 20 ml. of n-hexane. The column was eluted with 600 ml. of 
1:1 benzene-n-hexane. The first 200 ml. of eluted solution were discarded; 
the next 300 ml. were collected, and the solvent was evaporated. The 
yellow oil residue was evacuated for two days at a pressure of 0.03 mm. 
and room temperature. The proton magnetic resonance spectrum of the 
resulting oil was consistent with the structure. Anal. Calcd. for C.sub.28 
H.sub.42 O.sub.2 : C, 81.9; H, 10.3. Found: C, 81.8; H, 10.3. 
EXAMPLE VII 
4-Hydroxybutyl all-trans-Retinoate 
A solution of retinoyl chloride was prepared by stirring 3.0 g. of 
all-trans-acid and 0.92 g. of phosphorous trichloride in 25 ml. of dry 
benzene for about two hours. A solution of 6.0 ml. of 1,4-butanediol and 
8.0 ml. of pyridine was stirred magnetically, cooled to 4.degree. C., and 
the retinoyl chloride solution was added during five minutes. The reaction 
mixture was stirred at 20.degree. C. for 50 minutes, and then at 
43.degree. C. for 15 minutes, all under a nitrogen atmosphere. The 
lightamber reaction mixture was diluted with 20 ml. of ethyl ether. The 
resulting solution was washed with two 20-ml. portions of 5 percent 
hydrochloric acid. 20 ml. of cold 10 percent sodium bicarbonate solution, 
and 20 ml. of cold brine solution. The washed ether solution was then 
dried over magnesium sulfate. 
The washed and dried solution was placed on 80 ml. of alumina and eluted 
successively with 200 ml. of ethyl ether and 600 ml. of ethyl acetate. 
Crude product was concentrated from the ethyl acetate eluate and again 
placed on alumina (75 ml.) with the aid of 20 ml. of ethyl ether. The 
product was eluted from the alumina with 1,400 ml. of ethyl ether. 
Composition of the fractions was monitored by thinlayer chromatography. 
The appropriate fractions were combined, the ether evaporated, and the 
residual viscous yellow oil was evacuated at a pressure of 0.005 mm. for 
24 hours. The proton magnetic resonance spectrum of the product was 
consistent with the structure. Anal. Calcd. for C.sub.24 H.sub.36 O.sub.3 
: C, 77.4; H, 9.74. Found: C, 77.4; H, 9.96. 
EXAMPLE VIII 
All-trans-Retinoyloxyacetyl-3,4,5-Trimethoxybenzene: 
Potassium retinoate was made by neutralizing 3.00 g. of all-trans-retinoic 
acid in 30 ml. of tetrahydrofuran with 15.6 ml. of 0.640 N methanolic 
potassium hydroxide. The solvent was evaporated in a rotary evaporator, 
and the residue was dried at a pressure of less than 0.5 mm. for several 
hours. 
Powdered potassium retinoate (3.03 g.) in 20 ml. of hexamethylphosphoramide 
was stirred overnight at room temperature with 2.89 g. of 
2-bromo-3',4',5'-trimethoxyacetophenone. The turbid yellow reaction 
mixture was poured into 30 ml. of cold 5% hydrochloric acid, precipitating 
a sticky yellow solid. The solid hardened when washed by decantation with 
60 ml. of cold water. The solid was dissolved in 200 ml. ethyl ether, and 
the ether solution was washed with five 25-ml. portions of cold water. 
After drying over sodium sulfate, the ether solution was evaporated 
leaving a yellow powder. 
The powder was recrystallized twice from 1:2 chloroform-methanol (7.5 ml. 
per gram), giving yellow crystals, melting point 
123.0.degree.-123.5.degree. C. The proton magnetic resonance spectrum of 
the product was consistent with the structure. Anal. Calcd. for C.sub.31 
H.sub.40 O.sub.6 : C, 73.2; H, 7.93. Found: C, 73.3; H, 7.93. 
EXAMPLE IX 
4-(All-trans-Retinoyl)-Aminophenol 
A solution of retinoyl chloride was prepared by magnetically stirring 3.00 
g. of all-trans-retinoic acid and 0.92 g. of phosphorous trichloride for 
2.25 hours in 50 ml. of dry benzene. During 21 minutes, the retinoyl 
chloride solution was then added to a solution of 5.46 g. of 4-aminophenol 
in 16 ml. of anhydrous N,N-dimethylformamide and 2 ml. of anhydrous ethyl 
ether, while stirring under a nitrogen atmosphere and cooling in an ice 
bath. Stirring was then continued for three hours at room temperature and 
for an hour more at 50.degree. C. 
The reaction mixture was diluted with 150 ml. of ethyl ether. The ether 
solution was extracted with two 25-ml. portions of cold 5% hydrochloric 
acid and then was washed with four 25-ml. portions of cold water. After 
the washed solution was dried over sodium sulfate, the solvent was 
evaporated, leaving a dark-yellow solid. The solid was recrystallized 
first from methanol (6 ml. per gram), then from 1:1.7 chloroform-n-hexane 
(8 ml. per gram). The product had a melting point of 
159.degree.-160.degree. C. The proton magnetic resonance spectrum of the 
product was consistent with the structure with no extraneous resonances. 
Anal. Calcd. for C.sub.26 H.sub.33 NO.sub.2 : C, 79.8; H, 8.49; N, 3.58. 
Found: C, 79.5; H, 8.67; N, 3.56. 
EXAMPLE X 
Following the method of Example IV, but substituting an equivalent amount 
of acetone for the trans-.beta.-ionone used therein, there is prepared 
acetone (all-trans-retinoyl)hydrazone; m.p. 174.degree.-175.degree. C. 
EXAMPLE XI 
Following the method of Example V, but substituting an equivalent amount of 
N-hydroxyphthalimide for the N-hydroxysuccinimide used therein, there is 
prepared N-(all-trans-retinoyloxy)-phthalimide; m.p. 
177.degree.-178.degree. C. 
EXAMPLE XII 
Following the method of Example VIII, but substituting an equivalent amount 
of the appropriate halogen-containing compound for the 
2-bromo-3',4',5'-trimethoxyacetophenone used therein, the following are 
prepared: 
______________________________________ 
Compound m.p. (.degree.C.) 
______________________________________ 
Cholesteryl all-trans-Retinoyloxyacetate 
104-106 
Mixed m- and p-vinylbenzyl all-trans- 
Retinoates Liquid 
4-Bromobenzyl all-trans-Retinoate 
70.0-70.5 
all-trans-Retinoyloxyacetylbenzene 
132-133 
4-(all-trans-Retinoyloxyacetyl)-bromobenzene 
136-137 
4-(all-trans-Retinoyloxyacetyl)- 
methoxybenzene 126-127 
4-(all-trans-Retinoyloxyacetyl)- 
nitrobenzene 151-152 
4-(all-trans-Retinoyloxyacetyl)-phenol 
180-181 
4-(all-trans-Retinoyloxyacetyl)-toluene 
125-126 
4-(all-trans-Retinoyloxyacetyl)-benzo- 
nitrile 178-179 
4-(all-trans-Retinoyloxyacetyl)-ethoxy- 
benzene 124.5-125.5 
4-(all-trans-Retinoyloxyacetyl)- 
acetoxybenzene 132--133 
2-(all-trans-Retinoyloxyacetyl)-naphthalene 
120-121 
4-(all-trans-Retinoyloxyacetyl)-biphenyl 
142-143 
all-trans-Retinoyloxyacetyl-2,5-dimethoxy- 
benzene 98-99 
all-trans-Retinoyloxyacetyl-2,4-dichloro- 
benzene 1:06-107 
all-trans-Retinoyloxyacetyl-2,4-dimethyl- 
benzene 117.5-1118.5 
all-trans-Retinoyloxyacetyl-3,4-diacetoxy- 
diacetoxy- 
benzene 123--124 
all-trans-Retinoyloxyacetyl-2,4,6-tri- 
methylbenzene 116-117 
______________________________________ 
EXAMPLE XIII 
Following the method of Example IX, but substituting an equivalent amount 
of the appropriate amine for the 4-aminophenol used therein, the following 
are prepared: 
______________________________________ 
Compound m.p. (.degree. C.) 
______________________________________ 
N-n-Propyl all-trans-retinamide 
113-115 
N-Tert.-butyl all-trans-retinamide 
139-141 
N-(1,1,3,3-Tetramethyl)-butyl all-trans- 
retinamide Glass 
N-(all-trans-Retinoyl)-morpholine 
82-84 
Methyl 4-(all-trans-Retinoylamino)- 
salicylate 198-199 
N-(all-trans-Retinoyl)-imidazole 
113-115 
1-Nicotinoyl-2-(all-trans-retinoyl)-hydrazine 
191-194 
1-(all-trans-Retinoyl)-benzotriazole 
140-141 
1-(all-trans-Retinoyl)-1,2,4-triazole 
141-142 
N-[.beta.-(3,4-Dimethoxyphenyl)ethyl]-all-trans- 
retinamide 140-142 
2-(all-trans-Retinoylamino)-benzothiazole 
219-221 
______________________________________ 
The use of the compounds of the invention is illustrated by the following 
example. All parts are by weight. 
EXAMPLE XIV 
The following ingredients are homogeneously mixed to produce a formulation 
useful as a human sunscreening cream for topical application to the skin: 
______________________________________ 
Ingredient Parts 
______________________________________ 
Glyceryl Stearate 10.0 
Isopropyl Myristate 10.0 
Spermaceti 5.0 
Cetyl Alcohol 2.5 
Steareth-20 2.625 
Steareth-2 0.375 
Propylene Glycol 5.0 
Xanthan Gum 0.3 
Sorbic Acid 0.2 
Butylated Hydroxytoluene 
0.05 
Active Ingredient 2.5 
Water 61.45 
______________________________________ 
The active ingredient is any of the compounds of the present invention.