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Patent 1051917 Summary

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(12) Patent: (11) CA 1051917
(21) Application Number: 217455
(54) English Title: CARBOXYLATE SALTS OF ALKANOLAMINE ESTERS OF PARA DIALKYLAMINOBENZOIC ACID AND THEIR USE AS SUN-SCREENING AGENTS
(54) French Title: CARBOXYLATES D'ESTERS D'ALCANOLAMINES ET D'ACIDE PARA-DIALKYLAMINOBENZOIQUE POUR CREMES SOLAIRES
Status: Expired
Bibliographic Data
Abstracts

English Abstract



ABSTRACT

Sun-screening compounds, useful to protect the skin
and hair against deleterious effect upon exposure to ultra-
violet radiation, of the formula:

Image

where R1 and R2 are independently straight or branched chain
lower alkyl; Y is C2-C6 alkylene; X is R3-COO?, HOOC-R4-COO?
or ?OOC-R4-COO?, where R3 is alkyl of 1 to 18 carbon atoms
and R4 is alkylene of 1 to 18 carbon atoms; and n is 1 when
X is R3-COO? or HOOC-R4-COO? or n is 2 when X is
?OOC-R4-COO?.
Sun-screening compositions containing such compounds and a
cosmetically acceptable diluent or carrier, and methods of
using such compositions, are also disclosed.


Claims

Note: Claims are shown in the official language in which they were submitted.


THE EMBODIMENTS OF THE INVENTION IN WHICM AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Sun-screening compounds of the formula:


Image


where R1 and R2 are independently straight or branched chain lower alkyl;
Y is C2-C6 alkylene; X is R3-COO ?, HOOC-R4-COO ? or ? OOC-R4-COO ?, where
R3 is alkyl of 1 to 18 carbon atoms and R4 is alkylene of 1 to 18 carbon
atoms; and n is 1 when X is R3-COO ? or HOOC-R4-COO ? or n is 2 when X is
? OOC-R4-COO ? .
2. A compound according to Claim 1, wherein R1 and R2 are straight
or branched chain alkyl of 1 to 3 carbon atoms.

3. A compound according to Claim 1 or 2, wherein R3 is straight or
branched chain alkyl of 7 to 17 carbon atoms.

4. A compound according to claim 1, wherein X is R3-COO ? , R3 is
straight or branched chain alkyl of 7 to 17 carbon atoms and n is 1.
5. A compound according to claim 1, wherein X is HOOC-R4-COO ? and
n is 1.

6. A compound according to Claim 5, wherein R4 is lower alkylene.

7. A compound according to claim 1, wherein X is ? OOC-R4-COO ? and
n is 2.

8. A compound according to Claim 7, wherein R4 is lower alkylene.

14

9. A compound according to Claim 1 which 1


Image


10. A compound according to Claim 1 which is


Image



11. A compound according to Claim 1 which is



Image




12. A compound according to Claim 1 which is


Image


13. A compound according to Claim 1 which is



Image



14. A compound according to Claim 1 which is



Image


15. A compound according to Claim 1 which is


Image

16

16. A compound according to claim 1 which is



Image

17. A sun-screening composition, comprising an amount effective to
absorb ultraviolet radiation of the compound of claim 1 together with a
cosmetically acceptable diluent or carrier.

18. A method of protecting skin or hair from ultraviolet radiation
which comprises applying to the skin or hair the composition of claim 17.

17

Description

Note: Descriptions are shown in the official language in which they were submitted.


1051917
The present invention relates to sun-screenine coT~ositions,
methods of using the same and novel sun-screening compounds.
Ultraviolet radiation on the skin, such as from the sun, of a
wavelength of 290 - 313 mu is known to produce erythema, particularly in
fair skinned subJects. On the other hand, ultraviolet radiation of from
315 - 320 mu to 350 - 400 mu promotes a tanning of the skin. To be effec-
tive, a sun-screening composition must at least remove substantially all of
the burning rays, and in many instances a good portion of the tanning rays.
It is, therefore, an ob~ect of this invention to provide novel
sun-screening compounds that are effective to prevent erythema.
It is a further ob~ect of the invention to provide new sun-screen-
ing compositions containing the sun-screening compounds of the invention.
These ob~ects are provided by the provision of a sun-screening
compound of formula (I):




~ > ~--~ COOy~ ~ y




where Rl and R2 are independently straight or branched chain lower alkyl,
Y is C2-C6 Plkylene; X is R3-COO e, HOOC-R4-COO ~or ~OOC-R4-COO ~,
where R3 is alkyl of 1 to lô carbon atoms and R4 is alkylene of 1 to 18
carbon atoms; and n is 1 when X is R3-COO ~ or HOOC-R4-COO or n is 2 when
X isG~ OOC-R~-COO~. Such compounds show absorption of ultraviolet light
in the range of 290 - 315 mu and have good substantivity on the skin.
The term lower alkyl denotes a univalent saturated branched or
straight hydrocarbon chain containing from 1 to 6 carbon atoms. Represen-

tative of such lower aIkyl groups are thus methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec. butyl, tert. butyl, pentyl, isopentyl, neopentyl,
tert. pentyl, hexyl, and the like. Ther term alkylene of 2 to 6 carbon atoms
denotes a divalent saturated straight or branched hydrocarbon obtained by
removing a hydrogen atom from the lower alkyl defined above, excluding

-- 1 --

1051917
methyl.
The term alkyl of 1 to 18 carbon atoms denotes a univalent sat-
urated branched or straight hydrocarbon chain containin~ from 1 to 1~ car-
bon atoms. Representative of such alkyl groups are thus methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec. butyl, tert. butyl, pentyl,
isopentyl, neopentyl, tert. pentyl, hexyl, isohexyl, heptyl, octyl, nonyl,
decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl,
heptadecyl, and the like. The term alkylene of 1 to 18 carbon atoms denotes
a divalent saturated branched or straight hydrocarbon chain obtained by
removing a hydrogen atom from the alkyl defined above.
In a preferred embodiment of the invention Rl and R2 are C1-C3
straight or branched chain alkyl.
Itis further preferred to employ compounds in which the anion, X,
is derived from a higher saturated aliphatic carboxylic acid, such as a
C8-C18 saturated aliphatic monocarboxylic acid, since such compounds are
water-insoluble and thus resist removal from the skin by water washing.
Compounds of this type have the ~ormula (II):




(II) ~ ~ ~ ~ GOOY~ 3-C00




where Rl, R2 and Y are as defined above, and R3 is straight or branched
chain aIkyl of 7 to 17 carbon atoms.
In another preferred embodiment of the invention, the anion, X,
is derived from a saturated aliphatic dicarboxylic acid ~HOOC-R4-COOH), and

n is 1 or 2, preferably 2. ~he double salt of the dicarboxylic acid is
preferred over the mono-salt, since the double salt shows improved affinity
for the skin. Such compounds have the formula (III):




-- 2 --


- : ~ -. :

105~9~7


(III) ~ > ~ COOY-4 ~ Z R COO ~




where Rl, R2, R4 and n are as defined above Z is -COOH or -COO ~ , and n is
1 when Z is -COOH and n is 2 when Z is -COO ~ . Preferably, the dicarboxylic
acid is one where R4 is lower alkylene, and most preferably alkylene of 1 to
4 carbon atoms.
Compounds which are active as sun-screening agents benzylacetone,
quninie sulfate and ethyl umbelliferone. Alkyl esters of ~-dialkylamino-
benzoic acid have also been proposed for use as sun-screening agents in

United States Patents 2,853,423, 3,402,207, and 3,479,428. In view of this
highly empirical nature of the ability of a compound selectively to absorb
ultraviolet radiation in the narrow range of 290 - 315 mu, it was not
expected that the compounds of formula (I) would be useful as sun-screening
agents.
Dialkylaminoalkyl esters of diakylamino benzoic acid are proposed
in ~nited States Patent 820,830, but such compounds are strong bases (pH 11- ~ .
12 in aqueous solution) and hence would be too irritating and harmful to the
eyes and skin for application to the skin or hair. The hydrochloride salt
of diethylaminoethyl ~-dimethylaminobenzoate is described as a local
anesthetic in Chem. Abstracts, 63:1657c. So far as we are aware, the sun-
screening compounds of formula (I) are novel.
The compounds of formula (I) can be prepared by reacting dialkyl-
aminoalkyl ~-dialkylaminobenzoate with the desired aliphatic mono- or
dicarboxylic acid according to processes A or B.


1~35~91~



A. n~ OOY~ + R3COOH - > (1)
R2




where n is one and Rl, R2, R3 and Y are as defined above.
/

B. ~ COoy_~ + R4-(COOH~2~


where n is 1 or 2, and R1 R2 and R4 are defined above, (II) being the mono-
salt (Z is COOH) when n is one or the double salt (Z is COO ~ ) when n is
two.
The dialkylaminoalkyl ~-dialkylaminobenzoate is known, e.g. see
United States Patent ô20,830, and can conveniently be made by alkylating an `alkyl ~-aminobenzoate with an alkyl halide in an organic solvent, and react-
10 ing the resulting alkyl ~-dialkylaminobenzoate with a dialkylaminoalkanol.
For use in the reactions (A) or (B), the dialkylaminoalkyl p-
dialkylaminobenzoate may be:
dimethylaminoethyl ~-dimethylaminobenzoate
diethylaminoethyl ~-dipropylaminobenzoate
dimethylaminoethyl ~-dipentylaminobenzoate
` di-i-propylaminoethyl ~-dihexylaminobenzoate
dihexylaminoethyl -di-propylaminobenzoate
dimethylaminobutyl p-diethylaminobenzoate
dimethylaminohexyl ~-diethylaminobenzoate
2-dimethylamino-2-methyl-ethyl ~-dimethylamino-benzoate
The aliphatic monocarboxylic acid R3-COOH used in reaction (A) may
be acetic acid, n- or i-propanoic acid, n- or _-valeric acid, caprylic acid,

1051917
otanoic acid, capric acid, lauric acid, rnyristic acid, ~almitic acid and
stearic acid.
The aliphatic dicarboxylic acid R4-(COOH)2 used in reaction (B)
may be malonic acid, succinic acid, adipic acid, 2, 2'-dirnethylglutaric
acid, suberic acid, sebacic acid, dodecanedioic acid, tetradecanedioic acid,
hexadecanedioic acid and nonadecanedioic acid.
The following are representative sun-screening compounds of for-
m~a (I):
1. N,N-dimethyl-N-(p-diethylaminobenzoyloxyethyl)-ammonium acetate
2. N,N-dimethyl-N-(~-diethylaminobenzoyloxyethyl)-ammonium caprylate
3. N,N-dimethyl-N-(~-diethylaminobenzoyloxyethyl)-ammonium hexanoate
4. N,N-dimethyl-N-(~-diethylaminobenzoyloxyethyl)-ammonium laurate
5. N,N-dimethyl-N-(~-dimethylaminobenzoyloxyethyl)-ammonium acetate
6. N,N-dimethyl-N-(p-dimethylaminobenzoyloxybutyl)-ammonium propionate
7. N,N-dimethyl-N-(~-diethylaminobenzoyloxyethyl)-ammonium stearate
8. N,N-dihexyl-N-(~-dipropylaminobenzoyloxyethyl)-ammonium acetate
9. bis-fN,N-dimethyl-N-(~-diethylaminobenzoyloxyethyl)-ammoniumJ -malonate
10. N,N-dimethyl-N-(~-diethylaminobenzoyloxyethyl)-ammonium succinate
11. bis-~N,N-dimethyl-N-(~-diethylaminobenzoyloxyethyl)-ammonium~- succinate
12. N,N-diethyl-N-(~-diethylaminobenzoyloxyethyl)-ammonium adipate
13. bis-~N,N-dimethyl-N-(~-diethylaminobenzoyloxyethyl)-ammonium~ -adipate
The sun-screening agents of formula (I) are applied to the skin
in the form of a sun-screen composition comprising the compound of formula
(I) and a cosmetically acceptable diluent or carrier. The term "cosmetical-
ly acceptable diluent or carrier" denotes a non-toxic, non-irritating sub-
stance t~hich when mixed with the compound of formula (I) makes the compound
more suitable to be applied to the skin. The compositions can thus be
solutions, oils, lotions, ointments, liquid or solid creams, aerosols and
the like.
3Q The sun-screening composition of the invention is formed by admix-
ing, dissolving or dispersing the sun-screening compound of formula (I) into
the desired cosmetically acceptable diluent or carrier. Solutions are
5 --


:.

iOSl~i7
formed by dissolvin~ the sun-screening cornpound in water or other sol~erlt.
Oils are prepared by using vegetable and/or mineral oils, such as sesarne oil
and/or white mineral oil as the cosmetically acceptable diluent or carrier.
Crea~s may be prepared by addin~ lanolin and a suitable absorbent base to
the vegetable and/or mineral oils. Oil-in-water emulsions may be employed
as the vehicle to form lotions, but are not preferred since such compositions
tend to wash off more easily than others.
An alcoholic lotion containing an alcohol, such as ethanol or
isopropanol, and a film-forming substance as the cosmetically acceptable
diluent or carrier is preferred, since this tends to provide more permanent
protection even after exposure of the skin to water. Preferred film-forming
agents for alcoholic lotions are castor oil, lauryl and oleyl alcohols,
glycol and glyceryl ricinoleates, glycol and glyceryl laurates, glycol and
glyceryl oleates, mannitol and sorbitol oleate, lPurate, or ricinoleate,
butyl stearate, ethyl oleate, laurate, orricinoleate and methyl oleate,
laurate or ricinoleate.
Perfumes, anti-oxidants, colorants, insect repellants and the like
may be included in the sun-screening composition, if desired.
The sun-screening composition of the invention contains an effec-

~0 tive amount of the sun-screening compound of formula (I) to prevent erythema.
In general, an amount of 0.2 to 10%, preferably 1-3%, by weight of the total
composition, of the sun-screening compound of formula (I) may be used. The
composition is applied topically every few hours, as needed, in the same
manner as conventional sun-screening compositions.
The c~npounds of the invention may also be used to protect blond
and light-colored hair from the deleterious effects of ultraviolet radia-
tion. In this case, the compounds of formula (I) are admixed with the
cosmetically acceptable diluent or carrier to provide a composition contain-
ing from 0.05 to 10% by weight, preferably 2 to 5% by weight, of the com-

pound of formula (I). The hair-protection compositions are applied to the

hair in the same manner as a conventional hair lotion, hair cream or hair
tonic, before exposure to ultra-violet radiation, and thereafter as desired.
- 6 -



1051917
Cosmetically acceptable diluents or carriers used in such co~ventional hairpreparations May be used in the hair-protection composition of the inven-
tion.
In the Examples, the following procedures were used:
Test Procedure on Skin
Reference solution of the candidate compound in 50/50 ethanol-
water solvent are prepared in concentrations of 2% by weight and below.
Such solutions are applied to the skin and dried in air. Examination of the
treated section of skin under UV light reveals a bluish-white color for un-

treated skin and brownish-black to black color for treated skin.
A 2% by weight solution of the candidate compound in 50% ethanol-
50% water is then rubbed into the skin, dried in air, and part of the air-
dried surface is rinsed with water for two minutes. Examination of the
rinsed and unrinsed sections of skin was then made in UV (black) light. The
retention of the W absorber on the skin is determined by observing the
color of the treated and untreated sections under W light and comparing the
color to the reference solutions.
Tests for sunburn protection are carried out by applying a 2% by
weight solution of the candidate compound in 50% ethanol-50% water to a
small patch of skin, followed by exposure to sun for two hours. To be suc-
cessful, a compound must prevent erythema after exposure for two hours to
the sun at a latitude of New York City.
Test Procedure for Hair
The substantivity of the candidate compound to hair is tested in
the following manner. The candidate compound is dissolved in 100 mls. of
water to provide an 0.1% by weight aqueous solution. 10 gms. of hair is
immersed in the resulting aqueous solution, stirred for 1/2 hour, removed,
rinsed and dried. The W absorption of the aqueous solution into which the
hair was immersed is measured both before and after the immersion of the
hair in the solution using the same technique described above. The percent
of the compound left after rinsing determines the amount of substantivity.
The following Examples illustrate the invention. Parts and per-

-- 7 --



.. ~

10~1917
centages are by weight unless otherwise stated.
Example 1
Preparation and application to the skin of:




5 2)2~ ~ 3 ~ C43C00 ~




148 g. ethyl ~-aminobenzoate, 4.5 g. ethyl iodide and 600 ml.
ethanol were heated in an autoclave for 6 hours at 185C. Then the solvent
and excess ethyl iodide were evaporated at 120C. under atmospheric pres-
sure, producing about 150 g. ethyl _~iethylaminobenzoate.
70 g. of this product and 86 g. dimethylaminoethanol, in the
presence of 1 gram of sodium methoxide, were heated to 140 C for 24 hours
while distilling off the ethanol that was liberated. The product was ex-
tracted with 200 ml. water and 100 ml. benzene, the water layer removed and
the benzene evaporated from the water layer to give about 80 g. crude
dimethylaminoethyl ester of ~-diethylaminobenzoic acid.
This crude material was then treated with an equimolar amount of
glacial acetic acid, 50 ml. benzene and 50 ml. water. The mixture separated
into two phases of which the bottom phase was an aqueous solution of essen-

tislly pure N,N-dimethyl-~ -diethylaminobenzoyloxyethyl)-ammonium acetate. ~`
Psrt of the aqueous solution is evaporated to dryness to give the pure
acetste.
Part of the aqueous solution containing the acetate was diluted

with wster to a 5% by weight aqueous solution. This was applied to skin by
rubbing. Skin so treated, on exposure to sun, was protected against burning
in contrast to untreated skin. The product also showed resistance to removal
by water treatment in contrast to a commercially available UV agent having
the formula:


c




., . .~. ., . :
:, , ,. .. :

l~Slgl7

OH




CO ~ OH




(Uvinul MS-40)
When a 0.1% by weight aqueous solution of the acetate at a pH 8
was applied to the skin and to hair it was found to have 75% substantivity.
The maximum absorption of the acetate is at 313 mu.
Exam~le 2
Preparation and application to the skin of:


~C2)24~COOC2447(c43)~ C11423C


Part of the crude dimethylaminoethyl ester o~ ~-diethylamino-

benzoic acid obtained in Example 1 is mixed, in equimolar amounts, with
lauric acid to form a homogeneous liquid which sets up to a gel on cooling

to room temperature. The product is N,N-dimethyl-N-(~-diethylaminobenzoyl-
oxyethyl)-ammonium laurate, which is insoluble in water, but dissolves in a
50~50 water-alcohol mixture (by volume). The laurate salt is substantive to

skin, does not wash off to any great extent, and affords protection against
the deleterious effects of the sun. Maximum absorption is at 313 mu.
Examp}e 3
Preparation and application to the skin of:

lOS1~17



~13C)2N ~ ~ ~ CH3C00 O




82.5 g. ethyl p-aminobenzoate, 100 ml. methanol and 65 e. dimethyl
sulfate were mixed and gradually heated to 75 C. After 3 hours the charge
was treated with 50 g. sodium carbonate to delta paper neutrality. It was
then treated with 100 ml. benzene and 200 ml. water and the layers separated.
The upper layer was evaporated free from benzene to give 80 e. ethyl ~-
dimethyl-aminobenzoate.
This was then treated as in Example 1 with dimethyl-aminoethanol
and then with glacial acetic acid to yield an aqueous solution of N,N-

dimethyl-N-(~-dimethylamino-benzoyloxyethyl)-ammonium acetate.
Application to the skin was carried out as in Example 1 giving
commensurate results. Maximum absorption is at 303 mu.
Example 4
Preparation and application to the skin of:



(X3C)2N _ ~ COOC4X31(CH ~ C2X5C00




In the ma~mer of Example 3, this compound was prepared with the
exception that dimethylaminobutanol was substituted for the dimethylamino-
ethanol, and propionic acid for the glacial acetic acid
This product had good skin substantivity and good protective
powers against UV light when applied to skin and hair. Maximum absorptivity
is at 303 mu.




-- 10 --

~OS1~17
Example 5
Preparation and application to the skin of:




5 2 2 4~cooc2Hl~l(cn ~ C17ll35C(3




Following the procedure of Example 2, equimolar amounts of
dimetl~laminoethanol ester of ~-diethylaminobenzoate and stearic acid were
combined to produce N,N-dimethyl-N-(~-diethylaminobenzoyloxyethyl)-ammonium
stearate, which was water insoluble, but soluble in 50/50 alcohol-water. It
had excellent substantivity on the skin, did not wash off and gave good
protection against sunburn. Maximum absorption is at 313 mu.


1051917


Example 6
Preparatlon of:




~ 5 2) 2 ~ ~ 2


80 gms. of the crude dlmethylamlnoethyl ester
of p-diethylamlnobenzolc acld ls treated wlth half the
equlmolar amount of succlnic acld, 50 mls. of benzene and
50 mls. of water. The mlxture ls stlrred and heated at 70C
for two hours. Evaporatlon o~ the benzene and water glves
the compound above.
Example 7
Preparatlon Or:
- -

(H5C2)2 ~ Cooc2H4~(cH3)2 TH22cooOH
L

~ his material ls prepared ln the manner descrlbed ln
Example 6 except that an equimolar amount of succinlc acld ls
used lnstead o~ half an equlmolar amount.

~o519il7



Example 8
Preparatlon of:
_

. ~ ~2 2

(115C2)2N ~COOC2H41 I(CH3)2 CH2CH2C-



Thls material ls prepared ln the manner descrlbed
ln Example 6 except that half an equlmolar amount of adlplc
acld ls used lnstead of half an equlmolar amount of succlnlc
acld,




-- ~T --

Representative Drawing

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Administrative Status

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Administrative Status

Title Date
Forecasted Issue Date 1979-04-03
(45) Issued 1979-04-03
Expired 1996-04-03

Abandonment History

There is no abandonment history.

Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
G A F CORPORATION
Past Owners on Record
None
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Drawings 1994-04-18 1 6
Claims 1994-04-18 4 69
Abstract 1994-04-18 1 18
Cover Page 1994-04-18 1 17
Description 1994-04-18 13 428