DE2509647A1 - NEW DERIVATIVES OF DIALKYLAMINOALKYL- P-DIALKYL-AMINOBENZOAEUREESTERS - Google Patents

Description

PATENT LAWYERS

Dlpl.-lng. P.WIRTH Dr. V. SCHMIED-KOWARZIK DJpWng. G. DANNENBERG Dr. P. WEINHOLD Dr. D. GUDEL

281134 β FRANKFURT AM MAIN

TELEPHONE (0611)

287014 QR. ESCHENHEIMER STRASSE 38

SK / SK

FDN-660

GAF Corporation

140 West 51st Street

New »York, N.Y. /UNITED STATES

New derivatives of dialkylaminoalkyl-p-dialkyl aminobenzoic acid esters

The present invention relates to new sunscreen preparations, on procedures for their use and on new sun protection compounds.

UV rays, e.g. from the sun, with a length of 290-313 As is well known, m and u cause erythema, especially in fair-skinned people. On the other hand, UV radiation with a wavelength of 315-320 rryu to 350-400 m accelerates the tanning of the skin. Around To be effective, a sunscreen must at least essentially all burning rays and in many cases one filter out a large part of the tanning rays.

It is therefore an object of the present invention to provide new sunscreen compounds which are effective in preventing erythema are. The present invention further relates to new sun protection preparations which contain the sun protection compounds according to the invention contain.

509846/1046

The sun protection compounds according to the invention correspond to following formula I:

H -

in which R. and R., independently of one another, represent a straight or branched chain lower alkyl group; Y is a C1, alkylene group; R _{3 represents} a C _{fl R} alkyl group; X is a cosmetically acceptable mono- or divalent anion and η has a value of 1 or 2 to provide an electrically neutral connection. X preferably represents a halide, sulfate, phosphate, p- (lower-alkyl) -benzenesulfonate, benzoate, R.-COO ^, HOOC-R ₅ -CUO® or ® OCC-R ₅ -COO, where R ^ is a C _{1 18} alkyl group and R ₅ is a C .. "alkylene group .. These compounds exhibit an absorption of UV light in the range of 290-315 m / U and have a good substantivity on the skin. The compounds of the formula I are water-soluble, but the degree of water solubility decreases when the number of carbon atoms in R and / or R and / or R ₅ increases.

The term "lower alkyl" means a monovalent saturated or branched hydrocarbon chain with 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert .-Pen- tyl, hexyl, etc. The term "alkylene group having 2-6 carbon atoms" means a divalent saturated, straight or branched hydrocarbon which, by removing one hydrogen atom from the above lower alkyl groups exclusively

509846/1046

Methyl was obtained.

The term "alkyl group having 1-18 carbon atoms" and
"Alkyl group with 8-18 carbon atoms" means a monovalent saturated branched or straight hydrocarbon chain with 1-18 or 8-18 carbon atoms, such as 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, octadecyl, etc. The terms "alkylene group having 1-18 carbon atoms" and "alkyl group having 8-18 carbon atoms" mean a divalent saturated branched one
or straight hydrocarbon chain, which by removing one
Hydrogen atom obtained from the above-mentioned alkyl groups
has been.

The term "halide" refers to chloride, bromide,
Godide and fluoride, preferably chloride or bromide,

In a preferred embodiment of the present invention
FL and R stand for a straight or branched C ₁ alkyl group.

Furthermore, compounds are preferably used in which R stands for a C ^ _1ß alkyl group, since the substantivity
of the compound of formula I is the larger, the more carbon atoms R 1 contains.

50984b / 1046

Furthermore, compounds are preferably used in which the anion, R.-COO for a C _{7 1?} Alkyl group stands as it is derived, for example, from a higher saturated aliphatic carboxylic acid, for example a C _{ß 1ß} saturated aliphatic monocarboxylic acid, since these compounds have reduced water solubility and thus resist removal from the skin by washing with water.

In another preferred embodiment of the present invention becomes the anion, X ,. derived from a saturated aliphatic dicarboxylic acid (HOOC-Rt - COOH), and η has a value of 1 or 2, preferably 2. The double salt of the dicarboxylic acid is preferred over the Fionosalt, since the former is an improved one Has an affinity for the skin. These compounds have the formula IA:

-N- < ^{/ λ} > -COOY-I R.

(Ia)

ZR _C -COO ^V

", R ₃ and R ₅ as well as η have the above meaning, C)

in which R ₁ , R

C)
Z is -COOH or -COO ^ and η = 1 when Z is COOH, and has a value of 2 when Z is -COO ^ . the

The carboxylic acid is preferably one in which R ₁ .

represents lower alkylene, in particular with 1-4 carbon atoms,

509846/1046

Compounds effective as sunscreen agents are known and include such diverse compounds as dibenzylacetone, quinine sulfate and ethylumbellifieron. Also alkyl esters of p-dialkylaminobenzoic acid are proposed as sunscreens in U.S. Patents 2,853,423, 3,403,207, and 3,479,428. In view of the highly empirical nature of a compound's ability to selectively emit UV radiation in the narrow range of 290-315 m / U to absorb, was not to be expected that the compounds of the formula I would be effective as a sunscreen.

Monoquaternary ammonium compounds that act as intermediates useful in the manufacture of therapeutic agents have been suggested in U.S. Patent 2,717,905. In contrast in addition, the sun protection compounds of formula I are new.

The quaternary salts of formula I, in which X is a halide can be prepared by adding about etoichiometric amounts of one at room temperature, with or without a solvent Dialkylaminoalkyl-p-dialkylaminobenzoates II and an alkyl halide III for the formation of the quaternary ammonium halide IV according to

implements the following procedure (a):
(A) 'R

N,

OOY-l

+ R -halideX

(II)

'-COOY-

(III)

Halide ©

509846/1046

- O -

EJab8i have R. to R, the above meaning and "halide" stands for chloride, bromide, 3odide or fluoride, preferably chloride or bromide.

The compounds of the formula I in which X has another meaning as a halide can be obtained by reacting the quaternary ammonium halide IU with silver oxide to form the monoquaternary Ammonium hydroxide are formed. The excess silver oxide and precipitated silver halide are filtered off, and then done the aqueous solution of the monoquaternary ammonium hydroxide with a corresponding acid, e.g. sulfonic acid, phosphoric acid, p- (lower-alkyl) -benzenesulfonic acid, benzoic acid or a mona or dicarboxylic acid of the formula R-CGOH or R, - (COOH), for introduction of the desired anion implemented.

The quaternary ammonium halide IV can also be mixed with the desired acid in approximately stoichiometric amounts according to process (B) or (C) implemented:

(b) R ₄ -COOH + (IV) (I)
where R. has the above meaning

(c) n (H00C-R ₅ -Cü0H) + (IV) (la)

where η has a value of 1 or 2 and R _{5 has} the above meaning.

The dialkylaminoalkyl p-dialkylaminobenzoate used in process (A) II is known (see e.g. US patent 820 830) and can be conveniently obtained by alkylating an alkyl p-aminobenzoate with an alkyl halide in an organic solvent and

509846/1046

- 7 Reaction of the resulting alkyl p-dialkylaminobenzoates with a Dialkylaminoalkanol are produced.

ζ. Β.

In process (a) / the following dialkylaminoalkyl-p-dialkyl aminobenzoate used u / earth:

Dimethylaminoethyl p-dimethylaminobenzoate

Diethylaminoethyl p-dipropylaminobenzoate

Dimethylaminoethyl p-dipentylaminobenzoate

Diisopropylaminoethyl p-dihexylaminobenzoate

Dihexylaminoethyl p-diisopropylaminobenzoate

Dimethylaminobutyl p-diethylaminobenzoate

Dimethylaminohexyl p-diethylaminobenzoate

2-dimethylamine-2-methylethyl-p-dimethylamine-benzoate.

The alkylahlogenide III used in method (A) is also

e.g.
known and can be / bromooctane, chlorooctane, dodoctane, fluoroctane, bromononane, chlorordecane, bromundecane, bromododecane, chlorotetradecane, chlorhexadecane, bromooctadecane, chlorooctadecane and iodoctadecane.

The aliphatic monocarboxylic acid used in reaction (B)

e.g.
R.-COOH can be acetic acid, n- or isopropanoic acid, n- or isovaleric acid, caprylic acid, octanoic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid and nonadecanoic acid.

The aliphatic dicarboxylic acid used in reaction (C)

e.g.

R ₅ - (COOH) ₂ can be / f-ialonic acid, succinic acid, adipic acid, 2,2'-dimethylgutaric acid, suberic acid, sebacic acid, dodecanedioic acid, tetradecanedioic acid, hexadecanedioic acid and nonadecanedioic acid.

The following sun protection compounds correspond to formula I:

509846/1046

1) Dimethyloctyl-ip-diethylaminobenzoyloxyäthylJ-ammonium bromide

2) Dimethyloctyl-ip-diethylarninobenzoyloxyäthylJ-ammonium acetate

3) Dihexyloctyl (p-diethylaminobenzoyloxyethyl) ammonium laurate

4) Dimathyloctyl (p-diethylaminobenzoyloxyethyl) ammonium stearate

5) Dimethyldecyl (p-dihexylaminobenzoyloxyethyl) ammonium chloride

6) Dimethyldodecyl (p-dimethylaminobenzoyloxyethyl) ammonium

2-ethylhexanoate

7) Dimethyloctadecyl ^ p-dimethylaminobenzoyloxyäthylJ-ammonium-

bromide

8) Whore t hy loctadecyl - '(ρ-dimet hylaminob8nzayloxyäthyl) -ammonium-

2-ethylhexanoate

9) Dimethyldodecyl- (p-dimethylaminobenzoyloxybutyl) -ammonium-

capylate

10) bis- / pimethyloctyl-tp-diethylaminobenzoyloxyethyl) -ammonium7-

malonat

11) bis- ^ dimethyldodecyl- (p-dimethylaminobenzoyloxybutyl) -

ammonium J7 succinate

12) Dimethyldodecyl (p-däthylaminobenzoyloxyäthyl) ammonium

succinate.

The sunscreens of the formula I are applied to the skin in the form of a sunscreen preparation which contains the compound of the formula I and a cosmetically acceptable diluent or
Includes carrier. The term "cosmetically acceptable diluent or carrier" refers to a non-toxic, non-irritating substance which, when mixed with the compound of
Formula I makes the latter more suitable for application to the skin. The preparations can thus be solutions, oils, lotions, ointments, liquid or solid creams, aerosols, etc.

509846/1 CU6

The sun protection preparations according to the invention can be formed by mixing the sunscreen compound of formula I into the desired, cosmetically acceptable carrier or diluent, dissolves or disperses. Solutions are made by Dissolve the sunscreen compound in water or another solvent. Oils are made using vegetable oils and / or mineral oils, such as sesame oil and / or white mineral oil, as cosmetically acceptable diluents or carriers. Creams can be made by adding lanolin and a suitable one

(Material)

absorbent base / add to vegetable and / or mineral oils. Oil-in-water emulsions can be used as carriers for the formation of lotions, but this is not so convenient since these preparations are easier to wash off than others.

An alcoholic lotion containing an alcohol such as ethanol or isopropanol and a film-forming substance as a cosmetically acceptable diluent or carrier is preferred because it provides more permanent protection even when the skin is exposed to water. Preferred film-forming agents for alcoholic lotions are castor oil, lauryl and oleyl alcohol, glycol and glyceryl _{oleate t} mannitol or sorbitoleate, laurate or ricin oleate, butyl stearate, ethyl oleate, laruate or ricinoleate and methyl oleate, laurate or ricinoleate.

Perfumes, Antioxidants, dyes, insect repellants, etc. be incorporated.

509846/1046

The sun protection preparations according to the invention contain a for Preventing erythema, effective amount of the sunscreen compound of the formula I. The latter can usually be used in an amount of 0.01-10 wt .- ^, preferably 0.05-3 wt .- ^ c, of the total preparation will. The preparation is applied locally every few hours as required, in the same way as normal sunscreen preparations .

The compounds according to the invention can also be used to protect blond and light colored hair from the harmful effects of UV radiation. In this case, the compounds of the formula I are mixed with a cosmetically acceptable diluent or carrier to create a preparation that contains 0.05-10% by weight , preferably 2-5% by weight , of the compound of the formula I. The hair protection preparations are applied to the hair in the same way for a customary hair lotion, hair cream or hair tonic before and, if necessary, also after the UV irradiation. The cosmetically acceptable diluents and carriers used in conventional hair preparations can be used in the hair protection preparations according to the invention.

In the following examples, the following procedures were used:

Test procedure on the skin

There are reference solutions of the test compound in 50:50 ethanol:. Water solvent in concentrations of 2 wt -%, and made lower. These solutions were applied to the skin and allowed to air dry. The examination of the treated skin section under UV light showed a for the untreated skin

509846/1046

bluish-white color and a brownish-black to black Color for the treated skin.

Then became a 2-geuj. -% solution of the test compound in 50:50 ethanol: water driven into the skin, air-dried, and part of the air-dried surface was rinsed with water for 2 minutes. The rinsed and non-rinsed sections of skin were then examined in UU light (schujarz). The retention of the UV absorber on the skin was determined by examining the color of the treated and untreated section under UV light and comparing it with the color of the reference solutions.

Tests for protection against sunburn were carried out using a 2% by weight ide Dissolution of the test compound in 50:50 ethanol: water applied to a small area of skin and then exposed to the sun for 2 hours suspended. To be successful, a compound must erythema after 2 hours of exposure to the sun at New York latitude prevent.

Test method for hair

The substantivity of the test compound on hair was as follows Tested manner: the test compound was dissolved in 100 ecm of water to make a 0.1% strength by weight aqueous solution. 10 g of hair were put into the obtained aqueous solution immersed, stirred for half an hour, removed, rinsed and dried. The UV absorption of the aqueous solution in which the hair was dipped before and after dipping the hair in the solution according to the above described method measured. The percentage of compound left after rinsing determines the amount of substantivity.

509846/1046

The following examples illustrate the present invention without limiting it. Unless otherwise stated, all parts and percentages are parts by weight and% by weight.

Example 1_

Making and applying the following compound to the skin:

where X = Br

(Connection A)

^C 8 ^H

8 ^H 17l

or CH ₃ CDD

(Connection B)

148 g of ethyl p-aminobenzoate, 4.5 g of ethyl jadide and 600 ecm of ethanol were heated to 185 ° C. in an autoclave for 6 hours. Then solvent and excess ethyl iodide were evaporated under atmospheric pressure at 12O ⁰ C., yielding approximately 150 g Äthy1-p-diäthylaminobenzoat received.

70 g of this product, 2 g of sodium methoxide and 86 g of dimethylaminoethanol were ^{heated to 140 °} C. for 24 hours, the released ethanol being distilled off. The product uuurde extracted with 200 ecm water and 100 ecm benzene, the water layer removed and the benzene evaporated; about 80 g of crude dimethylaminoethyl ester of p-dimethylaminobenzoic acid were obtained in this way.

26.4 g of this compound were mixed with 21 g of bromooctane and 100 "ecm Isopropanol mixed. The mixture was refluxed for 24 hours heated and the product evaporated to dryness on a steam bath to give compound (A). A watery, 0.1% solution of the compound (A) was applied to the skin

509846/1046

and provided protection against sunburn, but allowed tanning.

10% sodium acetate (based on the weight of the solution) was added to a 1- ^ aqueous solution of the compound (A). The compound (B) precipitated, was filtered off and dried.

When 10 g of hair were treated with 100 ecm aqueous solution containing 0.1 % compound (B), the hair was protected against damage from exposure to UV light. The substance was 75? A obtained by determining the K value of the solution before and after dipping the hair. Similar substantivity and protective properties were also found when applied to the skin.

If the pH of the aqueous solution was adjusted to 8.5, so the compound (B) had higher substantivity on the skin and gave a good treasure from sunburn.

The maximum absorption of compounds (A) and (B) is 313 m / U.
Example 2

Making and applying the following compound to the skin;

C ₈ H ₁₇

509846/1046

A 0.1% aqueous solution of the compound (A) from Example 1 was adjusted to a pH of 7.0 with sodium laurate salt. The skin treated with this preparation was protected against sunburn. The skin substantivity was excellent. The maximum absorption is 313 rrwu.
Example 3

Making and applying the following compound to the skin;

is there

X = Br "

(Compound C} or

CH, (CH _n ) ¹

₂₅ (connection D)

26.4 g of dimethylaminoethyl ester of p-dimethylaminobenzoate were mixed with 28 g bromododecane and 100 ecm isopropanol. The mixture uiurde heated to reflux for 24 hours and the product on evaporated to dryness on a steam bath; thus compound (C) was obtained.

An aqueous 0.1- ^ solution of compound (C) was with Sodium 2-ethylhexoate to form compound (D) on one pH adjusted to 7.0.

The maximum absorption of compound (D) was 313 m, u. the Skin substantivity of the compound (D) ujar excellent, and it showed a high degree of protection against sunburn.

509846/1 046

Example 4_

Making and applying the following compound to the skin:

where X ~ = Br "(compound E) _ or X CH_fCH )

_25th

(Compound F)

82.5 g of ethyl p-aminobenzoate, 100 ecm of methanol and 65 g of dimethyl sulfate were mixed and gradually heated to 75 C. After 3 For hours the feed was treated with 50 g sodium carbonate until neutral on Delta paper. Then with 100 ecm Benzene and 200 ecm of water treated and the layers separated. The upper layer was freed from benzene by evaporation and delivered BO g of ethyl p-dimethylaminobenzoate.

22.1 g of this product, 0.50 g of sodium methoxide and 50 g of diethylaminoethanol were heated to 140 ° C. for 24 hours, with the released Ethanol was distilled off. The product was extracted with 200 ecm of water and 100 ecm of benzene, and the water layer was removed and the benzene evaporated from the water layer; about 80 g of crude diethylaminoethyl ester of p-dimethylaminobenzoic acid were obtained in this way.

This product was then mixed with 23 g of bromooctadecane and 100 ecm of isopropanol mixed. The mixture was refluxed for 24 hours and the product converted to compound (E) on a steam bath. evaporated to dryness.

509846/1048

An aqueous 0.1% solution of compound (E) was formed of compound (F) with sodium 2-ethylhexoate to .einem pH set from 7.0; Compound (F) was highly skin substantive and gave excellent protection against sunburn.

Example 5

According to Example 2, 10% sodium stearate was added to a 1% aqueous solution of the compound (A), whereby the following compound was obtained:

CH.

Θ /

CQOC ₅ H ₁₁ N

2 l \ -

CH.

^C 8 ^H i7

C ₁₇ H ₃₅ COO

This compound branched off an absorption at 313 m / U, gave one excellent protection against sunburn on the skin by UV * radiation and had a high level of substantivity.

Example 6

An aqueous 0.1% solution

(H ₅ C ₂ ) ₂ N

was used with half the equimolar amount of the disodium salt of succinic acid to form the compound

CH ₂ COO

H ₂ COO

implemented. The precipitated product was filtered off from the mixture and dried.

509846/1046

example

Eliminate aqueous 0.1 / o solution

was with an equimolar amount of the monosodium salt of Succinic acid

CH ₂ COONa

COOH

handled and delivered the following connection:

COOC ₂ HN

CH.

CH.

^C 12 ^H 25

CH ₂ COO

CH ₂ COOH

The precipitated product was filtered off from the mixture and dried.

509846/1046

Claims (14)

Claims before 1, -. New derivatives of dialkylaminoalkyl-p-dialkylaminobenzoic acid esters the formula: in which R ₁ and R independently of one another represent a straight or branched-chain lower alkyl group; Y represents a C 1-6 alkylene group; R 1 represents a C "" alkyl group; X is a cosmetically acceptable mono- or divalent anion; and η has a value of 1 or 2 to form an electrically neutral connection. 2.- Compounds according to claim 1, characterized in that X stands for halide, sulfate, phosphate, p- (lower-alkyl) -benzenesulfonate, benzoate, R. _{-COO ^, HOOC-R 5} -COO ^ or ODC-R ₅ -COO ®, where R.'für is a C ₁ alkyl group _1B and R ₅ is a C _ia alkylene "group. 3.- Compounds according to claim 1 and 2, characterized in that R ₁ and R "stand for a straight or branched-chain alkyl group with 1-3 carbon atoms. 4.- Compounds according to claim 1 to 3, characterized in that R-, for a straight or branched chain alkyl group with 11-18 carbon atoms. 5, - connections according to claim 1 to 4, characterized in that, that X is a halide. 509846/1046 6.- Compounds according to claim 1 to 4, characterized in that that X stands for RA-COO ^ and η has a value of 1. 7.- Compounds according to claim 6, characterized in that R. for a C _{7 1?} Alkyl group. 8, - connections according to claim 1 to 4, characterized in that / CN that X stands for HOOC-R ₅ -COO ^w and η has a value of 1. 9.- Compounds according to claim 8, characterized in that R _{5 is} lower alkylene. 10.- Compounds according to claim 1 to 4, characterized in that X is, OCC-R ₅ -COO ^ and η has a value of 2. , OCC-R ₅ -COO 11.- Compounds according to claim 10, characterized in that R _{5 is} lower alkylene. 12.- Compounds according to claim 1, namely: Br COOC H ₁ N-CH 2t \ 3 ° 8 ^H 17 CH COO C _n H ₂₃ COO 509846 / 1Q46 COOC.H, N CH. -CH. ^C 12 ^H 25 2 ^H 5 p) CHCOO (H ₃ O ₂ N - // ΛΤ / C ₀ H • C..H ™ Br J / OuQG ^ H ₁₁ rl CH ° 8 ^Η 1ΐ 4 6/10 46 < ^H 5 ^C 2 ^} 2 - 21 - COOC H., N
2 4 (H ₅ c ₂ ) ₂ η— CH CH 3 12 ¹ CH. CH CH ₂ COO CH, , COO 3 ^C 12 ^H 25 COO CH COOH 2 13.- Sunscreen preparations, include one to absorb UV radiation effective amount of a l / compound according to claim 1 to 12 along with a cosmetically acceptable diluent or carrier. 14. Preparation according to claim 13, characterized in that the compound sneezes in an amount effective for preventing erythema. * < The patent attorney: 'i-' ^Λ 'ii 6