Sun-screening compounds I
United States Patent [191 Strobe] SUN-SCREENING COMPOUNDS I [75] Inventor: Albert Frederick Strobel, Delmar,  
 [73] Assignee: GAF Corporation, New York, NY.  
 [22] Filed: Apr. 29, 1974 21 Appl. No.: 465,247  
 [52] US. Cl 260/404.5, 260/472, 424/60 [5 l] Int. Cl. ..C11c 3/00 [58] Field of Search 260/4045, 472  
 [56] References Cited UNITED STATES PATENTS 3,536,723 10/1970 Ghelardoni ct al. 260/472 Primary E.\&#39;aminer-Lorraine A. Weinberger Assistant Examiner-L. A. Thaxton Attorney, Agent, or Firm-Walter C. Kehm; Samson B. Leavitt [57] ABSTRACT Sun-screening compounds, useful to protect the skin and hair against deleterious effects upon exposure to ultraviolet radiation, of the formula:  
 [451 Apr. 1, 1975 COOYNH 16 Claims, No Drawings SUN-SCREENING COMPOUNDS I be effective, 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 object of this invention to provide novel sun-screening compounds that are effective to prevent erythema.  
  It is a further object of the invention to provide new sun-screening compositions containing the sunscreening compounds of the invention.  
  These objects are provided by the provision of a sunscreening compound of formula (1):  
 where R and R are independently straight or branched chain lower alkyl; Y is C -C alkylene; X is R COO, HOOCR COO&#39; or OOC--R- COO&#39;, where R is alkyl of l to 18 carbon atoms and R is alkylene of l to 18 carbon atoms; and n is 1 when X is R COO or I-IOOCR COO or n is 2 when X is OOCR COO. Sucn 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. Representative of such lower alkyl groups are thus methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, tert. butyl, pentyl, isopentyl,  
 neopentyl, tert. pentyl, hexyl, and the like. The termalkylene 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 methyl.  
  The term alkyl of l to 18 carbon atoms denotes a univalent saturated branched or straight hydrocarbon chain containing from 1 to 18 carbon 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&#39;ofthe invention, R and R are C,-C straight or branched chain alkyl.  
  It is further preferred to employ compounds in which the anion, X, is derived from a higher saturated aliphatic carboxylic acid, such as a C -C saturated ali-.  
  hydrochloride phatic monocarboxylic acid, since such compounds are water-insoluble and thus resist removal from the skin by water washing. Compounds of this type have the formula (II):  
  a; 2 /N coov-n-H R -coo where R R and Y are as defined above, and R is straight or branched chain alkyl of 7 to 17 carbon atoms.  
  In another preferred embodiment of the invention, the anion, X, is derived from a saturated aliphatic dicarboxylic acid (I-IOOCR -COOH), and n is 1 or 2, preferably 2. The 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):  
  g 2 (In) ]\N cooY-N H Z-RL-COOG where R R R and n are as defined above, Z is COOI-I or --COO, and n is 1 when Z is COOI-I and n is 2 when Z is -COO&#39;. Preferably, the dicarboxylic acid is one where R, is lower alkylene, and most preferably alkylene of 1 to 4 carbon atoms.  
  Compounds which are active as sun-screening agents are known and include such widely diverse compounds as dibenzylacetone, quinine sulfate and ethyl umbelliferone. Alkyl esters of p-dialkylaminobenzoic acid have also been proposed for use as sun-screening agents in U.S. Pat. Nos. 2,853,423; 3,403,207; 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 mg, 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 U.S. Pat. No. 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  
  salt of diethylaminoethyl pdimethylaminobenzoate 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 dialkylaminoalkyl p-dialkylaminobenzoate with the desired aliphatic monoor dicarboxylic acid according to processes A or B.  
 &#39; n r CO0Y-N R C001-1q 1) where n is one and R,, R R and Y are as defined above.  
 + a -(coom gur) where n is l or 2, and R R and R are defined above, (II) being the monosalt (Z is COOI-I) when n is one or the double salt (Z is COO) when n is two.  
  The dialkylaminoalkyl p-dialkylaminobenzoate is known, e.g. see US. Pat. No. 820,830, and can conveniently be made by alkylating an alkyl paminobenzoate with an alkyl halide in an organic solvent, and reacting the resulting alkyl pdialkylaminobenzoate with a dialkylaminoalkanol.  
  For use in the reactions (A) or (B), the dialkylaminoalkyl p-dialkylaminobenzoate may be:  
 dimethylaminoethyl p-dimethylaminobenzoate diethylaminoethyl p-dipropylaminobenzoate dimethylaminoethyl p-dipentylaminobenzoate di-i-propylaminoethyl p-dihexylaminobenzoate dihexylaminoethyl p-dii-propylaminobenzoate dimethylaminobutyl p-diethylaminobenzoate dimethylaminohexyl p-diethylaminobenzoate 2-dimethylamino-2-methyl-ethyl dimethylaminobenzoate The aliphatic monocarboxylic acid R COOI-I used in reaction (A) may be acetic acid, nor i-propanoic acid, nor i-valeric acid, caprylic acid, octanoic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid.  
  The aliphatic dicarboxylic acid R (COOI-I) used in reaction (B) may be malonic acid, succinic acid, adipic acid, 2, 2&#39;-dimethylglutaric acid, suberic acid, sebacic acid, dodecanedioic acid, tetradecanedioic acid, hexadecanedioic acid and nonadecanedioic acid.  
  The following are representative sun-screening compounds of formula (I):  
 1 N,N-dimethyl-N-( p-diethylaminobenzoyloxyethyl)-ammonium acetate N,N-dimethyl-N-(p-diethylaminobenzoyloxyethyl )-ammonium caprylate 3. N,N-dimethyl-N-( p-diethylaminobenzoyloxyethyl)-ammonium hexanoate N,N-dimethyl-N-(p-diethylaminobenzoyloxyethyl)-ammonium laurate 5. N,N-dimethyl-N-(p-dimethylaminobenzoyloxyethyl)-ammonium acetate N,N-dimethyl-N-(p-dimethylaminobenzoyloxybutyl)-ammonium propionate N,N-dimethyl-N-(p-diethylaminobenzoyloxyethyl )-ammonium stearate N,N-dihexyl-N-(p-dipropylaminobenzoyloxyethyl)-ammonium acetate 9. bis-[N,N-dimethyl-N-(pdiethylaminobenzoyloxyethyl)-ammonium]- malonate l0. N,N-dimethyl-N-(p-diethylaminobenzoyloxyethyl)-ammonium succinate l l. bis-[N,N-dimethyl-N-(pdiethylaminobenzoyloxyethyl)-ammonium]- succinate 12. N,N-diethyl-N-( p-diethylaminobenzoyloxyethyl)-ammonium adipate 13. bis-[N,N-dimethyl-N-(pdiethylaminobenzoyloxyethyl)-ammonium]- adipate I I The sun-screening agents of formula (I) are applied to the skin in the form of a sunscreen composition comprising the compound of formula (I) and a cosmetically acceptable diluent or carrier. The term cosmetically acceptable diluent or carrier denotes a nontoxic, non-irritating substance which 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.  
  The sun-screening composition of the invention is formed by admixing, dissolving or dispersing the sunscreening compound of formula (I) into the desired cosmetically acceptable diluent or carrier. Solutions are formed by dissolving the sun-screening compound in water or other solvent. Oils are prepared by using vegetable and/or mineral oils, such as sesame oil and/or white mineral oil as the cosmetically acceptable diluent or carrier. Creams may be prepared by adding 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, laurate, 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 effective amount of the sun-screening compound of formula (I) to prevent erythema. In general, an amount of 0.2 to 10 percent, preferably 1-3 percent, 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 compounds of the invention may also be used to protect blond and light-colored hair from the deleterious effects of ultraviolet radiation. In this case, the compounds of formula (I) are admixed with the cosmetically acceptable diluent or carrier to provide a composition containing from 0.05 to 10 percent by weight, preferably 2 to 5 percent by weight, of the compound 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 ultraviolet radiation, and thereafter as desired. Cosmetically&#39; acceptable diluents or carriers used in such conventional hair preparations may be used in the hair-protection composition of the invention.  
 In the Examples, the following procedures were used:  
 TEST PROCEDURE ON SKIN Reference solutions of the candidate compound in 50/50 ethanol-water solvent are prepared in concentrations of 2 percent 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 untreated skin and brownish-black to black for treated skin.  
  A 2 percent by weight solution of the candidate compound in 50 percent ethanol-5O percent water is then rubbed into the skin, dried in air, and part of the airdried 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 UV absorber on the skin is determined by observing 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 percent by weight aqueous solution. gms. of hair is immersed in the resulting aqueous solution, stirred for one-half hour, removed, rinsed and dried. The UV 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 percentages are by weight unless otherwise stated.  
 (H C N EXAMPLE 1 Preparation and application to the skin of:  
  Q cooc a r uca ca coo.  
  70 g. of this product and 86 g. dimethylaminoethanol, in-the preseilce of 1 gram of sodium methoxide, were heated to 140C. for 24 hours while distilling off the ethanol that was liberated. The product was extracted with 200 ml. water and 100 ml. benzene, the water layer removed and the benzene evaporated from the water layerto give about 80 g. crude dimethylaminoethyl ester of p-diethylaminobenzoic acid.  
  This crude material was then treated with an equimolar amount of glacial acetic acid, ml. benzene and 50 ml. water. The mixture separated into two phases of which the bottom phase was an&#39;aqueous solution of essentially pure N,N-dimethyl-N-(pdiethylaminobenzoyloxyethyl)-ammonium acetate. Part of the aqueous solution is evaporated to dryness to give the pure acetate.  
  Part of the aqueous solution containing the acetate was diluted with water to a 5 percent 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:  
 it was found to have 75 percent substantivity.  
 The maximum absorption of the acetate is at 3 13 m .1..  
 EXAMPLE 2 Preparation and application to the&#39;skin of:  
  9 COOC2H4T(CH3) 2 Part of the crude dimethylaminoethyl ester of p- S diethylaminobenzoic acid obtained in Example l 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- (p-diethylaminobenzoyloxyethyl)-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 mp..  
 EXAMPLE 3 Preparation and application to the skin of:  
  8 C H COO 82.5 g. ethyl p-aminobenzoate, 100 ml. methanol and 65 g. dimethyl sulfate were mixed and gradually heated to 75C. 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 g. ethyl p-dimethylaminobenzoate.  
  This was then treated as in Example 1 with dimethylaminoethanol and then with glacial acetic acid to yield an aqueous solution of N,N-dimethyl-N-(pdimethylaminobenzoyloxyethyl)-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:  
  0 If( c a coo (H C N In the manner of Example 3, this compound was pre- 50 pared with the exception that dimethylaminobutanol was substituted for the dimethylaminoethanol, and propionic acid for the glacial acetic acid.  
  This product had good skin substantivity and good protective powers against UV light when applied to (H C N skin and hair. Maximum absorptivity is at 303 m EXAMPLE 5 Preparation and application to the skin of:  
 10 amounts EXAMPLE 6 Preparation of:  
 H CH COO- 00C H N (CH 2 CH COO- EXAMPLE 7 Preparation of:  
 H CH COO- CH COOH OOC H N (CH 2 2 This material is prepared in the manner described in Example 6 except that an equimolar amount of succinic acid is used instead of half an equimolar amount.  
 EXAMPLE 8 Preparation of:  
  cu cu coo- 0OC2H4N(CH3)2 2 2 This material is prepared in the manner described in Example 6 except that half an equimolar amount of adipic acid is used instead of half an equimolar amount of succinic acid.  
 I claim:  
 (H C N l. A compound of the formula:  
  n cooy-u-a x&#39; R where R and R are independently straight or branched chain lower alkyl; Y is C C alkylene; X is R --COO HOOCR COO* or OOCR- COO where R is alkyl of l to 18 carbon atoms and R is alkylene of 1 to 18 carbon atoms; and n is 1 when X is R -COO or HOOCR.,COO&#39; or n is 2 when X is OOCR -COO (H C N 2. The compound according to claim 1, wherein R and R are straight or branched chain alkyl of 1 to 3 carbon atoms.  
  3. The compound according to claim 2, wherein R is straight or branched chain alkyl of 7 to 17 carbon 40 atoms.  
  4. The compound according to claim 1, wherein X is R COO R is straight or branched chain alkyl of 7 to 17 carbon atoms and n is 1.  
  5. The compound according to claim 1, wherein X is HOOC-R.,-COO and n is l.  
  6. The compound according to claim 5, wherein R is lower alkylene.  
  7. The compound according to claim 1, wherein X is 50 OOCR COO and n is 2.  
  8. The compound according to claim 7, wherein R is lower alkylene.  
 9. The compound according to claim 1 which is 10. The compound according to claim 1 which is i 6 C0QC H N(CH 2 l l C0O 11. The compound according to claim 1 which is 9 9 (H C) N COOC H E(CH 2 CH COO 12. The compound according to claim 1 which is 0 (11 C) N COOC H liI (CH 2 C H COO 13. The compound according to claim 1 which is G 6 COOC H Ii1(CH 2 C H COO 14. The compound according to claim 1 which is 16. The compound according to claim 1 which is a ca cu coocu cn coo- 2 2 (u c n ooc u u (ca 2 665 (u c 2N cooc n r ucn 2 cn coo