MXPA98000488A - Derivados de arilaminometilencan - Google Patents

Abstract

The arylaminomethylene camphor derivatives of the formula (I): wherein the double bond C = C is in the Z or E configuration, and the variables have the following meanings: R 1 H, CH 3, R 2 H, C 1 -C 6 alkyl, cycloalkyl of C3-C8, C2-C6 alkenyl, C3-C8 cycloalkenyl, aryl or substituted aryl, R3 H, C1-C6 alkyl, C3-C8 cycloalkyl, aryl, substituted aryl, C1-C6 alkoxy, acyl C1-C8, Ar aryl, substituted aryl, hetaryl or substituted hetaryl, are used as sun blocking agents, especially in cosmetic and pharmaceutical formulations

Description

DERIVADOS DE ARILAMINOMETILENCA FOR The present invention relates to the aryl inomethylenecamphor derivatives of the formula (1), Rl and its use as antisun agents, eially in cosmetic and pharmaceutical formulations. Sunscreen filters based on camphor derivatives are known. DE 23 36 219 discloses sulphonated benzylidene and cynidincanfor derivatives which are unsubstituted or substituted in the 4-position of the phenyl ring by methyl, methoxy or chloro. DE 34 45 712 describes a series of unsaturated camphor derivatives, preferably benzylidenecamphor derivatives, which are suitable as medicaments for treating skin disorders. DE 44 26 216 discloses benzylidenecamphor derivatives which can be used as sunscreens and to prevent inflammations and skin disorders. DE 44 24 489 describes a process for preparing substituted 4-methylidencinnamic acid derivatives. The sun filters based on amides vinylogas are in the same way known. DE 33 16 287 discloses a series of vinyl iron amides having an open chain structure and are suitable as light filters in antisun composition. The requirements to be met by an antisun agent proposed to be used as a UV-A filter are numerous (Sunscreens, ed. N.J. Lowe, N.A. Shaath, marcel Dek er Inc., New York 1990, 230-231). The most important are: 1) It has its maximum absorption in the UV-A region from 320 to 360 nm; 2) has a high ific absorption in this region; 3) is colorless, ie the absorption above 400 nm should be excessively small to avoid coloring of the protective product of the skin or clothing after use; 4) is photo- and thermostable; 5) is compatible with the skin and does not cause irritating or toxic effects on the skin; 6) adheres well to the skin; 7) is compatible with cosmetic substances and easily soluble in solvents and cosmetic compositions; 8) is isomerically pure.

Known illidecanfor derivatives are broadband UV filters that have an inadequate protective effect in the UV-A region. Furthermore, its solubility, ifically in the oil phase, is unsatisfactory for some applications. An object of the present invention is to provide a suitable compound as a UV-A filter and having a particularly good photostability, good solubility in the oil phase and a pronounced maximum absorption in the UV-A region. We have found that this goal is achieved by the arylaminomethylidenecamphor compounds of the formula (1), wherein the double bond C = C is in the Z or E configuration, and R2-H, C? -C6 alkyl, C3-C8 cycloalkyl, alkenyl C¿-C0 / cycloalkenyl of Cj-Cb / aryl, and substituted aryl, RJ = H, C? -C6 alkyl, C3-C8 cycloalkyl, aryl, and substituted aryl, C? -Cb alkoxy, C? -Cb acyl, Ar = aryl, substituted aryl, hetaryl, substituted hetaryl, an excellent way (1) is prepared by reacting the hydroxymethylene camphor compounds of the formula (2) (prepared as described in L. Claisen, Ann. 281, 1894, 306) with amines of the formula (3) in the presence of a base or an acid , with or without the addition of one or more solvents, from 0 to 200 ° C. (2) and (3) are reacted in equimolar amounts to prepare a compound according to the invention. The reaction is usually carried out in protic solvents, for example, methanol or ethanol. However, it can also be carried out in ethers, for example, diethyl ether or tetrahydrofuran in parafinic mixtures of Ci-C? or in other aliphatic or aromatic solvents such as hexane, toluene or xylene. However, it is also possible to carry out the reaction without solvent. Preferably, the reaction is carried out in lower alcohols and, to obtain a good space-time yield, only enough solvent is used to produce a mixture that can be stirred at the reaction temperature. (2) and (3) can be reacted in any sequence. The catalyst may be initially present or, otherwise, it can be dosed in the reaction. The reaction can also be carried out as a reaction in a vessel. In the same way, it is also possible that (2) can be introduced first together with the catalyst, and (3) can be dosed in the reaction and vice versa. It is also possible to introduce the catalyst first together with (3) and dose (2). The reaction can be carried out at a temperature in the range from 0o to + 200 ° C. The preferred temperature range is from 20 ° C to 100 ° C. The temperature range from 60 to 90 ° C is particularly preferred. The reaction time will depend directly on the temperature. In general, the reaction is completed after 1 to 5 hours in the particularly preferred temperature range. At lower temperatures or lower steady state concentrations, the reaction time can increase considerably and takes up to 48 hours. The catalysts that can be used are any organic or inorganic base or also mixtures of these. Examples of the common basic catalysts are pyridine, trimethylamine or inorganic carbonates. The bases may be present in homogeneous or heterogeneous form in the reaction mixture. The catalysts preferably used in the reaction are organic or inorganic acids or also mixtures thereof. The inorganic acids which may be used are, inter alia, hydrochloric acid, sulfuric acid, nitric acid and / or phosphoric acid. The organic acids which may be used are, inter alia, formic acid, acetic acid, oxalic acid, succinic acid, ascorbic acid and / or sulfonic acids such as methanesulfonic acid or toluenesulfonic acid. In addition, the acid ion exchangers are in the same way suitable as catalysts for the reaction of (2) with (3). The required product (1) is isolated by conventional techniques such as sedimentation, filtration, centrifugation, phase separation and solvent extraction. The required product (1) can be purified by recrystallization from organic solvents and mixtures thereof and / or water. Mixtures containing alcohols are preferred. The purification can also be carried out by fractional melting and chromatographic methods, as well as by distillation. The compounds (1) according to the invention can contain a camphor portion (Ri = CH3) or a norcanfor moiety (R1 = H).

R "has the following meaning: H; Ci-C alkyl, preferably Cj-C4 alkyl such as n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; C3-Ca cycloalkyl, preferably cyclopropyl, cyclobutyl cyclopentyl, cyclohexyl, C¿-Cfe alkenyl preferably vinyl and propenyl, cycloalkenyl of C¿-CB, preferably cyclopentenyl and cyclohexenyl, aryl or substituted aryl, preferably phenyl, mono- or disubstituted phenyl, naphthyl or hetaryl, furyl, thienyl or pyridyl R "has the following meaning: H; C? -Cb alkyl, preferably C? -C4 alkyl methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; C 1 -C a cycloalkyl, preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; aryl or substituted aryl, preferably phenyl, mono- or disubstituted phenyl, C?-CB alkoxy, preferably methoxy, ethoxy, n-propoxy or isopropoxy; C? -Cd acyl, preferably for ilo, acetyl, propionyl, pivaloyl, n-butyryl, isobutyryl, benzoyl. Ar has the following meaning: Aryl, preferably phenyl, naphthyl; hetaryl, preferably furyl, thienyl, pyrryl or pyridyl; substituted aryl, preferably mono- or disubstituted phenyl; substituted hetaryl, preferably furyl, thienyl, pyrryl or mono- or disubstituted pyridyl, wherein the substituents may be identical or different and have the following meanings: alkyl, cycloalkyl, alkoxy, amino, alkylamino, hydroxyl, halogen, acyl, particularly preferably acyloxy or acylamino, and alkoxycarbonyl or aminocarbonyl, carboxyl, sulfo or inosulfonyl. The C = C double bond in the aryl inomethylenecanfor derivatives (1) according to the invention is present both in the E configuration and the Z configuration after the synthesis. The crystallization preferably results in compounds of the formula (1) in which the substituents of the C = C double bond are in the trans position. The compounds (1), according to the invention, are distinguished by their high photostability and are particularly suitable as antisun agents, especially as UV-A filters, in particular for cosmetic and pharmaceutical applications. However, the UV filter effect can also be used to stabilize plastics, coloring formulations or surface coatings. The cosmetic products or compositions contain the compounds (1) in general, in amounts from 0.1 to 15%, preferably from 5-10% of the weight of the formulation, in addition to the excipients and diluents customary in cosmetics, with or without conventional cosmetic auxiliaries. The nature of the carrier, of the auxiliaries or diluents determines whether the finished sunscreen product is a solution, an oil and cream, ointment, lotion, gel or powder. Compositions of these types are found, for example, in the journal Seifen, Ole, Fette, achse 81995), 147. Cosmetic auxiliaries traditionally used and suitable as additives are, for example, emulsifiers, such as ethoxylated fatty alcohols, acid esters sorbitan fatty acids or lanolin derivatives, thickeners such as carboxymethylcellulose or crosslinked polyacrylic acid, preservatives and perfumes. Sunscreen oils are based, for example, on vegetable oils such as peanut oil, olive oil, sesame oil, cottonseed oil, coconut oil, grapeseed oil, castor oil, and, in particular, liquid petrolatum or, in particular, liquid paraffin esters of synthetic fatty acids and glycerides. Examples of ointment bases are petrolatum, lanolin, eucerin or polyethylene glycols. Examples of cream base are higher fat creams, glycerol, Tylose polysaccharides and creams, and creams based on cetyl alcohol fats and waxes, lanolin cream, cocoa butter, beeswax, stearic acid, stearyl alcohol, glycerol, oil and natural or mineral fats. Examples of emulsion bases are mixtures of stearyl glycol, a vegetable and / or mineral oil such as almond oil, liquid paraffin and petrolatum and water or mixtures of ethyl alcohol, water, lanolin and tragacanth or mixtures of ethyl alcohol, stearin, water, tragacanth and glycerol or mixtures of stearic acid, liquid paraffin, propyl or isopropyl alcohol and water. The compounds according to the invention can be used as the only UV absorbers in the appropriate compositions; however, it can also be used in combination with other UV absorbers, especially UV-B absorbers. Examples of these compounds are ethyl p-aminobenzoate, 2-ethylhexyl p-methoxycinnamate, 2-ethylhexyl 2-cyano-3,3-diphenylacrylate, 2-phenylbenzimidazole sulfonic acid and the salts, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid, 3- (4-methylbenzylidene) -d, 1-camphor, 2,, 6-tris (p-2-ethylhexoxycarbonylanilino) -1,3,5-triazine. The following general method is particularly preferred for preparing the compounds (1) according to the invention: Equimolar amounts (22 mmol) of the hydroxymethylenecarp (2) compound and of the amine (3) are dissolved in 20 ml of methanol and, after the addition of 0.1 ml of concentrated hydrochloric acid is heated at 65 ° C for 2 h. After the reaction mixture has cooled to 10 ° C, the required product (1) crystallizes and can be isolated analytically pure by filtration, washing and subsequently with drying.

Example 1 4 g (22 mmol) of hydroxyethylene camphor is reacted with 5.45 g (22 mmol) of 2-ethylhexyl p-aminobenzoate by the general method to obtain 9 g of a compound of the formula: UV (CH3OH):? Max «358 nm, Ei1 * 1044 GO: ? - 3220, 2959, 1711, 1692, 1636, 1602 (s), 1587, 1263 (s) 1176, 1105, 1072 cpr1. 1H-NMR (CDC13): d = 9.87 (d, ÍH, J * 11.2 Hz., 7.95 <d, 2H, J = 7.6 Hz), 6.91 (ra, 3H), 4.16 (d, 2H, J - 8.2 Hz), 2.40 (m, 1H), m (ip, 1.63 (m, 2H), (?, I na v Example 2 4 g (22 mmol) of hydroxymethylene camphor is reacted with 4.29 g (22 mmol) of butyl o-aminobenzoate by the general method to obtain 4.9 g of a compound of the formula: ÜV (CH3OH):? ^ Ax = 358 nm, Ei1 = 802 IR: v «3274, 2943, 1687, 1622 (s), 1602, 1592, 1272, 1246, 1156 cpr1. iH-NMR (CDC13) 10.13 (d, ÍH, J - 16.2 Hz), 7.98 (d, ÍH, J = 6.9 Hz), 7.68 < d, ÍH, J = 16.2 Hz), 7.49 (t. ÍH, J = 7.2 Hz), 7.21 (d, ÍH, J - 6.9 Hz), 6.87 (d, ÍH, J ~ 7.2 Hz), 4.37 (t, 2H, J = 8.1 Hz), 2.81 (m, ÍH), 2.11 (m,? A) 1.4-1.6 < p », 9H), 0.99 (m, 10H).

Example 3 Compounds 3.1 to 3.15 set forth in Table 1 were prepared as Examples 1 and 2.

Table 1

Claims (1)

1. CLAIMS An arylaminomethylene camphor derivative of the formula (1) R1 - H, CH3, RH, Ci-Ce alkyl, C3-C8 cycloalkyl, C0-C0 alkenyl, C3-Cb cycloalkenyl, aryl, and substituted aryl, RH, C? -C6 alkyl, C3-C8 cycloalkyl, aryl, substituted aryl, C? -Cb alkoxy, C? -CH acyl, Ar aryl, substituted aryl, hetaryl or substituted hetaryl, The compound, according to claim 1, wherein the double The C = C bond is in the E configuration. The compound according to claim 1, wherein R "is CH3, R '= R' = H and Ar is 2- (alkoxycarbonyl) phenyl. according to claims 1-3 as an antisun agent The use, according to claim 4, in cosmetic or pharmaceutical formulations.