AU587211B2

AU587211B2 - Ultra violet agents

Info

Publication number: AU587211B2
Application number: AU49689/85A
Authority: AU
Inventors: Bruce Edward Chalker; Walter Clark Dunlap
Original assignee: Australian Institute of Marine Science
Current assignee: Australian Institute of Marine Science
Priority date: 1984-10-10
Filing date: 1985-10-03
Publication date: 1989-08-10
Anticipated expiration: 2005-10-03
Also published as: ES547726A0; ES8801184A1; GR852436B; EP0196328A1; EP0196328A4; AU4968985A; WO1986002350A1; ZA857767B

Description

ULTRA VIOLET AGENTS

THIS INVENTION relates to a new and useful class of ultra violet light absorbing compounds and to their use in sunscreen compositions and the protection of paint films and plastics materials from solar degradation.

Chemical compounds which absorb light in the ϋV portion of the spectrum (i.e. UV agents) have a number of important commercial applications. The best known of these are probably their use as sunscreen agents to protect the skin from the erythermal effect of sunlight and to shield paint films and plastics materials from solar degradation. They have also been used elsewhere as, for example, as energy transfer means in UV light crosslinking of certain polymers. Common commercially available UV agents include for example, para amino benzoic acid derivatives, benzotriazoles, benzophenones, methoxycinnamates and salicylates. It has also been proposed, for example in United Kingdom Patent Application 2 , 120, 549 A, that certain vinylogous amide compounds may also be used as sunscreen agents.

All of these UV agents exhibit strong radiation absorption in the UV region, the actual value of the absorption maximum being important in relating the compounds to their intended end use. For example, it is known that human skin is particularly sensitive to damage at wavelengths between about 290-320 nm (nanometer), the so-called UV-B region, with some likely carryover of harmful effects into the wavelength in excess of 320 nm, the UV-A region. On the other hand UV agents used to protect plastics and paint films commonly have absorption maxima in the region of 340-355 nm and higher.

Thus in general, useful UV agents for commercial purposes will have absorption maxima in excess of about 290 nm. They should also have acceptable permanence, stability and compatibility with media to which they are to be applied or incorporated. In particular, when the UV agents are to be used on living tissue, they must be non-toxic and not otherwise harmful to the host surface. These various criteria are often in conflict and limit the choice of UV agents available for specific end uses. Furthermore, the final selection, when it is made, is often a compromise in which for example, efficacy must be sacrificed for stability or freedom from toxic side-effects.

We have observed that certain mycosporin amino acids which exist in the living tissue of the pacific staghorn coral Acropora Formase are functional UV absorbing agents in corals inhabiting the shallow water, coral reef environment. While these appear to be potentially attractive as commercial UV agents, their utility is questionable because of the difficulty of isolating them from their biological sources and due also to their lack of adequate chemical stability.

We have now discovered that we can prepare certain synthetic analogues of those natural materials, which preserve their characteristic UV-absorbing chromophore within a chemically stable host structure.

The chromophore has the structure:

Surprisingly we have found, in particular, that the oxygen subsitutent at the 2 position is fundamental to the UV absorption characteristics UV compounds of the invention. Thus for example it has been observed that certain compounds containing the above chromophore have an absorption maximum at 305-340 nm. When analogous carbonylsare prepared in which there is no oxygen function at the 2 position (e.g. ethyl 3-octylamino-2-butencate) then the absorption maximum drops to about 285 nm, which is significantly below the abovementioned useful absorption range achieved by UV compounds of this invention. Preferred novel UV absorbing compounds of the invention, which are particularly useful in sunscreens are of formula (2) or (3) below:

wherein R₁ is selected from hydrogen, alkyl or alkenyl;

NR₂ is an amino group or a secondary or tertiary amine moiety in which the N atom bears either one or two unsubstituted or substituted alkyl, aryl or alkenyl groups which may be the same or different when two are present;

R is a moiety selected from alkyl, substituted alkyl, hydroxyl, carboxylic acid, ester or ether at positions 4, 5 or 6 on the ring;

n is 0-4. As mentioned hereinabove , the oxygen atom at the 2- position on the ring structure is a characteristic feature of all of our novel compositions.

When the substituent R ₁ is alkyl or alkenyl, it may be a straight or branched chain, which in turn may bear further substituent groups or be interrupted by a hetero-atom. For example R₁ may be methyl, ethyl, propyl, methoxy methyl or methoxy ethyl. It may also be cyclic, for example it may be cyclohexly. Our most preferred compositions are those in which R₁ is an alkyl chain containing 1 - 4 carbon atoms.

In its simplest form, -NR₂ is a amino group. One or both of the hydrogen atoms of that group may be replaced as described hereinabove by the same or different substituents selected from alkyl, aryl or alkenyl groups, which may themselves be branched, linear or contain a cyclical structure. The selected substituent may itself contain a further substituent. When both hydrogen atoms are replaced, the substituent groups may together form a carbocyclic or heterocyclic ring system.

Thus suitable components -NR₂ are, for example, cyclohexylamino, anilino, undecylamino, hexylamino, octylamino, decylamino, heptylamino, benzylamino, octadecylamino, pentylamino, nonylamino, N-methyl-N-benzylamino, di-butylamino, N-morpholino dodecylamino, phenethylamino, 1,1,3,3 tetramethyl butylamino, N-pyrolidinyl, N-piperidenyl, di-butylamino, N-methyl-N-cyclohexylamino, components of the structures -NHCH₂COOCE₃, -NHCH (CH₃)COOCH₃ , -NHCH(CH₂OH)COOCH₃ and -NHCH(HO-4-C₆H₄)COOCH₃.

Preferably structures are those in which -NR₂ is alkylamino, arylamino, amino acid and amino acid ester. When long term stability of the molecule is of major concern, it is most preferred that -NR₂ be a disubstituted amino.

The composition of the component R when present, is not usually critical and it is chosen with regard to such factors as, for example, the required solubility of hydrophilic/lipophilic balance of the molecule as a whole. Thus suitable components R are, for example, alkyl, substituted alkyl, hydroxyl, alkoxy, carboxylic acid ester or ester moieties. That is R may be, for example, 5-hydroxyl, 5 carboxylic acid or ester thereof, 5-hydroxymethyl, 5,5-dimethyl, 5-t-butyl and 4,4,6,6-tetramethyl.

Preferred compositions are those in which the component R when present, is methyl or ethyl.

The compounds (4c) below may be prepared by an appropriate standard method of organic synthesis. For example, compounds of this invention may conveniently be prepared via 3-substituted-2-hydroxy-(or 2-alkoxy-)-cycloalk-2-enones (4a, 4b) where the 3-substituent may be a hydroxyl or a a) R₁=H ; X =OH,Cl,Br b) R₁ = alkyl; X =OH,CI,Br c) R1 = alkyl; X = NR₂

(where m = 2 or 3 and R₁, NR₂ and (R)_n are as hereinbefore defined). suitable function which can serve as a leaving group e.g., -C1 or -Br. Compounds (4a) are acidic and can be alkylated at the 2-hydroxyl group with suitable alkylating agents such as dialkyl sulphates, alkyl tosylates or diazoalkanes (when there is no 3-hydroxyl) to give the alkyl derivatives (4b). Compounds (4b) can be reacted with amino compounds to effect a substitution at the 3-position to give compounds (4c). Compounds of structure (4a) may be prepared by a number of routes from various starting materials depending on the desired size and substitution of the carbocycle. The following procedures are illustrative. Reduction of 1,2,3 trihydroxy benzenes gives 2,3 dihydroxy cyclohex-2-enones and halogenation with copper chloride gives 3-chloro-2-hydroxy-cyclohex-2 enones. These compounds (4a) may then be converted to the compounds of the invention by the methods indicated hereinabove.

One of the potentially most useful applications of these UV agents is their incorporation in sunscreen preparations for skin protection. For this purpose we prefer that the selected UV agent have an absorption maximum in the region of 305-340 nm. In general this will require that the UV compound according to our invention will comprise a six-membered ring as structure (2) since derivatives of the five-membered enaminoketones tend to absorb UV-light in the region of 287-297 nm. Thus, for our purposes as sun-screen agents, we prefer to use compounds according to structure (2).

The UV compounds of the invention are readily compounded by the standard methods of the art into, for example, creams or lotions, making use of conventional emollients, emulsifiers, preservatives, anti-oxidants, perfumes and colouring agents.

By way of illustration only, suitable emollients are, mineral oil, squalene, octyl palmitate, cocoa butter, sesame oil, and pristane, either singly or in combination. Typical emulsifiers including for example, polyoxyethylene (3) olyl ether, polyglyceryl-4-oleate and polysorbate 80. The invention is illustrated by the following examples, in which all parts are given by weight.

Example 1

Preparation of 3-chloro-2-hydroxy-cyclopent-2-enone

Cyclopentanone (16 g, 0.15 mol) and cupric chloride (240 g, 1.5 mol) were refluxed for 1.5 h in 800 ml of a 50% solution of dioxane in water. This was allowed to cool, then water (400 ml) was added, filtered and extracted 3-5 times with diethyl ether (total 2.0 1). The organic phase was backwashed with water (200 ml), dried over sodium sulphate and evaporated to collect crude product, mp 130°. The crude material was dissolved in a large quantity of dichloromethane, treated with charcoal and filtered. This solution was evaporated to a suspension then filtered to collect the product as pale yellow crystals, mp 140-141°C.

Example 2

Preparation of 3-bromo-2-hydroxy-cyclopent-2-enone

Water (200 ml) containing 80 ml of 48% hydrogen bromide and cyclopentanone (67.2 g, 0.8 mol) was cooled to 5°C. Bromine (123.6 g, 2.4 mol) was added dropwise over 6 h while maintaining the temperature between 5-15°C. The reaction vessel was then left overnight in a large water bath. The resulting orange solution was added to water (1.5 1) and the organic phase separated. This was vigorously stirred in water (2 1) for 48 h. The aqueous phase was continuously extracted with diethyl ether. The extracts were dried over sodium sulphate and evaporated to collect a brown solid, mp 148°.

Example 3

Preparation of 3-chloro-2-methoxy-cyclopent-2-enone

3-Chloro-2-hydroxy-cyclopent-2-enone (2.8 g, 21.13 mmol) was dissolved in methanol (15 ml) and cooled to 0°C. To this mixture, an ethereal solution of diazomethane (42 mmol) was added portionwise with swirling. This was then allowed to warm to room temperature overnight. Polymeric material was then filtered off and the filtrate evaporated under reduced pressure to leave a yellow oil. This was purified by column chromatography on silica gel using 30:70 dichloromethane: petroleum spirit resulting in a pale yellow oil. Example 4 Preparation of 3-cyclohexylamino-2-methoxy-cyclopent-2-enone

Into a 5 ml glass vial, fitted with a rubber septum and under an atmosphere of nitrogen were placed 3-chloro-2-methoxycyclopent-2-enone (0.5 g, 3.4 mmol), triethylamine (0.48 ml, 3.4 mmol) and cyclohexylamine (0.51 g, 5.1 mmol). This was heated at 30°C for 42 h. The contents were then dissolved in methanol (3 ml) and treated with one equivalent of sodium hydroxide dissolved in the minimum amount of methanol. The solvent and triethylamine were evaporated and the residue dissolved in dichloromethane, then filtered. The filtrate was evaporated to give crude product in near quantitative yield. The oil was distilled by Kugelrohr distillation giving a pale yellow oil which crystallized when triturated with diethyl ether, mp 105-106°.

Examples 5 to 12

The compounds described in Table 1 and Table 2 below were prepared following essentially the same procedure described in Example 4.

Example 13

Preparation of 2,3-hydroxy-cyclohex-2-enone

Pyrogallol (1,2,3-trihydroxybenzene, 75 g; 0.6 mol) was charged in a 1 liter hydrogenation bomb and a cooled (0°) solution of aqueous sodium hydroxide (24 g in 150 ml H₂O ) was added under nitrogen. Raney nickel catalyst ( approx. 4 g; activity W-2) was admixed under nitrogen. Hydrogenation was conducted at room temperature for 24 hours at a pressure of 1000 psi H2 with constant shaking. The resulting mauve coloured solution was filtered through celite (diatomaceous earth) to remove the nickel catalyst and the filtrate was cooled to -5°C. Acidification to pH 3-4 yielded a silky greywhite solid. The solid was collected by filtration, dried, and recrystalization from benzene gave a pale yellow solid, m.p. 114-115°. Evaporation of the filtrate to a volume of 100 mis and continuous extraction (24 h) with benzene afforded an additional quantity of dihydropyrogallol (2,3-dihydroxycyclohex-2-enone) after drying (Na₂ SO₄) and crystalization from benzene.

Example 14

Preparation of 3-cyclohexyla_mino-2-hydroxy-cyclohex-2-enone

2,3-Dihydroxy-cyclohex-2-enone (3.8 g; 0.03 mol) was dissolved in chloroform (100 ml) and cooled to 5°C. Cyclonexylamine hydrochloride (4.1 g; 0.03 mol) was added with stirring under nitrogen. Triethylamine (dried over molecular sieves) was added dropwise to pH 6.6 and the mixture refluxed for 16 hours during which the pH was adjusted to maintain between 6.2 and 6.7. The progress of the reaction was monitored by UV-spectroscopy. At completion of the condensation reaction the chloroform was removed under reduced pressure and the residue extracted into ether. The product was obtained on evaporation of the ether and vacuum distillation (190-200°/100 mTorr).

Examples 15 to 17

The compounds described in Table 3 and Table 4 below were prepared following essentially the same proceedures described in Example 14.

Example 18

Preparation of 3-hydroxy-2-_methoxy-cyclohex-2-enone

2,3-Dihydroxy-cyclohex-2-enone (15 g) was dissolved in 4N NaOH (45 ml) and cooled to 5°C. Dimethyl sulfate (18 ml; freshly distilled and stored over KOH pellets) was added dropwise with vigorous stirring while maintaining the internal temperature below 10°C. The reaction was maintained above pH 7 throughout the addition while under an atmosphere of nitrogen. A further quantity of 4N NaOH (45 ml) was added after the addition of dimethyl sulfate was completed and the reaction was allowed to stir overnight (16 h) at room temperature. The mixture was cooled to 5°C and acidified to congo red with 4N H₂SO₄ while still under nitrogen. The resulting yellow solution was evaporated to ca. half-volume andthe product removed by continuous extraction (48 h) with ether. The ether extract was dried (Na₂SO₄) and evaporation afforded a yellow oil which crystalized under vacuum (50 mTorr). Recrystalization from benzene:hexane gave 3-hydroxy-2methoxy-cyclohex-2-enone as pale yellow needles, m.p. 109¬110°C.

Example 19

Preparation of Methyl N-(2-m_ethoxy-cyclohex-2-enone-3-yl)glycinate

3-Hydroxy-2-methoxy-cyclohex-2-enone (4.26 g; 0.03 mol) was dissolved in chloroform (100 ml) and cooled to 5°C. Methyl glycinate hydrochloride (3.77 g; 0.03 mol) was added with stirring under nitrogen. Triethylamine (dried over molecular sieves) was added dropwise until pH 6.6. The mixture was refluxed for 72 h during while the pH was maintained between 5.7-6.6. Progress of the reaction was determined by UV-spectroscopy. At completion of the condensation reaction the chloroform was removed under vacuum and the residue was chromatographed on silica-gel with light petroleum (b.p. 60-80°) and methanol (10%). The fraction containing the product was evaporated and the residue crystalized from light petroleum (b.p. 60-80°): chloroform to give the product as brown crystals which decomposed rapidly on exposure to air or while in solution.

Examples 20 - 24

The compounds described in Table 5 and Table 6 below were prepared following essentially the proceedures described in Example 19. Example 25

Preparation of 2-methoxy-3-pentylamino-cyclohex-2-enone

3-Hydroxy-2-methoxy-cyclohex-2-enone (5.69 g; 0.04 mol) was admixed with n-pentylamine (5.23 g; 0.06 mol). The reaction mixture was heated to reflux with stirring under an atmosphere of nitrogen for 24 hours. Progress of the condensation reaction was determined by UV-spectroscopy. At completion of the reaction excess amine was removed under reduced pressure and the residue distilled between 136-142°C at a pressure of 65 mTorr. The product distillate was refractionated using a micro-distillation apparatus at equivalent temperature and pressure.

Examples 26 - 42

The compounds described in Table 7 and Table 8 below were prepared following essentially the proceedures described in Example 25.

Example 44

Preparation of 2-ethoxy-3-octylaιnino-cyclohex-2-enone

2-Ethoxy-3-hydroxy-cyclohex-2-enone (6.25 g; 0.04 mol) was admixed with n-octylamine (10.28 g; 0.06 mol). The reaction was heated to 140°C for 20 h with vigorous stirring under an atmosphere of nitrogen. Progress of the condensation reaction was determined by UV-spectroscopy. At completion of the condensation reaction the product was obtained by distillation (160-164°C/65 mTorr) and the distillate refractionated in a micro-distillation apparatus.

Example 43

Preparation of 2-ethoxy-3-hvdroxy-cyclohex-2-enone

2,3-Dihydroxy-cyclohex-2-enone (15 g) was dissolved in ethanol (50 ml) and cooled to 5°C in an ice bath. Aqueous 4NNaOH (45 ml) was added to the ethanolic solution under nitrogen. Diethyl sulfate (22 ml) was added dropwise with vigorous stirring while maintaining the internal temperature below 10°C. The reaction was maintained above pH 7 throughout the addition under an atmosphere of nitrogen. A further quantity of 4N NaOH (45 ml) was added after the addition of diethyl sulfate was completed and the reaction allowed to stir at room temperature for 24 h. The organic solvent was removed under reduced pressure. The resulting aqueous solution was cooled to 5°C and acidified to congo red with 4N H₂SO₄. The product was removed from the aqueous phase by continuous extraction (48 h) with ether. The ether extract was dried (Na₂SO₄) and evaporation afforded a dark yellow oil which solidified on drying under vacuum (50 mTorr). The product was purified by column chromatography on silica-gel (benzene:ethanol). Evaporation of the solvents gave a light yellow oil which solidified on drying under vacuum. Recrystalisation from benzene:ethanol (charcoal) gave 2-ethoxy3-hydroxy-cyclohex-2-enone as pale yellow needless, m.p. 91¬93°C. Examples 45 - 50

The compounds described in Table 9 and Table 10 below were prepared following essentially the proceedures described in Example 44.

Example 51

Preparation of 5-tertiary-butyl-3-chloro-2-hydroxycyclohex-2-enone

A solution of 4-tertiary-butyl-cyclohexanone (7.71 g, 0.05 mol) and copper (II) chloride dihydrate (131.2 g, 0.75 mol) in water (200 ml) and dioxane (200 ml) was heated under reflux for 2 hours. After cooling to room temperature, the mixture was extracted with ether (2 x 150 ml) and the combined organic extracts were dried (anhydrous magnesium sulphate), then concentrated under reduced pressure. The residue was purified by column chromatography (40-63 μm silica gel) using 30% hexane in dichloromethane as eluant to give 5-tertiary-butyl-3-chloro2-hydroxy-cyclohex-2-enone as a white crystalline solid, mp 85-86°C.

Example 52

Preparation of 5-tertiary-butyl-3-chloro-2-m_ethoxy cyclohex-2-enone

A solution of diazomethane (1.26 g, 0.03 mol) in diethyl ether (90 ml), was added portionwise to an ice cold solution of 5-tertiary-butyl-3-chloro-2-hydroxy-cγclohex-2-enone (2.03 g, 0.01 mol) in methanol (20 ml). After standing for 1 hour at 0°C, then overnight at room temperature, the solution was concentrated under reduced pressure, diluted with diethyl ether (20 ml), filtered and the filtrate concentrated under reduced pressure to leave a colourless oil. Examples 53 - 54

The compounds described in table 11 and table 12 below were prepared following essentially the same procedure described in Example 4.

Example 55

UV-Stability of 2-alkoxy-3-a_mino-cyclohex-2-enones

A selection of 2-alkoxy-3-amino-cyclohex-2-enones were tested for UV-stability and compared with compounds contained in commercial preparations of common use as sun-screening agents. These data are tabulated in Table 13. The apparatus used in this proceedure is outlined by D. S. Berger in "Specification and design of solar ultraviolet simulators" (J. Invest. Derm., 53 (3), 192, 1969) incorporating a Sellotape 636 or 672 filter as replacement for the specified Schott WG 320 filter. A Hitachi 150-20 spectrophotometer was used to record

UV specta and to determine the maximum absorbance. Dilute solutions (~ 3 x 10^{- 6}M) of the selected compounds described in this invention dissolved in isopropyl alcohol were irradiated for periods of time specified in Table 13. The UV spectrum was recorded to determine any shift in the absorption wavelength (λ max) and to determine the absorptivity (A) value. The formation of decomposition products also absorbing at λ max were determined (if any) by HPLC separation using isocratic elution (MeOH : H₂O, 80:20; PIC B6, 0.01M, pH 3.0) on a 3 μ microsorb, C-18 reverse-phase column. The samples tested proved to be quite stable (max. loss ~ 3%) and comparable with

2 commercial sunscreens, 2-ethylhexyl N,N-dimethyl-p-benzoate

((A); Escalol 507) and 2-ethylhexyl p-methoxy-cinnamate ((B);

Neo Heliopan UV).

Claims

The claims defining the invention are as follows: 1. An ultra violet light absorbing compound containing the chromophore
2. A compound as claimed in claim 1 having the formula:

(1) (2)

wherein R₁ is selected from hydrogen, alkyl or alkenyl; NR₂ is an amino group or a secondary or tertiary amine moiety in which the N atom bears either one or two unsubstituted or substituted alkyl, aryl or alkenyl groups which may be the same or different when two are present; R is a moiety selected from alkyl, substituted alkyl, hydroxyl, carboxylic acid, ester or ether at positions 4, 5 or 6 on the ring; n is 0-4.
3. A compound as claimed in claim 2 wherein R is an alkyl group bearing further substituent groups or is an alkyl group interrupted by a hetero-atom.
4. A compound as claimed in claim 2 wherein R₁ is methyl, ethyl, propyl, methoxy methyl or methoxy ethyl.
5. A compound as claimed in claim 2 wherein R₁ is cyclohexyl.
6. A compound as claimed in claim 2 wherein R₁ is an alkyl chain containing 1-4 carbon atoms.
7. A compound as claimed in claim 2 wherein -NR₂ is an amino group.
8. A compound as claimed in claim 2 wherein NR₂ is a secondary or tertiary amine moiety.
9. A compound as claimed in claim 2 wherein both hydrogen atoms of the amino group are replaced by a substituent groups which may together form a carbocyclic or heterocyclic ring system.
10. A compound as claimed in claim 2 wherein -NR₂ is selected from cyclohexylamino, anilino, undecylamino, hexylamino, octylamino, decylamino, heptylamino, benzylamino, octadecylamino, pentylamino. nonylamino, N-methyl-N-benzylamino, di-butylamino, N-morpholino dodecylamino, phenethylamino, 1 , 1 , 3 , 3 tetramethyl butylamino, N-pyrolidinyl, N-piperidenyl, di-butylamino, N-methyl-N-cyclohexylamino, components of the structures -NHCE₂COOCH₃, -NHCH(CH₃)COOCH₃, -NHCH (CH₂OH)COOCH₃, and -NHCH(HO-4-C₆H₄)COOCH₃.
11. A compound as claimed in claim 2 wherein NR₂ is alkylamino, arylamino amino acid or amino acid ester.
12. A compound as claimed in claim 2 wherein NR₂ is disubstituted amino.
13. A compound as claimed in claim 2 wherein R is selected from 5-hydroxyl 5-carboxylic acid or ester thereof 5-hydroxymethyl, 5,5-dimethyl, 5-t-Jsutyl and 4,4,6,6-tetramethyl.
14. A compound as claimed in claim 2 wherein R is methyl or ethyl.
15. A compound as claimed in claim 1 substantially as herein described with reference to any one of the Examples 1-46.
16. A composition useful for absorbing UV light containing a compound as claimed in any preceding claim.
17. A sunscreen protective composition wherein the active ingredient is a compound as claimed in any preceding claim.
18. A process for preparing an ultra-violet light absorbing compound by the reaction of a compound according to structure 4(b) herein with an amino compound to give a compound according to structure 4(c) herein.
19. A process of preparing a sunscreen protective composition by the incorporation of an ultra violet light absorbing compound according to any one of claims 1-15 into a cream or lotion carrier base.