Patent Publication Number: US-5830441-A

Title: Photostable UV absorbent containing A-cyano cinnamyl moiety

Description:
FIELD OF THE INVENTION 
     The present invention relates to active UV absorption agents having a maximum absorption above 340 nm wavelength and having improved stability and solubility in polar organic solvents and other formulating components. Instant absorption agents are highly effective in protecting the skin or hair against damage caused by the most harmful UV radiation. 
     BACKGROUND OF THE INVENTION 
     Solar radiation is generally classified as UV-C in the range of 200-280 nm which is effectively filtered by the ozone layer; UV-B in the range of 290-320 nm which causes skin tanning and UV-A in the range of 320-400 nm. UV-A is subdivided into regions UV-A I at 320 to 340 nm and UV-A II at 340 to 400 nm wavelength. While people with highly sensitive skin may suffer sunburn at radiation as low as 335-340 nm, those of normal skin sensitivity or darker skinned individuals can tolerate higher radiation; however, even these individuals are subject to skin damage caused by solar radiation above 340 nm. In addition to causing sunburn and brown age spots, radiation above 340 nm is associated with premature skin aging such as loss of skin elasticity and wrinkle formation. Also, radiation at these high levels has been particularly identified as a leading cause of skin cancer. A few methoxyphenol ketones which initially possess maximum absorption at about 350 nm, notably avobenzone (PARSOL® 1789) have been proposed as sunscreening agents, however, these have been found to lack stability and photodegrade upon exposure to illumination within a short time, e.g. less than 0.5 hour, to 250 nm maximum absorption and little or no absorption above 300 nm. Accordingly it is desirable to develop a sunscreen which is stable and selectively effective against radiation above 340 nm, particularly with a maximum absorption in the range of 345-365 nm, which is photostable but non-toxic and which is economical to produce. As a sunscreen, the desired chemical should be odorless and substantially colorless over an extended period of use. The present invention achieves these objectives with a group of chemicals economically produced in a one-step process. 
     An object of this invention is to provide a compound specifically directed to radiation absorption in the 345-365 nm wavelength range. 
     Another object is to provide a sunscreen which has extended solubility in polar solvents and which exhibits a capability of hydrogen bonding with other components of a personal care formulation. 
     Still another object is to provide a sunscreen having improved hair and skin substantivity. 
     These and other benefits and advantages of the present invention will become apparent from the following description and disclosure. 
     THE INVENTION 
     For the purpose of this invention &#34;lower alkyl&#34;, &#34;lower alkoxy&#34; and &#34;lower alkylene&#34; are radicals containing 1 to 4 carbon atoms. Where &#34;alkyl&#34; is not otherwise characterized, the radical includes 1 to 18 carbon atoms. 
     In accordance with this invention there is provided a photostable sunscreening agent effective in the range above 340 nm wavelength having the formula: ##STR3## wherein R is --CO(R 2 ) or phenyl optionally substituted with lower alkyl and/or lower alkoxy; 
     R 2  is --alkyl, --)(C 2+  alkyl), ##STR4## n has a value of from 2 to 8; 
     S and T each independently are hydroxy, lower alkyl, lower alkoxy or, when R 2  is alkyl or alkoxy, S can also be phenyl and when R 2  is alkoxy, T is alkoxy or S+T taken with the phenyl ring forms a naphthyl radical or a fused benzodioxol-5-yl heterocyclic radical; 
     k+l has a value of from 0 to 3 with the proviso that, when R 2  is --O(alkyl), T is --O(lower alkyl) and the value of l is at least 2; 
     R 3  is hydrogen or lower alkylene; 
     R 4 , R 5  and R 6  are each independently C 1  to C 18  alkyl or one of R 4 , R 5  and R 6  can be phenyl and 
     A is an anion. 
     Representative compounds of the above formula include cyanocinnamate esters, such as the polyalkoxy substituted species 
     
         ______________________________________                                    
 ##STR5##                                                                 
                    λ.sub.max                                      
                    (nm) ε                                        
                                 E.sub.1                                  
______________________________________                                    
Methyl α-cyano-3,4-dimethoxy cinnamate                              
                      359    23,000  930                                  
Ethyl α-cyano-3,4-dimethoxy cinnamate                               
                      359    24,000  920                                  
Ethyl α-cyano-2,4-dimethoxy cinnamate                               
                      363    36,000  1380                                 
Ethyl α-cyano-3,4,5-trimethoxy cinnamate                            
                      345    20,000  690                                  
Ethyl α-cyano-3,4-methylenedioxy cinnamate                          
                      361    22,300  910                                  
Ethyl α-cyano-3-methoxy-4-hydroxy cinnamate                         
                      364    25,700  1040                                 
Propyl α-cyano-3,4-dimethoxy cinnamate                              
                      359    23,650  860                                  
Isopropyl α-cyano-3,4-dimethoxy cinnamate                           
                      359    23,650  860                                  
Ethyl α-cyano-3-methyl-5-methoxy cinnamate                          
                      348                                                 
Butyl α-cyano-3,4-dimethoxy cinnamate                               
                      359    23,100  800                                  
Pentyl α-cyano-3,4-dimethoxy cinnamate                              
                      359    23,600  780                                  
Isoamyl α-cyano-3,4-dimethoxy cinnamate                             
                      359    23,600  780                                  
Isoamyl α-cyano-3,5-dimethoxy cinnamate                             
                      365    25,100  870                                  
Isoamyl α-cyano-3,4-ethoxy cinnamate                                
                      361    19,250  670                                  
Isoamyl α-cyano-3,-methylenedioxy cinnamate                         
                      361    19,250  670                                  
Hexyl α-cyano-3,4-dimethoxy cinnamate                               
                      359    24,100  760                                  
Heptyl α-cyano-3,4-dimethoxy cinnamate                              
                      359    23,800  720                                  
Octyl α-cyano-3,4-dimethoxy cinnamate                               
                      359    23,400  680                                  
2-Ethylhexyl α-cyano-3,4-dimethoxy cinnamate                        
                      359    23,400  680                                  
Decyl α-cyano-3,4-dimethoxy cinnamate                               
                      359    23,100  620                                  
Dodecyl α-cyano-3,4-dimethoxy cinnamate                             
                      359    23,600  590                                  
Hexadecyl α-cyano-3,4-dimethoxy cinnamate                           
                      359    21,300  470                                  
______________________________________                                    
 
    
     Of the above species, the branched alkyl esters of at least 4 carbon atoms in the alkyl group are preferred. the α-phenyl cinnamonitrile species 
     
         ______________________________________                                    
                    λ.sub.max                                      
                    (nm) ε                                        
                                 E.sub.1                                  
______________________________________                                    
 ##STR6##                                                                 
α-Phenyl-3,4-dimethoxy cinnamonitrile                               
                      347    22,500  850                                  
α-Tolyl-3,4-dimethoxy cinnamonitrile                                
                      348    22,100  910                                  
α-4&#39;-methoxyphenyl-3,4-dimethoxy                                    
                      353    29,000  980                                  
cinnamonitrile                                                            
α-3&#39;,4&#39;-dimethoxyphenyl-3,4-dimethoxy                               
                      359    26,000  800                                  
cinnamonitrile                                                            
α-4&#39;-methoxyphenyl-4-methoxy cinnamonitrile                         
                      343    29,500  1110                                 
3&#39;,4&#39;-dimethoxyphenyl-4-methoxy                                           
                      350    27,500  930                                  
cinnamonitrile                                                            
α-3&#39;,4&#39;-dimethoxyphenyl-3-ethoxy                                    
                      350    27,500  930                                  
cinnamonitrile                                                            
α-3&#39;,4&#39;-dimethoxyphenyl-4-isopropyl                                 
                      343    22,400  730                                  
cinnamonitrile                                                            
α-3&#39;,4&#39;-dimethoxyphenyl-4-phenyl                                    
                      355    29,600  870                                  
cinnamonitrile                                                            
α-4&#39;-methoxyphenyl-2,4-dimethoxy                                    
                      356    25,300  860                                  
cinnamonitrile                                                            
the ketone species                                                        
 ##STR7##                                                                 
t-Butyl α-cyano 3,4-dimethoxy cinnamyl                              
                      367    19,100  700                                  
ketone                                                                    
t-Butyl α-cyano 4-methoxy cinnamyl ketone                           
                      348    24,000  990                                  
t-Butyl α-cyano 4-phenyl cinnamyl ketone                            
                      343    29,500  1020                                 
iso-propyl α-cyano-phenyl cinnamyl ketone                           
                      --     --      --                                   
n-butyl α-cyano 4-phenyl cinnamyl ketone                            
                      --     --      --                                   
______________________________________                                    
the α-cyano cinnamide species                                       
 ##STR8##                                                                 
Dimethylamino N-propyl α-cyano-                                     
                      353    23,400  740                                  
3,4-dimethoxy cinnamide                                                   
Dimethylamino N-propyl α-cyano-                                     
                      --     --      --                                   
4-methoxy cinnamide                                                       
______________________________________                                    
the quaternized α-cyano cinnamide species                           
 ##STR9##                                                                 
______________________________________                                    
 
    
     including dodecyl tosylate quaternized N,N,N-dimethyl propyl amino propyl α-cyano-3,4-dimethoxy cinnamide, dodecyl tosylate quaternized N,N,N-dimethyl propyl amino propyl α-cyano 4-methoxy cinnamide, chloride or bromide quaternized N,N,N-dimethyl ethyl amino butyl α-cyano 3-methoxy cinnamide, trimethyl ammonium chloride quaternized N,N,N-diethyl methyl amino hexyl α-cyano α-cyano 3,4,5-trimethoxy cinnamide, lauryl sulfonate quaternized N,N,N-dimethyl dodecyl amino propyl α-cyano 3,5-diethoxy cinnamide, tosylate quaternized dimethyl octyl amino propyl β-methyl-α-cyano 3,4-dimethoxy cinnamate, etc. 
     the heterocyclic benzodioxol-yl species ##STR10## including ethyl α-cyano-4,5-dioxole cinnamate, λ max 361; pentyl α-cyano-4,5-dioxole cinnamate, λ max 361; isoamyl α-cyano-4,5-dioxole cinnamate; t-butyl α-cyano-4,5-dioxole cinnamate; ethyl α-cyano-4,5-dioxole-3-methoxy cinnamate and the like. 
     and the naphthyl cyano species ##STR11## 
     Of the above active sunscreen agents, the dialkoxy α-cyano cinnamate compounds, particularly the isoamyl- and hexyl- α-cyano-3,4-dimethoxy cinnamates, and the quaternized dialkoxy α-cyano cinnamides, particularly the dodecyl tosylate quaternized salt of dimethylamino N-propyl α-cyano 3,4-dimethoxy cinnamide, are preferred. Multiple alkoxy groups on a terminal phenyl radical is found to provide a distinct advantage over the monoalkoxy substituted homolog. It is now discovered that the multiple alkoxy substituents on a terminal phenyl ring provides a significant advantage in resonance of the compound. Specifically the oxygen of an alkoxy in the para (p) position carries a positive charge, whereas the oxygen of an alkoxy in an adjacent or meta (m) position on the ring stabilizes the positively charged p-oxygen by interspacial interaction. In addition to the superior photostability of the present multisubstituted alkoxy cinnamyl compounds, these sunscreening agents possess selective maximum absorptions in the 345-365 nm wavelength range. Hence the present di- or tri- alkoxy substituted cyano cinnamates are significantly more photostable over extended periods of use and offer better protection of the skin and/or hair from the most damaging rays of the sun. Further, as a result of the additional alkoxy substitution in a functional terminal position in their structure, the present sunscreening agents distribute uniformly in traditional cosmetic carriers such as furan, triglycerides, polyethylene glycol, alcohols, e.g. isopropanol, alkanes, e.g. cyclohexane, hexane, octane, etc., vegetable oils and waxes as well as more polar solvents. This advantage enhances their solubility and dispersability for subsequent formulation in aqueous solutions which in turn leads to the formation of a more uniformly dispersed film on the skin which is necessary for good photoprotection. 
     For use in personal care formulations the present sunscreens can be employed in mixtures with each other or with minor amounts of other known sunscreening agents to extend the absorption range of the later. 
     In cosmetic or pharmaceutical formulations, the present products can be applied to the skin or hair as a spray, cream, lotion, gel, emulsion or microdispersion and can be used as the sole sunscreening agent or can be employed in admixture with conventional sunscreens to provide effective protection. Generally the concentration of total sunscreening agent in a formulation is between about 0.25 and about 9 wt. %, preferably from about 0.5 to about 6 wt. %, based on the total composition. 
     The formulation may also include, in addition to a carrier, conventional excipients such as, for example, a thickener, emollient, humectant, diluent, surfactant, hair or skin conditioner, hair dye, preservative, antifoaming agent, fragrance, coloring agent and/or propellant when employed as an aerosol spray. Generally, such excipients can make up to 15 wt. % of the total composition but usually do not exceed 10 wt. %. 
     The present sunscreening compounds can be economically prepared in a one step process according to the following generic equation ##STR12## where R&#39; is hydrogen or lower alkyl. The mole ratio of aldehyde (a) to cyanide (b) can vary somewhat but is preferably as close to stoichiometry as is convenient to maintain. Within the broad scope of the above equation preparation of the cinnamate sunscreens is described by the general equation: ##STR13## 
     The preparation of the present ketones is shown by ##STR14## and the preparation of phenyl cinnamonitriles by ##STR15## 
     The preparation of the cinnamonitriles can be described by the equation ##STR16## whereas the preparation of the quaternized amides is shown by the equation ##STR17## 
     The present compounds are prepared under mild alkaline conditions including a temperature of from about 75° C. to about 150° C., preferably from about 80° C. to about 120° C. over a period of between about 0.5 and about 5 hours, at a pH of from about 9 to about 14, preferably at a pH of 10-12. In this process the aldehyde reactant is introduced in solution and mixed with the cyanide component in about an equimolar proportion. The concentration of aldehyde in solution is conveniently between about 5 and about 70 wt. %, although this concentration can be higher or lower depending on the needs of subsequent formulation in a personal care or topical pharmaceutical composition. Preferred solvents for the aldehyde component include toluene, cyclohexane, octane, ethanol and isopropanol. 
     The aldehyde and cyanide are reacted in the presence of between about 1 and about 10 wt. % of a deprotonization catalyst such as piperidine, pyridine, sodium methoxide, an organic lithium salt such as lithium diisopropylamide or any other conventional deprotonization catalyst. If desired, the product can be purified by crystallization; however, the products of this invention are generally obtained in good yield and high selectivity. 
    
    
     DESCRIPTION OF THE DRAWINGS 
     The appended Figures provide meaningful comparisons between the present invention and sunscreens of the prior art. 
     FIG. 1 illustrates the critical difference between the mono- methoxy substituted isoamyl cyano cinnamate (curve 1) and the di- methoxy substituted isoamyl cyano cinnamate of the present invention (curve 2). The absorption of the former, having a maximum at about 340 nm falls off down to 260 nm. Surprisingly, the maximum absorption for the present dimethoxy isoamyl cyano cinnamate is maintained at 360 nm and effective light protection is extended up to about 390 nm. 
     FIG. 2 compares mono methoxy hexyl cyano cinnamate (curve 3) with dimethoxy hexyl cyano cinnamate (curve 4). As can be observed, the monomethoxy substituted ester has a significantly narrower peak absorption range than the correspondingly dimethoxy substituted isoamyl ester so that the dimethoxy ester depicted provides a greater effective absorption in the harmful UV-A II range. The increased absorption is indicated by the hatched area in FIG. 2. 
     FIG. 3 illustrates the photodegradation of a diketone sunscreen, avobenzone (PARSOL® 1789) in acetonitrile, before illumination (curve 5) and after illumination (curve 6). The rapid absorption decline of PARSOL® 1789 in the wavelength range from about 350 nn after 30 minute illumination detracts from its use as an effective UV-A sunscreen. 
     Having broadly described the present invention, reference is now had to the accompanying examples which illustrate preferred embodiments and comparisons with the colsest sunscreens of the prior art. It is to be understood that the scope of this invention is not to be limited to the following examples but is defined by the foregoing disclosure and the appended claims. 
    
    
     EXAMPLE 1 
     Preparation of α-Cyanocinnamates 
     Into a four neck round bottom glass flask, equipped with a Dean-Stark receiver, a water cooling condenser, a nitrogen purge, an overhead mechanical agitator and a temperature control, was charged 50 g of 3,4-dimethoxy benzaldehyde, 37 g of ethyl cyanoacetate, 2.5 g of piperidine and 150 ml of toluene. The resulting mixture was agitated under reflux for 2 hours at about 110° C. during which time water of the ensuing condensation reaction was intermittently removed. After completion of the reaction, the product ethyl-3,4-dimethoxy-α-cyano cinnamate, was recovered and subjected to washing with 150 ml of deionized water followed by rotary evaporation to remove toluene solvent. The residue was then recrystallized from toluene to produce a pale yellow solid product in 90% yield. 
     EXAMPLE 2 
     Example 1 was repeated except that 4-phenyl benzaldehyde was substituted for 3,4-dimethoxy benzaldehyde and 2.6 g of piperidine deprotonization catalyst was employed. The corresponding product, ethyl-α-cyano-4-phenyl cinnamate was recovered as a white solid in 90% yield. 
     EXAMPLE 3 
     Example 1 was repeated except that the hexyl ester of cyanoacetic acid was substituted for cyano methyl acetate. The corresponding product, hexyl 3,4-dimethoxy-α-cyano cinnamate was recovered as an off white solid in 93% yield. 
     EXAMPLE 4 
     Repetition of Example 1 with 3-methoxy-4-hydroxy benzaldehyde substituted for 3,4-dimethoxy benzaldehyde provides the corresponding ethyl 3-methoxy-4-hydroxy-α-cyano cinnamate as a light yellow solid product in about 85% yield. 
     EXAMPLE 5 
     Repetition of Example 1 with the isoamyl ester of cyanoacetic acid substituted for methyl cyano acetate provides the corresponding isoamyl ester of 3,4-dimethoxy-α-cyano cinnamic acid as a pale yellow solid product in greater than 85% yield. 
     EXAMPLE 6 
     Preparation of Cyano Cinnamyl Ketones 
     Repetition of Example 1 with cyanoacetone substituted for methyl cyano acetate provides the corresponding t-butyl ketone of 3,4-dimethoxy-α-cyano cinnamic acid as an off cream colored solid product in greater than 80% yield. 
     EXAMPLE 7 
     Preparation of Cyano Cinnamonitriles 
     Using the equipment of Example 1, 37 g of benzoylacetonitrile and 5 g of sodium methoxide were added to 50 g of 3,4-dimethoxy benzaldehyde dissolved in 100 ml of ethanol. The resulting mixture was agitated for 2 hours at room temperature and for an additional 2 hours at 80° C. The product was cooled and formed a precipitate which was filtered, washed with water and recrystallized from ethanol before drying. The resulting product was recovered as a cream colored solid in 90% yield. 
     EXAMPLE 8 
     Preparation of Cyano Cinnamides 
     Again using the equipment of Example 1, 46 g of dimethylaminopropyl amine was added to 50 g of ethyl cyanoacetate in 50 ml of toluene in the absence of a catalyst. The mixture was agitated under reflux for 2 hours, after which the ethanol by-product was removed. The remaining contents was then cooled to room temperature and 75 g of 3,4-dimethoxy benzaldehyde in 50 ml of toluene and 3.8 g of piperidine catalyst were then added. This mixture was agitated under reflux for 2 hours at about 110° C. during which water of the condensation reaction was removed. Toluene solvent was then removed by rotary evaporation and the dried residue was recrystallized from isopropanol. After washing with about 150 ml of water, the product, dimethylamino N-propyl α-cyano-3,4-dimethoxycinnamide having the structure: ##STR18## was recovered as a creamy white solid in 92% yield. 
     EXAMPLE 9 
     Preparation of Quaternized Cyano Cinnamides 
     Using the same equipment described above, 56 g of dodecyl tosylate was added to 50 g of the product of Example 8 dissolved in 150 ml of isopropanol. The mixture was agitated and maintained at 100° C. for 2 hours after which the isopropanol was removed by rotary evaporation. The cooled, water washed tosylate quaternized product was recovered as a light yellow solid in quantitative yield. 
     EXAMPLE 10 
     Comparative Data on Photostability 
     The half life of the product of Example 1, namely 3,4-dimethoxy-α-cyano ethylcinnamate, was compared to that of 4-methoxy-α-cyano ethylcinnamate and the results of this comparison are reported in Table I below. 
     
                       TABLE I                                                     
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COMPOUND              HALF LIFE                                           
______________________________________                                    
ethyl 4-methoxy-α-cyano cinnamate                                   
                      1.0                                                 
ethyl 3,4-dimethoxy-α-cyano cinnamate                               
                      1.8                                                 
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     EXAMPLE 11 
     The rate of photodegradation of the present dimethoxy α-cyano cinnamates and the results of this comparison are reported in following Table II. 
     
         ______________________________________                                    
                       HALF LIFE                                          
COMPOUND               (OVER 10 HOURS)                                    
______________________________________                                    
isoamyl 4-methoxy-α-cyano cinnamate                                 
                       1.07                                               
isoamyl 3,4-dimethoxy-α-cyano cinnamate                             
                       1.45                                               
hexyl 4-methoxy-α-cyano cinnamate                                   
                       1.0                                                
hexyl 3,4-dimethoxy-α-cyano cinnamate                               
                       1.44                                               
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     The astonishing results of the comparisons reported in Examples 10 and 11 where half-life of the present compounds was almost doubled emphasizes the discovery of this invention concerning the need for a proton stabilizer acting on a mono alkoxy substituted phenyl ring in the cyano cinnamate sunscreens.