3-amino-tetrahydro-1,3-thiazine-2,4-diones, utilization thereof and skin treating compositions containing said compounds
The invention relates to 3-amino-tetrahydro-1,3-thiazin-2,4-diones as well as skin treating compositions containing said compounds. 
     The skin forms the limiting layer between the organism and its environment. Therefore, the most important task of the skin consists of protecting the inside of the body against exogenic influences. Our skin is in daily contact with substances wich are strange to the body and partially hostile to the body and in particular hostile to the skin. Particularly frequent contact of the unprotected skin with these substances, which very often are job related (hairdressers, dentists, housewives), sooner or later results in more or less damage to the skin. For preventing or at least for reducing such skin damage principally two types of intervention was hitherto used: a protective skin protection as well as a conserving skin care. 
     The protective skin protection consists in that the skin is treated before coming into contact with the strange i.e., foreign skin substance, so as to substantially exclude any direct contact between the skin surface and the damaging substances. The preparations which assure a protective skin protection effect, do so on a chemical-physical basis without interfering with the physiology of the skin. Such preparations must fulfill the following requirements: They should be impermeable and insoluble with respect to most of the exogenic harmful substances; they should have a good skin compatability; they should be easily applied to the skin surface and also easily removed therefrom; they should not interfere with the feel of the hands, so as not to interfere with the workability of the hands and should also have a certain prolonged period of effectiveness. The disadvantage of known preparations of this type is that they are not able to fullfill all these requirements to the optimum degree required. 
     It is an objective in the conserving skin care to make the skin less allergic when coming into contact with skin damaging substances. The protecting substances are already contained in the washing substances. Their efects differ in accordance with different types of skin protection measures sought and, which take effect effect by adsorption at the skin surface, lubricating measures, acidifying measures and deswelling measures. Here too, the essential disadvantage of these skin protective measures consists in that they are not effective in the same manner against attack by the different environmental harmful substances. 
     In contrast thereto, skin treating compositions containing a 3-amino-tetrahydro-1,3-thiazine-2,4-dione of the general formula I ##STR1## wherein R 1  and R 2  each represent H, alkyl, hydroxyalkyl, carboxyalkyl, halogenalkyl, cyanoalkyl, alkoxyalkyl, cycloalkyl, alkenyl, alkinyl, arylalkyl, arylalkyl substituted in the aryl moiety, aryl, alkyl-, halogen-, nitro-, alkoxy-, aryloxy-, cyano substituted aryl, acyl, thiazolyl, thienyl, benzthiazolyl, 1,3,4-thiadiaxolyl, oxazolyl, benzoxazolyl, 1,3,5-oxadiazolyl, pyrazolyl, 1,2,4-triazolyl, benzimidazolyl, pyridinyl, pyrimidinyl, purinyl, pyridazinyl, triazinyl, benzotriazinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazolyl, pteridinyl, quinoxalinyl, acridinyl, or R 1  and R 2  taken together stand for alkylidene arylidene and heterocyclic-methylidene, wherein heterocyclic represents furan thiophene, pyrrole, pyridine, isozazole, thiazole, imidazole, 1,2,3-triazole, pyrazole, indole, benzthiazole, quinoline isoquinoline, quinoxaline, carbazole pteridine  or where R 1  and R 2  together with the nitrogen atom, to which they are bound, are part of a herocyclic ring and in this ring represent the segment--(CH 2 ) n  --X--(CH 2 ) m  --, wherein X=CH 2 , O, S, NR&#39; (R&#39;=alkyl, arylalkyl, aryl), n=0 to 3 and m=1 to 3, provided that n is O, only when X=CH 2 , 
     R 3  represents H, alkyl, cycloalkyl, carboxyl, arylalkyl, aryl or substituted aryl, 
     R 4  represents H, alkyl, cycloalkyl, arylalkyl, aryl or substituted aryl, 
     R 5  is H, alkyl, substituted alkyl, cycloalkyl, arylalkyl, aryl, substituted aryl, 2-furyl or substituted 2-furyl, and 
     R 6  represents H, alkyl, substituted alkyl, cycloalkyl, arylalkyl, aryl or substituted aryl, 
     fullfill all requirements which are required from a skin protection preparation in view of its novel effectiveness. 
     Therefore, the subject matter of the described invention is skin treatment compositions containing physiologically compatible carriers, characterized by a content of at least one compound of the general formula I. 
     The skin treating compositions is accordance with the invention may be present in any given form of preparation suitable for skin treating compositions, for example, as a clear, colored or turbid solution, as a dispersion, emulsion, in form of a foam or as a preparation which can be sprayed from an aerosol container by means of a pump or by means of a propellent gas. Preferably, they are present in ointment, cream or gel form. Preparations, which may be considered in accordance with the invention are, for example, cosmetic skin treating compositions, such as day creams, night creams, nutritive creams, skin protection creams, sun protection creams, sun protection sprays, cold protection creams, as well as lipsticks, skin milk preparations, skin lotions and skin protection gels. 
     The concentration of the compounds of the general formula I amounts to about 0.1 to 5% by weight, preferably 0.5 to 3% by weight in the skin treating compositions. The compounds of formula I may be present alone or in a mixture in the composition. 
     The formulation of the skin treating composition constitutes a mixture of the compounds in accordance with formula I with physiologically compatible constituents, like carriers and admixed materials, i.e., adjuvants which are customary for such preparations. 
     Customary carriers and admixed materials in solutions, creams, emulsions or gels are, for example, solvents, as for example water, lower aliphatic alcohols, for example, ethanol, propanol and isopropanol, or glycols, such as glycerin and propylene glycol, furthermore netting agents or emulsifiers from the classes of the anionic, cationic, amphoteric or nonionogenic surface active substances, like fatty alcohol sulfates, alkyl sulfonates, alkyl benzene sulfonates, alkyl trimethyl ammonium salts, alkyl betaines, oxyethylated nonylphenols, fatty acid alkanolamides, oxyethylated fatty acid esters, furthermore thickeners, like higher fatty alcohols, fatty acid esters, starch, cellulose derivatives, Vaseline, stearin, ceresin, paraffin oil and fatty acids, as well as remedial substances, like lanolin, lanolin derivatives, cholesterin, pantothenic acid, sorbital, betaine, almond oil, avacado oil, bees wax and spermaceti. 
     Further customary admixed materials are, for example, cosmetic resins, dyes, perfume oils, propellent gases as well as preservatives, like, for example, p-hydroxybenzoic acid, sorbic acid, salicylic acid, formaldehyde and hexachlorophene. The compositions may contain bases, as, for example, triethanolamine for forming salts. 
     The manufacture of the skin treating compositions is carried out in the manner customary for such preparations in that the compounds of formula I, which serve a the active ingredient, are admixed with the constituents acting as carrier substances for the skin treating compositions and are then combined with the further constituents of the composition into a final product. The compounds of the general formula I which are contained in the skin treating composition described here cause following repeated topical applications a thickening of the outermost skin layer, namely of the dead keratin layer which, above all, is responsible for the natural skin protection. Due to the thickening of the keratin layer the skin becomes more resistant to any contact with environmental harmful substances, thereby providing an optimum skin protection in this manner. Since the skin protection, which is assured by these compounds, consists in that the natural skin protection is strengthened, the skin protection compositions in accordance with the invention, which contain the compounds in accordance with formula I, do not have the disadvantages which can be observed with conventional skin protection compositions. The skin treatment compositions in accordance with the invention may be applied independent of the time of the contact of the harmful substance with the skin surface. Hence, they never will intefere with an operating process, since they are no longer present on the skin surface at this point in time. The skin protection cannot be removed (for example, by washing), since it is obtained by the new condition of the skin (thickening). Simultaneously, the compounds of the general formula I effect a strengthening of the natural sun protection. This additional sun protection is also obtained by the thickening of the keratin layer which is obtained after the treatment with the skin treating composition in accordance with the invention. A thickening of the keratin layer causes an increased absorption of light or sun rays. This novel prophylactic sun protection (pre-sun) has clear advantages with respect to the efficiency obtained with the conventional sun protection compositions. The customary sun protection compositions are applied onto the skin surface and their absorption capacity, i.e., their ability provide light protection depends on the applied thickness of the layer. These preparations may interfere in that they are too oily, for example, thereby soiling the clothing. They will be rinsed off during bathing or showering, for example, and therefore must be reapplied. In contrast thereto, the compositions in accordance with the invention can be applied independent of the time of exposure the sun in that it can be applied repeatedly topically 3 to 4 weeks before starting a summer vacation, for example, so that it offers a long lasting protection, which cannot be washed off, against sunburn and other chronic light induced damage at the time of vacation thanks to the thickened keratin. 
     In a similar manner, the compositions in accordance with the invention which contain the 3-amino-tetrahydro-1,3-thiazine-2,4-diones of formula I, are able to provide a protection cold cold on exposed and sensitive body areas, for example, on the face and hands which are particularly exposed to poor weather conditions. Therefore, the compositions may be considered for use by skiers and high mountain athletes, for example, as a preventive protection against extreme cold. Thanks to their keratin thickening effect the skin treating compositions in accordance with the invention are able to offer an effective cold protection which does not have the uncomfortable side effects of the preparations which stress the skin and remain on the skin surface, because here too, it is merely a strengthening of the natural cold protection. 
     With increasing age, the outer layer of the skin, the so-called outer skin or epidermis, becomes thinner. The thinning of the epidermis is responsible for the skin&#39;s surface getting its parchment-like appearance, so that sebaceous glands, retention cysts, pigment spots as well as fine blood vessels become more visible, thus generating the typical condition of a so-called old skin. Since the compositions in accordance with the invention are able not only to thicken the keratin layer, which represents only a part of the epidermis, but is able to thicken the total epidermis, they represent an effective composition for a prophylactic treatment of skin aging. 
     Advantageously, the skin treating compositions in accordance with the invention should be used in such a manner that repeatedly and preferably 1 to 2 times a day the composition is applied to the corresponding skin areas about 2 to 3 weeks before a desired thickening of the keratin or the epidermis should be obtained. 
     The skin thickening effect of the compositions in accordance with the invention was demonstrated on hairless mice in the following manner: 
     2% by weight of the compounds a,e and h were topically applied to one side of the body of hairless mice (hr/hr) in form of a 50% by volume ethanolic solution over two and one half weeks every day, except Saturday and Sunday. At the end of the treatment time, the animals were killed and a 1×1.5 cm large piece of skin was removed from both body sides and histologically processed. The thickness of the upper skin was measured at about 100 locations and the average skin thickness was established. The thickening of the upper skin can be expressed as the quotient of the average thickness of the treated upper skin and the average thickness of the untreated skin. This quotient is stated as the thickening factor. The compounds in accordance with the invention resulted in thickening factors which were between 1.2 and 2.1. 
     The 3-amino-tetrahydro-1,3-thiazine-2,4-diones of formula I in accordance with the invention contained in the described skin treating compositions are novel. 
     Examples of novel compounds in accordance with the invention of formula I are 
     (a) 3-dimethylamino-5,5-diphenyl-tetrahydro-1,3-thiazine-2,4-dione 
     (b) 3-(N-acetyl-N-phenyl)-amino-5,5-diphenyl-tetrahydro-1,3-thiazine-2,4-dione 
     (c) 3-[N-acetyl-N-(4-chlorphenyl)]-amino-5,5-diphenyl-tetrahydro-1,3-thiazine-2,4-dione 
     (d) 3-[N-acetyl-N-(4-nitrophenyl)]-amino-5,5-diphenyltetrahydro-1,3-thiazine-2,4-dione 
     (e) 3-diphenylamino-5,5-diphenyl-tetrahydro-1,3-thiazine-2,4-dione 
     (f) 3-dimethylamino-5,5-di-(4-tolyl)-tetrahydro-1,3-thiazine-2,4-dione 
     (g) 3-(1-perhydroazepinyl)-tetrahydro-1,3-thiazine-2,4-dione 
     (h) 3-(4-morpholinyl)-tetrahydro-1,3-thiazine-2,4-dione 
     (i) 3-(1-perhydroazepinyl)-5,5-di-(4-tolyl)-tetrahydro-1,3-thiazine-2,4-dione 
     The manufacture of compounds of formula I is performed by oxidation of the corresponding 3-amino-tetrahydro-2-thioxo-1,3-thiazine-4-ones with chromic anhydride in acetic acid. The manufacture of these initial compounds is described in German laid open patent 2 937 184 as well as in the literature W Hanefeld et al., Archiv der Pharmazie, Weinheim, 315 (2) pages 103-119 (1982). 
     The process described there for making the 3-amino-4-oxo-2-thioxo-tetrahydro-1,3-thiazine of formula II consists in that hydrazine, a N-mono-substituted hydrazine, an N,N-disubstituted hydrazine, the salts of these compounds or hydrazones of aldehydes or ketones are reacted with dithiocarbazate in a suitable polar solvent, preferably in ethanol/pyridine, with carbon disulfide and a base, preferably soda lye, potash lye or a tertiary amine, subsequently reacting a β-lactone with to the salt of the dithiocarbazide acid-2-carboxy ethyl ester and after removing the solvent cyclizing the ester either by (A) by heating with acetanhydride and some drops of concentrated sulfuric acid directly to 3-amino-4-oxo-2-thioxotetrahydro-1,3-thiazine or (B) by adding hydrochloric acid transferring it to the free acid and then cyclizing it to the 3-amino-4-oxo-2-thioxo-tetrahydro-1,3-thiazine with acetanhydride/sulfuric acid. 
     The process is explained in more detail by the following reaction diagram wherein R 1 ,R 2 ,R 3 ,R 4 ,R 5  and R 6  have the aforementioned stated meanings: ##STR2## 
     For manufacturing the 3-amino-tetrahydro-1,3-thiazine-2,4-diones in accordance with the invention of formula I, the corresponding 3-amino-tetrahydro-2-thioxo-1,3-thiazine-4-on of formula II is dissolved in 10 times of the amount by weight acetic acid and is reacted with 3 times the amount of Mol chromic acid anhydride in accordance the following reaction equation by heating for 1 to 2 hours under reflux to the desired product of formula I. ##STR3## Subsequently, the reaction mixture is mixed with water until the start of turbidity and then cooled. The separated crystals of the 3-amino-tetrahydro-1,3-thiazine-2,4-dione are vacuumed off, washed with water, dried and subsequently recrystallized with a suitable solvent, for example, toluol, a mixture of acetone/water or diethyl ether/petroleum ether. 
     The following examples explain the subject matter of the invention in more detail. 
    
    
     EXAMPLES OF SKIN TREATING COMPOSITIONS 
     
         ______________________________________                                    
Composition for skin protection                                           
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Lotion                                                                    
2.5 g  3-dimethylamino-5,5-diphenyl-tetrahydro-1,3-                       
       thiazine-2,4-dione                                                 
3.5 g  glycerin mono stearate, selfemulsifying                            
2.0 g  oleic acid                                                         
5.0 g  glycerin                                                           
1.0 g  triethanolamine                                                    
5.0 g  ethanol (96% by volume)                                            
0.3 g  perfume and preservative                                           
80.7 g water                                                              
100.0 g                                                                   
Gel                                                                       
3.0 g  3-[N--acetyl-N--(4-chlorphenyl)]-amino-5,5-di-                     
       phenyl-tetrahydro-1,3-thiazine-2,4-dione                           
15.0 g ethanol (96% by volume)                                            
1.0 g  acrylic acid homopolymerisate                                      
10.0 g glycerin                                                           
0.8 g  triethanolamine                                                    
0.4 g  perfume and conserving composition                                 
69.8 g water                                                              
100.0 g                                                                   
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Pre-sun preparations (Sun protection compositions)                        
______________________________________                                    
Lotion                                                                    
2.0 g  3-diphenylamino-5,5-diphenyl-tetrahydro-1,3-                       
       thiazine-2,4-dione                                                 
3.0 g  glycerin mono stearate, self emulsifying                           
3.0 g  isopropylmyristate                                                 
2.0 g  glycerin                                                           
0.3 g  perfume and preservative                                           
89.7 g water                                                              
100.0 g                                                                   
Emulsion                                                                  
2.5 g  3-dimethylamino-5,5-diphenyl-tetrahydro-1,3-                       
       thiazine-2,4-dione                                                 
3.0 g  glycerin mono stearate                                             
2.0 g  cetyl-stearyl alcohol (DAB 7)                                      
1.5 g  cetyl-stearyl alcohol, with 12 Mol ethylene oxide                  
       oxethylized                                                        
1.5 g  cetyl-stearyl alcohol, with 20 Mol ethylene oxide                  
       oxethylized                                                        
0.5 g  hydrated castor oil                                                
10.5 g 2-octyldodecanol                                                   
6.0 g  paraffin oil, viscous                                              
0.4 g  perfume and conserving composition                                 
72.6 g water                                                              
100.0 g                                                                   
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Preparations for prophylactic cold protection                             
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Milk                                                                      
2.0 g  3-[N--acetyl-N--(4-nitrophenyl)]-amino-5,5-diphenyl-               
       tetrahydro-1,3-thiazine-2,4-dione                                  
5.8 g  sorbitanmonostearate                                               
2.2 g  sorbitanmonooleate                                                 
8.0 g  almond oil                                                         
5.0 g  oleic acid decylester                                              
3.0 g  2-octyldodecanol                                                   
6.0 g  perhydrosqualen                                                    
2.0 g  glycerin                                                           
1.8 g  propylene glycol                                                   
3.0 g  perfume and preservative                                           
61.2 g water                                                              
100.0 g                                                                   
Gel                                                                       
3.0 g  3-diphenylamino-5,5-diphenyltetrahydro-1,3-thiazine-2,             
       4-dione                                                            
15.0 g ethanol (96% by volume)                                            
1.0 g  acrylic acid homopolymerizate                                      
10.0 g glycerin                                                           
0.8 g  triethanolamine                                                    
0.4 g  perfume and preservative                                           
69.8 g water                                                              
100.0 g                                                                   
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Preparations for prophylactic treatment of aged skin                      
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Nutritive Cream                                                           
1.5 g  3-dimethylamino-5,5-diphenyl-tetrahydro-1,3-thiazine-              
       2,4-dione                                                          
25.0 g 1:1 condensate of citric acid-di-stearyl ester                     
       and pentaerythrite-di-coconut oil acid ester                       
10.0 g oleic acid decylester                                              
10.0 g isopropylmyristate                                                 
0.3 g  perfume and preservative                                           
53.2 g water                                                              
100.0 g                                                                   
Antiwrinkle Cream                                                         
2.5 g  3-[N--acetyl-N--(4-chlorphenyl)]-amino-5,5-diphenyl-               
       tetrahydro-1,3-thiazine-2,4-dione                                  
7.0 g  glycerin mono palmitate distearate                                 
7.0 g  stearic acid, three times pressed                                  
1.5 g  jojoba oil                                                         
5.0 g  isoproylmyristate                                                  
2.0 g  glycerin                                                           
0.9 g  triethanolamine                                                    
3.0 g  perfume and preservative                                           
71.7 g water                                                              
100.0 g                                                                   
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     EXAMPLES OF MANUFACTURE 
     Manufacture of 3-dimethylamino-5,5-diphenyl-tetrahydro-1,3-thiazine-2,4-dione (a): 
     6.85 g (20 mMol) 3-dimethylamino-5,5-diphenyl-2-thioxo-tetrahydro-1,3-thiazine-4-one are dissolved by heating in 7.0 g acetic acid and compounded with 6.0 g (60 mMol) CrO 3 . After settling down of the violent exothermic reaction one heats up to the boiling point for one hour. One compounds with water until turbidity sets in and then the reaction mixture is cooled. The precipitated crystal are vacuumed off, washed off with water to a substantially colorless state and recrystallized with acetone/water. The physical data and analysis values can be seen in the following table. 
     For the remainder of the compositions of the general formula I in accordance with the invention (compositions a-i), the preparation of the corresponding 2-thioxo-composition is performed in an analogous manner as described above for composition (a). Depending on the substance (see table) one can use as a solvent for the recrystallization toluol, ethanol, diethyl ether/petroleum ether or diethyl ether/ethanol. The size of the individual charges were between 1.5 and 20 mMol. 
     The carbamoyl-C═O-band of the C 2  appears at 1660-1680 cm -1  in the IR spectras of the compositions of formula I. The lactan-C═O-band of the C 4  can be observed at 1695-1730 cm -1 . The additional acetyl-C═O band occurs at 1740 cm -1  in the compositions b to d. 
     
                                           TABLE                                   
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3-amino-tetrahydro-1,3-thiazine-2,4-diones in accordance                  
with the invention of general formula I                                   
                                 Melting point °C.                 
                                           Yield         N  S             
                                 (recrystallisation                       
                                           in  summation                  
                                                         calculated       
R.sup.1   R.sup.2                                                         
               R.sup.3                                                    
                      R.sup.4                                             
                             R.sup.5,R.sup.6                              
                                 from)     theory                         
                                               (Mol mass)                 
                                                         found            
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a CH.sub.3                                                                
          CH.sub.3                                                        
               C.sub.6 H.sub.5                                            
                      C.sub.6 H.sub.5                                     
                             H   195-200   76  C.sub.18 H.sub.18 N.sub.2  
                                               O.sub.2 S  8.58            
                                                             9.82         
                                 (Aceton/Water)                           
                                               (326.42)   8.57            
                                                             9.56         
b C.sub.6 H.sub.5                                                         
           ##STR4##                                                       
               C.sub.6 H.sub.5                                            
                      C.sub.6 H.sub.5                                     
                             H   178-181 (toluol)                         
                                           60  C.sub.24 H.sub.20 N.sub.2  
                                               O.sub.3 S (420.50)         
                                                          6.66 6.59       
                                                             7.62 7.82    
c 4-ClC.sub.6 H.sub.4                                                     
           ##STR5##                                                       
               C.sub.6 H.sub.5                                            
                      C.sub.6 H.sub.5                                     
                             H   177-179 (toluol)                         
                                           74  C.sub.24 H.sub.19 ClN.sub.2
                                                O.sub.3 S (450.95)        
                                                          6.21 6.05       
                                                             7.11 7.20    
d 4-NO.sub.2C.sub.6 H.sub.4                                               
           ##STR6##                                                       
               C.sub.6 H.sub.5                                            
                      C.sub.6 H.sub.5                                     
                             H   198-199.5 (toluol)                       
                                           71  C.sub.24 H.sub.19 N.sub.3  
                                               O.sub.5 S (461.50)         
                                                          9.11 8.88       
                                                             6.95 6.76    
e C.sub.6 H.sub.5                                                         
          C.sub.6 H.sub.5                                                 
               C.sub.6 H.sub.5                                            
                      C.sub.6 H.sub.5                                     
                             H   132-136   71  C.sub.28 H.sub.22 N.sub.2  
                                               O.sub.2 S  6.22            
                                                             7.12         
                                 (toluol)      (450.56)   6.02            
                                                             7.32         
f CH.sub.3                                                                
          CH.sub.3                                                        
               4-CH.sub.3C.sub.6 H.sub.4                                  
                      4-CH.sub.3C.sub.6 H.sub.4                           
                             H   190-192   65  C.sub.20 H.sub.22 N.sub.2  
                                               O.sub.2 S  7.90            
                                                             9.05         
                                 (toluol)      (354.47)   7.60            
                                                             8.82         
g (CH.sub.2).sub.6                                                        
               H      H      H   68-70     68  C.sub.10 H.sub.16 N.sub.2  
                                               O.sub.2 S 12.27            
                                                            14.04         
                                 diethyl ether/                           
                                               (228.31)  12.05            
                                                            13.87         
                                 petrol ether                             
h (CH.sub.2).sub.2O(CH.sub.2).sub.2                                       
               H      H      H   112-114   73  C.sub.8 H.sub.12 N.sub.2   
                                               O.sub.3 S 12.95            
                                                            14.83         
                                 ethanol/diethyl                          
                                               (216.26)  12.79            
                                                            14.91         
                                 ester                                    
i (CH.sub.2).sub.6                                                        
               4-CH.sub.3C.sub.6 H.sub.4                                  
                      4-CH.sub.3C.sub.6 H.sub.4                           
                             H   73-75     62  C.sub.24 H.sub.28 N.sub.2  
                                               O.sub.2 S  6.86            
                                                             7.85         
                             H   ethanol       (408.56)   6.72            
                                                             7.83         
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