Patent Publication Number: US-2009240048-A1

Title: Alpha-crystalline form of substituted selenoxanthenes and the method of its preparation

Description:
RELATED APPLICATIONS 
     This application claims priority to Russian Patent Application No. 2008109966, filed on Mar. 18, 2008, which is incorporated herein by reference in its entirety. 
     FIELD OF THE INVENTION 
     This invention pertains to field of organic chemistry, medicine, pharmacology, foods and cosmetics industry, particularly, to manufacturing technology of selenoxanthenes; the invention may be used in manufacturing of food supplements, pharmaceutical and cosmetic products, having bioactive properties, of a wide spectrum of activity. 
     BACKGROUND OF THE INVENTION 
     Known substitution derivatives of selenoxanthenes (RU 2213092, RU 2239632) have a following structural formula: 
     
       
         
         
             
             
         
       
     
     At this time, substitution derivatives of selenoxanthenes are manufactured in its amorphous form, the main disadvantage of which is its instability for storage; the compound has a low friability with tendency to clump. 
     Selenoxanthene and the method of its preparation are described in Patents RU 2213092, RU 2239632 and RU 2281007. These publications note that the product can recrystallize from ethanol or acetone. 
     Said compound&#39;s utilization and activity are described in the above-mentioned publications, specifically, in RU 2281007. According to this patent, 9-phenyl-symmetrical-octahydroselenoxanthene exhibits antioxidant, detoxifying, hypolipidemic, immunomodulating and immunocorrecting, anti-atherogenic, anti-atherosclerotic and anabolic properties. A report on toxicological properties of selenoxanthene (O.V. Meralenko, MVD, Ph.D. Laboratory of Bioactive Substances, Belgorod Agricultural Academy, 1996) demonstrates that substitution derivatives of selenoxanthene are highly toxic when administered intragastrically at LD50=725+75 mg/kg. The above indications limit the application of the substitution derivatives of selenoxanthene for food supplements and pharmaceutical compounds. 
     SUMMARY OF THE INVENTION 
     The inventors&#39; main objective was to obtain a non-toxic substitution derivative of selenoxanthene, with is stable for storage and has a high friability. 
     To achieve the above objective, proposed is a compound such as a selenoxanthene of α-crystalline form, with its powder X-ray diffractogram (obtained from a Cu-K X-ray source) having characteristic diffractions (in degrees of the diffraction angle 2theta) as follows: 6.0, 12.0, 15.0, 17.0, 19.0, 20.0, 21.5, 21.7, 20.9, 25.0, 27.0, 28.0, 29.0, 37.0, as shown below in  FIG. 1 . 
     The powder X-ray diffractogram was obtained using a D8 Advance diffractometer (Bruker) (T=298K, λCu-Kα X-ray source, Göbel (Goebel) mirrors, theta-2theta scan with 0.02+ step). 
     The above and other features of the invention including various novel details of construction and combinations of parts, and other advantages, will now be more particularly described with reference to the accompanying drawings and pointed out in the claims. It will be understood that the particular method and device embodying the invention are shown by way of illustration and not as a limitation of the invention. The principles and features of this invention may be employed in various and numerous embodiments without departing from the scope of the invention. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       In the accompanying drawings, reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale; emphasis has instead been placed upon illustrating the principles of the invention. Of the drawings: 
         FIG. 1  shows an X-ray diffractogram. 
     
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     Experiment Description 
     X-ray structural analysis 
     Crystal of the compound H is tetragonal belonging to space group P-42 1 c, at T=100K a=b=19.5515(15) Å, c=8.0074(6) Å, V=3060.9(4) Å 3 , Z(Z′)=8 (1), F(000)=1360, d calc =1.429 g·sm −3 , μ=24.42 mm −1 . Intensities of 12,199 diffractions were measured using an automatic diffractometer SMART APEX II CCD (Bruker) (T=100 K, λMo-Kα- X-ray source, graphite monochromator, (φ- and ω- scans, θ max =58°), subsequent calculations were based on 4,063 independent diffractions (R(int)=0.0444). X-ray absorption calculations were done using the SADABS software package (G. M. Sheldrick,  SADABS, V 2.01,  Bruker/Siemens Area Detector Absorption Correction Program;  Bruker AXS Inc., Madison, Wis. 1998). The structure was determined via a direct method and full-matrix least-squares refinement in anisotropic approximation for non-hydrogen atoms. Positions of the hydrogen atoms were calculated geometrically and all of them were approximated by isotropic approximation with fixed positional and temperature parameters. Final divergence factors are: R 1 =0.0306 for 3506 independent diffractions with I&gt;2σ(I) and wR 2 =0.0614, and GOF=0.999 for all independent reflections. All calculations were performed using SHELXTL PLUS (Version 5.10) software package (G. M. Sheldrick,  SHELXTL, V 5.10, Bruker AXS Inc., Madison, Wis, 1998). 
     
       
         
           
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Crystal data and structure refinement for H. 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Identification code 
                 H 
               
               
                 Empirical formula 
                 C19 H22 Se 
               
               
                 Formula weight 
                 329.33 
               
               
                 Temperature 
                 100(2) K 
               
               
                 Wavelength 
                 0.71073 Å 
               
               
                 Crystal system 
                 Tetragonal 
               
               
                 Space group 
                 P-42 1 c 
               
               
                 Unit cell dimensions 
                 a = 19.5515(15) Å = 90°. 
               
               
                   
                 b = 19.5515(15) Å = 90°. 
               
               
                   
                 c = 8.0074(6) Å = 90°. 
               
               
                 Volume 
                 3060.9(4) Å 3   
               
               
                 Z 
                 8 
               
               
                 Density (calculated) 
                 1.429 Mg/m 3   
               
               
                 Absorption coefficient 
                 2.442 mm −1   
               
               
                 F(000) 
                 1360 
               
               
                 Crystal size 
                 0.45 × 0.40 × 0.40 mm 3   
               
               
                 Theta range for data collection 
                 1.47 to 28.99°. 
               
               
                 Index ranges 
                 −21 &lt;= h &lt;= 26, −26 &lt;= k &lt;= 
               
               
                   
                 19, −10 &lt;= 1 &lt;= 8 
               
               
                 Reflections collected 
                 12199 
               
               
                 Independent reflections 
                 4063 [R(int) = 0.0444] 
               
               
                 Completeness to theta = 28.99° 
                 99.9% 
               
               
                 Absorption correction 
                 Semi-empirical from equivalents 
               
               
                 Max. and min. transmission 
                 0.377 and 0.340 
               
               
                 Refinement method 
                 Full-matrix least-squares on F 2   
               
               
                 Data/restraints/parameters 
                 4063/0/182 
               
               
                 Goodness-of-fit on F 2   
                 0.999 
               
               
                 Final R indices for 3506 refl. 
                 R1 = 0.0306, wR2 = 0.0586 
               
               
                 with [I &gt; 2sigma(I)] 
               
               
                 R indices (all data) 
                 R1 = 0.0410, wR2 = 0.0614 
               
               
                 Absolute structure parameter 
                 0.007(8) 
               
               
                 Extinction coefficient 
                 0.0022(2) 
               
               
                 Largest diff. peak and hole 
                 0.438 and −0.334 e · Å −3   
               
               
                   
               
            
           
         
       
     
     The production is obtained as follows. An amorphous powder (produced by a known technology) is crystallized either from a weak polar solvent selected from a group containing methanol, isopropanol, or from an aprotonic solvent selected from a group containing chloroform, hexane. 
     To prove the achievement of the technical result, the data assessing the proposed compound&#39;s acute toxicity are presented. The general toxicity study has shown no toxic effects following a single administration (intragastrically) to rats of the dosage of 1000 mg/kg of body mass of the anumal, which is more than a 1000 times greater that average therapeutic dose. 
     Physical and chemical data of the amorphous and crystalline forms are presented in the following table: 
     
       
         
           
               
               
               
               
               
             
               
                   
                   
               
               
                   
                 Angle of 
                 Melting 
                 Storage life, 
                   
               
               
                   
                 repose, ° 
                 point, ° C. 
                 months 
                 Appearance 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Compound 
                 52° 
                 95-96° 
                 6 
                 Beige powder 
               
               
                 according to 
               
               
                 patent RU 
               
               
                 2281007 
               
               
                 (acetone) 
               
               
                 Crystalline 
                 43° 
                 96.8° 
                 24 
                 Yellow needle- 
               
               
                 form (hexane) 
                   
                   
                   
                 like crystals 
               
               
                   
               
            
           
         
       
     
     Implementation of the method: 
     To produce 9-(o-oxyphenyl)-symmetrical-octahydroselenoxanthene, 12.5 g of 9-(o-oxyphenyl)-octahydro-10-oxoxanthene was placed in a three-neck flask with a magnetic stirrer and attached to a gas source. 30 ml of acetic acid:acetic anhydride (4:1) solution was then added. The reaction was stirred with nitrogen gas being blown through the liquid for 30 minutes; after 30 minutes nitrogen is replaced with hydrogen selenide. The rate of hydrogen selenide introduction is 2-3 bubbles per second. After initial 30 minutes of hydrogen selenide introduction, 1.0 ml of a concentrated hydrochloric acid was added to the reaction every hour. The total time of reaction in the presence of hydrogen selenide was 6 hours, after which the hydrogen selenide gas was replaced with the nitrogen gas for another 40 minutes. The reaction mixture was then refrigerated and after 24 hours the precipitate was filtrated and washed with hydrochloric acid and ethanol. The product yield was 11.5 g. 
     EXAMPLE 1.  
     Re-crystallization was carried out as follows: 10 g of the amorphous product was placed in a 250 ml flask and 85 ml of hexane was added. The solution was brought to a boil and filtrated. After the crystals fell out, they were filtrated, washed with cold ethanol and dried at 40° C. The product yield was 8.7 g, the melting temperature of 96.8° C. 
     EXAMPLE 2.  
     Re-crystallization was carried out as follows: 10 g of the amorphous product was placed in a 500 ml flask and 250 ml of isopropanol were added. The solution was brought to a boil and filtrated. After the crystals fell out, they were filtrated, washed with cold ethanol and dried at 40° C. The product yield was 9.2 g, the melting temperature of 96.6° C. 
     While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.