Abstract:
Novel antineoplastic ailanthone derivatives (IIb) represented by the following formula wherein R 2  is C 5  -C 18  α,β-unsaturated acyl group and its related compounds are disclosed. ##STR1## Particularly, some of the above compounds are far more effective than mitomycin C against mouse lymphocytic leucemia p388. 
     These compounds can be synthesized from known ailanthone via important intermediates, triacyloxy ailanthone, represented by the formula: ##STR2## wherein R 1  is acyl group.

Description:
This is a continuation of application Ser. No. 421,200, filed 9/22/82, now abandoned. 
    
    
     FIELD OF THE INVENTION 
     This invention relates to novel antineoplastic ailanthone derivatives, and, more particularly, it relates to 15β-hydroxyailanthone-15-carboxylic acid esters represented by the following formulae (IIa and IIb) and a useful intermediate for preparing the above esters represented by the following formula (I); to a method for preparing the compounds (I, IIa and IIb); and to the use of the compounds (IIa and IIb) as an antitumor agent. ##STR3## wherein R 1  represents acyl group and R 2  represents C 5  -C 18  α,β-unsaturated acyl group. 
     BACKGROUND OF THE INVENTION 
     For the past 30 years, many efforts were continuously made to find antineoplastic agents from natural sources and to synthesize their analogues. As the result, a few of them have been clinically used as antitumor agent. However, effective antitumor agents generally have the defect of high toxicity. Therefore, there is nothing to be satisfied in view of chemotherapy against malignant tumors. 
     SUMMARY OF THE INVENTION 
     The present inventors have heretofore noticed to ailanthone (11β,20-epoxy-1β,11α,12α-trihydroxypicrasa-3,13(21)-diene-2,16-dione) represented by the following formula (III), which is contained in the bark of &#34;tree of heaven&#34; (Japanese name &#34;Shinju&#34; or &#34;Niwaurushi&#34;; Ailanthus altissima, Swingle, Simarubaceae), and have synthesized its many derivatives for antineoplastic screening test. Thus, we have found that 15-carboxylic acid esters of 15β-hydroxyailanthone, especially, esters with C 5  -C 18  α,β-unsaturated carboxylic acid show marked antineoplastic activity. 
     For instance, the compounds (I, IIa and IIb) of the present invention can be synthesized from ailanthone (III) as the starting material, according to the following scheme. ##STR4## wherein R 1  is acyl group and R 2  is C 5  -C 18  α,β-unsaturated acyl group. 
     That is, ailanthone; (III), which can be extracted and isolated from the bark of &#34;tree of heaven&#34; according to usual manner, is acylated as usual with an acylating agent such as acetic anhydride, acetyl chloride, benzoyl chloride or chloroacetyl chloride to give 1,12,20-triacyloxy compound (IV). During this transformation, C-11 hemiacetal bond is cleaved to give 11-keto-20-alcohol. 
     Then, the above triacyloxy compound whose alcohol is acylated (IV) is reduced with a selective reducing agent such as sodium borohydride thereby only C-16 ketone of the compound (IV) is selectively reduced to secondary alcohol (V). This alcohol is a mixture of stereoisomers. Then, the alcohol (V) is dehydrated to corresponding compound (VI) with a dehydrating agent such as phosphoryl chloride or phosphorus pentoxide and this unsaturated compound (VI) is further oxidized with N-methylmorpholine-N-oxide and osmium tetraoxide to the corresponding 15,16-dihydroxy compound (VII). Then, the resulting compound (VII) can be converted to 16-ketone compound (I) which is one of the present compounds, by mild oxidation with silver oxide. 
     Finally, the ketone (I) is esterified with C 5  -C 18  α,β-unsaturated carboxylic acid, cesium fluoride and 1-ethyl-2-fluoropyridinium tetrafluoroborate or 1-methyl-2-fluoropyridinium tosylate to give the desired compound (IIa). Moreover, the compound (IIa) is hydrolyzed with an alkali to give another desired compound (IIb). 
     The substituent R 2  of the compound (IIa) or (IIb) is C 5  -C 18  α,β-unsaturated acyl group such as 3-methyl crotonoyl, cis- or trans-2-pentenoyl, cis- or trans-2-hexenoyl, cis- or trans-2-heptenoyl, cis- or trans-2-octenoyl, cis- or trans-2-nonenoyl, cis- or trans-2-decenoyl, cis- or trans-2-undecenoyl, cis- or trans-2-dodecenoyl, cis- or trans-2-tridecenoyl, cis- or trans-2-tetradecenoyl, cis- or trans-2-pentadecenoyl, cis- or trans-2-hexadecenoyl, cis- or trans-2-heptadecenoyl, and cis- or trans-2-octadecenoyl groups. 
     The esterification reaction to give the compound (IIa) can be carried out by several usual manners such as by reacting the compound (I) with an anhydride or a halide of α-, β-unsaturated carboxylic acid or with above acid in the presence of trifluoroacetone as a dehydrating agent. However, according to our experiments, the above reaction with 1-ethyl-2-fluoropyridinium tetrafluoroborate or 1-methyl-2-fluoropyridinium tosylate and cesium fluoride as a dehydrating agent appears to be preferable in view of the yield of the desired compound. 
     The compound (IIa) can be hydrolyzed to the compound (IIb) under a mild hydrolysis condition. If stronger condition is used, even C-15 ester per se is also hydrolyzed. Therefore, it is preferable that above transformation is carried out in an alcoholic solution of alkali metal alkoxide for a long period of time. 
    
    
     BRIEF DESCRIPTION OF THE DRAWING 
     The attached drawing is a stereoscopic structural view of 15β-hydroxy ailanthone triacetate (I:R 1  =CH 3  CO--) obtained by X-ray diffraction and computer analysis of the crystal. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     (A) Physico-chemical Data of the Present Compound 
     (i) Compound I (R 1  =CH 3  CO--) 
     Form: colorless needles 
     mp: 231°-232° C. 
     Specific rotation (SR): [α] D   25  +20.5° (c=0.20, CHCl 3 ) 
     Infrared spectrum (IR) (KBr, cm -1 ): 3540, 1760, 1740, 1680 
     Ultraviolet absorption (UV) (λ max   EtOH ): 238 nm (ε=9000), 203 nm (ε=5400) 
     Proton NMR (NMR) (CDCl 3 , δ ppm): 1.41, s(3H, 10--CH 3 ); 1.95, s(3H, 4--CH 3 ); 2.03, 2.08, 2.10, s(each 3H, 3×--OCOCH 3 ); 3.01, brd(1H, 5--H); 3.14, d, J=12 Hz(1H, 14β--H); 3.18, d, J=2 Hz(1--H, 15β--OH); 3.56, s(1H, 9α--H); ##STR5## 4.69, t, (1H, 7β--H); 5.16, s(1H, 12--H); 5.04, dd, J=2 Hz, 12 Hz(1H, 15α--H); ##STR6## 5.46, s(1H, 1--H); 6.04, q(1H, 3--H) 
     Mass spectrum (MS) (m/e): M +  518, 476, 458, 416, 392, 374 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               60.27  5.80Calcd.              60.23  5.83______________________________________ 
    
     X-ray diffraction analysis 
     R-value: (0.071 except |FOBS|=0) 
     Crystallization: Recrystallized from ethanol-water 
     Specific gravity: 1.37 
     Space group: P2 1  (monoclinic) Z=2 
     lattice constants: 
     a=10.254Å (σ(a)=0.001) 
     b=14.560Å (σ(b)=0.002) 
     c=8.4670Å (σ(c)=0.0009) 
     β=101.45° (σ(β)=0.01°) 
     (ii) Compound IIa (R 1  =CH 3  CO--) 
     General formula ##STR7## (1) n=14 
     Form: amorphous 
     SR: [α] D   24  -2.00° (c=0.15, CHCl 3 ) 
     IR (KBr, cm -1 ): 1750, 1740, 1730, 1680 
     UV (λ max   EtOH ): 210 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 0.90 (terminal --CH 3 ); 1.28(5&#39;-17&#39;CH 2 ); 1.45(3H, s, 10--CH 3 ); 1.97(3H, s, 4--CH 3 ); 2.04, 2.10, 2.16(3H, s, ##STR8## 3.12(1H, brd, 5--H); 3.34(1H, d, J=12 Hz, 14--H); 3.58, 4.58(1H, d, J=12 Hz, --CH 2  --O--); 3.72(1H, s, 9--H); 4.74(1H, t, 7--H); 5.26(1H, s, 12--H); 5.42(1H, s, 1--H); 5.30, 5.50(1H, s, ##STR9## 5.86(1H, dt, J=16, 1 Hz, 2&#39;--H); 6.06(1H, brs, 3--H); 6.28(1H, d, J=12 Hz, 15--H); 7.08(1H, dt, J=16, 7 Hz, 3&#39;--H) 
     MS (m/e): 782, 740, 698, 680, 638, 514, 490, 472 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               67.37  7.89Calcd.              67.52  7.93______________________________________ 
    
     (2) n=13 
     Form: amorphous 
     IR (KBr, cm -1 ): 1750, 1740, 1730, 1580 
     UV (λ max   EtOH ): 210 nm, 238 nm 
     NMR (CDCl 3 , ppm): 1.28(5&#39;-16&#39;CH 2 ) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               67.01  7.79Calcd.              67.19  7.81______________________________________ 
    
     (3) n=12 
     Form: amorphous 
     SR: [α] D   23  -4.35° (c=0.23, CHCl 3 ) 
     IR (KBr, cm -1 ): 1760, 1750, 1730, 1680 
     UV (λ max   EtOH ): 210 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28 (5&#39;-15&#39;--CH 2 ) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               66.71  7.73Calcd.              66.84  7.69______________________________________ 
    
     (4) n=11 
     Form: amorphous 
     IR (KBr, cm -1 ): 1760, 1740, 1730, 1680 
     UV (λ max   EtOH ): 210 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28 (5&#39;-14&#39;--CH 2  --) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               66.30  7.55Calcd.              66.49  7.57______________________________________ 
    
     (5) n=10 
     Form: amorphous 
     SR: [α] D   24  -1.58° (c=0.19, CHCl 3 ) 
     IR (KBr, cm -1 ): 1760, 1740, 1730, 1680 
     UV (λ max   EtOH ): 210 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28 (5&#39;-13&#39;--CH 2  --) 
     MS (m/e): 726, 684, 642, 624, 582, 458, 434, 416 
     
         ______________________________________Elemental analysis  C      H______________________________________Found               66.03  7.43Calcd.              66.10  7.49______________________________________ 
    
     (6) n=9 
     Form: amorphous 
     SR: [α] D   24  -1.18° (c=0.17, CHCl 3 ) 
     IR (KBr, cm -1 ): 1740, 1730, 1680 
     UV (λ max   EtOH ): 210 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28 (5&#39;-12&#39;--CH 2  --) 
     MS (m/e): 712, 670, 628, 500, 476, 458 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               65.80  7.34Calcd.              65.71  7.35______________________________________ 
    
     (7) n=8 
     Form: amorphous 
     SR: [α] D   24  -3.46° (c=0.26, CHCl 3 ) 
     IR (KBr, cm -1 ): 1760, 1750, 1740, 1680 
     UV (λ max   EtOH ): 210 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28 (5&#39;-11&#39;--CH 2  --) 
     MS (m/e): 698, 656, 638, 614, 596, 458, 434, 416 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               65.22  7.22Calcd.              65.31  7.21______________________________________ 
    
     (8) n=7 
     Form: amorphous 
     SR: [α] D   27  -9.38° (c=0.16, CHCl 3 ) 
     IR (KBr, cm -1 ): 1750, 1740, 1680 
     UV (λ max   EtOH ): 210 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28 (5&#39;-10&#39;--CH 2  --) 
     MS (m/e): 684, 642, 600, 472, 448, 430 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               64.82  7.03Calcd.              64.91  7.02______________________________________ 
    
     (9) n=6 
     Form: amorphous 
     SR: [α] D   27  -7.50° (c=0.20, CHCl 3 ) 
     IR (KBr, cm -1 ): 1760, 1740, 1690 
     UV (λ max   EtOH ): 210 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28 (5&#39;-9&#39;--CH 2  --) 
     MS (m/e): 670, 628, 586, 458, 434, 416 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               64.24  6.88Calcd.              64.46  6.91______________________________________ 
    
     (10) n=5 
     Form: amorphous 
     SR: [α] D   24  +6.47° (c=0.17, CHCl 3 ) 
     IR (KBr, cm -1 ): 1760, 1740, 1680 
     UV (λ max   EtOH ): 210 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28 (5&#39;-8&#39;--CH 2  --) 
     MS (m/e): 656, 614, 572, 444, 420, 402 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               63.90  6.77Calcd.              64.01  6.75______________________________________ 
    
     (11) n=4 
     Form: amorphous 
     IR (KBr, cm -1 ): 1760, 1750, 1730, 1680 
     UV (λ max   EtOH ): 210 nm, 238 nm 
     NMR (CDCl 3 , δppm): 1.28 (5&#39;-7&#39;--CH 2  --) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               63.36  6.56Calcd.              63.54  6.59______________________________________ 
    
     (12) n=3 
     Form: amorphous 
     IR (KBr, cm -1 ): 1760, 1730, 1680 
     UV (λ max   EtOH ): 210 nm, 238 nm 
     NMR (CDCl 3 , δppm): 1.28 (5&#39;-6&#39;--CH 2  --) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               62.91  6.33Calcd.              63.06  6.37______________________________________ 
    
     (13) n=2 
     Form: amorphous 
     IR (KBr, cm -1 ): 1760, 1750, 1730, 1680 
     UV (λ max   EtOH ): 210 nm, 238 nm 
     NMR (CDCl 3 , δppm): 1.28 (5&#39;--CH 2  --) 
     (14) ##STR10## 
     Form: amorphous 
     IR (KBr, cm -1 ): 1760, 1750, 1730, 1680 
     NMR (CDCl 3 , δppm): 1.45(10--CH 3 ); 1.95(4--CH 3 ); 2.04, 2.10, 2.17 ##STR11## (CH 2  O--); 3.72(s, 9--H); 4.74(t, 7--H); 5.24(s, 12--H); 5.31, 5.50 ##STR12## 5.42(s, 1-H); 5.72(t, 2--H); 6.05(brs, 3--H); 6.26(d, J=12 Hz, 15--H) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               61.90  6.03Calcd.              62.01  6.02______________________________________ 
    
     (iii) Compound, IIa (R 1  =CH 3  CO--) 
     General formula ##STR13## (1) n=7 
     Form: amorphous 
     SR: [α] D   26  -22.3° (c=0.39, CHCl 3 ) 
     IR (KBr, cm -1 ): 1750, 1690 
     UV (λ max   EtOH ): 213 nm (ε=19200), 240 nm(sh)(ε=12800) 
     NMR (CDCl 3 , δppm): 0.84(3H, t, terminal--CH 3 ); 1.42(3H, s, 10--CH 3 ); 1.93(3H, s, 4--CH 3 ); 2.00, 2.07, 2.13(each 3H, s, ##STR14## 3.08(1H, brd, 5--H); 3.28(1H, d, J=12 Hz, 14--H); 3.56, 4.56(each 1H, d, J=12 Hz, --CH 2  O--); 3.67(1H, s, 9--H); 4.70(1H, t, 7--H); 5.20(1H, s, 12--H); 5.27, 5.47(each 1H, s, ##STR15## 5.40(1H, s, 1--H); 5.76(1H, dt, J=12 Hz, 2&#39;--H); 6.02(1H, brs, 3--H); 6.24(1H, d, J=12 Hz, 15--H); 6.36(1H, dt, J=12 Hz, 8 Hz, 3&#39;--H) 
     MS (m/e): 684(M + ), 642, 600, 458, 416 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               65.01  7.17Calcd.              64.89  7.07______________________________________ 
    
     (2) n=0 
     Form: amorphous 
     SR: [α D   26  -23.8° (c=0.24, CHCl 3 ) 
     IR (KBr, cm -1 ): 1750, 1690 
     UV (λ max   EtOH ): 213 nm (ε=19600), 240 nm(sh)(ε=12600) 
     NMR (CDCl 3 , δ ppm): 0.84(3H, t, terminal --CH 3 ); 1.42(3H, s, 10--CH 3 ); 1.93(3H, s, 4--CH 3 ); 2.00, 2.07, 2.13(each 3H, s, ##STR16## 3.08(1H, brd, 5--H); 3.28(1H, d, J=12 Hz, 14--H); 3.56, 4.56(each, 1H, d, J=12 Hz, --CH 2  O--); 3.67(1H, s, 9--H); 4.70(1H, t, 7--H); 5.20(1H, s, 12--H); 5.27, 5.47(each 1H, s, ##STR17## 5.40(1H, s, 1--H); 5.76(1H, dt, J=12 Hz, 1 Hz, 2&#39;--H); 6.02(1H, brs, 3--H); 6.24(1H, d, J=12 Hz, 15--H); 6.36(1H, dt, J=12 Hz, 8 Hz, 3&#39;--H) 
     MS (m/e): 726(M + ), 684, 642, 458, 416 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               66.29  7.32Calcd.              66.10  7.49______________________________________ 
    
     (iv) Compound, IIb 
     General formula ##STR18## (1) n=14 
     Form: amorphous 
     SR: [α] D   27  +56.1° (c=0.13, CHCl 3 ) 
     IR (KBr, cm -1 ): 3250, 1760, 1730, 1670 
     UV (λ max   EtOH ): 214 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 0.90 (terminal--CH 3 ); 1.23(3H, s, 10--CH 3 ); 1.28(brs, 5&#39;-17&#39;CH 2 ); 2.04(3H, s, 4--CH 3 ); 3.08(1H, s, 9--H); 3.55, 3.93 (1H, d, J=8 Hz, --CH 2  O--); 4.07(1H, s, 12--H); 4.21(1H, s, 1--H); 4.63(1H, t, 7--H); 5.87(1H, dt, J=16 Hz, 1 Hz, 2&#39;--H); 5.18, 5.36(1H, s, ##STR19## 5.73(1H, d, J=11 Hz, 15--H); 6.16(1H, brs, 3--H); 7.06(1H, dt, J=16 Hz, 7 Hz, 3&#39;--H) 
     MS (m/e): 656, 638, 612, 568 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               68.68  8.33Calcd.              68.76  8.34______________________________________ 
    
     (2) n=13 
     Form: amorphous 
     IR (KBr, cm -1 ): 3300, 1760, 1730, 1670 
     UV (λ max   EtOH ): 214 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28(brs, 5&#39;-16&#39;--CH 2  --) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               69.01  8.45Calcd.              69.13  8.47______________________________________ 
    
     (3) n=12 
     Form: amorphous 
     SR: [α] D   23  +50.0° (c=0.15, CHCl 3 ) 
     IR (KBr, cm -1 ): 3300, 1760, 1730, 1670 
     UV (λ max   EtOH ): 214 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28(brs, 5&#39;-15&#39;--CH 2  --) 
     MS (m/e): 628, 610, 600, 586, 568, 558, 556, 540 
     High resolution MS: Found m/e 628.3595 
     (Calcd. for C 36  H 52  O 9 , m/e 628,3610) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               68.68  8.33Calcd.              68.76  8.34______________________________________ 
    
     (4) n=11 
     Form: amorphous 
     IR (KBr, cm -1 ): 3310, 1760, 1730, 1670 
     UV (λ max   EtOH ): 214 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28(brs, 5&#39;-14&#39;--CH 2  --) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               68.19  8.18Calcd.              68.38  8.20______________________________________ 
    
     (5) n=10 
     Form: amorphous 
     SR: [α] D   23  +38.2° (c=0.11, CHCl 3 ) 
     IR (KBr, cm -1 ): 3320, 1760, 1730, 1670 
     UV (λ max   EtOH ): 214 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28(5 1  -13 1  --CH 2  --) 
     MS (m/e): 600, 582, 572, 558, 516, 512, 434, 416 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               67.81  8.07Calcd.              67.98  8.05______________________________________ 
    
     (6) n=9, 
     Form: amorphous 
     SR: [α] D   25  +37.9° (c=0.28, CHCl 3 ) 
     IR (KBr, cm -1 ): 3300, 1760, 1730, 1670 
     UV (λ max   EtOH ): 214 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28(5&#39;-12&#39;--CH 2  --) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               67.40  7.87Calcd.              67.55  7.90______________________________________ 
    
     (7) n=8 
     Form: amorphous 
     SR: [α] D   23  +49.2° (c=0.12, CHCl 3 ) 
     IR (KBr, cm -1 ): 3300, 1760, 1730, 1670 
     UV (λ max   EtOH ): 214 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28(5&#39;-11&#39;--CH 2  --) 
     High resolution MS: Found m/e 572.2940 
     (Calcd. for C 32  H 44  O 9 , m/e 572.2983) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               66.98  7.74Calcd.              66.61  7.74______________________________________ 
    
     (8) n=7 
     Form: amorphous 
     SR: [α] D   23  +36.0° (c=0.15, CHCl 3 ) 
     IR (KBr, cm -1 ): 3250, 1760, 1730, 1670 
     UV (λ max   EtOH ): 214 nm, 238 nm 
     MS (m/e): 558, 540, 530, 516, 486, 470 
     High resolution MS: Found m/e 558.2807 
     (Calcd. for C 31  H 42  O 9 , m/e 558.2825) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               66.45  7.58Calcd.              66.65  7.58______________________________________ 
    
     (9) n=6 
     Form: amorphous 
     SR: [α] D   27  +53.0° (c=0.20, CHCl 3 ) 
     IR (KBr, cm -1 ): 3250, 1750, 1720, 1660 
     UV (ν max   EtOH ): 214 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28(brs, 5&#39;-9&#39;--CH 2  --) 
     MS (m/e): 544, 526, 516, 502, 498, 472, 458, 456 
     High resolution MS: Found m/e 544.2694 
     (Calcd. for C 30  H 40  O 9 , m/e 544.2672) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               66.07  7.39Calcd.              66.16  7.40______________________________________ 
    
     (10) n=5 
     Form: amorphous 
     SR: [α] D   23  +45.0° (c=0.16, CHCl 3 ) 
     IR (KBr, cm -1 ): 3300, 1760, 1730, 1660 
     UV (λ max   EtOH ): 214 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28(brs, 5&#39;-8&#39;--CH 2  --) 
     MS (m/e): 530, 512, 502, 488, 458, 442 
     High resolution MS: Found m/e 530,2510 
     (Calcd. for C 29  H 38  O 9 , m/e 530.2513) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               65.50  7.19Calcd.              65.64  7.22______________________________________ 
    
     (11) n=4 
     Form: amorphous 
     IR (KBr, cm -1 ): 3300, 1760, 1730, 1660 
     UV (λ max   EtOH ): 214 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28(brs, 5&#39;-7&#39;--CH 2  --) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               64.93  6.95Calcd.              65.11  6.98______________________________________ 
    
     (12) n=3 
     Form: amorphous 
     IR (KBr, cm -1 ): 3310, 1760, 1730, 1660 
     UV (λ max   EtOH ): 214 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28(brs, 5&#39;-6&#39;--CH 2  --) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               64.29  6.79Calcd.              64.53  6.82______________________________________ 
    
     (13) n=2 
     Form: amorphous 
     IR (KBr, cm -1 ): 3300, 1750, 1730, 1660 
     UV (λ max   EtOH ): 214 nm, 238 nm 
     NMR (CDCl 3 , δ ppm): 1.28(brs, 5 1  --CH 2  --) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               63.78  6.58Calcd.              63.28  6.60______________________________________ 
    
     (14) ##STR20## 
     Form: Colorless needles 
     mp: 168°-169° C. 
     SR: [α] D   24  +56.1° (c=0.38, CHCl 3 ) 
     IR (KBr, cm -1 ): 3400, 1740, 1720, 1670 
     UV (λ max   EtOH ): 218 nm (ε=24500) 
     NMR (CDCl 3 , δ ppm): 1.94, 2.19 ##STR21## 
     MS (m/e): 474, 456, 446, 432, 402, 386, 374 
     High resolution MS: Found m/e 474.1907 
     (Calcd. for C 25  H 30  O 9 , m/e 474.1890) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               63.11  6.29Calcd.              63.28  6.37______________________________________ 
    
     (v) Compound, IIb 
     General formula ##STR22## (1) n=7 
     Form: amorphous 
     SR: [α] D   26  +50.0° (c=0.10, CHCl 3 ) 
     IR (KBr, cm -1 ): 3300, 1750, 1720, 1660 
     UV (λ max   EtOH ): 216 nm (ε=18700), 240 nm(sh) (ε=10200) 
     NMR (CDCl 3 , δppm): 0.84(3H, t, terminal--CH 3 ); 1.16(3H, s, 10--CH 3 ); 2.00(3H, s, 4--CH 3 ); 3.02(1H, s, 9--H); 3.50, 3.89(1H, d, J=8 Hz, --CH 2  O--); 4.01(1H, s, 12--H); 4.12(1H, s, 1--H); 4.59(1H, t, 7--H); 5.13, 5.32(each 1H, s, ##STR23## 5.66(1H, d, J=11 Hz, 15--H); 5.80(1H, dt, J=12 Hz, 1 Hz, 2&#39;--H); 6.12(1H, brs, 3--H); 6.34(1H, dt, J=12 Hz, 8 Hz, 3&#39;--H) 
     MS (m/e): 558, 540, 530, 514, 485, 470 
     High resolution MS: Found m/e 558.2841 
     Calcd, for C 31  H 42  O 9 , m/e 558.2828 
     (2) n=10 
     Form: amorphous 
     SR: [α] D   26  +41.3° (c=0.15, CHCl 3 ) 
     IR (KBr, cm -1 ): 3300, 1750, 1720, 1660 
     UV (λ max   EtOH ): 217 nm(ε=17900), 240 nm(ε=11300) 
     NMR (CDCl 3 , δppm): 0.84(3H, t, terminal--CH 3 ); 1.16(3H, s, 10--CH 3 ); 2.00(3H, s, 4--C H 3 ); 3.02(1H, s, 9--H); 3.50, 3.89(1H, d, J=8 Hz, --CH 2  O--); 4.01(1H, s, 12--H); 4.12(1H, s, 1--H); 4.59(1H, t, 7--H); 5.13, 5.32(each 1H, s, ##STR24## 5.66(1H, d, J=11 Hz, 15--H); 5.80(1H, dt, J=12 Hz, 1 Hz, 2&#39;--H); 6.12(1H, brs, 3--H); 6.34(1H, dt, J=12 Hz, 8 Hz, 3&#39;--H) 
     MS (m/e): 600(M + ), 582, 572, 556, 527, 512 
     High resolution MS: Found m/e 600.3298 
     Calcd. for C 34  H 48  O 9 , m/e 600.3298 
     PREPARATION OF COMPOUNDS 
     As hereinbefore described, the compounds (I, IIa and IIb) can be derived from known ailanthone (III) as follows: 
     EXAMPLE 1 
     Ailanthone triacetate (1,12,20-triacetyl ailanthone)(IV) 
     87.4 g (0.23M) of ailanthone was dissolved in 870 ml of anhydrous pyridine and 1700 ml of acetic anhydride was added to the solution. The reaction mixture was allowed to stand for 20 hours at room temperature and then evaporated in vacuo to precipitate out a crystalline substance. This crystalline substance was recrystallized from methanol to give 108.6 g (yield 93%) of compound (IV) as colorless needles. This compound was in agreement with known ailanthone triacetate in view of its physico-chemical data and further it did not show any melting point depression in the mix-melting test with the authentic sample of compound (IV). 
     EXAMPLE 2 
     16-hydroxyailanthone-triacetate(1,12,20-triacetylailanthone-16-ol)(V) 
     15 g (30 mM) of ailanthone triacetate was dissolved in the mixed solvent containing 1.5 l of each of tetrahydrofurane and ethanol. To the solution, 2.25 g (60 mM) of sodium borohydride was added under ice-cooling. The reaction mixture was stirred for 2 hours under ice-cooling and thereafter a saturated aqueous ammonium chloride solution was added. Then, water was added so as to redissolve the formed precipitates and the organic solvent was evaporated in vacuo. The remaining liquid was extracted five times with methylene chloride and fractioned solvent layers were washed twice with water, then washed with saturated salt solution and finally dried over anhydrous magnesium sulfate. This dried extract was then evaporated in vacuo to give 14.7 g of the compound (V) as colorless powder. Yield: 98% 
     Form: amorphous 
     SR: [α] D   24  +5.00° (c=0.14, CHCl 3 ) 
     IR (KBr, cm -1 ): 3450, 1750, 1740, 1680 
     MS (m/e): M +  504, 462, 444, 420, 402, 378, 360 
     High resolution MS: Found m/e 504.2013 
     Calcd. for C 26  H 32  O 10  m/e 504.1996) 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               61.76  6.39Calcd.              61.89  6.39______________________________________ 
    
     EXAMPLE 3 
     15,16-dehydroailanthone-triacetate(1,12,20-triacetylailanthone-15-ene)(VI) 
     3.48 g (6.9 mM) of compound (V) was dissolved in 35 ml of pyridine and to the solution thus obtained 2.1 g (12.9 mM) of phosphoryl chloride was added. The reaction mixture was refluxed for 5 minutes under argon atmosphere, followed by addition of ice in order to quench the reaction, and then pyridine was evaporated in vacuo. The remaining oily residue was diluted with water and extracted five times with ethyl acetate. The fractioned organic solvent layers were joined together and washed twice with saturated salt solution followed by drying over anhydrous sodium sulfate. The dried extract was condensed in vacuo to yield colorless crystals. The crystals were recrystallized from ethanol to give 2.01 g of the desired compound (VI) as colorless crystals. Yield: 60% 
     Form: colorless needles 
     mp: 186°-187° C. 
     SR: [α] D   25  -2.86° (c=0.21, CHCl 3 ) 
     IR (KBr, cm -1 ): 1760, 1680 
     UV (λ max   EtOH ): 206 nm(ε=12000), 238 nm(ε=11400) 
     NMR (CDCl 3 , δppm): 1.44, s(3H, 10--CH 3 ); 1.94, s(3H, 4--CH 3 ); 2.04, s(9H, --OAcX3); 3.24, d(1H, 5α--H); 3,44, t(1H, 14β--H); 3.68, s(1H, 9α--H); ##STR25## (--CH 2  --OAc); 4.16, t(1H, 7β--H); 4.66, dd, J=7 Hz, 3 Hz (1H, 15--H); 5.15, s(1H, 12--H); 5.24, s(1H, 1--H); ##STR26## 5.98 q J=1 Hz (1H, 3--H); 6.41, dd, J=3 Hz, 7 Hz (1H, 16--H) 
     MS (m/e): M +  486, 444, 426, 402, 384, 360, 342 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               64.08  6.20Calcd.              64.19  6.22______________________________________ 
    
     EXAMPLE 4 
     15,16-dihydroxyailanthone-triacetate(1,12,20-triacetylailanthone-15,16-diol)(VII) 
     First, a solution of an oxidizing agent was prepared in the following manner: 5.06 g (43 mM) of N-methylmorpholine N-oxide was dissolved in a mixture containing 72.5 ml of water and 29.0 ml of acetone. To this solution, 21.8 mg (0.0857 mM) of osmium tetroxide in 10 ml of t-butanol was added to give the desired solution of the oxidizing agent. 
     To the above oxidized solution, 13.45 g (17.6 mM) of 1,12,20-triacetylailanthone-15-ene (VI) was added and the resulting solution was diluted with 145 ml of acetone. The reaction mixture was stirred at room temperature for 24 hours, followed by further addition of 290 mg (2.79 mM) of sodium hydrogen sulfite. Then water was poured into the mixture, whereby the solution was homogenized. The solution thus obtained was then condensed in vacuo and the residue was adjusted to pH 2 with 2N HCl. The residue was then saturated with salt, and extracted 5 times with ethyl acetate and the combined extract was then dried over anhydrous sodium sulfate. The dried extract was then evaporated in vacuo to give the diol compound (VII) as colorless powder. (This compound was a mixture of C-16 stereoisomers so that it was impossible to be crystallized.) 
     The above powder was then chromatographed on 25 g of silica gel (CC-7) (prepared by Mallinckrodt Co.) and eluted with ethyl acetate to obtain 13 g of pure product. Yield: 90% 
     Form: amorphous 
     SR: [α] D   25  +3.81° (c=0.21, CHCl 3 ) 
     IR (cm -1 ): 3450, 1760, 1740, 1680 
     MS (m/e): M 30   520, 502, 478, 460, 436, 418, 400, 376, 358 
     High resolution MS: Found m/e 520.1958 
     Calcd. for C 26  H 32  O 11  m/e 520.1943 
     
         ______________________________________Elemental analysis: C      H______________________________________Found               59.82  6.21Calcd.              59.99  6.20______________________________________ 
    
     EXAMPLE 5 
     15β-hydroxyailanthone-triacetate(1,12,20-triacetylailanthone-15β-ol)(I) 
     17.4 g (33.4 mM) of diol compound (VII) was dissolved in 850 ml of anhydrous acetonitrile, followed by the addition of 52.2 g (421 mM) of activated silver oxide. The mixture was refluxed for 1 hour. After cooling to room temperature, the silver salt was removed from the mixture with cerite. Evaporation of the solvent from the reaction mixture gave 22.6 g of an oily substance. This substance was chromatographed on 300 g of above-described silica gel (CC-7) and eluted with the mixture of ethyl acetate and chloroform (4:6 by volume). The eluate was condensed and the residue was recrystallized from acetone-ether mixture to give 10.4 g of 1,12,20-triacetylailanthone-15β-ol (I). The overall yield of the compound (I) from compound (IV) was 31.7%. 
     EXAMPLE 6 
     15β-hydroxyailanthone triacetate-α,β-unsaturated carboxylic acid esters (IIa) 
     The compound (IIa) of the present invention can be prepared from the above compound (I) by the following general procedure. 
     1.24 equivalent of an α,β-unsaturated carboxylic acid and 1.50 equivalent of 1-ethyl-2-fluoropyridinium tetrafluoroborate or 1-methyl-2-fluoropyridinium tosylate were dissolved in anhydrous methylene chloride and 4.87 equivalent of cesium fluoride was added thereto. This solution was then stirred for 30 minutes at room temperature. To this solution, 1.00 g (1.93 mM) of compound (I) (15β-hydroxyailanthonetriacetate was added in one portion. The mixture was then further stirred at room temperature for 20 hours and the reaction was stopped. 
     The reaction mixture was then extracted three times with methylene chloride. The combined extract was then washed twice with saturated sodium hydrogen carbonate solution and further washed twice with saturated salt solution, and then dried over anhydrous magnesium sulfate, followed by condensation to remove the solvent. The remaining oily substance was then chromatographed on CC-7 silica gel (as described above) and eluted with a mixture of benzene-ethyl acetate (9:11 by volume) to obtain the compound (IIa) as a colorless oily substance. The following Table 1 shows the yields of several compounds (IIa) obtained according to this general procedure. 
     
                       TABLE 1______________________________________           Amount of aliphatic                          Yield of IIaType of aliphatic acid           acid (mg)      mg (%)______________________________________trans-2-octadecenoic acid           677            1.16 (77)trans-2-heptadecenoic acid           643            1.10 (74)trans-2-hexadecenoic acid           610            1.02 (70)trans-2-pentadecenoic acid           576            1.07 (75)trans-2-tetradecenoic acid           542            1.18 (84)trans-2-tridecenoic acid           509            1.26 (92)trans-2-dodecenoic acid           475            1.28 (95)trans-2-undecenoic acid           442            1.25 (95)trans-2-decenoic acid           408            1.16 (90)trans-2-nonenoic acid           374            1.04 (89)trans-2-octenoic acid           341            1.24 (93)trans-2-heptenoic acid           307            1.21 (95)trans-2-hexenoic acid           274            1.19 (95)3-methylcrotonic acid           240            0.905 (78)cis-2-undecenoic acid           356            0.978 (74)cis-2-tetradecenoic acid           436            1.083 (74)______________________________________ 
    
     EXAMPLE 7 
     15β-hydroxyailanthone-α,β-unsaturated carboxylic acid esters (IIb) 
     The compound (IIb) can be prepared from the above compound (IIa) by the following general procedure. 
     1.0 mM of the compound (IIa) obtained according to Example 6 was dissolved in a methanolic solution of 0.01N potassium methoxide. The resulting solution was then stirred for 2 hours under N 2  atmosphere. The reaction mixture was then adjusted to pH 4-5 with 1N HCl and thereafter the solvent was distilled off. The residue was then extracted three times with methylene chloride after the addition of water. The fractionated methylene chloride layers were washed twice with saturated aqueous saline and dried over anhydrous magnesium sulfate. The solvent was removed from the dried extract in vacuo and the residue thus obtained was chromatographed on silica gel (Kiesel gel-60, Merck, 70-230 mesh ASTM) and then eluted with the mixture of ethyl acetate-hexane (5:2 by volume) to give a pure compound (IIb). In addition, the mixture of monoacetate and diacetate fractionated by the above chromatography was re-acetylated with ten times amount of pyridine and twenty times amount of acetic anhydride at room temperature for 48 hours, and then hydrolyzed as in the above. Thus, the desired compound (IIb) can further be recovered. 
     The following Table 2 shows the yields of several compounds (IIb) obtained according to this general procedure. 
     
                       TABLE 2______________________________________Type of starting compound (IIa)               Yield of IIb (%)______________________________________trans-2-octadecenoate               40trans-2-heptadecenoate               42trans-2-hexadecenoate               43trans-2-pentadecenoate               40trans-2-tetradecenoate               47trans-2-tridecenoate               49trans-2-dodecenoate 50trans-2-undecenoate 51trans-2-decenoate   54trans-2-nonenoate   50trans-2-octenoate   52trans-2-heptenoate  44trans-2-hexenoate   33trans-2-pentenoate  343-methylcrotonate   34cis-2-undecenoate   40cis-2-tetradecenoate               41______________________________________ 
    
     Antineoplastic Activity of the Compounds of Present Invention 
     Materials 
     Animals: Mouse (BDF 1 , female, 4-5 weeks, average body weight: 18 g) 
     Cells: Mouse lymphocytic leukemia p388 
     Medicine: Compounds (IIb)(n=5(trans),6(trans), 7(trans),8(trans),9(trans),10(trans), 12(trans),14(trans),7(cis) and 10(cis)) 
     Method 
     10 6  cells of mouse lymphocytic leukemia p388 were intraperitoneally injected to BDF 1  mouse (6 mice per group). From the 2nd day after the injection, the destined amount of the medicine as shown in following Table 3 was administered for 5 days continuously. Thereafter, the surviving percentages (ILS) of the administered mice were calculated by the following equations. 
     
                       TABLE 3______________________________________ ##STR27##100--100%     Dose (mg/kg)Medicine (IIb)       30     10       5   3     1   0.5______________________________________n = 5(trans)       84     55       37  --    --  --n = 6(trans)       100    54       50  --    --  --n = 7(trans)       80     74       69  --    --  --n = 8(trans)       84     65       63  --    --  --n = 9(trans)       86     64       46  --    --  --n = 10(trans)       102    67       47  --    --  --n = 12(trans)       78     51       45  --    --  --n = 14(trans)       47      6        6  --    --  --n = 7(cis)  66     54       39  --    --  --n = 10(cis) 64     56       34  --    --  --control*    --     --       --  --    83  --______________________________________ *Mitomycin C was used as the positive control 
    
     As shown by the above Table 3, the compound (IIb) is markedly effective against mouse lymphocytic leukemia p338. Especially, the compound of n=6(trans) and n=10(trans) are so effective that they can prolong the life of the administered group as much as twice or more as compared to that of the control group and far more effective than that of known mitomycin C administered group. This fact will give a preferably aspect to the use of the compound of this invention as a novel antitumor agent. 
     While the invention has been described in detail and with reference to specific embodiment thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.