SJG 136

SJG-136 has been used in trials studying the treatment of Recurrent Fallopian Tube Cancer, Secondary Acute Myeloid Leukemia, de Novo Myelodysplastic Syndromes, Recurrent Ovarian Epithelial Cancer, and Secondary Myelodysplastic Syndromes, among others.

Solid bis-SEM-dilactam 8 (100 mg, 0.12 mmol) was dissolved in a mixture of ethanol (3 mL) and THF (3 ml_). Lithium borohydride (22 mg, 2.3 mmol) was added in one portion and the reaction mixture was allowed to stir for 1h under nitrogen. LC/MS revealed completion of the reaction. The reaction mixture was partitioned between water (35 mL) and chloroform (50 mL). The organic phase was washed with water (35 mL), brine (35 mL), dried over magnesium sulphate and concentrated by rotary evaporation under vacuum. The residue was redissolved in a mixture of chloroform (2 mL), ethanol (2 mL) and water (2.5 mL). Silica gel (4g) was added and the mixture was allowed to stir for 48h. The mixture was filtered through a sinter funnel and washed with a mixture of chloroform / methanol (90:10 v/v). The filtrate was extracted with chloroform, washed with brine, dried over magnesium sulphate and concentrated by rotary-evaporation under vacuum. The residue was purified by flash chromatography (gradient elution: 100percent CHCISolid bis-SEM-dilactam 8 (100 mg, 0.12 mmol) was dissolved in a mixture of ethanol (3 mL) and THF (3 ml_). Lithium borohydride (22 mg, 2.3 mmol) was added in one portion and the reaction mixture was allowed to stir for 1h under nitrogen. LC/MS revealed completion of the reaction. The reaction mixture was partitioned between water (35 mL) and chloroform (50 mL). The organic phase was washed with water (35 mL), brine (35 mL), dried over magnesium sulphate and concentrated by rotary evaporation under vacuum. The residue was redissolved in a mixture of chloroform (2 mL), ethanol (2 mL) and water (2.5 mL). Silica gel (4g) was added and the mixture was allowed to stir for 48h. The mixture was filtered through a sinter funnel and washed with a mixture of chloroform / methanol (90:10 v/v). The filtrate was extracted with chloroform, washed with brine, dried over magnesium sulphate and concentrated by rotary-evaporation under vacuum. The residue was purified by flash chromatography (gradient elution: 100percent CHCISolid bis-SEM-dilactam 8 (100 mg, 0.12 mmol) was dissolved in a mixture of ethanol (3 mL) and THF (3 ml_). Lithium borohydride (22 mg, 2.3 mmol) was added in one portion and the reaction mixture was allowed to stir for 1h under nitrogen. LC/MS revealed completion of the reaction. The reaction mixture was partitioned between water (35 mL) and chloroform (50 mL). The organic phase was washed with water (35 mL), brine (35 mL), dried over magnesium sulphate and concentrated by rotary evaporation under vacuum. The residue was redissolved in a mixture of chloroform (2 mL), ethanol (2 mL) and water (2.5 mL). Silica gel (4g) was added and the mixture was allowed to stir for 48h. The mixture was filtered through a sinter funnel and washed with a mixture of chloroform / methanol (90:10 v/v). The filtrate was extracted with chloroform, washed with brine, dried over magnesium sulphate and concentrated by rotary-evaporation under vacuum. The residue was purified by flash chromatography (gradient elution: 100% CHCI3 to 97:3 v/v CHCI3/MeOH). The pure fractions were pulled and the solvent removed by rotary-evaporation under vacuum to give the desired product SJG-136 as a mixture of imine and carbinolamine methyl ethers. (46 mg, 70%).Analytical Data: LC/MS 2.50 min (ES-) m/z (relative intensity) 555.06 ([M - H]-, 100); Analytical description identical to previously published by Gregson ef a/., J. Med. Chem. 2001 , 44, 1161-1174. However, the [O.]D value was found to be higher than reported: [alpha]20D = +766 (c = 0.37, HPLC CHCI3) (lit [alpha]20D = +358 (c = 0.07, CHCI3)). This was expected, as the optical rotation measurement is very sensitive to the chloroform purity and the ratio of imine / carbinolamine adducts[00106] This example illustrates a method of preparing 5H-Pyrrolo [2, 1-c] [1, 4] benzodiazepin-5-one, 8, 8'- [1, 3-propanediylbis (oxy) ] bis [11-methoxy-1, 2, 3, 10, 11, 11a- hexahydro-7-methoxy-2-methylidene- (11aS, 11'aS) (methanol adduct of NSC-694501) (Figure 2) in accordance with an embodiment of the invention. [00107] 5H-Pyrrolo [2, 1-c] [1, 4] benzodiazepin-5-one, 8, 8'- [1, 3- propanediylbis (oxy)] bis [1, 2, 3, l la-tetrahydro-7-methoxy-2-methylene- (llaS, 11'aS) ([00120] This example illustrates a method of preparing 5H-Pyrrolo [2, 1-c} [1, 4] benzodiazepin-5-one, 8, 8'- [1, 3-propanediylbis (oxy)] bis [ll-t-butylamino-1, 2, 3, 10, 11, 1 la-hexahydro-7-methoxy-2-methylidene- (1 laS, l l'aS) (t-butylamine adduct of NSC- 694501) in accordance with an embodiment of the invention (Figure 6).; [00121] Anhydrous t-butylamine (3 mL) was added to a sample of SH-Pyrrolo [2, 1-c] [1, 4] benzodiazepin-5-one, 8, 8'- [1, 3-propanediylbis (oxy) ] bis [l, 2, 3, 1 la-tetrahydro-7- methoxy-2-methylene- (llaS, 11'aS) (5. 56 mg, 10 pmol) and the reaction mixture was allowed to stir in a flask fitted with a CaCl2 drying tube for 24 h. Excess solvent was removed by evaporation in vacuo, and the resulting t-butylamine adduct was weighed (6.94 mg, 99%) and analysed by 1H NMR/COSY techniques in d6-DMSO : 1H NMR (500 MHz, d6-DMSO) 8 7. 28 (s, H6-S), 7.21 (s, H6-R), 6.85 (d, J= 6.27 Hz, NH-R), 6.62 (s, H9-R), 6.39 (s, H9-S), 6.05 (br s, NH-aminal), 5.53 (br s, NH-S), 5.12 and 5. 08 (s x 2, =CH2), 5.05- 4. 85 (m, =CH2 and H11-R), 4.54 (d, J= 8.7 Hz, H11-S), 4.40-3. 95 (m, -OCH2CH2CH2O- and H3), 3.94-3. 83 (m, Hl la-R), 3.80 and 3.79 (s x 2, 7-OCH3), 3.69-3. 58 (m, HI la-S), 3.00-2. 85 (m, H1), 2.67 (d, J = 16. 8 Hz, H1-R), 2.56 (d, J= 16.1 Hz, H1-S), 2.35-2. 15 (m, - OCH2CH2CH2O-). The persistence of N10-Cl 1 imine signals was observed in this spectrum[00114] This example illustrates a method of preparing 5H-Pyrrolo [2, 1-c] [1, 4] benzodiazepin-5-one, 8, 8'- [1, 3-propanediylbis (oxy) ] bis [11-(4-methyl-phenylthio)-1, 2, 3, 10, 11, 11a-hexahydro-7-methoxy-2-methylidene- (11aS, 11'aS) (thiophenol adduct of NSC-694501) (Figure 4) in accordance with an embodiment of the invention.; [00115] 5H-Pyrrolo [2, 1-c] [1, 4] benzodiazepin-5-one, 8, 8'- [1, 3- propanediylbis (oxy) ] bis [l, 2, 3, lla-tetrahydro-7-methoxy-2-methylene- (llaS, 11'aS) (NSC-694501) (-5-6. 5 mg, -10-12 u. mol) in anhydrous THF (1 mL) was treated withp- methylthiophenol (2 mol equivalents) and the reaction mixture was allowed to stir under nitrogen for 24 h to form the methylthiophenol adduct. Excess solvent was removed by evaporation in vacuo and the resulting solid compound was weighed and analysed by 1H NMR/COSY techniques in d6-DMSO : 1H NMR (500 MHz, d6-DMSO) 6 7. 48 (d, J= 8. 0 Hz, thioether Ar-3'H-S), 7.45-7. 38 (m, NH-R and thioether Ar 3'H-R), 7.21 (d, J= 8.0 Hz, thioether Ar-2'H-S), 7.16 (d, J= 7.8 Hz, thioether Ar-2'H-R), 6.99 (s, H6-S), 6.89 (s, H6- R), 6.50 (s, H9-S), 6.45 (s, H9-R), 5.79 (s, NH-S), 5.16 (d, J= 6.4 Hz, Hll-R), 5.07 and 5.04 (s x 2, =CH2), 4.76 (d, J= 10. 9 Hz, H11-S), 4.28 (d, J= 16. 3 Hz, H3), 4.25-4. 21 (m, Hl la-R), 4.19 (d, J= 16. 5 Hz, H3), 4.14-4. 00 (m, -OCH2CH2CH2O-), 3. 85-3. 76 (m, Hl la-, S), 3.69 (s, 7-OCH3), 3.15 (dd, J= 16.3, 8.5 Hz, H1-R), 3.08-3. 05 (m, Hl-5), 2.93 (d, J= 16.4 Hz, H1-R), 2.80-2. 70 (m, H1-S), 2.35-2. 15 (m, -OCH2CH2CH2O- and -PhCH3). Figure 5 shows the formulas of certain diastereomers obtained herein and in Examples 7-8 below

Molecular Weight:556.6
XLogP3:1.9
Hydrogen Bond Acceptor Count:8
Rotatable Bond Count:8
Exact Mass:556.23218475
Monoisotopic Mass:556.23218475
Topological Polar Surface Area:102
Heavy Atom Count:41
Complexity:1020
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes