Selinexor

KPT-330, analog of KPT-185, is an orally bioavailable selective CRM1 inhibitor.IC50 value: Target: CRM1in vitro: As the clinical candidate analog of KPT-185, KPT-330 exhibits similar effects on the viability of T-ALL cells and elicits rapid apoptotic response. KPT-330 also reduces cell growth in MOLT-4, Jurkat, HBP-ALL, KOPTK-1, SKW-3, and DND-41 cell lines, with IC50 values of 34-203 nM [1]. in vivo: KPT-330 dramatically suppresses the growth of T-ALL cells (MOLT-4) and AML cells (MV4–1

Selinexor is a first-in-class selective inhibitor of nuclear transport (SINE) compound. It is currently approved for the treatment of multiple myeloma, a cancer which forms from antibody-producing plasma cells. This condition is typically treated with high dose [bortezomib] and dexamethasone chemotherapy followed by autologous stem-cell transplant. Other chemotherapies for multiple myeloma include [lenalidomide] and [dexamethasone], [thalidomide], and may include [melphalan] if the patient is not eligible for transplant. Selinexor was approved by the FDA in June 2019. It was granted fast track and orphan designation as well as accelerated approval based on single arm, open label trial data. The Bortezomib, Selinexor, and Dexamethasone in Patients With Multiple Myeloma (BOSTON) trial is planned to finish in 2020.|Selinexor is an orally available, small molecule inhibitor of CRM1 (chromosome region maintenance 1 protein, exportin 1 or XPO1), with potential antineoplastic activity. Selinexor modifies the essential CRM1-cargo binding residue cysteine-528, thereby irreversibly inactivates CRM1-mediated nuclear export of cargo proteins such as tumor suppressor proteins (TSPs), including p53, p21, BRCA1/2, pRB, FOXO, and other growth regulatory proteins. As a result, this agent, via the approach of selective inhibition of nuclear export (SINE), restores endogenous tumor suppressing processes to selectively eliminate tumor cells while sparing normal cells. CRM1, the major export factor for proteins from the nucleus to the cytoplasm, is overexpressed in a variety of cancer cell types.

In a 3-L, 3-necked, round-bottomed flask were charged 60.0 gr (Z)-3-(3-(3, 5- bis(trifluoromethyl)phenyl)- 1 H- 1, 2, 4-triazol- 1 -yl)acrylic acid (SLN- 105, prepared according to examples 27), Ethyl acetate (0.42 lit, 7V) and Acetonitrile (0.3 lit, 5V) at 20-25°C. Charged 2-hydrazino pyrazine (19.8 gr, 1.05 eq) then cooled to 0 to 5°C. Charged EDC .HC1 (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride) (49. lgr 1 .Seq) at 0 to 5°C. The reaction mass was stirred for 3hrs and monitored by HPLC (till SLN-105 NMT 1.0percent). Once the reaction completes, charge water (0.2lit, 2V) and stirred for 15-30 mm at 15-20°C, settled and separated the organic layer. Collected the organic layer and washed with sodium bicarbonate solution (0.Slit, SV). Finally washed the organic layer with water (0.2lit, 2 V) and combined the collected organic layer containing the product. The solvent is distilled off under vacuum at 50 to 60°C for 30 mm. To the obtained solid, added absolute Ethanol (0.6lit, 1OV) and stirred for 30mm at 20-25°C then cooled to 0-5°C and stirred for 1 hr at 0-5°C. Filtered the compound under vacuum at 20-25°C and washed with Ethanol (0.2lit, 2V). The wet cake was dried at 55-60°C under vacuum (600 to 700 mm Hg) for 4 hrs. (Yield 83percent).Synthesis of (Z)-3-(3-(3, 5-bis(trifluoromethyl)phenyl)-lH-l, 2, 4-triazol- 1 -yl)-N'-(pyrazin-2-yl)acr lohydrazide (1-3 .A 50-mL, 3-necked, round-bottomed flask was charged with a suspension of (Z)-3-(3- (3, 5-bis(trifluoromethyl)phenyl)-lH-l, 2, 4-triazol-l-yl)acrylic acid (0.200 g) in 1 :1 CH2C12: AcOEt (25 mL). 2-Hydrazinopyrazine (0.062 g) was added at -40 °C followed by T3P (50percent) (0.432g) and DIPEA (0.147 g). The reaction mixture was stirred for 30 min at -40 °C before being concentrated under reduced pressure (35 °C, 20 mmHg). The crude oil was purified by preparative TLC using 5percent MeOH in CHExample-4: Preparation of Selinexor (0507) (0508) (Z)-3-(3-(3, 5-bis(trifluoromethyl)phenyl)-1 H-1 , 2, 4-triazol-1 -yl)acrylic acid (10 g) was combined with a mixture of acetonitrile (1 00 mL) and ethyl acetate (50 mL) then added the 2-hydrazinylpyrazine (3.76 g) and stirred for 5 min. Reaction mixture was cooled to 0°C and diisopropyl ethyl amine (16.63 ml) and then Propylphosphonic anhydride (T50ml three-necked flask was added 0.2g compound 1, 0.24gDBACO, 20mlDMF, stirred to dissolve, to the reaction systemDropping the compound obtained in Step 8, a DMF solution, after the addition was completed, stirring was continued for 3.5 hours; After the reaction, to the system plus20ml of water and 50ml of ethyl acetate, the organic phase is evaporated to dryness, and then ethyl acetate and petroleum ether are recrystallized to obtain 0.158g of compound 5Rate of 50.9percent.50ml three-necked flask was added 0.2g compound 1, 0.24gDBACO, 20mlDMF, stirred to dissolve, to the reaction systemDropping the compound obtained in Step 8, a DMF solution, after the addition was completed, stirring was continued for 3.5 hours; After the reaction, to the system plus20ml of water and 50ml of ethyl acetate, the organic phase is evaporated to dryness, and then ethyl acetate and petroleum ether are recrystallized to obtain 0.158g of compound 5Rate of 50.9percent.In a 3-L, 3-necked, round-bottomed flask were charged 60.0 gr (Z)-3-(3-(3, 5- bis(trifluoromethyl)phenyl)- 1 H- 1, 2, 4-triazol- 1 -yl)acrylic acid (SLN- 105, prepared according to examples 27), Ethyl acetate (0.42 lit, 7V) and Acetonitrile (0.3 lit, 5V) at 20-25°C. Charged 2-hydrazino pyrazine (19.8 gr, 1.05 eq) then cooled to 0 to 5°C. Charged EDC .HC1 (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride) (49. lgr 1 .Seq) at 0 to 5°C. The reaction mass was stirred for 3hrs and monitored by HPLC (till SLN-105 NMT 1.0percent). Once the reaction completes, charge water (0.2lit, 2V) and stirred for 15-30 mm at 15-20°C, settled and separated the organic layer. Collected the organic layer and washed with sodium bicarbonate solution (0.Slit, SV). Finally washed the organic layer with water (0.2lit, 2 V) and combined the collected organic layer containing the product. The solvent is distilled off under vacuum at 50 to 60°C for 30 mm. To the obtained solid, added absolute Ethanol (0.6lit, 1OV) and stirred for 30mm at 20-25°C then cooled to 0-5°C and stirred for 1 hr at 0-5°C. Filtered the compound under vacuum at 20-25°C and washed with Ethanol (0.2lit, 2V). The wet cake was dried at 55-60°C under vacuum (600 to 700 mm Hg) for 4 hrs. (Yield 83percent).Synthesis of (Z)-3-(3-(3, 5-bis(trifluoromethyl)phenyl)-lH-l, 2, 4-triazol- 1 -yl)-N'-(pyrazin-2-yl)acr lohydrazide (1-3 .A 50-mL, 3-necked, round-bottomed flask was charged with a suspension of (Z)-3-(3- (3, 5-bis(trifluoromethyl)phenyl)-lH-l, 2, 4-triazol-l-yl)acrylic acid (0.200 g) in 1 :1 CH2C12: AcOEt (25 mL). 2-Hydrazinopyrazine (0.062 g) was added at -40 °C followed by T3P (50percent) (0.432g) and DIPEA (0.147 g). The reaction mixture was stirred for 30 min at -40 °C before being concentrated under reduced pressure (35 °C, 20 mmHg). The crude oil was purified by preparative TLC using 5percent MeOH in CH2C12 as mobile phase (under ammonia atmosphere) to afford 40 mg (yield: 16percent) of (Z)-3-(3-(355-bis(trifluoromethyl)phenyl)-lH-l, 2, 4-triazol-l- yl)-N'-(pyrazin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) delta , 10.53 (s, 1H), 9.59 (s, 1H), 9.14 (s, 1H), 8.53 (s, 2H), 8.29 (s, 1H), 8.13 (s, 1H), 8.06-8.07 (m, 1H), 7.92-7.93 (d, J=2.8 Hz, 1H), 7.51-7.53 (d, J=10.4 Hz, 1H), 6.07-6.10 (d, J=10.4 Etazeta, IotaEta); LCMS for CnHi2F6N70 [M+H]+ predicted: 444.31, found: 444.49 (RT 2.70 min, purity: 95.78percent).Example-4: Preparation of Selinexor (0507) (0508) (Z)-3-(3-(3, 5-bis(trifluoromethyl)phenyl)-1 H-1 , 2, 4-triazol-1 -yl)acrylic acid (10 g) was combined with a mixture of acetonitrile (1 00 mL) and ethyl acetate (50 mL) then added the 2-hydrazinylpyrazine (3.76 g) and stirred for 5 min. Reaction mixture was cooled to 0°C and diisopropyl ethyl amine (16.63 ml) and then Propylphosphonic anhydride (T3P, 33.31 mL) was added at 0°C and stirred the reaction mixture for 2.5 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with cold water (100 mL) and extracted the product with ethyl acetate (2 x 150 mL). The combined organic layer was dried over sodium sulphate and evaporated the solvent under vacuum at 40°C to obtain the crude product as yellow syrup. The obtained crude product was combined with dichloromethane (1 00 mL) and filtered the solid and washed with dichloromethane (2 x 50 mL). The solid was dried under vacuum at 40°C to obtain the title compound with purity by HPLC of 99.86percent. Yield : 7 g

Molecular Weight:443.3
XLogP3:3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:12
Rotatable Bond Count:5
Exact Mass:443.09292697
Monoisotopic Mass:443.09292697
Topological Polar Surface Area:97.6
Heavy Atom Count:31
Complexity:621
Defined Bond Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes