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Amcenestrant (SAR 439859)

January 26, 2023 3:15 am / Leave a comment

Amcenestrant (SAR 439859)

アムセネストラント

Molecular Weight	554.48
Formula	C₃₁H₃₀Cl₂FNO₃
CAS No.	2114339-57-8

6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid

Amcenestrant

8-(2,4-dichlorophenyl)-9-(4-{[(3 S )-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro – 5H- Benzo[7]annulene-3-carboxylic acid

8-(2,4-Dichlorophenyl)-9-(4-{[(3 S )-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5 H -benzo [7]annulene-3-carboxylic acid

C31H30Cl2FNO3 : _554.48 [ 2114339-57-8 ] _{_} _ _{_} _ _{_}_

Efficacy	Antineoplastic, Selective estrogen receptor downregulator
Comment	Selective estrogen receptor downregulator (SERD) Treatment of breast cancer

SAR439859 (compound 43d) is an orally active, nonsteroidal and selective estrogen receptor degrader (SERD). SAR439859 is a potent ER antagonist and has ER degrading activity with an EC₅₀ of 0.2 nM for ERα degradation. SAR439859 demonstrates robust antitumor efficacy and limited cross-resistance in ER⁺ breast cancer.

Amcenestrant is an orally available, nonsteroidal selective estrogen receptor degrader/downregulator (SERD), with potential antineoplastic activity. Upon oral administration, amcenestrant specifically targets and binds to the estrogen receptor (ER) and induces a conformational change that promotes ER degradation. This prevents ER-mediated signaling and inhibits both the growth and survival of ER-expressing cancer cells.

Amcenestrant is reported to be a selective estrogen receptor degrader (SERD) which has estrogen receptor antagonist properties and accelerates the proteasomal degradation of the estrogen receptor. Amcenestrant is under clinical investigation as an anticancer agent, in particular for treatment of breast cancer.

The compound and processes for preparation thereof are described in International Publication No. WO 2017/140669.

Crystalline forms are described in International Publication No. WO 2021/116074.

PAPER

Journal of Medicinal Chemistry (2020), 63(2), 512-52

https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01293

6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3- yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic Acid (43d).

To a solution of 6-(2,4-dichloro-phenyl)-5-[4-[1-(3-fluoropropyl)-pyrrolidin-3-yloxy]-phenyl]-8,9-dihydro-7H-benzocycloheptene-2-carboxylic acid methyl ester (42d) (80 mg, 140.72 μmol) in methanol (5 mL) was added 5 N NaOH (562.88 μL), the reaction mixture was heated to 60 °C for 5 h, and the solvent was removed under reduced pressure. The residue was taken up in water (10 mL), and aqueous HCl (5 M) was added to pH 7. The slurry was extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of dichloromethane, acetonitrile, and methanol (90/5/5 v/v/v) to give 60 mg (77%) of 6- (2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]- oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d). 1 H NMR (400 MHz, DMSO-d6): 1.68 (m, 1H), 1.79 (dm, J = 25.3 Hz, 2 H), 2.07 to 2.23 (m, 5H), 2.38 (m, 1H), 2.46 (t, J = 7.2 Hz, 2H), 2.52 (m, 1H), 2.62 (m, 1H), 2.55 to 2.89 (m, 3H), 4.47 (td, J = 6.2 and 47.6 Hz, 2H), 4.72 (m, 1H), 6.63 (d, J = 8.9 Hz, 2H), 6.71 (m, 3H), 7.18 (d, J = 8.4 Hz, 1H), 8.26 (dd, J = 2.0 and 8.4 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 12.3 (m, 1H). LCMS: 554 (M + H)+ .

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023287938&_cid=P22-LDCH1V-08798-1

Amcenestrant can be prepared according to methods known from the literature, for example U.S. Patent No. 9,714,221.

Example 1: Preparation of amorphous Amcenestrant

[00164] Amcenestrant (20 mg, prepared according to U.S. Patent No. 9,714,221) was dissolved in ethyl acetate (0.2 mL) at room temperature (25°C). Solution was left in opened flask at RT for 16 days, until all the solvent evaporated. Obtained solid was analyzed by XRPD.

PATENT

U.S. Patent No. 9,714,221

https://patents.google.com/patent/US9714221B1/en

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017140669

Example 51. 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid

Methode B:

Step 1 : 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.

To a solution of methyl 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide (D5) (150 mg, 298.56 μιηοΙ), in dioxane (12 ml) and water (2 ml), was added 2,4-dichlorophenyl-boronic acid (62.67 mg, 328.41 μηηοΙ), Cs₂C0₃ (204.48 mg, 626.97 μηιοΙ), and Pd(dppf)CI₂ (14.63 mg, 17.91 μιηοΙ). The reaction mixture was heated at 90°C for 3 hours, and partitioned between AcOEt and water. The phases were separated and the organic phase washed with brine, dried over MgS0₄ and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) to give 80 mg (47%) of 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.

LC/MS (m/z, MH⁺): 568

Step 2 : 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid

7. The slurry was extracted with DCM, dried over MgS0₄ and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (90/5/5; V/V/V) to give 60 mg (77%) of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019020559

Intermediate (c). Tert-butyl (3S)-3-[4-(4,4_!5_!5-tetramethyl-1 _!3,2-dioxaborolan-2yl)phenoxy]pyrrolidine-1 -carboxylate

To a solution of commercially available 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (a) (82.7 g, 364.51 mmol) in THF (2 L) was added under argon (R)-1 -N-Boc-3-hydroxypyrrolidine (b) (84.43 g, 437.41 mmol) followed by Ν,Ν,Ν’,Ν’-tetramethylazodicarboxamide (99.1 g, 546.77 mmol). The clear reaction mixture turned orange and triphenylphosphine (143.41 g, 546.77 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours, meanwhile a precipitate of triphenylphosphine oxide formed (Ph₃P=0). The reaction mixture was poured in water (1 .5 L) and extracted with ethyl acetate (AcOEt) (3×1 .5 L). Gathered organic phases were dried over magnesium sulfate (MgS0₄), filtered and concentrated under reduced pressure. The residue was taken up into diisopropylether (1 .5 L) and the solid formed (Ph₃P=0) was filtered. The solvent was concentrated under reduced pressure and the residue purified by column chromatography eluting with a mixture of heptane with AcOEt (90/10; v/v) to give 145 g (100%) of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1 -carboxylate (c) as a colorless oil.

¹H NMR (400 MHz, DMSO-d6, δ ppm): 1 .27 (s : 12H); 1 .39 (s : 9H); 2.05 (m : 1 H); 2.14 (m : 1 H); 3.37 (3H); 3.55 (m : 1 H); 5.05 (s : 1 H); 6.94 (d, J = 8.4 Hz : 2H); 7.61 (d, J = 8.4 Hz : 2H)

Intermediate (d). (3S)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine, hydrochloride

To a solution of (S)-tert-butyl 3-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1 -carboxylate (c) (80 g, 195.23 mmol) in MeOH (450 ml) was added slowly HCI 4N in dioxane (250 ml).

After 1 .5 hours, the reaction mixture was concentrated under reduced pressure and the residue was taken up into Et₂0 with stirring to give a solid which then was filtered and dried under vacuum to give 61.8 g (95%) of (3S)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine, hydrochloride (d) as a white powder.

¹H NMR (400 MHz, DMSO-d6, δ ppm): 1.28 (s : 12H); 2.10 (m : 1 H); 2.21 (m : 1 H); 3.31 (3H); 3.48 (m : 1 H); 5.19 (m : 1 H); 6.97 (d, J = 8.4 Hz : 2H); 7.63 (d, J = 8.4 Hz : 2H); 9.48 (s : 1 H); 9.71 (s : 1 H).

LC/MS (m/z, MH⁺): 290

Intermediate (e). (3S)-1 -(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine

To a suspension of (S)-3-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine hydrochloride (d) (20 g, 61.42 mmol) in acetonitrile (100 ml), was added K₂C0₃ (21 .22 g, 153.54 mmol) and 1 -iodo-3-fluoropropane (12.15 g, 61.42 mmol), under argon. The reaction

mixture was stirred at 40°C for 24 hours. After cooling to room temperature, the reaction mixture was filtered and washed with acetonitrile. The filtrate was concentrated under reduced pressure and the residue was taken up in DCM and the solid formed was filtered and washed with DCM. The filtrate was concentrated to give 21.5 g (100%) of (3S)-1 -(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) as a yellow foam.

¹H NMR (400 MHz, DMSO-d6, δ ppm): 1.27 (s : 12H); 1 .77 (m : 2H); 1 .84 (m : 1 H); 2.27 (m : 1 H); 2.41 (m : 1 H); 2.49 (2H); 2.62 (dd, J = 2.6 and 10.4Hz : 1 H); 2.69 (m : 1 H); 2.83 (dd, J = 6.2 and 10.4Hz : 1 H); 4.47 (td, J = 6.2 and 47Hz : 2H) ; 4.99 (m : 1 H); 6.77 (d , J = 8.4 Hz : 2H); 7.58 (d, J = 8.4 Hz : 2H).

LC/MS (m/z, MH⁺): 350

Intermediate (B). 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate

To a solution of 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A) (1 .52 g, 8.63 mmol), in acetone (60 ml), was added K₂C0₃ (1 .19 g, 8.63 mmol) and pivaloyl chloride (1.06 ml, 8.63 mmol). The reaction mixture was stirred at room temperature for 16 hours, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane in AcOEt (100/0 to 85/15, v/v) to give 1.55 g (69%) of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate (B) as a colorless oil.

¹H NMR (400 MHz, DMSO-d6, δ ppm): 7.65 (d, 1 H); 7.10-7.04 (m, 2H); 2.95 (t, 2H); 2.68 (t, 2H); 1 .85-1 .65 (m, 4H).

LC/MS (m/z, MH⁺): 261

Intermediate (C). 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate

To a solution of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate (B) (15 g, 57.62 mmol) in DCM (500 ml) was added dropwise under argon pyridine (7.28 ml, 86.43 mmol) and trifluoromethanesulfonic anhydride (19.58 ml, 1 15.24 mmol). The reaction mixture was stirred at room temperature for 2 hours and ice (200 g) was added. The phases were separated, the aqueous phase was washed with DCM and the gathered organic phases were dried over MgS0₄, filtered and evaporated under reduced pressure to give 22 g (97%) of 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate (C) as a white solid.

LC/MS (m/z, MH-): 391

Intermediate (D). 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimeth lpropanoate

To a solution of 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (C) (22 g, 56.07 mmol) and (3S)-1 -(3-fluoropropyl)-3-[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) (20.56 g, 58.87 mmol) in dioxane (420 ml) and water (120 ml) was added under argon Pd(dppf)CI₂ (2.75 g, 3.36 mmol) and Cs₂C0₃ (36.57 g, 1 12.13 mmol). The reaction mixture was stirred for 1 hour at room temperature and was partitioned between water and DCM. The aqueous phase was washed with DCM and the gathered organic phases dried over MgS0₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0 to 5%; V/V) to give 31 g (100 %) of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (D).

LC/MS (m/z, MH⁺): 466

Intermediate (E). 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol

To a solution under argon of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (D) (24.8 g, 53.26 mmol) in MeOH (300 ml), was added NaOH 5M (23 ml, 1 15.00 mmol). The reaction mixture was stirred for 2 hours at room temperature. pH was then adjusted to 7 by addition of 6N aqueous HCI solution. The MeOH was concentrated under reduced pressure, then DCM was added. The organic phase was dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/ MeOH from 100/0 to 95/05 to give 18.8 g (93%) of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (E) as a beige solid.

LC/MS (m/z, MH⁺): 382

Intermediate (F). 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate

To a solution of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (E) (20.6 g, 54.00 mmol) in DCM (200 ml) and pyridine (6.55 ml, 81 .00 mmol), cooled to 5°C (ice bath), was added dropwise trifluoromethanesulfonic anhydride (18.93 ml, 108.00 mmol) under argon, and the reaction temperature was maintained <15°C. The ice bath was removed, and the brown suspension was stirred at room temperature for 2 hours. Ice (200 g) and DCM (200 ml) were added and the phases separated. The organic phase was dried over MgS0₄, and concentrated under reduced pressure. The residue was

purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 24.7 g (89.1 %) of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (F) as a brown oil.

LC/MS (m/z, MH⁺): 514

Intermediate (G). Methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (F) (10.1 g, 19.67 mmol) in DMF (66 ml) and MeOH (33 ml), were added Pd(dppf)CI₂ (909 mg, 1.18 mmol) and diisopropylethylamine (7.21 ml). The black suspension was carbonylated in an autoclave at 70°C under 5 bars of CO for 5 hours. The reaction mixture was filtered, then the filtrate was partially concentrated under reduced pressure. The residue was partitioned between AcOEt and water. The organic phase was washed with water (2x 100 ml), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCIW MeOH from 100/0 to 95/05 to give 7.13 g (86%) of methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (G) as a brown gum.

LC/MS (m/z, MH⁺): 424

Intermediate (A1 ). 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yltrifluoromethanesulfonate

To a solution of commercially available 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A) (18.5 g, 105 mmol) in DCM (185 ml) and lutidine (13.35 ml, 1 13.505 mmol), cooled at 5°C under argon, was added dropwise trifluoromethanesulfonic anhydride (20.22 ml,

123.29 mmol) while keeping temperature between 10 and 20°C. The reaction mixture was stirred for 1 hour at 5°C then at room temperature for 1 hour.

Then, ice (200 g) was added and the slurry partitioned between water and DCM. The organic phase was washed with aqueous NaHC0₃ solution, dried over MgS0₄, filtered off and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane/AcOEt from 100 to 90/10 to give 28.2 g (87%) of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate (A1 ) as an orange oil. LC/MS (m/z, MH⁺): 309

Intermediate (B1 ). Methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate

To a solution of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate (A1 ) (5.03 g, 16.32 mmol) in DMF (24 ml) and MeOH (12 ml), were added Pd(dppf)CI₂ (754 mg, 0.98 mmol) and diisopropylethylamine (6 ml). The black suspension was carbonylated in an autoclave at 70°C under 5 bars of CO for 2.5 hours. The reaction mixture was filtered, then the filtrate was partially concentrated under reduced pressure, and the residue, was partitioned between AcOEt and water. The organic phase was washed with water (2x 75 ml) and aqueous HCI 0.5 N, dried over MgS0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane/AcOEt from 100/0 to 90/10 to give 3.4 g (95%) of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (B1 ) as a colorless oil.

LC/MS (m/z, MH⁺): 219

Intermediate (C1 ). Methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (B1 ) (18,19 g, 83,34 mmol) in DCM (500 ml) and anhydrous pyridine (1 1 ml, 130,56 mmol), cooled at 5°C under argon, was added dropwise trifluoromethanesulfonic anhydride (30 ml, 176,54 mmol). The reaction mixture, a thick suspension, was stirred at room temperature for 24 hours, then ice was added and partitioned between water and DCM. The organic phase was dried over MgS0₄, filtered off and concentrated under reduced pressure to give 29 g (100%) of methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (C1 ) as a yellow gum.

LC/MS (m/z, MH⁺): 351

Intermediate (G). Methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (C1 ) (29 g, 82.9 mmol), (3S)-1 -(3-fluoropropyl)-3-[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) (28.9 g, 82.9 mmol), in dioxane (225 ml) were added Pd(dppf)CI₂ under argon, complex with DCM (3.73 g, 4.57 mmol) and Cs₂C0₃ 1 .5 M aqueous solution (1 1 1.12 ml, 166.68 mmol). The reaction mixture was stirred at 60°C for 1 hour.

After cooling to room temperature, the reaction mixture was poured into a mixture of water (500 ml) and AcOEt (400ml). The organic phase was washed with brine, dried over MgS0₄, filtered on celite and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 23 g (65%) of methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (G) as a brown gum.

LC/MS (m/z, MH⁺): 424

Intermediate (H). Methyl 8-bromo-9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide

To a solution of methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro- 5H-benzo[7]annulene-3-carboxylate (G) (13.93 g, 32.89 mmol), in DCM (150 ml) was added under argon pyridinium tribromide (15.78 g, 44.41 mmol). The reaction mixture was stirred for 1 hour at room temperature. Water (200 ml) was added, organic phase was then dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 16.4 g (85%) of methyl 8-bromo-9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro- 5H-benzo[7]annulene-3-carboxylate hydrobromide (H) as a yellow meringue.

LC/MS (m/z, MH⁺): 502

Intermediate (I). 6-(2,4-dichloro-phenyl)-5-{4-[1 -(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}- -dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.

To a solution of methyl 8-bromo-9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide (H) (150 mg, 298.56 μηηοΙ), in dioxane (12 ml) and water (2 ml), was added 2,4-dichlorophenyl-boronic acid (62.67 mg, 328.41 μηιοΙ), Cs₂C0₃ (204.48 mg, 626.97 μπιοΙ), and Pd(dppf)CI₂ (14.63 mg, 17.91 mol). The reaction mixture was heated at 90°C for 3 hours, and partitioned between AcOEt and water. The phases were separated and the organic phase washed with brine, dried over MgS0₄ and concentrated under reduced pressure. The residue was purified by column

chromatography eluting with a mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) to give 80 mg (47%) of 6-(2,4-dichloro-phenyl)-5-{4-[1 -(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (I).

LC/MS (m/z, MH⁺): 568

Compound (1 ). 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen -2-carboxylic acid

To a solution of 6-(2,4-dichloro-phenyl)-5-{4-[1 -(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (I) (80 mg, 140.72 μηηοΙ) in MeOH (5 ml) was added a solution of NaOH (562.88 μΙ, 5 M) and the reaction mixture was heated at 60°C for 5 hours and the solvent removed under reduced pressure. The residue was taken up in water (10 ml) and aqueous HCI (5 M) added to pH 7. The slurry was extracted with DCM, dried over MgS0₄ and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (90/5/5; V/V/V) to give 60 mg (77%) of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid. ¹H NMR (400 MHz, DMSO-d6, δ ppm): 1 .68 (m, 1 H); 1 ,79 (dm, J=25.3 Hz, 2 H); 2.07 to 2.23 (m, 5 H); 2.38 (m, 1 H); 2.46 (t, J=7.2 Hz, 2 H); 2.52 (m, 1 H); 2.62 (m, 1 H); 2.55 to 2.89 (m, 3 H); 4.47 (td, J=6.2 and 47.6 Hz, 2 H); 4.72 (m, 1 H); 6.63 (d, J=8.9 Hz, 2 H); 6.71 (m, 3 H); 7.18 (d, J=8.4 Hz, 1 H); 8.26 (dd, J=2.0 and 8.4 Hz, 1 H); 7.58 (d, J=2,0 Hz, 1 H); 7.63 (d, J=8.4 Hz, 1 H); 7.79 (s, 1 H); 12.3 (m, 1 H)

LC/MS (m/z, MH+): 554

//////////////

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C1CC2=C(C=CC(=C2)C(=O)O)C(=C(C1)C3=C(C=C(C=C3)Cl)Cl)C4=CC=C(C=C4)OC5CCN(C5)CCCF

Tremelimumab

October 27, 2022 2:33 am / Leave a comment

(Light chain)
DIQMTQSPSS LSASVGDRVT ITCRASQSIN SYLDWYQQKP GKAPKLLIYA ASSLQSGVPS
RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YYSTPFTFGP GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Heavy chain)
QVQLVESGGG VVQPGRSLRL SCAASGFTFS SYGMHWVRQA PGKGLEWVAV IWYDGSNKYY
ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARDP RGATLYYYYY GMDVWGQGTT
VTVSSASTKG PSVFPLAPCS RSTSESTAAL GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA
VLQSSGLYSL SSVVTVPSSN FGTQTYTCNV DHKPSNTKVD KTVERKCCVE CPPCPAPPVA
GPSVFLFPPK PKDTLMISRT PEVTCVVVDV SHEDPEVQFN WYVDGVEVHN AKTKPREEQF
NSTFRVVSVL TVVHQDWLNG KEYKCKVSNK GLPAPIEKTI SKTKGQPREP QVYTLPPSRE
EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP MLDSDGSFFL YSKLTVDKSR
WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K
(Disulfide bridge: L23-L88, L134-L194, L214-H139, H22-H96, H152-H208, H265-H325, H371-H429, H227-H’227, H228-H’228, H231-H’231, H234-H’234)

Fab fragment of tremelimumab (blue) binding CTLA-4 (green). From PDB entry 5GGV.

Tremelimumab

Formula	C6500H9974N1726O2026S52
CAS	745013-59-6
Mol weight	146380.4722

FDA APPROVED2022/10/21, Imjudo

PEPTIDE, CP 675206

Antineoplastic, Immune checkpoint inhibitor, Anti-CTLA4 antibody
Disease	Hepatocellular carcinoma

Tremelimumab (formerly ticilimumab, CP-675,206) is a fully human monoclonal antibody against CTLA-4. It is an immune checkpoint blocker. Previously in development by Pfizer,^[1] it is now in investigation by MedImmune, a wholly owned subsidiary of AstraZeneca.^[2] It has been undergoing human trials for the treatment of various cancers but has not attained approval for any.

Imjudo (tremelimumab) in combination with Imfinzi approved in the US for patients with unresectable liver cancer

PUBLISHED24 October 2022

https://www.astrazeneca.com/media-centre/press-releases/2022/imfinzi-and-imjudo-approved-in-advanced-liver-cancer.html

24 October 2022 07:00 BST

Approval based on HIMALAYA Phase III trial results which showed single priming dose of Imjudo added to Imfinzi reduced risk of death by 22% vs. sorafenib

AstraZeneca’s Imjudo (tremelimumab) in combination with Imfinzi (durvalumab) has been approved in the US for the treatment of adult patients with unresectable hepatocellular carcinoma (HCC), the most common type of liver cancer. The novel dose and schedule of the combination, which includes a single dose of the anti-CTLA-4 antibody Imjudo 300mg added to the anti-PD-L1 antibody Imfinzi 1500mg followed by Imfinzi every four weeks, is called the STRIDE regimen (Single Tremelimumab Regular Interval Durvalumab).

The approval by the US Food and Drug Administration (FDA) was based on positive results from the HIMALAYA Phase III trial. In this trial, patients treated with the combination of Imjudo and Imfinzi experienced a 22% reduction in the risk of death versus sorafenib (based on a hazard ratio [HR] of 0.78, 95% confidence interval [CI] 0.66-0.92 p=0.0035).¹ Results were also published in the New England Journal of Medicine Evidence showing that an estimated 31% of patients treated with the combination were still alive after three years, with 20% of patients treated with sorafenib still alive at the same duration of follow-up.²

Liver cancer is the third-leading cause of cancer death and the sixth most commonly diagnosed cancer worldwide.^3,4 It is the fastest rising cause of cancer-related deaths in the US, with approximately 36,000 new diagnoses each year.^5,6

Ghassan Abou-Alfa, MD, MBA, Attending Physician at Memorial Sloan Kettering Cancer Center (MSK), and principal investigator in the HIMALAYA Phase III trial, said: “Patients with unresectable liver cancer are in need of well-tolerated treatments that can meaningfully extend overall survival. In addition to this regimen demonstrating a favourable three-year survival rate in the HIMALAYA trial, safety data showed no increase in severe liver toxicity or bleeding risk for the combination, important factors for patients with liver cancer who also have advanced liver disease.”

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: “With this first regulatory approval for Imjudo, patients with unresectable liver cancer in the US now have an approved dual immunotherapy treatment regimen that harnesses the potential of CTLA-4 inhibition in a unique combination with a PD-L1 inhibitor to enhance the immune response against their cancer.”

Andrea Wilson Woods, President & Founder, Blue Faery: The Adrienne Wilson Liver Cancer Foundation, said: “In the past, patients living with liver cancer had few treatment options and faced poor prognoses. With today’s approval, we are grateful and optimistic for new, innovative, therapeutic options. These new treatments can improve long-term survival for those living with unresectable hepatocellular carcinoma, the most common form of liver cancer. We appreciate the patients, their families, and the broader liver cancer community who continue to fight for new treatments and advocate for others.”

The safety profiles of the combination of Imjudo added to Imfinzi and for Imfinzi alone were consistent with the known profiles of each medicine, and no new safety signals were identified.

Regulatory applications for Imjudo in combination with Imfinzi are currently under review in Europe, Japan and several other countries for the treatment of patients with advanced liver cancer based on the HIMALAYA results.

Notes

Liver cancer
About 75% of all primary liver cancers in adults are HCC.³ Between 80-90% of all patients with HCC also have cirrhosis.⁷Chronic liver diseases are associated with inflammation that over time can lead to the development of HCC.⁷

More than half of patients are diagnosed at advanced stages of the disease, often when symptoms first appear.⁸ A critical unmet need exists for patients with HCC who face limited treatment options.⁸ The unique immune environment of liver cancer provides clear rationale for investigating medications that harness the power of the immune system to treat HCC.⁸

HIMALAYA
HIMALAYA was a randomised, open-label, multicentre, global Phase III trial of Imfinzi monotherapy and a regimen comprising a single priming dose of Imjudo 300mg added to Imfinzi 1500mg followed by Imfinzi every four weeks versus sorafenib, a standard-of-care multi-kinase inhibitor.

The trial included a total of 1,324 patients with unresectable, advanced HCC who had not been treated with prior systemic therapy and were not eligible for locoregional therapy (treatment localised to the liver and surrounding tissue).

The trial was conducted in 181 centres across 16 countries, including in the US, Canada, Europe, South America and Asia. The primary endpoint was overall survival (OS) for the combination versus sorafenib and key secondary endpoints included OS for Imfinzi versus sorafenib, objective response rate and progression-free survival (PFS) for the combination and for Imfinzi alone.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi was recently approved to treat patients with advanced biliary tract cancer in the US based on results from the TOPAZ-1 Phase III trial. It is the only approved immunotherapy in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiotherapy and is the global standard of care in this setting based on the PACIFIC Phase III trial.

Imfinzi is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage small cell lung cancer (ES-SCLC) based on the CASPIAN Phase III trial. In 2021, updated results from the CASPIAN trial showed Imfinzi plus chemotherapy tripled patient survival at three years versus chemotherapy alone.

Imfinzi is also approved for previously treated patients with advanced bladder cancer in several countries.

Since the first approval in May 2017, more than 100,000 patients have been treated with Imfinzi.

As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several gastrointestinal (GI) cancers, ovarian cancer, endometrial cancer, and other solid tumours.

Imfinzi combinations have also demonstrated clinical benefit in metastatic NSCLC in the POSEIDON Phase III trial.

Imjudo
Imjudo (tremelimumab) is a human monoclonal antibody that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Imjudo blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death.

Beyond HIMALAYA, Imjudo is being tested in combination with Imfinzi across multiple tumour types including locoregional HCC (EMERALD-3), SCLC (ADRIATIC) and bladder cancer (VOLGA and NILE).

Imjudo is also under review by global regulatory authorities in combination with Imfinzi and chemotherapy in 1st-line metastatic NSCLC based on the results of the POSEIDON Phase III trial, which showed the addition of a short course of Imjudo to Imfinzi plus chemotherapy improved both overall and progression-free survival compared to chemotherapy alone.

AstraZeneca in GI cancers
AstraZeneca has a broad development programme for the treatment of GI cancers across several medicines spanning a variety of tumour types and stages of disease. In 2020, GI cancers collectively represented approximately 5.1 million new diagnoses leading to approximately 3.6 million deaths.⁹

Within this programme, the Company is committed to improving outcomes in gastric, liver, biliary tract, oesophageal, pancreatic, and colorectal cancers.

Imfinzi (durvalumab) is being assessed in combinations in oesophageal and gastric cancers in an extensive development programme spanning early to late-stage disease across settings.

The Company aims to understand the potential of Enhertu (trastuzumab deruxtecan), a HER2-directed antibody drug conjugate, in the two most common GI cancers, colorectal and gastric cancers. Enhertu is jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

Lynparza (olaparib) is a first-in-class PARP inhibitor with a broad and advanced clinical trial programme across multiple GI tumour types including pancreatic and colorectal cancers. Lynparza is developed and commercialised in collaboration with MSD (Merck & Co., Inc. inside the US and Canada).

AstraZeneca in immuno-oncology (IO)
Immunotherapy is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s immuno-oncology (IO) portfolio is anchored in immunotherapies that have been designed to overcome evasion of the anti-tumour immune response. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumour types.

The Company is pursuing a comprehensive clinical trial programme that includes Imfinzi as a single treatment and in combination with Imjudo (tremelimumab) and other novel antibodies in multiple tumour types, stages of disease, and lines of treatment, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient.

In addition, the ability to combine the IO portfolio with radiation, chemotherapy, and targeted small molecules from across AstraZeneca’s oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

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Mechanism of action

Tremelimumab aims to stimulate an immune system attack on tumors. Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism (immune checkpoint) that interrupts this destruction. Tremelimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy the cancer cells.^[3] This is immune checkpoint blockade.

Tremelimumab binds to the protein CTLA-4, which is expressed on the surface of activated T lymphocytes and inhibits the killing of cancer cells. Tremelimumab blocks the binding of the antigen-presenting cell ligands B7.1 and B7.2 to CTLA-4, resulting in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation; subsequently, B7.1 or B7.2 may interact with another T-cell surface receptor protein, CD28, resulting in a B7-CD28-mediated T-cell activation unopposed by B7-CTLA-4-mediated inhibition.

Unlike Ipilimumab (another fully human anti-CTLA-4 monoclonal antibody), which is an IgG1 isotype, tremelimumab is an IgG2 isotype.^[4]^[5]

Clinical trials

Melanoma

Phase 1 and 2 clinical studies in metastatic melanoma showed some responses.^[6] However, based on early interim analysis of phase III data, Pfizer designated tremelimumab as a failure and terminated the trial in April 2008.^[1]^[7]

However, within a year, the survival curves showed separation of the treatment and control groups.^[8] The conventional Response Evaluation Criteria in Solid Tumors (RECIST) may underrepresent the merits of immunotherapies. Subsequent immunotherapy trials (e.g. ipilimumab) have used the Immune-Related Response Criteria (irRC) instead.

Mesothelioma

Although it was designated in April 2015 as orphan drug status in mesothelioma,^[9] tremelimumab failed to improve lifespan in the phase IIb DETERMINE trial, which assessed the drug as a second or third-line treatment for unresectable malignant mesothelioma.^[10]^[11]

Non-small cell lung cancer

In a phase III trial, AstraZeneca paired tremelimumab with a PD-L1 inhibitor, durvalumab, for the first-line treatment of non-small cell lung cancer.^[12] The trial was conducted across 17 countries, and in July 2017, AstraZeneca announced that it had failed to meet its primary endpoint of progression-free survival.^[13]

References

^ Jump up to:^a ^b “Pfizer Announces Discontinuation of Phase III Clinical Trial for Patients with Advanced Melanoma”. Pfizer.com. 1 April 2008. Retrieved 5 December 2015.
^ Mechanism of Pathway: CTLA-4 Inhibition^{[permanent dead link]}
^ Antoni Ribas (28 June 2012). “Tumor immunotherapy directed at PD-1”. New England Journal of Medicine. 366 (26): 2517–9. doi:10.1056/nejme1205943. PMID 22658126.
^ Tomillero A, Moral MA (October 2008). “Gateways to clinical trials”. Methods Find Exp Clin Pharmacol. 30 (8): 643–72. doi:10.1358/mf.2008.30.5.1236622. PMID 19088949.
^ Poust J (December 2008). “Targeting metastatic melanoma”. Am J Health Syst Pharm. 65 (24 Suppl 9): S9–S15. doi:10.2146/ajhp080461. PMID 19052265.
^ Reuben, JM; et al. (1 Jun 2006). “Biologic and immunomodulatory events after CTLA-4 blockade with tremelimumab in patients with advanced malignant melanoma”. Cancer. 106 (11): 2437–44. doi:10.1002/cncr.21854. PMID 16615096. S2CID 751366.
^ A. Ribas, A. Hauschild, R. Kefford, C. J. Punt, J. B. Haanen, M. Marmol, C. Garbe, J. Gomez-Navarro, D. Pavlov and M. Marsha (May 20, 2008). “Phase III, open-label, randomized, comparative study of tremelimumab (CP-675,206) and chemotherapy (temozolomide [TMZ] or dacarbazine [DTIC]) in patients with advanced melanoma”. Journal of Clinical Oncology. 26 (15S): LBA9011. doi:10.1200/jco.2008.26.15_suppl.lba9011.^{[permanent dead link]}
^ M.A. Marshall, A. Ribas, B. Huang (May 2010). “Evaluation of baseline serum C-reactive protein (CRP) and benefit from tremelimumab compared to chemotherapy in first-line melanoma”. Journal of Clinical Oncology. 28 (15S): 2609. doi:10.1200/jco.2010.28.15_suppl.2609.^{[permanent dead link]}
^ FDA Grants AstraZeneca’s Tremelimumab Orphan Drug Status for Mesothelioma [1]
^ “Tremelimumab Fails Mesothelioma Drug Trial”. Archived from the original on 2016-03-06. Retrieved 2016-03-06.
^ AZ’ tremelimumab fails in mesothelioma trial
^ “AstraZeneca’s immuno-oncology combo fails crucial Mystic trial in lung cancer | FierceBiotech”.
^ “AstraZeneca reports initial results from the ongoing MYSTIC trial in Stage IV lung cancer”.

///////////Tremelimumab, Imjudo, APPROVALS 2022, FDA 2022, PEPTIDE, CP 675206, Antineoplastic, Immune checkpoint inhibitor, Anti-CTLA4 antibody

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Futibatinib

October 7, 2022 8:35 am / Leave a comment

Futibatinib

フチバチニブ

Formula	C22H22N6O3
CAS	1448169-71-8
Mol weight	418.4485

2022/9/30 FDA APPROVED, Lytgobi

Antineoplastic, Receptor tyrosine kinase inhibitor
Disease	Cholangiocarcinoma (FGFR2 gene fusion)

1-[(3S)-3-[4-amino-3-[2-(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one

TAS-120, TAS 120, TAS120; Futibatinib

Futibatinib, also known as TAS-120 is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) with potential antineoplastic activity. FGFR inhibitor TAS-120 selectively and irreversibly binds to and inhibits FGFR, which may result in the inhibition of both the FGFR-mediated signal transduction pathway and tumor cell proliferation, and increased cell death in FGFR-overexpressing tumor cells. FGFR is a receptor tyrosine kinase essential to tumor cell proliferation, differentiation and survival and its expression is upregulated in many tumor cell types.

SYN

Patent Document 1: International Publication WO 2007/087395 pamphlet
Patent Document 2: International Publication WO 2008/121742 pamphlet
Patent Document 3: International Publication WO 2010/043865 pamphlet
Patent Document 4: International Publication WO 2011/115937 pamphlet

Unlicensed Document 1 : J. Clin. Oncol. 24, 3664-3671 (2006)
Non-licensed Document 2: Mol. Cancer Res. 3, 655-667 (2005)
Non-licensed Document 3: Cancer Res. 70, 2085-2094 (2010)
Non-licensed Document 4: Clin. Cancer Res. 17, 6130-6139 (2011)
Non-licensed Document 5: Nat. Med. 1, 27-31 (1995)

WO2020095452

WO2020096042

WO2020096050

WO2019034075

WO2015008844

WO2015008839

WO2013108809

SYN

US9108973

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019034075&_cid=P10-L8Y7CQ-04809-1

Reference Example 1: WXR1

Compound WXR1 was synthesized according to the route reported in patent WO2015008844. ¹ H NMR(400MHz, DMSO-d ₆ )δ8.40(d,J=3.0Hz,1H),6.93(d,J=2.5Hz,2H),6.74-6.52(m,2H),6.20-6.16( m,1H), 5.74-5.69(m,1H), 5.45-5.61(m,1H), 4.12-3.90(m,2H), 3.90-3.79(m,8H), 2.47-2.30(m,2H). MS m/z: 419.1[M+H] ⁺

PAPER

Bioorg Med Chem, March 2013, Vol.21, No.5, pp.1180-1189

SYN

WO2015008844

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015008844&_cid=P10-L8Y448-45990-1

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020095452&_cid=P10-L8Y49P-48096-1

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Clinical data

Trade names	Lytgobi
Other names	TAS-120
License data	US DailyMed: Futibatinib
Routes of administration	By mouth
Drug class	Antineoplastic
ATC code	L01EN04 (WHO)
Legal status
Legal status	US: ℞-only ^[1]
Identifiers
show IUPAC name
CAS Number	1448169-71-8
PubChem CID	71621331
IUPHAR/BPS	9786
DrugBank	DB15149
ChemSpider	58877816
UNII	4B93MGE4AL
KEGG	D11725
ChEMBL	ChEMBL3701238
PDB ligand	TZ0 (PDBe, RCSB PDB)
Chemical and physical data
Formula	C₂₂H₂₂N₆O₃
Molar mass	418.457 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI

Futibatinib, sold under the brand name Lytgobi, is a medication used for the treatment of cholangiocarcinoma (bile duct cancer).^[1]^[2] It is a kinase inhibitor.^[1]^[3] It is taken by mouth.^[1]

Futibatinib was approved for medical use in the United States in September 2022.^[1]^[2]^[4]

Medical uses

Futibatinib is indicated for the treatment of adults with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements.^[1]^[2]

Names

Futibatinib is the international nonproprietary name (INN).^[5]

References

^ Jump up to:^a ^b ^c ^d ^e ^f “Lytgobi (futibatinib) tablets, for oral use” (PDF). Archived (PDF) from the original on 4 October 2022. Retrieved 4 October 2022.
^ Jump up to:^a ^b ^c https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2022/214801Orig1s000ltr.pdf Archived 4 October 2022 at the Wayback Machine This article incorporates text from this source, which is in the public domain.
^ “Lytgobi (Futibatinib) FDA Approval History”. Archived from the original on 4 October 2022. Retrieved 4 October 2022.
^ “FDA Approves Taiho’s Lytgobi (futibatinib) Tablets for Previously Treated, Unresectable, Locally Advanced or Metastatic Intrahepatic Cholangiocarcinoma” (Press release). Taiho Oncology. 30 September 2022. Archived from the original on 4 October 2022. Retrieved 4 October 2022 – via PR Newswire.
^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81”. WHO Drug Information. 33 (1). hdl:10665/330896.

External links

“Futibatinib”. Drug Information Portal. U.S. National Library of Medicine.

//////////Futibatinib, Lytgobi, FDA 2022, APPROVALS 2022, フチバチニブ , ANTINEOPLASTIC, TAS 120

C=CC(N1C[C@@H](N2N=C(C#CC3=CC(OC)=CC(OC)=C3)C4=C(N)N=CN=C42)CC1)=O

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Ropeginterferon alfa-2b

November 25, 2021 2:41 am / Leave a comment

PCDLPQTHSL GSRRTLMLLA QMRRISLFSC LKDRHDFGFP QEEFGNQFQK AETIPVLHEM
IQQIFNLFST KDSSAAWDET LLDKFYTELY QQLNDLEACV IQGVGVTETP LMKEDSILAV
RKYFQRITLY LKEKKYSPCA WEVVRAEIMR SFSLSTNLQE SLRSKE
(Disulfide bridge: 2-99, 30-139)

Ropeginterferon alfa-2b

AOP2014

CAS 1335098-50-4

UNII981TME683S

FDA APPROVED, 2021/11/12, BESREMI

PEPTIDE, Antineoplastic, Antiviral

Polycythemia vera (PV) is the most common Philadelphia chromosome-negative myeloproliferative neoplasm (MPN), characterized by increased hematocrit and platelet/leukocyte counts, an increased risk for hemorrhage and thromboembolic events, and a long-term propensity for myelofibrosis and leukemia.^1,2 Interferon alfa-2b has been used for decades to treat PV but requires frequent dosing and is not tolerated by all patients.² Ropeginterferon alfa-2b is a next-generation mono-pegylated type I interferon produced from proline-IFN-α-2b in Escherichia coli that has high tolerability and a long half-life.^4,6 Ropeginterferon alfa-2b has shown efficacy in PV in in vitro and in vivo models and clinical trials.^3,4

Ropeginterferon alfa-2b was approved by the FDA on November 12, 2021, and is currently marketed under the trademark BESREMi by PharmaEssentia Corporation.⁶

Ropeginterferon alfa-2b, sold under the brand name Besremi, is a medication used to treat polycythemia vera.^[1]^[2]^[3]^[4] It is an interferon.^[1]^[3] It is given by injection.^[1]^[3]

The most common side effects include low levels of white blood cells and platelets (blood components that help the blood to clot), muscle and joint pain, tiredness, flu-like symptoms and increased blood levels of gamma-glutamyl transferase (a sign of liver problems).^[3] Ropeginterferon alfa-2b can cause liver enzyme elevations, low levels of white blood cells, low levels of platelets, joint pain, fatigue, itching, upper airway infection, muscle pain and flu-like illness.^[2] Side effects may also include urinary tract infection, depression and transient ischemic attacks (stroke-like attacks).^[2]

It was approved for medical use in the European Union in February 2019,^[3] and in the United States in November 2021.^[2]^[5] Ropeginterferon alfa-2b is the first medication approved by the U.S. Food and Drug Administration (FDA) to treat polycythemia vera that people can take regardless of their treatment history, and the first interferon therapy specifically approved for polycythemia vera.^[2]

https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-rare-blood-disease#:~:text=FDA%20NEWS%20RELEASE-,FDA%20Approves%20Treatment%20for%20Rare%20Blood%20Disease,FDA%2DApproved%20Option%20Patients%20Can%20Take%20Regardless%20of%20Previous%20Therapies,-ShareFor Immediate Release:November 12, 2021

Today, the U.S. Food and Drug Administration approved Besremi (ropeginterferon alfa-2b-njft) injection to treat adults with polycythemia vera, a blood disease that causes the overproduction of red blood cells. The excess cells thicken the blood, slowing blood flow and increasing the chance of blood clots.

“Over 7,000 rare diseases affect more than 30 million people in the United States. Polycythemia vera affects approximately 6,200 Americans each year,” said Ann Farrell, M.D., director of the Division of Non-Malignant Hematology in the FDA’s Center for Drug Evaluation and Research. “This action highlights the FDA’s commitment to helping make new treatments available to patients with rare diseases.”

Besremi is the first FDA-approved medication for polycythemia vera that patients can take regardless of their treatment history, and the first interferon therapy specifically approved for polycythemia vera.

Treatment for polycythemia vera includes phlebotomies (a procedure that removes excess blood cells though a needle in a vein) as well as medicines to reduce the number of blood cells; Besremi is one of these medicines. Besremi is believed to work by attaching to certain receptors in the body, setting off a chain reaction that makes the bone marrow reduce blood cell production. Besremi is a long-acting drug that patients take by injection under the skin once every two weeks. If Besremi can reduce excess blood cells and maintain normal levels for at least one year, then dosing frequency may be reduced to once every four weeks.

The effectiveness and safety of Besremi were evaluated in a multicenter, single-arm trial that lasted 7.5 years. In this trial, 51 adults with polycythemia vera received Besremi for an average of about five years. Besremi’s effectiveness was assessed by looking at how many patients achieved complete hematological response, which meant that patients had a red blood cell volume of less than 45% without a recent phlebotomy, normal white cell counts and platelet counts, a normal spleen size, and no blood clots. Overall, 61% of patients had a complete hematological response.

Besremi can cause liver enzyme elevations, low levels of white blood cells, low levels of platelets, joint pain, fatigue, itching, upper airway infection, muscle pain and flu-like illness. Side effects may also include urinary tract infection, depression and transient ischemic attacks (stroke-like attacks).

Interferon alfa products like Besremi may cause or worsen neuropsychiatric, autoimmune, ischemic (not enough blood flow to a part of the body) and infectious diseases, which could lead to life-threatening or fatal complications. Patients who must not take Besremi include those who are allergic to the drug, those with a severe psychiatric disorder or a history of a severe psychiatric disorder, immunosuppressed transplant recipients, certain patients with autoimmune disease or a history of autoimmune disease, and patients with liver disease.

People who could be pregnant should be tested for pregnancy before using Besremi due to the risk of fetal harm.

Besremi received orphan drug designation for this indication. Orphan drug designation provides incentives to assist and encourage drug development for rare diseases.

The FDA granted the approval of Besremi to PharmaEssentia Corporation.

Medical uses

In the European Union, ropeginterferon alfa-2b is indicated as monotherapy in adults for the treatment of polycythemia vera without symptomatic splenomegaly.^[3] In the United States it is indicated for the treatment of polycythemia vera.^[1]^[2]^[5]

History

The effectiveness and safety of ropeginterferon alfa-2b were evaluated in a multicenter, single-arm trial that lasted 7.5 years.^[2] In this trial, 51 adults with polycythemia vera received ropeginterferon alfa-2b for an average of about five years.^[2] The effectiveness of ropeginterferon alfa-2b was assessed by looking at how many participants achieved complete hematological response, which meant that participants had a red blood cell volume of less than 45% without a recent phlebotomy, normal white cell counts and platelet counts, a normal spleen size, and no blood clots.^[2] Overall, 61% of participants had a complete hematological response.^[2] The U.S. Food and Drug Administration (FDA) granted the application for Ropeginterferon_alfa-2b orphan drug designation and granted the approval of Besremi to PharmaEssentia Corporation^[2]

REF

Bartalucci N, Guglielmelli P, Vannucchi AM: Polycythemia vera: the current status of preclinical models and therapeutic targets. Expert Opin Ther Targets. 2020 Jul;24(7):615-628. doi: 10.1080/14728222.2020.1762176. Epub 2020 May 18. [Article]
How J, Hobbs G: Use of Interferon Alfa in the Treatment of Myeloproliferative Neoplasms: Perspectives and Review of the Literature. Cancers (Basel). 2020 Jul 18;12(7). pii: cancers12071954. doi: 10.3390/cancers12071954. [Article]
Verger E, Soret-Dulphy J, Maslah N, Roy L, Rey J, Ghrieb Z, Kralovics R, Gisslinger H, Grohmann-Izay B, Klade C, Chomienne C, Giraudier S, Cassinat B, Kiladjian JJ: Ropeginterferon alpha-2b targets JAK2V617F-positive polycythemia vera cells in vitro and in vivo. Blood Cancer J. 2018 Oct 4;8(10):94. doi: 10.1038/s41408-018-0133-0. [Article]
Gisslinger H, Zagrijtschuk O, Buxhofer-Ausch V, Thaler J, Schloegl E, Gastl GA, Wolf D, Kralovics R, Gisslinger B, Strecker K, Egle A, Melchardt T, Burgstaller S, Willenbacher E, Schalling M, Them NC, Kadlecova P, Klade C, Greil R: Ropeginterferon alfa-2b, a novel IFNalpha-2b, induces high response rates with low toxicity in patients with polycythemia vera. Blood. 2015 Oct 8;126(15):1762-9. doi: 10.1182/blood-2015-04-637280. Epub 2015 Aug 10. [Article]
EMA Approved Products: Besremi (ropeginterferon alfa-2b ) solution for injection [Link]
FDA Approved Drug Products: BESREMi (ropeginterferon alfa-2b-njft) injection [Link]

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References

^ Jump up to:^a ^b ^c ^d ^e https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761166s000lbl.pdf
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l “FDA Approves Treatment for Rare Blood Disease”. U.S. Food and Drug Administration (FDA) (Press release). 12 November 2021. Retrieved 12 November 2021. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Besremi EPAR”. European Medicines Agency (EMA). Retrieved 14 November 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ Wagner SM, Melchardt T, Greil R (March 2020). “Ropeginterferon alfa-2b for the treatment of patients with polycythemia vera”. Drugs of Today. Barcelona, Spain. 56 (3): 195–202. doi:10.1358/dot.2020.56.3.3107706. PMID 32282866. S2CID 215758794.
^ Jump up to:^a ^b “U.S. FDA Approves Besremi (ropeginterferon alfa-2b-njft) as the Only Interferon for Adults With Polycythemia Vera” (Press release). PharmaEssentia. 12 November 2021. Retrieved 14 November 2021 – via Business Wire.

External links

“Ropeginterferon alfa-2b”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT01193699 for “Safety Study of Pegylated Interferon Alpha 2b to Treat Polycythemia Vera (PEGINVERA)” at ClinicalTrials.gov
Clinical trial number NCT02218047 for “AOP2014 vs. BAT in Patients With Polycythemia Vera Who Previously Participated in the PROUD-PV Study. (CONTI-PV)” at ClinicalTrials.gov

Clinical data
Trade names	Besremi
Other names	AOP2014, ropeginterferon alfa-2b-njft
License data	EU EMA: by INNUS DailyMed: Ropeginterferon_alfa
Pregnancy category	Contraindicated
Routes of administration	Subcutaneous
Drug class	Interferon
ATC code	L03AB15 (WHO)
Legal status
Legal status	US: ℞-only ^[1]^[2]EU: Rx-only ^[3]
Identifiers
CAS Number	1335098-50-4
DrugBank	DB15119
UNII	981TME683S
KEGG	D11027

/////////Ropeginterferon alfa-2b, FDA 2021, APPROVALS 2021, BESREMI, PEPTIDE, Antineoplastic, Antiviral, AOP 2014, PharmaEssentia

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Tisotumab vedotin

October 4, 2021 9:31 am / Leave a comment

A first-in-human antibody–drug conjugate: Hope for patients with advanced solid tumours? | Immunopaedia

Tisotumab vedotin

チソツマブベドチン (遺伝子組換え)Immunoglobulin G1, anti-(human blood-coagulation factor III) (human monoclonal HuMax-TF heavy chain), disulfide with human monoclonal HuMax-TF κ-chain, dimer, tetrakis(thioether) with N-[[[4-[[N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1-oxohexyl]-L-valyl-N⁵-(aminocarbonyl)-L-ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-L-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide

HuMax-TF-ADC
Immunoglobulin G1, anti-(human tissue factor) (human monoclonal HuMax-TF heavy chain), disulfide with human monoclonal HuMax-TF κ-chain, dimer, tetrakis(thioether) with N-[[[4-[[N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1-oxohexyl]-L-valyl-N⁵-(aminocarbonyl)-L-ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-L-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide

Protein Sequence

Sequence Length: 1324, 448, 448, 214, 214multichain; modified (modifications unspecified)

Formula	C6418H9906N1710O2022S44.(C68H106N11O15)n
Efficacy	Antineoplastic
Disease	Cervical cancer
Comment	Antibody-drug conjugateCAS:1418731-10-8

HuMax-TF-ADC
Tisotumab vedotin
Tisotumab vedotin [WHO-DD]
UNII-T41737F88A
WHO 10148

US FDA APPROVED 2021/9/20 , TIVDAK

25 Great American USA Animated Flags Gifs

FDA grants accelerated approval to tisotumab vedotin-tftv for recurrent or metastatic cervical cancer……….. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tisotumab-vedotin-tftv-recurrent-or-metastatic-cervical-cancer

On September 20, 2021, the Food and Drug Administration granted accelerated approval to tisotumab vedotin-tftv (Tivdak, Seagen Inc.), a tissue factor-directed antibody and microtubule inhibitor conjugate, for adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

Approval was based on innovaTV 204, an open-label, multicenter, single-arm clinical trial (NCT03438396). Efficacy was evaluated in 101 patients with recurrent or metastatic cervical cancer who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including at least one prior platinum-based chemotherapy regimen. Sixty-nine percent of patients had received bevacizumab as part of prior systemic therapy. Patients received tisotumab vedotin-tftv 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity.

The main efficacy outcome measures were confirmed objective response rate (ORR) as assessed by an independent review committee (IRC) using RECIST v1.1 and duration of response (DOR). The ORR was 24% (95% CI: 15.9%, 33.3%) with a median response duration of 8.3 months (95% CI: 4.2, not reached).

The most common adverse reactions (≥25%), including laboratory abnormalities, were hemoglobin decreased, fatigue, lymphocytes decreased, nausea, peripheral neuropathy, alopecia, epistaxis, conjunctival adverse reactions, hemorrhage, leukocytes decreased, creatinine increased, dry eye, prothrombin international normalized ratio increased, activated partial thromboplastin time prolonged, diarrhea, and rash. Product labeling includes a boxed warning for ocular toxicity.

The recommended dose is 2 mg/kg (up to a maximum of 200 mg for patients ≥100 kg) given as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

View full prescribing information for Tivdak.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

A fully human monoclonal antibody specific for tissue factor conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable valine-citrulline linker.

Tisotumab vedotin, sold under the brand name Tivdak is a human monoclonal antibody used to treat cervical cancer.^[1]

Tisotumab vedotin was approved for medical use in the United States in September 2021.^[1]^[2]

Tisotumab vedotin is the international nonproprietary name (INN).^[3]

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References

^ Jump up to:^a ^b ^c ^d https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761208s000lbl.pdf
^ “Seagen and Genmab Announce FDA Accelerated Approval for Tivdak (tisotumab vedotin-tftv) in Previously Treated Recurrent or Metastatic Cervical Cancer”. Seagen. 20 September 2021. Retrieved 20 September 2021 – via Business Wire.
^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75”. WHO Drug Information. 30 (1): 159–60. hdl:10665/331046.

External links

“Tisotumab vedotin”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03438396 for “A Trial of Tisotumab Vedotin in Cervical Cancer” at ClinicalTrials.gov
Clinical trial number NCT03245736 for “Tisotumab Vedotin Continued Treatment in Patients With Solid Tumors” at ClinicalTrials.gov
Clinical trial number NCT02001623 for “Tisotumab Vedotin (HuMax-TF-ADC) Safety Study in Patients With Solid Tumors” at ClinicalTrials.gov
Clinical trial number NCT02552121 for “Tisotumab Vedotin (HuMax-TF-ADC) Safety Study in Patients With Solid Tumors” at ClinicalTrials.gov

Monoclonal antibody
Type	Whole antibody
Source	Human
Target	Tissue factor (TF)
Clinical data
Trade names	Tivdak
Other names	Tisotumab vedotin-tftv
License data	US DailyMed: Tisotumab_vedotin
Pregnancy category	Contraindicated^[1]
Routes of administration	Intravenous
Drug class	Antineoplastic
ATC code	None
Legal status
Legal status	US: ℞-only ^[1]
Identifiers
CAS Number	1418731-10-8
UNII	T41737F88A
KEGG	D11814

//////////Tisotumab vedotin, チソツマブベドチン (遺伝子組換え) , FDA 2021, APPROVALS 2021, Antineoplastic, CERVICAL CANCER, CANCER, MONOCLONAL ANTIBODY, UNII-T41737F88A, WHO 10148

Pepinemab, VX 15

August 23, 2021 9:10 am / Leave a comment

(Heavy chain)
QVQLVQSGAE VKKPGSSVKV SCKASGYSFS DYYMHWVRQA PGQGLEWMGQ INPTTGGASY
NQKFKGKATI TVDKSTSTAY MELSSLRSED TAVYYCARYY YGRHFDVWGQ GTTVTVSSAS
TKGPSVFPLA PCSRSTSEST AALGCLVKDY FPEPVTVSWN SGALTSGVHT FPAVLQSSGL
YSLSSVVTVP SSSLGTKTYT CNVDHKPSNT KVDKRVESKY GPPCPPCPAP EFLGGPSVFL
FPPKPKDTLM ISRTPEVTCV VVDVSQEDPE VQFNWYVDGV EVHNAKTKPR EEQFNSTYRV
VSVLTVLHQD WLNGKEYKCK VSNKGLPSSI EKTISKAKGQ PREPQVYTLP PSQEEMTKNQ
VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG SFFLYSRLTV DKSRWQEGNV
FSCSVMHEAL HNHYTQKSLS LSLGK
(Light chain)
DIVMTQSPDS LAVSLGERAT INCKASQSVD YDGDSYMNWY QQKPGQPPKL LIYAASNLES
GVPDRFSGSG SGTDFTLTIS SLQAEDVAVY YCQQSNEDPY TFGQGTKLEI KRTVAAPSVF
IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS GNSQESVTEQ DSKDSTYSLS
STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC
(Disulfide bridge: H22-H96, H132-L218, H145-H201, H224-H’224, H227-H’227, H259-H319, H365-H423, H’22-H’96, H’132-L’218, H’145-H’201, H’259-H’319, H’365-H’423, L23-L92, L138-L198, L’23-L’92, L’138-L’198)

Pepinemab

VX15/2503

Antineoplastic, Anti-human semaphorin 4D antibody

Monoclonal antibody
Treatment of solid tumors, multiple sclerosis and Huntington’s disease

Formula	C6442H9910N1702O2052S48
MOL WGT	145481.0022

Moab VX15/2503
Pepinemab
UNII-BPZ4A29SYE
VX-15
VX15
VX15/2503

Product name	Pepinemab Biosimilar – Anti-SEMA4D mAb – Research Grade
Source	CAS 2097151-87-4
Species	Chimeric,Humanized
Expression system	Mammalian cells

OriginatorVaccinex
DeveloperBristol-Myers Squibb; Children’s Oncology Group; Emory University; Merck KGaA; National Cancer Institute (USA); Teva Pharmaceutical Industries; UCLAs Jonsson Comprehensive Cancer Center; Vaccinex
ClassAntibodies; Antidementias; Antineoplastics; Immunotherapies; Monoclonal antibodies
Mechanism of ActionCD100 antigen inhibitors

Orphan Drug StatusYes – Huntington’s disease
New Molecular EntityYes

Phase IIHuntington’s disease
Phase I/IIAlzheimer’s disease; Non-small cell lung cancer; Osteosarcoma; Solid tumours; Squamous cell cancer
Phase IColorectal cancer; Malignant melanoma; Pancreatic cancer
No development reportedMultiple sclerosis

22 May 2021Pepinemab is still in phase I trials for Colorectal cancer and Pancreatic cancer in USA (NCT03373188)
17 May 2021Phase-I/II clinical trials in Squamous cell cancer (Combination therapy, Late-stage disease, Metastatic disease, Recurrent, Second-line therapy or greater) in USA (IV) (NCT04815720)
17 May 2021Vaccinex plans a phase I/II trial for Alzheimer’s disease (In volunteers), in H2 2021

Semaphorin 4D (SEMA4D) plays a role in multiple cellular processes that contribute to the pathophysiology of neuroinflammatory/neurodegenerative diseases. SEMA4D is, therefore, a uniquely promising target for therapeutic development.

Pepinemab is a novel monoclonal antibody that blocks the activity of SEMA4D, and preclinical testing has demonstrated the beneficial effects of anti-SEMA4D treatment in a variety of neurodegenerative disease models. Vaccinex is committed to the development of this potentially important antibody that has the potential to help people with different neurodegenerative disorders that share common mechanisms of pathology.

Note: Pepinemab (VX15/2503) is an investigational drug currently in clinical studies. It has not been demonstrated to be safe and effective for any disease indication. There is no guarantee that pepinemab (VX15/2503) will be approved for the treatment of any disease by the U.S. Food and Drug Administration or by any other health authority worldwide.

////////////////////Pepinemab, VX15/2503, vx 15, Antineoplastic, Anti-human semaphorin 4D antibody, Monoclonal antibody, solid tumors, multiple sclerosis, Huntington’s disease, PEPTIDES

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Belzutifan

August 19, 2021 2:45 am / Leave a comment

3-(((1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile.png

Belzutifan

CAS 1672668-24-4

383.34 g·mol^{−1 C₁₇H₁₂F₃NO₄S}

3-[[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1H-inden-4-yl]oxy]-5-fluorobenzonitrile

MK-6482, PT-2977, UNII-7K28NB895L, 7K28NB895L

3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile

3-{[(1s,2s,3r)-2,3-Difluoro-1-Hydroxy-7-(Methylsulfonyl)-2,3-Dihydro-1h-Inden-4-Yl]oxy}-5-Fluorobenzonitrile

GTPL11251, PT 2977 [WHO-DD], BDBM373040

FDA APPROVED 8/13/2021, Welireg

To treat von Hippel-Lindau disease under certain conditions

EMA Drug Information

Disease/Condition	Treatment of von Hippel-Lindau disease
Active Substance	3-(((1S,2S,3R)-2,3-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile
Status of Orphan Designation	Positive
Decision Date	2020-08-21

FDA approves belzutifan for cancers associated with von Hippel-Lindau disease

On August 13, 2021, the Food and Drug Administration approved belzutifan (Welireg, Merck), a hypoxia-inducible factor inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.

Belzutifan was investigated in the ongoing Study 004 (NCT03401788), an open-label clinical trial in 61 patients with VHL-associated RCC (VHL-RCC) diagnosed based on a VHL germline alteration and with at least one measurable solid tumor localized to the kidney. Enrolled patients had other VHL-associated tumors, including CNS hemangioblastomas and pNET. Patients received belzutifan 120 mg once daily until disease progression or unacceptable toxicity.

The primary efficacy endpoint was overall response rate (ORR) measured by radiology assessment, as assessed by an independent review committee using RECIST v1.1. Additional efficacy endpoints included duration of response (DoR), and time- to- response (TTR). An ORR of 49% (95% CI:36, 62) was reported in patients with VHL-associated RCC. All patients with VHL-RCC with a response were followed for a minimum of 18 months from the start of treatment. The median DoR was not reached; 56% of responders had DoR ≥ 12 months and a median TTR of 8 months. In patients with other VHL-associated non-RCC tumors, 24 patients with measurable CNS hemangioblastomas had an ORR of 63% and 12 patients with measurable pNET had an ORR of 83%. Median DoR was not reached, with 73% and 50% of patients having response durations ≥ 12 months for CNS hemangioblastomas and pNET, respectively.

The most common adverse reactions, including laboratory abnormalities, reported in ≥ 20% of patients who received belzutifan were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Anemia and hypoxia from belzutifan use can be severe. In Study 004, anemia occurred in 90% of patients and 7% had Grade 3 anemia. Patients should be transfused as clinically indicated. The use of erythropoiesis stimulating agents for treatment of anemia is not recommended in patients treated with belzutifan. In Study 004, hypoxia occurred in 1.6% of patients. Belzutifan can render some hormonal contraceptives ineffective, and belzutifan exposure during pregnancy can cause embryo-fetal harm.

The recommended belzutifan dosage is 120 mg administered orally once daily with or without food.
View full prescribing information for Welireg.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA), Health Canada, and the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom. The application reviews are ongoing at the other regulatory agencies.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, as well as the Assessment Aid and the Product Quality Assessment Aid, voluntary submissions from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately 1 month ahead of the FDA goal date.

This application was granted priority review for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Belzutifan, sold under the brand name Welireg, is a medication used for the treatment of von Hippel–Lindau disease-associated renal cell carcinoma.^[1]^[2]^[3]^[4]^[5]^[6] It is taken by mouth.^[1]

The most common side effects include decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea.^[2]

Belzutifan is an hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor.^[1]^[2]^[7]

Belzutifan is the first drug to be awarded an “innovation passport” from the UK Medicines and Healthcare products Regulatory Agency (MHRA).^[8]^[4] Belzutifan was approved for medical use in the United States in August 2021.^[2]^[9] Belzutifan is the first hypoxia-inducible factor-2 alpha inhibitor therapy approved in the U.S.^[9]

Medical uses

Belzutifan is indicated for treatment of adults with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.^[2]

PATENT

WO 2019191227

https://patents.google.com/patent/WO2019191227A1/en

PATENT

WO 2015035223

https://patents.google.com/patent/WO2015035223A1/enScheme 9

[01237] 3-r(15,25.3 ?^‘)-2.3-difluoro-l-hvdroxy-7-methylsulfonyl-indan-4- νΠο^χν-5-fluoro-benzonitrile (Compound 289)[01238] Step A: r(15.2/?V4- -cvano-5-fluoro-phenoxy)-2-fluoro-7- methylsulfonyl-indan-l -vH acetate: To a stirred solution of 3-fluoro-5-[(15,27?)-2-fluoro-l – hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile (2.00 g, 5.47 mmol) in DCM (27 mL) was added 4-(dimethylamino)pyridine (0.2 g, 1.64 mmol) and triethylamine (1.53 mL, 10.9 mmol). Acetic anhydride (1.00 mL, 10.9 mmol) was added dropwise at 0 °C under nitrogen. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHC0₃ and brine, dried andconcentrated. The residue was purified by flash chromatography on silica gel (20-40% EtOAc/hexane) to give [(lS,2/?)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl- indan-l-yl] acetate (1.95 g, 87%). LCMS ESI (+) m/z 408 (M+H).[01239] Step B: Γ( 1 .25.35)-3-bromo-4-(3-cvano-5-fluoro-Dhenoxy)-2-fluoro- 7-methylsulfonyl-indan-l-yll acetate and f(15.25,3/?)-3-bromo-4-(3-cyano-5-fluoro- phenoxy)-2-fluoro-7-methylsulfonyl-indan-l -yl1 acetate: To a stirred solution of [(15,2/?)-4- (3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-] -yl] acetate (1.95 g, 4.79 mmol) in 1 ,2-dichloroethane (24 mL) was added N-bromosuccinimide (0.94 g, 5.27 mmol) and 2,2′-azobisisobutyronitrile (8 mg, 0.05 mmol). The reaction mixture was heated at 80 °C for 3 hours. After cooling, the reaction mixture was diluted with DCM, washed with saturated aqueous NaHC0₃ and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (20-30% EtOAc hexane) to give [(lS,2S,3S)-3-bromo- 4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-l-yl] acetate (1 .52 g, 65%). LCMS ESI (+) m/z 486, 488 (M+H). Further elution with 30-50% EtOAc/hexane gave the more polar product [(lS,2S,3/?)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7- methylsulfonyl-indan-l -yl] acetate (0.583 g, 25%). LCMS ESI (+) m/z 486, 488 (M+H). [01240] Step C: rd5.2^.3 V4-(3-cvano-5-fluoro-phenoxy)-2-fluoro-3- hvdroxy-7-methylsulfonyl-indan- 1 -yll acetate: To a combined mixture of [(1 ,25,35)-3- bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-l -yl] acetate and [( 15,2S,3/?)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan- 1 -yl] acetate prepared in Step B (2.05 g, 4.22 mmol) were added 1 ,2-dimethoxyethane (28 mL) and water (0.050 mL) followed by silver perchlorate hydrate (1.42 g, 6.32 mmol). The reaction mixture was heated at 70 °C for 2 hours. After cooling, the reaction mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed with water and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (20-50%) to give [(15,2/?,35)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan- 1 -yl] acetate (0.416 g, 23%) as the less polar product. LCMS ESI (+) m/z 441 (M+NH₄⁺). Further elution with 60% EtOAc/hexane gave [(15,2/?,3R)-4-(3-cyano-5-fluoro-phenoxy)-2- fluoro-3-hydroxy-7-methylsulfonyl-indan-l-yl] acetate (0.58 g, 32 %). LCMS ESI (+) m/z 441 (M+NH₄⁺).[01241] Step D: r(15.25.3/? -4-(3-cvano-5-fluoro-phenoxyV2.3-difluoro-7- methylsulfonyl-indan-l-vH acetate: To a stirred solution of [(15,2/?,35)-4-(3-cyano-5-fluoro- phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-l-yl] acetate (416 mg, 0.98 mmol) in DCM (10 mL) was added (diethylamino)sulfur trifluoride (DAST) (0.26 mL, 2.0 mmol) at – 78 °C under nitrogen. The reaction mixture was allowed to warm to 0 °C and stirred for 15 minutes. The reaction was quenched by saturated aqueous NaHC0₃. The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (20-40% EtOAc/hexane) to give [(15,25,3/?)- 4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-7-methylsulfonyl-indan-l -yl] acetate (310 mg, 74%). LCMS ESI (+) m/z 426 (M+H).[01242] Step E: 3-r(15.25.3^)-2.3-difluoro-l-hvdroxy-7-methylsulfonyl-indan-4-vnoxy-5-fluoro-benzonitrile (Compound 289): Prepared as described in Example 288 Step F substituting [(l ?)-4-(3-cyano-5-fluoro-phenoxy)-3,3-difluoro-7-methylsulfonyl-indan- 1-yl] acetate with [(15,25,3/?)-4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-7-methylsulfonyl- indan-l-yl] acetate. LCMS ESI (+) m/z 384 (M+H); Ή NMR (400 MHz, CDC1₃): δ 8.13 (d, 1H), 7.31-7.25 (m, 1 H), 7.23-7.19 (m, 1 H), 7.14-7.09 (m, 1H), 7.04 (d, 1H), 6.09-5.91 (m, 1 H), 5.87-5.80 (m, 1 H), 5.25-5.05 (m, 1H), 3.32 (s, 3H), 2.95 (d, 1H).
PatentWO 2016145032https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016145032&tab=PCTDESCRIPTIONCOMPD 289

PATENTWO 2016145045WO 2016168510WO 2016057242WO 2019191227

PMID	Publication Date	Title	Journal
31282155	2019-08-08	3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2α (HIF-2α) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma	Journal of medicinal chemistry

Publication Number	Title	Priority Date
WO-2020146758-A1	Methods to treat mitochondrial-associated dysfunctions or diseases	2019-01-10
WO-2020092100-A1	Solid dispersions and pharmaceutical compositions comprising a substituted indane and methods for the preparation and use thereof	2018-10-30
TW-202003430-A	Methods of reducing inflammation of the digestive system with inhibitors of HIF-2-alpha	2018-03-28
WO-2019191227-A1	Methods of reducing inflammation of the digestive system with inhibitors of hif-2-alpha	2018-03-28
US-2019151347-A1	Compositions and methods of modulating hif-2a; to improve muscle generation and repair	2017-11-20

Publication Number	Title	Priority Date	Grant Date
US-2019048421-A1	Biomarkers of response to hif-2-alpha inhibition in cancer and methods for the use thereof	2015-09-21
WO-2017053192-A1	Biomarkers of response to hif-2-alpha inhibition in cancer and methods for the use thereof	2015-09-21
US-10335388-B2	Combination therapy of a HIF-2-alpha inhibitor and an immunotherapeutic agent and uses thereof	2015-04-17	2019-07-02
US-2018140569-A1	Combination therapy of a hif-2-alpha inhibitor and an immunotherapeutic agent and uses thereof	2015-04-17
US-2019282535-A1	Combination therapy of a hif-2-alpha inhibitor and an immunotherapeutic agent and uses thereof	2015-04-17

Publication Number	Title	Priority Date	Grant Date
WO-2016168510-A1	Combination therapy of a hif-2-alpha inhibitor and an immunotherapeutic agent and uses thereof	2015-04-17
US-10786480-B2	Combination therapy of a HIF-2-Î± inhibitor and an immunotherapeutic agent and uses thereof	2015-04-17	2020-09-29
US-10278942-B2	Compositions for use in treating pulmonary arterial hypertension	2015-03-11	2019-05-07
US-10512626-B2	Compositions for use in treating glioblastoma	2015-03-11	2019-12-24
US-2018042884-A1	Compositions for use in treating glioblastoma	2015-03-11

Publication Number	Title	Priority Date	Grant Date
US-2018177754-A1	Compositions for use in treating pulmonary arterial hypertension	2015-03-11
US-2019015377-A1	Compositions for Use in Treating Pulmonary Arterial Hypertension	2015-03-11
WO-2016145032-A1	Compositions for use in treating pulmonary arterial hypertension	2015-03-11
WO-2016145045-A1	Compositions for use in treating glioblastoma	2015-03-11
US-10098878-B2	HIF-2Î± inhibitors for treating iron overload disorders	2014-10-10	2018-10-16

Publication Number	Title	Priority Date	Grant Date
US-2020190031-A1	Aryl ethers and uses thereof	2013-09-09
US-9896418-B2	Aryl ethers and uses thereof	2013-09-09	2018-02-20
US-9908845-B2	Aryl ethers and uses thereof	2013-09-09	2018-03-06
US-9969689-B2	Aryl ethers and uses thereof	2013-09-09	2018-05-15
WO-2015035223-A1	Aryl ethers and uses thereof	2013-09-09

Merck Team Wins 2021 Pete Dunn Award

‎05-17-2021 10:52 AM

The ACS Green Chemistry Institute (GCI) Pharmaceutical Roundtable honors the work of Stephen Dalby, François Lévesque, Cecilia Bottecchia and Jonathan McMullen at Merck with the 2021 Peter J. Dunn Award for Green Chemistry & Engineering Impact in the Pharmaceutical Industry. The team’s innovation is titled, “Greener Manufacturing of Belzutifan (MK-6482) Featuring a Photo-Flow Bromination.”

Belzutifan is an important new drug used in the treatment of cancer and other non-oncology diseases. Acquired by Merck in 2019 through the purchase of Peloton Therapeutics, a new, greener manufacturing process for its synthesis was needed. Over the next 18 months, the team developed a more direct route from commodity chemical to API, employed new reaction conditions, particularly in the oxidation sequence, and incorporated new technology, photo-flow.

Despite this accelerated timeline, the team achieved a five-fold improvement in overall yield with a commensurate 73% reduction in process mass intensity (PMI) compared to the original route. Notably, the Merck team also developed a visible light-initiated radical bromination performed in flow. According to the L.-C. Campeau, Executive Director and Head of Process Chemistry and Discovery Process Chemistry at Merck, this is the “first example of a photo-flow reaction run on manufacturing scale at Merck and represents the linchpin of the synthesis.”

The improved process for Belzutifan, which is expected to launch this year, will reduce the waste associated with its manufacture and is aligned with Merck’s corporate sustainability goals.

“The Merck team delivered an excellent example of the application of innovative technologies to develop a more sustainable synthesis of the pharmaceutically-active compound, Belzutifan,” comments Paul Richardson, Director of Oncology and Chemical Synthesis at Pfizer and Co-Chair of the ACS GCI Pharmaceutical Roundtable. “Using the guiding principles of green chemistry, for example, in the use of catalysis and a relatively benign reaction media, further illustrate the Merck team’s work as worthy of recognition for the 2021 Peter Dunn Award.”

The award will be presented at the June 11 GC&E Friday, part of the 25th Annual Green Chemistry & Engineering Conference. During this session from 10 a.m. – 1 p.m., Stephen Dalby & Jon MacMullen will be discussing the details of this innovative process.

References

^ Jump up to:^a ^b ^c ^d https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215383s000lbl.pdf
^ Jump up to:^a ^b ^c ^d ^e ^f “FDA approves belzutifan for cancers associated with von Hippel-Lindau”. U.S. Food and Drug Administration (FDA). 13 August 2021. Retrieved 13 August 2021. This article incorporates text from this source, which is in the public domain.
^ “Belzutifan”. SPS – Specialist Pharmacy Service. 18 March 2021. Retrieved 25 April 2021.
^ Jump up to:^a ^b “MHRA awards first ‘innovation passport’ under new pathway”. RAPS (Press release). Retrieved 25 April 2021.
^ “Merck Receives Priority Review From FDA for New Drug Application for HIF-2α Inhibitor Belzutifan (MK-6482)” (Press release). Merck. 16 March 2016. Retrieved 25 April 2021 – via Business Wire.
^ “FDA Grants Priority Review to Belzutifan for von Hippel-Lindau Disease–Associated RCC”. Cancer Network. Retrieved 26 April 2021.
^ {{cite journal |vauthors=Choueiri TK, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, McDermott DF, Michaelson MD, Appleman LJ, Thamake S, Perini RF, Zojwalla NJ, Jonasch E | display-authors=6 |title=Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis |journal=Nat Med |volume= |issue= |pages= |date=April 2021 |pmid=33888901 |doi=10.1038/s41591-021-01324-7 }
^ “First Innovation Passport awarded to help support development and access to cutting-edge medicines”. Medicines and Healthcare products Regulatory Agency (MHRA) (Press release). 26 February 2021. Retrieved 14 August 2021.
^ Jump up to:^a ^b “FDA Approves Merck’s Hypoxia-Inducible Factor-2 Alpha (HIF-2α) Inhibitor Welireg (belzutifan) for the Treatment of Patients With Certain Types of Von Hippel-Lindau (VHL) Disease-Associated Tumors” (Press release). Merck. 13 August 2021. Retrieved 13 August 2021 – via Business Wire.

External links

“Belzutifan”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT04195750 for “A Study of Belzutifan (MK-6482) Versus Everolimus in Participants With Advanced Renal Cell Carcinoma (MK-6482-005)” at ClinicalTrials.gov
Clinical trial number NCT03401788 for “A Phase 2 Study of Belzutifan (PT2977, MK-6482) for the Treatment of Von Hippel Lindau (VHL) Disease-Associated Renal Cell Carcinoma (RCC) (MK-6482-004)” at ClinicalTrials.gov

Clinical data

Pronunciation	bell-ZOO-ti-fan
Trade names	Welireg
Other names	MK-6482, PT2977
License data	US DailyMed: Belzutifan
Routes of administration	By mouth
Drug class	Antineoplastic
ATC code	None
Legal status
Legal status	US: ℞-only ^[1]^[2]
Identifiers
show IUPAC name
CAS Number	1672668-24-4^[KEGG]
PubChem CID	117947097
ChemSpider	59053536
UNII	7K28NB895L
KEGG	D11954
ChEMBL	ChEMBL4585668
PDB ligand	72Q (PDBe, RCSB PDB)
Chemical and physical data
Formula	C₁₇H₁₂F₃NO₄S
Molar mass	383.34 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI

/////////Belzutifan, Welireg, FDA 2021, APPROVALS 2021, MK 6482, PT 977, Antineoplastic

CS(=O)(=O)C1=C2C(C(C(C2=C(C=C1)OC3=CC(=CC(=C3)C#N)F)F)F)O

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Tucidinostat, Chidamide

June 29, 2021 6:48 am / Leave a comment

Tucidinostat, Chidamide

ツシジノスタット

2021/6/23 PMDA JAPAN APPROVED,

Hiyasta

Formula	C22H19FN4O2
CAS	1616493-44-7
Mol weight	390.4103

Antineoplastic, Histone deacetylase inhibitor

Chidamide (Epidaza) is a histone deacetylase inhibitor (HDI) developed in China.^[1] It was also known as HBI-8000.^[2] It is a benzamide HDI and inhibits Class I HDAC1, HDAC2, HDAC3, as well as Class IIb HDAC10.^[3]

Chidamide is approved by the Chinese FDA for relapsed or refractory peripheral T-cell lymphoma (PTCL), and has orphan drug status in Japan.^[2]^{[better source needed]} As of April 2015 it is only approved in China.^[1]

Chidamide is being researched as a treatment for pancreatic cancer.^[4]^[5]^[6] However, it is not US FDA approved for the treatment of pancreatic cancer.

Chidamide (Epidaza®), a class I HDAC inhibitor, was discovered and developed by ChipScreen and approved by the CFDA in December 2014 for the treatment of recurrent of refractory peripheral T-cell lymphoma. Chidamide, also known as CS055 and HBI- 8000, is an orally bioavailable benzamide type inhibitor of HDAC isoenzymes class I 1–3, as well as class IIb 10, with potential antineoplastic activity. It selectively binds to and inhibits HDAC, leading to an increase in acetylation levels of histone protein H3.74 This agent also inhibits the expression of signaling kinases in the PI3K/ Akt and MAPK/Ras pathways and may result in cell cycle arrest and the induction of tumor cell apoptosis. Currently, phases I and II clinical trials are underway for the treatment of non-small cell lung cancer and for the treatment of breast cancer, respectively.

Chemical Synthesis

The scalable synthetic approach to chidamide very closely follows the discovery route. The sequence began with the condensation of commercial nicotinaldehyde (52) and malonic acid (53) in a mixture of pyridine and piperidine. Next, activation of acid 54 with N,N0-carbonyldiimidazole (CDI) and subsequent reaction with 4-aminomethyl benzoic acid (55) under basic conditions afforded amide 56 in 82% yield. Finally, activation of 56 with CDI prior to treatment with 4-fluorobenzene- 1,2-diamine (57) and subsequent treatment with TFA and THF yielded chidamide (VIII) in 38% overall yield from 52. However, no publication reported that mono-N-Boc-protected bis-aniline was used to approach Chidamide.

References

^ Jump up to:^a ^b Lowe D (April 2015). “China’s First Homegrown Pharma”. Seeking Alpha.
^ Jump up to:^a ^b “Chipscreen Biosciences Announces CFDA Approval of Chidamide (Epidaza) for PTCLs in China”. PR Newswire Association LLC.
^ “HUYA Bioscience International Grants An Exclusive License For HBI-8000 In Japan And Other Asian Countries To Eisai”. PR Newswire Association LLC. February 2016.
^ Qiao Z, Ren S, Li W, Wang X, He M, Guo Y, et al. (April 2013). “Chidamide, a novel histone deacetylase inhibitor, synergistically enhances gemcitabine cytotoxicity in pancreatic cancer cells”. Biochemical and Biophysical Research Communications. 434 (1): 95–101. doi:10.1016/j.bbrc.2013.03.059. PMID 23541946.
^ Guha M (April 2015). “HDAC inhibitors still need a home run, despite recent approval”. Nature Reviews. Drug Discovery. 14 (4): 225–6. doi:10.1038/nrd4583. PMID 25829268. S2CID 36758974.
^ Wang SS (2015-04-02). “A New Cancer Drug, Made in China”. The Wall Street Journal. Retrieved 13 April 2015.

Clinical data

Trade names	Epidaza
Other names	Tucidinostat
Identifiers
show IUPAC name
CAS Number	1616493-44-7
PubChem CID	9800555
ChemSpider	7976319
UNII	87CIC980Y0
Chemical and physical data
Formula	C₂₂H₁₉FN₄O₂
Molar mass	390.418 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI

/////Tucidinostat, Antineoplastic, Histone deacetylase inhibitor, ツシジノスタット , Epidaza, Chidamide, APPROVALS 2021, JAPAN 2021

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Dostarlimab

May 12, 2021 3:42 am / Leave a comment

(Heavy chain)
EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYDMSWVRQA PGKGLEWVST ISGGGSYTYY
QDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCASPY YAMDYWGQGT TVTVSSASTK
GPSVFPLAPC SRSTSESTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS
LSSVVTVPSS SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP
PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE QFNSTYRVVS
VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS QEEMTKNQVS
LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS
CSVMHEALHN HYTQKSLSLS LGK
(Light chain)
DIQLTQSPSF LSAYVGDRVT ITCKASQDVG TAVAWYQQKP GKAPKLLIYW ASTLHTGVPS
RFSGSGSGTE FTLTISSLQP EDFATYYCQH YSSYPWTFGQ GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H130-L214, H143-H199, H222-H’222, H225-H’225, H257-H317, H363-H421, H’22-H’96, H’130-L’214, H’143-H’199, H’257-H’317, H’363-H’421, L23-L88, L134-L194, L’23-L’88, L’194-L’134)

>Heavy Chain
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISGGGSYTYY
QDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTK
GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP
PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS
CSVMHEALHNHYTQKSLSLSLGK

>Light Chain
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTLHTGVPS
RFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

References:

Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]

Dostarlimab

Immunoglobulin G4, anti-(programmed cell death protein 1 (PDCD1)) (humanized clone ABT1 γ4-chain), disulfide with humanized clone ABT1 κ-chain, dimer

Protein Sequence

Sequence Length: 1314, 443, 443, 214, 214multichain; modified (modifications unspecified)

GSK-4057190
GSK4057190
TSR 042
TSR-042
WBP-285
ANB 011

Formula	C6420H9832N1680O2014S44
CAS	2022215-59-2
Mol weight	144183.6677

Jemperli FDA 2021/4/22 AND EMA 2021/4/21

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Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody medication used for the treatment of endometrial cancer.^[1]^[2]^[3]^[4]

The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation.^[1]^[2] The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased.^[1]^[2]

Dostarlimab is a programmed death receptor-1 (PD-1)–blocking antibody.^[1]^[2]

Dostarlimab was approved for medical use in the United States in April 2021.^[1]^[2]^[5]

NAME	DOSAGE	STRENGTH	ROUTE	LABELLER	MARKETING START	MARKETING END
Jemperli	Injection	50 mg/1mL	Intravenous	GlaxoSmithKline LLC	2021-04-22	Not applicable

Medical uses

Dostarlimab is indicated for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen.^[1]^[2]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC) for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior platinum-containing regimen.

Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors. The efficacy population consisted of 71 patients with dMMR recurrent or advanced endometrial cancer who progressed on or after a platinum-containing regimen. Patients received dostarlimab-gxly, 500 mg intravenously, every 3 weeks for 4 doses followed by 1,000 mg intravenously every 6 weeks.

The main efficacy endpoints were overall response rate (ORR) and duration of response (DOR), as assessed by blinded independent central review (BICR) according to RECIST 1.1. Confirmed ORR was 42.3% (95% CI: 30.6%, 54.6%). The complete response rate was 12.7% and partial response rate was 29.6%. Median DOR was not reached, with 93.3% of patients having durations ≥6 months (range: 2.6 to 22.4 months, ongoing at last assessment).

Serious adverse reactions occurred in 34% of patients receiving dostarlimab-gxly. Serious adverse reactions in >2% of patients included sepsis , acute kidney injury , urinary tract infection , abdominal pain , and pyrexia . The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation. The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased. Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The recommended dostarlimab-gxly dose and schedule (doses 1 through 4) is 500 mg every 3 weeks. Subsequent dosing, beginning 3 weeks after dose 4, is 1,000 mg every 6 weeks until disease progression or unacceptable toxicity. Dostarlimab-gxly should be administered as an intravenous infusion over 30 minutes.

View full prescribing information for Jemperli.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

FDA also approved the VENTANA MMR RxDx Panel as a companion diagnostic device for selecting endometrial cancer patients for treatment with dostarlimab-gxly.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Side effects

Serious adverse reactions in >2% of patients included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and pyrexia.^[1]^[2]

Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.^[1]^[2]

History

Like several other available and experimental monoclonal antibodies, it is a PD-1 inhibitor. As of 2020, it is undergoing Phase I/II and Phase III clinical trials.^[6]^[7]^[8] The manufacturer, Tesaro, announced prelimary successful results from the Phase I/II GARNET study.^[6]^[9]^[10]

In 2020, the GARNET study announced that Dostarlimab was demonstrating potential to treat a subset of women with recurrent or advanced endometrial cancer.^[11]

April 2021, Dostarlimab is approved for the treatment of recurrent or advanced endometrial cancer with deficient mismatch repair (dMMR), which are genetic anomalies abnormalities that disrupt DNA repair.^[12]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC).^[1] Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors.^[1]

Society and culture

Legal status

On 25 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Jemperli, intended for the treatment of certain types of recurrent or advanced endometrial cancer.^[13] The applicant for this medicinal product is GlaxoSmithKline (Ireland) Limited.^[13]

References[

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k “FDA grants accelerated approval to dostarlimab-gxly for dMMR endometri”. U.S. Food and Drug Administration(FDA) (Press release). 22 April 2021. Retrieved 22 April 2021. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ “Jemperli- dostarlimab injection”. DailyMed. Retrieved 28 April 2021.
^ Statement On A Nonproprietary Name Adopted By The USAN Council – Dostarlimab, American Medical Association.
^ World Health Organization (2018). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 119” (PDF). WHO Drug Information. 32 (2).
^ “FDA grants accelerated approval for GSK’s Jemperli (dostarlimab-gxly) for women with recurrent or advanced dMMR endometrial cancer” (Press release). GlaxoSmithKline. 22 April 2021. Retrieved 22 April 2021 – via PR Newswire.
^ Jump up to:^a ^b Clinical trial number NCT02715284 for “A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov
^ Clinical trial number NCT03981796 for “A Study of Dostarlimab (TSR-042) Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Patients With Recurrent or Primary Advanced Endometrial Cancer (RUBY)” at ClinicalTrials.gov
^ Clinical trial number NCT03602859 for “A Phase 3 Comparison of Platinum-Based Therapy With TSR-042 and Niraparib Versus Standard of Care Platinum-Based Therapy as First-Line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer (FIRST)” at ClinicalTrials.gov
^ “Data from GARNET study indicates robust activity of dostarlimab in patients with advanced or recurrent endometrial cancer”. Tesaro (Press release). Retrieved 1 January 2020.
^ Scalea B (28 May 2019). “Dostarlimab Effective in Endometrial Cancer Regardless of MSI Status”. Targeted Oncology. Retrieved 1 January 2020.
^ “GSK Presents New Data from the GARNET Study Demonstrating Potential of Dostarlimab to Treat a Subset of Women with Recurrent or Advanced Endometrial Cancer – Drugs.com MedNews”. Drugs.com. Retrieved 29 April 2020.
^ “FDA Approves New Immunotherapy for Endometrial Cancer”. Medscape. Retrieved 23 April 2021.
^ Jump up to:^a ^b “Jemperli: Pending EC decision”. European Medicines Agency (EMA) (Press release). 25 February 2021. Retrieved 22 April 2021.

External links

“Dostarlimab”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02715284 for “Study of TSR-042, an Anti-programmed Cell Death-1 Receptor (PD-1) Monoclonal Antibody, in Participants With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov

Kaplon H, Muralidharan M, Schneider Z, Reichert JM: Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. doi: 10.1080/19420862.2019.1703531. [Article]
Temrikar ZH, Suryawanshi S, Meibohm B: Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients. Paediatr Drugs. 2020 Apr;22(2):199-216. doi: 10.1007/s40272-020-00382-7. [Article]
Green AK, Feinberg J, Makker V: A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer. Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-7. doi: 10.1200/EDBK_280503. [Article]
Deshpande M, Romanski PA, Rosenwaks Z, Gerhardt J: Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability. Cancers (Basel). 2020 Nov 10;12(11). pii: cancers12113319. doi: 10.3390/cancers12113319. [Article]
FDA Approved Drug Products: Jemperli (dostarlimab-gxly) for intravenous injection [Link]
FDA News Release: FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer [Link]
Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]

Monoclonal antibody
Type	Whole antibody
Source	Humanized
Target	PCDP1
Clinical data
Trade names	Jemperli
Other names	TSR-042, WBP-285, dostarlimab-gxly
License data	US DailyMed: Dostarlimab
Routes of administration	Intravenous
Drug class	Antineoplastic
ATC code	L01XC40 (WHO)
Legal status
Legal status	US: ℞-only ^[1]^[2]
Identifiers
CAS Number	2022215-59-2
PubChem SID	384585344
DrugBank	DB15627
UNII	P0GVQ9A4S5
KEGG	D11366
Chemical and physical data
Formula	C₆₄₂₀H₉₈₃₂N₁₆₉₀O₂₀₁₄S₄₄
Molar mass	144325.73 g·mol⁻¹

/////////Dostarlimab, PEPTIDE, ANTINEOPLASTIC, CANCER, ドスタルリマブ , GSK 4057190, GSK4057190, TSR 042, TSR-042, WBP-285, FDA 2021, EU 2021

Sitravatinib

March 22, 2021 12:17 pm / Leave a comment

Sitravatinib

1-N‘-[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

1-N’-[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

MG-91516

1,1-Cyclopropanedicarboxamide, N-[3-fluoro-4-[[2-[5-[[(2-methoxyethyl)amino]methyl]-2-pyridinyl]thieno[3,2-b]pyridin-7-yl]oxy]phenyl]-N’-(4- fluorophenyl)-

N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

シトラバチニブ; ситраватиниб , سيترافاتينيب , 司曲替尼 ,

Formula	C33H29F2N5O4S
Cas	1123837-84-2
Mol weight	629.6763

MG-516

Sitravatinib (MGCD516)

UNII-CWG62Q1VTB

CWG62Q1VTB

MGCD-516

MGCD516

Antineoplastic, Receptor tyrosine kinase inhibitor

Sitravatinib (MGCD516) is an experimental drug for the treatment of cancer. It is a small molecule inhibitor of multiple tyrosine kinases.

Sitravatinib is being developed by Mirati Therapeutics.^[1]

Ongoing phase II trials include a trial for liposcarcoma,^[2] a combination trial for non-small cell lung cancer,^[3] and a combination trial with nivolumab for renal cell carcinoma.^[4]

Mirati Therapeutics and licensee BeiGene are developing sitravatinib, an oral multitargeted kinase inhibitor which inhibits Eph, Ret, c-Met and VEGF-1, -2 and -3, DDR, Trk, Axl kinases, CHR4q12, TYRO3 and Casitas B-lineage, in combination with immune checkpoint inhibitors, for treating advanced solid tumors.

In March 2021, sitravatinib was reported to be in phase 3 clinical development.

PDT PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009026717

WO2009026717 , in which sitravatinib was first disclosed, claiming heterocyclic compounds as multi kinase inhibitors.

Scheme 10

Example 52
N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7- yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide

Step 1 : tert-Butyl (6-(7-(2-Fluoro-4-(1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxamido)phenoxy)thieno [3 ,2-b]pyridin-2-yl)pyridin-3 -y l)methyl(2-methoxyethyl)carbamate (146)
To aniline 126 (0.58 g, 1.1 mmol) and DIPEA (0.58 mL, 0.43 g, 3.3 mmol) in dry DMF

(20 mL) was added 1-(4-fluorophenylcarbamoyl)cyclopropanecarbpxylic acid (0.35 g, 1.5 mmol) and HATU (0.72 g, 1.9 mmol) and the mixture was stirred at r.t. for 18 h. It was then partitioned between ethyl acetate and water, the organic phase was washed with water, IM NaOH, brine, dried (MgSO₄), filtered, and concentrated. Silica gel chromatography (ethyl acetate) afforded title compound Ϊ46 (0.60 g, 74 % yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.40 (s, 1H), 10.01 (s, 1H), 8.52-8.49 (m, 2H), 8.33 (s, 1H), 8.27-8.24 (m, 1H), 7.92-7.88 (m, 1H), 7.78 (dd, J = 8.2, 2.1 Hz, 1H) 7.65-7.60 (m, 2H), 7.52-7.42 (m, 2H), 7.14 (t, J = 8.8 Hz, 2H), 6.65 (d, J = 5.1 Hz 1H), 4.47 (s, 2H), 3.42-3.30 (m, 4H), 3.22 (s, 3H), 1.46-1.30 (m, 13H). MS (m/z): 730.1 (M+H).
Step 2. N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-blpyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (147)
To the compound 146 (0.59 g, 0.81 mmol) in dichloromethane (50 mL) was added TFA (3 mL). The solution was stirred for 18 h then concentrated. The residue was partitioned between dichloromethane and 1 M NaOH, and filtered to remove insolubles. The organic phase was collected, washed with IM NaOH, brine, dried (MgSO₄), filtered, and concentrated to afford title compound 147 (0.35 g, 69 % yield).

1H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.40 (s, 1H), 10.01 (s, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.92-7.87 (m, 2H), 7.65-7.61 (m, 2H), 7.52-7.43 (m, 2H), 7.17-7.12 (m, 2H), 6.64 (d, J = 5.5 Hz, 1H), 3.77 (s, 2H), 3.40 (t, J = 5.7 Hz, 2H), 3.23 (s, 3H), 2.64 (t, J = 5.7 Hz, 2H), 1.46 (br s, 4H). MS (m/z): 630.1 (M+H).

PATENT

WO 2009026720

https://patents.google.com/patent/WO2009026720A1

PATENT

WO-2021050580

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021050580&tab=PCTDESCRIPTION&_cid=P12-KMKJ94-73521-1

Novel, stable crystalline polymorphic forms (form D) of sitravatinib , useful for treating a multi tyrosine kinase-associated cancer eg sarcoma, glioma, non-small cell lung, bladder, kidney, ovarian, gastric, breast or liver cancer.

International publication No. W02009/026717A disclosed compounds with the inhibition activities of multiple protein tyrosine kinases, for example, the inhibition activities of VEGF receptor kinase and HGF receptor kinase. In particular, disclosed N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane- 1,1 -di carboxamide (Compound 1) is a multi-tyrosine kinase inhibitor with demonstrated potent inhibition of a closely related spectrum of tyrosine kinases, including RET, CBL, CHR4ql2, DDR and Trk, which are key regulators of signaling pathways that lead to cell growth, survival and tumor progression.

[003]

Compound 1

[004] Compound 1 shows tumor regression in multiple human xenograft tumor models in mice, and is presently in human clinical trials as a monotherapy as well as in combination for

treating a wide range of solid tumors. Compound 1 is presently in Phase 1 clinical trial for patients with advanced cancer, in Phase 2 studies for patients with advanced liposarcoma and non-small cell lung cancer (NSCLC).

[005] The small scale chemical synthesis of the amorphous Compound 1 had been disclosed in the Example 52 (compound 147) of W02009/026717A, however, in order to prepare the API of Compound 1 with high quality and in large quantity, crystalline forms of Compound 1 would be normally needed so the process impurities could be purged out by recrystallization.

Practically, it is difficult to predict with confidence which crystalline form of a particular compound will be stable, reproducible, and suitable for phamaceutical processing. It is even more difficult to predict whether or not a particular crystalline solid state form will be produced with the desired physical properties for pharmaceutical formulations.

[006] For all the foregoing reasons, there is a great need to produce crystalline forms of Compound 1 that provide manufacturing improvements of the pharmaceutical composition.

The present invention advantageously addresses one or more of these needs.

EXAMPLE 1

Preparation of N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2- yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-l,l- dicarboxamide (Compound 1)

[0085] This Example illustrates the preparation ofN-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane- 1,1 -di carboxamide (Compound 1).

[0086] Step 1: N-(Y6-bromopyridin-3-vDmethvD-2-methoxyethan-l-amine (Compound 1A)

Compound 1A

[0087] To a stirred solution of 2-Methoxyethylamine (3.0 eq) in dichloromethane (DCM) (12 vol) was added Molecular sieves (0.3 w/w) and stirred for 2 hours at 25±5°C under nitrogen atmosphere. The reaction mass water content was monitored by Karl Fischer analysis until the water content limit reached 0.5 % w/w. Once the water content limit was reached, the reaction mass cooled to 5±5°C and 6-bromonicotinaldehyde (1.0 eq) was added lot wise over period of 30 minutes to the above reaction mass at 5±5°C. The reaction mass was stirred for 30±5 minutes at 5±5°C and acetic acid (1.05 eq) was added drop wise at 5±5°C. After completion of the addition, the mass was slowly warmed to 25±5°C and stirred for 8 h to afford Compound 1 A. The imine formation was monitored by HPLC.

[0088] Step 2: tert-butyl (Y6-brom opyri din-3 -vQmethvO(2-m ethoxy ethvDcarbamate (Compound

IB)

Compound 1B

[0089] Charged Compoud 1A (1.0 eq) in THF (5.0 vol) was added and the reaction mass was stirred for 30 minutes at 25±5°C under nitrogen atmosphere. The reaction mass was cooled to temperature of about 10±5°C. Di-tert- butyl dicarbonate (1.2 eq) was added to the reaction mass at 10±5°C under nitrogen atmosphere and the reaction mass temperature was raised to 25±5°C and the reaction mass for about 2 hours. The progress of the reaction was monitored by HPLC. After IPC completion, a prepared solution of Taurine (1.5 eq) in 2M aq NaOH (3.1 vol) was charged and stirred at 10±5°C for 16 h to 18 h. The reaction mass was further diluted with 1M aq.NaOH solution (3.7 vol) and the layers were separated. The aqueous layer was extracted with DCM (2 x 4.7vol) and the extract combined with the organic layer. The combined organic layers were washed with 1M aq.NaOH solution (3.94 vol), followed by water (2×4.4 vol), and dried over sodium sulfate (2.0 w/w) . The filtrate was concentrated under reduced pressure below 40° C until no distillate was observed. Tetrahydrofuran (THF) was sequentially added (1×4 vol and lx 6vol) and concentrated under reduced pressure below 40°C until no distillate was observed to obtained Compound IB as light yellow colored syrup liquid.

[0090] Step 3: tert-butyl 7-chlorothieno[3.2-b1pyridin-2-yl)pyridin-3-yl )methyl)(2-

methoxyethvDcarbamate (Compound 1C)

Compound 1C

[0091] To a stirred solution of 7-chlorothieno[3,2-b]pyridine (1.05 eq) in tetrahydrofuran (7 vol) was added n-butyl lithium (2.5 M in hexane) drop wise at -15±10°C and stirred for 90 minutes at same temperature under nitrogen atmosphere. Zinc chloride (1.05 eq) was added to the reaction mass at -15±10°C. The reaction mass was slowly warmed to 25±5°C and stirred for 45 minutes under nitrogen atmosphere to afford Compound 1C. The progress of the reaction was monitored by HPLC.

[0092] Step 4: tert-butyl (Y6-(7-(4-amino-2-fluorophenoxy)thieno[3.2-b1pyridin-2-v0pyridin-3-vDmethvD(2-methoxyethvDcarbamate (Compound ID)

Compound 1D

[0093] 3-fluoro-4-hydroxybenzenaminium chloride (1.2 eq) in DMSO (3.9 vol) at 25±5°C was charged under nitrogen atmosphere and the reaction mass was stirred until observance of a clear solution at 25±5°C. t-BuOK was added lot wise under nitrogen atmosphere at 25±10°C. The reaction mass temperature was raised to 45±5°C and maintained for 30 minutes under nitrogen atmosphere. Compound 1C was charged lot-wise under nitrogen atmosphere at 45±5°C and stirred for 10 minutes at 45± 5°C.The reaction mixture was heated to 100± 5°C and stirred for 2 hrs. The reaction mass is monitored by HPLC.

[0094] After reaction completion, the reaction mass was cooled to 10± 5°C and quenched with chilled water (20 vol) at 10±5°C. The mass temperature was raised to 25± 5°C and stirred for 7-8 h. The resulting Compound ID crude was collected by filtration and washed with 2 vol of water. Crude Compound ID material taken in water (10 vol) and stirred for up to 20 minutes at 25±5°C. The reaction mass was heated to 45±5°C and stirred for 2-3 h at 45±5°C, filtered and vacuum-dried.

[0095] Crude Compound ID was taken in MTBE (5 vol) at 25±5°C and stirred for about 20 minutes at 25±5°C. The reaction mass temperature was raised to 45±5°C, stirred for 3-4 h at 45±5°C and then cooled to 20±5°C. The reaction mass was stirred for about 20 minutes at 20±5°C, filtered, followed by bed wash with water (0. 5 vol) and vacuum-dried.

[0096] The crude material was dissolved in acetone (10 vol) at 25±5°C and stirred for about 2h at 25±5°C. The reaction mass was filtered through a celite bed and washed with acetone (2.5 vol). The filtrate was slowly diluted with water (15 vol) at 25±5°C. The reaction mass was stirred for 2-3 h at 25±5°C, filtered and bed washed with water (2 vol) & vacuum-dried to afford Compound ID as brown solid.

[0097] Step 5 : 1 -((4-((2-(5-(((tert-butoxycarbonv0(2-methoxy ethvOaminolmethvOpyri din-2 -yl )thieno[3.2-b]pyridin-7-yl )oxy)-3 -fluorophenyl icarbamoyl level opropane-1 -carboxylic acid (Compound IE)

Compound 1E

[0098] To a solution of Compound ID (1.0 eq.) in tetrahydrofuran (7 vol.), aqueous potassium carbonate (1.0 eq.) in water (8 vol.) was added. The solution was cooled to 5±5°C, and stirred for about 60 min. While stirring, separately triethylamine (2.0 eq.) was added to a solution of 1,1-cyclopropanedicarboxylic acid (2.0 eq.) in tetrahydrofuran (8 vol.), at 5±5°C, followed by thionyl chloride (2.0 eq.) and stirred for about 60 min. The acid chloride mass was slowly added to the Compound ID solution at 5±5°C. The temperature was raised to 25±5°C and stirred for 3.0 h. The reaction was monitored by HPLC analysis.

[0099] After reaction completion, the mass was diluted with ethyl acetate (5.8 vol.), water (5.1 vol.), 10% (w/w) aqueous hydrochloric acid solution (0.8 vol.) and 25% (w/w) aqueous sodium chloride solution (2 vol.). The aqueous layer was separated and extracted with ethyl acetate (2 x 5 vol.). The combined organic layers were washed with a 0.5M aqueous sodium bicarbonate solution (7.5 vol.). The organic layer was treated with Darco activated charcoal (0.5 w/w) and sodium sulfate (0.3 w/w) at 25±5°C for 1.0 h. The organic layer was filtered through celite and washed with tetrahydofuran (5.0 vol.). The filtrate was concentrated under vacuum below 50°C to about 3 vol and co-distilled with ethyl acetate (2 x 5 vol.) under vacuum below 50°C up to ~ 3.0 vol. The organic layer was cooled to 15±5°C, stirred for about 60 min., filtered, and the solid was washed with ethyl acetate (2.0 vol.). The material was dried under vacuum at 40±5°C until water content was less than 1% to afford Compound IE as brown solid.

[00100] Step 6: tert-butyl (Y6-(7-(2-fluoro-4-(T-(Y4-fluorophenvDcarbamovDcvclopropane-l-carboxamido)phenoxy)thieno[3.2-b]pyridin-2-v0pyri din-3 – (2-
methoxyethvDcarbamate (Compound IF)

[00101] Pyridine (1.1 eq.) was added to a suspension of Compound IE (1.0 eq.) in tetrahydrofuran (10 vol.) and cooled to 5±5°C. Thionyl chloride (2.0 eq.) was added and stirred for about 60 min. The resulting acid chloride formation was confirmed by HPLC analysis after quenching the sample in methanol. Separately, aqueous potassium carbonate (2.5 eq.) solution (7.0 vol. of water) was added to a solution of 4-fluoroaniline (3.5 eq.) in tetrahydrofuran (10 vol.), cooled to 5±5°C, and stirred for about 60 min. The temperature of the acid chloride mass at 5±5°C was raised to a temperature of about 25±5°C and stirred for 3 h. The reaction monitored by HPLC analysis.

[00102] After completion of the reaction, the solution was diluted with ethyl acetate (25 vol.), the organic layer was separated and washed with a 1M aqueous sodium hydroxide solution (7.5 vol.), a 1M aqueous hydrochloric acid solution (7.5 vol.), and a 25% (w/w) aqueous sodium chloride solution (7.5 vol.). The organic layer was dried and and filtered with sodium sulfate (1.0 w/w). The filtrate was concentrated ~ 3 vol under vacuum below 50°C and co-distilled with ethyl acetate (3 x 5 vol.) under vacuum below 50°C to ~ 3.0 vol. Ethyl acetate (5 vol.) and MTBE (10 vol.) were charged, heated up to 50±5°C and stirred for 30-60 min. The mixture was cooled to 15±5°C, stirred for about 30 min., filtered, and the solid was washed with ethyl acetate (2.0 vol.). MGB3 content was analyzed by HPLC analysis. The material was dried under vacuum at 40±5°C until the water content reached about 3.0% to afford Compound IF as brown solid.

[00103] Step 7 : N-(3-fluoro-4-((2-(5-(((2-methoxyethv0amino)methv0pyridin-2-yl )thieno[3.2-b]pyridin-7-yl )oxy)phenyl)-N-(4-fluorophenyl level opropane-1. 1 -dicarboxamide (Compound 1)

Compound 1

[0100] To a mixture of Compound IF in glacial acetic acid (3.5 vol.) concentrated hydrochloric acid (0.5 vol.) was added and stirred at 25±5°C for 1.0 h. The reaction was monitored by HPLC analysis.

[0101] After reaction completion, the mass was added to water (11 vol.) and stirred for 20±5°C for 30 min. The pH was adjusted to 3.0 ± 0.5 using 10% (w/w) aqueous sodium bicarbonate solution and stirred for 20±5°C for approximately 3.0 h.. The mass was filtered, washed with water (4 x 5.0 vol.) and the pH of filtrate was checked after every wash. The material was dried under vacuum at 50±5°C until water content was about 10%.

[0102] Crude Compound 1 was taken in ethyl acetate (30 vol.), heated to 70±10°C, stirred for 1.0 h., cooled to 25±5°C, filtered, and washed with ethyl acetate (2 vol.). The material was dries under vacuum at 45±5°C for 6.0 h.

[0103] Crude Compound 1 was taken in polish filtered tetrahydrofuran (30 vol.) and pre washed Amberlyst A-21 Ion exchange resin and stirred at 25±5°C until the solution became clear. After getting the clear solution, the resin was filtered and washed with polish filtered tetrahydrofuran (15 vol.). The filtrate was concentrated by -50% under vacuum below 50°C and co-distilled with polish filtered IPA (3 x 15.0 vol.) and concentrated up to -50% under vacuum below 50°C. Charged polish filtered IPA (15 vol.) was added and the solution concentrated under vacuum below 50°C to – 20 vol. The reaction mass was heated to 80±5°C, stirred for 60 min. and cooled to 25±5°C. The resultant reaction mass was stirred for about 20 hours at 25±5°C. The reaction mass was cooled to 0±5°C, stirred for 4-5 hours, filtered, and washed with polish filtered IPA (2 vol.). The material was dried under vacuum at 45±5°C, until the water content was about 2%, to obtain the desired product Compound 1. ¾-NMR (400 MHz, DMSO- d): 510.40 (s, 1H), 10.01 (s, 1H), 8.59 – 8.55 (m, 1H), 8.53 (d, J= 5.6 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J= 8.0 Hz, 1H), 7.96 – 7.86 (m, 2H), 7.70 – 7.60 (m, 2H), 7.56 – 7.43 (m, 2H), 7.20 – 7.11 (m, 2H), 6.66 (d, J= 5.6 Hz, 1H), 3.78 (s, 2H), 3.41 (t, J= 5.6 Hz, 2H), 3.25 (s, 3H), 2.66 (t, J= 5.6 Hz, 2H), 1.48 (s, 4H)ppm. MS: M/e 630 (M+l)⁺.

EXAMPLE 2

Preparation of Crystalline Form D of N-(3-fluoro-4-((2-(5-(((2- methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4- fluorophenyl)cyclopropane-l, 1-dicarboxamide

EXAMPLE 2A: Preparation of Compound 1 Crystalline Form D

[0104] To a 50 L reactor, 7.15 Kg of Compound 1, 40 g of Form D as crystal seed and 21 L acetone (>99%) were added. The mixture was heated to reflux ( ~56 °C) for 1~2 h. The mixture was agitated with an internal temperature of 20±5 °C for at least 24 h. Then, the suspension was filtered and washed the filter cake with 7 L acetone. The wet cake was dried under vacuum at <45 °C, to obtain 5.33 kg of Compound 1 of desired Form D

[0105] X-Ray Powder Diffraction (XRPD)

The XRPD patterns were collected with a PAN alytical X’ Pert PRO MPD diffractometer using auincident beam of Cu radiation produced using au Optix long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu Ka X -rays through the specimens and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify the observed position of the Si Ill peak is consistent with the NIST-certified position. A specimen of each sample was sandwiched between 3 -pm -thick films and analyzed in transmission geometly. A beam-stop, short autiscatter extension, and an autiscatter knife edge were used to minimize the background generated by air. Sober slits for the incident aud diffracted beauls were used to minimize broadening from axial divergence. The diffraction patterns were collected using a scanning position-sensitive detector (X’Celerator) located 240 mm from the specimens and Data Collector software v. 2.2b. Pattern Match v2.3.6 was used to create XRPD patterns.

[0106] The X-ray powder diffraction (XRPD) pattern was used to characterize the Compound 1 obtained, which showed that the Compound 1 was in Crystalline Form D of Compound 1 (Compound 1 Form D), see Figure 1A. The XRPD pattern yielded is substantially the same as that shown in Figure 3C.

[0107] Differential Scanning Calorimetry (DSC)

[0108] DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Temperature calibration was performed using octane, phenyl salicylate, indium, tin, and zinc. The TAWN sensitivity was 11.9. The samples were placed into aluminum DSC pans, covered with lids, and the weights were accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The pan lids were pierced prior to sample analyses. The method name on the thermograms is an abbreviation for the start and end temperature as well as the heating rate; e.g., -30-250-10 means “from ambient to 250°C, at 10°C/min.” The nitrogen flow rate was 50.0 mL/min. This instrument does not provide gas pressure value as required by USP because it is the same as atmospheric pressure.

[0109] A broad small endotherm with a peak maximum at approximately 57°C to 62°C (onset ~20°C to 22°C) followed by a sharp endotherm with a peak maximum at approximately 180°C (onset ~178°C) were observed. These events could be due to the loss of volatiles and a melt, respectively (see Figure IB).

[0110] In an alternative embodiment Form D was prepared as follows. Designated Material O was suspended in 600 pL of acetone. Initial dissolution was observed followed by re precipitation. The amount of suspended solids was not measured because the target of the experiment was to get a suspension with enough solids to slurry isolate and collect XRPD data. Based on the solubility of Form D in acetone a very rough estimate for the scale of the experiment is about 80-100mg. The suspension was stirred at ambient temperature for approximately 2 5 weeks after which the solids were isolated by centrifugation with filtration. XRPD data appeared to be consistent with Form D The sample was then dried in vacuum oven at ~40 °C for ~2 5 hours. The XRPD pattern of the final solids was consistent with Form D EXAMPLE 2B: Preparation of Compound 1 Form D

[0111] 427.0 mg of Compound 1 was dissolved in 5 mL of THF to obtain a clear brown solution. The resulting solution was filtered, and the filtrate evaporated under flow of nitrogen. A sticky solid was obtained, which was dried under vacuum in room temperature for ~5 min, still a sticky brown solid obtained. It was dissolved in 0.2 mL of EtOAc and sonicated to dissolve. The solution obtained was stirred at room temperature for 15 min and a solid precipitated. The resulting solid was added 0.4 mL of EtOAc and stirred in room temperature for 21 h 40 min to ontian a suspension. The solid was spparated from mother liquor by centrifugation, then the resulting solid was resuspended the in 0.6 mL of EtOAc and stirred in room temperature for 2 days. The solid was isolated by centrifugation, to obtain Compound 1 of desired Form D.

[0112] The X-ray powder diffraction (XRPD) pattern was used to characterize the Compound 1 obtained, which showed that the Compound 1 was in Crystalline Form D of Compound 1 (Compound 1 Form D).

EXAMPLE 2C: Preparation of Compound 1 Form D

[0113] Single crystal X-ray diffraction data of Compound 1 was collected at 180 K on a Rigaku XtaLAB PRO 007HF(Mo) diffractometer, with Mo Ka radiation (l = 0.71073 A). Data reduction and empirical absorption correction were performed using the CrysAlisPro program. The structure was solved by a dual-space algorithm using SHELXT program. All non-hydrogen atoms could be located directly from the difference Fourier maps. Framework hydrogen atoms were placed geometrically and constrained using the riding model to the parent atoms. Final structure refinement was done using the SHELXL program by minimizing the sum of squared deviations of F2 using a full-matrix technique.

Preparation of Compound 1 Form D ( a Single Crystal )

[0114] Compound 1 Form D was dissolved in a mixture of acetone/ ACN (1/2) with the concentration of Compound 1 at ~7 mg/mL. A block single crystal was obtained, which was a single crystal.

[0115] The XRPD pattern was used to characterize the single crystal of Compound 1 Form D obtained, see Figure 2A. The crystal structural data are summarized in Table IB. The refined single crystal structure were shown in Figure 2B. The single crystal structure of Compound 1 Form D is in the P-1 space group and the triclinic crystal system. The terminal long alkyl chain is found to have large ellipsoids, indicating high mobility with disordered atoms.

[0116] The theoretical XRPD calculated from the single crystal structure and experimental XRPD are essentially similar (Figure 2A). A few small peaks are absent or shift because of orientation preference, disorder and tested temperature (180 K for single crystal data and 293 K for experimental one).

[0117] Table IB. Crystal Data and Structure Refinement for Compound 1 Form D (a Single Crystal)

References

Identifiers

show IUPAC name
CAS Number	1123837-84-2
ChemSpider	52083477
UNII	CWG62Q1VTB
KEGG	D11140
Chemical and physical data
Formula	C₃₃H₂₉F₂N₅O₄S
Molar mass	629.68 g·mol⁻¹
3D model (JSmol)	Interactive image
hide SMILESCOCCNCc1ccc(nc1)c2cc3c(s2)c(ccn3)Oc4ccc(cc4F)NC(=O)C5(CC5)C(=O)Nc6ccc(cc6)F
hide InChIInChI=1S/C33H29F2N5O4S/c1-43-15-14-36-18-20-2-8-25(38-19-20)29-17-26-30(45-29)28(10-13-37-26)44-27-9-7-23(16-24(27)35)40-32(42)33(11-12-33)31(41)39-22-5-3-21(34)4-6-22/h2-10,13,16-17,19,36H,11-12,14-15,18H2,1H3,(H,39,41)(H,40,42)Key:WLAVZAAODLTUSW-UHFFFAOYSA-N

///////////// sitravatinib, phase 3, シトラバチニブ , MGCD516, MG-516, Sitravatinib (MGCD516), UNII-CWG62Q1VTB, CWG62Q1VTB, MGCD-516, ситраватиниб , سيترافاتينيب , 司曲替尼 , Antineoplastic, MGCD 516

#sitravatinib, #phase 3, #シトラバチニブ , #MGCD516, #MG-516#Sitravatinib (MGCD516), #UNII-#CWG62Q1VTB, #CWG62Q1VTB, #MGCD-516, ситраватиниб , سيترافاتينيب , 司曲替尼 , #Antineoplastic, #MGCD516

COCCNCC1=CN=C(C=C1)C2=CC3=NC=CC(=C3S2)OC4=C(C=C(C=C4)NC(=O)C5(CC5)C(=O)NC6=CC=C(C=C6)F)F

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Approval based on HIMALAYA Phase III trial results which showed single priming dose of Imjudo added to Imfinzi reduced risk of death by 22% vs. sorafenib

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