Rucaparib, PF-01367338 for the treatment of patients with advanced ovarian cancer and in patients with locally advanced or metastatic breast cancer.

Rucaparib, PF-01367338

283173-50-2 cas

6H-Pyrrolo[4,3,2-ef][2]benzazepin-6-one, 8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-

6H- Azepino[5,4,3-cd]indol-6-one, 8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl] -

8-Fluoro-2-[4-[(methylamino)methyl]phenyl]-1,3,4,5- tetrahydro-6H-azepino[5,4,3-cd]indol-6-one;

8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one

8-Fluoro-2-(4-methylaminomethyl-phenyI)-l,3,4,5-tetrahydro-azepino[5,4,3- cd]indol-6-one

MW..C₁₉ H₁₈ F N₃ O

cas of csa salt—–1327258-57-0

773059-19-1 (hydrochloride)
773059-22-6 (L-tartrate)
773059-23-7 (acetate)

459868-92-9 PHOSPHATE

AG-014699
AG-14699
CO-338
PF-01367338
AG-014447 (free base)
AG-14447 (free base)

Agouron (Originator)
Pfizer (Originator)

WO 2014052550, WO 2014037313, WO 2000042040WO 2004087713WO 2005012305

Inhibition of poly(ADP ribose) polymerase, or PARP, is an exciting new mechanism for the treatment of cancer.(1) The PARP enzyme is responsible for repair of damaged DNA in both normal and tumor cells, and inhibition of this repair mechanism is expected to make the cell more likely to undergo apoptosis. Preclinical work has shown that PARP inhibitors coadministered with a standard chemotherapuetic agent are more effective than the standard treatment alone

Rucaparib is a NAD+ ADP-ribosyltransferase inhibitor in phase II clinical development at Cancer Research UK for the treatment of patients with advanced ovarian cancer and in patients with locally advanced or metastatic breast cancer. Clovis Oncology is conducting early clinical evaluation of rucaparib for the treatment of triple negative breast cancer or ER/PR +, HER2 negative with known BRCA1/2 mutations p2 and for the treatment of gBRCA mutation breast cancer.. Pfizer discontinued development of rucaparibin 2011.In 2011, the compound was licensed to Clovis Oncology by Pfizer for the treatment of cancer. In 2012, orphan drug designation was assigned in the U.S. and the E.U. for the treatment of ovarian cancer. The compound 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3- cd]indol-6-one represented by formula is a small molecule inhibitor of poly(ADP-ribose) polymerase (PARP). 8-Fluoro-2-{4- [(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one and salts thereof, is disclosed in U.S. Patent No. 6,495,541 and PCT Application No. PCT/IB2004/000915, International Publication No. WO 2004/087713, the disclosures of which are incorporated herein by reference in their entireties. U.S. Provisional Patent Applications No. 60/612,459 and 60/679,296, entitled “Polymorphic Forms of the Phosphate Salt of 8-Fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H- azepino[5,4,3-cd]indol-6-one,” the disclosures of which are incorporated herein by reference in their entireties, describe novel polymorphic forms of the phosphate salt of 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one, and methods for their preparation. U.S. Provisional Patent Applications No. 60/612,458; and 60/683,006, entitled “Therapeutic Combinations Comprising Poly(ADP-Ribose) Polymerases Inhibitor,” the disclosures of which are incorporated herein by reference in its entirety, describe pharmaceutical combinations of 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one.

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http://www.google.com/patents/WO2000042040A1?cl=en

Example IIII:8-Fluoro-2-(4-methylaminomethyl-phenyI)-l,3,4,5-tetrahydro-azepino[5,4,3- cd]indol-6-one 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-lH-azepino[5,4,3-cd]indol-2-yl)- benzaldehyde (100 mg, 0.32 mmol; prepared in a manner similar to that described for compound 12 for 2-bromo-8-fluoro-l,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and 4-formylphenylboronic acid) was reacted with methylamine (1.62 mmol) as described for Compound PPP to yield 8-fluoro-2-(4-methylaminomethyl-phenyl)- l,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 32 mg (31%) as a yellow solid: m.p. 1543-155 °C; Η NMR (300 MHz, d₆-DMSO) 2.28 (s, 3H), 3.04 (m, 2H), 3.40 (m, 2H), 3.69 (s, 2H), 7.32 (dd, 7= 9.0, 2.4 Hz, IH), 7.44 (m, 3H), 7.57 (d, 7= 8.1 Hz, 2H), 8.25 (br t, IH), 11.67 (br s, IH). HRMS (MALDI MH+) Calcd for C₁₉H₁₈N₃OF: 324,1512. Found: 325.1524. Anal. (C₁₉H₁₈N₃OF03 H₂O) C, H, N.

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Org. Process Res. Dev., 2012, 16 (12), pp 1897–1904

DOI: 10.1021/op200238p

http://pubs.acs.org/doi/full/10.1021/op200238p

Novel PARP inhibitor 1 is a promising new candidate for treatment of breast and ovarian cancer. A modified synthetic route to 1 has been developed and demonstrated on 7 kg scale. In order to scale up the synthesis to multikilogram scale, several synthetic challenges needed to be overcome. The key issues included significant thermal hazards present in a Leimgruber–Batcho indole synthesis, a low-yielding side-chain installation, a nonrobust Suzuki coupling and hydrogen cyanide generation during a reductive amination. In addition to these issues, changing from intravenous to oral delivery required a new salt form and therefore a new crystallization procedure. This contribution describes development work to solve these issues and scaling up of the new process in the pilot plant.

8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (1) To a solution of aqueous sodium hydroxide (40% w/w, 3.6 kg, 2.0 equiv) in water (88 L, 14 L/kg) and methanol (35 L, 5.5 L/kg) was added 12 ……………………………………………………deleted……………………..and dried at 45 °C under vacuum to give 1 as a 1:1 THF solvate (5.57 kg, 14.08 mol, 84% yield); mp (THF) dec at 220 °C; δ_H: (400 MHz, DMSO-d₆) 2.25 (s, 3H), 2.99–3.01 (m 2H), 3.65 (s, 2H), 7.27 (dd, 1H, J = 2.4, 9.3 Hz), 7.39 (dd, 1H, J = 2.4, 9.3 Hz), 7.42 (d, 2H, J = 8.5 Hz), 7.53 (d, 2H, J = 8.3 Hz), 8.18 (t, br, 1H, J = 5.7 Hz), 11.60 (s, 1H); δ_C: (100 MHz, DMSO-d₆) 28.74, 35.58, 41.84, 54.74, 100.47 (d, J = 25.8 Hz), 109.44 (d, J = 25.8 Hz), 111.47, 123.19, 125.72 (d, J = 8.8 Hz), 127.55, 128.20, 129.86, 135.38 (d, J = 3.7 Hz), 136.67 (d, J = 12.4 Hz), 140.52, 158.31 (d, J = 233), 168.39. 8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (S)-camphorsulfonate Salt (21) To a slurry of 1 (5.32 kg, 13.48 mol) in isopropanol (30 L, 5.5 L/kg) and water (39 L, 7.3 L/kg) was added a solution of (S)-camphorsulfonic acid (3.75 kg, 16.18 mol, 1.2 equiv) in water (10.6 L, 2 L/kg). The resultant slurry was then heated to 70 °C and held for 1 h to ensure dissolution. …………………………..deleted…………………..C to give 21 as a white crystalline solid (7.09 kg, 12.76 mol, 95% yield); mp (IPA/water) 303 °C; δ_H: (400 MHz, DMSO-d₆) 0.74 (s, 3H), 1.05 (s, 3H), 1.28 (m, 1H), 1.80 (d, 1H, J = 18.0 Hz), 1.81–1.88 (m, 1H), 1.93 (app t, 1H, J = 4.5 Hz), 2.24 (m, 1H), 2.41 (d, 1H, J = 14.6 Hz), 2.62 (s, 3H), 2.66–2.72 (m, 1H), 2.91 (d, 1H, J = 14.7 Hz), 3.04–3.07 (m, br, 2H), 3.36–3.45 (m, br, 2H), 4.20 (s, 2H), 7.37 (dd, 1H, J = 2.4, 9.3 Hz), 7.44 (dd, 1H, J = 2.4, 11.0 Hz), 7.63 (d, 2H, J = 8.3 Hz), 7.71 (d, 2H, J = 8.3 Hz), 8.26 (t, br, 1H, J = 5.5 Hz), 11.76 (s, 1H); δ_C: (100 MHz, DMSO-d₆) 19.51, 20.02, 24.14, 26.37, 28.74, 32.28, 41.77, 42.13, 42.22, 46.71, 47.00, 51.06, 58.21, 100.65 (d, J = 25.8 Hz), 109.72 (d, J = 25.8 Hz), 112.41, 123.03, 126.04 (d, J = 8.7 Hz), 127.98, 130.19, 131.22, 132.22, 134.50, 136.83 (d, J = 12.0 Hz), 158.52 (d, J = 235 Hz), 168.27, 216.24. …………………. WO 2006033003 http://www.google.com/patents/WO2006033003A1?cl=en The compound 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3- cd]indol-6-one represented by formula is a small molecule inhibitor of poly(ADP-ribose) polymerase (PARP). 8-Fluoro-2-{4- [(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one and salts thereof, is disclosed in U.S. Patent No. 6,495,541 and PCT Application No. PCT/IB2004/000915, International Publication No. WO 2004/087713, the disclosures of which are incorporated herein by reference in their entireties. U.S. Provisional Patent Applications No. 60/612,459 and 60/679,296, entitled “Polymorphic Forms of the Phosphate Salt of 8-Fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H- azepino[5,4,3-cd]indol-6-one,” the disclosures of which are incorporated herein by reference in their entireties, describe novel polymorphic forms of the phosphate salt of 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one, and methods for their preparation. U.S. Provisional Patent Applications No. 60/612,458; and 60/683,006, entitled “Therapeutic Combinations Comprising Poly(ADP-Ribose) Polymerases Inhibitor,” the disclosures of which are incorporated herein by reference in its entirety, describe pharmaceutical combinations of 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one. Example 13. Synthesis of 8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3.4.5-tetrahvdro-azepinor5.4.3- ccflindol-6-one (15) i Lactam 14 (14.42 g, 0.038 mol) was dissolved in hydrobromic acid in acetic acid (30%-32%, 140 ml). The reaction solution was stirred for 46 hours at room temperature in a 500ml flask that was connected to an ethanolamine scrubber system. HPLC analysis indicated the completion of the reaction. Ice (30 g) was added to the reaction solution followed by addition of aqueous NaOH (327 ml, 10 M, 3.27 mol) while the temperature was maintained between 25 ⁰C and 35 ⁰C. When addition of NaOH was complete, the pH was 10. The resulting solid was collected by filtration, washed with water (2 x 50 ml). The filter cake was then suspended in water (125 ml) and stirred for 2 hours. The solid was collected by filtration, washed with water (2 x 25 ml) and dried to afford 10.76 g of product (88% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 2.577(s, 3H), 3.053(m, 2H), 3.406(m, 2H), 4.159(s, 2H), 7.36(dd, 1 H, J= 2.4 Hz and J= 9.3 Hz), 7.44(dd, 1 H, J= 2.4 Hz and J= 11.1 Hz), 7.63(d, 2H, J=8.1 Hz), 7.70(d, 2H, J= 8.1 Hz), 8.265(t, 1H, J= 5.7 Hz), 11.77(s, 1 H). Exact mass calculated for C₁₉H₁₉FN₃O: 324.1512. Found: 324.1497.