Rucaparib

Rucaparib is an inhibitor of PARP with Ki of 1.4 nM for PARP1 in a cell-free assay, and also shows binding affinity to eight other PARP domains.

Rucaparib is a member of the class of azepinoindoles that is 1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one carrying additional 4-[(methylamino)methyl]phenyl and fluoro substituents at positions 2 and 8 respectively. It is an inhibitor of poly (ADP-ribose) polymerase and is used (as the camsylate salt) as monotherapy for advanced ovarian cancer and deleterious germline or somatic BRCA mutation. It has a role as an EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor and an antineoplastic agent. It is an azepinoindole, a member of caprolactams, an organofluorine compound and a secondary amino compound. It is a conjugate base of a rucaparib(1+).|Rucaparib is a potent mammalian poly(ADP-ribose) polymerase (PARP) 1, 2 and 3 inhibitor with anticancer properties. PPAR is an enzyme that plays an essential role in DNA repair by activating response pathways and facilitating repair, and defects in these repair mechanisms have been demonstrated in various malignancies, including cancer. Regulation of repair pathways is critical in promoting necessary cell death. BRCA genes are tumor suppressor genes mediate several cellular process including DNA replication, transcription regulation, cell cycle checkpoints, apoptosis, chromatin structuring and homologous recombination (HR). Homologous recombination deficiency (HRD), along with PPAR inhibition, is a vulnerability that enhances the cell death pathway when the single mutations alone would permit viability. Ovarian cancer commonly possesses defects in DNA repair pathways such as HRD due to BRCA mutations or otherwise. There are three main types of ovarian cancer: epithelial (90%), germ cell (5%) and sex cord stromal cell (5%). Epithelial ovarian, being the most common, fifth leading cause of cancer-related deaths in women in the United States. Advanced ovarian cancer particularly poses challenges due to reduced therapeutic response rates from standard platinum-based chemotherapy and overall survival rates. Rucaparib has shown to induce cytotoxicity in tumor cell lines with deficiencies in BRCA1/2 and other DNA repair genes. Of all the BRCA1/2 mutations in ovarian cancer, most are due to germline mutations (18%), and approximately 7% represent somatic mutations acquired within the tumor. The indication of rucaparib as an oral monotherapy in patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer was granted accelerated approval in 2016 for selected patients who have previously received greater than two lines of platinum-based therapy. It is currently marketed in the US under the brand name Rubraca that contains rucaparib camsylate as the active ingredient. The identification of patients who are eligible for rucaparib therapy is performed via *in vitro* diagnostic tests to detect the presence of a deleterious BRCA mutation (germline and/or somatic). The FDA-approved test qualitatively detects sequence alterations in BRCA1 and BRCA2 (BRCA1/2) genes. More information can be found on the FDA Website. While rucaparib is indicated for deleterious BRCA mutation (germline and/or somatic)-associated advanced ovarian cancer, there is evidence that its antitumor activity is also clinically effective against ovarian tumors with high homologous recombination deficiency (HRD) loss of heterozygosity (LOH).|Rucaparib is a Poly(ADP-Ribose) Polymerase Inhibitor. The mechanism of action of rucaparib is as a Poly(ADP-Ribose) Polymerase Inhibitor.|Rucaparib is a small molecule inhibitor of poly ADP-ribose polymerase that is used in the therapy of selected patients with refractory and advanced ovarian carcinoma. Rucaparib therapy is associated with a moderate rate of transient elevations in serum aminotransferase during therapy, but has not been linked to instances of clinically apparent liver injury.|Rucaparib is an orally bioavailable tricyclic indole and inhibitor of poly(ADP-ribose) polymerases (PARPs) 1 (PARP1), 2 (PARP2) and 3 (PARP3), with potential chemo/radiosensitizing and antineoplastic activities. Upon administration, rucaparib selectively binds to PARP1, 2 and 3 and inhibits PARP-mediated DNA repair. This enhances the accumulation of DNA strand breaks, promotes genomic instability and induces cell cycle arrest and apoptosis. This may enhance the cytotoxicity of DNA-damaging agents and reverse tumor cell resistance to chemotherapy and radiation therapy. PARPs are enzymes activated by single-strand DNA breaks that catalyze the post-translational ADP-ribosylation of nuclear proteins, which induces signaling and the recruitment of other proteins to repair damaged DNA. The PARP-mediated repair pathway plays a key role in DNA repair and is dysregulated in a variety of cancer cell types.

2-Bromo-8-fluoro-4, 5-dihydro-lH-azepino[5, 4, 3-cd]indol-6(3H)-one (10 g; 35.3 mmol), prepared according to process described in Example 3, sodium carbonate (3.74 g; 35.3 mmol), bis(triphenylphosphine)palladium(II) diacetate (0.529 g; 0.71 mmol) and (4-((methylamino)methyl)phenyl)boronic acid solution (75 ml; 45.9 mmol), prepared according to process described in Example 2, are charged into a three-necked round bottom flask, followed by inertisation with nitrogen. A previously degassed mixture of methanol (130 mL) and water (40 mL) is added and the reaction mixture is stirred at 60°C for 4 hours. The reaction mixture is cooled to ambient temperature followed by addition of activated carbon. The mixture is stirred at ambient temperature for one hour, heated to 50 °C, stirred for another hour and then filtered through a layer of celite. The solution of 8-fluoro-2-(4- ((methylamino)methyl)phenyl)-4, 5-dihydro-lH-azepino[5, 4, 3-cd]indol-6(3H)-one is concentrated to about 110 mL, heated to 40°C followed by dropwise addition of water (40 mL). Reaction mixture is cooled to ambient temperature and stirred for 17 hours at ambient temperature and additional one hour at 0-5°C. Solid is filtered off, washed with water and dried in vacuum oven at 50°C for 5 hours. Crude material (9.5 g) is suspended in methanol (95mL) at reflux temperature and stirred for 20 minutes. Suspension is than cooled down and stirred for 17 hours at ambient temperature and 1.5 hour at 0-5°C. Crystals are filtered off, washed with methanol and dried in vacuum oven at 50°C for 4 hours to obtain 6.82 g of Rucaparib base.2-Bromo-8-fluoro-4, 5-dihydro-lH-azepino[5, 4, 3-cd]indol-6(3H)-one (10 g; 35.3 mmol), prepared according to process described in Example 3, sodium carbonate (3.74 g; 35.3 mmol), bis(triphenylphosphine)palladium(II) diacetate (0.529 g; 0.71 mmol) and (4-((methylamino)methyl)phenyl)boronic acid solution (75 ml; 45.9 mmol), prepared according to process described in Example 2, are charged into a three-necked round bottom flask, followed by inertisation with nitrogen. A previously degassed mixture of methanol (130 mL) and water (40 mL) is added and the reaction mixture is stirred at 60°C for 4 hours. The reaction mixture is cooled to ambient temperature followed by addition of activated carbon. The mixture is stirred at ambient temperature for one hour, heated to 50 °C, stirred for another hour and then filtered through a layer of celite. The solution of 8-fluoro-2-(4- ((methylamino)methyl)phenyl)-4, 5-dihydro-lH-azepino[5, 4, 3-cd]indol-6(3H)-one is concentrated to about 110 mL, heated to 40°C followed by dropwise addition of water (40 mL). Reaction mixture is cooled to ambient temperature and stirred for 17 hours at ambient temperature and additional one hour at 0-5°C. Solid is filtered off, washed with water and dried in vacuum oven at 50°C for 5 hours. Crude material (9.5 g) is suspended in methanol (95mL) at reflux temperature and stirred for 20 minutes. Suspension is than cooled down and stirred for 17 hours at ambient temperature and 1.5 hour at 0-5°C. Crystals are filtered off, washed with methanol and dried in vacuum oven at 50°C for 4 hours to obtain 6.82 g of Rucaparib base.Add 300 g of acetonitrile to a 500 ml stainless steel autoclave, 33.2 g (0.05 mole)2- [1- (4-N-methyl-N-benzylaminomethyl) benzoyl-3-benzenesulfonate] n-propyl-3-nitro-5-fluorobenzoate ( Compound V1, prepared from Example 2), 1.0 g of a 10% palladium-carbon catalyst was replaced with nitrogen three times, and then hydrogen gas was passed in, keeping the hydrogen pressure at 0.1-0.2 MPa, and reacting at 20-25 C for 5 hours.Replaced with nitrogen three times, filtered to remove palladium carbon, transferred the filtrate to a four-necked flask, added 20 g of 10% ammonia acetonitrile solution, reacted at 55-60 C for 5 hours, cooled to 10-15 C, filtered, washed with 20 g of acetonitrile, and dried 15.3 g of rucaparib(I) was obtained with a yield of 94.6% and a liquid phase purity of 99.7%.Add 300 g of acetonitrile to a 500 ml stainless steel autoclave, 32.5 g (0.05 mol) 2- [1- (4-N-methyl-N-benzylaminomethyl) benzoyl-3-p-toluenesulfonate] n-propyl-3-nitro Methyl-5-fluorobenzoate (Compound V1, prepared from Example 1), 1.0 g of 10% palladium-carbon catalyst, after nitrogen substitution for three times, hydrogen gas was passed in, maintaining the hydrogen pressure at 0.1-0.2 MPa, and reaction at 20-25 C 5 hours. Replaced with nitrogen three times, filtered to remove palladium on carbon, transferred the filtrate to a four-necked flask, added 15 g of 17% ammonia water, reacted at 50-55 C for 6 hours, cooled to 10-15 C, filtered, washed with 20 g of acetonitrile, and dried to obtain 15.1 g of rucaparib(I), yield 93.2%, liquid phase purity 99.8%.0.43 g of sodium hydroxide dissolved in a mixture of 42 mL of water and 16.5 mL of methanol at 25+5C and then cooled to l5+5C, to this was added 3 g of Rucaparib S-Camsylate salt for 10 min. Further, 42 mL of water was added to the reaction suspension and stirred for lh at 20+5C. The reaction mass was filtered and dried under vacuum at 50 C for 2 h. The product obtained was identified as Rucaparib form ML Yield: 2.2 g

Molecular Weight:323.4
XLogP3:2.5
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:323.14339037
Monoisotopic Mass:323.14339037
Topological Polar Surface Area:56.9
Heavy Atom Count:24
Complexity:466
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes