Veliparib

Abbott Laboratories

2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide

CAS number:  912444-00-9 (Veliparib),

912445-05-7 (Veliparib dihydrochloride)

Mechanism of Action:poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitor
Indiction:cancer treatment

Development Status:Phase III

Drug Company: AbbVie

PARP Inhibitor Veliparib (ABT-888)

Systematic (IUPAC) name
2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide
Clinical data
Legal status	experimental
Identifiers
ATC code	None
PubChem	CID 11960529
DrugBank	DB07232
ChemSpider	10134775
UNII	01O4K0631N
ChEMBL	CHEMBL506871
Chemical data
Formula	C13H16N4O
Mol. mass	244.29 g/mol

Veliparib (ABT-888)^[1] is a potential anti-cancer drug acting as a PARP inhibitor. It kills cancer cells by blocking a protein called PARP, thereby preventing the repair of DNA or genetic damage in cancer cells and possibly making them more susceptible to anticancer treatments. Veliparib may make whole brain radiation treatment work more effectively against brain metastases from NSCLC.

It inhibits both PARP1 and PARP2.^[2][3]

AbbVie’s Veliparib (ABT-888,), an inhibitor of poly ADP-ribose polymerase 1 and 2 (PARP 1 and PARP 2), is being investigated in multiple tumor types, including 3 phase III studies, all initiated this year, in neoadjuvant treatment of triple-negative breast cancer (clinical trial number:NCT02032277), non-small cell lung cancer (NSCLC, clinical trial number:NCT02106546) and HER2-negative, BRCA1 and/or BRCA2-positive breast cancer (clinical trial number:NCT02163694).

AbbVie, which was spun off from Abbott Laboratories in early 2013, is currently looking to buy Irish drug maker Shire for $46 billion. The proposed deal follows Pfizer’s failed $120 billion attempt to buy AstraZeneca. Humira, AbbVie’s rheumatoid arthritis drug and the world’s top-selling drug last year, accounts for 60% of company revenue and is going off-patent in at the end of 2016.  The threat of growing competition for Humira may be a major motivation for AbbVie.

Clinical trials

Numerous phase I clinical trials are in progress.^[4]

A phase I/II clinical trial for use with/out doxorubicin (for Metastatic or Unresectable Solid Tumors or Non-Hodgkin Lymphoma) started in 2008 and is due to complete in 2010.^[5] Results (inc MTD) with topotecan.^[6]

A phase II clinical trial for metastatic melanoma has started recruiting.^[7] Due to end Dec 2011.

A phase II clinical trial for metastatic breast cancer has started recruiting.^[8] Due to end Nov 2011.

A phase II clinical trial for add-on to Radiation Therapy for Patients with Brain Metastases from Non-Small Cell Lung Cancer.

It was included in the I-SPY2 breast cancer trial,^[9] and there are encouraging data from that study ^[10]

A phase I clinical trial for prostate cancer in men who carry the BRCA mutation is underway and is now recruiting (as of May 2013).^[11]

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http://www.google.com/patents/US20060229289

EXAMPLE 1

2-(2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide EXAMPLE 1A 1-benzyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate

A solution of 1-benzyl 2-methyl pyrrolidine-1,2-dicarboxylate (15.0 g, 57 mmol) and iodomethane (7.11 ml, 114 mmol) in THF (100 mL) was treated with NaN(TMS)₂ (1.0 M solution in THF, 114 mL, 114 mmol) at −75° C. under nitrogen. The temperature of the cooling bath was then slowly raised to −20° C. within 1 h and the mixture was stirred at the same temperature for another 3 h. After quenching with water, the mixture was acidified with 2 N HCl (˜100 mL) and was partitioned between water (400 mL) and EtOAc (400 mL). The organic phase was washed with brine and concentrated. The residue was purified by flash column chromatography (silica gel, EtOAc/hexane) to give Example 1A (15.15 g, Yield: 96%). MS (DCI/NH₃) m/z 278 (M+H)⁺.

EXAMPLE 1B

1-[(benzyloxy)carbonyl]-2-methylpyrrolidine-2-carboxylic acid

A solution of Example 1A (15.15 g, 54.63 mmol) in a mixture of THF (100 mL) and water (50 mL) was treated with LiOH.H₂O (4.58 g, 109.26 mmol) in water (50 mL). Methanol was added until a transparent solution formed (60 mL). This solution was heated at 60° C. for overnight and the organic solvents were removed under vacuum. The residual aqueous solution was acidified with 2 N HCl to pH 2 and was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO₄), filtered and concentrated to give Example 1B as a white solid (13.72 g, 95.4% yield). MS (DCI/NH₃) m/z 264 (M+H)⁺.

EXAMPLE 1C

benzyl 2-({[2-amino-3-(aminocarbonyl)phenyl]amino}carbonyl)-2-methylpyrrolidine-1-carboxylate

A solution of Example 1B (13.7 g, 52 mmol) in a mixture of pyridine (60 mL) and DMF (60 mL) was treated with 1,1′-carbonyldiimidazole (9.27 g, 57.2 mmol) at 45° C. for 2 h. 2,3-Diamino-benzamide dihydrochloride (11.66 g, 52 mmol), which was synthesized as described in previous patent application WO0026192, was added and the mixture was stirred at rt overnight. After concentration under vacuum, the residue was partitioned between ethyl acetate and diluted sodium bicarbonate aqueous solution. The slightly yellow solid material was collected by filtration, washed with water and ethyl acetate, and dried to give Example 1C (16.26 g). Extraction of the aqueous phase with ethyl acetate followed by concentration, filtration and water-EtOAc wash, provided additional 1.03 g of Example 1C. Combined yield: 84%. MS (APCI) m/z 397 (M+H)⁺.

EXAMPLE 1D

benzyl 2-[4-(aminocarbonyl)-1H-benzimidazol-2-yl]-2-methylpyrrolidine-1-carboxylate

A suspension of Example 1C (17.28 g, 43.6 mmol) in acetic acid (180 mL) was heated under reflux for 2 h. After cooling, the solution was concentrated and the residual oil was partitioned between ethyl acetate and sodium bicarbonate aqueous solution. The organic phase was washed with water and concentrated. The residue was purified by flash column chromatography (silica gel, 3-15% CH₃OH in 2:1 EtOAc/hexane) to provide Example 1D (16.42 g, Yield: 99%).

MS (APCI) m/z 379 (M+H)⁺.

EXAMPLE 1E 2-(2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide

A solution of Example 1D (15.0 g, 40 mmol) in methanol (250 ml) was treated with 10% Pd/C (2.8 g) under 60 psi of hydrogen for overnight. Solid material was filtered off and the filtrate was concentrated. The residual solid was recrystallized in methanol to give 7.768 g of Example 1E as free base. The bis-HCl salt was prepared by dissolving the free base in warm methanol and treating with 2 equivalents of HCl in ether (10.09 g). MS (APCI) m/z 245 (M+H)⁺; ¹H NMR (500 MHz, D₂O): δ 1.92 (s, 3 H), 2.00-2.09 (m, 1 H), 2.21-2.29 (m, 1 H), 2.35-2.41 (m, 1 H), 2.52-2.57 (m, 1 H), 3.54-3.65 (m, 2 H), 7.31 (t, J=7.93 Hz, 1 H), 7.68 (dd, J=8.24, 0.92 Hz, 1 H), 7.72 (dd, J=7.63, 0.92 Hz, 1 H); Anal. Calcd for C₁₃H₁₆N₄O.2 HCl: C, 49.22; H, 5.72N, 17.66. Found: C, 49.30; H, 5.60; N, 17.39.

EXAMPLE 3 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide EXAMPLE 3A benzyl(2R)-2-[4-(aminocarbonyl)-1H-benzimidazol-2-yl]-2-methylpyrrolidine-1-carboxylate

Example 1D (1.05 g, 2.8 mmol) was resolved on chiral HPLC (Chiralcel OD, 80/10/10 hexane/EtOH/MeOH). The faster eluting peak was collected and concentrated to provide Example 3A (99.4% e.e., 500 mg). MS (APCI) m/z 379 (M+H)⁺.

EXAMPLE 3B 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide

A solution of Example 3A (500 mg, 1.32 mmol) in methanol (10 ml) was treated with 10% Pd/C (150 mg) under hydrogen for overnight (balloon). Solid material was filtered off and the filtrate was concentrated. The residual solid was further purified by HPLC (Zorbax C-18, CH₃CN/H₂O/0.1%TFA) and was converted to bis-HCl salt to provide Example 4 as white solid (254 mg). Co-crystallization of the free base with 1 equivalent of L-tartaric acid in methanol gave a single crystal that was suitable for X-ray study. The X-ray structure with L-tartaric acid was assigned the R-configuration. MS (APCI) m/z 245 (M+H)⁺; ¹H NMR (500 MHz, D₂O): δ 2.00 (s, 3 H), 2.10-2.19 (m, 1 H), 2.30-2.39 (m, 1 H), 2.45-2.51 (m, 1 H), 2.61-2.66 (m, 1 H), 3.64-3.73 (m, 2 H), 7.40 (t, J=7.95 Hz, 1 H), 7.77 (d, J=8.11 Hz, 1 H), 7.80 (d, J=7.49 Hz, 1 H); Anal. Calcd for C₁₃H₁₆N₄O.2 HCl: C, 49.22; H, 5.72; N, 17.66. Found: C, 49.10; H, 5.52; N, 17.61.

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WO2009049111

http://www.google.com/patents/WO2009049111A1?cl=en

EXAMPLE 1 Preparation of ABT-888 Crystalline Form 1 A mixture of ABT-888 dihydrochloride (10 g) was stirred in saturated potassium bicarbonate (50 mL) and n-butanol (50 mL) until the ABT-888 dihydrochloride completely dissolved. The aqueous layer was extracted with a second portion of n-butanol then discarded. The extracts were combined, washed with 15% sodium chloride solution (50 mL) and concentrated. The concentrate was chase distilled three times with heptane (50 mL),dissolved in refluxing 2-propanol (45 mL) and filtered hot. The filtrate was cooled to ambient temperature with stirring over 18 hours, cooled to 0-5⁰C, stirred for 1 hour, and filtered. The filtrant was washed with 2-propanol and dried in a vacuum oven at 45-50⁰C with a slight nitrogen purge.

EXAMPLE 2

Preparation of ABT-888 Crystalline Form 2

A mixture of ABT-888 in methanol, in which the ABT-888 was completely dissolved, was concentrated at about 35 ⁰C, and the concentrate was dried to a constant weight.

EXAMPLE 3 Preparation of ABT-888 Crystalline Form 1

15 16

Step 1 : 2-(2-methyl-2-pyrrolidino)-benzimidazole-4-carboxamide 2 HCl (15) is dissolved in water (3.5 kg / kg 15) at 20 + 5 ⁰C. Dissolution of 15 in water results in a solution of pH 0 – 1.

Step 2: The reaction is run at 20 – 25 ⁰C. One equivalent of sodium hydroxide is added, raising the pH to 2 – 3 with only a mild exotherm (10⁰C observed with rapid addition of 1.0 equiv.). This generates a solution that remains clear for several days even when seeded with free base crystals. 3N NaOH (1.0 equiv., 1.25 kg / kg 15) is charged and the solution polish filtered into the crystallizer/ reactor.

Step 3: 5% Na₂CO₃ (1.5 equiv., 10.08 kg / kg 15) is then filtered into the crystallizer over 2 hours. Nucleation occurs after approximately l/6th of the Na₂CO₃ solution is added (-0.25 equiv.)

Step 4: The slurry is mixed for NLT 15 min before sampling (typically 1 to 4 hours (2.5 mg/mL product in the supernatant)). The slurry is filtered at 20⁰C and washed with 6 portions of water (1.0 kg / kg 15 each). Each wash was applied to the top of the cake and then pressured through. No mixing of the wetcake was done.

Step 5 : The solids are then dried. Drying was performed at 50⁰C keeping the Cogeim under vacuum while applying a slight nitrogen bleed. The agitator blade was left in the cake to improve heat transfer to the cake. It was rotated and lifted out of the cake once per hour of drying to speed the drying process while minimizing potential crystal attrition that occurs with continuous agitator use. In one embodiment of Step 1, the volume of water for dissolution of the Dihydrochloride (15) is about 1.3 g water/g 15. In another embodiment of Step 1,, the volume of water for dissolution is about 1.3 g to about 4 g water/g 15. In another embodiment of Step 1, the volume of water for dissolution is 1.3 g to 3.5 g water/g 15. In another embodiment of Step 1, the volume of water for dissolution is 3.5 g water/g 15.

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(2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide

excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of 3a (2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, ABT-888), currently in human phase I clinical trials. Compound 3a displayed excellent potency against both the PARP-1 and PARP-2 enzymes with a Ki of 5 nM and in a C41 whole cell assay with an EC50 of 2 nM. In addition, 3a is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast cancer xenograft model in combination with either carboplatin or cyclophosphamide.

References

External links

http://kdwn.com/2013/12/16/new-drug-study-method-show-breast-cancer-promise/

Penning, Thomas D. et al. Discovery of the Poly(ADP-ribose) Polymerase (PARP) Inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the Treatment of Cancer. Journal of Medicinal Chemistry, 52(2), 514-523; 2009

Zhu, Guidong. 2-​((R)​-​2-​Methylpyrrolidin-​2-​yl)​-​1H-​benzimidazole-​4-​carboxamide crystalline form 2 compositions and preparation for treating cancer. PCT Int. Appl. (2009), WO2009049109 A1 20090416

Kolaczkowski, Lawrence . 2-​((R)​-​2-​Methylpyrrolidin-​2-​yl)​-​1H-​benzimidazole-​4-​carboxamide (ABT-​888) crystalline form I and its pharmaceutical composition for cancer treatment. PCT Int. Appl. (2009), WO2009049111 A1 20090416.
Zhu, Gui-Dong; Gong, Jianchun; Gandhi, Virajkumar B.; Penning, Thomas D.; Giranda, Vincent L. Preparation of 1H-​benzimidazole-​4-​carboxamides as poly(ADP-​ribose)​polymerase (PARP) inhibitors. U.S. Pat. Appl. Publ. (2006), US20060229289 A1 20061012.