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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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AG 014699, Rucaparib


AG014699

AG 014699, Rucaparib


AG014699, the phosphate salt of AG14447, which has improved aqueous solubility, has been selected for clinical trial.AG014699 is a tricyclic indole poly(ADP-Ribose) polymerase (PARP) inhibitor with potential antineoplastic activity.



M.Wt: 421.3593
Formula: C19H21FN3O5P
CAS No: 459868-92-9

 

Figure

Rucaparib, PF-01367338283173-50-2  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-one8-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)
Clovis Oncology
WO 2014052550, WO 2014037313, WO 2000042040WO 2004087713WO 2005012305

Rucaparib (AG 014699) is a PARP inhibitor being investigated as a potential anti-cancer agent.

Rucaparib inhibits “the contraction of isolated vascular smooth muscle, including that from the tumours of cancer patients. It also reduces the migration of some cancer and normal cells in culture.”[1]

It can be taken orally in tablet form.[2]

It has undergone phase I clinical trials for patients with advanced solid tumours.[3] It is in phase II clinical trials for metastatic breastand ovarian cancer with known BRCA1 or BRCA2 mutation.[4][2]

It is thought that 20% of women with ovarian cancer who are not BRCA positive might also benefit from PARP inhibitors. Clinical trials are beginning (as of April, 2014)

As of November 2012 four clinical trials of rucaparib were recruiting patients.[5]
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 aloneRucaparib 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

 

Figure imgf000002_0001

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.

 

 

PATENT

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

Figure imgf000100_0001

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.

 

PAPER

Org. Process Res. Dev., 2012, 16 (12), pp 1897–1904
DOI: 10.1021/op200238p

http://pubs.acs.org/doi/full/10.1021/op200238pAbstract ImageNovel 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;
δH: (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);
δC: (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;
δH: (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);
δC: (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.
PATENT
WO 2006033003

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

 

Figure imgf000002_0001

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.

Figure imgf000011_0003

Figure imgf000011_0004

 

Example 13. Synthesis of 8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3.4.5-tetrahvdro-azepinor5.4.3- ccflindol-6-one (15) i

 

Figure imgf000018_0002

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.

UPDATES

 

  • OriginatorClovis Oncology; Foundation Medicine
  • ClassDiagnostic agents

Highest Development Phases

  • RegisteredOvarian cancer
  • Phase IIIFallopian tube cancer; Peritoneal cancer
  • Clinical Phase UnknownCancer

Most Recent Events

  • 19 Dec 2016Registered for Ovarian cancer (Diagnosis) in USA
  • 23 Aug 2016Preregistration for Ovarian cancer (Diagnosis) in USA (unspecified route)
  • 05 May 2016Clovis Oncology announces intention to submit PMA application to US FDA

CDxBRCA; FoundationFocus CDxBRCA; Rubraca companion diagnostic

Rucaparib phosphateis in phase Ⅲ clinical trials for the treatment of patients with advanced ovarian cancer, fallopian tube cancer and ovarian cancer.  It was granted breakthrough therapy designation by FDA for the treatment of ovarian cancer in 2015.

The compound was originally developed by Pfizer, then licensed to Clovis Oncology by Pfizer in 2011 for the treatment of cancer.

str1

str1

SYN FROM BOOK

str1

An external file that holds a picture, illustration, etc. Object name is nihms560379f1.jpg
Examples of PARP-1 inhibitors
1H NMR PREDICT
str2str1
13C NMR PREDICT
str1str2
A CLIP

Original synthesis procedure and route (DOI: 10.1021/op200238p)

Complete report here

Optimized route

Initial route:

  • 5-Fluoro-2-methylbenzoic acid (molbase): 550$/kg (84.78$/mol)
  • Phthalimidoacetaldehyde diethyl acetal (molbase): 2369$/kg (623.73$/mol)
  • 4-Formylphenylboronic acid (molbase) : 350 $/kg (52.48$/mol)

Total: 3269$/kg (760.99$/mol)

Optimized route:

  • 4-Bromobenzaldehyde (molbase): 101$/kg (18.69$/mol)
  • 5-Chlorovaleryl chloride (molbase): 141 $/kg (21.86$/mol)
  • 3,5-Difluorobenzonitrile (molbase): 150 $/kg (20.87$/mol)

Total: 392$/kg (61.42$/mol)

Process & R&D Chemist / C.Chem: Pharma & Micro-Electronic, Proces

https://davidleborgnechimie.blogspot.in/p/blog-page_6.html

Drug Name:Rucaparib PhosphateResearch Code:AG-014699; AG-14699; CO-338; PF-01367338Trade Name:MOA:Poly ADP-ribose polymerase (PARP) inhibitorIndication:Ovarian cancer; Fallopian tube cancer; Peritoneum cancerStatus:Phase III (Active)Company:Pfizer (Originator) , Clovis Oncology

283173-50-2 (Rucaparib );
459868-92-9 (Rucaparib Phosphate)

Route 1

Reference:1. WO2006033003A1.

Route 2

Reference:1. Org. Process Res. Dev. 2012, 16, 1897-1904.

 

Clovis Oncology receives Breakthrough Therapy designation for rucaparib for treatment of advanced ovarian cancer in patients with BRCA-mutated tumours

7 April 2015  •  Author: Victoria White

Clovis Oncology has announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for the Company’s investigational agent rucaparib as monotherapy treatment of advanced ovarian cancer in patients who have received at least two lines of prior platinum-containing therapy, with BRCA-mutated tumours, inclusive of both germline BRCA (gBRCA) and somatic BRCA (sBRCA) mutations.

http://www.europeanpharmaceuticalreview.com/30569/news/industry-news/clovis-oncology-receives-breakthrough-therapy-designation-for-rucaparib-for-treatment-of-advanced-ovarian-cancer-in-patients-with-brca-mutated-tumours/

2525 28th Street
Suite 100
Boulder, CO 80301
Tel: 303.625.5000
Fax: 303.245.0360

are a biopharmaceutical company focused on acquiring, developing and commercializing cancer treatments in the United States, Europe and other international markets. Our development programs are targeted at specific subsets of cancer, combining personalized medicine with companion diagnostics to direct therapeutics to those patients most likely to benefit from them.

We have three product candidates in clinical development: rociletinib (CO-1686), which is in Phase II development for the treatment of non-small cell lung cancer; rucaparib, which is in Phase II and Phase III clinical trials for the treatment of ovarian cancer; and lucitanib, which is in Phase II clinical trials for the treatment of breast and lung cancers. We have received Breakthrough Therapy designation from the FDA for rociletinib and rucaparib. We maintain global rights for rociletinib and rucaparib, and U.S. and Japanese rights to lucitanib.

Map of Boulder, CO 80301, USA

///////////

CNCc1ccc(cc1)-c1[nH]c2cc(F)cc3C(=O)NCCc1c23

Boulder, Colorado

 

 

  1. Boulder, Colorado – Wikipedia, the free encyclopedia

    en.wikipedia.org/wiki/Boulder,_Colorado

    Location in Boulder County and the State of Colorado. Coordinates: … ZIP codes,80301-80310, 80314, 80321-80323, 80328, 80329. Area code(s), Both 303  …

     

View of Boulder from Bear Peak

View of Boulder from Bear Peak

 

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PARP Inhibitor.. Veliparib (ABT-888) 维利帕尼


Veliparib skeletal.svg

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)

Also known as: ABT-888, 912444-00-9, ABT 888, carboxamide, CHEBI:62880, 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, ABT888, Veliparib
Molecular Formula: C13H16N4O   Molecular Weight: 244.29234

 

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 Yes
ChEMBL CHEMBL506871
Chemical data
Formula C13H16N4O 
Mol. mass 244.29 g/mol

 

2-10-2012
PARP1 TARGETED THERAPY
4-17-2009
2-{(R)-2-METHYLPYRROLIDIN-2-YL)-1H-BENZIMIDAZOLE-4-CARBOXAMIDE CRYSTALLINE FORM 1

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.

Synthesis of Veliparib_ABT-888_PARP inhibitor_cancer drug_ AbbVie 艾伯维抗肿瘤药物维利帕尼的化学合成

 

Chemical structure for Veliparib

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]

……………….

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)(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.

……………….

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

Figure imgf000021_0001

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.

 

……………………

J. Med. Chem.200952 (2), pp 514–523
DOI: 10.1021/jm801171j

Abstract Image

 

 

(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

  1.  “ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models” May 2007
  2.  http://www.cancer.gov/drugdictionary/?CdrID=496464
  3.  “ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models”, 2007
  4.  http://clinicaltrialsfeeds.org/clinical-trials/results/term=Drug:+ABT-888
  5.  “ABT-888 and Cyclophosphamide With Versus Without Doxorubicin in Treating Patients With Metastatic or Unresectable Solid Tumors or Non-Hodgkin Lymphoma”
  6.  Phase I Study of ABT-888, a PARP Inhibitor, in Combination with Topotecan Hydrochloride in Adults with Refractory Solid Tumors and Lymphomas.. July 2011. doi:10.1158/0008-5472.CAN-11-1227.
  7.  “A Study Evaluating Efficacy of ABT-888 in Combination With Temozolomide in Metastatic Melanoma”
  8.  “ABT-888 and Temozolomide for Metastatic Breast Cancer”
  9.  “Breast cancer study aims to speed drugs, cooperation”, March 2010
  10.  http://www.centerwatch.com/news-online/article/5737/new-presurgery-combination-therapy-for-triple-negative-breast-cancer
  11.  “Veliparib in Treating Patients With Malignant Solid Tumors That Did Not Respond to Previous Therapy. Clinical Trial NCT00892736”
4-1-2013
Design, synthesis and biological evaluation of novel imidazo[4,5-c]pyridinecarboxamide derivatives as PARP-1 inhibitors.
Bioorganic & medicinal chemistry letters
8-15-2013
Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose)polymerase inhibitors.
Bioorganic & medicinal chemistry letters
8-1-2013
Identification of potent Yes1 kinase inhibitors using a library screening approach.
Bioorganic & medicinal chemistry letters
5-1-2010
A rapid and sensitive method for determination of veliparib (ABT-888), in human plasma, bone marrow cells and supernatant by using LC/MS/MS.
Journal of pharmaceutical and biomedical analysis
1-22-2009
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

External links

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

US8013168 Oct 10, 2008 Sep 6, 2011 Abbott Laboratories Veliparib crystal structure; an anticancer PARP inhibitor
US8372987 Oct 10, 2008 Feb 12, 2013 Abbvie Inc. Title compound is Veliparib, a Poly(ADP-ribose) polymerase i.e. PARP inhibitor; anticancer agent
US20060229289 * Apr 11, 2006 Oct 12, 2006 Gui-Dong Zhu 2-(2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide, aka veliparib, for example; poly(ADP-ribose)polymerase inhibitors; antiinflammatory, antitumor agents; Parkinson’s disease

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.

 

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