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SEN 826

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SEN 826
CAS 1160833-51-1
C25 H31 N5 O, 417.55
Methanone, [1-[3-(1-methyl-1H-benzimidazol-2-yl)phenyl]-4-piperidinyl](4-methyl-1-piperazinyl)-
CAS HBr SALT 1612250-71-1

WO2009074300 product patent

Russell John Thomas, Mohr Gal.La Pericot, Giacomo Minetto, Annette Cornelia Bekker, Pietro Ferruzzi
Applicant Siena Biotech S.P.A.
Image result for Siena Biotech S.P.A.
Siena Biotech S.p.A. operates as a drug discovery and development company which develops a portfolio of disease modifying small molecule therapeutics for oncology and neurodegenerative diseases. Its products include blood-brain barrier penetrant compounds, which are in pipeline, for the treatment of brain cancers and peripheral tumors capable of metastasizing to the brain; clinical candidates for Alzheimer’s disease; and SEN196, a Sirtuin 1 inhibitor against Huntington disease. The company also provides contract research services, drug discovery, integrated chemistry, in-vitro technologies, and preclinical technologies. Siena Biotech S.p.A. has a strategic partnership with Aptuit Inc. The company was founded in 2000 and is based in Siena, Italy. Siena Biotech S.p.A operates as a subsidiary of THERAMetrics holding AG
Russell Thomas

Russell Thomas

https://www.linkedin.com/in/russell-thomas-0317464/

PLEASE MAIL ME AT amcrasto@gmail.com if picture is a mistake or cal +919323115463

The SMO receptor mediates Hedgehog (Hh) signaling critical to development, differentiation, growth, and cell migration. In normal conditions, activation of the pathway is induced by binding of specific endogenous ligands (i.e., Sonic Hh) to its receptor Patched (Ptch), which in turns reverts the Ptch inhibitory effect on SMO. SMO activation ultimately determines specific target genes activation through a family of three transcription factors, Gli1, Gli2 and Gli3.
Although Hh signaling is significantly curtailed in adults, it retains functional roles in stem cell maintenance, and aberrant Hh signaling has been described in a range of tumours.
Mutational inactivation of the inhibitory pathway components results in a constitutive ligand-independent activation seen in tumours such as basal cell carcinoma (BCC) and medulloblastoma. Ligand-dependent activation is seen in tumours such as prostate cancer, pancreatic cancer, gastrointestinal malignancies, melanoma, gliomas, breast cancer, ovarian cancer, leukemia, and B-cell lymphomas. A significant body of evidence supports the conclusion that SMO receptor antagonism will block the downstream signaling events.
As part of a program to address unmet medical need with regard to tumours in the CNS, Siena Biotech has designed and investigated selective antagonists of the SMO receptor. The newly designed API development candidate SEN826 1  is part of a group of potent antagonists of the Hedgehog pathway.
SYNTHESIS

PATENT

WO 2009074300

Figure imgf000025_0001

Figure imgf000019_0002

Figure

The synthesis starts with the formation of the 2-arylbenzimidazole derivative 6 which can be carried out starting from N-methylphenylenediamine 2 (Method A; blue path in Scheme 1) or employing o-phenylenediamine 4 in the ring closure reaction followed by N-methylation (Method B; orange path in Scheme 1). Sodium hydrogen sulfite is used to promote the condensation of the corresponding o-phenylenediamine with the Br-aromatic aldehyde 3.(6b) The next step is the coupling of the aryl bromide with isonipecotic ethyl ester in Buchwald conditions. After acidic hydrolysis with HCl under microwave irradiation, the final amide 1 was synthesized with CDI as coupling agent.

PAPER

A Scalable Route to the SMO Receptor Antagonist SEN826: Benzimidazole Synthesis via Enhanced in Situ Formation of the Bisulfite–Aldehyde Complex

Process Chemistry Unit, Siena Biotech SpA, 53100 Siena, Italy
Compound Management & Analysis Unit, Siena Biotech SpA, 53100 Siena, Italy
Org. Process Res. Dev., 2014, 18 (6), pp 699–708
Abstract Image

A practical and scalable route to the SMO antagonist SEN826 1 is described herein, including the discussion of an alternative approach to the synthesis of the target molecule. The optimized route consists of five chemical steps. A new and efficient access to the key intermediate 6 via the bisulfite–aldehyde complex was developed, significantly enhancing the yields and reducing costs. As a result, a synthetic procedure for preparation of multihundred gram quantities of the final product has been developed.

1 as hydrobromide salt. Yield: 71%.
UPLC–MS: tR = 1.24 min; m/z = 418 [M + 1]+.
HRMS calcd for C25H33N5O [M + 1]+ 418.26069, found 418.26075.
HPLC: tR = 5.99 min; purity 99.1%.
1H NMR (400 MHz DMSO-d6): δ 9.80 (broad, 1H), 7.89 (m, 1H), 7.77 (m, 1H), 7.55–7.45 (m, 3H), 7.38 (s, 1H), 7.24 (m, 2H), 4.48–4.15 (m, 2H), 3.96 (s, 3H), 3.86 (m, 2H), 3.55–3.15 (m, 3H), 3.10–2.82 (m, 6H), 2.81 (s, 3H), 1.76–1.57 (m, 4H).
13C NMR (100 MHz DMSO-d6): δ 173.5, 152.3, 151.5, 135.1, 135.0, 130.5, 126.2, 125.6, 125.3, 119.9, 119.1, 117.1, 116.5, 113.0, 53.2, 48.2, 42.7, 38.8, 37.4, 33.1, 28.2.
Water content (KF): 3.5 wt %.
Pd content (ICP-MS): 128 ppm.
Bromine content (ionic exchange LC): 20 wt % (1.2 equiv).
str1 str2
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DR ANTHONY CRASTO

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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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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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