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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, 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...... , 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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CEP-26401 Irdabisant; Histamine H3 Receptor Antagonists


313.3941, C18 H23 N3 O2

Histamine H3 Receptor Antagonists in phase 1


3(2H)-Pyridazinone, 6-[4-[3-[(2R)-2-methyl-1-pyrrolidinyl]propoxy]phenyl]-




Cephalon Inc, innovator


CEP-26401 is a histamine H3 receptor antagonist in phase I clinical development at Cephalon to improve cognition in Alzheimer’s disease patients and for the treatment of schizophrenia. Cephalon was acquired by Teva in October 2011.


CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H3 receptor (H3R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H3R was demonstrated in radioligand binding displacement assays in rat brain membranes (Ki = 2.7 ± 0.3 nM) and recombinant rat and human H3R-expressing systems (Ki = 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively).

CEP-26401 displayed potent antagonist and inverse agonist activities in [35S]guanosine 5′-O-(γ-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H3R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC50 = 0.1 ± 0.003 mg/kg), and antagonism of the H3R agonist R-α-methylhistamine- induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED50 = 0.06 mg/kg).

CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H3R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders.

CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics


. …………………………. str revealed by


By Carmen Drahl • Posted in    




WO 2008013838 or

Example 11

    • Figure imgb0089

Step 1.

    • [0174]
      Figure imgb0090
    • A mixture of 1-(4-hydroxyphenyl)ethanone (20.4 g, 150 mmol), K2CO3 (62.1 g, 3.0 eq.), and 3-bromo-1-chloropropane (29.6 mL, 2.0 eq.) in CH3COCH3 (200 mL) was heated to 65 °C overnight. The mixture was filtered, washed with acetone, and concentrated to dryness. The crude product was dissolved in 150 mL of CH2Cl2, and washed with saturated NaHCO3, NaCl solution and dried over Na2SO4. Concentration to dryness under vaccum afforded product (31.5 g, 99 % yield): MS m/z 213 (M + H).

Step 2.

    • Figure imgb0091
    • A mixture of the product from step 1 1 (4.6 g, 1.0 eq.) and glyoxalic acid monohydrate (4.6g, 1.0 eq.) was stirred in 15 mL of acetic acid at 100 °C for 2 h. The solvent was evaporated and to the residue was added 25 mL of water, and cooled to 0 °C while conc. aqueous NH4OH was added to pH 8. To this mixture, hydrazine hydrate (4.76 mL, 2 eq.) was added and heated to 100 °C for 1 h. The resulting solid was filtered, washed with water. The crude material was dissolved in CH2Cl2/MeOH and purified by column chromatography with CH2Cl2 to 10 % MeOH in CH2Cl2; Mp 191-3 °C; MS m/z 265 (M + H).

Step 3.

  • Figure imgb0092
  • A mixture of the product from step 2 (5.5 g, 21 mmol), K2CO3 (3.5 eq, 10.1g), 100 mg ofNaI, and R-2-methylpyrrolidine hydrochloride (2 eq., 5.1 g) in 250 mL of acetonitrile was heated to 80 °C for 2 days. The reaction mixture was then filtered, washed with CH2Cl2 (2 x 50mL), and concentrated. The residue was dissolved in 200 mL of CH2Cl2, and washed with saturated NaHCO3, saturated NaCl, dried with Na2SO4 and concentrated. The residue was purified by ISCO graduate chromatography with 100% CH2Cl2 to 5%MeOH: 95% CH2Cl2:0.5 mL of 2-aminopropane and then to 10%MeOH: 90% CH2Cl2:0.5 mL of 2-aminopropane to give the product. The product was dissolved in 15 mL of MeOH and then added 30 mL of 0.5 N HCl in EtOH. Evaporation of the solvent, and crystallization from MeOH: Et2O afforded the example 11 as the HCl salt (2.65g, 41 %): Mp 240-2 °C; MS m/z 314 (M + H).



Bioorg Med Chem Lett. 2012 Jun 15;22(12):4198-202. doi: 10.1016/j.bmcl.2012.04.001.



Bioorganic and Medicinal Chemistry Letters, 2014 ,  vol. 24,   5  p. 1303 – 1306

Full-size image (14 K)


Journal of Medicinal Chemistry, 2011 ,  vol. 54,   13  p. 4781 – 4792

Abstract Image

6-{4-[3-(R)-2-Methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (8a)

A mixture of 7 (5.5 g, 21 mmol), K2CO3 (10.1 g, 73.5 mmol), NaI (100 mg), and (R)-2-methylpyrrolidine hydrochloride (5.1 g, 42 mmol) in acetonitrile (250 mL) was heated at 80 °C for 3 days. The reaction was complete by HPLC analysis. The mixture was filtered, washed with CH2Cl2 (2 × 50 mL), and concentrated. The residue was dissolved in CH2Cl2 (200 mL) and washed with saturated NaHCO3, saturated NaCl solution, dried with Na2SO4, and concentrated. The product was purified by ISCO chromatography using 100% CH2Cl2 to 9:1:05 CH2Cl2/MeOH/i-PrNH2. The pure product was dissolved in MeOH (15 mL), filtered through 0.45 μm filter, and then 30 mL of 0.5 N HCl in EtOH was added. The solvent was concentrated and the product crystallized from MeOH–ether to give 8a·HCl (2.65 g, 41%, 99% purity). Mp 240–242 °C (MeOH–ether). 1H NMR (DMSO-d6 δ): 1.39 (d, 3H, J = 6.8 Hz), 1.64 (m, 1H), 1.95 (m, 2H), 2.17 (m, 5H), 3.07 (m, 2H), 3.40 (m, 2H), 3.61 (m, 1H), 4.15 (m, 2H), 6.96 (d, 1H, J = 10.0 Hz), 7.05 (d, 2H, J = 8.64 Hz), 7.81 (d, 2H, J = 8.64 Hz), 8.0 (d, 1H, J = 10.0 Hz), 10.52 (bs, 1H), 13.08 (s, 1H). LCMS m/z: 314 (M + 1). Anal. (C18H23ClN3O2·0.4H2O) C, H, N.
Synthesis of 6-{4-[3-(R)-2-Methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (8a). Method B

3-Chloro-6-{4-[3-((R)-2-methylpyrrolodin-1-yl)propoxy]phenylpyridazine 13 (0.1 g 0.3 mmol) in 3 mL of glacial acetic acid and sodium acetate (0.027 g, 0.33 mmol) was heated to 115 °C for 2 h. The mixture was cooled to room temperature and then concentrated. The residue was dissolved in EtOAc and washed with saturated NaHCO3, saturated NaCl solution and dried over Na2SO4. The product was purified using ISCO silica gel chromatography (EtOAc/EtOH/NH4OH 9:1:0.5) to give 8a an off white solid (0.081 g, 86% yield, 98% purity). This compound was identical in its physical and spectral properties to that synthesized by method A.
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