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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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Cetuximab sarotalocan sodium

Cetuximab Sarotalocan Sodium (Genetical Recombination)

Cetuximab Sarotalocan Sodium is an antibody-drug-conjugate (molecular weight: 156,000-158,000) consisting of tetrasodium salt of Sarotalocan (6-({[3-({(OC-6-13)-bis({3-[bis(3-sulfopropyl)(3-sulfonatopropyl)azaniumyl]propyl}dimethylsilanolato-κOO‘)[(phtalocyaninato(2-)κN29N30N31N32)-1-yl]silicon}oxy)propoxy]carbonyl}amino)hexanoyl (C70H96N11O24S6Si3; molecular weight: 1,752.22)) attached to an average of 2-3 Lys residues of Cetuximab.

[2166339-33-7 , Cetuximab sarotalocan]

Cetuximab sarotalocan sodium


Enarodustat (JAN).png
Enarodustat Chemical Structure



JTZ 951

Mol weight340.3333


Anti-anemic, Hypoxia inducible factor-prolyl hydroxylase (HIF-PH) inhibitor

Originator Japan Tobacco
Developer Japan Tobacco; JW Pharmaceutical
Class Acetic acids; Amides; Antianaemics; Pyridones; Small molecules; Triazoles
Mechanism of Action Hypoxia-inducible factor-proline dioxygenase inhibitors

Preregistration Anaemia

27 Dec 2019 Japan Tobacco and SalubrisBio enter into a development and marketing agreement for enarodustat (JTZ 951) in China, Hong Kong, Macau and Taiwan for Anaemia
29 Nov 2019 Preregistration for Anaemia in Japan (PO)
31 Oct 2019 Phase I development in Anaemia is ongoing in USA

Enarodustat is a potent and orally active factor prolyl hydroxylase inhibitor, with an EC50 of 0.22 μM. Enarodustat has the potential for renal anemia treatment


WO 2011007856


ACS Medicinal Chemistry Letters (2017), 8(12), 1320-1325


Abstract Image

Inhibition of hypoxia inducible factor prolyl hydroxylase (PHD) represents a promising strategy for the discovery of a next generation treatment for renal anemia. We identified several 5,6-fused ring systems as novel scaffolds of the PHD inhibitor on the basis of pharmacophore analysis. In particular, triazolopyridine derivatives showed potent PHD2 inhibitory activities. Examination of the predominance of the triazolopyridines in potency by electrostatic calculations suggested favorable π–π stacking interactions with Tyr310. Lead optimization to improve the efficacy of erythropoietin release in cells and in vivo by improving cell permeability led to the discovery of JTZ-951 (compound 14), with a 5-phenethyl substituent on the triazolopyridine group, which increased hemoglobin levels with daily oral dosing in rats. Compound 14 was rapidly absorbed after oral administration and disappeared shortly thereafter, which could be advantageous in terms of safety. Compound 14 was selected as a clinical candidate.

(7-Hydroxy-5-phenethyl-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)glycine (14)

To a solution of SI-5 (2.28 g, 6.19 mmol) in EtOH (9.1 mL) was added 2N NaOH aq. (12.4 mL, 24.8 mmol) at room temperature. After stirring at 90 °C for 2 h, 6N HCl aq. (4.1 mL, 24.6 mmol). This was allowed to gradually cool with stirring and crystals were precipitated. The crystals were collected by filtration to give the title compound 14 (2.16 g, 103% yield). 1H NMR (400 MHz, DMSO-D6) δ: 14.22 (s, 1H), 12.98 (br s, 1H), 9.84 (t, J = 5.6 Hz, 1H), 8.58 (s, 1H), 7.33– 7.18 (m, 5H), 6.80 (s, 1H), 4.22 (d, J = 5.6 Hz, 2H), 3.40 (t, J = 7.7 Hz, 2H), 3.12 (t, J = 7.7 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ: 170.28, 167.70, 165.32, 152.95, 148.53, 146.49, 140.05, 128.33, 128.20, 126.17, 106.72, 95.56, 41.00, 31.95, 31.72. HRMS m/z: [M+H]+ calcd for C17H17N4O4, 341.1244; found, 341.1243. Anal. (C17H16N4O4) calcd C 59.99%, H 4.74%, N 16.46%; found C 60.02%, H, 4.78%, N, 16.42%. Melting point: 186 °C Purity: 100.0%.


 WO 2018097254


US 20200017492

/////////////Enarodustat, 2020 APPROVALS, JAPAN 2020, エナロデュスタット  , JTZ 951, ENAROY, 2020 APPROVALS, 

Sofpironium bromide

Sofpironium bromide.png

File:Sofpironium bromide.jpg

Sofpironium bromide


BBI 4000

[(3R)-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidin-1-ium-3-yl] (2R)-2-cyclopentyl-2-hydroxy-2-phenylacetate;bromide

C22H32NO5. Br
BASE 1628251-49-9
Mol weight

PMDA APPROVED JAPAN 2020/9/25, Ecclock


Sofpironium Bromide

1-ambo-(3R)-3-{[(R)-(Cyclopentyl)hydroxy(phenyl)acetyl]oxy}-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidinium bromide

C22H32BrNO5 : 470.4



WO 2018026869

Certain glycopyrronium salts and related compounds, as well as processes for making and methods of using these glycopyrronium salts and related compounds, are known. See, for example, US Patent No. 8,558,008, which issued to assignee Dermira, Inc. See also, for example, US Patent No. 2,956,062, which issued to assignee Robins Co Inc. A H. See also, for example, International Patent Application Publication Nos. WO 98/00132 Al and WO 2009/00109A1, both of which list applicant Sepracor, Inc., as well as US Patent Nos. 6,063,808 and 6,204,285, both of which issued to assignee Sepracor, Inc. Certain methods of treating hyperhidrosis using glycopyrronium salts and related compounds are known. See, for example GB 1,080,960. Certain forms of applying glycopyrrolate compounds to a subject are known. See, for example US Patent Nos. 6,433,003 and 8,618,160, both of which issued to assignee Rose U; also US Patent Nos. 7,060,289; 8,252,316; and 8,679,524, which issued to PurePharm, Inc.

[0004] One glycopyrronium salt which is useful in certain medical applications is the following compound:

Figure imgf000003_0001

[0005] As illustrated above, the absolute configuration at the three asymmetric chiral positions is 2R3’R1’RS. This means that the carbon indicated with the number, 2, has the stereochemical R configuration. The carbon indicated with the number, 3′, also has the stereochemical R configuration. The quatemary ammonium nitrogen atom, indicated with a positive charge, may have either the R or the S stereochemical configuration. As drawn, the compound above is a mixture of two diastereoisomers.

[0006] Certain processes for making glycopyrronium salts are known. However, these processes are not as safe, efficient, stereospecific, or stereoselective as the new processes disclosed herein, for example with respect to large-scale manufacturing processes. Certain publications show that higher anticholinergic activity is attributed to the 2R3’R configuration. However, to date, processes for making the 2R3’R isomers, as well as the 2R3’R1’R isomers are low yielding, involve too many reaction steps to be economically feasible, use toxic materials, and/or are not sufficiently stereospecific or stereoselective with respect to the products formed.


[0179] The below synthetic description refers to the numbered compounds illustrated in FIG. 2. Numbers which refer to these compounds in FIG. 2 are bolded and underlined in this Example.

[0180] Synthesis of R(-)-Cyclopentylmandelic acid (4)

[0181] R(-)-cyclopentylmandelic acid (compound 4) can be synthesized starting with

R(-)-mandelic acid (compound 1) according to Example 1.

[0182] Step 1 : Making Compound 2.

[0183] R(-)-mandelic acid (1) was suspended in hexane and mixed with pivaldehyde and a catalytic amount of trifluoromethanesulfonic acid at room temperature to form a mixture. The mixture was warmed to 36 °C and then allowed to react for about 5 hours. The mixture was then cooled to room temperature and treated with 8% aqueous sodium bicarbonate. The aqueous layer was removed and the organic layer dried over anhydrous sodium sulfate. After filtration and removal of the solvent under vacuum, the crude product was recrystallized to give (5R)-2-(tert-butyl)-5-phenyl-l,3-dioxolan-4-one (compound 2) in 88% yield (per S-enantiomer yield).

[0184] Step 2: Making Compound 3.

[0185] Compound 2 was reacted with lithium hexamethyl disilazide (LiHMDS) in hexane at -78 °C under stirring for one hour. Next, cyclopentyl bromide was added to the reaction mixture including compound 2 and LiHMDS . The reaction was kept cool for about four (4) hours and then slowly warmed to room temperature and allowed to react for at least twelve (12) more hours. The resulting mixture was then treated with 10% aqueous ammonium chloride. The aqueous layer was discarded and the organic layer dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the residue recrystallized from hexane to give pure product (5R)-2-(tert-butyl)-5-cyclopentyl-5-phenyl- l,3-dioxolan-4-one (3) in 63% yield (per S-enantiomer yield).

[0186] Step 3: Making Compound 4.

[0187] R(-)-cyclopentylmandelic acid (compound 4) was prepared by providing compound 3 in aqueous methanolic potassium hydroxide at 65 °C for four hours. After cooling this mixture to room temperature and removing the methanol under vacuum, the aqueous solution was acidified with aqueous hydrochloric acid. The aqueous solution was then extracted twice with ethyl acetate and the organic phase dried with anhydrous sodium sulfate. After removing the solvent and performing a recrystallization, pure R(-)- cyclopentylmandelic acid (compound 4) was obtained in 62% yield (based on S-enantiomer yield).

[0188] Next, a racemic mixture of l -methyl-3-pyrridinol (20) was provided:

Figure imgf000045_0001

[0189] Synthesis of 2R3 ‘R-glycopyrrolate base (8)

[0190] Step 4: Making Compound 8.

[0191] Enantiomerically pure R(-)-cyclopentylmandelic acid (4) was coupled to racemic l-methyl-3-pyrridinol (20) using 1, 1 -carbonyldiimideazole (CDI) activated esterification to make an enantiomerically pure mixture of the following erythro- and threo- glycopyrrolate bases (compounds 8 and 21, respectively):

Figure imgf000045_0002

[0192] The 2R3’R-glycopyrrolate base (compound 8) was then resolved using the 5- nitroisophthalate salt procedure in Finnish Patent 49713, to provide enantiomerically pure 2R3 Έ. {erythro) as well as pure 2R3 ‘S {threo). In this example, the 2R3 ‘S {threo) was discarded. The 2R3 Έ. {erythro) was separated as stereomerically pure compound 8.

[0193] Step 6: Making Compound 9.

[0194] The glycopyrrolate base, compound 8, was treated in dry acetonitrile with methyl bromoacetate at room temperature under stirring for three (3) hours. The crude product was dissolved in a small volume of methylene chloride and poured into dry ethyl ether to obtain a precipitate. This procedure was repeated three times to provide (3R)-3-((R)- 2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-l -(2-ethoxy-2-oxoethyl)-l-methylpyrrolidin-l – ium bromide, also known as 3′(R)-[R-Cyclopentylphenylhydroxyacetoy]- -ethyl- l ‘methoxycarbonylpyrrolidinium bromide (compound 9) in 89% yield. Compound 9 included the following stereoisomers:

Figure imgf000046_0001


Synthesis of 9a, 9b, 13a, and 13b.

Synthesis of 9a, 9b, 13a, and 13b.

Publication Number Title Priority Date Grant Date
US-2019161443-A1 Processes for making, and methods of using, glycopyrronium compounds 2016-08-02

CTID Title Phase Status Date
NCT02058264 A Safety, Tolerability and Preliminary Efficacy Study of BBI-4000 in Subjects With Axillary Hyperhidrosis Phase 1 Completed 2014-09-11

NIPH Clinical Trials Search of Japan

CTID Title Phase Status Date
JapicCTI-184249 A repeatedly applied study of BBI-4000 in patients with primary hyperhidrosis complete 2018-12-13
JapicCTI-184003 A long term safety study of BBI-4000 gel in patients with primary axillary hyperhidrosis complete 2018-06-15
JapicCTI-183948 A confirmatory study of BBI-4000 gel in patients with primary axillary hyperhidrosis complete 2018-05-07
UMIN000020546 A skin irritation study of BBI-4000 in healthy adult males (phase 1) Complete: follow-up complete 2016-01-18

////////////Sofpironium bromide, Ecclock, 2020 APPROVALS, JAPAN 2020, Anhidrotic, ソフピロニウム臭化物 , BBI 4000


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