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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 AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, 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 38 lakh plus views on New Drug Approvals Blog in 227 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 He has total of 32 International and Indian awards

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OTERACIL POTTASIUM

August 3, 2022 2:38 am / Leave a comment

ChemSpider 2D Image | RR4580000 | C4H2KN3O4

OTERACIL

UNII4R7FFA00RX, CAS Number2207-75-2, WeightAverage: 195.175, Monoisotopic: 194.96823705, Chemical FormulaC₄H₂KN₃O₄

[K+].OC1=NC(=NC(=O)N1)C([O-])=O

1,3,5-Triazine-2-carboxylic acid, 1,4,5,6-tetrahydro-4,6-dioxo-, potassium salt (1:1)

218-627-5[EINECS]

2207-75-2[RN]

4,6-Dihydroxy-1,3,5-triazine-2-carboxylic acid potassium salt

KOX
NSC 28841
Oxonate
Oxonate, potassium

CDSCO APPROVED,01.02.2022

File:Animated-Flag-India.gif - Wikimedia Commons

Gimeracil bulk & Oteracil potassium bulk and Tegafur 15mg/20mg, Gimeracil 4.35mg/5.8mg and Oteracil 11.8mg/15.8mg capsules

indicated in adults for the treatment of advanced gastric cancer when given in combination with cisplatin.

Oteracil Potassium is the potassium salt of oxonate, an enzyme inhibitor that modulates 5- fluorouracil (5-FU) toxicity. Potassium oxonate inhibits orotate phosphoribosyltransferase, which catalyzes the conversion of 5-FU to its active or phosphorylated form, FUMP. Upon oral administration, Oxonate is selectively distributed to the intracellular sites of tissues lining the small intestines, producing localized inhibitory effects within the gastrointestinal tract. As a result, 5-FU associated gastrointestinal toxic effects are reduced and the incidence of diarrhea or mucositis is decreased in 5-FU related therapy.

Oteracil is an adjunct to antineoplastic therapy, used to reduce the toxic side effects associated with chemotherapy. Approved by the European Medicines Agency (EMA) in March 2011, Oteracil is available in combination with Gimeracil and Tegafur within the commercially available product “Teysuno”. The main active ingredient in Teysuno is Tegafur, a pro-drug of Fluorouracil (5-FU), which is a cytotoxic anti-metabolite drug that acts on rapidly dividing cancer cells. By mimicking a class of compounds called “pyrimidines” that are essential components of RNA and DNA, 5-FU is able to insert itself into strands of DNA and RNA, thereby halting the replication process necessary for continued cancer growth.

Oteracil’s main role within Teysuno is to reduce the activity of 5-FU within normal gastrointestinal mucosa, and therefore reduce’s gastrointestinal toxicity ¹. It functions by blocking the enzyme orotate phosphoribosyltransferase (OPRT), which is involved in the production of 5-FU.

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RESEARCHGATE

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SYNTHESIS

https://patents.google.com/patent/CN103435566A/zh

SYN

https://europepmc.org/article/pmc/pmc7717319

Poje et al. reported a two-step, gram-scale preparation of the TS-1 additive oteracil 21 (Scheme 16).²²⁶ Iodine-mediated-oxidation of uric acid 116 produced dehydroallantoin 117 as the major product, and subsequent treatment with potassium hydroxide resulted in the rearranged product oteracil 21.²²⁷

An external file that holds a picture, illustration, etc.
Object name is nihms-1649941-f0037.jpg

Synthesis of Oteracil 21^a

^aReagents and conditions: (a) LiOH, I₂, H₂O, 5 °C, 5 min, then AcOH, 75%; (b) aq KOH, 20 min, rt, 82%.

(226) Poje M; Sokolić-Maravić L The mechanism for the conversion of uric acid into allantoin and dehydro-allantoin: A new look at an old problem. Tetrahedron 1986, 42 (2), 747–751. [Google Scholar]

(227) Sugi M; Igi M EP Patent 0957096, 1999.

EP0957096A1 *1998-05-111999-11-17SUMIKA FINE CHEMICALS Co., Ltd.Method for producing potassium oxonate

CN101475539A *2009-02-112009-07-08鲁南制药集团股份有限公司Refining method for preparing high-purity oteracil potassium

CN102250025A *2011-05-182011-11-23深圳万乐药业有限公司Preparation method suitable for industrially producing oteracil potassium

CN102746244A *2012-07-272012-10-24南京正大天晴制药有限公司Refining method of oteracil potassium

//////////OTERACIL POTTASIUM, KOX, NSC 28841, Oxonate, Oxonate potassium, INDIA 2022, APPROVALS 2022, CANCER

[K+].OC1=NC(=NC(=O)N1)C([O-])=O

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GIMERACIL

August 2, 2022 2:50 am / Leave a comment

GIMERACIL

C₅H₄ClNO_2, 145.54

103766-25-2

5-chloro-4-hydroxy-1H-pyridin-2-one

5-Chloro-2,4-dihydroxypyridine

5-chloropyridine-2,4-diol

5-Chloro-4-hydroxy-2(1H)-pyridone

Ts-1 (TN)

CDSCO APPROVED,01.02.2022

Gimeracil bulk & Oteracil potassium bulk and Tegafur 15mg/20mg, Gimeracil 4.35mg/5.8mg and Oteracil 11.8mg/15.8mg capsules

indicated in adults for the treatment of advanced gastric cancer when given in combination with cisplatin.

Combination of
Tegafur	Antineoplastic drug
Gimeracil	Enzyme inhibitor
Oteracil	Enzyme inhibitor
Clinical data
Trade names	Teysuno, TS-1
Other names	S-1^[1]
AHFS/Drugs.com	UK Drug Information
License data	EU EMA: by Tegafur
Pregnancy category	Contraindicated
Routes of administration	By mouth
ATC code	L01BC53 (WHO)
Legal status
Legal status	UK: POM (Prescription only) ^[2]EU: Rx-only ^[3]In general: ℞ (Prescription only)
Identifiers
CAS Number	150863-82-4
PubChem CID	54715158

Tegafur/gimeracil/oteracil, sold under the brand names Teysuno and TS-1,^[3]^[4] is a fixed-dose combination medication used for the treatment of advanced gastric cancer when used in combination with cisplatin,^[3] and also for the treatment of head and neck cancer, colorectal cancer, non–small-cell lung, breast, pancreatic, and biliary tract cancers.^[5]^: 213

The most common severe side effects when used in combination with cisplatin include neutropenia (low levels of neutrophils, a type of white blood cell), anaemia (low red blood cell counts) and fatigue (tiredness).^[3]

Tegafur/gimeracil/oteracil (Teysuno) was approved for medical use in the European Union in March 2011.^[3] It has not been approved by the U.S. Food and Drug Administration (FDA).^[5]^: 213

Medical uses

In the European Union tegafur/gimeracil/oteracil is indicated in adults for the treatment of advanced gastric cancer when given in combination with cisplatin.^[3]

Contraindications

In the European Union, tegafur/gimeracil/oteracil must not be used in the following groups:

people receiving another fluoropyrimidine (a group of anticancer medicines that includes tegafur/gimeracil/oteracil) or who have had severe and unexpected reactions to fluoropyrimidine therapy;^[3]
people known to have no DPD enzyme activity, as well as people who, within the previous four weeks, have been treated with a medicine that blocks this enzyme;^[3]
pregnant or breastfeeding women;^[3]
people with severe leucopenia, neutropenia, or thrombocytopenia (low levels of white cells or platelets in the blood);^[3]
people with severe kidney problems requiring dialysis;^[3]
people who should not be receiving cisplatin.^[3]

Mechanism of action

Tegafur is the actual chemotherapeutic agent. It is a prodrug of the active substance fluorouracil (5-FU).^[3] Tegafur, is a cytotoxic medicine (a medicine that kills rapidly dividing cells, such as cancer cells) that belongs to the ‘anti-metabolites’ group. Tegafur is converted to the medicine fluorouracil in the body, but more is converted in tumor cells than in normal tissues.^[3] Fluorouracil is very similar to pyrimidine.^[3] Pyrimidine is part of the genetic material of cells (DNA and RNA).^[3] In the body, fluorouracil takes the place of pyrimidine and interferes with the enzymes involved in making new DNA.^[3] As a result, it prevents the growth of tumor cells and eventually kills them.^[3]

Gimeracil inhibits the degradation of fluorouracil by reversibly blocking the dehydrogenase enzyme dihydropyrimidine dehydrogenase (DPD). This results in higher 5-FU levels and a prolonged half-life of the substance.^[6]

Oteracil mainly stays in the gut because of its low permeability, where it reduces the production of 5-FU by blocking the enzyme orotate phosphoribosyltransferase. Lower 5-FU levels in the gut result in a lower gastrointestinal toxicity.^[6]

Within the medication, the molar ratio of the three components (tegafur:gimeracil:oteracil) is 1:1:0.4.^[7]

The maximum tolerated dose differed between Asian and Caucasian populations (80 mg/m2 and 25 mg/m2 respectively), perhaps due to differences in CYP2A6 genotype.^[5]^: 213

Research

It is being developed for the treatment of hepatocellular carcinoma.^[8] and has activity in esophageal,(Perry Chapter 33) breast,^{[citation needed]} cervical,^{[citation needed]} and colorectal cancer.^[9]

Tegafur
Gimeracil
Oteracil potassium

References

^ Liu TW, Chen LT (201). “S-1 with leucovorin for gastric cancer: how far can it go?”. Lancet Oncol. 17 (1): 12–4. doi:10.1016/S1470-2045(15)00478-7. PMID 26640038.
^ “Teysuno 20mg/5.8mg/15.8mg hard capsules – Summary of Product Characteristics (SmPC)”. (emc). Retrieved 30 July 2020.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r “Teysuno EPAR”. European Medicines Agency (EMA). Retrieved 30 July 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ “ティーエスワン患者さん・ご家族向け総合情報サイト | 大鵬薬品工業株式会社”.
^ Jump up to:^a ^b ^c DeVita, DeVita; Lawrence, TS; Rosenberg, SA (2015). DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology (10th ed.). LWW. ISBN 978-1451192940.
^ Jump up to:^a ^b A. Klement (22 July 2013). “Dreier-Kombination gegen Magenkrebs: Teysuno”. Österreichische Apothekerzeitung (in German) (15/2013): 23.
^ Peters GJ, Noordhuis P, Van Kuilenburg AB et al. (2003). “Pharmacokinetics of S-1, an oral formulation of ftorafur, oxonic acid and 5-chloro-2,4-dihydroxypyridine (molar ratio 1:0.4:1) in patients with solid tumors”. Cancer Chemother. Pharmacol. 52 (1): 1–12. doi:10.1007/s00280-003-0617-9. PMID 12739060. S2CID 10858817.
^ “BCIQ”.
^ Miyamoto Y, Sakamoto Y, Yoshida N, Baba H (2014). “Efficacy of S-1 in colorectal cancer”. Expert Opin Pharmacother. 15 (12): 1761–70. doi:10.1517/14656566.2014.937706. PMID 25032886. S2CID 23637808.

External links

“Tegafur”. Drug Information Portal. U.S. National Library of Medicine.
“Gimeracil”. Drug Information Portal. U.S. National Library of Medicine.
“Oteracil”. Drug Information Portal. U.S. National Library of Medicine.

Gimeracil is an adjunct to antineoplastic therapy, used to increase the concentration and effect of the main active componets within chemotherapy regimens. Approved by the European Medicines Agency (EMA) in March 2011, Gimeracil is available in combination with Oteracil and Tegafur within the commercially available product “Teysuno”. The main active ingredient in Teysuno is Tegafur, a pro-drug of Fluorouracil (5-FU), which is a cytotoxic anti-metabolite drug that acts on rapidly dividing cancer cells. By mimicking a class of compounds called “pyrimidines” that are essential components of RNA and DNA, 5-FU is able to insert itself into strands of DNA and RNA, thereby halting the replication process necessary for continued cancer growth.

Gimeracil’s main role within Teysuno is to prevent the breakdown of Fluorouracil (5-FU), which helps to maintin high enough concentrations for sustained effect against cancer cells ². It functions by reversibly and selectively blocking the enzyme dihydropyrimidine dehydrogenase (DPD), which is involved in the degradation of 5-FU ¹. This allows higher concentrations of 5-FU to be achieved with a lower dose of tegafur, thereby also reducing toxic side effects.

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Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs. - Abstract - Europe PMC

An external file that holds a picture, illustration, etc. Object name is nihms-1649941-f0002.jpg

SYNTHESIS

https://www.semanticscholar.org/paper/A-Convenient-Synthesis-of-Gimeracil-Li-Zhu/8c04bd3d12699b5c7b9f55cf4723cc0aaf7e3d70

SYN

https://europepmc.org/article/pmc/pmc7717319

Synthesis of Gimeracil 20^a

^aReagents and conditions: (a) CH₃C(OCH₃)₃, MeOH, then (CH₃)₂NHCH(OCH₃)₂, reflux, 92%; (b) aq AcOH, 130 °C, 2 h, 95%; (c) SO₂Cl₂, HOAc, 50 °C, 0.5 h, 91%; (d) 40% H₂SO₄, 130 °C, 4 h, 91%; (e) SO₂Cl₂, HOAc, 50 °C, 45 min, 86%; (f) 75% H₂ SO₄, 140 °C, 3 h, then NaOH, then pH 4–4.5, 89%

In 1953, Kolder and Hertog reported a synthesis of the TS-1 additive gimeracil 20, which was completed in seven steps using 4-nitropyridine N-oxide as starting material.²²² Later, Yano et al. reported an alternative gram-scale synthesis (Scheme 15).²²³ The one-pot, three component condensation of malononitrile 111, 1,1,1-trimethoxyethane, and 1,1-dimethyoxytrimethylamine generated the dicyano intermediate 112, which was into 2(1H)-pyridinone 113.²²⁴ Selective chlorination of 113 was followed by acid-mediated demethylation, hydrolysis, and decarboxylation, to afford gimeracil 20. Interestingly, Xu et al. found that treatment of intermediate 113 with sulfuryl chloride resulted in dichloro 115 formation, which could still be converted to gimeracil 20 by treatment with sulfuric acid.²²⁵

(222) Kolder CR; den Hertog HJ Synthesis and reactivity of 5-chloro-2,4-dihydroxypyridine. Rec. Trav. Chim 1953, 72, 285–295. [Google Scholar]

(223) Yano S; Ohno T; Ogawa K Convenient and practical synthesis of 5-chloro-4-hydroxy-2(1H)-pyridinone. Heterocycles 1993, 36, 145–148. [Google Scholar]

(224) Mittelbach M; Kastner G; Junek H Synthesen mit Nitrilen, 71. Mitt. Zur Synthese von 4-Hydroxynicotinsaure aus Butadiendicarbonitrilen. Arch. Pharm 1985, 318 (6), 481–486. [Google Scholar]

(225) Xu Y; Mao D; Zhang F CN Patent 1915976, 2007.

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OC1=CC(=O)NC=C1Cl

Desidustat

July 9, 2020 4:52 am / Leave a comment

Ranjit Desai

Inventor of Oxemia (Desidustat), a breakthrough PHD inhibitor approved for Chronic Kidney Diseases (CKD) / Accomplished pharma executive / 4 INDs in 4 years, ZYDUS LIFESCIENCES

DESIDUSTAT

Formal Name

N-[[1-(cyclopropylmethoxy)-1,2-dihydro-4-hydroxy-2-oxo-3-quinolinyl]carbonyl]-glycine

CAS Number 1616690-16-4

Molecular Formula C₁₆H₁₆N₂O₆

Formula Weight 332.3

FormulationA crystalline solid

λ_max233, 291, 335

2-(1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid

desidustat

Glycine, N-((1-(cyclopropylmethoxy)-1,2-dihydro-4-hydroxy-2-oxo-3-quinolinyl)carbonyl)-

N-(1-(Cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycine

ZYAN1 compound

(1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl) glycine in 98% yield, as a solid. MS (ESI-MS): m/z 333.05 (M+H) ⁺. ¹H NMR (DMSO-d ₆): 0.44-0.38 (m, 2H), 0.62-0.53 (m, 2H), 1.34-1.24 (m, 1H), 4.06-4.04 (d, 2H), 4.14-4.13 (d, 2H), 7.43-7.39 (t, 1H), 7.72-7.70 (d, 1H), 7.89-7.85 (m, 1H), 8.11-8.09 (dd, 1H), 10.27-10.24 (t, 1H), 12.97 (bs, 1H), 16.99 (s, 1H). HPLC Purity: 99.85%

Desidustat | C16H16N2O6 - PubChem

Oxemia (Desidustat) has received approval from the Drug Controller General of India. This was an incredible team effort by Zydans across the organization and I am so proud of what we have accomplished. Oxemia is a breakthrough treatment for Anemia associated with Chronic Kidney Disease in Patients either on Dialysis or Not on Dialysis, and will help improve quality of life for CKD patients. Team #zydus , on to our next effort!

Desidustat (INN, also known as ZYAN1) is a drug for the treatment of anemia of chronic kidney disease. This drug with the brand name Oxemia is discovered and developed by Zydus Life Sciences.^[1] The subject expert committee of CDSCO has recommended the grant of permission for manufacturing and marketing of Desidustat 25 mg and 50 mg tablets in India,based on some conditions related to package insert, phase 4 protocols, prescription details, and GCP.^[2] Clinical trials on desidustat have been done in India and Australia.^[3] In a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study, a mean hemoglobin increase of 1.57, 2.22, and 2.92 g/dL in desidustat 100, 150, and 200 mg arms, respectively, was observed.^[4] The Phase 3 clinical trials were conducted at additional lower doses as of 2019.^[5] Desidustat is developed for the treatment of anemia as an oral tablet, where currently injections of erythropoietin and its analogues are drugs of choice. Desidustat is a HIF prolyl-hydroxylase inhibitor. In preclinical studies, effects of desidustat was assessed in normal and nephrectomized rats, and in chemotherapy-induced anemia. Desidustat demonstrated hematinic potential by combined effects on endogenous erythropoietin release and efficient iron utilization.^[6]^[7] Desidustat can also be useful in treatment of anemia of inflammation since it causes efficient erythropoiesis and hepcidin downregulation.^[8] In January 2020, Zydus entered into licensing agreement with China Medical System (CMS) Holdings for development and commercialization of desidustat in Greater China. Under the license agreement, CMS will pay Zydus an initial upfront payment, regulatory milestones, sales milestones and royalties on net sales of the product. CMS will be responsible for development, registration and commercialization of desidustat in Greater China.^[9] It has been observed that desidustat protects against acute and chronic kidney injury by reducing inflammatory cytokines like IL-6 and oxidative stress ^[10] A clinical trial to evaluate the efficacy and safety of desidustat tablet for the management of Covid-19 patients is ongoing in Mexico, wherein desidustat has shown to prevent acute respiratory distress syndrome (ARDS) by inhibiting IL-6.^[11] Zydus has also received approval from the US FDA to initiate clinical trials of desidustat in chemotherapy Induced anemia (CIA).^[12]. Desidustat has met the primary endpoints in the phase 3 clinical trials and Zydus had filed the New Drug Application (NDA) to DCGI in November, 2021.^[13]\

CLIP

https://www.businesstoday.in/industry/pharma/story/zydus-receives-dcgi-approval-for-new-drug-oxemia-what-you-need-to-know-324966-2022-03-07

Zydus receives DCGI approval for new drug Oxemia; what you need to know

The new drug is an oral, small molecule hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, Zydus said in a statement.

Gujarat-based pharma company Zydus Lifesciences on Monday received the Drugs Controller General of India (DCGI) approval for its new drug application for a first-of-its-kind oral treatment for anemia associated with Chronic Kidney Disease (CKD) – Oxemia (Desidustat).

The new drug is an oral, small molecule hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, the drug firm said in a statement.

Desidustat showed good safety profile, improved iron mobilization and LDL-C reduction in CKD patients in DREAM-D and DREAM-ND Phase III clinical trials, conducted in approximately 1,200 subjects. Desidustat provides CKD patients with an oral convenient therapeutic option for the treatment of anemia. The pharma major did not, however, declare the cost per dose if the drug is available in the market.

“After more than a decade of research and development into the science of HIF-PH inhibitors, results have demonstrated that Oxemia addresses this unmet need and additionally reduces hepcidin, inflammation and enables better iron mobilization. This advancement offers ease of convenience for the patient and will also reduce the disease burden by providing treatment at an affordable cost, thereby improving the quality of life for patients suffering from Chronic Kidney Disease,” Chairman of Zydus Lifesciences Pankaj Patel said.

Chronic Kidney Disease (CKD) is a progressive medical condition characterised by a gradual loss of kidney function and is accompanied by comorbidities like anemia, cardiovascular diseases (hypertension, heart failure and stroke), diabetes mellitus, eventually leading to kidney failure.

PATENT

US277539705

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=C922CC7937C0B6D7F987FE395E8B6F34.wapp2nB?docId=US277539705&_cid=P21-KCEB8C-83913-1

Patent applications WO 2004041818, US 20040167123, US 2004162285, US 20040097492 and US 20040087577 describes the utility of N-arylated hydroxylamines of formula (IV), which are intermediates useful for the synthesis of certain quinolone derivatives (VI) as inhibitors of hepatitis C (HCV) polymerase useful for the treatment of HCV infection. In these references, the compound of formula (IV) was prepared using Scheme 1 which involves partial reduction of nitro group and subsequent O-alkylation using sodium hydride as a base.

(MOL) (CDX)

The patent application WO 2014102818 describes the use of certain quinolone based compound of formula (I) as prolyl hydroxylase inhibitors for the treatment of anemia. Compound of formula (I) was prepared according to scheme 2 which involved partial reduction of nitro group and subsequent O-alkylation using cesium carbonate as a base.

(MOL) (CDX)

The drawback of process disclosed in WO 2014102818 (Scheme 2) is that it teaches usage of many hazardous reagents and process requires column chromatographic purification using highly flammable solvent at one of the stage and purification at multi steps during synthesis, which is not feasible for bulk production.

Scheme 3:

(MOL) (CDX)

Scheme 4.

(MOL) (CDX)

The process for the preparation of compound of formula (I-a) comprises the following steps:

Step 1′a Process for Preparation of ethyl 2-iodobenzoate (XI-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, Ethanol (1.25 L) charged at room temperature. 2-iodobenzoic acid (250 g, 1.00 mol) was added in one lot at room temperature. Sulphuric acid (197.7 g, 2.01 mol) was added carefully in to reaction mixture at 20 to 35° C. The reaction mixture was heated to 80 to 85° C. Reaction mixture was stirred for 20 hours at 80 to 85° C. After completion of reaction distilled out ethanol at below 60° C. The reaction mixture was cooled down to room temperature. Water (2.5 L) was then added carefully at 20 to 35° C. The reaction mixture was then charged with Ethyl acetate (1.25 L). After complete addition of ethyl acetate, reaction mixture turned to clear solution. At room temperature it was stirred for 5 to 10 minutes and separated aqueous layer. Aqueous layer then again extracted with ethyl acetate (1.25 L) and separated aqueous layer. Combined organic layer then washed with twice 10% sodium bicarbonate solution (2×1.25 L) and twice process water (2×1.25L) and separated aqueous layer. Organic layer then washed with 30% brine solution (2.5 L) and separated aqueous layer. Concentrated ethyl acetate in vacuo to get ethyl 2-iodobenzoate in 95% yield, as an oil, which was used in next the reaction, without any further purification. MS (ESI-MS): m/z 248.75 (M+H). ¹H NMR (CDCl ₃): 1.41-1.37 (t, 3H), 4.41-4.35 (q, 2H), 7.71-7.09 (m, 1H), 7.39-7.35 (m, 1H), 7.94-7.39 (m, 1H), 7.96-7.96 (d, 1H). HPLC Purity: 99.27%

Step-2 Process for the Preparation of ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)aminolbenzoate (XII-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, toluene (1.5 L) was charged at room temperature. Copper (I) iodide (15.3 g, 0.08 mol) was added in one lot at room temperature. Glycine (39.1 g, 0.520 mol) was added in one lot at room temperature. Reaction mixture was stirred for 20 minutes at room temperature. Ethyl 2-iodobenzoate (221.2 g, 0.801 mol) was added in one lot at room temperature. Tert-butyl (cyclopropylmethoxy)carbamate (150 g, 0.801 mol) was added in one lot at room temperature. Reaction mixture was stirred for 20 minutes at room temperature. Potassium carbonate (885.8 g, 6.408 mol) and ethanol (0.9 L) were added at 25° C. to 35° C. Reaction mixture was stirred for 30 minutes. The reaction mixture was refluxed at 78 to 85° C. for 24 hours. Reaction mixture was cooled to room temperature and stirred for 30 minutes. The reaction mixture was then charged with ethyl acetate (1.5 L). After complete addition of ethyl acetate, reaction mixture turned to thick slurry. At room temperature it was stirred for 30 minutes and the solid inorganic material was filtered off through hyflow supercel bed. Inorganic solid impurity was washed with ethyl acetate (1.5 L), combined ethyl acetate layer was washed with twice water (2×1.5 L) and separated aqueous layer. Organic layer washed with 30% sodium chloride solution (1.5 L) and separated aqueous layer. Ethyl acetate was concentrated in vacuo to get ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)amino)benzoate in 89% yield, as an oil, which was used in next the reaction, without any further purification. MS (ESI-MS): m/z 357.93 (M+Na). ¹H NMR (CDCl ₃): 0.26-0.23 (m, 2H), 0.52-0.48 (m, 2H), 1.10-1.08 (m, 1H), 1.38-1.35 (t, 3H), 1.51 (s, 9H), 3.78-3.76 (d, J=7.6 Hz, 2H), 4.35-4.30 (q, J=6.8 Hz, 2H), 7.29-7.25 (m, 1H), 7.49-7.47 (m, 2H), 7.78-7.77 (d, 1H). HPLC Purity: 88.07%

Step 3 Process for the Preparation of ethyl 2-((cyclopropylmethoxy)amino)benzoate (XIII-a)

(MOL) (CDX)

In a 10 L fixed glass assembly, dichloromethane (2.4 L) was charged at room temperature. Ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)amino)benzoate (200 g, 0.596 mol) was charged and cooled externally with ice-salt at 0 to 10° C. Methanolic HCl (688.3 g, 3.458 mol, 18.34% w/w) solution was added slowly drop wise, over a period of 15 minutes, while maintaining internal temperature below 10° C. Reaction mixture was warmed to 20 to 30° C., and stirred at 20 to 30° C. for 3 hours. The reaction mixture was quenched with addition of water (3.442 L). Upon completion of water addition, the reaction mixture turn out to light yellow coloured solution. At room temperature it was stirred for another 15 minutes and separated aqueous layer. Aqueous layer was again extracted with Dichloromethane (0.8 L). Combined dichloromethane layer then washed with 20% sodium chloride solution (1.0 L) and separated aqueous layer. Concentrated dichloromethane vacuo to get Ethyl 2-((cyclopropylmethoxy)amino)benzoate in 92% yield, as an oil. MS (ESI-MS): m/z 235.65 (M+H) ⁺. ¹H NMR (CDCl ₃): 0.35-0.31 (m, 2H), 0.80-0.59 (m, 2H), 0.91-0.85 (m, 1H), 1.44-1.38 (t, 3H), 3.76-3.74 (d, 2H), 4.36-4.30 (q, 2H), 6.85-6.81 (t, 1H), 7.36-7.33 (d, 1H), 7.92-7.43 (m, 1H), 7.94-7.93 (d, 1H), 9.83 (s, 1H). HPLC Purity: 87.62%

Step 4 Process for the Preparation of ethyl 24N-(cyclopropylinethoxy)-3-ethoxy-3-oxopropanamido)benzoate (XIV-a)

(MOL) (CDX)

In a 2 L fixed glass assembly, Acetonitrile (0.6 L) was charged at room temperature. Ethyl 2-((cyclopropylmethoxy)amino)benzoate (120 g, 0.510 mol) was charged at room temperature. Ethyl hydrogen malonate (74.1 g, 0.561 mol) was charged at room temperature. Pyridine (161.4 g, 2.04 mol) was added carefully in to reaction mass at room temperature and cooled externally with ice-salt at 0 to 10° C. Phosphorous oxychloride (86.0 g, 0.561 mol) was added slowly drop wise, over a period of 2 hours, while maintaining internal temperature below 10° C. Reaction mixture was stirred at 0 to 10° C. for 45 minutes. The reaction mixture was quenched with addition of water (1.0 L). Upon completion of water addition, the reaction mixture turns out to dark red coloured solution. Dichloromethane (0.672 L) was charged at room temperature and it was stirred for another 15 minutes and separated aqueous layer. Aqueous layer was again extracted with dichloromethane (0.672 L). Combined dichloromethane layer then washed with water (0.400 L) and 6% sodium chloride solution (0.400 L) and separated aqueous layer. Mixture of acetonitrile and dichloromethane was concentrated in vacuo to get Ethyl 2-(N-(cyclopropylmethoxy)-3-ethoxy-3-oxopropanamido)benzoate in 95% yield, as an oil. MS (ESI-MS): m/z 350.14 (M+H) ^l. ¹H NMR (DMSO-d ₆): 0.3-0.2 (m, 2H), 0.6-0.4 (m, 2H), 1.10-1.04 (m, 1H), 1.19-1.15 (t, 3H), 1.29-1.25 (t, 3H), 3.72-3.70 (d, 2H), 3.68 (s, 2H), 4.17-4.12 (q, 2H), 4.25-4.19 (q, 2H), 7.44-7.42 (d, 1H), 7.50-7.46 (t, 1H), 7.68-7.64 (m, 1H), 7.76-7.74 (d, 1H). HPLC Purity: 86.74%

Step 5: Process for the Preparation of ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2 dihydroquinolline-3-carboxylate (XY-a)

(MOL) (CDX)

In a 10 L fixed glass assembly under Nitrogen atmosphere, Methanol (0.736 L) was charged at room temperature. Ethyl 2-(N-(cyclopropylmethoxy)-3-ethoxy-3-oxopropanamido)benzoate (160 g, 0.457 mol) was charged at room temperature. Sodium methoxide powder (34.6 g, 0.641 mol) was added portion wise, over a period of 30 minutes, while maintaining internal temperature 10 to 20° C. Reaction mixture was stirred at 10 to 20° C. for 30 minutes. The reaction mixture was quenched with addition of ˜1N aqueous hydrochloric acid solution (0.64 L) to bring pH 2, over a period of 20 minutes, while maintaining an internal temperature 10 to 30° C. Upon completion of aqueous hydrochloric acid solution addition, the reaction mixture turned to light yellow coloured slurry. Diluted the reaction mass with water (3.02 L) and it was stirred for another 1 hour. Solid material was filtered off and washed twice with water (2×0.24 L). Dried the compound in fan dryer at temperature 50 to 55° C. for 6 hours to get crude ethyl 1-(cyclopropylmetboxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate as a solid.

Purification

In a 10 L fixed glass assembly, DMF (0.48 L) was charged at room temperature. Crude ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (120 g) was charged at room temperature. Upon completion of addition of crude compound, clear reaction mass observed. Reaction mixture stirred for 30 minutes at room temperature. Precipitate the product by addition of water (4.8 L), over a period of 30 minutes, while maintaining an internal temperature 25 to 45° C. Upon completion of addition of water, the reaction mixture turned to light yellow colored slurry. Reaction mixture was stirred at 25 to 45° C. for 30 minutes. Solid material was filtered off and washed with water (0.169 L). Dried the product in fan dryer at temperature 50 to 55° C. for 6 hours to get pure ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate in 81% yield, as a solid. MS (ESI-MS): m/z 303.90 (M+H) ⁺. ¹H NMR (DMSO-d ₆): 0.37-0.35 (m, 2H), 0.59-0.55 (m, 2H), 1.25-1.20 (m, 1H), 1.32-1.29 (t, 3H), 3.97-3.95 (d, 2H), 4.36-4.31 (q, 2H), 7.35-7.31 (in, 1H), 7.62-7.60 (dd, 1H), 7.81-7.77 (m, 1H), 8.06-7.04 (dd, 1H). HPLC Purity: 95.52%

Step 6 Process for the Preparation of ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate (XVI-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, tetrahydrofuran (0.5 L) was charged at room temperature. Ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (100 g, 0.329 mol) was charged at room temperature. Glycine ethyl ester HCl (50.7 g, 0.362 mol) was charged at room temperature. N,N-Diisopropylethyl amine (64 g, 0.494 mol) was added carefully in to reaction mass at room temperature and heated the reaction mass at 65 to 70° C. Reaction mixture was stirred at 65 to 70° C. for 18 hours. The reaction mixture was quenched with addition of water (2.5 L).

Upon completion of water addition, the reaction mixture turns out to off white to yellow coloured slurry. Concentrated tetrahydrofuran below 55° C. in vacuo and reaction mixture was stirred at 25 to 35° C. for 1 hour. Solid material was filtered off and washed with water (3×0.20 L). Dried the compound in fan dryer at temperature 55 to 60° C. for 8 hours to get crude ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate as a solid.

Purification

In a 2 L fixed glass assembly, Methanol (1.15 L) was charged at room temperature. Crude ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate (100 g) was charged at room temperature. The reaction mass was heated to 65 to 70° C. Reaction mass was stirred for 1 h at 65 to 70° C. Removed heating and cool the reaction mass to 25 to 35° C. Reaction mass stirred for 1 h at 25 to 35° C. Solid material was filtered off and washed with methanol (0.105 L). The product was dried under fan dryer at temperature 55 to 60° C. for 8 hours to get pure ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate in 80% yield, as a solid. MS (ESI-MS): m/z 360.85 (M+H) ⁺. ¹H NMR (DMSO-d ₆): 0.39 (m, 2H), 0.60-0.54 (m, 2H), 1.23-1.19 (t, 3H), 1.31-1.26 (m, 1H), 4.04-4.02 (d, 2H), 4.18-4.12 (q, 2H), 4.20-4.18 (d, 2H), 7.40-7.36 (m, 1H), 7.70-7.68 (d, 1H), 7.87-7.83 (m, 1H), 8.08-8.05 (dd, 1H), 10.27-10.24 (t, 1H). HPLC Purity: 99.84%

Step 7: Process for the Preparation of (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycine (I-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, methanol (0.525 L) was charged at room temperature. Ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (75 g, 0.208 mol) was charged at room temperature. Water (0.30 L) was charged at room temperature. Sodium hydroxide solution (20.8 g, 0.520 mol) in water (0.225 L) was added carefully at 30 to 40° C. Upon completion of addition of sodium hydroxide solution, the reaction mass turned to clear solution. Reaction mixture stirred for 30 minutes at 30 to 40° C. Diluted the reaction by addition of water (2.1 L). Precipitate the solid by addition of hydrochloric acid solution (75 mL) in water (75 mL). Upon completion of addition of hydrochloric acid solution, the reaction mass turned to off white colored thick slurry. Reaction mixture was stirred for 1 h at room temperature. Solid material was filtered off and washed with water (4×0.375 L). The compound was dried under fan dryer at temperature 25 to 35° C. for 6 hours and then dried for 4 hours at 50 to 60° C. to get (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl) glycine in 98% yield, as a solid. MS (ESI-MS): m/z 333.05 (M+H) ⁺. ¹H NMR (DMSO-d ₆): 0.44-0.38 (m, 2H), 0.62-0.53 (m, 2H), 1.34-1.24 (m, 1H), 4.06-4.04 (d, 2H), 4.14-4.13 (d, 2H), 7.43-7.39 (t, 1H), 7.72-7.70 (d, 1H), 7.89-7.85 (m, 1H), 8.11-8.09 (dd, 1H), 10.27-10.24 (t, 1H), 12.97 (bs, 1H), 16.99 (s, 1H). HPLC Purity: 99.85%

Polymorphic Data (XRPD):

References[edit]

^ “Zydus receives DCGI approval for new drug Oxemia; what you need to know”.
^ CDSCO, SEC Committee. “SEC meeting to examine IND proposals, dated 29.12.2021”. CDSCO website Govt of India. CDSCO. Retrieved 19 January 2022.
^ Kansagra KA, Parmar D, Jani RH, Srinivas NR, Lickliter J, Patel HV, et al. (January 2018). “Phase I Clinical Study of ZYAN1, A Novel Prolyl-Hydroxylase (PHD) Inhibitor to Evaluate the Safety, Tolerability, and Pharmacokinetics Following Oral Administration in Healthy Volunteers”. Clinical Pharmacokinetics. 57 (1): 87–102. doi:10.1007/s40262-017-0551-3. PMC 5766731. PMID 28508936.
^ Parmar DV, Kansagra KA, Patel JC, Joshi SN, Sharma NS, Shelat AD, Patel NB, Nakrani VB, Shaikh FA, Patel HV; on behalf of the ZYAN1 Trial Investigators. Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study. Am J Nephrol. 2019 May 21;49(6):470-478. doi: 10.1159/000500232.
^ “Zydus Cadila announces phase III clinical trials of Desidustat”. 17 April 2019. Retrieved 20 April 2019 – via The Hindu BusinessLine.
^ Jain MR, Joharapurkar AA, Pandya V, Patel V, Joshi J, Kshirsagar S, et al. (February 2016). “Pharmacological Characterization of ZYAN1, a Novel Prolyl Hydroxylase Inhibitor for the Treatment of Anemia”. Drug Research. 66 (2): 107–12. doi:10.1055/s-0035-1554630. PMID 26367279.
^ Joharapurkar AA, Pandya VB, Patel VJ, Desai RC, Jain MR (August 2018). “Prolyl Hydroxylase Inhibitors: A Breakthrough in the Therapy of Anemia Associated with Chronic Diseases”. Journal of Medicinal Chemistry. 61 (16): 6964–6982. doi:10.1021/acs.jmedchem.7b01686. PMID 29712435.
^ Jain M, Joharapurkar A, Patel V, Kshirsagar S, Sutariya B, Patel M, et al. (January 2019). “Pharmacological inhibition of prolyl hydroxylase protects against inflammation-induced anemia via efficient erythropoiesis and hepcidin downregulation”. European Journal of Pharmacology. 843: 113–120. doi:10.1016/j.ejphar.2018.11.023. PMID 30458168. S2CID 53943666.
^ Market, Capital (20 January 2020). “Zydus enters into licensing agreement with China Medical System Holdings”. Business Standard India. Retrieved 20 January 2020 – via Business Standard.
^ Joharapurkar, Amit; Patel, Vishal; Kshirsagar, Samadhan; Patel, Maulik; Savsani, Hardikkumar; Jain, Mukul (22 January 2021). “Prolyl hydroxylase inhibitor desidustat protects against acute and chronic kidney injury by reducing inflammatory cytokines and oxidative stress”. Drug Development Research. 82 (6): 852–860. doi:10.1002/ddr.21792. PMID 33480036. S2CID 231680317.
^ “Zydus’ trials of Desidustat shows positive results for Covid-19 management”. The Hindu Business Line. The Hindu. Retrieved 25 January 2021.
^ “Zydus receives approval from USFDA to initiate clinical trials of Desidustat in cancer patients receiving chemotherapy”. PipelineReview.com. La Merie Publishing. Retrieved 22 January 2021.
^ “Stock Share Price | Get Quote | BSE”.

ANALYSIS

https://patentscope.wipo.int/search/en/result.jsf?inchikey=IKRKQQLJYBAPQT-UHFFFAOYSA-N

Countries

Desidustat
Clinical data

Other names	ZYAN1
Identifiers
IUPAC name [show]
CAS Number	1616690-16-4
UNII	Y962PQA4KS
Chemical and physical data
Formula	C₁₆H₁₆N₂O₆
Molar mass	332.312 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] C1CC1CON2C3=CC=CC=C3C(=C(C2=O)C(=O)NCC(=O)O)O
InChI [hide] InChI=1S/C16H16N2O6/c19-12(20)7-17-15(22)13-14(21)10-3-1-2-4-11(10)18(16(13)23)24-8-9-5-6-9/h1-4,9,21H,5-8H2,(H,17,22)(H,19,20) Key:IKRKQQLJYBAPQT-UHFFFAOYSA-N

Date

CTID	Title	Phase	Status	Date
NCT04215120	Desidustat in the Treatment of Anemia in CKD on Dialysis Patients	Phase 3	Recruiting	2020-01-02
NCT04012957	Desidustat in the Treatment of Anemia in CKD	Phase 3	Recruiting	2019-12-24

////////// DESIDUSTAT, ZYDUS CADILA, COVID 19, CORONA VIRUS, PHASE 3, ZYAN 1, OXEMIA, APPROVALS 2022, INDIA 2022

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Ranjit Desai

Step 1′a Process for Preparation of ethyl 2-iodobenzoate (XI-a)

Step-2 Process for the Preparation of ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)aminolbenzoate (XII-a)

Step 3 Process for the Preparation of ethyl 2-((cyclopropylmethoxy)amino)benzoate (XIII-a)

Step 4 Process for the Preparation of ethyl 24N-(cyclopropylinethoxy)-3-ethoxy-3-oxopropanamido)benzoate (XIV-a)

Step 5: Process for the Preparation of ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2 dihydroquinolline-3-carboxylate (XY-a)

Purification

Step 6 Process for the Preparation of ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate (XVI-a)

Purification

Step 7: Process for the Preparation of (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycine (I-a)

Polymorphic Data (XRPD):

References[edit]

ANALYSIS

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