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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 LIFE SCIENCES 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 PLUS year tenure till date June 2021, 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, 90 Lakh plus views on dozen plus blogs, 233 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 33 lakh plus views on New Drug Approvals Blog in 233 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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Tirzepatide


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Tirzepatide.svg
tirzepatide
ChemSpider 2D Image | tirzepatide | C225H347N47O69
Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing | Organic Process Research & Development

Tirzepatide

チルゼパチド

LY3298176,

FormulaC225H348N48O68
CAS2023788-19-2
Mol weight4813.4514

FDA APPROVED 2022/5/13, Mounjaro

ClassAntidiabetic agent
GLP-1 receptor agonist
EfficacyAntidiabetic, Gastric inhibitory polypeptide receptor agonist, Glucagon-like peptide 1 (GLP-1) receptor agonist
  DiseaseType 2 diabetes mellitus

Tirzepatide is an agonist of human glucose-dependent insulinotropic polypeptide (GIP) and human glucagon-like peptide-1 (GLP-1) receptors, whose amino acid residues at positions 2 and 13 are 2-methylAla, and the C-terminus is amidated Ser. A 1,20-icosanedioic acid is attached to Lys at position 20 via a linker which consists of a Glu and two 8-amino-3,6-dioxaoctanoic acids. Tirzepatide is a synthetic peptide consisting of 39 amino acid residues.

C225H348N48O68 : 4813.45
[2023788-19-2]

L-​Serinamide, L-​tyrosyl-​2-​methylalanyl-​L-​α-​glutamylglycyl-​L-​threonyl-​L-​phenylalanyl-​L-​threonyl-​L-​seryl-​L-​α-​aspartyl-​L-​tyrosyl-​L-​seryl-​L-​isoleucyl-​2-​methylalanyl-​L-​leucyl-​L-​α-​aspartyl-​L-​lysyl-​L-​isoleucyl-​L-​alanyl-​L-​glutaminyl-​N6-​[(22S)​-​22,​42-​dicarboxy-​1,​10,​19,​24-​tetraoxo-​3,​6,​12,​15-​tetraoxa-​9,​18,​23-​triazadotetracont-​1-​yl]​-​L-​lysyl-​L-​alanyl-​L-​phenylalanyl-​L-​valyl-​L-​glutaminyl-​L-​tryptophyl-​L-​leucyl-​L-​isoleucyl-​L-​alanylglycylglycyl-​L-​prolyl-​L-​seryl-​L-​serylglycyl-​L-​alanyl-​L-​prolyl-​L-​prolyl-​L-​prolyl-

Other Names

  • L-Tyrosyl-2-methylalanyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L-isoleucyl-2-methylalanyl-L-leucyl-L-α-aspartyl-L-lysyl-L-isoleucyl-L-alanyl-L-glutaminyl-N6-[(22S)-22,42-dicarboxy-1,10,19,24-tetraoxo-3,6,12,15-tetraoxa-9,18,23-triazadotetracont-1-yl]-L-lysyl-L-alanyl-L-phenylalanyl-L-valyl-L-glutaminyl-L-tryptophyl-L-leucyl-L-isoleucyl-L-alanylglycylglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-L-prolyl-L-serinamide

Tirzepatide, sold under the brand name Mounjaro,[1] is a medication used for the treatment type 2 diabetes.[2][3][4] Tirzepatide is given by injection under the skin.[2] Common side effects may include nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort and abdominal pain.[2]

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones involved in blood sugar control.[2] Tirzepatide is a first-in-class medication that activates both the GLP-1 and GIP receptors, which leads to improved blood sugar control.[2] Tirzepatide was approved for medical use in the United States in May 2022.[2]

SYN

https://pubs.acs.org/doi/10.1021/acs.oprd.1c00108

Abstract Image

The large-scale manufacture of complex synthetic peptides is challenging due to many factors such as manufacturing risk (including failed product specifications) as well as processes that are often low in both yield and overall purity. To overcome these liabilities, a hybrid solid-phase peptide synthesis/liquid-phase peptide synthesis (SPPS/LPPS) approach was developed for the synthesis of tirzepatide. Continuous manufacturing and real-time analytical monitoring ensured the production of high-quality material, while nanofiltration provided intermediate purification without difficult precipitations. Implementation of the strategy worked very well, resulting in a robust process with high yields and purity.

PATENT

  • WO2016111971
  • US2020023040
  • WO2019245893
  • US2020155487
  • US2020155650
  • WO2020159949CN112592387
  • WO2021066600CN112661815
  • WO2021154593
  • US2021338769

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Medical uses

Tirzepatide in indicated to improve blood sugar control in adults with type 2 diabetes, as an addition to diet and exercise.[2]

Contraindications

Tirzepatide should not be used in people with a personal or family history of medullary thyroid cancer or in people with multiple endocrine neoplasia syndrome type 2.[2]

Adverse effects

Preclinical, phase I, and phase II trials have indicated that tirzepatide exhibits similar adverse effects to other established GLP-1 receptor agonists, such as GLP-1 receptor agonist dulaglutide. These effects occur largely within the gastrointestinal tract.[5] The most frequently observed adverse effects are nausea, diarrhoea and vomiting, which increased in incidence with the dosage amount (i.e. higher likelihood the higher the dose). The number of patients who discontinued taking tirzepatide also increased as dosage increased, with patients taking 15 mg having a 25% discontinuation rate vs 5.1% for 5 mg patients and 11.1% for dulaglutide.[6] To a slightly lesser extent, patients also reported reduced appetite.[5] Other side effects reported were dyspepsia, constipation, abdominal pain, dizziness and hypoglycaemia.[7][8]

Pharmacology

Tirzepatide is an analogue of gastric inhibitory polypeptide (GIP), a human hormone which stimulates the release of insulin from the pancreas. Tirzepatide is a linear polypeptide of 39 amino acids which has been chemically modified by lipidation to improve its uptake into cells and its stability to metabolism.[9] The compound is administered as a weekly subcutaneous injection.[10] It completed phase III trials globally in 2021.[11][12]

Mechanism of action

Tirzepatide has a greater affinity to GIP receptors than to GLP-1 receptors, and this dual agonist behaviour has been shown to produce greater reductions of hyperglycemia compared to a selective GLP-1 receptor agonist.[3] Signaling studies have shown that this is due to tirzepatide mimicking the actions of natural GIP at the GIP receptor.[13] However, at the GLP-1 receptor, tirzepatide shows bias towards cAMP (a messenger associated with regulation of glycogen, sugar and lipid metabolism) generation, rather than β-arrestin recruitment. This combination of preference towards GIP receptor and distinct signaling properties at GLP-1 suggest this biased agonism increases insulin secretion.[13] Tirzepatide has also been shown to increase levels of adiponectin, an adipokine involved in the regulation of both glucose and lipid metabolism, with a maximum increase of 26% from baseline after 26 weeks, at the 10 mg dosage.[3]

Chemistry

Structure

Tirzepatide is an analog of the human GIP hormone with a C20 fatty-diacid portion attached, used to optimise the uptake and metabolism of the compound.[9] The fatty-diacid section (eicosanedioic acid) is linked via a glutamic acid and two (2-(2-aminoethoxy)ethoxy)acetic acid units to the side chain of the lysine residue. This arrangement allows for a much longer half life, extending the time between doses, because of its high affinity to albumin.[14]

Synthesis

The synthesis of tirzepatide was first disclosed in patents filed by Eli Lilly and Company.[15] This uses standard solid phase peptide synthesis, with an allyloxycarbonyl protecting group on the lysine at position 20 of the linear chain of amino acids, allowing a final set of chemical transformations in which the sidechain amine of that lysine is derivatized with the lipid-containing fragment.

Large-scale manufacturing processes have been reported for this compound.[16]

History

Indiana-based pharmaceutical company Eli Lilly and Company first applied for a patent for a method of glycemic control using tirzepatide in early 2016.[15] The patent was published late that year. After passing phase 3 clinical trials, Lilly applied for FDA approval in October 2021 with a priority review voucher.[17]

Following the completion of the pivotal SURPASS-2 trial no. NCT03987919, the company announced on 28 April that tirzepatide had successfully met their endpoints in obese and overweight patients without diabetes.[18] Alongside results from the SURMOUNT-1 trial no. NCT04184622, they suggest that tirzepatide may potentially be a competitor for existing diabetic medication semaglutide, manufactured by Novo Nordisk.[19][20]

In industry-funded preliminary trials comparing tirzepatide to the existing diabetes medication semaglutide (an injected analogue of the hormone GLP-1), tirzepatide showed minor improvement of reductions (2.01%–2.30% depending on dosage) in glycated hemoglobin tests relative to semaglutide (1.86%).[21] A 10 mg dose has also been shown to be effective in reducing insulin resistance, with a reduction of around 8% from baseline, measured using HOMA2-IR (computed with fasting insulin).[3] Fasting levels of IGF binding proteins like IGFBP1 and IGFBP2 increased following tirzepatide treatment, increasing insulin sensitivity.[3] A meta-analysis published by Dutta et al. showed that over 1-year clinical use, tirzepatide was observed to be superior to dulaglutide, semaglutide, degludec, and insulin glargine with regards to glycemic efficacy and obesity reduction. Tirzepatide is perhaps the most potent agent developed to date to tackle the global problem of “diabesity“.[22]

Society and culture

Names

Tirzepatide is the international nonproprietary name (INN).[23]

References

  1. Jump up to:a b “Highlights of prescribing information” (PDF). accessdata.fda.gov. FDA. May 2022. Retrieved 14 May 2022.
  2. Jump up to:a b c d e f g h i “FDA Approves Novel, Dual-Targeted Treatment for Type 2 Diabetes”U.S. Food and Drug Administration (FDA) (Press release). 13 May 2022. Retrieved 13 May 2022. Public Domain This article incorporates text from this source, which is in the public domain.
  3. Jump up to:a b c d e Thomas MK, Nikooienejad A, Bray R, Cui X, Wilson J, Duffin K, et al. (January 2021). “Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes”The Journal of Clinical Endocrinology and Metabolism106 (2): 388–396. doi:10.1210/clinem/dgaa863PMC 7823251PMID 33236115.
  4. ^ Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, et al. (December 2018). “LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept”Molecular Metabolism18: 3–14. doi:10.1016/j.molmet.2018.09.009PMC 6308032PMID 30473097.
  5. Jump up to:a b Min T, Bain SC (January 2021). “The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials”Diabetes Therapy12 (1): 143–157. doi:10.1007/s13300-020-00981-0PMC 7843845PMID 33325008.
  6. ^ Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, et al. (November 2018). “Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial”The Lancet392 (10160): 2180–2193. doi:10.1016/S0140-6736(18)32260-8PMID 30293770.
  7. ^ Frias JP, Nauck MA, Van J, Benson C, Bray R, Cui X, et al. (June 2020). “Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens”Diabetes, Obesity & Metabolism22 (6): 938–946. doi:10.1111/dom.13979PMC 7318331PMID 31984598.
  8. ^ Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, Rodríguez Á (February 2022). “Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial”. JAMA327 (6): 534–545. doi:10.1001/jama.2022.0078PMID 35133415.
  9. Jump up to:a b Ahangarpour M, Kavianinia I, Harris PW, Brimble MA (January 2021). “Photo-induced radical thiol-ene chemistry: a versatile toolbox for peptide-based drug design”. Chemical Society Reviews. Royal Society of Chemistry. 50 (2): 898–944. doi:10.1039/d0cs00354aPMID 33404559S2CID 230783854.
  10. ^ Bastin M, Andreelli F (2019). “Dual GIP-GLP1-Receptor Agonists In The Treatment Of Type 2 Diabetes: A Short Review On Emerging Data And Therapeutic Potential”Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy12: 1973–1985. doi:10.2147/DMSO.S191438PMC 6777434PMID 31686879.
  11. ^ “Tirzepatide significantly reduced A1C and body weight in people with type 2 diabetes in two phase 3 trials from Lilly’s SURPASS program” (Press release). Eli Lilly and Company. 17 February 2021. Retrieved 28 October 2021 – via PR Newswire.
  12. ^ “Lilly : Phase 3 Tirzepatide Results Show Superior A1C And Body Weight Reductions In Type 2 Diabetes”Business Insider. RTTNews. 19 October 2021. Retrieved 28 October 2021.
  13. Jump up to:a b Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, et al. (September 2020). “Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist”JCI Insight5 (17). doi:10.1172/jci.insight.140532PMC 7526454PMID 32730231.
  14. ^ Østergaard S, Paulsson JF, Kofoed J, Zosel F, Olsen J, Jeppesen CB, et al. (October 2021). “The effect of fatty diacid acylation of human PYY3-36 on Y2 receptor potency and half-life in minipigs”Scientific Reports11 (1): 21179. Bibcode:2021NatSR..1121179Odoi:10.1038/s41598-021-00654-3PMC 8551270PMID 34707178.
  15. Jump up to:a b US patent 9474780, Bokvist BK, Coskun T, Cummins RC, Alsina-Fernandez J, “GIP and GLP-1 co-agonist compounds”, issued 2016-10-25, assigned to Eli Lilly and Co
  16. ^ Frederick MO, Boyse RA, Braden TM, Calvin JR, Campbell BM, Changi SM, et al. (2021). “Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing”. Organic Process Research & Development25 (7): 1628–1636. doi:10.1021/acs.oprd.1c00108S2CID 237690232.
  17. ^ Sagonowsky, Eric (26 October 2021). “As Lilly gears up for key 2022 launches, Trulicity, Taltz and more drive solid growth”Fierce Pharma. Retrieved 9 April 2022.
  18. ^ Kellaher, Colin (28 April 2022). “Eli Lilly’s Tirzepatide Meets Main Endpoints in Phase 3 Obesity Study >LLY”Dow Jones Newswires. Retrieved 29 April 2022 – via MarketWatch.
  19. ^ Kahan, Scott; Garvey, W. Timothy (28 April 2022). “SURMOUNT-1: Adults achieve weight loss of 16% or more at 72 weeks with tirzepatide”healio.com. Retrieved 29 April 2022.
  20. ^ Taylor, Nick Paul (28 April 2022). “SURMOUNT-able: Lilly’s tirzepatide clears high bar set by Novo’s Wegovy in obesity”FierceBiotech. Retrieved 29 April 2022.
  21. ^ Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, et al. (August 2021). “Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes”. The New England Journal of Medicine385 (6): 503–515. doi:10.1056/NEJMoa2107519PMID 34170647S2CID 235635529.
  22. ^ Dutta D, Surana V, Singla R, Aggarwal S, Sharma M (November–December 2021). “Efficacy and safety of novel twincretin tirzepatide a dual GIP and GLP-1 receptor agonist in the management of type-2 diabetes: A Cochrane meta-analysis”. Indian Journal of Endocrinology and Metabolism25 (6): 475–489. doi:10.4103/ijem.ijem_423_21.
  23. ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81”. WHO Drug Information33 (1). hdl:10665/330896.

Further reading

External links

  • “Tirzepatide”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03954834 for “A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone (SURPASS-1)” at ClinicalTrials.gov
  • Clinical trial number NCT03987919 for “A Study of Tirzepatide (LY3298176) Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes (SURPASS-2)” at ClinicalTrials.gov
  • Clinical trial number NCT03882970 for “A Study of Tirzepatide (LY3298176) Versus Insulin Degludec in Participants With Type 2 Diabetes (SURPASS-3)” at ClinicalTrials.gov
  • Clinical trial number NCT03730662 for “A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)” at ClinicalTrials.gov
  • Clinical trial number NCT04039503 for “A Study of Tirzepatide (LY3298176) Versus Placebo in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin (SURPASS-5)” at ClinicalTrials.gov

CLIP

https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-mounjarotm-tirzepatide-injection-first-and

FDA approves Lilly’s Mounjaro™ (tirzepatide) injection, the first and only GIP and GLP-1 receptor agonist for the treatment of adults with type 2 diabetes

May 13, 2022

Download PDF

Mounjaro delivered superior A1C reductions versus all comparators in phase 3 SURPASS clinical trials

While not indicated for weight loss, Mounjaro led to significantly greater weight reductions versus comparators in a key secondary endpoint

Mounjaro represents the first new class of diabetes medicines introduced in nearly a decade and is expected to be available in the U.S. in the coming weeks

INDIANAPOLIS, May 13, 2022 /PRNewswire/ — The U.S. Food and Drug Administration (FDA) approved Mounjaro™ (tirzepatide) injection, Eli Lilly and Company’s (NYSE: LLY) new once-weekly GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Mounjaro has not been studied in patients with a history of pancreatitis and is not indicated for use in patients with type 1 diabetes mellitus.

As the first and only FDA-approved GIP and GLP-1 receptor agonist, Mounjaro is a single molecule that activates the body’s receptors for GIP and GLP-1, which are natural incretin hormones.1

“Mounjaro delivered superior and consistent A1C reductions against all of the comparators throughout the SURPASS program, which was designed to assess Mounjaro’s efficacy and safety in a broad range of adults with type 2 diabetes who could be treated in clinical practice. The approval of Mounjaro is an exciting step forward for people living with type 2 diabetes given the results seen in these clinical trials,” said Juan Pablo Frías, M.D., Medical Director, National Research Institute and Investigator in the SURPASS program.

Mounjaro will be available in six doses (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg) and will come in Lilly’s well-established auto-injector pen with a pre-attached, hidden needle that patients do not need to handle or see.

The approval was based on results from the phase 3 SURPASS program, which included active comparators of injectable semaglutide 1 mg, insulin glargine and insulin degludec. Efficacy was evaluated for Mounjaro 5 mg, 10 mg and 15 mg used alone or in combination with commonly prescribed diabetes medications, including metformin, SGLT2 inhibitors, sulfonylureas and insulin glargine. Participants in the SURPASS program achieved average A1C reductions between 1.8% and 2.1% for Mounjaro 5 mg and between 1.7% and 2.4% for both Mounjaro 10 mg and Mounjaro 15 mg. While not indicated for weight loss, mean change in body weight was a key secondary endpoint in all SURPASS studies. Participants treated with Mounjaro lost between 12 lb. (5 mg) and 25 lb. (15 mg) on average.1

Side effects reported in at least 5% of patients treated with Mounjaro include nausea, diarrhea, decreased appetite, vomiting, constipation, indigestion (dyspepsia), and stomach (abdominal) pain. The labeling for Mounjaro contains a Boxed Warning regarding thyroid C-cell tumors. Mounjaro is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.1

“Lilly has a nearly 100-year heritage of advancing care for people living with diabetes – never settling for current outcomes. We’re not satisfied knowing that half of the more than 30 million Americans living with type 2 diabetes are not reaching their target blood glucose levels,” said Mike Mason, president, Lilly Diabetes. “We are thrilled to introduce Mounjaro, which represents the first new class of type 2 diabetes medication introduced in almost a decade and embodies our mission to bring innovative new therapies to the diabetes community.”

Mounjaro is expected to be available in the United States in the coming weeks. Lilly is committed to helping people access the medicines they are prescribed and will work with insurers, health systems and providers to help enable patient access to Mounjaro. Lilly plans to offer a Mounjaro savings card for people who qualify. Patients or healthcare professionals with questions about Mounjaro can visit www.Mounjaro.com or call The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979).

Tirzepatide is also under regulatory review for the treatment of type 2 diabetes in Europe, Japan and several additional markets. A multimedia gallery is available on Lilly.com.

About the SURPASS clinical trial program
The SURPASS phase 3 global clinical development program for tirzepatide began in late 2018 and included five global registration trials and two regional trials in Japan. These studies ranged from 40 to 52 weeks and evaluated the efficacy and safety of Mounjaro 5 mg, 10 mg and 15 mg as a monotherapy and as an add-on to various standard-of-care medications for type 2 diabetes. The active comparators in the studies were injectable semaglutide 1 mg, insulin glargine and insulin degludec. Collectively, the five global registration trials consistently demonstrated A1C reductions for participants taking Mounjaro across multiple stages of their type 2 diabetes journeys, from an average around five to 13 years of having diabetes.2-8

  • SURPASS-1 (NCT03954834) was a 40-week study comparing the efficacy and safety of Mounjaro 5 mg (N=121), 10 mg (N=121) and 15 mg (N=120) as monotherapy to placebo (N=113) in adults with type 2 diabetes inadequately controlled with diet and exercise alone. From a baseline A1C of 7.9%, Mounjaro reduced participants’ A1C by a mean of 1.8%* (5 mg) and 1.7%* (10 mg and 15 mg) compared to 0.1% for placebo. In a key secondary endpoint, from a baseline weight of 189 lb., Mounjaro reduced participants’ weight by a mean of 14 lb.* (5 mg), 15 lb.* (10 mg) and 17 lb.* (15 mg) compared to 2 lb. for placebo.2,3
  • SURPASS-2 (NCT03987919) was a 40-week study comparing the efficacy and safety of Mounjaro 5 mg (N=470), 10 mg (N=469) and 15 mg (N=469) to injectable semaglutide 1 mg (N=468) in adults with type 2 diabetes inadequately controlled with ≥1500 mg/day metformin alone. From a baseline A1C of 8.3%, Mounjaro reduced participants’ A1C by a mean of 2.0% (5 mg), 2.2%* (10 mg) and 2.3%* (15 mg) compared to 1.9% for semaglutide. In a key secondary endpoint, from a baseline weight of 207 lb., Mounjaro reduced participants’ weight by a mean of 17 lb. (5 mg), 21 lb.* (10 mg) and 25 lb.* (15 mg) compared to 13 lb. for semaglutide.4,5
  • SURPASS-3 (NCT03882970) was a 52-week study comparing the efficacy of Mounjaro 5 mg (N=358), 10 mg (N=360) and 15 mg (N=358) to titrated insulin degludec (N=359) in adults with type 2 diabetes treated with metformin with or without an SGLT-2 inhibitor. From a baseline A1C of 8.2%, Mounjaro reduced participants’ A1C by a mean of 1.9%* (5 mg), 2.0%* (10 mg) and 2.1%* (15 mg) compared to 1.3% for insulin degludec. From a baseline weight of 208 lb., Mounjaro reduced participants’ weight by a mean of 15 lb.* (5 mg), 21 lb.* (10 mg) and 25 lb.* (15 mg) compared to an increase of 4 lb. for insulin degludec.6
  • SURPASS-4 (NCT03730662) was a 104-week study comparing the efficacy and safety of Mounjaro 5 mg (N=328), 10 mg (N=326) and 15 mg (N=337) to insulin glargine (N=998) in adults with type 2 diabetes inadequately controlled with at least one and up to three oral antihyperglycemic medications (metformin, sulfonylureas or SGLT-2 inhibitors), who have increased cardiovascular (CV) risk. The primary endpoint was measured at 52 weeks. From a baseline A1C of 8.5%, Mounjaro reduced participants’ A1C by a mean of 2.1%* (5 mg), 2.3%* (10 mg) and 2.4%* (15 mg) compared to 1.4% for insulin glargine. From a baseline weight of 199 lb., Mounjaro reduced weight by a mean of 14 lb.* (5 mg), 20 lb.* (10 mg) and 23 lb.* (15 mg) compared to an increase of 4 lb. for insulin glargine.7
  • SURPASS-5 (NCT04039503) was a 40-week study comparing the efficacy and safety of Mounjaro 5 mg (N=116), 10 mg (N=118) and 15 mg (N=118) to placebo (N=119) in adults with inadequately controlled type 2 diabetes already being treated with insulin glargine, with or without metformin. From a baseline A1C of 8.3%, Mounjaro reduced A1C by a mean of 2.1%* (5 mg), 2.4%* (10 mg) and 2.3%* (15 mg) compared to 0.9% for placebo. From a baseline weight of 210 lb., Mounjaro reduced participants’ weight by a mean of 12 lb.* (5 mg), 17 lb.* (10 mg) and 19 lb.* (15 mg) compared to an increase of 4 lb. for placebo.8

*p<0.001 for superiority vs. placebo or active comparator, adjusted for multiplicity
p<0.05 for superiority vs. semaglutide 1 mg, adjusted for multiplicity

About Mounjaro™ (tirzepatide) injection1
Mounjaro™ (tirzepatide) injection is FDA-approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. As the first and only FDA-approved GIP and GLP-1 receptor agonist, Mounjaro is a single molecule that activates the body’s receptors for GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1). Mounjaro will be available in six doses (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg) and will come in Lilly’s well-established auto-injector pen with a pre-attached, hidden needle that patients do not need to handle or see.

PURPOSE AND SAFETY SUMMARY WITH WARNINGS
Important Facts About MounjaroTM (mown-JAHR-OH). It is also known as tirzepatide.

  • Mounjaro is an injectable prescription medicine for adults with type 2 diabetes used along with diet and exercise to improve blood sugar (glucose).
  • It is not known if Mounjaro can be used in people who have had inflammation of the pancreas (pancreatitis). Mounjaro is not for use in people with type 1 diabetes. It is not known if Mounjaro is safe and effective for use in children under 18 years of age.

Warnings
Mounjaro may cause tumors in the thyroid, including thyroid cancer. Watch for possible symptoms, such as a lump or swelling in the neck, hoarseness, trouble swallowing, or shortness of breath. If you have a symptom, tell your healthcare provider.

  • Do not use Mounjaro if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC).
  • Do not use Mounjaro if you have Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
  • Do not use Mounjaro if you are allergic to tirzepatide or any of the ingredients in Mounjaro.

Mounjaro may cause serious side effects, including:

Inflammation of the pancreas (pancreatitis). Stop using Mounjaro and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back.

Low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use Mounjaro with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include dizziness or light-headedness, sweating, confusion or drowsiness, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability, or mood changes, hunger, weakness and feeling jittery.

Serious allergic reactions. Stop using Mounjaro and get medical help right away if you have any symptoms of a serious allergic reaction, including swelling of your face, lips, tongue or throat, problems breathing or swallowing, severe rash or itching, fainting or feeling dizzy, and very rapid heartbeat.

Kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration), which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration.

Severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use Mounjaro. Tell your healthcare provider if you have stomach problems that are severe or will not go away.

Changes in vision. Tell your healthcare provider if you have changes in vision during treatment with Mounjaro.

Gallbladder problems. Gallbladder problems have happened in some people who use Mounjaro. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include pain in your upper stomach (abdomen), fever, yellowing of skin or eyes (jaundice), and clay-colored stools.

Common side effects
The most common side effects of Mounjaro include nausea, diarrhea, decreased appetite, vomiting, constipation, indigestion, and stomach (abdominal) pain. These are not all the possible side effects of Mounjaro. Talk to your healthcare provider about any side effect that bothers you or doesn’t go away.

Tell your healthcare provider if you have any side effects. You can report side effects at 1-800-FDA-1088 or www.fda.gov/medwatch.

Before using

  • Your healthcare provider should show you how to use Mounjaro before you use it for the first time.
  • Before you use Mounjaro, talk to your healthcare provider about low blood sugar and how to manage it.

 Review these questions with your healthcare provider:

  • Do you have other medical conditions, including problems with your pancreas or kidneys, or severe problems with your stomach, such as slowed emptying of your stomach (gastroparesis) or problems digesting food?
  • Do you take other diabetes medicines, such as insulin or sulfonylureas?
  • Do you have a history of diabetic retinopathy?
  • Are you pregnant or plan to become pregnant or breastfeeding or plan to breastfeed? It is not known if Mounjaro will harm your unborn baby.
  • Do you take birth control pills by mouth? These may not work as well while using Mounjaro. Your healthcare provider may recommend another type of birth control when you start Mounjaro or when you increase your dose.
  • Do you take any other prescription medicines or over-the-counter drugs, vitamins, or herbal supplements?

How to take

  • Read the Instructions for Use that come with Mounjaro.
  • Use Mounjaro exactly as your healthcare provider says.
  • Mounjaro is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm.
  • Use Mounjaro 1 time each week, at any time of the day.
  • Do not mix insulin and Mounjaro together in the same injection.
  • If you take too much Mounjaro, call your healthcare provider or seek medical advice promptly.

Learn more
For more information, call 1-800-LillyRx (1-800-545-5979) or go to www.mounjaro.com.

This information does not take the place of talking with your healthcare provider. Be sure to talk to your healthcare provider about Mounjaro and how to take it. Your healthcare provider is the best person to help you decide if Mounjaro is right for you.

MounjaroTM and its delivery device base are trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

Please click to access full Prescribing Information and Medication Guide.

TR CON CBS MAY2022

About Lilly
Lilly unites caring with discovery to create medicines that make life better for people around the world. We’ve been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 47 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world’s most significant health challenges, redefining diabetes care, treating obesity and curtailing its most devastating long-term effects, advancing the fight against Alzheimer’s disease, providing solutions to some of the most debilitating immune system disorders, and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we’re motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/newsroom or follow us on FacebookInstagramTwitter and LinkedIn. P-LLY

Lilly Cautionary Statement Regarding Forward-Looking Statements

This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Mounjaro™ (tirzepatide 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg and 15 mg) injection as a treatment to improve glycemic control in adults with type 2 diabetes, the timeline for supply of Mounjaro to become available, and certain other milestones and ongoing clinical trials of Mounjaro and reflects Lilly’s current beliefs and expectations. However, as with any pharmaceutical product or medical device, there are substantial risks and uncertainties in the process of research, development and commercialization. Among other things, there can be no guarantee that Mounjaro will be commercially successful, that future study results will be consistent with results to date, or that we will meet our anticipated timelines for the commercialization of Mounjaro. For further discussion of these and other risks and uncertainties, see Lilly’s most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

References

  1. Mounjaro. Prescribing Information. Lilly USA, LLC.
  2. Rosenstock, J, et. al. Efficacy and Safety of Once Weekly Tirzepatide, a Dual GIP/GLP-1 Receptor Agonist Versus Placebo as Monotherapy in People with Type 2 Diabetes (SURPASS-1). Abstract 100-OR. Presented virtually at the American Diabetes Association’s 81st Scientific Sessions; June 25-29.
  3. Rosenstock, J, et. al. (2021). Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143-155. doi: 10.1016/S0140-6736(21)01324-6.
  4. Frías JP, Davies MJ, Rosenstock J, et al; for the SURPASS-2 Investigators. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6)(suppl):503-515. doi: 10.1056/NEJMoa2107519
  5. Frias, J.P. Efficacy and Safety of Tirzepatide vs. Semaglutide Once Weekly as Add-On Therapy to Metformin in Patients with Type 2 Diabetes. Abstract 84-LB. Presented virtually at the American Diabetes Association’s 81st Scientific Sessions; June 25-29.
  6. Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 2021;398(10300):583-598. doi: 10.1016/S0140-6736(21)01443-4
  7. Del Prato S, Kahn SE, Pavo I, et al; for the SURPASS-4 Investigators. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet. 2021;398(10313):1811-1824. doi: 10.1016/S0140-6736(21)02188-7
  8. Dahl D, Onishi Y, Norwood P, et al. Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial. JAMA. 2022;327(6):534-545. doi:10.1001/jama.2022.0078

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https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-delivered-225-weight-loss-adults-obesity-or

Lilly’s tirzepatide delivered up to 22.5% weight loss in adults with obesity or overweight in SURMOUNT-1

April 28, 2022

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Participants taking tirzepatide lost up to 52 lb. (24 kg) in this 72-week phase 3 study

63% of participants taking tirzepatide 15 mg achieved at least 20% body weight reductions as a key secondary endpoint

INDIANAPOLIS, April 28, 2022 /PRNewswire/ — Tirzepatide (5 mg, 10 mg, 15 mg) achieved superior weight loss compared to placebo at 72 weeks of treatment in topline results from Eli Lilly and Company’s (NYSE: LLY) SURMOUNT-1 clinical trial, with participants losing up to 22.5% (52 lb. or 24 kg) of their body weight for the efficacy estimandi. This study enrolled 2,539 participants and was the first phase 3 global registration trial evaluating the efficacy and safety of tirzepatide in adults with obesity, or overweight with at least one comorbidity, who do not have diabetes. Tirzepatide met both co-primary endpoints of superior mean percent change in body weight from baseline and greater percentage of participants achieving body weight reductions of at least 5% compared to placebo for both estimandsii. The study also achieved all key secondary endpoints at 72 weeks.

For the efficacy estimand, participants taking tirzepatide achieved average weight reductions of 16.0% (35 lb. or 16 kg on 5 mg), 21.4% (49 lb. or 22 kg on 10 mg) and 22.5% (52 lb. or 24 kg on 15 mg), compared to placebo (2.4%, 5 lb. or 2 kg). Additionally, 89% (5 mg) and 96% (10 mg and 15 mg) of people taking tirzepatide achieved at least 5% body weight reductions compared to 28% of those taking placebo.

In a key secondary endpoint, 55% (10 mg) and 63% (15 mg) of people taking tirzepatide achieved at least 20% body weight reductions compared to 1.3% of those taking placebo. In an additional secondary endpoint not controlled for type 1 error, 32% of participants taking tirzepatide 5 mg achieved at least 20% body weight reductions. The mean baseline body weight of participants was 231 lb. (105 kg).

“Obesity is a chronic disease that often does not receive the same standard of care as other conditions, despite its impact on physical, psychological and metabolic health, which can include increased risk of hypertension, heart disease, cancer and decreased survival,” said Louis J. Aronne, MD, FACP, DABOM, director of the Comprehensive Weight Control Center and the  Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine, obesity expert at NewYork-Presbyterian/Weill Cornell Medical Center and Investigator of SURMOUNT-1. “Tirzepatide delivered impressive body weight reductions in SURMOUNT-1, which could represent an important step forward for helping the patient and physician partnership treat this complex disease.”

For the treatment-regimen estimandiii, results showed:

  • Average body weight reductions: 15.0% (5 mg), 19.5% (10 mg), 20.9% (15 mg), 3.1% (placebo)
  • Percentage of participants achieving body weight reductions of ≥5%: 85% (5 mg), 89% (10 mg), 91% (15 mg), 35% (placebo)
  • Percentage of participants achieving body weight reductions of ≥20%: 30% (5 mg, not controlled for type 1 error), 50% (10 mg), 57% (15 mg), 3.1% (placebo)

The overall safety and tolerability profile of tirzepatide was similar to other incretin-based therapies approved for the treatment of obesity. The most commonly reported adverse events were gastrointestinal-related and generally mild to moderate in severity, usually occurring during the dose escalation period. For those treated with tirzepatide (5 mg, 10 mg and 15 mg, respectively), nausea (24.6%, 33.3%, 31.0%), diarrhea (18.7%, 21.2%, 23.0%), vomiting (8.3%, 10.7%, 12.2%) and constipation (16.8%, 17.1%, 11.7%) were more frequently experienced compared to placebo (9.5% [nausea], 7.3% [diarrhea], 1.7% [vomiting], 5.8% [constipation]).

Treatment discontinuation rates due to adverse events were 4.3% (5 mg), 7.1% (10 mg), 6.2% (15 mg) and 2.6% (placebo). The overall treatment discontinuation rates were 14.3% (5 mg), 16.4% (10 mg), 15.1% (15 mg) and 26.4% (placebo).

Participants who had pre-diabetes at study commencement will remain enrolled in SURMOUNT-1 for an additional 104 weeks of treatment following the initial 72-week completion date to evaluate the impact on body weight and the potential differences in progression to type 2 diabetes at three years of treatment with tirzepatide compared to placebo.

“Tirzepatide is the first investigational medicine to deliver more than 20 percent weight loss on average in a phase 3 study, reinforcing our confidence in its potential to help people living with obesity,” said Jeff Emmick, MD, Ph.D., vice president, product development, Lilly. “Obesity is a chronic disease that requires effective treatment options, and Lilly is working relentlessly to support people with obesity and modernize how this disease is approached. We’re proud to research and develop potentially innovative treatments like tirzepatide, which helped nearly two thirds of participants on the highest dose reduce their body weight by at least 20 percent in SURMOUNT-1.”

Tirzepatide is a novel investigational once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist, representing a new class of medicines being studied for the treatment of obesity. Tirzepatide is a single peptide that activates the body’s receptors for GIP and GLP-1, two natural incretin hormones. Obesity is a chronic, progressive disease caused by disruptions in the mechanisms that control body weight, often leading to an increase in food intake and/or a decrease in energy expenditure. These disruptions are multifactorial and can be related to genetic, developmental, behavioral, environmental and social factors. To learn more, visit Lilly.com/obesity.

Lilly will continue to evaluate the SURMOUNT-1 results, which will be presented at an upcoming medical meeting and submitted to a peer-reviewed journal. Additional studies are ongoing for tirzepatide as a potential treatment for obesity or overweight.

About tirzepatide

Tirzepatide is a once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist that integrates the actions of both incretins into a single novel molecule. GIP is a hormone that may complement the effects of GLP-1 receptor agonists. In preclinical models, GIP has been shown to decrease food intake and increase energy expenditure therefore resulting in weight reductions, and when combined with GLP-1 receptor agonism, may result in greater effects on markers of metabolic dysregulation such as body weight, glucose and lipids. Tirzepatide is in phase 3 development for adults with obesity or overweight with weight-related comorbidity and is currently under regulatory review as a treatment for adults with type 2 diabetes. It is also being studied as a potential treatment for non-alcoholic steatohepatitis (NASH) and heart failure with preserved ejection fraction (HFpEF). Studies of tirzepatide in obstructive sleep apnea (OSA) and in morbidity/mortality in obesity are planned as well.

About SURMOUNT-1 and the SURMOUNT clinical trial program

SURMOUNT-1 (NCT04184622) is a multi-center, randomized, double-blind, parallel, placebo-controlled trial comparing the efficacy and safety of tirzepatide 5 mg, 10 mg and 15 mg to placebo as an adjunct to a reduced-calorie diet and increased physical activity in adults without type 2 diabetes who have obesity, or overweight with at least one of the following comorbidities: hypertension, dyslipidemia, obstructive sleep apnea or cardiovascular disease. The trial randomized 2,539 participants across the U.S., Argentina, Brazil, China, India, Japan, Mexico, Russia and Taiwan in a 1:1:1:1 ratio to receive either tirzepatide 5 mg, 10 mg or 15 mg or placebo. The co-primary objectives of the study were to demonstrate that tirzepatide 10 mg and/or 15 mg is superior in percentage of body weight reductions from baseline and percentage of participants achieving ≥5% body weight reduction at 72 weeks compared to placebo. Participants who had pre-diabetes at study commencement will remain enrolled in SURMOUNT-1 for an additional 104 weeks of treatment following the initial 72-week completion date to evaluate the impact on body weight and potential differences in progression to type 2 diabetes at three years of treatment with tirzepatide compared to placebo.

All participants in the tirzepatide treatment arms started the study at a dose of tirzepatide 2.5 mg once-weekly and then increased the dose in a step-wise approach at four-week intervals to their final randomized maintenance dose of 5 mg (via a 2.5 mg step), 10 mg (via steps at 2.5 mg, 5 mg and 7.5 mg) or 15 mg (via steps at 2.5 mg, 5 mg, 7.5 mg, 10 mg and 12.5 mg).

The SURMOUNT phase 3 global clinical development program for tirzepatide began in late 2019 and has enrolled more than 5,000 people with obesity or overweight across six clinical trials, four of which are global studies. Results from SURMOUNT-2, -3, and -4 are anticipated in 2023.

About Lilly 

Lilly unites caring with discovery to create medicines that make life better for people around the world. We’ve been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 47 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world’s most significant health challenges, redefining diabetes care, treating obesity and curtailing its most devastating long-term effects, advancing the fight against Alzheimer’s disease, providing solutions to some of the most debilitating immune system disorders, and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we’re motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/newsroom or follow us on FacebookInstagramTwitter and LinkedInP-LLY

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https://www.pu-kang.com/Tirzepatide-results-superior-A1C-and-body-weight-reductions-compared-to-insulin-glargine-in-adults-with-type-2-diabetes-id3348038.html

Tirzepatide results superior A1C and body weight reductions compared to insulin glargine in adults with type 2 diabetes

Tirzepatide results superior A1C and body weight reductions compared to insulin glargine in adults with type 2 diabetes

Newly published data show that participants maintained A1C and weight control up to two years in SURPASS-4, the largest and longest SURPASS trial completed to dateNo increased cardiovascular risk identified with tirzepatide; hazard ratio of 0.74 observed for MACE-4 events

SURPASS-4 is the largest and longest clinical trial completed to date of the phase 3 program studying tirzepatide as a potential treatment for type 2 diabetes. The primary endpoint was measured at 52 weeks, with participants continuing treatment up to 104 weeks or until study completion. The completion of the study was triggered by the accrual of major adverse cardiovascular events (MACE) to assess CV risk. In newly published data from the treatment period after 52 weeks, participants taking tirzepatide maintained A1C and weight control for up to two years.

The overall safety profile of tirzepatide, assessed over the full study period, was consistent with the safety results measured at 52 weeks, with no new findings up to 104 weeks. Gastrointestinal side effects were the most commonly reported adverse events, usually occurring during the escalation period and then decreasing over time.

“We are encouraged by the continued A1C and weight control that participants experienced past the initial 52 week treatment period and up to two years as we continue to explore the potential impact of tirzepatide for the treatment of type 2 diabetes,” said John Doupis, M.D., Ph.D., Director, Diabetes Division and Clinical Research Center, Iatriko Paleou Falirou Medical Center, Athens, Greece and Senior Investigator for SURPASS-4.

Tirzepatide is a novel investigational once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that integrates the actions of both incretins into a single molecule, representing a new class of medicines being studied for the treatment of type 2 diabetes.

SURPASS-4 was an open-label global trial comparing the safety and efficacy of three tirzepatide doses (5 mg, 10 mg and 15 mg) to titrated insulin glargine in 2,002 adults with type 2 diabetes with increased CV risk who were treated with between one and three oral antihyperglycemic medicines (metformin, a sulfonylurea or an SGLT-2 inhibitor). Of the total participants randomized, 1,819 (91%) completed the primary 52-week visit and 1,706 (85%) completed the study on treatment. The median study duration was 85 weeks and 202 participants (10%) completed two years.

Study participants had a mean duration of diabetes of 11.8 years, a baseline A1C of 8.52 percent and a baseline weight of 90.3 kg. More than 85 percent of participants had a history of cardiovascular events. In the insulin glargine arm, the insulin dose was titrated following a treat-to-target algorithm with the goal of fasting blood glucose below 100 mg/dL. The starting dose of insulin glargine was 10 units per day, and the mean dose of insulin glargine at 52 weeks was 43.5 units per day.

About tirzepatide
Tirzepatide is a once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that integrates the actions of both incretins into a single novel molecule. GIP is a hormone that may complement the effects of GLP-1. In preclinical models, GIP has been shown to decrease food intake and increase energy expenditure therefore resulting in weight reductions, and when combined with a GLP-1 receptor agonist, may result in greater effects on glucose and body weight. Tirzepatide is in phase 3 development for blood glucose management in adults with type 2 diabetes, for chronic weight management and heart failure with preserved ejection fraction (HFpEF). It is also being studied as a potential treatment for non-alcoholic steatohepatitis (NASH).

About SURPASS-4 and the SURPASS clinical trial program
SURPASS-4 (NCT03730662) is a randomized, parallel, open-label trial comparing the efficacy and safety of tirzepatide 5 mg, 10 mg and 15 mg to insulin glargine in adults with type 2 diabetes inadequately controlled with at least one and up to three oral antihyperglycemic medications (metformin, sulfonylureas or SGLT-2 inhibitors), who have increased cardiovascular (CV) risk. The trial randomized 2,002 study participants in a 1:1:1:3 ratio to receive either tirzepatide 5 mg, 10 mg or 15 mg or insulin glargine. Participants were located in the European Union, North America (Canada and the United States), Australia, Israel, Taiwan and Latin America (Brazil, Argentina and Mexico). The primary objective of the study was to demonstrate that tirzepatide (10 mg and/or 15 mg) is non-inferior to insulin glargine for change from baseline A1C at 52 weeks in people with type 2 diabetes and increased CV risk. The primary and key secondary endpoints were measured at 52 weeks, with participants continuing treatment up to 104 weeks or until study completion. The completion of the study was triggered by the accrual of major adverse cardiovascular events (MACE). Study participants enrolled had to have a mean baseline A1C between 7.5 percent and 10.5 percent and a BMI greater than or equal to 25 kg/m2 at baseline. All participants in the tirzepatide treatment arms started the study at a dose of tirzepatide 2.5 mg once-weekly and then increased the dose in a step-wise approach at four-week intervals to their final randomized maintenance dose of 5 mg (via a 2.5 mg step), 10 mg (via steps at 2.5 mg, 5 mg and 7.5 mg) or 15 mg (via steps at 2.5 mg, 5 mg, 7.5 mg, 10 mg and 12.5 mg). All participants in the titrated insulin glargine treatment arm started with a baseline dose of 10 units per day and titrated following a treat-to-target algorithm to reach a fasting blood glucose below 100 mg/dL.

The SURPASS phase 3 global clinical development program for tirzepatide has enrolled more than 20,000 people with type 2 diabetes across 10 clinical trials, five of which are global registration studies. The program began in late 2018, and all five global registration trials have been completed.

About Diabetes

Approximately 34 million Americans2 (just over 1 in 10) and an estimated 463 million adults worldwide3 have diabetes. Type 2 diabetes is the most common type internationally, accounting for an estimated 90 to 95 percent of all diabetes cases in the United States alone2. Diabetes is a chronic disease that occurs when the body does not properly produce or use the hormone insulin.

Clinical data
Trade namesMounjaro
Other namesLY3298176, GIP/GLP-1 RA
License dataUS DailyMedTirzepatide
Routes of
administration
subcutaneous
Drug classAntidiabeticGLP-1 receptor agonist
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
showIUPAC name
CAS Number2023788-19-2
PubChem CID156588324
IUPHAR/BPS11429
DrugBankDB15171
ChemSpider76714503
UNIIOYN3CCI6QE
KEGGD11360
ChEMBLChEMBL4297839
Chemical and physical data
FormulaC225H348N48O68
Molar mass4813.527 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

////////////Tirzepatide, FDA 2022, APPROVALS 2022, Mounjaro, PEPTIDE, チルゼパチド ,  LY3298176,

UNIIOYN3CCI6QE

pharma1

chart 1 Structure of GLP-1 & TZP & Exenatide & Somalutide

MONENSIN


Monensin A.svg
ChemSpider 2D Image | Monensin | C36H62O11
17090-79-8.png

モネンシン;

MONENSIN

Elancoban [veterinary] (TN)

  • Molecular FormulaC36H62O11
  • Average mass670.871 Da

1,6-dioxaspiro[4.5]decane-7-butanoic acid, 2-[(2S,2’R,3’S,5R,5’R)-2-ethyloctahydro-3′-methyl-5′-[(2S,3S,5R,6R)-tetrahydro-6-hydroxy-6-(hydroxymethyl)-3,5-dimethyl-2H-pyran-2-yl][2,2′-bifuran]-5-yl]-9-hydroxy-β-methoxy-α,γ,2,8-tetramethyl-, (αS,βR,γS,2S,5R,7S,8R,9S)-

17090-79-8[RN]

241-154-0[EINECS]

(2S,3R,4S)-4-[(2S,5R,7S,8R,9S)-2-{(2S,2’R,3’S,5R,5’R)-2-Ethyl-5′-[(2S,3S,5R,6R)-6-hydroxy-6-(hydroxymethyl)-3,5-dimethyltetrahydro-2H-pyran-2-yl]-3′-methyloctahydro-2,2′-bifuran-5-yl}-9-hydroxy-2,8-di methyl-1,6-dioxaspiro[4.5]dec-7-yl]-3-methoxy-2-methylpentanoic acid

монензин[Russian]

مونانسين[Arabic]

莫能星[Chinese]

Antibiotic, Antifungal, Antiprotozoal

Monensin sodium salt 90-95% (TLC)

Synonym(s):

Monensin A sodium salt

Empirical Formula (Hill Notation):C36H61NaO11

CAS Number:22373-78-0

Molecular Weight:692.85

Beilstein:4122200

Title: Monensin

CAS Registry Number: 17090-79-8

CAS Name: 2-[5-Ethyltetrahydro-5-[tetrahydro-3-methyl-5-[tetrahydro-6-hydroxy-6-(hydroxymethyl)-3,5-dimethyl-2H-pyran-2-yl]-2-furyl]-2-furyl]-9-hydroxy-b-methoxy-a,g,2,8-tetramethyl-1,6-dioxaspiro[4.5]decane-7-butyric acid

Additional Names: monensic acid (obsolete)

Manufacturers’ Codes: A-3823A

Molecular Formula: C36H62O11, Molecular Weight: 670.87

Percent Composition: C 64.45%, H 9.32%, O 26.23%

Literature References: Polyether antibiotic. Major factor in antibiotic complex isolated from Streptomyces cinnamonensis. Discovery and isolation: Haney, Hoehn, Antimicrob. Agents Chemother.1967, 349. Production: Haney, Hoehn, US3501568 (1970 to Lilly). Structure: Agtarap et al.,J. Am. Chem. Soc.89, 5737 (1967). Crystal structure studies: Lutz et al.,Helv. Chim. Acta53, 1732 (1970); ibid.54, 1103 (1971). Fermentation studies: Stark et al.,Antimicrob. Agents Chemother.1967, 353. Chemistry: Agtarap, Chamberlin, ibid. 359. Stereocontrolled total synthesis: T. Fukuyama et al.,J. Am. Chem. Soc.101, 262 (1979); D. B. Collum et al.,ibid.102, 2117, 2118, 2120 (1980). 13C-NMR study: J. A. Robinson, D. L. Turner, Chem. Commun.1982, 148. Biosynthesis: Day et al.,Antimicrob. Agents Chemother.4, 410 (1973). Review: Stark, “Monensin, A New Biologically Active Compound Produced by a Fermentation Process”, in Fermentation Advances, Pap. Int. Ferment. Symp., 3rd, 1968, D. Perlman, Ed. (Academic Press, New York, 1969) pp 517-540.

Properties: Crystals, mp 103-105° (monohydrate). [a]D +47.7°. pKa 6.6 (in 66% DMF). Very stable under alkaline conditions. Slightly sol in water; more sol in hydrocarbons; very sol in other organic solvents. LD50 of monensin complex in mice, chicks (mg/kg): 43.8 ± 5.2, 284 ± 47 orally (Haney, Hoehn).

Melting point: mp 103-105° (monohydrate)

pKa: pKa 6.6 (in 66% DMF)

Optical Rotation: [a]D +47.7°

Toxicity data: LD50 of monensin complex in mice, chicks (mg/kg): 43.8 ± 5.2, 284 ± 47 orally (Haney, Hoehn)

Derivative Type: Sodium salt

Trademarks: Coban (Elanco); Romensin (Elanco); Rumensin (Elanco)

Molecular Formula: C36H61NaO11, Molecular Weight: 692.85

Percent Composition: C 62.41%, H 8.87%, Na 3.32%, O 25.40%

Properties: mp 267-269°. [a]D +57.3° (methanol). Slightly sol in water; more sol in hydrocarbons; very sol in other organic solvents.

Melting point: mp 267-269°

Optical Rotation: [a]D +57.3° (methanol)

Therap-Cat-Vet: Coccidiostat. Feed additive to improve feed efficiency in ruminants.

Monensin is a polyether antibiotic isolated from Streptomyces cinnamonensis.[1] It is widely used in ruminant animal feeds.[1][2]

The structure of monensin was first described by Agtarap et al. in 1967, and was the first polyether antibiotic to have its structure elucidated in this way. The first total synthesis of monensin was reported in 1979 by Kishi et al.[3]

SYN

File:Monensin.png

SYN

Production / synthesis Monensin is produced in vivo by Streptomyces cinnamonensis as a natural defense against competing bacteria. Monensin presents a formidable challenge to synthetic chemists as it possesses 17 asymmetric centers on a backbone of only 26 carbon atoms. Although its total synthesis has been described (e.g., Kishi et al., 1979), the high complexity of monensin makes an extraction from the bacterium the most economical procedure for its production. The total synthesis has 56 steps and a yield of only 0.26%. The chemical precursors are 2-allyl-1,3-propanediol and 2- (furan-2-yl)acetonitrile. The method used for synthesizing monensin is based on the principle of “absolute asymmetric synthesis”. Molecules are constructed out of prefabricated building blocks in the correct conformation, aiming for higher yields of the desired enantiomer. New stereocenters are also introduced. Using this method, monensin is assembled in two parts, a larger right side and a smaller left one. The penultimate step is connecting the left and the right halves of monensin, which are independently generated, in an Aldol-condensation. The two halves’ keto end groups (C7/ C8) are linked by eliminating a water molecule. The C7 atom is favored over the C1 atom, because it is more reactive. For catalyzing this step, Yoshito Kishi’s group used iPr2NMgBr (Hauser base) and THF to coordinate it at a temperature of − 78°C. Thus, they were able to isolate the molecule in the right conformation at a ratio of 8:1. Due to the low temperature required for a high yield of the correct enantiomer, the reaction is very solw. One of the most difficult steps is the last one: the connection of the spiro center. This is due to a characteristic feature of spiro compounds; they open and close very easily. Therefore, the conditions for forming the right conformation must be optimal in the last step of synthesis. The biosynthesis in a cell culture of Streptomyces cinnamonensis involves a complex medium containing, among other components, glucose, soybean oil, and grit. Cultivation is carried out for a week at a temperature of 30°C and under constant aeration. Product isolation requires filtration, acidification to pH3, extraction with chloroform and purification with activated carbon. In this way, a few grams per liter of monensin are produced and isolated. For crystallization, azeotropic distillation is necessary. In vivo, polyether backbones are assembled by modular polyketide synthases and are modified by two key enzymes, epoxidase and epoxide hydrolase, to generate the product. Precursors of the polyketide pathway are acetate, butyrate and propionate.

SYN

The final-stage aldol addition in Yoshito Kishi‘s 1979 total synthesis of monensin. (1979). “Synthetic studies on polyether antibiotics. 6. Total synthesis of monensin. 3. Stereocontrolled total synthesis of monensin”. J. Am. Chem. Soc. 101 (1): 262–263. DOI:10.1021/ja00495a066.

File:Monensin total synthesis Kishi 1979 JACS final stage aldol coupling.png

SYN

A polyether antibiotic, Monensin was the first member of this class of molecules to be structurally characterized.1 The structural features of these polyethers comprise of a terminal carboxylic acid, multiple cyclic ether rings (ex. Tetrahydrofuran and tetrahydropyran), a large amount of stereocenters and (for many of these molecules) one or more spiroketal moieties.2 Monensin was introduced into the market in 1971 and is used to fight coccidial infections in poultry and as an additive in cattle feed.3 Of the 26 carbon atom’s in Monensin’s backbone, 17 are stereogenic and six of those are contiguous. Coupled with a spiroketal moiety, three hydrofuran rings and two hydropyran rings, the molecule was an attractive synthetic target.

1. Agtarap, A.; Chamberlain, J.W.; Pinkerton, M.; Stein-rauf, L. J. Am. Chem. Soc. 1967, 89, 5737 2. Polyether Antibiotics : Naturally Occurring Acid Ionophores. Westley J.W.; Marcel Dekker: New York (1982) Vol. 1-2. 3. Stark, W.M. In Fermentation Advances, Perlman, D., Ed., Academic Press: New York, 1969, 517

Retrosynthetic Analysis of Monensin

//////////

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Mechanism of action

The structure of the sodium (Na+) complex of monensin A.

Monensin A is an ionophore related to the crown ethers with a preference to form complexes with monovalent cations such as: Li+, Na+, K+, Rb+, Ag+, and Tl+.[4][5] Monensin A is able to transport these cations across lipid membranes of cells in an electroneutral (i.e. non-depolarizing) exchange, playing an important role as an Na+/H+ antiporter. Recent studies have shown that monensin may transport sodium ion through the membrane in both electrogenic and electroneutral manner.[6] This approach explains ionophoric ability and in consequence antibacterial properties of not only parental monensin, but also its derivatives that do not possess carboxylic groups. It blocks intracellular protein transport, and exhibits antibioticantimalarial, and other biological activities.[7] The antibacterial properties of monensin and its derivatives are a result of their ability to transport metal cations through cellular and subcellular membranes.[8]

Uses

Monensin is used extensively in the beef and dairy industries to prevent coccidiosis, increase the production of propionic acid and prevent bloat.[9] Furthermore, monensin, but also its derivatives monensin methyl ester (MME), and particularly monensin decyl ester (MDE) are widely used in ion-selective electrodes.[10][11][12]

In laboratory research, monensin is used extensively to block Golgi transport.[13][14][15]

Toxicity

Monensin has some degree of activity on mammalian cells and thus toxicity is common. This is especially pronounced in horses, where monensin has a median lethal dose 1/100th that of ruminants. Accidental poisoning of equines with monensin is a well-documented occurrence which has resulted in deaths.[16]

References

  1. Jump up to:a b Daniel Łowicki and Adam Huczyński (2013). “Structure and Antimicrobial Properties of Monensin A and Its Derivatives: Summary of the Achievements”BioMed Research International2013: 1–14. doi:10.1155/2013/742149PMC 3586448PMID 23509771.
  2. ^ Butaye, P.; Devriese, L. A.; Haesebrouck, F. (2003). “Antimicrobial Growth Promoters Used in Animal Feed: Effects of Less Well Known Antibiotics on Gram-Positive Bacteria”Clinical Microbiology Reviews16 (2): 175–188. doi:10.1128/CMR.16.2.175-188.2003PMC 153145PMID 12692092.
  3. ^ Nicolaou, K. C.; E. J. Sorensen (1996). Classics in Total Synthesis. Weinheim, Germany: VCH. pp. 185–187. ISBN 3-527-29284-5.
  4. ^ Huczyński, A.; Ratajczak-Sitarz, M.; Katrusiak, A.; Brzezinski, B. (2007). “Molecular structure of the 1:1 inclusion complex of Monensin A lithium salt with acetonitrile”. J. Mol. Struct. 871 (1–3): 92–97. Bibcode:2007JMoSt.871…92Hdoi:10.1016/j.molstruc.2006.07.046.
  5. ^ Pinkerton, M.; Steinrauf, L. K. (1970). “Molecular structure of monovalent metal cation complexes of monensin”. J. Mol. Biol. 49 (3): 533–546. doi:10.1016/0022-2836(70)90279-2PMID 5453344.
  6. ^ Huczyński, Adam; Jan Janczak; Daniel Łowicki; Bogumil Brzezinski (2012). “Monensin A acid complexes as a model of electrogenic transport of sodium cation”Biochim. Biophys. Acta1818 (9): 2108–2119. doi:10.1016/j.bbamem.2012.04.017PMID 22564680.
  7. ^ Mollenhauer, H. H.; Morre, D. J.; Rowe, L. D. (1990). “Alteration of intracellular traffic by monensin; mechanism, specificity and relationship to toxicity”Biochim. Biophys. Acta1031 (2): 225–246. doi:10.1016/0304-4157(90)90008-ZPMC 7148783PMID 2160275.
  8. ^ Huczyński, A.; Stefańska, J.; Przybylski, P.; Brzezinski, B.; Bartl, F. (2008). “Synthesis and antimicrobial properties of Monensin A esters”. Bioorg. Med. Chem. Lett. 18 (8): 2585–2589. doi:10.1016/j.bmcl.2008.03.038PMID 18375122.
  9. ^ Matsuoka, T.; Novilla, M.N.; Thomson, T.D.; Donoho, A.L. (1996). “Review of monensin toxicosis in horses”. Journal of Equine Veterinary Science16: 8–15. doi:10.1016/S0737-0806(96)80059-1.
  10. ^ Tohda, Koji; Suzuki, Koji; Kosuge, Nobutaka; Nagashima, Hitoshi; Watanabe, Kazuhiko; Inoue, Hidenari; Shirai, Tsuneo (1990). “A sodium ion selective electrode based on a highly lipophilic monensin derivative and its application to the measurement of sodium ion concentrations in serum”Analytical Sciences6 (2): 227–232. doi:10.2116/analsci.6.227.
  11. ^ Kim, N.; Park, K.; Park, I.; Cho, Y.; Bae, Y. (2005). “Application of a taste evaluation system to the monitoring of Kimchi fermentation”. Biosensors and Bioelectronics20 (11): 2283–2291. doi:10.1016/j.bios.2004.10.007PMID 15797327.
  12. ^ Toko, K. (2000). “Taste Sensor”. Sensors and Actuators B: Chemical64 (1–3): 205–215. doi:10.1016/S0925-4005(99)00508-0.
  13. ^ Griffiths, G.; Quinn, P.; Warren, G. (March 1983). “Dissection of the Golgi complex. I. Monensin inhibits the transport of viral membrane proteins from medial to trans Golgi cisternae in baby hamster kidney cells infected with Semliki Forest virus”The Journal of Cell Biology96 (3): 835–850. doi:10.1083/jcb.96.3.835ISSN 0021-9525PMC 2112386PMID 6682112.
  14. ^ Kallen, K. J.; Quinn, P.; Allan, D. (1993-02-24). “Monensin inhibits synthesis of plasma membrane sphingomyelin by blocking transport of ceramide through the Golgi: evidence for two sites of sphingomyelin synthesis in BHK cells”. Biochimica et Biophysica Acta (BBA) – Lipids and Lipid Metabolism1166 (2–3): 305–308. doi:10.1016/0005-2760(93)90111-lISSN 0006-3002PMID 8443249.
  15. ^ Zhang, G. F.; Driouich, A.; Staehelin, L. A. (December 1996). “Monensin-induced redistribution of enzymes and products from Golgi stacks to swollen vesicles in plant cells”. European Journal of Cell Biology71 (4): 332–340. ISSN 0171-9335PMID 8980903.
  16. ^ “Tainted feed blamed for 4 horse deaths at Florida stable”. 2014-12-16.
Names
Preferred IUPAC name(2S,3R,4S)-4-[(2S,5R,7S,8R,9S)-2-{(2S,2′R,3′S,5R,5′R)-2-Ethyl-5′-[(2S,3S,5R,6R)-6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3′-methyl[2,2′-bioxolan]-5-yl}-9-hydroxy-2,8-dimethyl-1,6-dioxaspiro[4.5]decan-7-yl]-3-methoxy-2-methylpentanoic acid
Other namesMonensic acid
Identifiers
CAS Number17090-79-8 
3D model (JSmol)Interactive image
ChEBICHEBI:27617 
ChEMBLChEMBL256105 
ChemSpider389937 
ECHA InfoCard100.037.398 
E numberE714 (antibiotics)
KEGGD08228 
PubChemCID441145
UNII906O0YJ6ZP 
CompTox Dashboard (EPA)DTXSID4048561 
showInChI
showSMILES
Properties
Chemical formulaC36H62O11
Molar mass670.871 g/mol
Appearancesolid state, white crystals
Melting point104 °C (219 °F; 377 K)
Solubility in water3×10−6 g/dm3 (20 °C)
Solubilityethanolacetonediethyl etherbenzene
Pharmacology
ATCvet codeQA16QA06 (WHOQP51AH03 (WHO)
Related compounds
Relatedantibioticsionophores
Related compoundsMonensin A methyl ester,
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).☒verify (what is ?)Infobox references

///////////MONENSIN, Elancoban, VETERINARY, Coccidiostat, A-3823A, A 3823A

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Ferric derisomaltose


2D chemical structure of 1345510-43-1
Ferric derisomaltose.png

Ferric derisomaltose

WeightAverage: 562.297
Monoisotopic: 562.117975Chemical FormulaC18H34FeO16

Monover, JAPAN 2022, 2022/3/28

Monoferric (TN);
Monover (TN)

Anti-anemic, Hematinic, Supplement (iron)

CAS 1345510-43-1

デルイソマルトース第二鉄

  • NS32
  • WHO 9712
  • UNII-AHU547PI9H
Originator CompanyPharmacosmos
Active CompaniesNippon Shinyaku Co Ltd;Pharmacosmos A/S;Wasserburger Arzneimittelwerk Gmbh;Zealand University Hospital

iron(3+) (2S,3R,4R,5R)-6-{[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-({[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}methyl)oxan-2-yl]oxy}hexane-1,2,3,4,5-pentol

  • alpha-D-Glucan, (1-6)-, reduced, reaction products with iron hydroxide (Fe(OH)3)

Ferric derisomaltose is an iron injection used in the treatment of iron deficiency anemia.

Ferric derisomaltose, sold under the brand name Monoferric, is a medication for the treatment of iron deficiency anemia (IDA) in adults who have intolerance to oral iron or have had unsatisfactory response to oral iron or who have non-hemodialysis dependent chronic kidney disease (NDD-CKD).[1] It was approved for use in the United States in January 2020.[1][2][3] It is given intravenously.[1]

Iron deficiency is an extremely common condition and is the most frequent cause of anemia worldwide. Iron deficiency results when iron intake, iron stores, and loss of iron from the body do not adequately support production of erythrocytes, also known as red blood cells. Though it is generally considered non life-threatening, iron deficiency may considerably affect quality of life.3

Ferric derisomaltose is a form of iron used in the treatment of iron deficiency. This drug is a complex of iron (III) hydroxide and derisomaltose. The latter is an iron carbohydrate oligosaccharide that works to release iron. Ferric derisomaltose was developed by Pharmacosmos Therapeutics ad was granted FDA approval in January 2020.8,9 Clinical trials show that it is non-inferior to iron sucrose, another form of iron that is often administered in iron deficiency, and less likely to cause serious hypersensitivity that is associated with other forms of injectable iron.1,4

This drug is indicated for the treatment of iron deficiency anemia in adult patients who have experienced intolerance to oral iron preparations or insufficient clinical response to orally administered iron. Ferric derisomaltase is also indicated for patients with non-hemodialysis dependent chronic kidney disease.8 In Australia and United Kingdom, ferric derisomaltase is indicated for cases in which rapid delivery of iron is required.10,11

Iron deficiency is an extremely common condition and is the most frequent cause of anemia worldwide. Iron deficiency results when iron intake, iron stores, and loss of iron from the body do not adequately support production of erythrocytes, also known as red blood cells. Though it is generally considered non life-threatening, iron deficiency may considerably affect quality of life. Ferric derisomaltose is a form of iron used in the treatment of iron deficiency. This drug is a complex of iron (III) hydroxide and derisomaltose. The latter is an iron carbohydrate oligosaccharide that works to release ironFerric derisomaltose was developed by Pharmacosmos Therapeutics ad was granted FDA approval in January 2020. Clinical trials show that it is non-inferior to [iron sucrose], another form of iron that is often administered in iron deficiency, and less likely to cause serious hypersensitivity that is associated with other forms of injectable iron.

Monoferric is an iron replacement product containing ferric derisomaltose for intravenous infusion. Ferric derisomaltose is an iron carbohydrate complex with a matrix structure composed of interchanging layers of ferric hydroxide and the carbohydrate derisomaltose. Derisomaltose consists of linear, hydrogenated isomaltooligosaccharides with an average molecular weight of 1000 Da and a narrow molecular weight distribution that is almost devoid of mono-and disaccharides.

Ferric derisomaltose has an average molecular weight of 155,000 Da and has the following empirical formula:

{FeO(1-3X) (OH)(1+3X) (C6H5O73-)X}, (H20)T, –
(C6H10O6)R(-C6H10O5-)Z(C6H13O5)R, (NaCl)Y

X= 0.0311; T = 0.25; R = 0.14; Z = 0.49; Y = 0.14

Iron atoms placed in the electronegative cavities of the 3-D structure between and within the derisomaltose molecules. A schematic representation is presented below

MONOFERRIC (ferric derisomaltose) Structural Formula Illustration

Monoferric is a sterile, dark brown, non-transparent aqueous solution with pH 5.0-7.0, containing ferric derisomaltose dissolved in water for injections and filled into Type I glass vials.

Each 1 mL of solution contains 100 mg of elemental iron as ferric derisomaltose in water for injection.

Each 1 mL of solution contains 100 mg of elemental iron as ferric derisomaltose in water for injection.

Mkt.
Status
Active IngredientProprietary NameAppl. No.Dosage FormRouteStrengthTE CodeRLDRSApplicant Holder
RXFERRIC DERISOMALTOSEMONOFERRICN208171SOLUTIONINTRAVENOUS1GM/10ML (100MG/ML) RLDRSPHARMACOSMOS AS
DISCNFERRIC DERISOMALTOSEMONOFERRICN208171SOLUTIONINTRAVENOUS100MG/ML (100MG/ML) RLD PHARMACOSMOS AS
DISCNFERRIC DERISOMALTOSEMONOFERRICN208171SOLUTIONINTRAVENOUS500MG/5ML (100MG/ML) RLD PHARMACOSMOS AS
Mkt.
Status
Active IngredientProprietary NameAppl. No.Dosage FormRouteStrengthTE Code>RLDRSApplicant Holder

MONOFERRIC (FERRIC DERISOMALTOSE)
1GM/10ML (100MG/ML)
Marketing Status: Prescription

Active Ingredient: FERRIC DERISOMALTOSE
Proprietary Name: MONOFERRIC
Dosage Form; Route of Administration: SOLUTION; INTRAVENOUS
Strength: 1GM/10ML (100MG/ML)
Reference Listed Drug: Yes
Reference Standard: Yes
TE Code:
Application Number: N208171
Product Number: 003
Approval Date: Jan 16, 2020
Applicant Holder Full Name: PHARMACOSMOS AS
Marketing Status:  Prescription
Patent and Exclusivity Information

Patent and Exclusivity for: N208171

Product 003
FERRIC DERISOMALTOSE (MONOFERRIC) SOLUTION 1GM/10ML (100MG/ML)

Patent Data

Product NoPatent NoPatent ExpirationDrug SubstanceDrug ProductPatent Use CodeDelist RequestedSubmission Date
003881530108/14/2029DSDPU-2734 02/14/2020
0031041483103/25/2029DSDP  02/14/2020

PATENT

AU2009342799B2

US10414831B2 

US2012010166A1 

 US2014303364A1 

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References

  1. Jump up to:a b c d “Monoferric- ferric derisomaltose solution”DailyMed. 24 January 2020. Retrieved 16 February 2020.
  2. ^ “Monoferric approval letter” (PDF). U.S. Food and Drug Administration (FDA). 16 January 2020. Retrieved 16 February 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ “Drug Approval Package: Monoferric Injection”U.S. Food and Drug Administration (FDA). 7 May 2020. Retrieved 13 August 2020.

External links

Clinical data
Trade namesMonoferric
AHFS/Drugs.comMonograph
License dataUS DailyMedFerric_derisomaltose
Routes of
administration
Intravenous (IV)
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
showIUPAC name
CAS Number1345510-43-1
PubChem CID86278348
DrugBankDB15617
UNIIAHU547PI9H
KEGGD11808
Chemical and physical data
FormulaC18H34FeO16+3
Molar mass562.299 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

/////////////Ferric derisomaltose, デルイソマルトース第二鉄 , APPROVALS 2022, JAPAN 2022, NS32, WHO 9712

[Fe+3].OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@H](O)[C@H]1O

wdt-1

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Difamilast


img

Difamilast (JAN/USAN).png

2D chemical structure of 937782-05-3

Difamilast

PMDA Moizerto, JAPAN APPROVED 2021/9/27

ジファミラスト

ディファミラスト;

地法米司特

N-({2-[4-(difluoromethoxy)-3-(propan-2-yloxy)phenyl]-1,3- oxazol-4-yl}methyl)-2-ethoxybenzamide

OPA-15406

Formula
C23H24F2N2O5
CAS
937782-05-3
Mol weight
446.4439

MM 36; MM-36-Medimetriks-Pharmaceuticals; Moizerto; OPA-15406

Efficacy
Anti-inflammatory, Phosphodiesterase IV inhibitor
Comment
Treatment of atopic dermatitis

  • Originator
    Otsuka Pharmaceutical Development & Commercialization
  • DeveloperMedimetriks Pharmaceuticals; Otsuka Pharmaceutical Development & Commercialization
  • ClassBenzamides; Nonsteroidal anti-inflammatories; Oxazoles; Skin disorder therapies
  • Mechanism of ActionType 4 cyclic nucleotide phosphodiesterase inhibitors
  • RegisteredAtopic dermatitis
  • 27 Sep 2021Registered for Atopic dermatitis (In adolescents, In children, In adults) in Japan (Topical)
  • 11 Nov 2020Otsuka Pharmaceutical completes a phase III trial in Atopic dermatitis (In children, In adolescents, In adults) in Japan (Topical) (NCT03961529)
  • 28 Sep 2020Preregistration for Atopic dermatitis in Japan (In children, In adolescents, In adults) (Topical)

Fig. 1

Difamilast is under investigation in clinical trial NCT01702181 (A Safety Study to Evaluate the Use and Effectiveness of a Topical Ointment to Treat Adults With Atopic Dermatitis).

PATENT

JP 2021059538

https://patentscope.wipo.int/search/en/detail.jsf?docId=JP322244172&_cid=P20-L1WXG6-04592-1

Patent Documents 1 and 2 report an oxazole compound having a specific inhibitory action on phosphodiesterase 4 (PDE4) and a method for producing the same. PDE4 is the predominant PDE in inflammatory cells, inhibition of PDE4 increases intracellular cAMP concentration, and the increase in this concentration downregulates the inflammatory response through regulation of the expression of TNF-α, IL-23, and other inflammatory cytokines. .. Elevated cAMP levels also increase anti-inflammatory cytokines such as IL-10. Therefore, it is considered that the oxazole compound is suitable for use as an anti-inflammatory agent. For example, it may be useful for controlling skin eczema and dermatitis, including atopic dermatitis. Patent Document 3 describes an ointment that stably contains an oxazole compound having a specific inhibitory effect on PDE4 and can be efficiently absorbed into the skin. The contents of Patent Documents 1 to 3 are incorporated in the present specification by reference.

patcit 1 : International Publication No. 2007/058338 (Japanese Publication No. 2009-515872 )
patcit 2 : International Publication No. 2014/034958 (Japanese Publication No. 2015-528433 )
patcit 3 : International Publication No. 2017/115780

[Synthesis of Oxazole Compound (Type A Crystal)]
Compound (5) (white powder) was prepared by the method described in Example 352 of Patent Document 1 (International Publication No. 2007/088383).

[0060]
化合物(5)データ
N−({2−[4−(difluoromethoxy)−3−isopropoxyphenyl]oxazol−4−yl}methyl)−2−ethoxybenzamide
: white powder.
H NMR (400 MHz, CDCl3): δ = 8.56 (br s,
1H, NH), 8.23 (dd, J = 7.6 Hz, 1.6 Hz, 1H, ArH), 7.66 (s, 1H, ArH), 7.63 (d, J = 2.0 Hz, 1H, ArH), 7.58 (dd, J = 8.4 Hz, 2.0 Hz, 1H, ArH), 7.44−7.39 (m, 1H, ArH), 7.21 (d, J = 8.0 Hz, 1H, ArH), 7.08−7.04 (m, 1H, ArH), 6.94 (d, J = 8.0 Hz, 1H, ArH), 6.61 (t, J = 75.2 Hz, 1H, CHF ), 4.68 (sept, J = 6.0 Hz, 1H, CH), 4.62
(d, J = 6.0 Hz, 2H, CH ), 4.17 (q, J = 6.93, 2H, CH ), 1.48 (t, J = 7.2 Hz, 3H,
CH ), 1.39 (d, J = 5.6 Hz, 6H, 2CH ).
[Preparation of B-type crystal 2]
Using the obtained B-type crystal as a seed crystal, it was examined to further prepare a B-type crystal. Specifically,
B-type crystals were prepared as follows according to the method described in Patent Document 3 (International Publication No. 2017/115780).

[0072]
[Chem. 6]

[0073]
Compound (1) 20.00 g (66.8 mmol) and 17.28 g (134 mmol) of diisopropylethylamine were added to 300 mL of ethyl acetate to cool the mixture, and 11.48 g (100 mmol) of methanesulfonyl chloride was introduced into the compound (1) at 10 to 30 ° C. Stir for hours. Subsequently, 17.41 g (200 mmol) of lithium bromide was added, and the mixture was stirred at 20 to 35 ° C. for 1 hour. 100 mL of water was added to the reaction solution to separate the layers, and the organic layer was concentrated under reduced pressure. 300 mL of ethyl acetate was added to the concentrated residue to dissolve it, and the mixture was concentrated again under reduced pressure. 200 mL of N, N-dimethylformamide and 17.33 g (93.6 mmol) of phthalimide potassium were added to the concentrated residue, and the mixture was reacted at 75 to 85 ° C. for 1 hour. 200 mL of water was added to the reaction solution to precipitate crystals, and the precipitated crystals were collected by filtration and dried at 80 ° C. to obtain 27.20 g (yield 95.01%) of compound (3).

[0074]
[Chem. 7]

[0075]
Compound (3) 20.00 g (46.7 mmol), 40 mL of a 40% aqueous methylamine solution, 40 mL of methanol, and 100 mL of water were mixed and reacted under reflux for 30 minutes. 200 mL of cyclopentyl methyl ether (CPME) and 20 mL of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75 ° C. to separate the liquids. A mixed solution of 100 mL of water and 20.00 g of sodium chloride was added to the organic layer, and the temperature was adjusted again to 65 to 75 ° C. to separate the liquids. 5 mL of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. Precipitated crystals were collected by filtration to obtain 27.58 g of wet crystals of compound (4).

[0076]
Wet crystals (46.7 mmol) of compound (4) were mixed with 120 mL of ethyl acetate and 7.1 mL (51.4 mmol) of triethylamine, and the mixture was stirred at 20 to 30 ° C. for 1 hour. To the reaction solution, 10.09 g (60.7 mmol) of 2-ethoxybenzoic acid and 11.63 g (60.7 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) were added, and 20 to 30 were added. The reaction was carried out at ° C. for 1 hour. 60 mL of water and 6 mL of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50 ° C. to separate the solutions. 60 mL of water and 6 mL of a 25%
aqueous sodium hydroxide solution were added to the organic layer, the temperature was adjusted again to 40 to 50 ° C., the liquid was separated, and the organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25% aqueous sodium hydroxide solution, and 0.6 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. Activated carbon was removed by filtration, washed with 12 mL of ethanol, the filtrate was cooled, and 10 mg of B-type crystals (seed crystals) were added to precipitate crystals. Precipitated crystals were collected by filtration and dried at 60 ° C. to obtain 18.38 g (yield 88.18%) of crystals of compound (5).

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017115780

Production Example 1: Production 1 of Compound (3)
Compound (3) was produced in accordance with the following reaction scheme.

[0146]
[Chem. 11]

[0147]
10.00 g (55.5 mmol) of compound (1a) and 9.20 g (66.6 mmol) of potassium carbonate were added to 40 ml of N,N-dimethylformamide and 6 ml of water, and the mixture was stirred until exotherm subsided. 16.92 g (111 mmol) of sodium chlorodifluoroacetate was added thereto, and the mixture was reacted at 95 to 110°C for 3 hours. 80 ml of butyl acetate and 80 ml of water were added to the reaction solution, and the solution was partitioned. 80 ml of water was added again to the organic layer, followed by partitioning. 3 ml of concentrated hydrochloric acid was added to the organic layer, and the mixture was stirred at 60 to 70°C for 30 minutes. 40 ml of water and 10 ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the mixture was partitioned. 5.93 g (61.1 mmol) of sulfamic acid and 10 ml of water were added to the organic layer, and 22.08 g (61.0 mmol) of a 25% sodium chlorite aqueous solution was added dropwise thereto at a temperature of 20°C or below. The mixture was reacted at 20°C or below for 15 minutes, and 10 ml of a 25% sodium hydroxide aqueous solution was added dropwise thereto at a temperature of 20°C or below, followed by pouring in 83.95 g (66.6 mmol) of a 10% sodium sulfite aqueous solution. Additionally, 2 ml of concentrated hydrochloric acid was added and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 40 ml of methanol, 80 ml of water, and 10 ml of a 25% sodium hydroxide aqueous solution were added to the concentrated residue to dissolve the residue, and 5 ml of concentrated hydrochloric acid was added dropwise thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 11.81 g (yield: 86.4%) of compound (3) as a white powder.

[0148]

1H-NMR (CDCl 3) δ: 7.70 (2H,dd,J = 6.4 Hz,2.0 Hz),7.22 (1H,d,J = 9.2 Hz),6.66 (1H,t,J = 74.8 Hz),4.66(1H,sept,J = 6.0 Hz),1.39 (6H,d,J = 6.0 Hz).

Production Example 2: Production 2 of Compound (3)
Compound (3) was produced in accordance with the following reaction scheme.

[0149]
[Chem. 12]

[0150]
10.00 g (53.2 mmol) of compound (1b), 9.55 g (69.1 mmol) of potassium carbonate, and 8.50 g (69.1 mmol) of isopropyl bromide were added to 40 ml of N,N-dimethylformamide, and the mixture was reacted at 75 to 85°C for 2 hours. 80 ml of butyl acetate and 80 ml of water were added to the reaction solution, and the mixture was partitioned. 5.68 g (58.5 mmol) of sulfamic acid and 10 ml of water were added to the organic layer, and 21.15 g (58.5 mmol) of a 25% sodium chlorite aqueous solution was added dropwise thereto at 20°C or below, followed by reaction for 15 minutes. 10 ml of a 25% sodium hydroxide aqueous solution was added thereto at 20°C or below, and subsequently 80.41 g (63.8 mmol) of a 10% sodium sulfite aqueous solution was poured in. Additionally, 2 ml of concentrated hydrochloric acid was added, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 40 ml of methanol, 80 ml of water, and 10 ml of a 25% sodium hydroxide aqueous solution were added to the concentrated residue, and the residue was dissolved, followed by dropwise addition of 5 ml of concentrated hydrochloric acid to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 12.09 g (yield: 92.4%) of compound (3) as a white powder.

[0151]
Production Example 3: Production of Compound (7)
Compound (7) was produced in accordance with the following reaction scheme.

[0152]
[Chem. 13]
Production Example 4: Production of Compound (11)
Compound (11) was produced in accordance with the following reaction scheme.

[0160]
[Chem. 14]

[0161]
Synthesis of Compound (9)
20.00 g (66.8 mmol) of compound (7) and 17.28 g (134 mmol) of N,N-diisopropylethylamine were added to 300 ml of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was poured in and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was added thereto and reacted at 20 to 35°C for 1 hour. 100 ml of water was added to the reaction solution, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 300 ml of ethyl acetate was added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 ml of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue and reacted at 75 to 85°C for 1 hour. 200 ml of water was added to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 25.90 g (yield: 90.5%) of compound (9) as a white powder.

[0162]
1H-NMR (DMSO-d 6) δ: 8.22 (1H,s),7.94-7.86 (4H,m),7.58 (1H,d,J = 2.0 Hz),7.52 (1H,dd,J = 8.8 Hz,2.4 Hz),7.30 (1H,d,J = 8.4 Hz),7.14 (1H,t,J = 74.2 Hz),4.78-4.69 (3H,m),1.30 (6H,d,J = 6.0 Hz).

[0163]
Synthesis of Compound (10)
15.00 g (35.0 mmol) of compound (9) was mixed with 30 ml of a 40% methylamine aqueous solution, 30 ml of methanol, and 75 ml of water, and reacted under reflux for 30 minutes. 150 ml of cyclopentyl methyl ether (CPME) and 15 ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75°C, followed by partitioning. A mixture of 150 ml of water and 7.50 g of sodium chloride was added to the organic layer, and the temperature was adjusted to 65 to 75°C again, followed by partitioning. 3.75 ml of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C, thereby obtaining 11.95 g (yield: quant.) of compound (10) as a white powder.

[0164]
1H-NMR (DMSO-d 6) δ: 8.51 (3H,br-s),8.29 (1H,s),7.64 (1H,d,J = 2 Hz),7.59 (1H,dd,J = 8.0 Hz,1.6 Hz),7.37 (1H,d,J = 8.4 Hz),7.18 (1H,t,J = 74.0 Hz),4.72 (1H,sept,J = 6.1 Hz),4.03 (2H,s),1.33 (6H,d,J = 6.4 Hz).

[0165]
Synthesis of Compound (11)
13.30 g (39.7 mmol) of compound (10) was mixed with 3.83 g (37.8 mmol) of triethylamine and 108 ml of ethyl acetate, and stirred at 20 to 30°C for 1 hour. 9.78 g (58.9 mmol) of 2-ethoxybenzoic acid and 11.28 g (58.8 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 54 ml of water and 5.4 ml of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50°C, followed by partitioning. 54 ml of water and 5.4 ml of a 25% sodium hydroxide aqueous solution were added to the organic layer, and the temperature was adjusted to 40 to 50°C again. The mixture was partitioned, and the organic layer was concentrated under reduced pressure. 45 ml of ethanol, 18 ml of water, 5.4 ml of a 25% sodium hydroxide aqueous solution, and 0.54 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated carbon was removed by filtration, and the filtrate was washed with 11 ml of ethanol. The filtrate was cooled, and a seed crystal was added thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 35°C, thereby obtaining 12.88 g (72.6%) of compound (11) as a white powder.

[0166]
1H-NMR (CDCl 3) δ: 8.56 (1H,br-s),8.23 (1H,dd,J = 7.6 Hz,1.6 Hz),7.66 (1H,s),7.63 (1H,d,J = 2.0 Hz),7.58 (1H,dd,J = 8.4 Hz,2.0 Hz),7.44-7.39 (1H,m),7.21 (1H,d,J = 8.0 Hz),7.08-7.04 (1H,mH),6.94 (1H,d,J = 8.0 Hz),6.61 (1H,t,J = 75.2 Hz),4.68 (1H,sept,J = 6.0 Hz),4.62 (2H,d,J = 6.0 Hz),4.17 (2H,q,J = 6.93),1.48 (3H,t,J = 7.2 Hz),1.39 (6H,d,J = 5.6 Hz).

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019194211


*DIPEA: Diisopropylethylamine, CPME: Cyclopentyl methyl ether,
DMF: N,N-dimethylformamide, 2-EBA: 2-Ethoxybenzoic acid,
WSC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

Type B Crystal Preparation 2
Analysis was conducted to further prepare the type B crystal using the obtained type B crystal as a seed crystal. More specifically, the type B crystal was prepared as follows, in accordance with the method disclosed in PTL 3 (WO2017/115780).

[0072]

[0073]
20.00 g (66.8 mmol) of compound (1) and 17.28 g (134 mmol) of diisopropylethylamine were added to 300 mL of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was poured in and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was added thereto, and the mixture was stirred at 20 to 35°C for 1 hour. 100 mL of water was added to the reaction solution, and the mixture was separated, followed by concentration of the organic layer under reduced pressure. 300 mL of ethyl acetate was added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 mL of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue, and reacted at 75 to 85°C for 1 hour. 200 mL of water was added to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 27.20 g (yield: 95.01%) of compound (3).

[0074]

[0075]
20.00 g (46.7 mmol) of compound (3), 40 mL of a 40% methylamine aqueous solution, 40 mL of methanol, and 100 mL of water were mixed and reacted for 30 minutes under reflux. 200 mL of cyclopentyl methyl ether (CPME) and 20 mL of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75°C, followed by separation. A mixture of 100 mL of water and 20.00 g of sodium chloride was added to the organic layer, and the temperature was adjusted to 65 to 75°C again, followed by separation. 5 mL of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration, thereby obtaining 27.58 g of compound (4) as a wet crystal.

[0076]
The wet crystal (46.7 mmol) of compound (4) was mixed with 120 mL of ethyl acetate and 7.1 mL (51.4 mmol) of triethylamine, and stirred at 20 to 30°C for 1 hour. 10.09 g (60.7 mmol) of 2-ethoxybenzoic acid and 11.63 g (60.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 60 mL of water and 6 mL of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50°C, followed by separation. 60 mL of water and 6 mL of a 25% sodium hydroxide aqueous solution were added to the organic layer, and the temperature was adjusted to 40 to 50°C again. The mixture was separated, and the organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25% sodium hydroxide aqueous solution, and 0.6 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated carbon was removed by filtration, and the filtrate was washed with 12 mL of ethanol. The filtrate was cooled, and 10 mg of the type B crystal (a seed crystal) was added thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C, thereby obtaining 18.38 g (88.18%) of compound (5).

PATENT

WO2014034958A1

WO2007058338A2

WO2007058338A9

WO2007058338A3

US9181205B2

US2015239855A1

USRE46792E

US2020078340A1

US2017216260A1

US2019070151A1

US2009221586A1

US8637559B2

US2014100226A1

///////////

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/////////////Difamilast, JAPAN 2021, APPROVALS 2021, ジファミラスト ,  MM 36,  MM-36-Medimetriks-Pharmaceuticals,  Moizerto, OPA-15406, OPA 15406, 地法米司特

O=C(NCC1=COC(C2=CC=C(OC(F)F)C(OC(C)C)=C2)=N1)C3=CC=CC=C3OCC

INTrmediate No.CAS No.DIFAM-001177429-27-5DIFAM-00293652-48-3DIFAM-0031574285-26-9DIFAM-00470-23-5DIFAM-0051574285-28-1DIFAM-0061574285-30-5DIFAM-0071574285-32-7DIFAM-0081574285-36-1DIFAM-0091574285-38-3DIFAM-010DIFAM-0111574285-40-7DIFAM-0121574285-43-0DIFAM-013134-11-2Difamilast937782-05-3

TOLDIMFOS SODIUM


Toldimfos sodium.png
Structure of TOLDIMFOS SODIUM

TOLDIMFOS SODIUM

C9H12NNaO2P+  , 220.16

Toldimfos sodium

575-75-7

Sodium (4-(dimethylamino)-2-methylphenyl)phosphinate

UNII-6139240O1E

sodium;[4-(dimethylamino)-2-methylphenyl]-oxido-oxophosphanium

EINECS 209-391-4

C9H13NO2P.Na

DTXSID4060361

AKOS015960346

VZ33686

AC-10524

FT-0657398

575-75-7

Sodium (4-(dimethylamino)-2-methylphenyl)phosphinate

UNII-6139240O1E

sodium;[4-(dimethylamino)-2-methylphenyl]-oxido-oxophosphanium

Phosphinic acid, [4-(dimethylamino)-2-methylphenyl]-, sodium salt

6139240O1E

Phosphinic acid, (4-(dimethylamino)-2-methylphenyl)-, sodium salt

Phosphinic acid, P-(4-(dimethylamino)-2-methylphenyl)-, sodium salt (1:1)

Toldimfos is an aromatic phosphorus compound which falls between phosphorous itself and phosphoric acid in the stages of oxidation. Toldimfos sodium is the sodium salt of 2- methyl-4-(dimethylamino)phenylphosphinic acid. It is used to treat and prevent diseases associated with parturition and peri-partum period, developmental and nutritional disorders in young animals, and bone growth disorders and tetany or paresis caused by calcium, magnesium, and phosphorus metabolism disorders. Toldimfos has been used as a human medicine since 1920. While it is no longer indicated for human use, it is used in horses, cattle, sheep, pigs, and goats, and administered by intravenous, intramuscular, or subcutaneous injection. No specific data on the pharmacodynamic action of toldimfos was submitted. The precise mode of action of toldimfos is unknown and it is questionable whether the effect of toldimfos is simply a matter of the substitution of deficient phosphorus. It appears more likely that the effect of toldimfos arises due to multiple stimulation of metabolism with the body.

Toldimfos sodium trihydrate.png

Toldimfos sodium trihydrate

5787-63-3

2D chemical structure of 57808-64-7

Toldimfos [INN:BAN]
57808-64-7

Toldimfos Sodium

CAS Registry Number: 575-75-7

CAS Name: (4-Dimethylamino-o-tolyl)phosphonous acid sodium salt

Additional Names: sodium (4-dimethylamino-o-tolyl)phosphonate; p-dimethylamino-o-toluenephosphonous acid sodium salt

Trademarks: Foston (Hoechst); Tonofosfan (Hoechst)

Molecular Formula: C9H13NNaO2P, Molecular Weight: 221.17

Percent Composition: C 48.87%, H 5.92%, N 6.33%, Na 10.39%, O 14.47%, P 14.00%

Literature References: Prepd from N,N-dimethyl-m-toluidine and phosphorus trichloride: Benda, Schmidt, DE397813 (1924 to Cassella), Frdl.14, 1409.

Derivative Type: Trihydrate

CAS Registry Number: 5787-63-3

Properties: Scales, needles, or prisms from alc. Freely sol in cold water, hot alcohol.

Therap-Cat-Vet: Phosphorus source.

SYN

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011026571

PATENT

https://patents.google.com/patent/CN103830261A/en

China’s animal husbandry fast development is the important motivity that promotes China’s agricultural and rural economy development, improves farmers’ income.The disease relevant with Nutrition and Metabolism of serious harm animal health is in rising trend in recent years, the direct economic loss that raising poultry nutritive metabolic disease causes over ten billion to China’s animal husbandry every year, and indirect economic loss is difficult to estimate.

Due to the life-time service of chemicals, will cause some poultrys, poultry product drug residue is serious, this is harm humans healthy not only, also affecting the export of farm produce earns foreign exchange, therefore, tackle this problem, research and development are efficient, the new Nutrition and Metabolism medicine of low toxicity, wide spectrum will have huge market.

Toldimfos (Toldimfos Sodium) belongs to the nutritional supplementation medicine of phosphorus supplement, can be used as benzenephosphonic acid (Phenylphosphinicacid, BPA) succedaneum uses, can be used for treating the disease relevant with childbirth and perinatal stage of the food animals such as horse, cattle, pig, sheep, the diseases such as the bone lengthening obstacle being caused by calcium, magnesium, phosphorus metabolism obstacle.

Toldimfos has higher water solublity, mainly excretes through urine rapidly with the former medicine form of not metabolism in animal body, and the half-life is short, can in tissue, not accumulate.

Toldimfos is developed by German Hoechst company, the symptom such as since nineteen twenty, once physical weakness, chronic stress, depression, mental muscle power postoperative for human treatment, that catch was overtired.Now be not used in the mankind, be mainly used in animal.Its commodity are called onofosfan.

In sum, toldimfos, as a kind of nutritional supplementation medicine of new and effective noresidue, has wide market prospect in China.The development of this product will be made outstanding contributions to the sound development of China’s animal husbandry, remarkable economic and social benefits with application.

PATENT

https://patents.google.com/patent/WO2004003198A1/ja

///////////

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//////////TOLDIMFOS SODIUM, HOECHST,  Foston, Tonofosfan, 

O.O.O.[Na+].CN(C)c1ccc(c(C)c1)P(=O)[O-]

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CRENOLANIB


Crenolanib.svg
ChemSpider 2D Image | Crenolanib | C26H29N5O2

Crenolanib

  • Molecular FormulaC26H29N5O2
  • Average mass443.541 Da

1-(2-{5-[(3-Methyl-3-oxetanyl)methoxy]-1H-benzimidazol-1-yl}-8-quinolinyl)-4-piperidinamine

1-(2-{5-[(3-methyloxetan-3-yl)methoxy]-1H-benzimidazol-1-yl}quinolin-8-yl)piperidin-4-amine

1-[2-[5-[(3-methyl-3-oxetanyl)methoxy]-1H-benzimidazol-1-yl]-8-quinolinyl]-4-piperidinamine

4-Piperidinamine, 1-[2-[5-[(3-methyl-3-oxetanyl)methoxy]-1H-benzimidazol-1-yl]-8-quinolinyl]-

670220-88-9[RN]

9459

UNII-LQF7I567TQ

креноланиб

كرينولانيب

克拉尼布

CP-868,596-26 or AR-868,596-26

Crenolanib besylate.png

Crenolanib besylate
CAS#: 670220-93-6 (besylate)
Chemical Formula: C32H35N5O5S

Molecular Weight: 601.72

Crenolanib besylate (CP-868,596-26 or AR-868,596-26, 4-piperidinamine, 1-[2-[5-[(3-Methyl-3-oxetanyl) methoxy]-1H-benzimidazol-1-yl]- 8-quinolinyl]-, monobenzenesulfonate) is an investigational inhibitor being developed by AROG Pharmaceuticals, LLC. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including acute myeloid leukemia (AML),[1][2] gastrointestinal stromal tumor (GIST),[3] and glioma.[4] Crenolanib is an orally bioavailable benzamidazole that selectively and potently inhibits signaling of wild-type and mutant isoforms of class III receptor tyrosine kinases (RTK) FLT3 (FMS-like Tyrosine Kinase 3), PDGFR α (Platelet-Derived Growth Factor Receptor), and PDGFR β. Unlike most RTK inhibitors, crenolanib is a type I mutant-specific inhibitor that preferentially binds to phosphorylated active kinases with the ‘DFG in’ conformation motif.[5]

CN 109678849

PATENT

WO/2022/060421CRENOLANIB FOR TREATING TRK KINASE ASSOCIATED PROLIFERATIVE DISORDERS

PATENT

WO/2022/060422CRENOLANIB FOR TREATING PAIN

PAPER

https://www.nature.com/articles/s41598-018-21839-3

figure 1

PAPER

 Chembiochem : a European journal of chemical biology (2019), 20(14), 1783-1788.

PATENT

CN 109678849

PATENT

WO 2018118598

https://patents.google.com/patent/WO2018118598A1/en

PAT

US 20170121321

PAT

CN 107382984

https://patents.google.com/patent/CN107382984A/en

Embodiment is as follows:

The synthesis of the chloro- 8- trifluoromethanesulfonic acids base quinoline (Ι) of 2-

Compound 2- chloro-8-hydroxyquinolines 50g, DMF150ml, trifluoromethanesulfchloride chloride 53g, triethylamine 25g are added to 250ml In three-necked bottle, stir.Temperature control reacts 20~30h at 25~30 DEG C.After reaction completely, the solid of precipitation is filtered, filter cake is used Wash washing, 40 DEG C of forced air dryings, the chloro- 8- trifluoromethanesulfonic acids base benzimidazoles of gained off-white powder 2- in n-hexane 20ml × 3 83.39g yield 95.78%.

The synthesis of (base of piperidines -4) the quinoline t-butyl carbamates of 2- chloro- 8 (II)

BINAP 0.2g, toluene 70ml are added into 250ml three-necked bottles, temperature control stirs 1h at 20~25 DEG C.Added again into bottle The chloro- 8- trifluoromethanesulfonic acids base quinoline 10g of 2-, piperidin-4-yl t-butyl carbamate 6.41g, potassium carbonate 7.8g, stir lower by instead Answer liquid to be heated to 80 DEG C~100 DEG C, keep 20~30h of this thermotonus.TLC is detected, and whether reaction is complete.Reaction is complete, stops Only heat.20~30 DEG C are cooled to, dichloroethanes 50ml is added, adds diatomite to filter out the solid in reaction solution, filter cake second Acetoacetic ester 150ml is washed., 20~25 DEG C of stirring 8h.The solid separated out in solution is filtered out, filtrate is molten with 5% disodium hydrogen phosphate Liquid 2x50ml is washed.Organic phase is concentrated to dryness again, adds acetonitrile 50ml, 20~25 DEG C of 10~20h of stirring and crystallizing.Filtering analysis The solid gone out, 40 DEG C of forced air dryings obtain the tertiary fourth of yellow solid 10.69g, 2- chloro- 8 (piperidin-4-yl) benzimidazole carbamic acid Ester, yield 92.3%.

The synthesis of 5- (3- methy oxetane -3- methoxyl groups) benzimidazole (III)

Compound 3- methyl -3- oxetane methanols 30.77g, THF140ml, metallic sodium 6.95g are added to the necks of 250ml tri- In bottle, 66 DEG C of backflow 4h are heated under stirring, 55 DEG C is cooled to, then adds 5- hydroxybenzimidazole 40.4g, stir lower heat Backflow, react 20~24h.

Ethyl acetate 100ml is added into reaction bulb, 0.5h dissolvings are stirred at 30~50 DEG C, are then reduced to -5 DEG C, are added dropwise just Hexane 30ml, stirs 1h, and suction filtration obtains light yellow solid, 40 DEG C of dryings to constant weight, obtains 56.41 grams, yield 85.8%.

(1- { 2- [5- (3- methvl-oxetan -3- ylmethoxies)-benzimidazole -1- bases]-quinoline-8-yl }-piperazine The synthesis of pyridine -4- bases-t-butyl carbamate (IV)

II (50 grams), III (30.14 grams), potassium carbonate 80g, DIPHOS 4.3g, toluene 700ml, are added in 2L three-necked bottles, add Enter acid chloride 0.9g, stir.Stirring is lower to heat up, and temperature control reacts 24~30h at 80~100 DEG C.After the completion of reaction, it is cooled to 55 DEG C add dichloroethanes 700ml.10min is stirred, adds the solid in diatomite filtering reacting liquid, the filter cake chloroethenes of 500ml bis- Alkane rinses.Concentrate the filtrate to it is dry, add ethyl acetate 480ml, be heated to flowing back, be cooled to 20~25 DEG C of 10~20h of crystallization. The solid separated out is filtered, 50 DEG C of forced air dryings, obtains white solid, the amount of obtaining 70.51g, yield 93.90%.

(1- { 2- [5- (3- methvl-oxetan -3- ylmethoxies)-benzimidazole -1- bases]-quinoline-8-yl } -4- The synthesis of amino piperidine (V)

By compound (1- { 2- [5- (3- methvl-oxetan -3- ylmethoxies)-benzimidazole -1- bases]-quinoline -8- Base }-piperidin-4-yl-t-butyl carbamate 5g, caustic alcohol 2.8g, 2- methyltetrahydrofuran 30ml and water 0.08ml be added to In 100ml three-necked bottles, stir.The mixture is heated to flowing back, and stirs 3~4h under reflux.

TLC is detected, and reaction is complete.Stop heating, add purified water 60ml, extracting and demixing.Aqueous phase is extracted with 2 × 20ml of ethyl acetate Take, merge organic phase, washed with saturated nacl aqueous solution 20ml.Be concentrated under reduced pressure organic phase, and 30ml is added into condensate residue Ethyl acetate, in 20~25 DEG C of stirring and crystallizing 6h.The solid separated out is filtered, filtrate decompression is concentrated to dryness.Added into residue 24ml ethyl acetate, in 20~25 DEG C of 10~12h of stirring and crystallizing.Filter the solid separated out, dry white solid product, the amount of obtaining 3.68g, yield 90.3%.

1H NMR test (referring to accompanying drawing)

(d6-DMSO):δ 9.176 (s, 1H), δ 8.88-8.91 (d, 1H, J=8.7Hz), δ 8.51-8.53 (d, 1H, J= 9.0Hz), δ 8.13-8.15 (d, 1H, J=9.0Hz), δ 7.6 (d, 1H, J=7.5Hz), 7.49 (t, 1H, J=7.9Hz) 7.39 (d, 1H, J=2.4Hz), 7.29 (d, 1H, J=7.6Hz), 7.19 (dd, 1H, J=9.2hz, 2.5Hz) 4.56 (d, 2H, J= 5.6Hz), 4.34 (d, 2H, J=5.7Hz), 4.14 (s, 2H), 3.74 (d, 2H, J=10.1Hz), 2.77 (m, 3H), 1.91 (d, 2H, J=11.1Hz), 1.68 (m, 2H), 1.41 (s, 3H)

SET 2

///////////

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Background

Type III Receptor tyrosine kinase, including FLT3PDGFRα and PDGFRβ, have been directly implicated in the pathogenesis of epithelialmesenchymal, and hematological malignancies.[6]

Mutations of FLT3 comprise one of the most frequently identified types of genetic alterations in Angiomyolipoma.[7][8] Approximately one-third of AML patients present with a mutation in this gene.[9] The majority of these mutations result in constitutive activation of downstream signaling pathways and aberrant cell growth.[7] Mutations in FLT3 have also been reported in acute lymphoblastic leukemia (ALL)[10] and myelodysplastic syndrome (MDS).[11]

Activating mutations in PDGFRA have been detected in 5-12% of Gastrointestinal stromal tumor.[12] Fusion of PDGFRA has been found to be responsible for hematological malignances like hypereosinophilic syndrome.[13] The amplification of chromosome 4q12, the site of the PDGFRA gene[citation needed], has been identified in 13-29% of adult gliomas[citation needed] and in 29% to 36% of diffuse intrinsic pontine gliomas (DIPG)[citation needed], a subset of high-grade gliomas (HGG) in pediatric patients. Activation of PDGFRB, a third member of the type III RTK family, has been implicated in the development of chronic myelomonocytic leukemia due to the fusion of PDGFRB with the TEL gene.[13] Furthermore, PDGFB translocation to the COL1A1 gene locus has been identified to be responsible for dermatofibrosarcoma protuberans (DFSP).[13] In cancer cells, PDGFR promotes tumor development and migration via proto-oncogenic downstream mediators like AKT and MEK[citation needed]. In stromal fibroblastsPDGFRα activation leads to local tissue invasion, production and secretion of VEGF, and elevated intratumoral interstitial pressure[citation needed]. In stromal pericytesPDGFRβ activation mediates vascular stability.[13] Thus, either FLT3 or PDGF/PDGFR pathway is the primary driver of oncogenesis in the above malignancies and can be targeted by crenolanib therapy[citation needed].

Mechanism

FLT3: wild-type and mutant

Crenolanib inhibits both wild type FLT3 and its constitutively active mutations. In vitro studies have shown that crenolanib has low Kd for the FLT3 enzyme with constitutively activating internal tandem duplication (ITD) mutations and tyrosine kinase domain (TKD) mutations, D835H and D835Y, as compared to wild type. Crenolanib tightly binds to FLT3-ITD, FLT3-D835H and FLT3-D835Y with Kd of 0.74 nM, 0.4 nM, and 0.18 nM, respectively.[14] Crenolanib inhibits the phosphorylation of the FLT3-ITD receptor in transfected TF-1 cells and the FLT3-D835Y TKD mutation in transfected Ba/F3 cells at nanomolar IC50 concentrations of 1.3 nM and 8.8 nM, respectively.[15] Immunoblot experiments performed in the Molm14 FLT3-ITD positive cell line show that crenolanib inhibits downstream signaling of FLT3 at a concentration of 10 nM.[15] MTT assay measurements of crenolanib cytotoxicity evaluated in the FLT3-ITD expressing cell lines Molm14 and MV411, showed that crenolanib is toxic at IC50 concentrations of 7 nM and 8 nM, respectively.[15]

PDGFRα: wild-type and mutant

Crenolanib has been shown to inhibit PDGFRα with an IC50 of 0.4 ng/mL in porcine aortic epithelial cell lines. In Chinese hamster ovary (CHO) cells expressing PDGFRα, crenolanib inhibited the phosphorylation of wild type PDGFRα at an IC50 of 10 nM.[16] Additionally, crenolanib completely blocked PDGFRα phosphorylation and downstream AKT signaling at a concentration between 0.1 and 1 uM in Ink4a/Arf-/- mouse astrocytes transfected to stably co-express both human PDGFRα and PDGF AA.[17] The lung cancer cell line H1703, which is reported to have amplification of both PDGFRA (4q12) and PDGFC (4q32) genes on chromosome 4, and also overexpress PDGFRα, was sensitive to crenolanib with an IC50 of ~80 nM.[18] In CHO cells expressing an activating exon 18 (D842V) PDGFRα mutation, crenolanib was effective at an IC50 of 6nM and IC90 of 25nM. In addition, crenolanib also inhibited phosphorylation of the double mutants PDGFRα (V561D + D842V and T674I + D842V).[16]

PDGFRβ: wild-type

Crenolanib has been shown to inhibit PDGFRβ with an IC50 of 0.8 ng/mL in porcine aortic epithelial cell lines. Crenolanib inhibits the ability of recombinant PDGFRβ to phosphorylate a synthetic tyrosine substrate (poly-glutamic acid-tyrosine), with an IC50 of 0.4 ng/mL. Evaluation of the antitumor activity of crenolanib in a genetically engineered BSG DIPG mouse model showed that it is highly selective for PDGFRβ with an IC50 of 10 nM when measured by BrdU assay and 1.25 uM by MTT assay.

C-Kit: wild-type and mutant

Crenolanib has been shown to have IC50 and Kd values of 67 nM and 78 nM, respectively, for wild type c-KIT in in vitro assays[citation needed]. Similar assays show that crenolanib inhibits c-KIT activating mutations D816H and D816V with IC50 concentrations of 5.4 and 2.5 nM, respectively.[14][citation needed] Human bone marrow progenitor cell growth assays showed that crenolanib has modest effects on GM-CSF and BFUE driven colony formation at the IC50 concentration of 20 nM.[15]

Clinical

Phase I single-agent[19] and Phase Ib combination[20] studies have investigated the clinical pharmacology of crenolanib in patients with cancer. Pharmacokinetic and safety studies of Crenolanib administered alone or in combination with docetaxel with or without axitinib have been completed. Results suggest that Crenolanib is well tolerated as a single agent, and can also be safely combined with docetaxel and axitinib due to their non-overlapping toxicity profiles.

Clinical trials

  • Clinical trial number NCT01229644 for “A Phase II Study of Crenolanib (CP-868,596), a Selective and Potent Inhibitor of PDGFR, for the Treatment of Adult Gliomas” at ClinicalTrials.gov
  • Clinical trial number NCT01243346 for “Phase II Study of Crenolanib (CP-868,596), for the Treatment of Patients With Advanced Gastrointestinal Stromal Tumors With the D842-related Mutations and Deletions in the PDGFRA Gene” at ClinicalTrials.gov
  • Clinical trial number NCT01393912 for “PDGFR Inhibitor Crenolanib in Children/Young Adults With Diffuse Intrinsic Pontine Glioma or Recurrent High-Grade Glioma” at ClinicalTrials.gov
  • Clinical trial number NCT01522469 for “Phase II Study of Crenolanib in Subjects With Relapsed/Refractory AML With FLT3 Activating Mutations” at ClinicalTrials.gov
  • Clinical trial number NCT01657682 for “A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations” at ClinicalTrials.gov

References

  1. ^ “A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations – Full Text View”. ClinicalTrials.gov. Retrieved 2014-04-08.
  2. ^ “Phase II Study of Crenolanib in Subjects With Relapsed/Refractory AML With FLT3 Activating Mutations – Full Text View”. ClinicalTrials.gov. Retrieved 2014-04-08.
  3. ^ “Phase II Study of Crenolanib (CP-868,596), for the Treatment of Patients With Advanced Gastrointestinal Stromal Tumors With the D842-related Mutations and Deletions in the PDGFRA Gene – Full Text View”. ClinicalTrials.gov. Retrieved 2014-04-08.
  4. ^ “PDGFR Inhibitor Crenolanib in Children/Young Adults With Diffuse Intrinsic Pontine Glioma or Recurrent High-Grade Glioma – Full Text View”. ClinicalTrials.gov. Retrieved 2014-04-08.
  5. ^ A. Ramachandran; H. Marshall; V. Jain. “CRENOLANIB, A NOVEL TYPE I, MUTANT -SPECIFIC INHIBITOR OF CLASS III RECEPTOR TYROSINE KINASES, PREFERENTIALLY BINDS TO PHOSPHORYLATED KINASES” (PDF). gistsupport.org. Retrieved 2014-04-08.
  6. ^ Lemmon, Mark A.; Schlessinger, Joseph (2010). “Cell Signaling by Receptor Tyrosine Kinases”Cell141 (7): 1117–34. doi:10.1016/j.cell.2010.06.011PMC 2914105PMID 20602996.
  7. Jump up to:a b Takahashi, S (2011-04-01). “Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: biology and therapeutic implications”J Hematol Oncol4: 13. doi:10.1186/1756-8722-4-13PMC 3076284PMID 21453545.
  8. ^ Cancer Genome Atlas Research Network; Ley, T. J.; Miller, C.; Ding, L.; Raphael, B. J.; Mungall, A. J.; Robertson, A.; Hoadley, K.; Triche Jr, T. J.; Laird, P. W.; Baty, J. D.; Fulton, L. L.; Fulton, R.; Heath, S. E.; Kalicki-Veizer, J.; Kandoth, C.; Klco, J. M.; Koboldt, D. C.; Kanchi, K. L.; Kulkarni, S.; Lamprecht, T. L.; Larson, D. E.; Lin, L.; Lu, C.; McLellan, M. D.; McMichael, J. F.; Payton, J.; Schmidt, H.; Spencer, D. H.; et al. (2013). “Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia”New England Journal of Medicine368 (22): 2059–2074. doi:10.1056/NEJMoa1301689ISSN 0028-4793PMC 3767041PMID 23634996.
  9. ^ “The Impact of FLT3 Mutations on the Development of Acute Myeloid Leukemias”. Hindawi.com. Retrieved 2014-04-08.
  10. ^ Xu, F; Taki, T; Yang, HW; Hanada, R; Hongo, T; Ohnishi, H; Kobayashi, M; Bessho, F; Yanagisawa, M; Hayashi, Y (2014-01-24). “Tandem duplication of the FLT3 gene is found in acute lymphoblastic leukaemia as well as acute myeloid leukaemia but not in myelodysplastic syndrome or juvenile chronic myelogenous leukaemia in children”Br. J. Haematol105 (1): 155–62. doi:10.1111/j.1365-2141.1999.01284.xPMID 10233379S2CID 40898615.
  11. ^ Yokota, S; Kiyoi, H; Nakao, M; Iwai, T; Misawa, S; Okuda, T; Sonoda, Y; Abe, T; Kahsima, K; Matsuo, Y; Naoe, T (2014-01-24). “Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines”Leukemia11 (10): 1605–9. doi:10.1038/sj.leu.2400812PMID 9324277.
  12. ^ Heinrich, M. C.; Corless, CL; Duensing, A; McGreevey, L; Chen, CJ; Joseph, N; Singer, S; Griffith, DJ; Haley, A; Town, A; Demetri, GD; Fletcher, CD; Fletcher, JA (2003). “PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors”. Science299 (5607): 708–10. doi:10.1126/science.1079666PMID 12522257S2CID 11725958.
  13. Jump up to:a b c d Östman, Arne; Heldin, Carl‐Henrik (2007). PDGF Receptors as Targets in Tumor Treatment. Advances in Cancer Research. Vol. 97. pp. 247–274. doi:10.1016/S0065-230X(06)97011-0ISBN 9780120066971PMID 17419949.
  14. Jump up to:a b Muralidhara, C.; Ramachandran, A.; Jain, V. K. (2012). “Abstract 3683: Crenolanib, a novel Type I, mutant-specific inhibitor of Class III receptor tyrosine kinases, preferentially binds to phosphorylated kinases”. Cancer Research72 (8 Supplement): 3683. doi:10.1158/1538-7445.AM2012-3683.
  15. Jump up to:a b c d Galanis, A.; Rajkhowa, T.; Muralidhara, C.; Ramachandran, A.; Levis, M. (2012). “Abstract 3660: Crenolanib: A next generation FLT3 inhibitor”. Cancer Research72 (8 Supplement): 3660. doi:10.1158/1538-7445.am2012-3660.
  16. Jump up to:a b Heinrich, M. C.; Griffith, D.; McKinley, A.; Patterson, J.; Presnell, A.; Ramachandran, A.; Debiec-Rychter, M. (2012). “Crenolanib Inhibits the Drug-Resistant PDGFRA D842V Mutation Associated with Imatinib-Resistant Gastrointestinal Stromal Tumors”Clinical Cancer Research18 (16): 4375–84. doi:10.1158/1078-0432.CCR-12-0625PMID 22745105.
  17. ^ Yang, X.-L.; Mashimo, T.; Su, Y.; Vemireddy, V.; Guntipalli, P.; Ramachandran, A.; Chaudhary, P.; Mickey, B.; Hatanpaa, K.; Maher, E.; Bachoo, R. M. (2011). “Abstract 1111: Preclinical evaluation of CP868,596, a novel PDGFR Inhibitor for treatment of glioblastoma”. Cancer Research71 (8 Supplement): 1111. doi:10.1158/1538-7445.am2011-1111.
  18. ^ Peyton, M.; Chaudhary, P.; Ramachandran, A.; Minna, J. (2011). “Abstract 3601: CP-868,596, a highly potent and selective PDGFR TKI inhibits growth of PDGFR -driven lung cancer cells”. Cancer Research71 (8 Supplement): 3601. doi:10.1158/1538-7445.am2011-3601.
  19. ^ Lewis, N. L.; Lewis, L. D.; Eder, J. P.; Reddy, N. J.; Guo, F.; Pierce, K. J.; Olszanski, A. J.; Cohen, R. B. (2009). “Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients with Advanced Cancers”Journal of Clinical Oncology27 (31): 5262–9. doi:10.1200/jco.2009.21.8487PMC 2773478PMID 19738123.
  20. ^ Michael, M; Vlahovic, G; Khamly, K; Pierce, K J; Guo, F; Olszanski, A J (2010). “Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor”British Journal of Cancer103 (10): 1554–61. doi:10.1038/sj.bjc.6605941PMC 2990584PMID 20959830.

External links

Names
IUPAC name1-(2-{5-[(3-methyloxetan-3-yl)methoxy]-1H-benzimidazol-1-yl}quinolin-8-yl)piperidin-4-amine
Other namesCP-868,596; AR-868,596-26
Identifiers
CAS Number670220-88-9 
3D model (JSmol)Interactive image
ChEBICHEBI:145365
ChEMBLChEMBL2105728 ChEMBL2146086 
ChemSpider8541584 
IUPHAR/BPS7882
KEGGD10102 
PubChemCID10366136
UNIILQF7I567TQ 
CompTox Dashboard (EPA)DTXSID50985873 
showInChI
showSMILES
Properties
Chemical formulaC26H29N5O2
Molar mass443.551 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒ verify (what is  ?)
Infobox references

//////////Crenolanib, UNII-LQF7I567TQ, креноланиб , كرينولانيب , 克拉尼布, CP-868,596-26,  AR-868,596-26

CC1(COc2ccc3c(c2)ncn3c4ccc5cccc(N6CCC(N)CC6)c5n4)COC1.OS(=O)(=O)c7ccccc7

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TRIAMCINOLONE


Triamcinolone ball-and-stick animation.gif
Triamcinolone.svg
ChemSpider 2D Image | Triamcinolone | C21H27FO6

TRIAMCINOLONE

  • Molecular FormulaC21H27FO6
  • Average mass394.434 Da

(11β,16α)-9-Fluoro-11,16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione

(8S,9R,10S,11S,13S,14S,16R,17S)-9-Fluor-11,16,17-trihydroxy-17-(hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-on

(8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11,16,17-trihydroxy-17-(hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one

(8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11,16,17-trihydroxy-17-(hydroxyacétyl)-10,13-diméthyl-6,7,8,9,10,11,12,13,14,15,16,17-dodécahydro-3H-cyclopenta[a]phénanthrén-3-one

(8S,9R,10S,11S,13S,14S,16R,17S)-9-Fluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one

124-94-7[RN]

16a-Hydroxy-9a-fluoroprednisolone

1ZK20VI6TY

204-718-7[EINECS]

755

9a-Fluoro-16a-hydroxyprednisolone

TU3850000

トリアムシノロン[Japanese]

去炎松[Chinese]

Triamcinolone

CAS Registry Number: 124-94-7

CAS Name: (11b, 16a)-9-Fluoro-11,16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione

Additional Names: D1-9a-fluoro-16a-hydroxyhydrocortisone; 9a-fluoro-16a-hydroxyprednisolone; D1-16a-hydroxy-9a-fluorohydrocortisone; 16a-hydroxy-9a-fluoroprednisolone

Manufacturers’ Codes: CL-19823

Trademarks: Aristocort (Lederle); Kenacort (BMS); Ledercort (tabl.) (Lederle); Omcilon (BMS); Tricortale (Bergamon); Volon (BMS)

Molecular Formula: C21H27FO6, Molecular Weight: 394.43

Percent Composition: C 63.95%, H 6.90%, F 4.82%, O 24.34%

Literature References: Prepn: Bernstein et al.,J. Am. Chem. Soc.78, 5693 (1956); 81, 1689 (1959); Thoma et al.,ibid.79, 4818 (1957); Bernstein et al., Allen et al.,US2789118US3021347 (1957, 1962, both to Am. Cyanamid). Comprehensive description: K. Florey, Anal. Profiles Drug Subs.1, 367-396, 423-442 (1972); D. H. Sieh, ibid.11, 593-614, 651-661 (1982).

Properties: Crystals, mp 269-271°. mp also reported as 260-262.5°. [a]D25 +75° (acetone). uv max: 238 nm (e 15800).

Melting point: mp 269-271°; mp also reported as 260-262.5°

Optical Rotation: [a]D25 +75° (acetone)

Absorption maximum: uv max: 238 nm (e 15800)

………………………………

Derivative Type: 16,21-Diacetate

CAS Registry Number: 67-78-7

CAS Name: (11b,16a)-16,21-Bis(acetyloxy)-9-fluoro-11,17-dihydroxypregna-1,4-diene-3,20-dione

Additional Names: 16a,21-diacetoxy-9a-fluoro-11b,17a-dihydroxy-1,4-pregnadiene-3,20-dione

Trademarks: Cenocort (Central Pharm.); CINO-40 (Tutag); Tracilon (Savage)

Molecular Formula: C25H31FO8, Molecular Weight: 478.51

Percent Composition: C 62.75%, H 6.53%, F 3.97%, O 26.75%

Properties: Solvated crystals, mp 186-188° (with effervescence, mp 235° after drying). [a]D25 +22° (chloroform). uv max: 239 nm (e 15200).

Melting point: Solvated crystals, mp 186-188° (with effervescence, mp 235° after drying)

Optical Rotation: [a]D25 +22° (chloroform)

Absorption maximum: uv max: 239 nm (e 15200)

Therap-Cat: Glucocorticoid., Therap-Cat-Vet: Glucocorticoid., Keywords: Glucocorticoid.

///////////////////////

Triamcinolone Acetonide

Triamcinolone Acetonide

CAS Registry Number: 76-25-5

CAS Name: (11b,16a)-9-Fluoro-11,21-dihydroxy-16,17-[1-methylethylidenebis(oxy)]pregna-1,4-diene-3,20-dione

Additional Names: 9a-fluoro-11b,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone; 9a-fluoro-16a-hydroxyprednisolone acetonide; triamcinolone 16a,17-acetonide; 9a-fluoro-11b,21-dihydroxy-16a,17a-isopropylidenedioxy-1,4-pregnadiene-3,20-dione; 9a-fluoro-16a,17-isopropylidenedioxyprednisolone

Trademarks: Adcortyl (BMS); Azmacort (Aventis); Delphicort (Lederle); Extracort (Basotherm); Ftorocort (Gedeon Richter); Kenacort-A (BMS); Kenalog (Apothecon); Ledercort Cream (Lederle); Nasacort (Aventis); Respicort (Mundipharma); Rineton (Sanwa); Solodelf (Cyanamid); Tramacin (J & J); Triam (Lichtenstein); Tricinolon (Kaken); Vetalog (Solvay); Volon A (BMS); Volonimat (BMS)

Molecular Formula: C24H31FO6, Molecular Weight: 434.50

Percent Composition: C 66.34%, H 7.19%, F 4.37%, O 22.09%

Literature References: Prepd by stirring a suspension of triamcinolone in acetone in the presence of a trace of perchloric acid: Fried et al.,J. Am. Chem. Soc.80, 2338 (1958); Bernstein et al.,ibid.81, 1689 (1959); Bernstein, Allen, US2990401 (1961 to Am. Cyanamid). Alternate synthesis using 2,3-dibromo-5,6-dicyanoquinone: Hydorn, US3035050 (1962 to Olin Mathieson). Clinical trial in chronic asthma: I. L. Bernstein et al.,Chest81, 20 (1982). Comprehensive description: K. Florey, Anal. Profiles Drug Subs.1, 397-421 (1972); D. H. Sieh, ibid.11, 615-649 (1982).

Properties: Crystals, mp 292-294°. [a]D23 +109° (c = 0.75 in chloroform). uv max (abs alc.): 238 nm (e 14600). Sparingly sol in methanol, acetone, ethyl acetate.

Melting point: mp 292-294°

Optical Rotation: [a]D23 +109° (c = 0.75 in chloroform)

Absorption maximum: uv max (abs alc.): 238 nm (e 14600)

………………..

Derivative Type: 21-Acetate

Properties: Crystals, mp 268-270°. [a]D23 +92° (c = 0.59 in chloroform).

Melting point: mp 268-270°

Optical Rotation: [a]D23 +92° (c = 0.59 in chloroform)

Derivative Type: 21-Disodium phosphate

CAS Registry Number: 1997-15-5

Trademarks: Aristosol (Lederle)

Molecular Formula: C24H30FNa2O9P, Molecular Weight: 558.44

Percent Composition: C 51.62%, H 5.41%, F 3.40%, Na 8.23%, O 25.79%, P 5.55%

………………….

Derivative Type: 21-Hemisuccinate

Trademarks: Solutedarol (Specia)

Molecular Formula: C28H35FO9, Molecular Weight: 534.57

Percent Composition: C 62.91%, H 6.60%, F 3.55%, O 26.94%

Therap-Cat: Glucocorticoid; antiasthmatic (inhalant); antiallergic (nasal).

Therap-Cat-Vet: Glucocorticoid.

Keywords: Antiallergic (Steroidal, Nasal); Antiasthmatic (Steroidal, Inhalant); Glucocorticoid.

//////////////////////////

Title: Triamcinolone Benetonide

CAS Registry Number: 31002-79-6

CAS Name: (11b,16a)-21-[3-(Benzoylamino)-2-methyl-1-oxopropoxy]-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dione

Additional Names: 9-fluoro-11b,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone 21-ester with N-benzoyl-2-methyl-b-alanine; 9a-fluoro-16a-hydroxyprednisolone 16a,17a-acetonide 21-(b-benzoylamino)isobutyrate; triamcinolone acetonide b-benzoylaminoisobutyrate; TBI

Trademarks: Tibicorten (Stiefel)

Molecular Formula: C35H42FNO8, Molecular Weight: 623.71

Percent Composition: C 67.40%, H 6.79%, F 3.05%, N 2.25%, O 20.52%

Literature References: Prepn: C. Cavazza et al.,DE2047218eidem,US3749712 (1971, 1973 both to Sigma-Tau). Pharmacology: E. T. Ordonez, Arzneim.-Forsch.21, 248 (1971). Percutaneous absorption by rats and rabbits: W. H. Down et al.,Toxicol. Lett.1, 95 (1977). Clinical study: D. J. Tazelaar, J. Int. Med. Res.5, 338 (1977). HPLC analysis: S. Muck et al.,Boll. Chim. Farm.120, 240 (1981). For structure see Triamcinolone Acetonide.

Properties: Crystalline powder, mp 203-207°. [a]D20 +96 ±3° (c = 1 in ethanol). Sol in methanol, acetone, ethanol, dioxane, pyridine, DMF, chloroform. Insol in water.

Melting point: mp 203-207°

Optical Rotation: [a]D20 +96 ±3° (c = 1 in ethanol)

Therap-Cat: Glucocorticoid; anti-inflammatory (topical).

Keywords: Glucocorticoid

////////////////////////

Triamcinolone Hexacetonide

CAS Registry Number: 5611-51-8

CAS Name: (11b,16a)-21-(3,3-dimethyl-1-oxobutoxy)-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dione

Additional Names: 9-fluoro-11b,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone, 21-(3,3-dimethylbutyrate); 21-tert-butylacetate-9a-fluoro-11b-hydroxy-16a,17a-(isopropylidenedioxy)pregna-1,4-diene-3,20-dione; 21-(3,3-dimethylbutyryloxy)-9a-fluoro-11b-hydroxy-16a,17a-(isopropylidenedioxy)pregna-1,4-diene-3,20-dione; triamcinolone acetonide tert-butyl acetate; TATBA

Manufacturers’ Codes: CL-34433

Trademarks: Aristospan (Fujisawa); Hexatrione (Lederle); Lederlon (Lederle); Lederspan (Lederle)

Molecular Formula: C30H41FO7, Molecular Weight: 532.64

Percent Composition: C 67.65%, H 7.76%, F 3.57%, O 21.03%

Literature References: The hexacetonide ester of the potent glucocorticoid, triamcinolone, q.v. Prepn of syringeable suspension: Nash, Naeger, US3457348 (1969 to Am. Cyanamid). Anti-inflammatory activity in rabbits: I. M. Hunneyball, Agents Actions11, 490 (1981). Early clinical studies: Bilka, Minn. Med.50, 483 (1967); Layman, Peterson, ibid. 669. Clinical studies of intra-articular therapy in arthritis: R. C. Allen et al.,Arthritis Rheum.29, 997 (1986); M. Talke, Fortschr. Med.104, 742 (1986). Toxicity study: Tonelli, Steroids8, 857 (1966). Comprehensive description: V. Zbinovsky, G. P. Chrekian, Anal. Profiles Drug Subs.6, 579-595 (1977). For structure see Triamcinolone Acetonide.

Properties: Fine, white, needle-like crystals, mp 295-296° (dec), also reported as mp 271-272° (dec). uv max (ethanol): 238 nm (e 15500). [a]D25 +90±2° (c = 1.13% in chloroform). Soly in g/100 ml at 25°: chloroform and dimethylacetamide >5; ethyl acetate 0.77, methanol 0.59, diethyl carbonate 0.50, glycerin 0.42, propylene glycol 0.13; absolute alcohol 0.03; water 0.0004.

Melting point: mp 295-296° (dec); mp 271-272° (dec)

Optical Rotation: [a]D25 +90±2° (c = 1.13% in chloroform)

Absorption maximum: uv max (ethanol): 238 nm (e 15500)

Therap-Cat: Anti-inflammatory.

Keywords: Glucocorticoid.

Product Ingredients

INGREDIENTUNIICASINCHI KEY
Triamcinolone acetonideF446C597KA76-25-5YNDXUCZADRHECN-JNQJZLCISA-N
Triamcinolone diacetateA73MM2Q32P67-78-7XGMPVBXKDAHORN-RBWIMXSLSA-N
Triamcinolone hexacetonideI7GT1U99Y95611-51-8TZIZWYVVGLXXFV-FLRHRWPCSA-N

Triamcinolone is a glucocorticoid used to treat a wide variety of inflammatory conditions of organ systems and tissues.

Triamcinolone is a glucocorticoid used to treat certain skin diseases, allergies, and rheumatic disorders among others.[6] It is also used to prevent worsening of asthma and COPD.[6] It can be taken in various ways including by mouth, injection into a muscle, and inhalation.[6]

Common side effects with long-term use include osteoporosiscataractsthrush, and muscle weakness.[6] Serious side effects may include psychosis, increased risk of infections, adrenal suppression, and bronchospasm.[6] Use in pregnancy is generally safe.[7] It works by decreasing inflammation and immune system activity.[6]

Triamcinolone was patented in 1956 and came into medical use in 1958.[8] It is available as a generic medication.[9] In 2019, it was the 107th most commonly prescribed medication in the United States, with more than 6 million prescriptions.[10][11]

PATENT

Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Skin diseases are the medical condition that affects the skin, hair, nails and related muscle and glands.

Skin disorders vary greatly in symptoms and severity. They can be temporary or permanent, and may be painless or painful. Some have situational causes, while others may be genetic. Some skin conditions are minor, and others can be lifethreatening.

There are many different types of skin disorders which include rashes, dermatoses or skin eruptions. Such rashes, dermatoses or skin eruptions include acute, inflammatory reactions of the skin caused by an allergic or irritant reaction, other forms of eczema, lichen simplex chronicus. Chronic nature includes seborrheic dermatitis, psoriasis, and atopic dermatitis or caused by infection, irritation or aggravation of another condition such as occurs with acne, other rashes, dermatoses or skin eruptions, inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses, contact dermatitis, impetigo, urticarial and scabies.

Typical symptoms of the skin disorders include but not limited to raised bumps that are red or white, a rash, which might be painful or itchy, scaly or rough skin peeling skin, ulcers, open sores or lesions, dry, cracked skin, discolored patches of skin, fleshy bumps, warts, or other skin growths, changes in mole color or size a loss of skin pigment, excessive flushing or the like.

Atopic dermatitis (AD), also known as eczema or atopic eczema, is a type of inflammation of the skin (dermatitis). Atopic dermatitis (AD) is common worldwide. People of all ages from newborns to adults and older live with this condition. Symptoms range from excessively dry, itchy skin to painful, itchy rashes that cause sleepless nights and interfere with everyday life.

Topical corticosteroids have been the mainstay of treatment for atopic dermatitis over the past years, further the cure for atopic dermatitis involves Lifestyle modification, balanced diet intake, self-care measures, phototherapy, wet wrap therapy, use of medications like tacrolimus, pimecrolimus, crisaborole, dupilumab, ciclosporin, methotrexate, interferon gamma- lb, mycophenolate mofetil, and azathioprine or the like.

Triamcinolone Acetonide is a synthetic corticosteroid. Chemically it is [Pregna-1, 4-diene-3, 20-dione, 9-fluoro-l l, 21 -dihydroxy- 16, 17-[(1 methylethylidene) bis-(oxy)]-, (HP, 16a)-] with the empirical formula C24H31FO6 and molecular weight 434.50. Triamcinolone Acetonide is represented by compound of structural formula I

Triamcinolone Acetonide topical cream and ointment with strengths 0.025%, 0.1% and 0.5% (containing 0.25 mg/gm, 1 mg/gm & 5 mg/gm Triamcinolone Acetonide respectively) were approved in USA prior to Jan 1, 1982 under the trade name “Triamcinolone Acetonide” and were indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.

The commercially available products or product known in the prior art produces side effects such as burning, itching, irritation, or dryness of skin at site of application, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae and miliaria.

Pediatric patients may demonstrate greater susceptibility to topical triamcinolone -induced HPA axis suppression and Cushing’s syndrome than mature patients because of a larger skin surface area to body weight ratio. Hypothalamic -pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome and intracranial hypertension have been reported in children receiving topical triamcinolone. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Chronic corticosteroid therapy may interfere with the growth and development of children.

Making low dose compositions can present technical and economic challenges that are not present for higher dose formulations.

Examples

The following table 1 shows cream formulation containing lOO.OOmcg per gm, 50.00mcg per gm and 25.00mcg per gm of Triamcinolone Acetonide

Table – 1: cream

Drug Strength IQOmcg/gm 50mcg/gm 25mcg/gm

lOO.OOmcg per gm and for lOOgm, it is lO.OOmg*

50.00mcg per gm and for lOOgm, it is 5.00mg*

25.00mcg per gm and for lOOgm, it is 2.50mg**

Manufacturing process:

a) Dispensing following excipients – isopropyl myristate, glyceryl monostearate and white soft paraffin in vessel I;

b) Dispensing the following excipients – polysorbate 40 and purified water in vessel II;

c) Dispensing the following excipients methyl paraben, propylene glycol in vessel III; wherein methyl paraben is dissolved in propylene glycol to form a clear solution;

d) Dispensing the following active & excipients triamcinolone acetonide or salt thereof, propylene glycol in vessel IV; wherein triamcinolone acetonide or salt thereof is dissolved in propylene glycol to form clear solution;

e) Adding content of step (c) into content of step (b) and stirring to form uniform and homogeneous emulsion;

f) Heating content of step (b) and step (a) at about 75 °C and stirring to form a homogenous uniform emulsion;

g) Cooling the above emulsion gradually to temperature of about 25 °C – 30°C h) Adding the content of step (d) to the primary emulsion of (f) with constant stirring; and

i) Making up the volume of the emulsion with purified water to the required quantity.

SYN

DOI: 10.1021/ja01516a043

File:Triamcinolone acetonide synthesis.png

CLIP

Corticosteroids

R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006

Triamcinolone

Triamcinolone, 9a-fluoro-11b,16a,17,21-tetrahydroxypregna-1, 4-dien-3,20-dione (27.1.61), differs from dexamethsone in terms of chemical structure in that the a methyl group at C16 is replaced with a hydroxyl group. It is synthesized from the 21-O-acetate of hydrocortisone 27.1.17. In the first stage, both carbonyl groups of this compound undergo ketalization by ethylene glycol. Next, the hydroxyl group in the resulting diketal 27.1.53 is replaced with chlorine using thionyl chloride, and the product undergoes dehydrochlorination using an alkaline, during which the 21-O-acetyl group also is hydrolyzed. Acetylating the hydroxyl group once again with acetic anhydride gives a triene 27.1.54. Reacting this with osmium tetroxide gives the vicinal diol 27.1.55. The secondary hydroxyl group at C16 of this product undergoes acetylation by acetic anhydride in pyridine, which forms the diacetate 27.1.56. Treating the product with N-bromoacetamide in chloric acid gives a bromohydrin (27.1.57), which upon reaction with potassium acetate is transformed to an epoxide (27.1.58). Opening of the epoxide ring, using hydrofluoric acid, gives the corresponding 9-fluoro-11-hydroxy derivative 27.1.59. Upon microbiological dehydrogenation, the C1–C2 bond is oxidized to a double bond, forming triamcinolone acetate (27.1.60), the acetyl group of which is hydrolyzed, forming the desired triamcinolone (27.1.61) [30–32].

Triamcinolone is similar to dexamethasone in terms of pharmacological action, and it is better tolerated in some cases. Synonyms of this drug are ledercort, cenocort, delsolon, and others.

SYN

Drugs for Treating Respiratory System Diseases

Ruben Vardanyan, Victor Hruby, in Synthesis of Best-Seller Drugs, 2016

Triamcinolone–Nasacort

The synthesis of triamcinolone (23.2.1) starts from ketalization of cortisol 21-acetate (23.2.8) using ethylene glycol. Dehydration of the obtained compound (23.2.9) for creation of a double bond in position 16,17 of the steroid skeleton through the series of sequential reactions of chlorination, dehydrochlorination, hydrolysis, and acetylation produces 21-acetoxy-4,9(11),16-pregnatriene-3,20-dione (23.2.10), treatment of which with osmium tetroxide in benzene and pyridine produced diol (23.2.11), the secondary hydroxyl group of which, in position 16, was acetylated with acetic anhydride in pyridine to produce the diacetate (23.2.12). The obtained compound in dioxane and water was treated with N-bromoacetamide and 10% perchloric acid to yield bromohydrine (23.2.13). Dehydrobromination of the bromohydrine (23.2.13) with anhydrous potassium acetate in refluxing ethanol produced the epoxy-derivative (23.2.14). Opening of the epoxide ring in (23.2.14) with anhydrous hydrogen fluoride in chloroform produced (23.2.15). Microbiological dehydrogenation of the obtained product with Corynebacterium simplex produced crude diacetate (23.2.16), saponification of which produced triamcinolone (23.2.1) [108-110] (Scheme 23.7.).

Scheme 23.7. Synthesis of triamcinolone.

Triamcinolone is commonly used in the treatment of respiratory inflammation and improves airway reactivity, decreasing respiratory problems. Strangely, there are only few reviews of the pharmacotherapy of triamcinolone [111-113].

SYN

CAS-RNFormulaChemical NameCAS Index Name
426-39-1C25H33FO816α,21-diacetoxy-11β,17-dihydroxy-3,20-dioxo-9-fluoro-4-pregnenePregn-4-ene-3,20-dione, 16,21-bis(acetyloxy)-9-fluoro-11,17-dihydroxy-, (11β,16α)-
96670-24-5C25H30O816α,21-diacetoxy-3,20-dioxo-17-hydroxy-9β,11β-epoxy-1,4-pregnadiene9β-Pregna-1,4-diene-3,20-dione, 9,11β-epoxy-16α,17,21-trihydroxy-, 16,21-diacetate

SYN

https://patents.google.com/patent/WO2016120891A1/en

Glucocorticoids have a number of diverse effects in different body tissues. Glucocorticoids, in topical, oral and inhaled formulations, are useful for their anti-inflammatory and immunosuppressive properties. Several glucocorticoids such as budesonide and ciclesonide are used for treatment of several disorders.

The synthesis and purification of glucocorticoids have been disclosed at different instances. However, most of these synthetic procedures involve toxic solvents or long reaction times and are ineffective for large scale synthesis. For instance, US 3,92,9768 discloses a process for preparation of budesonide by reacting 16, 17-dihydroxy compound with aldehyde in solvents such as dioxane, methylene chloride or their combinations.

DE 4129535 discloses a process for the synthesis of Ciclesonide which involves the intermediate 16A, 17-[(7?,S)-cyclohexylmethylenedioxy]-l 13, 21-dihydroxy-pregna-l 4- dien-3,20-one which is obtained by an acid catalysed reaction of 11 , 16 , 17, 21-tetra hydroxypregna-l,4-dien-3,20-one with cyclohexane aldehyde.

WO 02/38584 discloses the synthesis of Ciclesonide by reacting corresponding 16, 17-ketals with a cyclohexane aldehyde in the presence of 70% perchloric acid, 1-nitropropane as solvent. However, perchloric acid is a dangerous solvent and can cause serious accidents with fatal consequences.

US Patent No. 6169178 relates to a process for the preparation of budesonide and of 16, 17- acetals of pregnane derivatives structurally co-related thereto comprising treating 16, 17-dios or of 16, 17-ketals or cyclic acetals with aldehydes in the presence of aqueous hydrobromic acid or hydroiodic acid used as reaction catalyst or solvents. However, hydroiodic and other hydrohalic solvents are corrosive, light sensitive and expensive. Further, these acids also post environmental problems. Notwithstanding the use of hydrohalo acids requires use of special equipment since they are extremely corrosive and consequently increase the cost of production.

US 5,55,6964 discloses a process for the preparation of budesonide by reacting 16 – Hydroxy Prednisolone in acetonitrile in the presence of /^-toluene sulfonic acid as a catalyst. There are certain other patents that use alkyl sulfonic acid instead of aryl sulfonic acid for the synthesis of budesonide or similar compounds. However, sulfonic acids are hazardous solvents and FDA has expressed significant concern over the presence or traces of sulfonic acid in pharmaceutical products. Hence, there is a need to have a process for the synthesis 16, 17- acetals of pregnane compounds that is industrially scalable and which does not involve the use of harmful solvents.

Figure imgf000006_0001
Figure imgf000007_0001

Example- 1: Process for preparation of 16-HPN from 3TR

Stage-I

Figure imgf000013_0001
Figure imgf000013_0002

Stage- 1 Stage-I I

Figure imgf000014_0001

Stage-IV

Figure imgf000014_0002

1 6-HPN acetate 1 6-HPN

Scheme 2: Synthesis of 16HPN from 3TR

Stage-I (oxidation)

Charge 750L of acetone (50 volume), 39L of purified water (2.60 volume) and 15 Kg of 3TR (40.93mol) in a SS Reactor at ambient temperature. Cool to -7°C to -5°C than added 6.0L of formic acid (159.03 mol) and 9.0 kg of potassium permanganate (56.95 mol). Maintain at – 5°Cto -3°C for 30 minutes. In-process check by TLC, 3TR should be less than 1.0%. Added 1.5kg sodium metabisulphite (7.89 mol solution in 12L of purified water at -5°C to -3°C then added 3.0 kg of hyflow super cell at 15°C (+2°C) and filter through 10.0 kg of hyflowbed at 27°C(+3°C) and wash with 150L of acetone Added 1.5 kg of activated charcoal, Stir and filter through hyflow bed and wash with 60L of acetone. Total filtrate was distilled under reduced pressure, while maintaining temperature below 45°C. Added 81L of purified water and cool to 5°C+5°C. Filter through centrifuge and wash with 156L of purified water. Wet material is dry at 60°+5°C till moisture less than 0.50%, Yield=15 kg, HPLC purity=98%.

Stage-II (Bromination)

Charge 75L of tetrahydrofuran, 16L of purified water and 15.0 kg of Stage-I (37.46 mol) in a glass reactor. Cool to -6°C (+2°C) and added 7.50 kg of dibromantin (26.23 mol) and 0.60L of perchloric acid (9.38 mol) and maintain at -6°C (+2°C) for one hour. In-process check by TLC, stage-I should be less than 0.50%. Reaction mass is quench in 390L of purified water at ~5°C. Raised the temperature to 25°C and maintained for 01 hour, filter through centrifuge and wash with 828L of purified water or till neutral pH. Wet material is dry at 40°C+5°C till moisture content should be less than 10%, Yield=21.0kg, HPLC purity=97%.

Stage-Ill (Debromination)

Charge 68.0L of N, N-dimethyl formamide(3.238volume) and 21.0kg of stage-II (42.22 mol) in glass reactor, start argon gas purging and cool to -5°C. Charge 13.0L of N,N- dimethylformamide (0.619volume) , 9.70L of dimethylsulfoxide(0.462volume), 1.62kg of chromium chloride hexahydrate (6.51 mol) and 1.94 kg of zinc dust (0.703 mol). Cool to – 10°Cand added 5.50L of thioglycolic acid (79.21 mol). Maintain for one hour while maintaining temperature around -10°C. In-process check by TLC, stage-II should be less than 1.0%. Added 310 L of purified water and cool to 0°C. Filter through centrifuge and wash with 1600L of purified water. Wet material is dry at 60°C+ (5°C) till moisture content less than 6.0%, Yield=15.0kg, HPLC Purity=90%.

Charge 150L of methylene chloride (10 volume), 150L of methanol (10 volume.) and 15.0kg (30.16 mol) of stage-Ill in a SS Reactor. Heat to clear solution then added 3.0 kg of activated charcoal (20%) and reflux for 04 hours, Filter through hyflow bed and wash with 75L of methylene chloride (5 volume), and 75L of methanol (5 volume) mixture. Total filtrate is distilled till last drop and added 75L (5 volume) of methylene dichloride, reflux for 04 hours than cool to 40°C+(5°C), Filter through centrifuge and wash with 15L (one volume) of methylene chloride. Wet material is dry at 60°C (+5°C) till moisture contents less than 1.0% (Yield =13.0kg, HPLC Purity=96%). Further charge 65.0L (5volume) of ethyl acetate and 13.0 kg (1.0 mol) of purified material. Heat to reflux and maintain for 04 hours under reflux, then cool to 40°C. Filter through centrifuge and wash with 13.0L (one volume) of ethyl acetate. Wet material is dry at 60°C (+5°C) till moisture contents less than 0.50%, Yield=12.0kg, HPLC Purity=98.6%.

Stage-IV (Deacetylation)

Charge 5.83L of methanol (10 volume) and 5.83L of methylene chloride (10 volume) in a glass flask and added 583 gm of 16-HPN acetate(1.397mol) at RT. Start argon gas purging and cool to 0°C to 5°C under argon purging. Prepare 11.66 gm of sodium hydroxide (0.2915mol) solution in 0.583L of methanol (one volume) under argon purging and cool to 0°Cto 5°C. Sodium hydroxide solution is charge in reaction mass at 0°C to 5°C. Maintained the reaction mass at 0°C to 5°C for one hour, In-process check by TLC against 16-HPN acetate it should be nil. Adjust pH to neutral by 21.40ml of acetic acid (0.3742 mol); distill under reduced pressure while maintaining temperature below 40°C, till dry. Cool to ambient temperature and added 1.166L of purified water (02 volume). Cool to 0°C and maintain for one hour. Filter and wash with 300ml of purified water. Dry at 60°C (+5°C) till moisture content less than 1.0%, Yield=490gm (93.50%), HPLC Purity=98.97%, Single impurity= 0.40%. Example 2: Process of synthesis of Budesonide from 16-HPN

Figure imgf000016_0001

16-HPN Budesonide

Charge 800 ml of aqueous hydrochloric acid (8 volume) in a glass flask, start nitrogen gas purging and Cool to -5°C and maintain for 15 min. then added 100 gm of stage-I (0.27 mol) at -5°C and stir for 15 min., added 30 ml of N-butyraldehyde (0.33 mol) while maintaining temperature -5°C to 0°C in around 30 minutes and maintain at 0°C to 5°C for 150 min. under stirring. In-process check by TLC against stage-I, it should be nil. Reaction mass is quench in 1200 ml of purified water (12 volume) at 5°C to 10°C and stir for 15 min. Added solution of 100 kg of sodium bicarbonate (1.19 mol) and 1 ml of purified water (10 volume) in reaction mass at 5°C to 10°C. Stir at 5°C to 10°C for 15 min. Filter and wash with purified water till neutral pH. Wet material is dry at 50°C (+5°C) till moisture contents less than 1.0 %, Yield =110 gm (96.49%), HPLC purity=96.45%, single impurity=1.29%, Epimer-A=47.76%, Epimer-B=49.69%.

(Purification)

Charge 2.5 L of methanol (25 volume) in a Glass flask and added 100 gm of above mentioned crude product. Dissolved at 25°C+5°C till clear solution, added 10 gm of activated charcoal and stir for 30 min. than filter through hyflow bed and wash with 200 ml of methanol (2 volume). Combined filtrates charged in a Glass flask and cool to 10°C to 15°C and added 5.40 L of purified water (54 volume) at 5°Cto 10°C, stir for 15min., filter and wash with purified water. Wet material is dry at 50°C (+5°C) under vacuum till moisture content less than 0.50%, Output=90.0gm, HPLC purity=99.66%, single impurity=0.1%, Epimer-A=44.47%, Epimer-B=55.01%.

Example 2.1: Scale-up process of manufacturing of Budesonide from 16-HPN

Charge 40 L of aqueous hydrochloric acid (8 volume) in a glass flask, start nitrogen gas purging and Cool to – 10°C and maintain for 15 min. then added 5.0 kg of stage-I (13.315 mol) at – 10°C and stir for 45 min. added 1.5 L of N-butyraldehyde (16.68 mol) while maintaining temperature -7°C to – 11°C in around 30 minutes and maintain at -2°C to -6°C for 60 min. under stirring In-process check by TLC against stage-I, it should be nil. Reaction mass is quench in 60 L of purified water (12 volume) at 5°C to 10°C and stir for 15 min. Added solution of 5.0 kg of sodium bicarbonate (59.525 mol) and 50L of purified water (10 volume) in reaction mass at 5°Cto 10°C. Stir at 5°C to 10°C for 15 min. Filter and wash with purified water till neutral pH. Wet material is dry at 50°C (+5°C) till moisture contents less than 1.0 %, Yield =5.293 kg (94.46%), HPLC purity=95.45%, single impurity=1.45%, Epimer-A=53.51 %, Epimer-B=43.78% Effect of temperature and its variation on epimer ratio (A and B) with respect to batch size (From lab to commercial batch)

Example 3: Process for synthesis ofCiclesonide from 16HPN

Preparation of cyclohexane carboxaldehydemetabisulphite complex

200gm of Cyclohexane carboxaldehyde (1.786 mol) was dissolved in 3.0L of denatured sprit (15 volume) and a solution of 190gm of sodium metabisulphite (1.827 mol) in 300ml of purified water (1.5 volume) was added. The resulting precipitate was filtered and washed with 1.0L of denatured sprit(5.0 volume) and dried under vacuum at 50°C, till moisture content less than 6.00%, Yield=400gm (97 %)

Stage I: Preparation of stage-I from 16-HPN

Figure imgf000018_0001

Cyclohexane carboxaldehyde

sodium metabisulphite complex

170gm of 16-HPN (0.4528 mol) was suspended in 3.40L of dichloromethane (20 volume) and treated with 340ml of 70% perchloric acid. (5.65 mol) and 110.5gm of cyclohexane carboxaldehyde metabisulphite complex (0.512 mol) was added in lots while maintaining the temperature between 0°Cto 5°C. The reaction mass was stirred at 0°C to 5°C for 03 hours. In- process check by TLC 16-HPN should be nil and then neutralized with 10% aqueous sodium bicarbonate solution. The organic layer was separated and concentrated under vacuum to obtain a residue which was stripped with methanol (1.0 volume). The solvent was concentrated and the residue was dissolved by refluxing in methanol (5.0 volume). The clear solution was cooled to 0°C to 5.0°C and the resulting solid was filtered and dried at 50°C till moisture content less than 0.50%, Yield=170.0gm (80.0%), HPLC purity=91.68%.

Stage -II Preparation of Ciclesonide from Stage -I

Figure imgf000019_0001

Stage-I Ciclesonide

158gm of stage-I (0.34mol) was suspended in 1.58L of methylene chloride (10.0 volume) at 25°C to 30°C. The reaction mass was chilled to 0°C to 5°C and 81.0ml of triethylamine(0.581 mol) was added, followed by the addition of 79.0ml of isobutyryl chloride [0.75 mol; diluted with 79.0 ml of methylene chloride (0.50 volume)] slowly at 0° to 5°C and maintained at same temperature for 60min. In-process check by TLC, Stage-I should be nil. The reaction mass was diluted with 2.53L of purified water (16.0 volume) , the organic layer was separated and washed with purified water till neutral pH, than organic layer was separated and concentrated under vacuum to obtained a residue. The residue was dissolved by refluxing in 948ml of methanol (6.0 volume); the clear solution was cooled to 0°C to 5°C under stirring and filtered. The product was dried under vacuum at ~50°C till moisture contents comes less than 0.50%, Yield=158.0 gm (87.0%), HPLC purity=95.74%.

(Purification)

120gm of Ciclesonide crude was dissolved by refluxing in 600ml of methanol. The clear solution was chilled to 20°C under stirring and filtered. The product was dried under vacuum at 90°C till moisture content less than 0.50%. Yield=105 gm (87.50%), HPLC purity=99.7 %.

Example 4: Process for synthesis of Desonide from 16HPN acetate

Stage-I : Preparation of Desonide acetate from 16 HPN acetate

Figure imgf000019_0002

Desonide acetate

16HPN acetate 190.0 ml of acetone (7.0 volume) was charged in a glass flask under nitrogen blanketing than added 27 gm of 16HPN acetate (0.0645mol) at ambient temperature. Temperature raised to 28°C (+2°C) and stir for 20 minutes. 1.35 ml of perchloric acid 70% (0.02 lmol) was added at 28°C (+2°C) and stir for 30 minutes. Temperature further raised to 35°C and stir for 60 minutes. In-process check by TLC against 16HPN acetate, it should be nil. Reaction mass cooled to 10°C, filtered and washed with purified water till neutral pH (~7) and finally washed with acetone. Wet material dried at 50°C+5°C till moisture content less than 0.50% to get stage-I. Yield =23gm (77.76%), HPLC Purity=98.28%

Stage-II: Preparation of Desonide from Desonide acetate

Figure imgf000020_0001

Desonide

Desonide acetate

200 ml of methanol (10 volume) and 200ml of methylene dichloride (10 volume) was charged in a glass flask and start argon gas purging. 20 gm of stage- 1st (0.0436mol) was added at ambient temperature. Cool to 0°C+5°C. 0.40gm of sodium hydroxide (O.Olmol) solution in 20ml of methanol (l.Ovolume) was added at 0°C+5°C. Stir at 0°C+5°C for 120 minutes. In-process check by TLC against stage- 1st it should be nil. Adjust pH to neutral (~7) by 2.0ml of acetic acid at 0°C+5°C. Distilled the solvent from reaction mass under vacuum while maintaining temperature below 40°C till the volume get reduced to 3 to 4 volume of the input. Cool to 0°C and further added 60ml of purified water and stir for 30 minutes. Filtered, washed with purified water till neutral pH (~7). Wet material dried at 50°C+5°C till moisture content less than 0.50% to get crude Desonide. Yield =14.70gm (80.92%), HPLC Purity=88.15%.

(Purification)

140 ml of methanol (10 volume) and 140 ml of methylene chloride (10 volume) was charged in a glass flask and added 14.0 gm of crude material (0.034mol) than stir till clear solution. Added 1.5 gm of activated charcoal and stir for 30 minutes than filtered through hyflow supercel bed and washed with 30ml of methanol and 30ml of methylene chloride mixture. Combined filtrate and distilled the solvent from reaction mass under vacuum while maintaining temperature below 40°C till the volume reduced to 3 to 4 volume of the input. Cool to 0°C. Filtered the reaction mass and washed with 10ml of precooled methanol. Wet material was dried at 50°C+5°C till moisture content less than 0.50% to get Desonide. Yield=8.60gm, HPLC Purity= 99.43%

Figure imgf000021_0001

lOOgm of 3TR (0.27 mol.)was suspended in 1300ml (13 volume) acetone. Cooled it to -5°C to -10°C than added 4.0 ml (0.062 mol.) perchloric acid solution and 50gm of dibromantin. Maintained the reaction at same temperature for 02 hours. In-process check by TLC against 3TR it should be nil. Added lOOgm of potassium carbonate solution (0.723 mol.) in 5 lots and reaction was maintained at 35°C+2°C. In-process check by TLC against step-I reaction mass, it should be nil. Cooled to 0°C (+5°C) and adjust pH neutral (~7) by 36ml of acetic acid (0.63 mol.). Added 3.0L of purified water (30 volume). Filter and washed with purified water till neutral pH (~7). Wet material was dried at 45°C (+2°C) till moisture content less than 0.50%. Yield =87gm, (83.36%), HPLC Purity=97.883%.

Stage – II:

Figure imgf000021_0002

80gm of stage-I (0.21 mol) was dissolved in 4.0L of acetone (50 volume) and 208ml of purified water (2.6 volume). Cool to -5°C (+2°C) than added 32ml of formic acid (0.85 mol.) and 48gm of potassium permagnate (0.30 mol.) at -5°C (+2°C). Reaction was maintained at – 5°C+2°Cfor one hour. In-process check by TLC against stage-I it should be nil. Added 8gm of sodium metabisulphite (0.042 mol.) In 80 ml purified water (01 volume) solution at -5°C (+2°C). Temperature raised up to 27°C and filtered through hyflow bed and washed with acetone. Acetone was distilled under vacuum till 3 to 4volume of stage-I than cool to 0°C to 5°C and added 480ml of purified water stir and filter and washed with purified water to get wet stage-II. Wet material was dried at 50°C (+5°C) till moisture content less than 3.0%. Yield =78.30gm, (89.88%), HPLC Purity=99.178%. Stage -III:

Figure imgf000022_0001

Stage-ll Stage-

300ml of hydrofluoric acid (12.60mol) was cooled at -25°C to -30°C than added 75gm of stage-II (0.180mol). Reaction was maintained at -25°C to -30°C for 04 hours. In-process check by TLC against stage-II, it should be nil. Reaction mass was cooled to -50°C than added 45ml of acetone (0.60volume) at -45°C to -50°C. Reaction was maintained at -45°C to -50°C for 02 hours. In-process check by TLC against before acetone reaction mass. Added 565ml of purified water at 0°C and 340ml of liq. ammonia at ~20°C than reaction mass was quenched in 410ml of liq. ammonia and 735ml of purified water solution at 15°C (+2°C), stir and filter and washed with purified water till neutral pH. Wet material was dried at 45°C to 50°C, Yield =78.50gm, (91.48%), HPLC Purity=91.593%.

(Purification)

76 gm of stage-Ill Crude (0.16 mol.) was dissolved in 760ml of methylene chloride (lOvolume) and 760ml of methanol (lOvolume) mixture at ambient temperature. Stir till clear solution and added 7.6gm of activated charcoal (0. lOvolume) than stir for 30minutes, filter through hyflow bed and washed with methanol (one volume) and methylene chloride (one volume) mixture. Total filtrate was distilled under vacuum till 3 to 4 volume of input. Cool to 0°C to 5°C and stir for 02 hours. Filtered and washed with minimum precooled methanol, Wet material was dried 45°C to 50°C till moisture contents less than 0.50%, Yield=62gm, HPLC Purity=98.633%.

Stage – IV (Process for synthesis of Triamcinolone acetonide from Stage – III):

Figure imgf000022_0002

Stage- Ill Triamcinolone acetonide

60gm of stage-Ill (0.13 mol) was dissolved in 600ml of methanol (lOvolume) and 600ml of methylene chloride (lOvolume) mixture under argon bubbling. Cool to -5°C+2°C and added 1.2gm of sodium hydroxide (0.03mol.) solution in 60ml of methanol (Olvolume) at -5°C (+2°C). Reaction maintained at -5°C (+2°C) for 03 hours. In-process check by TLC against stage-Ill, it should be nil. Adjust pH neutral (~7) by adding 1.8ml of acetic acid at -5°C (+2°C). Reaction mass was distilled at below 40°C under vacuum till 3 to 4 volume of input. Cool to 30°C and added 120ml of purified water, stir for one hour than filter and washed with purified water till neutral pH (~7). Wet material was dried at 45°C to 50°C till moisture content less than 0.50%, Yield =52gm, (95.04%), HPLC Purity=99.21%

(Purification)

50gm of crude material (0.12 mol.) was dissolved in 1100ml of acetone (22volume) and 100ml of purified water (02volume) at 50°C than added 2.5gm of activated charcoal and stir for one hour at same temperature, Filter through hyflow bed and washed with 120ml of acetone (2.40volume). Filtrate was distilled below 40°C under vacuum till 3 to 4 volume of input. Cool to 0°C to 5°Cand maintained for one hour at same temperature. Filter and washed with water. Wet material was dried at 45°C to 50°C till moisture content less than 0.50%, Yield=43gm, HPLC Purity=99.40%.

Example 6: Process for synthesis of Flunisolide from 16HPN acetate Stage -I (Preparation of Desonide acetate from 16HPN acetate):

Figure imgf000023_0001

1 6 H PN acetate eson e acetate

140ml of acetone (7 volume) was charged in glass flask and start argon blanketing than added 20 gm of 16-HPN acetate (0.048mol) at ambient temperature. Cooled to 28°C (+2°C). 1.0ml of perchloric acid 70% (0.016mol) was added at 28°C (+2°) C and stirred for 30 minutes. Temperature raised up to 35°Cand stirred for 60 minutes. In-process check by TLC against 16-HPN acetate, it should be nil. Reaction mass was cooled to 10°C (+2°C). Reaction mass was filtered and washed with purified water till neutral pH (~7) to get wet material. Wet material was dried at 50°C+5°C till moisture content less than 0.50% to get stage-lst. Yield=17.40gm, (79.40%), HPLC Purity=98.241%.

Stage -II (Preparation of Desonide from Desonide acetate):

Figure imgf000023_0002

170ml of methanol (lOvolume) and 170ml of methylene chloride (lOvolume) was charged in a glass flask and start inert atmosphere. 17gm of stage-lst (0.037mol) was added at ambient temperature. Cooled to -5°C. 0.4gm of sodium hydroxide (O.Olmol) solution in 17ml of methanol was added at 0°C (+5°C). Reaction mass was stirred for 02 hours at 0°C (+5°C). In- process check by TLC against stage- 1st it should be nil. Neutral pH (~7) was adjusted by acetic acid. Reaction mass was distilled under vacuum at below 40°C till ~ 100ml. Concentrated mass was cooled to 0°C (+5°C) and stir for one hour. Reaction mass was filtered and washed with precooled methanol to get wet material. Wet material was dried at 50°C (+5°C) till moisture content less than 0.50% to get stage-2nd. Yield=14.0gm, (90.67%), HPLC Purity=99.426%, Single impurity=0.136%.

Stage -III (Preparation of Flunisolide acetate from Desonide):

Figure imgf000024_0001

Desonide Flunisolide acetate

50ml of isopropenyl acetate (5 volume) was charged in a glass flask and added lOgm of stage-2nd (0.024mol) at ambient temperature than heated to 65°C and added 1.5ml of methane sulphonic acid (0.023mol) and temperature raised up to 80°C and stir for one hour. In-process check by TLC against stage-2, it should be nil. Reaction mass cooled to 25°C and adjust pH neutral (~7) by triethylamine. Reaction mass was distilled under vacuum till last drop and degases with acetonitrile. 90ml of acetonitrile (09 volume) was added and cooled to -5°C and than further added 10ml of purified water. lOgm of selectfluor(0.028mol) was added in two lots at 0°C(+5°C) in 02 volume of acetonitrile. Reaction mass was stirred at 10°C to 15°C for 12 hours. In-process check by TLC against before selectfluor reaction mass it should be nil. Adjust pH neutral (~7) by liq. ammonia solution at 0°C+5°C. Reaction mass was quenched in 500ml of purified water (lOOvolume) at ambient temperature. Reaction mass was filtered and washed with purified water till neutral pH (~7). Wet material was dried at 45°C+5°C till moisture content less than 0.50% to get stage-3rd. Yield=8.60gm, (75.17%), HPLC Purity= 94.12%.

Stage -IV (Preparation of Flunisolide from Flunisolide acetate):

Figure imgf000024_0002

Flunisolide acetate Flunisolide

80ml of methanol (lOvolume) and 80ml of methylene chloride (lOvolume) was charged in a glass flask under inert atmosphere at ambient temperature than added 8.0gm of stage-3r (0.017mol) at ambient temperature. Cooled to -5°C and added 0.16gm of sodium hydroxide (0.004mol) solution in 8ml of methanol at -5°C(+5°C) and stir for 02 hours at -5°C(+5°C). In-process check by TLC against stage-3 ‘ it should be nil. Adjust pH neutral(~7) by acetic acid and reaction mass was distilled under vacuum at below 40°C(+5°C) till ~40ml of volume. Cool to 0°C to 5°C and stir for one hour. Reaction mass was filtered and washed with precooled methanol to get wet material. Wet material was dried at 45°C (+5°C) till moisture content less than 0.50% to get Flunisolide crude. Yield=6.0gm, (82.30%), HPLC Purity=86.50%.

(Purification)

6.0gm of crude Flunisolide(0.014mol) was dissolved in 65ml of ethyl acetate (10.83volume) and 35ml of n-hexane (5.83volume) mixture and clear solution was passed through 60gm of silica gel column. Column was washed with 975ml of ethyl acetate (162.5volume) and 525ml of ft-hexane (87.5volume) mixture. Eluted fraction was distilled under vacuum till 3 to 4 volume of input than cooled it to 0°C and filter to get wet material. Wet material was dried at 50°C (+5°C) till moisture content less than 0.50% to get Flunisolide. Yield=4.28gm, HPLC Purity=95.60%.

Example 7: Process for synthesis of Triamcinolone from 3TR

S

Figure imgf000025_0001

lOOgm of 3TR (0.27mol) was suspended in 1300ml (13 volume) acetone. Cool to -5°C to- 10°C than added 4.0 ml (0.062mol) perchloric acid solution and 50gm of dibromantin. Reaction maintained at same temperature for 02 hours. In-process check by TLC against 3TR, it should be nil. Added lOOgm of potassium carbonate solution (0.723 mol) in 5 lots and reaction was maintained at 35°C (+2°C). In-process check by TLC against step-I reaction mass, it should be nil. Cool to 0°C+5°Cand adjust pH neutral (~7) by 36ml of acetic acid (0.63 mol). Added 3.0L of purified water (30 volume). Filter and washed with purified water till neutral pH (~7). Wet material was dried at 45°C (+2°C) till moisture content less than 0.50% to get stage-I. Yield=85.30gm, (81.74%), HPLC Purity=96.54%. Stage -II:

Figure imgf000026_0001

80gm of stage-I (0.21 mol) was dissolved in 4.0L of acetone (50 volume) and 208ml of purified water (2.6 volume). Cool to -5°C (+2°C) than added 32ml of formic acid (0.85 mol.) and 48gm of potassium per magnate (0.30 mol) at -5°C (+2°C). Reaction was maintained at same temperature for one hour. In-process check by TLC against stage-I, it should be nil. Added sodiummetabisulphite solution (8 gm in 80 ml of water) at -5°C+2°C. Temperature was raised up to 27°C and filtered through hyflow bed and washed with acetone. Acetone was distilled under vacuum till 3 to 4 volume of stage-I than further cooled to 0°C to 5°C and added 480ml of purified water, stirred, filter and washed with purified water to get wet stage- II. Wet material was dried at 50°C (+5°C) till moisture content less than 3.0% to get stage-II. Yield=82gm, (94.13%), HPLC Purity=97.75%.

Stage -III:

Figure imgf000026_0002

Stage-II Triamcinolone acetate

160ml of hydrofluoric acid (70%) (6.72mol) was cooled at -25°C to -30°C than added 40gm of stage-II (0.096mol). Reaction was maintained at -25°C to -30°C for 04 hours. In-process check by TLC against stage-II, it should be nil. Added 280ml of purified water at 0°C and 650ml of liq. ammonia at 20°C than reaction mass was quenched in 200ml of liq. ammonia and 500ml of purified water solution at 15°C(+2°C), stirred, filtered and washed with purified water till neutral pH(~7). Wet material was dried at 45°C to 50°C to get stage-Ill Yield=40gm, (95.42%), HPLC Purity=88.71%

(Purification)

40gm of stage-Ill crude (0.0916 mol) was refluxed in 160ml of acetone. Cool to 0°C. Filtered and washed with minimum precooled acetone. Wet material was dried at 50°C+5°C till moisture content comes less than 0.50% to get stage-Ill. Yield=24.9gm HPLC Purity=95.17%.

Figure imgf000027_0001

24gm of stage-Ill (0.055mol) was dissolved in 240ml of methanol (lOvolume) and 240ml of methylene chloride (lOvolume) mixture under argon bubbling. Cool to -5°C+2°C and added 0.48gm of sodium hydroxide (0.012mol) solution in 24ml of methanol (Olvolume) at – 5°C+2°C. Reaction was maintaining at -5°C (+2°C) for 03hours. In-process check by TLC against stage-Ill, it should be nil. Adjust pH neutral by adding 0.70ml of acetic acid at -5°C (+2°C). Reaction mass distilled at below 40°C under vacuum till 04-05 volume of input. Cooled to 0°C+5°Cand stir for one hour than filtered and washed with minimum precooled methanol. Wet material was dried at 45°C to 50°C till moisture content less than 0.50%. Yield=18.50gm, (85.29%), HPLC Purity=98.60%.

Example 8: Process for synthesis of Triamcinolone Hexacetonide from 3TR

S

Figure imgf000027_0002

lOOgm of 3TR (0.27288 mol) was suspended in 1300ml (13 volume) acetone. Cool to -5°C to -10°C than added 4.0 ml (0.0625 mol) perchloric acid solution and 50gm of dibromantin. Reaction was maintained at same temperature for 02 hours. In-process check by TLC against 3TR, it should be nil. Added lOOgm of potassium carbonate solution (0.723 mol) in 5 lots and reaction was maintained at 35°C (+2°C). In-process check by TLC against step-I reaction mass, it should be nil. Cool to 0°C (+5°C) and adjust pH neutral (~7) by 36ml of acetic acid (0.63 mol). Added 3.0L of purified water (30 volume). Filter and washed with purified water till neutral pH. Wet material was dried at45°C(+2°C) till moisture content less than 0.50% to get stage-lst. Yield =87gm, (83.36%), HPLC Purity=97.883%. Stage-II :

Figure imgf000028_0001

80gm of stage-I (0.21 mol) was dissolved in 4.0L of acetone (50 volume) and 208ml of purified water (2.6 volume). Cool to -5°C than added 32ml of formic acid (0.85 mol.) and 48gm of potassium permanganate (0.30 mol) at -5°C+2°C. Reaction maintained at -5°C (+2°C) for one hour. In-process check by TLC against stage-I, it should be nil. Added sodium metabisulphite solution (8 gm in 80 ml water) at -5°C (+2°C). Temperature raised up to 27°Cand filtered through hyflow bed and washed with acetone. Acetone was distilled under vacuum till 3 to 4 volume of stage-I than cooled to 0°C to 5°C and added 480ml of purified water, stirred, filtered and washed with purified water to get wet stage-II. Wet material was dried at 50°C (+5°C) till moisture content less than 3.0% to get stage-2nd. Yield=78.30gm, (89.88%), HPLC Purity=99.18%.

Stage – III:

Figure imgf000028_0002

300ml of hydrofluoric acid (12.60mol) was cooled at -25°C to -30°C than added 75gm of stage-II (0.180mol). Reaction was maintained at -25°C to -30°C for 04 hours. In-process check by TLC against stage-II. It should be nil. Reaction mass was cooled to -50°C than added 45ml of acetone (0.60volume) at -45°C to -50°C. Reaction maintained at -45°Cto – 50°C for 02 hours. In-process check by TLC against reaction input, it should be nil. Added 565ml of purified water at 0°C and 340ml of liq. ammonia at 20°C than reaction mass was quenched in 410ml of liq. ammonia and 735ml of purified water solution at 15°C(+2°C), stirred, filtered and washed with purified water till neutral pH (~7). Wet material was dried at 45°C to 50°Cto get stage-3rd. Yield=78.50gm, (91.48%), HPLC Purity=91.59%.

(Purification)

76 gm of stage-Ill Crude (0.16 mol) was dissolved in 760ml of methylene chloride (01 volume) and 760ml of methanol (lOvolume) mixture at ambient temperature. Stirred till clear solution and added 7.6gm of activated charcoal (0. lOvolume) than further stir for 30 minutes and filtered through hyflow bed and washed with methanol (one volume) and methylene chloride (one volume) mixture. Total filtrate was distilled under vacuum till 3 to 4 volume of input. Cooled to 0°C to 5°Cand stir for 02 hours. Filtered and washed with minimum precooled methanol. Wet material was dried at 45°C to 50°C till moisture content less than 0.50% to get purified stage-3rd. Yield=62gm, HPLC Purity=98.633%

Stage -IV : (Preparation of Triamcinolone acetonide from Stage – III)

Figure imgf000029_0001

Stage- Ill Triamcinolone acetonide

60gm of stage-Ill (0.1259 mol) dissolved in 600ml of methanol (lOvolume) and 600ml of methylene chloride (lOvolume) mixture under inert atmosphere. Cool to -5°C and added 1.2gm of sodium hydroxide (0.03mol) solution in 60ml of methanol (Olvolume) at -5°C (+2°C). Reaction maintained at -5°C+2°C for 03 hours. In-process check by TLC against stage-Ill, it should be nil. Adjust pH neutral (~7) by adding 1.8ml of acetic acid at -5°C+2°C. Reaction mass was distilled below 40°C under vacuum till 3 to 4 volume of input. Cool to

30°C and added 120ml of purified water, stir for one hour than filtered and washed with purified water till neutral pH (~7). Wet material was dried at 45°C to 50°C till moisture content less than 0.50% to get stage-4111 (Triamcinolone acetonide). Yield=52gm, (95.04%), HPLC Purity=99.21%.

(Purification)

50gm of crude material (0.12 mol) dissolved in 1100ml of acetone (22volume) and 100ml of purified water (02volume) at 50°C than added 2.5gm of activated charcoal and stirred for one hour at same temperature. Filter through hyflow bed and washed with 120ml acetone (2.40volume). Filtrate was distilled below 40°C under vacuum till 3 to 4 volume of input. Cool to 0°C to 5°C and maintained for one hour at same temperature. Filtered and washed with water. Wet material was dried at 45°C to 50°C till moisture content less than 0.50% to get purified stage-4th. Yield =43gm, HPLC Purity=99.40%

-V: (Preparation of Triamcinolone Hexacetonide from Triamcinolone acetonide):

Figure imgf000029_0002

50ml of pyridine (lOvolume) charged in a glass flask and added lOgm of Triamcinolone acetonide (0.023mol) at ambient temperature. Heated to 80°C to 90°C than added 10ml of 3, 3-dimethyl butyryl chloride (O.l lmol) at 80°C to 90°C. Stirred at 80°C to 90°C for 02 hours. In-process check by TLC against Triamcinolone acetonide, it should be nil. Reaction mass cooled to ambient temperature and reaction mass was quenched in 1000ml of purified water (lOOvolume) at ambient temperature, stir for one hour than filtered and washed with purified water till neutral pH (~7). Wet material was dried at 50°C (+5°C) till moisture content less than 1.0% to get stage-5th (Triamcinolone Hexacetonide). Yield=12gm, (97.90%), HPLC Purity=98.63%.

(Purification)

120ml of methanol and 120ml of methylene chloride charged in a glass flask and added 12gm of crude material, stir till clear solution than added 1.2gm of activated charcoal and stir for 30 minutes. Filtered through hyflow bed and washed with 12ml of methanol and 12ml of methylene chloride mixture. Total filtrate was distilled under vacuum at below 40°C till 5 to 6 volume of crude. Cooled to 0°C+5°C and stir for one hour. Filtered and washed with 12ml of precooled methanol. Wet material was dried at 40°C+5°C till moisture content less than 0.50% to get TrimcinolneHexacetonide. Yield=8.8gm, HPLC Purity=99.625%//////////////////////////////////////////

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Medical uses

Aristocort brand triamcinolone cream

Triamcinolone is used to treat a number of different medical conditions, such as eczemaalopecia areatalichen sclerosuspsoriasisarthritisallergiesulcerative colitislupussympathetic ophthalmiatemporal arteritisuveitisocular inflammationkeloidsurushiol-induced contact dermatitisaphthous ulcers (usually as triamcinolone acetonide), central retinal vein occlusion, visualization during vitrectomy and the prevention of asthma attacks.[12][13][14]

The derivative triamcinolone acetonide is the active ingredient in various topical skin preparations (cream, lotion, ointment, aerosol spray) designed to treat skin conditions such as rash, inflammation, redness, or intense itching due to eczema[15] and dermatitis.[16]

Contraindications

Contraindications for systemic triamcinolone are similar to those of other corticoids. They include systemic mycoses (fungal infections) and parasitic diseases, as well as eight weeks before and two weeks after application of live vaccines. For long-term treatment, the drug is also contraindicated in people with peptic ulcers, severe osteoporosis, severe myopathy, certain viral infectionsglaucoma, and metastasizing tumours.[17]

There are no contraindications for use in emergency medicine.[4]

Side effects

Further information: Glucocorticoid § Side effects

Side effects of triamcinolone are similar to other corticoids. In short-term treatment up to ten days, it has very few adverse effects; however, sometimes gastrointestinal bleeding is seen, as well as acute infections (mainly viral) and impaired glucose tolerance.[4]

Side effects of triamcinolone long-term treatment may include coughing (up to bronchospasms), sinusitismetabolic syndrome–like symptoms such as high blood sugar and cholesterol, weight gain due to water retention, and electrolyte imbalance, as well as cataractthrushosteoporosis, reduced muscle mass, and psychosis.[5][6][17] Triamcinolone injections can cause bruising and joint swelling.[5] Symptoms of an allergic reaction include rash, itch, swelling, severe dizziness, trouble breathing,[18] and anaphylaxis.[17]

Overdose

No acute overdosing of triamcinolone has been described.[17]

Interactions

Drug interactions are mainly pharmacodynamic, that is, they result from other drugs either adding to triamcinolone’s corticoid side effects or working against its desired effects. They include:[4][17]

Triamcinolone and other drugs can also influence each other’s concentrations in the body, amounting to pharmacokinetic interactions such as:[4][17]

Pharmacology

Mechanism of action

Further information: Glucocorticoid § Mechanism of action

Triamcinolone is a glucocorticoid that is about five times as potent as cortisol, but has very little mineralocorticoid effects.[4]

Pharmacokinetics

When taken by mouth, the drug’s bioavailability is over 90%. It reaches highest concentrations in the blood plasma after one to two hours and is bound to plasma proteins to about 80%. The biological half-life from the plasma is 200 to 300 minutes; due to stable complexes of triamcinolone and its receptor in the intracellular fluid, the total half-life is significantly longer at about 36 hours.[4][5]

A small fraction of the substance is metabolized to 6-hydroxy- and 20-dihydro-triamcinolone; most of it probably undergoes glucuronidation, and a smaller part sulfation. Three quarters are excreted via the urine, and the rest via the faeces.[4][17]

Due to corticoids’ mechanism of action, the effects are delayed as compared to plasma concentrations. Depending on the route of administration and the treated condition, the onset of action can be from two hours up to one or two days after application; and the drug can act much longer than its elimination half-life would suggest.[4][5]

Chemistry

Triamcinolone is a synthetic pregnane corticosteroid and derivative of cortisol (hydrocortisone) and is also known as 1-dehydro-9α-fluoro-16α-hydroxyhydrocortisone or 9α-fluoro-16α-hydroxyprednisolone as well as 9α-fluoro-11β,16α,17α,21-tetrahydroxypregna-1,4-diene-3,20-dione.[20][21]

The substance is a light-sensitive, white to off-white, crystalline powder, or has the form of colourless, matted crystals. It has no odour or is nearly odourless. Information on the melting point varies, partly due to the substance’s polymorphism: 260 to 263 °C (500 to 505 °F), 264 to 268 °C (507 to 514 °F), or 269 to 271 °C (516 to 520 °F) can be found in the literature.[4]

Solubility is 1:500 in water and 1:240 in ethanol; it is slightly soluble in methanol, very slightly soluble in chloroform and diethylether, and practically insoluble in dichloromethane. The specific rotation is {\displaystyle [\alpha ]_{D}^{20}}{\displaystyle [\alpha ]_{D}^{20}} +65° to +72° cm³/dm·g (1% in dimethylformamide).[4]

Society and culture

In 2010, TEVA and Perrigo launched the first generic inhalable triamcinolone.[22]

According to Chang et al. (2014), “Triamcinolone acetonide (TA) is classified as an S9 glucocorticoid in the 2014 Prohibited List published by the World Anti-Doping Agency, which caused it to be prohibited in international athletic competition when administered orally, intravenously, intramuscularly or rectally”.[23]

See also

References

  1. ^ “Kenalog Intra-articular / Intramuscular Injection – Summary of Product Characteristics (SmPC)”(emc). 10 June 2020. Retrieved 20 August 2020.
  2. ^ “Nasacort Allergy 55 micrograms/dose Nasal Spray suspension – Summary of Product Characteristics (SmPC)”(emc). 30 August 2018. Retrieved 20 August 2020.
  3. ^ “Adcortyl Intra-Articular/Intradermal Injection 10mg/ml – Summary of Product Characteristics (SmPC)”(emc). 11 December 2017. Retrieved 20 August 2020.
  4. Jump up to:a b c d e f g h i j k l m n Dinnendahl V, Fricke U, eds. (2004). Arzneistoff-Profile (in German). Vol. 10 (19 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. Triamcinolon. ISBN 978-3-7741-9846-3.
  5. Jump up to:a b c d e f Triamcinolone (systemic) Professional Drug Facts. Accessed 2020-08-19.
  6. Jump up to:a b c d e f g “Triamcinolone Monograph for Professionals”Drugs.com. American Society of Health-System Pharmacists. Retrieved 3 March 2019.
  7. ^ “Triamcinolone Use During Pregnancy”Drugs.com. Retrieved 3 March 2019.
  8. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 486. ISBN 978-3-527-60749-5.
  9. ^ Vallerand, April Hazard (2018). Davis’s Drug Guide for Nurses. F.A. Davis. p. 365. ISBN 978-0-8036-7000-6.
  10. ^ “The Top 300 of 2019”ClinCalc. Retrieved 16 October 2021.
  11. ^ “Triamcinolone – Drug Usage Statistics”ClinCalc. Retrieved 16 October 2021.
  12. ^ Triamcinolone – Drugs.com
  13. ^ Triamcinolone Inhalation – Drugs.com
  14. ^ Alcon Receives FDA Approval of Triesence Injectable Triamcinolone Suspension for Use in Eye Surgery – Drugs.com
  15. ^ Chong M, Fonacier L (December 2016). “Treatment of Eczema: Corticosteroids and Beyond”. Clinical Reviews in Allergy & Immunology51 (3): 249–262. doi:10.1007/s12016-015-8486-7PMID 25869743S2CID 44337035.
  16. ^ Eichenfield LF, Tom WL, Berger TG, Krol A, Paller AS, Schwarzenberger K, et al. (July 2014). “Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies”Journal of the American Academy of Dermatology71 (1): 116–32. doi:10.1016/j.jaad.2014.03.023PMC 4326095PMID 24813302Topical corticosteroids (TCS) are used in the management of AD in both adults and children and are the mainstay of anti-inflammatory therapy.
  17. Jump up to:a b c d e f g Haberfeld H, ed. (2020). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Volon 4 mg-Tabletten.
  18. ^ “Drugs and Treatments – Nasacort AQ Nasl – Patient Handout”WebMD. Retrieved 2008-03-24.
  19. ^ Moore CD, Roberts JK, Orton CR, et al. (2012). “Metabolic Pathways of Inhaled Glucocorticoids by the CYP3A Enzymes”Drug Metab. Dispos41 (2): 379–389. doi:10.1124/dmd.112.046318PMC 3558858PMID 23143891.
  20. ^ Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 1228–. ISBN 978-1-4757-2085-3.
  21. ^ Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 1054–. ISBN 978-3-88763-075-1.
  22. ^ Perrigo Announces Launch Of Generic Version Of Nasacort AQ – CBS Detroit
  23. ^ Chang CW, Huang TY, Tseng YC, Chang-Chien GP, Lin SF, Hsu MC (November 2014). “Positive doping results caused by the single-dose local injection of triamcinolone acetonide”Forensic Science International244: 1–6. doi:10.1016/j.forsciint.2014.07.024PMID 25126738.

External links

Clinical data
Trade namesKenalog, Nasacort, Adcortyl, others
Other namesshowClick show to see
AHFS/Drugs.comMonograph
MedlinePlusa601122
License dataUS DailyMedTriamcinolone
Pregnancy
category
AU: A
Routes of
administration
By mouthtopicalintranasalintramuscularintra-articular, intra-synovial
ATC codeA01AC01 (WHOC05AA12 (WHO), D07AB09 (WHO),H02AB08 (WHO), R01AD11(WHO), R03BA06 (WHO), S01BA05 (WHO)
Legal status
Legal statusAU: S4 (Prescription only) / S3UK: POM (Prescription only) / P[1][2][3]US: ℞-only / OTC (Nasacort, intranasal)In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability>90%[4]
Protein binding68%[citation needed]
MetabolismLiver[4]
Onset of action(2–)24(–48) hours[4][5]
Elimination half-life200–300 minutes (plasma), up to 36 hours (total)[4]
ExcretionUrine (75%) and faeces (25%)[5]
Identifiers
showIUPAC name
CAS Number124-94-7 
PubChem CID31307
IUPHAR/BPS2870
DrugBankDB00620 
ChemSpider29046 
UNII1ZK20VI6TY
KEGGD00385 
ChEBICHEBI:9667 
ChEMBLChEMBL1451 
CompTox Dashboard (EPA)DTXSID1040742 
ECHA InfoCard100.004.290 
Chemical and physical data
FormulaC21H27FO6
Molar mass394.439 g·mol−1
3D model (JSmol)Interactive image
Specific rotation{\displaystyle [\alpha ]_{D}^{20}}{\displaystyle [\alpha ]_{D}^{20}} +65° to +72°
Melting point260 to 271 °C (500 to 520 °F)
Solubility in water2
showSMILES
showInChI
  (what is this?)  (verify)

///////////////TRIAMCINOLONE, TU3850000, トリアムシノロン , 去炎松 , Glucocorticoid

[H][C@@]12C[C@@H](O)[C@](O)(C(=O)CO)[C@@]1(C)C[C@H](O)[C@@]1(F)[C@@]2([H])CCC2=CC(=O)C=C[C@]12C

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ENSITRELVIR


S-217622 structure.png
CID 162533924.png

Ensitrelvir

S-217622, S 217622, Xocova, SHIONOGI,

6-[(6-chloro-2-methylindazol-5-yl)amino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione

CAS 2647530-73-0

C22H17ClF3N9O2531.9
SynonymsBDBM513874bioRxiv20220126.477782, S-217622
Ensitrelvir fumarate

Ensitrelvir fumarate
CAS No. : 2757470-18-9

C22 H17 Cl F3 N9 O2 . C4 H4 O4

1,3,5-Triazine-2,4(1H,3H)-dione, 6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]dihydro-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-, (6E)-, (2E)-2-butenedioate (1:1)

Formula:C26H21ClF3N9O6
M. Wt. :647.95

A Phase 1 study of S-217622 in healthy adult participants (jRCT2031210202)

Japan Registry of Clinical Trials Web Site 2021, July 16

Ensitrelvir[1] (code name S-217622, brand name Xocova)[2] is an antiviral drug developed by Shionogi in partnership with Hokkaido University, which acts as an orally active 3C-like protease inhibitor for the treatment of COVID-19 infection.[3][4] It is taken by mouth, and has been successfully tested against the recently emerged Omicron variant.[5]

About S-217622

S-217622, a therapeutic drug for COVID-19, is a 3CL protease inhibitor created through joint research between Hokkaido University and Shionogi. SARS-CoV-2 has an enzyme called 3CL protease, which is essential for the replication of the virus. S-217622 suppresses the replication of SARS-CoV-2 by selectively inhibiting 3CL protease. Shionogi has already been submitting the non-clinical, manufacturing/CMC data, and clinical trial data obtained so far to the PMDA. Currently the Phase 3 part of a Phase 2/3 clinical trial in patients with mild/moderate symptoms and the Phase 2b/3 part in patients with asymptomatic/only mild symptoms are in progress.

SYN

Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19

 View ORCID ProfileYuto Unoh,  View ORCID ProfileShota Uehara,  View ORCID ProfileKenji Nakahara,  View ORCID ProfileHaruaki Nobori, Yukiko Yamatsu,  View ORCID ProfileShiho Yamamoto,  View ORCID ProfileYuki Maruyama,  View ORCID ProfileYoshiyuki Taoda,  View ORCID ProfileKoji Kasamatsu,  View ORCID ProfileTakahiro Suto, Kensuke Kouki,  View ORCID ProfileAtsufumi Nakahashi, Sho Kawashima,  View ORCID ProfileTakao Sanaki, Shinsuke Toba, Kentaro Uemura, Tohru Mizutare,  View ORCID ProfileShigeru Ando,  View ORCID ProfileMichihito Sasaki,  View ORCID ProfileYasuko Orba,  View ORCID ProfileHirofumi Sawa,  View ORCID ProfileAkihiko Sato,  View ORCID ProfileTakafumi Sato,  View ORCID ProfileTeruhisa Kato,  View ORCID ProfileYuki Tachibana

doi: https://doi.org/10.1101/2022.01.26.477782

https://www.biorxiv.org/content/10.1101/2022.01.26.477782v1.full

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral non-covalent, non-peptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug-design strategy. S-217622 exhibited antiviral activity in vitro against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel non-covalent inhibitor could be a potential oral agent for treating COVID-19.

Chemistry

The synthetic scheme for compound 1 is described in Scheme 1. Starting from the pyrazole derivative 4, cyclization with Ethyl isocyanatoacetate and CDI was conducted, giving 5 in 90% yield. Then, an alkylation with 5-bromomethyl-1,2,3-trifluorobenzene followed by introduction of a 4-difluoromethoxy-2-methylaniline unit, to give 7 (40% in 2 steps). The ester group in 7 was hydrolyzed and then amidated with methylamine, yielding 1 (58% in 2 steps). Compound 2 was synthesized similarly as shown in Scheme 2.

S-217622 (3) was synthesized as described in Scheme 3. Starting from known compound 9,21 an alkylation with 1-(bromomethyl)-2,4,5-trifluorobenzene gave 10 in 93% yield. Then, the 3-tert-Bu group was removed and the triazole unit was introduced, and the substitution of the SEt moiety with the indazole unit finally gave S-217622 (3).

21 Kai, H.; Kameyama, T.; Horiguchi, T.; Asahi, K.; Endoh, T.; Fujii, Y.; Shintani, T.; Nakamura, K.; Matsumoto, S.; Hasegawa, T.; Oohara, M.; Tada, Y.; Maki, T.; Iida, A. Preparation of triazine derivatives and pharmaceutical compound that contains same and exhibits analgesic activity. WO 2012020749 A1, Feb 16, 2012

Scheme 1.

Scheme 1.

Reagents and Conditions: (a) ethyl isocyanato-acetate, DBU, CDI, DMA, –10 °C to rt, 90%; (b) 5-bromomethyl-1,2,3-trifluorobenzene, N,N-diisopropylethylamine, DMA, 60 °C; (c) 4-difluoromethoxy-2-methylaniline, tert-butanol, 100 °C, 40% in 2 steps; (d) (i) NaOH aq., THF/MeOH, rt; (ii) methylamine, HATU, N,N-diisopropylethylamine, THF, rt., 58% in 2 steps.

Scheme 2.

Scheme 2.

Reagents and Conditions: (a) 6-chloro-2-methyl-2H-indazol-5-amine, tert-amyl alcohol, 100 °C, 44% in 2 steps from 5; (b) (i) NaOH aq., THF/MeOH, rt; (ii) methylamine, HATU, N,N-diisopropylethylamine, THF, rt., 29% in 2 steps.

Scheme 3.

Scheme 3.

Reagents and Conditions: (a) 1-(bromomethyl)-2,4,5-trifluorobenzene, K2CO3, MeCN, 80 °C, 93%; (b) TFA, rt, 97%; (c) 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride, K2CO3, DMF, 60 °C, 45%; (d) 6-chloro-2-methyl-2H-indazol-5-amine, LHMDS, THF, 0 °C to rt., 25%.

(6E)-6-[(6-Chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione (3, S-217622)

To a solution of 12 (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL) was added LHMDS (1M in THF; 1.46 mL, 1.46 mmol) dropwisely at 0 °C. The reaction mixture was stirred at 0 °C for 2.5 h and then at rt for 40 min. The reaction was quenched with aqueous NH4Cl solution, and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH gradient, 0-20% MeOH). The solid was recrystallized from acetone/H2O to afford 3 (S-217622) (95.3 mg, 25%) as a pale brown solid. 1H NMR (400 MHz, DMSO-d6, DCl in D2O) δ 3.90 (3H, s), 4.15 (3H, s), 5.04 (2H, s), 5.26 (2H, s), 7.44 (1H, m), 7.52-7.65 (2H, m), 7.73 (1H, s), 8.40 (1H, s), 9.31 (1H, s). 13C NMR (100 MHz, DMSO-d6, DCl in D2O) δ 37.34, 38.04, 40.06, 40.29, 106.16 (dd, J = 28.2, 21.6 Hz), 116.46-116.70, 116.70, 120.54-120.76, 120.76, 125.93, 129.10, 132.35, 143.84, 145.98, 146.38 (ddd, J = 241.4, 12.5, 3.7 Hz), 146.60, 148.52 (td, J = 247.7, 13.6 Hz), 150.43, 150.50, 155.22 (ddd, J = 244.3, 10.3, 2.2 Hz), 155.58. HRMS-ESI (m/z): [M + H]+ calcd for [C22H18 F3ClN9O2]+ 532.1219; found 532.1221.

Preparation of Compound 3 (S-217622) fumaric acid co-crystal

A mixture of 3 (S-217622) (1.17 g, 2.2 mmol) and fumaric acid (278 mg, 2.4 mmol) in EtOAc (5.9 mL) was stirred at room temperature for 45 min. The suspension was filtrated to afford 3 (S-217622) fumaric acid co-crystal (1.37 g, 95 %) as a white solid. 1H NMR (400 MHz, pyridine-d5) δ 3.64 (s, 3H), 3.99 (s, 3H), 5.56 (s, 2H), 5.61 (s, 2H), 7.16-7.25 (m, 2H), 7.44 (s, 2H), 7.81 (s, 1H), 7.89 (s, 1H), 7.89-7.97 (m, 1H), 8.32 (s, 1H).

Notes

SHIONOGI has applied for a patent covering 12, and 3 (S-217622). Y.U., S.U., K.N., H.N., Y.Y., S.Y., Y.M., Y.T., K.K., T.S., K.K., A.N., S.K., T.S., S.T., K.U., T.M., S.A., A.S., T.S., T.K., and Y.T. are employees of SHIONOGI & Co., Ltd. S.U., K.N., H.N., Y.M., Y.T., K.K., T.S., K.K., S.K., TS, S.T., K.U., T.S., and T.K. are shareholders in SHIONOGI & Co., Ltd. M.S., Y.O., and H.S. are financially supported by the joint research fund from SHIONOGI & Co., Ltd.

see spectrum at end of page

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Oral antiviral medications, in addition to vaccines, are expected to play an important role in treating coronavirus disease 2019 (COVID-19), which is caused by infection with the severe acute respiratory disease coronavirus-2 (SARS-CoV-2).

These drugs must have significant antiviral activity, as well as target specificity, oral bioavailability, and metabolic stability. Although several antiviral compounds have been reported as possible SARS-CoV-2 inhibitors in vitro, only a few of these drugs have been shown to be effective in vivo.

Ensitrelvir, a novel SARS-CoV-2 antiviral

Ensitrelvir (code name S-217622, brand name Xocova),  is a new inhibitor of the SARS-CoV-2 major protease (Mpro), also known as 3C-like protease, has been shown to reduce the viral load and help alleviate the severity of SARS-CoV-2 in infected hamsters. In cells, low nanomolar to sub-micromolar doses of S-217622 suppress viral growth. In hamsters, oral treatment of S-217622 showed excellent pharmacokinetic qualities and hastened recovery from acute SARS-CoV-2 infection.

S-217622 also demonstrated antiviral effectiveness against SARS-CoV-2 variants of concern (VOCs), such as the highly pathogenic Delta variant and the newly discovered Omicron variant. Overall, these findings show that S-217622, which is an antiviral drug that is currently being tested in Phase II/III clinical trials, has impressive antiviral efficiency and effectiveness against SARS-CoV-2 and could be a viable oral treatment option for COVID-19.

History

It has reached Phase III clinical trials.[3] The Japanese government is reportedly considering allowing Shionogi permission to apply for approval for medical use before the final steps of trials are completed, potentially speeding up the release for sale. This conditional early approval system has previously been used in Japan to accelerate the progression to market of other antiviral drugs targeting COVID-19, including remdesivir and molnupiravir.[6] In a study of 428 patients, viral load was reduced, but symptoms were not significantly reduced. [7]

It became the first Japanese domestic pill to treat COVID-19, third to be regulatorally approved in Japan; in February 2022.[8]

NEW DRUG APPROVALS

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$10.00

References

  1. ^ World Health Organization (2021). “International Nonproprietary Names for Pharmaceutical Substances. Proposed INN: List 126” (PDF). WHO Drug Information35 (4): 1135.
  2. ^ Xocova: Powerful New Japanese Pill for Coronavirus Treatment. BioPharma Media, February 2022
  3. Jump up to:a b Unoh Y, Uehara S, Nakahara K, Nobori H, Yamatsu Y, Yamamoto S, et al. (January 2022). “Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19”. bioRxivdoi:10.1101/2022.01.26.477782S2CID 246367525.
  4. ^ “Shionogi presents positive Ph II/III results for COVID-19 antiviral S-217622”thepharmaletter.com. 31 January 2022.
  5. ^ Shionogi’s new COVID pill appears to ease omicron symptoms. Nikkei Asia, 21 December 2021
  6. ^ Japan to consider early approval for Shionogi COVID-19 pill. Japan Times, 8 February 2022
  7. ^ https://www.reuters.com/business/healthcare-pharmaceuticals/japans-shionogi-seeks-approval-oral-covid-19-drug-2022-02-25/[bare URL]
  8. ^ “Japan’s Shionogi seeks approval for COVID-19 pill”. Reuters. Reuters. 25 February 2022.
Clinical data
Other namesS-217622
Identifiers
showIUPAC name
PubChem CID162533924
Chemical and physical data
FormulaC22H17ClF3N9O2
Molar mass531.88 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

Journal reference:

///////////Ensitrelvir, S-217622, S 217622, Xocova, SHIONOGI, CORONA VIRUS, covid 19

Cyclobenzaprine


Cyclobenzaprine 3D.gif
Cyclobenzaprine2.svg
ChemSpider 2D Image | cyclobenzaprine | C20H21N

Cyclobenzaprine

  • Molecular FormulaC20H21N
  • Average mass275.387 Da
  • MK-130
  • TNX-102

1-(3-Dimethylaminopropylidene)-2,3:6,7-dibenzo-4-suberene

1-Propanamine, 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-[ACD/Index Name]

206-145-8[EINECS]

3-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine

303-53-7[RN]

5-(3-Dimethylaminopropylidene)dibenzo[a,e]cycloheptatriene

циклобензаприн[Russian][INN]

سيكلوبنزابرين[Arabic][INN]

环苯扎林[Chinese][INN]

 Cyclobenzaprine, CAS Registry Number: 303-53-7

CAS Name: 3-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine

Additional Names:N,N-dimethyl-5H-dibenzo[a,d]cyclohepten-D5,g-propylamine; 5-(3-dimethylaminopropylidene)dibenzo[a,e]cycloheptatriene; 1-(3-dimethylaminopropylidene)-2,3:6,7-dibenzo-4-suberene; proheptatriene

Manufacturers’ Codes: MK-130; Ro-4-1577; RP-9715

Molecular Formula: C20H21N, Molecular Weight: 275.39

Percent Composition: C 87.23%, H 7.69%, N 5.09%

Literature References: Prepn: GB858187 (1961 to Hoffmann-La Roche); Villani et al.,J. Med. Pharm. Chem.5, 373 (1962); Winthrop et al.,J. Org. Chem.27, 230 (1962). Pharmacology: C. D. Barnes, W. L. Adams, Neuropharmacology17, 445 (1978); N. N. Share, ibid. 721; and toxicology: J. Metysova et al.,Arch. Int. Pharmacodyn. Ther.144, 481 (1963). Metabolism: G. Belvedere et al.,Biomed. Mass Spectrom.1, 329 (1974); H. B. Hucker et al.,Drug Metab. Dispos.6, 184 (1978). Bioavailability: eidem,J. Clin. Pharmacol.17, 719 (1977). Clinical studies: J. V. Basmajian, Arch. Phys. Med. Rehabil.5, 58 (1978); B. R. Brown, J. Womble, J. Am. Med. Assoc.240, 1151 (1978). Comprehensive description: M. L. Cotton, G. R. B. Down, Anal. Profiles Drug Subs.17, 41-72 (1988).

Properties: bp1 175-180°. uv max: 224, 289 nm (log e 4.57, 4.02), (Villani et al.)

Boiling point: bp1 175-180°

Absorption maximum: uv max: 224, 289 nm (log e 4.57, 4.02), (Villani et al.)

Derivative Type: Hydrochloride

CAS Registry Number: 6202-23-9

Trademarks: Flexeril (Merck & Co.); Flexiban (Merck & Co.)

Molecular Formula: C20H21N.HCl, Molecular Weight: 311.85

Percent Composition: C 77.03%, H 7.11%, N 4.49%, Cl 11.37%

Literature References: Use as muscle relaxant: N. N. Share, FR2100873 (1972 to Frosst), C.A.78, 47801n (1973).

Properties: Crystals from isopropanol, mp 216-218°. Soly in water: >20 g/100 ml. Freely sol in water, methanol, ethanol; sparingly sol in isopropanol; slightly sol in chloroform, methylene chloride. Practically insol in hydrocarbons. uv max: 226, 295 nm (e 52300, 12000). LD50 in mice (mg/kg): 35 i.v., 250 orally (Metysova).

Melting point: mp 216-218°

Absorption maximum: uv max: 226, 295 nm (e 52300, 12000)

Toxicity data: LD50 in mice (mg/kg): 35 i.v., 250 orally (Metysova)

Therap-Cat: Muscle relaxant (skeletal).

Keywords: Muscle Relaxant (Skeletal).

Cyclobenzaprine, a centrally-acting muscle relaxant, was first synthesized in 196111 and has been available for human use since 1977.10 It was initially studied for use as antidepressant given its structural similarity to tricyclic antidepressants – it differs from Amitriptyline by only a single double bond.11,10 Since its approval, it has remained relatively popular as an adjunctive, short-term treatment for acute skeletal muscle spasms secondary to musculoskeletal injury.

Cyclobenzaprine (sold under the brand name Flexeril, among others) is a medication used for muscle spasms from musculoskeletal conditions of sudden onset.[6] It is not useful in cerebral palsy.[6] It is taken by mouth.[6] Use is not recommended for more than a few weeks.[6]

Common side effects include headache, feeling tired, dizziness, and dry mouth.[6] Serious side effects may include an irregular heartbeat.[6] There is no evidence of harm in pregnancy, but it has not been well studied in this population.[6] It should not be used with an MAO inhibitor.[6] How it works is unclear.[6]

Cyclobenzaprine was approved for medical use in the United States in 1977.[6] It is available as a generic medication.[6] In 2019, it was the 45th most commonly prescribed medication in the United States, with more than 15 million prescriptions.[7][8] It was not available in the United Kingdom as of 2012.[9]

Synthesis Reference

Villani, F.J.; US. Patent 3,409,640; November 5,1968; assigned to Schering Corporation.

Paper

By: Gowda, Narendra B.; Rao, Gopal Krishna; Ramakrishna, Ramesha A.

Tetrahedron Letters (2010), 51, (43), 5690-5693.

https://www.sciencedirect.com/science/article/abs/pii/S0040403910014668

A  simple and convenient protocol for deoxygenation of aliphatic and aromatic N-oxides to the corresponding amines in good to excellent yield using sodium borohydride–Raney nickel in water is reported. Other functional moieties such as alkenes, halides, ethers, and amides are unaffected under the present reaction condition.

Graphical abstract

Cyclobenzaprine N-oxide, CAS RN: 6682-26-4

Dissolve (1 mmol) of cyclobenzaprine N-oxide in 2.5 mL of water at 60 °C. 2. Add Raney nickel (0.10 g, W6 grade) to the solution. 3. Stir the reaction mixture for 10 minutes. 4. Add (2 mmol) of sodium borohydride slowly in portions over 15-20 minutes to the reaction mixture. 5. Stir the reaction mixture at the same temperature for 2.5 hours (the completion of the reaction as monitored by TLC). 6. Once the reaction is completed, add chloroform (50 mL) to the reaction mixture. 7. Filter the resulted mixture to remove Raney nickel. 8. Dry the chloroform layer over anhydrous magnesium sulfate. 9. Filter the reaction mixture. 10. Evaporate the solvent under vacuum. 11. Purify the obtained residue through short path flash chromatography with silica gel and chloroform.

1H NMR (400 MHz, CDCl3) δ: 1.12 (s, 6H, N-CH3), 1.23- 1.34 (m, 4H, CH2), 4.58 (t, J= 4.0 Hz, 1H, CH), 5.82(d, J= 4.0 Hz, 2H, CH), 6.21- 6.33 (m, 8H, ArH).

13C NMR (100 MHz, CDCl3) δ: 27.89, 45.93, 60.12, 127.40, 127.55, 128.30, 128.59, 128.92, 129.33, 129.45, 129.67, 131.74, 131.96, 132.40, 134.63, 135.39, 137.97, 142.95, 143.30.

SYN

File:Cyclobenzaprine synthesis.png

PATENT

https://patents.google.com/patent/WO2012098563A2/en

Cyclobenzaprine hydrochloride, chemically known as 5-(3-dimethylaminopropylidene)- dibenzo (a,e) cycloheptatriene hydrochloride (Formula I),

Figure imgf000002_0001

Formula I is a commonly prescribed tricyclic amine having muscle relaxant pharmaceutical activity. After sustaining an injury, muscle spasms may occur to stabilize the affected body part and prevent further damage. Cyclobenzaprine hydrochloride is used to treat such muscle spasm associated with acute, painful musculoskeletal conditions.

Few multistep processes for the preparation of this tricyclic amine are already available in the literature which involves isolation and purification of intermediate compounds. The conventional route of synthesis as reported in US3454643, ES8201950 includes preparation of Grignard reagent (GR) of 3-dimethylaminopropyl chloride in a first step, reacting with 5-dibenzosuberenone (Formulall) in a second step. The reaction mass was extracted with benzene, solid obtained was recrystallized from alcohol to produce 5- hydroxy intermediate (Formula III) and further dehydrated in third step using acetyl chloride or acetic anhydride in presence of chloroform as a solvent medium followed by purging HC1 gas to produce hydrochloride salt (Formula I). CH,

CI-(CH2)3 NS

CH,

Dimeth laminopropyl chloide

Figure imgf000003_0001

Di methy lam i nopropy I 5-dibenzosubrenone – y roxy compoun magnesium chloide

(Formula II) (Formula III)

Figure imgf000003_0002

Cyclobenzaprine base Cyclobenzaprine hydrochloride

(Formula IV) (Formula I)

The multistep synthesis is cumbersome and use of hazardous solvents and reagents like chloroform, benzene and acetyl chloride etc are not recommended for the preparation of pharmaceutical substances.

J. Org. Chem. Vol. 27, 230-240 (1961) also portrayed similar procedure for the synthesis of cyclobenzaprine hydrochloride, wherein 5-hydroxy compound of formula III was isolated and recrystallized before dehydration reaction.

Synthetic Comm. 11 (3), 241-246 (1981) described a process which involves isolation and purification of the intermediate at magnesium -complex stage. Hydrolysis of the isolated complex afforded desired tricyclic amine. GB858186 and GB858187 jointly described a process which comprises preparation of 5- hydroxy compound (Formula III) and subsequent conversion of the same to cyclobenzaprine hydrochloride. However the overall yield reported is significantly low.

In a different approach, a high temperature dehydrogenation of amitriptyline base resulting in formation of cyclobenzaprine hydrochloride is reported in Indian patent application 387/CHE/2005.

Figure imgf000004_0001

. EXAMPLE:

In a reaction vessel, THF (1 10ml), magnesium turnings 20gm (0.823mole) were charged and the mixture was warmed to 45-55°C for 20 min. A solution of l OOgm (0.823mole) of 3-dimethylaminopropyl chloride prepared in 1 10ml THF was added dropwise to the reaction mixture by controlling the reflux generated due to reaction initiation and maintained for 2hrs. The formed Grignard reagent was then cooled to 0-5°C and a solution of lOOgm (0.485mole) 5-dibenzosuberenone prepared in 220ml THF was charged to the reaction mass at temperature below 10°C. The reaction mass was stirred for 45 min at temperature 10-15°C. The absence of 5-dibenzosuberenone was checked by TLC and 770ml of 20% aq. HC1 was charged to the reaction mass at a temperature below 10°C. The reaction mass was then heated to 70-80°C for 3 hrs. The acidic mass was neutralized by using aqueous Na2C03 solution and extracted with 900ml methylene dichloride. The solvent was removed completely under reduced pressure and oil thus formed was dissolved in 450ml IPA and acidified with 240 ml of 20% IPA .HC1 solution and stirred for 2 hrs at 0-5°C for complete precipitation. The precipitate is filtered, recrystallized from IPA (800 ml) and dried to obtain 1 18 gm (78%) white crystalline cyclobenzaprine hydrochloride with purity 99.93% by HPLC.

Figure imgf000006_0003

PATENT

US3454643A *

PATENT

CN101260046A *

CN102976955A *

WO2019014651A1

WO2020044102A1 *

CN 111393305

CLIP

Muscle Relaxants

R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006

Cyclobenzaprine

Cyclobenzaprine, N,N-dimethyl-3-(dibenzo[a,d]cyclohepten-5-ylidene) propylamine (15.3.9), is synthesized by reacting 5H-dibenzo[a,d]cyclohepten-5-one with 3-dimethylaminopropylmagnesium chloride and subsequent dehydration of the resulting carbinol (15.3.8) in acidic conditions into cyclobenzaprine (15.3.9) [30–32].

Cyclobenzaprine is structurally similar to tricyclic antidepressants. It acts at the brain stem level. It is used as an adjuvant agent for relieving muscle spasms associated with severe diseased conditions of the muscle. A synonym of this drug is flexeril.

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Medical use

Cyclobenzaprine is used, in conjunction with physical therapy, to treat muscle spasms that occur because of acute musculoskeletal conditions.[10] After sustaining an injury, muscle spasms to stabilize the affected body part occur, which may increase pain to prevent further damage. Cyclobenzaprine is used to treat such muscle spasms associated with acute, painful musculoskeletal conditions.[11] It decreases pain in the first two weeks,[12][13] peaking in the first few days, but has no proven benefit after two weeks.[12][14] Since no benefit is proven beyond that, therapy should not be continued long-term.[11] It is the best-studied muscle relaxer.[12] It is not useful for spasticity due to neurologic conditions such as cerebral palsy.[11][15]

A 2004 review found benefit for fibromyalgia symptoms, with a reported number needed to treat of 4.8 (meaning that 1 person out of every 4.8 benefits from treatment) for pain reduction, but no change in fatigue or tender points.[16] A 2009 Cochrane review found insufficient evidence to justify its use in myofascial pain syndrome.[17] It may also be used along with other treatments for tetanus.[18]

Side effects

Cyclobenzaprine results in increased rates of drowsiness (38%), dry mouth (24%), and dizziness (10%).[14] Drowsiness and dry mouth appear to intensify with increasing dose.[19] The sedative effects of cyclobenzaprine are likely due to its antagonistic effect on histamineserotonin, and muscarinic receptors.[medical citation needed]

Agitation is a common side effect observed, especially in the elderly. Some experts[who?] believe that cyclobenzaprine should be avoided in elderly patients because it can cause confusion, delirium, and cognitive impairment.[20][21] In general, the National Committee for Quality Assurance recommends avoiding the use of cyclobenzaprine in the elderly because of the potential for more severe side effects.[22]

Dysphagia, a life-threatening side-effect, may rarely occur.[23] Treatment protocols and support should follow the same as for any structurally related tricyclic, such as tricyclic antidepressants.[24]

Overdose

The most common effects of overdose are drowsiness and tachycardia.[11] Rare but potentially critical complications are cardiac arrestabnormal heart rhythms, severe low blood pressureseizures, and neuroleptic malignant syndrome.[11] Life-threatening overdose is rare,[11] however, as the median lethal dose is about 338 milligrams/kilogram in mice and 425 mg/kg in rats.[11] The potential harm is increased when central nervous system depressants and antidepressants are also used; deliberate overdose often includes alcohol among other drugs.[11]

Interactions

Cyclobenzaprine has major contraindications with monoamine oxidase inhibitors (MAOIs). At least one study also found increased risk of serotonin syndrome when cyclobenzaprine was taken with the serotonergic drugs duloxetine or phenelzine.[25]

These substances may interact with cyclobenzaprine:

Cyclobenzaprine may affect the medications used in surgical sedation and some surgeons request that patients temporarily discontinue its use prior to surgery.[26]

Pharmacology

Cyclobenzaprine is a centrally acting muscle relaxant.[27] Cyclobenzaprine is a 5-HT2 receptor antagonist; it relieves muscle spasm through action on the central nervous system at the brain stem, rather than targeting the peripheral nervous system or muscles themselves.[28]

Pharmacodynamics

SiteCBPNCBPActionRef
5-HT1A5.33.2Agonist[29]
5-HT2A5.213Antagonist[29]
5-HT2B100???Antagonist[29]
5-HT2C5.243Antagonist[29]
α1A5.634ND[29]
α2A4.36.4Antagonist[29]
α2B21150ND[29]
α2C2148ND[29]
H11.35.6ND[29]
M17.930ND[29]
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Pharmacokinetics

Cyclobenzaprine has an oral bioavailability of about 55% and approximately 93% is bound to proteins in plasma. The half-life of the drug is 18 hours and it has a plasma clearance of 0.7 litres per minute.[27][30][31]

Comparison to other medications

Cyclobenzaprine has been found to be not inferior to tizanidineorphenadrine, and carisoprodol in the treatment of acute lower back pain, although none have been proven to be effective for long-term use (beyond two weeks of treatment). No differences in pain or spasm scores were noted among these agents, nor when compared to benzodiazepines.[32] However, nonbenzodiazepine (including cyclobenzaprine) treatment was found to have a lower risk of medication abuse and continuation of use against medical advice.[medical citation needed] Side effects such as sedation and ataxia are also less pronounced with nonbenzodiazepine antispasmodics.[medical citation needed]

In a study on the treatment of musculoskeletal pain treatment with cyclobenzaprine alone or in combination with ibuprofen, no significant differences in pain scores were noted among the three treatment groups. Peak benefit was found to occur on day seven of the treatment for all groups.[33]

Formulations

Cyclobenzaprine 10mg tablets

By mouth, cyclobenzaprine is marketed as Apo-Cyclobenzaprin, Fexmid, Flexeril and Novo-Cycloprine. It is available in generic form. A once-a-day, extended-release formulation, Amrix, is available.[34] Cyclobenzaprine is also used by compounding pharmacies in topical creams.[citation needed]

References

  1. ^ Micromedex® 2010 – DRUGDEX Evaluations (Cyclobenzaprine Hydrochloride)
  2. ^ “Cyclobenzaprine Hydrochloride Tablets USP Revised: April 2005 Rx only”nih.gov. Retrieved 1 October 2016.
  3. ^ Teva Pharmaceuticals USA, Inc (May 2016). “AMR40470 (Amrix) Prescribing Information” (PDF).
  4. ^ U.S. Food and Drug Administration. “NDA 17-821/S-045 Flexeril (Cyclobenzaprine HCl) Tablets” (PDF).
  5. ^ Teva Pharmaceuticals USA, Inc (May 2016). “AMR40470 (Amrix) Prescribing Information” (PDF).
  6. Jump up to:a b c d e f g h i j k “Cyclobenzaprine Monograph for Professionals”Drugs.com. AHFS. Retrieved 22 December 2018.
  7. ^ “The Top 300 of 2019”ClinCalc. Retrieved 16 October 2021.
  8. ^ “Cyclobenzaprine – Drug Usage Statistics”ClinCalc. Retrieved 16 October 2021.
  9. ^ “Fibromyalgia, psychiatric comorbidity, and the somatosensory cortex”British Journal of Medical Practitioners5 (2): a522. 2012.
  10. ^ Yang YW, Macdonald JB, Nelson SA, Sekulic A (December 2017). “Treatment of vismodegib-associated muscle cramps with cyclobenzaprine: A retrospective review”. Journal of the American Academy of Dermatology77 (6): 1170–1172. doi:10.1016/j.jaad.2016.12.017PMID 29132849S2CID 8265576.
  11. Jump up to:a b c d e f g h i “Cyclobenzaprine- cyclobenzaprine hydrochloride tablet, film coated”DailyMed. 30 December 2019. Retrieved 26 September 2020.
  12. Jump up to:a b c Chou R, Peterson K, Helfand M (August 2004). “Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review”Journal of Pain and Symptom Management28 (2): 140–75. doi:10.1016/j.jpainsymman.2004.05.002PMID 15276195.
  13. ^ van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM (2003). Van Tulder MW (ed.). “Muscle relaxants for non-specific low back pain”The Cochrane Database of Systematic Reviews2 (2): CD004252. doi:10.1002/14651858.CD004252PMC 6464310PMID 12804507.
  14. Jump up to:a b Browning R, Jackson JL, O’Malley PG (July 2001). “Cyclobenzaprine and back pain: a meta-analysis”Archives of Internal Medicine161 (13): 1613–20. doi:10.1001/archinte.161.13.1613PMID 11434793.
  15. ^ Ashby P, Burke D, Rao S, Jones RF (October 1972). “Assessment of cyclobenzaprine in the treatment of spasticity”Journal of Neurology, Neurosurgery, and Psychiatry35 (5): 599–605. doi:10.1136/jnnp.35.5.599PMC 494138PMID 4563483.
  16. ^ Tofferi JK, Jackson JL, O’Malley PG (February 2004). “Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis”Arthritis and Rheumatism51 (1): 9–13. doi:10.1002/art.20076PMID 14872449.
  17. ^ Leite FM, Atallah AN, El Dib R, Grossmann E, Januzzi E, Andriolo RB, da Silva EM (July 2009). “Cyclobenzaprine for the treatment of myofascial pain in adults”The Cochrane Database of Systematic Reviews (3): CD006830. doi:10.1002/14651858.CD006830.pub3PMC 6481902PMID 19588406.
  18. ^ Smith BT (2014). Pharmacology for Nurses. Jones & Bartlett Publishers. p. 122. ISBN 9781449689407.
  19. ^ “Flexeril: Side effects”RxList.com. Archived from the original on 12 September 2008. Retrieved 22 February 2010.
  20. ^ “Long-term Use of Cyclobenzaprine for Pain: A Review of the Clinical Effectiveness”. CADTH Rapid Response Reports. Ottawa, Ontario: Canadian Agency for Drugs and Technologies in Health. 23 February 2015. PMID 25763449.
  21. ^ Potentially inappropriate medications for the elderly according to the revised Beers criteria. 2012. Duke Clinical Research Institute website. [1]
  22. ^ “High risk medications” (PDF). National Committee for Quality Assurance. Archived from the original (PDF) on 1 February 2010. Retrieved 22 February 2010.
  23. ^ “MEDICATIONS AND DYSPHAGIA/ SWALLOWING RISKS” (PDF).
  24. ^ Chabria SB (July 2006). “Rhabdomyolysis: a manifestation of cyclobenzaprine toxicity”Journal of Occupational Medicine and Toxicology1 (1): 16. doi:10.1186/1745-6673-1-16PMC 1540431PMID 16846511.
  25. ^ Keegan MT, Brown DR, Rabinstein AA (December 2006). “Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs”. Anesthesia and Analgesia103 (6): 1466–8. doi:10.1213/01.ane.0000247699.81580.ebPMID 17122225.
  26. ^ Medical Practice of William H. Gorman, M.D. (18 February 2014). “Medications to Avoid, Continue, or Stop – Before & After Surgery”.
  27. Jump up to:a b “Cyclobenzaprine”http://www.drugbank.ca.
  28. ^ Kobayashi H, Hasegawa Y, Ono H (September 1996). “Cyclobenzaprine, a centrally acting muscle relaxant, acts on descending serotonergic systems”. European Journal of Pharmacology311 (1): 29–35. doi:10.1016/0014-2999(96)00402-5PMID 8884233.
  29. Jump up to:a b c d e f g h i j k “Cyclobenzaprine (CBP) and Its Major Metabolite Norcyclobenzaprine (nCBP) Are Potent Antagonists of Human Serotonin Receptor 2a (5HT2a), Histamine Receptor H-1 and á-Adrenergic Receptors: Mechanistic and Safety Implications for Treating Fibromyalgia Syndrome by Improving Sleep Quality”ACR Meeting Abstracts. Retrieved 27 January 2022.
  30. ^ “Cyclobenzaprine”pubchem.ncbi.nlm.nih.gov.
  31. ^ Winchell GA, King JD, Chavez-Eng CM, Constanzer ML, Korn SH (January 2002). “Cyclobenzaprine pharmacokinetics, including the effects of age, gender, and hepatic insufficiency”. Journal of Clinical Pharmacology42 (1): 61–9. doi:10.1177/0091270002042001007PMID 11808825S2CID 7749001.
  32. ^ “Medscape: Medscape Access”medscape.com. Retrieved 1 October 2016.
  33. ^ Childers MK, Petri M, Laudadio C, Harrison D, Silber S, Bowen D (2004). “Comparison of cyclobenzaprine alone versus cyclobenzaprine plus ibuprofen in patients with acute musculoskeletal spasm and pain”Annals of Emergency Medicine44 (4): S87–S88. doi:10.1016/j.annemergmed.2004.07.286.
  34. ^ “Patient Web site for Amrix (Cyclobenzaprine Hydrochloride Extended‐Release Capsules)”amrix.com. Retrieved 1 October 2016.
Clinical data
Trade namesFlexeril, Amrix, others
AHFS/Drugs.comMonograph
MedlinePlusa682514
License dataUS DailyMedCyclobenzaprine
Routes of
administration
By mouth
ATC codeM03BX08 (WHO)
Legal status
Legal statusUS: ℞-onlyIn general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability33–55%[1][2]
Protein binding93%
Metabolismmajor: CYP3A4CYP1A2; minor: CYP2D6N-demethylation[5]
MetabolitesNorcyclobenzaprine
Elimination half-life32 hours (extended-release, range 8-37 hours),[3] 18 hours (immediate release, range 8–37 hours)[4]
ExcretionKidney
Identifiers
showIUPAC name
CAS Number303-53-7 
PubChem CID2895
IUPHAR/BPS7152
DrugBankDB00924 
ChemSpider2792 
UNII69O5WQQ5TI
KEGGD07758 
ChEBICHEBI:3996 
ChEMBLChEMBL669 
CompTox Dashboard (EPA)DTXSID0046933 
ECHA InfoCard100.005.588 
Chemical and physical data
FormulaC20H21N
Molar mass275.395 g·mol−1
3D model (JSmol)Interactive image
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Pyritinol


Pyritinol.svg
ChemSpider 2D Image | pyritinol | C16H20N2O4S2
Pyritinol.png

Pyritinol

  • Molecular FormulaC16H20N2O4S2
  • Average mass368.471 Da

1098-97-1[RN]

1308

214-150-1[EINECS]

233-178-5[EINECS]

3,3′-[Dithiobis(methylene)]bis[5-hydroxy-6-methyl-4-pyridinemethanol]

4-Pyridinemethanol, 3,3′-[dithiobis(methylene)]bis[5-hydroxy-6-methyl-

пиритинол[Russian][INN]

بيريتينول[Arabic][INN]

吡硫醇[Chinese][INN]

 Pyritinol, CAS Registry Number: 1098-97-1

CAS Name: 3,3¢-[Dithiobis(methylene)]bis[5-hydroxy-6-methyl-4-pyridinemethanol]

Additional Names: bis(4-hydroxymethyl-5-hydroxy-6-methyl-3-pyridylmethyl) disulfide; bis[(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methyl] disulfide; dipyridoxolyldisulfide; pyridoxine-5-disulfide; pyrithioxin

Molecular Formula: C16H20N2O4S2, Molecular Weight: 368.47

Percent Composition: C 52.15%, H 5.47%, N 7.60%, O 17.37%, S 17.40%

Literature References: Prepn: Zima, Schorre, US3010966 (1961 to E. Merck); Iwanami et al.,Bitamin36, 122 (1967); J. Vitaminol.14, 321, 326 (1968). HPLC determn in urine: K. Kitao et al.,Chem. Pharm. Bull.25, 1335 (1977). Pharmacokinetics and metabolism: Darge et al.,Arzneim.-Forsch.19, 5, 9, (1969); Nowak, Schorre, ibid. 11. Clinical trial in dementia: S. Hoyer et al.,ibid.27, 671 (1977); A. J. Cooper, R. V. Magnus, Pharmacotherapeutica2, 317 (1980); in cerebrovascular disorders: Y. Tazaki et al.,J. Int. Med. Res.8, 118 (1980).

Properties: Crystals, mp 218-220°.

Melting point: mp 218-220°

Derivative Type: Dihydrochloride monohydrate

Trademarks: Biocefalin (Benvegna); Bonifen (Merck KGaA); Enbol (Chugai); Encephabol (Merck KGaA); Enerbol (Polfa); Epocan (Merck KGaA); Life (SIT)

Molecular Formula: C16H20N2O4S2.2HCl.H2O, Molecular Weight: 459.41

Percent Composition: C 41.83%, H 5.27%, N 6.10%, O 17.41%, S 13.96%, Cl 15.43%

Properties: mp 184°. Note: Has no vitamin B6 activity.

Melting point: mp 184°

Therap-Cat: Nootropic.

Keywords: Nootropic.

Derivatives

Dihydrochloride monohydrate

  • Formula:C16H20N2O4S2 • 2HCl • H2O
  • MW:459.42 g/mol
  • CAS-RN:10049-83-9
  • EINECS:233-178-5
  • LD50:221 mg/kg (M, i.v.); 5786 mg/kg (M, p.o.);
    300 mg/kg (R, i.v.); 6 g/kg (R, p.o.)

Pyritinol has been used in trials studying the treatment of Dementia, Depression, Schizophrenia, Anxiety Disorders, and Psychosomatic Disorders.

Pyritinol also called pyridoxine disulfide or pyrithioxine (European drug names Encephabol, Encefabol, Cerbon 6) is a semi-synthetic water-soluble analog of vitamin B6 (Pyridoxine HCl). It was produced in 1961 by Merck Laboratories by bonding 2 vitamin B6 compounds (pyridoxine) together with a disulfide bridge. Since the 1970s, it has been a prescription and OTC drug in several countries for cognitive disorders, rheumatoid arthritis,[1] and learning disorders in children. Since the early 1990s it has been sold as a nootropic dietary supplement in the United States.

SYN

CAS-RNFormulaChemical NameCAS Index Name
39984-49-1C8H10Br3NO3,4-bis(bromomethyl)-5-hydroxy-6-methylpyridine hydrobromide3-Pyridinol, 4,5-bis(bromomethyl)-2-methyl-
92147-37-0C11H15NO3S2ethylxanthic acid [5-hydroxy-4-(hydroxymethyl)-6-methyl-3-pyridyl]methyl esterXanthic acid, ethyl-, [5-hydroxy-4-(hydroxymethyl)-6-methyl-3-pyridyl]methyl ester
140-89-6C3H5KOS2potassium ethylxanthogenateCarbonodithioic acid, O-ethyl ester, potassium salt
File:Pyritinol synthesis01.svg

PATENT

PATENT

https://patents.google.com/patent/CN103992268A/en

Pyritinol, it is the derivative of vitamin B6, for nootropic agents, can promote glucose and amino acid metabolism in brain, improve whole body assimilation, increase Flow of carotid artery, improve cerebral blood flow (CBF), be applicable to the dizzy distending pain, insomnia, hypomnesis of cerebral trauma sequela, encephalitis and meningitis sequela etc., the improvement of absent minded, emotional change; Also for cerebral arteriosclerosis, senile dementia mental symptom etc.

The pyritinol of applying clinically at present, it is pyritinol hydrochloride, be specially the monohydrate of hydrochloride, its chemical name is 3,3-(dithio methylene radical) two (5-hydroxyl-6-methyl-pyridine methane) dihydrochloride monohydrate, has recorded in < < Chinese Pharmacopoeia version > > in 2010.The preparation of this product listing has sheet, capsule and sterile powder injection, and its injection easily causes venous stimulation when clinical application, has greatly limited clinical application.The powder injection of pyritinol hydrochloride easy caking after standing storage, not soluble or dissolve and thoroughly cause liquid unclarity, particulate matter to exceed standard and easily cause the untoward reactions such as Microembolization during use.

CN101003509A discloses hydrobromate and the mesylate of pyritinol, record its stability having had, solvability and bland advantage, but in fact, Hydrogen bromide pyritinol, methylsulfonic acid pyritinol store easy moisture absorption under normal condition, in purification refine, be difficult to separate out with conventional crystallization method, need loaded down with trivial details aftertreatment technology, Hydrogen bromide and methylsulfonic acid have strong corrodibility in addition, comparatively difficult to its suitability for industrialized production.

CN101066266A discloses organic acid salt of pyritinol and preparation method thereof, wherein preferred pyritinol nicotinate.Yet, in nicotinic acid pyritinol water solvability a little less than, and nicotinic acid pyritinol preparation technology used dry-out benzene, toxicity is larger, and aftertreatment technology is complicated, is not suitable for suitability for industrialized production.

Yet, existing pyritinol or its salt, or pyritinol salt exists defect in the use, or the production technique that obtains this pyritinol salt is unsuitable for suitability for industrialized production.For this reason, need to provide a kind of safe, pyritinol salt and production method thereof of stablizing, meeting industrialization production requirements.

Embodiment 1: pyritinol maleate synthetic

Get 5.0g pyritinol powder, drop in reaction flask, add 100ml purified water, then under agitation add toxilic acid 3.8g, finish, be heated to 60-65 ℃ and stir 30min and all dissolve to solid, remove heating fluid, stirred crystallization under room temperature, separate out a large amount of white solids, use a small amount of cold water washing, 45 ℃ of vacuum-dryings, obtain white powder 5.97g, yield 72.9%.Purity: 99.5%; M.p.:134~137 ℃; Ultimate analysis (C16H20N2O4S22C4H4O4): C:47.9%, H:4.8%, N:4.6%, S:10.6%, O:32.1% (theory: C:48.0%, H:4.7%, N:4.7%, S:10.7%, O:32.0%); 1H-NMR (600MHz, DMSO) δ: 2.39 (6H, s), 3.93 (4H, s), 4.76 (4H, s), 6.18 (4H, s), 7.87 (2H, s).By the 1H-NMR (Fig. 2) of toxilic acid pyritinol and the 1H-NMR (Fig. 1) of pyritinol contrast, in a part toxilic acid pyritinol, contain 2 molecule toxilic acids.

Embodiment 2: pyritinol maleate synthetic

Get 5.0g pyritinol powder, drop in reaction flask, add 100ml ethanol, then under agitation add toxilic acid 3.0g, finish, be heated to return stirring 30min and all dissolve to solid, remove heating fluid, stirred crystallization under room temperature, separate out a large amount of white solids, use a small amount of cold water washing, 45 ℃ of vacuum-dryings, obtain white powder 5.50g, yield 67.5%.After measured, the toxilic acid pyritinol that structure makes with embodiment 1.

PATENT

https://patents.google.com/patent/CN105153021A/en

Embodiment 1

Toxilic acid 3.8g is dissolved in 100ml ethanol, be warming up to 60 DEG C clearly molten, add pyritinol 5.0g, stir clearly molten, react 1 hour, cooling crystallization, filter, solid is drying under reduced pressure at 50 DEG C, obtains white crystalline solid toxilic acid pyritinol crystal form A 4.9g.X-ray powder diffraction analysis, as Fig. 1, its 2 θ value is as following table.

Embodiment 2

Toxilic acid 3.8g is dissolved in 100ml acetone, be warming up to 45 DEG C clearly molten, add pyritinol 5.0g, stir clearly molten, react 1.5 hours, cooling crystallization, filter, solid is drying under reduced pressure at 50 DEG C, obtains white crystalline solid 5.2g.It is toxilic acid pyritinol crystal form A that dry product does X-ray powder diffraction.

Embodiment 3

Toxilic acid 3.8g is dissolved in and adds 100ml Virahol, be warming up to 60 DEG C clearly molten, add pyritinol 5.0g, stir clearly molten, react 2 hours, cooling crystallization, filter, solid is drying under reduced pressure at 50 DEG C, obtains white crystalline solid 5.1g.It is toxilic acid pyritinol crystal form A that dry product does X-ray powder diffraction.

PATENT

https://patents.google.com/patent/CN101066266A/en

Specific embodiment:

Embodiment 1: nicotinic acid pyritinol salt synthetic

Get nicotinic acid 24.6g, fully be dissolved in the 300ml anhydrous benzene, heated and stirred is to molten entirely, under complete molten state, add pyritinol 40.5g, reflux mixture 3 hours, TLC thin layer identification (developing solvent: ethyl acetate: ethanol: glacial acetic acid=5: 6: 0.6) fully, the cooling back adds the 200ml dehydrated alcohol slightly, mixture is put into refrigerator fully cool off, sucking filtration is separated out white crystals, with a small amount of cold absolute ether washing solid.65 ℃ of vacuum dryings get 62.1g nicotinic acid pyritinol salt, yield 89.7%.Determination of acid-basetitration nicotinic acid and pyritinol content are measured moisture with the karl Fischer method.The result is: nicotinic acid 37.2%, and pyritinol 62.0%, water 5.8%, approaching with theoretical value, contain 2 water of crystallization.Elementary analysis: theoretical value C52.8% H5.3% O25.2%N6.6% S10.1%; Measured value C52.4% H5.2% O25.1%N6.5% S10.0%.

Embodiment 2: fumaric acid pyritinol salt synthetic

Get fumaric acid 11.6g, fully be dissolved in the 300ml anhydrous benzene, heated and stirred is to molten entirely, under complete molten state, add pyritinol 40.5g, reflux mixture 3 hours, TLC thin layer identification (developing solvent: ethyl acetate: ethanol: glacial acetic acid=5: 4: 0.8) fully, the cooling back adds the 200ml dehydrated alcohol slightly, mixture is put into refrigerator fully cool off, sucking filtration is separated out white crystals, with a small amount of cold absolute ether washing solid.65 ℃ of vacuum dryings get 49.9g fumaric acid pyritinol salt, yield 88.9%.Determination of acid-basetitration fumaric acid and pyritinol content are measured moisture with the karl Fischer method.The result is: fumaric acid 20.8%, and pyritinol 72.7%, water 6.5%, approaching with theoretical value, contain 2 water of crystallization.Elementary analysis: theoretical value C49.6% H5.0%O26.4% N5.8% S13.2%; Measured value C49.4% H5.2% O26.5% N5.9%S13.1%.

PATENT

https://patents.google.com/patent/CN102516297A/en

Embodiment 1: the preparation of compd A

With Pyrithioxine hydrochloride 10g, be dissolved in the 20ml pyridine, slowly drip POCl3 solution 10ml under the room temperature; Drip and finish, stirring at room reaction 12 hours slowly adds the 100g frozen water and stirred hydrolysis reaction 2 hours; Toluene gradation extraction 30ml * 3, water layer evaporated under reduced pressure, Virahol dissolution residual substance; Filter, evaporate to dryness gets compd A 4.2g.

Embodiment 2: the preparation of compd B

With Pyrithioxine hydrochloride 10g, be dissolved in the 40ml THF, add 4gNaH, 30 ℃ were stirred 2 hours; Add the 20ml POCl3, stirring reaction 16 hours slowly adds the 100g frozen water and stirred hydrolysis reaction 2 hours; ETHYLE ACETATE gradation extraction 30ml * 3, the water layer evaporated under reduced pressure adds 80ml Virahol dissolution residual substance; Add 40ml water, freezing crystallization gets compd B 5.6g.

Embodiment 3: the preparation of Compound C

With Pyrithioxine hydrochloride 10g, be dissolved in the 40ml THF, add 4gNaH, 30 ℃ were stirred 2 hours; Add the 20ml chloroiodomethane, stirring reaction 16 hours, 60 ℃ of evaporated under reduced pressure add 20ml acetonitrile dissolution residual substance; As midbody, other gets triethylamine 9ml and is dissolved in the 10ml acetonitrile, drips 3.6ml phosphoric acid, after dropping finishes; Stir down and slowly splash into midbody, continued 60 ℃ of stirring reactions 12 hours, steaming desolventizes; Residue adds water 20ml dissolving, and water layer filters clarification, and freeze-drying promptly gets compd B 6.7g.

Embodiment 4: the preparation of Compound D

Serine 3 grams, ethylene bromohyrin 2.5g, N with the BOC protection; N-Dimethylamino pyridine 3g and NSC 57182 3g are dissolved in the THF; Stirring at room 10 hours, vacuum concentration is with the thick product of chromatography purification (with the ETHYLE ACETATE/normal hexane wash-out of normal hexane to 30%); Merging filtrate, evaporate to dryness gets intermediate A; Pyrithioxine hydrochloride 2g and intermediate A 2.5g are dissolved with THF 30ml, add triphenyl phosphorus 2g, slowly drip diethyl azodiformate solution 2ml, room temperature reaction 5 hours; Reaction is finished, and evaporated under reduced pressure adds ETHYLE ACETATE 50ml dissolving, filters insolubles; With the thick product of chromatography purification (with the ETHYLE ACETATE/normal hexane wash-out of normal hexane to 10%), merging filtrate, evaporate to dryness dissolves with methylene dichloride 20ml then; Feed hydrogen chloride gas to saturated, stirring reaction 5 hours filters; Get the hydrochloride of Compound D, transferring pH behind the use dissolved in distilled water is about 8, and the water layer lyophilize gets Compound C 0.27g.

Embodiment 5: the preparation of compd E

Get compd A 10g, be dissolved in the 30ml Virahol, add 25gBoc-Ser-OBZL in batches, 50 ℃ of stirring reactions; HPLC monitoring react to compd B less than 5%, add 0.1M hydrochloric acid soln 20ml, 60 ℃ of heating hydrolysis 5 hours are regulated pH to 7; Evaporated under reduced pressure adds anhydrous alcohol solution, removes by filter insolubles, evaporated under reduced pressure; Add the 5ml water dissolution, filtering, lyophilize get compd E 6.9g

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Availability

It is approved for “symptomatic treatment of chronically impaired brain function in dementia syndromes” and for “supportive treatment of sequelae of craniocerebral trauma” in various European countries, including Austria, Germany, France, Italy, Portugal, and Greece. In France it is also approved for rheumatoid arthritis as a disease modifying drug, on the basis of the results of clinical trials. In many countries it is available over the counter and is widely advertised on the internet as being for “memory disturbances.”

Effects

review refs needed

Adverse effects

Adverse effects include nausea, headache,[2] and rarely allergic reaction (mild skin reactions).[3] A 2004 survey of six case reports suggested a link between pyritinol and severe cholestatic hepatitis when on several drugs for certain diseases.[4]

Other rare side effects: acute pancreatitis[5] and photoallergic eruption.[6]

References

  1. ^ Lemmel EM (May 1993). “Comparison of pyritinol and auranofin in the treatment of rheumatoid arthritis. The European Multicentre Study Group”. British Journal of Rheumatology32 (5): 375–82. doi:10.1093/rheumatology/32.5.375PMID 8495257.
  2. ^ Nachbar F, Korting HC, Vogl T (1993). “Erythema multiforme-like eruption in association with severe headache following pyritinol”. Dermatology187 (1): 42–6. doi:10.1159/000247196PMID 8324277.
  3. ^ de Groot, Anton C.; Nater, Johan Pieter; Weyland, J. Willem. Unwanted Effects of Cosmetics and Drugs Used in Dermatology.[full citation needed][page needed]
  4. ^ Maria V, Albuquerque A, Loureiro A, Sousa A, Victorino R (March 2004). “Severe cholestatic hepatitis induced by pyritinol”BMJ328 (7439): 572–4. doi:10.1136/bmj.328.7439.572PMC 381054PMID 15001508.
  5. ^ Straumann A, Bauer M, Pichler WJ, Pirovino M (August 1998). “Acute pancreatitis due to pyritinol: an immune-mediated phenomenon”. Gastroenterology115 (2): 452–4. doi:10.1016/S0016-5085(98)70212-4PMID 9679051.
  6. ^ Tanaka M, Niizeki H, Shimizu S, Miyakawa S (October 1996). “Photoallergic drug eruption due to pyridoxine hydrochloride”. The Journal of Dermatology23 (10): 708–9. doi:10.1111/j.1346-8138.1996.tb02685.xPMID 8973037S2CID 28810619.
  •  Media related to Pyritinol at Wikimedia Commons
Clinical data
ATC codeN06BX02 (WHO)
Pharmacokinetic data
Elimination half-life2.5 hours
Identifiers
showIUPAC name
CAS Number1098-97-1 
PubChem CID14190
ChemSpider13561 
UNIIAK5Q5FZH2R
KEGGD02160 
ChEMBLChEMBL488093 
CompTox Dashboard (EPA)DTXSID3048362 
ECHA InfoCard100.012.864 
Chemical and physical data
FormulaC16H20N2O4S2
Molar mass368.473 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (what is this?)  (verify)

//////////////Pyritinol, пиритинол , بيريتينول , 吡硫醇 , Nootropic,

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