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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

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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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IMIPRIDONE


img
7-Benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-A]pyrido[3,4-E]pyrimidin-5(4H)-one.png
2D chemical structure of 1616632-77-9

IMIPRIDONE

CAS No. : 1616632-77-9

Molecular Weight, 386.4964

Related CAS #: 41276-02-2 (TIC10 isomer)   1616632-77-9 (free base)   1638178-82-1 (HCl)   1777785-71-3 (HBr)   2007141-57-1 (2HBr)

TIC 10, 0NC 201, OP 10

Synonym: ONC201; ONC 201; ONC-201; NSC350625; NSC-350625; NSC 350625; TIC10; TIC 10; TIC-10; TRAIL inducing compound 10; imipridone

7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4H)-one

2,4,6,7,8,9-Hexahydro-4-((2-methylphenyl)methyl)-7-phenylmethyl)imidazo)(1,2-a)pyrido(3,4-e)pyrimidin-5(1H)-one

ONC-201 Dihydrochloride.png

ONC-201 Dihydrochloride

C24H28Cl2N4O

459.4

UNII-53VG71J90J

53VG71J90J

Q27896336

1638178-82-1

Imidazo(1,2-a)pyrido(3,4-E)pyrimidin-5(1H)-one, 2,4,6,7,8,9-hexahydro-4-((2-methylphenyl)methyl)-7-(phenylmethyl)-, hydrochloride (1:2)

  • A TRAIL-dependent antitumor agent.

TIC10 (ONC-201) is a potent, orally active, and stable tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) inducer which acts by inhibiting Akt and ERK, consequently activating Foxo3a and significantly inducing cell surface TRAIL. TIC10 can cross the blood-brain barrier.

ONC-201, also known as TIC10, is a potent, orally active, and stable small molecule that transcriptionally induces TRAIL in a p53-independent manner and crosses the blood-brain barrier. TIC10 induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of TIC10. TIC10 inactivates kinases Akt and extracellular signal-regulated kinase (ERK), leading to the translocation of Foxo3a into the nucleus, where it binds to the TRAIL promoter to up-regulate gene transcription. TIC10 is an efficacious antitumor therapeutic agent that acts on tumor cells and their microenvironment to enhance the concentrations of the endogenous tumor suppressor TRAIL.

Akt/ERK Inhibitor ONC201 is a water soluble, orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B) and extracellular signal-regulated kinase (ERK), with potential antineoplastic activity. Upon administration, Akt/ERK inhibitor ONC201 binds to and inhibits the activity of Akt and ERK, which may result in inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathway as well as the mitogen-activated protein kinase (MAPK)/ERK-mediated pathway. This may lead to the induction of tumor cell apoptosis mediated by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/TRAIL death receptor type 5 (DR5) signaling in AKT/ERK-overexpressing tumor cells. The PI3K/Akt signaling pathway and MAPK/ERK pathway are upregulated in a variety of tumor cell types and play a key role in tumor cell proliferation, differentiation and survival by inhibiting apoptosis. In addition, ONC201 is able to cross the blood-brain barrier.

STR1

SYN

Organic & Biomolecular Chemistry, 19(39), 8497-8501; 2021

Herein, we present a copper-catalyzed tandem reaction of 2-aminoimidazolines and ortho-halo(hetero)aryl carboxylic acids that causes the regioselective formation of angularly fused tricyclic 1,2-dihydroimidazo[1,2-a]quinazolin-5(4H)-one derivatives. The reaction involved in the construction of the core six-membered pyrimidone moiety proceeded via regioselective N-arylation–condensation. The presented protocol been successfully applied to accomplish the total synthesis of TIC10/ONC201, which is an active angular isomer acting as a tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL): a sought after anticancer clinical agent.

Graphical abstract: Tandem copper catalyzed regioselective N-arylation–amidation: synthesis of angularly fused dihydroimidazoquinazolinones and the anticancer agent TIC10/ONC201

7-Benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4H)-one (6): Pale orange semi-solid, 202 mg (0.521 mmol), 52 % Rf = 0.25 (CH3OH/CHCl3 5:95); IR 1490, 1610, 1644, 2882, 2922 cm-1 ; 1H-NMR (500 MHz, CDCl3) δ = 2.39 (s, 3H), 2.54 (t, J = 5.5 Hz, 2H), 2.72 (t, J = 5.7 Hz, 2H), 3.31 (s, 2H), 3.67 (s, 2H), 3.84-3.91 (m, 4H), 5.04 (s, 2H), 7.02-7.04 (m, 1H), 7.08-7.12 (m, 3H), 7.26- 7.34 (m, 5H). 13C{1H}-NMR (101 MHz, CDCl3) δ = 19.3, 26.8, 43.4, 46.9, 48.2, 49.6, 50.45, 62.3, 102.1, 125.2, 125.9, 126.8, 127.4, 128.45, 129.2, 130.2, 134.2, 135.6, 137.9, 145.7, 153.3, 161.4; MS (ESI, m/z): [M+H]+ 387; HRMS (ESI, m/z): calcd for C24H27N4O [M+H]+ found 387.2183.

PATENT

https://patents.google.com/patent/WO2017132661A2/en

Scheme 1.

Figure imgf000028_0002
Figure imgf000028_0003

Scheme 2.

Figure imgf000029_0001
Figure imgf000029_0002
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CLIP

https://mdanderson.elsevierpure.com/en/publications/discovery-and-clinical-introduction-of-first-in-class-imipridone-Discovery and clinical introduction of first-in-class imipridone ONC201

Abstract

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.

////////////IMIPRIDONE, TIC 10, ONC 201, NSC 350625, OP 10, Fast Track Designation, Orphan Drug Designation, Rare Pediatric Disease Designation, PHASE 3, GLIOMA, CHIMERIX

O=C1N(CC2=CC=CC=C2C)C3=NCCN3C4=C1CN(CC5=CC=CC=C5)CC4

Tirzepatide


YXEGTFTSDY SIXLDKIAQK AFVQWLIAGG PSSGAPPPS

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

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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

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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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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

CLIP

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

CLOSANTEL


Closantel.png
FIGURE 1

CLOSANTEL

Closantel

57808-65-8

N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodobenzamide

MW 663.1,

C22H14Cl2I2N2O2
Closantel Sodium

Closantel Sodium

CAS NO. 61438-64-0

FORMULAC22H13Cl2I2N2O2.Na
M. WT685.06

Closantel

CAS Registry Number: 57808-65-8

CAS Name:N-[5-Chloro-4-[(4-chlorophenyl)cyanomethyl]-2-methylphenyl]-2-hydroxy-3,5-diiodobenzamide

Manufacturers’ Codes: R-31520

Trademarks: Flukiver (Janssen); Seponver (Ethnor)

Molecular Formula: C22H14Cl2I2N2O2, Molecular Weight: 663.07

Percent Composition: C 39.85%, H 2.13%, Cl 10.69%, I 38.28%, N 4.22%, O 4.83%

Literature References: Salicylanilide derivative. Prepn: M. A. C. Janssen, V. K. Sipido, BE839481eidem,US4005218 (1976, 1977 both to Janssen). Effectiveness against Taenia pisiformis in rabbits: R. A. F. Chevis et al.,Vet. Parasitol.7, 333 (1980); against Ancylostoma caninum: J. Guerrero et al.,J. Parasitol.68, 616 (1983); against Fasciola hepatica in sheep: B. E. Stromberg et al.,ibid.70, 446 (1984). Prolonged effect on Haemonchus contortus in sheep: C. A. Hall et al.,Res. Vet. Sci.31, 104 (1981). Acts by uncoupling oxidative phosphorylation: H. Van den Bossche et al.,Arch. Int. Physiol. Biochim.87, 851 (1979); H. J. Kane et al.,Mol. Biochem. Parasitol.1, 347 (1980).

Properties: Crystals from methanol, mp 217.8°.

Melting point: mp 217.8°

Therap-Cat-Vet: Anthelmintic.

N-{5-chloro-4-[(4-chlorophenyl)(cyano)methyl]-2-methylphenyl}-2-hydroxy-3,5-diiodobenzamide is an aromatic amide resulting from the formal condensation of the carboxy group of 3,5-diiodosalicylic acid with the amino group of aniline substituted at positions 2, 4, and 5 by methyl, (4-chlorophenyl)(cyano)methyl, and methyl groups respectively. It is a nitrile, a member of phenols, an organoiodine compound, a monocarboxylic acid amide, an aromatic amide and a member of monochlorobenzenes.

Closantel is a broad-spectrum antiparasitic agent used against
    several species and developmental stages of trematodes, nematodes and
    arthropods.  The anti-trematode activity of closantel is mainly used
    against liver fluke.  The anti-nematode and anti-arthropod activity is
    especially used against those species which feed on blood or plasma. 

         The drug is widely used in sheep and cattle and can be used
    either parenterally (s.c. or i.m.) or orally for both prophylactic and
    therapeutic purposes and is available as drench, bolus and injectable
    formulations.  Closantel has also been combined with mebendazole and
    several other benzimidazoles in drench formulations for sheep and with
    levamisole in a bolus for cattle (Marsboom et al., 1989). 
    Closantel has not been evaluated previously by the Joint FAO/WHO
    Expert Committee on Food Additives.

PATENT

https://patents.google.com/patent/CN102180811B/en

Closantel sodium (Closantel Sodium) is a kind of very strong oxidative phosphorylation uncoupler, can suppress the mitochondrial phosphorylation process of polypide, nematode and insect etc. are contacted with blood circulation closely or sucking blood property worm all has and efficiently kills effect, be a kind of broad-spectrum de-worming medicine of efficient, low toxicity, it is huge on market a very large development potentiality.

And 4-chloro-phenyl–(the chloro-4-amino of 2–5-aminomethyl phenyl) cyano group methane is a kind of key intermediate for the synthesis of closantel sodium.But in prior art, the report of the synthetic method of relevant 4-chloro-phenyl–(the chloro-4-amino of 2–5-aminomethyl phenyl) cyano group methane is actually rare, is mainly the iron powder reducing synthetic method.As United States Patent (USP) (US4005218) relates to a kind of with the chloro-α of 4–[the chloro-4-of 2-(hydroxyl imido grpup)-5-methyl-2, the 5-phenylidene] benzyl cyanide (I) is raw material, with excessive iron powder, in ammonium chloride, water and toluene mixing solutions, heating reflux reaction, filter, clean filter cake with a large amount of solvents as tetrahydrofuran (THF) or 4-methyl-2 pentanone, filtrate boils off solvent, then adds the toluene recrystallization to obtain 4-chloro-phenyl–(the chloro-4-amino of 2–5-aminomethyl phenyl) cyano group methane (II).This reaction equation is:

But it is loaded down with trivial details that the shortcoming of the method is operating procedure, the supplementary material consumption is large, and, with producing a large amount of scrap iron powder after iron powder reducing, comparatively thickness, easily comprise product and impurity, and cost recovery is very high, and labour intensity is large, larger to the pollution effect of environment; And product yield and product quality lower.

//////////

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PATENTS

CN103054846

WO2015048718

US2015164934

WO2016038035

CN105687172

WO2018013890

WO2018210449

WO2019222349

CN111150725

CN112294793

///////CLOSANTEL, veterinary

CC1=CC(=C(C=C1NC(=O)C2=C(C(=CC(=C2)I)I)O)Cl)C(C#N)C3=CC=C(C=C3)Cl

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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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SIBUTRAMINE


Sibutramine.svg

SIBUTRAMINE

  • Molecular FormulaC17H26ClN
  • Average mass279.848 Da

1-(4-Chlorophenyl)-N,N-dimethyl-a-(2-methylpropyl)cyclobutane methanamine

1-[1-(4-Chlorophenyl)cyclobutyl]-N,N,3-trimethyl-1-butanamine

106650-56-0[RN]

106650-56-0 (Sibutramine );

125494-59-9 (Sibutramine HCl Monohydrate);

84485-00-7 (Sibutramine HCl);

6124

UNII:WV5EC51866, WV5EC51866

сибутрамин[Russian]

سيبوترامين[Arabic]

西布曲明[Chinese]

Drug Name:Sibutramine Hydrochloride Hydrate

Research Code:BTS-54524

Trade Name:Meridia®

MOA:Serotonin-norepinephrine reuptake inhibitor

Indication:Obesity

Status:Withdrawn

Company:Abbott (Originator)

Sibutramine hydrochloride monohydrate, KES-524, BTS-54524, Meridia, Reductil

Sibutramine, formerly sold under the brand name Meridia among others, is an appetite suppressant which has been discontinued in many countries. Until 2010, it was widely marketed and prescribed as an adjunct in the treatment of obesity along with diet and exercise. It has been associated with increased cardiovascular events and strokes and has been withdrawn from the market in several countries and regions including Australia,[1] Canada,[2] China,[3] the European Union,[4] Hong Kong,[5] India,[6] MexicoNew Zealand,[7] the Philippines,[8] Thailand,[9] the United Kingdom,[10] and the United States.[11] However, the drug remains available in some countries.[12]

Sibutramine was originally developed in 1988 by Boots in Nottingham, UK,[13] and marketed by Knoll Pharmaceuticals after BASF/Knoll AG purchased the Boots Research Division in 1995, and was most recently manufactured and marketed by Abbott Laboratories before its withdrawal from most markets. It has been sold under a variety of brand names including Reductil, Meridia, Siredia, and Sibutrex. It is classified as a Schedule IV controlled substance in the United States.

Sibutramine hydrochloride hydrate was approved by the U.S. Food and Drug Administration (FDA) on Nov 16, 1997. It was developed and marketed as Meridia® by Abbott in the US.

Sibutramine hydrochloride hydrate is a serotonin-norepinephrine reuptake inhibitor, it produces its therapeutic effects by norepinephrine, serotonin and dopamine reuptake inhibition. Meridia® is indicated for the management of obesity, including weight loss and maintenance of weight loss, and should be used in conjunction with a reduced calorie diet.

Meridia® is available as capsule for oral use, containing 5, 10 or 15 mg of Sibutramine hydrochloride hydrate. The recommended dose is initiated at 10 mg once daily with or without food and may increase to 15 mg once daily.

Sibutramine has been withdrawn from the market in several countries and regions since 2010, owning to its side effect that associated with increased cardiovascular events and strokes.Route 1

Reference:1. US4746680A / US4806570A.

2. US4929629A.

SYN

File:Sibutramin synthesis.PNG

SYN

File:Sibutramine Synthesis.png

SYN

PAT

https://patents.google.com/patent/KR20060019351A/en

Sibutramine hydrochloride (Sibutramine HCl: C 17 H 26 CIN HCl) is a chemical name {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -dimethylamine hydrochloride, and has the structure of Formula 1 .

Figure 112004038703885-PAT00001

Sibutramine was originally developed as a drug for the treatment of depression and was found to give weight to patients taking this drug. It was developed as an anti-obesity drug. Let your appetite decrease.

Korean Patent Publication No. 1990-274 (corresponding patent DE3212682 (Boots), filed Oct. 21, 1982; priority GB 1981.4.6.) For the preparation of 1- (1-arylcyclobutyl) alkylamine derivative comprising sibutramine It is described. The method for synthesizing sibutramine described in this document proceeds in a total of five steps as follows.

Step A

Figure 112004038703885-PAT00002

1- (4-chlorophenyl) -1-cyclobutyl cyanide is obtained from 4-Chlorobenzyl cyanide. Examples of the actual synthesis method described in this document are as follows.

After dissolving 25 g of 4-chlorobenzyl cyanide and 15 ml of 1,3-dibromopropane in 150 ml of DMSO, the solution was dissolved in nitrogen at room temperature (20-35 ° C.) and 7.5 g of NaH dispersed in mineral oil. And 200 ml of DMSO was added dropwise. The mixture was stirred at room temperature for 2 hours, 8 ml of IPA was added dropwise, and 110 ml of water was added dropwise. The mixture is filtered through CELITE ™ and the solid residue is washed with ether. The ether layer is separated, washed with water, dried, evaporated and vacuum distilled at high temperature to separate the desired 1- (4-chlorophenyl) -1-cyclobutyl cyanide. The total reaction time of this step is 5 hours and the yield from the starting material is 78%.

Step B

Figure 112004038703885-PAT00003

1- [1- (4-chlorophenyl) -cyanobutyl] -3-methyl-butan-1-one is obtained from 1- (4-chlorophenyl) -1-cyclobutyl cyanide. Specific synthesis examples are as follows. 35.2 g of 1- (4-chlorophenyl) -1-cyclobutyl cyanide are dissolved in 100 ml of ether and this solution is added to the product prepared by the reaction of 32 g of propylbromide and 6.36 g of magnesium. The ether is replaced with toluene and the mixture is heated under reflux for 1 hour. After adding water, concentrated hydrochloric acid is added, and the mixture is heated under reflux for 1 hour. The mixture obtained in the same manner as in the previous step was treated with ether, water, dried and evaporated and then vacuum distilled to give the desired 1- [1- (4-chlorophenyl) -cyanobutyl] -3-methyl-butan-1-one. To separate. The reaction time of this step is a total of 22 hours, the yield is 81%. The target product is bp 100-120 ° C / 0.2 mm / Hg.

Step C

Figure 112004038703885-PAT00004

N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl from 1- [1- (4-chlorophenyl) -cyanobutyl] -3-methyl-butan-1-one } Formamide is obtained. Specific synthesis examples are as follows. To 23.5 ml of formamide, 37 g (0.14 mol) of 1- [1- (4-chlorophenyl) -cyanobutyl] -3-methyl-butan-1-one and 9 ml of HCOOH were added dropwise at 160-170 ° C. The temperature is maintained at 175 ° C. to 180 ° C. for 24 hours. The mixture is extracted with ether and concentrated to afford an oil, which crystallizes the desired N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} formamide from petroleum ether. The reaction time of this step is a total of 24 hours, the yield is 39%. The target is mp 110-112 ° C.

Step D

Figure 112004038703885-PAT00005

1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride from N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} formamide Get Specific synthesis examples are as follows. 4 g of N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} formamide, 25 ml of 2-methoxyethyl ether, 10 ml of water and 22 ml of concentrated hydrochloric acid were refluxed for 18 hours. Stir under. Dilute with water, wash with ether, and add 35 ml of 5M aqueous NaOH solution. After completion of the process by treatment with ether, water and brine, treated with magnesium sulfate, filtered and concentrated. The concentrated crude product is saturated with hydrochloric acid dissolved in 20 ml of ether. The resulting solid is filtered, concentrated and crystallized with petroleum ether to give the desired product 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride. The reaction time of this step is a total of 20 hours, the yield is 96% oil, 46% hydrochloride. The target product is mp 163-165 ° C.

Step E

Figure 112004038703885-PAT00006

The final target from 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -dimethyl Amine hydrochloride, ie sibutramine hydrochloride, is obtained. Specific synthesis examples are as follows. 3.3 g of 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride, 2.99 g of HCOOH and 1 ml of water are mixed while cooling. 3.93 ml of 37% aqueous formaldehyde is added and heated at 85-95 ° C. for 18 hours. Excess hydrochloric acid is added and the solution is evaporated to dryness. 5N NaOH solution is added, extracted with ether and concentrated to give a pale yellow oil. This oil is dissolved in a mixture of 4 mL IPA, 20 mL ether and 2 mL hydrochloric acid is added dropwise. Concentrate, repeatedly dissolve in ethanol and concentrate again. Polishing with petroleum ether gives a yellow solid and recrystallizes with acetone to give the final target sibutramine hydrochloride. The reaction time of this step is a total of 18 hours, the yield is 80%. The target product is mp 195-197 ° C. The yield in 5 steps (A to E) is 18.9%.

As described above, the conventional sibutramine synthesis method has a total of five steps, which is complicated and takes a long time, and requires high temperature vacuum distillation (step A). Since the reaction proceeds at the high temperature of the raw material there was a problem that the yield is reduced. In fact, the synthesis was performed by applying the conventional sibutramine synthesis method, the total yield was very low as 18.9%.

First step

4-Chlorobenzyl cyanide is reacted with 1,3-dibromopropane to give 1- (4-chlorophenyl) -1-cyclobutyl cyanide.

Figure 112004038703885-PAT00007

In a flask at room temperature (20-35 ° C.), 14.1 g (352 mmol) of NaH dispersed in mineral oil (200%) and 200 ml of DMSO were added. 25 g (160 mmol) of 4-chlorobenzyl cyanide and 1,3- A solution of 36 g (176 mmol) of dibromopropane dissolved in 200 ml of DMSO was added dropwise. The mixture is stirred at room temperature for 2 hours, 10 ml of IPA is added dropwise and 200 ml of water is added dropwise. The mixture is filtered through a CELITE ™ filter and the solid residue is washed with ether. The ether layer is separated, washed with water, filtered, concentrated and dried to give 34.72 g of crude product of 1- (4-chlorophenyl) -1-cyclobutyl cyanide. The yield of crude product is 109.8%.

2nd step

1- (4-chlorophenyl) -1-cyclobutyl cyanide isobutyl magnesium bromide is reacted to obtain 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine.

Figure 112004038703885-PAT00008

10 g (52 mmol) of 1- (4-chlorophenyl) -1-cyclobutyl cyanide was dissolved in 25 ml of toluene at room temperature, followed by addition of a 2.0 M solution of isobutyl magnesium bromide dissolved in 40 ml of diethyl ether. The mixture is heated at reflux at a temperature of at least 105 ° C. for 2 hours. After completion of the reaction at 0 ° C. with methanol, 2.4 g of NaBH 4 was added to the mixture at 0-25 ° C. and stirred for 1 hour or more. Concentrate, treat with ether, water, concentrate again, and vacuum dry. The yield of crude product is 91.6%.

3rd step

The amine group of 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine was dimethylated to obtain {1- [1- (4-chlorophenyl) -cyclobutyl]-which is the final object of the present invention. 3-methylbutyl} -dimethylamine hydrochloride, ie sibutramine hydrochloride, is obtained.

Figure 112004038703885-PAT00009

5.02 g of 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine and 10 ml of HCOOH are mixed with cooling. 6 ml of 37% aqueous formaldehyde is added and heated at 85-95 ° C. for 18 hours. Excess 2M HCl is added and the solution is evaporated to dryness. 5N NaOH solution is added, extracted with ether and concentrated to give a pale yellow oil. After dissolving in a small amount of ether, ether saturated with HCl gas is slowly added dropwise at 0 ° C. The solid obtained was filtered and dried in vacuo to give 5.12 g of sibutramine hydrochloride as the final target. Yield of the product is 92%, mp 193.5-194.8 ° C. The total yield of the first to third stages is 52.7%. The H 1 NMR results of the final product are as follows: H 1 NMR (CDCl 3 ) 1.058 (6H, dd), 1.400 (2H, m), 1.508 (2H, m), 2.193 (3H, d), 2.316 (2H , m), 2.784 (2H, m), 2.910 (3H, d), 2.967 (1H, m), 3.568 (1H, m), 7.386 (2H, d), 7.638 (2H, d), 10.771 (1H, s)

The present invention is to shorten the process that was conventionally carried out in five steps to three steps to greatly shorten the process as well as to eliminate the difficult and time-consuming high-temperature vacuum distillation process to enable mass production In addition, it is possible to greatly reduce production time and production costs by improving the process step by step, and to reduce the production cost by showing a yield improvement effect nearly three times that of the conventional synthesis method in terms of overall yield.

Claims (3)

Hide Dependent

  1. In the method for synthesizing {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -dimethylamine from 4-chlorobenzyl cyanide,(a) reacting 4-chlorobenzyl cyanide with 1,3-dibromopropane to obtain 1- (4-chlorophenyl) -1-cyclobutyl cyanide;(b) To isobutyl magnesium bromide dissolved in diethyl ether is added to 1- (4-chlorophenyl) -1-cyclobutyl cyanide dissolved in toluene, and the mixture is refluxed at a temperature of 105 ° C. or higher at 1-3 ° C. Heating and cooling for a period of time, followed by addition of NaBH 4 at 0-25 ° C., followed by stirring for at least 1 hour to obtain 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine;(c) Dimethylating the amine group of 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine to yield {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methyl Improved synthesis method of sibutramine consisting of a three-step reaction comprising the step of obtaining butyl} -dimethylamine.
  2. The method according to claim 1,In step (a), the solution of 4-chlorobenzyl cyanide and 1,3-dibromopropane dissolved in DMSO is added dropwise to the mixture of NaH and DMSO dispersed in mineral oil, followed by filtration. , Washing, concentrating and drying to obtain a crude product of 1- (4-chlorophenyl) -1-cyclobutyl cyanide, and proceeding to the next step (b) as it is without distillation at high temperature. Improved Synthesis of Sibutramine.
  3. The method according to claim 1,In step (c), 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine is mixed with formaldehyde in a free base state, and 37% aqueous formaldehyde is added thereto, and 85 An improved method for synthesizing sibutramine, characterized in that sibutramine hydrochloride is obtained by heating at -95 ° C for 15-22 hours followed by addition of hydrochloric acid.

 SYN

DE 3212682; GB 2098602; US 4806570

4-Chlorobenzyl cyanide (I) is cycloalkylated with 1,3-dibromopropane to yield 1-(4-chlorophenyl)cyclobutyl cyanide (II). The cyclobutyl cyanide (II) is treated with 2-methylpropyl magnesium bromide te give the imine salt (III), which may be either hydrolyzed to the ketone (IV), which is then formylaminated with formamide and formic acid and subsequently hydrolyzed, or reduced with sodium borohydride in ethanol to give 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (V). Eschweiler-Clarke methylation and hydrochloride formation yield N-[1-[1-(4-chlorophenyl)cyclo butyl]-3-methylbutyl]-N,N-dimethylamine hydrochloride monohydrate

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Medical uses

Sibutramine has been used to produce appetite suppression for the purpose of attaining weight loss in the treatment of patients with obesity.

Contraindications

Sibutramine is contraindicated in patients with:

Side effects

A higher number of cardiovascular events has been observed in people taking sibutramine versus control (11.4% vs. 10.0%).[15] In 2010 the FDA noted the concerns that sibutramine increases the risk of heart attacks and strokes in patients with a history of cardiovascular disease.[15]

Frequently encountered side effects are: dry mouth, paradoxically increased appetite, nauseastrange taste in the mouth, upset stomach, constipation, trouble sleeping, dizziness, drowsiness, menstrual cramps/pain, headache, flushing, or joint/muscle pain.

In a 2016 Cochrane review sibutramine was found to substantially increase blood pressure and heart rate in some patients, in the updated review in 2021 sibutramine was not included since the drug had been withdrawn from the market.[16] When used, regular blood pressure monitoring needed to be performed.

The following side effects are infrequent but serious and require immediate medical attention: cardiac arrhythmiasparesthesia, mental/mood changes (e.g., excitement, restlessness, confusion, depression, rare thoughts of suicide).

Symptoms that require urgent medical attention are seizures, problems urinating, abnormal bruising or bleeding, melenahematemesisjaundicefever and rigorschest painhemiplegia, abnormal vision, dyspnea and edema.

Currently, no case of pulmonary hypertension has been noted. (Fenfluramine, of the 1990s “Fen-Phen” combo, forced excess release of neurotransmitters—a different action. Phentermine was uninvolved in the rare—but clinically significant—heart issues of fenfluramine.)

Interactions

Sibutramine has a number of clinically significant interactions. The concomitant use of sibutramine and monoamine oxidase inhibitors (MAOIs, such as selegiline) is not indicated, as it may increase the risk of serotonin syndrome, a somewhat rare but serious adverse drug reaction.[17] Sibutramine should not be taken within two weeks of stopping or starting an MAOI. Taking both sibutramine and certain medications used in the treatment of migraines—such as ergolines and triptans—as well as opioids, may also increase the risk for serotonin syndrome, as may the use of more than one serotonin reuptake inhibitor at the same time.[17]

The concomitant use of sibutramine and drugs which inhibit CYP3A4, such as ketoconazole and erythromycin, may increase plasma levels of sibutramine.[18] Sibutramine does not affect the efficacy of hormonal contraception.[17]

Pharmacology

Pharmacodynamics

CompoundSERTNETDAT
Sibutramine298–2,800350–5,451943–1,200
Desmethylsibutramine152049
  (R)-Desmethylsibutramine44412
  (S)-Desmethylsibutramine9,200870180
Didesmethylsibutramine201545
  (R)-Didesmethylsibutramine140138.9
  (S)-Didesmethylsibutramine4,3006212
Values are Ki (nM).

Sibutramine is a serotonin–norepinephrine reuptake inhibitor (SNRI) that, in humans, reduces the reuptake of norepinephrine (by ~73%), serotonin (by ~54%), and dopamine (by ~16%),[21] thereby increasing the levels of these substances in synaptic clefts and helping enhance satiety; the serotonergic action, in particular, is thought to influence appetite. Older anorectic agents such as amphetamine and fenfluramine force the release of these neurotransmitters rather than affecting their reuptake.[22]

Despite having a mechanism of action similar to tricyclic antidepressants, sibutramine has failed to demonstrate antidepressant properties in animal studies. It was approved by the U.S. Food and Drug Administration (FDA) in November 1997[23] for the treatment of obesity.

Sibutramine is reported to be a prodrug to two active metabolitesdesmethylsibutramine (M1; BTS-54354) and didesmethylsibutramine (M2; BTS-54505), with much greater potency as MRIs.[24][25]

Unlike other serotonergic appetite suppressants like fenfluramine, sibutramine and its metabolites have only low and likely inconsequential affinity for the 5-HT2B receptor.[21]

Pharmacokinetics

Sibutramine is well absorbed from the gastrointestinal tract (77%), but undergoes considerable first-pass metabolism, reducing its bioavailability. The drug itself reaches its peak plasma level after 1 hour and has also a half-life of 1 hour. Sibutramine is metabolized by cytochrome P450 isozyme CYP3A4 into two pharmacologically-active primary and secondary amines (called active metabolites 1 and 2) with half-lives of 14 and 16 hours, respectively. Peak plasma concentrations of active metabolites 1 and 2 are reached after three to four hours. The following metabolic pathway mainly results in two inactive conjugated and hydroxylated metabolites (called metabolites 5 and 6). Metabolites 5 and 6 are mainly excreted in the urine.

Chemistry

Sibutramine has usually been used in the form of the hydrochloride monohydrate salt.

Detection in body fluids

Sibutramine and its two active N-demethylated metabolites may be measured in biofluids by liquid chromatographymass spectrometry. Plasma levels of these three species are usually in the 1–10 μg/L range in persons undergoing therapy with the drug. The parent compound and norsibutramine are often not detectable in urine, but dinorsibutramine is generally present at concentrations of >200 μg/L.[26][27][28]

Society and culture

Regulatory approval

Studies are ongoing into reports of sudden death, heart failurerenal failure and gastrointestinal problems. Despite a 2002 petition by Ralph Nader-founded NGO Public Citizen,[29] the FDA made no attempts to withdraw the drug, but was part of a Senate hearing in 2005.[30] Similarly, David Graham, FDA “whistleblower”, testified before a Senate Finance Committee hearing that sibutramine may be more dangerous than the conditions it is used for.[31]

Between January 2003 and November 2005, a large randomized-controlled “Sibutramine Cardiovascular OUTcomes” (SCOUT) study with 10,742 patients examined whether or not sibutramine administered within a weight management program reduces the risk for cardiovascular complications in people at high risk for heart disease and concluded that use of silbutramine had a RR 1.16 for the primary outcome (composit of nonfatal MI, nonfatal CVA, cardiac arrest, and CV death).[32]

In a dissenting article, “Sibutramine: gone, but not forgotten”, David Haslam (chairman of the National Obesity Forum) says that the SCOUT study is flawed as it only covered high-risk patients and did not consider obese patients who do not have cardiovascular complications or similar contraindications [33]

On January 21, 2010, the European Medicines Agency recommended suspension of marketing authorizations for sibutramine based on the SCOUT study results.[34]

In August 2010 the FDA added a new contraindication for patients over 65 years of age due to the fact that clinical studies of sibutramine did not include sufficient numbers of such patients.[14]

Abbott Laboratories announced on October 8, 2010 that it is withdrawing sibutramine from the US market under pressure from the FDA, citing concerns over minimal efficacy coupled with increased risk of adverse cardiovascular events.[35]

Counterfeit weight-loss products

On December 22, 2008, the United States Food and Drug Administration issued an alert to consumers naming 27 different products marketed as “dietary supplements” for weight loss, that illegally contain undisclosed amounts of sibutramine.[36][37] In March 2009, Dieter Müller et al. published a study of sibutramine poisoning cases from similar Chinese “herbal supplements” sold in Europe, containing as much as twice the dosage of the legally licensed drug.[38]

An additional 34 products were recalled by the FDA on April 22, 2009, further underscoring the risks associated with unregulated “herbal supplements” to unsuspecting persons. This concern is especially relevant to those with underlying medical conditions incompatible with undeclared pharmaceutical adulterants.[39] In January 2010, a similar alert was issued for counterfeit versions of the over-the-counter weight loss drug Alli sold over the Internet. Instead of the active ingredient orlistat, the counterfeit drugs contain sibutramine, and at concentrations at least twice the amount recommended for weight loss.[40]

In March 2010 Health Canada advised the public that illegal “Herbal Diet Natural” had been found on the market, containing sibutramine, which is a prescription drug in Canada, without listing sibutramine as an ingredient.[41] In October 2010 FDA notified consumers that “Slimming Beauty Bitter Orange Slimming Capsules contain the active pharmaceutical ingredient sibutramine, a prescription-only drug which is a stimulant. Sibutramine is not listed on the product label.”[42]

In October 2010 the MHRA in the UK issued a warning regarding “Payouji tea” and “Pai You Guo Slim Capsules” which were found to contain undeclared quantities of sibutramine.[43]

On December 30, 2010 the FDA released a warning regarding “Fruta Planta” dietary products, which were found to contain undeclared amounts of sibutramine. The recall stated that “there is NO SAFE formula on the US market and that all versions of Fruta Planta contain sibutramine. All versions of the formula are UNSAFE and should not be purchased from any source.”[44]

Some illegal weight loss products imported into Ireland have been found to contain sibutramine.[45][46] Similar concerns have been raised in Australia, where illegal imported supplements have been found to contain sibutramine, resulting in public alerts from Australia’s Therapeutic Goods Administration.[47]

In October 2011, the FDA warned that 20 brands of dietary supplements were tainted with sibutramine.[48] In a 2018 study FDA has found synthetic additives including sibutramine in over 700 diet supplements marketed as “natural”, “traditional” or “herbal remedies”.[49]

References

  1. ^ “Sibutramine (Reductil) – withdrawal in Australia”Therapeutic Goods Administration (Tga). Therapeutic Goods Administration, Department of Health, Australian Government. 2010. Retrieved 2014-10-06.
  2. ^ Health Canada Endorsed Important Safety Information on MERIDIA (Sibutramine Hydrochloride Monohydrate): Subject: Voluntary withdrawal of Meridia (sibutramine) capsules from the Canadian market.
  3. ^ “Notification of Termination of Production, Sale, and Usage of Sibutramine Preparations and Their Active Pharmaceutical Ingredient”. sda.gov in People’s Republic of China. October 30, 2010. Retrieved 2011-05-21.
  4. ^ (in German) Sibutramin-Vertrieb in der Europäischen Union ausgesetzt [1]Abbott Laboratories in Germany. Press Release 2010-01-21. Retrieved 2010-01-27
  5. ^ “De-registration of pharmaceutical products containing sibutramine” (Press release). info.gov in Hong Kong. November 2, 2010. Retrieved 2010-11-08.
  6. ^ “Banned Medicines” (Press release). Ministry of Health and Family Welfare. February 10, 2011. Retrieved 2011-03-15.
  7. ^ “Withdrawal of Sibutramine (Reductil) in New Zealand” (Press release). MedSafe in New Zealand. October 11, 2010. Retrieved 2012-11-06.
  8. ^ “FDA warns online sellers of banned slimming pills”. January 12, 2014. Retrieved February 20, 2014.
  9. ^ “Thai FDA reveals voluntary withdrawal of sibutramine from the Thai market” (PDF) (Press release). Food and Drug Administration of Thailand. October 20, 2010. Retrieved 2010-12-22.
  10. ^ “Top obesity drug sibutramine being suspended”BBC News. 2010-01-22. Retrieved 2010-01-22.
  11. ^ Rockoff JD, Dooren JC (October 8, 2010). “Abbott Pulls Diet Drug Meridia Off US Shelves”The Wall Street Journal. Retrieved 8 October 2010.
  12. ^ “Sibutramine – Drugs.com”drugs.com.
  13. ^ Buckett WR, Thomas PC, Luscombe GP (1988). “The pharmacology of sibutramine hydrochloride (BTS 54 524), a new antidepressant which induces rapid noradrenergic down-regulation”. Progress in Neuro-Psychopharmacology & Biological Psychiatry12 (5): 575–84. doi:10.1016/0278-5846(88)90003-6PMID 2851857S2CID 24787523.
  14. Jump up to:a b c “The FDA August 2010 drug safety update”fda.gov.
  15. Jump up to:a b “Early Communication about an Ongoing Safety Review of Meridia (sibutramine hydrochloride)”. United States Food and Drug Administration. 1 February 2010. Archived from the original on 6 January 2012.
  16. ^ Siebenhofer, Andrea; Winterholer, Sebastian; Jeitler, Klaus; Horvath, Karl; Berghold, Andrea; Krenn, Cornelia; Semlitsch, Thomas (2021-01-17). “Long-term effects of weight-reducing drugs in people with hypertension”The Cochrane Database of Systematic Reviews1: CD007654. doi:10.1002/14651858.CD007654.pub5ISSN 1469-493XPMC 8094237PMID 33454957.
  17. Jump up to:a b c “Meridia Side Effects, and Drug Interactions”. RxList.com. 2007. Retrieved 2007-04-29.
  18. ^ (in Portuguese) Cloridrato de sibutramina monoidratado. Bula. [Sibutramine hydrochloride monohydrate—label information]. Medley (2007).
  19. ^ Nisoli E, Carruba MO (October 2000). “An assessment of the safety and efficacy of sibutramine, an anti-obesity drug with a novel mechanism of action”. Obesity Reviews1 (2): 127–39. doi:10.1046/j.1467-789x.2000.00020.xPMID 12119986S2CID 20553857.
  20. ^ Rothman RB, Baumann MH (May 2009). “Serotonergic drugs and valvular heart disease”Expert Opinion on Drug Safety8 (3): 317–29. doi:10.1517/14740330902931524PMC 2695569PMID 19505264.
  21. Jump up to:a b “Meridia (sibutramine hydrochloride monohydrate) Capsules CIV. Full Prescribing Information” (PDF). Abbott Laboratories, North Chicago, IL 60064, U.S.A. Retrieved 6 February 2016.
  22. ^ Heal DJ, Aspley S, Prow MR, Jackson HC, Martin KF, Cheetham SC (August 1998). “Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine”. International Journal of Obesity and Related Metabolic Disorders. 22 Suppl 1: S18–28, discussion S29. PMID 9758240.
  23. ^ “FDA APPROVES SIBUTRAMINE TO TREAT OBESITY” (Press release). U.S. Food and Drug Administration. November 24, 1997. Retrieved 2007-04-29.
  24. ^ Kim KA, Song WK, Park JY (November 2009). “Association of CYP2B6, CYP3A5, and CYP2C19 genetic polymorphisms with sibutramine pharmacokinetics in healthy Korean subjects”. Clinical Pharmacology and Therapeutics86 (5): 511–8. doi:10.1038/clpt.2009.145PMID 19693007S2CID 24789264.
  25. ^ Hofbauer K (2004). Pharmacotherapy of obesity : options and alternatives. Boca Raton, Fla: CRC Press. ISBN 978-0-415-30321-7.
  26. ^ Jain DS, Subbaiah G, Sanyal M, et al. Liquid chromatography/electrospray ionization tandem mass spectrometry validated method for the simultaneous quantification of sibutramine and its primary and secondary amine metabolites in human plasma and its application to a bioequivalence study. Rapid Comm. Mass Spec. 20: 3509-3521, 2006.
  27. ^ Thevis M, Sigmund G, Schiffer AK, Schänzer W. Determination of N-desmethyl- and N-bisdesmethyl metabolites of Sibutramine in doping control analysis using liquid chromatography-tandem mass spectrometry. Eur. J. Mass Spec. 12: 129-136, 2006.
  28. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1426–1427.
  29. ^ Wolfe SM, Sasich LD, Barbehenn E (March 19, 2002). “Petition to FDA to ban the diet drug sibutramine (MERIDIA) (HRG Publication #1613)”Public Citizen. Retrieved 2007-04-29.
  30. ^ Japsen B (13 March 2005). “FDA weighs decision on Meridia; Health advisory likely for Abbott obesity drug”. Chicago Tribune. Chicago, Illinois. p. 1.
  31. ^ Hearing of 17 November 2004. Related CBS news item 19 November 2004.
  32. ^ James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, Torp-Pedersen C, Sharma AM, Shepherd GM, Rode RA, Renz CL (September 2010). “Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects” (PDF). The New England Journal of Medicine363 (10): 905–17. doi:10.1056/NEJMoa1003114hdl:2437/111825PMID 20818901.
  33. ^ Haslam D (April 2010). “Sibutramine: gone, but not forgotten” (PDF). Pract Diab Int27 (3): 96–97. doi:10.1002/pdi.1453. Archived from the original (PDF) on 26 July 2015.
  34. ^ “European Medicines Agency recommends suspension of marketing authorisations for sibutramine” (PDF). European Medicines Agency. January 21, 2010. Archived from the original (PDF) on 2010-04-01.
  35. ^ Pollack A (October 8, 2010). “Abbott Labs Withdraws Meridia From Market”The New York Times.
  36. ^ “FDA warns consumers about tainted weight loss pills” (Press release). U.S. Food and Drug Administration. 22 December 2008.
  37. ^ “Consumer directed questions and answers about FDA’s initiative against contaminated weight loss products”. U.S. Food and Drug Administration Center for Drug Evaluation and Research. 22 December 2008.
  38. ^ Müller D, Weinmann W, Hermanns-Clausen M (March 2009). “Chinese slimming capsules containing sibutramine sold over the Internet: a case series”Deutsches Ärzteblatt International106 (13): 218–22. doi:10.3238/arztebl.2009.0218PMC 2680571PMID 19471631.
  39. ^ 34 weight loss products recalledWebMD, 22 April 2009.
  40. ^ “Fake Alli diet pills can pose health risks”CNN.com. January 23, 2010. Retrieved 2010-01-24.
  41. ^ “Herbal diet product poses heart risk”. CBC News. March 26, 2010.
  42. ^ “FDA Alert: Slimming Beauty Bitter Orange Slimming Capsules: Undeclared Drug Ingredient”drugs.com.
  43. ^ “Press release: Warning over unlicensed herbal Payouji tea and Pai You Guo Slim Capsules”United Kingdom Medicines & Healthcare Products Regulatory Agency. 20 October 2010. Archived from the original on 9 February 2012.
  44. ^ “PRock Marketing, LLC Issues a Voluntary Nationwide Recall of All weight loss formulas and variation of formulas of Reduce Weight Fruta Planta/Reduce Weight Dietary Supplement”. United States Food and Drug Administration. Archived from the original on 23 March 2012.
  45. ^ Pope C. “Seizures of illegal medicines rise”The Irish Times.
  46. ^ “FDA Alert: Slim Xtreme Herbal Slimming Capsule: Undeclared Drug Ingredient”drugs.com.
  47. ^ “Majestic slimming capsules: Safety advisory”Therapeutic Goods Administration. Australian Government. 9 November 2012.
  48. ^ Carroll L (19 October 2011). “‘Natural’ diet pills tainted with banned prescription drug”MSNBC. Archived from the original on 11 January 2012.
  49. ^ Cohen, Ronnie (12 October 2018). “No Wonder It Works So Well: There May Be Viagra In That Herbal Supplement”NPR.org. Retrieved 2018-10-14.

External links

Sibutramine (top),
(S)-(−)-sibutramine (bottom)
Clinical data
Trade namesMeridia, others
Other namesBTS-54524
AHFS/Drugs.comMonograph
MedlinePlusa601110
Pregnancy
category
AU: CNo human data exists; inconclusive evidence of teratogenic potential in animal studies
Routes of
administration
Oral (capsules)
ATC codeA08AA10 (WHO)
Legal status
Legal statusUS: Schedule IV
Pharmacokinetic data
BioavailabilityAbsorption 77%, considerable first-pass metabolism
Protein binding97%, (94% for its desmethyl metabolites, M1 & M2)
MetabolismHepatic (CYP3A4-mediated)
Elimination half-life1 hour (sibutramine), 14 hours (M1) & 16 hours (M2)
ExcretionUrine (77%), feces (8%)
Identifiers
showIUPAC name
CAS Number106650-56-0 
766462-77-5 (chlorosibutramine)
PubChem CID5210
IUPHAR/BPS2586
DrugBankDB01105 
ChemSpider5021 
UNIIWV5EC51866
KEGGD08513 
ChEMBLChEMBL1419 
CompTox Dashboard (EPA)DTXSID1023578 
ECHA InfoCard100.130.097 
Chemical and physical data
FormulaC17H26ClN
Molar mass279.85 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (verify)

/////////////SIBUTRAMINE, UNII:WV5EC51866, WV5EC51866, сибутрамин , سيبوترامين , 西布曲明 , ABOTT, OBESITY

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Olipudase alfa


HPLSPQGHPA RLHRIVPRLR DVFGWGNLTC PICKGLFTAI NLGLKKEPNV ARVGSVAIKL
CNLLKIAPPA VCQSIVHLFE DDMVEVWRRS VLSPSEACGL LLGSTCGHWD IFSSWNISLP
TVPKPPPKPP SPPAPGAPVS RILFLTDLHW DHDYLEGTDP DCADPLCCRR GSGLPPASRP
GAGYWGEYSK CDLPLRTLES LLSGLGPAGP FDMVYWTGDI PAHDVWHQTR QDQLRALTTV
TALVRKFLGP VPVYPAVGNH ESTPVNSFPP PFIEGNHSSR WLYEAMAKAW EPWLPAEALR
TLRIGGFYAL SPYPGLRLIS LNMNFCSREN FWLLINSTDP AGQLQWLVGE LQAAEDRGDK
VHIIGHIPPG HCLKSWSWNY YRIVARYENT LAAQFFGHTH VDEFEVFYDE ETLSRPLAVA
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RETYGLPNTL PTAWHNLVYR MRGDMQLFQT FWFLYHKGHP PSEPCGTPCR LATLCAQLSA
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Olipudase alfa

Xenpozyme, Japan 2022, APPROVALS 2022, 2022/3/28

PEPTIDE, オリプダーゼアルファ (遺伝子組換え)

Alternative Names: Acid sphingomyelinase Niemann Pick disease type B – Sanofi; Acid-sphingomyelinase – Sanofi; GZ-402665; Recombinant human acid sphingomyelinase – Sanofi; rhASM – Sanofi; Sphingomyelinase-C (synthetic human) – Sanofi; Synthetic human sphingomyelinase-C – Sanofi; Xenpozyme

FormulaC2900H4373N783O791S24
CAS927883-84-9
Mol weight63631.0831
EfficacyLysosomal storage disease treatment, Enzyme replacement (acid sphingomyelinase)
CommentEnzyme replacement therapy product
Treatment of Niemann-Pick disease type A/B
  • OriginatorGenzyme Corporation
  • DeveloperSanofi
  • ClassRecombinant proteins; Sphingomyelin phosphodiesterases
  • Mechanism of ActionSphingomyelin-phosphodiesterase replacements
  • Orphan Drug StatusYes – Niemann-Pick diseases
  • RegisteredNiemann-Pick diseases
  • 28 Mar 2022Registered for Niemann-Pick diseases (In adolescents, In children, In adults) in Japan (IV) – First global approval
  • 09 Feb 2022FDA assigns PDUFA action date of (03/07/2022) for Olipudase alfa (In children, In adults) for Niemann-Pick diseases
  • 09 Feb 2022Adverse e

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Olipudase Alfa Improves Lung Function, Spleen Volume in ASMD

Olipudase Alfa Improves Lung Function, Spleen Volume in ASMD

https://www.empr.com/home/mpr-first-report/worldsymposium-2021/olipudase-alfa-chronic-visceral-acid-sphingomyelinase-efficacy/embed/#?secret=x9Jl0tjBl4#?secret=4RmoWVLWaQ

Olipudase alfa was associated with significant improvements in clinically relevant disease end points among patients with chronic visceral acid sphingomyelinase (ASM) deficiency (ASMD), according to results from the phase 2/3 ASCEND trial presented at the 17th Annual WORLDSymposium.

ASMD is a rare, debilitating lysosomal storage disease characterized by a deficiency of the enzyme acid sphingomyelinase, which results in the accumulation of sphingomyelin in various tissues of the body. Olipudase alfa is an investigational enzyme replacement therapy designed to replace deficient or defective ASM.

The multicenter, randomized, double-blind, placebo-controlled ASCEND trial evaluated the efficacy and safety of olipudase alfa in 36 adults with chronic visceral ASMD. Patients were randomly assigned 1:1 to receive olipudase alfa 3mg/kg intravenously every 2 weeks or placebo for 52 weeks. The coprimary end points were the percent change in spleen volume and percent-predicted diffusing capacity of the lung for carbon monoxide (DLCO).

At week 52, treatment with olipudase alfa resulted in a 39.45% reduction in spleen volume, compared with a 0.5% increase for placebo (P <.0001). A decrease in spleen volume of at least 30% was observed in 17 patients (94%) treated with olipudase afla compared with no patients treated with placebo. Additionally, olipudase alfa significantly improved lung function by 22% from baseline compared with 3% for patients receiving placebo (P =.0004), as measured by percent predicted DLCO.

Olipudase alfa also met key secondary end points including a 31.7% reduction in liver volume (vs a 1.4% reduction for placebo; P <.0001) and a 16.8% improvement in mean platelet counts (vs 2.5% with placebo; P =.019) at week 52. Significant improvements in HDL, LDL, AST, ALT, chitotriosidase (54% vs 12% with placebo; P =.0003), and lyso-sphingomyelin (78% vs 6% with placebo) were also observed in the olipudase alfa group at week 52.

With regard to Splenomegaly Related Score, a patient-reported outcome measurement that evaluates patient symptoms associated with an enlarged spleen, findings showed no meaningful difference between olipudase alfa and placebo (-8 point vs -9.3 points, respectively).

As for safety, olipudase alfa was well tolerated with most adverse events being mild to moderate in severity. There were no treatment-related serious adverse events and no adverse event-related discontinuations.

Disclosure: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

Reference

Wasserstein M, Arash-Kaps L, Barbato A, et al. Adults with chronic acid sphingomyelinase deficiency show significant visceral, pulmonary, and hematologic improvements after enzyme replacement therapy with olipudase-alfa: 1-year results of the ASCEND placebo-controlled trial. Presented at: 17th Annual WORLDSymposium; February 8-12, 2021. Abstract 265.

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https://www.sanofi.com/en/media-room/press-releases/2021/2021-12-06-14-00-00-2346501

EMA accepts regulatory submission for olipudase alfa, the first potential therapy for ASMD

  • Olipudase alfa has been granted PRIority MEdicines (PRIME) designation in Europe, Breakthrough Therapy designation in the United States, and SAKIGAKE designation in Japan
  • European regulatory decision anticipated second half of 2022

DECEMBER 6, 2021

The European Medicines Agency (EMA) has accepted for review under an accelerated assessment procedure the Marketing Authorization Application (MAA) for olipudase alfa, Sanofi’s investigational enzyme replacement therapy which is being evaluated for the treatment of acid sphingomyelinase deficiency (ASMD). Historically referred to as Niemann-Pick disease (NPD) type A and type B, ASMD is a rare, progressive, and potentially life-threatening disease for which no treatments are currently approved. The estimated prevalence of ASMD is approximately 2,000 patients in the U.S., Europe (EU5 Countries) and Japan. If approved, olipudase alfa will become the first and only therapy for the treatment of ASMD.

Today’s milestone has been decades in the making and our gratitude goes to the ASMD community who has stood by us with endless patience while olipudase alfa advanced through clinical development,” said Alaa Hamed, MD, MPH, MBA, Global Head of Medical Affairs, Rare Diseases, Sanofi. “Olipudase alfa represents the kind of potentially life-changing innovation that is possible when industry, medical professionals and the patient community work together toward a common goal.”

The MAA is based on positive results from two separate clinical trials (ASCEND and ASCEND-Peds) evaluating olipudase alfa in adult and pediatric patients with non-central nervous system (CNS) manifestations of ASMD type A/B and ASMD type B.

Olipudase alfa has received special designations from regulatory agencies worldwide, recognizing the innovation potential of the investigational therapy.

“Scientific innovation is the greatest source of hope for people living with diseases like ASMD where there are no approved treatments and is a critical component for ensuring a viable healthcare ecosystem,” said Bill Sibold, Executive Vice President of Sanofi GenzymeAt Sanofi, we have a long history of pioneering scientific innovation, and we remain committed to finding solutions to address unmet medical needs, including those of the rare disease community.”

The EMA awarded olipudase alfa the PRIority MEdicines designation, also known as PRIME, intended to aid and expedite the regulatory process for investigational medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options.

The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to olipudase alfa. This designation is intended to expedite the development and review of drugs intended to treat serious or life-threatening diseases and conditions. The criteria for granting Breakthrough Therapy designation include preliminary clinical evidence indicating that the molecule may demonstrate substantial improvement on a clinically significant endpoint over available therapies.

In Japan, olipudase alfa was awarded the SAKIGAKE designation, which is intended to promote research and development in Japan for innovative new medical products that satisfy certain criteria, such as the severity of the intended indication. In September, Sanofi filed the J-NDA submission for olipudase alfa.

About ASMD

ASMD results from a deficient activity of the enzyme acid sphingomyelinase (ASM), which is found in special compartments within cells called lysosomes and is required to breakdown lipids called sphingomyelin. If ASM is absent or not functioning as it should, sphingomyelin cannot be metabolized properly and accumulates within cells, eventually causing cell death and the malfunction of major organ systems. The deficiency of the lysosomal enzyme ASM is due to disease-causing variants in the sphingomyelin phosphodiesterase 1 gene (SMPD1). The estimated prevalence of ASMD is approximately 2,000 patients in the U.S., Europe (EU5 Countries) and Japan.

ASMD represents a spectrum of disease caused by the same enzymatic deficiency, with two types that may represent opposite ends of a continuum sometimes referred to as ASMD type A and ASMD type B. ASMD type A is a rapidly progressive neurological form of the disease resulting in death in early childhood due to central nervous system complications. ASMD type B is a serious and potentially life-threatening disease that predominantly impacts the lungs, liver, and spleen, as well as other organs. ASMD type A/B represents an intermediate form that includes varying degrees of neurologic involvement. Patients with ASMD type A/B or ASMD type B were studied in the ASCEND trial program. Another type of NPD is NPD type C, which is unrelated to ASMD.

About olipudase alfa

Olipudase alfa is an investigational enzyme replacement therapy designed to replace deficient or defective ASM, allowing for the breakdown of sphingomyelin. Olipudase alfa is currently being investigated to treat non-CNS manifestations of ASMD. Olipudase alfa has not been studied in ASMD type A patients. Olipudase alfa is an investigational agent and the safety and efficacy have not been evaluated by the FDA, EMA, or any other regulatory authority worldwide.

About Sanofi

Sanofi is dedicated to supporting people through their health challenges. We are a global biopharmaceutical company focused on human health. We prevent illness with vaccines, provide innovative treatments to fight pain and ease suffering. We stand by the few who suffer from rare diseases and the millions with long-term chronic conditions.

With more than 100,000 people in 100 countries, Sanofi is transforming scientific innovation into healthcare solutions around the globe.

///////Olipudase alfa,  japan 2022, APPROVALS 2022, Xenpozyme, PEPTIDE, オリプダーゼアルファ (遺伝子組換え) , ORPHAN DRUG, GZ-402665 , GZ 402665

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(Disulfide bridge: H7-H12, H27-H43, H108-L98, H156-H170, H181-H209, L16-L27, L21-L36, L38-L47, L55-L66, L62-L75, L77-L90)

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  • PRT-4445
  • PRT064445

Andexanet alfa, sold under the trade name Andexxa among others, is an antidote for the medications rivaroxaban and apixaban, when reversal of anticoagulation is needed due to uncontrolled bleeding.[1] It has not been found to be useful for other factor Xa inhibitors.[2] It is given by injection into a vein.[2]

Common side effects include pneumonia and urinary tract infections.[2] Severe side effects may include blood clotsheart attacksstrokes, or cardiac arrest.[2] It works by binding to rivaroxaban and apixaban.[2]

It was approved for medical use in the United States in May 2018.[1] It was developed by Portola Pharmaceuticals.[3]

ndexanet alfa is a recombinant human coagulation Factor Xa that promotes blood coagulation. It was developed by Portola Pharmaceuticals and was approved in in May 2018. It is marketed as Andexxa for intravenous injection or infusion and is indicated for the reversal of anticoagulation in combination with rivaroxaban and apixaban in cases of life-threatening or uncontrolled bleeding. Rivaroxaban and apixaban are Factor Xa inhibitors that promote anticoagulation in situations where blood clotting is unfavourable, such as in deep vein thrombosis and pulmonary embolism. However, the use of these agents is associated with a risk for uncontrollable bleeding episodes that can lead to can cause serious or fatal bleeding. Andexanet alfa is currently under regulatory review by the European Union and is undergoing clinical development in Japan 1.

Andexanet alfa works by binding to Factor Xa inhibitors and prevent them from interacting with endogenous Factor Xa. It displayed high affinity (0.53–1.53 nmol/L) to apixaban, betrixaban, edoxaban and rivaroxaban 1. However, the effectiveness of andexanet alfa on treating bleeding related to any FXa inhibitors other than apixaban and rivaroxaban was not demonstrated, thus such use is limited 7. Its pharmacokinetic properties are not reported to be affected by factor Xa inhibitors 1. Andexanet alfa retains the structural similarity to that of endogenous human factor Xa, but exists in its mature functional form without the need for activation via the intrinsic or extrinsic coagulation pathways 5 and remains catalytically inactive due to structural modification 1. The procoagulation potential of andexanet alfa is eliminated through the removal of a 34-residue fragment containing Gla: via this truncation, andexanet alfa is unable to bind to membrane surfaces and assemble the prothrombinase complex 5. It also prevents andexanet alfa from taking up space on phospholipid surface membranes, so that native FXa may bind and assemble the prothrominase complex 5. The amino acid residue modification from serine to alanine in the binding site of the catalytic domain allows more effective binding to FXa inhibitors and deters the andexanet alfa from converting prothrombin to thrombin 5.

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Structure of andexant alfa. Andexanet alfa is a modified activated human factor Xa (FXa) that binds FXa with high affinity and a 1:1 stoichiometric ratio but does not have intrinsic catalytic activity (the amino acid serine at position 419 is replaced by alanine) and lacks the membrane-binding-carboxyglutamic acid domain (Gla domain) of native FX. The Gla domains are responsible for the binding of FXa to phospholipids

Structure of andexant alfa. Andexanet alfa is a modified activated human factor Xa (FXa) that binds FXa with high affinity and a 1:1 stoichiometric ratio but does not have intrinsic catalytic activity (the amino acid serine at position 419 is replaced by alanine) and lacks the membrane-binding-carboxyglutamic acid domain (Gla domain) of native FX. The Gla domains are responsible for the binding of FXa to phospholipids

Medical uses

Andexanet alfa is used to stop life threatening or uncontrollable bleeding in people who are taking rivaroxaban or apixaban.[1]

There are no randomised clinical trials as of 2019. Studies in healthy volunteers show that the molecule binds factor Xa inhibitors and counters their anti-Xa-activity.[4] The only published clinical trial is a prospective, open label, single group study.[5] This study reports results on 352 people and demonstrates a reduction of anti-Xa-activity while also showing an excellent or good hemostatic efficacy in 82%. While people who were expected to die in 30 days were excluded from the study, 14% of participants died. There was no relationship between hemostatic efficacy and reduced anti-Xa-activity.[6] The FDA has demanded a randomised clinical trial: the first results are not expected before 2023.[7]

Adverse effects

Common side effects include pneumonia and urinary tract infections.[2] Severe side effects may include blood clots or cardiac arrest.[2]

Andexanet alfa has a boxed warning that it is associated with arterial and venous blood clots, ischemic events, cardiac arrest, and sudden deaths.[1]

Pharmacology

Mechanism of action

Andexanet alfa is a biologic agent, a recombinant modified version of human activated factor X (FXa).[8] Andexanet alfa differs from native FXa due to the removal of a 34 residue fragment that contains the Gla domain. This modification reduces andexanet alfa’s procoagulant potential. Additionally, a serine to alanine (S419A) mutation in the active site eliminates its activity as a prothrombin to thrombin catalyst, but still allows the molecule to bind to FXa inhibitors.[9] FXa inhibitors bind to andexanet alfa with the same affinity as to natural FXa. As a consequence in the presence of andexanet alfa natural FXa is partially freed, which can lead to effective hemostasis.[3][10] In other words, it acts as a decoy receptor. Andexanet alfa reverses effect of all anticoagulants that act directly through FXa or by binding antithrombin III. The drug is not effective against factor IIa inhibitor dabigatran.[11]

History[edit]

It was approved in the United States in 2018 based on data from two phase III studies on reversing the anticoagulant activity of FXa inhibitors rivaroxaban and apixaban in healthy volunteers.[4] As a condition of its accelerated approval there is a study being conducted comparing it to other currently used reversal agents (“usual care”).[5][12]

Society and culture

Economics

Initial pricing (AWP) is $58,000 per reversal (800 mg bolus + 960 mg infusion, $3,300 per 100 mg vial) which is higher than reversal agents for other DOAC agents (idarucizumab for use in dabigatran reversal is $4,200 per reversal).[13]

References

  1. Jump up to:a b c d e “Andexxa- andexanet alfa injection, powder, lyophilized, for solution”DailyMed. 21 September 2020. Retrieved 12 November 2020.
  2. Jump up to:a b c d e f g “Andexxa Monograph for Professionals”Drugs.com. Retrieved 19 December 2018.
  3. Jump up to:a b Dolgin E (March 2013). “Antidotes edge closer to reversing effects of new blood thinners”Nature Medicine19 (3): 251. doi:10.1038/nm0313-251PMID 23467222S2CID 13340319.
  4. Jump up to:a b Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA (December 2015). “Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity”New England Journal of Medicine373 (25): 2413–24. doi:10.1056/NEJMoa1510991PMID 26559317.
  5. Jump up to:a b Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, et al. (April 2019). “Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors”New England Journal of Medicine380 (14): 1326–1335. doi:10.1056/NEJMoa1814051PMC 6699827PMID 30730782.
  6. ^ Justin Morgenstern, “Andexanet Alfa: More garbage science in the New England Journal of Medicine”, First10EM blog, February 11, 2019. Available at: https://first10em.com/andexanet-alfa/.
  7. ^ “A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor”. 11 January 2022.
  8. ^ Lu, Genmin; DeGuzman, Francis R.; Lakhotia, Sanjay; Hollenbach, Stanley J.; Phillips, David R.; Sinha, Uma (2008-11-16). “Recombinant Antidote for Reversal of Anticoagulation by Factor Xa Inhibitors”. Blood112 (11): 983. doi:10.1182/blood.V112.11.983.983ISSN 0006-4971.
  9. ^ Kaatz, Scott; Bhansali, Hardik; Gibbs, Joseph; Lavender, Robert; Mahan, Charles E.; Paje, David G. (2017-09-13). “Reversing factor Xa inhibitors – clinical utility of andexanet alfa”Journal of Blood Medicine8: 141–149. doi:10.2147/JBM.S121550PMC 5602457PMID 28979172.
  10. ^ Lu G, Deguzman FR, Hollenbach SJ, et al. (March 2013). “A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa”. Nature Medicine19 (4): 446–51. doi:10.1038/nm.3102PMID 23455714S2CID 11235887.
  11. ^ H. Spreitzer (23 December 2013). “Neue Wirkstoffe – Andexanet Alfa”. Österreichische Apothekerzeitung (in German) (26/2013): 40.
  12. ^ “Trial of Andexanet in ICH Patients Receiving an Oral FXa Inhibitor”ClinicalTrials.gov. 11 January 2022.
  13. ^ “Lexi Comp Drug Information Online”. 24 May 2018.

Further reading

External links

Clinical data
Trade namesAndexxa, Ondexxya, others
Other namesCoagulation factor Xa (recombinant), inactivated-zhzo, PRT06445, r-Antidote, PRT4445
AHFS/Drugs.comMonograph
License dataUS DailyMedAndexanet_alfa
Routes of
administration
Intravenous injection
ATC codeV03AB38 (WHO)
Legal status
Legal statusUK: POM (Prescription only)US: ℞-only [1]EU: Rx-only
Pharmacokinetic data
MetabolismNot studied
Elimination half-life5 h to 7 h
Identifiers
showIUPAC name
CAS Number1262449-58-0
IUPHAR/BPS7576
DrugBankDB14562
ChemSpidernone
UNIIBI009E452R
KEGGD11029
ChEMBLChEMBL3301583

//////////Andexanet alfa, JAPAN 2022, APPROVALS 2022, アンデキサネットアルファ (遺伝子組換え) , Ondexxya , PRT-4445, PRT064445

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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

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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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