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Sodium zirconium cyclosilicate, ナトリウムジルコニウムシクロケイ酸塩

September 10, 2018 1:50 pm / Leave a comment

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Sodium zirconium cyclosilicate

ZS-9, ZS 9, UZSi-9

CAS 242800-27-7, H₂ O₃ Si . x H₂ O . ²/₃ Na . ¹/₃ Zr, Sodium zirconium cyclosilicate; Silicic acid (H2SiO3), Sodium zirconium(4+) salt (3:2:1), hydrate

USAN CAS 17141-74-1, H₆ O₉ Si₃ . 2 Na . Zr, Silicic acid (H₂SiO₃), sodium zirconium(4+) salt (3:2:1), hydrate, Sodium zirconium silicate (Na₂ZrSi₃O₉) hydrate

ナトリウムジルコニウムシクロケイ酸塩

ZrH4O6. 3H4SiO4. 2H2O. 2Na, 561.6068, AS IN kegg

Molecular Formula, H6-O9-Si3.2Na.Z, Molecular Weight, 371.5004 as in chemid plus

APPROVED FDA 2018/5/18, LOKELMA, NDA 207078

APPROVED EMA 2018/3/22, LOKELMA

ATC code: V03AE10

UNII-D652ZWF066

TREATMENT	selective cation exchanger Treatment of hyperkalemia

Sodium zirconium cyclosilicate (ZS-9) is a selective oral sorbent that traps potassium ions throughout the gastrointestinal tract. It is being developed by ZS Pharma and AstraZeneca for the treatment of hyperkalemia (elevated serum potassium levels).^[1]

The product was originated at ZS Pharma, a wholly owned subsidiary of AstraZeneca. In 2015, ZS Pharma was acquired by AstraZeneca.

Hyperkalaemia is the presence of an abnormally high concentration of potassium in the blood. Most data on the occurrence of hyperkalaemia have been obtained from studies of hospitalised patients, and the incidence ranges from 1 to 10%. There is no agreed definition of hyperkalaemia, since the raised level of potassium at which a treatment should be initiated has not been established. The European Resuscitation Council guidelines consider hyperkalaemia to be a serum potassium (S-K) level > 5.5 mmol/L, with mild elevations defined as 5.5 to 5.9 mmol/L, moderate as 6.0-6.4 mmol/L, and severe as ≥ 6.5 mmol/L. The guidelines also note that extracellular potassium levels are usually between 3.5 and 5.0 mmol/L, which is considered the normal range for adults. However, a number of recent retrospective studies have shown the risk of mortality is increased even with only modest elevations of S-K. Mortality risk has been shown to be significantly higher in chronic kidney disease (CKD) patients with S-K levels > 5.0 mmol/L. In acute myocardial infarction patients, a mean postadmission S-K ≥ 5.5 mmol/L during hospitalisation corresponded to a 12-fold increase in death compared with S-K levels between 3.5 and 4.5 mmol/L but, more importantly, S-K levels between 4.5 and 5.0 mmol/L, which is within the normal range, were associated with a 2-fold increased risk of mortality compared with S-K between 3.5 and 4.5 mmol/L.

Sodium zirconium cyclosilicate (ZS) has been developed as treatment for hyperkalaemia. The indication applied for is: Treatment of hyperkalaemia in adult patients, acute and extended use. ZS is an inorganic cation exchange crystalline compound. ZS has a high capacity to selectively entrap monovalent cations, specifically excess potassium and ammonium ions, over divalent cations such as calcium and magnesium, in the gastrointestinal tract. The high specificity of ZS for potassium is attributable to the chemical composition and diameter of the micro pores, which act in an analogous manner to the selectivity filter utilized by physiologic potassium channels. The exchange with potassium ions occurs throughout the gastrointestinal tract with onset in the upper part of the gastrointestinal tract. The trapped potassium ions are excreted from the body via the faeces, thereby reducing any excess and resolving hyperkalaemia. As claimed by the applicant, ZS demonstrates improved capacity, selectivity, and speed for entrapping excess potassium over currently available options for the treatment of hyperkalaemia. The proposed commercial formulation of ZS is a non-absorbed, insoluble, white crystalline powder for suspension with a specific particle size distribution profile. The proposed starting dose of ZS for reversal of hyperkalaemia (when serum potassium is > 5.0 mmol/l) is up to 10 g/day, divided in 3 doses (TID) to achieve normokalaemia.

EMA

The chemical name of the active substance is hydrogen sodium zirconium (IV) silicate hydrate. Due to the natural variability in the manufacturing process of the active substance, it is expected to have the formula Na~1.5H~0.5ZrSi3O9 • 2–3 H2O and relative molecular mass in the range of 390.5 – 408.5. The WHO chose not to designate an INN for the active substance, and a USAN sodium zirconium cyclosilicate is used throughout the dossier and this CHMP AR. The active substance has the following structure:

Figure 1. Stick-and-ball (left) and polyhedral (right) unit cell structural representation of the main framework of the microporous sodium zirconium cyclosilicate active substance. Red = zirconium, green = silicon, blue = oxygen atoms. Cations are not pictured.

The structure of sodium zirconium cyclosilicate is a cubic cell arrangement of octahedrally coordinated Zr and tetrahedrally coordinated Si units that interconnect through oxygen bridges as Zr–O–Si and Si–O–Si. The two types of units are observed in a ratio 1:3, respectively, and repeat orderly to form a three-dimensional framework characteristic of the compound. The framework acquires its negative charge from the octahedral fractions, [ZrO6]2– , and features channels and cavities that interconnect and locate the positive ions that counter-balance the negative charge of the framework. Electrostatic interactions between the framework and the cations allow for mobility and possibility of exchange with other cations that would fit and pass the free pore openings of ~ 3.0 Å. The uniform micropore structure allows a high exchange capacity and selectivity for potassium (K+) and ammonium (NH4 +) cations, providing the compound with its distinctive ion-exchange selectivity features responsible for its mode of action. In vitro characterisation of ion selectivity of sodium zirconium cyclosilicate was provided by the applicant and considered satisfactory

The structure of sodium zirconium cyclosilicate was confirmed using synchrotron powder diffraction, standard X-ray powder diffraction, 29Si magic angle spinning solid nuclear magnetic resonance studies (29Si-MASNMR), Fourier transform infrared spectroscopy, inductive coupled plasma-optical emission spectrometry, wave dispersive X-ray microprobe analysis and thermo-gravimetric analysis. Calculations using proprietary software were also used for structure elucidation. The active substance is a white crystalline powder. Bonding interactions in the main framework are considered primarily of covalent nature, with some ionic contribution due to the difference in electronegativity between Si–O and Zr–O. The covalent bonding interactions in all directions within the crystals make sodium zirconium cyclosilicate a compound insoluble in water or in organic solvents. It is neither hygroscopic nor sensitive to light and it is resistant to heat. During the hydrothermal synthesis, the possibility that other crystalline phases are formed exists. The observed crystalline forms are controlled by the manufacturing process parameters and release specifications. Sodium zirconium cyclosilicate is considered to be a new active substance. The applicant demonstrated that neither it, nor its derivatives have ever been active substances in medicinal products authorised in the EU………http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004029/WC500246776.pdf

TGA

DOC]Australian Public Assessment Report for Sodium zirconium … – TGA

https://www.tga.gov.au/…/auspar-sodium-zirconium-cyclosilicate-hydrate-180129.doc…

Jan 29, 2018 – The sponsor has submitted an application to register a new chemical entity Lokelma,sodium zirconium cyclosilicate hydrate powder for …

The chemical formula of sodium zirconium cyclosilicate hydrate is Na~1.5H~0.5ZrSi₃O₉.2-3H₂O.

The drug substance ‘sodium zirconium cyclosilicate hydrate’ (abbreviated to ZS) is a white crystalline powder. The structure of ZS is summarised as a cubic cell arrangement of octahedrally coordinated zirconium Zr ([ZrO₆]^2-) and tetrahedrally coordinated silicon Si ([SiO₄]0) units that interconnect through oxygen bridges as Zr-O-Si and Si-O-Si. The two types of units are observed in a ratio of 1:3, respectively, and repeat orderly to form a three dimensional framework characteristic of the compound. The framework acquires its negative charge from the octahedral fractions, [ZrO₆]^2- and features channels and cavities that interconnect and locate the positive ions (sodium, Na⁺, and hydrogen, H⁺) that counter balance the negative charge of the framework.

The manufacturing process is tightly controlled in terms of order of addition of starting material, reaction and crystallisation temperatures, mixing speeds and times, and minimum number of rinses, in order to meet expected yields of the drug substance of an expected quality. In process quality control tests [information redacted] are applied during the manufacturing process to ensure the formation of the correct crystalline structure and batch to batch consistency.

Sodium zirconium cyclosilicate hydrate is completely insoluble.

The drug substance forms part of a family of zirconium silicates that have specific ion exchange properties. Its mechanism of action is based on the cations within its porous crystalline structure, and their ability to freely exchange with a select group of monovalent cations, most specifically the potassium (K⁺) and ammonium (NH⁴⁺) cations. The pore size within the three dimensional crystalline structure has been measured at ~3Å (2.4 x 3.5 Å^[1]), which is sufficiently wide enough to trap the potassium monovalent cations which have an approximate ionic diameter of 2.98Å.

The particle size of the drug substance is controlled to maintain a non-systemic mode of action. The sponsor adequately justified not routinely controlling the size of larger particles in the drug substance as differences in particle size were shown to not affect performance as measured by potassium ion exchange capacity (KEC), and there was no correlation between KEC and D90 for clinical lots manufactured.

There are two alternate zirconium silicate crystalline phases which may be formed in the reaction process; Crystalline Phase A (CPA) and Crystalline Phase B (CPB). These layered, two-dimensional structures also exhibit ion exchange properties, although their ion selectivity is less specific for the potassium K⁺ cations compared to the desired drug substance. PXRD techniques are used to differentiate between the desired drug substance and levels of CPA and CPB. Appropriate limits are applied in the drug substance specification to limit the content of these crystalline phases in the drug substance/drug product.

The quality of the drug substance is controlled by an acceptable specification that includes test and limits for Appearance, Identification (by FTIR and PXRD), KEC , Crystalline Phase A , Crystalline Phase B , Zirconium content , Silicon content , Hafnium content , Moisture content , Particle Size , and Elemental Impurities.

^[1] 1 Å = 0.1 nm.

Image result for Sodium zirconium cyclosilicate

Background

Hyperkalemia occurs in 3 to 10% of hospitalized patients^[2] but is often mild. Hyperkalemia can arise from impaired renal function, potassium-sparing diuretics and renin–angiotensin system blockers (e.g., ACE inhibitors, angiotensin receptor blockers, spironolactone) and diabetes mellitus.^[2]^[3]^[4]^[5]

There is no universally accepted definition of what level of hyperkalemia is mild, moderate, or severe.^[6] However, if hyperkalemia causes any ECG change it is considered a medical emergency^[6] due to a risk of potentially fatal abnormal heart rhythms (arrhythmia) and is treated urgently.^[6] serum potassium concentrations greater than 6.5 to 7.0 mmol/L in the absence of ECG changes are managed aggressively.^[6]

Hyperkalemia, particularly if severe, is a marker for an increased risk of death.^[2] However, there is disagreement regarding whether a modestly elevated serum potassium level directly causes significant problems. One viewpoint is that mild to moderate hyperkalemia is a secondary effect that denotes significant underlying medical problems.^[2] Accordingly, these problems are both proximate and ultimate causes of death,^[2] and adjustment of potassium may not be helpful. Alternatively, hyperkalemia may itself be an independent risk factorfor cardiovascular mortality.^[7]

Several approaches are used in the treatment of hyperkalemia.^[6] In October 2015, the U.S. Food and Drug Administration (FDA) approved patiromer which works by binding free potassium ions in the gastrointestinal tract and releasing calcium ions for exchange. Previously, the only approved product was sodium polystyrene sulfonate (Kayexalate),^[8] an organic ion-exchange resin that nonspecifically binds cations (e.g., calcium, potassium, magnesium) in the gastrointestinal tract. The effectiveness of sodium polystyrene sulfonate has been questioned: a study in healthy subjects showed that laxatives alone were almost as effective in increasing potassium secretion as laxatives plus Kayexalate.^[9] In addition, use of sodium polystyrene sulfonate, particularly if formulated with high sorbitol content, is uncommonly but convincingly associated with colonic necrosis.^[6]^[8]^[10]^[11]

Mechanism of action

Cross-sections of ZS-9 pores with three different ions (K⁺ = potassium, Na⁺ = sodium, Ca²⁺ = calcium). The specificity for potassium is thought to be caused by the diameter and composition of the pores, which resembles potassium channels.

ZS-9 is a zirconium silicate. Zirconium silicates have been extensively used in medical and dental applications because of their proven safety.^[12] 11 zirconium silicates were screened by an iterative optimization process. ZS-9 selectively captures potassium ions, presumably by mimicking the actions of physiologic potassium channels.^[13] ZS-9 is an inorganic cation exchanger crystalline with a high capacity to entrap monovalent cations, specifically potassium and ammonium ions, in the GI tract. ZS-9 is not systemically absorbed; accordingly, the risk of systemic toxicity may be minimized.

Clinical studies

A phase 2 clinical trial in 90 patients with chronic kidney disease and mild-to-moderate hyperkalemia found a significantly greater reduction in serum potassium with ZS-9 than placebo. ZS-9 was well tolerated, with a single adverse event (mild constipation).^[14]

A double-blind, phase 3 clinical trial in 753 patients with hyperkalemia and underlying chronic kidney disease, diabetes, congestive heart failure, and in patients on renin–angiotensin system blockers compared ZS-9 with placebo.^[15] Patients were randomly assigned to receive either ZS-9 (1.25 g, 2.5 g, 5 g, or 10 g) or placebo 3 times daily for 48 hours (acute phase). Patients who achieved normokalemia (serum potassium of 3.5-4.9 mmol/L) were randomly assigned to receive ZS-9 or placebo once daily for 12 additional days (maintenance phase). At the end of the acute phase, serum potassium significantly decreased in the 2.5 g, 5 g, and 10 g ZS-9 groups. During the maintenance phase, once daily 5 g or 10 g ZS-9 maintained serum potassium at normal levels. Adverse events, including specifically gastrointestinal effects, were similar with either ZS-9 or placebo.^[15]

A double-blind, phase 3 clinical trial in 258 patients with hyperkalemia and underlying chronic kidney disease, diabetes, congestive heart failure, and in patients on renin–angiotensin system blockers compared ZS-9 with placebo.^[16] All patients received 10 g ZS-9 three times daily for 48 hours in the initial open-label phase. Patients who achieved normokalemia (serum potassium 3.5-5.0 mEq/L) were randomly assigned to receive either ZS-9 (5 g, 10 g, or 15 g) or placebo once daily for 28 days (double-blind phase). 98% of patients (n=237) achieved normokalemia during the open-label phase. During the double-blind phase, once daily 5 g, 10 g, and 15 g ZS-9 maintained serum potassium at normal levels in a significantly higher proportion of patients (80%, 90%, and 94%, respectively) than placebo (46%). Adverse events were generally similar with either ZS-9 or placebo. Hypokalemiaoccurred in more patients in the 10 g and 15 g ZS-9 groups (10% and 11%, respectively), versus none in the 5 g ZS-9 or placebo groups.^[16]

Regulatory

In the United States, regulatory approval of ZS-9 was rejected by the Food and Drug Administration in May 2016 due to issues associated with manufacturing.^[17] On May 18th, 2018, the FDA approved ZS-9 (now known as Lokelma®) for treatment of adults with hyperkalemia.^[18]

PATENT

WO 2012109590

PATENT

WO 2015070019

https://patents.google.com/patent/WO2015070019A1/en

The present invention relates to novel zirconium silicate (“ZS”) compositions which are preferably sodium zirconium cyclosilicates having an elevated level of ZS-9 crystalline form relative to other forms of zirconium cyclosilicates (i.e., ZS-7) and zirconium silicates (i.e., ZS-8, ZS-11). The ZS compositions are preferably sodium zirconium cyclosilicate compositions where the crystalline form has at least 95% ZS-9 relative to other crystalline forms of zirconium silicate. The ZS compositions of the present invention unexpectedly exhibit a markedly improved in vivo potassium ion absorption profile and rapid reduction in elevate levels of serum potassium.

[004] Preferably ZS compositions of the present invention are specifically formulated at particular dosages to remove select toxins, e.g., potassium ions or ammonium ions, from the gastrointestinal tract at an elevated rate without causing undesirable side effects. The preferred formulations are designed to remove and avoid potential entry of particles into the bloodstream and potential increase in pH of urine in patients. The formulation is also designed to release less sodium into the blood. These compositions are particularly useful in the therapeutic treatment of hyperkalemia and kidney disease. The present invention also relates to pharmaceutical granules, tablets, pill, and dosage forms comprising the microporous ZS as an active ingredient. In particular, the granules, tablets, pills or dosage forms are compressed to provide immediate release, delayed release, or specific release within the subject. Also disclosed are microporous ZS compositions having enhanced purity and potassium exchange capacity (“KEC”). Methods of treating acute, sub-acute, and chronic hyperkalemia have also been investigated. Disclosed herein are particularly advantageous dosing regimens for treating different forms of hyperkalemia using the microporous ZS compositions noted above. In addition, the present invention relates to methods of co-administering microporous ZS compositions in combination with other pharmacologic drugs that are known to induce, cause, or exacerbate the hyperkalemic condition.

Patent

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US20110097401A1 *2009-06-122011-04-28Meritage Pharma, Inc.Methods for treating gastrointestinal disorders

US20120213847A1 *2011-02-112012-08-23ZS Pharma, Inc.Microporous zirconium silicate for the treatment of hyperkalemia

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Family To Family Citations

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References

Jump up^ “ZS-9. A selective potassium binder”. ZS-Pharma.
^ Jump up to:^a ^b ^c ^d ^e Elliott, M. J.; Ronksley, P. E.; Clase, C. M.; Ahmed, S. B.; Hemmelgarn, B. R. (2010). “Management of patients with acute hyperkalemia”. Canadian Medical Association Journal. 182 (15): 1631–5. doi:10.1503/cmaj.100461. PMC 2952010 . PMID 20855477.
Jump up^ Stevens, M. S.; Dunlay, R. W. (2000). “Hyperkalemia in hospitalized patients”. International Urology and Nephrology. 32 (2): 177–80. doi:10.1023/A:1007135517950. PMID 11229629.
Jump up^ Navaneethan, S. D.; Yehnert, H.; Moustarah, F.; Schreiber, M. J.; Schauer, P. R.; Beddhu, S. (2009). “Weight Loss Interventions in Chronic Kidney Disease: A Systematic Review and Meta-analysis”. Clinical Journal of the American Society of Nephrology. 4 (10): 1565–74. doi:10.2215/CJN.02250409. PMC 2758256 . PMID 19808241.
Jump up^ Tamirisa, K. P.; Aaronson, K. D.; Koelling, T. M. (2004). “Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure”. American Heart Journal. 148(6): 971–8. doi:10.1016/j.ahj.2004.10.005. PMID 15632880.
^ Jump up to:^a ^b ^c ^d ^e ^f Taal, M.W.; Chertow, G.M.; Marsden, P.A.; Skorecki, K.; Yu, A.S.L.; Brenner, B.M. (2012). Brenner and Rector’s The Kidney (Chapter 17, page 672, 9th ed.). Elsevier. ISBN 978-1-4160-6193-9.
Jump up^ Fang, J.; Madhavan, S.; Cohen, H.; Alderman, M. H. (2000). “Serum potassium and cardiovascular mortality”. Journal of General Internal Medicine. 15 (12): 885–90. doi:10.1046/j.1525-1497.2000.91021.x. PMC 1495719 . PMID 11119186.
^ Jump up to:^a ^b Watson, M.; Abbott, K. C.; Yuan, C. M. (2010). “Damned if You Do, Damned if You Don’t: Potassium Binding Resins in Hyperkalemia”. Clinical Journal of the American Society of Nephrology. 5 (10): 1723–6. doi:10.2215/CJN.03700410. PMID 20798253.
Jump up^ Emmett, M.; Hootkins, R. E.; Fine, K. D.; Santa Ana, C. A.; Porter, J. L.; Fordtran, J. S. (1995). “Effect of three laxatives and a cation exchange resin on fecal sodium and potassium excretion”. Gastroenterology. 108 (3): 752–60. doi:10.1016/0016-5085(95)90448-4. PMID 7875477.
Jump up^ Sterns, R. H.; Rojas, M.; Bernstein, P.; Chennupati, S. (2010). “Ion-Exchange Resins for the Treatment of Hyperkalemia: Are They Safe and Effective?”. Journal of the American Society of Nephrology. 21 (5): 733–5. doi:10.1681/ASN.2010010079. PMID 20167700.
Jump up^ Kamel, K. S.; Schreiber, M. (2012). “Asking the question again: Are cation exchange resins effective for the treatment of hyperkalemia?”. Nephrology Dialysis Transplantation. 27(12): 4294–7. doi:10.1093/ndt/gfs293. PMID 22989741.
Jump up^ Denry I, Kelly JR. State of the art of zirconia for dental applications. Dental Materials. Volume 24, Issue 3, March 2008, Pages 299–307
Jump up^ =Stavros, F (2014). “Characterization of Structure and Function of ZS-9, a K⁺ Selective Ion Trap”. PLOS ONE. 9 (12): e114686. doi:10.1371/journal.pone.0114686. PMC 4273971 . PMID 25531770.
Jump up^ Ash SR, et al. “Safety and efficacy of ZS-9, a novel selective cation trap, for treatment of hyperkalemia in CKD patients.” American Society of Nephrology 2013 conference, Late-Breaking Abstract.
^ Jump up to:^a ^b Packham DK, et al. (2014). “Sodium zirconium cyclosilicate in hyperkalemia”. New England Journal of Medicine. 372 (3): 222–31. doi:10.1056/NEJMoa1411487. PMID 25415807.
^ Jump up to:^a ^b Kosiborod M, et al. (2014). “Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia”. Journal of the American Medical Association. 312 (21): 2223–33. doi:10.1001/jama.2014.15688. PMID 25402495.
Jump up^ Ben Adams (May 27, 2016). “AstraZeneca’s $2.7B hyperkalemia drug ZS-9 rejected by FDA”. FierceBiotech.
Jump up^ https://www.drugs.com/history/lokelma.html

Sodium zirconium cyclosilicate
Clinical data
Crystal structure of ZS-9. Blue spheres = oxygen atoms, red spheres = zirconium atoms, green spheres = silicon atoms.
Trade names	Lokelma
Routes of administration	Oral
ATC code	none
Legal status
Legal status	US: Rx-only
Pharmacokinetic data
Bioavailability	Not absorbed
Excretion	Stool
Identifiers
IUPAC name [show]
CAS Number	242800-27-7
UNII	D652ZWF066
KEGG	D10727

//////////////Sodium zirconium cyclosilicate, ナトリウムジルコニウムシクロケイ酸塩 , FDA 2018, EMA, 2018, EU 2018, ZS 9, UZSi-9

O[Si]1(O[Si](O[Si](O1)(O)O)(O)O)O.[Na+].[Na+].[Zr

Glycopyrronium bromide, гликопиррония бромид , بروميد غليكوبيرونيوم , 格隆溴铵 , グリコピロニウム臭化物

September 6, 2018 9:32 am / Leave a comment

ChemSpider 2D Image | glycopyrronium bromide | C19H28BrNO3

Glycopyrronium bromide

гликопиррония бромид [Russian] [INN]

بروميد غليكوبيرونيوم [Arabic] [INN]

格隆溴铵 [Chinese] [INN]

グリコピロニウム臭化物

Cas 596-51-0,

3-Hydroxy-1,1-dimethylpyrrolidinium bromide α-cyclopentylmandelate (6CI,7CI)
Pyrrolidinium, 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl-, bromide (9CI)
Pyrrolidinium, 3-hydroxy-1,1-dimethyl-, bromide, α-cyclopentylmandelate (8CI)
1,1-Dimethyl-3-hydroxypyrrolidinium bromide α-cyclopentylmandelate
AHR-504

Asecryl
Copyrrolate
Gastrodyn
Glycopyrrolate
Glycopyrrolate bromide
Glycopyrrone bromide
Glycopyrronium bromide
NSC 250836
NSC 251251
NSC 251252
NVA 237
Nodapton
Robanul
Robinul
Seebri
Tarodyl
Tarodyn
β-1-Methyl-3-pyrrolidyl-α-cyclopentylmandelate methobromide

CAS FREE FORM OF ABOVE 13283-82-4

3-{[Cyclopentyl(hydroxy)phenylacetyl]oxy}-1,1-dimethylpyrrolidiniumbromide

3-Hydroxy-1,1-dimethylpyrrolidinium bromide α-cyclopentylmandelate

596-51-0 [RN]

Glycopyrrolate, ATC:A03AB02

Use:anticholinergic, antispasmodic
Chemical name:3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide
Formula:C₁₉H₂₈BrNO_3,MW:398.34 g/mol

EINECS:209-887-0
LD₅₀:15 mg/kg (M, i.v.); 570 mg/kg (M, p.o.);
709 mg/kg (R, p.o.)

Title: Glycopyrrolate

CAS Registry Number: 596-51-0

CAS Name: 3-[(Cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide

Additional Names: 3-hydroxy-1,1-dimethylpyrrolidinium bromide a-cyclopentylmandelate; a-cyclopentylmandelic acid ester with 3-hydroxy-1,1-dimethylpyrrolidinium bromide; 1-methyl-3-pyrrolidyl a-cyclopentylmandelate methobromide; 1-methyl-3-pyrrolidyl a-phenyl-a-cyclopentylglycolate methobromide; 3-(2-phenyl-2-cyclopentylglycoloyloxy)-1,1-dimethylpyrrolidinium bromide; glycopyrronium bromide

Manufacturers’ Codes: AHR-504

Trademarks: Nodapton; Robanul; Robinul (Robins); Tarodyl; Tarodyn

Molecular Formula: C19H28BrNO3

Molecular Weight: 398.33

Percent Composition: C 57.29%, H 7.09%, Br 20.06%, N 3.52%, O 12.05%

Literature References: Synthetic, quaternary ammonium anticholinergic. Prepn: Franko, Lunsford, J. Med. Pharm. Chem.2, 523 (1960); Lunsford, US2956062 (1960 to A. H. Robins). Pharmacodynamics: E. Kaltiala et al.,J. Pharm. Pharmacol.26, 352 (1974). Toxicology: B. V. Franko et al.,Toxicol. Appl. Pharmacol.17, 361 (1970). Clinical comparison with atropine in anaesthetic practice: F. Kongsrud, S. Sponheim, Acta Anaesthesiol. Scand.26, 620 (1982); A. I. Webb, R. M. McMurphy, Am. J. Vet. Res.48, 1733 (1987); B. V. G. Malling et al.,Br. J. Anaesth.60, 426 (1988). Brief review of pharmacology and clinical use: R. K. Mirakhur, J. W. Dundee, Anaesthesia38, 1195-1204 (1983).

Properties: White crystals from butanone, mp 193.2-194.5°. Sol in water. LD50 (72 hr.) in female mice, female rats (mg/kg): 107, 196 i.p.; in male rats (mg/kg): 1150 orally (Franko).

Melting point: mp 193.2-194.5°

Toxicity data: LD50 (72 hr.) in female mice, female rats (mg/kg): 107, 196 i.p.; in male rats (mg/kg): 1150 orally (Franko)

Therap-Cat: Antispasmodic; preanesthetic medicant.

Therap-Cat-Vet: Preanesthetic medicant.

Keywords: Antimuscarinic; Antispasmodic

ALSO

Pyrrolidinium, 3-[[(2R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl]oxy]-1,1-dimethyl-, bromide (1:1), (3S)-rel–

Cas 51186-83-5

Pyrrolidinium, 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl-, bromide, (R*,S*)-(±)-
Pyrrolidinium, 3-[[(2R)-cyclopentylhydroxyphenylacetyl]oxy]-1,1-dimethyl-, bromide, (3S)-rel- (9CI)
erythro-Glycopyrronium bromide

FREE FORM OF ABOVE 740028-90-4

NMR analysis of the diastereomers of glycopyrronium bromide
Finnish Chemical Letters (1975), (3-4), 94-6

Michael Woehrmann, Lara Terstegen, Stefan Biel, Thomas Raschke, Svenja-Kathrin Cerv, Werner Zilz, Sven Untiedt, Thomas Nuebel, Uwe Schoenrock, Heiner Max, Helga Biergiesser, Yvonne Eckhard, Heike Miertsch, Heike Foelster, Cornelia Meier-Zimmerer, Bernd Traupe, Inge Kruse, “GLYCOPYRROLATE IN COSMETIC PREPARATIONS.” U.S. Patent US20090208437, issued August 20, 2009.US20090208437

EMA

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002691/WC500133700.pdf

Glycopyrronium bromide, the active substance of Enurev Breezhaler, is a well known active substance, chemically designated as 3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium bromide or (3RS)-3-[(2SR)-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide, and has the following structure:

It is a white, non-hygroscopic powder, freely soluble in water, soluble in ethanol (96%), very slightly soluble in methylene chloride. The substance is also freely soluble in simulated lung fluid (phosphate buffer pH 7.4). Glycopyrronium bromide is a quaternary ammonium salt (ionic compound) and it is completely ionized between pH 1 and 14. It is a racemic mixture of the 3R,2S and 3S,2R stereoisomers. No optical rotation is seen in solution. Only single polymorphic form (crystalline Form A) has been reported.

Glycopyrronium bromide is a medication of the muscarinic anticholinergic group. It does not cross the blood–brain barrier and consequently has no to few central effects. It is available in by mouth, intravenous, and inhalated forms.It is a synthetic quaternary amine. It was developed by Sosei and licensed to Novartis in 2005. The cation, which is the active moiety, is called glycopyrronium (INN)^[1] or glycopyrrolate (USAN).In June 2018, glycopyrronium was approved by the FDA to treat excessive underarm sweating becoming the first drug developed specifically to reduce excessive sweating.^[2]

Glycopyrrolate is a muscarinic antagonist used as an antispasmodic, in some disorders of the gastrointestinal tract, and to reduce salivation with some anesthetics.

Glycopyrrolate is a synthetic quaternary ammonium that is an anticholinergic agent with antispasmodic activity. Glycopyrrolate competitively binds to peripheral muscarinic receptors in the autonomic effector cells of, and inhibits cholinergic transmission in smooth muscle, cardiac muscle, the sinoatrial (SA) node, the atrioventricular (AV) node, exocrine glands and in the autonomic ganglia. Blockage of cholinergic transmission, in smooth muscle cells located in the gastrointestinal tract and the bladder, causes smooth muscle relaxation and prevents the occurrence of painful spasms. In addition, glycopyrrolate inhibits the release of gastric, pharyngeal, tracheal, and bronchial secretions.

Glycopyrrolate is an anticholinergic agent used to treat gastrointestinal conditions associated with intestinal spasm and to decrease secretions during anesthesia. Glycopyrrolate has not been implicated in causing liver enzyme elevations or clinically apparent acute liver injury.

Glycopyrronium (as the bromide salt glycopyrrolate) is a synthetic anticholinergic agent with a quaternary ammonium structure. A muscarinic competitive antagonist used as an antispasmodic, in some disorders of the gastrointestinal tract, and to reduce salivation with some anesthetics. In October 2015, glycopyrrolate was approved by the FDA for use as a standalone treatment for Chronic obstructive pulmonary disease (COPD), as Seebri Neohaler.

Medical uses

In anesthesia, glycopyrronium injection can be used as a before surgery in order to reduce salivary, tracheobronchial, and pharyngealsecretions, as well as decreasing the acidity of gastric secretion. It is also used in conjunction with neostigmine, a neuromuscular blocking reversal agent, to prevent neostigmine’s muscarinic effects such as bradycardia.

It is also used to reduce excessive saliva (sialorrhea),^[3]^[4]^[5] and Ménière’s disease.^[6]

It decreases acid secretion in the stomach and so may be used for treating stomach ulcers, in combination with other medications.

It has been used topically and orally to treat hyperhidrosis, in particular, gustatory hyperhidrosis.^[7]^[8]

In inhalable form it is used to treat chronic obstructive pulmonary disease (COPD). Doses for inhalation are much lower than oral ones, so that swallowing a dose will not have an effect.^[9]^[10]

Side effects

Since glycopyrronium reduces the body’s sweating ability, it can even cause hyperthermia and heat stroke in hot environments. Dry mouth, difficulty urinating, headaches, diarrhea and constipation are also observed side effects of the medication. The medication also induces drowsiness or blurred vision, an effect exacerbated by the consumption of alcohol.

Pharmacology

Mechanism of action

Glycopyrronium blocks muscarinic receptors,^[11] thus inhibiting cholinergic transmission.

Pharmacokinetics

Glycopyrronium bromide affects the gastrointestinal tracts, liver and kidney but has a very limited effect on the brain and the central nervous system. In horse studies, after a single intravenous infusion, the observed tendencies of glycopyrronium followed a tri-exponential equation, by rapid disappearance from the blood followed by a prolonged terminal phase. Excretion was mainly in urine and in the form of an unchanged drug. Glycopyrronium has a relatively slow diffusion rate, and in a standard comparison to atropine, is more resistant to penetration through the blood-brain barrier and placenta.^[12]

Research

It has been studied in asthma.^[13]^[14]

Synthesis

https://data.epo.org/publication-server/rest/v1.0/publication-dates/20090513/patents/ep1856041nwb1/document.html

Image result for Glycopyrronium bromide synthesis

PATENT

https://patents.google.com/patent/CN103819384A/en

Image result for Glycopyrronium bromide synthesis

Figure CN103819384AD00041

PAtent

https://patents.google.com/patent/CN103159659A/en

Image result for Glycopyrronium bromide synthesis

glycopyrrolate (I)

Methyl ethyl ketone (20mL) IOOmL three-necked flask was added 8 (4.6g, 15mmol) was, at (Γ5 ° C was added dropwise dibromomethane (2.9g, 30mmol) in butanone (5 mL) was added dropwise completed, continued The reaction was stirred for 15min, and a white solid precipitated, was allowed to stand 36h at room temperature, filtered off with suction, the filter cake was sufficiently dried to give crude ketone was recrystallized twice to give a white powdery crystals I (3.9g, 66%) mp 191~193 ° C chromatographic purity 99.8% [HPLC method, mobile phase: lmol / L triethylamine acetate – acetonitrile – water (1: 150: 49); detection wavelength: 230nm, a measurement of the area normalization method] .MS m / z: 318 ( m-BrO 1HNMR (CD3OD) δ:! 1.33~1.38 (m, 2H), 1.55~1.70 (m, 6H), 2.11~2.21 (m, 1H), 2.67~2.80 (m, 1H), 3.02 (m, 1H), 3.06 (s, 3H), 3.23 (s, 3H), 3.59~3.71 (m, 3H), 3.90 (dd, /=13.8,1H), 5.47 (m, 1H), 7.27 (t, 1H) , 7.35 (t, 2H), 7.62 (dd, 2H) .13C bandit R (DMSO) δ: 27.0, 27.4, 28.0, 31.3, 47.8, 53.8, 54.3, 66.0, 71.3, 74.6, 81.1, 126.9,128.7,129.3 , 143.2 17 5.00

Patent

https://patents.google.com/patent/WO2016204998A1/en

Image result for Glycopyrronium bromide synthesis

PATENT

https://patents.google.com/patent/EP2417106B1/en

Glycopyrronium bromide, also known as 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide or glycopyrrolate, is an antimuscarinic agent that is currently administered by injection to reduce secretions during anaesthesia and or taken orally to treat gastric ulcers.
[0003]

It has the following chemical structure:
[0004]
United States patent US 2,956,062 discloses that 1-methyl-3-pyrrolidyl alpha-cyclopentyl mandelate and can be prepared from methyl alpha cyclopentylmandelate and that the methyl bromide quaternary salt can be prepared by saturating a solution of 1-methyl-3-pyrrolidyl alpha-cyclopentyl mandelate in dry ethyl acetate with methyl bromide and filtering the crystalline solid that appears on standing.
[0005]
The process of US 2,956,062 for preparing 1-methyl-3-pyrrolidyl alpha-cyclopentyl mandelate involves transesterifying methyl glycolate with an amino alcohol under the influence of metallic sodium to give a glycolate intermediate. Metallic sodium is highly reactive, which poses health and safety risks that make its use undesirable on an industrial scale for commercial manufacture.
[0006]
The process of US 2,956,062 requires preparing the methylester in a previous step and alkylating the amino esters in a later step to form the desired quaternary ammonium salts.
[0007]
The process of US 2,956,062 provides a mixture of diastereoisomers. The relative proportions of the diastereoisomers can vary widely between batches. This variation can give rise to surprising differences when preparing dry powder formulations from glycopyrronium bromide, which can cause problems when formulating such dry powders for pharmaceutical use.
[0008]
United States patent application US 2007/0123557 discloses 1-(alkoxycarbonylmethyl)-1-methylpyrrolidyl anticholinergic esters. It describes coupling (R)-cyclopentylmandelic acid with (R,S)-1-methyl-pyrrolidin-3-ol under Mitsunobu conditions to give pure (R)-stereoisomeric compounds that are reacted with a bromoacetate to give the desired esters. It should be noted however that the chemicals used in Mitsunobu reactions, typically dialkyl azodicarboxylates and triphenylphosphine, pose health, safety and ecological risks that make their use undesirable on an industrial scale for commercial manufacture. They are also generally too expensive to source and too laborious to use in commercial manufacture.
[0009]
United States patent application US 2006/0167275 discloses a process for the enrichment of the R, R- or S, S-configured glycopyrronium isomers and their thienyl analogues having R, S or S, R configuration.
[0010]
WO 03/087094 A2 discloses new therapeutically useful pyrrolidinium derivatives, processes for their preparation and pharmaceutical compositions containing them.

Image result for Glycopyrronium bromide synthesis

EXAMPLE Example 1 Preparation of (3S,2’R)- and (3R,2’S)-3-[(cyclopentyl-hydroxyphenylacetyl)-oxy]-1,1-dimethylpyrrolidinium bromide

[0071]
30 g of cyclopentyl mandelic acid, dissolved in 135 g dimethylformamide (DMF), were treated with 27 g carbonyldiimidazole at 18°C (in portions) to form the “active amide”. After the addition of 16.9 g of 1-methyl-pyrrolidin-3-ol, the mixture was heated to 60°C within 1 hour and stirred for 18 hours at this temperature. After checking for complete conversion, the mixture was cooled and 200 g water was added. The mixture was extracted with 200 g toluene and the extract was washed with water three times. The organic phase was concentrated to obtain cyclopentyl-hydroxy-phenyl-acetic acid 1-methyl-pyrrolidin-3-yl ester as an about 50% solution in toluene, ready to use for the next step.
[0072]
This solution was diluted with 120 g of n-propanol and cooled to 0°C. 16.8 g methyl bromide was introduced and the mixture was stirred for 2 hours and then gradually heated to 60°C to evaporate the excess methyl bromide into a scrubber. The mixture was then cooled to 50°C and seed crystals were added to facilitate crystallisation. The temperature was then slowly reduced over 18 hours to 15°C. The solid was then isolated by filtration to obtain 22.7 g after drying. It was composed mainly of one pair of enantiomers, a racemic mixture of (3S,2’R)- and (3R,2’S)-3-[(cyclopentyl-hydroxyphenylacetyl)-oxy]-1,1-dimethylpyrrolidinium bromide, with a purity greater than 90% (by HPLC). The other pair of diastereoisomers ((3R,2’R)- and (3S,2’S)-3-[(cyclopentyl-hydroxyphenyl-acetyl)-oxyl-1,1-dimethylpyrrolidinium bromide) remains mainly in the filtrate as those compounds are significantly more soluble in n-propanol than the other stereoisomers.
[0073]
The solid obtained is further recrystallised in n-propanol (1:10 wt) to give pure (3S,2’R)- and (3R,2’S)-3-[(cyclopentyl-hydroxyphenylacetyl)-oxy]-1,1-dimethylpyrrolidinium bromide i.e. purity > 99.9% as determined by high performance liquid chromatography (HPLC).
[0074]

This process is summarised in the following reaction scheme:

Reference Example 2 Preparation of cyclopentyl-hydroxy-phenyl-acetic acid 1-methyl-pyrrolidin-3yl-ester in toluene

[0075]
1 g of cyclopentyl mandelic acid was suspended in 4.7 g of toluene and 1.5 g of carbonyldiimidazole were added as a solid. After 30 minutes 0.69 g of 1-methyl-pyrrolidin-3-ol and 20 mg of sodium tert-butylate were added. The mixture was stirred at room temperature for 18 hours then water was added. After stirring the phases were separated and the organic phase was washed with water twice and evaporated to obtain an approximately 50% solution of cyclopentyl-hydroxy-phenyl-acetic acid 1-methyl-pyrrolidin-3yl-ester in toluene.

Example 3 Preparation of 2-cyclopentyl-2-hydroxy-1-imidazol-1-yl-2-phenyl-ethanone, the active intermediate

[0076]
The imidazolidyl derivative of cyclopentylmandelic acid was prepared and isolated as a solid by the following method:
[0077]
10 g of cyclopentylmandelic acid were suspended in 30 ml of acetonitrile and the mixture was cooled to 0°C. 10.3 g of carbonyldiimidazole were added as a solid and the mixture was warmed to room temperature for 2 hours. Carbon dioxide evolved as a gas as a precipitate formed. The mixture was then cooled to 5°C and the solid was filtered, washed with acetonitrile and dried in vacuum at 40°C to obtain 7.3 g of pure 2-cyclopentyl-2-hydroxy-1-imidazol-1-yl-2-phenyl-ethanone.
[0078]

This process is summarised in the following reaction scheme:
[0079]
High resolution MS-spectroscopy revealed the molecular formula of the compound (as M+H) to be C₁₆H₁₉O₂N₂ with an exact mass of 271.14414 (0.14575ppm deviation from the calculated value).
¹H-NMR-spectroscopy (600MHz, DMSO-d₆): 1.03-1.07 (m, 1H), 1.25-1.30 (m, 1H), 1.35-1.40 (m, 1H), 1.40-1.50 (m, 1H), 1.53-1.56 (m, 2H), 1-60-1.67 (m, 1H), 1.75-1.84 (m, 1H), 1.03 – 1.85 (8H, 8 secondary CH₂-protons in the cyclopentylring, H-C11, H-C12, H-C13, H-C14); 2.7-2.9 (m, 1H, H-C10); 6.76 (1H, H-C5); 6.91 (1H, H-C4); 7.29 (1H, H-C18); 7.39 (2H, H-C17, H-C19); 7.49 (2H, H-C16, H-C20); 7.65 (1H, H-C2).

[0080]

The compound was characterised by IR-spectroscopy (measured as a solid film on a BRUKER TENSOR 27 FT-IR spectrometer over a wave number range of 4000-600 cm^-1 with a resolution of 4 cm^-1). An assignment of the most important bands is given below:

Wavenumber (cm^-1)	Assignments
3300 ∼ 2500	O-H stretching
3167, 3151, 3120	Imidazole CH stretching
2956, 2868	Cyclopentyl CH stretching
1727	C=O stretching
1600, 1538, 1469	Aromatic rings stretching
735	Mono-subst. benzene CH o.o.p. bending
704	Mono-subst. benzene ring o.o.p. bending

SYN

PAPER

https://link.springer.com/article/10.1007/s41981-018-0015-4

Journal of Flow Chemistry, pp 1–8| Cite as

Sequential α-lithiation and aerobic oxidation of an arylacetic acid – continuous-flow synthesis of cyclopentyl mandelic acid

Open Access

Communications

First Online: 09 August 2018

Image result for Glycopyrronium bromide synthesis

The medicinal properties of glycopyrronium bromide (glycopyrrolate, 4) were first identified in the late 1950s [1]. Glycopyrrolate is an antagonist of muscarinic cholinergic receptors and is used for the treatment of drooling or excessive salivation (sialorrhea) [2], excess sweating (hyperhidrosis) [3], and overactive bladder and for presurgery treatment. In addition, it has recently been introduced as an effective bronchodilator for the treatment of chronic obstructive pulmonary disease (COPD) for asthma patients [4]. Glycopyrrolate displays few side effects because it does not pass through the blood brain barrier. Cyclopentyl mandelic acid (CPMA, 1), or its corresponding ester derivatives, are key intermediates in the synthetic routes to 4. CPMA (1) reacts with 1-methyl-pyrrolidin-3-ol (2) to form tertiary amine 3. N-Methylation of 3 by methyl bromide gives quaternary ammonium salt glycopyrrolate 4 as a racemate (Scheme 1) [5].

Scheme 1

Synthesis of glycopyrrolate 4 from CPMA (1)

CPMA (1) is a synthetically challenging intermediate to prepare (Scheme 2). Routes A to D are most likely to be the commercially applied methods because these procedures are described in patents [5]. The published descriptions for the yields of 1 range from 28 to 56% for routes A to D. Ethyl phenylglyoxylate is reacted with cyclopentyl magnesium bromide to form an ester which is then hydrolyzed (route A) [6]. Phenylglyoxylic acid can be reacted in a similar manner with cyclopentyl magnesium bromide to directly form 1 (route B) [7]. Alternatively, the inverse addition of phenyl-Grignard reagent to cyclopentyl glyoxylic acid ester is reported (route C) [8]. Cyclopentyl glyoxylic acid ester can also be reacted with cyclopentadienyl magnesium bromide which is followed by an additional hydrogenation step with Pd/C and H₂ to afford 1 (route D) [9, 10].

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018154597&recNum=&maxRec=1000&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

EXA M PL E S

EXAM PL E 1

Scheme 1

ST E P I

To a stirred solution of N-methyl pyrrol i din- 3-ol (2, 1 equiv) and Et₃N (1.2 equiv) in dichloromethane was added a solution of 2-cyclopentyl-2-oxoacetyl chloride (1, 1.1 equiv) in DCM at O °C under nitrogen atmosphere for 20 min. The resulting solution was allowed to stir at room temperature over 10h. After completion, the mixture was quenched with water and extracted with diethyl ether to afford the pure product (3A).

Similarly, the product 3A is also obtained by reaction of 2 with other reagents, phenyl oxalic acid, methyl phenyl oxalate, and phenyl hemi-oxaldehyde respectively as shown in Scheme 1.

ST E P II

To a mixture of bromobenzene (2.2 equiv) and Mg metal (2.2 equiv) in TH F (15 mL) was stirred over a period of 30 min at 0 · C. To this mixture, a solution of 1 -methyl pyrrol idin-3-yl 2-cyclopentyl-2-oxoacetate (3, 1 equiv) in T HF was added in portions over a period of 30 min. Up on completion, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was separated and concentrated in vacuo. The resulting residue was purified by column chromatography to afford the pure product (5).

ST E P III

To a solution of compound 5 (1 equiv) in acetonitrile and chloroform mixture (10 mL, 2:3) was added methyl bromide (4 equiv). The mixture was stirred at room temperature for 72h. The solvents were evaporated, and the resulting residue was washed with diethyl ether to afford the pure product (6) as a white solid.

EXAM PL E 2

Scheme 2

ST E P I

To a stirred solution of N-methyl pyrrol i din- 3-ol (2, 1 equiv) and Et₃N (1.2 equiv) in dichloromethane was added a solution of 2- oxo-2- phenyl acetyl chloride (1.1 equiv) in dichloromethane at 0 °C under nitrogen atmosphere for 15 min. The resulting solution was allowed to stir at room temperature over 12h. After completion, the mixture was quenched with water and extracted with diethyl ether to afford the pure product (3B).

Similarly, the product 3B is also obtained by reaction of 2 with other reagents, phenyl oxalic acid, methyl phenyl oxalate, and phenyl hemi-oxaldehyde respectively as shown in Scheme 2.

ST E P II

To a mixture of cyclopentyl bromide (4, 2.2 equiv) and Mg metal (2.2 equiv) in THF (15 mL) was stirred over a period of 30 min at 0 – C. To this mixture, a solution of 1-methylpyrrolidin-3-yl-2-oxo-2-phenylacetate (3B, 1 equiv) in TH F was added in portions over a period of 30 min. Up on completion, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was separated and concentrated in vacuo. The resulting residue was purified by column chromatography to afford the pure product (5).

ST E P III

To a solution of compound 5 (1 equiv) in acetonitrile and chloroform mixture (10 mL, 2:3) was added methyl bromide (4 equiv). The mixture was stirred at room temperature for 75h. The solvents were evaporated, and the resulting residue was washed with diethyl ether to afford the pure product (6) as a white solid.

The invention has been described in detail with reference to preferred embodiments thereof. However, it will be appreciated by those skilled in the art that changes may be made in these embodiments without departing from the principles and nature of the invention, the scope of which is defined in the appended claims and their equivalents.

CN102388021A *2009-04-092012-03-21诺瓦提斯公司Process for preparing pyrrolidinium salts

CN102627595A *2012-03-092012-08-08徐奎Method for preparation of glycopyrronium bromide

CN103159659A *2011-12-192013-06-19沈阳药科大学Preparation method of muscarinic receptor antagonist glycopyrronium bromide

References

Jump up^ Bajaj V, Langtry JA (July 2007). “Use of oral glycopyrronium bromide in hyperhidrosis”. Br. J. Dermatol. 157 (1): 118–21. doi:10.1111/j.1365-2133.2007.07884.x. PMID 17459043.
Jump up^ “FDA OKs first drug made to reduce excessive sweating”. AP News. Retrieved 2018-07-02.
Jump up^ Mier RJ, Bachrach SJ, Lakin RC, Barker T, Childs J, Moran M (December 2000). “Treatment of sialorrhea with glycopyrrolate: A double-blind, dose-ranging study”. Arch Pediatr Adolesc Med. 154 (12): 1214–8. doi:10.1001/archpedi.154.12.1214. PMID 11115305.
Jump up^ Tscheng DZ (November 2002). “Sialorrhea – therapeutic drug options”. Ann Pharmacother. 36 (11): 1785–90. doi:10.1345/aph.1C019. PMID 12398577.^{[permanent dead link]}
Jump up^ Olsen AK, Sjøgren P (October 1999). “Oral glycopyrrolate alleviates drooling in a patient with tongue cancer”. J Pain Symptom Manage. 18 (4): 300–2. doi:10.1016/S0885-3924(99)00080-9. PMID 10534970.
Jump up^ Maria, Sammartano Azia; Claudia, Cassandro; Pamela, Giordano; Andrea, Canale; Roberto, Albera (1 December 2012). “Medical therapy in Ménière’s disease”. Audiological Medicine. 10 (4): 171–177. doi:10.3109/1651386X.2012.718413 – via Taylor and Francis+NEJM.
Jump up^ Kim WO, Kil HK, Yoon DM, Cho MJ (August 2003). “Treatment of compensatory gustatory hyperhidrosis with topical glycopyrrolate”. Yonsei Med. J. 44 (4): 579–82. doi:10.3349/ymj.2003.44.4.579. PMID 12950111.
Jump up^ Kim WO, Kil HK, Yoon KB, Yoon DM (May 2008). “Topical glycopyrrolate for patients with facial hyperhidrosis”. Br. J. Dermatol. 158 (5): 1094–7. doi:10.1111/j.1365-2133.2008.08476.x. PMID 18294315.
Jump up^ “EPAR – Product information for Seebri Breezhaler” (PDF). European Medicines Agency. 28 September 2012.
Jump up^ Tzelepis G, Komanapolli S, Tyler D, Vega D, Fulambarker A (January 1996). “Comparison of nebulized glycopyrrolate and metaproterenol in chronic obstructive pulmonary disease”. Eur. Respir. J. 9 (1): 100–3. doi:10.1183/09031936.96.09010100. PMID 8834341.
Jump up^ Haddad EB, Patel H, Keeling JE, Yacoub MH, Barnes PJ, Belvisi MG (May 1999). “Pharmacological characterization of the muscarinic receptor antagonist, glycopyrrolate, in human and guinea-pig airways”. Br. J. Pharmacol. 127 (2): 413–20. doi:10.1038/sj.bjp.0702573. PMC 1566042 . PMID 10385241.
Jump up^ Rumpler, M.J.; Colahan, P.; Sams, R.A. (2014). “The pharmacokinetics of glycopyrrolate in Standardbred horses”. J. Vet Pharmacol Ther. 37 (3): 260–8. doi:10.1111/jvp.12085. PMID 24325462.
Jump up^ Hansel TT, Neighbour H, Erin EM, et al. (October 2005). “Glycopyrrolate causes prolonged bronchoprotection and bronchodilatation in patients with asthma”. Chest. 128 (4): 1974–9. doi:10.1378/chest.128.4.1974. PMID 16236844.
Jump up^ Gilman MJ, Meyer L, Carter J, Slovis C (November 1990). “Comparison of aerosolized glycopyrrolate and metaproterenol in acute asthma”. Chest. 98 (5): 1095–8. doi:10.1378/chest.98.5.1095. PMID 2225951.

Glycopyrronium bromide
Clinical data

Trade names	Robinul, Cuvposa, Seebri, Qbrexza, others
License data	EU EMA: by INN
Pregnancy category	AU: B2 US: B (No risk in non-human studies)
ATC code	A03AB02 (WHO) R03BB06(WHO)
Legal status
Legal status	AU: S4 (Prescription only) US: ℞-only
Identifiers
IUPAC name [show]
CAS Number	51186-83-5
PubChemCID	11693
ChemSpider	11201
UNII	V92SO9WP2I
ECHA InfoCard	100.008.990
Chemical and physical data
Formula	C₁₉H₂₈BrNO₃
Molar mass	398.335 g/mol
3D model (JSmol)	Interactive image

Glycopyrronium
Clinical data

AHFS/Drugs.com	Monograph
MedlinePlus	a602014
Pregnancy category	US: B (No risk in non-human studies)
Routes of administration	By mouth, intravenous, inhalation
ATC code	A03AB02 (WHO) R03BB06 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Elimination half-life	0.6–1.2 hours
Excretion	85% renal, unknown amount in the bile
Identifiers
IUPAC name [show]
CAS Number	596-51-0
PubChem CID	3494
IUPHAR/BPS	7459
DrugBank	DB00986
ChemSpider	3374
UNII	V92SO9WP2I
KEGG	D00540
ChEMBL	CHEMBL1201335
ECHA InfoCard	100.008.990
Chemical and physical data
Formula	C₁₉H₂₈NO₃⁺
Molar mass	318.431 g/mol
3D model (JSmol)	Interactive image

///////////Glycopyrronium bromide, гликопиррония бромид , بروميد غليكوبيرونيوم , 格隆溴铵 , 596-51-0, Glycopyrrolate, ATC:A03AB02, Use:anticholinergic, antispasmodic, グリコピロニウム臭化物 ,

C[N+]1(CCC(C1)OC(=O)C(C2CCCC2)(C3=CC=CC=C3)O)C.[Br-]

Stiripentol, スチリペントール

September 3, 2018 7:55 am / Leave a comment

ChemSpider 2D Image | Stiripentol | C14H18O3

Stiripentol

スチリペントール

STIRIPENTOL; Diacomit; 49763-96-4; BCX 2600; Estiripentol; Stiripentolum

CAS:	137767-55-6 49763-96-4

(E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-ol

Molecular Formula:	C₁₄H₁₈O₃
Molecular Weight:	234.295 g/mol

UNII

R02XOT8V8I, Diacomit

fda approval 2018/8/20

Stiripentol (marketed as Diacomit by Laboratoires Biocodex) is an anticonvulsant drug used in the treatment of epilepsy. It is approved for the treatment of Dravet syndrome, an epilepsy syndrome. It is unrelated to other anticonvulsants and belongs to the group of aromatic allylic alcohols.

Medical use

It is used in some countries as an add-on therapy with sodium valproate and clobazam for treating children with Dravet syndromewhose seizures are not adequately controlled.^[1]^[2]^[3] As of 2017 it was not known whether stiripentol remains useful as children become adolescents nor as they become adults.^[4]

Adverse effects

Very common (more than 10% of people) adverse effects include loss of appetite, weight loss, insomnia, drowsiness, ataxia, hypotonia, and dystonia.^[3]

Common (between 1% and than 10% of people) adverse effects include neutropenia (sometimes severe), aggressiveness, irritability, behavior disorders, opposing behavior, hyperexcitability, sleep disorders, hyperkinesias, nausea, vomiting, and elevated gamma-glutamyltransferase.^[3]

Interactions

Stiripentol inhibits several cytochrome P450 isoenzymes and so interacts with many anticonvulsants and other medicines.^[3]

Pharmacology

As with most anticonvulsants, the precise mechanism of action is unknown. Regardless, stiripentol has been shown to have anticonvulsant effects of its own.

Stiripentol increases GABAergic activity. At clinically relevant concentrations, it enhances central GABA neurotransmission through a barbiturate-like effect, since it increases the duration of opening of GABA-A receptor channels in hippocampal slices.^[5] It has also been shown to increase GABA levels in brain tissues by interfering with its reuptake and metabolism.^[6] Specifically, it has been shown to inhibit lactate dehydrogenase, which is an important enzyme involved in the energy metabolism of neurons. Inhibition of this enzyme can make neurons less prone to fire action potentials, likely through activation of ATP-sensitive potassium channels.^[7]

Stiripentol also improves the effectiveness of many other anticonvulsants, possibly due to its inhibition of certain enzymes, slowing the drugs’ metabolism and increasing blood plasma levels.^[3]

Chemistry

Stiripentol is an α-ethylene alcohol; its chemical formula is 4,4-dimethyl-1-[3,4-(methylendioxy)-phenyl]-1penten-3-ol. It is chiral and is marketed as an equimolar racemic mixture. The R enantiomer appears to be around 2.5 times more active than the S enantiomer.^[8]

Paper

Tetrahedron: Asymmetry

Volume 24, Issues 5–6, 31 March 2013, Pages 285-289

https://www.sciencedirect.com/science/article/abs/pii/S0957416613000529

Synthesis of the antiepileptic (R)-Stiripentol by a combination of lipase catalyzed resolution and alkene metathesis

https://doi.org/10.1016/j.tetasy.2013.02.006

The enantiopure (ee >99%) antiepileptic (R)-(+)-Stiripentol has been stereoselectively synthesized via cross metathesis of 5-vinylbenzo[d][1,3]dioxole 1 and (R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2. A novel one-pot two-step pathway for the synthesis of 5-vinylbenzo[d][1,3]dioxole 1 starting from 3,4-dihydroxycinnamic acid has been introduced. A lipase catalyzed kinetic resolution access to enantiopure (R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2 (ee >99%) has also been developed.

Image result for Stiripentol synthesis

Stiripentol (CAS NO.: 49763-96-4), with other name of 4,4-Dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-penten-3-ol, could be produced through many synthetic methods.

Following is one of the reaction routes:

Synthesis of Stiripentol

The synthesis of [14]-labeled stiripentol has been published:The reaction of 3,4-methylenedioxybromobenzene (I) with 14CO₂ by means of butyllithium in ether gives 3,4-methylenedioxybenzoic acid (II), which is reduced with LiAlH₄ to the corresponding benzyl alcohol (III). Oxidation of (III) with CrO₃-pyridine affords the aldehyde (IV), which is condensed with methyl tert-butyl ketone (V) by means of NaOH in refluxing ethanol to give the labeled pentanone (VI). Finally, this compound is reduced to [14C]-labeled stiripentol with NaBH4 in methanol


合成路线图解说明:The condensation of 3,4-methylenedioxybenzaldehyde (I) with 3,3-dimethyl-2-butanone (II) by means of NaOH in ethanol-water gives 4,4-dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-penten-3-one (III), which is reduced with NaBH4 in methanol.

合成路线图解说明:The synthesis of [14]-labeled stiripentol has been published: The reaction of 3,4-methylenedioxybromobenzene (I) with 14CO2 by means of butyllithium in ether gives 3,4-methylenedioxybenzoic acid (II), which is reduced with LiAlH4 to the corresponding benzyl alcohol (III). Oxidation of (III) with CrO3-pyridine affords the aldehyde (IV), which is condensed with methyl tert-butyl ketone (V) by means of NaOH in refluxing ethanol to give the labeled pentanone (VI). Finally, this compound is reduced to [14C]-labeled stiripentol with NaBH4 in methanol.

History

Stiripentol was discovered in 1978 by scientists at Biocodex and clinical trials started over the next few years.^[8] It was originally developed for adults with focal seizures, but failed a Phase III trial.^[4]

In December 2001 the European Medicines Agency (EMA) granted stiripentol orphan drug status (designation number EU/3/01/071) for the treatment of severe myoclonic epilepsy of infancy (SMEI, also known as Dravet’s syndrome) in children and in 2007, the EMA granted the drug a marketing authorisation for use of the drug as an add-on to other anti-seizure drugs.^[3] It was approved in Canada for this use in 2012.^[9] As of 2017 it was also approved for this use in Japan.^[2]

As of 2014 it was not approved in the US, and parents of children with Dravets were paying around $1,000 for a month supply to obtain it from Europe.^[10]

Stiripentol
Clinical data

Trade names	Diacomit
AHFS/Drugs.com	International Drug Names
License data	EU EMA: by INN
Routes of administration	Oral
ATC code	N03AX17 (WHO)
Legal status
Legal status	AU: Unscheduled
Identifiers
IUPAC name [show]
CAS Number	49763-96-4
PubChem CID	5311454
IUPHAR/BPS	5469
ChemSpider	4470940
UNII	R02XOT8V8I
KEGG	D05928
ECHA InfoCard	100.051.329
Chemical and physical data
Formula	C₁₄H₁₈O₃
Molar mass	234.30 g·mol⁻¹
3D model (JSmol)	Interactive image

References

Jump up^ Brigo, F; Igwe, SC; Bragazzi, NL (18 May 2017). “Antiepileptic drugs for the treatment of infants with severe myoclonic epilepsy”. The Cochrane Database of Systematic Reviews. 5: CD010483. doi:10.1002/14651858.CD010483.pub4. PMID 28521067.
^ Jump up to:^a ^b Nickels, KC; Wirrell, EC (May 2017). “Stiripentol in the Management of Epilepsy”. CNS drugs. 31 (5): 405–416. doi:10.1007/s40263-017-0432-1. PMID 28434133.
^ Jump up to:^a ^b ^c ^d ^e ^f “Diacomit (stiripentol) SPC” (PDF). EMA. 8 January 2014. Retrieved 1 October 2017. For updates see EMA index page
^ Jump up to:^a ^b Nabbout, R; Camfield, CS; Andrade, DM; Arzimanoglou, A; Chiron, C; Cramer, JA; French, JA; Kossoff, E; Mula, M; Camfield, PR (April 2017). “Treatment issues for children with epilepsy transitioning to adult care”. Epilepsy & Behavior. 69: 153–160. doi:10.1016/j.yebeh.2016.11.008. PMID 28188045.
Jump up^ Quilichini PP, Chiron C, Ben-Ari Y, Gozlan H (2006). “Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels”. Epilepsia. 47 (4): 704–16. doi:10.1111/j.1528-1167.2006.00497.x. PMID 16650136.
Jump up^ Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ (2005). “Stiripentol. A novel antiepileptic drug” (PDF). Pharmacological reports : PR. 57 (2): 154–60. PMID 15886413.
Jump up^ Sada N, Lee S, Katsu T, Otsuki T, Inoue T (2015). “Targeting LDH enzymes with a stiripentol analog to treat epilepsy”. Science. 347 (6228): 1362–67. doi:10.1126/science.aaa1299. PMID 25792327.
^ Jump up to:^a ^b “Scientific evaluation” (PDF). EMA. 2007.
Jump up^ “Stiripentol (Diacomit): For Severe Myoclonic Epilepsy in Infancy (Dravet Syndrome)” (PDF). Canadian Agency for Drugs and Technologies in Health. April 2015.
Jump up^ Kossoff, E (January 2014). “Stiripentol for dravet syndrome: is it worth it?”. Epilepsy Currents. 14 (1): 22–3. doi:10.5698/1535-7597-14.1.22. PMC 3913306 . PMID 24526870.

////////////Stiripentol, fda 2018, Diacomit, 49763-96-4, BCX 2600, Estiripentol, Stiripentolum

CC(C)(C)C(C=CC1=CC2=C(C=C1)OCO2)O

Sucroferric oxyhydroxide, 含糖酸化鉄, スクロオキシ水酸化鉄

September 3, 2018 7:51 am / Leave a comment

Image result for Sucroferric oxyhydroxide KEGG

Sucroferric oxyhydroxide

Iron sucrose (USP);
Ferric oxide, saccharated;
Sucroferric oxyhydroxide;
Venofer (TN)

含糖酸化鉄;
スクロオキシ水酸化鉄

Molecular Formula:	C₁₂H₂₉Fe₅Na₂O₂₃
Molecular Weight:	866.546 g/mol

CAS:

8047-67-4

CAS REGISTRY NUMBER 12134-57-5, 8047-67-4

disodium;(2R,3R,4S,5S,6R)-2-[(2S,3S,4S,5R)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol;iron(3+);oxygen(2-);hydroxide;trihydrate

Iron sugar; Saccharated iron; Sucroferric oxyhydroxide; Saccharated iron oxide; Saccharated ferric oxide; Ferrivenin

Ferric oxyhydroxide; Ferrihydrite; Iron oxyhydroxide; P-TOL; PA-21; PA21-1; Phosphate binder – Vifor Pharma; suroferric oxyhydroxide tablets; Velphoro

NDC 49230-645-51

Iron saccharate (Sucroferric oxyhydroxide or Iron Sucrose) is used as a source of iron in patients with iron deficiency anemia with chronic kidney disease (CKD), including those who are undergoing dialysis (hemodialysis or peritoneal) and those who do not require dialysis. Due to less side effects than iron dextran, iron saccharate is more preferred in chronic kidney disease patients.

Mixture of polynuclear iron(III)-oxyhydroxide, starch and sucrose

VIFOR FRESENIUS MEDICAL CARE RENAL PHARMA FRANCE

Approved in US

Indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis.

THERAPEUTIC CLAIM Oral phosphate binder, treatement of elevated
phosphate levels in patients undergoing dialysis
CHEMICAL DESCRIPTIONS
1. Ferric hydroxide oxide
2. Mixture of iron(III) oxyhydroxide, sucrose, starches
3. Polynuclear iron(III) oxyhydroxide stabilized with sucrose and starches
structure
O =Fe -OH
MOLECULAR FORMULA FeHO2•xC12H22O11•y(C6H10O5)n

SPONSOR Vifor (International) Inc.
CODE DESIGNATIONS PA21
CAS REGISTRY NUMBER 12134-57-5

ClassFerric compounds; Hyperphosphataemia therapies
Mechanism of ActionPhosphate binding modulators

MarketedHyperphosphataemia

24 Jun 2018Biomarkers information updated
19 Jun 2018Kissei Pharmaceutical completes a phase III trial in Hyperphosphataemia (Treatment-experienced) in Japan (PO) (UMIN000023657)
09 Jun 2017Phase-II clinical trials in Hyperphosphataemia in Austria (PO) (NCT03010072)

Image result for Sucroferric oxyhydroxide

Sucroferric oxyhydroxide is a brown, amorphous powder. The drug substance is relatively poorly defined, so that the manufacturing process is particularly important. Sucroferric oxyhydroxide is prepared by basifying a ferric chloride solution, giving a polynuclear iron(III)-oxyhydroxide suspension which is mixed with potato and maize starches and sucrose. Vifor states that the sucrose stabilises the iron core and thus maintain the high phosphate adsorption capacity while the starches function as processing aids, but they are added simultaneously and the drug substance is probably a complex mixture of species.

The solubility of the active moiety, polynuclear iron oxyhydroxide, is evidently low in the gastrointestinal (GI) tract so that iron absorption is low. Aqueous solubility at different pH has been very poorly quantified. Vifor states that the “sucrose part is soluble in water, iron(III)-oxyhydroxide/starch mixture is practically insoluble in water.” While the iron oxide particle size is important in determining the phosphate binding, it is relatively difficult to directly measure. The sucrose/starch “wrapped” drug substance particle size is established and the process is controlled, but it does not correlate well with phosphate adsorption. Sucroferric oxyhydroxide cannot be controlled in the manner of a well-defined molecular drug and some variability between batches is likely. The drug substance specification includes a phosphate adsorption test. Vifor has tested the adsorption of a range of other in vivo chemical species to sucroferric oxyhydroxide and not identified any likely to be strongly bound, or affect phosphate binding, except for oxalate. Some drugs, however, do interact, for example alendronate is strongly absorbed (and the PI warnings in that context should be generalised to all bisphosphonates, not just identify the single drug in class studied)….https://www.tga.gov.au/sites/default/files/auspar-sucroferric-oxyhydroxide-150219.pdf

EMA

Name	Active substance	Therapeutic area	Date of authorisation / refusal					Has current safety alert	Status
Velphoro	mixture of polynuclear iron(III)-oxyhydroxide, sucrose and starches	HyperphosphatemiaRenal Dialysis	26/08/2014						Authorised

Product details

Name	Velphoro
Agency product number	EMEA/H/C/002705
Active substance	mixture of polynuclear iron(III)-oxyhydroxide, sucrose and starches
International non-proprietary name(INN) or common name	mixture of polynuclear iron(III)-oxyhydroxide, sucrose and starches
Therapeutic area	HyperphosphatemiaRenal Dialysis
Anatomical therapeutic chemical (ATC) code	V03AE05
Additional monitoring	This medicine is under additional monitoring. This means that it is being monitored even more intensively than other medicines. For more information, see medicines under additional monitoring.

Publication details

Marketing-authorisation holder	Vifor Fresenius Medical Care Renal Pharma France
Revision	5
Date of issue of marketing authorisation valid throughout the European Union	26/08/2014

Contact address:

Vifor Fresenius Medical Care Renal Pharma France
100-101 Terrasse Boieldieu
Tour Franklin- La Défense 8
92042 Paris la Défense Cedex
France

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002705/WC500175254.pdf

Sucroferric oxyhydroxide (INN; trade name Velphoro, by Vifor Fresenius Medical Care Renal Pharma) is a non-calcium, iron-based phosphate binder used for the control of serum phosphorus levels in adult patients with chronic kidney disease (CKD) on haemodialysis(HD) or peritoneal dialysis (PD).^[1] It is used in form of chewable tablets.

Hyperphosphatemia

In a healthy person, normal serum phosphate levels are maintained by the regulation of dietary absorption, bone formation and resorption, equilibration with intracellular stores, and renal excretion.^[2] When kidney function is impaired, phosphate excretion declines. Without specific treatment, hyperphosphataemia occurs almost universally, despite dietary phosphate restriction and conventional dialysis treatment.^[2]^[3] In patients on dialysis, hyperphosphataemia is an independent risk factor for fractures, cardiovascular disease and mortality.^[4]^[5] Abnormalities in phosphate metabolism such as hyperphosphatemia are included in the definition of the new chronic kidney disease–mineral and bone disorder (CKD-MBD).^[5]

Structure and mechanism of action

Sucroferric oxyhydroxide comprises a polynuclear iron(III)-oxyhydroxide core that is stabilised with a carbohydrate shell composed of sucrose and starch.^[6]^[7] The carbohydrate shell stabilises the iron(III)-oxyhydroxide core to preserve the phosphate adsorption capacity.

Dietary phosphate binds strongly to sucroferric oxyhydroxide in the gastrointestinal (GI) tract. The bound phosphate is eliminated in the faeces and thereby prevented from absorption into the blood. As a consequence of the decreased dietary phosphate absorption, serum phosphorus concentrations are reduced.

Medical uses

Sucroferric oxyhydroxide is approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the control of serum phosphorus levels in patients with chronic kidney disease (CKD) on dialysis.^[1]^[8]

Adverse effects

The most frequently reported adverse drug reactions reported from trials were diarrhoea and discoloured faeces.^[1]^[8] The vast majority of gastrointestinal adverse events occurred early during treatment and abated with time under continued dosing.^[1]

Interactions

Drug-interaction studies and post hoc analyses of Phase 3 studies showed no clinically relevant interaction of sucroferric oxyhydroxide with the systemic exposures to losartan, furosemide, omeprazole, digoxin, and warfarin,^[9] the lipid-lowering effects of statins,^[10] and oral vitamin D receptor agonists.^[11] According to the European label (Summary of Product Characteristics), medicinal products that are known to interact with iron (e.g. doxycycline) or have the potential to interact with Velphoro should be administered at least one hour before or two hours after Velphoro.^[1] This allows sucroferric oxyhydroxide to bind phosphate as intended and be excreted without coming into contact with medications in the gut that it might interact with. According to the US prescribing information, Velphoro should not be prescribed with oral levothyroxine.^[8] The combination of sucroferric oxyhydroxide and levothyroxine is contraindicated because sucroferric oxyhydroxide contains iron, which may cause levothyroxine to become insoluble in the gut, thereby preventing the intestinal absorption of levothyroxine.^[12]

Chewability

The chewability of sucroferric oxyhydroxide compares well with that of Calcimagon, a calcium containing tablet used as a standard for very good chewability.^[13] Tablets of sucroferric oxyhydroxide easily disintegrated in artificial saliva.

Effectiveness and phosphate binding

Clinical Phase 3 studies showed that sucroferric oxyhydroxide achieves and maintains phosphate levels in compliance with the KDOQI guidelines.^[14]^[15] The reduction in serum phosphate levels of sucroferric oxyhydroxide-treated patients was non-inferior to that in sevelamer-treated patients. The required daily pill burden was lower with sucroferric oxyhydroxide.^[14]

Sucroferric oxyhydroxide binds phosphate under empty and full stomach conditions and across the physiologically relevant pH range of the GI tract.^[7]

In a retrospective, real-world study, hyperphosphatemic peritoneal dialysis patients who were prescribed to switch to sucroferric oxyhydroxide from sevelamer, lanthanum carbonate, or calcium acetate had significant reductions in serum phosphorus levels, along with a 53% decrease in the prescribed daily pill burden.^[16]

Sucroferric oxyhydroxide nonproprietary drug name

https://www.ama-assn.org/resources/doc/…/sucroferric–oxyhydroxide.pdf‎

1. February 27, 2013. N13/36. STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL. USAN (ZZ-19). SUCROFERRIC …

The US Food and Drug Administration has given the green light to Vifor Fresenius Medical Care Renal Pharma’s hyperphosphatemia drug Velphoro.

The approval for Velphoro (sucroferric oxyhydroxide), formerly known as PA21, is based on Phase III data demonstrated that the drug successfully controls the accumulation of phosphorus in the blood with the advantage of a much lower pill burden than the current standard of care in patients with chronic kidney disease on dialysis, namely Sanofi’s Renvela (sevelamer carbonate). read this at

http://www.pharmatimes.com/Article/13-11-28/FDA_okays_Vifor_Fresenius_phosphate_binder_Velphoro.aspx

Velphoro (PA21) receives US FDA approval for the treatment of hyperphosphatemia in Chronic Kidney Disease Patients on dialysis
Velphoro(sucroferric oxyhydroxide) has received US Food and Drug Administration (FDA) approval for the control of serum phosphorus levels in patients with Chronic Kidney Disease (CKD) on dialysis. Velphoro will be launched in the US by Fresenius Medical Care North America in 2014.

Velphoro (previously known as PA21) is an iron-based, calcium-free, chewable phosphate binder. US approval was based on a pivotal Phase III study, which met its primary and secondary endpoints. The study demonstrated that Velphoro^® successfully controls hyperphosphatemia with fewer pills than sevelamer carbonate, the current standard of care in patients with CKD on dialysis. The average daily dose to control hyperphosphatemia was 3.3 pills per day after 52 weeks.

Velphoro was developed by Vifor Pharma. In 2011, all rights were transferred to Vifor Fresenius Medical Care Renal Pharma, a common company of Galenica and Fresenius Medical Care. In the US, Velphorowill be marketed by Fresenius Medical Care North America, a company with a strong marketing and sales organization, and expertise in dialysis care. The active ingredient of Velphoro is produced by Vifor Pharma in Switzerland.

Hyperphosphatemia, an abnormal elevation of phosphorus levels in the blood, is a common and serious condition in CKD patients on dialysis. Most dialysis patients are treated with phosphate binders. However, despite the availability of a number of different phosphate binders, up to 50% of patients depending on the region are still unable to achieve and maintain their target serum phosphorus levels. In some patients, noncompliance due to the high pill burden and poor tolerability appear to be key factors in the lack of control of serum phosphorus levels. On average, dialysis patients take approximately 19 pills per day with phosphate binders comprising approximately 50% of the total daily pill burden. The recommended starting dose of Velphoro is 3 tablets per day (1 tablet per meal).

Full results from the pivotal Phase III study involving more than 1,000 patients were presented at both the 50^th ERA-EDTA (European Renal Association European Dialysis and Transplant Association) Congress in Istanbul, Turkey, in May 2013, and the American Society of Nephrology (ASN) Kidney Week in Atlanta, Georgia, in November 2013. Velphorowas shown to be a potent phosphate binder, with lower pill burden and a good safety profile.

Based on these data, Vifor Fresenius Medical Care Renal Pharma believes that Velphoro offers a new and effective therapeutic option for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis.
The regulatory processes in Europe, Switzerland and Singapore are ongoing and decisions are expected in the first half 2014. Further submissions for approval are being prepared.

PATENT

https://patents.google.com/patent/WO2016038541A1/en

Hyperphosphatemia is associated with significant increase in morbidity and mortality, and may induce severe complications, such as hypocalcemia, decreasing of vitamin-D production and metastatic calcification. Hyperphosphatemia is also contributing to the increased incidence of cardiovascular disease among dialysis-dependent patients. The phosphate binding capacity of iron oxide hydroxides is known in the art. The possible medical application of iron hydroxides and iron oxide hydroxides as phosphate adsorbents is also described.

US 4,970,079 patent discloses a method of controlling serum phosphate level in patients by iron oxy-hydroxides which bind to ingested phosphate. US 5,514,281 patent also discloses a process for the selective elimination of inorganic phosphate from body fluids by using a polynuclear metal oxyhydroxide preferably iron (III) oxyhydroxide.

US 6,174,442 patent describes an adsorbent for phosphate and a process for the preparation thereof, which contains polynuclear β-iron hydroxide stabilized by carbohydrates and/or humic acid.

In order to obtain an iron-based compound which can be used as a pharmaceutical, it is necessary to have an iron-based compound which is stable. It is known that iron oxide- hydroxide is not a stable compound with time ageing occurs. Ageing usually not only involves crystallization but also particle enlargement. Such ageing may alter the phosphate binding of an iron oxide -hydroxide based phosphate adsorbent. Accordingly, there exists a need for a process for manufacturing of an iron containing phosphate adsorbent. The process needs to be scalable, robust and consistently producing an iron containing phosphate adsorbent of the required pharmaceutical grade.

Examples

In examples which are intended to illustrate embodiments of the invention but which are not intended to limit the scope of the invention: ) Method of Making an Iron Containing Phosphate Adsorbent

To a solution of 1.96 kg sodium carbonate dissolved in 12.5 liter water, solution of 2.5 kg iron (III) chloride hexahydrate dissolved in 17.5 liter water was added at a temperature of 5 – 10°C. The resulting mixture was stirred for 90 to 120 minutes at 5 – 10°C. (25.0×3) liter water was added to the reaction mass and raised the temperature at 15 – 20°C with stirring. Stopped the stirring, settled precipitate and the supernatant water was removed. The precipitate was filtered and washed with 1.25 liter water. A suspension of the precipitate was prepared in water. To this, 875.0 gm sucrose and 695.0 gm potato starch were added and stirred for 120 minutes at 25 – 35°C. Cooled the reaction mass at 10 – 15°C and stirred for 90 to 120 minutes. 25.0 liters cold acetone was added to the reaction mass at 10 – 15°C and stirred for 90 to 120 minutes. The final product was filtered and washed with 1.25 liter cold acetone and further dried under vacuum at 30-35°C.

Yield: 2.08 kg ) Large-scale Method of Making an Iron Containing Phosphate Adsorbent

An aqueous solution of sodium carbonate and an aqueous solution of iron (III) chloride hexahydrate were mixed at a temperature of 5 – 10°C, optionally in the presence of solvent- 1. A volume of aqueous solution of sodium carbonate necessary to maintain the pH at about 7.0 to form a colloidal suspension of ferric hydroxide. The resulting mixture was stirred for 90 to 120 minutes at 5 – 10°C. Water was added to the reaction mass with stirring. Stopped the stirring, settled precipitated product and the water was decanted or siphoned. The precipitated product was further filtered and washed with using water. Suspension of the precipitated product was prepared in the water. Subsequently, sucrose and starch were added in to the suspension and stirred for 120 minutes at 25 – 35°C. Cooled the reaction mixture at 10 – 15°C and stirred for 90 to 120 minutes. Solvent-2 was added to the reaction mixture at 10 – 15°C and stirred for 90 to 120 minutes. The product was filtered and washed with the solvent-2 and further dried under vacuum at 30-35°C. Few illustrative examples provided in Table- 1, wherein the iron containing phosphate adsorbents were prepared according to the process of example-2 using the respective combination of Solvent- 1 and Solvent-2 as given in the table:

Table-1

3) Physical Properties of an Iron Containing Phosphate Adsorbents prepared as per above example-2.

> BET active Surface Area:

· Instrument : Surface area analyzer

• Condition : Surface area (m²/gm) at N2.P/P0 = 10%

Table-2

> Phosphate Binding Capacity at pH 3.0:

· Method : Ion Chromatography Instrument : Metrohm IC equipped with pump, Injector, conductivity detector and recorder.

Column Dionex Ion Pac AS-11 (4.0 x 250mm), 13μπι

Guard column Dionex Ion Pac AG-11 (4.0 x 50mm), 13μπι

Buffer preparation Weigh accurately about 2.118g of Sodium carbonate and 180mg of Sodium hydroxide in 1700mL water.

Mobile phase preparation : Buffer and acetonitrile (1700:300).

Results: Phosphate binding of an iron containing phosphate adsorbents obtained by following the process of the present invention found in the range of 30 mg/gm to 60 mg/gm. Particle Size Distribution:

Instrument Model : Malvern Mastersizer 2000 Particle size analyzer

Sampling Unit : Hydro 2000S

Analysis Model : General Purpose

Dispersant : 0.1% Span 85 in n-Hexane

Dispersant RI : 1.380

Stirrer Speed : 2200 RPM

Absorption : 1

Particle RI : 1.5

Obscuration : 10% to 20%

Sample Measurement time : 12 seconds

Background Measurement time : 12 seconds Table-3

Particle size distribution

Example no.

d(0.9) (μηι)

3d 43.67

3e 65.37

3f 37.75

Publication numberPriority datePublication dateAssigneeTitle

US4970079A1989-06-051990-11-13Purdue Research FoundationMethod and composition of oxy-iron compounds for treatment of hyperphosphatemia

US5514281A1992-11-241996-05-07B. Braun Melsungen AgProcess for the selective elimination of inorganic phosphate from liquids by means of adsorbent materials modified with polynuclear metal oxyhydroxides

US6174442B11995-12-192001-01-16Vifor (International) AgAdsorbent for phosphate from an aqueous medium, production and use of said adsorbent

EP1932808A1 *2006-12-142008-06-18Novartis AGIron(III)-Carbohydrate based phosphate adsorbent

WO2009062993A1 *2007-11-162009-05-22Vifor (International) AgPharmaceutical compositions

WO2010015827A2 *2008-08-052010-02-11Medical Research CouncilPhosphate binding materials and their uses

Image result for Sucroferric oxyhydroxide KEGG

References

^ Jump up to:^a ^b ^c ^d ^e “Velphoro (sucroferric oxyhydroxide). Summary of Product Characteristics”(PDF). EMA. Archived from the original on October 21, 2014. Retrieved 24 October 2014.
^ Jump up to:^a ^b Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, Saran R, Wang AY, Yang CW (July 2013). “Chronic kidney disease: global dimension and perspectives”. Lancet. 382(9888): 260–72. doi:10.1016/S0140-6736(13)60687-X. PMID 23727169.
Jump up^ Hutchison AJ, Smith CP, Brenchley PE (September 2011). “Pharmacology, efficacy and safety of oral phosphate binders”. Nature Reviews. Nephrology. 7 (10): 578–89. doi:10.1038/nrneph.2011.112. PMID 21894188.
Jump up^ Isakova T, Gutiérrez OM, Chang Y, Shah A, Tamez H, Smith K, Thadhani R, Wolf M (February 2009). “Phosphorus binders and survival on hemodialysis”. Journal of the American Society of Nephrology. 20 (2): 388–96. doi:10.1681/ASN.2008060609. PMC 2637053 . PMID 19092121.
^ Jump up to:^a ^b “KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)”. Kidney International Supplement. 76 (113): S1–130. August 2009. doi:10.1038/ki.2009.188. PMID 19644521.
Jump up^ Vifor Fresenius Medical Care Renal Pharma. Product Monograph 2015.
^ Jump up to:^a ^b Wilhelm M, Gaillard S, Rakov V, Funk F (April 2014). “The iron-based phosphate binder PA21 has potent phosphate binding capacity and minimal iron release across a physiological pH range in vitro”. Clinical Nephrology. 81 (4): 251–8. doi:10.5414/cn108119. PMID 24656315.
^ Jump up to:^a ^b ^c “Highlights of Prescribing information for Velphoro”. Fresenius. September 2014.
Jump up^ Chong E, Kalia V, Willsie S, Winkle P (December 2014). “Drug-drug interactions between sucroferric oxyhydroxide and losartan, furosemide, omeprazole, digoxin and warfarin in healthy subjects”. Journal of Nephrology. 27 (6): 659–66. doi:10.1007/s40620-014-0080-1. PMC 4242982 . PMID 24699894.
Jump up^ Levesque V, Chong EMF, Moneuse P (2013). “Post-hoc analysis of pharmacodynamic interaction of PA21 with statins in a Phase 3 study of PA21 in dialysis patients with hyperphosphatemia”. J Am Soc Nephrol. 24: 758A.
Jump up^ Floege J, Botha J, Chong E et al. (31 May 2014). PA21 does not interact with oral vitamin D receptor agonists: a post hoc analysis of a Phase 3 study. ERA-EDTA congress. Amsterdam, The Netherlands. Abstract no. SP257.
Jump up^ Prescribing Information. Synthroid (levothyroxine). Chicago, IL: Abbott Laboratories. March 1, 2008.
Jump up^ Lanz M, Baldischweiler J, Kriwet B, Schill J, Stafford J, Imanidis G (December 2014). “Chewability testing in the development of a chewable tablet for hyperphosphatemia”. Drug Development and Industrial Pharmacy. 40 (12): 1623–31. doi:10.3109/03639045.2013.838583. PMID 24010939.
^ Jump up to:^a ^b Floege J, Covic AC, Ketteler M, Rastogi A, Chong EM, Gaillard S, Lisk LJ, Sprague SM (September 2014). “A phase III study of the efficacy and safety of a novel iron-based phosphate binder in dialysis patients”. Kidney International. 86 (3): 638–47. doi:10.1038/ki.2014.58. PMC 4150998 . PMID 24646861.
Jump up^ Floege J, Covic AC, Ketteler M, Mann JF, Rastogi A, Spinowitz B, Chong EM, Gaillard S, Lisk LJ, Sprague SM (June 2015). “Long-term effects of the iron-based phosphate binder, sucroferric oxyhydroxide, in dialysis patients”. Nephrology, Dialysis, Transplantation. 30(6): 1037–46. doi:10.1093/ndt/gfv006. PMC 4438742 . PMID 25691681.
Jump up^ Kalantar-Zadeh K, Parameswaran V, Ficociello LH, Anderson L, Ofsthun NJ, Kwoh C, Mullon C, Kossmann RJ, Coyne DW (2018). “Real-World Scenario Improvements in Serum Phosphorus Levels and Pill Burden in Peritoneal Dialysis Patients Treated with Sucroferric Oxyhydroxide”. American Journal of Nephrology. 47 (3): 153–161. doi:10.1159/000487856. PMC 5906196 . PMID 29514139.

Sucroferric oxyhydroxide
Clinical data
Trade names	Velphoro
AHFS/Drugs.com	Consumer Drug Information
License data	EU EMA: by polynuclear iron(III)-oxyhydroxide
Pregnancy category	US: B (No risk in non-human studies) EU, Japan: No risk in non-human studies
Routes of administration	Oral (chewable tablets)
ATC code	V03AE05 (WHO)
Legal status
Legal status	US: ℞-only EU: Rx only Japan: prescription only
Chemical and physical data
Formula	Varies

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 2 (FDA Orange Book Patent ID)
Patent	6174442
Expiration	Dec 19, 2018
Applicant	VIFOR FRESENIUS
Drug Application	N205109 (Prescription Drug: VELPHORO. Ingredients: SUCROFERRIC OXYHYDROXIDE)

from FDA Orange Book

FDA Orange Book Patents: 2 of 2 (FDA Orange Book Patent ID)
Patent	9561251
Expiration	Jan 23, 2030
Applicant	VIFOR FRESENIUS
Drug Application	N205109 (Prescription Drug: VELPHORO. Ingredients: SUCROFERRIC OXYHYDROXIDE)

Patent ID	Title	Submitted Date	Granted Date
US6174442	Adsorbent for phosphate from an aqueous medium, production and use of said adsorbent	1998-06-02	2001-01-16
US9561251	PHARMACEUTICAL COMPOSITIONS	2008-11-13	2010-09-30

from PubChem

/////////////Sucroferric oxyhydroxide, EU 2014, Iron sugar, Saccharated iron, Sucroferric oxyhydroxide, Saccharated iron oxide, Saccharated ferric oxide, Ferrivenin, 含糖酸化鉄, スクロオキシ水酸化鉄 , NDC 49230-645-51

C(C1C(C(C(C(O1)OC2(C(C(C(O2)CO)O)O)CO)O)O)O)O.O.O.O.[OH-].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[Na+].[Na+].[Fe+3].[Fe+3].[Fe+3].[Fe+3].[Fe+3]

Vericiguat, ベルイシグアト

September 1, 2018 12:03 pm / Leave a comment

Image result for vericiguat

Vericiguat

BAY 102; BAY-1021189; MK-1242

1350653-20-1
Chemical Formula: C19H16F2N8O2

Molecular Weight: 426.3878

Vericiguat; 1350653-20-1; UNII-LV66ADM269; Methyl (4,6-diamino-2-(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)carbamate; BAY-1021189; LV66ADM269

Methyl (4,6-diamino-2-(5-fluoro-1-((2-fluorophenyl)methyl)-1H-pyrazolo(3,4-b)pyridin-3-yl(pyrimidin-5-yl)carbamate

methyl N-[4,6-diamino-2-[5-fluoro-1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]carbamate

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridi- n-3-yl]pyrimidin-5-yl}carbamate

Originator Bayer HealthCare Pharmaceuticals
Developer Bayer HealthCare Pharmaceuticals; Merck & Co
Mechanism of Action Guanylate cyclase stimulants
Phase III Chronic heart failure

Phase I Coronary artery disease

28 May 2018 Phase II VITALITY HFpEF trial for Chronic heart failure in Austria, USA, Belgium, Portugal, Canada, Spain, Hungary and Greece (PO) (EudraCT2018-000298-65) (NCT03547583)
17 May 2018 Phase-I clinical trials in Coronary artery disease (In adults, In the elderly) in Moldova and Germany (PO) (NCT03504982)
20 Apr 2018 Bayer in collaboration with Merck Sharp & Dohme Corp. plans a phase I trial for Coronary Artery Disease in the Netherlands, Moldova and Germany (NCT03504982)

Vericiguat, also known as BAY1021189 or BAY10-21189, is a potent and orally active sGC stimulator (Soluble Guanylate Cyclase Stimulator). Direct stimulation of soluble guanylate cyclase (sGC) is emerging as a potential new approach for the treatment of renal disorders. sGC catalyzes the formation of cyclic guanosine monophosphate (cGMP), deficiency of which is implicated in the pathogenesis of chronic kidney disease (CKD).

Vericiguat, discovered at Bayer, is the first soluble guanylate cyclase (sGC) stimulator. Vericiguat is currently being studied in a Phase III clinical program for the treatment of heart failure with reduced ejection fraction (HFrEF)

ベルイシグアト
Vericiguat

C₁₉H₁₆F₂N₈O₂ : 426.38
[1350653-20-1]

Vericiguat hydrochloride.png

Vericiguat hydrochloride

cas 1350658-96-6

PHASE 3 MERCK/BAYER

Chemical Names:	UNII-5G76IGF54K; 5G76IGF54K; ; 1350658-96-6; Carbamic acid, N-(4,6-diamino-2-(5-fluoro-1-((2-fluorophenyl)methyl)-1H-pyrazolo(3,4-b)pyridin-3-yl)-5-pyrimidinyl)-, methyl ester, hydrochloride (1:1); Methyl (4,6-diamino-2-(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridin-3-yl)pyrimidin-5-yl)carbamate hydrochloride
Molecular Formula:	C₁₉H₁₇ClF₂N₈O₂
Molecular Weight:	462.846 g/mol

Image result for DRUG FUTURE Vericiguat

Clip

https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0036-1590758.pdf

Image result for vericiguat

Significance: Vericiguat (BAY 1021189) is an orally available soluble guanylate cyclase (sGC) stimulator that has entered phase-three trials for the once-daily treatment of chronic heart failure. Key steps in the synthesis depicted are (1) construction of the 5-fluoro-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate C by condensation of the 5-amino-1H-pyrazole-3-carboxylate A with the aldehyde B and (2) construction of the pyrimidine-4,5,6-triamine derivative H through reaction of [(E)-phenyldiazenyl]malononitrile (G) with amidine F.

Comment: Experimental details are provided for the noteworthy four-step synthesis (not shown) of the crystalline 2-fluoro-(3-morpholin-4-yl)acrylaldehyde B from commercially available 2,2,3,3- tetrafluoro-1-propanol. The synthesis of pyrazole A is described in a patent (A. Straub et al. WO 2000/006569 A1). The [(E)-phenyldiazenyl]malononitrile (G) was generated in situ by reaction of phenyldiazonium chloride with malononitrile.

24. Yield 2.2 g (70%). 1 H NMR (400 MHz, DMSO-d6): δ = 8.89 (dd, J = 9.0, 2.8 Hz, 1H), 8.66 (m, 1H), 7.99 and 7.67 (2 br s, 1H), 7.32−7.40 (m, 1H), 7.19−7.26 (m, 1H), 7.10−7.19 (m, 2H), 6.22 (br s, 4H), 5.79 (s, 2H), 3.62 (br s, 3H). LC-MS (method d): tR (min) = 0.79. MS (ESI +): m/z = 427 [M + H]+

PATENT

US 8,802,847

https://patentscope.wipo.int/search/en/detail.jsf?docId=US82113239&recNum=1&maxRec=2&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=FP%3A%28US+8802847%29&tab=PCTDescription

Example 13

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridi- n-3-yl]pyrimidin-5-yl}carbamate

Method A:

4.0 g (77.0% by weight, 8.36 mmol) of the compound from Example 12 in 37.9 ml of isopropanol were heated to 35.degree. C. and then 0.84 ml (10.87 mmol) of methyl chloroformate was added dropwise. The mixture was stirred at 35.degree.-40.degree. C. for 20 h and heated to 50.degree. C., and 9.5 ml of methanol were added. Subsequently, 1.9 ml of triethylamine were added dropwise within 0.5 h and rinsed in with 1.3 ml of methanol, and the mixture was stirred at 50.degree. C. for 1 h. Thereafter, the reaction mixture was cooled to RT and stirred at RT for 1 h, and the solids were filtered off with suction, washed three times with 8 ml each time of ethanol, suction-dried and dried in a vacuum drying cabinet at 50.degree. C. under a gentle nitrogen stream. This gave 3.4 g of crude product. 3.0 g of the crude product were stirred in 8 ml of DMSO for 5 min, 13.0 ml of ethyl acetate and 50 mg of activated carbon were added, and the mixture was heated at reflux (84.degree. C.) for 15 min. The suspension was hot-filtered and the filter residue was washed with 1.9 ml of ethyl acetate.sup.1). 60 ml of ethyl acetate and 16 ml of ethanol were heated to 60.degree. C., and the combined filtrates were added dropwise and stirred at 60.degree. C. for 1.5 h. The suspension was cooled to RT within 25 min, stirred for a further 1.5 h, cooled further to 0.degree.-5.degree. C. and stirred for a further 1 h. The solids were filtered off with suction, washed twice with 6.4 ml each time of ethyl acetate, suction-dried and dried in a vacuum drying cabinet at 50.degree. C. under a gentle nitrogen stream. This gave 2.2 g (70.0% of theory) of the title compound. 1) According to the preparation process described, the di-dimethyl sulphoxide solvate is obtained at this point, and this is characterized in Tables 2 and 4 by the reflections in the x-ray diffractogram and bands in the IR spectrum.

MS (ESIpos): m/z=427 (M+H).sup.+

.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=3.62 (br s, 3H), 5.79 (s, 2H), 6.22 (br s, 4H), 7.10-7.19 (m, 2H), 7.19-7.26 (m, 1H), 7.32-7.40 (m, 1H), 7.67 and 7.99 (2 br s, 1H), 8.66 (m, 1H), 8.89 (dd, 1H) ppm.

The di-dimethyl sulphoxide solvate of the compound of the formula (I) has the advantage of much better filterability than the substance in the prior art. Furthermore, the preparation process via the di-dimethyl sulphoxide solvate of the compound of the formula (I) leads to a very high purity of the compound of the formula (I).

Method B:

4.0 g (10.8 mmol) of the compound from Example 12 Method B in 37.9 ml of isopropanol were heated to 35.degree. C. and then 1.1 ml (14.1 mmol) of methyl chloroformate were added dropwise. The mixture was stirred at 35.degree.-40.degree. C. for 16.5 h and cooled to RT, and 2.1 ml of aqueous ammonia (28%) were added. Subsequently, 4.2 ml of water were added and the mixture was stirred for 2.5 h. The solids were filtered off with suction, washed twice with 5 ml each time of water, suction-dried and dried in a vacuum drying cabinet at 50.degree. C. under a gentle nitrogen stream. This gave 4.4 g of crude product.

Method C:

4.0 g (10.8 mmol) of the compound from Example 12 Method B in 37.9 ml of isopropanol were heated to 35.degree. C. and then 1.1 ml (14.1 mmol) of methyl chloroformate were added dropwise. The mixture was stirred at 35.degree.-40.degree. C. for 16.5 h, and 9.5 ml of methanol were added at 50.degree. C. Subsequently, 2.42 ml of triethylamine were added dropwise within 20 min and rinsed in with 1.3 ml of methanol, and the mixture was stirred at 50.degree. C. for 1 h. Thereafter, the reaction mixture was cooled to RT and stirred at RT for 1 h, and the solids were filtered off with suction, washed three times with 8 ml each time of methanol, suction-dried and dried in a vacuum drying cabinet at 50.degree. C. under a gentle nitrogen stream. This gave 4.3 g of crude product.

Method D:

6.9 g of the crude product were stirred in 18.4 ml of DMSO for 5 min, 30.0 ml of ethyl acetate and 115 mg of activated carbon were added, and the mixture was heated at reflux (84.degree. C.) for 15 min. The suspension was hot-filtered and the filter residue was washed with 4.4 ml of ethyl acetate. 138 ml of ethyl acetate were heated to 50.degree. C., and the combined filtrates were added dropwise and stirred at 45-50.degree. C. for 1 h. The suspension was cooled to 0.degree.-5.degree. C. within 1.5 h and stirred for a further 1 h. The solids were filtered off with suction, washed twice with 14.8 ml each time of ethyl acetate and suction-dried for 1 h. 6.4 g of the di-dimethyl sulphoxide solvate were obtained as a moist product.sup.1).

Method E:

2.0 g of the di-dimethyl sulphoxide solvate were stirred at reflux temperature in 40 ml of ethyl acetate and 11.1 ml of ethanol for 17 h, cooled to RT and stirred for a further 1 h. The solids were filtered off with suction, washed four times with 1.4 ml each time of ethyl acetate and dried in a vacuum drying cabinet at 50.degree. C. under a gentle nitrogen stream. This gave 1.4 g of the title compound present in polymorph I.

Method F:

0.5 g of the di-dimethyl sulphoxide solvate were stirred at reflux temperature in 12.5 ml of solvent for 17 h, cooled to RT and stirred for a further 1 h. The solids were filtered off with suction, washed with 2 ml of solvent and suction-dried for 30 min. This gave 0.3 g of the title compound present in polymorph I.

The following solvents were used:

1.) 9 ml of ethyl acetate/3.5 ml of ethanol/0.3 ml of water

2.) 12.5 ml of isopropanol

3.) 12.5 ml of isopropanol/0.3 ml of water

4.) 12.5 ml of methanol

5.) 12.5 ml of methanol/0.3 ml of water

6.) 12.5 ml of acetonitrile

7.) 12.5 ml of acetone

8.) 12.5 ml of tetrahydrofuran,

9.) 12.5 ml of methyl tert-butyl ether

Table 1 indicates the reflections of the x-ray diffractogram. Table 3 shows the bands of the IR spectrum.

The compound (I) in crystalline polymorph I is notable for higher stability and more particularly for the fact that it is stable in the micronization process and hence no conversion and recrystallization takes place.

The compound of the formula (I) can be prepared by processes described above. This affords the compound of the formula (I) in a crystal polymorph referred to hereinafter as polymorph I. Polymorph I has a melting point of 257.degree. C. and a characteristic x-ray diffractogram featuring the reflections (2 theta) 5.9, 6.9, 16.2, 16.5, 24.1 and 24.7, and a characteristic IR spectrum featuring the band maxima (in cm.sup.-1) 1707, 1633, 1566, 1475, 1255 and 1223 (Tables 1 and 3, FIGS. 1 and 5).

Surprisingly, four further polymorphs, a monohydrate, a dihydrate, a DMF/water solvate and a di-dimethyl sulphoxide solvate, and also a triacetic acid solvate of the compound of the formula (I) were found. The compound of the formula (I) in polymorph II melts at approx. 253.degree. C.; the compound of the formula (I) in polymorph III has a melting point of approx. 127.degree. C. Polymorph IV of the compound of the formula I melts at a temperature of 246.degree. C., while polymorph V has a melting point of 234.degree. C. The monohydrate contains approx. 4.1% water, the dihydrate contains 7.8% water, the DMF/water solvate contains 13.6% dimethylformamide and 0.9% water, the di-DMSO solvate contains 26.8% dimethyl sulphoxide and the triacetic acid solvate contains 29.7% acetate. Each of the crystalline forms mentioned has a characteristic x-ray diffractogram and IR spectrum (Tables 2 and 3, FIGS. 1-4, 6-14).

TABLE 1
X-ray diffractometry for polymorphs I to V

FIGURES

FIG. 1: IR spectrum of the compound of the formula (I) in polymorphs I, II and III

FIG. 2: IR spectrum of the compound of the formula (I) in polymorphs IV, V and as the triacetic acid solvate

FIG. 3: IR spectrum of the compound of the formula (I) as the di-DMSO solvate, DMF/water solvate and monohydrate

FIG. 4: IR spectrum of the compound of the formula (I) as the dihydrate

FIG. 5: X-ray diffractogram of the compound of the formula (I) in polymorph I

FIG. 6: X-ray diffractogram of the compound of the formula (I) in polymorph II

FIG. 7: X-ray diffractogram of the compound of the formula (I) in polymorph III

FIG. 8: X-ray diffractogram of the compound of the formula (I) in polymorph IV

FIG. 9: X-ray diffractogram of the compound of the formula (I) in polymorph V

FIG. 10: X-ray diffractogram of the compound of the formula (I) as the triacetic acid solvate

FIG. 11: X-ray diffractogram of the compound of the formula (I) as the di-DMSO solvate

FIG. 12: X-ray diffractogram of the compound of the formula (I) as the DMF-water solvate

FIG. 13: X-ray diffractogram of the compound of the formula (I) as the monohydrate

FIG. 14: X-ray diffractogram of the compound of the formula (I) as the dihydrate

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US73469313&recNum=&maxRec=1000&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example 11A

2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine

(MOL) (CDX)

Variant A: Preparation Starting from Example 7A:

In pyridine (30 ml), 378 mg (0.949 mmol) of the compound from Example 7A were introduced and then 143 mg (0.135 mmol) of palladium (10% on carbon) were added. The mixture was hydrogenated overnight at RT under standard hydrogen pressure. The suspension was then filtered through kieselguhr and the filtercake was washed with ethanol. The filtrate was concentrated and yielded 233 mg (81% purity, 51% of theory) of the desired compound, which was reacted without further purification.

Variant B: Preparation Starting from Example 10A:

In DMF (800 ml), 39.23 g (85.75 mmol) of the compound from Example 10A were introduced and then 4 g of palladium (10% on carbon) were added. The mixture was hydrogenated with stirring overnight under standard hydrogen pressure. The batch was filtered over kieselguhr and the filter product was washed with a little DMF and then with a little methanol, and concentrated to dryness. The residue was admixed with ethyl acetate and stirred vigorously, and the precipitate was filtered off with suction, washed with ethyl acetate and diisopropyl ether and dried under a high vacuum over Sicapent.

Yield: 31.7 g (100% of theory)

LC-MS (method 2): R _t=0.78 min

MS (ESIpos): m/z=369 (M+H) ⁺

Working Examples

Example 1

Methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate

(MOL) (CDX)

In pyridine (600 ml), 31.75 g (86.20 mmol) of the compound from Example 11A were introduced under argon and cooled to 0° C. Then a solution of 6.66 ml (86.20 mmol) of methyl chloroformate in dichloromethane (10 ml) was added dropwise and the mixture was stirred at 0° C. for 1 h. Thereafter the reaction mixture was brought to RT, concentrated under reduced pressure and co-distilled repeatedly with toluene. The residue was stirred with water/ethanol and then filtered off on a frit, after which it was washed with ethanol and ethyl acetate. Subsequently the residue was again stirred with diethyl ether, isolated by filtration with suction and then dried under a high vacuum.

Yield: 24.24 g (65% of theory)

LC-MS (method 2): R _t=0.79 min

MS (ESIpos): m/z=427 (M+H) ⁺

¹H NMR (400 MHz, DMSO-d ₆): δ=3.62 (br. s, 3H), 5.79 (s, 2H), 6.22 (br. s, 4H), 7.10-7.19 (m, 2H), 7.19-7.26 (m, 1H), 7.32-7.40 (m, 1H), 7.67 and 7.99 (2 br. s, 1H), 8.66 (m, 1H), 8.89 (dd, 1H).

Patent ID	Title	Submitted Date	Granted Date
US2016324856	USE OF SGC STIMULATORS FOR THE TREATMENT OF NEUROMUSCULAR DISORDERS	2015-01-13
US2016158233	SGC STIMULATORS OR SGC ACTIVATORS AND PDE5 INHIBITORS IN COMBINATION WITH ADDITIONAL TREATMENT FOR THE THERAPY OF CYSTIC FIBROSIS	2014-07-21	2016-06-09
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US9845300	PROCESS FOR PREPARING SUBSTITUTED 5-FLUORO-1H-PYRAZOLOPYRIDINES	2017-02-17
US9604948	PROCESS FOR PREPARING SUBSTITUTED 5-FLUORO-1H-PYRAZOLOPYRIDINES	2015-07-10	2016-01-14

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US9150573	Process for preparing substituted 5-fluoro-1H-pyrazolopyridines	2014-07-01	2014-10-23
US8802847	Process for preparing substituted 5-fluoro-1H-pyrazolopyridines	2012-11-26	2014-08-12
US2016129004	SUBSTITUTED 5-FLUORO-1H-PYRAZOLOPYRIDINES AND THEIR USE	2016-01-15	2016-05-12
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Patent ID	Title	Submitted Date	Granted Date
US2017273977	SUBSTITUTED 5-FLUORO-1H-PYRAZOLOPYRIDINES AND THEIR USE	2016-11-10
US8921377	Substituted 5-fluoro-1H-pyrazolopyridines and their use	2013-03-27	2014-12-30
US8420656	Substituted 5-fluoro-1H-pyrazolopyridines and their use	2012-01-26
US9096592	BICYCLIC AZA HETEROCYCLES, AND USE THEREOF	2011-08-31	2014-05-29
US2014038956	Use of sGC stimulators, sGC activators, alone and combinations with PDE5 inhibitors for the treatment of systemic sclerosis (SSc).	2011-05-24	2014-02-06

REFERENCES

1: Gheorghiade M, Greene SJ, Butler J, Filippatos G, Lam CS, Maggioni AP, Ponikowski P, Shah SJ, Solomon SD, Kraigher-Krainer E, Samano ET, Müller K, Roessig L, Pieske B; SOCRATES-REDUCED Investigators and Coordinators. Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction: The SOCRATES-REDUCED Randomized Trial. JAMA. 2015 Dec 1;314(21):2251-62. doi: 10.1001/jama.2015.15734. PubMed PMID: 26547357.

2: Tschöpe C, Pieske B. [New therapy concepts for heart failure with preserved ejection fraction]. Herz. 2015 Apr;40(2):194-205. doi: 10.1007/s00059-015-4210-x. German. PubMed PMID: 25737289.

3: Stasch JP, Schlossmann J, Hocher B. Renal effects of soluble guanylate cyclase stimulators and activators: a review of the preclinical evidence. Curr Opin Pharmacol. 2015 Apr;21:95-104. doi: 10.1016/j.coph.2014.12.014. Epub 2015 Jan 31. Review. PubMed PMID: 25645316.

4: Pieske B, Butler J, Filippatos G, Lam C, Maggioni AP, Ponikowski P, Shah S, Solomon S, Kraigher-Krainer E, Samano ET, Scalise AV, Müller K, Roessig L, Gheorghiade M; SOCRATES Investigators and Coordinators. Rationale and design of the SOluble guanylate Cyclase stimulatoR in heArT failurE Studies (SOCRATES). Eur J Heart Fail. 2014 Sep;16(9):1026-38. doi: 10.1002/ejhf.135. Epub 2014 Jul 24. PubMed PMID: 25056511.

5: Stasch JP, Evgenov OV. Soluble guanylate cyclase stimulators in pulmonary hypertension. Handb Exp Pharmacol. 2013;218:279-313. doi: 10.1007/978-3-642-38664-0_12. Review. PubMed PMID: 24092345.

////////////////Vericiguat, BAY 102, BAY-1021189, MK-1242, ベルイシグアト , PHASE 3, MERCK, BAYER

COC(=O)NC1=C(N=C(N=C1N)C2=NN(C3=NC=C(C=C23)F)CC4=CC=CC=C4F)N

Ferric Maltol, マルトール第二鉄

August 31, 2018 1:43 pm / Leave a comment

Ferric maltol.png

Ferric Maltol

Iron, tris(3-hydroxy-2-methyl-4H-pyran-4-onato-O3,O4)-

Molecular Formula:	C₁₈H₁₅FeO₉
Molecular Weight:	431.154 g/mol

iron(3+);2-methyl-4-oxopyran-3-olate

RN: 33725-54-1
UNII: MA10QYF1Z0

Feraccru

Ferric maltol; UNII-MA10QYF1Z0; MA10QYF1Z0; Ferric maltol (INN); Ferric maltol [INN]; 33725-54-1

Shield Therapeutics, under license from Vitra Pharmaceuticals

UPDATE

Originator University of Cambridge; University of London
Developer Shield Therapeutics
Class Antianaemics; Ferric compounds; Pyrones; Small molecules
Mechanism of Action Iron replacements

Marketed Iron deficiency anaemia

Most Recent Events

26 Jul 2019 Registered for Iron deficiency anaemia (In adults) in USA (PO)
24 Apr 2019 Swissmedic approves a extension of the approved indication for ferric maltol to include treatment of all adults with iron deficiency (ID) with or without anaemia
14 Mar 2019 The European Patent Office decides in favour of Shield Therapeutics in relation to the group’s patent No. 2 668 175

The US Food and Drug Administration (FDA) has approved oral ferric maltol(Accrufer, Shield Therapeutics) AUG 2019 for the treatment of iron deficiency in adults.

The product is already approved in the European Union and Switzerland for the treatment of iron deficiency in adults, where it is sold as Feraccru.

OLD DATA NDA filing expected in US in 2H 2018, Ph 3 trial is planned in 2018/19 for treatment of iron deficiency anemia (IDA) in children., Expected dose form: Oral Capsule; 30 mg

Treatment of iron deficiency anemia (IDA) associated with inflammatory bowel disease (IBD) and Chronic Kidney disease.

Iron deficiency anaemia (IDA) occurs when iron levels are insufficient to support red blood cell production and is defined – according to the WHO – as haemoglobin levels below 13 g/dL in men over 15 years, below 12 g/dL in non-pregnant women over 15 years, and below 11 g/dL in pregnant women. Iron is absorbed at the apical surface of enterocytes to be transported by ferroportin, the only known iron exporter, across the basolateral surface of the enterocyte into circulation. Inflammation from IBD interferes with iron absorption by causing an increase in hepcidin, a peptide hormone synthesized in the liver that inhibits ferroportin activity. Anaemia is the most common extra-intestinal complication of inflammatory bowel disease (IBD) and although it often involves a combination of IDA and anaemia of chronic disease, IDA remains an important contributor in this condition due to chronic intestinal bleeding and decreased iron intake (from avoidance of foods that may exacerbate symptoms of IBD). In a variety of populations with IBD, the prevalence of iron deficiency anaemia ranges from 36%-76%. The serum markers of iron deficiency are low ferritin, low iron, raised total iron binding capacity, raised red cell protoporhyrin and increased transferrin binding receptor (sTfR). Serum ferritin is the most powerful test for iron deficiency. The cut-off level of ferritin which is diagnostic varies between 12-15 µg/L. Higher levels of serum ferritin do not exclude the possibility of iron deficiency, and a serum ferritin level of <100 μg/L may still be consistent with iron deficiency in patients with IBD. A transferrin saturation of <16% is indicative of iron deficiency, either absolute or functional. Other findings on a complete blood count panel that are suggestive of iron deficiency anaemia, but are not considered diagnostic, include microcytosis, hypochromia, and elevation of red cell distribution width.

A deficiency of iron can have a significant impact on a patient’s quality of life. Appropriate diagnosis and treatment of iron deficiency anaemia are important to improve or maintain the quality of life of patients. The goals of treatment are to treat the underlying cause, limit further blood loss or malabsorption, avoid blood transfusions in haemodynamically stable patients, relieve symptoms, and improve quality of life. More specifically, therapeutic goals of treatment include normalizing haemoglobin levels within 4 weeks (or achieving an increase of >2 g/dL) and replenishing iron stores (transferrin saturation >30%). Oral iron supplementation has been considered standard treatment because of an established safety profile, lower cost, and ease of administration. It has been shown to be effective in correcting anaemia and repleting iron stores. One concern with higher doses of daily oral iron is intolerance due to GI side effects. Symptoms include nausea, vomiting, diarrhea, abdominal pain, constipation, and melena-like stools. Guidelines on the Diagnosis and Management of Iron Deficiency and Anaemia in Inflammatory Bowel Diseases recommend IV iron therapy over oral iron supplementation in the treatment of iron deficiency anaemia in patients with IBD, citing faster and prolonged response to treatment, decreased irritation of existing GI inflammation, improved patient tolerance, and improved quality of life. Patients with severe anaemia (haemoglobin level of <10 g/dL), failure to respond or intolerance to oral iron therapy, severe intestinal disease or patients receiving concomitant erythropoietin are recommended indications for IV iron therapy. Other conditions where patients should be considered for first-line IV therapy over oral therapy include congestive heart failure, upper GI bleeding, and in situations where rapid correction of anaemia may be required.

Across EU there are several iron (Fe+2) oral preparations as ferrous fumarate, ferrous gluconate, ferrous sulphate and ferrous glycine sulfate, formulated as tablet, solution or gastroresistent capsules. All ferrous compounds are oxidised in the lumen of the gut or within the mucosa with release of activated hydroxyl radicals, which may attack the gut wall and can effect a range of gastrointestinal symptoms and discomfort. Ferric preparations also exist but with less bioavailability. Across EU there are also several IV products on the market: iron (III) hydroxide dextran complex, iron sucrose, ferric carboxymaltose, iron isomaltoside. IV iron therapy, however, is inconvenient, invasive and associated with the risk of rare but serious hypersensitivityreactions; it is used in those situations when oral preparations cannot be used or when there is a need to deliver iron rapidly. Feraccru is a trivalent iron, oral iron replacement preparation. The active substance of Feraccru is ferric maltol (also known as 3-hydroxy-2-methyl-4H-pyrane-4-one iron (III) complex, or ST10, or ferric trimaltol or ferric maltol) an oral ferric iron/maltol complex. It is presented as red hard gelatine capsules containing 30 mg iron (ferric iron). Maltol is a sugar derivative that strongly chelates iron in the ferric form (FeIII) rendering the iron stable and available for absorption. Upon dissociation of the ferric maltol complex, the maltol molecules are absorbed and glucuronidated in the intestinal wall, and within the liver during first pass metabolism, and subsequently eliminated from the body in the urine. The iron is absorbed via the endogenous dietary iron uptake system. The indication finally agreed with the CHMP was: Feraccru is indicated in adults for the treatment of iron deficiency anaemia (IDA) in patients with inflammatory bowel disease (IBD) (see section 5.1). The proposed dosage is one 30 mg capsule twice daily on an empty stomach, corresponding to 60 mg ferric iron per day. There was agreement in the paediatric investigation plan to grant a deferral and a waiver for iron as iron (III)-maltol complex (EMEA-001195-PIP01-11).The PDCO granted a waiver in infants under 6 months of age and a referral for the completion of the planned paediatric studies (ST10-021 PK-PED/ST10-01-102, an open label, randomised, multiple-dose, parallel PK study and ST10-01-303, a randomised, open label comparative safety and efficacy study of ST10 and oral ferrous sulphate as comparator) until the adult studies are completed.

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002733/WC500203504.pdf

SYN

Patent

https://patents.google.com/patent/WO2017167963A1/en

The sugar derivative maltol is a hydroxypyrone (IUPAC name: 3- hydroxy-2-methyl-4£f-pyran-4-one) and it strongly chelates iron and the resulting complex (ferric trimaltol) is well absorbed, unlike many other ferric iron therapies. Ferric trimaltol appears well tolerated even in populations highly susceptible to gastrointestinal side-effects, such as IBD patients (Harvey et al . , 1998), and as such it provides a valuable alternative to patients who are intolerant of oral ferrous iron products, notably in place of intravenous iron. Clinical trials using ferric trimaltol have been carried out, see for example, Gasche et al., 2015.

However, despite the evidence of bioavailability and tolerability for ferric trimaltol, its clinical development has been limited by the absence of adequate synthetic routes. In particular, most manufacturing processes require the use of organic solvents, which increase manufacturing costs, for example to deal with post-synthesis solvent removal, and require additional safety measures, for example to deal with flammability . Critically, solvent-based syntheses are not robust and often generate ferric hydroxide, described in the prior art to be an unwanted impurity of the synthesis.

WO 03/097627 (Vitra Pharmaceuticals Limited) describes the synthesis of ferric trimaltol from iron salts of carboxylic acids in aqueous solution at a pH greater than 7. In a first

synthesis, ferric citrate is added to a solution of sodium hydroxide at room temperature and maltol is added to a second solution of sodium hydroxide at pH 11.6. The ferric citrate solution is added to the maltol solution, leading to the

production of a deep red precipitate. This composition is then evaporated until dryness and the material is powdered and dried. Alternative syntheses are described using ferrous fumarate or ferrous gluconate as the iron carboxylate salt starting material, and by dissolving maltol in sodium carbonate solution in place of sodium hydroxide. However, despite the fact that this process is fully aqueous, several of the iron carboxylate salts employed are expensive, especially as they need to be pharmaceutical grade if the ferric trimaltol is to be suitable for human administration. More importantly, this process introduces high levels of

carboxylates (equimolar to iron or greater) to the synthesis that are not easily removed by filtration or centrifugation of the ferric trimaltol cake. Instead these water soluble contaminants must be washed off (e.g. water washed), but this would result in considerable losses of the product due to the amphipathic nature of ferric trimaltol.

WO 2012/101442 (Iron Therapeutic Holdings AG) describes the synthesis of ferric trimaltol by reacting maltol and a non- carboxylate iron salt in an aqueous solution at alkaline pH .

However, despite the lower cost of non-carboxylate iron salts, pharmaceutically appropriate grades are still required if the ferric trimaltol is to be suitable for human administration and hence are comparatively expensive starting materials.

Importantly, the use of non-carboxylate iron salts (e.g. ferric chloride) results in the addition of considerable levels of the respective counter-anion (e.g. three moles of chloride per every mole of iron) of which a significant part is retained in the filtration (or centrifugation) cake and thus must be washed off. As such, WO 2012/101442 does not address the problem of product losses in WO 03/097627. Furthermore, the addition of a non- carboxylate iron salt (e.g. ferric chloride) to a very alkaline solution, as described in WO 2012/101442, promotes the formation of stable iron oxides, which is an unwanted contaminant in ferric trimaltol . As a consequence, further costly and time-consuming processing of the material would be required for manufacturing .

Overall, the cost of the current aqueous syntheses is driven by regulatory demands for low levels of toxic heavy metals and residual reagents in the final pharmaceutical formulation, which force the use of highly purified, and thus expensive, iron salts as well as thorough washing of the final product (resulting in significant losses of product) . This will impact on the final price of ferric trimaltol and potentially limits patient access to this therapy. As such, there is a need for a process that can use lower iron grades and limited wash cycles, whilst producing ferric trimaltol of adequate purity.

Ferric maltols are a class of compounds that include ferric trimaltol, a chemical complex formed between ferric iron (Fe³⁺) and the hydroxypyrone, maltol (IUPAC name: 3-Hydroxy-2-methyl-4£f- pyran-4-one) , in a molar ratio of ferric iron to maltol of 3:1. Maltol strongly chelates the ferric iron and the resulting complex (ferric trimaltol which may also be written as ferric tri-maltol) is well absorbed, in contrast to some other ferric iron supplements, fortificants and therapies. Maltol binds metal cations mainly in the form of a dioxobidentate ligand in a similar manner proposed for other 4 ( 1H) -pyranones :

Structure of maltol (3-hydroxy-2-methyl-4 (H) -pyran-4-one) and dioxo-chelation to metal cations (M) such as iron. For ferric trimaltol three maltol groups surround one iron.

Examples

Example 1: Ferric trimaltol from L-lyslne coated ferric hydroxide

Synthesis of lysine-coated ferric hydroxide colloid

14.87g FeCl3. 6H20 was added to 25 mL UHP water and stirred until dissolved. 14.9g NaOH 5M was then added drop-wise to this solution with constant stirring, during which a ferric hydroxide colloid was gradually produced. This colloidal suspension was then added to a L-Lysine suspension (5.02g in 25mL ddH₂<D) .

Ferric trimaltol synthesis

7 g NaOH pellets was added to 25 mL UHP water and stirred until dissolved. Next, 24.5g maltol was added and stirred until dissolved. Then, the suspension of lysine-coated ferric

hydroxide colloids was gradually added to the maltol with vigorous stirring, producing a dark red precipitate (with a significant brown hue) . This suspension was incubated overnight during which time it became lighter and the brown hue

disappeared. This precipitate was then recovered by

centrifugation (4500 rpm x 5min) and dried overnight (50°C) .

Example 2: Ferric trimaltol from L-lysine modified ferric hydroxide

Synthesis of lysine-modified ferric hydroxide gel

14.87g FeCl₃.6H₂0 and 5.02g L-Lysine were added to 25 mL UHP water and stirred until dissolved. 32 mL NaOH 5M was then gradually added to this solution producing a ferric hydroxide gel .

Ferric trimaltol synthesis

7 g NaOH pellets was added to 25 mL UHP water and stirred until dissolved. Next, 24.5g maltol was added and stirred until dissolved. Next, the lysine-modified ferric hydroxide gel was gradually added to this solution with vigorous stirring. A 1.2 M HC1 solution was then used to drop the pH of the solution to 10, which was then incubated for 70 min. Finally, a dark red precipitate (i.e., ferric trimaltol) was recovered by

centrifugation (4500 rpmx5min) and dried overnight (45°C) .

Example 3: Absence of ferric hydroxide in ferric trimaltol

Ferric trimaltol is soluble in ethanol whereas ferric hydroxide (a potential contaminant) is not. As such ferric trimaltol powders produced as per Examples 1 and 2 were dissolved in ethanol. The material from Example 2 dissolved completely confirming the absence of iron hydroxides whereas the material from Example 1 did not. This supported the preference in the present invention for ligand modification, rather just surface coating, to ensure full conversion to ferric trimaltol .

Example 4: Ferric trimaltol from tartrate-modified ferric hydroxide

Synthesis of tartrate-modified ferric hydroxide gel

14.87g FeCl₃.6H₂0 (0.055 mol) was added to 25 mL UHP water and stirred until dissolved. 4.12 g tartaric acid (0.0275 mol) was added to this solution and stirred until dissolved. 38 mL NaOH 5M was then gradually added to this solution producing a ferric hydroxide gel .

Ferric trimaltol synthesis

2 g NaOH pellets was added to 25 mL UHP water and stirred until dissolved. Next, 24.5g maltol was added and stirred. This produced a slurry in which most of the maltol remained

undissolved. Next, the tartrate-modified ferric hydroxide gel was gradually added to this solution with vigorous stirring during which the remainder of maltol dissolved. After 15 min a dark red precipitate (i.e. ferric trimaltol) had been formed and pH had stabilised at 8.5. The material was then washed by (1)

centrifuging, (2) disposing of the supernatant and (3)

resuspending in water back to its original volume. Finally, the material was recovered by centrifugation (4500 rpm x 5min) and dried overnight (50°C) . Previously disclosed synthetic processes for the production of ferric trimaltol under aqueous conditions require the addition of NaOH (or other suitable bases) for conversion of maltol from its protonated form to its deprotonated form prior to complexation of iron. However this results in the formation of unwanted sodium ions which must be washed off. In contrast, the use of ferric hydroxides according to the methods of the present invention reduces the requirements for base and associated counter cation (e.g. sodium), which is a favourable feature. Note that ferric hydroxides are represented above as Fe (OH) 3 for illustrative purposes only. Different iron hydroxides possess different structures and elemental compositions (see Cornell & Schwertmann, The Iron Oxides Structure, Properties, Reactions, Occurrence and Uses. 2nd edition, 1996, VCH Publishers, New York) . Example 5: Ferric trimaltol from tartrate-modified ferric hydroxide (with removal of contaminants from ferric hydroxide)

Material prepared as in Example 4, except excess reactants and reaction products (e.g. unbound tartaric acid, sodium chloride) were removed from the ferric hydroxide gel. This was achieved by centrifuging the ferric hydroxide gel after its synthesis and discarding the supernatant, which contained unwanted soluble species. Finally, the ferric hydroxide gel was re-suspended in water back to its original volume prior to being added to a maltol slurry.

Example 6: Ethanolic clean up for ferric trimaltol produced from ligand coated ferric hydroxide

Ferric trimaltol precipitate was purified as it contained an unwanted iron oxide fraction. Part of the wet pellet recovered by centrifugation (4.5 g) was dissolved in 1L ethanol. The iron oxide fraction (which remained undissolved) was then removed by filtration, producing a turbidity-free solution. Next, ethanol was evaporated (40°C in a rotavapor under vacuum) producing a concentrated ferric trimaltol slurry. This was then recovered and oven dried overnight at 50°C.

PATENT

https://patents.google.com/patent/WO2012101442A1/en

Comparative Example 1

Preparation of Iron Trimaltol from Pure Maltol Maltol was dissolved in an aqueous solution of ferric chloride and ferric trimaltol was precipitated upon the addition of sodium hydroxide.

An accurate mass of ferric chloride hexahydrate granules (330g) was dissolved in distilled water to yield a pH of 0.6. To this solution, an equimolar amount of maltol was added (490g in total, initially 250g) and allowed to dissolve with continuous stirring. The pH of this solution was found to be zero and the colour of this solution was deep- purple. Spectroscopy showed that the initial solution was mainly a 1 :1 Fe/maltol mixture with some 1 :2 component. The remaining maltol was added. After an hour of stirring, sodium hydroxide (147g NaOH in 750 ml water) was added dropwise to the solution until a pH of 8.3 was achieved. The solution and precipitate were red. The precipitate was collected using a Buchner funnel under vacuum. The precipitate was dried at 40°C under vacuum.

Maltol is only slightly soluble in an aqueous acidic reaction medium. After an hour of stirring, traces of undissolved maltol were visible on the surface of the ferric chloride/maltol solution, on the walls of the reaction vessel and on the stirrer. Upon addition of sodium hydroxide, there appeared to be lumps of a brownish-black substance on the walls of the reaction vessel and on the stirrer which seemed to add to the impurities in the desired product.

An attempt to heat the ferric chloride/maltol solution so as to assist the maltol to dissolve in the ferric chloride solution resulted in a burnt, off spec, colour iron maltol sample. This method also produces two by-products which consume expensive maltol namely Fe(OH)₂ (Maltol) and Fe (OH) (Maltol)₂.

The sodium hydroxide solution has to be added extremely slowly to prevent “gumming up” and formation of undesirable lumps at the bottom of the reaction vessel. A yield of about 78% ferric trimaltol was obtained using this method of preparation.

When maltol is added to a ferric chloride solution at a low pH, no ferric trimaltol is formed and ferric hydroxide is generated with ferric monomaltol and a small percentage of ferric dimaltol species. The charge neutralisation of these complexes is either the hydroxy! functional group or the chloride anion. This addition also results in the formation of black deposits and gums consisting of ferric chloride/ferric hydroxide polymers. These black deposits are also produced if the solutions are heated. Therefore it is not possible to obtain the correct stoichiometry for the formation of ferric trimaltol and manufacture a pharmaceutically acceptable product using this method.

The addition of maltol to an aqueous solution of ferric or ferrous chloride was deemed impractical for scale up and manufacturing purposes and Examples 2 to 4 investigate the addition of the iron chlorides to maltol in solution.

The problem of working in an aqueous environment

Ferric chloride as a hydrated ion in aqueous solution is a strong Lewis acid with a Ka of 7x 10³ and ferrous chloride as a hydrated ion in aqueous solution is also a strong Lewis acid with a Ka of 5 x 10^“9. Over the desired range for using iron chlorides as starting materials for the synthesis of ferric trimaltol, ferric chloride in aqueous solution has a pH value in the range of 1-3 and ferrous chloride has a pH in the range of 3-5. Furthermore, commercial solutions of iron chlorides have a pH circa 1 because they are stabilised by the addition of hydrochloric acid to prevent the precipitation of ferric hydroxide species.

The present invention recognises that maltol is virtually insoluble at these low pH values and has limited solubility when dissolved in water in the pH range 6-8. The maximum aqueous solubility is 1g/100m! at 20°C. However, the solubility of maltol can be increased to 10g/100ml by heating to near boiling temperatures. Maltol is stable in aqueous solution at these temperatures and this property has been employed in Example 4 to synthesise ferric trimaltol. At low pH values ferric trimaltol is not the preferred species due to disproportionation. In order to obtain significant amounts of ferric trimaltol using a stoichiometric ratio of iron salt to hydroxypyrone of 1 :3, the eventual pH of the solution must exceed 7 since below that pH ferric dimaltol and monomaltol species will exist. Therefore two methods of increasing the pH were researched 1) using sodium carbonate and 2) using sodium hydroxide. Other alkali hydroxides could be used such as potassium hydroxide. The sodium carbonate neutralisation was found to be less preferable due to C0₂ generation. This research lead to an improved synthesis of ferric trimaltol.

Example 2

Maltol was dissolved in an aqueous solution of sodium hydroxide and iron maltol was precipitated upon the addition of ferric chloride.

In view of some of the difficulties experienced in Example 1 , and the fact that maltol is very soluble in aqueous alkali hydroxide solutions, it was decided to change the manufacturing procedure.

The initial work using this method of preparation showed that a 90% yield was achieved. Various operating parameters were then optimised and the following procedure outlines the final method chosen. A yield of 95% was then achieved. An accurate mass of sodium hydroxide pellets (20g) was dissolved in distilled water to yield a pH of 13.50. An equimolar amount of maltol (63g) was added to this aqueous solution of NaOH to give a clear yellow coloured solution with a pH of 11.6. Almost immediately a stoichiometric amount of ferric chloride (45g) was added slowly to this solution to give a pH of 7.1 and a red precipitate formed, which was then collected using a Buchner funnel under vacuum. The precipitate was then dried at 40°C under vacuum.

Adding the maltol solution in sodium hydroxide to ferric chloride as in method 1 is not preferred since it gives an off spec product and gums and a black precipitate.

Maltol is very soluble in aqueous alkali hydroxide solutions giving a yellow solution. The concentration of the hydroxide solution preferably does not exceed 20%.

This method is advantageous since it has the potential to produce only one by-product viz, ferric hydroxide Fe(OH)₃ which consumes some of the iron intended to complex with the maltol. This is not easily measurable in the presence of iron maltol and so the following method was used to measure the ferric hydroxide. Fe(OH)₃ is insoluble in ethanol and so the iron maltol product was dissolved in ethanol. It was found that small amounts of Fe(OH)₃ may be present in the batches of iron maltol synthesized according to Example 2.

Taking the extremes of the specification, in one embodiment, the amount of Fe(OH)₃ present in the active material may not exceed 2 wt. % Fe(OH)₃ based on the total weight of the composition. In view of its well known inert characteristics the level of this compound is adequately controlled and a final specification including controlled ferric hydroxide should be acceptable.

The mass balance for maltol and iron was closed at 99%.

A yield of 95% iron maltol was obtained using this method of preparation.

Example 3

Maltol was dissolved in an aqueous solution of Sodium Carbonate and Iron Maltol was precipitated upon the addition of Ferric Chloride.

An accurate mass of sodium carbonate (Na₂C0₃) (53g) was dissolved in distilled water to give a solution having pH = 11.5. An equimolar amount of maltol (65g) was added to this aqueous alkali solution to give a murky creme coloured solution of pH = 9.9. A stoichiometric amount of a ferric chloride solution was added drop wise to this solution to a pH of 8.00. A further 15 grams of Na₂C0₃ was added to this solution to increase the pH to 9.00. The remainder of the ferric chloride solution was then added to give a solution pH = 8.77 and a red coloured precipitate appeared.

The precipitate was collected using a Buchner funnel under vacuum. The precipitate was then dried at 40°C under vacuum. The release of C0₂ during the reaction tends to make this process less desirable due to foaming on the surface. The final product is a gellike solid when wet and the removal of moisture during drying can therefore be time consuming. The process may not be preferred but the ferric trimaltol produced could be acceptable.

Example 4 Maltol was dissolved in water and heated to a near boiling temperature and ferric or ferrous chloride was added to form a 1 :1/1:2 mixture of ferric maltol. The solution was allowed to cool and was added to maltol dissolved in sodium hydroxide. Stage 1

Depending on the batch size required, the ferric chloride was added slowly to a maltol solution in water at a pH of 6-7. The solubility of maltol is greatly enhanced up to 10g/100ml by heating to temperatures above 60°C. Addition of ferric chloride or ferrous chloride and monitoring the pH of the solution and maintaining the pH> 3 mainly produces ferric dimaltol species but very little ferric trimaltol. Above pH 3, no ferric hydroxide appeared to be generated. Ferric monomaltol and dimaltol species either with hydroxy or chloride giving the charge neutralisation are very soluble and a concentrated solution in excess of 30g/100ml can be generated. In order to obtain the correct stoichiometry for the formation of ferric trimaltol, further maltol is required and the pH needs to be corrected to values higher than 7.

As anhydrous ferrous or ferric chloride either 126g or 162g in 200ml of water can be added to a litre of water containing 120g of maltol. This ratio of iron to maltol does not provide sufficient maltol to produce any significant amounts of ferric trimaltol which does not precipitate at this stage.

Stage 2 Maltol in alkaline solution has been described as set out above. Conveniently, because maltol solutions up to 20% in sodium hydroxide have a pH circa 11.6, mixing of this solution with the ferric mono/dimaltol solutions from stage 1 yields a precipitate of ferric trimaltol with a deep characteristic burgundy red colour of high purity as determined by UV-vis spectroscopy. The filtrate yields product which is suitable for a GMP (good manufacturing process). The sodium chloride which is generated by this process is found in the supernatant since it has a much higher solubility at 35g/100ml than ferric trimaltol. The small amounts of sodium chloride in the ferric trimaltol can be reduced, if required, by washing in water. A further, surprising feature of the research resulted from work on ferrous chloride. Ferrous chloride may be substituted in stage 1 to form ferric dimaltol since the maltol was found to auto-oxidise the ferrous to ferric during the process of chelation. One aspect of this work which was considered to be potentially very useful if larger batch sizes were required arose from the finding that being a weaker Lewis acid than ferric chloride the pH of the starting solution was in excess of 3. Therefore the risk of generating ferric hydroxide was lower than with the use of ferric chloride at higher concentrations.

Ferrous and ferric chloride in solution or as a solid may be added to an alkaline solution of maltol in sodium hydroxide, combining stages 1 & 2. Providing a small excess of maltol up to about 10% is added then a precipitate of ferric trimaltol with a small amount of maltol is obtained. Such a preparation would be satisfactory as a GMP ferric trimaltol product.

PATENT

https://patents.google.com/patent/WO2017167963A1/en

AMPLE 1

Synthesis of ferric trimaltol using ferric citrate

NaOH (12g, 0.3 moles) is dissolved in water (50 ml) to form a sodium hydroxide solution. 20 ml of the sodium hydroxide solution is placed in a separate vessel.

Ferric citrate (30g, 0.11 moles) is slowly added to the sodium hydroxide solution in the separate vessel at room temperature with gentle stirring. Further portions of the sodium hydroxide solution are added to the solution of ferric citrate, as necessary, in order to ensure that all of the ferric citrate is dissolved.

Maltol (49g, 0.39 moles) is added to the remaining volume of sodium hydroxide solution and dissolved. The pH of the maltol solution is 11.6.

The ferric citrate solution is slowly added to the maltol solution with gentle stirring. A deep red precipitate forms; the supernatant is a deep red colour.

The solution is slowly evaporated to dryness at 60 to 80° C until the material is suitable for powdering. The material is powdered and the powder is then dried to a constant weight.

The yield of the final product is 87g. The final product comprises ferric trimaltol and sodium citrate. The product was assayed, using elemental analysis, for iron and sodium content. The iron content is 7.89% (theoretical 7.8%) and the sodium content is 13.45%.

The pH of a solution of the final product in water was measured. The pH of a 1% solution of the product by total weight of aqueous solution is 9.9 at 20°C.

EXAMPLE 2

Synthesis of ferric trimaltol using ferrous fumarate

NaOH (40g, 1 mole) is dissolved in water (100 ml) to form a sodium hydroxide solution. The pH of the solution is approximately 13.0.

Ferrous fumarate (170g, 1 mole) is slowly added to the sodium hydroxide solution at room temperature with gentle stirring.

Maltol (408g, 3.23 moles) is added to a separate volume of sodium hydroxide (40g, 1 mole) dissolved in water (100 ml) and dissolved. The pH of the solution is approximately 11.

The ferrous fumarate solution is slowly added to the maltol solution with gentle stirring. A deep red precipitate forms; the supernatant is a deep red colour.

The solution is slowly evaporated to dryness at 60 to 80^° C until the material is suitable for powdering. The material is powdered and the powder is then dried to a constant weight. The yield of the final product is 615g.

The final product comprises ferric trimaltol and sodium fumarate.

EXAMPLE 3

Synthesis of ferric trimaltol using sodium carbonate to vary pH

Sodium carbonate (2.5g) is dissolved in 10ml of distilled water at room temperature. The pH of the solution is 11.6. Maltol (9.6g – three molar equivalents of sodium carbonate) is added to the sodium carbonate solution to give a cream coloured solution having a pH of 10.0.

A stoichiometric amount of ferric citrate (5g, allowing for a small excess of maltol) in an aqueous solution of sodium hydroxide (lg in 5ml of distilled water) is added slowly to the solution of maltol. The pH of the combined solutions is about 9. A red precipitate appears which is separated by decantation and dried at 80°C in an oven.

The red precipitate is ferric trimaltol, as confirmed by UV-Vis spectrometry.

EXAMPLE 4

Synthesis of ferric trimaltol using ferrous gluconate

Potassium hydroxide (5.5g) is dissolved in 50ml of distilled water at room temperature. To 25ml of this solution, maltol (16.5g, 0.13 moles) is added and gently heated to form a clear solution. To the other 25ml aliquot of the potassium hydroxide solution ferrous gluconate (22.5g) is added. This is gently heated to form a dark green saturated solution. The ferrous gluconate solution is added to the maltol solution and immediately a colour change to dark brown is noted.

On cooling, a deep brown precipitate forms (which is ferric trimaltol). The supernatant is a deep brown solution containing ferric trimaltol and potassium gluconate. The precipitate and the supernatant are dried separately at 80°C in an oven. The ferric trimaltol is a deep red brown powder with a characteristic caramel odour and UV-vis spectrum in aqueous solution.

EXAMPLE 5

Synthesis of ferric trimaltol using solid ferrous gluconate

Example 4 was repeated with the modification that the maltol is added to all of the 50 ml solution of potassium hydroxide and then solid ferrous gluconate is added directly to the maltol solution. This method gives similar end products to Example 4.

EXAMPLE 6

Synthesis of ferric trimaltol using sodium ferrous citrate

A 20% solution w/v of sodium ferrous citrate in distilled water is prepared from 7.5g of sodium ferrous citrate in 37.5ml of water. The solution of sodium ferrous citrate is dark green with an iron content of about 20%. A solution of maltol (containing 10g/50ml) in 20% sodium hydroxide is added to the solution of sodium ferrous citrate. A characteristic deep red/brown iron complex of ferric trimaltol is formed.

EXAMPLE 7

Synthesis of ferric trimaltol using solid sodium ferrous citrate

Example 6 was repeated using the same amounts and concentrations of components but the method is varied in that solid sodium ferrous citrate (7.5g) is added directly to the maltol solution (containing lOg of maltol in 50ml). Ferric trimaltol is formed using this alternative method.

EXAMPLE 8

Synthesis of ferric trimaltol using sodium ferric citrate

A 20% solution w/v of sodium ferric citrate in distilled water is prepared from 7.5g of sodium ferric citrate in 37.5ml of water. The solution of sodium ferric citrate is dark brown with an iron content of about 20%.

A solution of maltol (containing 10g/50ml) in 20% sodium hydroxide is added to the solution of sodium ferric citrate. A characteristic deep red/brown iron complex of ferric trimaltol is formed. EXAMPLE 9

Example 8 was repeated using the same amounts and concentrations of components but the method is varied in that solid sodium ferric citrate (7.5g) is added directly to the maltol solution (containing lOg of maltol in 50ml). Ferric trimaltol is formed using this alternative method.

If any of Examples 3 to 9 are repeated using maltol in a neutral or acidic aqueous medium, such as for example in buffered citric acid, brown/black impurities appear and insoluble fractions are formed (probably of ferric hydroxide) and the UN-vis spectra of the solutions are not correct. In particular, there is a peak shift towards 510nm indicating the formation of mono or dimaltol complexes or compounds.

PATENT

WO 2017167970

POLYMORPH

GB 2531742

PATENT

WO 2016066555

https://patents.google.com/patent/WO2016066555A1/en

An adequate supply of iron to the body is an essential requirement for tissue growth and the maintenance of good health in both man and animals. Moreover, in certain pathological conditions where there is an insidious blood loss, or where there is a mal-distribution of iron in the body, there may be a state of low iron stores in the body leading to an iron deficiency and a concomitant chronic anaemia. This is seen in inflammatory diseases of the gastrointestinal tract, such as gastric and peptic ulcers, reflux oesophagitis, ulcerative colitis and Crohn’s disease.

Anaemia can also follow operations that result in serious blood loss and can be associated with gastrointestinal infections, such as those caused by Helicobacter pylori.

Ferric maltol comprises a complex of one ferric iron and three maltol anions and has the following molecular formula: (C₆H₅0₃)3Fe. Maltol is also known as 3-hydroxy-2-methyl-4- pyrone.

Polymorphic forms occur where the same composition of matter crystallises in a different lattice arrangement, resulting in different thermodynamic properties and stabilities specific to the particular polymorphic form. WO 03/097627 A1 discloses a method of forming iron hydroxypyrone compounds.

EP 0 159 917 A3 describes a pharmaceutical composition containing a hydroxypyrone-iron complex. WO 2012/101442 A1 discloses a method of forming iron hydroxypyrone compounds.

Schlindwein et al (Dalton Transactions, 2006, Vol. 10, pages 1313-1321) describes lipophilic 3-hydroxy-4-pyridinonate iron(lll) complexes. Ferric maltol has been known for about 100 years but no polymorphs have been identified or studied prior to this invention.

We have now found that it is possible to produce different polymorphs of ferric maltol, which crystalline forms may be referred to herein as the “compounds of the invention”. One polymorph form can be preferable in some circumstances when certain aspects, such as ease of preparation and stability, such as thermodynamic stability are required. In other situations, a different polymorph may be preferred for greater solubility and/or superior pharmacokinetics. The polymorphs of the invention can provide advantages in terms of improved or better bioavailability or improved or better stability or solubility.

The term “ferric maltol” as used herein refers to both ferric trimaltol and the designation INN ferric maltol. In one aspect of the invention there is provided a Form I polymorph of ferric maltol characterized by a powder X-ray diffraction pattern comprising characteristic crystalline peaks expressed in degrees 2-theta at each of 15.6 and 22.5 ± 0.25 or 0.2 degrees, optionally wherein the Form I polymorph comprises greater than about 92 wt.% ferric maltol based on the weight of the polymorph, such as greater than about 95 wt.%, preferably greater than about 96 wt.%, or about 98 wt.%, or about 99 wt.% such as about 99.8 wt.%.

In a further aspect of the invention there is provided a Form II polymorph of ferric maltol characterized by a powder X-ray diffraction pattern comprising a peak expressed in degrees 2-theta at 8.3 ± 0.25 degrees.

In a yet further aspect of the invention there is provided a Form III polymorph of ferric maltol characterized by a powder X-ray diffraction pattern comprising a peak expressed in degrees 2-theta at 7.4 ± 0.25 degrees. In a still further aspect of the invention there is provided a Form IV polymorph of ferric maltol characterized by a powder X-ray diffraction pattern comprising peaks expressed in degrees 2-theta at 9.5 and 14.5 ± 0.2 degrees.

The measurements of degrees 2-theta generally refer to measurements at ambient temperature, such as from about 5 to about 40°C, preferably about 10 to about 30°C. The relative intensities of the peaks can vary, depending on the sample preparation technique, the sample mounting procedure, the particular instrument employed, and the morphology of the sample. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, XRPD peak assignments for the polymorphs of the invention, as defined herein in any embodiment, can vary by, for example, ± 0.2, such as ±0.1 or ±0.05. The term “about” in relation to XRPD peak values may include for example, ±0.25 or ± 0.2, such as ±0.1 or ±0.05. These ranges may apply to any of the peak values in degrees referred to herein.

In another embodiment of the invention, there is provided a process for the preparation of a ferric maltol polymorph, such as Form I or Form II polymorph, which comprises combining ferric citrate with maltol anions to form a mixture comprising ferric maltol and wherein the process comprises the use of a ferric maltol seed crystal. The seed crystal may comprise a Form I and/or Form II polymorph as described herein and these polymorphs may be prepared using the methods described herein.

In another aspect of the invention, there is provided a process for the preparation of Form I polymorph, which comprises combining ferric citrate with maltol anions to form a mixture comprising ferric maltol polymorph Form I wherein the process comprises the use of a ferric maltol seed crystal comprising Form I and/or Form II polymorph and preferably wherein the polymorph formed is washed (typically with water) prior to drying.

In a further aspect of the invention, there is provided a process for the preparation of Form II polymorph, which comprises combining ferric citrate with maltol anions in solution to form a mixture comprising ferric maltol polymorph Form II, wherein the process preferably comprises the use of a ferric maltol seed crystal comprising Form I and/or Form II polymorph and preferably wherein the polymorph formed is washed (typically with water) prior to drying.

The invention also provides a pharmaceutical composition comprising a polymorph according to the invention, or mixtures thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier. In addition, the invention provides a composition comprising Form I and Form II polymorphs as defined herein.

In an aspect of the invention, the polymorph of the invention is for use in the prevention or treatment of iron deficiency with or without anaemia in a subject. The anaemia is preferably iron deficiency anaemia.

In a further aspect of the invention there is provided the use of a polymorph of the invention for the manufacture of a medicament for the prevention or treatment of iron deficiency with or without anaemia in a subject. The anaemia is preferably iron deficiency anaemia.

The invention further provides a method for the prevention or treatment of iron deficiency with or without anaemia which method comprises the administration of a polymorph according to the invention to a subject in need of such treatment. The anaemia is preferably iron deficiency anaemia.

Preferably the polymorphs of the invention are obtained in forms that are greater than about 90%, such as greater than about 95%, crystalline (e.g. greater than about 98% crystalline and, particularly, 100%, or nearly 100%, crystalline). By “substantially crystalline” we include greater than about 60%, preferably greater than about 75%, and more preferably greater than about 80% (such as about 90%) crystalline. The degree (%) of crystallinity may be determined by the skilled person using X-ray powder diffraction (XRPD). Other techniques, such as solid state NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) microcalorimetry and calculations of the true density may also be used.

The polymorphs of the invention may be characterised by an X-ray powder diffraction pattern comprising the following characteristic crystalline peaks with approximate 2-Theta values (in degrees) as well as an indication of the relative intensity of those peaks in brackets, where a percentage relative intensity of approximately 25- 00% is termed “vs” (very strong), approximately 10-25% is termed “s” (strong), approximately 3-10% is termed “m” (medium) and approximately 1-3% is termed “w” (weak).

Form I: The Form I polymorph preferably comprises characteristic crystalline peaks with 2-Theta values (in degrees) of around (i.e. at about or at approximately) 15.6 and 22.5 ± 0.25, or 0.2 degrees. The diffraction pattern typically does not comprise peaks at one or more, or all, or each of, about 6.9, 7.4, 8.3, 9.3, 10.5, or about 11.8 degrees, such as 8.3 or 11.8 ± 0.25, or ± 0.2, or ±0.1 such as about ±0.05 degrees.

Form II:

The form II polymorph preferably comprises a characteristic crystalline peak with 2-Theta value (in degrees) of around (i.e. at about or at approximately) 8.3 ± 0.25, or ± 0.2, or +0.1 such as about ±0.05 degrees. The diffraction pattern typically does not comprise peaks at one or more, or all, or each of, about 6.9, 7.4, 9.3, 9.5, 10.5, 11.4 or about 13.7 degrees, such as 11.4 or 13.8 ±0.25, or ±0.2, or ±0.1 such as about ±0.05 degrees.

The Form III polymorph preferably comprises a characteristic crystalline peak with 2-Theta value (in degrees) of around (i.e. at about or at approximately) 7.4 ±0.3, ±0.25, or 0.2, or ±0.1 such as about ±0.05 degrees. The diffraction pattern typically does not comprise peaks at one or more, or two or more, or three or more or each of, about 6.9, 8.3, 9.5, 11.3, 12.0, 12.5, 12.9, 14.5, or about 15.8 degrees, such as 6.9, 9.5, 11.3 ±0.25, or ±0.2, or ±0.1 such as about ±0.05 degrees.

The form IV polymorph preferably comprises a characteristic crystalline peaks with 2-Theta values (in degrees) of around (i.e. at about or at approximately) 9.5 and 14.5 +0.2, or ±0.1 such as about ±0.05 degrees. The diffraction pattern typically does not comprise peaks at one or more, or two or more, or three or more or each of, about 6.9, 8.3, 10.5, 11.7, 12.0, 12.2, 12.5, 13.0, 13.4, and about 15.8 degrees, such as 6.9, 8.3, 11.7 ±0.25, or ±0.2, or ±0.1 such as about ±0.05 degrees.

Example 1 : Form I 9.04 kg ferric citrate was combined with 29 litres of purified water. Separately, 12.2 kg of maltol was combined with 15.2 litres of sodium hydroxide solution (20 % w/w). The ferric citrate and sodium hydroxide were charged into a vessel with the addition of 4 litres of water and then stirred at 20 to 25°C. A seed was then added. The seed was 65g of ferric maltol polymorph in 12 litres of water. The seed crystal was prepared by the same process as described in Example 1 but without the use of a seed crystal. The seed was added to the vessel to aid a consistent crystallisation/precipitation. The mixture was held in the vessel, as a suspension, to allow crystal growth and then filtered and washed three times, each time with 13 litres of water. The resulting solid was dried at less than 80°C and produced 13.25 kg of dried ferric maltol.

The ferric maltol in Example 1 was produced on a scale of 12 to 15 kg in different batches. The analysis of the ferric maltol produced showed the % w/w of iron present was about 12.8 to 13.0 and the % w/w of maltol present was about 87.6 to 89.3.

Patent

Publication numberPriority datePublication dateAssigneeTitle

EP0159917A2 *1984-04-191985-10-30National Research Development CorporationPharmaceutical composition containing a hydroxypyrone-iron complex

WO2003097627A1 *2002-05-182003-11-27Vitra Pharmaceuticals LimitedMethod of forming iron hydroxypyrone compounds

WO2012101442A1 *2011-01-272012-08-02Iron Therapeutics Holdings AgProcess

Family To Family Citations

EP0107458B1 *1982-10-221987-07-29National Research Development CorporationPharmaceutical compositions

GB2531742B2014-10-282016-10-05Iron Therapeutics Holdings AgPolymorphs of ferric maltol

* Cited by examiner, † Cited by third party

Publication numberPriority datePublication dateAssigneeTitle

Family To Family Citations

GB2531742B2014-10-282016-10-05Iron Therapeutics Holdings AgPolymorphs of ferric maltol

WO2003097627A1 *2002-05-182003-11-27Vitra Pharmaceuticals LimitedMethod of forming iron hydroxypyrone compounds

US20080188555A1 *2007-02-062008-08-07Jonathan Joseph PowellLigand modified poly oxo-hydroxy metal ion materials, their uses and processes for their preparation

WO2012101442A1 *2011-01-272012-08-02Iron Therapeutics Holdings AgProcess

REFERENCES

Inorganica Chimica Acta (1990), 170(2), 241-3

Dalton Transactions (2006), (10), 1313-1321.

EP 0,107,458 [ 1984, to National Research Development Corporation]

Journal of Chemical Research, Synopses (1980), (9), 314.

Chemistry for Sustainable Development (2007) 15(4), PP- 448 – 458

US 5,028,411 [ 1991, to National Research Development Corporation]

Journal of Coordination Chemistry (1978), 8(1), 27-33

Polyhedron (1988), 7(19-20), 1973-9.

US 7,459,569 [2008, to Vitra Pharmaceuticals Limited].

Journal of Pharmaceutical Sciences (1972), 61(8), 1209-12

WO 2012 / 101,442 [ 2012, to Iron Therapeutics Holdings Ag]

Chemistry Letters (1975), (4), 339-42

//////////////Ferric Maltol, マルトール第二鉄 , Feraccru, FDA 2019

CC1=C(C(=O)C=CO1)[O-].CC1=C(C(=O)C=CO1)[O-].CC1=C(C(=O)C=CO1)[O-].[Fe+3]

LAFUTIDINE, ラフチジン

August 29, 2018 8:42 am / Leave a comment

Lafutidine ChemSpider 2D Image | lafutidine | C22H29N3O4S

LAFUTIDINE

N-[4-[4-(Piperidin-1-ylmethyl)pyridin-2-yloxy]-(Z)-but-2-en-1-yl]-2-(furfurylsulfinyl)acetamide

- FRG-8813
- ATC:A02B

Use:antisecretory, gastric H₂-antagonist
(+)-2-[(2-furanylmethyl)sulfinyl]-N-[(2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-butenyl]acetamide
Formula:C₂₂H₂₉N₃O₄S

MW:431.56 g/mol
CAS-RN:118288-08-7

(±)-2-(Furfurylsulfinyl)-N-(4-(4-(piperidinomethyl)-2-pyridyl)oxy-(Z)-2-butenyl)acetamide
(Z)-2-((2-Furanylmethyl)sulfinyl)-N-(4-((4-(1-piperidinylmethyl)-2-pyridinyl)oxy)-2-butenyl)acetamide
118288-08-7

FRG‐8813、2‐(Furfurylsulfinyl)‐N‐[(Z)‐4‐[[4‐(piperidinomethyl)‐2‐pyridinyl]oxy]‐2‐butenyl]acetamide、ロクチジン、Loctidine、ラフチジン・・・

2-[(furan-2-ylmethyl)sulfinyl]-N-[(2Z)-4-{[4-(piperidin-1-ylmethyl)pyridin-2-yl]oxy}but-2-en-1-yl]acetamide

49S4O7ADLC

7173

Acetamide, 2-[(2-furanylmethyl)sulfinyl]-N-[(2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-yl]- [ACD/Index Name]

lafutidine [INN] [Wiki]

UNII:49S4O7ADLC

(Z)-2-((Furan-2-ylmethyl)sulfinyl)-N-(4-((4-(piperidin-1-ylmethyl)pyridin-2-yl)oxy)but-2-en-1-yl)acetamide

Lafutidine , also named N-[4-[4-(piperidin-1-ylmethyl)pyridin-2-yloxy]-(Z)-but-2-en-1-yl]-2-(furfurylsulfinyl)acetamide, is a histamine H₂ receptor antagonist that was first produced in Japan by Taiho and UCB Japan for the oral treatment of peptic ulcers in 2000. In 2010 it was approved for the treatment of mild gastroesophageal reflux disease, and in 2012 it was approved to help improve symptoms of gastric mucosal lesions due to gastritis

Lafutidine (INN) is a second generation histamine H₂ receptor antagonist having multimodal mechanism of action and used to treat gastrointestinal disorders. It is marketed in Japan and India.

Medical use

Lafutidine is used to treat gastric ulcers, duodenal ulcers, as well as wounds in the lining of the stomach associated with acute gastritis and acute exacerbation of chronic gastritis.^[1]^[2]

Adverse effects

Adverse events observed during clinical trials included constipation, diarrhea, drug rash, nausea, vomiting and dizziness.^[2]

Mechanism of action

Like other H₂ receptor antagonists it prevents the secretion of gastric acid.^[2] It also activates calcitonin gene-related peptide, resulting in the stimulation of nitric oxide (NO) and regulation of gastric mucosal blood flow, increases somatostatin levels also resulting in less gastric acid secretion, causes the stomach lining to generate more mucin, inhibits neutrophil activation thus preventing injury from inflammation, and blocks the attachment of Helicobacter pylori to gastric cells.^[2]

Image result for LAFUTIDINE SYNTHESIS

Trade names

It is marketed in Japan as Stogar by UCB^[1] and in India as Lafaxid by Zuventus Healthcare.^[2]

N-[4-[4-(Piperidin-1-ylmethyl)pyridin-2-yloxy]-(Z)-but-2-en-1-yl]-2-(furfurylsulfinyl)acetamide 1 as a white solid (15.8 kg, 91.3%).(2,3)

¹H NMR (600 MHz, CDCl₃): δ 1.43 (m, 2H), 1.56–1.60 (m, 4H), 2.36 (m, 4H), 3.34 (d, 1H, J = 14.4 Hz), 3.40 (s, 2H), 3.59 (d, 1H, J = 14.4 Hz), 4.10 (t, 2H, J = 6.6 Hz), 4.17 (d, 1H, J = 13.8 Hz), 4.31 (d, 1H, J = 13.8 Hz), 4.93 (d, 2H, J = 6.6 Hz), 5.67–5.69 (m, 1H), 5.83–5.87 (m, 1H), 6.39 (dd, 1H, J = 1.8, 3.0 Hz), 6.47 (d, 1H, J = 3.0 Hz), 6.72 (s, 1H), 6.87 (d, 1H, J = 5.4 Hz), 7.19 (s, 1H), 7.43 (d, 1H, J = 1.8 Hz), 8.03 (d, 1H, J = 5.4 Hz).

¹³C NMR (150 MHz, CDCl₃): δ 24.2, 26.0, 26.0, 37.2, 50.2, 53.4, 54.6, 54.6, 61.4, 62.4, 110.8, 111.3, 112.2, 117.7, 128.4, 128.9, 143.3, 143.9, 146.3, 151.5, 163.6, 163.6.

IR (KBr): 3325, 2935, 1638, 1613, 1041 cm^–1.

ESI-MS: m/z 431.1.

Increasing the Purity of Lafutidine Using a “Suicide Substrate”

Chengjun Wu , Zhen Li, Chunchao Wang, Yanan Zhou, and Tiemin Sun *

Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, P. R. China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00070

*E-mail: suntiemin@126.com.

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00070/suppl_file/op8b00070_si_001.pdf

CLIP

http://www.drugfuture.com/synth/syndata.aspx?ID=145925

EP 0282077; JP 1988225371; JP 1989230556; JP 1989230576; US 4912101

1) The reaction of 2-bromo-4-(piperidin-1-ylmethyl)pyridine (I) with 4-amino-2(Z)-buten-1-ol (II) by means of NaH in THF gives 4-[4-(piperidin-1-ylmethyl)pyridin-2-yloxy]-2(Z)-buten-1-amine (III), which is then condensed with 2-(2-furylmethylsulfinyl)acetic acid (IV) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDCD) in dichloromethane.

EP 0582304; JP 1994192195

The condensation of 2-chloro-4-(piperidin-1-ylmethyl)pyridine (V) with 4-(tetrahydropyranyloxy)-2(Z)-buten-1-ol (VI) by means of NaH in THF gives 4-(piperidin-1-ylmethyl)-2-[4-(tetrahydropyranyloxy)-2(Z)-butenyloxy)pyridine (VII), which is deprotected with 4-methylbenzenesulfonic acid in methanol, yielding the free butenol (VIII). The acylation of (VIII) with methanesulfonyl chloride in toluene affords the corresponding mesylate (IX), which is finally condensed with 2-(2-furylmethylsulfonyl)acetamide (X) (obtained from the corresponding 4-nitrophenyl ester (XI) with ammonia) by means of potassium tert-butoxide in toluene.

Chem Pharm Bull 1998,46(4),616

A new synthesis of lafutidine has been described: The condensation of 2-bromopyridine-4-carbaldehyde ethylene ketal (I) with 4-(tetrahydropyranyloxy)-2(Z)-buten-1-ol (II) by means of NaOH, K2CO3 and tetrabutylammonium bisulfate in refluxing toluene gives the corresponding substitution product (III), which by treatment with pyridinium p-toluenesulfonate (PPTS) in hot ethanol yields the 2(Z)-butenol (IV). The reaction of (IV) with SOCl2 and then with potassium phthalimide (V) affords the substituted phthalimide (VI), which by treatment with hydrazine hydrate in refluxing methanol gives the 2(Z)-butenamine (VII). The condensation of (VII) with 2-(2-furylmethylsulfinyl)acetic acid 4-nitrophenyl ester (VIII) in THF yields the expected amide (IX), which is treated with p-toluenesulfonic acid in refluxing acetone/water to eliminate the ethylene ketal protecting group yilding the aldehyde (X). Finally, this compound is reductocondensed with piperidine (XI) by means of NaBH4 in ethanol.

CLIP

Synthesis Path

Lafutidine

CAS Registry Number: 118288-08-7

CAS Name: 2-[(2-Furanylmethyl)sulfinyl]-N-[(2Z)4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-butenyl]-acetamide

Additional Names: 2-(furfurylsulfinyl)-N-[(Z)-4-[[4-(piperidinomethyl)-2-pyridyl]oxy]-2-butenyl]acetamide

Manufacturers’ Codes: FRG-8813

Trademarks: Protecadin (Taiho); Stogar (Fujirebio)

Molecular Formula: C22H29N3O4S

Molecular Weight: 431.55

Percent Composition: C 61.23%, H 6.77%, N 9.74%, O 14.83%, S 7.43%

Literature References: Second generation histamine H2-receptor antagonist. Prepn of racemate: N. Hirakawa et al., EP 282077; eidem, US 4912101 (1988, 1990 both to Fujirebio); and pharmacology: eidem, Chem. Pharm. Bull. 46, 616 (1998). Pharmacology: S. Onodera et al., Jpn. J. Pharmacol. 68, 161 (1995). Mode of action study: M. Umeda et al., J. Gastroenterol. Hepatol. 14, 859 (1999). Gastroprotective effects in rats: H. Ajioka et al., Pharmacology 61, 83 (2000). Clinical pharmacokinetics: S. Haruki et al.,Yakuri to Chiryo 23, 3049 (1995). Toxicology study: A. Broadmeadow et al., Oyo Yakuri 50, 167 (1995).

Properties: Prepd as the (±) mixture, crystals from benzene-hexane, mp 92.7-94.9°. Slightly bitter taste. Freely sol in DMF, glacial acetic acid; sol in methanol; sparingly sol in dehydrated ethanol; very slightly sol in ether. Practically insol in water.

Melting point: mp 92.7-94.9°

Therap-Cat: Antiulcerative.

Keywords: Antiulcerative; Histamine H2-Receptor Antagonist.

References

^ Jump up to:^a ^b UCB Japan Revised: April 2005 Stogar tablets
^ Jump up to:^a ^b ^c ^d ^e Zuventus Healthcare Ltd. India Lafaxid tablets

- a EP 582 304 (Fujirebio; 5.8.1993; J-prior. 7.8.1992).

preparation of 2-benzenesulfonyl-4-methylpyridine:
- EP 931 790 (Kuraray; 26.1.1999; J-prior. 26.1.1998).

chlorination of 2-benzenesulfonyl-4-methylpyridine:
- JP 10 231 288 (Kuraray; 2.9.1998; J-prior. 21.2.1997).
- WO 9 626 188 (Sagami Res. Center; 21.2.1996; J-prior. 22.2.1995).
- b EP 282 077 (Fujirebio; 11.3.1988; J-prior. 13.3.1987).
- US 4 912 101 (Fujirebio; 27.3.1990; J-prior. 13.3.1987).

preparation of I:
- JP 10 231 288 (Kuraray; 2.9.1998; J-prior. 21.2.1997).

chlorination of 2-chloromethylpyridines forming 2-chloro-4-trichloromethylpyridine:
- EP 557 967 (Central Glass Co.; 1.9.1993; J-prior. 24.2.1993).

treatment of I with (Z)-4-(tetrahydro-2H-pyran-2-yloxy)-2-buten-1-ol:
- US 5 382 589 (Fujirebio; 17.1.1995; J-prior. 27.1.1992).

preparation of furfuryl acetate and derivatives:
- JP 8 198 844 (Fujirebio; 6.8.1996; J-prior. 23.1.1995).
- JP 8 198 843 (Fujirebio; 6.8.1996; J-prior. 23.1.1995).
- JP 07 010 860 (Central Glass Co.; 13.1.1995; J-prior. 25.6.1993).
- JP 07 010 864 (Central Glass Co.; 13.1.1995; J-prior. 25.6.1993).

2-(furfurylsulfinyl)acetic acid nitrophenyl ester:
- JP 07 010 862 (Central Glass Co.; 13.1.1995; J-prior. 25.6.1993).

4-(tetrahydro-2-pyranyloxy)-2(Z)-buten-1-ol from 2(Z)-butene-1,4-diol:
- Nishiguchi, T. et al.: J. Org. Chem. (JOCEAH) 63, 23, 8183 (1998).
- Davis, K. J. et al.: Synth. Commun. (SYNCAV) 29, 10, 1679 (1999).
- Nishiguchi, T. et al.: J. Chem. Soc., Perkin Trans. 1 (JCPRB4) 1995, 24, 2491.

Lafutidine
Clinical data

AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
ATC code	A02BA08 (WHO)
Identifiers
IUPAC name [show]
CAS Number	118288-08-7
PubChem CID	5282136
ChemSpider	4445337
UNII	49S4O7ADLC
KEGG	D01131
ECHA InfoCard	100.118.935
Chemical and physical data
Formula	C₂₂H₂₉N₃O₄S
Molar mass	431.54 g/mol
3D model (JSmol)	Interactive image

/////////////////LAFUTIDINE, ラフチジン , FRG-8813, ATC:A02B

FRG‐8813

2‐(Furfurylsulfinyl)‐N‐[(Z)‐4‐[[4‐(piperidinomethyl)‐2‐pyridinyl]oxy]‐2‐butenyl]acetamide

ロクチジン

Loctidine

ラフチジン

Laftidine

2‐[[(2‐Furyl)methyl]sulfinyl]‐N‐[(Z)‐4‐[[4‐(piperidinomethyl)‐2‐pyridyl]oxy]‐2‐butenyl]acetamide

N‐[(Z)‐4‐[4‐(Piperidinomethyl)‐2‐pyridyloxy]‐2‐butenyl]‐2‐(furfurylsulfinyl)acetamide

(Z)‐2‐フルフリルスルフィニル‐N‐[4‐(4‐ピペリジノメチル‐2‐ピリジルオキシ)‐2‐ブテニル]アセトアミド

ストガー

Stogar

プロテカジン

Protecadin

(+)‐ラフチジン

(+)‐Laftidine

ラフルチジン

Laflutidine

(Z)‐2‐Furfurylsulfinyl‐N‐[4‐(4‐piperidinomethyl‐2‐pyridyloxy)‐2‐butenyl]acetamide

2‐[[(2‐フリル)メチル]スルフィニル]‐N‐[(Z)‐4‐[[4‐(ピペリジノメチル)‐2‐ピリジル]オキシ]‐2‐ブテニル]アセトアミド

N‐[(Z)‐4‐[4‐(ピペリジノメチル)‐2‐ピリジルオキシ]‐2‐ブテニル]‐2‐(フルフリルスルフィニル)アセトアミド

2‐(フルフリルスルフィニル)‐N‐[(Z)‐4‐[[4‐(ピペリジノメチル)‐2‐ピリジニル]オキシ]‐2‐ブテニル]アセトアミド

C1CCN(CC1)CC2=CC(=NC=C2)OCC=CCNC(=O)CS(=O)CC3=CC=CO3

Plazomicin sulfate, プラゾマイシン硫酸塩 ,

August 28, 2018 9:47 am / Leave a comment

ChemSpider 2D Image | Plazomicin | C25H48N6O10

Plazomicin

Molecular FormulaC₂₅H₄₈N₆O₁₀
Average mass592.683 Da

(2S)-4-Amino-N-[(1R,2S,3S,4R,5S)-5-amino-4-{[(2S,3R)-3-amino-6-{[(2-hydroxyéthyl)amino]méthyl}-3,4-dihydro-2H-pyran-2-yl]oxy}-2-{[3-désoxy-4-C-méthyl-3-(méthylamino)-β-L-arabinopyranosyl]oxy}-3-hyd roxycyclohexyl]-2-hydroxybutanamide [French][ACD/IUPAC Name]

1154757-24-0 [RN]

9522

ACHN-490

Plazomicin sulfate.png

Image result for Plazomicin sulfate

Plazomicin Sulfate

Molecular Formula:	C₂₅H₅₀N₆O₁₄S
Molecular Weight:	690.763 g/mol

Plazomicin Sulfate; UNII-A78L6MT746; Plazomicin Sulfate [USAN]; A78L6MT746; 1380078-95-4; Plazomicin sulfate (USAN),

ACHN 490 sulfate

6′-(hydroxylethyl)-1-(haba)-sisomicin

Plazomicin is a neoglycoside antibiotic with activity against a broad range of Gram-positive and Gram-negive pathogens. Plazomicin showed potent in vitro activity against multidrug-resistant Klebsiella pneumoniae and Escherichia coli.

Mechanism of ActionProtein synthesis inhibitors

Orphan Drug StatusNo
New Molecular EntityYes

Highest Development Phases

MarketedUrinary tract infections
RegisteredPyelonephritis
PreregistrationBacteraemia; Nosocomial pneumonia
PreclinicalGram-negative infections
No development reportedRespiratory tract infections; Tularaemia; Yersinia infections

Most Recent Events

27 Jun 2018Registered for Pyelonephritis (Treatment-resistant) in USA (IV)- First Global Approval
27 Jun 2018Registered for Urinary tract infections (Treatment-resistant) in USA (IV)- First Global Approval
26 Jun 2018Achaogen receives complete response letter from the FDA for Plazomicin in Bloodstream infection

Synonyms: O-2-Amino-2,3,4,6-tetradeoxy-6-[(2-hydroxyethyl)amino]-α-D-glycero-hex-4-enopyranosyl-(1→4)-O-[3-deoxy-4-C-methyl-3-(methylamino)-β-L-arabinopyranosyl-(1→6)]-N1-[(2S)-4-amino-2-hydroxy-1-oxobutyl]-2-deoxy-D-streptamine; ACHN 490;

CAS Number: 1154757-24-0

Sulfate 1380078-95-4, プラゾマイシン硫酸塩;

Achaogen (USA)Phase II completed

Mol. Formula: C25H48N6O10

Aminoglycosides, Broad-spectrum,

Mol. Weight: 592.68

FDA

Click to access 210303Orig1s000lbl.pdf

Developed by Achaogen biopharmaceuticals, plazomicin is a next-generation aminoglycoside synthetically derived from [DB12604]. The structure of plazomicin was established via appending hydroxylaminobutyric acid to [DB12604] at position 1 and 2-hydroxyethyl group at position 6′ [A33942]. It was designed to evade all clinically relevant aminoglycoside-modifying enzymes, which contribute to the main resistance mechanism for aminoglycoside therapy [A33942]. However, acquired resistance of aminoglycosides may arise through over expression of efflux pumps and ribosomal modification by bacteria, which results from amino acid or rRNA sequence mutations [A33942]. Like other aminoglycosides, plazomicin is ineffective against bacterial isolates that produce 16S rRNA methyltransferases [FDA Label]. Plazomicin mediates the antibacterial activity against pathogens including carbapenem-resistant (CRE) and extended-spectrum beta-lactamase (ESBL) producing _Enterobacteriaceae_. It mediates the antibacterial activity by binding to bacterial 30S ribosomal subunit and inhibiting protein synthesis [FDA Label]. On June 28th, 2018, plazomicin sulfate was approved by the FDA for use in adult patients for the treatment of complicated urinary tract infections (cUTI) including Pyelonephritis. It is marketed as Zemdri and is administered via once-daily intravenous infusion.

Developed by Achaogen biopharmaceuticals, plazomicin is a next-generation aminoglycoside synthetically derived from Sisomicin. The structure of plazomicin was established via appending hydroxylaminobutyric acid to Sisomicin at position 1 and 2-hydroxyethyl group at position 6′ ^[1]. It was designed to evade all clinically relevant aminoglycoside-modifying enzymes, which contribute to the main resistance mechanism for aminoglycoside therapy ^[1]. However, acquired resistance of aminoglycosides may arise through over expression of efflux pumps and ribosomal modification by bacteria, which results from amino acid or rRNA sequence mutations ^[1]. Like other aminoglycosides, plazomicin is ineffective against bacterial isolates that produce 16S rRNA methyltransferases ^[Label]. Plazomicin mediates the antibacterial activity against pathogens including carbapenem-resistant (CRE) and extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae. It mediates the antibacterial activity by binding to bacterial 30S ribosomal subunit and inhibiting protein synthesis ^[Label]. On June 28th, 2018, plazomicin sulfate was approved by the FDA for use in adult patients for the treatment of complicated urinary tract infections (cUTI) including Pyelonephritis. It is marketed as Zemdri and is administered via once-daily intravenous infusion.

Plazomicin (INN,^[1] ZEMDRI) is a next-generation aminoglycoside (“neoglycoside”) antibacterial derived from sisomicin by appending a hydroxy-aminobutyric acid (HABA) substituent at position 1 and a hydroxyethyl substituent at position 6′.^[2]^[3]

Plazomicin has been reported to demonstrate in vitro synergistic activity when combined with daptomycin or ceftobiprole versus methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant S. aureus (VRSA) and against Pseudomonas aeruginosawhen combined with cefepime, doripenem, imipenem or piperacillin/tazobactam.^[3] It also demonstrates potent in vitro activity versus carbapenem-resistant Acinetobacter baumannii.^[4]

In 2012, U.S. Food and Drug Administration granted fast track designation for the development and regulatory review of plazomicin.^[5]

It is being developed by Achaogen, Inc. to treat serious bacterial infections due to multidrug-resistant Enterobacteriaceae, including carbapenem-resistant Enterobacteriaceae (CRE)^[6] and was in Phase III clinical trials as of April 7, 2016.^[7]

In June 2018 the FDA approved plazomicin (ZEMDRI) for adults with complicated urinary tract infections (cUTI), including pyelonephritis, caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Enterobacter cloacae, in patients who have limited or no alternative treatment options. Zemdri is an intravenous infusion, administered once daily.^[8]^[9] The FDA declined approval for treating bloodstream infections due to lack of effectiveness.^[10]

To continue the development of plazomicin, the company has received a contract option of US$ 60M from the Biomedical Advanced Research and Development Authority (BARDA) to support a global Phase III clinical study. The study will evaluate plazomicin in treating patients with serious Gram-negative bacterial infections due to carbapenem-resistant Enterobacteriaceae. The study is expected to start in the fourth quarter of 2013 [4].

PATENT

WO 2009067692

WO 2010132770

PAPER

Synthesis and spectrum of the neoglycoside ACHN-490
Antimicrobial Agents and Chemotherapy (2010), 54, (11), 4636-4642

https://aac.asm.org/content/54/11/4636

FIG. 1.

FIG. 2.

FIG. 3.

PAPER

Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes
ACS Infectious Diseases (2018), 4, (6), 980-987.

https://pubs.acs.org/doi/abs/10.1021/acsinfecdis.8b00001

PAPER

Effects of the 1-N-(4-Amino-2S-hydroxybutyryl) and 6′-N-(2-Hydroxyethyl) Substituents on Ribosomal Selectivity, Cochleotoxicity, and Antibacterial Activity in the Sisomicin Class of Aminoglycoside Antibiotics
ACS Infectious Diseases (2018), 4, (7), 1114-1120.

https://pubs.acs.org/doi/abs/10.1021/acsinfecdis.8b00052

Syntheses of the 6′-N-(2-hydroxyethyl) and 1-N-(4-amino-2S-hydroxybutyryl) derivatives of the 4,6-aminoglycoside sisomicin and that of the doubly modified 1-N-(4-amino-2S-hydroxybutyryl)-6′-N-(2-hydroxyethyl) derivative known as plazomicin are reported together with their antibacterial and antiribosomal activities and selectivities. The 6′-N-(2-hydroxyethyl) modification results in a moderate increase in prokaryotic/eukaryotic ribosomal selectivity, whereas the 1-N-(4-amino-2S-hydroxybutyryl) modification has the opposite effect. When combined in plazomicin, the effects of the two groups on ribosomal selectivity cancel each other out, leading to the prediction that plazomicin will exhibit ototoxicity comparable to those of the parent and the current clinical aminoglycoside antibiotics gentamicin and tobramycin, as borne out by ex vivo studies with mouse cochlear explants. The 6′-N-(2-hydroxyethyl) modification restores antibacterial activity in the presence of the AAC(6′) aminoglycoside-modifying enzymes, while the 1-N-(4-amino-2S-hydroxybutyryl) modification overcomes resistance to the AAC(2′) class but is still affected to some extent by the AAC(3) class. Neither modification is able to circumvent the ArmA ribosomal methyltransferase-induced aminoglycoside resistance. The use of phenyltriazenyl protection for the secondary amino group of sisomicin facilitates the synthesis of each derivative and their characterization through the provision of sharp NMR spectra for all intermediates.

https://pubs.acs.org/doi/suppl/10.1021/acsinfecdis.8b00052/suppl_file/id8b00052_si_001.pdf

4 (19 mg, 40%). [α]D 25 = +46.5 (c = 0.01, H2O);

1 H NMR (600 MHz, D2O): δ 5.51 ( s, 1H, H-1ʹ), 5.16 (t, J = 3.5 Hz, H, H-4ʹ), 4.99 (d , J = 4.0 Hz, 1H, H-1ʹʹ), 4.11 (dd , J =9.4 Hz, 3.9 Hz, 1H, CH(OH)CH2CH2), 4.00 (d , J = 12.8 Hz, 1H, H-5ʹʹ), 3.99-3.93 (m, 1H, H-1), 3.84 (dd, J = 11.0 Hz, 4.0 Hz, 1H, H-2ʹʹ), 3.81 (t, J = 9.9 Hz, 1H, H-4), 3.77 (t, J = 5.3 Hz, 1H, H-2ʹ), 3.71 (t, J = 5.1 Hz, 2H, NHCH2CH2O), 3.69 – 3.65 (m, 2H, H-6, H-6ʹ), 3.64 – 3.44 (m , 2H, H-5, H-6ʹ), 3.35 – 3.26 (m , 1H, H-3), 3.24 (d, J = 12.8 Hz, 1H, H-5ʹʹ), 3.15 (d, J = 11.0 Hz, 1H, H-3ʹʹ), 3.09 – 3.06 (m, 2H, NHCH2CH2O), 3.01 (t, J = 7.2 Hz, 2H, CH(OH)CH2CH2), 2.74 (s, 3H, NCH3), 2.58 – 2.52 (m, 1H, H-3ʹ), 2.29 – 2.24 (m, 1H, H-3ʹ), 2.07 (dt, J = 13.2 Hz, 4.4 Hz, 1H, H-2), 2.04 – 1.98 (m, 1H, CH(OH)CH2CH2), 1.84 – 1.79 (m, 1H, CH(OH)CH2CH2), 1.64 (q, 1H, J = 12.5 Hz, H-2), 1.17 (s, 3H, 4ʹʹ-CH3);

13C NMR (151 MHz, D2O): δ 181.2 (s, CH3COOH), 175.4 (s, NHCO), 141.7 (s, C-5ʹ), 102.5 (s, C-4ʹ), 98.0 (s, C-1ʹʹ), 96.9 (s, C-1ʹ), 79.8 (s, C-4), 78.8 (s, C-6), 73.8 (s, C-5), 69.8 (s, C-4ʹʹ), 69.4 (s, CH(OH)CH2CH2), 66.8 (s, C-5ʹʹ), 65.9 (s, C-2ʹʹ), 64.2 (s, C-3ʹʹ), 56.4 (s, NHCH2CH2O), 48.8 (s, C-1), 48.31 (s, NHCH2CH2O), 48.26 (s, C-3), 47.9 (s, C-6ʹ), 45.9 (s, C2ʹ), 36.8 (s, CH(OH)CH2CH2), 34.9 (s, NCH3), 30.7 (s, CH(OH)CH2CH2), 30.4 (s, C-2), 23.1 (s, CH3COOH), 23.0 (s, C-3ʹ), 20.8 (s, 4ʹʹ-CH3).

ESI-HRMS: m/z calcd. for C25H49N6O10 [M+H]+ 593.3510, found: 593.3481.

PATENT

http://www.google.com/patents/US20100099661

Common Intermediates Sisomicin

Amberlite IRA-400 (OH form) (200 g) was washed with MeOH (3×200 m1). To a stirring suspension of the washed resin in MeOH (150 mL) was added sisomicin sulfate (20.0 g, 0.029 mol) and the mixture was stirred overnight. The resin was then filtered and washed with MeOH (100 mL) and the combined organic layers were concentrated to dryness to yield the desired sisomicin (11.57 g, 0.026 mol, 89.6% yield): MS m/e [M+H]⁺ calcd 448.3, found 448.1.

Example 1 6′-(2-Hydroxy-ethyl)-1-(4-amino-2(S)-hydroxy-butyryl)-sisomicin

6′-(2-tert-Butyldimethylsililoxy-ethyl)-2′,3,3″-triBoc-1-(N-Boc-4-amino-2(S)-hydroxy-butyryl)-sisomicin

2′,3,3″-triBoc-1-(N-Boc-4-amino-2(S)-hydroxy-butyryl)-sisomicin (0.10 g, 0.105 mmol) was treated with tert-butyldimethylsilyloxy acetaldehyde following Procedure 1-Method A to yield the desired 6′-(2-tert-butyldimethylsilyloxy-ethyl)-2′,3,3″-triBoc-1-(N-Boc-4-amino-2(S)-hydroxy-butyryl)-sisomicin (MS m/e [M+H]⁺ calcd 1107.6, found 1107.4), which was carried through to the next step without further purification.

6′-(2-Hydroxy-ethyl)-1-(4-amino-2(S)-hydroxy-butyryl)-sisomicin

6′ -(2-tert-butyldimethylsililoxy-ethyl)-2′,3,3″-triBoc-1-(N-Boc-4-amino-2(S)-hydroxy-butyryl)-sisomicin (0.105 mmol) was submitted to Procedure 3-Method B for Boc removal to yield a crude, which was purified by RP HPLC Method 1-Column A to yield 6′-(2-hydroxy-ethyl)-1-(4-amino-2(S)-hydroxy-butyryl)-sisomicin: MS m/e [M+H]⁺ calcd 593.3, found 593.2, [M+Na]⁺615.3 ; CLND 97.5% purity.

Achaogen. Study for the treatment of complicated urinary tract infection and acute pyelonephritis.Available online: http://www.clinicaltrials.gov/ct2/show/NCT01096849 (accessed on 11 April 2013).
Zhanel, G.G.; Lawson, C.D.; Zelenitsky, S.; Findlay, B.; Schweizer, F.; Adam, H.; Walkty, A.; Rubinstein, E.; Gin, A.S.; Hoban, D.J.; et al. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev. Anti-Infect. Ther. 2012, 10, 459–473, doi:10.1586/eri.12.25.
Endimiani, A.; Hujer, K.M.; Hujer, A.M.; Armstrong, E.S.; Choudhary, Y.; Aggen, J.B.; Bonomo, R.A. ACHN-490, a neoglycoside with potent in vitro activity against multidrug-resistant Klebsiella pneumoniae isolates. Antimicrob. Agents Chemother. 2009, 53, 4504–4507.
Achaogen. Achaogen pipeline. Available online: http://www.achaogen.com (accessed on 30 August 2012).
Achaogen. Achaogen Awarded $60M Contract Option by BARDA for the Clinical Development of Plazomicin. Available online: http://www.achaogen.com/news/151/15 (accessed on 19 June 2013).
Achaogen. Achaogen announces all objectives met in Phase 2 Plazomicin complicated urinary tract infections study and start of first-in-human study with ACHN-975. Available online: http://www.achaogen.com/uploads/news/id148/Achaogen_PressRelease_2012–05–15.pdf (accessed on 10 April 2013).
Achaogen. Achaogen Announces Agreement with FDA on a Special Protocol Assessment for a Phase 3 Clinical Trial of Plazomicin to Treat Infections Caused by Carbapenem-Resistant Enterobacteriaceae (CRE); Achaogen: San Francisco, CA, USA, 2013.
Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin
US2010099661

4-23-2010

ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS


US2010099661	4-23-2010	ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS

Patent ID	Title	Submitted Date	Granted Date
US9688711	ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS	2016-01-20
US9266919	ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS	2014-07-17	2015-02-12

Patent ID	Title	Submitted Date	Granted Date
US8383596	ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS	2010-04-22
US8822424	Antibacterial aminoglycoside analogs	2013-01-04	2014-09-02
US2012208781	AMINOGLYCOSIDE DOSING REGIMENS	2011-11-11	2012-08-16
US2012214759	TREATMENT OF KLEBSIELLA PNEUMONIAE INFECTIONS WITH ANTIBACTERIAL AMINOGLYCOSIDE COMPOUNDS	2011-11-11	2012-08-23
US2012214760	TREATMENT OF URINARY TRACT INFECTIONS WITH ANTIBACTERIAL AMINOGLYCOSIDE COMPOUNDS	2011-11-11	2012-08-23

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Jump up^ “WHO Drug Information, Vol. 26, No. 3, 2012. International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 68”(PDF). World Health Organization. p. 314. Retrieved 27 April 2016.
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Plazomicin
Names

IUPAC name (2S)-4-Amino-N-[(1R,2S,3S,4R,5S)-5-amino-4-[[(2S,3R)-3-amino-6-[(2-hydroxyethylamino)methyl]-3,4-dihydro-2H-pyran-2-yl]oxy]-2-[(2R,3R,4R,5R)-3,5-dihydroxy-5-methyl-4-(methylamino)oxan-2-yl]oxy-3-hydroxycyclohexyl]-2-hydroxybutanamide
Other names 6′-(hydroxylethyl)-1-(HABA)-sisomicin
Identifiers
CAS Number	1154757-24-0
3D model (JSmol)	Interactive image
ChEMBL	ChEMBL1650559
ChemSpider	26390008
KEGG	D10151
PubChem CID	42613186
UNII	LYO9XZ250J
InChI [show]
SMILES [show]
Properties
Chemical formula	C₂₅H₄₈N₆O
Molar mass	592.683 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F],

Achaogen is a clinical-stage biopharmaceutical company passionately committed to the discovery, development, and commercialization of novel antibacterials to treat multi-drug resistant, or MDR, gram-negative infections.

Achaogen (a-KAY-o-jen) is developing plazomicin, its lead product candidate, for the treatment of serious bacterial infections due to MDR Enterobacteriaceae, including carbapenem-resistant Enterobacteriaceae, or CRE. In 2013, the Centers for Disease Control and Prevention identified CRE as a “nightmare bacteria” and an immediate public health threat that requires “urgent and aggressive action.” We expect to initiate a Phase 3 superiority trial of plazomicin in the first quarter of 2014.

CRE are one of many types of MDR gram-negative pathogens threatening patients. Bacteria such as Pseudomonas aeruginosa, Acinetobacter baumannii, and extended-spectrum beta-lactamase producing Enterobacteriaceae each pose “serious” resistance threats, according to the CDC, and also drive a great need for new, safe, and effective antibiotics. We have assembled the chemistry and microbiology expertise and capabilities required to develop new agents for the treatment of gram-negative infections. Plazomicin was the first clinical candidate from our gram-negative antibiotic discovery engine. In addition, our research and development pipeline includes two antipseudomonal programs targeting P. aeruginosa—a program to discover and develop small molecule inhibitors of LpxC, which is an enzyme essential for the synthesis of the outer membrane of gram-negative bacteria, and a therapeutic antibody program. We are also pursuing small molecule research programs targeting other essential gram-negative enzymes.

Achaogen has built an exceptional research and development team with deep expertise in the discovery and development of new drugs from research through commercialization. Our executive team has over 60 years of combined industry experience, and a proven track record of leadership, global registration, and lifecycle management for over 20 products. Our facility is located on the shores of the San Francisco Bay, ten minutes from the San Francisco International Airport, and only fifteen minutes from downtown San Francisco.

Image result for Plazomicin sulfate

ZEMDRITM (plazomicin) Approved by FDA for the Treatment of Adults with Complicated Urinary Tract Infections (cUTI)

https://globenewswire.com/news-release/2018/06/26/1529573/0/en/ZEMDRITM-plazomicin-Approved-by-FDA-for-the-Treatment-of-Adults-with-Complicated-Urinary-Tract-Infections-cUTI.html

― ZEMDRI is a new treatment for patients with cUTI, including pyelonephritis, due to certain Enterobacteriaceae ―

― ZEMDRI is the only once-daily aminoglycoside therapy approved for use in cUTI ―

― ZEMDRI has microbiological activity against pathogens designated by the CDC as urgent and serious public health threats, including carbapenem-resistant (CRE) and extended spectrum beta-lactamase (ESBL)- producing Enterobacteriaceae ―

SOUTH SAN FRANCISCO, Calif., June 26, 2018 (GLOBE NEWSWIRE) — Achaogen, Inc. (NASDAQ:AKAO), a biopharmaceutical company developing and commercializing innovative antibacterial agents to address multidrug resistant (MDR) gram-negative infections, today announced that the U.S. Food and Drug Administration (FDA) has approved ZEMDRI™ (plazomicin) for adults with complicated urinary tract infections (cUTI), including pyelonephritis, caused by certain Enterobacteriaceae in patients who have limited or no alternative treatment options. ZEMDRI is an intravenous infusion, administered once daily.

“The approval of ZEMDRI marks a significant milestone for Achaogen and we are excited to offer healthcare practitioners a new treatment option for patients with certain serious bacterial infections. ZEMDRI is designed to retain its potent activity in the face of certain difficult-to-treat MDR infections, including CRE and ESBL- producing Enterobacteriaceae,” said Blake Wise, Achaogen’s Chief Executive Officer. “Today’s milestone was made possible by our employees, by patients and investigators involved in our clinical trials, and by BARDA, who contributed significant funding for the development of ZEMDRI. This marks an important step in our commitment to fighting MDR bacteria and we are excited to launch ZEMDRI, a much needed once-daily antibiotic.”

“Bacteria continue to circumvent existing antibiotics, making certain infections notoriously hard to treat and putting some patients at high risk for mortality,” said James A. McKinnell, Assistant Professor of Medicine at the David Geffen School of Medicine and LA Biomed at Harbor-UCLA. “Aminoglycosides are a familiar and very effective class of antibiotics. I look forward to adding plazomicin to my short list of available treatment options and to its potential impact on patient outcomes.”

Regarding the potential indication for plazomicin for the treatment of bloodstream infection (BSI), the FDA issued a Complete Response Letter (CRL) stating that the CARE study does not provide substantial evidence of effectiveness of plazomicin for the treatment of BSI. The Company intends to meet with the FDA to determine whether there is a feasible resolution to address the CRL.

Achaogen will work with hospitals, providers, and insurers to ensure patients are able to receive this treatment. Patients, physicians, pharmacists, or other healthcare professionals with questions about ZEMDRI should contact 1.833.252.6400 or visit www.ZEMDRI.com.

ZEMDRI Phase 3 Clinical Results
The approval of ZEMDRI is supported in part by data from the EPIC (Evaluating Plazomicin In cUTI) clinical trial, which was the first randomized controlled study of once-daily aminoglycoside therapy for the treatment of cUTI, including pyelonephritis.

In the Phase 3 EPIC cUTI trial, ZEMDRI demonstrated non-inferiority to meropenem for the co-primary efficacy endpoints of composite cure (clinical cure and microbiological eradication) in the microbiological modified intent-to-treat (mMITT; N=388) population at Day 5 and test-of-cure (TOC) visit (Day 17 + 2). Composite cure rates at Day 5 were 88.0% (168/191) for ZEMDRI vs 91.4% (180/197) for meropenem (difference -3.4%, 95% CI, -10.0 to 3.1). Composite cure rates at TOC were 81.7% (156/191) for ZEMDRI vs 70.1% (138/197) for meropenem (difference 11.6%, 95% CI, 2.7 to 20.3). Composite cure at the TOC visit in patients with concomitant bacteremia at baseline was achieved in 72.0% (18/25) of patients in the ZEMDRI group and 56.5% (13/23) of patients in the meropenem group. The most common side effects (≥1% of patients treated with ZEMDRI) were decreased kidney function, diarrhea, hypertension, headache, nausea, vomiting, and hypotension.¹

The FDA approved a breakpoint of <= 2 mcg/mL; greater than 99% of Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae in U.S. surveillance are susceptible to Zemdri when applying this breakpoint.²

About cUTI
cUTI is defined as a UTI occurring in a patient with an underlying complicating factor of the genitourinary tract, such as a structural or functional abnormality.³ Patients with pyelonephritis, regardless of underlying abnormalities of the urinary tract, are considered a subset of patients with cUTI.⁴ An estimated 3 million cases of cUTI are treated in the hospital setting in the US each year.⁵ Enterobacteriaceae are the most common pathogens causing cUTIs⁶, and resistance within this family is a global concern. High rates of resistance to previous mainstays of therapy necessitate alternative treatment options. Ineffectively managed cUTI can lead to increased treatment failure rates, recurrence of infection, increased re-hospitalization, and increased morbidity and mortality. cUTI infections place an economic burden on hospitals and payers.^6,7

About ZEMDRI
ZEMDRI is an aminoglycoside with once-daily dosing that has activity against certain Enterobacteriaceae, including CRE and ESBL- producing Enterobacteriaceae. Achaogen’s EPIC clinical trial successfully evaluated the safety and efficacy of ZEMDRI in adult patients with cUTI, including pyelonephritis. ZEMDRI was engineered to overcome aminoglycoside-modifying enzymes, the most common aminoglycoside-resistance mechanism in Enterobacteriaceae, and has in vitro activity against ESBL- producing, aminoglycoside- resistant, and carbapenem- resistant isolates. The Centers for Disease Control and Prevention (CDC) has characterized ESBL- producing Enterobacteriaceae as a “serious threat” and CRE as “nightmare bacteria”, which is an immediate public health threat that requires urgent and aggressive action.

Working in the Lab

Achaogen, Inc.

Blake Wise, Chief Executive Officer at Achaogen

Achaogen, Inc.

High-Resolution Achaogen company logo

Achaogen, Inc.

/////////Plazomicin, ZEMDRI, FDA 2018, fast track designation, Plazomicin SULFATE, ACHN 490 sulfate, cUTI, Achaogen

CC1(COC(C(C1NC)O)OC2C(CC(C(C2O)OC3C(CC=C(O3)CNCCO)N)N)NC(=O)C(CCN)O)O

CN[C@@H]1[C@@H](O)[C@@H](O[C@H]2[C@@H](C[C@H](N)[C@@H](O[C@H]3OC(CNCCO)=CC[C@H]3N)[C@@H]2O)NC(=O)[C@@H](O)CCN)OC[C@]1(C)O

Inotersen sodium, イノテルセンナトリウム

August 27, 2018 12:58 pm / Leave a comment

Inotersen sodium.png

2D chemical structure of 1432726-13-0

Inotersen sodium,

UNII: 950736UC77

Data Source for DNA, d(P-thio)((2′-O-(2-methoxyethyl))m5rU-(2′-O-(2-methoxyethyl))m5rC-(2′-O-(2-methoxyethyl))m5rU-(2′-O-(2-methoxyethyl))m5rU-(2′-O-(2-methoxyethyl))rG-G-T-T-A-m5C-A-T-G-A-A-(2′-O-(2-methoxyethyl))rA-(2′-O-(2-methoxyethyl))m5rU-(2′-O-(2-methoxyethyl))m5rC-(2′-O-(2-methoxyethyl))m5rC-(2′-O-(2-methoxyethyl))m5rC)

STR https://chem.nlm.nih.gov/chemidplus/rn/1432726-13-0

IUPAC Condensed

Thy-MeOEt(-2)Ribf-sP-m5Cyt-MeOEt(-2)Ribf-sP-Thy-MeOEt(-2)Ribf-sP-Thy-MeOEt(-2)Ribf-sP-Gua-MeOEt(-2)Ribf-sP-dGuo-sP-dThd-sP-dThd-sP-dAdo-sP-m5Cyt-dRibf-sP-dAdo-sP-dThd-sP-dGuo-sP-dAdo-sP-dAdo-sP-Ade-MeOEt(-2)Ribf-sP-Thy-MeOEt(-2)Ribf-sP-m5Cyt-MeOEt(-2)Ribf-sP-m5Cyt-MeOEt(-2)Ribf-sP-m5Cyt-MeOEt(-2)Ribf.19Na+

IUPAC

O2′-(2-methoxyethyl)-5-methyl-P-thio-uridylyl-(3′->5′)-O2′-(2-methoxyethyl)-5-methyl-P-thio-cytidylyl-(3′->5′)-O2′-(2-methoxyethyl)-5-methyl-P-thio-uridylyl-(3′->5′)-O2′-(2-methoxyethyl)-5-methyl-P-thio-uridylyl-(3′->5′)-O2′-(2-methoxyethyl)-P-thio-guanylyl-(3′->5′)-2′-deoxy-P-thio-guanylyl-(3′->5′)-P-thio-thymidylyl-(3′->5′)-P-thio-thymidylyl-(3′->5′)-2′-deoxy-P-thio-adenylyl-(3′->5′)-2′-deoxy-5-methyl-P-thio-cytidylyl-(3′->5′)-2′-deoxy-P-thio-adenylyl-(3′->5′)-P-thio-thymidylyl-(3′->5′)-2′-deoxy-P-thio-guanylyl-(3′->5′)-2′-deoxy-P-thio-adenylyl-(3′->5′)-2′-deoxy-P-thio-adenylyl-(3′->5′)-O2′-(2-methoxyethyl)-P-thio-adenylyl-(3′->5′)-O2′-(2-methoxyethyl)-5-methyl-P-thio-uridylyl-(3′->5′)-O2′-(2-methoxyethyl)-5-methyl-P-thio-cytidylyl-(3′->5′)-O2′-(2-methoxyethyl)-5-methyl-P-thio-cytidylyl-(3′->5′)-O2′-(2-methoxyethyl)-5-methyl-cytidine sodium salt

イノテルセンナトリウム

Formula	C230H299N69O121P19S19. 19Na
Cas	1432726-13-0 Antisense oligonucleotide; TTR mRNA
Mol weight	7600.7669

ClassAntisense oligonucleotides; Neuroprotectants
Mechanism of ActionPrealbumin expression inhibitors

Orphan Drug StatusYes – Amyloid polyneuropathy
New Molecular Entity Yes

Highest Development Phases

RegisteredAmyloid polyneuropathy
Phase IIAmyloidosis; Cardiomyopathies

Most Recent Events

07 Aug 2018PTC Therapeutics announces intention to submit regulatory application in Latin America
06 Aug 2018Akcea Therapeutics intends to launch inotersen in Germany after Summer 2018
02 Aug 2018Inotersen licensed to PTC Therapeutics in Latin America

UNII-950736UC77; 950736UC77; Inotersen sodium; Inotersen sodium [USAN]; ISIS 420915 salt; 1432726-13-0

////////////////Inotersen sodium, eu 2018, イノテルセンナトリウム ,

SMILES

[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].COCCO[C@@H]1[C@H](O)[C@@H](COP(=O)([S-])O[C@@H]2[C@@H](COP(=O)([S-])O[C@@H]3[C@@H](COP(=O)([S-])O[C@@H]4[C@@H](COP(=O)([S-])O[C@@H]5[C@@H](COP(=O)([S-])O[C@H]6C[C@@H](O[C@@H]6COP(=O)([S-])O[C@H]7C[C@@H](O[C@@H]7COP(=O)([S-])O[C@H]8C[C@@H](O[C@@H]8COP(=O)([S-])O[C@H]9C[C@@H](O[C@@H]9COP(=O)([S-])O[C@H]%10C[C@@H](O[C@@H]%10COP(=O)([S-])O[C@H]%11C[C@@H](O[C@@H]%11COP(=O)([S-])O[C@H]%12C[C@@H](O[C@@H]%12COP(=O)([S-])O[C@H]%13C[C@@H](O[C@@H]%13COP(=O)([S-])O[C@H]%14C[C@@H](O[C@@H]%14COP(=O)([S-])O[C@H]%15C[C@@H](O[C@@H]%15COP(=O)([S-])O[C@@H]%16[C@@H](COP(=O)([S-])O[C@@H]%17[C@@H](COP(=O)([S-])O[C@@H]%18[C@@H](COP(=O)([S-])O[C@@H]%19[C@@H](COP(=O)([S-])O[C@@H]%20[C@@H](CO)O[C@H]([C@@H]%20OCCOC)N%21C=C(C)C(=O)NC%21=O)O[C@H]([C@@H]%19OCCOC)N%22C=C(C)C(=NC%22=O)N)O[C@H]([C@@H]%18OCCOC)N%23C=C(C)C(=O)NC%23=O)O[C@H]([C@@H]%17OCCOC)N%24C=C(C)C(=O)NC%24=O)O[C@H]([C@@H]%16OCCOC)n%25cnc%26C(=O)NC(=Nc%25%26)N)n%27cnc%28C(=O)NC(=Nc%27%28)N)N%29C=C(C)C(=O)NC%29=O)N%30C=C(C)C(=O)NC%30=O)n%31cnc%32c%31ncnc%32N)N%33C=C(C)C(=NC%33=O)N)n%34cnc%35c%34ncnc%35N)N%36C=C(C)C(=O)NC%36=O)n%37cnc%38C(=O)NC(=Nc%37%38)N)n%39cnc%40c%39ncnc%40N)n%41cnc%42c%41ncnc%42N)O[C@H]([C@@H]5OCCOC)n%43cnc%44c%43ncnc%44N)O[C@H]([C@@H]4OCCOC)N%45C=C(C)C(=O)NC%45=O)O[C@H]([C@@H]3OCCOC)N%46C=C(C)C(=NC%46=O)N)O[C@H]([C@@H]2OCCOC)N%47C=C(C)C(=NC%47=O)N)O[C@H]1N%48C=C(C)C(=NC%48=O)N

CC1=CN(C(=O)NC1=O)C2CC(C(O2)COP(=S)([O-])OC3CC(OC3COP(=S)([O-])OC4CC(OC4COP(=S)([O-])OC5C(OC(C5OCCOC)N6C=NC7=C6N=C(NC7=O)N)COP(=S)([O-])OC8C(OC(C8OCCOC)N9C=C(C(=O)NC9=O)C)COP(=S)([O-])OC1C(OC(C1OCCOC)N1C=C(C(=O)NC1=O)C)COP(=O)(OC1C(OC(C1OCCOC)N1C=C(C(=NC1=O)N)C)COP(=S)([O-])OC1C(OC(C1OCCOC)N1C=C(C(=O)NC1=O)C)CO)[S-])N1C=NC2=C1N=C(NC2=O)N)N1C=C(C(=O)NC1=O)C)OP(=S)([O-])OCC1C(CC(O1)N1C=NC2=C1N=CN=C2N)OP(=S)([O-])OCC1C(CC(O1)N1C=C(C(=NC1=O)N)C)OP(=S)([O-])OCC1C(CC(O1)N1C=NC2=C1N=CN=C2N)OP(=S)([O-])OCC1C(CC(O1)N1C=C(C(=O)NC1=O)C)OP(=S)([O-])OCC1C(CC(O1)N1C=NC2=C1N=C(NC2=O)N)OP(=S)([O-])OCC1C(CC(O1)N1C=NC2=C1N=CN=C2N)OP(=S)([O-])OCC1C(CC(O1)N1C=NC2=C1N=CN=C2N)OP(=S)([O-])OCC1C(C(C(O1)N1C=NC2=C1N=CN=C2N)OCCOC)OP(=S)([O-])OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)([O-])OCC1C(C(C(O1)N1C=C(C(=NC1=O)N)C)OCCOC)OP(=S)([O-])OCC1C(C(C(O1)N1C=C(C(=NC1=O)N)C)OCCOC)OP(=S)([O-])OCC1C(C(C(O1)N1C=C(C(=NC1=O)N)C)OCCOC)O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]

Amfonelic acid, амфонеловая кислота , حمض أمفونيليك , 安福萘酸 , アンホネル酸

August 27, 2018 8:00 am / Leave a comment

ChemSpider 2D Image | amfonelic acid | C18H16N2O3 Amfonelic acid.png

Amfonelic acid

Molecular FormulaC₁₈H₁₆N₂O₃
Average mass308.331 Da

1,8-Naphthyridine-3-carboxylic acid, 1-ethyl-1,4-dihydro-4-oxo-7-(phenylmethyl)-

15180-02-6 [RN]

1-Ethyl-1,4-dihydro-4-oxo-7-(phenylmethyl)-1,8-naphthyridine-3-carboxylic Acid

2324

RR302AR19Y

NSC 100638

амфонеловая кислота [Russian] [INN]

حمض أمفونيليك [Arabic] [INN]

安福萘酸 [Chinese] [INN]

Lopac0_000416

MFCD00055095 [MDL number]

NCA

NSC-100638

UNII:RR302AR19Y

UNII-RR302AR19Y

Win 25,978

Amfonelic acid (AFA; WIN 25,978) is a research chemical and dopaminergic stimulant with antibiotic properties.^[1]

History

The stimulant properties of AFA were discovered serendipitously at Sterling-Winthrop in the midst of research on the antibiotic nalidixic acid.^[1] In addition to behaving as antibiotics, it was found that many derivatives of nalidixic acid have either stimulant or depressant effects on the central nervous system.^[2] Researchers at Sterling-Winthrop found that AFA had a higher potency and therapeutic indexthan cocaine or amphetamine and so it was singled out for further study.^[1]^[3] A small number of clinical trials were held in the 1970s, but when it was found that AFA exacerbated psychotic symptoms in schizophrenic patients and produced undesirable stimulant properties in geriatric depressives clinical evaluation of AFA was discontinued.^[1] AFA remains a widely used pharmacological tool for study of the brain’s reward system, dopamine pathways, and the dopamine transporter.^[1] Since 2013 AFA has been sold on the gray market and there are numerous anecdotal reports detailing its non-medical use.^[1]

Pharmacology

In studies it proved to be a potent and highly selective dopamine reuptake inhibitor (DRI) in rat brain preparations.^[4]^[5] A study found a moderately long half-life of approximately 12 hours and a dopaminergic potency approximately 50 fold that of methylphenidate in rat brain preparations.^[6] Despite lack of direct serotonin activity, rats treated with subchronic doses of amfonelic acid display subsequent decreases in 5HT and 5HIAA.^[7] Amfonelic acid displays no activity in the norepinephrine system.^[8]

Despite its different mechanism of action, amfonelic acid displays discriminatory substitution with 150% the stimulant potency of dextroamphetamine.^[9] Amfonelic acid has been shown to be neuroprotective against methamphetamine damage to dopamine neurons.^[10] It also increases the effects of the antipsychotic drugs haloperidol, trifluoperazine and spiperone.^[11] Rats are shown to self-administer amfonelic acid in a dose-dependent manner.^[12]

Though AFA was discovered in the course of antibiotic research, there is very little data available on the drug’s antimicrobial activity. In 1988 the biologist G.C. Crumplin wrote, “[AFA] is less active against bacteria than are many other 4-quinolones, but studies in our laboratory on selected mammalian cell lines have shown it to be markedly more toxic to these cells than are the 4-quinolones that are more active antibacterial agents. Furthermore, it can be shown that sublethal doses induced marked changes in the pattern of proteins produced by the cell, thus suggesting a possible effect of 4-quinolones on gene transcription in mammalian cells.”^[13] When evaluated via broth microdilution the MIC of AFA for Escherichia coli is 125 μg/mL, a concentration thirty times higher than the MIC for nalidixic acid in the same E. coli strain.^[1]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g Morris, Hamilton (October 2015). “Sad Pink Monkey Blues”. Harper’s Magazine. Retrieved 2015-09-19.
Jump up^ US patent 3590036, “Naphthyridine-3-carboxylic Acids, Their Derivatives and Preparation Thereof”
Jump up^ Aceto, M.A. (1970). “Pharmacologic properties and mechanism of action of amfonelic acid”. European Journal of Pharmacology. 10: 344–354. doi:10.1016/0014-2999(70)90206-2. PMID 4393073.
Jump up^ Fuller, R. W.; Perry, K. W.; Bymaster, F. P.; Wong, D. T. (1978). “Comparative effects of pemoline, amfonelic acid and amphetamine on dopamine uptake and release in vitro and on brain 3,4-dihydroxyphenylacetic acid concentration in spiperone-treated rats”. Journal of Pharmacy and Pharmacology. 30 (3): 197–198. doi:10.1111/j.2042-7158.1978.tb13201.x. PMID 24701.
Jump up^ McMillen, B. A.; Shore, P. A. (1978). “Amfonelic acid, a non-amphetamine stimulant, has marked effects on brain dopamine metabolism but not noradrenaline metabolism: Association with differences in neuronal storage systems”. Journal of Pharmacy and Pharmacology. 30 (7): 464–466. doi:10.1111/j.2042-7158.1978.tb13293.x. PMID 27622.
Jump up^ Izenwasser, S.; Werling, L. L.; Cox, B. M. (1990). “Comparison of the effects of cocaine and other inhibitors of dopamine uptake in rat striatum, nucleus accumbens, olfactory tubercle, and medial prefrontal cortex”. Brain Research. 520 (1–2): 303–309. doi:10.1016/0006-8993(90)91719-W. PMID 2145054.
Jump up^ McMillen, BA; Scott, SM; Williams, HL (1991). “Effects of subchronic amphetamine or amfonelic acid on rat brain dopaminergic and serotonergic function”. Journal of neural transmission. General section. 83 (1–2): 55–66. doi:10.1007/BF01244452. PMID 2018630.
Jump up^ Agmo, A; Belzung, C; Rodríguez, C (1997). “A rat model of distractibility: Effects of drugs modifying dopaminergic, noradrenergic and GABAergic neurotransmission”. Journal of neural transmission (Vienna, Austria : 1996). 104 (1): 11–29. doi:10.1007/BF01271291. PMID 9085190.
Jump up^ Aceto, MD; Rosecrans, JA; Young, R; Glennon, RA (1984). “Similarity between (+)-amphetamine and amfonelic acid”. Pharmacology Biochemistry and Behavior. 20 (4): 635–7. doi:10.1016/0091-3057(84)90316-2. PMID 6728880.
Jump up^ Pu, C; Fisher, JE; Cappon, GD; Vorhees, CV (1994). “The effects of amfonelic acid, a dopamine uptake inhibitor, on methamphetamine-induced dopaminergic terminal degeneration and astrocytic response in rat striatum”. Brain Research. 649 (1–2): 217–24. doi:10.1016/0006-8993(94)91067-7. PMID 7953636.
Jump up^ Waldmeier, PC; Huber, H; Heinrich, M; Stoecklin, K (1985). “Discrimination of neuroleptics by means of their interaction with amfonelic acid: An attempt to characterize the test”. Biochemical Pharmacology. 34 (1): 39–44. doi:10.1016/0006-2952(85)90097-8. PMID 2857083.
Jump up^ Porrino, LJ; Goodman, NL; Sharpe, LG (1988). “Intravenous self-administration of the indirect dopaminergic agonist amfonelic acid by rats”. Pharmacology Biochemistry and Behavior. 31 (3): 623–6. doi:10.1016/0091-3057(88)90240-7. PMID 2908003.
Jump up^ Crumplin, G.C. (1988). “Aspects of Chemistry in the Development of the 4-Quinolone Antibacterial Agents”. Reviews of Infectious Diseases. 10 Suppl 1 (10): S2–S9. doi:10.1093/clinids/10.Supplement_1.S2. PMID 3279494.

External links

Amfonelic acid
Clinical data

ATC code	none
Legal status
Legal status	In general: uncontrolled
Identifiers
IUPAC name [show]
CAS Number	15180-02-6
PubChem CID	2137
ChemSpider	2052
UNII	RR302AR19Y
KEGG	D02897
ChEMBL	CHEMBL35337
Chemical and physical data
Formula	C₁₈H₁₆N₂O₃
Molar mass	308.3329 g/mol
3D model (JSmol)	Interactive image
SMILES [hide] CCN1C=C(C(=O)C2=C1N=C(C=C2)CC3=CC=CC=C3)C(=O)O

////////////Amfonelic acid, RR302AR19Y, амфонеловая кислота , حمض أمفونيليك , 安福萘酸 , アンホネル酸

CCN1C=C(C(=O)C2=C1N=C(C=C2)CC3=CC=CC=C3)C(=O)O

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