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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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A call to (green) arms: a rallying cry for green chemistry and engineering for CO2 capture, utilisation and storage

September 22, 2018 10:04 am / Leave a comment

Green Chemistry International

Graphical abstract: A call to (green) arms: a rallying cry for green chemistry and engineering for CO2 capture, utilisation and storage

A call to (green) arms: a rallying cry for green chemistry and engineering for CO₂ capture, utilisation and storage

Julien Leclaire*^a and David J. Heldebrant*^b

Author affiliations

*Corresponding authors

^aUniversité Claude Bernard Lyon 1 – CNRS, France
E-mail: julien.leclaire@univ-lyon1.fr

^bPacific Northwest National Lab, USA
E-mail: david.heldebrant@pnnl.gov

Abstract

Chemists, engineers, scientists, lend us your ears… Carbon capture, utilisation, and storage (CCUS) is among the largest challenges on the horizon and we need your help. In this perspective, we focus on identifying the critical research needs to make CCUS a reality, with an emphasis on how the principles of green chemistry (GC) and green engineering can be used to help address this challenge. We identify areas where GC principles can readily improve the energy or atom efficiency of processes or reduce the environmental impact. Conversely, we also identify dilemmas where the…

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Technetium (99mTc) tetrofosmin, テトロホスミンテクネチウム (99mTc)

September 22, 2018 9:59 am / Leave a comment

Technetium Tc-99m tetrofosmin.png

Technetium (^99mTc) tetrofosmin, 99mTc-Tetrofosmin

テトロホスミンテクネチウム (99mTc)

Formula	C₃₆H₈₀O₁₀P₄Tc
Molar mass	895.813 g/mol

CAS Number	127455-27-0 127502-06-1 (tetrofosmin)

UNII42FOP1YX93

2-[bis(2-ethoxyethyl)phosphanyl]ethyl-bis(2-ethoxyethyl)phosphane;technetium-98;dihydrate

Technetium Tc 99m tetrofosmin; Technetium Tc-99m tetrofosmin; TECHNETIUM TC-99M TETROFOSMIN KIT; Tc-99m tetrofosmin; Technetium-99 tetrofosmin; Technetium (99mTc) tetrofosmin

Title: Tetrofosmin

CAS Registry Number: 127502-06-1

CAS Name: 6,9-Bis(2-ethoxyethyl)-3,12-dioxa-6,9-diphosphatetradecane

Additional Names: ethylenebis[bis(2-ethoxyethyl)phosphine]

Manufacturers’ Codes: P53

Molecular Formula: C18H40O4P2

Molecular Weight: 382.46

Percent Composition: C 56.53%, H 10.54%, O 16.73%, P 16.20%

Literature References: Prepn: J. D. Kelly et al., EP 337654; eidem, US 5045302 (1989, 1991 both to Amersham). Pharmacology and determn of radiochemical purity: idem et al., J. Nucl. Med. 34, 222 (1993). Clinical biodistribution: B. Higley et al., ibid. 30. Clinical trial as a myocardial perfusion imaging agent: B. L. Zaret et al., Circulation 91, 313 (1995).

Derivative Type: 99mTc-Complex

CAS Registry Number: 127455-27-0

Additional Names: 99mTc tetrofosmin; [99mTc(tetrofosmin)2O2]+

Manufacturers’ Codes: PPN1011

Trademarks: Myoview (GE Healthcare)

Molecular Formula: C36H80O10P499mTc

Technetium Tc-99m Tetrofosmin is a radiopharmaceutical consisting of tetrofosmin, composed of two bidentate diphosphine ligands chelating the metastable radioisotope technetium Tc-99 (99mTc), with potential imaging activity upon SPECT (single photon emission computed tomography). Upon administration, technetium Tc 99m tetrofosmin is preferentially taken up by, and accumulates in, myocardial cells. Upon imaging, myocardial cells can be visualized and changes in ischemia and/or perfusion can be detected.

Pharmacology from NCIt

Technetium Tc-99m tetrofosmin is a drug used in nuclear myocardial perfusion imaging. The radioisotope, technetium-99m, is chelated by two 1,2-bis[di-(2-ethoxyethyl)phosphino]ethane ligands which belong to the group of diphosphines and which are referred to as tetrofosmin. It is a lipophilic technetium phosphine dioxo cation that was formulated into a freeze-dried kit which yields an injection.[A31592] Technetium Tc-99m tetrofosmin was developed by GE Healthcare and FDA approved on February 9, 1996.

from DrugBank

Technetium Tc-99m tetrofosmin is a drug used in nuclear myocardial perfusion imaging. The radioisotope, technetium-99m, is chelated by two 1,2-bis[di-(2-ethoxyethyl)phosphino]ethane ligands which belong to the group of diphosphines and which are referred to as tetrofosmin. It is a lipophilic technetium phosphine dioxo cation that was formulated into a freeze-dried kit which yields an injection.^[1] Technetium Tc-99m tetrofosmin was developed by GE Healthcare and FDA approved on February 9, 1996.

Technetium (^99mTc) tetrofosmin is a drug used in nuclear medicine cardiac imaging. It is sold under the brand name Myoview (GE Healthcare). The radioisotope, technetium-99m, is chelated by two 1,2-bis[di-(2-ethoxyethyl)phosphino]ethane ligands which belong to the group of diphosphines and which are referred to as tetrofosmin.^[1]^[2]

Image result for Technetium (99mTc) tetrofosmin synthesis

Tc-99m tetrofosmin is rapidly taken up by myocardial tissue and reaches its maximum level in approximately 5 minutes. About 66% of the total injected dose is excreted within 48 hours after injection (40% urine, 26% feces). Tc-99m tetrofosmin is indicated for use in scintigraphic imaging of the myocardium under stress and rest conditions. It is used to determine areas of reversible ischemia and infarcted tissue in the heart. It is also indicated to detect changes in perfusion induced by pharmacologic stress (adenosine, lexiscan, dobutamine or persantine) in patients with coronary artery disease. Its third indication is to assess left ventricular function (ejection fraction) in patients thought to have heart disease. No contraindications are known for use of Tc-99m tetrofosmin, but care should be taken to constantly monitor the cardiac function in patients with known or suspected coronary artery disease. Patients should be encouraged to void their bladders as soon as the images are gathered, and as often as possible after the tests to decrease their radiation doses, since the majority of elimination is renal. The recommended dose of Tc-99m tetrofosmin is between 5 and 33 millicuries (185-1221 megabecquerels). For a two-dose stress/rest dosing, the typical dose is normally a 10 mCi dose, followed one to four hours later by a dose of 30 mCi. Imaging normally begins 15 minutes following injection.^[3]

Image result for Technetium (99mTc) tetrofosmin synthesis

Amersham (formerly Nycomed Amersham , now GE Healthcare ) has developed and launched 99mTc-tetrofosmin (Myoview) as an injectable nuclear imaging agent for ischemic heart disease in several major territories and for use in detecting breast tumors

Technetium (^99mTc) tetrofosmin is a drug used in nuclear medicine cardiac imaging. It is sold under the brand name Myoview (GE Healthcare). The radioisotope, technetium-99m, is chelated by two 1, 2-bis-[bis-(2-ethoxyethyl)phosphino] ethane ligands, which belong to the group of diphosphines and which are referred to as tetrofosmin and has the structural Formula 1 :

Formula 1

^99mTc -based radiopharmaceuticals are commonly used in diagnostic nuclear medicine, especially for in vivo imaging (e.g. via immunoscintigraphy or radiolabeling). Usually cold kits are manufactured in advance in accordance with strict requirements of Good Manufacturing Practice (GMP) Guidelines, containing the chemical ingredients (e.g. ^99mTc -coordinating ligands, preservatives) in lyophilized form. The radioactive isotope ^99mTc (ti/2 = 6h) is added to those kits shortly before application to the patient via intravenous or subcutaneous injection.

^99mTc -Tetrofosmin is also described to be useful for tumor diagnostics, in particular of breast cancer and parathyroid gland cancer, and for multidrug resistance (MDR) research.

US5045302 discloses ^99mTc-coordinating diphosphine ligands (L), wherein one preferred example thereof is the ether functionalized diphosphine ligand l,2-bis[bis(2-ethoxy- ethyl)phosphino]ethane according to Formula 1, called tetrofosmin (“P53”), that forms a dimeric cationic technetium (V) dioxo phosphine complex, [TCO2L2] with ^99mTc, useful as myocardial imaging agent. Example 1 of said patent described the process for preparing tetrofosmin by reacting ethyl vinyl ether, bis(diphosphino)ethane in the presence of a-azo-isobutyronitrile (AIBN) in a fischer pressure-bottle equipped with a teflon stirring bar followed by removal of volatile materials and non-distillable material obtained, as per below mentioned Scheme 1.

Scheme 1

Formula 2 Formula 3 Formula 1

CN 1184225 C discloses tetrofosmin salts containing chloride or bromide or aryl sulfonates as negatively charged counter ions, which can be used for the preparation of a ^99mTc- Tetrofosmin radiopharmaceutical composition. According to this patent tetrofosmin hydrochloride is a viscous liquid. Own experiments of the inventors of the present invention revealed that the halide salts of tetrofosmin are hygroscopic oils, which are complicated to handle, e.g. when weighed. The oily and hygrospcopic

properties of tetrofosmin hydrochloride hampers its use in pharmaceutical preparations. Attempts to synthesize the subsalicylate salt of tetrofosmin failed because the starting material sulfosalicylic acid was not soluble in ether in the concentration specified in the patent (3.4 g in 15 ml).

WO2006/064175A1 discloses tetrofosmin was converted to tetrofosmin subsalicylate by reaction with 2.3 to 2.5 molar equivalents of 5-sulfosalicyclic acid at room temperature in ethanol, followed by recrystallisation from ethanol/ether.

WO2015/114002A1 relates to tetrafluoroborate salt of tetrafosmin and its process for the preparation thereof. Further this application also discloses one-vial and two vial kit formulation with tetrafluoroborate salt of tetrafosmin.

The article Proceedings of the International Symposium, 7th, Dresden, Germany, June 18-22, 2000 by Amersham Pharmacia Biotech UK Limited titled “The synthesis of [¹⁴C]tetrofosmin, a compound vital to the development of Myoview, Synthesis and Applications of Isotopically Labelled Compounds” disclosed a process for the preparation of tetrofosmin as per below mentioned Scheme 2:

Scheme 2

Formula 1A Formula 7

The starting material was bis(2- ethoxyethyl)benzylphosphine of Formula 4 . This was prepared from benzyl phosphonate, PhCH2P(0)(OEt)2 by reduction with lithium aluminium hydride to give the intermediate benzylphosphine, PhCH₂PH₂, followed by a photolysis reaction in the presence of ethyl vinyl ether to give compound of Formula 4. The compound of Formula 4 in acetonitrile was treated with dibromo[U-¹⁴C]ethane to give compound of Formula 6, further it was treated with excess of 30% aqueous sodium hydroxide in ethanol. The mixture was stirred at room temperature for 24 hours. The solvent was removed and the residue was treated with excess concentrated hydrochloric acid at 0°C. Aqueous work up gave compound of Formula 7. Then compound of Formula 7 in dry benzene was treated with hexachlorodisilane and hydrolysed with excess 30% aqueous sodium hydroxide at 0°C. Aqueous work up followed by flash column chromatography on silica gave [bisphosphinoethane- 1,2-¹⁴C]tetrofosmin of formula 1A.

The article Polyhedron (1995), 14(8), 1057-65, titled “Synthesis and characterization of Group 10 metal complexes with a new trifunctional ether phosphine. The X-ray crystal structures of bis[bis(2-ethoxyethyl)benzylphosphine]dichloronickel(II) and bis[bis(2-ethoxyethyl)benzylphosphine]chlorophenylnickel(II)” disclosed the process for the preparation of bis(2-ethoxyethyl)benzylphosphine as per below mentioned Scheme 3:

Scheme 3

Formula 8 Formula 9 Formula 4

The compound bis(2-ethoxyethyl)benzylphosphine of Formula 4 was prepared by first reduction of diethylbenzylphosphonate of Formula 8 using lithium aluminium hydride to obtain benzyl phosphine of Formula 9 followed by radical catalysed coupling reaction with ethyl vinyl ether carried out by using UV photolysis.

Tetrofosmin is extremely sensitive to atmospheric oxygen, which makes synthesis of the substance, as well as manufacturing and handling of the kit complicated as the substance has constantly to be handled in an oxygen free atmosphere.

High purity and stability under dry and controlled conditions are pivotal requirements for chemical compounds used as active ingredients in pharmaceuticals.

The processes disclosed in prior art for the preparation of compound of Formula 4 involves that coupling reaction of benzyl phosphine of Formula 9 with ethyl vinyl ether carried out by using photolytic conditions. Such technology is expensive as it requires separate instruments including isolated facility (to avoid the UV radiation exposure etc.), also it is not suitable for commercial scale production.

PATENT

WO-2018162964

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018162964&tab=PCTDESCRIPTION&maxRec=1000

Example 1

Preparation of benzyl phosphine:

A mixture of lithium aluminium hydride (25 g) in methyl tertiary butyl ether (MTBE) (800 ml) was cooled to 0 to 5°C and added a solution of diethylbenzylphosphonate in methyl tertiary butyl ether (100 g in 200ml). The temperature of reaction mixture was raised to 25 to 30 °C and stirred for 14 to 16 hour. After completion of the reaction, the reaction mixture was cooled to 0 to 5°C and 6N hydrochloric acid was added slowly. Further raised the temperature of reaction mixture to 25 to 30 °C and stirred for 30-45 minutes. The layers were separated, the aqueous layer was extracted with MTBE (250ml) and the combined organic layer was washed with deoxygenated water. The organic layer was dried over sodium sulfate and concentrated to obtain the title compound as non-distillable liquid.

Example 2

Preparation of benzylbis(2-ethoxyethyl)phosphane:

To a mixture of benzyl phosphine (obtained from example 1) and vinyl ethyl ether (250 ml) in pressure RB flask was added a-azo-isobutyronitrile (AIBN) (1.5g). The resulting reaction mixture was maintained at 80 to 90°C for 14 to 16 hours. The mixture was cooled to 20 to 30°C and AIBN (0.5g) added, then continued to heat the reaction mixture at 80 to 90°C for 6 to 7 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature and distilled under vacuum to obtain title compound as an oil (107 g).

Example 3

Preparation of Ethane- 1,2-diylbis (benzylbis(2-ethoxyethyl) phosphonium) bromide:

To a mixture of benzylbis(2-ethoxyethyl)phosphane 107.g) in acetonitrile (100ml) in pressure bottle was added 1, 2-dibromoethane (30.5 g). The reaction mixture was maintained at 80 to 90°C for 20 to 25 hours. After completion of the reaction, the reaction mass was cooled to room temperature and stirred for 45 to 60 minutes to obtain the solid. To the solid obtained was added methyl tertiary butyl ether (MTBE) (500ml) and stirred at room temperature for 2 to 3 hour. The reaction mass was filtered, washed with MTBE and suck dried. Further the filtered solid was heated in acetone (400ml) at 50 to 55°C for 2 to 3 hour. Then cooled the reaction mixture to room temperature, stirred, filtered and washed with acetone to obtain the title compound as white solid. (85g)

Example 4

Preparation of Ethane- 1, 2-diylbis (bis (2-ethoxy ethyl) phosphine oxide):

To a mixture of Ethane- 1,2-diylbis (benzylbis(2-ethoxyethyl) phosphonium) bromide (80g) in ethanol (480 ml) was added an aq. solution of sodium hydroxide ( 48g in 160 ml water) at room temperature. The reaction mass was maintained at 25 to 35°C for 10 to 12 hour. After completion of the reaction, the reaction mass was cone, under vacuum to obtained the residue. The residue was dissolved in deoxygenated water (400 ml) and washed with MTBE (400 ml x 2). The layers were separated, the aqueous layer was cooled to 10 to 20°C and 6N hydrochloric acid (200 ml) was added slowly. Then extracted the aqueous layer with dichloromethane (2000 ml), washed the organic layer with deoxygenated water (160 ml), dried the organic layer using sodium sulfate, filtered, and distilled under vacuum to obtain the residue. Further MTBE (160 ml x 2) was added to the residue and continued distillation under vacuum, degassed to obtain the solid. To the obtained solid, MTBE (400 ml) was added and heated at 45 to 50°C for 1-2 hour, further slowly cooled the reaction mass to 25 to 30°C, filtered the solid product. Again MTBE (400 ml) was added to the solid product and heated at 45 to 50°C for 1-2 hour, further slowly cooled the reaction mass to 25 to 30°C, filtered, washed with MTBE and dried under vacuum to obtain the title compound as white solid (32g).

Example 5

Preparation of tetrofosmin free base:

To a mixture of ethane- 1, 2-diylbis (bis (2-ethoxyethyl) phosphine oxide (18g) in toluene (180ml) in pressure RB flask argon/nitrogen gas was purged for 5 minute and hexachlorodisilane (30g) was added. The reaction mixture was heated to 80 to 90°C, stirred for 10 to 12 hour, further slowly cooled to -5 to 0°C and slowly added 30% aqueous sodium hydroxide solution (45g sodium hydroxide in 150 ml deoxygenated water) the temperature of reaction mixture was raised to 25 to 30°C and stirred for 1 to 2 hour. The layers were separated and the aq. layer was extracted with Toluene (180 ml). The combined organic layer was washed with deoxygenated water (180 ml). Further dried the organic layer using sodium sulfate, distilled under vacuum to obtain the residue of tetrofosmin free base (15.5g).

Example 6

Preparation of tetrofosmin disulfosalicylate salt:

To the residue of tetrofosmin free base (15.5g) was added an aq. solution of 5-sulfosalicylic acid dihydrate (21.6g in 75ml deoxygenated water) and stirred at 25 to 30°C for 25 to 30 minutes. Further heated the reaction mass to 55 to 60°C, stirred for 15 to 30 minute, slowly cooled the reaction mass to 10 to 15°C and stirred for 1-2 hour. Filtered, washed with chilled deoxygenated water, and dried under vacuum to obtain the title compound as white solid. (30g).

Example 7

Preparation of Form J of tetrofosmin disulfosalicylate salt:

An aq. solution of 5-sulfosalicylic acid dihydrate (21.6g in 75ml deoxygenated water) was added slowly into tetrofosmin free base (15.5g) and stirred at room temperature for 30 to 40 minutes. The temperature of reaction mixture was further raised to 50 to 60°C, stirred for 20 to 30 minute, cooled the reaction mass to 10 to 15°C and stirred for 1-2 hour. Filtered, washed with chilled deoxygenated water, and dried under vacuum to obtain the title compound.

PATENT

EP337654 ,

PATENT

US9549999

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 1 (FDA Orange Book Patent ID)
Patent	9549999
Expiration	Mar 10, 2030
Applicant	GE HEALTHCARE
Drug Application	N020372 (Prescription Drug: MYOVIEW 30ML. Ingredients: TECHNETIUM TC-99M TETROFOSMIN KIT) N020372 (Prescription Drug: MYOVIEW. Ingredients: TECHNETIUM TC-99M TETROFOSMIN KIT)

from FDA Orange Book

References

Jump up^ Kelly JD, Alan M. Forster AM, Higley B, et al. (February 1993). “Technetium-99m-Tetrofosmin as a new radiopharmaceutical for myocardial perfusion imaging”. Journal of Nuclear Medicine. 34 (2): 222–227. PMID 8429340.
Jump up^ Elhendy A, Schinkel AF, et al. (December 2005). “Risk stratification of patients with angina pectoris by stress 99mTc-tetrofosmin myocardial perfusion imaging”. Journal of Nuclear Medicine. 46 (12): 2003–2008. PMID 16330563.
Jump up^ Myoview package insert. Arlington Heights, IL: GE Healthcare, 2006, Aug.

Technetium (^99mTc) tetrofosmin
Clinical data

Routes of administration	Intravenous
ATC code	V09GA02 (WHO)
Pharmacokinetic data
Bioavailability	N/A
Identifiers
CAS Number	127455-27-0 127502-06-1 (tetrofosmin)
Chemical and physical data
Formula	C₃₆H₈₀O₁₀P₄Tc
Molar mass	895.813 g/mol

Patent ID	Title	Submitted Date	Granted Date
US9549999	RADIOPHARMACEUTICAL COMPOSITION	2010-09-23

External links

Myoview Prescribing Information Page

hide v t e Diagnostic radiopharmaceuticals (ATC: V09)
Central nervous system	^99mTc (Exametazime) ¹²³I (Ioflupane Iofetamine Iomazenil) ¹⁸F (Florbetapir, Flutemetamol)
Skeletal system	^99mTc (Medronic acid)
Renal	¹²³I (Sodium iodohippurate) ⁶⁴Cu (Cu-ETS2)
Gastrointestinal/Hepatic	⁷⁵Se (SeHCAT)
Respiratory system	¹³³Xe ^81mKr ^99mTc (MAA)
Cardiovascular system	^99mTc (Sestamibi Tetrofosmin) ¹¹¹In (Imciromab) ⁸²Rb (Rubidium chloride)
Inflammation/infection	^99mTc (Exametazime Sulesomab Tilmanocept) ¹¹¹In ⁶⁷Ga
Tumor	^99mTc (Arcitumomab Votumumab Hynic-octreotide) ¹¹¹In (Capromab pendetide Satumomab pendetide) ¹²⁵I ( Minretumomab) ¹²³I / ¹³¹I (Iobenguane) ¹⁸F(Fluciclovine Fludeoxyglucose Fluoroethyltyrosine Sodium fluoride)
Adrenal cortex	¹²³I ¹²⁵I ¹³¹I (Iodocholesterol)
Radionuclides (including tracers)	positron (PET): ¹⁸F ¹¹C ⁶⁴Cu ¹³N ¹⁵O ⁶⁸Ga gamma ray/photon (SPECT/scintigraphy): ^99mTc ¹²³I ¹²⁵I ¹³¹I ¹¹¹In ⁵⁷Co ¹⁵³Sm ¹³³Xe ⁵¹Cr ^81mKr ²⁰¹Tl ⁶⁷Ga ⁷⁵Se

//////////99mTc-Tetrofosmin, Technetium (99mTc) tetrofosmin, テトロホスミンテクネチウム (99mTc)

CCOCCP(CCOCC)CCP(CCOCC)CCOCC.CCOCCP(CCOCC)CCP(CCOCC)CCOCC.O.O.[Tc]

Diazoxide choline

September 20, 2018 2:11 am / Leave a comment

Diazoxide choline.png

Image result for Diazoxide choline

Diazoxide choline,

RN: 1098065-76-9
UNII: 2U8NRZ7P8L

Diazoxide choline; UNII-2U8NRZ7P8L; 2U8NRZ7P8L; YLLWQNAEYILHLV-UHFFFAOYSA-N

Molecular Formula:	C₁₃H₂₀ClN₃O₃S
Molecular Weight:	333.831 g/mol

Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, compd. with 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine dioxide (1:1)

7-Chloro-3-methyl-2H-1,2,4-benzothiadiazine dioxide compd. with 2-hydroxy-N,N,N-trimethylethanaminium (1:1)

7-chloro-3-methyl-1$l^{6},2,4-benzothiadiazin-2-ide 1,1-dioxide;2-hydroxyethyl(trimethyl)azanium

Diazoxide

CAS: 364-98-7 FREE FORM

2H-1,2,4-Benzothiadiazine, 7-chloro-3-methyl-, 1,1-dioxide

4H-1,2,4-Benzothiadiazine, 7-chloro-3-methyl-, 1,1-dioxide (7CI)
3-Methyl-7-chloro-1,2,4-benzothiadiazine 1,1-dioxide
7-Chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide
Diazoxide
Dizoxide

Eudemine injection
Hyperstat
Hypertonalum
Mutabase
NSC 64198
NSC 76130
Proglicem
Proglycem
SRG 95213
Sch 6783

Diazoxide

CAS Registry Number: 364-98-7

CAS Name: 7-Chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide

Additional Names: 3-methyl-7-chloro-1,2,4-benzothiadiazine 1,1-dioxide

Manufacturers’ Codes: SRG-95213

Trademarks: Eudemine Injection (Schering); Proglicem (Essex); Hyperstat (Schering); Hypertonalum (Essex); Mutabase (Schering); Proglycem (Schering)

Molecular Formula: C8H7ClN2O2S

Molecular Weight: 230.67

Percent Composition: C 41.66%, H 3.06%, Cl 15.37%, N 12.14%, O 13.87%, S 13.90%

Literature References: Hypotensive agent that inhibits secretion of insulin from pancreatic beta cells. Prepn: A. A. Rubin et al.,Science 133, 2067 (1961); J. G. Topliss et al., US 2986573; eidem, US 3345365 (1961, 1967 both to Schering); Raffa, Monzani, Farmaco Ed. Sci. 17, 244 (1962). Crystal and molecular structure: G. Bandoli, M. Nicolini, J. Cryst. Mol. Struct. 7, 229 (1978). Review of effect on insulin secretion: Nutr. Rev. 30, 194-198 (1972); of pharmacology and efficacy in hypertension: J. Koch-Weser, N. Engl. J. Med. 294, 1271-1274 (1976).

Properties: Crystals from dil alc, mp 330-331°. uv max (methanol): 268 nm (e 11300). Sol in alcohol and alkaline solns. Insol in water.

Melting point: mp 330-331°

Absorption maximum: uv max (methanol): 268 nm (e 11300)

Therap-Cat: Antihypoglycemic; antihypertensive.

Keywords: Antihypertensive; Thiazides and Analogs; Antihypoglycemic.

Diazoxide (INN; brand name Proglycem^[1]) is a potassium channel activator, which causes local relaxation in smooth muscle by increasing membrane permeability to potassium ions. This switches off voltage-gated calcium ion channels, preventing calcium flux across the sarcolemma and activation of the contractile apparatus.

In the United States, this agent is only available in the oral form and is typically given in hospital settings.^[2]

Medical uses

Diazoxide is used as a vasodilator in the treatment of acute hypertension or malignant hypertension.^[3]

Diazoxide also inhibits the secretion of insulin by opening ATP-sensitive potassium channel of beta cells of the pancreas, thus it is used to counter hypoglycemia in disease states such as insulinoma (a tumor producing insulin)^[4] or congenital hyperinsulinism.

Diazoxide acts as a positive allosteric modulator of the AMPA and kainate receptors, suggesting potential application as a cognitive enhancer.^[5]

Side effects

The Food and Drug Administration published a Safety Announcement in July 2015 highlighting the potential for development of pulmonary hypertension in newborns and infants treated with this drug.^[2]Diazoxide interferes with insulin release through its action on potassium channels.^[6] Diazoxide is one of the most potent openers of the K+ ATP channels present on the insulin producing beta cells of the pancreas. Opening these channels leads to hyperpolarization of cell membrane, a decrease in calcium influx, and a subsequently reduced release of insulin.^[7] This mechanism of action is the mirror opposite of that of sulfonylureas, a class of medications used to increase insulin release in Type 2 Diabetics. Therefore, this medicine is not given to non-insulin dependent diabetic patients.

SYN

Medicinal Chemistry Research, 12(9), 457-470; 2004

PATENT

WO 2009006483

https://patents.google.com/patent/WO2009006483A1/enIt

PATENT

US 20120238554

PATENT

WO 2013130411

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013130411&recNum=95&docAn=US2013027676&queryString=Telmisartan%20OR%20Hydrochlorothiazide&maxRec=4800

able 16. Characterization of Forms A and B of Diazoxide Choline Salt In

Screening Study

Experiment Form A Form B

*Maj or peaks (2-Θ):

Form A (9.8, 10.5, 14.9, 17.8, 17.9, 18.5, 19.5, 22.1, 22.6, 26.2, 29.6, 31.2);

Form B (8.9, 10.3, 12.0, 18.3, 20.6, 24.1, 24.5, 26.3, 27.1, 28.9).

** Unique FTIR (ATR) absorbances (cm ¹):

Form A (2926, 2654, 1592, 1449, 1248);

Form B (3256, 2174, 2890, 1605, 1463, 1235).

6.1.5.1. Solubility Screen in organic solvents.

[00725] Diazoxide choline, prepared in MEK using choline hydroxide as 50 wt % solution in water (see above) displayed some solubility in the following solvents:

acetonitrile, acetone, ethanol, IPA, MEK, DMF, and methanol. These solvents were chosen due to differences in functionality, polarity, and boiling points and their ability to dissolve diazoxide. Other solvents which showed poor ability to dissolve salts were used as antisolvents and in slurry experiments where some solubility was observed: dioxane, MTBE, EtOAc, IP Ac, THF, water, cyclohexane, heptane, CH2C12, and toluene.

[00726] Solvents for crystallizations during screening were chosen based on the solubility screen summarized in Table 17. Crystallizations of diazoxide choline from all conditions afforded a total of two forms, A and B. Forms A and B were found to be anhydrous polymorphs of diazoxide choline. Form B was observed to be generated from most solvents used. It was difficult to isolate pure Form A on large scales (>50 mg) as conditions observed to produce Form A on a smaller scale (approximately 50 mg or less) were found to result in Form B or mixtures of both forms on larger scales. Based on room-temperature slurry experiments, anhydrous Form B was found to be the most thermodynamically stable form in this study. Form A readily converted to Form B in all slurry solvents utilized.

Table 17. Solubility Screen for Diazoxide Choline Salt

Solvent Cmpd Solvent Cone. Temp. Soluble

(mg) (mL) (mg/niL) (°C)

CH2CI2 1.3 5.00 0.26 55 Partially

Toluene 1.4 5.00 0.28 55 No

.1.5.2. Single-Solvent Crystallizations

[00727] Fast cooling procedure: Diazoxide (approximately 20 mg) was weighed out into vials and enough solvent (starting with 0.25 mL) was added until the material completely dissolved at elevated temperature. After hot filtration the vials were placed in a refrigerator (4 °C) for 16 hours. After the cooling-process the samples were observed for precipitates which were isolated by filtration. Vials not demonstrating precipitates were evaporated down to dryness using a gentle stream of nitrogen. All solids were dried in vacuo at ambient temperature and 30 in. Hg.

[00728] Slow cooling procedure: Diazoxide (approximately 30 mg of choline salt) was weighed out into vials and enough solvent was added until the material went into solution at elevated temperature. After hot filtration the vials were then slowly cooled to room temperature at the rate of 20 °C/h and stirred at room temperature for 1-2 hours. All solids were dried in vacuo at ambient temperature and 30 in. Hg.

[00729] Based on the initial solubility study, seven solvents were selected for the fast-cooling crystallization: acetonitrile, acetone, ethanol, IPA, MEK, DMF, and methanol. Table 18 shows a list of the solvents that were used and the amount of solvent needed to dissolve the material. After the cooling-process precipitates were noticed in samples # 2, 3, 5, and 6, the solids were isolated by filtration. The other samples (# 1, 4, and 7) were evaporated down to dryness using a gentle stream of nitrogen. The diazoxide choline salts were found to be consistent with Form A by XRPD analysis for all solids with the exception of sample #2 (consistent with the freeform) and sample #5 (consistent with Form B with preferred orientation observed).

Table 18. Single- Solvent Crystallization of Diazoxide Choline Salt Using Fast- Cooling Procedure

[00730] In accordance with the data obtained from fast-cooling experiments, four solvents which showed precipitation of solids were chosen for the slow-cooling experiments: MeOH, EtOH, MeCN, and IPA (Table 19). All obtained analyzable solids of the choline salt were found to be consistent with Form B by XRPD with the exception of Entry #1 which was consistent with diazoxide freeform and Entry #2 which was not analyzable. Mother liquor of Entry #2 was concentrated to dryness and the residual solids were analyzed by XRPD and found to be Form B material. As a result of obtaining freeform material from the single- solvent crystallizations in methanol, three more alcohols were tested for the single- solvent crystallizations using fast- and slow-cooling procedures. Tables 20 and 21 provide a list of the solvents that were used and the amount of solvent needed to dissolve the material. XRPD patterns of the fast-cooling procedure showed freeform of diazoxide from isobutanol, Form B from isoamyl alcohol, and Form A from tert-amyl alcohol compared to the slow-cooling procedure, which afforded Form B material from all three solvents.

Table 19. Single-Solvent Crystallization of Diazoxide Choline Salt Using Slow- Cooling Procedure

Table 20. Single- Solvent Crystallization of Diazoxide Choline Salt Using Fast- Cooling Procedure

Table 21. Single-Solvent Crystallization of Diazoxide Choline Salt Using Slow- Cooling Procedure

[00731] The results of the choline salt single- solvent fast- and slow-cooling crystallizations (see Tables 19 to 21) indicated that Form A was more likely to be isolated with fast-cooling profiles and Form B with slow-cooling profiles.

6.1.5.3. Binary Solvent Crystallizations

[00732] Binary- solvent crystallizations of the choline salt were performed using four primary solvents (MeOH, EtOH, IPA, and MeCN) and nine cosolvents (MTBE, EtOAc, IPAc, THF, c-hexane, heptane, toluene, CH2CI2, and dioxane) with a fast-cooling profile (supra). XRPD patterns showed that Form B was obtained from mixtures of MeOH with MTBE, EtOAc, IPAc, toluene, and dioxane. As shown in Table 22, Form A was obtained from mixtures of MeOH with THF and with CH2CI2 after evaporating the solvent to dryness. The mixtures of MeOH with cyclohexane and heptane provided the freeform of diazoxide. All solids obtained from fast-cooling procedures with EtOH, IPA, and MeCN as primary solvents provided Form B material.

Table 22. Binary-Solvent Crystallizations of Choline Salt of Diazoxide Using Fast- Cooling Procedure and MeOH as a Primary Solvent

* Solids were dissolved at 62 °C.

** Freeform of diazoxide.

[00733] Binary- solvent recrystallizations of the choline salt with the slow-cooling procedure were performed using two primary solvents (IPA and MeCN) and nine cosolvents (MTBE, EtOAc, IPAc, THF, c-hexane, heptane, toluene, CH2C12, and dioxane). All solids obtained from a slow-cooling procedure with IPA and MeCN as primary solvents provided Form B material based on XRPD analysis. The results of

binary- solvent crystallizations indicated that Form B was the most thermodynamic ally stable form of diazoxide choline.

6.1.5.4. Binary Solvent Crystallizations Using Water as a Cosolvent

[00734] In an attempt to investigate the formation of hydrates of the choline salt, experiments was performed using fast- and slow-cooling procedures and water as a cosolvent.

[00735] The fast cooling procedure (supra) was used with the exception of using different primary solvents which were miscible with water: acetone, acetonitrile, DMF, IPA, i-BuOH, i-AmOH, and t-AmOH. Water was utilized in these crystallizations as a cosolvent. All solids obtained from the fast-cooling procedure with water as the cosolvent provided diazoxide freeform material by XRPD analysis.

[00736] To compare the results obtained from the fast-cooling procedure a set of experiments was performed using a slow-cooling procedure and water as a cosolvent. All obtained solids were analyzed by XRPD and afforded patterns consistent with diazoxide freeform. Without wishing to be bound by theory, these results suggest that the conditions used for crystallization caused dissociation of the choline salt. A small amount of a second crop was obtained in each sample, but only two samples were analyzable by XRPD and indicated that the samples were freeform material. All mother liquors were evaporated to dryness and the residual solids were also analyzed by XRPD to afford patterns consistent with Form B of the choline salt.

6.1.5.5. Metastable Zone Width Estimation

[00737] Form B: To produce a robust process, an understanding of the solubility profiles of the various solid forms under consideration is required. From a practical standpoint, this involves the measurement of the metastable zone width (MSZW) of pure forms, whereby the saturation and supersaturation curves of the different forms are generated over a well defined concentration and temperature range. This knowledge can then be used to design a crystallization protocol that should ideally favor a selective crystal growth of the desired form.

[00738] Form B of diazoxide choline salt showed moderate solubility in a solvent mixture made of MeCN/MeOH/MtBE (10: 1: 12, volume ratios). The wide width of the metastable zone as shown in Table 23 gives many seeding options. During the MSZW measurement, aliquots from the crystallizing material were withdrawn and analyzed by XRPD to ensure that no form conversion occurred during the experiment. Indeed, the material remained unchanged during the test.

Table 23. Meta-Stable Zone Width For Form B Diazoxide Choline Salt in

MeCN/MeOH/MtBE (10:1:12) (v/v).

[00739] Form A: The metastable zone width for Form could not be estimated because this polymorphic form converted during the experiment to Form B.

6.1.5.6. Crystallization of Form A of Diazoxide Choline Salt

[00740] The choline salt of diazoxide (160.3 mg) was dissolved in 1 mL of IPA at 55 °C which was then passed through a Millipore 0.45 μΜ filter into a clean vial. This vial was placed in freezer a -20 °C overnight. Solids were not noticed and the flask was scratched with a micro- spatula. The vial was placed back in the freezer and nucleation was noticed after ten minutes. The solids were collected by vacuum filtration and washed with 1 mL of MtBE. The solids were dried in vacuo at 40 °C and 30 in. Hg to afford 70 mg (43.6% recovery) of Form A as determined by XRPD.

6.1.5.7. 500-mg Scale Crystallization of Form B of Diazoxide Choline Salt

[00741] The choline salt of diazoxide (524.3 mg) was dissolved in 3 mL of IPA at 78 °C and this solution was then cooled to 55 °C for the addition of MtBE. The MtBE (4 mL) was added until nucleation was observed. After nucleation the batch was allowed to cool to room temperature at a rate of 20 °C /h. The solids were collected by vacuum filtration and washed with 1 mL of MtBE. The solids were dried in vacuo at 40 °C and 30 in. of Hg to afford 426.7 mg (81.3% recovery) of Form B as determined by XRPD.

6.1.5.8. 2-g Scale Crystallization of Form B of Diazoxide Choline Salt

[00742] The choline salt of diazoxide (2.0015 g) was dissolved in 5.5 mL of IPA at 78 °C to afford a clear solution. This solution was passed through a Millipore Millex FH 0.45 μΜ filter. This solution was then cooled to 55 °C. MtBE was added in 1 mL portions, with a two minute interval between portions. Nucleation was noted after the second addition of MtBE. This suspension was allowed to cool to room temperature at a rate of 20 °C /h and stirred at this temperature for 16 hours. The solids were collected by vacuum filtration and washed with 1 mL of MtBE. The solids were dried in vacuo at 40 °C and 30 in. of Hg to afford 1.6091 g (80.4% recovery) of Form B as determined by XRPD.

6.1.5.9. Detection of Form Impurities

[00743] Mixtures of diazoxide choline Forms A and B were prepared by adding a minor amount of Form A to Form B. Samples were lightly ground by hands with a mortar and pestle for approximately one minute. Samples were then analyzed by XRPD analysis. XRPD analysis was found to be suitable for detecting 5% of Form A in Form B.

References

Jump up^ Diazoxide, drugs.com
^ Jump up to:^a ^b “FDA Drug Safety Communication: FDA warns about a serious lung condition in infants and newborns treated with Proglycem (diazoxide)” (Press release). Food and Drug Administration. July 16, 2015. Retrieved 2015-07-19.
Jump up^ van Hamersvelt HW, Kloke HJ, de Jong DJ, Koene RA, Huysmans FT (August 1996). “Oedema formation with the vasodilators nifedipine and diazoxide: direct local effect or sodium retention?”. Journal of Hypertension. 14 (8): 1041–5. doi:10.1097/00004872-199608000-00016. PMID 8884561.
Jump up^ Huang Q, Bu S, Yu Y, et al. (January 2007). “Diazoxide prevents diabetes through inhibiting pancreatic beta-cells from apoptosis via Bcl-2/Bax rate and p38-beta mitogen-activated protein kinase”. Endocrinology. 148 (1): 81–91. doi:10.1210/en.2006-0738. PMID 17053028.
Jump up^ Randle, John C.R.; Biton, Catherine; Lepagnol, Jean M. (15 November 1993). “Allosteric potentiation by diazoxide of AMPA receptor currents and synaptic potentials”. European Journal of Pharmacology. 247 (3): 257–65. doi:10.1016/0922-4106(93)90193-D. PMID 8307099.
Jump up^ Panten, Uwe; Burgfeld, Johanna; Goerke, Frank; Rennicke, Michael; Schwanstecher, Mathias; Wallasch, Andreas; Zünkler, Bernd J.; Lenzen, Sigurd (1989-04-15). “Control of insulin secretion by sulfonylureas, meglitinide and diazoxide in relation to their binding to the sulfonylurea receptor in pancreatic islets”. Biochemical Pharmacology. 38 (8): 1217–1229. doi:10.1016/0006-2952(89)90327-4.
Jump up^ Doyle, Máire E.; Egan, Josephine M. (2003-03-01). “Pharmacological Agents That Directly Modulate Insulin Secretion”. Pharmacological Reviews. 55 (1): 105–131. doi:10.1124/pr.55.1.7. ISSN 1521-0081. PMID 12615955.

Patent ID	Title	Submitted Date	Granted Date
US2013309301	SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF	2012-11-07	2013-11-21
US2013040942	SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF	2012-07-06	2013-02-14
US2010028429	SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF	2010-02-04
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US2010256360	SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF	2010-10-07

Patent ID	Title	Submitted Date	Granted Date
US2012238554	SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF	2012-02-27	2012-09-20
US7799777	SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF	2007-08-16	2010-09-21
US2009062264	SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF	2009-03-05
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Diazoxide
Clinical data

Trade names	Proglycem
AHFS/Drugs.com	Monograph
Pregnancy category	AU: C US: C (Risk not ruled out)
Routes of administration	Oral, intravenous
ATC code	C02DA01 (WHO) V03AH01 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Protein binding	90%
Metabolism	Hepatic oxidation and sulfate conjugation
Elimination half-life	21-45 hours
Excretion	Renal
Identifiers
IUPAC name [show]
CAS Number	364-98-7
PubChem CID	3019
IUPHAR/BPS	2409
DrugBank	DB01119
ChemSpider	2911
UNII	O5CB12L4FN
KEGG	D00294
ChEBI	CHEBI:4495
ChEMBL	CHEMBL181
ECHA InfoCard	100.006.063
Chemical and physical data
Formula	C₈H₇ClN₂O₂S
Molar mass	230.672 g/mol
3D model (JSmol)	Interactive image
SMILES [hide] Clc1ccc2c(c1)S(=O)(=O)/N=C(\N2)C
InChI [hide] InChI=1S/C8H7ClN2O2S/c1-5-10-7-3-2-6(9)4-8(7)14(12,13)11-5/h2-4H,1H3,(H,10,11) Key:GDLBFKVLRPITMI-UHFFFAOYSA-N

//////////////Diazoxide choline

CC1=NC2=C(C=C(C=C2)Cl)S(=O)(=O)[N-]1.C[N+](C)(C)CCO

Zoledronic acid

September 17, 2018 1:34 pm / Leave a comment

Zoledronic acid

- CGP-42446, ZOL-446
- ATC:M05BA08
Use:antineoplastic, bone resorption inhibitor, biphosphonate
Chemical name:[1-hydroxy-2-(1H-imidazol-1-yl)ethylidene]bis[phosphonic acid]
Formula:C₅H₁₀N₂O₇P₂

MW:272.09 g/mol
CAS-RN:118072-93-8

Derivatives

Zoledronate disodium.png

Disodium salt tetrahydrate

Formula:C₅H₈N₂Na₂O₇P₂ • 4H₂O
MW:388.11 g/mol
CAS-RN:165800-07-7

Trisodium salt hydrate

Formula:C₅H₇N₂Na₃O₇P₂ • 2/5H₂O
MW:1726.21 g/mol
CAS-RN:165800-08-8

Zoledronic Acid

CAS Registry Number: 118072-93-8; 165800-06-6 (monohydrate)

CAS Name: [1-Hydroxy-2-(1H-imidazol-1-yl)ethylidene]bisphosphonic acid

Additional Names: 2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid

Manufacturers’ Codes: CGP-42446

Trademarks: Zometa (Novartis)

Molecular Formula: C5H10N2O7P2

Molecular Weight: 272.09

Percent Composition: C 22.07%, H 3.70%, N 10.30%, O 41.16%, P 22.77%

Literature References: Bisphosphonate antiresorptive agent. Prepn: JPKokai 88 150291; K. A. Jaeggi, L. Wilder, US4939130(1988, 1990 both to Ciba-Geigy). Effect on bone metabolism: J. R. Green et al.,J. Bone Miner. Res.9, 745 (1994). Determn in plasma by enzyme inhibition assay: F. Risser et al.,J. Pharm. Biomed. Anal.15, 1877 (1997). Series of articles on pharmacology and clinical experience: Br. J. Clin. Pract. Suppl.87, 15-22 (1996). Clinical trial in tumor-induced hypercalcemia: J. J. Body, Cancer80, 1699 (1997); of i.v. infusion in osteoporosis: I. R. Reid et al., N. Engl. J. Med.346, 653 (2002); in bone metastases of prostate cancer: F. Saad et al., J. Natl. Cancer Inst.94, 1458 (2002). Review of pharmacology and therapeutic use: J.-J. Body, Expert Opin. Pharmacother.4, 567-580 (2003).

Properties: Crystals from water, mp 239° (dec).

Melting point: mp 239° (dec)

disodium;hydroxy-[1-hydroxy-1-[hydroxy(oxido)phosphoryl]-2-imidazol-1-ylethyl]phosphinate;tetrahydrate

cas 165800-07-7

Derivative Type: Disodium salt tetrahydrate

CAS Registry Number: 165800-07-7

Additional Names: Zoledronate disodium

Manufacturers’ Codes: CGP-42446A

Molecular Formula: C5H8N2Na2O7P2.4H2O

Molecular Weight: 388.11

Percent Composition: C 15.47%, H 4.16%, N 7.22%, Na 11.85%, O 45.35%, P 15.96%

Derivative Type: Trisodium salt hydrate

CAS Registry Number: 165800-08-8

Additional Names: Zoledronate trisodium

Manufacturers’ Codes: CGP-42446B

Molecular Formula: (C5H7N2Na3O7P2)5.2H2O

Molecular Weight: 1726.21

Percent Composition: C 17.39%, H 2.28%, N 8.11%, Na 19.98%, O 34.29%, P 17.94%

Therap-Cat: Bone resorption inhibitor.

Keywords: Antiosteoporotic; Antipagetic; Bone Resorption Inhibitor.

INGREDIENT	UNII	CAS	INCHI KEY
Zoledronate disodium	7D7GS1SA24	165800-07-7	IEJZOPBVBXAOBH-UHFFFAOYSA-L
Zoledronate trisodium	ARL915IH66	165800-08-8	Not applicable
Zoledronic acid hemipentahydrate	1K9U67HDID	Not Available	AZZILOGHCMYHQY-UHFFFAOYSA-N
Zoledronic acid monohydrate	6XC1PAD3KF	165800-06-6	FUXFIVRTGHOMSO-UHFFFAOYSA-N

Zoledronate (zoledronic acid, marketed by Novartis under the trade names Zometa and Reclast) is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer. It can also be used to treat hypercalcemia of malignancy and can be helpful for treating pain from bone metastases.

An annual dose of Zoledronate may also prevent recurring fractures in patients with a previous hip fracture.

Zoledronate is a single 5 mg infusion for the treatment of Paget’s disease of bone. In 2007, the FDA also approved Reclast for the treatment of postmenopausal osteoporosis.

Zoledronic acid, also known as zoledronate, is a medication used to treat a number of bone diseases.^[1] This include osteoporosis, high blood calcium due to cancer, bone breakdown due to cancer, and Paget’s disease of bone.^[1] It is given by injection into a vein.^[1]

Common side effects include fever, joint pain, high blood pressure, diarrhea, and feeling tired.^[1] Serious side effects may include kidney problems, low blood calcium, and osteonecrosis of the jaw.^[1] Use during pregnancy may result in harm to the baby.^[1] It is in the bisphosphonate family of medications.^[1] It works by blocking the activity of osteoclast cells and thus decreases the breakdown of bone.^[1]

Zoledronic acid was approved for medical use in the United States in 2001.^[1] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.^[3] The wholesale cost in the developing world is between 5.73 USD and 26.80 USD per vial.^[4] In the United Kingdom, as of 2015, a dose costs the NHS about 220 pounds.^[5]

Medical uses

Bone complications of cancer

Zoledronic acid is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer, as well as for treating osteoporosis.^[6] It can also be used to treat hypercalcemia of malignancy and can be helpful for treating pain from bone metastases.^[7]

It can be given at home rather than in hospital. Such use has shown safety and quality-of-life benefits in people with breast cancer and bone metastases.^[8]

Osteoporosis

Zoledronic acid may be given as a 5 mg infusion once per year for treatment of osteoporosis in men and post-menopausal women at increased risk of fracture.^[9]

In 2007, the U.S. Food and Drug Administration (FDA) also approved it for the treatment of postmenopausal osteoporosis.^[10]^[11]

Paget’s disease

A single 5 mg dose of zoledronic acid is used for the treatment of Paget’s disease.^{[medical citation needed]}^[12]

Contraindications

Poor renal function (e.g. CrCl<30 mL/min)^[13]
Hypocalcaemia
Pregnancy
Paralysis

Side effects

Side effects can include fatigue, anemia, muscle aches, fever, and/or swelling in the feet or legs. Flu-like symptoms are common after the first infusion, although not subsequent infusions, and are thought to occur because of its potential to activate human γδ T cells(gamma/delta T cells).

Kidneys

There is a risk of severe renal impairment. Appropriate hydration is important prior to administration, as is adequate calcium and vitamin D intake prior to Aclasta therapy in patients with preexisting hypocalcaemia, and for ten days following Aclasta in patients with Paget’s disease of the bone. Monitoring for other mineral metabolism disorders and the avoidance of invasive dental procedures for those who develop osteonecrosis of the jaw is recommended.^[14]

Zoledronate is rapidly processed via the kidneys; consequently its administration is not recommended for patients with reduced renal function or kidney disease.^[15] Some cases of acute renal failure either requiring dialysis or having a fatal outcome following Reclast use have been reported to the U.S. Food and Drug Administration (FDA).^[16] This assessment was confirmed by the European Medicines Agency (EMA), whose Committee for Medicinal Products for Human Use (CHMP) specified new contraindications for the medication on 15 December 2011, which include hypocalcaemia and severe renal impairment with a creatinine clearance of less than 35 ml/min.^[17]

Bone

A rare complication that has been recently observed in cancer patients being treated with bisphosphonates is osteonecrosis of the jaw. This has mainly been seen in patients with multiple myeloma treated with zoledronate who have had dental extractions.^[18]

Atypical fractures : After approving the drug on 8 July 2009, the European Medicines Agency conducted a class review of all bisphosphonates, including Zoledronate, after several cases of atypical fractures were reported.^[19] In 2008, the EMA’s Pharmacovigilance Working Party (PhVWP) noted that alendronic acid was associated with an increased risk of atypical fracture of the femur that developed with low or no trauma. In April 2010, the PhVWP noted that further data from both the published literature and post-marketing reports were now available which suggested that atypical stress fractures of the femur may be a class effect. The European Medicines Agency then reviewed all case reports of stress fractures in patients treated with bisphosphonates, relevant data from the published literature, and data provided by the companies which market bisphosphonates. The Agency recommended that doctors who prescribe bisphosphonate-containing medicines should be aware that atypical fractures may occur rarely in the femur, especially after long-term use, and that doctors who are prescribing these medicines for the prevention or treatment of osteoporosis should regularly review the need for continued treatment, especially after five or more years of use.^[19]

Mechanism of action

Zoledronic acid slows down bone resorption, allowing the bone-forming cells time to rebuild normal bone and allowing bone remodeling.^[20]

Research

Zoledronic acid has been found to have a direct antitumor effect and to synergistically augment the effects of other antitumor agents in osteosarcoma cells.^[21]

Zoledronate has shown significant benefits versus placebo over three years, with a reduced number of vertebral fractures and improved markers of bone density.^[22]^[11] An annual dose of zoledronic acid may also prevent recurring fractures in patients with a previous hip fracture.^[9]

Zoledronate also attenuates accumulation of DNA damage in mesenchymal stem cells and protects their function.^[23] Given this characteristic, its potential to affect conditions arising from stem-cell dysfunction makes it a promising medicine for a range of age-related diseases^[24]

With hormone therapy for breast cancer

An increase in disease-free survival (DFS) was found in the ABCSG-12 trial, in which 1,803 premenopausal women with endocrine-responsive early breast cancer received anastrozole with zoledronic acid.^[25] A retrospective analysis of the AZURE trial data revealed a DFS survival advantage, particularly where estrogen had been reduced.^[26]

In a meta-analysis of trials where upfront zoledronic acid was given to prevent aromatase inhibitor-associated bone loss, active cancer recurrence appeared to be reduced.^[27]

As of 2010 “The results of clinical studies of adjuvant treatment on early-stage hormone-receptor-positive breast-cancer patients under hormonal treatment – especially with the bisphosphonate zoledronic acid – caused excitement because they demonstrated an additive effect on decreasing disease relapses at bone or other sites. A number of clinical and in vitro and in vivo preclinical studies, which are either ongoing or have just ended, are investigating the mechanism of action and antitumoral activity of bisphosphonates.”^[28]

A 2010 review concluded that “adding zoledronic acid 4 mg intravenously every 6 months to endocrine therapy in premenopausal women with hormone receptor-positive early breast cancer … is cost-effective from a US health care system perspective”.^[29]

Synthesis

PAPER

J Med Chem 2002,45(17),3721

https://pubs.acs.org/doi/10.1021/jm020819i

Highly Potent Geminal Bisphosphonates. From Pamidronate Disodium (Aredia) to Zoledronic Acid (Zometa)

Leo Widler *, Knut A. Jaeggi, Markus Glatt, Klaus Müller, Rolf Bachmann, Michael Bisping, Anne-Ruth Born, Reto Cortesi, Gabriela Guiglia, Heidi Jeker, Rémy Klein, Ueli Ramseier, Johann Schmid, Gerard Schreiber, Yves Seltenmeyer, and Jonathan R. Green

Novartis Pharma Research, Arthritis and Bone Metabolism Therapeutic Area, CH-4002 Basel, Switzerland

J. Med. Chem., 2002, 45 (17), pp 3721–3738

DOI: 10.1021/jm020819i

Bisphosphonates (BPs) are pyrophosphate analogues in which the oxygen in P−O−P has been replaced by a carbon, resulting in a metabolically stable P−C−P structure. Pamidronate (1b, Novartis), a second-generation BP, was the starting point for extensive SAR studies. Small changes of the structure of pamidronate lead to marked improvements of the inhibition of osteoclastic resorption potency. Alendronate (1c, MSD), with an extra methylene group in the N-alkyl chain, and olpadronate (1h, Gador), the N,N-dimethyl analogue, are about 10 times more potent than pamidronate. Extending one of the N-methyl groups of olpadronate to a pentyl substituent leads to ibandronate (1k, Roche, Boehringer-Mannheim), which is the most potent close analogue of pamidronate. Even slightly better antiresorptive potency is achieved with derivatives having a phenyl group linked via a short aliphatic tether of three to four atoms to nitrogen, the second substituent being preferentially a methyl group (e.g., 4g, 4j, 5d, or 5r). The most potent BPs are found in the series containing a heteroaromatic moiety (with at least one nitrogen atom), which is linked via a single methylene group to the geminal bisphosphonate unit. Zoledronic acid (6i), the most potent derivative, has an ED₅₀ of 0.07 mg/kg in the TPTX in vivo assay after sc administration. It not only shows by far the highest therapeutic ratio when comparing resorption inhibition with undesired inhibition of bone mineralization but also exhibits superior renal tolerability. Zoledronic acid (6i) has thus been selected for clinical development under the registered trade name Zometa. The results of the clinical trials indicate that low doses are both efficacious and safe for the treatment of tumor-induced hypercalcemia, Paget’s disease of bone, osteolytic metastases, and postmenopausal osteoporosis.

SYN 1

AU 8781453; EP 0275821; JP 1988150291; US 4939130

Zoledronate sodium can be prepared by reaction of 2-(1-imidazolyl)acetic acid hydrochloride (I) with PCl3, with optional presence of phosphoric acid, in refluxing chlorobenzene, followed by hydrolysis with refluxing 9N hydrochloric acid and final formation of the sodium salt by treatment with aqueous NaOH.

SYN

PAPER

https://www.sciencedirect.com/science/article/pii/S0969804311006385

Image result for zoledronic acid synthesis

Clip

https://link.springer.com/article/10.1007/s11094-015-1205-0

A One-Pot and Efficient Synthesis of Zoledronic Acid Starting from Tert-butyl Imidazol-1-yl Acetate

A one-pot synthesis of zoledronic acid in high yield is described. The procedure involves a non-aqueous ester cleavage of the tert-butyl imidazol-1-yl acetate under dry conditions in the presence of methanesulfonic acid as solubilizer and chlorobenzene as solvent to afford in situthe corresponding imidazolium methanesulfonate salt which yields zoledronic acid upon reaction with phosphoric acid and phosphorus oxychloride. A possible chemical mechanism for the synthesis of this acid is described.

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Paper

https://www.beilstein-journals.org/bjoc/articles/4/42

Preparation of imidazol-1-yl-acetic acid tert-butyl ester (2)

To a solution of imidazole (10.0 g, 0.15 mol) in ethyl acetate (160 mL) was added powdered K₂CO₃ (29.0 g, 0.21 mol) followed by tert-butyl chloroacetate (25.7 mL, 0.18 mol) at room temperature and the mixture was refluxed for 10.0 h. After completion of the reaction as indicated by TLC (10% MeOH/CHCl₃, I₂ active), the reaction mass was quenched with cold water (80 mL) and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (2 × 80 mL) and the combined ethyl acetate layers were washed with brine, dried with anhydrous sodium sulfate and then concentrated under vacuum. The resulting solid was stirred with hexane (50 mL) at RT, filtered and washed with hexane (2 × 20 mL) to afford the title compound as an off-white solid (20.0 g, 75%). mp: 111.3–113.2 °C (Lit [10]: 111–113 °C). IR (cm⁻¹): 3458, 3132, 3115, 2999, 2981, 2884, 1740, 1508, 1380, 1288, 1236, 1154, 1079, 908, 855, 819, 745, 662, 583; ¹H NMR (300 MHz, CDCl₃) δ 1.47 (s, 9H), 4.58 (s, 2H), 6.94 (s, 1H), 7.09 (s, 1H), 7.49 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 27.7, 48.6, 82.9, 119.8, 129.2, 137.7, 166.3; MS (m/z) 183.0 [M+1, 100%], 127.0.

Preparation of imidazol-1-yl-acetic acid hydrochloride (6)

To a solution of imidazol-1-yl-acetic acid tert-butyl ester (2) (10.0 g, 0.05 mol) in dichloromethane (100 mL) was added titanium tetrachloride (8.0 mL, 0.07 mol) dropwise slowly at −15 to −10 °C over 1 h and the mixture was stirred at −5 to 0 °C for 2 h. Isopropyl alcohol (25 mL) was added at 0 to −10 °C over 0.5 h and the reaction mass was stirred at room temperature for 0.5 h. Additional isopropyl alcohol (125 mL) was added dropwise at room temperature over 0.5 h and the mixture was stirred for 1 h. Dichloromethane was distilled out under a low vacuum and the resulting crystalline solid precipitated was filtered to afford the title compound as an off-white crystalline solid (7.4 g, 83%). mp 200.3–202.3 °C; IR (cm⁻¹): 3175, 3125, 3064, 2945, 2869, 2524, 2510, 1732, 1581, 1547, 1403, 1223, 1193, 1081, 780, 650; ¹H NMR (300 MHz, D₂O + 3-(trimethylsilyl)propionic acid sodium salt) δ 5.1 (s, 3H, -CH₂– + HCl), 7.5 (br s, 2H), 8.7 (s, 1H); ¹³C NMR (75 MHz, D₂O + 3-(trimethylsilyl)propionic acid sodium salt) 52.7, 122.4, 125.9, 138.8, 172.8; MS (m/z) 127.0 [M+1, 100%]; HCl-content: found 21.8% (along with 3.25% moisture), calcd 22.43% for C₅H₆N₂O₂·HCl.

Preparation of zoledronic acid (7)

To a suspension of imidazol-1-yl-acetic acid hydrochloride (6) (7.0 g, 0.043 mol) and phosphorous acid (9.5 g, 0.116 mol) in chlorobenzene (50 mL) was added phosphorous oxychloride (9.6 ml, 0.103 mol) at 80–85 °C over a period of 2 h then heated to 90–95 °C for 2.5 h. The reaction mass was cooled to 60–65 °C and water (100 mL) was added at the same temperature. The aqueous layer was separated, collected and refluxed for 18 h. It was then cooled to room temperature and diluted with methanol (140 mL). The mixture was cooled to 0–5 °C and stirred for 3 h. The precipitated solid was filtered, washed with cold water followed by methanol and then dried under vacuum at 60 °C for 12 h to afford the title compound (6.6 g, 57% yield) as a white solid; mp 237–239 °C (lit [1] 239 °C with decomposition).

PATENT

https://patents.google.com/patent/CN104610357A/en

Sodium Zoledronic (Zoledronate sodium, I), chemical name [1-yl light -2- (lH- imidazol-1-yl) ethylidene] bisphosphonic acid monosodium salt monohydrate, is by the Novartis (Novartis) developed imidazole heterocyclic bisphosphonates, belongs to the third generation of bisphosphonates bisphosphonate drugs, in October 2000, first marketed in Canada. Subsequently approved in the European Union, the United States more than 80 countries or regions, trade name Zometa, for the treatment of hypercalcemia of malignancy (HCM) and multiple myeloma and bone metastases of solid tumors. The drug is effective in treating cancer caused by HCM, advanced bone metastases and Paget’s disease, reduce the incidence of skeletal related events, relieve symptoms and improve quality of life, is also expected to be used to treat osteoporosis. Compared with other similar drugs, high efficacy, dosage, ease of administration, better security, etc., is currently the only FDA-approved for metastatic bone tumor effective bisphosphonate drugs.Currently bisphosphonate drugs in our country is still in the initial stages of clinical applications, but in recent years has made rapid progress, broad market prospect.

[0003] The prior art synthesis reaction conditions zoledronate sodium harsh, toxicity and use methanol, chloroform and chlorobenzene, easily exceeding the amount of residual organic solvents, low yield, low product purity, contamination environment, does not meet the medical criteria, is not conducive to industrial production. Environmental pollution has attracted increasing attention around the world today, the development of new green efficient synthesis of a pharmaceutical drug synthesis is an important issue facing the Institute. In recent years, room temperature ionic liquids as a reaction medium is environmentally friendly, has been widely used in a variety of organic synthesis reactions. Compared with traditional organic solvents, ionic liquids have very low vapor pressure, non-flammable, good thermal stability, both as a reaction medium underway catalysis, can be recycled and many other advantages.

Image result for zoledronic acid synthesis

Example 1 of zoledronic alendronate

(1) Synthesis of imidazol-1-yl acetate were added successively imidazole (13.62g, 0.2mol) and [bmim] BF4 (IOOmL) a three-necked flask, heated with stirring warmed to 60 ° C, incubated under reflux was slowly added dropwise chlorination ethyl acetate (24. 51g, 0. 2mol), dropwise addition time is about 2h, dropwise, with stirring maintained at reflux for 16 h, the reaction monitored by TLC showed no starting material end point, completion of the reaction, cooled to room temperature, to give imidazole -1 – ethyl crude, about 24g, crude without purification, was used directly in the next reaction.

[0014] (2) Synthesis of imidazol-1-yl acetate hydrochloride A solution of 24g 1-yl imidazole prepared above was added crude ethyl necked flask, concentrated hydrochloric acid (34 mL), exotherm to 85 ° C, warmed to reflux heating was continued, the reaction was stirred at reflux for 10H, the reaction was completed, the solvent was evaporated under reduced pressure, 20ml of absolute ethanol was added to the residue, vigorously stirred for 2h, filtered off with suction, the filter cake finally at 80 ° C blast pressure and dried to give a white solid imidazol-1-yl acetate hydrochloride about 25. 65g, 79.4% overall yield.

[0015] (3) Synthesis of zoledronic acid monohydrate were added imidazol-1-yl acetate hydrochloride (17. 26g, 0. 137mol) a three-necked flask, in an ionic liquid with stirring – n-butyl-3- methylimidazolium tetrafluoroborate [bmim] BF4 (40mL) and concentration of 85% phosphoric acid solution (16mL), heating to 60 ° C was added dropwise phosphorus trichloride (30mL) , about 4h dropwise, reaction was continued under reflux for 4h at 65 ° C, the reaction was complete, cooled to 40 ° C, filtered off with suction, the filter cake was added to a molar concentration in 80mL 9mol / L hydrochloric acid, heated with stirring state the reaction was refluxed for 6h, the reaction was completed, filtered hot, the filter cake was added to a molar concentration in 80mL 9mol / L hydrochloric acid, the above-described operation is repeated to continue the combined filtrate was evaporated to dryness under reduced pressure to give a yellow oily residue was slowly added to the residue volume ratio of 1: 1 acetone – ethanol mixture 240 mL, was stirred, and the precipitated solid was 15min, filtered off with suction, the filter cake was recrystallized in 30mL of deionized water, suction filtered to give a white solid that is zoledronic acid monohydrate , about 35. 8g, yield 90.1%, determined by HPLC, purity> 98.5%.

After [0016] (4) Synthesis of zoledronic sodium phosphinate obtained above azole zoledronic acid monohydrate (46.4g, 0. 16mol) washed with water (450 mL of) was dissolved, was added sodium hydroxide (5. 6g, 0. IOmol), were refluxed for 30min, cooling and crystallization, filtration, to obtain a crude product zoledronate sodium, crude mother liquor was concentrated and then half with distilled water (410 mL), isopropanol (60 mL), heated to dissolve the combined, activated carbon bleaching, charcoal filtered off, cooling and crystallization, filtration, washed with water, dried at 40-60 ° C to about crystallization water containing one to give zoledronate sodium (42. 4g, 85%), total yield of more than 60% by HPLC assay, purity 99. 8%, mp239 ° C. IR: 711011 ^ 671 (^ 1 is the stretching vibration peak of the PC, 1643〇 ^ 1 = 0 (: stretching vibration peak, 3011〇 ^ 1 = (: – stretching vibration peak 11 ^ 1 is CN 1406〇 the stretching vibration, 1643CHT1 is C = N stretching vibration peak of 3447 (3485 ^^ (^ 1 is the stretching vibration peak of OH, 1459CHT1 symmetrical bending vibration of CH, 2830CHT1 stretching vibration of CH, 1324CHT1 is P = O the stretching vibration, 1094CHT1 stretching vibration peak of .1HNMR PO (400MHz, D20), S: 8.68 (lH, s), 7.48 (lH, s), 7.34 (lH, s), 4.67 (2H, t).

Effects [0017] Example 2 was added dropwise phosphorus trichloride fixed time on the yield other conditions remain unchanged, only the changes of phosphorus trichloride dropwise addition, dropping zoledronic Table 1 Effect of Sodium yield Experimental results show that excessive phosphorus trichloride was added dropwise, and instantly generate a large amount of gas, the reaction is very intense, the liquid splashing, a rapid rise in temperature, resulting in the low yield, if slowly added dropwise, the reaction rate is too slow, consumption too long, and therefore is the best 4h dropping time.

Zoledronic fixed effect of sodium yield other conditions remain unchanged, imidazol-1-yl acetic acid hydrochloride with phosphorus trichloride and phosphoric acid condensation reaction temperature is zoledronic acid monohydrate embodiment the reaction temperature Example 3 Effect yield (Table 2). The results show that, with increasing temperature, increasing the yield, but at higher temperatures to reflux, shows a decreasing trend in yield, due to decomposition sake phosphorus trichloride, resulting in reduction reaction. Further, when the temperature is too high, solvent evaporation and solvent leakage losses will increase, the reflux temperature is low, the reaction rate is slow, the reaction is insufficient, therefore the yield is low, and therefore the optimum reaction temperature is about 65 ° C.

Example 4

Effect of the ionic liquid frequency reuse sodium zoledronic yield of the reaction medium can be recovered and reused important concern is “green chemistry” used in the present embodiment examines the sodium ionic liquid used in the synthesis of zoledronic repeated use, the experiment results shown in Table 3. Seen from Table 3, the ionic liquid after 5 subsequent to use, product yield began to decrease, the ionic liquid may be recovered and reused effectively, and repeated five times using good performance, and therefore is an ionic liquid in this reaction green solvents may be recycled.

Example 5 different ionic liquids zoledronic same impact conditions were examined yield sodium 1-butyl-3-methylimidazolium tetrafluoroborate ionic liquids ([bmim] BF4), N- ethyl pyridinium tetrafluoroborate ([EPy] BF4), l- butyl-3-methylimidazolium hexafluorophosphate ([bmim] PF6), 1- hydroxyethyl-2,3-dimethyl imidazolium chloride (LOH), 1- propyl-3-carbonitrile methylimidazolium chloride (the LCN) and 1-carboxyethyl-3-methyl imidazolium chloride (LOOH) Effects of sodium zoledronic yield the results are shown in Table 4, the test results show little effect on the synthesis of ionic liquids yield.

Clip

Mar 5, 2013 –

Dr. Reddy’s Laboratories announced today that it has launched Zoledronic Acid Injection (4 mg/5 mL), a bioequivalent generic version of Zometa® (zoledronic acid) 4 mg/5 mL Injection in the US market on March 4, 2013, following the approval by the United States Food & Drug Administration (USFDA) of Dr. Reddy’s ANDA for Zoledronic Acid Injection (4 mg/5 mL).

Dr. Reddy’s Zoledronic Acid Injection 4 mg/5mL is available in a single use vial of concentrate.

Zoledronic acid (INN) or zoledronate (marketed by Novartis under the trade names Zometa, Zomera, Aclasta and Reclast) is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer, as well as for treating osteoporosis.It can also be used to treat hypercalcemia of malignancy and can be helpful for treating pain from bone metastases.

An annual dose of zoledronic acid may also prevent recurring fractures in patients with a previous hip fracture.

Reclast is a single 5 mg infusion for the treatment of Paget’s disease of bone. In 2007, the U.S. Food and Drug Administration (FDA) also approved Reclast for the treatment of postmenopausal osteoporosis.

About Dr. Reddy’s Laboratories Ltd.

Dr. Reddy’s Laboratories Ltd. (NYSE: RDY) is an integrated global pharmaceutical company, committed to providing affordable and innovative medicines for healthier lives. Through its three businesses – Pharmaceutical Services and Active Ingredients, Global Generics and Proprietary Products – Dr. Reddy’s offers a portfolio of products and services including APIs, custom pharmaceutical services, generics, biosimilars, differentiated formulations and NCEs. Therapeutic focus is on gastro-intestinal, cardiovascular, diabetology, oncology, pain management, anti-infective and pediatrics. Major markets include India, USA, Russia and CIS, Germany, UK, Venezuela, S. Africa, Romania, and New Zealand. For more information, log on to: http://www.drreddys.com

Zometa® is a registered trademark of Novartis AG

References

- US 4 939 130 (Ciba-Geigy; 3.7.1990; CH-prior. 21.11.1986).

transdermal formulation:
- EP 407 344 (Ciba-Geigy; appl. 28.6.1990; CH-prior. 7.7.1989).

treatment of angiogenesis:
- WO 2 000 071 104 (Novartis AG; appl. 19.5.2000; GB-prior. 21.5.1999).

PATENT

ApplicationPriority dateFiling dateTitle

CN 2015100011672015-01-052015-01-05Preparation method for sodium zoledronic acid

ApplicationFiling dateTitle

CN 2015100011672015-01-05Preparation method for sodium zoledronic acid

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k “Zoledronic Acid”. The American Society of Health-System Pharmacists. Retrieved 8 December 2017.
Jump up^ Drugs.com International trade names for zoledronic acid Page accessed Jan 14, 2015
Jump up^ “WHO Model List of Essential Medicines (20th List)” (PDF). World Health Organization. March 2017. Retrieved 29 June 2017.
Jump up^ “Single Drug Information”. International Medical Products Price Guide. Retrieved 9 December 2017.
Jump up^ British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 528. ISBN 9780857111562.
Jump up^ National Prescribing Service (2009). “Zoledronic Acid for Osteoporosis”. Medicines Update, Available at “Archived copy”. Archived from the original on April 23, 2010. Retrieved January 20, 2010.
Jump up^ http://www.health.gov.il/units/pharmacy/trufot/alonim/533.pdf Zomera prescribing information
Jump up^ Wardley, A; Davidson, N; Barrett-Lee, P; et al. (May 2005). “Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration”. Br. J. Cancer. 92 (10): 1869–76. doi:10.1038/sj.bjc.6602551. PMC 2361764 . PMID 15870721.
^ Jump up to:^a ^b Lyles K, et al. (2007). “Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture”. N. Engl. J. Med. 357 (18): 1799–809. doi:10.1056/NEJMoa074941. PMC 2324066 . PMID 17878149.
Jump up^ “Biotech PRESS RELEASE: Novartis’s Reclast Receives FDA Approval FOR Women With Postmenopausal Osteoporosis”, FierceBiotech, A Division of Questex A FierceMarkets Publication Aug 20, 2007. Retrieved 2018-03-27
^ Jump up to:^a ^b Black; et al. (2007). “Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis”. NEJM. 356 (18): 1809–1822. doi:10.1056/nejmoa067312. PMID 17476007.
Jump up^ “Paget’s Disease of Bone”. http://www.rheumatology.org. Retrieved 2015-07-09.
Jump up^ Vondracek, S. F. (2010). “Managing osteoporosis in postmenopausal women”. American Journal of Health-System Pharmacy. 67 (7 Suppl 3): S9–19. doi:10.2146/ajhp100076. PMID 20332498.
Jump up^ http://www.nps.org.au/__data/assets/pdf_file/0006/60945/nvcaclin.pdf
Jump up^ “Zometa 4mg/5ml Concentrate for Solution for Infusion”. medicines.org.uk.
Jump up^ “FDA Alert: Reclast (zoledronic acid): Drug Safety Communication – New Contraindication and Updated Warning on Kidney Impairment”. drugs.com.
Jump up^ “European Medicines Agency – Human medicines”. europa.eu.
Jump up^ Durie BG, Katz M, Crowley J (2005). “Osteonecrosis of the jaw and bisphosphonates”. N. Engl. J. Med. 353 (1): 99–102; discussion 99–102. doi:10.1056/NEJM200507073530120. PMID 16000365.
^ Jump up to:^a ^b “European Medicines Agency – Human medicines”. europa.eu.
Jump up^ Aclasta label- Australia
Jump up^ Koto K, Murata H, Kimura S, et al. (July 2010). “Zoledronic acid inhibits proliferation of human fibrosarcoma cells with induction of apoptosis, and shows combined effects with other anticancer agents”. Oncol. Rep. 24 (1): 233–9. doi:10.3892/or_00000851. PMID 20514467.
Jump up^ Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, Widmer A, Devogelaer JP, Kaufman JM, Jaeger P, Body JJ, Brandi ML, Broell J, Di Micco R, Genazzani AR, Felsenberg D, Happ J, Hooper MJ, Ittner J, Leb G, Mallmin H, Murray T, Ortolani S, Rubinacci A, Saaf M, Samsioe G, Verbruggen L, Meunier PJ (2002). “Intravenous zoledronic acid in postmenopausal women with low bone mineral density”. N. Engl. J. Med. 346 (9): 653–61. doi:10.1056/NEJMoa011807. PMID 11870242.
Jump up^ Juhi Misra, Sindhu T. Mohanty, Sanjeev Madan, James A. Fernandes, F. Hal Ebetino, R. Graham, G. Russell, Ilaria Bellantuono. (December 2015). Zoledronate attenuates accumulation of DNA damage in mesenchymal stem cells and protects their function. Stem Cells, doi:10.1002/stem.2255
Jump up^ “Bone drug protects stem cells from aging.” ScienceDaily. 17 December 2015
Jump up^ PMID 19213681 Gnant, Mlineritsch. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360:679-691 February 12, 2009 Full Free Text [1]
Jump up^ Coleman RE, Winter MC, Cameron D, et al. (March 2010). “The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer”. Br. J. Cancer. 102 (7): 1099–105. doi:10.1038/sj.bjc.6605604. PMC 2853093 . PMID 20234364.
Jump up^ Brufsky A, Bundred N, Coleman R, et al. (May 2008). “Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole”. Oncologist. 13 (5): 503–14. doi:10.1634/theoncologist.2007-0206. PMID 18515735.
Jump up^ Tonyali O, Arslan C, Altundag K (November 2010). “The role of zoledronic acid in the adjuvant treatment of breast cancer: current perspectives”. Expert Opin Pharmacother. 11(16): 2715–25. doi:10.1517/14656566.2010.523699. PMID 20977404.
Jump up^ Delea TE, Taneja C, Sofrygin O, Kaura S, Gnant M (August 2010). “Cost-effectiveness of zoledronic acid plus endocrine therapy in premenopausal women with hormone-responsive early breast cancer”. Clin. Breast Cancer. 10 (4): 267–74. doi:10.3816/CBC.2010.n.034. PMID 20705558.

Zoledronic acid
Clinical data


Trade names	Reclast, Zometa, others^[2]
AHFS/Drugs.com	Monograph
MedlinePlus	a605023
License data	EU EMA: by INN US FDA: Zoledronic_acid
Pregnancy category	D (U.S.)^[1]
Routes of administration	Intravenous
Drug class	Bisphosphonate^[1]
ATC code	M05BA08 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Protein binding	22%
Metabolism	Nil
Elimination half-life	146 hours
Excretion	Kidney (partial)
Identifiers
IUPAC name [show]
CAS Number	118072-93-8
PubChem CID	68740
IUPHAR/BPS	3177
DrugBank	DB00399
ChemSpider	61986
UNII	70HZ18PH24
KEGG	D08689
ChEMBL	CHEMBL924
PDB ligand	ZOL (PDBe, RCSB PDB)
Chemical and physical data
Formula	C₅H₁₀N₂O₇P₂
Molar mass	272.09 g/mol
3D model (JSmol)	Interactive image

Judith Aronhime, Revital Lifshitz-Liron, “Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation.” U.S. Patent US20050054616, issued March 10, 2005., US20050054616

/////////////////disodium zoledronate tetrahydrate, zoledronic acid, ZOMETA, CGP-42446, CGP-42446A

OC(CN1C=CN=C1)(P(O)(O)=O)P(O)(O)=O

Bepotastine Besilate, ベポタスチンベシル酸塩

September 17, 2018 10:28 am / Leave a comment

ChemSpider 2D Image | Bepotastine Besilate | C27H31ClN2O6S Bepotastine besilate.png

Bepotastine Besilate

ベポタスチンベシル酸塩

Molecular FormulaC₂₇H₃₁ClN₂O₆S
Average mass547.063 Da

UNII:6W18MO1QR3

(+)-(S)-4-(4-((4-Chlorophenyl)(2-pyridyl)methoxy)piperidino)butyric acid monobenzenesulfonate

(S)-4-(4-((4-chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)butanoic acid compound with benzenesulfonic acid (1:1)

190786-44-8 [RN]

125602-71-3 FREE FORM,

UNII: 6W18MO1QR3

1-Piperidinebutanoic acid, 4-[(S)-(4-chlorophenyl)-2-pyridinylmethoxy]-, benzenesulfonate (1:1) [ACD/Index Name]

4-{4-[(S)-(4-Chlorophenyl)(2-pyridinyl)methoxy]-1-piperidinyl}butanoic acid benzenesulfonate (1:1)

Talion [Trade name]

tau284

TAU-284DS, TAU-284

DA-5206
HL-151

SNJ-1773

- Use:antiallergic, antihistaminic

For the symptomatic treatment of itchy eyes (caused by IgE-induced mast cell degranulation) due to allergic conjunctivitis.

10 mg Tablets

For the treatment of allergic rhinitis

27.03.2017 CDSCO

APPROVED

USFDA

NDA 22-288 Bepotastine Besilate 1.5% Ophthalmic Solution ISTA Pharmaceuticals, Inc.

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/02228s000_ChemR.pdf

Drug Substance Bepotastine besilate is manufactured by Ube Industries and the information for the NDA is submitted through DMF #19966. Bepotastine besilate is a white crystalline powder with no odor and bitter taste. It is very soluble in but sparingly soluble in . It is stable when exposed to light, and optically active. The S-isomer is the active drug and is controlled as an impurity through synthesis. The distribution coefficient in 1-octanol is higher than in aqueous buffer in the pH 5-9 range. There are 10 potential impurities but only one impurity is above 0.1%. Two potential genotoxic impurities are controlled below . Residual is controlled below Bepotastine besilate is stable under long term storage conditions for (25ºC/60% RH) over 5 years

Bepotastine besilate was originally developed as an oral tablet dosage form and got approval in Japan in 2000 for allergic rhinitis. It is a non-sedating anti-allergic drug. The proposed NDA is an ophthalmic solution indicated for allergic conjunctivitis. Bepotastine besilate ophthalmic solution 1.5% is a sterile solution. It is an aqueous solution to be administered as drops at or near physiological pH range of tears. The formulation contains sodium chloride, monobasic sodium phosphate as dihydrate, benzalkonium chloride, sodium hydroxide and purified water; typically these components are used for , preservative action, pH adjustment,

INTRO

Bepotastine is a non-sedating, selective antagonist of the histamine 1 (H1) receptor. Bepotastine was approved in Japan for use in the treatment of allergic rhinitis and uriticaria/puritus in July 2000 and January 2002, respectively, and is marketed by Tanabe Seiyaku Co., Ltd. under the brand name Talion. It is available in oral and opthalmic dosage forms in Japan. The opthalmic solution is FDA approved since Sept 8, 2009 and is under the brand name Bepreve.

Tae Hee Ha, Chang Hee Park, Won Jeoung Kim, Soohwa Cho, Han Kyong Kim, Kwee Hyun Suh, “PROCESS FOR PREPARING BEPOTASTINE AND INTERMEDIATES USED THEREIN.” U.S. Patent US20100168433, issued July 01, 2010., US20100168433

BEPREVE^® (bepotastine besilate ophthalmic solution) 1.5% is a sterile, topically administered drug for ophthalmic use. Each mL of BEPREVE contains 15 mg bepotastine besilate.

Bepotastine besilate is designated chemically as (+) -4-[[(S)-p-chloro-alpha -2pyridylbenzyl] oxy]-1-piperidine butyric acid monobenzenesulfonate. The chemical structure for bepotastine besilate is:

BEPREVE® (bepotastine besilate) Structural Formula Illustration

Bepotastine besilate is a white or pale yellowish crystalline powder. The molecular weight of bepotastine besilate is 547.06 daltons. BEPREVE ophthalmic solution is supplied as a sterile, aqueous 1.5% solution, with a pH of 6.8.

The osmolality of BEPREVE (bepotastine besilate ophthalmic solution) 1.5% is approximately 290 mOsm/kg.

ベポタスチンベシル酸塩 JP17
Bepotastine Besilate

C₂₁H₂₅ClN₂O₃▪C₆H₆O₃S : 547.07
[190786-44-8]

Title: Bepotastine

CAS Registry Number: 190786-43-7

CAS Name: 4-[(S)-(4-Chlorophenyl)-2-pyridinylmethoxy]-1-piperidinebutanoic acid

Additional Names: betotastine

Molecular Formula: C21H25ClN2O3

Molecular Weight: 388.89

Percent Composition: C 64.86%, H 6.48%, Cl 9.12%, N 7.20%, O 12.34%

Literature References: Histamine H1-receptor antagonist. Prepn (stereochem. unspec.): A. Koda et al., EP 335586; eidem, US4929618 (1989, 1990 both to Ube). Prepn of optically active salts: J. Kita et al., EP 949260 (1999 to Ube; Tanabe Seiyaku). Pharmacology: M. Kato et al., Arzneim.-Forsch. 47, 1116 (1997). Suppression of IL-5 production: O. Kaminuma et al., Biol. Pharm. Bull. 21, 411 (1998). Antiallergic activity in animal models: M. Ueno et al., Pharmacology 57, 206 (1998).

Derivative Type: Benzenesulfonate salt

CAS Registry Number: 190786-44-8

Additional Names: Bepotastine besilate

Manufacturers’ Codes: TAU-284

Trademarks: Talion (Tanabe)

Molecular Formula: C21H25ClN2O3.C6H6O3S

Molecular Weight: 547.06

Percent Composition: C 59.28%, H 5.71%, Cl 6.48%, N 5.12%, O 17.55%, S 5.86%

Properties: Pale grey prisms from acetonitrile, mp 161-163°. [a]D20 +6.0° (c = 5 in methanol).

Melting point: mp 161-163°

Optical Rotation: [a]D20 +6.0° (c = 5 in methanol)

Therap-Cat: Antihistaminic.

Keywords: Antihistaminic.

Bepotastine (Talion, Bepreve) is a 2nd generation antihistamine.^[1] It was approved in Japan for use in the treatment of allergic rhinitisand urticaria/pruritus in July 2000 and January 2002, respectively. It is currently marketed in the United States under the brand-name Bepreve, by ISTA Pharmaceuticals.

Bepotastine besilate is a second-generation antihistamine that was launched in a tablet formulation under a collaboration between Tanabe Seiyaku and Ube in 2000 and in 2002 for the treatment of allergic rhinitis including sneeze, mucus discharge and solidified mucus, and for the treatment of urticaria, respectively. An orally disintegrating tablet was made available in Japan in 2006, while a dry syrup formulation for the treatment of allergic rhinitis was studied in clinical trials at Tanabe Seiyaku for the treatment of allergic rhinitis

Originally developed at Ube, bepotastine besilate was later licensed to Tanabe Seiyaku as part of a collaboration agreement. In 2010, rights were licensed to Dong-A and Mitsubishi Tanabe Pharma in Korea for the treatment of eye disorders.

Pharmacology

Bepotastine is available as an ophthalmic solution and oral tablet. It is a direct H₁-receptor antagonist that inhibits the release of histamine from mast cells.^[2] The ophthalmic formulation has shown minimal systemic absorption, between 1 and 1.5% in healthy adults.^[3] Common side effects are eye irritation, headache, unpleasant taste, and nasopharyngitis.^[3] The main route of elimination is urinary excretion, 75-90% excreted unchanged.^[3]

Marketing history

It is marketed in Japan by Tanabe Seiyaku under the brand name Talion. Talion was co-developed by Tanabe Seiyaku and Ube Industries, the latter of which discovered bepotastine. In 2001, Tanabe Seiyaku granted Senju, now owned by Allergan, exclusive worldwide rights, with the exception of certain Asian countries, to develop, manufacture and market bepotastine for ophthalmic use. Senju, in turn, has granted the United States rights for the ophthalmic preparation to ISTA Pharmaceuticals.

Sales and patents

In 2011, ISTA pharmaceuticals experienced a 2.4% increase in net revenues from 2010, which was driven by the sales of Bepreve. Their net revenue for 2011 was $160.3 million.^[4] ISTA Pharmaceuticals was acquired by Bausch & Lomb in March 2012 for $500 million.^[5] Bausch & Lomb hold the patent for bepotastine besilate (https://www.accessdata.fda.gov/scripts/cder/ob/docs/temptn.cfm. On November 26, 2014, Bausch & Lomb sue Micro Labs USA for patent infringement.^[6] Bausch & Lomb was recently bought out by Valeant Pharmaceuticals in May 2013 for $8.57 billion, Valeant’s largest acquisition to date, causing the company’s stock to rise 25% when the deal was announced.^[7]

Clinical trials

A Phase III clinical trial was carried out in 2010 to evaluate the effectiveness of bepotastine besilate ophthalmic solutions 1.0% and 1.5%.^[8] These solutions were compared to a placebo and evaluated for their ability to reduce ocular itchiness. The study was carried out with 130 individuals and evaluated after 15 minutes, 8 hours, or 16 hours. There was a reduction in itchiness at all-time points for both ophthalmic solutions. The study concluded that bepotastine besilate ophthalmic formulations reduced ocular itchiness for at least 8 hours after dosing compared to placebo. Phase I and II trials were carried out in Japan.

Studies have been performed in animals and bepotastine besilate was not found to be teratogenic in rats during fetal development, even at 3,300 times more that typical use in humans.^[3] Evidence of infertility was seen in rats at 33,000 times the typical ocular does in humans.^[3] The safety and efficacy has not been established in patients under 2 years of age and has been extrapolated from adults for patients under 10 years of age.^[3]

SYN

EP 0335586; JP 1989242574; JP 1990025465; JP 1993294929; US 4929618

The reaction of 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (I) with ethyl 4-bromobutyrate (II) by means of K2CO3 in refluxing acetone gives the corresponding condensation product (III), which is then hydrolyzed with NaOH in ethanol/water yielding compound (IV).

SYN 2

JP 1998237070; JP 2000198784; WO 9829409

A new synthesis of betotastine has been developed: The racemic 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (I) is submitted to optical resolution with N-acyl amino acids such as N-acetyl-L-phenylalanine (preferred), N-acetyl-L-leucine, N-(benzyloxycarbonyl)-L-phenylalanine, N-(benzyloxycarbonyl)-L-valine, N-(benzyloxycarbonyl)-L-threonine, N-(benzyloxycarbonyl)-L-serine or with (2R,3R)-3-(5-chloro-2-nitrophenylsulfanyl)-2-hydroxy-3-(4-methoxyphenyl)propionic acid (preferred) or (2R,3R)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylsulfanyl)propionic acid as chiral intermediates, yielding the (S)-isomer (II). The condensation of (II) with ethyl 4-bromobutyrate (III) by means of a base such as Na2CO3, NaHCO3, K2CO3 or KHCO3 gives the expected 4-(1-piperidinyl)butyric acid ester (IV), which is finally hydrolyzed with NaOH or KOH in aqueous ethanol or methanol.

SYN 3

CLIP

A Novel Synthetic Method for Bepotastine, a Histamine H1 Receptor …

journal.kcsnet.or.kr

A Novel Synthetic Method for Bepotastine, a Histamine H1 Receptor Antagonist

file:///C:/Users/91200291/Downloads/B130241_549.pdf

Scheme 1. Synthesis of bepotastine l-menthyl ester N-benzyloxycarbonyl-L-aspartic acid complex (3), bepotastine besilate (4) and bepotastine calcium (5). Reagents and conditions; i) 4-bromobutanoic acid l-menthyl ester, K2CO3, acetone, reflux, 7 h, 95-99%; ii) N-benzyloxycarbonyl-L-aspartic acid (NCbzLAA), ethyl acetate, rt, 12 h, 71-73%; iii) Ethyl acetate/H2O, NaHCO3, 97-99%; iv) EtOH:H2O = 1:1, NaOH, rt, 12 h, 3.0 N-HCl Neutralization, 92- 95%; v) AcOH, reflux, 12 h, racemization 97-100%; vi) Bezensulfonic acid, acetonitrile, rt, 12 h, 64-67%; vii) NaOH, H2O, CaCl2, rt, 12 h, 86-89%.

Synthesis of (S)-Bepotastine Besilate (4). Bepotastine (50 g, 0.13 mol) was dissolved in 500 mL of acetonitrile, and benzenesulfonic acid monohydrate (20 g, 0.11 mol) was added to the reaction mixture. Bepotastine besilate (0.5 g, 1.28 mmol) was seeded in the reaction mixture and stirred at rt for 12 h. The solid precipitate was filtered and dried. The product was obtained 38 g (yield: 64%, optical purity: 99.5% ee) as a pale white crystalline powder. Melting point: 161- 163 o C. Water: 0.2% (Karl-Fischer water determination). MS: m/z 389.1 [M+H]; 1 H-NMR (300 MHz, DMSO-d6) δ 9.2 (br s, 1H), 8.5 (d, J = 4.1 Hz, 1H), 7.8 (t, J = 7.7 Hz, 1H), 7.6 (m, 3H), 7.4 (m, 4H), 7.3 (m, 4H), 5.7 (s, 1H), 3.7 (br s, 2H), 3.3 (br s, 3H), 3.1 (br s, 2H), 2.3 (t, J = 14.1 Hz, 2H), 2.2 (m, 1H), 2.0 (m, 1H), 1.8 (m, 3H), 1.7 (m, 1H); IR (KBr, cm−1 ): 3422, 2996, 2909, 2735, 2690, 2628, 1719, 1592, 1572, 1488, 1470, 1436, 1411, 1320, 1274, 1221, 1160, 1123, 1066, 1031, 1014, 996, 849, 830, 771, 759, 727, 693, 612, 564

Synthesis

Patent ID	Title	Submitted Date	Granted Date
US9849121	AQUEOUS LIQUID PREPARATIONS AND LIGHT-STABILIZED AQUEOUS LIQUID PREPARATIONS	2014-10-10	2015-01-29
US2012225905	BEPOTASTINE COMPOSITIONS	2012-05-02	2012-09-06
US8883825	Aqueous liquid preparations and light-stabilized aqueous liquid preparations	2012-08-30	2014-11-11

Patent ID	Title	Submitted Date	Granted Date
US6638534	Preparation capable of releasing drug at target site in intestine	2001-01-29	2003-10-28
US2010168433	PROCESS FOR PREPARING BEPOTASTINE AND INTERMEDIATES USED THEREIN	2010-07-01
US7282589	Acid addition salt of optically active piperidine compound and process for preparing the same	2004-11-04	2007-10-16
US6307052	Acid-addition salts of optically active piperidine compound and process for producing the same		2001-10-23
EP0949260	ACID-ADDITION SALTS OF OPTICALLY ACTIVE PIPERIDINE COMPOUND AND PROCESS FOR PRODUCING THE SAME	1999-10-13	2002-05-22

Patent ID	Title	Submitted Date	Granted Date
US9446055	DISINTEGRATING PARTICLE COMPOSITION AND ORALLY RAPIDLY DISINTEGRATING TABLET	2010-08-11	2012-06-21
US2011257628	INSTRUMENT FOR ALLEVIATING ADDICTIVE DRUG CRAVING, METHOD FOR USING SAME AND METHOD FOR TREATING ADDICTIVE DRUG DEPENDENCE	2009-12-02	2011-10-20
US2013046240	BEPOTASTINE COMPOSITIONS	2011-10-06	2013-02-21
US2012328675	FILM PREPARATION CONTAINING MEDICAMENT WITH UNPLEASANT TASTE	2011-03-03	2012-12-27
US8771724	Percutaneous absorption enhancer and transdermal preparation using the same	2009-06-22	2014-07-08

Patent ID	Title	Submitted Date	Granted Date
US6780877	Acid addition salt of optically active piperidine compound and process for preparing the same	2002-02-28	2004-08-24
US8877168	Aqueous liquid preparations and light-stabilized aqueous liquid preparations	2014-06-25	2014-11-04
US8784789	Aqueous liquid preparations and light-stabilized aqueous liquid preparations	2003-07-30	2014-07-22
US2010137367	NOVEL CRYSTALLINE BEPOTASTINE METAL SALT HYDRATE, METHOD FOR PREPARING SAME, AND PHARMACEUTICAL COMPOSITION COMPRISING SAME	2010-06-03
US8900602	Disintegrating particle composition and orally rapidly disintegrating tablet	2010-08-11	2014-12-02

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 3 (FDA Orange Book Patent ID)
Patent	8784789
Expiration	Sep 5, 2024
Applicant	BAUSCH AND LOMB INC
Drug Application	N022288 (Prescription Drug: BEPREVE. Ingredients: BEPOTASTINE BESILATE)

from FDA Orange Book

FDA Orange Book Patents: 2 of 3 (FDA Orange Book Patent ID)
Patent	6780877
Expiration	Sep 19, 2019
Applicant	BAUSCH AND LOMB INC
Drug Application	N022288 (Prescription Drug: BEPREVE. Ingredients: BEPOTASTINE BESILATE)

from FDA Orange Book

FDA Orange Book Patents: 3 of 3 (FDA Orange Book Patent ID)
Patent	8877168
Expiration	Jul 30, 2023
Applicant	BAUSCH AND LOMB INC
Drug Application	N022288 (Prescription Drug: BEPREVE. Ingredients: BEPOTASTINE BESILATE)

from FDA Orange Book

Bepotastine
Clinical data

Trade names	Bepreve
AHFS/Drugs.com	International Drug Names
MedlinePlus	a610012
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	Oral, topical (eye drops)
ATC code	none
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	High (oral) Minimal (topical)
Protein binding	~55%
Excretion	Renal (75–90%)
Identifiers
IUPAC name [show]
CAS Number	125602-71-3
PubChem CID	2350
DrugBank	DB04890
ChemSpider	2260
UNII	HYD2U48IAS
KEGG	D09705
ChEBI	CHEBI:71204
ChEMBL	CHEMBL1201758
Chemical and physical data
Formula	C₂₁H₂₅ClN₂O₃
Molar mass	388.88 g/mol
3D model (JSmol)	Interactive image

References

- EP 335 586 (Ube Ind.; appl. 22.3.1989; J-prior. 25.3.1988).
- EP 485 984 (Ube Ind.; appl. 13.11.1991; J-prior. 15.11.1990).
- WO 9 829 409 (Ube Ind.; appl. 25.12.1997; J-prior. 26.12.1996).

racemization :
- JP 10 237 069 (Ube Ind.; appl. 21.2.1997).

References

Jump up^ H. Takahashi; A. Ishida-Yamamoto; H. Iizuka (September 2004). “Effects of bepotastine, cetirizine, fexofenadine, and olopatadine on histamine-induced wheal-and flare-response, sedation, and psychomotor performance”. Clinical and Experimental Dermatology. 29: 526–532. doi:10.1111/j.1365-2230.2004.01618.x.
Jump up^ “Bepotastine Monograph”. LexiComp.
^ Jump up to:^a ^b ^c ^d ^e ^f “Bepreve prescribing Information” (PDF).
Jump up^ [phx.corporate-ir.net/External.File?item…t=1 “2011 Net Revenues Increase to $160.3 Million On an Adjusted Cash Net Income Basis, ISTA Posts Second Year of Profitability Company Reaffirms 2012 Financial Guidance”] Check |url= value (help).
Jump up^ “Bausch & Lomb to Buy ISTA Pharmaceuticals for $500 Million”. DealBook. Retrieved 2015-12-05.
Jump up^ “Bausch & Lomb Inc. et al. v. Micro Labs USA, Inc. et al.”
Jump up^ “Valenant pharmaceuticals eyes China with Bausch deal”.
Jump up^ Macejko, Thomas T.; Bergmann, Mark T.; Williams, Jon I.; Gow, James A.; Gomes, Paul J.; McNamara, Timothy R.; Abelson, Mark B. (2010-07-01). “Multicenter Clinical Evaluation of Bepotastine Besilate Ophthalmic Solutions 1.0% and 1.5% to Treat Allergic Conjunctivitis”. American Journal of Ophthalmology. 150 (1): 122–127.e5. doi:10.1016/j.ajo.2010.02.007.

////////////Bepotastine Besilate, ベポタスチンベシル酸塩 ,Talion , tau284, TAU-284DS, TAU-284, DA-5206
HL-151 , SNJ-1773

C1CN(CCC1OC(C2=CC=C(C=C2)Cl)C3=CC=CC=N3)CCCC(=O)O.C1=CC=C(C=C1)S(=O)(=O)O

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.

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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

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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-]

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]

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

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

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

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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