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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK 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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Tasimelteon, タシメルテオン


ChemSpider 2D Image | Tasimelteon | C15H19NO2

Tasimelteon.png

Tasimelteon

N-([(1R,2R)-2-(2,3-Dihydro-1-benzofuran-4-yl)cyclopropyl]methyl)propanamide,

609799-22-6 [RN]
8985
Hetlioz [Trade name]
N-{[(1R,2R)-2-(2,3-Dihydro-1-benzofuran-4-yl)cyclopropyl]methyl}propanamide [ACD/IUPAC Name]
Propanamide, N-[[(1R,2R)-2-(2,3-dihydro-4-benzofuranyl)cyclopropyl]methyl]- [ACD/Index Name]
SHS4PU80D9

609799-22-6 cas, BMS-214778; VEC-162, ATC:N05CH03

  • Use:Treatment of sleep disorder; Melatonin receptor agonist
  • (1R,2R)-N-[2-(2,3-dihydrobenzofuran-4-yl)cyclopropylmethyl]propanamide
  • Formula:C15H19NO2, MW:245.3 g/mol
  • Hetlioz Vanda Pharmaceuticals, 2014

Approved fda 2014

EMA

Tasimelteon is a white to off-white crystalline powder, it is non hygroscopic, soluble in water across relevant pH values and freely soluble in alcohols, cyclohexane, and acetonitrile. Conducted in vivo studies demonstrate that tasimelteon is highly permeable substance. Photostability testing and testing on stress conditions demonstrated that the active substance degrades in light.

Tasimelteon exhibits stereoisomerism due to the presence of two chiral centres. Active substance is manufactured as a single, trans-1R,2R isomer. Enantiomeric purity is controlled routinely during manufacture of active substance intermediates by chiral HPLC/specific optical rotation and additionally controlled in the active substance. Stability data indicates tasimelteon is isomerically stable.

Polymorphism has been observed in polymorphic screening studies for tasimelteon and two forms have been identified. The thermodynamically more stable form has been chosen for development and the manufacturing process consistently yields active substance of single, desired polymorphic form. It was demonstrated that milling of the active substance does not affect polymorphic form. Polymorphism is additionally controlled in active substance release and shelf-life specifications using X-ray powder diffraction analysis.

Tasimelteon is synthesized in nine main steps using linear synthesis and using commercially available well-defined starting materials with acceptable specifications. Three intermediates are isolated for control of active substance quality including stereochemical control. The active substance is isolated by slow recrystallisation or precipitation of tasimelteon from an ethanol/water mixture which ensures the formation of desired polymorphic form. Up to two additional, optional recrystallisations may be performed for unmilled tasimelteon to ensure that milled tasimelteon active substance is of high purity. Seed crystals complying with active substance specifications can be used optionally. Active substance is jet milled (micronised) to reduce and control particle size, which is critical in finished product performance with regards to content uniformity and dissolution…….http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003870/WC500190309.pdf

launched in 2014 in the U.S. by Vanda Pharmaceuticals for the treatment of non-24-hour sleep-wake disorder in totally blind subjects. In 2015, the European Committee for Medicinal Products of the European Medicines Agency granted approval for the same indication.  In 2010 and 2011, orphan drug designations were assigned for the treatment of non-24 hour sleep/wake disorder in blind individuals without light perception in the U.S. and the E.U., respectively.

Tasimelteon (trade name Hetlioz) is a drug approved by the U.S. Food and Drug Administration (FDA)[2] in January 2014 for the treatment of non-24-hour sleep–wake disorder (also called Non-24, N24 and N24HSWD).[3] In June 2014, the European Medicines Agency accepted an EU filing application for tasimelteon[4] and in July 2015, the drug was approved in Europe for the treatment of non-24-hour sleep-wake rhythm disorder in totally blind adults,[5] but not in the rarer case of non-24 in sighted people.

Tasimelteon is a selective agonist for the melatonin receptors MT1 and MT2, similar to other members of the melatonin receptor agonistclass of which ramelteon (2005) and agomelatine (2009) were the first approved.[6] As a treatment for N24HSWD, as with melatonin or other melatonin derivatives, the patient may experience improved sleep timing while taking the drug. Reversion to baseline sleep performance occurs within a month of discontinuation.[7]

Image result for TASIMELTEON DRUG FUTURE

Development

Tasimelteon (previously known as BMS-214,778) was developed for the treatment of insomnia and other sleep disorders. A phase II trial on circadian rhythm sleep disorders was concluded in March 2005.[8] A phase III insomnia trial was conducted in 2006.[9] A second phase III trial on insomnia, this time concerning primary insomnia, was completed in June 2008.[10] In 2010, the FDA granted orphan drug status to tasimelteon, then regarded as an investigational medication, for use in totally blind adults with N24HSWD.[11] (Through mechanisms such as easing the approval process and extending exclusivity periods, orphan drug status encourages development of drugs for rare conditions that otherwise might lack sufficient commercial incentive.)

On completion of Phase III trials, interpretations of the clinical trials by the research team concluded that the drug may have therapeutic potential for transient insomnia in circadian rhythm sleep disorders.[12] A year-long (2011–2012) study at Harvard tested the use of tasimelteon in blind subjects with non-24-hour sleep-wake disorder. The drug has not been tested in children nor in any non-blind people.

FDA approval

In May 2013 Vanda Pharmaceuticals submitted a New Drug Application to the Food and Drug Administration for tasimelteon for the treatment of non-24-hour sleep–wake disorder in totally blind people. It was approved by the FDA on January 31, 2014 under the brand name Hetlioz.[3] In the opinion of Public Citizen, an advocacy group, the FDA erroneously allowed it to be labelled without stating that it is only approved for use by totally blind people.[13] However, FDA updated its press release on Oct. 2, 2014 to clarify the approved use of Hetlioz, which includes both sighted and blind individuals. The update did not change the drug labeling (prescribing information).[14]

Toxicity

Experiments with rodents revealed fertility impairments, an increase in certain cancers, and serious adverse events during pregnancy at dosages in excess of what is considered the “human dose”.[15][16]

As expected, advisors to the US Food and Drug Administration have recommended approval of Vanda Pharmaceuticals’ tasimelteon, to be sold as Hetlioz, for the treatment of non-24-hour disorder in the totally blind.http://www.pharmatimes.com/Article/13-11-14/FDA_panel_backs_Vanda_body_clock_drug_for_blind.aspx

The master body clock controls the timing of many aspects of physiology, behavior and metabolism that show daily rhythms, including the sleep-wake cycles, body temperature, alertness and performance, metabolic rhythms and certain hormones which exhibit circadian variation. Outputs from the

suprachiasmatic nucleus (SCN) control many endocrine rhythms including those of melatonin secretion by the pineal gland as well as the control of Cortisol secretion via effects on the hypothalamus, the pituitary and the adrenal glands. This master body clock, located in the SCN, spontaneously generates rhythms of approximately 24.5 hours. These non-24-hour rhythms are synchronized each day to the 24-hour day-night cycle by light, the primary environmental time cue which is detected by specialized cells in the retina and transmitted to the SCN via the retino-hypothalamic tract. Inability to detect this light signal, as occurs in most totally blind individuals, leads to the inability of the master body clock to be reset daily and maintain entrainment to a 24-hour day.

Non-24-Hour Disorder, Non-24, also referred to as Non-24-Hour Sleep-Wake Disorder, (N24HSWD) or Non-24-Hour Disorder, is an orphan indication affecting approximately 65,000 to 95,000 people in the U.S. and 140,000 in Europe. Non- 24 occurs when individuals, primarily blind with no light perception, are unable to synchronize their endogenous circadian pacemaker to the 24-hour light/dark cycle. Without light as a synchronizer, and because the period of the internal clock is typically a little longer than 24 hours, individuals with Non-24 experience their circadian drive to initiate sleep drifting later and later each day. Individuals with Non-24 have abnormal night sleep patterns, accompanied by difficulty staying awake during the day. Non-24 leads to significant impairment, with chronic effects impacting the social and occupational functioning of these individuals.

In addition to problems sleeping at the desired time, individuals with Non-24 experience excessive daytime sleepiness that often results in daytime napping.

The severity of nighttime sleep complaints and/or daytime sleepiness complaints varies depending on where in the cycle the individual’s body clock is with respect to their social, work, or sleep schedule. The “free running” of the clock results in approximately a 1-4 month repeating cycle, the circadian cycle, where the circadian drive to initiate sleep continually shifts a little each day (about 15 minutes on average) until the cycle repeats itself. Initially, when the circadian cycle becomes desynchronous with the 24h day-night cycle, individuals with Non-24 have difficulty initiating sleep. As time progresses, the internal circadian rhythms of these individuals becomes 180 degrees out of synchrony with the 24h day-night cycle, which gradually makes sleeping at night virtually impossible, and leads to extreme sleepiness during daytime hours.

Eventually, the individual’s sleep-wake cycle becomes aligned with the night, and “free-running” individuals are able to sleep well during a conventional or socially acceptable time. However, the alignment between the internal circadian rhythm and the 24-hour day-night cycle is only temporary.

In addition to cyclical nighttime sleep and daytime sleepiness problems, this condition can cause deleterious daily shifts in body temperature and hormone secretion, may cause metabolic disruption and is sometimes associated with depressive symptoms and mood disorders.

It is estimated that 50-75% of totally blind people in the United States (approximately 65,000 to 95,000) have Non-24. This condition can also affect sighted people. However, cases are rarely reported in this population, and the true rate of Non-24 in the general population is not known.

The ultimate treatment goal for individuals with Non-24 is to entrain or synchronize their circadian rhythms into an appropriate phase relationship with the 24-hour day so that they will have increased sleepiness during the night and increased wakefulness during the daytime. Tasimelteon

Tasimelteon is a circadian regulator which binds specifically to two high affinity melatonin receptors, Mella (MT1R) and Mellb (MT2R). These receptors are found in high density in the suprachiasmatic nucleus of the brain (SCN), which is responsible for synchronizing our sleep/wake cycle. Tasimelteon has been shown to improve sleep parameters in prior clinical studies, which simulated a desynchronization of the circadian clock. Tasimelteon has so far been studied in hundreds of individuals and has shown a good tolerability profile.

Tasimelteon has the chemical name: tr ns-N-[[2-(2,3-dihydrobenzofuran- 4-yl)cycloprop-lyl] methyl] propanamide, has the structure of Formula I:

Figure imgf000008_0001

Formula I

and is disclosed in US 5856529 and in US 20090105333, both of which are incorporated herein by reference as though fully set forth.

Tasimelteon is a white to off-white powder with a melting point of about 78°C (DSC) and is very soluble or freely soluble in 95% ethanol, methanol, acetonitrile, ethyl acetate, isopropanol, polyethylene glycols (PEG-300 and PEG- 400), and only slightly soluble in water. The native pH of a saturated solution of tasimelteon in water is 8.5 and its aqueous solubility is practically unaffected by pH. Tasimelteon has 2-4 times greater affinity for MT2R relative to MTIR. It’s affinity (¾) for MTIR is 0.3 to 0.4 and for MT2R, 0.1 to 0.2. Tasimelteon is useful in the practice of this invention because it is a melatonin agonist that has been demonstrated, among other activities, to entrain patients suffering from Non-24.

Metabolites of tasimelteon include, for example, those described in “Preclinical Pharmacokinetics and Metabolism of BMS-214778, a Novel

Melatonin Receptor Agonist” by Vachharajani et al., J. Pharmaceutical Sci., 92(4):760-772, which is hereby incorporated herein by reference. The active metabolites of tasimelteon can also be used in the method of this invention, as can pharmaceutically acceptable salts of tasimelteon or of its active metabolites. For example, in addition to metabolites of Formula II and III, above, metabolites of tasimelteon also include the monohydroxylated analogs M13 of Formula IV, M12 of Formula V, and M14 of Formula VI.

Formula IV

Figure imgf000010_0001

Formula V

MO

Figure imgf000010_0002

Formula VI

Thus, it is apparent that this invention contemplates entrainment of patients suffering free running circadian rhythm to a 24 hour circadian rhythm by administration of a circadian rhythm regulator (i.e., circadian rhythm modifier) capable of phase advancing and/or entraining circadian rhythms, such as a melatonin agonist like tasimelteon or an active metabolite oftasimelteon or a pharmaceutically acceptable salt thereof. Other MT1R and MT2R agonists, i.e., melatonin agonists, can have similar effects on the master body clock. So, for example, this invention further contemplates the use of melatonin agonists such as but not limited to melatonin, N-[l-(2,3-dihydrobenzofuran-4- yl)pyrrolidin-3-yl]-N-ethylurea and structurally related compounds as disclosed in US 6,211,225, LY-156735 ((R)-N-(2-(6-chloro-5-methoxy-lH-indol- 3yl) propyl) acetamide) (disclosed in U.S. Patent No. 4,997,845), agomelatine (N- [2-(7-methoxy-l-naphthyl)ethyl]acetamide) (disclosed in U.S. Patent No.

5,225,442), ramelteon ((S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno- [5,4-b] furan-8- yl)ethyl]propionamide), 2-phenylmelatonin, 8-M-PDOT, 2-iodomelatonin, and 6- chloromelatonin.

Additional melatonin agonists include, without limitation, those listed in U.S. Patent Application Publication No. 20050164987, which is incorporated herein by reference, specifically: TAK-375 (see Kato, K. et al. Int. J.

Neuropsychopharmacol. 2000, 3 (Suppl. 1): Abst P.03.130; see also abstracts P.03.125 and P.03.127), CGP 52608 (l-(3-allyl-4-oxothiazolidine-2-ylidene)-4- met- hylthiosemicarbazone) (See Missbach et al., J. Biol. Chem. 1996, 271, 13515-22), GR196429 (N-[2-[2,3,7,8-tetrahydro-lH-fur-o(2,3-g)indol-l- yl] ethyl] acetamide) (see Beresford et al., J. Pharmacol. Exp. Ther. 1998, 285, 1239-1245), S20242 (N-[2-(7-methoxy napth-l-yl) ethyl] propionamide) (see Depres-Brummer et al., Eur. J. Pharmacol. 1998, 347, 57-66), S-23478 (see Neuropharmacology July 2000), S24268 (see Naunyn Schmiedebergs Arch. June 2003), S25150 (see Naunyn Schmiedebergs Arch. June 2003), GW-290569, luzindole (2-benzyl-N-acetyltryptamine) (see U.S. Patent No. 5,093,352), GR135531 (5-methoxycarbonylamino-N-acetyltrypt- amine) (see U.S. Patent Application Publication No. 20010047016), Melatonin Research Compound A, Melatonin Agonist A (see IMSWorld R&D Focus August 2002), Melatonin

Analogue B (see Pharmaprojects August 1998), Melatonin Agonist C (see Chem. Pharm. Bull. (Tokyo) January 2002), Melatonin Agonist D (see J. Pineal Research November 2000), Melatonin Agonist E (see Chem. Pharm. Bull. (Tokyo) Febrary 2002), Melatonin Agonist F (see Reprod. Nutr. Dev. May 1999), Melatonin Agonist G (see J. Med. Chem. October 1993), Melatonin Agonist H (see Famaco March 2000), Melatonin Agonist I (see J. Med. Chem. March 2000), Melatonin Analog J (see Bioorg. Med. Chem. Lett. March 2003), Melatonin Analog K (see MedAd News September 2001), Melatonin Analog L, AH-001 (2-acetamido-8- methoxytetralin) (see U.S. Patent No. 5,151,446), GG-012 (4-methoxy-2- (methylene propylamide)indan) (see Drijfhout et al., Eur. J. Pharmacol. 1999, 382, 157-66), Enol-3-IPA, ML-23 (N-2,4-dinitrophenyl-5-methoxy-tryptamine ) (see U.S. Patent No. 4,880,826), SL-18.1616, IP-100-9 (US 5580878), Sleep Inducing Peptide A, AH-017 (see U.S. Patent No. 5,151,446), AH-002 (8-methoxy- 2-propionamido-tetralin) (see U.S. Patent No. 5,151,446), and IP-101.

Metabolites, prodrugs, stereoisomers, polymorphs, hydrates, solvates, and salts of the above compounds that are directly or indirectly active can, of course, also be used in the practice of this invention.

Melatonin agonists with a MT1R and MT2R binding profile similar to that of tasimelteon, which has 2 to 4 time greater specificity for MT2R, are preferred.

Tasimelteon can be synthesized by procedures known in the art. The preparation of a 4-vinyl-2,3-dihydrobenzofuran cyclopropyl intermediate can be carried out as described in US7754902, which is incorporated herein by reference as though fully set forth.

Pro-drugs, e.g., esters, and pharmaceutically acceptable salts can be prepared by exercise of routine skill in the art.

In patients suffering a Non-24, the melatonin and Cortisol circadian rhythms and the natural day/night cycle become desynchronized. For example, in patients suffering from a free-running circadian rhythm, melatonin and Cortisol acrophases occur more than 24 hours, e.g., >24.1 hours, prior to each previous day’s melatonin and Cortisol acrophase, respectively, resulting in desynchronization for days, weeks, or even months, depending upon the length of a patient’s circadian rhythm, before the melatonin, Cortisol, and day /night cycles are again temporarily synchronized.

Chronic misalignment of Cortisol has been associated with metabolic, cardiac, cognitive, neurologic, neoplastic, and hormonal disorders. Such disorders include, e.g., obesity, depression, neurological impairments.

Structure-activity relationship
SAR
Figure : Melatonin receptor agonists. The applied colors indicate the mutual properties with the general melatonin receptor agonists pharmacophore.

INTRODUCTION

Tasimelteon has the chemical name: trans-N-[[2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1yl]methyl]propanamide, has the structure of Formula I:

Figure US20130197076A1-20130801-C00001

and is disclosed in U.S. Pat. No. 5,856,529 and in US 20090105333, both of which are incorporated herein by reference as though fully set forth.

Tasimelteon is a white to off-white powder with a melting point of about 78° C. (DSC) and is very soluble or freely soluble in 95% ethanol, methanol, acetonitrile, ethyl acetate, isopropanol, polyethylene glycols (PEG-300 and PEG-400), and only slightly soluble in water. The native pH of a saturated solution of tasimelteon in water is 8.5 and its aqueous solubility is practically unaffected by pH. Tasimelteon has 2-4 times greater affinity for MT2R relative to MT1R. It’s affinity (Ki) for MT1R is 0.3 to 0.4 and for MT2R, 0.1 to 0.2. Tasimelteon is useful in the practice of this invention because it is a melatonin agonist that has been demonstrated, among other activities, to entrain patients suffering from Non-24.

SYNTHESIS

(1R-trans)-N-[[2 – (2,3-dihydro-4 benzofuranyl) cyclopropyl] methyl] propanamide PATENT: BRISTOL-MYERS SQUIBB PRIORITY DATE: 1996 HYPNOTIC

Synthesis Tasimelteon

PREPARATION OF XV

XXIV D-camphorsulfonic acid IS REACTED WITH THIONYL CHLORIDE TO GIVE

…………XXV (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonyl chloride

TREATED WITH

XXVI ammonium hydroxide

TO GIVE

XXVII (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonamide

TREATED WITH AMBERLYST15

….XXVIII (3aS, 6R) -4,5,6,7-tetrahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

TREATED WITH LAH, ie double bond is reduced to get

…..XV (3aS, 6R, 7aR)-hexahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

Intermediate

I 3-hydroxybenzoic acid methyl ester

II 3-bromo-1-propene

III 3 – (2-propenyloxy) benzoic acid methyl ester

IV 3-hydroxy-2-(2-propenyl) benzoic acid methyl ester

V 2,3-dihydro-4-hydroxy-2-benzofurancarboxylic acid methyl ester

VI benzofuran-4-carboxylic acid methyl ester

VII benzofuran-4-carboxylic acid

VIII 2,3-dihydro-4-benzofurancarboxylic acid

IX 2,3-dihydro-4-benzofuranmethanol

X 2,3-dihydro-4-benzofurancarboxaldehyde

XI Propanedioic acid

XII (E) -3 – (2,3-dihydro-4-benzofuranyl) propenoic acid

XIII thionyl chloride

XIV (E) -3 – (2,3-dihydro-4-benzofuranyl) propenoyl chloride

XV (3aS, 6R, 7aR)-hexahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

XVI (3aS,6R,7aR)-1-[(E)-3-(2,3-dihydro-4-benzofuranyl)-1-oxo-2-propenyl]hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

XVII (3aS,6R,7aR)-1-[[(1R,2R)-2-(2,3-dihydro-4-benzofuranyl)cyclopropyl]carbonyl]hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

XVIII [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanemethanol

XIX [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanecarboxaldehyde

XX hydroxylamine hydrochloride

XXI [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanecarbaldehyde oxime

XXII [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanemethanamine

XXIII propanoyl chloride

XXIV D-camphorsulfonic acid

XXV (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonyl chloride

XXVI ammonium hydroxide

XXVII (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonamide

XXVIII (3aS, 6R) -4,5,6,7-tetrahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

Bibliography

– Patents: Benzofuran and dihydrobenzofuran melatonergic agents: US5856529 (1999)

Priority: US19960032689P, 10 Dec. 1996 (Bristol-Myers Squibb Company, U.S.)

– Preparation III (quinazolines): US2004044015 (2004) Priority: EP20000402845, 13 Oct. 2000

– Preparation of VII (aminoalkylindols): Structure-Activity Relationships of Novel Cannabinoid Mimetics Eissenstat et al, J.. Med. Chem. 1995, 38, 3094-3105

– Preparation XXVIII: Towson et al. Organic Syntheses, Coll. Vol. 8, p.104 (1993) Vol. 69, p.158 (1990)

– Preparation XV: Weismiller et al. Organic Syntheses, Coll. Vol. 8, p.110 (1993) Vol. 69, p.154 (1990).

– G. Birznieks et al. Melatonin agonist VEC-162 Improves sleep onset and maintenance in a model of transient insomnia. Sleep 2007, 30, 0773 Abstract.

-. Rajaratnam SM et al, The melatonin agonist VEC-162 Phase time immediately advances the human circadian system, Sleep 2006, 29, 0159 Abstract.

-. AK Singh et al, Evolution of a manufacturing route for a highly potent drug candidate, 229th ACS Natl Meet, March 13-17, 2005, San Diego, Abstract MEDI 576.

– Vachharajani NN et al, Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist, J Pharm Sci. 2003 Apr; 92 (4) :760-72.

. – JW Scott et al, Catalytic Asymmetric Synthesis of a melotonin antagonist; synthesis and process optimization. 223rd ACS Natl Meet, April 7-11, Orlando, 2002, Abstract ORGN 186.

SYNTHESIS CONSTRUCTION AS IN PATENT

WO1998025606A1

GENERAL SCHEMES

Reaction Scheme 1

Figure imgf000020_0001

The syntheses of the 4-aryl-propenoic acid derivatives, 2 and 3, are shown in Reaction Scheme 1. The starting aldehydes, 1 , can be prepared by methods well known to those skilled in the art. Condensation of malonic acid with the aldehydes, 1, in solvents such as pyridine with catalysts such as piperidine or pyrrolidine, gives the 4-aryl- propenoic acid, 2. Subsequent conversion of the acid to the acid chloride using reagents such as thionyl chloride, phosphoryl chloride, or the like, followed by reaction with N,0-dimethyl hydroxylamine gives the amide intermediate 3 in good yields. Alternatively, aldehyde 1 can be converted directly to amide 3 using reagents such as diethyl (N-methoxy- N-methyl-carbamoylmethyl)phosphonate with a strong base such as sodium hydride.

Reaction Scheme 2

Figure imgf000020_0002

The conversion of the amide intermediate 3 to the racemic, trans- cyclopropane carboxaldehyde intermediate, 4, is shown in Reaction Scheme 2. Intermediate 3 was allowed to react with cyclopropanating reagents such as trimethylsulfoxonium iodide and sodium hydride in solvents such as DMF, THF, or the like. Subsequent reduction using reagents such as LAH in solvents such as THF, ethyl ether, or the like, gives the racemic, trans-cyclopropane carboxaldehyde intermediates, 4.

Reaction Scheme 3

Figure imgf000021_0001

Racemic cyclopropane intermediate 5 (R = halogen) can be prepared from intermediate 2 as shown in Reaction Scheme 3. Intermediate 2 was converted to the corresponding allylic alcohol by treatment with reducing agents such as sodium borohydride plus iodine in solvents such as THF. Subsequent acylation using reagents such as acetic anhydride in pyridine or acetyl chloride gave the allylic acetate which was allowed to react with cyclopropanating reagents such as sodium chloro-difluoroacetate in diglyme to provide the racemic, trans- cyclopropane acetate intermediates, 5. Reaction Scheme 4

Figure imgf000022_0001

The conversion of the acid 2 to the chiral cyclopropane carboxaldehyde intermediate, (-)-(trans)-4, is shown in Reaction Scheme 4. Intermediate 2 is condensed with (-)-2,10-camphorsultam under standard conditions, and then cyclopropanated in the presence of catalysts such as palladium acetate using diazomethane generated from reagents such as 1-methyl-3-nitro-1-nitrosoguanidine. Subsequent reduction using reagents such as LAH in solvents such as THF, followed by oxidation of the alcohol intermediates using reagents such as DMSO/oxalyl chloride, or PCC, gives the cyclopropane carboxaldehyde intermediate, (-)-(trans)-4, in good yields. The enantiomer, (+)-(trans)-4, can also be obtained employing a similar procedure using (+)-2,10- camphorsultam in place of (-)-2,10-camphorsultam.

When it is desired to prepare compounds of Formula I wherein m = 2, the alcohol intermediate may be activated in the conventional manner such as with mesyl chloride and treated with sodium cyanide followed by reduction of the nitrile group with a reducing agent such as LAH to produce the amine intermediate 6.

Reaction Scheme 5

Figure imgf000023_0001
Figure imgf000023_0002

Reaction Scheme 5 shows the conversion of intermediates 4 and 5 to the amine intermediate, 7, and the subsequent conversion of 6. or 7 to compounds of Formula I. The carboxaldehyde intermediate, 4, is condensed with hydroxylamine and then reduced with reagents such as LAH to give the amine intermediate, 7. The acetate intermediate 5 is hydrolyzed with potassium hydroxide to the alcohol, converted to the mesylate with methane sulfonyl chloride and triethyl amine in CH2CI2and then converted to the azide by treatment with sodium azide in solvents such as DMF. Subsequent reduction of the azide group with a reducing agent such as LAH produced the amine intermediate 7. Further reaction of 6 or 7 with acylating reagents gives compounds of Formula I. Suitable acylating agents include carboxylic acid halides, anhydrides, acyl imidazoles, alkyl isocyanates, alkyl isothiocyanates, and carboxylic acids in the presence of condensing agents, such as carbonyl imidazole, carbodiimides, and the like. Reaction Scheme 6

Figure imgf000024_0001

Reaction Scheme 6 shows the alkylation of secondary amides of Formula I (R2 = H) to give tertiary amides of Formula I (R2 = alkyl). The secondary amide is reacted with a base such as sodium hydride, potassium tert-butoxide, or the like, and then reacted with an alkylating reagent such as alkyl halides, alkyl sulfonate esters, or the like to produce tertiary amides of Formula I.

Reaction Scheme 7

Figure imgf000024_0002

Reaction Scheme 7 shows the halogenation of compounds of Formula I. The carboxamides, i (Q1 = Q2 = H), are reacted with excess amounts of halogenating agents such as iodine, N-bromosuccinimide, or the like to give the dihalo-compounds of Formula I (Q1 = Q2 = halogen). Alternatively, a stoichiometric amount of these halogenating agents can be used to give the monohalo-compounds of Formula I (Q1 = H, Q2 = halogen; or Q1 = halogen, Q2 = H). In both cases, additives such as lead IV tetraacetate can be used to facilitate the reaction. Biological Activity of the Compounds

The compounds of the invention are melatonergic agents. They have been found to bind human melatonergic receptors expressed in a stable cell line with good affinity. Further, the compounds are agonists as determined by their ability, like melatonin, to block the forskolin- stimulated accumulation of cAMP in certain cells. Due to these properties, the compounds and compositions of the invention should be useful as sedatives, chronobiotic agents, anxiolytics, antipsychotics, analgesics, and the like. Specifically, these agents should find use in the treatment of stress, sleep disorders, seasonal depression, appetite regulation, shifts in circadian cycles, melancholia, benign prostatic hyperplasia and related conditions

EXPERIMENTAL PROCEDURES

SEE ORIGINAL PATENT FOR CORECTIONS

Preparation 1

Benzofuran-4-carboxaldehyde

Step 1 : N-Methoxy-N-methyl-benzofuran-4-carboxamide

A mixture of benzofuran-4-carboxylic acid [Eissenstat, et al.. J. Medicinal Chemistry, 38 (16) 3094-3105 (1995)] (2.8 g, 17.4 mmol) and thionyl chloride (25 mL) was heated to reflux for 2 h and then concentrated in vacuo. The solid residue was dissolved in ethyl acetate (50 mL) and a solution of N,O-dimethylhydroxylamine hydrochloride (2.8 g) in saturated NaHC03(60 mL) was added with stirring. After stirring for 1.5 h, the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with saturated NaHCO3 and concentrated in vacuo to give an oil (3.2 g, 95.4%).

Step 2: Benzofuran-4-carboxaldehyde

A solution of N-methoxy-N-methyl-benzofuran-4-carboxamide (3.2 g, 16.6 mmol) in THF (100 mL) was cooled to -45°C and then LAH (0.7 g, 18.7 mmol) was added. The mixture was stirred for 15 min, allowed to warm to -5°C, and then recooled to -45°C. Saturated KHS04 (25 mL) was added with vigorous stirring, and the mixture was allowed to warm to room temperature. The precipitate was filtered and washed with acetone. The filtrate was concentrated in vacuo to give an oil (2.3 g, 94%). Preparation 2

2,3-Dihydrobenzofuran-4-carboxaldehyde

Step 1 : 2,3-Dihydrobenzofuran-4-carboxylic acid

Benzofuran-4-carboxylic acid (10.0 g, 61 .7 mmol) was hydrogenated (60 psi) in acetic acid (100 mL) over 10% Pd/C (2 g) for 12 hr. The mixture was filtered and the filtrate was diluted with water (500 mL) to give 2,3- dihydrobenzofuran-4-carboxylic acid as a white powder (8.4 g, 83%). A sample was recrystallized from isopropanol to give fine white needles (mp: 185.5-187.5°C).

Step 2: (2,3-Dihydrobenzofuran-4-yl)methanol

A solution of 2,3-dihydrobenzofuran-4-carboxylic acid (10 g, 61 mmol) in THF (100 mL) was stirred as LAH (4.64 g, 122 mmol) was slowly added. The mixture was heated to reflux for 30 min. The mixture was cooled and quenched cautiously with ethyl acetate and then with 1 N HCI (150 mL). The mixture was then made acidic with 12 N HCI until all the inorganic precipitate dissolved. The organic layer was separated, and the inorganic layer was extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, and then concentrated in vacuo. This oil was Kϋgelrohr distilled to a clear oil that crystallized upon cooling (8.53 g, 87.6%).

Step 3: 2.3-Dihydrobenzofuran-4-carboxaldehyde

DMSO (8.10 mL, 1 14 mmol) was added at -78°C to a stirred solution of oxalyl chloride in CH2CI2 (40 mL of a 2M solution). A solution of (2,3- dihydrobenzofuran-4-yl)methanol (8.53 g, 56.9 mmol) in CH2CI2 (35 mL) was added dropwise, and the solution stirred at -78°C for 30 min. Triethyl amine (33 mL, 228 mmol) was added cautiously to quench the reaction. The resulting suspension was stirred at room temperature for 30 min and diluted with CH2CI2 (100 mL). The organic layer was washed three times with water, and twice with brine, and then concentrated in vacuo to an oil (8.42 g, 100%) that was used without purification.

Preparation 16

(±)-(trans)-2-(2,3-Dihyd robenzofuran-4-yl)cyclopropane- carboxaldehyde

Step 1 : (±Htrans)-N-Methoxy-N-methyl-2-(2.3-dihydrobenzofuran-4- yhcyclopropanecarboxamide

Trimethylsulfoxonium iodide (9.9 g, 45 mmol) was added in small portions to a suspension of sodium hydride (1 .8 g, 45 mmol) in DMF (120 mL). After the foaming had subsided (10 min), a solution of (trans)- N-methoxy-N-methyl-3-(2,3-dihydrobenzofuran-4-yl)propenamide (3.5 g, 15 mmol) in DMF (60 mL) was added dropwise, with the temperature maintained between 35-40°C. The mixture was stirred for 3 h at room temperature. Saturated NH4CI (50 mL) was added dropwise and the mixture was extracted three times with ethyl acetate. The organic extracts were combined, washed with H2O and brine, dried over K2CO3, and concentrated in vacuo to give a white wax (3.7 g, 100%).

Step 2: (±)-(trans)- 2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane- carboxaldehyde

A solution of (±)-(trans)-N-methoxy-N-methyl-2-(2,3-dihydrobenzofuran- 4-yl)cyclopropanecarboxamide (3.7 g, 15 mmol) in THF (10 mL) was added dropwise to a rapidly stirred suspension of LAH (683 mg, 18 mmol) in THF (50 mL) at -45°C, maintaining the temperature below -40°C throughout. The cooling bath was removed, the reaction was allowed to warm to 5°C, and then the reaction was immediately recooled to -45°C. Potassium hydrogen sulfate (3.4 g, 25.5 mmol) in H20 (50 mL) was cautiously added dropwise, the temperature maintained below – 30°C throughout. The cooling bath was removed and the suspension was stirred at room temperature for 30 min. The mixture was filtered through Celite and the filter cake was washed with ether. The combined filtrates were then washed with cold 1 N HCI, 1 N NaOH, and brine. The filtrates were dried over MgSO4, and concentrated in vacuo to give a clear oil (2.6 g, 99%).

Preparation 18

(-)-(trans)-2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane-carboxaldehyde

Step 1 : (-Htrans)-N-[3-(2.3-Dihvdrobenzofuran-4-yl)-propenoyll-2.10- camphorsultam

To a solution of (-)-2,10-camphorsultam (8.15 g, 37.9 mmol) in 50 mL toluene at 0°C was added sodium hydride (1.67 g, 41.7 mmol). After stirring for 0.33 h at 0°C and 0.5 h at 20°C and recooling to 0°C, a solution of 3-(2,3-dihydrobenzofuran-4-yl)-2-propenoyl chloride
(37.9 mmol), prepared in situ from the corresponding acid and thionyl chloride (75 mL), in toluene (50 mL), was added dropwise. After stirring for 18 h at 20°C, the mixture was diluted with ethyl acetate and washed with water, 1 N HCI, and 1 N NaOH. The organic solution was dried and concentrated in vacuo to give 15.8 g of crude product. Recrystallization form ethanol-methanol (600 mL, 1 :1) gave the product (13.5 g, 92%, mp 199.5-200°C).

Step 2: (-)-N-[[(trans)-2-(2,3-Dihydrobenzofuran-4-yl)-cyclopropylj- carbonylj-2, 10-camphorsultam

1 -Methyl-3-nitro-1 -nitrosoguanidine (23.88g 163 mmol) was added in portions to a mixture of 10 N sodium hydroxide (60 mL) and ether (200 mL) at 0°C. The mixture was shaken vigorously for 0.25 h and the ether layer carefully decanted into a solution of (-)-N-[3-(2,3-dihydrobenzofuran-4-yl)-2-propenoyl]-2,10-camphorsultam (9.67 g, 25 mmol) and palladium acetate (35 mg) in methylene chloride (200 mL). After stirring for 18 h, acetic acid (5 mL) was added to the reaction and the mixture stirred for 0.5 h. The mixture was washed with 1 N HCI, 1 N NaOH and brine. The solution was dried, concentrated in vacuo and the residue crystallized twice from ethanol to give the product (6.67 g, 66.5%, mp 157-159°C).

Step 3: (-)-(trans)-2-(2,3-Dihydrobenzofuran-4-yl)cyclopropane- methanol

A solution of (-)-N-[(trans)-2-(2,3-dihydrobenzofuran-4-yl)cyclo-propanecarbonylj-2,10-camphorsultam (4.3 g, 10.7 mmol) in THF (50 mL) was added dropwise to a mixture of LAH (0.81 g, 21.4 mmol) in THF (50 mL) at -45°C. The mixture was stirred for 2 hr while it warmed to 10°C. The mixture was recooled to -40°C and hydrolyzed by the addition of saturated KHS0 (20 mL). The mixture was stirred at room temperature for 30 minutes and filtered. The precipitate was washed twice with acetone. The combined filtrate and acetone washes were concentrated in vacuo. The gummy residue was dissolved in ether, washed with 1 N NaOH and 1 N HCI, and then dried in vacuo to give the product (2.0 g, 98.4%).

Step 4: (-)-(trans)-2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane- carboxaldehyde DMSO (1.6 g, 21 mmol) was added to oxalyl chloride in CH2CI2(7.4 mL of 2 M solution, 14.8 mmole) at -78°C. The (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)-cyclopropylmethanol (2.0 g, 10.5 mmol) in CH2CI2(15 mL) was added. The mixture was stirred for 20 min and then triethylamine (4.24 g, 42 mmol) was added. The mixture was warmed to room temperature and stirred for 30 min. The mixture was diluted with CH2CI2 and washed with water, 1 N HCI, and then 1 N NaOH. The organic layer was dried and concentrated iι> vacuo to give the aldehyde product (1.98 g, 100%).

Preparation 24

(-)-(trans)-2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane-methanamine A mixture of (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane-carboxaldehyde (1.98 g, 10.5 mmol), hydroxylamine hydrochloride (2.29 g, 33 mmol), and 30% NaOH (3.5 mL, 35 mmol), in 5:1
ethanol/water (50 mL) was heated on a steam bath for 2 h. The solution was concentrated in vacuo. and the residue mixed with water. The mixture was extracted with CH2CI2. The organic extracts were dried and concentrated in vacuo to give a solid which NMR analysis showed to be a mixture of the cis and trans oximes. This material was dissolved in THF (20 mL) and added to solution of alane in THF [prepared from LAH (1.14 g, 30 mmol) and H2S04 (1.47 g, 15 mmol) at 0°Cj. The reaction was stirred for 18 h, and quenched successively with water (1.15 mL), 15% NaOH (1.15 mL), and then water (3.45 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was mixed with ether and washed with water and then 1 N HCI. The acid washes were made basic and extracted with CH2CI . The extracts were dried and concentrated in vacuo to give the amine product (1.4 g, 70.5%). The amine was converted to the fumarate salt in ethanol (mp: 197-198°C).
Anal. Calc’d for C12H15NO • C4H404: C, 62.94; H, 6.27; N, 4.59.
Found: C, 62.87; H, 6.31 ; N, 4.52.

FINAL PRODUCT TASIMELTEON

Example 2

(-)-(trans)-N-[[2-(2,3-Dihydrobenzofuran-4-yl)cycloprop-1-yl]methyl]propanamide

This compound was prepared similar to the above procedure using propionyl chloride and (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)- cyclopropanemethanamine to give an oil that solidified upon standing to an off-white solid (61 %, mp: 71-72°C). IR (NaCI Film): 3298, 1645, 1548, 1459, 1235 cm“1.

Mo5 : -17.3°

Anal. Calc’d for C15H19N02: C, 73.44; H, 7.87; N, 5.71 . Found: C, 73.28; H, 7.68; N, 5.58

SYNTHESIS

Synthesis Path

SYN

Tasimelteon (Hetlioz)Tasimelteon, which is marketed by Vanda Pharmaceuticals as Hetlioz and developed in partnership with Bristol-Myers Squibb,is a drug that was approved by the US FDA in January 2014 for the treatment of non-24-hour sleep–wake disorder (also called Non-24, N24 and N24HSWD).234 Tasimelteon is a melatonin MT1
and MT2 receptor agonist; because it exhibits a greater affinity to the MT2 receptor than MT1, is also known as Dual Melatonin
Receptor Agonist.234 Two randomized controlled trials (phases II
and III) demonstrated that tasimelteon improved sleep latency
and maintenance of sleep with a shift in circadian rhythms, and
therefore has the potential to treat patients with transient insomnia
associated with circadian rhythm sleep disorders.235 Preclinical
studies showed that the drug has similar phase-shifting properties
to melatonin, but with less vasoconstrictive effects.236 The most
likely scale preparation of the drug, much of which has been published
in the chemical literature, is described below in Scheme 44.
Activation of commercial bis-ethanol 250 with 2.5 equivalents
of the Vilsmeier salt 251 followed by treatment with base resulted
an intramolecular cyclization reaction with the proximal phenol
and concomitant elimination of the remaining imidate to deliver
the vinylated dihydrobenzofuran 252 in 76% yield.237 Interestingly,
this reaction could be performed on multi-kilogram scale, required
no chromatographic purification, and generated environmentallyfriendly
DMF and HCl as byproducts.237 Sharpless asymmetric
dihydroxylation of olefin 252 delivered diol 253 in 86% yield and
impressive enantioselectivity (>99% ee). This diol was then activated
with trimethylsilyl chloride and then treated with base to generate epoxide 254.238 Next, a modified Horner–Wadsworth–
Emmons reaction involving triethylphosphonoacetate (TEPA, 255)
was employed to convert epoxide 254 to cyclopropane 256.239
The reaction presumably proceeds through removal of the acidic
TEPA proton followed by nucleophilic attack at the terminal epoxide
carbon. The resulting alkoxide undergoes an intramolecular
phosphoryl transfer reaction resulting in an enolate, which then attacked the newly formed phosphonate ester in an SN2 fashion
resulting in the trans-cyclopropane ester, which was ultimately
saponified and re-acidified to furnish cyclopropane acid 256.239
Conversion of this acid to the corresponding primary amide preceded
carbonyl reduction with sodium borohydride. The resulting
amine was acylated with propionyl chloride to furnish tasimelteon
(XXXI) as the final product in 86% yield across the four-step
sequence.

PATENTS

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extra info

Org. Synth.199069, 154
(−)-D-2,10-CAMPHORSULTAM
[3H-3a,6-Methano-2,1-benzisothiazole, 4,5,6,7-tetrahydro-8,8-dimethyl-2,2-dioxide, (3aS)-]
Submitted by Michael C. Weismiller, James C. Towson, and Franklin A. Davis1.
Checked by David I. Magee and Robert K. Boeckman, Jr..
1. Procedure
(−)-2,10-Camphorsultam. A dry, 2-L, three-necked, round-bottomed flask is equipped with a 1.5-in egg-shaped Teflon stirring bar, a 250-mL addition funnel, and a 300-mL Soxhlet extraction apparatus equipped with a mineral oil bubbler connected to an inert-gas source. The flask is charged with 600 mL of dry tetrahydrofuran (THF) (Note 1) and6.2 g (0.16 mol) of lithium aluminum hydride (Note 2). Into the 50-mL Soxhlet extraction thimble is placed 35.0 g (0.16 mol) of (−)-(camphorsulfonyl)imine (Note 3) and the reaction mixture is stirred and heated at reflux. After all of the(camphorsulfonyl)imine has been siphoned into the reaction flask (3–4 hr), the mixture is allowed to cool to room temperature. The unreacted lithium aluminum hydride is cautiously hydrolyzed by dropwise addition of 200 mL of 1 Nhydrochloric acid via the addition funnel (Note 4). After the hydrolysis is complete the contents of the flask are transferred to a 1-L separatory funnel, the lower, silver-colored aqueous layer is separated, and the upper layer placed in a 1-L Erlenmeyer flask. The aqueous phase is returned to the separatory funnel and washed with methylene chloride (3 × 100 mL). After the reaction flask is rinsed with methylene chloride (50 mL), the organic washings are combined with the THF phase and dried over anhydrous magnesium sulfate for 10–15 min. Filtration through a 300-mL sintered-glass funnel of coarse porosity into a 1-L round-bottomed flask followed by removal of the solvent on arotary evaporator gives 33.5 g (95%) of the crude (−)-2,10-camphorsultam. The crude sultam is placed in a 250-mL Erlenmeyer flask and crystallized from approximately 60 mL of absolute ethanol. The product is collected on a 150-mL sintered-glass funnel of coarse porosity and dried in a vacuum desiccator to give 31.1 g (88%) of the pure sultam. A second crop of crystals can be gained by evaporating approximately half the filtrate; the residue is crystallized as above to give 1.4 g (4%). The combined yield of white crystalline solid, mp 183–184°C, [α]D −30.7° (CHCl3, c 2.3) is92% (Note 5) and (Note 6).
2. Notes
1. Tetrahydrofuran (Aldrich Chemical Company, Inc.) was distilled from sodium benzophenone.
2. Lithium aluminum hydride was purchased from Aldrich Chemical Company, Inc.
3. (−)-(Camphorsulfonyl)imine, [(7S)-(−)-10,10-dimethyl-5-thia-4-azatricyclo[5.2.1.03,7]dec-3-ene 5,5-dioxide] was prepared by the procedure of Towson, Weismiller, Lal, Sheppard, and Davis, Org. Synth., Coll. Vol. VIII1993, 104.
4. The addition must be very slow at first (1 drop/5 sec) until the vigorous reaction has subsided.
5. The NMR spectrum of (−)-2,10-camphorsultam is as follows: 1H NMR (CDCl3) δ: 0.94 (s, 3 H, CH3), 1.14 (s, 3 H, CH3), 1.33 (m, 1 H), 1.47 (m,, 1 H), 1.80–2.05 (5 H), 3.09 (d, 1 H, J = 14), 3.14 (d, 1 H, J = 14), 3.43 (m, 1 H), 4.05 (br s, 1 H, NH); 13C NMR (CDCl3) δ: 20.17 (q, CH3), 26.51 (t), 31.55 (t), 35.72 (t), 44.44 (d), 47.15 (s), 50.08 (t), 54.46 (s), 62.48 (d).
6. Checkers obtained material having the same mp (183–184°C) and [α]D − 31.8° (CHCl3c 2.3).
3. Discussion
(−)-2,10-Camphorsultam was first prepared by the catalytic hydrogenation of (−)-(camphorsulfonyl)imine overRaney nickel.2 Lithium aluminum hydride reduction was used by Oppolzer and co-workers in their synthesis of the sultam.3,4 However, because of the low solubility of the sultam in tetrahydrofuran, a large amount of solvent was required.4 In the procedure described here the amount of solvent is significantly reduced by using a Soxhlet extractor to convey the imine slowly into the reducing medium.5
Oppolzer’s chiral auxiliary,6 (−)-2,10-camphorsultam, is useful in the asymmetric Diels–Alder reaction,3,4 and for the preparation of enantiomerically pure β-substituted carboxylic acids7 and diols,8 in the stereoselective synthesis of Δ2-isoxazolines,9 and in the preparation of N-fluoro-(−)-2,10-camphorsultam, an enantioselective fluorinating reagent.10

References and Notes
  1. Department of Chemistry, Drexel University, Philadelphia, PA 19104.
  2. Shriner, R. L.; Shotton, J. A.; Sutherland, H. J. Am. Chem. Soc.193860, 2794.
  3. Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Helv. Chim. Acta198467, 1397.
  4. Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.; Vullioud, C. Tetrahedron198642, 4035.
  5. Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, G.; Carroll,, P. J. J. Am. Chem. Soc.1988110, 8477.
  6. Oppolzer, W. Tetrahedron198743, 1969.
  7. Oppolzer, W.; Mills, R. J.; Pachinger, W.; Stevenson, T. Helv. Chim. Acta198669, 1542; Oppolzer, W.; Schneider, P. Helv. Chim. Acta198669, 1817; Oppolzer, W.; Mills, R. J.; Réglier, M. Tetrahedron Lett.198627, 183; Oppolzer, W.; Poli. G.Tetrahedron Lett.198627, 4717; Oppolzer, W.; Poli, G.; Starkemann, C.; Bernardinelli, G. Tetrahedron Lett.198829, 3559.
  8. Oppolzer, W.; Barras, J-P. Helv. Chim. Acta198770, 1666.
  9. Curran, D. P.; Kim, B. H.; Daugherty, J.; Heffner, T. A. Tetrahedron Lett.198829, 3555.
  10. Differding, E.; Lang, R. W. Tetrahedron Lett.198829, 6087.

Org. Synth.199069, 158
(+)-(2R,8aS)-10-(CAMPHORYLSULFONYL)OXAZIRIDINE
[4H-4A,7-Methanooxazirino[3,2-i][2,1]benzisothiazole, tetrahydro-9,9-dimethyl-, 3,3-dioxide, [4aS-(4aα,7α,8aR*)]]
Submitted by James C. Towson, Michael C. Weismiller, G. Sankar Lal, Aurelia C. Sheppard, Anil Kumar, and Franklin A. Davis1.
Checked by David I. Magee and Robert K. Boeckman, Jr..
1. Procedure
A. (+)-(1S)-10-Camphorsulfonamide. Into a 2-L, two-necked, round-bottomed flask, equipped with a 250-mL dropping funnel, a magnetic stirring bar, and a reflux condenser fitted with an outlet connected to a disposable pipettedipped in 2 mL of chloroform in a test tube for monitoring gas evolution, were placed 116 g (0.5 mol) ofcamphorsulfonic acid (Note 1) and 750 mL of reagent-grade chloroform. The suspension of camphorsulfonic acid was heated to reflux and 71.4 g (43.77 mL, 0.6 mol, 1.2 equiv) of freshly distilled thionyl chloride was added dropwise over a 1-hr period. Heating was continued until gas evolution (sulfur dioxide and hydrogen chloride) had ceased (approximately 9–10 hr). The resultant solution of camphorsulfonyl chloride in chloroform was converted tocamphorsulfonamide without further purification.
In a 5-L, two-necked, round-bottomed flask fitted with a 250-mL dropping funnel and a mechanical stirrer was placed a solution of 1.6 L of reagent-grade ammonium hydroxide solution and the flask was cooled to 0°C in an ice bath. The solution of the crude camphorsulfonyl chloride, prepared in the preceding section, was added dropwise to the ammonium hydroxide solution at 0–10°C over a period of 1 hr. The reaction mixture was warmed to room temperature, stirred for 4 hr, the organic layer separated, and the aqueous layer was extracted with methylene chloride (3 × 250 mL). The combined organic layers were washed with brine (250 mL) and dried over anhydrousmagnesium sulfate. Removal of the solvent on the rotary evaporator gave 104.0 g (90%) of the crudecamphorsulfonamide (Note 2) and (Note 3).
B. (−)-(Camphorsulfonyl)imine. A 1-L, round-bottomed flask is equipped with a 2-in. egg-shaped magnetic stirring bar, a Dean–Stark water separator, and a double-walled condenser containing a mineral oil bubbler connected to an inert gas source. Into the flask are placed 5 g of Amberlyst 15 ion-exchange resin (Note 4) and 41.5 g of the crude(+)-(1S)-camphorsulfonamide in 500 mL of toluene. The reaction mixture is heated at reflux for 4 hr. After the reaction flask is cooled, but while it is still warm (40–50°C), 200 mL of methylene chloride is slowly added to dissolve any(camphorsulfonyl)imine that crystallizes. The solution is filtered through a 150-mL sintered glass funnel of coarse porosity an the reaction flask and filter funnel are washed with an additional 75 mL of methylene chloride.
Isolation of the (−)-(camphorsulfonyl)imine is accomplished by removal of the toluene on the rotary evaporator. The resulting solid is recrystallized from absolute ethanol (750 mL) to give white crystals, 34.5–36.4 g (90–95%), mp225–228°C; [α]D −32.7° (CHCl3, c 1.9) (Note 5).
C. (+)-(2R, 8aS)-10-Camphorylsulfonyloxaziridine. A 5-L, three-necked, round-bottomed Morton flask is equipped with an efficient mechanical stirrer, a 125-mm Teflon stirring blade, a Safe Lab stirring bearing (Note 6), and a 500-mL addition funnel. Into the flask are placed the toluene solution of (−)-(camphorsulfonyl)imine (39.9 g, 0.187 mol)prepared in Step B and a room-temperature solution of 543 g (3.93 mol, 7 equiv based on oxone) of anhydrouspotassium carbonate dissolved in 750 mL of water. The reaction mixture is stirred vigorously and a solution of 345 g (0.56 mol, 6 equiv of KHSO5) of oxone dissolved in 1250 mL of water is added dropwise in three portions over 45 min(Note 7) and (Note 8). Completion of the oxidation is determined by TLC (Note 9) and the reaction mixture is filtered through a 150-mL sintered-glass funnel of coarse porosity to remove solids. The filtrate is transferred to a 3-L separatory funnel, the toluene phase is separated and the aqueous phase is washed with methylene chloride (3 × 100 mL). The filtered solids and any solids remaining in the Morton flask are washed with an additional 200 mL of methylene chloride. The organic extracts are combined and washed with 100 mL of saturated sodium sulfite, dried over anhydrousmagnesium sulfate for 15–20 min, filtered, and concentrated on the rotary evaporator. The resulting white solid is crystallized from approximately 500 mL of hot 2-propanol to afford, after drying under vacuum in a desiccator, 35.9 g(84%) of white needles, mp 165–167°C, [α]D +44.6° (CHCl3, c 2.2) (Note 10) and (Note 11).
(−)-(2S,8aR)-10-(camphorylsulfonyl)oxaziridine is prepared in a similar manner starting from (−)-10-camphorsulfonic acid; mp 166–167°C, [α]D +43.6° (CHCl3, c 2.2).
2. Notes
1. (1S)-(+)-10-Camphorsulfonic acid was purchased from Aldrich Chemical Company, Inc.
2. The crude sulfonamide is contaminated with 5–10% of the (camphorsulfonyl)imine, the yield of which increases on standing.
3. The 1H NMR spectrum of (+)-(1S)-10-camphorsulfonamide is as follows: (CDCl3) δ: 0.93 (s, 3 H, CH3), 1.07 (s, 3 H, CH3), 1.40–2.50 (m, 7 H), 3.14 and 3.53 (AB quartet, 2 H, CH2-SO2J = 15.1), 5.54 (br s, 2 H, NH2).
4. Amberlyst 15 ion-exchange resin is a strongly acidic, macroreticular resin purchased from Aldrich Chemical Company, Inc.
5. The spectral properties of (−)-(camphorsulfonyl)imine are as follows: 1H NMR (CDCl3) δ: 1.03 (s, 3 H, CH3), 1.18 (s, 3 H, CH3), 1.45–2.18 (m, 6 H), 2.65 (m, 1 H), 3.10 and 3.28 (AB quartet, 2 H, CH2-SO2J = 14.0); 13C NMR (CDCl3) δ: 19.01 (q, CH3), 19.45 (q, CH3), 26.64 (t), 28.44 (t), 35.92 (t), 44.64 (d), 48.00 (s), 49.46 (t), 64.52 (s), 195.52 (s); IR (CHCl3) cm−1: 3030, 2967, 1366. Checkers obtained material having identical melting point and [α]D−32.3° (CHCl3, c 1.8).
6. The SafeLab Teflon bearing can be purchased from Aldrich Chemical Company, Inc. A glass stirring bearing lubricated with silicone grease is unsatisfactory because the dissolved salts solidify in the shaft, causing freezing.
7. Efficient stirring is important and indicated by a milky white appearance of the solution.
8. Occasionally batches of oxone purchased from Aldrich Chemical Company, Inc., have exhibited reduced reactivity in this oxidation. Oxone exposed to moisture prior to use also gives reduced reactivity in this oxidation. If this occurs, oxone is added until oxidation is complete as determined by TLC (Note 9). Potassium carbonate is added as needed to maintain the pH at approximately 9.0. Oxone stored in the refrigerator under an inert atmosphere has shown no loss in reactivity for up to 6 months.
9. Oxidation is generally complete after addition of the oxone solution. The oxidation is monitored by TLC as follows. Remove approximately 0.5 mL of the toluene solution from the nonstirring solution, spot a 250-μm TLC silica gel plate, elute with methylene chloride, and develop with 10% molybdophosphoric acid in ethanol and heating(camphorsulfonyl)imine Rf = 0.28 and (camphorylsulfonyl)oxaziridine Rf = 0.62. If (camphorsulfonyl)imine is detected, stirring is continued at room temperature until the reaction is complete (see (Note 8)). If the reaction mixture takes on a brownish color after addition of oxone and has not gone to completion after 30 min, the reaction mixture is filtered through a 150-mL sintered-glass funnel of coarse porosity, and the solids are washed with 50 mL of methylene chloride. The aqueous/organic extracts are returned to the 5-L Morton flask and stirred vigorously and 52 g (0.08 mol, 1 equiv KHSO5) of oxone is added over 5 min and stirring continued until oxidation is complete (approximately 10–15 min).
10. The submitters employed a toluene solution of crude imine prepared in Part B and obtained somewhat higher yields (90–95%). However, the checkers obtained yields in this range on one half the scale using isolatedsulfonylimine.
11. The spectral properties of (+)-(camphorsulfonyl)oxaziridine are as follows: 1H NMR (CDCl3) δ: 1.03 (s, 3 H, CH3), 1.18 (s, 3 H, CH3), 1.45–2.18 (m, 6 H), 2.65 (d, 1 H), 3.10 and 3.28 (AB quartet, 2 H, CH2-SO2J = 14.0); 13C NMR (CDCl3) δ: 19.45 (q, CH3), 20.42 (q, CH3), 26.55 (t), 28.39 (t), 33.64 (t), 45.78 (d), 48.16 (s), 48.32 (t), 54.07 (s), 98.76 (s). The checkers obtained material (mp 165–167°C) having [α]D +44.7° (CHCl3, c 2.2).
3. Discussion
Camphorsulfonamide, required for the preparation of the (camphorsulfonyl)imine, was previously prepared in two steps. The first step involved conversion of camphorsulfonic acid to the sulfonyl chloride with PCl5 or SOCl2. The isolated sulfonyl chloride was converted in a second step to the sulfonamide by reaction with ammonium hydroxide. This modified procedure is more efficient because it transforms camphorsulfonic acid directly to camphorsulfonamide, avoiding isolation of the camphorsulfonyl chloride.
(Camphorsulfonyl)imine has been reported as a by-product of reactions involving the camphorsulfonamide.2,3,4,5Reychler in 1898 isolated two isomeric camphorsulfonamides,2 one of which was shown to be the(camphorsulfonyl)imine by Armstrong and Lowry in 1902.3 Vandewalle, Van der Eycken, Oppolzer, and Vullioud described the preparation of (camphorsulfonyl)imine in 74% overall yield from 0.42 mol of the camphorsulfonyl chloride.6 The advantage of the procedure described here is that, by using ammonium hydroxide, the camphorsulfonyl chloride is converted to the sulfonamide in >95% yield.7 The sulfonamide is of sufficient purity that it can be used directly in the cyclization step, which, under acidic conditions, is quantitative in less than 4 hr. These modifications result in production of the (camphorsulfonyl)imine in 86% overall yield from the sulfonyl chloride.
In addition to the synthesis of enantiomerically pure (camphorylsulfonyl)oxaziridine7 and its derivatives,8 the(camphorsulfonyl)imine has been used in the preparation of (−)-2,10-camphorsultam (Oppolzers’ auxiliary),6,9 (+)-(3-oxocamphorysulfonyl) oxaziridine,10 and the N-fluoro-2,10-camphorsultam, an enantioselective fluorinating reagent.11
The N-sulfonyloxaziridines are an important class of selective, aprotic oxidizing reagents.121314 Enantiomerically pure N-sulfonyloxaziridines have been used in the asymmetric oxidation of sulfides to sulfoxides (30–91% ee),15selenides to selenoxides (8–9% ee).16 disulfides to thiosulfinates (2–13% ee),5 and in the asymmetric epoxidation of alkenes (19–65% ee).17,18 Oxidation of optically active sulfonimines (R*SO2N=CHAr) affords mixtures of N-sulfonyloxaziridine diastereoisomers requiring separation by crystallization and/or chromatography.3
(+)-(Camphorylsulfonyl)oxaziridine described here is prepared in four steps from inexpensive (1S)-(+)- or (1R)-(+)-10-camphorsulfonic acid in 77% overall yield.7 Separation of the oxaziridine diastereoisomers is not required because oxidation is sterically blocked from the exo face of the C-N double bond in the (camphorsulfonyl)imine. In general, (camphorsulfonyl)oxaziridine exhibits reduced reactivity compared to other N-sulfonyloxaziridines. For example, while sulfides are asymmetrically oxidized to sulfoxides (3–77% ee), this oxaziridine does not react with amines or alkenes.7 However, this oxaziridine is the reagent of choice for the hydroxylation of lithium and Grignard reagents to give alcohols and phenols because yields are good to excellent and side reactions are minimized.19 This reagent has also been used for the stereoselective oxidation of vinyllithiums to enolates.20
The most important synthetic application of the (camphorylsulfonyl)oxaziridines is the asymmetric oxidation of enolates to optically active α-hydroxy carbonyl compounds.14,21,22,23,24 Chiral, nonracemic α-hydroxy carbonylcompounds have been used extensively in asymmetric synthesis, for example, as chiral synthons, chiral auxiliaries, and chiral ligands. This structural array is also featured in many biologically active natural products. This oxidizing reagent gives uniformly high chemical yields regardless of the counterion, and stereoselectivities are good to excellent (50–95% ee).9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24 Since the configuration of the oxaziridine three-membered ring controls the stereochemistry, both α-hydroxy carbonyl optical isomers are readily available. Representative examples of the asymmetric oxidation of prochiral enolates by (+)-(2R,8aS)-camphorylsulfonyl)oxaziridine are given in Tables I and II.

This preparation is referenced from:

  • Org. Syn. Coll. Vol. 8, 110
  • Org. Syn. Coll. Vol. 9, 212
  • References and Notes
    1. Department of Chemistry, Drexel University, Philadelphia, PA 19104.
    2. Reychler, M. A. Bull. Soc. Chim. III188919, 120.
    3. Armstrong, H. E.; Lowry, T. M. J. Chem. Soc., Trans.190281, 1441.
    4. Dauphin, G.; Kergomard, A.; Scarset, A. Bull. Soc. Chim. Fr.1976, 862.
    5. Davis, F. A.; Jenkins, Jr., R. H.; Awad, S. B.; Stringer, O. D.; Watson, W. H.; Galloy, J. J. Am. Chem. Soc.1982104, 5412.
    6. Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.; Vullioud, C. Tetrahedron198642, 4035.
    7. Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, S.; Carroll, P. J. J. Am. Chem. Soc.1988110, 8477.
    8. Davis, F. A.; Weismiller, M. C.; Lal, G. S.; Chen, B. C.; Przeslawski, R. M. Tetrahedron Lett.198930, 1613.
    9. Oppolzer, W. Tetrahedron198743, 1969.
    10. Glahsl, G.; Herrmann, R. J. Chem. Soc., Perkin Trans. I1988, 1753.
    11. Differding, E.; Lang, R. W. Tetrahedron Lett.198829, 6087.
    12. For recent reviews on the chemistry of N-sulfonyloxaziridines, see: (a) Davis, F. A.; Jenkins, Jr., R. H. in “Asymmetric Synthesis,” Morrison, J. D., Ed.; Academic Press: Orlando, FL, 1984, Vol. 4, Chapter 4;
    13. Davis, F. A.; Haque, S. M. in “Advances in Oxygenated Processes,” Baumstark, A. L., Ed.; JAI Press: London, Vol. 2;
    14. Davis, F. A.; Sheppard, A. C. Tetrahedron198945, 5703.
    15. Davis, F. A.; McCauley, Jr., J. P.; Chattopadhyay, S.; Harakal, M. E.; Towson, J. C.; Watson, W. H.; Tavanaiepour, I. J. Am. Chem. Soc.1987109, 3370.
    16. Davis, F. A.; Stringer, O. D.; McCauley, Jr., J. M. Tetrahedron198541, 4747.
    17. Davis, F. A.; Chattopadhyay, S. Tetrahedron Lett.198627, 5079.
    18. Davis, F. A.; Harakal, M. E.; Awad, S. B. J. Am. Chem. Soc.1983105, 3123.
    19. Davis, F. A.; Wei, J.; Sheppard, A. C.; Gubernick S. Tetrahedron Lett.198728, 5115.
    20. Davis, F. A.; Lal, G. S.; Wei, J. Tetrahedron Lett.198829, 4269.
    21. Davis, F. A.; Haque, M. S.; Ulatowski, T. G.; Towson, J. C. J. Org. Chem.198651, 2402.
    22. Davis, F. A.; Haque, M. S. J. Org. Chem.198651, 4083; Davis, F. A.; Haque, M. S.; Przeslawski, R. M. J. Org. Chem.198954, 2021.
    23. Davis, F. A.; Ulatowski, T. G.; Haque, M. S. J. Org. Chem.198752, 5288.
    24. Davis, F. A.; Sheppard, A. C., Lal, G. S. Tetrahedron Lett.198930, 779.
    25. Davis, F. A.; Sheppard, A. C.; Chen, B. C.; Haque, M. S. J. Am. Chem. Soc.1990112, 6679.

a US 5 856 529 (Bristol-Myers Squibb; 5.1.1999; appl. 9.12.1997; USA-prior. 10.12.1996).

    • b US 7 754 902 (Vanda Pharms.; 13.7.2010; appl. 18.5.2006).
  • treatment of circadian rhythm disorders:

    • US 8 785 492 (Vanda Pharms.; 22.7.2014; appl. 25.1.2013; USA-prior. 26.1.2012).
  • synthesis cis-isomer:

    • US 6 214 869 (Bristol-Myers Squibb; 10.4.2001; appl. 25.5.1999; USA-prior. 5.6.1998).

Patents

  1. USUS5856529 A
  2. USUS8785492 B2
  3. US5856529
  4. US8785492
  5. US9060995
  6. US9549913
  7. US9539234
  8. US9730910
  9. USRE46604
  10. US9855241

References

  1. Jump up^ “Tasimelteon Advisory Committee Meeting Briefing Materials”(PDF). Vanda Pharmaceuticals Inc. November 2013.
  2. Jump up^ “FDA transcript approval minutes” (PDF). FDA. November 14, 2013.
  3. Jump up to:a b Food and Drug Administration (January 31, 2014). “FDA approves Hetlioz: first treatment for non-24 hour sleep-wake disorder”. FDA.
  4. Jump up^ “tasimelteon (Hetlioz) UKMi New Drugs Online Database”. Retrieved August 6, 2014.
  5. Jump up^ “HETLIOZ® Receives European Commission Approval for the Treatment of Non-24-Hour Sleep-Wake Disorder in the Totally Blind”MarketWatch. PR Newswire. 7 July 2015. Retrieved 8 July 2015.
  6. Jump up^ Vachharajani, Nimish N.; Yeleswaram, Krishnaswamy; Boulton, David W. (April 2003). “Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist”. Journal of Pharmaceutical Sciences92 (4): 760–72. doi:10.1002/jps.10348PMID 12661062.
  7. Jump up^ Sack, R. L.; Brandes, R. W.; Kendall, A. R.; Lewy, A. J. (2000). “Entrainment of Free-Running Circadian Rhythms by Melatonin in Blind People”. New England Journal of Medicine343 (15): 1070–7. doi:10.1056/NEJM200010123431503PMID 11027741.
  8. Jump up^ “Safety and Efficacy of VEC-162 on Circadian Rhythm in Healthy Adult Volunteers”. ClinicalTrials.gov. |accessdate=May 15, 2014
  9. Jump up^ “VEC-162 Study in Healthy Adult Volunteers in a Model of Insomnia”. ClinicalTrials.gov. Retrieved May 15, 2014.
  10. Jump up^ “VEC-162 Study in Adult Patients With Primary Insomnia”. ClinicalTrials.gov. Retrieved May 15, 2014.
  11. Jump up^ Lynne Lamberg. “Improving Sleep and Alertness in the Blind (Part 5)”Matilda Ziegler Magazine for the Blind. Retrieved May 15, 2014.
  12. Jump up^ Shantha MW Rajaratnam; Mihael H Polymeropoulos; Dennis M Fisher; Thomas Roth; Christin Scott; Gunther Birznieks; Elizabeth B Klerman (2009-02-07). “Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials”The Lancet373 (9662): 482–491. doi:10.1016/S0140-6736(08)61812-7PMID 19054552. Retrieved 2010-02-23.
  13. Jump up^ Carome, Michael (1 July 2015). “Outrage of the Month: FDA Makes Major Blunder After Approving Drug for Rare Sleep Disorder”Huffington Post. Retrieved 8 July 2015.
  14. Jump up^ Food and Drug Administration (January 31, 2014). “FDA NEWS RELEASE: FDA approves Hetlioz: first treatment for non-24 hour sleep–wake disorder in blind individuals”. FDA.
  15. Jump up^ “Side Effects Drug Center: Hetlioz Clinical Pharmacology”. RxList. February 10, 2014.
  16. Jump up^ “Side Effects Drug Center: Hetlioz Warnings and Precautions”. RxList. February 10, 2014. In animal studies, administration of tasimelteon during pregnancy resulted in developmental toxicity (embryofetal mortality, neurobehavioral impairment, and decreased growth and development in offspring) at doses greater than those used clinically.
Tasimelteon
Tasimelteon 2.svg
Tasimelteon ball-and-stick model.png
Clinical data
Trade names Hetlioz
License data
Pregnancy
category
  • US:C (Risk not ruled out)
Routes of
administration
Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability not determined in humans[1]
Protein binding 89–90%
Metabolism extensive hepatic, primarily CYP1A2 and CYP3A4-mediated
Elimination half-life 0.9–1.7 h / 0.8–5.9 h (terminal)
Excretion 80% in urine, 4% in feces
Identifiers
CAS Number
PubChemCID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
ECHA InfoCard 100.114.889Edit this at Wikidata
Chemical and physical data
Formula C15H19NO2
Molar mass 245.32 g/mol
3D model (JSmol)

ANTHONY MELVIN CRASTO

DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

//////////////BMS-214778, VEC-162, Tasimelteon, Hetlioz, FDA 2014, 609799-22-6 , BMS-214778, VEC-162, ATC N05CH03, タシメルテオン , EU 2015, VANDA, BMS, orphan drug designations
CCC(=O)NCC1CC1C2=C3CCOC3=CC=C2

Chemical and physical properties 

Tasimelteon has two stereogenic centers. Besides the medically used trans-1 R , 2 R isomer (in the picture above left), there are thus three further stereoisomers that do not arise in the synthesis.

Tasimelteon stereoisomerism.svg

Tasimelteon is a white to off-white crystalline non-hygroscopic substance, soluble in water at physiologically relevant pH levels and readily soluble in alcohols, cyclohexane and acetonitrile. The compound occurs in two crystal forms. It is an anhydrate melting at 74 ° C and a hemihydrate . [4] The hemihydrate is from about 35 ° C the water of hydration and converts thereby in the anhydrate form to. [4] The anhydrate crystallizes in a monoclinic lattice with the space group P 2 1 , and the hemihydrate crystallizes in a tetragonal lattice with the space group P 4 3 21 2. [4]

4  Kaihang Liu, Zhou Xinbo, Zhejing Xu, Bai Hongzhen, Jianrong Zhu Jianming Gu, Guping Tang, Liu Xingang, Hu Xiurong: anhydrate and hemihydrate of Tasimelteon: Synthesis, structure, and pharmacokinetic study in J. Pharm. Biomed. Anal. 151 (2018) 235-243, doi : 10.1016 / j.jpba.2017.12.035 .

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Glycopyrrolate Tosylate


Glycopyrrolate Tosylate.pngFigure US20130211101A1-20130815-C00001

Glycopyrrolate Tosylate

Molecular Formula: C26H35NO6S
Molecular Weight: 489.627 g/mol

(1,1-dimethylpyrrolidin-1-ium-3-yl) 2-cyclopentyl-2-hydroxy-2-phenylacetate;4-methylbenzenesulfonate

CAS 873295-46-6 , C19 H28 N O3 . C7 H7 O3 S, Pyrrolidinium, 3-[(2-cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1,1-dimethyl-, 4-methylbenzenesulfonate (1:1)

Glycopyrronium tosylate monohydrate

Molecular Formula, C19-H28-N-O3.C7-H8-O3-S.H2-O, Molecular Weight, 508.6522

https://chem.nlm.nih.gov/chemidplus/structure/1624259-25-1?maxscale=30&width=300&height=300

CAS 1624259-25-1, C19 H28 N O3 . C7 H7 O3 S . H2 O, Pyrrolidinium, 3-[(2-cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1,1-dimethyl-, 4-methylbenzenesulfonate, hydrate (1:1:1)

Dermira (Originator)

DRM-04
DRM-04B

  • DRM-04 tosylate monohydrate
  • DRM04
  • DRM04 tosylate
  • Glycopyrronium tosylate
  • Glycopyrronium tosylate monohydrate
  • Glycopyrronium tosylate [USAN]
  • UNII-1PVF6JLU7B
  • UNII-X2N5209428

In 2018, the product was approved in the U.S. for the treatment of primary axillary hyperhidrosis in adult and pediatric patients 9 years of age and older.

In 2016, Maruho signed an exclusive license agreement with Dermina for product development and marketing in Japan for the treatment of axillary hyperhidrosis.

PATENT

https://patents.google.com/patent/US8558008B2/en

PATENT

https://patents.google.com/patent/US20130211101A1/en

  • Glycopyrrolate is a quaternary ammonium cation of the muscarinic anticholinergic group. Glycopyrrolate, typically as a bromide salt, has been used in the treatment of a variety of conditions including diarrhea (U.S. Pat. Nos. 6,214,792 and 5,919,760), urinary incontinence (U.S. Pat. Nos. 6,204,285 and 6,063,808), and anxiety (U.S. Pat. No. 5,525,347). Additionally, U.S. Pat. No. 5,976,499 discloses a method for diagnosing cystic fibrosis in a patient by, in part, stimulating sweat production through the injection of a glycopyrrolate solution into a patient. Glycopyrrolate has also been used for the treatment of hyperhidrosis in US 20100276329.
  • [0002]
    Glycopyrrolate has previously been made available as a bromide salt or an acetate salt. The bromide salt of glycopyrrolate is sold as Rubinol®. The term “glycopyrrolate” as used in the label for Rubinol® refers to the bromide salt which is more formally referred to as glycopyrronium bromide.
    • Example 6 Glycopyrrolate Tosylate

    • [0124]
      In a dark room, silver tosylate (3.5 g) was dissolved in water (˜100 mL) by sonication. The solution was heated to approximately 40° C. and additional water was added (˜15 mL). An equimolar amount of glycopyrrolate bromide (5 g) (mixture of R,S and S,R diastereomers) was added and immediately resulted in a yellow precipitate. The slurry was stirred at approximately 40° C. overnight, and then slowly cooled while stirring to ambient temperature. At ambient temperature, the solids were vacuum filtered and the wet cake was washed three times with approximately 10 mL of water. The mother liquor was collected and filtered two times through a 0.2 μm nylon filter with glass microfiber (GMF). A clear solution was observed after filtration and was lyophilized at approximately −50° C. After 6 days, a mixture of white, needle-like and slightly sticky, glassy solids was observed. Toluene (˜20 mL) was added, and the slurry was briefly sonicated and then stirred at ambient temperature. Additional toluene (˜80 mL) was added for easier stirring, and the mixture was allowed to stand at ambient conditions for 1 day. Solids of glycopyrrolate tosylate were collected by vacuum filtration and vacuum drying at ambient temperature for 1 day.

Example 7 Preparation of Glycopyrrolate Tosylate

    • [0125]
      A slurry of equimolar amounts of glycopyrrolate acetate and p-toluenesulfonic acid was prepared in isopropanol (1 mL). The mixture was stirred at ambient temperature. Additional isopropanol (0.5 mL) was added to improve stirring, and the mixture was stirred overnight. Solids of glycopyrrolate tosylate were isolated by vacuum filtration and analyzed.

Example 8 Preparation of Glycopyrrolate Tosylate Form D

    • [0126]
      Glycopyrrolate tosylate (1.0569 g) made from Example 6 was dissolved in 4 mL ACN/H2O (50/50 vol/vol) by sonication. The solution was filtered through 0.2 μm nylon filter into a clean vial. The solvent was allowed to partially evaporate from an open vial under ambient conditions. Further evaporation was subsequently performed under nitrogen gas flow. A gel resulted which was vacuum dried at 40° C. for 1 day. Toluene (5 mL) was added and the mixture was sonicated for approximately 10 minutes causing white solids to precipitate. The mixture was stirred at ambient temperature for 1 day. The solids were isolated by vacuum filtration and the wet cake was washed with approximately 10 mL of toluene. The solids were vacuum dried at ambient temperature for 1 day. After vacuum drying the solids were placed in a vial which remained uncapped and placed inside a relative humidity chamber (˜97%). The chamber was placed inside an oven at 41° C. After 6 days, the solids were analyzed by XRPD showing Form D.

Example 9 Single Crystal Preparation of Form D

    • [0127]
      Glycopyrrolate tosylate (54.9 mg) made from Example 6 was dissolved in EtOAc/DMF (87/13 vol/vol) at approximately 55° C. at 24 mg/ml. The solution was hot filtered through a 0.2 μm nylon filter into a pre-warmed vial. The vial containing the solution was first placed in a dry ice/acetone bath and then in a freezer (approximately −25 to −10° C.). After 3 days, the solution was re-heated to approximately 50° C. and additional EtOAc was added for 96/4 EtOAc/DMF (vol/vol) at 7 mg/ml. The solution was quickly removed from elevated temperature and placed in the freezer. Solids were isolated by decanting the solvent and drying the solids under ambient conditions.
    • [0128]
      Single Crystal Data Collection
    • [0129]
      A colorless chunk of C26H37NO7S [C7H7O3S, C19H28NO3, H2O] having approximate dimensions of 0.23×0.20×0.18 mm, was mounted on a fiber in random orientation. Preliminary examination and data collection were performed with Cu Kα radiation (λ=1.54184 Å) on a Rigaku Rapid II diffractometer equipped with confocal optics. Refinements were performed using SHELX97.

Example 10 Preparation of Dehydrated Form D

    • [0130]
      A mixture of glycopyrrolate tosylate solids, including Form C and Form D, and a trace amount of silver tosylate was kept over P2Oat ambient temperature for 18 days. The resulting solids were composed of a mixture of dehydrated Form D with a trace of silver tosylate as shown by XRPD analysis.

Example 11 Preparation of Form C Glycopyrrolate Tosylate

    • [0131]
      Glycopyrrolate tosylate Form D, containing trace amounts of Form C and silver tosylate, was heated on an Anton Paar TTK 450 stage and XRPD patterns were collected in situ in the range 3.5-26° (2θ). All heating steps were at approximately 10° C./min. The stage was heated in incremental steps of 20° C. from 25 to 125° C. At each step, an XRPD pattern was collected over approximately 4 minutes. The stage was then heated to 135° C. and an XRPD pattern was collected over approximately 16 minutes and after heating further to 145° C., a pattern was collected in approximately 31 minutes. The sample was subsequently cooled to 25° C. at approximately 24° C./min, upon which a final XRPD pattern was collected over approximately 16 min. The XRPD pattern of this final pattern was indexed as Form C.

Example 12 Preparation of Form C Glycopyrrolate Tosylate

    • [0132]
      Glycopyrrolate tosylate Form D from Example 6 was heated to an approximate temperature in the range 143-149° C. under a continuous nitrogen purge for approximately 3.3 hours. The vial containing the solids was capped, placed on a lab bench and allowed to cool down to room temperature. At room temperature, the vial was placed in a jar containing P2O5. The sample was prepared for XRPD analysis under nitrogen which confirmed production of Form C.

Example 13 Preparation of Form C Glycopyrrolate Tosylate

    • [0133]
      Glycopyrrolate tosylate (59.5 mg) from Example 6 was dissolved in acetone at approximately 50° C. at 27 mg/ml. The solution was hot filtered through a 0.2 μm nylon filter into a pre-warmed vial. The vial was capped and left on the hot plate which was subsequently turned off to allow the sample to cool slowly to ambient temperature. At ambient temperature the solution was stirred causing white solids to precipitate. The solids were isolated by vacuum filtration and the wet cake was washed with approximately 2 ml of acetone. XRPD analysis resulted in Form C.

Example 14 Amorphous Glycopyrrolate Tosylate

  • [0134]
    Glycopyrrolate tosylate from Example 6 was melted and cooled repeatedly until the majority of the solids had the appearance of a glass by microscopy. XRPD analysis indicated that the “glassy” sample was observed to be amorphous. A 2.2% weight loss was observed by TGA from 25 to 250° C. of the amorphous glycopyrrolate tosylate. The onset of the glass transition temperature was measured at 11.6° C.

In a dark room, silver tosylate (3.5 g) was dissolved in water (~ 100 mL) by sonication. The solution was heated to approximately 40°C. and additional water was added (-15 mL). An equimolar amount of glycopyrrolate bromide (5 g) (mixture of R,S and S,R diastereomers) was added and imme diately resulted in a yellow precipitate. The slurry was stirred at approximately 40°C. overnight, and then slowly cooled while stirring to ambient temperature. At ambient tempera ture, the solids were vacuum filtered and the wet cake was washed three times with approximately 10 mL of water. The mother liquor was collected and filtered two times through a 0.2 pm nylon filter with glass microfiber (GMF). A clear solution was observed after filtration and was lyophilized at approximately -50°C. After 6 days, a mixture of white, needle-like and slightly sticky, glassy solids was observed. Toluene (-20 mL) was added, and the slurry was briefly sonicated and then stirred at ambient temperature. Additional toluene (-80 mL) was added for easier stirring, and the mix ture was allowed to stand at ambient conditions for 1 day. Solids of glycopyrrolate tosylate were collected by vacuum filtration and vacuum drying at ambient temperature for 1 day. Glycopyrrolate Tosylate.

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

PAPER

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

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

Open Access

Communications

Image result for Glycopyrronium bromide synthesis

The medicinal properties of glycopyrronium bromide (glycopyrrolate, 4) were first identified in the late 1950s [1]. Glycopyrrolate is an antagonist of muscarinic cholinergic receptors and is used for the treatment of drooling or excessive salivation (sialorrhea) [2], excess sweating (hyperhidrosis) [3], and overactive bladder and for presurgery treatment. In addition, it has recently been introduced as an effective bronchodilator for the treatment of chronic obstructive pulmonary disease (COPD) for asthma patients [4]. Glycopyrrolate displays few side effects because it does not pass through the blood brain barrier. Cyclopentyl mandelic acid (CPMA, 1), or its corresponding ester derivatives, are key intermediates in the synthetic routes to 4. CPMA (1) reacts with 1-methyl-pyrrolidin-3-ol (2) to form tertiary amine 3N-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) [910].

Scheme 2

Existing synthetic pathways to CPMA (1)

Publication numberPriority datePublication dateAssigneeTitle
WO2014134510A1 *2013-02-282014-09-04Dermira, Inc.Glycopyrrolate salts
US8859610B22013-02-282014-10-14Dermira, Inc.Crystalline glycopyrrolate tosylate
US9006462B22013-02-282015-04-14Dermira, Inc.Glycopyrrolate salts
US20160052879A1 *2014-08-202016-02-25Dermira, Inc.Process for production of glycopyrronium tosylate
Family To Family Citations
WO2018026869A12016-08-022018-02-08Dermira, Inc.Processes for making, and methods of using, glycopyrronium compounds
Patent ID

Title

Submitted Date

Granted Date

US9440056 DEVICE AND METHOD FOR DISPENSING A DRUG
2015-09-29
2016-03-31
US2016058735 METHODS OF TREATING HYPERHIDROSIS
2015-08-27
2016-03-03
Patent ID

Title

Submitted Date

Granted Date

US2017157088 GLYCOPYRROLATE SALTS
2017-02-21
US9610278 Glycopyrrolate Salts
2016-01-07
2016-04-28
US2016052879 PROCESS FOR PRODUCTION OF GLYCOPYRRONIUM TOSYLATE
2015-08-19
2016-02-25
US9006461 CRYSTALLINE GLYCOPYRROLATE TOSYLATE
2013-09-11
2014-08-28
US2016243345 DEVICE AND METHOD FOR DISPENSING A DRUG
2016-05-04
2016-08-25
Patent ID

Title

Submitted Date

Granted Date

US2016354315 DOSAGE FORMS AND USE THEREOF
2016-06-03
US9259414 Glycopyrrolate Salts
2015-03-10
2015-07-16
US9006462 Glycopyrrolate Salts
2014-08-29
2014-12-18
US8558008 Crystalline glycopyrrolate tosylate
2013-02-28
2013-10-15
US8859610 Crystalline glycopyrrolate tosylate
2013-09-11
2014-10-14

///////////Glycopyrrolate Tosylate, DRM-04 , DRM-04B , FDA 2018, Qbrexza

CC1=CC=C(C=C1)S(=O)(=O)[O-].C[N+]1(CCC(C1)OC(=O)C(C2CCCC2)(C3=CC=CC=C3)O)C

Diazoxide choline


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

DiazoxideDiazoxide

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 2986573eidem, 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

  1. Jump up^ Diazoxide, drugs.com
  2. 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.
  3. 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 Hypertension14 (8): 1041–5. doi:10.1097/00004872-199608000-00016PMID 8884561.closed access publication – behind paywall
  4. 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”Endocrinology148 (1): 81–91. doi:10.1210/en.2006-0738PMID 17053028.open access publication – free to read
  5. 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 Pharmacology247 (3): 257–65. doi:10.1016/0922-4106(93)90193-DPMID 8307099.closed access publication – behind paywall
  6. 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 Pharmacology38 (8): 1217–1229. doi:10.1016/0006-2952(89)90327-4.
  7. Jump up^ Doyle, Máire E.; Egan, Josephine M. (2003-03-01). “Pharmacological Agents That Directly Modulate Insulin Secretion”Pharmacological Reviews55 (1): 105–131. doi:10.1124/pr.55.1.7ISSN 1521-0081PMID 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
US9381202 SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF
2013-03-18
2013-08-29
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
US9765043 SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF
2014-08-22
2014-12-11
US7572789 SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF
2009-06-11
2009-08-11

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

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

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

Zoledronic acid


 Thumb

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)
Zoledronate disodium.png
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 osteoporosishigh blood calcium due to cancerbone breakdown due to cancer, and Paget’s disease of bone.[1] It is given by injection into a vein.[1]

Common side effects include feverjoint painhigh blood pressure, diarrhea, and feeling tired.[1] Serious side effects may include kidney problemslow 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 skeletalfractures 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

Side effects

Side effects can include fatigueanemiamuscle achesfever, 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)

Novartis Pharma Research, Arthritis and Bone Metabolism Therapeutic Area, CH-4002 Basel, Switzerland
J. Med. Chem.200245 (17), pp 3721–3738
DOI: 10.1021/jm020819i
Abstract Image

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., 4g4j5d, 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.

Image result for zoledronic acid synthesis

Paper

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

str1 str2

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

Figure CN104610357AD00061

(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.

Figure CN104610357AD00071

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.

Figure CN104610357AD00072

Example 4

Figure CN104610357AD00081

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.

Figure CN104610357AD00082

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.

Figure CN104610357AD00083

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 ZometaZomeraAclasta 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

  1. 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.
  2. Jump up^ Drugs.com International trade names for zoledronic acid Page accessed Jan 14, 2015
  3. Jump up^ “WHO Model List of Essential Medicines (20th List)” (PDF). World Health Organization. March 2017. Retrieved 29 June 2017.
  4. Jump up^ “Single Drug Information”International Medical Products Price Guide. Retrieved 9 December 2017.
  5. Jump up^ British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 528. ISBN 9780857111562.
  6. 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.
  7. Jump up^ http://www.health.gov.il/units/pharmacy/trufot/alonim/533.pdf Zomera prescribing information
  8. 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. Cancer92 (10): 1869–76. doi:10.1038/sj.bjc.6602551PMC 2361764Freely accessiblePMID 15870721.
  9. Jump up to:a b Lyles K, et al. (2007). “Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture”N. Engl. J. Med357 (18): 1799–809. doi:10.1056/NEJMoa074941PMC 2324066Freely accessiblePMID 17878149.
  10. 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
  11. Jump up to:a b Black; et al. (2007). “Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis”NEJM356 (18): 1809–1822. doi:10.1056/nejmoa067312PMID 17476007.
  12. Jump up^ “Paget’s Disease of Bone”http://www.rheumatology.org. Retrieved 2015-07-09.
  13. Jump up^ Vondracek, S. F. (2010). “Managing osteoporosis in postmenopausal women”. American Journal of Health-System Pharmacy67 (7 Suppl 3): S9–19. doi:10.2146/ajhp100076PMID 20332498.
  14. Jump up^ http://www.nps.org.au/__data/assets/pdf_file/0006/60945/nvcaclin.pdf
  15. Jump up^ “Zometa 4mg/5ml Concentrate for Solution for Infusion”medicines.org.uk.
  16. Jump up^ “FDA Alert: Reclast (zoledronic acid): Drug Safety Communication – New Contraindication and Updated Warning on Kidney Impairment”drugs.com.
  17. Jump up^ “European Medicines Agency – Human medicines”europa.eu.
  18. Jump up^ Durie BG, Katz M, Crowley J (2005). “Osteonecrosis of the jaw and bisphosphonates”. N. Engl. J. Med353 (1): 99–102; discussion 99–102. doi:10.1056/NEJM200507073530120PMID 16000365.
  19. Jump up to:a b “European Medicines Agency – Human medicines”europa.eu.
  20. Jump up^ Aclasta label- Australia
  21. 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. Rep24 (1): 233–9. doi:10.3892/or_00000851PMID 20514467.
  22. 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. Med346 (9): 653–61. doi:10.1056/NEJMoa011807PMID 11870242.
  23. 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
  24. Jump up^ “Bone drug protects stem cells from aging.” ScienceDaily. 17 December 2015
  25. 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]
  26. 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. Cancer102 (7): 1099–105. doi:10.1038/sj.bjc.6605604PMC 2853093Freely accessiblePMID 20234364.
  27. 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”. Oncologist13 (5): 503–14. doi:10.1634/theoncologist.2007-0206PMID 18515735.
  28. 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 Pharmacother11(16): 2715–25. doi:10.1517/14656566.2010.523699PMID 20977404.
  29. 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 Cancer10 (4): 267–74. doi:10.3816/CBC.2010.n.034PMID 20705558.
Zoledronic acid
Zoledronic acid.svg
Zoledronic-acid-from-xtal-2003-3D-balls.png
Clinical data
Trade names Reclast, Zometa, others[2]
AHFS/Drugs.com Monograph
MedlinePlus a605023
License data
Pregnancy
category
Routes of
administration
Intravenous
Drug class Bisphosphonate[1]
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 22%
Metabolism Nil
Elimination half-life 146 hours
Excretion Kidney (partial)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
Chemical and physical data
Formula C5H10N2O7P2
Molar mass 272.09 g/mol
3D model (JSmol)

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

Arterolane Maleate


Arterolane.svg

Image result for Arterolane Maleate

Image result for Arterolane Maleate

Arteolane Maleate

C26H40N2O8
Molecular Weight: 508.612

CAS  959520-73-1

664338-39-0 (free base)   959520-73-1 (maleate)   959520-79-7 (acetate)   664338-40-3 (tosylate)   959520-82-2 (tartrate)   959520-83-3 (citrate)

N-(2-amino-2-methylpropyl)-2-((1R,3R,4”S,5R,5’s,7R)-dispiro[adamantane-2,3′-[1,2,4]trioxolane-5′,1”-cyclohexan]-4”-yl)acetamide maleate

Dispiro[cyclohexane-1,3′-[1,2,4]trioxolane-5′,2”-tricyclo[3.3.1.13,7]decane]-4-acetamide, N-(2-amino-2-methylpropyl)-, cis-, (2Z)-2-butenedioate (1:1)

APPROVED 4.11.2017 CDSCO

Arteolane Maleate and Piperaquine phosphate Dispersible tablets (37.5 mg +187.5 mg

Indicated in children aged 6 months to 12 years for the treatment of :
– Acute uncomplicated Plasmodium falciparum malaria infection
– Acute uncomplicated Plasmodium Vivax malaria infection
 Arterolane, also known as OZ-277, is an adenosine triphosphatase inhibitor potentially for the treatment of malaria.

Arterolane.png

cas 664338-39-0 

Arterolane

664338-39-0, UNII-3N1TN351VB, OZ277, RBX-11160, NCGC00274173-01
Molecular Formula: C22H36N2O4
 Molecular Weight: 392.53224
 cis-adamantane-2-spiro-3’-8’-[[[(2’-amino-2’ methylpropyl) amino] carbonyl] methyl] 1’,2’,4’-trioxaspiro [4.5] decane
cis-adamantane-2-spiro-3′-8′-[[[(2′- amino-2′-methylpropyl)amino]carbonyl]-methyl]- 1 ‘,2′,4’-trioxaspiro[4.5]decane

Arterolane, also known as OZ277 or RBx 11160, is a substance that was tested for antimalarial activity[1] by Ranbaxy Laboratories.[2] It was discovered by US and European scientists who were coordinated by the Medicines for Malaria Venture (MMV).[3] Its molecular structure is uncommon for pharmacological compounds in that it has both a ozonide (trioxolane) group and an adamantanesubstituent.[4]

Initial results were disappointing, and in 2007 MMV withdrew support, after having invested $20M in the research;[5] Ranbaxy said at the time that it intended to continue developing the drug combination on its own.[2] Ranbaxy started a Phase II clinical trial of arterolane, in combination with piperaquine in 2009 that published in 2015.[6][7]

In 2012, Ranbaxy obtained approval to market the arterolane/piperaquine combination drug in India, under the brand name Synriam,[5]and in 2014 received approval to market it in Nigeria, Uganda, Senegal, Cameroon, Guinea, Kenya and Ivory Coast; it had already received approval in Uganda.[8]

Ranbaxy launched India’s first new drug, SynriamTM, treating Plasmodium falciparummalaria in adults. The drug provides quick relief from most malaria-related symptoms, including fever, and has a high cure rate of over 95 %.

Just one tablet per day is required, for three days, instead of two to four tablets, twice daily, for three or more days with other medicines. The drug is independent of dietary restrictions for fatty foods or milk.

Ranbaxy developed Synriam as a fixed-dose combination of arterolane maleate and piperaquine phosphate, where arterolane is the new chemical entity (NCE) that was developed as an alternative to artemisinin. It is the first recently developed antimalarial not based on artemisinin, one of the most effective treatments for malaria, which has shown problems with resistance in recent years. Arterolane was discovered by a collaborative drug discovery project funded by the Medicines for Malaria Venture. Since SynriamTM has a synthetic source, unlike artemisinin-based drugs, production can be scaled up whenever required and a consistent supply can be maintained at a low cost.

The new drug, has been approved by the Drug Controller General of India (DCGI) for marketing in India and conforms to the recommendations of the World Health Organization (WHO) for using combination therapy in malaria. Ranbaxy is also working to make it available in African, Asian and South American markets where Malaria is rampant. SynriamTM trials are ongoing for Plasmodium vivax malaria and a paediatric formulation.

Derek Lowe of the famous In the Pipeline blog had written about arterolane in 2009. At the time it was in Phase III trial, which I assumed were the trials that Ranbaxy was conducting. But it turned out that arterolane was developed by a collaboration between researchers in the US, the UK, Switzerland and Australia who were funded by the World Health Organization and Medicines for Malaria Venture (a Swiss non-profit). They published this work in Nature in 2004 and further SAR (Structure Activity Relationship) studies in J Med Chem in 2010. So Ranbaxy did not develop the drug from scratch? But the press release quotes Arun Sawhney, CEO and Managing Director of Ranbaxy which misleads people to think so: “It is indeed gratifying to see that Ranbaxy’s scientists have been able to gift our great nation its first new drug, to treat malaria, a disease endemic to our part of the world. This is a historic day for science and technology in India as well as for the pharmaceutical industry in the country. Today, India joins the elite and exclusive club of nations of the world that have demonstrated the capability of developing a new drug”. So Ranbaxy mixes a known active compound (piperaquine) with a new compound that someone else found to be active (arterolane) and claims that they developed a new drug? In an interview in LiveMint, Sawhney says, “Ranbaxy spent around $30 million on Synriam and the contribution from DST [India’s Department of Science & Technology] was Rs.5 crore. The drug went through several phases of development since the project began in 2003. We did not look at this as a commercial development. Instead, this is a CSR [Corporate Social Responsibility] venture for us.” That’s a give away because developing a new drug from scratch has to cost more than $30 million + Rs.50 million.


Ranbaxy  now taken over by sun

SynriamTM

Generic Name
Arterolane Maleate and Piperaquine Phosphate Tablets
Composition
Each film coated tablet contains: Arterolane maleate equivalent to Arterolane ……………………………150 mg Piperaquinephosphate……………750 mg
Dosage Form
Tablets
Inactive ingredients:
Microcrystalline cellulose, Crospovidone, Magnesium stearate, Hydroxypropyl methyl cellulose/Hypromellose, Titanium dioxide, Macrogol/ Polyethylene glycol, Talc, Ferric Oxide (Yellow), Ferric Oxide (Red)

Description SynriamTM is a fixed dose combination of two antimalarial active ingredients arterolane maleate and piperaquine phosphate.

Arterolane maleate is a synthetic trioxolane compound. The chemical name of arterolane maleate is cis-adamantane-2-spiro-3’-8’-[[[(2’-amino-2’ methylpropyl) amino] carbonyl] methyl] 1’,2’,4’-trioxaspiro [4.5] decane hydrogen maleate. The molecular formula is C26H40N2O8 and molecular weight is 508.61. The structural formula is as follows:

MALARIA
Malaria is one of the most prevalent and deadly parasitic diseases in the world. Up to 289 million cases of malaria may have occurred in 2010, causing between 660,000 and 1.25 million deaths, mainly in Africa and mostly of children younger than 5 years.
(WHO: http://www.who.int/malaria/publications/world_malaria_report_2012/en/index.html; Fidock, D. A. Eliminating Malaria. Science 2013, 340, 1531-1533.)

The most serious problem in malaria treatment is that the parasites causing the disease, particularly the deadly Plasmodium falciparum, have developed resistance to widely used drugs, particularly chloroquine (CQ). Currently, the most efficacious therapies are combinations of an artemisinin-type compound with a long-lasting partner drug like lumefantrine, amodiaquine or mefloquine.

Malaria, the most common parasitic disease of humans, remains a major health and economic burden in most tropical countries. Large areas of Central and South America, Hispaniola (Haiti and the Dominican Republic), Africa, the Middle East, the Indian subcontinent, Southeast Asia, and Oceania are considered as malaria-risk areas. It leads to a heavy toll of illness and death, especially amongst children and pregnant women.

According to the World Health Organization, it is estimated that the disease infects about 400 million people each year, and around two to three million people die from malaria every year. There are four kinds of malaria parasites that infect human: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae.

Malaria spreads from one person to another by the bite of mosquito, Anopheles gambiae, which serves as vector. When a mosquito sucks the blood of human, sporozoites are transfused into the human body together with saliva of the mosquito. The sporozoites enter into the hepatocytes, reproduce asexually and finally enter into the blood stream. The parasites continue to multiply inside the red blood cells, until they burst and release large number of merozoites. This process continues, destroying a significant number of blood cells and causing the characteristic paroxysm (“chills and fever”) associated with the disease. In the red blood cells, some of the merozoites become male or female gametocytes. These gametocytes are ingested by the mosquito when it feeds on blood. The gametocytes fuse in the vector’s gut; sporozoites are produced and are migrated to the vector’s salivary glands.

The clinical symptoms of malaria are generally associated with the bursting of red blood cells causing an intense fever associated with chills that can leave the infected individual exhausted and bedridden. More severe symptoms associated with repeat infections and/or infection by Plasmodium falciparum include anaemia, severe headaches, convulsions, delirium and, in some instances, death.

Quinine, an antimalarial compound that is extracted from the bark of cinchona tree, is one of the oldest and most effective drugs in existence. Chloroquine and mefloquine are the synthetic analogs of quinine developed in 1940’s, which due to their effectiveness, ease of manufacture, and general lack of side effects, became the drugs of choice. The downside to quinine and its derivatives is that they are short-acting and have bitter taste. Further, they fail to prevent disease relapses and are also associated with side effects commonly known as “Chinchonism syndrome” characterized by nausea, vomiting, dizziness, vertigo and deafness. However, in recent years, with the emergence of drug- resistant strains of parasite and insecticide-resistant strains of vector, the treatment and/or control of malaria is becoming difficult with these conventional drugs.

Malarial treatment further progressed with the discovery of Artemisinin

(qinghaosu), a naturally occurring endoperoxide sesquiterpene lactone isolated from the plant Artemisia annua (Meshnick et al., Microbiol. Rev. 1996, 60, p. 301-315; Vroman et al., Curr. Pharm. Design, 1999, 5, p. 101-138; Dhingra et al., 2000, 66, p. 279-300), and a number of its precursors, metabolites and semi-synthetic derivatives which have shown to possess antimalarial properties. The antimalarial action of artemisinin is due to its reaction with iron in free heme molecules of the malaria parasite, with the generation of free radicals leading to cellular destruction. This initiated a substantial effort to elucidate its molecular mechanism of action (Jefford, dv. Drug Res. 1997, 29, p. 271-325; Cumming et al., Adv. Pharmacol. 1997, 37, p. 254-297) and to identify novel antimalarial peroxides (Dong and Vennerstrom, Expert Opin. Ther. Patents 2001, 1 1, p. 1753-1760).

Although the clinically useful artemisinin derivatives are rapid acting and potent antimalarial drugs, they have several disadvantages including recrudescence,

neurotoxicity, (Wesche et al., Antimicrob. Agents. Chemother. 1994, 38, p. 1813-1819) and metabolic instability (White, Trans. R. Soc. Trop. Med. Hyg., 1994, 88, p. 41-43). A fair number of these compounds are quite active in vitro, but most suffer from low oral activity (White, Trans. R. Soc. Trop. Med. Hyg., 1994, 88, p. 41-43 and van Agtmael et al., Trends Pharmacol. Sci., 1999, 20, p. 199-205). Further all these artemisinin derivatives are conventionally obtained from plant source and are therefore expensive. As the cultivation of the plant material is dependent on many factors including the weather conditions, the supply source thus becomes finite and there are chances of varying yield and potency. This leads to quality inconsistencies and supply constraints. As malaria is more prevalent in developing countries, a switch to cheaper and effective medicine is highly desirable.

Thus there exists a need in the art to identify new peroxide antimalarial agents, especially those which are not dependent on plant source and can be easily synthesized, are devoid of neurotoxicity, and which possess improved solubility, stability and pharmacokinetic properties.

Following that, many synthetic antimalarial 1 ,2,4-trioxanes (Jefford, Adv. Drug Res. 1997, 29, p. 271-325; Cumming et al., Adv. Pharmacol. 1997, 37, p. 254-297), 1,2,4,5-tetraoxanes (Vennerstrom et al., J. Med. Chem., 2000, 43, p. 2753-2758), and other endoperoxides have been prepared. Various patents/applications disclose means and method for treating malaria using Spiro or dispiro 1,2,4-trioxolanes for example, U.S.

Patent Application No. 2004/0186168 and U.S. Patent Nos. 6,486, 199 and 6,825,230. The present invention relates to solid dosage forms of the various spiro or dispiro 1 ,2,4- trioxolanes antimalarial compounds disclosed in these patents/applications and are incorporated herein by reference.

Active compounds representing various Spiro and dispiro 1 ,2,4-trioxolane derivatives possess excellent potency, efficacy against Plasmodium parasites, and a lower degree of neurotoxicity, in addition to their structural simplicity and ease of synthesis. Furthermore, these compounds have half-lives which are believed to permit short-term treatment regimens comparing favorably to other artemisinin-like drugs. In general, the therapeutic dose of trioxolane derivative may range between about 0.1-1000 mg/kg/day, in particular between about 1-100 mg/kg/day. The foregoing dose may be administered as a single dose or may be divided into multiple doses. For malaria prevention, a typical dosing schedule could be, for example, 2.0-1000 mg/kg weekly beginning 1-2 weeks prior to malaria exposure, continued up to 1-2 weeks post-exposure.

Monotherapy with artemisinin (natural or synthetic) class of drugs might cure the patients within 3 days, however perceiving the potential threat of the malarial parasite developing resistance towards otherwise very potent artemisinin class of drugs, WHO had strictly called for an immediate halt to the provision of single-drug artemisinin malaria pills. Combination therapy in case of malaria retards the development of resistance, improve efficacy by lowering recrudescence rate, provides synergistic effect, and increase exposure of the parasite to the drugs.

Artemsinin based combinations are available in the market for a long time.

Artemether-lumafentrine (Co-artem®) was the first fixed dose antimalarial combination containing an artemisinin derivative and has been known since 1999. This combination has passed extensive safety and efficacy trials and has been approved by more than 70 regulatory agencies. Co-artem® is recommended by WHO as the first line treatment for uncomplicated malaria.

Other artemisinin based combinations include artesunate and amodiaquine (Coarsucam®), and dihydroartemisin and piperaquine (Eurartesim®). Unfortunately, all the available artemisinin based combinations have complicated dosage regimens making it difficult and inconvenient for a patient to comply completely with the total prescribed duration. For example, the dosage regimen of Co-artem® for an adult having body weight of more than 35 kg includes 6 doses over three days. The first dose comprises four tablets initially, the second dose comprises four tablets after eight hours, the third to sixth doses comprise four tablets twice for another two days; making it a total of 24 tablets. The dosage regimen of Coarsucam® for an adult having body weight of more than 36 kg or age above 14 years includes three doses over three days; each dose comprises two tablets; making it a total of six tablets. The dosage regimen of Eurartesim® for an adult having body weight between 36 kg – 75 kg includes 3 doses over three days, each dose comprises of three tablets, making it a total of nine tablets.

It is evident that the available artemisinin-based combinations have a high pill burden on patients as they need to consume too many tablets. As noted above, this may increase the possibility of missing a few doses, and, consequently, could result in reduced efficacy due to non-compliance and may even lead to development of resistance for the drug. Therefore, there is an urgent and unmet need for anti-malarial combinations with a simplified daily dosing regimen that reduces the pill burden and would increase patient compliance.

Apart from simplifying the regimen, there are certain limitations for formulators developing formulations with trioxolones, the first being their susceptibility to degradation in presence of moisture that results in reduced shelf lives. Another is their bitter taste, which can result in poor compliance of the regimen or selection of another, possibly less effective, therapeutic agent.

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http://www.google.st/patents/US6906205

Figure US06906205-20050614-C00051

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http://www.google.st/patents/WO2013008218A1?cl=en

structural Formula II.

Figure imgf000013_0001

Formula II

Active compound includes one or more of the various spiro and dispiro trioxolane derivatives disclosed in U.S. Application No. 2004/0186168 and U.S. Patent Nos.

6,486,199 and 6,825,230, which are incorporated herein by reference. These trioxolanes are relatively sterically hindered on at least one side of the trioxolane heterocycle which provides better in vivo activity, especially with respect to oral administration. Particularly, spiro and dispiro 1,2,4-trioxolanes derivatives possess excellent potency and efficacy against Plasmodium parasites, and a lower degree of neurotoxicity.

The term “Active compound I” herein means cis-adamantane-2-spiro-3′-8′-[[[(2′- amino-2′-methylpropyl)amino]carbonyl]-methyl]- 1 ‘,2′,4’-trioxaspiro[4.5]decane hydrogen maleate. The Active compound I may be present in an amount of from about 5% to about 25%, w/w based on the total dosage form.

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http://www.google.st/patents/WO2007138435A2?cl=en

A synthetic procedure for preparing compounds of Formula I, salts of the free base c«-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methyl propyl) amino] carbonyl] methyl]- 1 ‘, 2′, 4’-trioxaspiro [4.5] decane has been disclosed in U.S. 6,906,205.

Figure imgf000002_0001

The process for the preparation of compounds of Formula I wherein a compound of Formula II (wherein R is lower alkyl) is reacted with a compound of Formula III (wherein R is lower alkyl) to obtain compound of Formula IV;

Figure imgf000005_0001
Figure imgf000005_0002

Formula Formula IV

followed by hydrolysis of the compounds of Formula IV to give a compound of Formula V;

Figure imgf000005_0003

Formula V followed by the reaction of the compound of Formula V with an activating agent, for example, methyl chloroformate, ethyl chloroformate, propyl chloro formate, n-butyl chloro formate, isobutyl chloroformate or pivaloyl chloride leads to the formation of mixed anhydride, which is reacted in situ reaction with 1 ,2-diamino-2-methyl propane to give a compound of Formula VI; and

Figure imgf000005_0004

Formula Vl reacting the compound of Formula VI with an acid of Formula HX (wherein X can be the same as defined earlier) to give compounds of Formula I.

Example 1 : Preparation of O-methyl-2-adamantanone oxime

To a solution of 2-adamantanone (50 g, 0.3328 mol, 1 equiv.) in methanol (0.25 lit), sodium hydroxide solution (15 g, 0.3761mol, 1.13 equiv, in 50 mL water) was added followed by methoxylamine hydrochloride (37.5 g x 81.59% Purity= 30.596 g, 0.366 mol, 1.1 equiv) at room temperature under stirring. The reaction mixture was stirred at room temperature for 1 to 2 h. The reaction was monitored by HPLC. The reaction mixture was concentrated at 40- 45°C under vacuum to get a thick residue. Water (250 mL) was added at room temperature and the reaction mixture was stirred for half an hour. The white solid was filtered, washed with water (50 mL), and dried at 40 to 45°C under reduced pressure. O-methyl 2- adamantanone oxime (57 g, 95 % yield) was obtained as a white solid.

(M++l) 180, 1HNMR (400 MHz, CDCl3 ): δ 1.98 – 1.79 (m, 12H), 2.53 (s, IH), 3.46 ( s, IH), 3.81 (s, 3H).

Example 2: Preparation of 4-(methoxycarbonvmethvPcvclohexanone A high pressure autoclave was charged with a mixture of methyl (4- hydroxyphenyl)acetate (50 g, 0.30 mol), palladium ( 5g) (10 %) on carbon (50 % wet) and O- xylene (250 mL). The reaction mixture was stirred under 110 to 115 psi of hydrogen pressure for 7 to 8 h at 1400C. The reaction was monitored by HPLC. The reaction mixture was then cooled to room temperature, and the catalyst was filtered off. Filtrate was concentrated under reduced pressure to get 4-(methoxycarbonylmethyl)cyclohexanone as light yellow to colorless oily liquid (48.7 g, 97.4 %).

(M++!) 171, ‘ HNMR (400 MHz, CDCl 3): δ 1.48 – 1.51 ( m, 2H), 2.1 1-2.07 (m, 2H), 2.4- 2.23 (m, 7H), 3.7 (s, 3H).

Example 3: Preparation of methyl (Is, 4s)-dispiro [cyclohexane-l, 3′-f 1,2,4] trioxolane-5′, 2″-tricvclor3.3.1.1371decan1-4-ylacetate

A solution of O-methyl-2-adamantanone oxime (example 1) (11.06 g, 61.7 mmol, 1.5 equiv.) and 4-(methoxycarbonymethyl)cyclohexanone (example 2) (7.0 g, 41.1 mmol, 1 equiv.) in cyclohexane ( 200ml) and dichloromethane (40 mL) was treated with ozone (ozone was produced with an OREC ozone generator [0.6 L/min. O2, 60 V] passed through an empty gas washing bottle that was cooled to -780C). The solvent was removed after the reaction was complete. After removal of solvents, the crude product was purified by crystallization from 80% aqueous ethanol (200 mL) to afford the title compound as a colorless solid. Yield: 10.83 g, 78%, mp: 96-980C; 1HNMR (500 Hz3CDCl3): δ 1.20-1.33 (m, 2H), 1.61-2.09 (m, 5 21H), 2.22 (d, J = 6.8Hz, 2H), 3.67(s,3H).

Example 4: Preparation of (Is, 4s)-dispiro [cyclohexane-1, 3′-[l,2,4] trioxolane-5′, 2″- tricvclo [3.3.1.137] decanl-4-ylacetic acid

Sodium hydroxide (3.86 g, 96.57 mmol, 3 equiv.) in water (80 mL) was added to a solution of methyl (\s, 4s)-dispiro [cyclohexane-1, 3′-[l,2,4] trioxolane-5′, 2″-tricyclo

10 [3.3.1.I37] decan]-4-ylacetate (example 3) (10.83 g, 32.19 mmol, 1 equiv.) in 95% ethanol (150 mL). The mixture was stirred at 500C for about 4 h, cooled to O0C, and treated with IM hydrochloric acid (129ml, 4 equiv). The precipitate was collected by filtration, washed with 50 % aqueous ethanol (150 mL) and dried in vacuum at 40 0C to give the title compound as colorless solid. Yield: 9.952 g, 96%, mp: 146-1480C ( 95% ethanol), 1HNMR (500 Hz,

15 CDCl3): δ 1.19-1.41 (m,2H), 1.60-2.05 (m,21H), 2.27 (d, J=6.8 Hz,2H).

Example 5: Preparation of c?s-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methyl propyl) amino] carbonyl] methyl]-! ‘, T , 4’-trioxaspiro [4.5] decane

Method A:

(Is, 4s)-dispiro[cyclohexane- 1 ,3 ‘-[ 1 ,2,4]trioxolane-5 ‘,2 ‘ ‘-tricyclo[3.3.1.137]decan]-4-

.0 ylacetic acid (example 4) (5 g ,15.5mmol, 1 equiv) was mixed with triethylamine (2.5 g , 24.8 mmol, 1.6 equiv) in 100ml of dichloromethane. The reaction mixture was cooled to – 1O0C to 00C. Ethyl chloro formate (1.68 g, 17 mmol, 1.0 equiv) in 15 mL dichloromethane was charged to the above reaction mixture at – 100C to 00C. The reaction mixture was stirred at the same temperature for 10 to 30 minutes. The resulting mixed anhydride reaction mixture

15 was added dropwise to a previously prepared solution of l,2-diamino-2-methylpropane (1.64 g, 18.6 mmol, 1.2 equiv), in 100 mL dichloromethane at -100C to O0C. The temperature of reaction mixture was raised to room temperature. The reaction mixture was stirred at the same temperature till the reaction was complete. Reaction monitoring was done by thin layer chromatography using 5 to 10% methanol in dichloromethane. The reaction was complete

>0 within 2 h. Nitrogen atmosphere was maintained throughout the reaction. Water (50 mL) was charged, organic layer was separated and washed with 10% sodium bicarbonate solution (50 mL) and water (50 mL) at room temperature. The organic layer was dried over sodium sulphate and the solvent was removed at 25 to 4O0C under reduced pressure. Hexane (50ml) was added to obtain residue under stirring at room temperature. The mixture was filtered and washed with 5 mL of chilled hexane. The solid was dried under reduced pressure at room 5 temperature.

Yield: 5.2 g (85.4 %), (M++l) 393, 1HNMR (400 MHz, DMSO-J6 ): δ 0.929 ( s, 6H), 1.105 – 1.079 (m, 2H), 1.887-1.641 (m, 21H), 2.030-2.017 (d, 2H), 2.928 (d, 2H).

Method B:

(Is, 4s)-dispiro [cyclohexane-1, 3′-[l,2,4] trioxolane-5′, 2″-tricyclo [3.3.1.I37]

10 decan]-4-ylacetic acid (example 4) (10 g, 31mmol, 1 equiv) was treated with isobutyl chloroformate (4.5 g, 33mmol, 1.1 equiv) in presence of organic base like triethyl amine (5 g, 49.6mmol, 1.6 equiv) at 00C to 7°C in 250ml of dichloromethane. The solution was stirred at O0C to 7°C for aboutlO to 30 minutes. To the above reaction mixture, previously prepared solution of l,2-diamino-2-methylpropane (3.27 g, 37 mmol, 1.2 equiv), in 50 mL of

15 dichloromethane was added at O0C to 7°C in one lot. The temperature of reaction mixture was raised to room temperature. The reaction mixture was stirred at the room temperature till reaction was over. Reaction monitoring was done by thin layer chromatography using 5 to 10% methanol in dichloromethane. Reaction was complete within 2 h. The reaction nitrogen atmosphere was maintained throughout the reaction. Water (250 mL) was charged, organic

20 layer was separated and washed with 10% sodium bicarbonate solution (200 mL) and water (100 mL) at room temperature and the solvent was removed at 25 to 4O0C under reduced pressure. Hexane (100ml) was added to the residue, under stirring, at room temperature. The mixture was filtered and washed with chilled hexane (10 mL). The resultant solid was dried under reduced pressure at room temperature. Yield: 10.63 g (87%), (M++l) 393, 1HNMR

>5 (400 MHz, DMSO-J6 ) :δ 0.928 ( s, 6H), 1.102 – 1.074 (m, 2H), 1.859-1.616 (m, 21H), 2.031- 2.013 (d, 2H), 2.94-2.925 (d, 2H). Method C:

(\s, 4s)-dispiro[cyclohexane-l,3′-[l,2,4]trioxolane-5′,2″-tricyclo[3.3.1.13>7]decan]-4- ylacetic acid (example 4) (5 g, 15.5mmol, 1 equiv) was treated with pivaloyl chloride (1.87 g, 15.5 mmol, 1 equiv) and triethylamine (2.5gm, 24.8mmol, 1.6 equiv) at -15°C to -100C in dichloromethane (125 mL). The solution was stirred at -150C to -100C for aboutlO to 30 minutes. It resulted in the formation of mixed anydride. To the above reaction mixture, previously prepared solution of 1 ,2-diamino-2-methylpropane (1.64 g, 18.6 mmol, 1.2 equiv) in 25 mL dichloromethane was added at -15°C to -100C. The temperature of reaction mixture was raised to room temperature. The reaction mixture was stirred at the room temperature till reaction was over. Reaction monitoring was done by thin layer chromatography using 5 to 10% methanol in dichloromethane. The reaction was complete within 2 h. Nitrogen atmosphere was maintained throughout the reaction. Water (125 mL) was charged, organic layer was separated and washed with 50 mL of 10% sodium bicarbonate solution and 125 mL of water, respectively at room temperature. Finally solvent was removed at 25 to 4O0C under reduced pressure. 50 mL of 5% Ethyl acetate – hexane solvent mixture was added to the residue under stirring at room temperature. The mixture was filtered and washed with 5 mL of chilled hexane. Solid was dried under reduced pressure at room temperature. Yield: 5.03 g (83 %), (M++l) 393, 1JINMR (400 MHz, OMSO-d6 ):δ 0.93 ( s, 6H), 1.113 – 1.069 (m, 2H), 1.861-1.644 (m, 21H), 2.033-2.015 (d, 2H), 2.948-2.933 (d, 2H).

Example 6: Preparation of c/s-adamantane-2-spiro-3′ -8 ‘-πT(2′-amino-2’ -methyl propyl) amino! carbonyl] methyli-l ‘, 2\ 4′-U-JoXaSpJrQ [4.51 decane maleate To a solution of c/s-adamantane-2-spiro-3′-8′-[[[(2′-amino-2’-methyl propyl) amino] carbonyl] methyl]-! ‘, 2′, 4’-trioxaspiro [4.5] decane (example 5) (60 g, 0.153 moles) in ethanol (150 mL) was added a solution of maleic acid (17.3 g, 0.15 moles, 0.98 equiv. in ethanol 90 mL) and the reaction mixture was stirred for about 1 h. To this clear solution, n- heptane (720 mL) was added at room temperature in 1 h and the reaction mixture was stirred for 3 h. It was then cooled to 0 to 100C and filtered. The cake was washed with n-heptane (60 mL) and dried under vacuum at 40-450C.

Yield: 67 g, 77.4%, mp: 1490C (decomp), (M++l) 393.5, 1HNMR (300 MHz, DMSO-^ ): δ 1.05-1.11 (2H,m), 1.18 (6H,s), 1.64-1.89 (21H,m), 2.07(2H,d), 3.21 (2H,d), 6.06 (2H,d), 7.797 (2H, bs), 8.07 (IH, t).

References

  1.  Dong, Yuxiang; Wittlin, Sergio; Sriraghavan, Kamaraj; Chollet, Jacques; Charman, Susan A.; Charman, William N.; Scheurer, Christian; Urwyler, Heinrich et al. (2010). “The Structure−Activity Relationship of the Antimalarial Ozonide Arterolane (OZ277)”. Journal of Medicinal Chemistry 53 (1): 481–91. doi:10.1021/jm901473sPMID 19924861.
  2.  Blow to Ranbaxy drug research plans at LiveMint.com, Sep 21 2007
  3.  Vennerstrom, Jonathan L.; Arbe-Barnes, Sarah; Brun, Reto; Charman, Susan A.; Chiu, Francis C. K.; Chollet, Jacques; Dong, Yuxiang; Dorn, Arnulf et al. (2004). “Identification of an antimalarial synthetic trioxolane drug development candidate”. Nature 430 (7002): 900–4.doi:10.1038/nature02779PMID 15318224.
  4.  In the Pipeline: “Ozonides As Drugs: What Will They Think Of Next?”, by Derek Lowe, November 23, 2009, at Corante.com
  5.  Indian company starts Phase III trials of synthetic artemisinin, May 4 2009, at the WorldWide Antimalarial Resistance Network
  6. http://www.nature.com/nature/journal/v430/n7002/full/nature02779.html
5-27-2011
PROCESS FOR THE PREPARATION OF DISPIRO 1,2,4-TRIOXOLANE ANTIMALARIALS (OZ277)
2-13-2009
STABLE DOSAGE FORMS OF SPIRO AND DISPIRO 1,2,4-TRIOXOLANE ANTIMALARIALS
6-15-2005
Spiro and dispiro 1,2,4-trioxolane antimalarials
11-31-2004
Spiro and dispiro 1,2,4-trixolane antimalarials

ANTIMALARIALS

http://www.rsc.org/chemistryworld/2013/03/new-antimalarial-drug-class-resistance-elq-300-quinolone

Antimalarial drugsSpeeding to a new lead

http://www.nature.com/nrd/journal/v9/n11/full/nrd3301.html

Structure of NITD609; the 1R,3Sconfiguration is fundamental for its antimalarial activity

References

  1. Jump up^ Dong, Yuxiang; Wittlin, Sergio; Sriraghavan, Kamaraj; Chollet, Jacques; Charman, Susan A.; Charman, William N.; Scheurer, Christian; Urwyler, Heinrich; et al. (2010). “The Structure−Activity Relationship of the Antimalarial Ozonide Arterolane (OZ277)”. Journal of Medicinal Chemistry53 (1): 481–91. doi:10.1021/jm901473sPMID 19924861.
  2. Jump up to:a b Blow to Ranbaxy drug research plans at LiveMint.com, Sep 21 2007
  3. Jump up^ Vennerstrom, Jonathan L.; Arbe-Barnes, Sarah; Brun, Reto; Charman, Susan A.; Chiu, Francis C. K.; Chollet, Jacques; Dong, Yuxiang; Dorn, Arnulf; et al. (2004). “Identification of an antimalarial synthetic trioxolane drug development candidate”. Nature430 (7002): 900–4. doi:10.1038/nature02779PMID 15318224.
  4. Jump up^ In the Pipeline: “Ozonides As Drugs: What Will They Think Of Next?”, by Derek Lowe; published November 23, 2009; retrieved November 17, 2015; at Sciencemag.org
  5. Jump up to:a b Akshat Rathi for Chemistry World. 3 May 2012 Ranbaxy launches new anti-malarial Synriam
  6. Jump up^ India Clinical trials registry CTRI/2009/091/000531
  7. Jump up^ Toure OA et al. Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate dispersible tablets in paediatric patients with acute uncomplicated Plasmodium falciparum malaria: a phase II, multicentric, open-label study. Malar J. 2015 Nov 25;14(1):469. Clinical Trial Registry India: CTRI/2009/091/000531. PMID 26608469 PMC4660726
  8. Jump up^ Staff, Business Standard. December 16, 2014 Ranbaxy receives approval for malaria drug Synriam from 7 African countries

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17: Abiodun OO, Brun R, Wittlin S. In vitro interaction of artemisinin derivatives or the fully synthetic peroxidic anti-malarial OZ277 with thapsigargin in Plasmodium falciparum strains. Malar J. 2013 Jan 31;12:43. doi: 10.1186/1475-2875-12-43. PubMed PMID: 23368889; PubMed Central PMCID: PMC3566918.

18: White NJ. Can new treatment developments combat resistance in malaria? Expert Opin Pharmacother. 2016 Jul;17(10):1303-7. doi: 10.1080/14656566.2016.1187134. PubMed PMID: 27191998.

19: Wang X, Dong Y, Wittlin S, Charman SA, Chiu FC, Chollet J, Katneni K, Mannila J, Morizzi J, Ryan E, Scheurer C, Steuten J, Santo Tomas J, Snyder C, Vennerstrom JL. Comparative antimalarial activities and ADME profiles of ozonides (1,2,4-trioxolanes) OZ277, OZ439, and their 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. J Med Chem. 2013 Mar 28;56(6):2547-55. doi: 10.1021/jm400004u. PubMed PMID: 23489135.

20: Marfurt J, Chalfein F, Prayoga P, Wabiser F, Wirjanata G, Sebayang B, Piera KA, Wittlin S, Haynes RK, Möhrle JJ, Anstey NM, Kenangalem E, Price RN. Comparative ex vivo activity of novel endoperoxides in multidrug-resistant plasmodium falciparum and P. vivax. Antimicrob Agents Chemother. 2012 Oct;56(10):5258-63. doi: 10.1128/AAC.00283-12. PubMed PMID: 22850522; PubMed Central PMCID: PMC3457353.

Arterolane
Arterolane.svg
Clinical data
Routes of
administration
Oral
ATC code
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C22H36N2O4
Molar mass 392.531 g/mol
3D model (JSmol)

////////////Arteolane Maleate, OZ-277, RBx-11160, OZ 277, RBx 11160, OZ277, RBx11160, IND 2017

O=C(NCC(C)(N)C)C[C@H](CC1)CC[C@@]21OC3(OO2)[C@H]4C[C@H]5C[C@@H]3C[C@@H](C4)C5.O=C(O)/C=C\C(O)=O

Bepotastine Besilate, ベポタスチンベシル酸塩


ChemSpider 2D Image | Bepotastine Besilate | C27H31ClN2O6SBepotastine 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

str1

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 335586eidem, 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 (TalionBepreve) 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

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.

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
Bepotastine
Bepotastine.svg
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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C21H25ClN2O3
Molar mass 388.88 g/mol
3D model (JSmol)

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

  1. 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 Dermatology29: 526–532. doi:10.1111/j.1365-2230.2004.01618.x.
  2. Jump up^ “Bepotastine Monograph”LexiComp.
  3. Jump up to:a b c d e f “Bepreve prescribing Information” (PDF).
  4. 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).
  5. Jump up^ “Bausch & Lomb to Buy ISTA Pharmaceuticals for $500 Million”DealBook. Retrieved 2015-12-05.
  6. Jump up^ “Bausch & Lomb Inc. et al. v. Micro Labs USA, Inc. et al.”
  7. Jump up^ “Valenant pharmaceuticals eyes China with Bausch deal”.
  8. 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 Ophthalmology150 (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

Fipronil, 芬普尼 , フィプロニル


2D chemical structure of fipronilChemSpider 2D Image | Fipronil | C12H4Cl2F6N4OS

120068-37-3.png

Fipronil

  • Molecular Formula C12H4Cl2F6N4OS
  • Average mass 437.148 Da
(±)-5-Amino-1-(2,6-dichloro-a,a,a-trifluoro-p-tolyl)-4-trifluoromethylsulfinylpyrazole-3-carbonitrile
(±)-Fipronil
120068-37-3 [RN]
1H-Pyrazole-3-carbonitrile, 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-
Fluocyanobenpyrazole
T5NNJ AR BG FG DXFFF& CCN DSO&XFFF EZ &&(RS) Form [WLN]
Termidor
UNII:QGH063955F
NCGC00094574-08
QA-6027
SPECTRUM1505354
TL8000532
UNII-QGH063955F
UPCMLD-DP011:002
UQ4430250
芬普尼 [Chinese]
フィプロニル
1H-Pyrazole-3-carbonitrile, 5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-((trifluoromethyl)sulfinyl)-
424-610-5 [EINECS]
5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethane)sulfinyl-1H-pyrazole-3-carbonitrile
5-amino-1-[4-(trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)-3-pyrazolecarbonitrile
8090115 [Beilstein]
HSDB 7051; RM 1601
Fipronil
CAS Registry Number: 120068-37-3
CAS Name: 5-Amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile
Additional Names: 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole; (±)-5-amino-1-(2,6-dichloro-a,a,a-trifluoro-p-tolyl)-4-trifluoromethylsulfinylpyrazole-3-carbonitrile
Manufacturers’ Codes: MB-46030
Trademarks: Frontline (Merial); Termidor (BASF)
Molecular Formula: C12H4Cl2F6N4OS
Molecular Weight: 437.15
Percent Composition: C 32.97%, H 0.92%, Cl 16.22%, F 26.08%, N 12.82%, O 3.66%, S 7.34%
Literature References: GABA-gated chloride channel blocker. Prototype of the phenylpyrazole insecticides known as fiproles. Prepn: I. G. Buntain et al., EP 295117 (1988 to May & Baker); L. R. Hatton et al., US 5232940 (1993). Mechanism of action study: L. M. Cole et al., Pestic. Biochem. Physiol. 46, 47 (1993). Comprehensive description: F. Colliot et al., Brighton Crop Prot. Conf. – Pests Dis. 1992, 29-34.
Properties: White solid, mp 200.5-201°. Vapor pressure (20°): 2.8 ´ 10-9 mm Hg. Log P (n-octanol/water): 4.0. Soly: water 2 mg/l; acetone >50%; corn oil >10,000 mg/l. LD50 in rats (mg/kg): 100 orally; >2000 dermally (Colliot); in mice (mg/kg): 32 i.p. (Cole).
Melting point: mp 200.5-201°
Log P: Log P (n-octanol/water): 4.0
Toxicity data: LD50 in rats (mg/kg): 100 orally; >2000 dermally (Colliot); in mice (mg/kg): 32 i.p. (Cole)
Use: Pesticide.
Therap-Cat-Vet: Ectoparasiticide.

APPROVED CDSCO INDIA 25.06.2018

Fipronil  50mg/134mg/268mg/402 mg spot on solution for cats and dogs , For treatment of flea and tick infestation in cats and dogs (for veterinary use only)

Fipronil is a broad-spectrum insecticide that belongs to the phenylpyrazole chemical family. Fipronil disrupts the insect central nervous system by blocking GABA-gated chloride channels and glutamate-gated chloride (GluCl) channels. This causes hyperexcitation of contaminated insects’ nerves and muscles. Fipronil’s specificity towards insects is believed to be due to its greater affinity to the GABA receptor in insects relative to mammals and its effect on GluCl channels, which do not exist in mammals.[1]

Because of its effectiveness on a large number of pests, fipronil is used as the active ingredient in flea control products for pets and home roach traps as well as field pest control for corn, golf courses, and commercial turf. Its widespread use makes its specific effects the subject of considerable attention. This includes ongoing observations on possible off-target harm to humans or ecosystems as well as the monitoring of resistance development.[2]

Use

Fipronil is or has been used in:

  • Under the trade name Regent, it is used against major lepidopteran (moth, butterfly, etc.) and orthopteran (grasshopper, locust, etc.) pests on a wide range of field and horticultural crops and against coleopteran (beetle) larvae in soils. In 1999, 400,000 hectares were treated with Regent. It became the leading imported product in the area of rice insecticides, the second-biggest crop protection market after cotton in China.[3]
  • Under the trade names Goliath and Nexa, it is employed for cockroach and ant control, including in the US. It is also used against pests of field corngolf courses, and commercial lawn care under the trade name Chipco Choice.[3]
  • It has been used under the trade name Adonis for locust control in Madagascar and Kazakhstan.[3]
  • Marketed under the names Termidor, Ultrathor, and Taurus in Africa and Australia, fipronil effectively controls termite pests, and was shown to be effective in field trials in these countries.[3]
  • Termidor has been approved for use against the Rasberry crazy ant in the Houston, Texas, area, under a special “crisis exemption” from the Texas Department of Agriculture and the Environmental Protection Agency. The chemical is only approved for use in Texascounties experiencing “confirmed infestations” of the newly discovered ant species.[4] Use of Termidor is restricted to certified pest control operators in the following states: Alaska, Connecticut, Nebraska, South Carolina, Massachusetts, Indiana, New York, and Washington.[citation needed]
  • In Australia, it is marketed under numerous trade names, including Combat Ant-Rid, Radiate and Termidor, and as generic fipronil
  • In the UK, provisional approval for five years has been granted for fipronil use as a public hygiene insecticide.[3]
  • Fipronil is the main active ingredient of Frontline TopSpot, Fiproguard, Flevox, and PetArmor (used along with S-methoprene in the ‘Plus’ versions of these products); these treatments are used in fighting tick and flea infestations in dogs and cats.
  • In New Zealand, fipronil was used in trials to control wasps (Vespula spp.), which are a threat to indigenous biodiversity.[5] It is now being used by the Department of Conservation to attempt local eradication of wasps,[6].[7][8]

Effects

Toxicity

Fipronil is classed as a WHO Class II moderately hazardous pesticide, and has a rat acute oral LD50 of 97 mg/kg.

It has moderate acute toxicity by the oral and inhalation routes in rats. Dermal absorption in rats is less than 1% after 24 h and toxicity is considered to be low. It has been found to be very toxic to rabbits.

The photodegradate MB46513 or desulfinylfipronil, appears to have a higher acute toxicity to mammals than fipronil itself by a factor of about 10.[9]

Symptoms of acute toxicity via ingestion includes sweating, nausea, vomiting, headache, abdominal pain, dizziness, agitation, weakness, and tonic-clonic seizures. Clinical signs of exposure to fipronil are generally reversible and resolve spontaneously. As of 2011, no data were available regarding the chronic effects of fipronil on humans. The U.S. EPA has classified fipronil as a group C (possible human) carcinogen based on an increase in thyroid follicular cell tumors in both sexes of the rat. However, as of 2011, no human data is available regarding the carcinogenic effects of fipronil.[10]

Two Frontline TopSpot products were determined by the New York State Department of Environmental Conservation to pose no significant exposure risks to workers applying the product. However, concerns were raised about human exposure to Frontline spray treatment in 1996, leading to a denial of registration for the spray product. Commercial pet groomers and veterinarians were considered to be at risk from chronic exposure via inhalation and dermal absorption during the application of the spray, assuming they may have to treat up to 20 large dogs per day.[3] Fipronil is not volatile, so the likelihood of humans being exposed to this compound in the air is low.[10]

In contrast to neonicotinoids such as acetamipridclothianidinimidacloprid, and thiamethoxam, which are absorbed through the skin to some extent, fipronil is not absorbed substantially through the skin.[11]

Detection in body fluids

Fipronil may be quantitated in plasma by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry to confirm a diagnosis of poisoning in hospitalised patients or to provide evidence in a medicolegal death investigation.[12]

Ecological toxicity

Fipronil is highly toxic for crustaceansinsects and zooplankton,[13] as well as beestermitesrabbits, the fringe-toed lizard, and certain groups of gallinaceous birds. It appears to reduce the longevity and fecundity of female braconid parasitoids. It is also highly toxic to many fish, though its toxicity varies with species. Conversely, the substance is relatively innocuous to passerineswildfowl, and earthworms.

Its half-life in soil is four months to one year, but much less on soil surface because it is more sensitive to light (photolysis) than water (hydrolysis).[14]

Few studies of effects on wildlife have been conducted, but studies of the nontarget impact from emergency applications of fipronil as barrier sprays for locust control in Madagascar showed adverse impacts of fipronil on termites, which appear to be very severe and long-lived. Also, adverse effects were indicated in the short term on several other invertebrate groups, one species of lizard (Trachylepis elegans), and several species of birds (including the Madagascar bee-eater).

Nontarget effects on some insects (predatory and detritivorous beetles, some parasitic wasps and bees) were also found in field trials of fipronil for desert locust control in Mauritania, and very low doses (0.6-2.0 g a.i./ha) used against grasshoppers in Niger caused impacts on nontarget insects comparable to those found with other insecticides used in grasshopper control. The implications of this for other wildlife and ecology of the habitat remain unknown, but appear unlikely to be severe.[3] Unfortunately, this lack of severity was not observed in bee species in South America. Fipronil is also used in Brazil and studies on the stingless bee Scaptotrigona postica have shown adverse reactions to the pesticide, including seizures, paralysis, and death with a lethal dose of .54 ng a.i./bee and a lethal concentration of .24 ng a.i./μl diet. These values are highly toxic in Scaptotrigona postica and bees in general.[15] Toxic baiting with fipronil has been shown to be effective in locally eliminating German wasps. All colonies within foraging range were completely eliminated within one week.[16][17][5]

In May 2003, the French Directorate-General of Food at the Ministry of Agriculture determined that a case of mass bee mortality observed in southern France was related to acute fipronil toxicity. Toxicity was linked to defective seed treatment, which generated dust. In February 2003, the ministry decided to temporarily suspend the sale of BASF crop protection products containing fipronil in France.[18] The seed treatment involved has since been banned.[citation needed] Fipronil was used in a broad spraying to control locusts in Madagascar in a program that began in 1997.[19]

Notable results from wildlife studies include:

  • Fipronil is highly toxic to fish and aquatic invertebrates. Its tendency to bind to sediments and its low water solubility may reduce the potential hazard to aquatic wildlife.[20]
  • Fipronil is toxic to bees and should not be applied to vegetation when bees are foraging.[20]
  • Based on ecological effects, fipronil is highly toxic to upland game birds on an acute oral basis and very highly toxic on a subacute dietary basis, but is practically nontoxic to waterfowl on both acute and subacute bases.[21]
  • Chronic (avian reproduction) studies show no effects at the highest levels tested in mallards (NOEC) = 1000 ppm) or quail (NOEC = 10 ppm). The metabolite MB 46136 is more toxic to the parent than avian species tested (very highly toxic to upland game birds and moderately toxic to waterfowl on an acute oral basis).[21]
  • Fipronil is very highly toxic to bluegill sunfish and highly toxic to rainbow trout on an acute basis.[21]
  • An early-lifestage toxicity study in rainbow trout found that fipronil affects larval growth with a NOEC of 0.0066 ppm and an LOEC of 0.015 ppm. The metabolite MB 46136 is more toxic than the parent to freshwater fish (6.3 times more toxic to rainbow trout and 3.3 times more toxic to bluegill sunfish). Based on an acute daphnia study using fipronil and three supplemental studies using its metabolites, fipronil is characterized as highly toxic to aquatic invertebrates.[21]
  • An invertebrate lifecycle daphnia study showed that fipronil affects length in daphnids at concentrations greater than 9.8 ppb.[21]
  • A lifecycle study in mysids shows fipronil affects reproduction, survival, and growth of mysids at concentrations less than 5 ppt.[21]
  • Acute studies of estuarine animals using oystersmysids, and sheepshead minnows show that fipronil is highly acutely toxic to oysters and sheepshead minnows, and very highly toxic to mysids. Metabolites MB 46136 and MB 45950 are more toxic than the parent to freshwater invertebrates (MB 46136 is 6.6 times more toxic and MB 45950 is 1.9 times more toxic to freshwater invertebrates).[21]

Colony collapse disorder

Fipronil is one of the main chemical causes blamed for the spread of colony collapse disorder among bees. It has been found by the Minutes-Association for Technical Coordination Fund in France that even at very low nonlethal doses for bees, the pesticide still impairs their ability to locate their hive, resulting in large numbers of forager bees lost with every pollen-finding expedition.[22] A synergistic toxic effect of fipronil with the fungal pathogen Nosema ceranae was recently reported[23]. The functional basis for this toxic effect is now understood: the synergy between fipronil and the pathogenic fungus induces changes in male physiology leading to infertility[24] A 2013 report by the European Food Safety Authorityidentified fipronil as “a high acute risk to honeybees when used as a seed treatment for maize and on July 16, 2013 the EU voted to ban the use of fipronil on corn and sunflowers within the EU. The ban took effect at the end of 2013.”[25][26]

Pharmacodynamics

Fipronil acts by binding to allosteric sites of GABAA receptors and GluCl receptors (of insects) as an antagonist (a form of noncompetitive inhibition). This prevents the opening of chloride ion channels normally encouraged by GABA, reducing the chloride ions’ ability to lower a neuron’s membrane potential. This results in an overabundance of neurons reaching action potential and likewise CNS toxicity via overstimulation.[27][28][29][30]

Acute oral LD50 (rat) 97 mg/kg
Acute dermal LD50 (rat) >2000 mg/kg

In animals and humans, fipronil poisoning is characterized by vomiting, agitation, and seizures, and can usually be managed through supportive care and early treatment of seizures, generally with benzodiazepine use.[31][32]

History

Fipronil was discovered and developed by Rhône-Poulenc between 1985 and 1987, and placed on the market in 1993 under the B2 U.S. Patent 5,232,940 B2. Between 1987 and 1996, fipronil was evaluated on more than 250 insect pests on 60 crops worldwide, and crop protection accounted for about 39% of total fipronil production in 1997. Since 2003, BASF holds the patent rights for producing and selling fipronil-based products in many countries.

2017 Fipronil eggs contamination

The 2017 Fipronil eggs contamination is an incident in Europe and South Korea involving the spread of insecticide contaminated eggs and egg products. Chicken eggs were found to contain Fipronil and distributed to 15 European Union countries, Switzerland, and Hong Kong.[33][34] Approximately 700,000 eggs are thought to have reached shelves in the UK alone.[35] Eggs at 44 farms in Taiwan were also found with excessive Fipronil levels.[36]

SYN

Figure US20130030190A1-20130131-C00009

SYN 2

SYN 3

SYN 4

PATENT

http://www.allindianpatents.com/patents/271132-a-process-for-the-synthesis-of-fipronil

5-Amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl
sulfinyl pyrazole or 5-Amino-[2,6-dichloro-4-(trif]uoromethyl)phenyl]-4-[-(1 (R,S)-trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile also known as Fipronil is a novel pesticide characterized by high efficiency, low toxicity and especially low residue.
There are various routes to synthesize Fipronil by oxidation of thiopyrazole with various other oxidizing agents in suitable solvents. Oxidation of sulfides is a very useful route for the preparation of sulfoxides. Literature is replete with the conversion of sulfides to sulfoxides and/or sulfones. However, most of the existing methods use expensive, toxic or rare oxidizing reagents, which are difficult to prepare, are very expensive and cannot be used on commercial scale. Many of these processes suffer from poor selectivity.
WO01/30760 describes oxidation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-pyrazole with trifluoro-acetic acid and hydrogen peroxide in the presence of boric acid. The quantity

of trifluoroacetic acid used is 14.5 molar equivalents. The patent also
discloses the preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethyl
phenyl)-3-cyano-4-trifluoromethylthio-pyrazole from 5-amino-1-(2,6-
dichloro-4-trifluoromethyl phenyl)-3-cyano pyrazole-4-yl disulphide.
European Patent publication No.295117 describes the preparation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulphinyl pyrazole starting from 2,6-Dichloro-4-trifluoromethylaniline to give an intermediate 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole which is oxidized with meta-chloroperbenzoic acid in chloroform to give desired product.
Oxidizing agents such as perbenzoic acids do not provide effective and regioselective oxidation of electron deficient sulfides such as trifluoromethylsulphides which are less readily oxidized than other sulfides. Trifluoroacetic acid and trichloroacetic acid are found to be very efficient and regioselective oxidation medium for oxidation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-pyrazole in presence of hydrogen peroxide. Trichloroacetic acid can not be used alone due to higher melting point. Trifluoroacetic acid on the other hand is very regioselective with respect to conversion and low by-products formation. However, it is expensive, water miscible, corrosive to metal as well as glass, comparatively lower boiling and it’s recovery (in anhydrous form) is complex in nature.
W000/35851/2000 talks about synthesis of 2,6-Dichloro-4-trifluoromethylaniline starting from 3,4,5-trichloro-benzotrifluoride in the presence of alkaline fluorides like lithium fluoride and ammonia in the

presence of N-methylpyrrolidone at 250°C to give 97% conversion and 87% selectivity. The main drawback of the above process is the synthesis of 3,4,5-trichlorobenzotrifluoride in high yield and purity. Chlorination of p-chlorobenzotrifluoride gives a mixture of 3,4,5-trichlorobenzotrifluoride in 72% GLC conversions, 3,4-dichloro and tetrachlorobenzotrifluoride. The process to get pure 3,4,5-isomer from this mixture by fractionation followed by crystallization is very tedious. Moreover in-spite of using very pure intermediates, substantial amount of an undesired isomer (3-amino-4,5-dichlorobenzotrifluoride) is also obtained.
Another approach to generate 3,4,5-trichlorobenzotrifluoride with high yield and purity is to perform denitrochlorination of 4-chloro-3,5-dinitrobenzotrifluoride in the presence of a catalyst as described in GB Patent 2154581A. Even though the process produces 3,4,5-trichlorobenzotrifluoide in high yield and purity, the reaction conditions are too drastic to be employed for an industrial process.
The known commercial processes for the manufacture of Fipronil uses corrosive and expensive chemical such as trifluoroaceticacid, hydrogen peroxide and m-chloroperbenzoicacid Trifluoroacetic acid is expensive and generally not used in large quantities, as well as of m-chloroperbenzoic acid is difficult to handle at commercial scale due to its un-stability and detonating effect. Also the raw material used such as 2,6-Dichloro-4-trifluoromethylaniline are not easily available or made. The overall process for the Fipronil as disclosed above is found to be unsatisfactory in one respect or the other.

Thus, there is felt a need for preparing Fipronil from easily available raw materials in a simple and economical manner at an industrial level, with high yields and purity.

PATENT

https://patents.google.com/patent/US20130030190A1/en

  • 5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulfinyl pyrazole or 5-Amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[-(1(R,S)-trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile also known as Fipronil is a novel pesticide characterized by high efficiency, low toxicity and especially low residue.
  • [0005]
    There are various routes to synthesize Fipronil by oxidation of thiopyrazole with various other oxidizing agents in suitable solvents. Oxidation of sulfides is a very useful route for the preparation of sulfoxides. Literature is replete with the conversion of sulfides to sulfoxides and/or sulfones. However, most of the existing methods use expensive, toxic or rare oxidizing reagents, which are difficult to prepare, are very expensive and cannot be used on commercial scale. Many of these processes suffer from poor selectivity.
  • [0006]
    WO01/30760 describes oxidation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-pyrazole with trifluoro-acetic acid and hydrogen peroxide in the presence of boric acid. The quantity of trifluoroacetic acid used is 14.5 molar equivalents. The patent also discloses the preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethyl phenyl)-3-cyano-4-trifluoromethylthio-pyrazole from 5-amino-1-(2,6-dichloro-4-trifluoromethyl phenyl)-3-cyano pyrazole-4-yl disulphide.
  • [0007]
    European Patent publication No. 295117 describes the preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulphinyl pyrazole starting from 2,6-Dichloro-4-trifluoromethylaniline to give an intermediate 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole which is oxidized with meta-chloroperbenzoic acid in chloroform to give desired product.
  • [0008]
    Oxidizing agents such as perbenzoic acids do not provide effective and regioselective oxidation of electron deficient sulfides such as trifluoromethylsulphides which are less readily oxidized than other sulfides. Trifluoroacetic acid and trichloroacetic acid are found to be very efficient and regioselective oxidation medium for oxidation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-pyrazole in presence of hydrogen peroxide. Trichloroacetic acid can not be used alone due to higher melting point. Trifluoroacetic acid on the other hand is very regioselective with respect to conversion and low by-products formation. However, it is expensive, water miscible, corrosive to metal as well as glass, comparatively lower boiling and it’s recovery (in anhydrous form) is complex in nature.
  • [0009]
    WO00/35851/2000 talks about synthesis of 2,6-Dichloro-4-trifluoromethylaniline starting from 3,4,5-trichloro-benzotrifluoride in the presence of alkaline fluorides like lithium fluoride and ammonia in the presence of N-methylpyrrolidone at 250° C. to give 97% conversion and 87% selectivity. The main drawback of the above process is the synthesis of 3,4,5-trichlorobenzotrifluoride in high yield and purity. Chlorination of p-chlorobenzotrifluoride gives a mixture of 3,4,5-trichlorobenzotrifluoride in 72% GLC conversions, 3,4-dichloro and tetrachlorobenzotrifluoride. The process to get pure 3,4,5-isomer from this mixture by fractionation followed by crystallization is very tedious. Moreover in-spite of using very pure intermediates, substantial amount of an undesired isomer (3-amino-4,5-dichlorobenzotrifluoride) is also obtained.
  • [0010]
    Another approach to generate 3,4,5-trichlorobenzotrifluoride with high yield and purity is to perform denitrochlorination of 4-chloro-3,5-dinitrobenzotrifluoride in the presence of a catalyst as described in GB Patent 2154581A. Even though the process produces 3,4,5-trichlorobenzotrifluoide in high yield and purity, the reaction conditions are too drastic to be employed for an industrial process.
  • [0011]
    The known commercial processes for the manufacture of Fipronil uses corrosive and expensive chemical such as trifluoroaceticacid, hydrogen peroxide and m-chloroperbenzoicacid Trifluoroacetic acid is expensive and generally not used in large quantities, as well as of m-chloroperbenzoic acid is difficult to handle at commercial scale due to its un-stability and detonating effect. Also the raw material used such as 2,6-Dichloro-4-trifluoromethylaniline are not easily available or made. The overall process for the Fipronil as disclosed above is found to be unsatisfactory in one respect or the other.
  • [0012]
    Thus, there is felt a need for preparing Fipronil from easily available raw materials in a simple and economical manner at an industrial level, with high yields and purity.

Figure US20130030190A1-20130131-C00009

    • Example 18

    • [0081]
      A mixture of 700 g of dichloroacetic acid and trichloroacetic acid was taken along with 300 g of chlorobenzene, 2 g of boric acid and 280 g of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thiopyrazole, the content were cooled to 15-20° C. Aqueous H20(44.2 g, 50%) was added and mass was stirred for 20 hrs. The mass was then processed and Fipronil was isolated by filtration. After work up as above, 269 g of Fipronil of purity 94% was obtained. The filtered Fipronil was then purified using chlorobenzene (5 ml/g) followed by mixture (1 ml/g, 80:20 v/v) of ethylacetate and chlorobenzene to get 232 g of Fipronil of greater than 97% purity.

Example 19 Purification of Fipronil

  • [0082]
    The fipronil prepared in example 18 of purity 97% was treated with a mixture (232 ml) of ethylacetate & chlorobenzene (80:20 v/v). This reaction mixture was heated to 85-90° C. & maintained for 1 hr. It was further cooled up to 30° C. in stages & filtered. Fipronil thus obtained had a purity of 98%. This cycle was repeated to obtain fipronil of above 98% purity.
  • [0083]
    The useful constituents from various streams of crystallization, leaching as above were reused and recycled, fipronil was isolated in 80-85% yield with purity of above 98%.

PATENT

CN 101250158 [2008 to Hunan Res Inst of of chemical Ind.]

WO2005/44806 A1, ; Page/Page column 7-8; 12 ;

WO2009/77853 A1, ; Page/Page column 28-29 ;

US 5,618,945 [1995, to Rhone-Poulenc]

CN 102060774

IN 178903 [1997, to Rallis India Ltd.]

WO 2009/077,853 [2009 to Vetoquinol SA ]

BG 109983 [2008 to BASF Agro B V]

US 8,507,693 [2013, to Gharda]

US 5,618,945 [1995, to Rhone-Poulenc]

WO 2007/122,440 [ 2007 to Gharda Chemicals Ltd.]

FR 2,925,493 [2009 to to Vetoquinol SA ]

CN 1176078 [ 2002 to Jiangsu Prov Inst of Pesticide]

EP 0,374,061 [ 1990 to Rhone Poulenc Agrochimie]

US 5,232,940 [1993, to May and Baker]

PAPER

Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), , # 24 p. 3371 – 3376

Synthesis 2008, 11, 1682-1684

Synthesis 2007, 22, 3507-3511

Tetrahedron Letters, , 2007, 48(48), 8518-8520

Tetrahedron Letters 2008 ,49. 3463-3465

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  23. Jump up^ Aufavure J., Biron D. G., Vidau C., Fontbonne R., Roudel M., Diogon M., Viguès B., Belzunces L. P., Delbac F., Blot N. (2012) Parasite – insecticide interactions: a case study of Nosema ceranae and fipronil synergy on honeybee. Scientific Reports 2:326 – DOI: 10.1038/srep00326
  24. Jump up^ Kairo G, Biron D.G, Ben A.F, Bonnet M, Tchamitchian S, Cousin M, … & Brunet J.L (2017) Nosema ceranae, Fipronil and their combination compromise honey bee reproduction via changes in male physiology]. Scientific reports, 7(1), 8556.
  25. Jump up^ “EFSA assesses risks to bees from fipronil”. 27 May 2013. Retrieved 29 May 2013.
  26. Jump up^ Carrington, Damian (16 July 2013). “EU to ban fipronil to protect honeybees”The Guardian. London.
  27. Jump up^ Cole, L. M.; Nicholson, R. A.; Casida, J. E. (1993). “Action of Phenylpyrazole Insecticides at the GABA-Gated Chloride Channel”Pestic. Biochem. Physiol46: 47–54. doi:10.1006/pest.1993.1035.
  28. Jump up^ Ratra, G. S.; Casida, J. E. (2001). “GABA receptor subunit composition relative to insecticide potency and selectivity”. Toxicol. Lett122: 215–222. doi:10.1016/s0378-4274(01)00366-6PMID 11489356.
  29. Jump up^ WHO. Pesticide Residues in Food – 1997: Fipronil; International Programme on Chemical Safety, World Health Organization: Lyon, 1997.
  30. Jump up^ Olsen RW, DeLorey TM (1999). “Chapter 16: GABA and Glycine”. In Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD. Basic neurochemistry: molecular, cellular, and medical aspects (Sixth ed.). Philadelphia: Lippincott-Raven. ISBN 0-397-51820-X.
  31. Jump up^ Ramesh C. Gupta (2007). Veterinary Toxicology. pp. 502–503. ISBN 978-0-12-370467-2.
  32. Jump up^ Mohamed F, Senarathna L, Percy A, Abeyewardene M, Eaglesham G, Cheng R, Azher S, Hittarage A, Dissanayake W, Sheriff MH, Davies W, Buckley NA, Eddleston M., Acute human self-poisoning with the N-phenylpyrazole insecticide fipronil–a GABAA-gated chloride channel blocker, J Toxicol Clin Toxicol. 2004;42(7):955-63.
  33. Jump up^ “Eggs containing fipronil found in 15 EU countries and Hong Kong”BBC News. 2017-08-11. Retrieved 2017-08-11.
  34. Jump up^ News, ABC. “EU: 17 nations get tainted eggs, products in growing scandal”ABC News. Archived from the original on 2017-08-11. Retrieved 2017-08-11.
  35. Jump up^ Boffey, Daniel (11 August 2017). “Egg contamination scandal widens as 15 EU states, Switzerland and Hong Kong affected”. The Guardian. Retrieved 11 August 2017.
  36. Jump up^ “Eggs at 44 farms in Taiwan found with excessive insecticide levels”. Taiwan News. 26 August 2017. Retrieved 26 August 2017.

External links

Fipronil
2D chemical structure of fipronil
3D chemical structure of fipronil
Names
IUPAC name

(RS)-5-Amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)pyrazole-3-carbonitrile
Other names

Fipronil
Fluocyanobenpyrazole
Termidor
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.102.312
KEGG
PubChem CID
UNII
Properties
C12H4Cl2F6N4OS
Molar mass 437.14 g·mol−1
Density 1.477-1.626 g/cm3
Melting point 200.5 °C (392.9 °F; 473.6 K)
Pharmacology
QP53AX15 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

/////////////Fipronil, INDIA 2018, フィプロニル , HSDB 7051, RM 1601, veterinary, ind 2018

C1=C(C=C(C(=C1Cl)N2C(=C(C(=N2)C#N)S(=O)C(F)(F)F)N)Cl)C(F)(F)F

“ DRUG APPROVALS INTERNATIONAL” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

FDA approves new kind of treatment Lumoxiti (moxetumomab pasudotox-tdfk) for hairy cell leukemia


The U.S. Food and Drug Administration today approved Lumoxiti (moxetumomab pasudotox-tdfk) injection for intravenous use for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL.

September 13, 2018

Release

The U.S. Food and Drug Administration today approved Lumoxiti (moxetumomab pasudotox-tdfk) injection for intravenous use for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL.

“Lumoxiti fills an unmet need for patients with hairy cell leukemia whose disease has progressed after trying other FDA-approved therapies,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This therapy is the result of important research conducted by the National Cancer Institute that led to the development and clinical trials of this new type of treatment for patients with this rare blood cancer.”

HCL is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cell that fights infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope. As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.

The efficacy of Lumoxiti was studied in a single-arm, open-label clinical trial of 80 patients who had received prior treatment for HCL with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of patients in the trial achieved durable CR, and the overall response rate (number of patients with partial or complete response to therapy) was 75 percent.

Common side effects of Lumoxiti include infusion-related reactions, swelling caused by excess fluid in body tissue (edema), nausea, fatigue, headache, fever (pyrexia), constipation, anemia and diarrhea.

The prescribing information for Lumoxiti includes a Boxed Warning to advise health care professionals and patients about the risk of developing capillary leak syndrome, a condition in which fluid and proteins leak out of tiny blood vessels into surrounding tissues. Symptoms of capillary leak syndrome include difficulty breathing, weight gain, hypotension, or swelling of arms, legs and/or face. The Boxed Warning also notes the risk of hemolytic uremic syndrome, a condition caused by the abnormal destruction of red blood cells. Patients should be made aware of the importance of maintaining adequate fluid intake, and blood chemistry values should be monitored frequently. Other serious warnings include: decreased renal function, infusion-related reactions and electrolyte abnormalities. Women who are breastfeeding should not be given Lumoxiti.

The FDA granted this application Fast Track and Priority Review designations. Lumoxiti also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Lumoxiti to AstraZeneca Pharmaceuticals.

///////////// Lumoxiti, moxetumomab pasudotox-tdfk, fda 2018, Fast Track, Priority Review designations,  Orphan Drug designation,

Lanadelumab, ラナデルマブ


(Heavy chain)
EVQLLESGGG LVQPGGSLRL SCAASGFTFS HYIMMWVRQA PGKGLEWVSG IYSSGGITVY
ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAYRR IGVPRRDEFD IWGQGTMVTV
SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ
SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKRV EPKSCDKTHT CPPCPAPELL
GGPSVFLFPP KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ
YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR
EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSKLTVDKS
RWQQGNVFSC SVMHEALHNH YTQKSLSLSP G
(Light chain)
DIQMTQSPST LSASVGDRVT ITCRASQSIS SWLAWYQQKP GKAPKLLIYK ASTLESGVPS
RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNTYWTFGQG TKVEIKRTVA APSVFIFPPS
DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS TYSLSSTLTL
SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC
(dimer; dishulfide bridge: H22-H96, H149-H205, H225-L213, H231-H’231, H234-H’234, H266-H326, H372-H430, H’22-H’96, H’149-H’205, H’225-L’213, H’266-H’326, H’372-H’430, L23-L88, L133-L193, L’23-L’88, L’133-L’193)

Lanadelumab

DX 2930

Fda approved 2018/8/23, Takhzyro

Formula
C6468H10016N1728O2012S48
Cas
1426055-14-2
Mol weight
145714.225

Peptide, Monoclonal antibody
Prevention of angioedema in patients with hereditary angioedema

Immunomodulator, Plasma kallikrein inhibitor

breakthrough therapyUNII: 2372V1TKXK

Image result for Lanadelumab

Image result for Lanadelumab

Lanadelumab (INN) (alternative identifier DX-2930[1]) is a human monoclonal antibody (class IgG1 kappa)[2] that targets plasma kallikrein (pKal)[1] in order to promote prevention of angioedema in patients with hereditary angioedema.[3][4] In phase 1 clinical trialsLanadelumab was well tolerated and was reported to reduce cleavage of kininogen in the plasma of patients with hereditary angioedeman and decrease the number of patients experiencing attacks of angioedema.[1][5][6][7] As of 2017 ongoing trials for Lanadelumab include two phase 3 studies focused on investigating the utility of Lanadelumab in preventing of acute angioedema attacks in hereditary angioedema patients[8][9]

Image result for Lanadelumab

This drug was produced by Dyax Corp and currently under development by Shire.[10] Lanadelumab has been designated by the U.S. Food and Drug Administration (FDA) as a breakthrough therapy.[11]

Image result for Lanadelumab

References

  1. Jump up to:a b c Banerji, Aleena; Busse, Paula; Shennak, Mustafa; Lumry, William; Davis-Lorton, Mark; Wedner, Henry J.; Jacobs, Joshua; Baker, James; Bernstein, Jonathan A. (2017-02-23). “Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis”. The New England Journal of Medicine376 (8): 717–728. doi:10.1056/NEJMoa1605767ISSN 1533-4406PMID 28225674.
  2. Jump up^ Kenniston, Jon A.; Faucette, Ryan R.; Martik, Diana; Comeau, Stephen R.; Lindberg, Allison P.; Kopacz, Kris J.; Conley, Gregory P.; Chen, Jie; Viswanathan, Malini (2014-08-22). “Inhibition of Plasma Kallikrein by a Highly Specific Active Site Blocking Antibody”The Journal of Biological Chemistry289 (34): 23596. doi:10.1074/jbc.M114.569061PMC 4156074Freely accessiblePMID 24970892.
  3. Jump up^ Statement On A Nonproprietary Name Adopted By The USAN Council – LanadelumabAmerican Medical Association.
  4. Jump up^ World Health Organization (2015). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 114”(PDF). WHO Drug Information29 (4).
  5. Jump up^ Chyung, Yung; Vince, Bradley; Iarrobino, Ryan; Sexton, Dan; Kenniston, Jon; Faucette, Ryan; TenHoor, Chris; Stolz, Leslie E.; Stevens, Chris (2014-10-01). “A phase 1 study investigating DX-2930 in healthy subjects”. Annals of Allergy, Asthma & Immunology113 (4): 460–466.e2. doi:10.1016/j.anai.2014.05.028ISSN 1534-4436PMID 24980392.
  6. Jump up^ “A Single Increasing Dose Study to Assess Safety and Tolerability of DX-2930 in Healthy Subjects – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 2017-03-24.
  7. Jump up^ “Double-Blind, Multiple Ascending Dose Study to Assess Safety, Tolerability and Pharmacokinetics of DX-2930 in Hereditary Angioedema (HAE) Subjects – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 2017-03-24.
  8. Jump up^ “Efficacy and Safety Study of DX-2930 to Prevent Acute Angioedema Attacks in Patients With Type I and Type II HAE – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 2017-03-24.
  9. Jump up^ “Long-term Safety and Efficacy Study of DX-2930 to Prevent Acute Angioedema Attacks in Patients With Type I and Type II HAE – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 2017-03-24.
  10. Jump up^ “Lanadelumab – AdisInsight”adisinsight.springer.com. Retrieved 2017-03-24.
  11. Jump up^ “Dyax Corp. Receives FDA Breakthrough Therapy Designation for DX-2930 for Prevention of Attacks of Hereditary Angioedema”http://www.businesswire.com. Retrieved 2017-03-24.
Lanadelumab
Monoclonal antibody
Type Whole antibody
Source Human
Target kallikrein
Clinical data
Synonyms DX-2930
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
UNII
Chemical and physical data
Formula C6468H10016N1728O2012S47
Molar mass 145.7 kDa

///////////Lanadelumab, Peptide, Monoclonal antibody, FDA 2018, ラナデルマブ ,Immunomodulator, Plasma kallikrein inhibitor, DX 2930,  breakthrough therapy, Takhzyro

“DRUG APPROVALS INTERNATIONAL” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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


242800-27-7.png

ZS-9 structure.png

Image result for Sodium zirconium cyclosilicate

str1

Sodium zirconium cyclosilicate

ZS-9, ZS 9, UZSi-9

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

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

ナトリウムジルコニウムシクロケイ酸塩

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

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

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

APPROVED EMA 2018/3/22, LOKELMA

ATC code: V03AE10

UNII-D652ZWF066

TREATMENT
selective cation exchanger
Treatment of hyperkalemia

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

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

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

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

EMA

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

str1

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

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

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

TGA

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

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

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

str1

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

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

Sodium zirconium cyclosilicate hydrate is completely insoluble.

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

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

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

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

[1] 1 Å = 0.1 nm.

Image result for Sodium zirconium cyclosilicate

Background

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

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

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

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

Mechanism of action

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

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

Clinical studies

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

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

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

Regulatory

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

PATENT

WO 2012109590

PATENT

WO 2015070019

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

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

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

Patent

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US3329480A *1963-10-181967-07-04Union Oil CoCrystalline zircono-silicate zeolites
US4581141A *1978-02-271986-04-08Purdue Research FoundationDialysis material and method for removing uremic substances
US20050220752A1 *2004-03-302005-10-06Dominique CharmotIon binding polymers and uses thereof
US20110097401A1 *2009-06-122011-04-28Meritage Pharma, Inc.Methods for treating gastrointestinal disorders
US20120213847A1 *2011-02-112012-08-23ZS Pharma, Inc.Microporous zirconium silicate for the treatment of hyperkalemia
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References

  1. Jump up^ “ZS-9. A selective potassium binder”. ZS-Pharma.
  2. Jump up to:a b c d e Elliott, M. J.; Ronksley, P. E.; Clase, C. M.; Ahmed, S. B.; Hemmelgarn, B. R. (2010). “Management of patients with acute hyperkalemia”Canadian Medical Association Journal182 (15): 1631–5. doi:10.1503/cmaj.100461PMC 2952010Freely accessiblePMID 20855477.
  3. Jump up^ Stevens, M. S.; Dunlay, R. W. (2000). “Hyperkalemia in hospitalized patients”. International Urology and Nephrology32 (2): 177–80. doi:10.1023/A:1007135517950PMID 11229629.
  4. Jump up^ Navaneethan, S. D.; Yehnert, H.; Moustarah, F.; Schreiber, M. J.; Schauer, P. R.; Beddhu, S. (2009). “Weight Loss Interventions in Chronic Kidney Disease: A Systematic Review and Meta-analysis”Clinical Journal of the American Society of Nephrology4 (10): 1565–74. doi:10.2215/CJN.02250409PMC 2758256Freely accessiblePMID 19808241.
  5. Jump up^ Tamirisa, K. P.; Aaronson, K. D.; Koelling, T. M. (2004). “Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure”. American Heart Journal148(6): 971–8. doi:10.1016/j.ahj.2004.10.005PMID 15632880.
  6. Jump up to:a b c d e f Taal, M.W.; Chertow, G.M.; Marsden, P.A.; Skorecki, K.; Yu, A.S.L.; Brenner, B.M. (2012). Brenner and Rector’s The Kidney (Chapter 17, page 672, 9th ed.). Elsevier. ISBN 978-1-4160-6193-9.
  7. Jump up^ Fang, J.; Madhavan, S.; Cohen, H.; Alderman, M. H. (2000). “Serum potassium and cardiovascular mortality”Journal of General Internal Medicine15 (12): 885–90. doi:10.1046/j.1525-1497.2000.91021.xPMC 1495719Freely accessiblePMID 11119186.
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  9. Jump up^ Emmett, M.; Hootkins, R. E.; Fine, K. D.; Santa Ana, C. A.; Porter, J. L.; Fordtran, J. S. (1995). “Effect of three laxatives and a cation exchange resin on fecal sodium and potassium excretion”. Gastroenterology108 (3): 752–60. doi:10.1016/0016-5085(95)90448-4PMID 7875477.
  10. Jump up^ Sterns, R. H.; Rojas, M.; Bernstein, P.; Chennupati, S. (2010). “Ion-Exchange Resins for the Treatment of Hyperkalemia: Are They Safe and Effective?”. Journal of the American Society of Nephrology21 (5): 733–5. doi:10.1681/ASN.2010010079PMID 20167700.
  11. Jump up^ Kamel, K. S.; Schreiber, M. (2012). “Asking the question again: Are cation exchange resins effective for the treatment of hyperkalemia?”. Nephrology Dialysis Transplantation27(12): 4294–7. doi:10.1093/ndt/gfs293PMID 22989741.
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  13. Jump up^ =Stavros, F (2014). “Characterization of Structure and Function of ZS-9, a K⁺ Selective Ion Trap”PLOS ONE9 (12): e114686. doi:10.1371/journal.pone.0114686PMC 4273971Freely accessiblePMID 25531770.
  14. Jump up^ Ash SR, et al. “Safety and efficacy of ZS-9, a novel selective cation trap, for treatment of hyperkalemia in CKD patients.” American Society of Nephrology 2013 conference, Late-Breaking Abstract.
  15. Jump up to:a b Packham DK, et al. (2014). “Sodium zirconium cyclosilicate in hyperkalemia”. New England Journal of Medicine372 (3): 222–31. doi:10.1056/NEJMoa1411487PMID 25415807.
  16. Jump up to:a b Kosiborod M, et al. (2014). “Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia”. Journal of the American Medical Association312 (21): 2223–33. doi:10.1001/jama.2014.15688PMID 25402495.
  17. Jump up^ Ben Adams (May 27, 2016). “AstraZeneca’s $2.7B hyperkalemia drug ZS-9 rejected by FDA”. FierceBiotech.
  18. Jump up^ https://www.drugs.com/history/lokelma.html
Sodium zirconium cyclosilicate
ZS-9 structure.png

Crystal structure of ZS-9. Blue spheres  =  oxygen atoms, red spheres  =  zirconium atoms, green spheres  =  silicon atoms.
Clinical data
Trade names Lokelma
Routes of
administration
Oral
ATC code
  • none
Legal status
Legal status
  • US: Rx-only
Pharmacokinetic data
Bioavailability Not absorbed
Excretion Stool
Identifiers
CAS Number
UNII
KEGG

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

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

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