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Orphan Drug Designation Granted for Epidiolex in Dravet syndrome by the FDA

November 20, 2013 3:33 am / 3 Comments on Orphan Drug Designation Granted for Epidiolex in Dravet syndrome by the FDA




Cannabidiol

Seven Expanded Access INDs granted by FDA to U.S. 
physicians to treat with Epidiolex 125 children suffering 
from intractable epilepsy syndromes -

LONDON, Nov. 15, 2013

GW Pharmaceuticals plc (AIM: GWP, Nasdaq: GWPH, “GW”) announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for Epidiolex(R), our product candidate that contains plant-derived Cannabidiol (CBD) as its active ingredient, for use in treating children with Dravet syndrome, a rare and severe form of infantile-onset, genetic, drug-resistant epilepsy syndrome. Epidiolex is an oral liquid formulation of a highly purified extract of CBD, a non-psychoactive molecule from the cannabis plant. Following receipt of this orphan designation, GW anticipates holding a pre-IND meeting with the FDA in the near future to discuss a development plan for Epidiolex in Dravet syndrome.

Dravet syndrome is a rare pediatric epilepsy syndrome with a distinctive but complex electroclinical presentation. Onset of Dravet syndrome occurs during the first year of life with clonic and tonic-clonic seizures in previously healthy and developmentally normal infants. Prognosis is poor and patients typically develop intellectual disability and life-long ongoing seizures. There are approximately 5,440 patients with Dravet in the United States and an estimated 6,710 Dravet patients in Europe. These figures may be an underestimate as this syndrome is reportedly underdiagnosed.

In addition to GW’s clinical development program for Epidiolex in Dravet syndrome, which is expected to commence in 2014, GW has also made arrangements to enable independent U.S. pediatric epilepsy specialists to treat high need pediatric epilepsy cases with Epidiolex immediately. To date in 2013, a total of seven “expanded access” INDs have been granted by the FDA to U.S. clinicians to allow treatment with Epidiolex of approximately 125 children with epilepsy. These children suffer from Dravet syndrome, Lennox-Gastaut syndrome, and other pediatric epilepsy syndromes. GW is aware of further interest from additional U.S. and ex-U.S. physicians to host similar INDs for Epidiolex. GW expects data generated under these INDs to provide useful observational data during 2014 on the effect of Epidiolex in the treatment of a range of pediatric epilepsy syndromes.

“I, together with many colleagues in the U.S. who specialize in the treatment of childhood epilepsy, very much welcome the opportunity to investigate Epidiolex in the treatment of Dravet syndrome. The FDA’s timely approval of the orphan drug designation for Epidiolex in Dravet syndrome is a key milestone that comes after many years of reported clinical cases that suggest encouraging evidence of efficacy for CBD in this intractable condition,” stated Dr. Orrin Devinsky, Professor of Neurology, Neurosurgery and Psychiatry in New York City. “With GW now making plans to advance Epidiolex through an FDA development program, we have the prospect for the first time of fully understanding the science of CBD in epilepsy with a view to making an appropriately tested and approved prescription medicine available in the future for children who suffer from this debilitating disease.”

“GW is proud to be at the forefront of this important new program to treat children with Dravet Syndrome and potentially other forms of intractable childhood epilepsy. For families in these circumstances, their lives are significantly impacted by constant and often times very severe seizures in children where all options to control these seizures have been exhausted,” stated Dr. Stephen Wright, GW’s R&D Director. “GW intends to advance a full clinical development program for Epidiolex in Dravet syndrome as quickly as possible, whilst at the same time helping families in the short term through supporting physician-led INDs to treat intractable cases. Through its efforts, GW aims to provide the necessary evidence to confirm the promise of CBD in epilepsy and ultimately enabling children to have access to an FDA-approved prescription CBD medicine.”

“This orphan program for Epidiolex in childhood epilepsy is an important corporate strategic priority for GW. Following receipt of today’s orphan designation, GW now intends to commence discussions with the FDA regarding the U.S. regulatory pathway for Epidiolex,” stated Justin Gover, GW’s Chief Executive Officer. “GW intends to pursue this development in-house and retains full commercial rights to Epidiolex.”

About Orphan Drug Designation

Under the Orphan Drug Act, the FDA may grant orphan drug designation to drugs intended to treat a rare disease or condition — generally a disease or condition that affects fewer than 200,000 individuals in the U.S. The first NDA applicant to receive FDA approval for a particular active ingredient to treat a particular disease with FDA orphan drug designation is entitled to a seven-year exclusive marketing period in the U.S. for that product, for that indication.

About GW Pharmaceuticals plc

Founded in 1998, GW is a biopharmaceutical company focused on discovering, developing and commercializing novel therapeutics from its proprietary cannabinoid product platform in a broad range of disease areas. GW commercialized the world’s first plant-derived cannabinoid prescription drug, Sativex(R), which is approved for the treatment of spasticity due to multiple sclerosis in 22 countries. Sativex is also in Phase 3 clinical development as a potential treatment of pain in people with advanced cancer. This Phase 3 program is intended to support the submission of a New Drug Application for Sativex in cancer pain with the U.S. Food and Drug Administration and in other markets around the world. GW has established a world leading position in the development of plant-derived cannabinoid therapeutics and has a deep pipeline of additional clinical-stage cannabinoid product candidates targeting epilepsy (including an orphan pediatric epilepsy program), Type 2 diabetes, ulcerative colitis, glioma and schizophrenia. For further information, please visit http://www.gwpharm.com.

Cannabidiol (CBD) is one of at least 85 cannabinoids found in cannabis.It is a major constituent of the plant, second to tetrahydrocannabinol (THC), and represents up to 40% in its extracts. Compared with THC, cannabidiol is not psychoactive in healthy individuals, and is considered to have a wider scope of medical applications than THC, including to epilepsy, multiple sclerosis spasms, anxiety disorders, bipolar disorder,schizophrenia,nausea, convulsion and inflammation, as well as inhibiting cancer cell growth. There is some preclinical evidence from studies in animals that suggests CBD may modestly reduce the clearance of THC from the body by interfering with its metabolism.Cannabidiol has displayed sedative effects in animal tests. Other research indicates that CBD increases alertness. CBD has been shown to reduce growth of aggressive human breast cancer cells in vitro, and to reduce their invasiveness.

FDA panel backs Vanda body clock drug Tasimelteon for blind

November 18, 2013 1:15 am / 1 Comment on FDA panel backs Vanda body clock drug Tasimelteon for blind

Tasimelteon

N-([(1R,2R)-2-(2,3-Dihydro-1-benzofuran-4-yl)cyclopropyl]methyl)propanamide, 609799-22-6 cas

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

Tasimelteon (BMS-214,778) is a drug which is under development for the treatment of insomnia and other sleep disorders.^[1] It is a selective agonistfor the melatonin receptors MT₁ and MT₂ in the suprachiasmatic nucleus of the brain, similar to older drugs such as ramelteon.^[2] It has been through Phase III trials successfully and was shown to improve both onset and maintenance of sleep, with few side effects.^[3]

A year-long (2011-2012) study at Harvard is testing the use of tasimelteon in blind subjects with non-24-hour sleep–wake disorder.^[4] In May 2013Vanda 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.^[5]

A drug being developed to treat transient insomnia in circadian rhythm sleep disorders (eg jet-lag. The drug appears to be effective in the dose range of 20 to 100mg with an advance in the melatonin rhythm of 2-3 hours with the higher dose

‘Time-bending drug’ for jet lag. BBC News. 2 December 2008
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 Sciences 92 (4): 760–72. doi:10.1002/jps.10348. PMID 12661062.
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)61812-7. PMID 19054552. Retrieved 2010-02-23.
Audio interview with Joseph Hull of Harvard, spring 2011
Vanda Pharmaceuticals seeks FDA approval

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.

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:

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

Formula V

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.

SAR

Figure : Melatonin receptor agonists. The applied colors indicate the mutual properties with the general melatonin receptor agonists pharmacophore.

WASHINGTON, June 5, 2013 /PRNewswire/ — Vanda Pharmaceuticals Inc. (Vanda) presented additional entrainment and patient-level clinical data at SLEEP 2013, the 27th Annual Meeting of Associated Professional Sleep Societies in Baltimore, from its SET (Safety and Efficacy of Tasimelteon) and RESET (Randomized-withdrawal study of the Efficacy and Safety of Tasimelteon to treat Non-24-Hour Disorder) Phase III studies of tasimelteon, a circadian regulator for the treatment of Non-24-Hour Disorder (Non-24) in totally blind individuals. Non-24 is a serious, rare and chronic circadian rhythm disorder that affects a majority of totally blind individuals who lack light perception and cannot entrain (synchronize) their master body clock to the 24-hour day. Currently there is no approved FDA treatment for Non-24.

In the SET study, tasimelteon achieved the primary endpoints of entrainment (synchronizing) of the melatonin (aMT6s) rhythm as compared to placebo and clinical response as measured by entrainment plus a score of greater than or equal to 3 on the Non-24 Clinical Response Scale (N24CRS). Tasimelteon also demonstrated significant improvement versus placebo across a number of sleep and wake parameters including measures of total sleep time, nap duration, and timing of sleep, as well as in the Clinical Global Impression of Change (CGI-C), an overall global functioning scale. In treated patients, daytime naps decreased by 46 minutes per day in the worst 25% of days in a cycle and nighttime sleep increased by 57 minutes per day during the worst 25% of nights in a cycle.

The RESET study demonstrated that continued treatment with 20mg of tasimelteon was required to maintain entrainment of melatonin and cortisol circadian rhythms in individuals with Non-24. Patients treated with tasimelteon maintained their clinical benefits while patients who received placebo showed significant deterioration in measures of nighttime sleep, daytime naps and timing of sleep. Furthermore, discontinuation of tasimelteon resulted in a rapid relapse of circadian entrainment and a return to misaligned circadian rhythms, reinforcing the importance of chronic therapy.

Study investigator, Steven W. Lockley, Ph.D., Associate Professor of Medicine, Division of Sleep Medicine, Brigham and Women’s Hospital, Harvard Medical School, commented, “the results clearly demonstrate that tasimelteon can entrain the circadian clock, and that continued treatment is necessary to maintain entrainment.”

About Tasimelteon: Tasimelteon is a circadian regulator in development for the treatment of Non-24. Tasimelteon is a dual melatonin receptor agonist (DMRA) with selective agonist activityat the MT1 and MT2 receptors.Tasimelteon’s ability to reset the master body clock in the suprachiasmatic nucleus (SCN) results in the entrainment of the body’s melatonin and cortisol rhythms with the 24-hour day-night cycle. The patent claiming tasimelteon as a new chemical entity extends through December 2022, assuming a 5-year extension to be granted under the Hatch-Waxman Act. Tasimelteon has been granted orphan drug designation for the treatment of Non-24 from both the U.S. and the European Union.

UPDATED ON JAN 2014

TASIMELTION, an orphan drug for non24

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

(1R-trans)-N-[[2-(2,3-dihydro-4-benzofuranyl)cyclopropyl]methyl]pro- pananamide VEC162

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

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

Bristol-Myers Squibb Company

PRODUCT PATENT

U.S. Pat. No. 5,856,529

CAS number	609799-22-6

Formula	C₁₅H₁₉N O₂
Mol. mass	245.3 g/mol

January 31, 2014 — The U.S. Food and Drug Administration today approved Hetlioz (tasimelteon), a melatonin receptor agonist, to treat non-24- hour sleep-wake disorder (“non-24”) in totally blind individuals. Non-24 is a chronic circadian rhythm (body clock) disorder in the blind that causes problems with the timing of sleep. This is the first FDA approval of a treatment for the disorder.

Non-24 occurs in persons who are completely blind. Light does not enter their eyes and they cannot synchronize their body clock to the 24-hour light-dark cycle.

http://www.drugs.com/newdrugs/fda-approves-hetlioz-first-non-24-hour-sleep-wake-disorder-blind-individuals-4005.html

VEC-162, BMS-214778, 609799-22-6, Hetlioz, Tasimelteon (USAN/INN), Tasimelteon [USAN:INN], UNII-SHS4PU80D9,

Tasimelteon

TASIMELTION , BMS-214,778) is a drug which is under development for the treatment of insomnia and other sleep disorders.^[1] It is a selective agonistfor the melatonin receptors MT₁ and MT₂ in the suprachiasmatic nucleus of the brain, similar to older drugs such as ramelteon.^[2] It has been through Phase III trials successfully and was shown to improve both onset and maintenance of sleep, with few side effects.^[3]

SEQUENCE

Discovered by Bristol-Myers Squibb (BMS) and co-developed with Vanda Pharmaceuticals, tasimelteon is a hypnotic family benzofuran. In Phase III development, it has an orphan drug status.

JAN2014.. APPROVED FDA

In mid-November 2013 the FDA announced their recommendation for the approval of Tasimelteon for the treatment of non-24-disorder.Tasimelteon effectively resets the circadian rhythm, helping to restore normal sleep patterns.http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM374388.pdf

January 2010: FDA granted orphan drug tasimelteon to disturbed sleep / wake in blind without light perception.

February 2008: Vanda has completed enrollment in its Phase III trial in chronic primary insomnia.

June 2007: Results of a Phase III trial for transient insomnia tasimelteon presented by Vanda at the 21st annual meeting of the Associated Professional Sleep Societies. These results demonstrated improvements in objective and subjective measures of sleep and its maintenance.

2004 Vanda gets a license tasimelteon (or BMS-214778 and VEC-162) from Bristol-Myers Squibb.

Previously, BMS-214778, identified as an agonist of melatonin receptors, has been the subject of pre-clinical studies for the treatment of sleep disorders resulting from a disturbance of circadian rhythms.The first Pharmacokinetic studies were performed in rats and monkeys.

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. Tasimelteon TASIMELTION

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 24 h 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 24 h 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.

INTRODUCTION

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

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 (K_i) 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

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

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

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

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

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

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

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.

Discovery and development of melatonin receptor agonists

References

‘Time-bending drug’ for jet lag. BBC News. 2 December 2008
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 Sciences 92 (4): 760–72. doi:10.1002/jps.10348. PMID 12661062.
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 Lancet 373 (9662): 482–491. doi:10.1016/S0140-6736(08)61812-7. PMID 19054552. Retrieved 2010-02-23.
Audio interview with Joseph Hull of Harvard, spring 2011
Vanda Pharmaceuticals seeks FDA approval
Recent progress in the development of agonists and antagonists for melatonin receptors.Zlotos DP.

Curr Med Chem. 2012;19(21):3532-49. Review.

7 Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist.

Vachharajani NN, Yeleswaram K, Boulton DW.J Pharm Sci. 2003 Apr;92(4):760-72.

TASIMELTION

PATENTS

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extra info

Org. Synth. 1990, 69, 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[5.2.1.0^3,7]dec-3-ene 5,5-dioxide] was prepared by the procedure of Towson, Weismiller, Lal, Sheppard, and Davis, Org. Synth., Coll. Vol. VIII, 1993, 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° (CHCl₃, c 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

Department of Chemistry, Drexel University, Philadelphia, PA 19104.
Shriner, R. L.; Shotton, J. A.; Sutherland, H. J. Am. Chem. Soc. 1938, 60, 2794.
Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Helv. Chim. Acta 1984, 67, 1397.
Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.; Vullioud, C. Tetrahedron 1986, 42, 4035.
Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, G.; Carroll,, P. J. J. Am. Chem. Soc. 1988, 110, 8477.
Oppolzer, W. Tetrahedron 1987, 43, 1969.
Oppolzer, W.; Mills, R. J.; Pachinger, W.; Stevenson, T. Helv. Chim. Acta 1986, 69, 1542; Oppolzer, W.; Schneider, P. Helv. Chim. Acta 1986, 69, 1817; Oppolzer, W.; Mills, R. J.; Réglier, M. Tetrahedron Lett. 1986, 27, 183; Oppolzer, W.; Poli. G.Tetrahedron Lett. 1986, 27, 4717; Oppolzer, W.; Poli, G.; Starkemann, C.; Bernardinelli, G. Tetrahedron Lett. 1988, 29, 3559.
Oppolzer, W.; Barras, J-P. Helv. Chim. Acta 1987, 70, 1666.
Curran, D. P.; Kim, B. H.; Daugherty, J.; Heffner, T. A. Tetrahedron Lett. 1988, 29, 3555.
Differding, E.; Lang, R. W. Tetrahedron Lett. 1988, 29, 6087.

Org. Synth. 1990, 69, 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-SO₂, J = 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-SO₂, J = 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 R_f = 0.28 and (camphorylsulfonyl)oxaziridine R_f = 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-SO₂, J = 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.¹² ¹³ ¹⁴ 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. III 1889, 19, 120.
3. Armstrong, H. E.; Lowry, T. M. J. Chem. Soc., Trans. 1902, 81, 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. 1982, 104, 5412.
6. Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.; Vullioud, C. Tetrahedron, 1986, 42, 4035.
7. Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, S.; Carroll, P. J. J. Am. Chem. Soc. 1988, 110, 8477.
8. Davis, F. A.; Weismiller, M. C.; Lal, G. S.; Chen, B. C.; Przeslawski, R. M. Tetrahedron Lett., 1989, 30, 1613.
9. Oppolzer, W. Tetrahedron 1987, 43, 1969.
10. Glahsl, G.; Herrmann, R. J. Chem. Soc., Perkin Trans. I 1988, 1753.
11. Differding, E.; Lang, R. W. Tetrahedron Lett. 1988, 29, 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. Tetrahedron 1989, 45, 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. 1987, 109, 3370.
16. Davis, F. A.; Stringer, O. D.; McCauley, Jr., J. M. Tetrahedron 1985, 41, 4747.
17. Davis, F. A.; Chattopadhyay, S. Tetrahedron Lett. 1986, 27, 5079.
18. Davis, F. A.; Harakal, M. E.; Awad, S. B. J. Am. Chem. Soc. 1983, 105, 3123.
19. Davis, F. A.; Wei, J.; Sheppard, A. C.; Gubernick S. Tetrahedron Lett. 1987, 28, 5115.
20. Davis, F. A.; Lal, G. S.; Wei, J. Tetrahedron Lett. 1988, 29, 4269.
21. Davis, F. A.; Haque, M. S.; Ulatowski, T. G.; Towson, J. C. J. Org. Chem. 1986, 51, 2402.
22. Davis, F. A.; Haque, M. S. J. Org. Chem. 1986, 51, 4083; Davis, F. A.; Haque, M. S.; Przeslawski, R. M. J. Org. Chem. 1989, 54, 2021.
23. Davis, F. A.; Ulatowski, T. G.; Haque, M. S. J. Org. Chem. 1987, 52, 5288.
24. Davis, F. A.; Sheppard, A. C., Lal, G. S. Tetrahedron Lett. 1989, 30, 779.
25. Davis, F. A.; Sheppard, A. C.; Chen, B. C.; Haque, M. S. J. Am. Chem. Soc. 1990, 112, 6679.

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Mast Ischemia Drug Gets Orphan Drug Designation

November 14, 2013 3:46 am / 1 Comment on Mast Ischemia Drug Gets Orphan Drug Designation

Wed, 11/13/2013

Mast Therapeutics Inc. announced that the U.S. Food and Drug Administration (FDA) has designated MST-188 for the treatment of acute limb ischemia as an orphan drug.http://www.dddmag.com/news/2013/11/mast-ischemia-drug-gets-orphan-drug-designation

MST-188 (purified poloxamer 188)

MST-188 is a purified form of a nonionic, triblock copolymer (poloxamer 188). It is an investigational agent that binds to hydrophobic surfaces on damaged cells and improves membrane hydration and lowers adhesion and viscosity, particularly under low shear conditions. MST-188 has the potential to reduce ischemic tissue injury and end-organ damage by restoring microvascular function, which is compromised in a wide range of serious and life-threatening diseases and conditions. We initially are developing MST-188 as a treatment for complications arising from sickle cell disease.

How MST-188 Works…

Background

Non-purified forms of poloxamer 188 (P188) have been used in foods, drugs and cosmetics since the 1950s. In the 1980s, extensive research on the mechanisms and potential clinical applications of P188 was conducted. Research has demonstrated that P188 binds to hydrophobic surfaces that develop when cells are damaged and restores normal hydrated surfaces, while having little or no activity in normal, healthy tissues. Research also has demonstrated that P188 prevents adhesion and aggregation of soluble fibrin and formed elements in the blood and maintains the deformability of red blood cells, the non-adhesiveness of unactivated platelets and granulocytes and the normal viscosity of blood. In addition, it is believed that P188 is not metabolized, but is excreted unchanged in the urine with a half-life of approximately four to six hours.

Formulations of P188 (non-purified and purified) have been studied in clinical trials involving nearly 4,000 individuals. It has been evaluated in the clinic to treat acute myocardial infarction, sickle cell disease and malaria, including a 2,950-patient, randomized, controlled study of P188 (non-purified) in acute myocardial infarction. The effectiveness of P188 also has been investigated in nonclinical studies of stroke, hemorrhagic shock, bypass surgery, adult respiratory distress syndrome, neurologic protection in deep hypothermic circulatory arrest, vasospasm, spinal cord injury, angioplasty, frostbite, amniotic fluid embolism, acute ischemic bowel disease and burns.

MST-188

Our(mast) purified form of P188, or purified P188, which is the active ingredient in MST-188, was designed to eliminate certain low molecular weight substances present in P188 (non-purified), which we believe were primarily responsible for the moderate to moderately severe elevations in serum creatinine levels (acute renal dysfunction) observed in prior clinical studies of P188 (non-purified). Purified P188 has been evaluated in multiple clinical studies by a prior sponsor, including a 255-patient, phase 3 study. In that study, purified P188 was generally well tolerated and there were no clinically significant elevations in serum creatinine among subjects who received purified P188 compared to placebo.

We believe that, as a rheologic, antithrombotic and cytoprotective agent, MST-188 has potential application in treating a wide range of diseases and conditions resulting from microvascular-flow abnormalities.

Sickle Cell Disease Market & Opportunity

More than $1.0 billion is spent annually in the U.S. to treat patients with sickle cell disease. Sickle cell disease is a genetic disorder characterized by the “sickling” of red blood cells, which normally are disc-shaped, deformable and move easily through the microvasculature carrying oxygen from the lungs to the rest of the body. Sickled, or crescent-shaped, red blood cells, on the other hand, are rigid and sticky and tend to adhere to each other and the vascular endothelium. Patients with sickle cell disease are known to experience severely painful episodes associated with the obstruction of small blood vessels by sickle-shaped red blood cells. These painful episodes are commonly known as acute crisis or vaso-occlusive crisis. Reduced blood flow to organs and bone marrow during vaso-occlusive crisis not only causes intense pain, but can result in tissue death, or necrosis. The frequency, severity and duration of these acute crises can vary considerably.

We (mast) estimate that, in the U.S., sickle cell disease results in over 95,000 hospitalizations and, in addition, approximately 69,000 emergency department treat-and-release encounters each year. When a patient with sickle cell disease makes an institutional visit, vaso-occlusive crisis is the primary diagnosis in approximately 77% of hospital admissions and 64% of emergency room treat-and-release encounters. In addition, although the number is difficult to measure, we estimate that the number of untreated sickle cell crisis events is substantial and in the hundreds of thousands in the U.S. each year. We believe that, if MST-188 is approved, as people with sickle cell disease are made aware of the new therapy, more people who suffer from acute crisis will seek treatment.

Development Status

We (mast) have initiated a Phase 3 clinical study of MST-188 for the treatment of sickle cell disease. The primary objective will be to demonstrate that MST-188 reduces the duration of vaso-occlusive crisis in patients with sickle cell disease. Please see our Clinical Trials page for more information regarding our phase 3 study of MST-188. In addition to the phase 3 study, we plan to conduct a number of smaller-scale clinical studies to further assess the efficacy, safety and tolerability of MST-188, and expect these studies to overlap with the phase 3 study.

Advaxis’s cancer vaccine gets FDA orphan status for treatment of HPV-associated head and neck cancer

November 8, 2013 3:29 am / 1 Comment on Advaxis’s cancer vaccine gets FDA orphan status for treatment of HPV-associated head and neck cancer

US-based clinical-stage biotechnology firm Advaxis has received orphan drug designation from the US Food and Drug Administration (FDA) for its lead drug candidate ADXS-HPV to treat human papillomavirus (HPV) associated head and neck cancer patients.

Advaxis’s cancer vaccine gets FDA orphan status for treatment of HPV-associated head and neck cancer

http://www.pharmaceutical-technology.com/news/newsadvaxis-cancer-vaccine-gets-fda-orphan-status-treatment-hpv-associated-head-neck-cancer?WT.mc_id=DN_News

PRINCETON, N.J., Nov 05, 2013 (BUSINESS WIRE) — Advaxis, Inc., /quotes/zigman/23528806/delayed/quotes/nls/adxs ADXS +2.61% , a leader in developing the next generation of cancer immunotherapies, announced that it has been granted Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD) for ADXS-HPV, its lead drug candidate, for the treatment of human papillomavirus (HPV)-associated head and neck cancer.

Orphan Drug Designation is granted to drug therapies intended to treat diseases or conditions that affect fewer than 200,000 people in the United States. Orphan Drug Designation entitles the sponsor to clinical protocol assistance with the FDA, as well as federal grants, tax credits, and potentially a seven year market exclusivity period.

“We are very pleased to have been granted an orphan drug designation for ADXS-HPV in this unmet medical need,” commented Dr. Robert Petit, Chief Scientific Officer of Advaxis. “Patients with head and neck cancer have limited treatment options and we hope to improve their survival by developing ADXS-HPV for this indication. We plan to initiate an additional Phase 1/2 study in early stage head and neck cancer for ADXS-HPV with a nationally recognized center of excellence, and we will continue the ongoing Phase 1 study being sponsored by the University of Liverpool and Aintree University Hospitals NHS Foundation Trust that is evaluating the safety and efficacy of ADXS-HPV when combined with standard chemotherapy and radiation treatment in patients with head and neck cancer.”

“Receiving orphan drug designation for ADXS-HPV in head and neck cancer is excellent news for a technology that may offer the potential to treat an indication with few therapy options, and, importantly, it helps define a clear path forward to registration,” commented Daniel J. O’Connor, President and Chief Executive Officer of Advaxis.

About Orphan Drug Designation

Under the Orphan Drug Act (ODA), the FDA may grant orphan designation to a drug or biological product intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making a drug or biological product available in the United States for this type of disease or condition will be recovered from sales of the product. The benefits of orphan drug designation can be substantial and include federal grants, tax credits, and potentially a seven year market exclusivity period once the product is approved, provided that the product is first to market.

In order for a sponsor to obtain orphan designation for a drug or biological product, an application must be submitted to OOPD, and the designation approved. The approval of an application for orphan designation is based upon the information submitted by the sponsor. A drug that has obtained orphan designation is said to have “orphan status.” Each designation request must stand on its own merit. Sponsors requesting designation of the same drug for the same indication as a previously designated product must submit their own data in support of their designation request. The approval of an orphan designation request does not alter the standard regulatory requirements and process for obtaining marketing approval. Safety and efficacy of a compound must be established through adequate and well-controlled studies.

About ADXS-HPV

ADXS-HPV is an immunotherapy that is designed to target cells expressing the HPV gene E7. Expression of the E7 gene from high-risk HPV variants is responsible for the transformation of infected cells into dysplastic and malignant tissues. Eliminating these cells can eliminate the dysplasia or malignancy. ADXS-HPV is designed to infect antigen-presenting cells and direct them to generate a powerful, cellular immune response to HPV E7. The resulting cytotoxic Tcells infiltrate and attack the tumors while specifically inhibiting tumor Tregs and MDSCs in the tumors that are protecting it.

About Head and Neck Cancer

Cancer of the head and neck includes cancers arising from mucosa lining the oral cavity, oropharynx, hypopharynx, larynx, sinonasal tract, and nasopharynx. The most common histologic type observed is squamous cell carcinoma; therefore, the term “head and neck squamous cell carcinoma” (HNSCC) is frequently used to imply squamous cell carcinomas involving these anatomical sites. Excessive tobacco and alcohol are important risk factors for HNSCCs overall, but human papillomavirus (HPV) is now recognized as the causative agent in a subset of HNSCCs.

While the incidence of head and neck cancers that are linked to alcohol and tobacco use as the primary risk factor has fallen in the past three decades, a trend attributed to decreasing tobacco use in the United States, the incidence of HPV-associated head and neck cancer has been increasing. The increase was observed particularly among young individuals (<60 years of age), men, and Caucasians. Studies have shown that oral HPV infection is likely to be sexually acquired, as the increase in the incidence of HPV-associated head and neck cancers may be attributed to changing sexual practices. According to the World Health Organization’s Human Papillomavirus and Related Cancers in the World Summary Report 2010, HPV is associated with 20-50% of oral squamous cell carcinomas. HPV-associated head and neck cancer is growing at an epidemic rate in western countries; and occurs more frequently (3:1) in men than women. In the United States, the number of HPV-positive head and neck cancer cases has already equaled the number of cervical cancer cases.

About Advaxis, Inc.

Advaxis is a clinical-stage biotechnology company developing the next generation of immunotherapies for cancer and infectious diseases. Advaxis immunotherapies are based on a novel platform technology using live, attenuated bacteria that are bio-engineered to secrete an antigen/adjuvant fusion protein(s) that is designed to redirect the powerful immune response all human beings have to the bacterium to the cancer itself.

ADXS-HPV is currently being evaluated in four clinical trials for human papillomavirus (HPV)-associated cancers: recurrent/refractory cervical cancer (India), locally advanced cervical cancer (GOG/NCI U.S. study, Clinical Trials.gov Identifier NCT01266460), head & neck cancer (CRUK study, Clinical Trials.gov Identifier NCT01598792), and anal cancer (BrUOG study, Clinical Trials.gov Identifier NCT01671488). Advaxis has over 15 distinct immunotherapies in various stages of development, developed directly by Advaxis and through strategic collaborations with recognized centers of excellence such as: the University of Pennsylvania, the Georgia Regents University Cancer Center, Brown University Oncology Group, and others.

ADXS-HPV is currently in Phase 1/2 clinical development for recurrent/refractory and advanced cervical cancer, HPV caused head and neck cancers, and anal cancer.

Links to ADXS-HPV trials:

The American Cancer Society estimates that there will be about 12,340 newly diagnosed cervical cancer cases and 7,060 newly diagnosed cases of anal cancer in the U.S. in 2013.

In 2009, the CDC reported that about 45% of women aged 20 to 24 had HPV. HPV causes a number of different types of cancer. The same types of genital HPV that cause cervical cancer (HPV-16, HPV-18) cause about 8 out of 10 squamous cell anal cancers. In addition, nearly half of cancers of the vulva and about 7 out of 10 vaginal cancers are HPV-related. Some other genital cancers (cancers of the penis and urethra) and some head and neck cancers (mostly the throat, tongue, and tonsils) are also related to high-risk types of HPV. For additional information about HPV, please visit: http://www.cancer.org/.

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DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

Aeterna Zentaris Submits New Drug Application to FDA for Macimorelin Acetate (AEZS-130) for Evaluation of AGHD

November 6, 2013 3:49 am / 2 Comments on Aeterna Zentaris Submits New Drug Application to FDA for Macimorelin Acetate (AEZS-130) for Evaluation of AGHD

Macimorelin

CAS 381231-18-1

Chemical Formula: C26H30N6O3

Exact Mass: 474.23794

Molecular Weight: 474.55480

Elemental Analysis: C, 65.80; H, 6.37; N, 17.71; O, 10.11

945212-59-9 (Macimorelin acetate)

AEZS-130
ARD-07
D-87875
EP-01572
EP-1572
JMV-1843

USAN (ab-26)
MACIMORELIN ACETATE

THERAPEUTIC CLAIM
Diagnostic agent for adult growth hormone deficiency (AGHD)
CHEMICAL NAMES
1. D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-, acetate (1:1)
2. N2-(2-amino-2-methylpropanoyl-N1-[(1R)-1-formamido-2-(1H-indol-3-yl)ethyl]- D-tryptophanamide acetate

MOLECULAR FORMULA
C26H30N6O3.C2H4O2
MOLECULAR WEIGHT
534.6

SPONSOR
Aeterna Zentaris GmbH
CODE DESIGNATIONS
D-87575, EP 1572, ARD 07
CAS REGISTRY NUMBER
945212-59-9

Macimorelin (also known as AEZS-130, EP-1572) is a novel synthetic small molecule, acting as a ghrelin agonist, that is orally active and stimulates the secretion of growth hormone (GH). Based on results of Phase 1 studies, AEZS-130 has potential applications for the treatment of cachexia, a condition frequently associated with severe chronic diseases such as cancer, chronic obstructive pulmonary disease and AIDS. In addition to the therapeutic application, a Phase 3 trial with AEZS-130 as a diagnostic test for growth hormone deficiencies in adults has been completed.

http://www.ama-assn.org/resources/doc/usan/macimorelin-acetate.pdf

QUEBEC, Nov. 5, 2013 /PRNewswire/ – Aeterna Zentaris Inc. (the “Company”) today announced that it has submitted a New Drug Application (“NDA”) to the U.S. Food and Drug Administration (“FDA”) for its ghrelin agonist, macimorelin acetate (AEZS-130). Phase 3 data have demonstrated that the compound has the potential to become the first orally-approved product that induces growth hormone release to evaluate adult growth hormone deficiency (“AGHD”), with accuracy comparable to available intravenous and intramuscular testing procedures. read at

http://www.drugs.com/nda/macimorelin_acetate_131105.html

http://www.ama-assn.org/resources/doc/usan/macimorelin-acetate.pdf

macimorelin (JMV 1843), a ghrelin-mimetic growth hormone secretagogue in Phase III for adult growth hormone deficiency (AGHD)

Macimorelin, a growth hormone modulator, is currently awaiting registration in the U.S. by AEterna Zentaris as an oral diagnostic test of adult growth hormone deficit disorder. The company is also developing the compound in phase II clinical trials for the treatment of cancer related cachexia. The compound was being codeveloped by AEterna Zentaris and Ardana Bioscience; however, the trials underway at Ardana were suspended in 2008 based on a company strategic decision. AEterna Zentaris owns the worldwide rights of the compound. In 2007, orphan drug designation was assigned by the FDA for the treatment of growth hormone deficit in adults.

New active series of growth hormone secretagogues
J Med Chem 2003, 46(7): 1191

WO 2001096300

WO 2007093820

…………………………

J Med Chem 2003, 46(7): 1191

http://pubs.acs.org/doi/full/10.1021/jm020985q

Synthetic Pathway for JMV 1843 and Analogues^a

^a Reagents and conditions: (a) IBCF, NMM, DME, 0 °C; (b) NH₄OH; (c) H₂, Pd/C, EtOH, HCl; (d) BOP, NMM, DMF, Boc-(d)-Trp-OH; (e) Boc₂O, DMAP cat., anhydrous CH₃CN; (f) BTIB, pyridine, DMF/H₂O; (g) 2,4,5-trichlorophenylformate, DIEA, DMF; (h) TFA/anisole/thioanisole (8:1:1), 0 °C; (i) BOP, NMM, DMF, Boc-Aib-OH; (j) TFA/anisole/thioanisole (8:1:1), 0 °C; (k) RP preparative HPLC.

TFA, H-Aib-(d)-Trp-(d)-gTrp-CHO (7). 6 (1 g, 1.7 mmol) was dissolved in a mixture of trifluoroacetic acid (8 mL), anisole (1 mL), and thioanisole (1 mL) for 30 min at 0 °C. The solvents were removed in vacuo, the residue was stirred in ether, and the precipitated TFA, H-Aib-(d)-Trp-(d)-gTrp-CHO was filtered. 7 was purified by preparative HPLC and obtained in 52% yield. ¹H NMR (400 MHz, DMSO-d₆) + correlation ¹H−¹H: δ 1.21 (s, 3H, CH₃ (Aib)), 1.43 (s, 3H, CH₃ (Aib)), 2.97 (m, 2H, (CH₂)_β), 3.1 (m, 2H, (CH₂)_β_‘), 4.62 (m, 1H, (CH)α_A and (CH)α_B), 5.32 (q, 0.4H, (CH)α‘_B), 5.71 (q, 0.6H, (CH)α‘_A), 7.3 (m, 4H, H₅ and H₆ (2 indoles)), 7.06−7.2 (4d, 2H, H_2A and H_2B (2 indoles)), 7.3 (m, 2H, H₄ or H₇ (2 indoles)), 7.6−7.8 (4d, 2H, H_4A and H_4B or H_7A and H_7B), 7.97 (s, 3H, NH₂ (Aib) and CHO (formyl)), 8.2 (d, 0.4H, NH_1B (diamino)), 8.3 (m,1H, NH_A and NH_B), 8.5 (d, 0.6H, NH_1A (diamino)), 8.69 (d, 0.6H, NH_2A (diamino)), 8.96 (d, 0.4H, NH_2B (diamino)), 10.8 (s, 0.6H, N¹H_1A (indole)), 10.82 (s, 0.4H, N¹H_1B (indole)), 10.86 (s, 0.6H, N¹H_2A (indole)), 10.91 (s, 0,4H, N¹H_2B (indole)). MS (ES), m/z: 475 [M + H]⁺, 949 [2M + H]⁺. HPLC t_R: 16.26 min (conditions A).

…………………………..

http://www.google.com/patents/US8192719

The inventors have now found that the oral administration of growth hormone secretagogues (GHSs) EP 1572 and EP 1573 can be used effectively and reliably to diagnose GHD.

EP 1572 (Formula I) or EP 1573 (Formula II) are GHSs (see WO 01/96300, Example 1 and Example 58 which are EP 1572 and EP 1573, respectively) that may be given orally.

EP 1572 and EP 1573 can also be defined as H-Aib-D-Trp-D-gTrp-CHO and H-Aib-D-Trp-D-gTrp-C(O)NHCH₂CH₃. Wherein, His hydrogen, Aib is aminoisobutyl, D is the dextro isomer, Trp is tryptophan and gTrp is a group of Formula III:

…………………………….

http://www.google.com/patents/US6861409

H-Aib-D-Trp-D-gTrp-CHO:

Example 1 H-Aib-D-Trp-D-gTrp-CHO

Total synthesis (percentages represent yields obtained in the synthesis as described below):

Z-D-Tr-NH₂

Z-D-Trp-OH (8.9 g; 26 mmol; 1 eq.) was dissolved in DME (25 ml) and placed in an ice water bath to 0° C. NMM (3.5 ml; 1.2 eq.), IBCF (4.1 ml; 1.2 eq.) and ammonia solution 28% (8.9 ml; 5 eq.) were added successively. The mixture was diluted with water (100 ml), and the product Z-D-Trp-NH₂precipitated. It was filtered and dried in vacuo to afford 8.58 g of a white solid.

Yield=98%.

C₁₉H₁₉N₃O₃, 337 g.mol⁻¹.

Rf=0.46 {Chloroform/Methanol/Acetic Acid (180/10/5)}.

¹H NMR (250 MHZ, DMSO-d⁶): δ 2.9 (dd, 1H, H_β, J_ββ′=14.5 Hz; J_βα=9.8 Hz); 3.1 (dd, 1H, H_β′, J_β′β=14.5 Hz; J_β′α=4.3 Hz); 4.2 (sextuplet, 1H, H_α); 4.95 (s, 2H, CH₂(Z); 6.9-7.4 (m, 11H); 7.5 (s, 1H, H²); 7.65 (d, 1H, J=7.7 Hz); 10.8 (s, 1H, N¹H).

Mass Spectrometry (Electrospray), m/z 338 [M+H]⁺, 360 [M+Na]⁺, 675 [2M+H]⁺, 697 [2M+Na]⁺.

Boc-D-Trp-D-Trp-NH₂

Z-D-Trp-NH₂(3 g; 8.9 mmol; 1 eq.) was dissolved in DMF (100 ml). HCl 36% (845 μl; 1.1 eq.), water (2 ml) and palladium on activated charcoal (95 mg, 0.1 eq.) were added to the stirred mixture. The solution was bubbled under hydrogen for 24 hr. When the reaction went to completion, the palladium was filtered on celite. The solvent was removed in vacuo to afford HCl, H-D-Trp-NH₂as a colorless oil.

In 10 ml of DMF, HCl, H-D-Trp-NH₂(8.9 mmol; 1 eq.), Boc-D-Trp-OH (2.98 g; 9.8 mmol; 1.1 eq.), NMM (2.26 ml; 2.1 eq.) and BOP (4.33 g; 1.1 eq.) were added successively. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (100 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo to afford 4.35 g of Boc-D-Trp-D-Trp-NH₂as a white solid.

Yield=85%.

C₂₇H₃₁N₅O₄, 489 g.mol⁻¹.

Rf=0.48 {Chloroform/Methanol/Acetic Acid (85/10/5)}.

¹H NMR (200 MHZ, DMSO-d⁶): δ 1.28 (s, 9H, Boc); 2.75-3.36 (m, 4H, 2 (CH₂)_β; 4.14 (m, 1H, CH_α); 4.52 (m, 1H, CH_α′); 6.83-7.84 (m, 14H, 2 indoles (10H), NH₂, NH (urethane) and NH (amide)); 10.82 (d, 1H, J=2 Hz, N¹H); 10.85 (d, 1H, J=2 Hz, N¹H).

Mass Spectrometry (Electrospray), m/z 490 [M+H]⁺, 512 [M+Na]⁺, 979 [2M+H]⁺.

Boc-D-(NiBoc)Trp-D-(NiBoc)Trp-NH₂

Boc-D-Trp-D-Trp-NH₂(3 g; 6.13 mmol; 1 eq.) was dissolved in acetonitrile (25 ml).

To this solution, di-tert-butyl-dicarbonate (3.4 g; 2.5 eq.) and 4-dimethylaminopyridine (150 mg; 0.2 eq.) were successively added. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane {5/5} to afford 2.53 g of Boc-D-(NⁱBoc)Trp-D-(NⁱBoc)Trp-NH₂as a white solid.

Yield=60%.

C₃₇H₄₇N₅O₈, 689 g.mol⁻¹.

Rf=0.23 {ethyl acetate/hexane (5/5)}.

¹H NMR (200 MHZ, DMSO-d⁶): δ 1.25 (s, 9H, Boc); 1.58 (s, 9H, Boc); 1.61 (s, 9H, Boc); 2.75-3.4 (m, 4H, 2 (CH₂)_β); 4.2 (m, 1H, CH_α′); 4.6 (m, 1H, CH_α); 7.06-8 (m, 14H, 2 indoles (10H), NH (urethane), NH and NH₂(amides)).

Mass Spectrometry (Electrospray), m/z 690 [M+H]⁺, 712 [M+Na]⁺, 1379 [2M+H]⁺, 1401 [2M+Na]⁺.

Boc-D-(NⁱBoc)Trp-D-g(NⁱBoc)Trp-H

Boc-D-(NⁱBoc)Trp-D-(NⁱBoc)Trp-NH2 (3 g; 4.3 mmol; 1 eq.) was dissolved in the mixture DMF/water (18 ml/7 ml). Then, pyridine (772 μl; 2.2 eq.) and Bis(Trifluoroacetoxy)IodoBenzene (2.1 g; 1.1 eq.) were added. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and aqueous saturated sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. Boc-D-NⁱBoc)Trp-D-g(NⁱBoc)Trp-H was used immediately for the next reaction of formylation.

Rf=0.14 {ethyl acetate/hexane (7/3)}.

C₃₆H₄₇N₅O₇, 661 g.mol⁻¹.

¹H NMR (200 MHZ, DMSO-d⁶): δ 1.29 (s, 9H, Boc); 1.61 (s, 18H, 2 Boc); 2.13 (s, 2H, NH₂(amine)); 3.1-2.8 (m, 4H, 2 (CH₂)_β); 4.2 (m, 1H, CH_α′); 4.85 (m, 1H, CH_α); 6.9-8 (m, 12H, 2 indoles (10H), NH (urethane), NH (amide)).

Mass Spectrometry (Electrospray), m/z 662 [M+H]⁺, 684 [M+Na]⁺.

Boc-D-(NⁱBoc)Trp-D-g(NⁱBoc)Trp-CHO

Boc-D-(NⁱBoc)Trp-D-g(NⁱBoc)Trp-H (4.3 mmol; 1 eq.) was dissolved in DMF (20 ml). Then, N,N-diisopropylethylamine (815 μl; 1.1 eq.) and 2,4,5-trichlorophenylformate (1.08 g; 1.1 eq.) were added. After 30 minutes, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane {5/5} to afford 2.07 g of Boc-D-(NⁱBoc)Trp-D-g(NⁱBoc)Trp-CHO as a white solid.

Yield=70%.

C₃₇H₄₇N₅O₈, 689 g.mol⁻¹.

Rf=0.27 {ethyl acetate/hexane (5/5)}.

¹H NMR (200 MHZ, DMSO-d⁶): δ 1.28 (s, 9H, Boc); 1.6 (s, 9H, Boc); 1.61 (s, 9H, Boc); 2.75-3.1 (m, 4H, 2 (CH₂)_β); 4.25 (m, 1H, (CH)α_A&B); 5.39 (m, 0.4H, (CH)α′_B); 5.72 (m, 0.6H, (CH)α′_A); 6.95-8.55 (m, 14H, 2 indoles (10H), NH (urethane), 2 NH (amides), CHO (formyl)).

Mass Spectrometry (Electrospray), m/z 690 [M+H]⁺, 712 [M+Na]⁺, 1379 [2M+H]⁺.

Boc-Aib-D-Trp-D-gTrp-CHO

Boc-D-(NⁱBoc)Trp-D-g(NⁱBoc)Trp-CHO (1.98 g; 2.9 mmol; 1 eq.) was dissolved in a -mixture of trifluoroacetic acid (16 ml), anisole (2 ml) and thioanisole (2 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, H-D-Trp-D-gTrp-CHO was filtered.

TFA, H-D-Trp-D-gTrp-CHO (2.9 mmol; 1 eq.), Boc-Aib-OH (700 mg; 1 eq.), NMM (2.4 ml; 4.2 eq.) and BOP (1.53 g; 1.2 eq.) were successively added in 10 ml of DMF. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to afford 1.16 g of Boc-Aib-D-Trp-D-gTrp-CHO as a white solid.

Yield=70%.

C₃₁H₃₈N₆O₅, 574 g.mol⁻¹.

Rf=0.26 {Chloroform/Methanol/Acetic Acid (180/10/5)}.

¹H NMR (200 MHZ, DMSO-d⁶): δ 1.21 (s, 6H, 2 CH₃(Aib)); 1.31 (s, 9H, Boc); 2.98-3.12 (m, 4H, 2 (CH₂)_β); 4.47 (m, 1H, (CH)α_A&B); 5.2 (m, 0.4H, (CH)α′_B); 5.7 (m, 0.6H, (CH)α′_A); 6.95-8.37 (m, 15H, 2 indoles (10H), 3 NH (amides), 1 NH (urethane) CHO (formyl)); 10.89 (m, 2H, 2 N¹H (indoles)).

Mass Spectrometry (Electrospray), ml/z 575 [M+H]⁺, 597 [M+Na]⁺, 1149 [2M+H]⁺, 1171 [2M+Na]⁺.

H-Aib-D-Trp-D-gTrT-CHO

Boc-Aib-D-Trp-D-gTrp-CHO (1 g; 1.7 nmmol) was dissolved in a mixture of trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole (1 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, H-Aib-D-Trp-D-gTrp-CHO was filtered.

The product TFA, H-Aib-D-Trp-D-gTrp-CHO was purified by preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm, 100 A).

Yield=52%.

C₂₆H₃₀N₆O₃, 474 g.mol⁻¹.

¹H NMR (400 MHZ, DMSO-d⁶)+¹H/¹H correlation: δ 1.21 (s, 3H, CH₃(Aib)); 1.43 (s, 3H, CH₃(Aib)); 2.97 (m, 2H, (CH₂)_β); 3.1 (m, 2H, (CH₂)_β′); 4.62 (m, 1H, (CH)α_A&B); 5.32 (q, 0.4H, (CH)α′_B); 5.71 (q, 0.6H, (CH)α′_A); 7.3 (m, 4H₅and H₆(2 indoles)); 7.06-7.2 (4d, 2H, H_2Aet H_2B(2 indoles)); 7.3 (m, 2H, H₄or H₇(2 indoles)); 7.6-7.8 (4d, 2H, H_4Aand H_4Bor H_7Aet H_7B); 7.97 (s, 3H, NH₂(Aib) and CHO (Formyl));8.2 (d, 0.4H, NH_1B(diamino)); 8.3 (m,1H, NH_A&B); 8.5 (d, 0.6H, NH_1A(diamino)); 8.69 (d, 0.6H, NH₂A (diamino)); 8.96 (d, 0.4H, NH_2B(diamino)); 10.8 (s, 0.6H, N¹H_1A(indole)); 10.82 (s, 0.4H, N¹H_1B(indole)); 10.86 (s, 0.6H, N¹H₂A (indole)); 10.91 (s, 0.4, N¹H_2B(indole)).

Mass Spectrometry (Electrospray), m/z 475 [M+H]⁺, 949 [2M+H]⁺.

………………………………

UPDATED INFO AS ON JAN 6 2014

Aeterna Zentaris NDA for Macimorelin Acetate in AGHD Accepted for Filing by the FDA

Quebec City, Canada, January 6, 2014 – Aeterna Zentaris Inc. (NASDAQ: AEZS) (TSX: AEZS) (the “Company”) today announced that the U.S. Food and Drug Administration (“FDA”) has accepted for filing the Company’s New Drug Application (“NDA”) for its ghrelin agonist, macimorelin acetate, in Adult Growth Hormone Deficiency (“AGHD”). The acceptance for filing of the NDA indicates the FDA has determined that the application is sufficiently complete to permit a substantive review.

The Company’s NDA, submitted on November 5, 2013, seeks approval for the commercialization of macimorelin acetate as the first orally-administered product that induces growth hormone release to evaluate AGHD. Phase 3 data have demonstrated the compound to be well tolerated, with accuracy comparable to available intravenous and intramuscular testing procedures. The application will be subject to a standard review and will have a Prescription Drug User Fee Act (“PDUFA”) date of November 5, 2014. The PDUFA date is the goal date for the FDA to complete its review of the NDA.

David Dodd, President and CEO of Aeterna Zentaris, commented, “The FDA’s acceptance of this NDA submission is another significant milestone in our strategy to commercialize macimorelin acetate as the first approved oral product for AGHD evaluation. We are finalizing our commercial plan for this exciting new product. We are also looking to broaden the commercial application of macimorelin acetate in AGHD for use related to traumatic brain injury victims and other developmental areas, which would represent significant benefit to the evaluation of growth hormone deficiency, while presenting further potential revenue growth opportunities for the Company.”

About Macimorelin Acetate

Macimorelin acetate, a ghrelin agonist, is a novel orally-active small molecule that stimulates the secretion of growth hormone. The Company has completed a Phase 3 trial for use in evaluating AGHD, and has filed an NDA to the FDA in this indication. Macimorelin acetate has been granted orphan drug designation by the FDA for use in AGHD. Furthermore, macimorelin acetate is in a Phase 2 trial as a treatment for cancer-induced cachexia. Aeterna Zentaris owns the worldwide rights to this novel patented compound.

About AGHD

AGHD affects about 75,000 adults across the U.S., Canada and Europe. Growth hormone not only plays an important role in growth from childhood to adulthood, but also helps promote a hormonally-balanced health status. AGHD mostly results from damage to the pituitary gland. It is usually characterized by a reduction in bone mineral density, lean mass, exercise capacity, and overall quality of life.

About Aeterna Zentaris

Aeterna Zentaris is a specialty biopharmaceutical company engaged in developing novel treatments in oncology and endocrinology. The Company’s pipeline encompasses compounds from drug discovery to regulatory approval.

back to home for more updates

DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

Cempra’s Taksta secures FDA orphan drug status for prosthetic joint infections treatment

November 1, 2013 4:10 am / 14 Comments on Cempra’s Taksta secures FDA orphan drug status for prosthetic joint infections treatment

FUSIDIC ACID, 6990-06-3

2-[(1S,2S,5R,6S,7S,10S,11S,13S,14Z,15R,17R)-13-(acetyloxy)-5,17-dihydroxy-2,6,10,11-tetramethyltetracyclo[8.7.0.0^2,7.0^11,15]heptadecan-14-ylidene]-6-methylhept-5-enoic acid

Taksta (CEM-102)
Clinical-stage pharmaceutical firm Cempra has secured orphan drug status from the US Food and Drug Administration (FDA) for its drug candidate Taksta (CEM-102) to treat patients with prosthetic joint infections (PJI).

Cempra’s Taksta secures FDA orphan drug status for prosthetic joint infections treatment

http://www.pharmaceutical-technology.com/news/newscempras-taksta-secures-fda-orphan-drug-status-prosthetic-joint-infections-treatment?WT.mc_id=DN_News

TAKSTA^TM (CEM-102)

Fusidic acid is a bacteriostatic antibiotic that is often used topically in creams and eyedrops, but may also be given systemically as tablets or injections. The global problem of advancing antimicrobial resistance has led to a renewed interest in its use recently.

Fusidic acid acts as a bacterial protein synthesis inhibitor by preventing the turnover ofelongation factor G (EF-G) from the ribosome. Fusidic acid is effective primarily ongram-positive bacteria such as Staphylococcus species, Streptococcus species, and Corynebacterium species. Fusidic acid inhibits bacterial replication and does not kill the bacteria, and is therefore termed bacteriostatic.

Fusidic acid is a true antibiotic, derived from the fungus Fusidium coccineum and was developed by Leo Laboratories in Ballerup, Denmark and released for clinical use in the 1960s. It has also been isolated from Mucor ramannianus and Isaria kogana. The drug is licensed for use as its sodium salt sodium fusidate, and it is approved for use under prescription in South Korea, Japan, UK, Canada, Europe, Australia, New Zealand, Thailand, India and Taiwan. A different oral dosing regimen, based on the compound’s Pharmacokinetic/pharmacodynamic (PK-PD) profile is in clinical development in the U.S. as Taksta.

Fusidic acid (TAKSTA^TM, CEM-102) is an antibiotic with a long history of safety and efficacy outside the United States. Cempra has exclusive rights to the supply of the compound for the U.S. market. Fusidic acid is orally active against gram-positive bacteria, including all S. aureus strains such as HA-MRSA and CA-MRSA. A novel dosing regimen has been successfully evaluated in a Phase II trial in patients with acute bacterial skin and skin structure infections (aBSSSI). Cempra is conducting a Phase II trial of TAKSTA for patients with prosthetic joint infections.

Profile of TAKSTA (CEM-102)
Prosthetic joint infections (PJI) occur in about 1% of hip replacements and 2% of knee replacements, translating to an incidence rate of about 10,000 per year in the U.S. at current hip and knee arthroplasty rates. There are few good options to treat these serious staphylococcal, often MRSA infections, which require long-term antibiotic treatment. Current therapy in the U.S. is with intravenous antibiotics such as vancomycin. An oral drug that can be safely administered for a long period of time could improve care and quality of life for these patients.

TAKSTA has shown potent activity against a large number of S. aureus strains, including CA-MRSA, HA-MRSA and linezolid-resistant strains, isolated in the U.S over a 10 year period. Its broad S. aureus coverage makes it useful for a broad range of clinical applications. Because of its safety and tolerability profile, TAKSTA could be ideal for patients suffering from staphylococcal infections that require long-term therapy such as patients with PJIs.

Cempra has developed a unique oral loading dose regimen to optimize key pathogen coverage and minimize drug resistance development. This regimen is incorporated in our Phase II trial to treat PJIs with TAKSTA in combination with rifampin, which is commonly used with injectible antibiotics such as vancomycin to treat PJIs.

Research on TAKSTA

Publications

The links for the articles go to subscription-based sites and may require a fee to view the article.

In Vitro Activity of CEM-102 (Fusidic Acid) Against Prevalent Clones and Resistant Phenotypes of Staphylococcus aureus
DF Sahm, J Deane, CM Pillar, P Fernandes
Antimicrobial Agents and Chemotherapy. June 2013 57: 4535-4346
http://aac.asm.org/content/57/9/4535

Efforts to Support the Development of Fusidic Acid in the United States
P Fernandes, D Pereira
Clinical Infectious Disease. June 2011 52:S542-6
http://www.ncbi.nlm.nih.gov/pubmed/21546632

Case report: Treatment of Chronic Osteomyelitis
CR Wolfe
Clinical Infectious Disease. June 2011 52:S538-41
http://cid.oxfordjournals.org/content/52/suppl_7/S538.long

The Safety Record of Fusidic Acid in Non-US markets: A Focus on Skin Infections
CN Kraus, BW Burnstead
Clinical Infectious Disease. June 2011 52:S527-37
http://cid.oxfordjournals.org/content/52/suppl_7/S527.long

A Randomized, Double-Blind Phase 2 Study Comparing the Efficacy and Safety of an Oral Fusidic Acid Loading-Dose Regimen to Oral Linezolid in the Treatment of Acute Bacterial Skin and Skin Structure Infections
JC Craft, SR Moriarty, K Clark, D Scott, TP Degenhardt, JG Still, GR Corey, A Das, P Fernandes
Clinical Infectious Disease. June 2011 52:S520-26
http://cid.oxfordjournals.org/content/52/suppl_7/S520.long

Application of Pharmacokinetic-Pharmacodynamic Modeling and the Justification of a Novel Fusidic Acid Dosing Regimen: Raising Lazarus from the Dead
BT Tsuji, OO Okusanya, JB Bulitta, A Forrest, SM Bhavnani, P Fernandes, PG Ambrose
Clinical Infectious Disease. June 2011 52:S513-19
http://cid.oxfordjournals.org/content/52/suppl_7/S513.long

Pharmacokinetics and Safety of Single, Multiple, and Loading Doses of Fusidic Acid in Healthy Subjects
JG Still, K Clark, TP Degenhardt, D. Scott, P. Fernandes, M. J. Gutierrez
Clinical Infectious Disease. June 2011 52:S504-12
http://cid.oxfordjournals.org/content/52/suppl_7/S504.long

Activity of Fusidic Acid Against Extracellular and Intracellular Staphylococcus aureus: Influence of pH and Comparison with Linezolid and Clindamycin
S Lemaire, F Van Bambeke, D Pierard, PC Appelbaum, PM Tulkens
Clinical Infectious Disease. June 2011 52:S493-503
http://cid.oxfordjournals.org/content/52/suppl_7/S493.long

Characterization of Global Patterns and the Genetics of Fusidic Acid Resistance
DJ Farrell, M Castanheira, I Chopra
Clinical Infectious Disease. June 2011 52:S487-92
http://cid.oxfordjournals.org/content/52/suppl_7/S493.long

In Vitro Antimicrobial Findings for Fusidic Acid Tested Against Contemporary (2008-2009) Gram-Positive Organisms Collected in the United States
RN Jones, RE Mendes, HS Sader, M Castanheira
Clinical Infectious Disease. June 2011 52:S477-86
http://cid.oxfordjournals.org/content/52/suppl_7/S477.long

New Rules for Clinical Trials in Patients with Acute Bacterial Skin and Skin Structure Iinfections: Do not Let the Perfect be the Enemy of the Good
GR Corey, ME Stryjewski
Clinical Infectious Disease. June 2011 52:S469-76
http://cid.oxfordjournals.org/content/52/suppl_7/S469.long

Introduction: Fusidic Acid Enters the United States
RC Moellering, GR Corey, ML Grayson
Clinical Infectious Disease. June 2011 52:S467-8
http://cid.oxfordjournals.org/content/52/suppl_7/S467.long

Evaluation of the Pharmacokinetics-Pharmacodynamics of Fusidic Acid Against Staphylococcus aureus and Streptococcus pyogenes Using In Vitro Infection Models: Implications for Dose Selection
OO Okusanya, BT Tsuji, JB Bulitta, A Forrest, CC Bulik, SM Bhavnani, P Fernandes, PG Ambrose
Diagnostic Microbiology & Infectious Disease. June 2011 70:101-11
http://www.ncbi.nlm.nih.gov/pubmed/21513848

In Vitro Activity of Fusidic Acid (CEM-102, Sodium Fusidate) Against Staphylococcus aureus Isolated from Cystic Fibrosis Patients and its Effect on the Activities of Tobramycin and Amikacin against Pseudomonas aeruginosa and Burkholderia cepacia
P McGhee, K Credito, L Beachel, PC Appelbaum, K Kosowaska-Shick
Antimicrobial Agents and Chemotherapy. June 2011 55:2417-19
http://www.ncbi.nlm.nih.gov/pubmed/21513848

Occurrence and Molecular Characterization of Fusidic Acid Resistance Mechanisms Among Staphylococcus spp. From European Countries (2008)
Castanheira, M., AA Watters, RE Mendes, DJ Farrell, RN Jones
Antimicrobial Agents and Chemotherapy. April 2010 65:1353-8
http://jac.oxfordjournals.org/content/65/7/1353.long

Update on Fusidic Acid (CEM-102) Tested Against Neisseria gonorrhoeae and Chlamydia trachomatis
R Jones, D Biedenbach, P Roblin, S Kohlhoff, M Hammerschlag
Antimicrobial Agents and Chemotherapy. October 2010 54: 4518-4519
http://aac.asm.org/cgi/content/citation/54/10/4518

Fusidic Acid Resistance Rates and Prevalence of Resistance Mechanisms Among Staphylococcus spp. Isolated in North America and Australia, 2007-2008
M Castanheira, AA Watters, JM Bell, JD Turnidge, RN Jones
Antimicrobial Agents and Chemotherapy. September 2010 54: 3614-3617
http://www.ncbi.nlm.nih.gov/pubmed/20566766

Spectrum of Activity, Mutation Rates, Synergistic Interactions, and the Effects of pH and Serum Proteins for Fusidic Acid (CEM-102)
D Biedenbach, P Rhomberg, R Mendes, R Jones
Diagnostic Microbiology & Infectious Disease. March 2010 66: 301-307
http://www.dmidjournal.com/article/S0732-8893(09)00424-6/abstract

Performance of Fusidic Acid (CEM-102) Susceptibility Testing Reagents: Broth Microdilution, Disk Diffusion, and Etest Methods as Applied to Staphylococcus aureus
R Jones, M Castanheira, P Rhomberg, L Woosley, M Pfaller
Journal of Clinical Microbiology. March 2010 48: 972-976
http://jcm.asm.org/cgi/content/abstract/48/3/972

Evaluation of the Activity of Fusidic Acid Tested Against Contemporary Gram-Positive Clinical Isolates From the USA and Canada
M Pfaller, M Castaneira, H Sader, R Jones
International Journal of Antimicrobial Agents. March 2010 35: 282-287
http://www.ijaaonline.com/article/S0924-8579(09)00510-X/abstract

6th ASM Conference on Biofilms 2012 (Sept 29-Oct 4) – Miami, FL 2012

Quantitative and qualitative assessment of antibiotic activity against Staphylococcus aureus biofilm.
Siala, W., M. P. Mingeot-Leclercq, P. M. Tulkens, and F. Van Bambeke.
Abstr. 6th Am. Soc. Microbiol. Conf. Biofilms, abstr A-179.
Download Poster

NACFC 2011

Activity of Fusidic Acid Against Methicillin-resistant Staphylococcus Aureus (MRSA) Isolated from CF Patients
Prabhavathi Fernandes, Donald Anderson, K. Kosowska-Shick, P. McGhee, L. Beachel and P.C. Appelbaum
Download Abstract | Download Poster

ECCMID 2011

Evaluation of L6 Ribosomal Protein Alterations in Fusidic Acid-Resistant Staphylococcus aureus: Fitness Cost and Time Kill Analysis
M Castanheira, RN Jones, LN Woosley, RE Mendes, GJ Moet, DJ Farrell
Download Abstract

Fusidic Acid Activity and Coverage of Gram-positive Pathogens Associated with Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in the USA (2008-2010)
RN Jones, DJ Farrell, HS Sader, M Castanheira
Download Abstract | Download Poster

IDSA 2010

Spectrum of Activity

Activity of Fusidic Acid Tested Against Contemporary Staphylococcus aureus Collected from United States Hospitals
M. Castanheira, R.E. Mendes, P.R. Rhomberg, R.N. Jones
Download Abstract | Download Poster

ICAAC 2010

Spectrum of Activity

Pharmacokinetics-Pharmacodynamics (PK-PD) of CEM- 102 (Sodium Fusidate) Against Streptococcus pyogenes Using In Vitro Pharmacodynamic Models (IVPM)
B. T. Tsuji, A. Forrest, P. A. Kelchlin, T. Brown, P. N. Holden, O. O. Okusanya, S. M. Bhavnani, P. Fernandes, P. G. Ambrose
Download Abstract | Download Poster

Activity of CEM-102 (sodium fusidate) against 40 MRSA from Cystic Fibrosis Patients
Cynthia Todd, Pamela Mcghee, and Peter Appelbaum
Download Abstract | Download Poster

Ability of CEM-102 (Fusidic Acid), Linezolid, Daptomycin to Select Resistant S.aureus Mutants at Steady-state Serum Levels
K. Kosowska-Shick, P. Mcghee, L. Beachel, P. C. Appelbaum;
Download Abstract | Download Poster

CEM-102 (Fusidic Acid) Maintains Potency against Resistant MRSA and Prevalent Hospital Acquired, Community Acquired,and Epidemic MRSA Clones
C.M. Pillar, M.K. Torres, D.F. Sahm and P. Fernandes
Download Abstract | Download Poster

In Vitro Activity Of Fusicic Acid (CEM-102) Against Resistant Strains Of Staphylococcus aureus
J. dubois, P. Fernandes
Download Abstract | Download Poster

Trade names and preparations

Fucidin (of Leo in Canada and the US)
Fucidin H (topical cream with corticosteroid – Leo)
Fucidin (of Leo in UK/ Leo-Ranbaxy-Croslands in India)
Fucidine (of Leo in France)
Fucidin (of Leo in Norway)
Fucidin (of Adcock Ingram, licenced from Leo, in South Africa)
Fucithalmic (of Leo in the UK, the Netherlands, Denmark and Portugal)
Fucicort (topical mixture with hydrocortisone)
Fucibet (topical mixture with betamethasone)
Ezaderm (topical mixture with betamethasone)(of United Pharmaceutical “UPM” in Jordan)
Fuci (of pharopharm in Egypt)
Fucizon (topical mixture with hydrocortisone of pharopharm in Egypt)
Foban (topical cream in New Zealand)
Betafusin (cream mixture with betamethasone valerate in Greece)
Fusimax (of Schwartz in India)
Fusiderm (topical cream and ointment by indi pharma in India)
Fusid (in Nepal)
Fudic (topical cream in India)
Fucidin (후시딘, of Dong Wha Pharm in South Korea)
Stanicid (in Serbia)
Dermy (Topical cream of W.Woodwards in Pakistan)
Fugen Cream (膚即淨軟膏 in Taiwan)
Phudicin Cream (in China; 夫西地酸^[24])
Dermofucin cream ,ointment and gel (in Jordan)
Optifucin viscous eye drops (of API in Jordan)
Verutex (of Roche in Brazil)
TAKSTA (of Cempra in U.S.)
Futasole (of Julphar in Gulf and north Africa)
Stanicid (2% ointment of Hemofarm in Serbia)
Fuzidin (tablets of Biosintez in Russia)
Fuzimet (ointment with methyluracil of Biosintez in Russia)
Axcel Fusidic Acid(2% cream and ointment of Kotra Pharma, Malaysia)

MORE INFO

Figure US08450300-20130528-C00002

Fusidic acid (FA) is a tetracyclic triterpenoid or fusidane (steroidal) antibiotic derived from the fungus Fusidium coccineum that inhibits bacterial protein synthesis. FA is effective against gram-positive bacteria such as Staphylococcusspecies and Corynebacterium species (L. Verbist, J. Antimicro. Chemo. 25, Suppl. B, 1-5 (1990); A. Bryskier, Fusidic Acid, Chapter 23, in Antimicrobial Agents: Antibacterials and Antifungals (Andre Bryskier, Ed., ASM Press, Washington, USA, 2005)). FA also has moderate activity against Group A beta-hemolytic streptococci, or Streptococcus pyogenes (L. Verbist, J. Antimicro. Chemo. 25, Suppl. B, 1-5 (1990); A. Bryskier, Fusidic Acid, Chapter 23, inAntimicrobial Agents: Antibacterials and Antifungals (Andre Bryskier, Ed., ASM Press, Washington, USA, 2005); Skov et al., Diag. Micro. Infect. Dis. 40:111-116 (2001)).

Fusidic acid, chemically (3α, 4α, 8α, 9α, 11α, 13α, 14α, 16α, 17Z)-16-(Acetyloxy)-3,11-dihydroxy-29-nordammara-17(20), 24-dien-21-oic acid, is an antibacterial agent. It is a well-known antibiotic with a unique steroid-like tetracyclic ring system structure, and it is the most potent of a small family of steroidal antibiotics, the fusidanes. It is produced by fermentation under controlled conditions of the fungus Fusidium Coccineum.
The excellent distribution in various tissues, low degree of toxicity and allergic reactions and the absence cross-resistance with other clinically used antibiotics has made fusidic acid a highly valuable antibiotic,especially for skin and eye infections. The drug is used clinically both in its acid form, and as the sodium salt (Fusidin®), however Fusidin® is more favored one because of its better solubility in water, enabling a fast absorption from gastro-intestinal tract. As a result, it is more preferable to use sodium salt of fusidin in oral solid forms.
Fusidin® has the actions and uses of fusidic acid, and it has been shown that it ameliorates the course of several organ-specific immuno-inflammatory diseases such as chronic uveitis, Behcet’s disease, type I diabetes mellitus, Guillain-Barre syndrome, hepatitis, sepsis, pancreatitis, formalin-induced edema, multiple sclerosis, and scleroderma, whereby fucidin formulations have a great importance in pharmaceutical production.
Fusidin® can be presented in various formulations that differ significantly in their pharmacokinetic behaviors such as oral tablets, oral suspensions, intravenous formulations and topical preparation. Considering oral tablets, many of the early clinical studies were performed with capsule containing sodium fusidate. This was also the formulation marketed for many years in several countries. It is currently available as an oral tablet containing the sodium salt. Originally the sodium salt was available as an enteric-coated form but later it was reformulated as a film-coated tablet that appears to be better tolerated and gives higher blood levels.
Fusidic acid sodium salt was used in capsules as well as in tablets which were coated enterically. However by this enteric coating, the active fusidic acid sodium salt was not released before the tablets reached the part of the gastrointestinal tract in which the enteric coating would be dissolved. Depending on the time of passage through the stomach together with the food and the pH in the gastrointestinal tract, this led to unpredictable variations in the blood concentration of the patient undergoing treatment. Because of these adverse differences in blood concentration, the tablets without enteric coating were produced. Now, sodium fusidate is available in tablet, oral solution and injection form
PCT/WO9603128 A (LEO PHARMACEUTICALS PRODUCTS LTD. ET.AL.) describes the preparation of fusidic acid sodium salt tablets without an enteric coating by using dry granulation method in which a roller compactor was used. The compacted material so produced was size reduced to form a granulate having a bulk density in the range 0.45 to 0.9 g/m³ which was then formed into tablets.

FA was developed for clinical use in the 1960s and it is approved for human use outside of the United States, such as in the UK, Canada, Europe, Israel, Australia and New Zealand. It is typically prescribed at doses of 500 mg TID for treating skin and skin structure infections caused by Staphylococcus aureus (A. Bryskier,Fusidic Acid, Chapter 23, in Antimicrobial Agents: Antibacterials and Antifungals(Andre Bryskier, Ed., ASM Press, Washington, USA, 2005); Collignon et al., Int’l J. Antimicrobial Agents 12:S45-S58 (1999); D. Spelman, Int’l J. Antimicrobial Agents 12:S59-S66 (1999)), although some physicians have routinely prescribed the compound at 500 mg BID for treating skin and skin structure infections due to the long half-life of the compound (Fusidic Acid, in Principles and Practice of Infectious Diseases, 6^thed. (Mandell et al. eds., Elsevier, 2006)).

Treatment using FA has been well studied and it is generally regarded as safe when administered to humans, as evidenced by the fact that the drug has been in continuous use for more than 40 years. There are, however, several characteristics of FA that have prevented use of the drug against a wider spectrum of bacteria and in the treatment in additional types of infection. For example, approved dosing regimens have been shown to select for bacterial resistance, such as in S. aureus. Approved dosing regimens provide low multiples of the MIC and as a result, S. aureus resistant mutants can be selected after the first day of dosing. Once resistance has developed, FA is not effective against the resistant strains. Resistance is reported to occur if FA is used as a single drug as the resistance frequency at 4 and 8 times the MIC is in the range of 10⁻⁶or 10⁻⁸(Evans et al., J. Clin. Path. 19:555-560 (1966); Hansson et al., J. Mol. Biol.348:939-949 (2005), Jensen et al., Acta Pathol Microbiol Scand. 60:271-284 (1964); Besier et al., Antimicrob. Agents Chemo., 49(4):1426-1431 (2005); Gemmell et al., J. Antimicrobial Chemo. 57:589-608 (2006)).

The dosage of the drug cannot be simply increased as a means of avoiding development of resistance. It is difficult to achieve high concentrations of FA in the blood due to the substantial protein binding of the drug (approximately 95-97%) (K. Christiansen, International Journal of Antimicrobial Agents 12:S3-S9 (1999); Coutant et al., Diagn Microbiol Infect Dis 25:9-13 (1996); D. Reeves, J. Antimicrob. Chemo. 20:467-476 (1987); J. Turnidge, Int’l J. Antimicrobial Agents12:S23-S34 (1999); Rieutord et al., Int’l J. Pharmaceutics 119:57-64 (1995)). Moreover, high dosages of FA are not well-tolerated by patients receiving the drug. High doses of FA (e.g., 1 gram TID) are required if the drug is to be used in the treatment of bone and joint infections, less susceptible bacteria and other serious infections. However, treatment regimens using high doses of the drug induce nausea and vomiting and are rejected by patients (Fusidic Acid, inPrinciples and Practice of Infectious Diseases, 6^thed. (Mandell et al. eds., Elsevier, 2006); K. Christiansen, International Journal of Antimicrobial Agents 12:S3-S9 (1999); Nordin et al., Eur. J. Clin. Res. 5:97-106 (1994)).

In view of the tremendous costs associated with the de novo development of new anti-bacterials, expanding the indications for drugs that have already been demonstrated to be safe and effective is strongly needed. Overcoming the limitations on the uses of FA would broaden the population of bacterial infections against which it could be used and thus meet this need.

In a specific commercial pharmaceutical formulation, fusidic acid is presently marketed [see Monographs in the European Pharmacopeia 5.0] as a hemihydrate, which is the only hemihydrate form which has been described.

Patent GB 930,786 discloses salts of fusidic acid with organic and inorganic bases, solvates of fusidic acid, namely a benzene solvate and a methanol solvate. This patent further discloses an unspecified fusidic acid form with IR absorption bands (KBr) at 1265, 1385, 1695, 1730 and 3450 cm^“1 and having a specific rotation [α]_D ²² of minus 9 degrees (1% solution in CHCI₃) obtainable by crystallisation of the methanol solvate of fusidic acid from ether. However, this form is distinct from the form of the present invention evident from the depicted IR spectrum in GB 930,786 which indicates that this form actually corresponds to the presently marketed hemihydrate form.

Solvates and salts of fusidic acid have also been disclosed in British patent GB 999,794. Patent ES 2208110 discloses two solvent free crystalline forms offusidic acid called Form I and Form II, and a crystalline hemihydrate called Form III which is identical to the presently marketed hemihydrate, respectively. The crystalline forms were identified and characterised by IR spectroscopy, differential scanning calorimetry, X-ray diffraction and melting points.

Patent WO 96/03128 discloses tablets containing a sodium salt form of fusidicacid and WO 86/03966 describes an ophthalmic gel composition comprising an undefined form of suspended fusidic acid.

GT Biologics obtains FDA orphan drug designation for paediatric Crohn’s drug

October 10, 2013 4:07 am / 2 Comments on GT Biologics obtains FDA orphan drug designation for paediatric Crohn’s drug

GT Biologics, a developer of live biotherapeutics for the treatment of autoimmune diseases, has received orphan drug designation from the US Food and Drug Administration (FDA) for its lead product candidate, Thetanix.

read all at

http://www.pharmaceutical-technology.com/news/newsgt-biologics-obtains-fda-orphan-drug-designation-for-paediatric-crohns-drug?WT.mc_id=DN_News

read all on

Bacteroides thetaiotaomicron

http://microbewiki.kenyon.edu/index.php/Bacteroides_thetaiotaomicron

Isavuconazole – Basilea reports positive results from study

October 2, 2013 1:35 am / 6 Comments on Isavuconazole – Basilea reports positive results from study

Isavuconazole

4-{2-[(1R,2R)-(2,5-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile

[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol;

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol

241479-67-4 CAS

946075-13-4 cas of SULPHATE (USAN) in phase 3Aspergillosis, Infection, candidal, RO-0098557

ROCHE Originator

ChemSpider 2D Image | Isavuconazole | C22H17F2N5OS

30 September 2013

StockMarketWire.com – Basilea Pharmaceutica has revealed positive topline data from the isavuconazole phase 3 invasive aspergillosis study (SECURE). http://www.stockmarketwire.com/article/4677530/Basilea-reports-positive-results-from-study.htmlThe antifungal agent isavuconazole is being co-developed with Astellas Pharma Inc.The randomized, double-blind isavuconazole study (SECURE) achieved its primary objective in demonstrating non-inferiority versus voriconazole for the primary treatment of invasive fungal disease caused by Aspergillus species or certain other filamentous fungi.

This post is updated in sept 2015……..

BAL-4815, 241479-67-4, Bal4815, AC1OCFHQ, UNII-60UTO373KE, , BAL 4815, FT-0670421

Molecular Formula: C₂₂H₁₇F₂N₅OS Molecular Weight: 437.465086

Isavuconazole (BAL4815; trade name Cresemba) is a triazole antifungal drug. Its prodrug, isavuconazonium sulfate (BAL8557), was granted approval by the U.S. Food and Drug Administration (FDA) on March 6, 2015^[1]

During its Phase III drug trials, Astellas partnered with Basilea Pharmaceutica, the developer of the drug, for rights to co-development and marketing of isavuconazole. ^[2]

On May 28, 2013, Basilea Pharmaceutica announced it had been granted orphan drug status by the FDA for treatment of aspergillosis.^[3] Since then, it has also been granted orphan drug status for the treatment of invasive candidiasis.^[4]

Isavuconazonium sulfate (BAL8557)—a prodrug of isavuconazole.

Isavuconazium chloride hydrochloride (BAL-8557), a prodrug of Basilea Pharmaceutica’s BAL-4815 (isavuconazole), is a triazole in phase III clinical trials for the oral and intravenous treatment of severe fungal infections, including candidemia and other invasive Candida infections and invasive aspergillosis in immunocompromised patients. Additional phase III trials are ongoing for the treatment of invasive fungal infections caused by rare fungi. Phase II trials are ongoing for the treatment of candidal esophageal infection. Isavuconazole is water-soluble, highly bioavailable and can be administered in convenient once-daily or once-weekly dosing regimens.Originally developed at Roche, the drug candidate was subsequently acquired by Basilea. In May 2006, isavuconazium received fast track designation from the FDA for the treatment of infections caused by yeasts and molds, including fluconazole-resistant Candida strains, Aspergillus and zygomycetes in patients with weakened immune systems. In 2010, the product was licensed to Astellas Pharma by Basilea Pharmaceutica for codevelopment and copromotion worldwide, including an option for Japan, for the treatment of fungal infection. In 2013, FDA designated isavuconazium as a Qualified Infectious Disease Product (QIDP) designation for the treatment of invasive aspergillosis.

ISAVUCONAZOLE

CLINICAL TRIALS…LINK

PATENTS

US8207352	6-27-2012	Process for the manufacture of enantiomerically pure antifungal azoles as ravuconazole and isavuconazole
US2011281918	11-18-2011	Antifungal Composition
US7803949	9-29-2010	PROCESS FOR PREPARATION OF WATER-SOLUBLE AZOLE PRODRUGS
US7459561	12-3-2008	N-substituted carbamoyloxyalkyl-azolium derivatives
US7189858	3-14-2007	N-phenyl substituted carbamoyloxyalkyl-azolium derivatives
US6812238	11-3-2004	N-substituted carbamoyloxyalkyl-azolium derivatives
US6300353	10-10-2001	Azoles for treatment of fungal infections

Several azoles are currently used for systemic mycoses. However, none of them fulfills the needs of clinical requirement in full extent, particularly with regard 0 to broad antifungal spectrum including aspergillus fumigatus, less drug-drug interaction, and appropriate plasma half-life for once a day treatment. Other clinical requirements which are not fulfilled by the azoles currently used, are efficacy against major systemic mycoses including disseminated aspergillosis, safety, and oral or parenteral formulations. Particularly, demand of a 5 parenteral administration of the azoles is increasing for the treatment of serious systemic mycoses. Most of the azoles on the market as well as under development are highly lipophilic molecules that make the parenteral formulation difficult.

Isavuconazole [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol; formula I, R¹and R³represent fluorine and R²represents hydrogen] as well as Ravuconazole [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol; formula I, R¹and R²represent fluorine and R³represents hydrogen] are useful antifungal drugs as reported in U.S. Pat. No. 5,648,372 from Feb. 1, 1995 or in U.S. Pat. No. 5,792,781 from Sep. 18, 1996 or in U.S. Pat. No. 6,300,353 from Oct. 9, 2001 (WO99/45008).

Since compounds of general formula I contain two adjacent chiral centers, synthesis of enantiomerically pure compound is complex and until now, all patented syntheses are not efficient enough and do not allow cost effective manufacturing on a technical scale:

Thus, U.S. Pat. Nos. 5,648,372 or 5,792,781 describe enantioselective synthesis of compounds of formula I (specifically Ravuconazole) from chiral 3-hydroxy-2-methyl propionic acid in 12 steps with overall yield lower than 5%. In another approach including 13 steps and low overall yield, (R)-lactic acid was used as the starting material (Chem. Pharm. Bull. 46(4), 623 (1998) and ibid. 46(7), 1125 (1998)).

Because both starting materials contain only one chiral center, in a number of inefficient steps, the second, adjacent chiral center has to be created by a diastereoselective reaction (using either Corey or Sharpless epoxidation method) which is not sufficiently selective leading mostly to a mixture of two diastereomers which have to be separated.

The second approach, based on (R)-methyl lactate, was recently very thoroughly optimized by BMS on a multi kilogram scale but it still does not fulfill requirements for cost effective manufacturing process (Organic Process Research & Development 13, 716 (2009)). The overall yield of this optimized 11 steps process is still only 16% (Scheme 1).

The manufacturing process for Isavuconazole is similar: Since Isavuconazole differentiates from Ravuconazole by only another fluorine substitution on the aromatic ring (2,5- instead of 2,4-difluorophenyl), the identical synthesis has been used (U.S. Pat. No. 6,300,353 from Oct. 9, 2001 and Bioorg. & Med. Chem. Lett. 13, 191 (2003)). Consequently, also this manufacturing process, based on (R)-lactic acid, faces the same problems: to many steps, extremely low overall yield and in addition to U.S. Pat. No. 6,300,353 claims even already known step as novel (claim 36).

Recent attempts to improve this concept as reported in WO 2007/062542 (Dec. 1, 2005), using less expensive, natural configured (S)-lactic acid, also failed: As already reported in U.S. Pat. No. 6,133,485 and in US 2003/0236419, the second chiral center was formed from an optically active allyl alcohol prepared in a few steps from (S)-lactic acid.

This allyl alcohol was subjected to Sharpless diastereoselective epoxidation providing first an opposite configured, epimeric epoxy alcohol which had to be then epimerized in an additional inversion step yielding finally the desired epoxy alcohol as the known precursor for Isavuconazole (U.S. Pat. No. 6,300,353). It is obvious that this process using less expensive (S)-lactic acid makes the entire process with an inversion step even more complex than the original approach.

Elegant and more efficient process has been claimed in US 2004/0176432 from Jun. 26, 2001) in which both chiral centers have been formed simultaneously, diastereo- and enantio-selectively pure in one single reaction step using chiral (R)-2-butynol as a chiral precursor in the presence of Pd(II)-catalyst and diethyl zinc (Scheme 2).

Since water soluble, (R)-2-butynol is expensive, recently identical process has been published, in which instead of (R)-2-butynol less water soluble and therefore, less expensive (R)-4-phenyl-3-butyn-2-ol was used (Synthetic Commun. 39, 1611 (2009)). Nevertheless, as incorrectly stated there, this process does not provide better diastereoselectivity than the original process using (R)-2-butynol: On the contrary disadvantage of this process is a very bad atom economy because huge phenyl group of (R)-4-phenyl-3-butyn-2-ol has to be “disposed” in oxidation step by the conversion of triple bond into carboxylic acid function.

All known processes for enantiomerically pure compounds of formula I have definitely too many operation steps and specifically very low overall yield. The chiral starting materials used, either 3-hydroxy-2-methyl propionic acid or (S)- or (R)-methyl lactate, contain only one chiral center and consequently, in number of steps, the second adjacent chiral center has to be ineffectively generated which makes the entire process long and expensive. The only known process, which generates both chiral centers simultaneously, requires again expensive chiral starting material (R)-2-butynol.

ISAVUCONAZOLE

…………………………………………….

US6812238

synthetic scheme A, starting from 4-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propionyl]morpholine [which can be prepared by a same procedure as described in Chem. Pharm. Bull. 41, 1035, 1993.]. This synthesis route has been described for example in European Patent Application No. 99101360.8.

(a)

………………………………………………………………………

US8207352

Example 1 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol

To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (43.7 g) in acetone (800 ml) a solution of (1R)-10-camphorsulfonic acid (23 g) in methanol (300 ml) was added and the mixture was heated under reflux until a clear solution was obtained. The solution was slowly cooled to rt, seeded with crystals of the title enantiomeric salt and let overnight. The solid was collected by filtration, washed with acetone and dried to provide (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (1R)-10-camphorsulfonate as white solid. This crude salt was then taken up in methylenechloride (100 ml) and water (ca. 100 ml) and the mixture was basified with aqueous sodium hydroxide solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride (50 ml) and combined. The organic phases were then washed twice with water (2×50 ml), dried with sodium sulfate, filtrated and the solvent removed under reduced pressure. The crude product was then mixed with isopropanol (ca. 150 ml), heated for 10 min, cooled to 0° C. and stirred for ca. 2 hrs. The product was collected, washed with isopropanol and dried under reduced pressure to provide the enantiomerically pure title compound (17.5 g, 41% yield, 99.1% ee);

m.p. 164-166° C.; [α]=−30° (c=1, methanol, 25° C.);

NMR (CDCl3): 1.23 (3H, d, J=8 Hz), 4.09 (1H, q, J=8 Hz), 4.26 (1H, d, J=14 Hz), 4.92 (1H, d, J=14 Hz), 5.75 (1H, s), 6.75-6.85 (2H, m), 7.45-7.54 (2H, m), 7.62 (1H, s), 7.69 (1H, s), 7.75 (1H, d, J=8 Hz), 7.86 (1H, s), 8.03 (1H, d, J=8 Hz).

The analytical data were identical with published (U.S. Pat. No. 5,648,372 and Chem. Pharm. Bull. 1998, 46, 623-630).

Example 2 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol

Racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (44 g) and (1R)-10-camphorsulfonic acid (20 g) were suspended in methanol (ca. 300 ml), the slurry was stirred intensively, warmed up to ca. 70° C. and a small addition of acetic acid was added to obtain a clear solution. After cooling of the solution to rt and then to 0° C., the mixture was seeded with enantiomerically pure salt and stirred for another 2 hrs. The crystalline solid was collected by filtration, washed with cooled methanol and dried under reduced pressure. The crystals were partitioned between methylenechloride (300 ml) and saturated aqueous sodium bicarbonate solution (200 ml). The organic layer was washed twice with water (50 ml), dried with magnesium sulphate, filtrated and evaporated under reduced pressure to give the title compound (16.9 g, 38% yield, 95% ee). The analytical data were identical with published (U.S. Pat. No. 5,648,372 or Chem. Pharm. Bull. 1998, 46, 623).

Example 3 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol

To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (10 g) in acetone (ca. 200 ml) a solution of (1R)-10-camphorsulfonic acid (3.9 g) in methanol (50 ml) was added and the mixture was heated shortly under reflux until a clear solution was obtained. The solution was then slowly cooled to rt, seeded with crystals of the desired enantiomeric salt and let overnight. The solid precipitate was collected by filtration, washed with acetone and dried to provide (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (1R)-10-camphorsulfonate as white solid. This salt was then taken up in methylenechloride and water and basified with aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride. The organic phases were combined, dried with sodium sulphate, filtrated and the solvent removed under reduced pressure. The crude product was then dissolved in ethanol, the slurry heated for 20 min, small amount of water was added, the solution slowly cooled to 0° C. and stirred for ca. 2 hrs. The product was collected, washed with cold ethanol and dried under reduced pressure to provide the title enantiomerically pure compound (3.9 g, 39% yield, 96% ee). The analytical date were identical with published in U.S. Pat. No. 6,300,353 B1 and WO 99/45008.

Example 4 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol

To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (100 g) in acetone (1000 ml) a solution of (1R)-10-camphorsulfonic acid (47 g) in methanol (500 ml) was added at rt, then slurry was heated under stirring to almost reflux for ca. 30 min, then cooled slowly to rt, seeded with the pure enantiomeric salt and stirred over night. The solid was collected by filtration, washed with methanol/acetone mixture, dried under reduced pressure. The residue was taken up with a solvent mixture of methylenechloride/water and after addition of saturated aqueous sodium bicarbonate solution the organic phase was separated and aqueous phase washed twice with methylenechloride. The combined organic phases were filtrated, the solvent removed under reduced pressure. Recrystallization of the crude product from aqueous ethanol provided enantiomerically pure title compound: 39 g (39% yield, 92% ee). The analytical data were identical with published: U.S. Pat. No. 6,300,353 and WO 99/45008.

Example 5 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol

A solution of the racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (4.4 g) and (1R)-10-camphorsulfonic acid (2 g) in toluene (40 ml) containing glacial acetic acid (0.6 ml) was warmed up to approximately 70° C., then allowed to cool slowly to 20° C., seeded with the pure enantiomeric salt whereupon the pure enantiomeric salt start to crystallize out. After ca. 2 hrs at this temperature the solid was collected, washed with cold toluene and dried. The crystals were taken with a solvent mixture of methylenechloride/water and after addition of aqueous saturated sodium bicarbonate solution the organic phase was separated and aqueous phase washed twice with methylenechloride. The combined organic phases were filtrated and the solvent removed under reduced pressure. Recrystallization of the crude product from aqueous ethanol provided enantiomerically pure title compound: 2 g (45% yield, 99% ee). The analytical data were identical with published: U.S. Pat. No. 6,300,353 and WO 99/45008.

…………………………………..

WO 1999045008

US6300353

The following synthetic scheme 1 illustrates the manufacture of one of the compounds of formula I′:

……………………………….

Bioorganic and medicinal chemistry letters, 2003 , vol. 13, 2 p. 191 – 196

http://www.sciencedirect.com/science/article/pii/S0960894X02008922

A highly potent water soluble triazole antifungal prodrug, RO0098557 (1), has been identified from its parent, the novel antifungal agent RO0094815 (2). The prodrug includes a triazolium salt linked to an aminocarboxyl moiety, which undergoes enzymatic activation followed by spontaneous chemical degradation to release 2. Prodrug 1 showed high chemical stability and water solubility and exhibited strong antifungal activity against systemic candidiasis and aspergillosis as well as pulmonary aspergillosis in rats.





Scheme 1. Figure options Figure 1. Structure of RO0098557 and RO0094815. Chemistry Scheme 1. We synthesized a series of new triazolium derivatives of Figure 1, Figure 3 and Scheme 1. CompoundsScheme 1 and Scheme 2, 6, 9, 10 and 11 were first prepared as outlined in Scheme 2 in order to analyze their stability and ability to release Figure 1, Figure 3 and Scheme 1. Next, aromatic analogues 18, 19, 20,21 and Figure 1, Figure 3 and Scheme 3 were synthesized for optimization of 11 to increase its water solubility and conversion rate. Compounds in the second series had sarcosine esters⁶ to make them water soluble, and they were also designed to generate acetaldehyde⁷ instead of formaldehyde for a better safety profile. The synthetic procedures for the second series of the derivatives are outlined in Scheme 3. Scheme 2. (a) ClCOOCH₂Cl, diisopropylethylamine, CH₂Cl₂, rt (quant); (b) Figure 1, Figure 3 and Scheme 1, CH₃CN, 80 °C (60%); (c) (1) ClCOOCH₂Cl, Et₃N, CH₂Cl₂, rt; (2) Ac₂O, pyridine, rt (30%, two steps); (d) (1) NaI, CH₃CN, 50 °C ; (2) Figure 1, Figure 3 and Scheme 1, CH₃CN, 50 °C (88%, two steps); Synthesis of Scheme 1 and Scheme 2: (1) N-3-hydroxypropyl-N-methylamine, ClCOOCH₂Cl, Et₃N, CH₂Cl₂, rt; (2) AcCl, Et₃N, CH₂Cl₂, rt (20%, two steps); (3) Figure 1, Figure 3 and Scheme 1, NaI, CH₃CN, 50 °C (82%); Synthesis of 10: (1) l-prolinol, ClCOOCH₂Cl, Et₃N, CH₂Cl₂, rt; (2) Ac₂O, pyridine, rt (<10%, 2 steps); (3) Figure 1, Figure 3 and Scheme 1, NaI, CH₃CN, 50 °C (92%); Synthesis of 11: (1) 2-hydroxymethyl-N-methylaniline, ClCOOCH₂Cl, diisopropylethylamine, CH₂Cl₂, rt; (2) Ac₂O, diisopropylethylamine, rt (20%, two steps); (3)Figure 1, Figure 3 and Scheme 1, cat. NaI, CH₃CN, reflux (63%). Figure options Scheme 3. (a) (1) oxalyl chloride, DMF, 0 °C; (2) KO^tBu, THF, −5 °C (97%, two steps); (b) CH₃NH₂, MeOH, rt (90%); (c) LiAlH₄, THF, 0 °C (80%); (d) (1) ClCOOCH(CH₃)Cl, diisopropylethylamine, CH₂Cl₂, 0 °C; (2) Boc-Sarcosine, WSCI, DMAP, CH₂Cl₂, 0 °C (84%, two steps); (e) (1) Figure 1, Figure 3 and Scheme 1, NaI, CH₃CN, 50 °C; (2) DOWEX-1 Cl⁻ form, aqueous MeOH, rt (65%, two steps); (f) (1) HCl, EtOAc, rt; (2) lyophilization (69%, two steps); Synthesis of 18: (1) (i) (4,5-difluoro-2-methylaminophenyl)methanol, ClCOOCH(CH₃)Cl, diisopropylethylamine, CH₂Cl₂, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH₂Cl₂, 0 °C (quant, two steps); (2) Figure 1, Figure 3 and Scheme 1, cat. NaI, CH₃CN, 80 °C; (50%,); (3) HCl, EtOAc, rt (90%); Synthesis of 19: (1) (i) 2-fluoro-6-methylaminophenyl)methanol, ClCOOCH(CH₃)Cl, diisopropylethylamine, CH₂Cl₂, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH₂Cl₂, 0 °C (74%, two steps); (2) Figure 1, Figure 3 and Scheme 1, cat. NaI, CH₃CN, reflux; (3) HCl, EtOAc, rt (29%, two steps); Synthesis of 20: (1) (i) (5-fluoro-2-methylaminophenyl)methanol, ClCOOCH(CH₃)Cl, diisopropylethylamine, CH₂Cl₂, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH₂Cl₂, 0 °C (91%, two steps); (2) Figure 1, Figure 3 and Scheme 1, cat. NaI, CH₃CN, 70 °C (72%); (3) HCl, EtOAc, rt (88%); Synthesis of 21: (1) (i) (4-chloro-2-methylaminophenyl)methanol, ClCOOCH(CH₃)Cl, diisopropylethylamine, CH₂Cl₂, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH₂Cl₂, 0 °C (71%, two steps); (2) Figure 1, Figure 3 and Scheme 1, CH₃CN, 65 °C; (3) HCl, EtOAc, rt (65%, two steps).

read more at

Boyd, B.; Castaner, J. BAL-4815/BAL-8557
Drugs Fut 2006, 31(3): 187

Antimicrobial Agents and Chemotherapy, 2008 , vol. 52, 4 p. 1396 – 1400

Ohwada, J.; Tsukazaki, M.; Hayase, T.; Oikawa, N.; Isshiki, Y.; Umeda, I.; Yamazaki, T.; Ichihara, S.; Shimma, N.Development of novel water antifungal, RO0098557
21st Med Chem Symp (November 28-30, Kyoto) 2001, Abst 1P-06

Ohwada, J.; Tsukazaki, M.; Hayase, T.; et al.
RO0098557, a novel water soluble azole prodrug for parenteral and oral administration (I). Design, synthesis, physicochemical properties and bioconversion42nd Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 27-30, San Diego) 2002, Abst F-820

Tasaka et al., Chem. Pharm. Bull. 41(6) pp. 1035-1042 (1993).

Clinical trials

There have been three phase III clinical trials of isavuconazole, ACTIVE, VITAL and SECURE. As of June 2015, SECURE and VITAL have been presented in abstract form and results from ACTIVE have not been released.^[9]

The SECURE trial compared voriconazole and isavuconazole in invasive fungal infections due to aspergillus. Isuvaconazole was found to be non-inferior to voriconazole, anothertriazole antifungal, with all cause mortality at 18.6%, compared to 20.2% in the voriconazole group. It additionally demonstrated a similar side effect profile.^[10]

Data from the VITAL study showed that isavuconazole could be used in treatment of invasive mucormycosis, but did not evaluate its clinical efficacy for this indication.^[11]

The ACTIVE trial is a comparison of isuvaconazole and caspofungin for invasive candida infections and results are anticipated in the second half of 2015.^[12]^[13]

References

[1]
Saboo, Alok. “Basilea Announces Global Partnership With Astellas for Its Antifungal Isavuconazole.” FierceBiotech. N.p., 24 Feb. 2010. Web.
“Basilea reports isavuconazole orphan drug designation by U.S. FDA.” Market Wired. 28 May 2013.
“FDA Grants Orphan Drug Designation to Astellas for Isavuconazole for the Treatment of Invasive Candidiasis.” News Releases. Astellas. 3 Nov 2014.
Cresemba (isovuconazole sulfate) [prescribing information]. Astella Pharma US, Inc. Revised March 2015.
Jump up^ “Aspergillosis.” Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 08 Sept. 2014.
Jump up^ “Astellas Receives FDA Approval for CRESEMBA® (isavuconazonium Sulfate) for the Treatment of Invasive Aspergillosis and Invasive Mucormycosis.” PR Newswire. N.p., 6 Mar. 2015.
Jump up^ “Isavuconazonium.” Micromedex Solutions. Truven Health Analytics, n.d. Web. <www.micromedexsolutions.com>.
Jump up^ Pettit, Natasha N.; Carver, Peggy L. (2015-07-01). “Isavuconazole A New Option for the Management of Invasive Fungal Infections”. Annals of Pharmacotherapy 49 (7): 825–842.doi:10.1177/1060028015581679. ISSN 1060-0280. PMID 25940222.
Mujais, A. “2014: M-1756. A Phase 3 Randomized, Double-Blind, Non-Inferiority Trial Evaluating Isavuconazole (ISA) vs. Voriconazole (VRC) for the Primary Treatment of Invasive Fungal Disease (IFD) Caused by Aspergillus spp. or other Filamentous Fungi (SECURE): Outcomes by Malignancy Status”. http://www.icaaconline.com. Retrieved 2015-06-19.
“Abstract: An Open-Label Phase 3 Study of Isavuconazole (VITAL): Focus on Mucormycosis (IDWeek 2014)”. idsa.confex.com. Retrieved 2015-06-19.
Ltd., Basilea. “Basilea Pharmaceutica – Portfolio – Isavuconazole”. http://www.basilea.com. Retrieved 2015-06-19.
“Isavuconazole (BAL8557) in the Treatment of Candidemia and Other Invasive Candida Infections – Full Text View – ClinicalTrials.gov”. clinicaltrials.gov. Retrieved 2015-06-19.

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US5900486	Sep 9, 1997	May 4, 1999	Hoffmann-La Roche Inc.	N-benzylazolium derivatives
AU4536497A				Title not available
EP0667346A2	Feb 3, 1995	Aug 16, 1995	Eisai Co., Ltd.	Azole antifungal agents, process for the preparation there of and intermediates
WO1992017474A1	Mar 26, 1992	Oct 15, 1992	Pfizer	Triazole antifungal agents

US5648372	Feb 1, 1995	Jul 15, 1997	Eisai Co., Ltd.	Antifungal agents, and compositions
US5686646 *	May 23, 1995	Nov 11, 1997	Schering-Plough Corporation	Chiral hydrazine derivatives
US5746840 *	Mar 28, 1997	May 5, 1998	Janssen Pharmaceutica, N.V.	Process for preparing enantiomerically pure 6-{4-chlorophenyl) (1 H-1,2,4-triazol-1-YL) methyl}-1-methyl-1 H-benzotriazole
US5792781	Sep 18, 1996	Aug 11, 1998	Eisai Co., Ltd.	Antifungal agents, processes for the preparation thereof, and intermediates
US6020497	Oct 9, 1998	Feb 1, 2000	Merck & Co., Inc.	3-substitutes isoxazolidines as chiral auxiliary agents
US6133485	Apr 15, 1998	Oct 17, 2000	Synphar Laboratories, Inc.	Asymmetric synthesis of 2-(2,4-difluorophenyl)-1-heterocycl-1-yl butan-2,3-diols
US6300353	Mar 5, 1999	Oct 9, 2001	Basilea Pharmaceutica Ag, A Swiss Company	Azoles for treatment of fungal infections
US6383233	Mar 7, 1997	May 7, 2002	Reuter Chemicscher Apparatebau Kg	Separation process
US6812238 *	Oct 31, 2000	Nov 2, 2004	Basilea Pharmaceutica Ag	N-substituted carbamoyloxyalkyl-azolium derivatives
US7151182 *	Sep 3, 2004	Dec 19, 2006	Basilea Pharmaceutica Ag	Intermediates for N-substituted carbamoyloxyalkyl-azolium derivatives
US7803949 *	Dec 20, 2006	Sep 28, 2010	Eisai R&D Management Co., Ltd.	Process for preparation of water-soluble azole prodrugs
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US20040176432	Jun 17, 2002	Sep 9, 2004	Milan Soukup	Intermediate halophenyl derivatives and their use in a process for preparing azole derivatives
WO2003002498A1 *	Jun 17, 2002	Jan 9, 2003	Basilea Pharmaceutica Ag	Intermediate halophenyl derivatives and their use in a process for preparing azole derivatives

Isavuconazole
Systematic (IUPAC) name


4-{2-[(1R,2R)-(2,5-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile
Clinical data
Trade names	Cresemba (prodrug form)
AHFS/Drugs.com	entry
Pregnancy category	US: C (Risk not ruled out)
Legal status	US: ℞-only ℞ (Prescription only)
Routes of administration	Oral, intravenous
Identifiers
ATC code	None
PubChem	CID: 6918485
ChemSpider	5293682
UNII	60UTO373KE
ChEBI	CHEBI:85979
ChEMBL	CHEMBL409153
NIAID ChemDB	416566
Chemical data
Formula	C₂₂H₁₇F₂N₅O S
Molecular mass	437.47 g/mol

/////

FDA grants Arzerra ‘breakthrough’ designation for use with chlorambucil in CLL

September 15, 2013 2:57 am / 3 Comments on FDA grants Arzerra ‘breakthrough’ designation for use with chlorambucil in CLL

The FDA today granted “breakthrough therapy” designation to ofatumumab for treatment of patients with chronic lymphocytic leukemia.

The designation applies to use of ofatumumab (Arzerra, GlaxoSmithKline) in combination with chlorambucil in patients with untreated CLL who unsuitable for fludarabine-based therapy.

Ofatumumab is a human monoclonal antibody that targets an epitope on the CD20 molecule encompassing parts of the small and large extracellular loops.

read all at

http://www.healio.com/hematology-oncology/hematologic-malignancies/news/online/%7b7ad941c8-330f-45db-a359-381088d89808%7d/fda-grants-arzerra-breakthrough-designation-for-use-with-chlorambucil-in-cll

MACITENTAN , 马昔腾坦 , ماسيتانتان , Мацитентан , マシテンタン

September 15, 2013 1:40 am / 4 Comments on MACITENTAN , 马昔腾坦 , ماسيتانتان , Мацитентан , マシテンタン

MACITENTAN

N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide,

N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl] -N’-propylsulfamide

CAS NO 441798-33-0

ACT-064992, Opsumit,UNII-Z9K9Y9WMVL
Mechanism of Action: Endothelin receptor antagonist (ERA)
Date of Approval: October 18, 2013(US)
Indication: Pulmonary Hypertension (PAH)
Company: Actelion Pharmaceuticals Ltd
PCT patent application: WO2002053557

FDA N204410, MACITENTANTABLET; ORAL10MG, OPSUMIT, ACTELION PHARMS LTD

Macitentan is achiral

Macitentan is a crystalline powder that is insoluble in water. In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive.

Mp 135–136 °C;………….J. Med. Chem., 2012, 55 (17), pp 7849–7861, DOI: 10.1021/jm3009103/CN 104447572

R_f (silica gel, heptane:ethyl acetate 1:1) 0.44.

LC-MS: t_R = 0.79 min, [M + H]⁺ = 588.86 (major isotope).

HR-LC-MS: t_R = 1.96 min; (m + H)/z = 586.9711, found = 586.9714.

¹H NMR (CDCl₃): δ 8.51 (s, 2 H), 8.49 (s, 1 H), 7.58–7.63 (m, 2 H), 7.16–7.21 (m, 2 H), 6.88 (s, 1 H), 5.61 (t, J = 6.2 Hz, 1 H), 4.72–4.76 (m, 2 H), 4.62–4.66 (m, 2 H), 2.99 (q, J = 6.8 Hz, 2 H), 1.61 (h, J = 7.3 Hz, 2 H), 0.97 (t, J = 7.4 Hz, 3 H)……………..J. Med. Chem., 2012, 55 (17), pp 7849–7861,DOI: 10.1021/jm3009103

¹³C NMR (CDCl₃): δ 11.6, 22.7, 46.1, 65.3, 65.9, 104.8, 112.4, 123.7, 128.0, 131.7, 133.0, 155.7, 156.4, 159.7, 163.5, 166.3…………….J. Med. Chem., 2012, 55 (17), pp 7849–7861,DOI: 10.1021/jm3009103

Macitentan (Opsumit® )is a novel dual endothelin receptor antagonist that resulted from a tailored drug discovery process. Macitentan has a number of potentially key beneficial characteristics – i.e., increased in vivo preclinical efficacy vs. existing ERAs resulting from sustained receptor binding and tissue penetration properties. A clinical pharmacology program indicated a low propensity of macitentan for drug-drug interactions.

Macitentan (ACT-064992) is a tissue-targeting dual ET(A)/ET(B) endothelin (ET) receptor antagonist designed for tissue targeting. Macitentan inhibited ET-1-induced contractions in isolated endothelium-denuded rat aorta (ET(A) receptors) and sarafotoxin S6c-induced contractions in isolated rat trachea (ET(B) receptors). In diabetic rats, chronic administration of macitentan decreased blood pressure and proteinuria and prevented end-organ damage. Treatment with macitentan enhanced the cytotoxicity mediated by paclitaxel as measured by the degree of apoptosis in tumor cells and tumor-associated endothelial cells. A Phase III clinical trial of macitentan was successfully completed in 2012.

Macitentan is an investigational drug being studied for the treatment of pulmonary arterial hypertension. It acts as a dualendothelin receptor antagonist and is being developed by Actelion.^[1] A Phase III clinical trial was successfully completed in 2012.^[2]

on 22 October 2012 – Actelion (SIX: ATLN) announced that it has submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) seeking approval for macitentan (Opsumit®) for the treatment of patients with pulmonary arterial hypertension

Actelion’s experimental lung drug macitentan prolonged overall survival by more than a third according to detailed study data, which the company hopes will convince investors it has a viable follow-up product to secure its commercial future.

Europe’s largest standalone biotech company wants the drug, which treats pulmonary arterial hypertension — a disease that causes high blood pressure in the arteries of the lungs — to replace blockbuster Tracleer.

Tracleer currently makes up 87 percent of sales but loses patent protection in 2015 and has also seen its market share eroded by Gilead’s Letairis.

Pharmacokinetics

Macitentan has an active metabolite, ACT-132577, which is an oxidative depropylation product. Both macitentan and ACT-132577 are mainly excreted in form of hydrolysis products via urine (about 2/3 of all metabolites) and faeces (1/3).^[3]

Co-administration of ciclosporin has only a slight effect on the concentrations of macitentan and its active metabolite, whilerifampicin decreases the area under the curve (AUC) of the drug’s blood plasma concentration by 79%, and ketoconazoleapproximately doubles it. This corresponds to the finding that macitentan is mainly metabolised via the liver enzyme CYP3A4.^[4]

SYNTHESIS

The synthesis begins with the reaction of chlorosulfonyl isocyanate (1) (dissolved in dichloromethane at 0 ° C) with one equivalent of tert-butanol. This produces a by BOC protected Aminosulfonylchlorid (2). With one equivalent of n-propylamine (dissolved in 3 eq. Of triethylamine, dichloromethane, at 0 ° C, RT 16 h) is produced by a hydrochloric acid elimination BOC-protected sulfamide (3). This is dissolved in 5 M HCl and dioxane (4-8 h), the BOC protecting group is cleaved. The sulfamide formed (4) is potassium tert-butoxide-(dissolved in MeOH, 3h) is converted to the potassium salt (5). Tert-butoxide potassium acts as a very strong base for deprotonation. This sulfamide potassium salt reacts with the nucleophilic substituents on the heteroaromatic Dichlorpyrimidinderivat (6) (dissolved in dimethyl sulfoxide, at room temperature, RT 42-72 h) under KCl-cleavage to a Monochlorpyrimidin intermediate (7). By treatment with ethylene glycol (dissolved in dimethyl ether, potassium-tert-butoxide,), the ethylene glycol side chain is generated (8). With 2-chloro-5-bromo-pyrimidine (dissolved in tetrahydrofuran, close, at 60-75 ° C) is formed under elimination of HCl in an S _N 1 reaction Macitentan (9)…………Journal of Medicinal Chemistry 55, 2012 S. 7849-7861, doi : 10.1021 / jm3009103 .

Synthesis of Macitentan

…………………………………………….

SYNTHESIS

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………………………….

SYNTHESIS

(WO2006/051502A2, JMC2012, 7849). Chlorosulfonyl isocyanate ( 1 ) reaction with tert-butyl alcohol 2 , which is then reacted with n-propylamine 3 . 3 de-boc protected through the acid after reaction with potassium t-butoxide 4 . Another compound 5 with NaH after acidic protons off with dimethyl carbonate ( 6 ) to obtain 7 . 7 and formamidine hydrochloride ( 8 ) to ring chlorinated later POCl3 9 . 9 and 4 SNAr reaction occurs 10 . 10under basic conditions with ethylene glycol SNAr reaction occurs again in alkaline conditions with11 SNAr reaction occurs MACITENTAN.

………………………

http://www.google.com/patents/WO2014155304A1?cl=en

LC-MS (Agilent MS detector G1956B with Agilent 1200 Binary Pump and DAD).

Parameters of the LC-MS method:

Injection volume: 2 |jL

Column: Kinetex C18, 2.6 μιη, 2.1 x 50 mm

Column flow rate: 1 mL/min

Eluents: Eluent A: water + 0.08% TFA

Eluent B: MeCN + 0.012% TFA

Gradient: 2.0 min 95% B

2.8 min 95% B

3.0 min 5% B

Temperature: 40°C Detector wavelength 210 nm

Preparation B: N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]- 4-pyrimidinyl] -N’-propylsulfamide (macitentan):

N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane- 1-sulfamide (200 g; 0.46 mol; see Example 2 or 3) and 5-bromo-2-chloropyrimidine (117 g; 0.60 mol; 1.3 eq) were dissolved in toluene (3 L) and DMF (400 mL). The reaction mixture was warmed up to 50°C and toluene (approx. 400 mL) was distilled our under reduced pressure. The mixture was cooled to 0 °C and tBuOK (156 g, 3 eq, 1.38 mol) was added portionwise. It was stirred at 20 °C for 1 h. Water (1 L) was added and the pH of the solution was adjusted to 3-5 using 33% aq. HC1. The mixture was heated to 50°C and the layers were separated. The org. phase was treated with charcoal at 50°C and filtered over Celite. The filter cake was rinsed with toluene. At 50°C, water (1 L) was added to the org. layer. The layers were separated. The org. layer was concentrated under reduced pressure to a total volume of 1 L and cooled to 0°C. The solid obtained was filtered off. It was rinsed with toluene and MeOH. The crude material was suspended in EA (1 L) and heated to 50°C. 300 mL of EA were distilled out and MeOH (400 mL) was added. The suspension was cooled down to 0°C. The solid was filtered off, rinsed with MeOH and dried under reduced pressure to afford the title compound as a white solid (225 g; 83% yield).

……………………

PAPER

http://pubs.acs.org/doi/abs/10.1021/jm3009103

J. Med. Chem., 2012, 55 (17), pp 7849–7861

DOI: 10.1021/jm3009103

Starting from the structure of bosentan (1), we embarked on a medicinal chemistry program aiming at the identification of novel potent dual endothelin receptor antagonists with high oral efficacy. This led to the discovery of a novel series of alkyl sulfamide substituted pyrimidines. Among these, compound 17 (macitentan, ACT-064992) emerged as particularly interesting as it is a potent inhibitor of ET_A with significant affinity for the ET_B receptor and shows excellent pharmacokinetic properties and high in vivo efficacy in hypertensive Dahl salt-sensitive rats. Compound 17 successfully completed a long-term phase III clinical trial for pulmonary arterial hypertension

N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (17)

………………………….. to give 17 (11.99 g, 88%) as a white powder;

mp 135–136 °C; R_f (silica gel, heptane:ethyl acetate 1:1) 0.44.

LC-MS: t_R = 0.79 min, [M + H]⁺ = 588.86 (major isotope).

HR-LC-MS: t_R = 1.96 min; (m + H)/z = 586.9711, found = 586.9714.

¹³C NMR (CDCl₃): δ 11.6, 22.7, 46.1, 65.3, 65.9, 104.8, 112.4, 123.7, 128.0, 131.7, 133.0, 155.7, 156.4, 159.7, 163.5, 166.3.

……………

WO 2015004265 click

Example 3 : N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)pr opane- 1- sulfamide (reaction in and work-up with MIBK):

EG (124 mL, 3.7 mol, 6.0 eq.) was added to a warm (40-50°C) suspension of the compound of Preparation A (150 g, 0.37 mol) in MIBK (600 mL). Solid KOtBu (114 g, 1.11 mol, 3.0 eq.) was added portionwise so that IT < 60°C. The mixture was stirred for

2- 3 h at 100-105°C. After completion of the reaction (LC-MS control), it was cooled to 50 °C. A 40%) aq. solution of citric acid monohydrate (300 mL) was added until pH 4 was reached. The layers were separated. The org. phase was washed with water (450 mL) and the layers were separated. Water (450 mL) was added and the mixture was warmed to 50°C. It was stirred at 50°C for 5 min. The layers were separated. The org. phase was concentrated under vacuum at 50°C until 200 mL of MIBK were removed. Hept (800 mL) was added dropwise at 70-75°C until turbidity was observed. The mixture was seeded with an analytically pure sample of N-(5-(4-bromophenyl)-6-(2 hydroxy ethoxy)pyrimidin-4-yl)propane-l-sulfamide and stirred at 60-65°C for 30 min. It was allowed to cool to 5°C within 5 h. It was filtered off, rinsed with a cold MIBK/Hept mixture (300 mL, 1 : 1) and dried under vacuum at 50°C to yield the title compound as a white solid (121 g; 76% yield).

The product had NMR data equivalent to those reported in Bolli et al, J. Med. Chem. (2012), 55, 7849-7861. [M+H]⁺ = 430 and 432. LC-MS: t_R = 1.46 min; purity: 98.4% a/a. Residual ethylene glycol (GC-FID): 530 ppm.

…….

CN 104447572 click

(l) Martin H. Bolli et al. Reported the synthesis of Marcy cefotetan follows:

[0008] The method W 5- (4- desert phenyl) -4,6-dichloro-chewing clever as a starting material, N- propyl amine Lai ugly bell in DMS0 as a reaction solvent, an alcohol bell as t a base under substitution reaction conditions, the reaction temperature needs of 24-7 to give

The intermediate compound 15, compound 15 in hexylene glycol dimethyl off as the reaction solvent, a tertiary alcohol under conditions with a strong base clock as hexanediol substitution reaction, l〇 (TC Reaction of 18-2 to give compound 17, Compound 17 was then reacted with 5-chloro-chewing desert -2 clever substitution reaction at tetraammine Qiao Nan as a reaction solvent, ammoniated axis as the alkali conditions, the reaction to give the final product of Marcy cefotetan The route every step the higher the yield, the experimental use of N- propyl amine Lai ugly bell hygroscopic, unstable and a long time before the two-step reaction, the reaction at the second step requires l〇 (TC high temperature 18-2 technology is not suitable for industrial production.

[0009] International Patent W02002 / 053557 discloses some preparation methods and other Massey cefotetan column derivative method at each step of the preparation of the reaction times are longer, some reactions up to 4 days, and the resulting intermediate are purified by column chromatography method is not suitable for industrial production.

A method for preparing Marcy cefotetan, comprising the steps of: (1) the compound of formula II with N- cyclopropyl sulfonamide compound of formula III 5- (4- bromophenyl) -4, 6- dichloropyrimidine substitution reaction is converted to the formula IV:

Compound (2) in the presence of a strong base of formula IV with a compound of formula V glycol substitution reaction to give a compound of formula VI:

Compound (3) a strong base of formula VI in the presence of a substitution reaction conditions to give a compound of formula I with a compound of formula W occurs:

, The resulting compound of formula I as Marcy cefotetan.

[00 pairs (3) N- [5- (4- desert) -6-mouth – [(5-desert -2- chew clever-yl) oxy] hexyl oxy] -4-chewing clever yl] -N ‘- Lai ugly propyl amine (Formula I) Synthesis

[0036] Weigh 20gN-5- (4- desert) -6- (2-2- light hexyl group -) 4- chew clever group -N ‘- Lai ugly propyl amine, 200ml dried DMS0 added to 1L H jar, add 20g of alcohol t-clock was added in portions, then add 17. 7g5- desert – dichloro chew clever, 30-4 (TC reduction reaction, the reaction and the reaction solution. a 10% sample skillfully acid to adjust PH value 3 to 4, the reaction mixture was added to 1000ml water, olive mix, suction. suction Massey cefotetan get wet crude product 42g, 450ml of methanol was added at room temperature and then beating 20min, filtration and dried 45C to give white solid was dried under vacuum to give 23.2 Marcy cefotetan yield;.. 85%

[0037] The compound (Formula I) relating to the physical and chemical properties, spectroscopic data are as follows:

[0038] branded point; 135-136 ° C; we NMR (300MHz, DMS0) 5 (egg m):… 9 8 (s, lH), 8 7 (s, 2H), 8 5 (s, l H,) 7. 5 (s, 2H), 7. 2 (s, IH), 7. 1 (s, 2H,) 4. 7 (s, 2H), 4. 6 (s, 2H,) 2. 8 (s, 2H,), 1. 5 (m, 2H,), 0. 81 (m, 3H), MS Qiaoqiao m / z 589 ([M + Tin +).

…………

see

WO 2002053557

http://www.google.com/patents/WO2002053557A1?cl=en

………..

NMR spectroscopy

Assignment of the signals mentioned in the text of the H-NMR spectrum of the drug Macitentan

¹ H-NMR

Solvent: CDCl ₃

δ 8.51 (s, 2H, CH) ¹¹ , 8.49 (s, 1 H, CH) ¹⁰ , 7.58 to 7.63 (m, 2H, CH) ⁹ , 7.16 to 7.21 ( m, 2H, CH) ⁸ , 6.88 (s, 1H, NH) ⁷ , 5.61 (t, J = 6.2 Hz, 1H, NH) ⁶ , 4.72 to 4.76 (m, 2H , CH ₂ ) ⁵ , 4.62 to 4.66 (m, 2H, CH ₂ ) ⁴ , 2.99 (q, J = 6.8 Hz, 2H, CH ₂ ) ³ , 1.61 (h, J = 7.3 Hz, 2H, CH₂ ) ² , 0.97 (t, J = 7.4 Hz, 3H, CH ₃ ) ¹ . ^{[Journal of Medicinal Chemistry 55, 2012 S. 7849-7861, doi : 10.1021 / jm3009103 .]}

……………………………………………………………………………………

Gatfield, John; Grandjean, Celia Mueller; Bur, Daniel; Bolli, Martin H.; Nayler, Oliver (2014): Proton assignment in macitentan as used in NMR interpretation.Figure_9.tif. PLOS ONE. 10.1371/journal.pone.0107809.g009.

¹³ C-NMR

Solvent: CDCl ₃

δ 11.6, 22.7, 46.1, 65.3, 65.9, 104.8, 112.4, 123.7, 128.0, 131.7, 133.0, 155.7, 156 , 4, 159.7, 163.5, 166.3. ^{[ Journal of Medicinal Chemistry 55, 2012 S. 7849-7861, doi : 10.1021 / jm3009103 . ]}

NMR PREDICT BY ME

1H NMR PREDICT

13C NMR PREDICT BY ME

COSY PREDICT BY ME, WORLDDRUGTRACKER ON A WHEELCHOPPER SCALING NEW HEIGHTS

REFERENCES

Bolli, M. H.; Boss, C.; Binkert, C.; Buchmann, S.; Bur, D.; Hess, P.; Iglarz, M.; Meyer, S.; Rein, J.; Rey, M.; Treiber, A.; Clozel, M.; Fischli, W.; Weller, T. (2012). “The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist”. Journal of Medicinal Chemistry 55 (17): 7849–7861. doi:10.1021/jm3009103. PMID 22862294.
“Macitentan”. Actelion. Retrieved 22 August 2012.
Bruderer, S.; Hopfgartner, G. R.; Seiberling, M.; Wank, J.; Sidharta, P. N.; Treiber, A.; Dingemanse, J. (2012). “Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans”. Xenobiotica 42 (9): 901–910.doi:10.3109/00498254.2012.664665. PMID 22458347.
Bruderer, S.; Äänismaa, P. I.; Homery, M. C.; Häusler, S.; Landskroner, K.; Sidharta, P. N.; Treiber, A.; Dingemanse, J. (2011).“Effect of Cyclosporine and Rifampin on the Pharmacokinetics of Macitentan, a Tissue-Targeting Dual Endothelin Receptor Antagonist”. The AAPS Journal 14 (1): 68–78. doi:10.1208/s12248-011-9316-3. PMC 3282010. PMID 22189899.
Bolli, M. H.; Boss, C.; Binkert, C.; Buchmann, S.; Bur, D.; Hess, P.; Iglarz, M.; Meyer, S.; Rein, J.; Rey, M.; Treiber, A.; Clozel, M.; Fischli, W.; Weller, T. (2012). “The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist“. Journal of Medicinal Chemistry, 2012, 55 (17): 7849–7861
Martin Bolli, Christoph Boss, Martine Clozel, Walter Fischli, Thomas Weller, Novel sulfamides and their use as endothelin receptor antagonists, WO2002053557 A1, CA2431675A1, CA2431675C, CN1524079A, CN100432070C, DE60118782D1, DE60118782T2, EP1345920A1, EP1345920B1, EP1693372A1, US7094781, US7285549, US20040077670, US20060178365,
Martin Bolli, Christoph Boss, Martine Clozel, Walter Fischli, Thomas Weller, Sulfamides as endothelin receptor antagonists for the treatment of cardiovascular diseases, WO2006051502
Martine Clozel, Therapeutic compositions containing macitentan,WO2010018549 A2, CA2731370A1, CN102099026A, CN102099026B, EP2315587A2, US20110136818(WO2006/051502A2, JMC2012, 7849). Chlorosulfonyl isocyanate ( 1 ) reaction with tert-butyl alcohol 2 , which is then reacted with n-propylamine 3 . 3 de-boc protected through the acid after reaction with potassium t-butoxide 4 . Another compound 5 with NaH after acidic protons off with dimethyl carbonate ( 6 ) to obtain 7 . 7 and formamidine hydrochloride ( 8 ) to ring chlorinated later POCl3 9 . 9 and 4 SNAr reaction occurs 10 . 10under basic conditions with ethylene glycol SNAr reaction occurs again in alkaline conditions with11 SNAr reaction occurs MAXI cefotetan.

External links

Actelion home page

Actelion Ltd

Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion’s first drug Tracleer®, an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union, Japan, Canada, Australia and Switzerland. Actelion, founded in late 1997, is a leading player in innovative science related to the endothelium – the single layer of cells separating every blood vessel from the blood stream. Actelion’s over 2,400 employees focus on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SIX Swiss Exchange (ticker symbol: ATLN) as part of the Swiss blue-chip index SMI (Swiss Market Index SMI®).

Macitentan
Systematic (IUPAC) name

N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide
Clinical data
Trade names	Opsumit
Pregnancy category	US: X (Contraindicated)
Legal status	US: ℞-only FDA approved drug
Routes of administration	Oral
Pharmacokinetic data
Metabolism	Hydrolysis, oxidation (CYP3A4)
Excretion	2/3 urine, 1/3 faeces
Identifiers
CAS Registry Number	441798-33-0
ATC code	C02KX04
PubChem	CID: 16004692
ChemSpider	13134960
ChEBI	CHEBI:76607
Synonyms	ACT-064992
Chemical data
Formula	C₁₉H₂₀Br₂N₆O₄S
Molecular mass	588.273 g/mol

Patent	Submitted	Granted
Sulfamides and their use as endothelin receptor antagonists [US7094781]	2004-04-22	2006-08-22
Sulfamides and their use as endothelin receptor antagonists [US7285549]	2006-08-10	2007-10-23
Stable Pharmaceutical Compositions Comprising a Pyrimidine – Sulfamide [US2008233188]	2008-09-25
Combination Comprising Paclitaxel for Treating Ovarian Cancer [US2010311774]	2010-12-09
Stable pharmaceutical compositions comprising a pyrimidine-sulfamide [US2010004274]	2010-01-07
SULFONYLUREA MODULATORS OF ENDOTHELIN RECEPTOR [US2011082151]	2011-04-07
ENDOTHELIN RECEPTOR ANTAGONISTS FOR EARLY STAGE IDIOPATHIC PULMONARY FIBROSIS [US2010022568]	2007-04-12	2010-01-28
THERAPEUTIC COMPOSITIONS CONTAINING MACITENTAN [US2011136818]	2011-06-09
Therapeutic Compositions Comprising a Specific Endothelin Receptor Antagonist and a PDE5 Inhibitor [US2009318459]	2009-12-24

Patent and Exclusivity

Patent Data

Appl No	Prod No	Patent No	Patent Expiration	Drug Substance Claim	Drug Product Claim	Patent Use Code
N204410	001	US7094781	Oct 12, 2022	Y	Y
N204410	001	US8268847	Apr 18, 2029			U – 1446
N204410	001	US8367685	Oct 4, 2028		Y	U – 1445

Exclusivity Data

Appl No	Prod No	Exclusivity Code	Exclusivity Expiration
N204410	001	ODE	Oct 18, 2020
N204410	001	NCE	Oct 18, 2018

U1446 METHOD OF TREATING PULMONARY HYPERTENSION COMPRISING ADMINISTERING MACITENTAN IN COMBINATION WITH A COMPOUND HAVING PHOSPHODIESTERASE-5 INHIBITORY PROPERTIES

U1445 METHOD OF TREATING PULMONARY ARTERIAL HYPERTENSION BY ADMINISTERING A PHARMACEUTICAL COMPOSITION COMPRISING MACITENTAN AND A POLYSORBATE, WHERIN THE POLYSORBATE REPRESENTS 0.1 TO 1% OF THE WEIGHT OF SAID PHARMACEUTICAL COMPOSITION

OPSUMIT (macitentan) is an endothelin receptor antagonist. The chemical name of macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide. It has a molecular formula of C₁₉H₂₀Br₂N₆O₄S and a molecular weight of 588.27. Macitentan is achiral and has the following structural formula:

OPSUMIT® (macitentan) Structural Formula Illustration

Macitentan is a crystalline powder that is insoluble in water. In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive.

OPSUMIT is available as a 10 mg film-coated tablet for once daily oral administration. The tablets include the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, and sodium starch glycolate Type A. The tablets are film-coated with a coating material containing polyvinyl alcohol, soya lecithin, talc, titanium dioxide, and xanthan gum.

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Gatfield, John; Grandjean, Celia Mueller; Bur, Daniel; Bolli, Martin H.; Nayler, Oliver (2014): Proton assignment in macitentan as used in NMR interpretation.Figure_9.tif. PLOS ONE. 10.1371/journal.pone.0107809.g009.

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