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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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Reldesemtiv


Reldesemtiv.png

Image result for Reldesemtiv

Reldesemtiv

CK-2127107

CAS 1345410-31-2

UNII-4S0HBYW6QE, 4S0HBYW6QE

MW 384.4 g/mol, MF C19H18F2N6O

1-[2-({[trans-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl]methyl}amino)pyrimidin-5-yl]-1H-pyrrole-3- carboxamide

1-[2-[[3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl]methylamino]pyrimidin-5-yl]pyrrole-3-carboxamide

Reldesemtiv, also known as CK-2127107, is a skeletal muscle troponin activator (FSTA) and is a potential treatment for people living with debilitating diseases and conditions associated with neuromuscular or non-neuromuscular dysfunction, muscular weakness, and/or muscle fatigue such as SMA, COPD, and ALS.

Cytokinetics , in collaboration with  Astellas , is developing reldesemtiv, the lead from a program of selective fast skeletal muscle troponin activators, in an oral suspension formulation, for the treatment of indications associated with neuromuscular dysfunction, including spinal muscular atrophy and amyotrophic lateral sclerosis.

  • Originator Cytokinetics
  • Developer Astellas Pharma; Cytokinetics
  • Class Pyridines; Pyrimidines; Pyrroles; Small molecules
  • Mechanism of Action Troponin stimulants
  • Orphan Drug Status Yes – Spinal muscular atrophy
  • Phase II Amyotrophic lateral sclerosis; Chronic obstructive pulmonary disease; Spinal muscular atrophy
  • Suspended Muscle fatigue
  • No development reported Muscular atrophy
  • 05 May 2019 Safety and efficacy data from the phase II FORTITUDE-ALS trial in Amyotrophic lateral sclerosis presented at the American Academy of Neurology Annual Meeting (AAN-2019)
  • 07 Mar 2019 Cytokinetics completes the phase III FORTITUDE-ALS trial for Amyotrophic lateral sclerosis in USA, Australia, Canada, Spain, Ireland and Netherlands (PO) (NCT03160898)
  • 22 Jan 2019 Cytokinetics plans a phase I trial in Healthy volunteers in the first quarter of 2019

Reldesemtiv, a next-generation, orally-available, highly specific small-molecule is being developed by Cytokinetics, in collaboration with Astellas Pharma, for the improvement of skeletal muscle function associated with neuromuscular dysfunction, muscle weakness and/or muscle fatigue in spinal muscular atrophy (SMA), chronic obstructive pulmonary disease (COPD) and amyotrophic lateral sclerosis (ALS). The drug candidate is a fast skeletal muscle troponin activator (FSTA) or troponin stimulant intended to slow the rate of calcium release from the regulatory troponin complex of fast skeletal muscle fibers. Clinical development for ALS, COPD and SMA is underway in the US, Australia, Canada, Ireland, Netherlands and Spain. No recent reports of development had been identified for phase I development for muscular atrophy in the US. Due to lack of of efficacy determined at interim analysis Cytokinetics suspended phase I trial in muscle fatigue in the elderly.

The cytoskeleton of skeletal and cardiac muscle cells is unique compared to that of all other cells. It consists of a nearly crystalline array of closely packed cytoskeletal proteins called the sarcomere. The sarcomere is elegantly organized as an interdigitating array of thin and thick filaments. The thick filaments are composed of myosin, the motor protein responsible for transducing the chemical energy of ATP hydrolysis into force and directed movement. The thin filaments are composed of actin monomers arranged in a helical array. There are four regulatory proteins bound to the actin filaments, which allows the contraction to be modulated by calcium ions. An influx of intracellular calcium initiates muscle contraction; thick and thin filaments slide past each other driven by repetitive interactions of the myosin motor domains with the thin actin filaments.

[0003] Of the thirteen distinct classes of myosin in human cells, the myosin-II class is responsible for contraction of skeletal, cardiac, and smooth muscle. This class of myosin is significantly different in amino acid composition and in overall structure from myosin in the other twelve distinct classes. Myosin-II forms homo-dimers resulting in two globular head domains linked together by a long alpha-helical coiled-coiled tail to form the core of the sarcomere’s thick filament. The globular heads have a catalytic domain where the actin binding and ATPase functions of myosin take place. Once bound to an actin filament, the release of phosphate (cf. ADP-Pi to ADP) signals a change in structural conformation of the catalytic domain that in turn alters the orientation of the light-chain binding lever arm domain that extends from the globular head; this movement is termed the powerstroke. This change in orientation of the myosin head in relationship to actin causes the thick filament of which it is a part to move with respect to the thin actin filament to which it is bound. Un-binding of the globular head from the actin filament (Ca2+ regulated) coupled with return of the catalytic domain and light chain to their starting conformation/orientation completes the catalytic cycle, responsible for intracellular movement and muscle contraction.

Tropomyosin and troponin mediate the calcium effect on the interaction on actin and myosin. The troponin complex is comprised of three polypeptide chains: troponin C, which binds calcium ions; troponin I, which binds to actin; and troponin T, which binds to tropomyosin. The skeletal troponin-tropomyosin complex regulates the myosin binding sites extending over several actin units at once.

Troponin, a complex of the three polypeptides described above, is an accessory protein that is closely associated with actin filaments in vertebrate muscle. The troponin complex acts in conjunction with the muscle form of tropomyosin to mediate the

Ca2+ dependency of myosin ATPase activity and thereby regulate muscle contraction. The troponin polypeptides T, I, and C, are named for their tropomyosin binding, inhibitory, and calcium binding activities, respectively. Troponin T binds to tropomyosin and is believed to be responsible for positioning the troponin complex on the muscle thin filament. Troponin I binds to actin, and the complex formed by troponins I and T, and tropomyosin inhibits the interaction of actin and myosin. Skeletal troponin C is capable of binding up to four calcium molecules. Studies suggest that when the level of calcium in the muscle is raised, troponin C exposes a binding site for troponin I, recruiting it away from actin. This causes the tropomyosin molecule to shift its position as well, thereby exposing the myosin binding sites on actin and stimulating myosin ATPase activity.

U.S. Patent No. 8962632 discloses l-(2-((((trans)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide, a next-generation fast skeletal muscle troponin activator (FSTA) as a potential treatment for people living with debilitating diseases and conditions associated with neuromuscular or non-neuromuscular dysfunction, muscular weakness, and/or muscle fatigue.

PATENT

WO 2011133888

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011133888&recNum=202&docAn=US2011033614&queryString=&maxRec=57668

PATENT

WO2016039367 ,

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016039367&tab=FULLTEXT

claiming the use of a similar compound for treating stress urinary incontinence.

Compound A is 1- [2-({[trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl] methyl} amino) pyrimidin-5-yl] -1H Pyrrole-3-carboxamide, which is the compound described in Example 14 of the aforementioned US Pat. The chemical structure is as shown below.
[Chemical formula 1]

PATENT

WO-2019133605

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019133605&tab=PCTDESCRIPTION&_cid=P11-JXY4C3-99085-1

Process for preparing reldesemtiv , a myosin, actin, tropomyosin, troponin C, troponin I, troponin T modulator, useful for treating neuromuscular disorders, muscle wasting, claudication and metabolic syndrome.

Scheme 1

[0091] Scheme 1 illustrates a scheme of synthesizing the compound of Formula (1C).

Scheme 2

[0092] Scheme 2 illustrates an alternative scheme of synthesizing the compound of Formula (1C).

M

TFAA DS, toluene

Et

to


HCI, H20

50°C

Scheme 3

[0093] Scheme 3 illustrates a scheme of converting the compound of Formula (1C) to the compound of Formula (II).

H2

Ni Raney

NH3

Scheme 4

[0094] Scheme 4 illustrates a scheme of converting the compound of Formula (II) to the compound of Formula (1).

Examples

[0095] To a flask was added N-methylpyrrolidone (30 mL), tert-butyl cyanoacetate (8.08 g) at room temperature. To a resulting solution was added potassium tert-butoxide (7.71 g), l,3-dibromo-2,2-dimethoxy propane (5.00 g) at 0 °C. To another flask, potassium iodide (158 mg), 2,6-di-tert-butyl-p-cresol (42 mg), N-methylpyrrolidone (25 mL) were added at room temperature and then resulting solution was heated to 165 °C. To this solution, previously prepared mixture was added dropwise at 140-165 °C, then stirred for 2 hours at 165 °C. To the reaction mixture, water (65 mL) was added. A resulting solution was extracted with toluene (40 mL, three times) and then combined organic layer was washed with water (20 mL, three times) and 1N NaOH aq. (20 mL). A resulting organic layer was concentrated below 50 °C under reduced pressure to give 3, 3 -dimethoxy cyclobutane- l-carbonitrile (66% yield,

GC assay) as toluene solution. 1H MR (CDCl3, 400 MHz) d 3.17 (s, 3H), 3.15 (s, 3H), 2.93-2.84 (m, 1H), 2.63-2.57 (m, 2H), 2.52-2.45 (m, 2H).

Example 2 Synthesis of methyl 3,3-dimethoxycyclobutane-l-carboxylate

[0096] A reactor was vacuumed to 0.02 MPa and less and then inerted with nitrogen to atmosphere for three times. MeOH (339.00 kg), 3-oxocyclobutanecarboxylic acid (85.19 kg, 746.6 mol, 1.0 eq.), Amberlyst-l5 ion exchange resin (8.90 kg, 10% w/w), and

trimethoxymethane (196.00 kg, 1847.3 mol, 2.5 eq.) were charged into the reactor and the resulting mixture was heated to 55±5°C and reacted for 6 hours to give methyl 3,3-dimethoxycyclobutane-l-carboxylate solution in MeOH. 1H NMR (CDCl3, 400 MHz) d 3.70 (s, 3H), 3.17 (s, 3H), 3.15 (s, 3H), 2.94-2.85 (m, 1H), 2.47-2.36 (m, 4H).

Example 3 Synthesis of 3, 3-dimethoxycyclobutane-l -carboxamide

[0097] The methyl 3, 3 -dimethoxy cyclobutane- l-carboxylate solution in MeOH prepared as described in Example 2 was cooled to below 25°C and centrifuged. The filter cake was washed with MeOH(7.00 kg) and the filtrate was pumped to the reactor. The solution was concentrated under vacuum below 55°C until the system had no more than 2 volumes. MeOH

(139.40 kg) was charged to the reactor and the solution was concentrated under vacuum below 55°C until the system had no more than 2 volumes. MeOH (130.00 kg) was charged to the reactor and the solution was concentrated under vacuum below 55°C until the system had no more than 2 volumes. Half of the resulting solution was diluted with MeOH (435.00 kg) and cooled to below 30°C. NH3 gas (133.80 kg) was injected into the reactor below 35°C for

24 hours. The mixture was stirred at 40±5°C for 72 hours. The resulting solution was

concentrated under vacuum below 50°C until the system had no more than 2 volumes.

MTBE(l8l.OO kg) was charged into the reactor. The resulting solution was concentrated under vacuum below 50°C until the system had no more than 2 volumes. PE (318.00 kg) was charged into the reactor. The resulting mixture was cooled to 5±5°C, stirred for 4 hours at 5±5°C, and centrifuged. The filter cake was washed with PE (42.00 kg) and the wet filter cake was put into a vacuum oven. The filter cake was dried at 30±5°C for at least 8 hours to give 3,3-dimethoxycyclobutane-l-carboxamide as off-white solid (112.63 kg, 94.7% yield). 1H NMR (CDCf, 400 MHz) d 5.76 (bs, 1H), 5.64 (bs, 1H), 3.18 (s, 3H), 3.17 (s, 3H), 2.84-2.76 (m, 1H), 2.45-2.38 (m, 4H).

[0098] A reactor was vacuumed to 0.02 MPa and less and then inerted with nitrogen to atmosphere for three times. Toluene (500.00 kg), 3,3-dimethoxycyclobutane-l-carboxamide (112.54kg, 706.9 mol, 1.0 eq.), and TEA (158.00 kg, 1561.3 mol, 2.20 eq) were charged into the reactor and the resulting mixture was cooled to 0+ 5°C. TFAA (164.00 kg, 781 mol, 1.10 eq.) was added dropwise at 0±5°C. The resulting mixture was stirred for 10 hours at 20±5°C and cooled below 5±5°C. H20 (110.00 kg) was charged into the reactor at below 15 °C. The resulting mixture was stirred for 30 minutes and the water phase was separated. The aqueous phase was extracted with toluene (190.00 kg) twice. The organic phases were combined and washed with H20 (111.00 kg). H20 was removed by azeotrope until the water content was no more than 0.03%. The resulting solution was cooled to below 20°C to give 3,3-dimethoxycyclobutane-l-carbonitrile solution in toluene (492.00 kg with 17.83% assay content, 87.9% yield).

Example 5 Synthesis of l-(3-fluoropyridin-2-yl)-3,3-dimethoxycyclobutane-l-carbonitrile

[0099] A reactor was vacuumed to 0.02 MPa and less and then inerted with nitrogen to atmosphere for three times. The 3,3-dimethoxycyclobutane-l-carbonitrile solution in toluene prepared as described in Example 4 (246.00 kg of a 17.8% solution of 3,3-dimethoxycyclobutane-l-carbonitrile in toluene, 1.05 eq.) and 2-chloro-3-fluoropyridine (39.17 kg, 297.9 mol, 1.00 eq.) were charged into the reactor. The reactor was vacuumed to 0.02 MPa and less and then inerted with nitrogen to atmosphere for three times. The mixture was slowly cooled to -20±5°C. NaHDMS (2M in THF) (165.71 kg, 1.20 eq) was added

dropwise at -20±5°C. The resulting mixture was stirred at -l5±5°C for 1 hour. The mixture was stirred until the content of 2-chloro-3-fluoropyridine is no more than 2% as measured by HPLC. Soft water (16.00 kg) was added dropwise at below 0°C while maintaining the reactor temperature. The resulting solution was transferred to another reactor. Aq. NH4Cl (10% w/w, 88.60 Kg) was added dropwise at below 0°C while maintaining the reactor temperature. Soft water (112.00 kg) was charged into the reactor and the aqueous phase was separated and collected. The aqueous phase was extracted with ethyl acetate (70.00 kg) and an organic phase was collected. The organic phase was washed with sat. NaCl (106.00 kg) and collected. The above steps were repeated to obtain another batch of organic phase. The two batches of organic phase were concentrated under vacuum below 70°C until the system had no more than 2 volumes. The resulting solution was cooled to below 30°C to give a l-(3-fluoropyridin-2-yl)-3, 3 -dimethoxy cyclobutane- l-carbonitrile solution. 1H NMR (CDC13, 400 MHz) d 8.42-8.38 (m, 1H), 7.50-7.45 (m, 1H), 7.38-7.33 (m, 1H), 3.28 (s, 3 H), 3.13 (s, 3H), 3.09-3.05 (m, 4H).

Example 6 Synthesis of I-(3-fluoropyridin-2-yl)-3-oxocyclohutanecarhonitrile

[0100] A reactor was vacuumed to 0.02 MPa and less and then inerted with nitrogen to atmosphere for three times. Water (603.00 kg) was added to the reactor and was stirred.

Concentrated HC1 (157.30 kg) was charged into the reactor at below 35°C. The l-(3-fluoropyridin-2-yl)-3, 3 -dimethoxy cyclobutane- l-carbonitrile solution prepared as described in Example 5 (206.00 kg) was charged into the reactor and the resulting mixture was heated to 50±5°C and reacted for 3 hours at 50±5°C. The mixture was reacted until the content of 1-(3 -fluoropyridin-2-yl)-3, 3 -dimethoxycyclobutane- l-carbonitrile was no more than 2.0% as measured by HPLC. The reaction mixture was cooled to below 30°C and extracted with ethyl acetate (771.00 kg). An aqueous phase was collected and extracted with ethyl acetate (770.00 kg). The organic phases were combined and the combined organic phase was washed with soft water (290.00 kg) and brine (385.30 kg). The organic phase was concentrated under vacuum at below 60°C until the system had no more than 2 volumes. Propan-2-ol (218.00 kg) was charged into the reactor. The organic phase was concentrated under vacuum at below

60°C until the system had no more than 1 volume. PE (191.00 kg) was charged into the reactor at 40±5 °C and the resulting mixture was heated to 60±5 °C and stirred for 1 hour at 60±5 °C. The mixture was then slowly cooled to 5±5 °C and stirred for 5 hours at 5±5 °C. The mixture was centrifuged and the filter cake was washed with PE (48.00 kg) and the wet filter cake was collected. Water (80.00 kg), concentrated HC1 (2.20 kg), propan-2-ol (65.00 kg), and the wet filter cake were charged in this order into a drum. The resulting mixture was stirred for 10 minutes at 20±5 °C. The mixture was centrifuged and the filter cake was washed with a mixture solution containing 18.00 kg of propan-2-ol, 22.50 kg of soft water, and 0.60 kg of concentrated HC1. The filter cake was put into a vacuum oven and dried at 30±5°C for at least 10 hours. The filter cake was dried until the weight did not change to give l-(3-fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile as off-white solid (77.15 kg, 68.0% yield). 1H NMR (CDCl3, 400 MHz) d 8.45-8.42 (m, 1H), 7.60-7.54 (m, 1H), 7.47-7.41 (m, 1H), 4.18-4.09 (m, 2H), 4.02-3.94 (m, 2H).

Example 7 Synthesis of I-(3-fhtoropyridin-2-yl)-3-hydroxycyclobulanecarbonilrile

[0101] To a solution of l-(3-fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile (231 g,

1.22 mol) in a mixture ofDCM (2 L) and MeOH (200 mL) was added NaBH4 portionwise at -78° C. The reaction mixture was stirred at -78°C. for 1 hour and quenched with a mixture of methanol and water (1 : 1). The organic layer was washed with water (500 mL><3), dried over Na2S04, and concentrated. The residue was purified on silica gel (50% EtO Ac/hexanes) to provide the title compound as an amber oil (185.8 g, 77.5%). Low Resolution Mass

Spectrometry (LRMS) (M+H) m/z 193.2.

Example 8 Synthesis of (ls,3s)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutane-l-carbonitrile

[0102] To a solution of 1 -(3 -fluoropyridin-2-yl)-3 -hydroxy cyclobutanecarbonitrile (185 g, 0.96 mol) in DCM (1 L) was added DAST portionwise at 0-10 °C. Upon the completion of addition, the reaction was refluxed for 6 hours. The reaction was cooled to rt and poured onto sat. NaHCCf solution. The mixture was separated and the organic layer was washed with water, dried over Na2S04, and concentrated. The residue was purified on silica gel (100% DCM) to provide the title compound as a brown oil (116g) in a 8: 1 transxis mixture. The above brown oil (107 g) was dissolved in toluene (110 mL) and hexanes (330mL) at 70 °C. The solution was cooled to 0 °C and stirred at 0 °C overnight. The precipitate was filtered and washed with hexanes to provide the trans isomer as a white solid (87.3 g). LRMS (M+H) m/z 195.1.

Example 9 Synthesis of ((lr,3r)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methanamine

[0103] A mixture of ( 1.v,3.v)-3-fluoro- 1 -(3-fluoropyridin-2-yl)cyclobutane- 1 -carbonitrile (71 g, 0.37 mol) and Raney nickel (~7 g) in 7N ammonia in methanol (700 mL) was charged with hydrogen (60 psi) for 2 days. The reaction was filtered through a celite pad and washed with methanol. The filtrate was concentrated under high vacuum to provide the title compound as a light green oil (70 g, 97.6%). LRMS (M+H) m/z 199.2.

Example 10 Synthesis of t-butyl 5-bromopyrimidin-2-yl((trans-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methyl) carbamate

[0104] A mixture of ((lr,3r)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methanamine (37.6 g, 190 mmol), 5-bromo-2-fluoropyrimidine (32.0 g, 181 mmol), DIPEA (71 mL, 407 mmol), and NMP (200 mL) was stirred at rt overnight. The reaction mixture was then diluted with EtOAc (1500 mL) and washed with saturated sodium bicarbonate (500 mL). The

organic layer was separated, dried over Na2S04, and concentrated. The resultant solid was dissolved in THF (600 mL), followed by the slow addition of DMAP (14 g, 90 mmol) and Boc20 (117.3 g, 542 mmol). The reaction was heated to 60° C. and stirred for 3 h. The reaction mixture was then concentrated and purified by silica gel chromatography

(EtO Ac/hex) to give 59.7 g oft-butyl 5-bromopyrimidin-2-yl((trans-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a white solid.

Example 11 Synthesis of t-butyl 5-(3-cyano- 1 H -pyrrol- 1 -yl)pyrimidin-2-yl(((lrans)-3-fhtoro-l-(3-fluoropyridin-2-yl)cyclohutyl)methyl)carhamate

[0105] To a solution oft-butyl 5-bromopyrimidin-2-yl((trans-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methyl) carbamate (1.0 g, 2.8 mmol) in 15 mL of toluene (degassed with nitrogen) was added copper iodide (100 mg, 0.6 mmol), potassium phosphate (1.31 g, 6.2 mmol), trans-N,N’-dimethylcyclohexane-l, 2-diamine (320 mg, 2.2 mmol), and 3-cyanopyrrole (310 mg, 3.6 mmol). The reaction was heated to 100 °C and stirred for 2 h. The reaction was then concentrated and purified by silica gel chromatography (EtOAc/hexanes) to afford 1.1 g of t-butyl 5-(3-cyano-lH-pyrrol-l-yl)pyrimidin-2-yl(((trans)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a clear oil.

Example 12 Synthesis of l-(2-((((trans)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide

[0106] To a solution oft-butyl 5-(3-cyano-lH-pyrrol-l-yl)pyrimidin-2-yl(((trans)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (1.1 g, 3.1 mmol) in DMSO (10 mL) was added potassium carbonate (1.3 g, 9.3 mmol). The mixture was cooled to 0 °C and hydrogen peroxide (3 mL) was slowly added. The reaction was warmed to rt and stirred for 90 min. The reaction was diluted with EtO Ac (75 mL) and washed three times with brine (50 mL). The organic layer was then dried over Na2S04, filtered, and concentrated to give a crude solid that was purified by silica gel chromatography (10% MeOH/CH2Cl2) to afford 1.07 g of a white solid compound. This compound was dissolved in 25% TFA/CH2CI2 and stirred for 1 hour. The reaction was then concentrated, dissolved in ethyl acetate (75 mL), and washed three times with saturated potassium carbonate solution. The organic layer was then dried over Na2S04, filtered, and concentrated to give a crude solid that was triturated with 75% ethyl acetate/hexanes. The resultant slurry was sonicated and filtered to give 500 mg of l-(2-((((trans)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3 -carboxamide as a white solid. LRMS (M+H=385).

REFERENCES

1: Andrews JA, Miller TM, Vijayakumar V, Stoltz R, James JK, Meng L, Wolff AA, Malik FI. CK-2127107 amplifies skeletal muscle response to nerve activation in humans. Muscle Nerve. 2018 May;57(5):729-734. doi: 10.1002/mus.26017. Epub 2017 Dec 11. PubMed PMID: 29150952.

2: Gross N. The COPD Pipeline XXXII. Chronic Obstr Pulm Dis. 2016 Jul 14;3(3):688-692. doi: 10.15326/jcopdf.3.3.2016.0150. PubMed PMID: 28848893; PubMed Central PMCID: PMC5556764.

//////////////CK-2127107, CK 2127107, CK2127107, Reldesemtiv, Cytokinetics,   Astellas, neuromuscular disorders, muscle wasting, claudication, metabolic syndrome, spinal muscular atrophy, amyotrophic lateral sclerosis, Orphan Drug Status, Spinal muscular atrophy, Phase II

C1C(CC1(CNC2=NC=C(C=N2)N3C=CC(=C3)C(=O)N)C4=C(C=CC=N4)F)F

FDA approves drug to treat ALS, Radicava (Edaravone) , эдаравон, إيدارافون , 依达拉奉 ,ラジカット,


Edaravone.svg

05/05/2017
The U.S. Food and Drug Administration today approved Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease.

May 5, 2017

Release

The U.S. Food and Drug Administration today approved Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease.

“After learning about the use of edaravone to treat ALS in Japan, we rapidly engaged with the drug developer about filing a marketing application in the United States,” said Eric Bastings, M.D., deputy director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This is the first new treatment approved by the FDA for ALS in many years, and we are pleased that people with ALS will now have an additional option.”

ALS is a rare disease that attacks and kills the nerve cells that control voluntary muscles. Voluntary muscles produce movements such as chewing, walking, breathing and talking. The nerves lose the ability to activate specific muscles, which causes the muscles to become weak and leads to paralysis. ALS is progressive, meaning it gets worse over time. The Centers for Disease Control and Prevention estimates that approximately 12,000-15,000 Americans have ALS. Most people with ALS die from respiratory failure, usually within three to five years from when the symptoms first appear.

Radicava is an intravenous infusion given by a health care professional. It is administered with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period. Subsequent treatment cycles consist of dosing on 10 of 14 days, followed by 14 days drug-free.

The efficacy of edaravone for the treatment of ALS was demonstrated in a six-month clinical trial conducted in Japan. In the trial, 137 participants were randomized to receive edaravone or placebo. At Week 24, individuals receiving edaravone declined less on a clinical assessment of daily functioning compared to those receiving a placebo.

The most common adverse reactions reported by clinical trial participants receiving edaravone were bruising (contusion) and gait disturbance.

Radicava is also associated with serious risks that require immediate medical care, such as hives, swelling, or shortness of breath, and allergic reactions to sodium bisulfite, an ingredient in the drug. Sodium bisulfite may cause anaphylactic symptoms that can be life-threatening in people with sulfite sensitivity.

The FDA granted this drug orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Radicava to Mitsubishi Tanabe Pharma America, Inc,

ChemSpider 2D Image | Edaravone | C10H10N2O

1-Phenyl-3-methyl-5-pyrazolone
3H-Pyrazol-3-one, 2,4-dihydro-5-methyl-2-phenyl- [ACD/Index Name]
89-25-8 [RN]
эдаравон [Russian]
إيدارافون [Arabic]
依达拉奉 [Chinese]
ラジカット,
MCI-186

Edaravone (brand name ラジカット, Radicut) is a nootropic and neuroprotective agent used for the purpose of aiding neurological recovery following acute brain ischemia and subsequent cerebral infarction.[1] It acts as a potent antioxidant and strongly scavenges free radicals, protecting against oxidative stress and neuronal apoptosis.[2][3][4] It has been marketed solely in Japan by Mitsubishi Pharma since 2001.[1] It is also marketed in India by Edinburgh Pharmaceuticals by the brand name Arone.

On June 26, 2015, Mitsubishi Tanabe Pharma Corporation announced it has received approval to market Radicut for treatment of ALS in Japan. The phase III clinical trial began in 2011 in Japan. The company was awarded Orphan Drug Designation for Radicut by the FDA and EU in 2015. Radicut is an intravenous drug and administrated 14 days followed by 14 days drug holiday.

The biotech company Treeway is developing an oral formulation of edaravone (TW001) and is currently in clinical development. Treeway was awarded orphan drug designation for edaravone by the EMA in November 2014 and FDA in January 2015.

Edaravone has been shown to attenuate methamphetamine– and 6-OHDA-induced dopaminergic neurotoxicity in the striatum and substantia nigra, and does not affect methamphetamine-induced dopamine release or hyperthermia.[5][6] It has also been demonstrated to protect against MPTP-mediated dopaminergic neurotoxicity to the substantia nigra, though notably not to the striatum.[7][8][9]

Image result for edaravone synthesis

Edaravone (CAS NO.: 89-25-8), with other name of 3-Methyl-1-phenyl-2-pyrazolin-5-one, could be produced through many synthetic methods.

Following is one of the synthesis routes: By direct cyclization of phenylhydrazine (I) with ethyl acetoacetate (II) in refluxing ethanol.

SYNTHESIS

Edaravone, chemical name: 3-methyl-1-phenyl-2-pyrazoline-5-one, of the formula: Formula: CiciHltlN2O, molecular weight: 174.20, the formula:

 

Figure CN101830852BD00031

[0004] Edaravone is a brain-protecting agent (free radical scavenger). Clinical studies suggest that N- acetyl aspartate (NAA) is a specific sign of the survival of nerve cells, dramatically reducing the initial content of cerebral infarction. In patients with acute cerebral infarction Edaravone suppressed reduce peri-infarct regional cerebral blood flow, so that the first concept of days after the onset of brain NAA glycerol content than the control group significantly increased. Preclinical studies suggest that rats after ischemia / reperfusion of ischemic intravenous edaravone, can prevent the progress of cerebral edema and cerebral infarction, and relieve the accompanying neurological symptoms, suppress delayed neuronal death. Mechanism studies suggest that edaravone can scavenge free radicals, inhibiting lipid peroxidation, thereby inhibiting brain cells, endothelial cells, oxidative damage nerve cells.

For the synthesis of edaravone reported some use of benzene and methyl ethyl ketone amide corpus obtained, but methyl ethyl ketone amide difficult to obtain and slow reaction, which now has basically been abandoned; some use benzene corpus and ethyl acetoacetate in ethanol (see US4857542A, Synthesis Example 1) or water (Dykhanov NN Ethyl and butyl acetoacetates, Med Prom SSSR, 1961,15 (1):. 42-45) refluxing the reaction of the reaction The resulting purity edaravone poor, and the yield is not high, only about 70%.

Edaravone, chemical name: 2,4_-dihydro-5-methyl-2-phenyl pyrazole -3H- – one, of the formula: CiciHltlN2O, molecular weight: 174.20, the formula:

Figure CN102285920BD00031

edaravone is a clear cerebral infarction harmful factors (free radicals), protection of new therapeutic agents for cerebral infarction nerve cells. Clinical studies have shown that N- acetyl aspartate (NAA) is a specific sign of the survival of nerve cells, dramatically reducing the initial content of cerebral infarction. When patients with acute cerebral infarction Edaravone, peri-infarct rCBF decrease has improved, and the first 28 days after the onset of brain NAA content was significantly higher than that in the control group glycerol. Mechanism studies suggest that edaravone can clear the brain is highly cytotoxic hydroxyl radicals, inhibiting the synthesis of lipids free radicals, which can suppress brain infarction after reperfusion edema, protecting brain from damage and improve nerve impairment symptoms, and the delayed neuronal death inhibition, to protect the brain.

 The first is by phenylhydrazine and methyl ethyl ketone amide (National API process compilation, 1980.737-739) condensation reaction in water at 50 ° C, a yield of up to 97%, but the raw material ketone amide ( CH3C0CH2C0NH2) are not readily available. Formula I

Edaravone synthetic route for the reaction:

Figure CN102285920BD00032

[0008] The second is to phenylhydrazine and ethyl acetoacetate in ethanol or water at reflux the reaction, sodium bisulfite as the preparation of the catalyst. From the perspective of the chemical reaction, acetyl ethyl ketone amide more than hydrazine reacted with benzene and ethyl acetoacetate more readily available, the price is cheaper, but lower reaction yield of about 70%. Formula 2 for the synthesis route Edaravone reaction formula:

Figure CN102285920BD00041

PATENT

https://www.google.com/patents/CN101830852B?cl=en

Figure CN101830852BD00041

1 Edaravone Synthesis Example [0023] Example

[0024] (1) Weigh benzene hydrochloride corpus 13. 5g (94mmol), was added to IOOml water, stirred for 0.5 hours, sodium hydroxide was added an equimolar 3. 76g, stirred for 0.5 hours; [0025] ( 2) To the reaction solution was added dropwise ethyl acetoacetate 11. 7g (90mmol), the reaction exotherm, the reaction was heated to reflux for 2.5 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 15. 5g;

[0026] (3) The crude product was added 30ml volume ratio of 2: 1 isopropanol – water, 2g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature a white solid was precipitated to give 14 a white crystalline powder. 8g, yield 90%, mpU9 ° C, with a purity of 99.9% 0

2 Edaravone Synthesis Example [0027] Example

[0028] (1) Weigh 15g of benzene hydrochloride corpus (I (Mmmol), was added to 120ml of water and stirred for 0.5 hours, sodium hydroxide was added an equimolar 4. 16g, stirred for 0.5 hours;

[0029] (2) To the reaction solution was added dropwise 13g of ethyl acetoacetate (lOOmmol), the reaction exotherm, the reaction was heated to reflux for 2.5 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 16. 7g;

(3) The crude product was added 40ml volume ratio of 2: 1 isopropanol – water, 2. 5g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature to precipitate a white solid, as a white crystalline powder 16. lg, a yield of 88.9%, mpU8 ° C, with a purity of 99.9% 0

3 Edaravone Synthesis Example [0031] Example

[0032] (1) Weigh 22g of benzene hydrochloride corpus (152mm0l), was added to 200ml of water and stirred for 0.5 hours, sodium hydroxide was added an equimolar 6. 08g, stirred for 0.5 hours;

[0033] (2) To the reaction solution was added dropwise 19g of ethyl acetoacetate (146mm0l), the reaction exotherm, the reaction was heated to reflux for 3 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 24. Sg;

[0034] (3) The crude product was added 50ml volume ratio of 2: 1 isopropanol – water, 3g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature a white solid was precipitated to give 23 a white crystalline powder. 2g, a yield of 87. 8%, mpU8 ° C, with a purity of 99.9% 0

[0035] Comparative Example

[0036] The ethyl acetoacetate 65g (0. 5mol) and 180ml of anhydrous ethanol mixed, with stirring at 50 ° C was added dropwise benzyl corpus 54g (0. 5mol) and a solution consisting of 30ml absolute ethanol, dropwise at reflux for 2 Bi hours, ethanol was distilled off 60ml, cooled, suction filtered, washed crystals with cold absolute ethanol twice, and dried in vacuo to give pale yellow crystals 70g. Recrystallized twice from absolute ethanol to give pale yellowish white crystals 56g (yield 65%).

PATENT

https://www.google.com/patents/CN102285920B?cl=en

Example 1: Preparation of phenylhydrazine edaravone.

[0024] a. Weigh 5.1g phenylhydrazine (47mmol), was added under stirring to water containing 45mL round-bottom flask, take appropriate concentrated hydrochloric acid solution was adjusted to pH 6.0 with PH meter.

[0025] b. To the above solution was slowly added dropwise ethyl acetoacetate 5.85g (45mmol), the reaction exotherm, was added 1.5g sodium dithionite (Na2S2O6), heated to 105 ° C to room temperature until reflux After 3h, heating was stopped, and then stirred, cooling, filtration, and dried to give a pale yellow granular edaravone crude.

[0026] c. With anhydrous ethanol recrystallization, filtration, and dried to obtain a white crystalline powder that is refined edaravone, 85% yield, 99.2% purity 0

[0027] Example 2: Preparation of phenylhydrazine hydrochloride edaravone.

[0028] a. Weigh 6.8g phenylhydrazine hydrochloride (47mmol), was added under stirring to water containing 45mL round-bottomed flask, the pH of the solution adjusted to 6.0 with aqueous ammonia.

[0029] b. To the above solution was slowly added dropwise ethyl acetoacetate 5.85g (45mmol), the reaction exotherm, 1.25g was added sodium dithionite (Na2S2O6), heated to 105 ° C to room temperature until reflux After 3h, heating was stopped, and then stirred, cooling, filtration, and dried to give a pale yellow granular edaravone crude.

[0030] c. With anhydrous ethanol recrystallization, filtration, and dried to obtain a white crystalline powder that is refined edaravone, 84% yield, with a purity of 99.2%. [0031] Comparative Example:

Under the [0032] state of agitation will phenylhydrazine 10.2g (94mmol) added to a round bottom flask equipped with IOOmL water in an appropriate amount of concentrated hydrochloric acid was dubbed the volume ratio of 1: 1 aqueous hydrochloric acid, with a PH adjusting pH of the solution was measured 6.0. After weighing Ethylacetoacetate 11.7g (90mmol) added to the reaction mixture, the reaction was exothermic and cooling to room temperature, sodium bisulfite (NaHSO3), heated to 105 ° C under reflux for 3h, the hot solution Water was added into the beaker and mechanical stirring, cooling, filtration, and dried to give the yellow edaravone crude, 73% yield, with a purity of 99.1%.

Figure CN102285920BD00042

CLIP

http://www.rsc.org/suppdata/books/184973/9781849739634/bk9781849739634-chapter%204.2.3.pdf

Edaravone:

IR (KBr) max/cm-1 : 3431, 3129, 1602, 1599, 1580;

1 H NMR (300 MHz, CDCl3): δ 7.86 (d, J = 7.5 Hz, 2H, ArH), 7.40 (m, 2H, ArH), 7.18 (m, 1H, ArH), 3.41 (d, J =0.6 Hz, 2H, CH2), 2.19 (s, 3H, CH3);

13C NMR (75 MHz, CDCl3): 170.6, 156.4, 130.1, 128.8, 125.0, 118.9, 43.1, 17.0;

1 H NMR (300 MHz, DMSO-d6): δ 11.5 (bs, 1H, NH), 7.71 (m, 2H, ArH), 7.40 (m, 2H, ArH), 7.22 (m, 1H, ArH), 5.36 (s, 1H, CH), 2.12 (s, 3H, CH3);

13C NMR (75 MHz, DMSO-d6):171.7, 158.9, 148.7, 139.2, 138.6, 129.3,125.4, 124.8, 118.4, 43.5, 17.1, 14.2.

These values are in accordance with the previous published in literature1 .

In the carbon spectrum in DMSO presented in Figure SM 4.2.3.1.8 is evident the presence of the two major tautomeric structures of edaravone, signals are identified by different colours in both structures in the figure. Also in the IR analysis of the solid material (Figure SM 4.2.3.1.9) is possible to see either the NH form (max/cm-1, 3129), the OH form (max/cm- 1 , 3431) and the C=O (max/cm-1, 1599) of the enol and keto tautomeric forms of edaravone.

1. S. Pal, J. Mareddy and N. S. Devi, J.  Braz. Chem. Soc., 2008, 19, 1207.

CLIP

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532008000600023

We have shown that the short reaction time, in combination with good yields can make microwave assisted reaction of hydrazines with β-ketoesters ideal for a rapid entry to pyrazolones. All the compounds synthesized are characterized by spectroscopic (1H NMR, IR and MS) data. While determination of tautomeric composition of compound 3 is quite challenging as eight possible tautomeric forms need to be considered, interestingly, two major tautomeric forms of compound 3a was observed in two different solvents. For example, it exists as 1,2-dihydro pyrazolone (T-1Figure 2) in DMSO and 2,4-dihydro form (T-2Figure 2) in chloroform as indicated by 1H NMR spectra (Figure 3). The olefinic proton of T-1 appeared at 5.36 δ whereas the methylene hydrogens appeared at 3.43 δ in case of T-2. Additionally, the NH proton of T-1 at 11.40 δ was not observed incase of T-2 confirmed the absence of NH in the 2,4-dihydro form. Existence of two major tautomeric forms was also observed in case compound 3b (see 1H NMR data in the experimental section). However, X-ray study on single crystal of 2-(4-chlorophenyl)-5-methyl-1,2-dihydro pyrazol-3-one (3i) indicates that 2-aryl pyrazol-3-ones e.g. 3a-b3e-f and 3i exist as 1,2-dihydro form in crystal state. 27 It is mention worthy that the aryl ring of all these 2-aryl pyrazol-3-ones remain twisted with respect to the pyrazole plane as indicated by the crystallographic data of 3i [the dihedral angle between the pyrazole and benzene ring planes was found to be 15.81 (11)º].27

 

 

 

5-Methyl-2-phenyl-1,2-dihydro pyrazol-3-one (3a)

mp 125-127 ºC (lit21 126-130 ºC); 

IR (KBr) νmax/cm-1: 3127, 1597, 1525, 1498, 1454;

 1H NMR (400 MHz, DMSO-d6δ 11.40 (bs, 1H), 7.71-7.69 (m, 2H), 7.42-7.38 (m, 2H), 7.21-7.18 (m, 1H), 5.36 (s, 1H), 2.10 (s, 3H); 

13C NMR (50 MHz, DMSO-d6δ 170.6, 156.2, 138.1, 128.8 (2C), 124.9, 118.9 (2C), 43.1, 16.9; 

Mass (CI, m/z) 175 (M+1, 100).

1H NMR (400 MHz, CDCl3)δ 7.85 (d, J 8.3 Hz, 2H), 7.40-7.37 (m, 2H), 7.24-7.18 (m, 1H), 3.43 (s, 2H), 2.20 (s, 3H).

21. Makhija, M. T.; Kasliwal, R. T.; Kulkarni, V. M.; Neamati, N.; Bioorg. Med. Chem. 200412, 2317.         [ Links ]

CN101830852A Mar 22, 2010 Sep 15, 2010 海南美兰史克制药有限公司 Edaravone compound synthesized by new method
CN102060771A Nov 18, 2009 May 18, 2011 南京长澳制药有限公司 Edaravone crystal form and preparation method thereof
CN102180834A Mar 24, 2011 Sep 14, 2011 江苏正大丰海制药有限公司 Preparation method for edaravone

References

  1. ^ Jump up to:a b Doherty, Annette M. (2002). Annual Reports in Medicinal Chemistry, Volume 37 (Annual Reports in Medicinal Chemistry). Boston: Academic Press. ISBN 0-12-040537-7.
  2. Jump up^ Watanabe T, Tanaka M, Watanabe K, Takamatsu Y, Tobe A (March 2004). “[Research and development of the free radical scavenger edaravone as a neuroprotectant]”. Yakugaku Zasshi (in Japanese). 124 (3): 99–111. doi:10.1248/yakushi.124.99. PMID 15049127.
  3. Jump up^ Higashi Y, Jitsuiki D, Chayama K, Yoshizumi M (January 2006). “Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger, for treatment of cardiovascular diseases”. Recent Patents on Cardiovascular Drug Discovery. 1 (1): 85–93. doi:10.2174/157489006775244191. PMID 18221078.
  4. Jump up^ Yoshida H, Yanai H, Namiki Y, Fukatsu-Sasaki K, Furutani N, Tada N (2006). “Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury”. CNS Drug Reviews. 12 (1): 9–20. doi:10.1111/j.1527-3458.2006.00009.x. PMID 16834755.
  5. Jump up^ Yuan WJ, Yasuhara T, Shingo T, et al. (2008). “Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons”. BMC Neuroscience. 9: 75. doi:10.1186/1471-2202-9-75. PMC 2533664Freely accessible. PMID 18671880.
  6. Jump up^ Kawasaki T, Ishihara K, Ago Y, et al. (August 2006). “Protective effect of the radical scavenger edaravone against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum”. European Journal of Pharmacology. 542 (1-3): 92–9. doi:10.1016/j.ejphar.2006.05.012. PMID 16784740.
  7. Jump up^ Kawasaki T, Ishihara K, Ago Y, Baba A, Matsuda T (July 2007). “Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a radical scavenger, prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the substantia nigra but not the striatum”. The Journal of Pharmacology and Experimental Therapeutics. 322 (1): 274–81. doi:10.1124/jpet.106.119206. PMID 17429058.
  8. Jump up^ Yokoyama H, Takagi S, Watanabe Y, Kato H, Araki T (June 2008). “Role of reactive nitrogen and reactive oxygen species against MPTP neurotoxicity in mice”. Journal of Neural Transmission (Vienna, Austria : 1996). 115 (6): 831–42. doi:10.1007/s00702-008-0019-6. PMID 18235988.
  9. Jump up^ Yokoyama H, Yano R, Aoki E, Kato H, Araki T (September 2008). “Comparative pharmacological study of free radical scavenger, nitric oxide synthase inhibitor, nitric oxide synthase activator and cyclooxygenase inhibitor against MPTP neurotoxicity in mice”. Metabolic Brain Disease. 23 (3): 335–49. doi:10.1007/s11011-008-9096-3. PMID 18648914.

External links

Edaravone
Edaravone.svg
Edaravone ball-and-stick model.png
Clinical data
Trade names Radicut
Routes of
administration
Oral
ATC code
  • none
Legal status
Legal status
  • Rx-only (JP)
Identifiers
Synonyms MCI-186
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.001.719
Chemical and physical data
Formula C10H10N2O
Molar mass 174.20 g/mol
3D model (Jmol)
////////// Radicava, edaravone, fda 2017, Lou Gehrig’s disease, amyotrophic lateral sclerosis,  Mitsubishi Tanabe, orphan drug designation89-25-8, эдаравон, إيدارافون , 依达拉奉 ,ラジカット,
O=C1CC(=NN1c1ccccc1)C
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