1-[2-(methylsulfanyl)-10H-phenothiazin-10-yl]ethanone

1-[2-(methylsulfanyl)-10H-phenothiazin-10-yl]ethanone (3): Off-white solid, yield. 93% (218 g),

m. p. 223-226 °C.

1H NMR (400 MHz, CDCl3, δ/ppm): 7.49 (d, 1H, arom H, J = 7.6 Hz), 7.46-7.42 (m, 2H, arom H), 7.36-7.32 (m, 2H, arom H), 7.28-7.22 (m, 1H, arom H), 7.13 (dd, 1H, arom H, J = 8.0 Hz and 1.6 Hz), 2.51 (s, 3H, -SCH3), 2.23 (s, 3H, -COCH3).

13C NMR (100 MHz, DMSO-d6, δ/ppm): 168.36, 139.19, 138.52, 137.74, 132.05, 128.07, 127.97, 127.78, 127.44, 127.19, 126.94, 124.60, 124.51, 22.71, 14.88.

MS m/z (ESI): 288.04 (M+H)+.

An efficient, practical, and commercially viable manufacturing process was developed with ≥99.7% purity and 31% overall yield (including four chemical reactions and one recrystallization) for an active pharmaceutical ingredient, called Metopimazine (1), an antiemetic drug used to prevent emesis during chemotherapy. The development of two in situ, one-pot methods in the present synthetic route helped to improve the overall yield of 1 (31%) compared with earlier reports (<15%). For the first time, characterization data of API (1), intermediates, and also possible impurities are presented. The key process issues and challenges were addressed effectively and achieved successfully.

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00052

//////////////////////

USA Viewership touched 3 lakhs on New Drug Approvals

USA Viewership touched 3 lakhs on New Drug Approvals

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Total 16.9 lakhs in 213 countries

Metopimazine

Metopimazine

RP-9965, EXP-999, NG-101

l-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide

CAS 14008-44-7

MF C₂₂ H₂₇ N₃ O₃ S₂

_{MW 445.60}

4-Piperidinecarboxamide, 1-[3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl]-

• Isonipecotamide, 1-[3-[2-(methylsulfonyl)phenothiazin-10-yl]propyl]- (7CI,8CI)
• 1-[3-[2-(Methylsulfonyl)-10H-phenothiazin-10-yl]propyl]-4-piperidinecarboxamide
• 1-[3-[2-(Methylsulfonyl)phenothiazin-10-yl]propyl]-4-piperidinecarboxamide
• 1-[3-[2-(Methylsulfonyl)phenothiazin-10-yl]propyl]isonipecotamide
• 2-Methylsulfonyl-10-[3-(4-carbamoylpiperidino)propyl]phenothiazine

• EXP 999
• Metopimazine
• RP 9965
• Vogalene
• metopimazine (gastroparesis), Neurogastrx

Sanofi (Originator)
Teva

Treatment of Nausea and Vomiting, APPROVED

Dopamine D3 receptor antagonist; Dopamine D2 receptor antagonist

Gastroprokinetic

Metopimazine (INN) is a phenothiazine antiemetic.

Metopimazine is an established antiemetic that has been approved and marketed for many years in Europe for the treatment of acute conditions. The compound does not cross the blood-brain-barrier, and is therefore free from central side effects, and is not associated with cardiovascular side effects

In May 2016, preclinical data were presented at the 2016 DDW in San Diego, CA. In rats, po NG-101 and domperidone did not penetrate the brain at therapeutically relevant concentrations, unlike metoclopramide. In dogs, the amplitude and frequency of antral contractions were increased by NG-101, whereas in rats, po metopimazine resulted in an increase in gastric emptying of solid foods. The blood-brain barrier was not readily crossed and there was no interaction with 5-HT3 or 5-HT4 receptors by NG-101 unlike metoclopramide and domperidone, respectively

Neurogastrx is investigating repurposed metopimazine (NG-101), a selective and peripherally restricted dopamine D2/D3 receptor antagonist, for the potential oral treatment of gastroparesis. By July 2014, preclinical studies were underway . SE BELOW REF

WO-2014105655: Methods for treating GI tract disorders
In May 2016, preclinical data were presented [SEE BELOW].

2016 May 24Abs 1079
NG101: A Potent and Selective Dopamine D2 Receptor Antagonist as a Potential Alternative to Metoclopramide and Domperidone for the Treatment of Gastroparesis
Digestive Disease Week
Cyril De Colle, Marieke van der Hart, Jiande Chen, Arash Rassoulpour, Pankaj J Pasricha

In July 2014, preclinical data were published. Metopimazine at 1mg/kg increased gastric motility in hound dogs. In studies in rodents, metopimazine at 3 and 10 mg/kg increased gastric emptying by 18 and 40%, respectively, compared with vehicle control

There is an increasing demand for antiemetic agents because of the most troublesome adverse effects of chemotherapy-induced nausea and emesis during cancer treatment.

However, the objective of complete prevention of emesis in all patients remains elusive. Therefore, there is a great demand for both development of (i) new antiemetic agents and (ii) new manufacturing processes for existing antiemetic agents. Metopimazine is an existing dopamine D₂-receptor antagonist with potent antiemetic properties. It is chemically known as l-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide , which belongs to nitrogen- and sulfur-containing tricyclic compounds (phenothiazine class of drugs) with interesting biological and pharmacological activities.

Recently, it has been found that Metopimazine plays a key role as an alternative to Ondansetron in the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderate to high emetogenic noncisplatin-based chemotherapy.It has been used in France for many years for the prevention and treatment of nausea and vomiting under the brand name of Vogalene

In 1959, the first synthesis and manufacture process of Metopimazine  was reported by Jacob et al.The synthesis starts from the protection of 2-(Methylsulfanyl)-10H-phenothiazine..Jacob, R. M.; Robert, J. G. German Patent No. DE1092476, 1959.

Later, in 1990, Sindelar et al. reported a modified process , which starts from synthesis of 4-(2-fluorophenylthio)-3-nitrophenylmethylsulfone..Sindelar, K.; Holubek, J.; Koruna, I.; Hrubantova, M.; Protiva, M. Collect. Czech. Chem. Commun. 1990, 55, 1586– 1601, DOI: 10.1135/cccc19901586

In 2010, Satyanarayana Reddy et al. reported a modified synthetic route which starts from either N-protection using acetyl chloride or N-alkylation using dihalopropane of 2-(methylsulfanyl)-10H-phenothiazine ..Satyanarayana Reddy, M.; Eswaraiah, S.; Satyanarayana, K. Indian Patent No. 360/CHE/2010 A, Aug 19, 2011.

Synthesis of 1-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)piperidine-4- carboxamide (1)-Metopimazine: Pale yellow color solid, yield. 65% (82 g), DSC 189 °C.

  

1H NMR (400 MHz, DMSO-d6, δ/ppm): 7.44 (d, 1H, arom H, J = 8.8 Hz), 7.37 (d, 2H, arom H, J = 8.0 Hz), 7.24 (t, 1H, arom H, J = 7.6 Hz), 7.16 (m, 2H, -NH2), 7.1 (d, 1H, arom H, J = 8.4 Hz), 6.99 (t, 1H, arom H, J = 7.6 Hz), 6.68 (s, 1H, arom H), 3.99 (t, 2H, -NCH2, J = 6.4 Hz), 3.23 (s, 3H, -S-CH3), 2.8-2.73 (m, 2H, -CH2-), 2.36 (t, 2H, -CH2-, J = 6.8 Hz), 2.02-1.96 (m, 1H, -CH-), 1.84-1.78 (m, 4H, 2-CH2-), 1.61-1.58 (m, 2H, -CH2-), 1.48-1.44 (m, 2H, - CH2-).

13C NMR (100 MHz, DMSO-d6, δ/ppm): 176.52, 145.41, 143.5, 140.12, 130.47, 128.03, 127.50, 127.25, 123.23, 122.16, 120.59, 116.38, 113.24, 54.82, 52.97, 44.64, 43.47, 41.7, 28.59, 23.52.

MS m/z (ESI): 446.21 (M+H)+.

SYNTHESIS

PATENT

IN 201641043070

IN 2013CH05689

IN 2013CH00361

IN 2010CH00360

DE 1092476/US 3130194

PAPER

A Simple and Commercially Viable Process for Improved Yields of Metopimazine, a Dopamine D₂-Receptor Antagonist

Venumanikanta Karicherla, Kumar Phani, Mohan Reddy Bodireddy, Kumar Babu Prashanth, Madhusudana Rao Gajula^*, and Kumar Pramod^* 

Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, Fourth Phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore, Karnataka 560 105, India

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00052

 

*E-mail: pramodkumar@microlabs.in. Tel: 0811 0415647, ext. 245. Mobile No.: +91 9008448247., *E-mail: gmadhusudanrao@yahoo.com.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.7b00052

An efficient, practical, and commercially viable manufacturing process was developed with ≥99.7% purity and 31% overall yield (including four chemical reactions and one recrystallization) for an active pharmaceutical ingredient, called Metopimazine (1), an antiemetic drug used to prevent emesis during chemotherapy. The development of two in situ, one-pot methods in the present synthetic route helped to improve the overall yield of 1 (31%) compared with earlier reports (<15%). For the first time, characterization data of API (1), intermediates, and also possible impurities are presented. The key process issues and challenges were addressed effectively and achieved successfully.

Synthesis of 1-(3-[2-(Methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide (1), Metopimazine

In ....................... The obtained compound (1) was dried in a hot air oven at 50 °C.

Pale yellow color solid, yield. 65% (82 g),

DSC 189 °C.

 

¹H NMR (400 MHz, DMSO-d_6, δ/ppm)_: 7.44 (d, 1H, arom H, J = 8.8 Hz), 7.37 (d, 2H, arom H, J = 8.0 Hz), 7.24 (t, 1H, arom H, J = 7.6 Hz), 7.16 (m, 2H, −NH₂), 7.1 (d, 1H, arom H, J = 8.4 Hz), 6.99 (t, 1H, arom H, J = 7.6 Hz), 6.68 (s, 1H, arom H), 3.99 (t, 2H, −NCH_2, J = 6.4 Hz), 3.23 (s, 3H, −S–CH₃), 2.8–2.73 (m, 2H, −CH₂−), 2.36 (t, 2H, −CH₂–, J = 6.8 Hz), 2.02–1.96 (m, 1H, −CH−), 1.84–1.78 (m, 4H, 2–CH₂−), 1.61–1.58 (m, 2H, −CH₂−), 1.48–1.44 (m, 2H, −CH₂−).

 

¹³C NMR (100 MHz, DMSO-d_6, δ/ppm)_: 176.52, 145.41, 143.5, 140.12, 130.47, 128.03, 127.50, 127.25, 123.23, 122.16, 120.59, 116.38, 113.24, 54.82, 52.97, 44.64, 43.47, 41.7, 28.59, 23.52.

 

MS m/z (ESI): 446.21 (M + H)^+.

 

 

Regulatory

• Vogalene
• metopimazina (Italian, Portuguese)
• metopimazin (Danish, Swedish)
• metopimazine (Dutch)
• metopimatsiini (Finnish)

Regulatory List Number

• EC No.: 237-818-4
• EINECS No.: 237-818-4

• Harmonized Tariff Code

  293430

 

REFERENCES

1.  Moda, Tiago L.; Bioorganic & Medicinal Chemistry 2007, 15(24), PG7738-7745 
2.  "Drugs - Synonyms and Properties" data were obtained from Ashgate Publishing Co. (US) 
3. Julou, Louis; Comptes Rendus des Seances de l'Academie des Sciences, Serie D: Sciences Naturelles 1968, 266(25), PG 2365-8 
4.  Bounoure, Frederic; Journal of Inclusion Phenomena and Macrocyclic Chemistry 2007, 57(1-4), PG191-195 
5.  Sindelar, Karel; Collection of Czechoslovak Chemical Communications 1990, 55(6), PG1586-601 
6.  "PhysProp" data were obtained from Syracuse Research Corporation of Syracuse, New York (US)
7.  Habibi-Yangjeh, Aziz; Bulletin of the Korean Chemical Society 2008, 29(4), PG833-841
8.  Metwally, Fadia H.; Bulletin of the Faculty of Pharmacy (Cairo University) 2006, 44(3), PG1-15 
9. WO-2014105655: Methods for treating GI tract disorders
10. 2016 May 24Abs 1079
    NG101: A Potent and Selective Dopamine D2 Receptor Antagonist as a Potential Alternative to Metoclopramide and Domperidone for the Treatment of Gastroparesis
    Digestive Disease Week
    Cyril De Colle, Marieke van der Hart, Jiande Chen, Arash Rassoulpour, Pankaj J Pasricha

Metopimazine

Clinical data
AHFS/Drugs.com	International Drug Names
ATC code	A04AD05 (WHO)
Identifiers
IUPAC name[show]
CAS Number	14008-44-7
PubChem CID	26388
ChemSpider	24584
UNII	238S75V9AV
ChEMBL	CHEMBL398615
ECHA InfoCard	100.034.367
Chemical and physical data
Formula	C22H27N3O3S2
Molar mass	445.6 g/mol
3D model (Jmol)	Interactive image
SMILES[hide] O=S(=O)(c2cc1N(c3c(Sc1cc2)cccc3)CCCN4CCC(C(=O)N)CC4)C

//////////////Metopimazine, Dopamine D₂-Receptor Antagonist, 14008-44-7, sanofi, teva, RP-9965, Nausea and Vomiting, EXP-999, NG-101, metopimazine, gastroparesis, Neurogastrx

NC(=O)C1CCN(CC1)CCCN2c4ccccc4Sc3ccc(cc23)S(C)(=O)=O

NMR EXAMPLES TO LEARN, (E)-5-Phenylpent-2-enal with real (lit) and predict data

(E)-5-Phenylpent-2-enal has the following physical and spectroscopic properties: 

¹H NMR (500 MHz, CDCl₃) δ: 2.66-2.71 (m, 2H), 2.85 (t, J = 7.5 Hz, 2 H), 6.15 (ddt, J = 15.8, 7.8, 1.4 Hz, 1 H), 6.87 (td, J = 15.7, 6.7 Hz, 1 H), 7.20-7.25 (m, 3 H), 7.31-7.34 (m, 2 H), 9.51 (d, J = 7.8 Hz, 1 H). 

¹³C NMR (125 MHz, CDCl₃) δ: 34.3, 34.4, 126.6, 128.5, 128.8, 133.6, 140.4, 157.4, 194.1. 

IR (neat) cm⁻¹: 3064, 3031, 2930, 1685, 1490, 1120. 

HRMS calcd. for C₁₁H₁₂O (MH⁺): 161.0966, found 161.0964. 

GC-MS (EI) m/z (relative intensity), 160 (8%, M⁺), 142 (14%), 129 (12%), 116 (75%), 92 (35%), 91 (100%), 77 (18%), 65 (60%), 51 (21%).

Purity by GC: 97% (t_R = 10.5 min; conditions same as in Note 7).

The material crystallizes in the freezer and has an approximate melting point of -12 to -14 °C.


1H NMR

13 C NMR

1H NMR AND 13C NMR PREDICT COMING.......

////////////////


O=C\C=C\CCc1ccccc1

2-pyrazolin-5-one

137-45-1 cas

• 3-Pyrazolin-5-one (8CI)
• Pyrazol-3(or 5)-ol (6CI,7CI)
• 1,2-Dihydro-3H-pyrazol-3-one
• 1,2-Dihydropyrazol-3-one
• 1H-Pyrazol-3-ol

• 1H-Pyrazol-5-ol
• 3-Hydroxypyrazole
• 3-Pyrazoline-5-one
• 3-Pyrazolone
• 4-Pyrazolin-3-one
• NSC 520837
• Pyrazol-3-ol
• Pyrazol-5-ol

Compound 1: Under stirring, to a solution of 5.81 g (50 mmol) of methyl (2E)-3-methoxyacrylate in methanol (5 mL) was hydrazine hydrate (2.75 g, 55 mmol) added and the mixture was refluxed for 1h. Evaporation under reduced pressure to dryness gave 4.13 g (98%) of a slightly yellowish powder, pure according to 1H NMR spectroscopy.

Melting point: 160–162 °C, crystal modifications starting at ~140 °C, (lit. [12] 162–164 °C).

1H-NMR (300 MHz, DMSO-d6, 28 °C, numbering for 1H-pyrazol-3-ol = form D) [13]: δ= 9.82 (br s, 2H, XH); 7.33 (d, 3 J(H5,H4)= 2.3 Hz, 1H, H5); 5.43 (d, 3 J(H4,H5)= 2.3 Hz, 1H, H4).

13C-NMR (75 MHz, DMSO-d6, 28 °C, numbering for 1H-pyrazol-3-ol = form D) [13]: δ= 161.0 (C3, 2 J(C3,H4)= 3.4 Hz, 3 J(C3,H5)= 9.2 Hz); 130.1 (C5, 1 J = 184.0 Hz, 2 J(C5,H4)= 8.2 Hz); 89.3 (C4, 1 J = 175.6 Hz, 2 J(C4,H5)= 8.7 Hz).

15N-NMR (50 MHz, DMSO-d6, 294 K) [14]: δ= –126.5; –192.0.

MS (m/z, %) [15]: 84 (M+ , 100); 55 (24).

Elemental Analysis: Calculated for C3H4N2O (84.08): C, 42.86%; H, 4.80%; N, 33.32%. Found: C, 42.75%; H, 4.65%; N, 33.15%.

References and /Notes:

1. J. Elguero, In 'Comprehensive Heterocyclic Chemistry: Pyrazoles and their Benzo Derivatives', Vol. 5; A. R. Katritzky and C. W. Rees, Eds., Pergamon Press, Oxford, 1984, 167–303.

2. Stanovnik, B.; Svete, J. Product class 1: Pyrazoles. Science of Synthesis 2002, 12, 15–225.

3. Eller, G. A.; Holzer, W. Heterocycles 2004, 63, 2537–2555.

4. Becker, W.; Eller, G. A.; Holzer, W. Synthesis 2005, 2583–2589.

5. Testa, E.; Fontanella, L. Farmaco 1971, 26, 1017–35.

6. Dorn, H.; Zubek, A. J. Prakt. Chem. 1971, 313, 1118–24.

7. Maywald, V.; Steinmetz, A.; Rack, M.; Gotz, N.; Gotz, R.; Henkelmann, J.; Becker, H.; Aiscar Bayeto, PCT Int. Appl. WO 0031042 A2 2000 (Chem. Abstr., 2000, 133, 4655).

8. Holzer, W.; Hallak, L. Heterocycles 2004, 63, 1311–1334, and references cited therein.

9. Cizmarik, J.; Lycka, A. Pharmazie 1988, 43, 794–795.

10. Holzer, W.; Kautsch, C.; Laggner, C.; Claramunt, R. M.; Perez-Torralba, M.; Alkorta, I.; Elguero, J. Molbank 2004 http://www.mdpi.org/molbank/molbank2006/m464.htm 2 von 3 24.02.2009 12:54 Tetrahedron 2004, 60, 6791–6805.

11. Sackus, A.; Holzer, W. manuscript in preparation.

12. Lingens, F.; Schneider-Bernloehr, H. Liebigs Ann. Chem. 1965, 686, 134–144.

13. The spectrum was obtained on a Varian UnityPlus 300 spectrometer (299.95 MHz for 1H, 75.43 MHz for 13C). The center of the solvent signal was used as an internal standard which was related to TMS with δ 2.49 ppm (1H NMR) and δ 39.5 ppm (13C NMR).

14. The spectrum was obtained on a Bruker Avance 500 spectrometer and was referenced against neat, external nitromethane (coaxial capillary). The signals were not unequivocally assigned to the N atoms. 15. The spectrum was obtained on a Shimadzu QP 1000 instrument (EI, 70eV).

Molbank 2006, M464 http://www.mdpi.net/molbank/ A one-step synthesis of pyrazolone Gernot A. Eller* and Wolfgang Holzer Department of Drug Synthesis, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria Phone: +43-1-4277-55634, e-mail: gernot.eller@univie.ac.at *Author to whom correspondence should be addressed

file:///C:/Users/91200291/Downloads/molbank-2006-M464.pdf

NMR IS EASY EVEN MOM CAN TEACH YOU

Patent

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=53A64F5E273ACA610ACAED2A3499BC0F.wapp2nA?docId=WO2015095792&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Synthesis of lH-pyrazol-3-ol

[0223] To a 100 mL round-bottom flask was added methyl (2E)-3-methoxyprop-2-enoate (11.6 g, 99.90 mmol, 1.00 equiv) and methanol (10.0 mL), followed by the addition of hydrazine hydrate (7.8 mL) dropwise with stirring. The resulting solution was stirred for 90 min at 85°C, then concentrated under vacuum to afford crude lH-pyrazol-3-ol as a white solid.

/////////////

3-(2-(Benzoylamino)ethyl)-1-phenyl-1H-pyrazol-5-yl benzoate

3-(2-(Benzoylamino)ethyl)-1-phenyl-1H-pyrazol-5-yl benzoate (14). Benzoyl chloride (0.230 mL, 2 mmol) was added to a stirred suspension of amine 6c (276 mg, 1 mmol) in a mixture of anhydrous dichloromethane (10 mL) and 4-methylmorpholine (0.66 mL, 6 mmol) and the mixture was stirred at r.t. for 12 h. Volatile component were evaporated in vacuo and the residue was chromatographed over silica gel (50% EtOAc/hexanes). Fractions containing the products were combined and evaporated in vacuo to give 14. Yellow solid, yield 79%, 326 mg,

mp 109– 112 °C,

IR (νmax, cm –1): 3289, 1753 (C=O), 1632 (C=O), 1445, 1315, 1247, 1076, 760, 697.

1 H NMR (300 MHz, CDCl3), δH 3.01 (2H, t, 3 JHH = 6.3 Hz, CH2CH2NH), 3.86 (2H, q, 3 JHH = 6.0 Hz, CH2CH2NH), 6.36 (1H, s, 4-H of pyrazole), 7.16 (3H, br s, NH), 7.31–7.53 (8H, m, 8H of Ph), 7.59–7.68 (3H, m, 3H of Ph), 7.78–7.83 (2H, m, 2H of Ph), 8.05–8.11 (2H, m, 2H of Ph).

13C NMR (126 MHz, DMSO-d6), δC 28.7, 38.9, 95.8, 122.7, 127.17, 127.23, 127.3, 128.3, 129.25, 129.30, 130.1, 131.1, 134.6, 134.8, 137.6, 144.0, 150.3, 161.8, 166.2. MS, m/z = 412 (MH+ ),

HRMS (ESI), m/z = 412.1649 (MH+ ), C25H22N3O3 requires 412.1656.

Anal. Calcd for C25H21N3O3 (411.45): C, 63.66; H, 6.16; N, 17.13%, Found: C, 63.47; H, 6.30; N, 16.91%.

Synthesis of 3-(2-aminoethyl)-5-hydroxy-1H-pyrazole derivatives

Uroš Grošelj; David Kralj; Jernej Wagger; Georg Dahmann; Branko Stanovnik; Jurij Svete

Skip other details (including permanent urls, DOI, citation information)

Volume 2012, Issue 3, Commemorative Issue in Honor of Prof. Rainer Beckert on the occasion of his 60th anniversary, pp. 49-65

DOI: http://dx.doi.org/10.3998/ark.5550190.0013.305

Edaravone эдаравон, إيدارافون , 依达拉奉 ,ラジカット,

FDA approves drug to treat ALS

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,

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,

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]

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:

[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:

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:

[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:

PATENT

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

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;

[0030] (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%.

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.

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-1, Figure 2) in DMSO and 2,4-dihydro form (T-2, Figure 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-b, 3e-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) ν_max/cm^-1: 3127, 1597, 1525, 1498, 1454;

 ¹H NMR (400 MHz, DMSO-d₆) δ 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-d₆) δ 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. 2004, 12, 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 2533664 . 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

• http://www.alstdi.org/news/radicut-approved-for-als-in-japan/
• http://www.mt-pharma.co.jp/e/release/nr/2015/pdf/e_MTPC150626_2.pdf
• http://www.alstdi.org/als-research/clinical-trials/168/
• http://informahealthcare.com/doi/pdfplus/10.3109/21678421.2014.959024

Edaravone

Clinical data
Trade names	Radicut
Routes of administration	Oral
ATC code	none
Legal status
Legal status	Rx-only (JP)
Identifiers
IUPAC name[show]
Synonyms	MCI-186
CAS Number	89-25-8
PubChem CID	4021
ChemSpider	3881
UNII	S798V6YJRP
KEGG	D01552
ChEBI	CHEBI:31530
ChEMBL	CHEMBL290916
ECHA InfoCard	100.001.719
Chemical and physical data
Formula	C10H10N2O
Molar mass	174.20 g/mol
3D model (Jmol)	Interactive image

////////// Radicava, edaravone, fda 2017, Lou Gehrig’s disease, amyotrophic lateral sclerosis,  Mitsubishi Tanabe, orphan drug designation, 89-25-8, эдаравон, إيدارافون , 依达拉奉 ,ラジカット,

O=C1CC(=NN1c1ccccc1)C