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