New Drug Approvals

Home » 0rphan drug status » MACITENTAN , 马昔腾坦 , ماسيتانتان , Мацитентан , マシテンタン

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

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

PAYPAL DONATIONS

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Categories

Blog Stats

  • 1,310,010 hits

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,782 other followers

add to any

Share

File:Macitentan skeletal.svg

MACITENTAN

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

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

CAS NO  441798-33-0

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

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

Macitentan is achiral

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

Mp 135–136 °C;………….J. Med. Chem., 2012, 55 (17), pp 7849–7861, DOI: 10.1021/jm3009103/CN 104447572
Rf (silica gel, heptane:ethyl acetate 1:1) 0.44.
LC-MS: tR = 0.79 min, [M + H]+ = 588.86 (major isotope).
HR-LC-MS: tR = 1.96 min; (m + H)/z = 586.9711, found = 586.9714.
 
1H NMR (CDCl3): δ 8.51 (s, 2 H), 8.49 (s, 1 H), 7.58–7.63 (m, 2 H), 7.16–7.21 (m, 2 H), 6.88 (s, 1 H), 5.61 (t, J = 6.2 Hz, 1 H), 4.72–4.76 (m, 2 H), 4.62–4.66 (m, 2 H), 2.99 (q, J = 6.8 Hz, 2 H), 1.61 (h, J = 7.3 Hz, 2 H), 0.97 (t, J = 7.4 Hz, 3 H)……………..J. Med. Chem., 2012, 55 (17), pp 7849–7861,DOI: 10.1021/jm3009103
13C NMR (CDCl3): δ 11.6, 22.7, 46.1, 65.3, 65.9, 104.8, 112.4, 123.7, 128.0, 131.7, 133.0, 155.7, 156.4, 159.7, 163.5, 166.3…………….J. Med. Chem., 2012, 55 (17), pp 7849–7861,DOI: 10.1021/jm3009103

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

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

Macitentan.png

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

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

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

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

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

Pharmacokinetics

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

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

SYNTHESIS

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

Synthesis of Macitentan

…………………………………………….

SYNTHESIS

http://www.yaopha.com/

YOU CAN READ AT YAOPHA.COM, lovely site to see for drugs

http://www.yaopha.com/%E8%8D%AF%E7%89%A9%E5%90%88%E6%88%90-drug-synthesis/opsumit-macitentan-%E9%A9%AC%E8%A5%BF%E6%9B%BF%E5%9D%A6/

Synthesis of Opsumit_Macitentan-pulmonary arterial hypertension-Actelion 肺动脉高压药物马西替坦的合成路线

联系我们 Contact US

如果您有关于yaopha.com的问题或建议请与我们联系,具体方式如下:

E-mail:contactus@yaopha.com

………………………….

SYNTHESIS

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

………………………

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

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

Parameters of the LC-MS method:

Injection volume: 2 |jL

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

Column flow rate: 1 mL/min

Eluents: Eluent A: water + 0.08% TFA

Eluent B: MeCN + 0.012% TFA

Gradient: 2.0 min 95% B

2.8 min 95% B

3.0 min 5% B

Temperature: 40°C Detector wavelength 210 nm

Figure imgf000003_0001

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

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

……………………

PAPER

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

J. Med. Chem., 2012, 55 (17), pp 7849–7861
DOI: 10.1021/jm3009103
Abstract Image

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

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

………………………….. to give 17 (11.99 g, 88%) as a white powder;
mp 135–136 °C; Rf (silica gel, heptane:ethyl acetate 1:1) 0.44.
LC-MS: tR = 0.79 min, [M + H]+ = 588.86 (major isotope).
HR-LC-MS: tR = 1.96 min; (m + H)/z = 586.9711, found = 586.9714.
1H NMR (CDCl3): δ 8.51 (s, 2 H), 8.49 (s, 1 H), 7.58–7.63 (m, 2 H), 7.16–7.21 (m, 2 H), 6.88 (s, 1 H), 5.61 (t, J = 6.2 Hz, 1 H), 4.72–4.76 (m, 2 H), 4.62–4.66 (m, 2 H), 2.99 (q, J = 6.8 Hz, 2 H), 1.61 (h, J = 7.3 Hz, 2 H), 0.97 (t, J = 7.4 Hz, 3 H).
13C NMR (CDCl3): δ 11.6, 22.7, 46.1, 65.3, 65.9, 104.8, 112.4, 123.7, 128.0, 131.7, 133.0, 155.7, 156.4, 159.7, 163.5, 166.3.

……………

WO 2015004265  click

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

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

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

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

…….

CN 104447572 click

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

Figure CN104447572AD00042

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

Figure CN104447572AD00043
Figure CN104447572AD00044

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

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

A method for preparing Marcy cefotetan, comprising the steps of: (1) the compound of formula II with N- cyclopropyl sulfonamide compound of formula III 5- (4- bromophenyl) -4, 6- dichloropyrimidine substitution reaction is converted to the formula IV:
Figure CN104447572AC00021
Compound (2) in the presence of a strong base of formula IV with a compound of formula V glycol substitution reaction to give a compound of formula VI:
Figure CN104447572AC00022
Compound (3) a strong base of formula VI in the presence of a substitution reaction conditions to give a compound of formula I with a compound of formula W occurs:
Figure CN104447572AC00023
, The resulting compound of formula I as Marcy cefotetan.

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

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

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

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

…………

see

WO 2002053557

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

………..

NMR spectroscopy 

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

1 H-NMR 

Solvent: CDCl 3

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

 ……………………………………………………………………………………

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

13 C-NMR 

Solvent: CDCl 3

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

NMR PREDICT BY ME

1H NMR PREDICT

Predict 1H proton NMR spectra GRAPH Predict 1H proton NMR spectra VAL

13C NMR PREDICT BY ME

Predict 13c  NMR spectra GRAPH Predict 13c  NMR spectra VAL

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

COSY NMR prediction (20)

REFERENCES

  1.  Bolli, M. H.; Boss, C.; Binkert, C.; Buchmann, S.; Bur, D.; Hess, P.; Iglarz, M.; Meyer, S.; Rein, J.; Rey, M.; Treiber, A.; Clozel, M.; Fischli, W.; Weller, T. (2012). “The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist”. Journal of Medicinal Chemistry 55 (17): 7849–7861. doi:10.1021/jm3009103PMID 22862294.
  2.  “Macitentan”. Actelion. Retrieved 22 August 2012.
  3.  Bruderer, S.; Hopfgartner, G. R.; Seiberling, M.; Wank, J.; Sidharta, P. N.; Treiber, A.; Dingemanse, J. (2012). “Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans”. Xenobiotica 42 (9): 901–910.doi:10.3109/00498254.2012.664665PMID 22458347.
  4.  Bruderer, S.; Äänismaa, P. I.; Homery, M. C.; Häusler, S.; Landskroner, K.; Sidharta, P. N.; Treiber, A.; Dingemanse, J. (2011).“Effect of Cyclosporine and Rifampin on the Pharmacokinetics of Macitentan, a Tissue-Targeting Dual Endothelin Receptor Antagonist”The AAPS Journal 14 (1): 68–78. doi:10.1208/s12248-011-9316-3PMC 3282010PMID 22189899.
  5. Bolli, M. H.; Boss, C.; Binkert, C.; Buchmann, S.; Bur, D.; Hess, P.; Iglarz, M.; Meyer, S.; Rein, J.; Rey, M.; Treiber, A.; Clozel, M.; Fischli, W.; Weller, T. (2012). “The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist“. Journal of Medicinal Chemistry, 2012, 55 (17): 7849–7861
  6. Martin Bolli, Christoph Boss, Martine Clozel, Walter Fischli, Thomas Weller, Novel sulfamides and their use as endothelin receptor antagonists, WO2002053557 A1, CA2431675A1, CA2431675C, CN1524079A, CN100432070C, DE60118782D1, DE60118782T2, EP1345920A1, EP1345920B1, EP1693372A1, US7094781, US7285549, US20040077670, US20060178365,
  7. Martin Bolli, Christoph Boss, Martine Clozel, Walter Fischli, Thomas Weller, Sulfamides as endothelin receptor antagonists for the treatment of cardiovascular diseases, WO2006051502
  8. Martine Clozel, Therapeutic compositions containing macitentan,WO2010018549 A2, CA2731370A1, CN102099026A, CN102099026B, EP2315587A2, US20110136818(WO2006/051502A2, JMC2012, 7849). Chlorosulfonyl isocyanate ( 1 ) reaction with tert-butyl alcohol 2 , which is then reacted with n-propylamine 3 . 3 de-boc protected through the acid after reaction with potassium t-butoxide 4 . Another compound 5 with NaH after acidic protons off with dimethyl carbonate ( 6 ) to obtain 7 . 7 and formamidine hydrochloride ( 8 ) to ring chlorinated later POCl3 9 . 9 and 4 SNAr reaction occurs 10 . 10under basic conditions with ethylene glycol SNAr reaction occurs again in alkaline conditions with11 SNAr reaction occurs MAXI cefotetan.

External links

Actelion Ltd

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

Macitentan
Macitentan skeletal.svg
Systematic (IUPAC) name
N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide
Clinical data
Trade names Opsumit
Pregnancy
category
  • US: X (Contraindicated)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Metabolism Hydrolysis, oxidation (CYP3A4)
Excretion 2/3 urine, 1/3 faeces
Identifiers
CAS Registry Number 441798-33-0
ATC code C02KX04
PubChem CID: 16004692
ChemSpider 13134960
ChEBI CHEBI:76607
Synonyms ACT-064992
Chemical data
Formula C19H20Br2N6O4S
Molecular mass 588.273 g/mol
Patent Submitted Granted
Sulfamides and their use as endothelin receptor antagonists [US7094781] 2004-04-22 2006-08-22
Sulfamides and their use as endothelin receptor antagonists [US7285549] 2006-08-10 2007-10-23
Stable Pharmaceutical Compositions Comprising a Pyrimidine – Sulfamide [US2008233188] 2008-09-25
Combination Comprising Paclitaxel for Treating Ovarian Cancer [US2010311774] 2010-12-09
Stable pharmaceutical compositions comprising a pyrimidine-sulfamide [US2010004274] 2010-01-07
SULFONYLUREA MODULATORS OF ENDOTHELIN RECEPTOR [US2011082151] 2011-04-07
ENDOTHELIN RECEPTOR ANTAGONISTS FOR EARLY STAGE IDIOPATHIC PULMONARY FIBROSIS [US2010022568] 2007-04-12 2010-01-28
THERAPEUTIC COMPOSITIONS CONTAINING MACITENTAN [US2011136818] 2011-06-09
Therapeutic Compositions Comprising a Specific Endothelin Receptor Antagonist and a PDE5 Inhibitor [US2009318459] 2009-12-24

Patent and Exclusivity 


Patent Data

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

Exclusivity Data

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

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

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

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

OPSUMIT® (macitentan) Structural Formula Illustration

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

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

//////


4 Comments

  1. saminakhan2001 says:

    Reblogged this on MEDCHEMEGYPT.

  2. medchemnintabelle says:

    Reblogged this on MedCheminAustralia.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Paypal Donate

DR ANTHONY CRASTO

Follow New Drug Approvals on WordPress.com

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,782 other followers

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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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

Personal Links

View Full Profile →

bloglovin

Follow my blog with Bloglovin The title of your home page You could put your verification ID in a comment Or, in its own meta tag Or, as one of your keywords Your content is here. The verification ID will NOT be detected if you put it here.
%d bloggers like this: