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Ambrisentan, أمبريسنتان , 安立生坦 ,アンブリセンタン


Ambrisentan structure.svgChemSpider 2D Image | ambrisentan | C22H22N2O4Ambrisentan.png

Ambrisentan

BSF-208075; LU-208075

(+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid

  • Molecular FormulaC22H22N2O4
  • Average mass378.421 Da
(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid
177036-94-1 [RN]
8128
HW6NV07QEC
أمبريسنتان [Arabic] [INN]
安立生坦 [Chinese] [INN]
QA-7701
UNII:HW6NV07QEC
BSF208075
Letairis
Letairis®
LU208075
Trade Name:Letairis® / Volibris®
MOA:Type A endothelin receptor (ETA) antagonist
Indication:Pulmonary arterial hypertension
Company:Abbott (Originator) , Gilead,GlaxoSmithKline
アンブリセンタン
Ambrisentan

C22H22N2O4 : 378.42
[177036-94-1

Ambrisentan (U.S. trade name Letairis; E.U. trade name Volibris; India trade name Pulmonext by MSN labs) is a drug indicated for use in the treatment of pulmonary hypertension.

The peptide endothelin constricts muscles in blood vessels, increasing blood pressure. Ambrisentan, which relaxes those muscles, is an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA).[1] Ambrisentan significantly improved exercise capacity (6-minute walk distance) compared with placebo in two double-blind, multicenter trials (ARIES-1 and ARIES-2).[2]

Ambrisentan was approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency, and designated an orphan drug, for the treatment of pulmonary hypertension.[3][4][5][6][7]

Ambrisentan is an endothelin receptor antagonist used in the therapy of pulmonary arterial hypertension (PAH). Ambrisentan has been associated with a low rate of serum enzyme elevations during therapy, but has yet to be implicated in cases of clinically apparent acute liver injury.

Ambrisentan was first approved by the U.S. Food and Drug Administration (FDA) on Jun 15, 2007, then approved by the European Medicines Agency (EMA) on Apr 21, 2008 and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Jul 23, 2010. In 2000, Abbott, originator of ambrisentan, granted Myogen (acquired by Gilead in 2006) a license to the compound for the treatment of PAH. In 2006, GlaxoSmithKline obtained worldwide rights to market the compound for PAH worldwide, with the exception of the U.S. It is marketed as Letairis® by Gilead in US.

Ambrisentan is an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA). It is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%).

Letairis® is available as film-coated tablet for oral use, containing 5 or 10 mg of free Ambrisentan. The recommended starting dose is 5 mg once daily with or without food, and increase the dose to 10 mg once daily if 5 mg is tolerated.

Recent Developments and Publications

Last Updated 9/2/2015
8/15/2015Reprod. Toxicol. Endothelin receptor activation mediates strong pulmonary vasoconstriction and positive inotropic effect on the heart. These physiologic effects are vital for the development of the fetal cardiopulmonary system. As such, endothelin receptor antagonists such as Ambrisentan are teratogenic.[8]
8/27/2015NEJM Ambrisentan when used in combination therapy with Tadalafil was found to be more efficacious in treating treatment naive patients with WHO class II or III Pulmonary Arterial Hypertension than monotherapy using either drug.[9]
Approval Date Approval Type Trade Name Indication Dosage Form Strength Company Review Classification
2007-06-15 Marketing approval Letairis Pulmonary arterial hypertension Tablet, Film coated 5 mg/10 mg Gilead Priority; Orphan
Approval Date Approval Type Trade Name Indication Dosage Form Strength Company Review Classification
2008-04-21 Marketing approval Volibris Pulmonary arterial hypertension Tablet, Film coated 5 mg/10 mg GlaxoSmithKline Orphan
Approval Date Approval Type Trade Name Indication Dosage Form Strength Company Review Classification
2010-07-23 Marketing approval Volibris Pulmonary arterial hypertension Tablet, Film coated 2.5 mg GlaxoSmithKline
Approval Date Approval Type Trade Name Indication Dosage Form Strength Company Review Classification
2010-10-19 Marketing approval 凡瑞克/Volibris Pulmonary arterial hypertension Tablet 5 mg GlaxoSmithKline
2010-10-19 Marketing approval 凡瑞克/Volibris Pulmonary arterial hypertension Tablet 10 mg GlaxoSmithKline

Clinical uses

Ambrisentan is indicated for the treatment of pulmonary arterial hypertension (WHO Group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening.

Image result for ambrisentan

Birth defects

Endothelin receptor activation mediates strong pulmonary vasoconstriction and positive inotropic effect on the heart. These physiologic effects are vital for the development of the fetal cardiopulmonary system. In addition to this, endothelin receptors are also known to play a role in neural crest cell migration, growth, and differentiation. As such, endothelin receptor antagonists such as Ambrisentan are known to be teratogenic.

Ambrisentan has a high risk of liver damage, and of birth defects if a woman becomes pregnant while taking it. In the U.S., doctors who prescribe it, and patients who take it, must enroll in a special program, the LETAIRIS Education and Access Program (LEAP), to learn about those risks. Ambrisentan is available only through specialty pharmacies.

External links

PATENT

WO9611914A1 / US7109205B2.

WO2010070658A2 / US2011263854A1.

WO2011004402A2 / US2012184573A1.

WO2013030410A2 / US2014011992A1.

CN103709106A.

CN103420811A.

str1

PATENT

https://patents.google.com/patent/WO2012167406A1/en

Ambrisentan and darusentan first reported in U. Med. Chem. 1996, 39, 2123-2128), as a selective antagonist of endothelin receptor A, followed by their pharmacological properties have been studied further, published in J. Med. Chem. 1996, 39, 2123-2128), US patent US 5932730, WO 2009/017777 A2 in. The formula (I), when R is methyl, Chinese name is (+) – ambrisentan, Chinese chemical name is (+) – (2S) -2 – [(4, 6- dimethyl-pyrimidine 2-yl) – oxy] -3-methoxy-3,3-diphenyl-propionic acid; English name is (+) – ambrisentan, English name: (S) -2- (4,6-dimethylpyrimidin -2-yloxy) -3-methoxy-3,3-diphenylpropanoic acid; when R is methoxy, Chinese as (+) – darusentan, Chinese chemical name is (+) – (2S) -2- [ (4,6-dimethoxypyrimidin-2-yl) – oxy] -3-methoxy-3,3-diphenyl-propionic acid; English name is (+ darusentan, English name: (S) – . 2- (4,6-dimethoxypyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropanoic acid ambrisentan now been approved by the FDA in the United States, the trade name Letairis, for the oral treatment of pulmonary hypertension; up Lu bosentan new drugs may be resistant hypertension (Resistant hypertension) of.

Existing ambrisentan or darusentan synthetic techniques include benzophenone Darzens reaction of an epoxy compound and a racemic methyl chloroacetate, the racemic epoxide opening catalyst in a solution of boron trifluoride diethyl ether ring to give the chiral alcohol latent after substitution reaction and then after hydrolysis reaction ambrisentan or darusentan. Existing obtained optically pure (+) – ambrisentan or (+) – darusentan methods rely mainly on resolution techniques. For example, the split is by a latent chiral alcohol or R- L- proline methyl phenethylamine, see WO 2010/070658 A2, WO 2011/004402 A2. It is well known as chiral utilization of raw materials is not high, resulting in increased costs, limiting industrial-scale applications.

 Example 1, (+) – ambrisentan ((2S) -2 – [(4,6- dimethyl-pyrimidin-2-yl) – oxy] -3-methoxy-3,3-diphenyl propionic acid) of

Preparation of 3,3-diphenyl-2,3-epoxy-propionate (1) (2S)

Figure imgf000006_0001

As indicated above Formula Scheme, wherein, Ph is phenyl; Ac is acetyl;

To a 50 L reactor equipped with a mechanical stirrer was added 3.0 L of acetonitrile was dissolved in 3,3-diphenyl acrylate (0.536 mol, 135.0 g), was dissolved in 1.5 L of acetonitrile to give a concentration of 0.12 M 4 M ethylenediamine of formula (IV) shown fructose derived chiral ketones and tetra-n-butylammonium hydrogen sulfate (36 mmol, 12.2 g), was then added containing 3.0 L Ι χ ΙΟ “an aqueous solution of disodium ; cooling liquid into the reaction vessel dissection, the kettle temperature adjusted to -5 ° C- + 5 ° C; was added in batches with stirring pulverized with the pulverizer medicine through a 1.85 kg potassium hydrogen sulfate complex salt mixture (Oxone®), and 0.78 kg NaHCO 3 (9.29mol), and takes about 4.5 hours complete addition of the above mixture, after the addition the reaction mixture was continued stirring the reaction under this condition (in the system, 3,3- diphenyl acrylate, over a potassium bisulfate salts and complexes of formula molar ratio of fructose derived chiral ketone (IV) is shown in h 5: 0.34), and the timing detection reactions by gas chromatography; the end of the reaction after 5 hours , 5.0 L of water was added to dilute the reaction solution, and extracted with 5.0 L of ethyl acetate; the aqueous phase was added 2.5 L of acetic Extracted with ethyl; organic phases were combined and concentrated to remove the solvent to give homogeneous Qing 162.56 g (2S) -3,3- diphenyl-2,3-epoxy-propionate, crude yield greater than 99%, No purification processing the next reaction, nuclear magnetic conversion was 92%, measured by HPLC enantiomeric excess of 86.9%, Analytical conditions: column model Chiralcel OD-H, n has a volume ratio of the embankment and isopropanol 98: 2 analysis of wavelength 210 nm, the mobile phase flow rate of 1 mL / min, t! = 9.5 min, t 2 = 13.01 min, 86.9% ee.

IR (fi lm) 1760, 1731 cm- 1; ¾ NMR [400 MHz, CDC1 3] δ 7.46-7.44 (m, 2H), 7.36-7.31 (m, 8H), 3.99 (m, 3H), 0.96 (t , J = 7.2Hz, 3H); 13 C NMR [100 MHz, CDC1 3] δ 166.99, 138.98, 135.62, 128.67, 128.53, 128.36, 128.13, 127.04, 66.57, 62.16, 61.43, 13.96.

(2) (2S) -2-phenyl-3,3-hydroxy-3-methoxy propionate

Figure imgf000006_0002

The step (1) 162.56 g obtained in unpurified (2S) – 3,3-diphenyl acrylate epoxy crude compound was dissolved in 100 mL of methanol, 1 mL of boron trifluoride etherate ((2S ) – mole fraction of ethylene-3,3-diphenyl acrylate and boron trifluoride diethyl ether ratio of 1: 0.013) for the epoxy ring opening reaction; after controlling the reaction temperature is 20 ° C, reacted for 8 hours , the reaction solution was concentrated, ethyl acetate and aqueous extraction of the reaction solution after the ethyl acetate was concentrated to give 166.0 g of intermediate (2S) -2- hydroxy-3-methoxy-3,3-diphenyl acetic acid ester, crude yield of 92%, measured by high performance liquid enantiomeric excess of 86.9%, Analytical conditions: column model Chiralcel OD-H, n-and isopropyl alcohol embankment has a volume ratio of 98: 2, the wavelength analysis 210 nm, mobile phase flow rate of 1 mL / min,

Figure imgf000007_0001

min, t 2 = 14.51 min, 85.8% ee .;

IR (film) 1769, 1758 cm “1; 1H NMR [400 MHz, CDC1 3] δ 7.50-7.28 (m, 10H), 5.18 (s, 1H), 4.10 (t, 2H), 3.20 (s, J = 7.2Hz, 3H), 3.03 (s , 1H), 1.17 (t, J = 7.2Hz, 3H); 13 C NMR [100 MHz, CDC1 3] δ 172.48, 141.13, 140.32, 128.97, 128.73, 128.99, 127.81, 127.76, 127.62, 85.01, 77.42, 61.76, 52.62, 14.07.

-3-methoxy-3,3-diphenyl propionate (3) (2S) -2- [- oxo – dimethyl-pyrimidin-2-yl)]

Figure imgf000007_0002

Step (2) obtained in 166.0 g of intermediate (2S) -2- hydroxy-3-methoxy-3,3-diphenyl-propionate were added N, N- dimethylformamide 750 mL , potassium carbonate 45.54 g, was added 4,6-dimethyl after stirring for about half an hour 2-methanesulfonyl-pyrimidin nucleophilic substitution reaction at 80 ° C in an oil bath, the system, (2S) -2- hydroxy -3-methoxy-3,3-diphenyl-ethyl, 4,6-dimethyl-2 molar fraction ratio methylsulfonylpyrimidine and potassium carbonate is 1: 1.2: 0.6; nuclear magnetic after complete consumption of starting material was monitored after about 3 hours, water was added and the reaction solution was extracted with ethyl acetate, the ethyl acetate layer was concentrated to give 237.70 g of intermediate (2S) -2 – [(4,6- dimethyl-pyrimidin-2-yl ) – oxy] -3-methoxy-3,3-diphenyl propionate, crude yield greater than 99%, measured by HPLC enantiomeric excess of 85.9%, Analytical conditions: column Chiralcel OD model volume -H, isopropanol and n has embankment ratio of 98: 2, analysis wavelength was 210 nm, the mobile phase flow rate of 1 mL / min, t ^ lO.15 min, t 2 = 11.87 min, 85.9% ee .

IR (film) 1750cm “VH NMR [400 MHz, CDC1 3] δ 7.45 (d, J = 7.2 Hz, 2H), 7.39 (d, J = 7.2 Hz, 2H), 7.33-7.19 (m, 7H), 6.70 (s, 1H), 6.12 ( s, 1H), 4.01-3.85 (m, 2H), 3.50 (s, 3H) 2.38 (s, 6H), 0.93 (t, J = 6.8 Hz, 3H); 13 C NMR [100 MHz, CDC1 3] δ 169.51, 168.70, 163.86, 142.50, 141.29, 128.54, 128.03, 127.97, 127.94, 127.47, 127.40, 115.03, 83.76, 79.23, 77.43, 60.66, 53.92, 23.99, 13.93;. Anal Calcd For C 24 H 26 N 2 O 4 : C, 70.92; H, 6.45; N, 6.89 Found:. C, 70.72; H, 6.47; N, 6.83.

(4) (28) -2 – [(4,6-dimethyl-2-yl) – oxy] -3-methoxy-3,3-diphenyl-propionic acid ((+) – Abe Students Tanzania) preparation

Figure imgf000007_0003

To step (3) 237.7 g of the intermediate obtained (2S) -2 – [(4,6- dimethyl-pyrimidin-2-yl) – oxy] -3-methoxy-3,3-diphenyl propionate was dissolved in 1.2 L of organic solvent is 1,4-dioxane was added 600 mL of an aqueous solution containing 92.3 g of sodium hydroxide (wherein, (2S) -2 – [(4,6- dimethyl pyrimidin-2-yl) – oxy] -3-methoxy-3,3-diphenyl propionate and sodium hydroxide molar fraction ratio of 1: 4), the reaction temperature was 80 ° C, the reaction after 8 hours, the reaction solution was concentrated, using (1 L, 0.5 L, 0.5 L) and extracted with ether to remove organic impurities, the aqueous phase was extracted after addition of hydrochloric acid to adjust pH 3, large amount of solid appears; then the aqueous phase was added 1.0 L ethyl acetate, filtered to remove insolubles (insolubles which was found after analysis racemic ambrisentan, 23.37 g), the organic layer was concentrated, i.e., optically pure can be obtained 103.9 g (+) – ambrisentan, from 3 , 3-diphenyl acrylate departure, the optically pure (+) – ambrisentan, a yield of 52.3%. A small amount of the obtained reaction with ambrisentan diazo embankment derived (2S) -2 – [(4,6- dimethyl-pyrimidin-2-yl) – oxy] -3-methoxy-3,3 methyl diphenyl measured enantiomeric excess ambrisentan. (2S) -2 – [(4,6- dimethyl-pyrimidin-2-yl) – oxy] -3-methoxy-3,3-diphenyl-propionic acid methyl ester: HPLC measured enantiomer excess of 99.1%, Analytical conditions: column model Chiralcel OD-H, n has a volume ratio of isopropanol embankment 98:! 2, analysis wavelength was 210 nm, the mobile phase flow rate of 1 mL / min, t = 11.61 min, t 2 = 14.05 min , 99.1% ee.

[a] D 25 = + 174.2 (c = 0.5, MeOH); mp> 150 ° C turns yellow,> 180 ° C into a black, 182 ° C melt; 1H NMR [400 MHz, CDC1 3] δ 7.43 ( d, J = Hz, 2H) , 7.29-7.19 (m, 8H), 6.63 (s, 1H), 6.30 (s, 1H), 3.26 (s, 3H) 2.31 (s, 6H); 13 C NMR [100 MHz, CDC1 3] δ 178.98,170.54, 169.70, 163.48, 139.91, 138.91, 128.77, 128.67, 128.22, 128.08, 115.34, 84.67, 77.55, 53.49, 23.93; 1H NMR [400 MHz, DMSO] δ 12.53 (s, 1H ), 7.34-7.20 (m, 10H) , 6.95 (s, 1H), 6.14 (s, 1H), 3.37 (s, 3H) 2.34 (s, 6H); 13 C NMR [100 MHz, DMSO] δ 169.01, 163.14, 142.59, 141.41, 127.80, 127.68, 127.64, 127.19, 126.95, 114.72, 83.12, 77.55, 52.99, 23.30.

CLIP

SEE https://www.pharmacodia.com/yaodu/html/v1/chemicals/a01610228fe998f515a72dd730294d87.html

CLIP

http://www.orgsyn.org/demo.aspx?prep=v89p0350#ref68

Image result for ambrisentan

Shi and coworkers recently obtained 120 g of virtually enantiopure (+)-ambrisentan (97) without the need for column chromatography (Scheme 23).68 (+)-Ambrisentan, an endothelin-1 receptor antagonist, is currently used to treat hypertension. Ketone 2-catalyzed epoxidation afforded 96 in 90% conversion and 85% ee. Compound 97 was further enriched via precipitation and filtration of the racemate.

  1. Peng, X.; Li, P.; Shi, Y. J. Org. Chem201277, 701-703.

Clip

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00184

Process Research for (+)-Ambrisentan, an Endothelin-A Receptor Antagonist

 Collaborative Innovation Center of Yangze River Delta Region Green PharmaceuticalsZhejiang University of Technology18 Chaowang Road, Hangzhou 310014, China
 Department of Pharmaceutial EngineeringChina Pharmaceutical University24 Tongjiaxiang, Nanjing 210009, China
§ Shanghai Institute of Pharmaceutical IndustryChina State Institute of Pharmacetical Industry285 Gebaini Road, Pudong, Shanghai 201203, China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00184
Publication Date (Web): August 6, 2018
Copyright © 2018 American Chemical Society
Abstract Image

An efficient and robust synthetic route to (+)-ambrisentan ((+)-AMB) was designed by recycling the unwanted isomer from the resolution mother liquors. The racemization of AMB in the absence of either acid or base in the given solvents was reported. The recovery process was developed to produce racemates with purities over 99.5%. The mechanism of the formation of the process-related impurities of (+)-AMB is also discussed in detail. (+)-AMB was obtained in 47% overall yield with >99.5% purity and 99.8% e.e. by chiral resolution with only one recycling of the mother liquors on a 100-g scale without column purification.

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00184/suppl_file/op8b00184_si_001.pdf

PaPER

https://pdfs.semanticscholar.org/3801/d5a98a526a4386c431e25d3ac99a328bfae2.pdf

CHEMICAL ENGINEERING TRANSACTIONS VOL. 46, 2015 A publication of The Italian Association of Chemical Engineering Online at http://www.aidic.it/cet Guest Editors: Peiyu Ren, Yancang Li, Huiping Song Copyright © 2015, AIDIC Servizi S.r.l., ISBN 978-88-95608-37-2; ISSN 2283-9216

Improved Synthesis Process of Ambrisentan and Darusentan Jian Lia , Lei Tian*b, c a School of Environmental Science, Nanjing Xiaozhuang University, 3601 Hongjing Road, Nanjing, Jiangsu, 211171, China b School of Petroluem Engineer, Yangtze University, Wuhan, Hubei, 430100, P. R. China c Key Laboratory of Exploration Technologies for Oil and Gas Resources (Yangtze University), Ministry of Education tianlei4665@163.com

2-hydroxy-3-phenoxy-3, 3-diphenylpropinate (5) was prepared from benzophenone via Darzens, methanolysis and hydrolysis reaction. The compound (5) was salified with (S)-dehydroabietylamine (7) and diasterotropic resolution was carried out to provide the key intermediate (S)-2-hydroxy-3-methoxy-3, 3-diphenylpropionic acid (6). Compound (6) was condensed with 2-methylsulfonyl-4, 6-dimethylpyrimidine and 2-methoxysulfonyl4, 6-dimethylpyrimidine to afford ambrisentan (1) and darusentan (7), respectively. Two products were with excellent charity and chemical purity. The total yield of the synthesis was 30.1% and 29.6%, respectively.

str1

Synthesis of methyl 3, 3-diphenyloxirane-2-carboxylate (3) To a solution of sodium methanolate (4.3 g, 79.6 mmol) in dry THF (25 mL) was added the solution of benzophenone (7.2 g, 39.5 mmol) and methyl chloroacetate (6.6 g, 60.8 mmol) in dry THF (15 mL) and stirred at -10 °C for 2 h. The mixture was quenched with water (50 mL). The solution was extracted with diethyl ether (80 mL×3). The organic phases were combined and washed with saturated NaCl. The solution was dried over Na2SO4, filtered, and evaporated under reduced pressure to afford a light yellow oil. The residue (3) can apply in next step without further purification (8.24 g, 82.1%). 1H-NMR (CDCl3): δ 3.52 (s, 3H), 3.99 (s, 1H), 7.32-7.45 (m, 10H).

Synthesis of 2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid (5)

To a solution of compound (3) (8.2 g, 31.6 mmol) in methanol (40 mL) was added p-toluene sulfonic acid (0.5 g) and stirred at for 0.5 h to afford the solution containing compound (4). Aqueous solution of NaOH (10% wt.) (60 mL) was added to the solution of compound (4) and the mixture was stirred at refluxed for 1h (ester disappeared by TLC). The solution was evaporated in order to remove a lot of methanol. The residue was acidified to pH 2 by conc. HCl. The solution was stirred for overnight and white solid stayed at the aqueous layer. The precipitate was filtered and deeply dried under vacuum to afford (5). (7.34 g, 85.3%). 1H-NMR (CDCl3): δ 3.22 (s, 3H), 5.14 (br, 1H), 5.20 (d, 1H), 7.18-7.37 (m, 10H), 12.30 (1H, br). Synthesis of (S)-2-hydroxy-3-methoxy-3, 3-diphenylpropanoate (6) The solution of compound (5) (14 g, 51.4 mmol) in methyltertiarybutylether (140 mL) was stirred and refluxed for 0.5 h. Dehydroabietylamine (7) (14.7 g, 51.4 mmol) in methyltertiarybutylether (50 mL) was added dropwise in 10 min. After addition, the reaction mixture was stirred for 1 h under reflux temperature. The reaction mixture was cooled to 0 °C and continued to stir for 2 h. The solid ((R, S)-diastereoisomers) was precipitated from the solution, filtered, washed with acetonitrile. The filtrate was diluted with water (100 mL) and acidified to pH 2 by conc. HCl. The aqueous solution was extracted with methylteriarybutylether (50 mL×4). The organic phases were combined and washed with water (80 mL). The organic phase was separated, dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford white residue. The residue was recystallized from toluene to afford (6) as a white solid. (5.53 g, 39.5%). 1H-NMR (CDCl3): δ 3.22 (s, 3H), 5.14 (br, 1H), 5.20 (d, 1H), 7.18-7.37 (m, 10H), 12.30 (1H, br). [α] 20 D =12.3°(c=1.8% in ethanol).

Synthesis of (+)-ambrisentan (1) To a solution of compound (6) (3.6 g, 13.1 mmol) and NaNH2 (1.0 g, 25.6 mmol) in DMF (20 mL) was added 4, 6-dimethyl-2-(methylsulfonyl) pyrimidine (3.63 g, 19.6 mmol) in DMF (10 mL) slowly. After addition, the reaction was stirred for 5 h at room temperature. The solution was quenched with water (20 mL) and acidified to pH 2 by 10% H2SO4 aqueous solution. The mixture was extracted with ethyl acetate (50 mL ×4). The combined organic layers were washed with water (30 mL) and saturated NaCl solution (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was recrystallized from iso-propyl alcohol (30 mL) and water (40 mL), and precipitate formed was filtered off. The cake was deeply dried under vacuum to afford (1) as a white solid. (4.27 g, 86.1%). 1H-NMR (CDCl3): δ 2.39 (s, 6H), 3.32 (s, 3H), 6.43 (s, 1H), 6.70 (s, 1H), 7.28-7.40 (m, 8H), 7.53-7.56 (d, 2H). MS-EI (m/z): 377(M-H). HPLC (XDB-C18, CH3OH/10mmol/L NaH2PO4 + 0.1% H3PO4 = 70/30, 1.0 mL/min): tR 5.2 min (>99.0%); ee= 99.0%.

Patent EP2547663A1

File:Ambrisentan synthesis.svg

Image result for ambrisentan

Title: Ambrisentan
CAS Registry Number: 177036-94-1
CAS Name: (aS)-a-[(4,6-Dimethyl-2-pyrimidinyl)oxy]-b-methoxy-b-phenylbenzenepropanoic acid
Manufacturers’ Codes: BSF-208075; LU-208075
Molecular Formula: C22H22N2O4
Molecular Weight: 378.42
Percent Composition: C 69.83%, H 5.86%, N 7.40%, O 16.91%
Literature References: Nonpeptide endothelin ETA receptor antagonist. Prepn: H. Riechers et al., WO 9611914eidemUS5932730 (1996, 1998 both to BASF); H. Riechers et al., J. Med. Chem. 39, 2123 (1996). Pharmacology: H. Vatter et al., Clin. Neuropharmacol. 26, 73 (2003). Clinical evaluation in pulmonary arterial hypertension: N. Galié et al., J. Am. Coll. Cardiol. 46, 529 (2005). Review of development and therapeutic potential: G. E. Billman, Curr. Opin. Invest. Drugs 3, 1483-1486 (2002).
Derivative Type: (±)-Form
CAS Registry Number: 713516-99-5
Properties: Crystals from diethylether, mp 190-191°.
Melting point: mp 190-191°
Therap-Cat: Antihypertensive.
Keywords: Antihypertensive; Endothelin Receptor Antagonist.

References

  1. Jump up^ Vatter H, Seifert V (2006). “Ambrisentan, a non-peptide endothelin receptor antagonist”. Cardiovasc Drug Rev24 (1): 63–76. doi:10.1111/j.1527-3466.2006.00063.xPMID 16939634.
  2. Jump up^ Frampton JE (2011). “Ambrisentan”. American Journal of Cardiovascular Drugs11 (4): 215–26. doi:10.2165/11207340-000000000-00000PMID 21623643.
  3. Jump up^ Pollack, Andrew (2007-06-16). “Gilead’s Drug Is Approved to Treat a Rare Disease”The New York TimesArchived from the original on May 24, 2013. Retrieved 2007-05-25.
  4. Jump up^ “U.S. Food and Drug Administration Approves Gilead’s Letairis Treatment of Pulmonary Arterial Hypertension” (Press release). Gilead Sciences. 2007-06-15. Archived from the original on 2007-09-27. Retrieved 2007-06-16.
  5. Jump up^ “FDA Approves New Orphan Drug for Treatment of Pulmonary Arterial Hypertension” (Press release). Food and Drug Administration. 2007-06-15. Archived from the original on 23 June 2007. Retrieved 2007-06-22.
  6. Jump up^ “GlaxoSmithKline’s Volibris (ambrisentan) receives authorisation from the European Commission for the treatment of Functional Class II and III Pulmonary Arterial Hypertension” (Press release). GlaxoSmithKline. 2008-04-25. Archived from the original on 30 April 2008. Retrieved 2008-04-29.
  7. Jump up^ Waknine, Yael (2005-05-09). “International Approvals: Ambrisentan, Oral-lyn, Risperdal”Medscape. Retrieved 2007-06-16.
  8. Jump up^ de Raaf MA, Beekhuijzen M, Guignabert C, Vonk Noordegraaf A, Bogaard HJ (2015). “Endothelin-1 receptor antagonists in fetal development and pulmonary arterial hypertension”. Reproductive Toxicology56: 45–51. doi:10.1016/j.reprotox.2015.06.048PMID 26111581.
  9. Jump up^ Galiè, Nazzareno; Barberà, Joan A.; Frost, Adaani E.; Ghofrani, Hossein-Ardeschir; Hoeper, Marius M.; McLaughlin, Vallerie V.; Peacock, Andrew J.; Simonneau, Gérald; Vachiery, Jean-Luc; Grünig, Ekkehard; Oudiz, Ronald J.; Vonk-Noordegraaf, Anton; White, R. James; Blair, Christiana; Gillies, Hunter; Miller, Karen L.; Harris, Julia H.N.; Langley, Jonathan; Rubin, Lewis J. (2015). “Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension”. New England Journal of Medicine373 (9): 834–44. doi:10.1056/NEJMoa1413687.
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Non-Patent Citation

Title
WANG, BIN ET AL.: ‘A Diacetate Ketone-Catalyzed Asymmetric Epoxidation of Olefins’ J. ORG. CHEM. vol. 74, 23 April 2009, pages 3986 – 3989 *

Publication numberPriority datePublication dateAssigneeTitle
Family To Family Citations
CN102276536B *2011-06-102015-04-29中国科学院化学研究所Preparation method of optically pure (+)-ambrisentan and optically pure (+)-darusentan
CN103420811B *2012-05-182015-04-15上海医药工业研究院Intermediate compound used for preparing Ambrisentan, preparation method thereof, and preparation of Ambrisentan
CN103524425A *2012-07-042014-01-22天津药物研究院Crystal form V of ambrisentan as well as preparation method and application thereof
CN102850300A *2012-09-182013-01-02中国科学院化学研究所Preparation method of alpha,beta-epoxy amide compounds
CN104592129A *2013-10-302015-05-06武汉启瑞药业有限公司Improved method used for preparing ambrisentan
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CN103755569A *2013-12-262014-04-30上海皓骏医药科技有限公司Preparation method for ambrisentan intermediate compound
Ambrisentan
Ambrisentan structure.svg
Clinical data
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU: X (High risk)
  • US: X (Contraindicated)
Routes of
administration
Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Undetermined
Protein binding 99%
Elimination half-life 15 hours (terminal)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
ECHA InfoCard 100.184.855 Edit this at Wikidata
Chemical and physical data
Formula C22H22N2O4
Molar mass 378.421 g/mol
3D model (JSmol)

/////////////Ambrisentan,  أمبريسنتان ,  安立生坦 , BSF-208075,  LU-208075, アンブリセンタン

CC1=CC(=NC(=N1)OC(C(=O)O)C(C2=CC=CC=C2)(C3=CC=CC=C3)OC)C

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TEBIPENEM PIVOXIL, テビペネムピボキシル , тебипенем пивоксил , تيبيبينام بيفوكسيل ,


Tebipenem pivoxil.png

ChemSpider 2D Image | tebipenem pivoxil | C22H31N3O6S2Image result for TEBIPENEM PIVOXIL

TEBIPENEM PIVOXIL

テビペネムピボキシル

тебипенем пивоксил [Russian] [INN]
تيبيبينام بيفوكسيل [Arabic] [INN]

2,2-dimethylpropanoyloxymethyl (4R,5S,6S)-3-[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Molecular Formula: C22H31N3O6S2
Molecular Weight: 497.625 g/mol

Tebipenem pivoxil; 161715-24-8; Orapenem; UNII-95AK1A52I8; TBPM-PI; Tebipenem pivoxil(L-084)

(+)-hydroxymethyl(4R,5S,6S )-6-[(1R )-1-hydroxyethyl]-4-methyl-7-oxo-3-{[1-(2-thiazolin-2-yl)-3-azetidinyl]thio}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate,2-pivalate

(4R,5R,6S)-3-[[1-(4,5-Dihydro-2-thiazolyl)-3-azetidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (2,2-dimethyl-1-oxopropoxy) methyl ester
[(2,2-Dimethylpropanoyl)oxy]methyl (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
161715-24-8 [RN]
1-Azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 3-[[1-(4,5-dihydro-2-thiazolyl)-3-azetidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-, (2,2-dimethyl-1-oxopropoxy)methyl ester, (4R,5S,6S)-
7924
95AK1A52I8
UNII:95AK1A52I8
2,2-dimethylpropanoyloxymethyl (4R,5S,6S)-3-[1-(4,5-dihydrothiazol-2-yl)azetidin-3-yl]sulfanyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
L 084
L084
L-084;Orapenem;L084;L 084
ME1211
MFCD17215369
L-084; ME-1211, SPR-994
TBPM-PI
MOA:Carbapenem antibiotic
Indication:Otitis Media; Otorhinolaryngological infection; Bacterial Pneumonia
Company:WYETH, Meiji Seika (Originator)
2009-04-22 japan approved

Tebipenem (brand name: Orapenem) is a broad-spectrum orally-administered antibiotic, from the carbapenem subgroup of β-lactam antibiotics. It was developed as a replacement drug to combat bacteria that had acquired antibiotic resistance to commonly used antibiotics.[1][2] Tebipenem is formulated as the ester tebipenem pivoxil due to the better absorption and improved bioavailability of this form.[3] It has performed well in clinical trials for ear infection and looks likely to be further developed in future.[4] It is only marketed in Japan.[5] Tebipenem is the first carbapenem whose prodrug form, the pivalyl ester, is orally available.[6]

Tebipenem pivoxil, an oral carbapenem prodrug, was launched in Japan in 2009 by Meiji Seika Pharma for the treatment of bacterial infection in children. The drug candidate was originally developed at Wyeth Pharmaceuticals (now Pfizer) and was subsequently licensed to Meiji Seika.

Tebipenem pivoxil was approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Apr 22, 2009. It was developed and marketed as Orapenem® by Meiji Seika in Japan.

In 2017, the product was licensed to Spero Therapeutics by Meiji Seika Pharma for worldwide development and commercialization, except in Japan and certain Asian countries, where Meiji will retain rights.

In 2017, the FDA granted the drug qualified infectious disease product designation for complicated urinary tract infections (cUTI), diabetic foot infections (DFI) and community acquired bacterial pneumonia (CABP)

Tebipenem pivoxil is a broad-spectrum orally-administered antibiotic, from the carbapenem subgroup of β-lactam antibiotics. Carbapenems are a class of beta-lactam antibiotics, which act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. It is used to treat otorhinolaryngological infection, otitis media and bacterial pneumonia.

Orapenem® is available as granules for oral use, containing 100 mg Tebipenem pivoxil/g granules. According to the weight of children, 4 mg/kg, and twice a day after dinner.

Image result for TEBIPENEM PIVOXIL

CLIP

Image result for TEBIPENEM PIVOXIL

Clip

https://www.pharmacodia.com/yaodu/html/v1/chemicals/8c465432a5c7eaa0f3fc7c03401ce607.html

PATENTS

WO 2015070394

US5659043

WO9721712

CN 103613526

CN 103012406

CN 102775410

CN 106083858

EP 1580191

PATENT

https://patents.google.com/patent/CN104341421A/en

 Alternatively Bipei Nan ester (Tebipenempivoxil) (I), chemical name: (+) – (4R, 5S, 6S) -6 – [(lR) -l- hydroxyethyl] -4-methyl-7 – oxo-3 [[1- (2-thiazol-2-yl) -3-azetidinyl] thio] -1-azabicyclo [3. 2.0] hept-2-ene 2-carboxylic acid methyl -2- pivaloyl), of the formula:

[0003]

Figure CN104341421AD00031

[0004] developed by the American company Pfizer, for Bipei Nan ester fine granules developed by the Japanese company Meiji, in February 2009 was approved in Japan, and listed in April 2009. Alternatively Bipei Nan prodrug esters are for Bipei Nan, the lower the water after oral administration of the parent drug esterase for Bipei Nan, penicillin-binding protein binding to bacteria (the PBP), inhibition of bacterial cell wall synthesis, and is the only can oral carbapenem antibiotics.

[0005] Alternatively esters Bipei Nan structural characteristics, is a C3-side chain is thiazolyl substituted azetidinyl group, while in the C2 position by matching volts carboxylic ester forming a prodrug, increased oral absorbability; its oral absorption is better than in most β_ lactam antibiotics already on the market now. Bipei Nan for a broad spectrum antibiotic; especially for the PRSP in recent years, mainly due to the infection caused by children (penicillin-resistant Streptococcus pneumoniae), MRSP (erythromycin-resistant Streptococcus pneumoniae) and Haemophilusinfluenzae (Haemophilus influenzae) showed a very strong antibacterial effect. Alternatively Bipei Nan as prodrugs compared to for Bipei Nan horses volts for Bipei Nan ester having a better absorption kinetics, has good stability.

[0006] TakeshiIsoda like literature SynthesesandPharmacokineticStudiesof ProdrugEstersfortheDevelopmentofOralCarbapenem, L-084 (TheJournalof Antibiotics (2006) 59, 241 – 247; doi:. 10 · 1038 / ja 2006. 34) discloses a method for the synthesis of ester Bipei Nan : the Bipei Nan Alternatively, benzyltriethylammonium chloride, and chloromethyl pivalate was dissolved in N, N- dimethylformamide was added a solution of N, N- diisopropylethylamine, in the reaction was stirred for 4h at 45 ° C, the reaction was cooled to complete 5 ° C, was added ethyl acetate and water, the mixture was adjusted with aqueous citric acid I.OM PH = 4, the organic phase was discarded, the aqueous phase was adjusted with potassium bicarbonate to PH = 7. 6, the mixture extracted with ethyl acetate, the organic phase was washed with water and aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, the residue was subjected to silica gel column to give a yellow solid which was slurried with ethyl acetate to give colorless crystals. The column chromatography method requires not only consume a large amount of organic solvent together IJ, and a long time, so this method is not suitable for industrial production. In addition, the resulting large solid slurried with ethyl acetate, a solid dispersion is not easy, affect the uniformity of the product.

[0007] Patent US5534510, EP0632039, JP10-195076 discloses a method for synthesizing Bipei Nan ester is: dissolved after lyophilization for Bipei Nan aqueous sodium bicarbonate, lyophilized solid was dissolved in N, N- two dimethylformamide, adding a specific acid, methyl iodide, LH stirred at room temperature, ethyl acetate was added the reaction was completed, the organic phase was washed with saturated aqueous sodium bicarbonate, washed with brine, dried over anhydrous magnesium sulfate, the solvent was removed, the residue was subjected Alternatively Bipei Nan silica gel column to give the ester.The Mr. Fang Fati Bipei Nan for Bipei Nan into the sodium salt of pivalic acid with methyl iodide, prior to lyophilization to remove water required for the reaction, or affect the subsequent reaction with methyl iodide pivalate, lyophilized difficult when enlarged and the operation will take longer, the method further column chromatography operations shall therefore not suitable for industrial production.

[0008] Chinese patent CN102633801A disclosed for the preparation of esters Bipei Nan, including the following steps of: for Bipei Nan I. 37g, N, N- 11 ml of dimethylformamide, potassium carbonate 0 · 5g, tetrabutylphosphonium bromide 0 · 03g, reaction at 0 · 5h -KTC, Stuttgart dropwise at this temperature, methyl iodide 〇.88g acid, ethyl acetate was added the reaction was completed Ilml insolubles were filtered off, the filtrate was washed with water 22ml, water Ilml phase was extracted once with ethyl acetate, the combined ethyl acetate, washed with water and ethyl acetate are added 11 ml of water, adjusted to 3.5 with aqueous citric acid, phases were separated, the aqueous phase washed with ethyl acetate Ilml with the aqueous phase is added acetic acid 22ml ethyl ester, was adjusted to 7.5 with aqueous sodium bicarbonate, phase separation, washed with water and 22ml ethyl acetate, the ethyl acetate phase over anhydrous sodium sulfate was added 0. 5g, dried decolorizing charcoal, the filtrate was concentrated to a volume, stirring crystallization, cooling to 〇~5 ° C followed by stirring crystallization, filtration, and dried to give a white solid 〇.54g. Pivalate methyl iodide using the method of low-temperature reaction, post-treatment operation complicated, solvent volume, increasing both cost and environmental pollution, and methyl iodide pivalate unstable, expensive, not suitable for industrial production.

Figure CN104341421AD00041

 Example 1

[0029] Alternatively the Bipei Nan 18g, N, N- dimethylformamide 162mL, potassium 6. 54g, tetrabutylammonium bromide (λ45g, the reaction 60min, was added dropwise at this temperature at 25 ° C for chloromethyl pivalate 8. 93g, after the completion of the reaction, water was added and stirred for 10 minutes, 320ml, 160ml ethyl acetate was added to extract the aqueous phase extracted with ethyl acetate and once with 160ml ethyl acetate were combined, washed with water, phase separation, ethyl acetate washed with water 640ml paint ester, the ethyl acetate phase over anhydrous sodium sulfate was added 60g, decolorizing charcoal and dried, and the filtrate was concentrated, was added dropwise 25 ° C under stirring for crystallization 162mL isopropyl ether, filtered and dried to give a white solid 17. 64g. purity by HPLC 99.87%, the yield was 89.7%.

[0030] TBPN1HNMR data (CDCl3):. 5 989-5 978ppm (1H, d, 5 5, H-13.), 5 858-5 847ppm (1H, d, 5 5, Η-13.)… , 4 · 436-4. 390ppm (2H, m, H-22e, H-24e), 4. 232-4. 217ppm (2H, m, H-2, H-9), 4. 173-4. 146ppm (1H, m, H-21), 4. 039-3. 960ppm (4H, m, H-22a, H-24a, H-28), 3. 402-3. 372ppm (2H, t, 7. 5 , H-27), 3. 243-3. 230ppm (1H, m, H-3), 3. 199-3. 167ppm (1H, m, H-8), I. 348-1. 337ppm (3H, d, 5. 5, H-1), I. 24ppm (12H, m, H-17, H-18, H-19, H-10) ·

[0031] TBPN13C bandit R data (CDCl3):.. 176 958ppm (1C, C-15), 172 425ppm (1C, C-4), 164.286ppm (lC, C-25), 159.397ppm (lC, C- ll), 150.363ppm (lC, C-7), 124.570ppm (1C, C-6), 79.826 (1C, C-13), 65. 824ppm (1C, C-2), 60. 905ppm (1C, C -28), 59. 990ppm (1C, C-24), 59. 850ppm (lC, C-3), 58. 164ppm (1C, C-22), 56. 257ppm (lC, C-9), 43. 939ppm (1C, C-8), 38. 767ppm (1C, C-16), 36. 339ppm (1C, C-27), 33. 170 (1C, C-21), 26. 887ppm (3C, C- 17, C-18, C-19), 21.962ppm (lC, Cl), 16.805ppm (1C, C-10)

Patent

Publication numberPriority datePublication dateAssigneeTitle
CN102276611A *2011-05-182011-12-14深圳万乐药业有限公司Recrystallization method for purifying esters for Bipei Nan
CN102532139A *2010-12-072012-07-04重庆医药工业研究院有限责任公司Method for preparing tebipenem
CN102633801A *2012-03-132012-08-15深圳科兴生物工程有限公司Method for preparing tebipenem ester
F

Publication numberPriority datePublication dateAssigneeTitle

CN106543186A *2016-11-072017-03-29山东大学Monocrystal A of tebipenem pivoxil and preparation method thereof
KR101774812B1 *2016-05-272017-09-06(주)하이텍팜Preparation method for tebipenem pivoxil

PAPER

Chem. Pharm. Bull. 2006, 54, 1408-1411.

https://www.jstage.jst.go.jp/article/cpb/54/10/54_10_1408/_pdf

PAPER

J. Antibiot. 200659, 241-247.

PRESENTATION

Abe, T.; Hayashi, K.; Mihira, A.; Satoh, C.; Tamai, S.; Yamamoto, S.; Hikida, M.; Kumagai, T.; Kitamura, M.
L-084, a new oral carbapenem: Synthesis and structure-activity relationships of C2-substituted 1beta-methylcarbapenems
38th Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 24-27, San Diego) 1998, Abst F-64

CLIP

EP 0632039; EP 0717042; JP 1996053453; US 5534510; US 5659043; US 5783703

Halogenation of allylamine (I) with either bromine or sulfuryl chloride produced the corresponding (halomethyl)aziridines (II). Subsequent treatment of (II) with n-butyllithium at -78 C yielded 1-azabicyclobutane (III). Opening of the bicyclic system of (III) with formic acid followed by acid hydrolysis provided 3-hydroxyazetidine (IV). This was condensed with 2-(methylsulfanyl)thiazoline (V) to give thiazolinylazetidine (VI). Alternatively, 3-hydroxyazetidine (IV) was condensed with 2-chloroethyl isothiocyanate (VII) to give the intermediate thiourea (VIII), which cyclized to the thiazoline (VI). Conversion of the hydroxyl group of (VI) into the thioacetate (IX) was carried out by either coupling with thioacetic acid under Mitsunobu conditions or by conversion to mesylate (X) followed by displacement with potassium thioacetate. The required thiol (XI) was then obtained from (IX) by basic hydrolysis of the thioacetate ester.

1-azabicyclobutane (III) was opened with thioacetic acid with concomitant N-acetylation yielding (XII). Further acid hydrolysis of (XII) gave 3-mercaptoazetidine (XIII). Condensation of (XIII) with either 2-(methylthio)thiazoline (V) or 2-chloroethyl isothiocyanate (VII) then produced thiazolinylazetidine (XI).

A further procedure consisted in the opening of 1-azabicyclobutane (III) with 2-mercaptothiazoline (XIV) to give (XV). Subsequent rearrangement of (XV) in the presence of methanesulfonic acid produced thiazolinyl azetidine (XI).

Condensation of (phosphoryloxy)carbapenem (XVI) with 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (XI) gave thioether (XVII). The p-nitrobenzyl ester group of (XVII) was then deprotected with Zn powder to afford the target carboxylic acid.

References

  1. Jump up^ El-Gamal, M. I.; Oh, C. H. (2010). “Current status of carbapenem antibiotics”. Current Topics in Medicinal Chemistry10 (18): 1882–1897. doi:10.2174/156802610793176639PMID 20615191.
  2. Jump up^ Fujimoto, K.; Takemoto, K.; Hatano, K.; Nakai, T.; Terashita, S.; Matsumoto, M.; Eriguchi, Y.; Eguchi, K.; Shimizudani, T.; Sato, K.; Kanazawa, K.; Sunagawa, M.; Ueda, Y. (2012). “Novel Carbapenem Antibiotics for Parenteral and Oral Applications: In Vitro and in Vivo Activities of 2-Aryl Carbapenems and Their Pharmacokinetics in Laboratory Animals”Antimicrobial Agents and Chemotherapy57 (2): 697–707. doi:10.1128/AAC.01051-12PMC 3553697Freely accessiblePMID 23147735.
  3. Jump up^ Kato, K.; Shirasaka, Y.; Kuraoka, E.; Kikuchi, A.; Iguchi, M.; Suzuki, H.; Shibasaki, S.; Kurosawa, T.; Tamai, I. (2010). “Intestinal Absorption Mechanism of Tebipenem Pivoxil, a Novel Oral Carbapenem: Involvement of Human OATP Family in Apical Membrane Transport”. Molecular Pharmaceutics7 (5): 1747–1756. doi:10.1021/mp100130bPMID 20735088.
  4. Jump up^ Sugita, R. (2013). “Good transfer of tebipenem into middle ear effusion conduces to the favorable clinical outcomes of tebipenem pivoxil in pediatric patients with acute otitis media”. Journal of Infection and Chemotherapy19 (3): 465–471. doi:10.1007/s10156-012-0513-5PMID 23393013.
  5. Jump up^ Rossi, S, ed. (7 August 2014). “Tebipenem Pivoxil”Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 6 April 2015.
  6. Jump up^ Hazra, S; Xu, H; Blanchard, J (June 2014). “Tebipenem, a New Carbapenem Antibiotic is a Slow Substrate that Inhibits the β-Lactamase from Mycobacterium tuberculosis” (PDF). Biochemistry53 (22): 3671–3678. doi:10.1021/bi500339jPMC 4053071Freely accessiblePMID 24846409.
Patent ID

Title

Submitted Date

Granted Date

US2014296257 High-Loading Water-Soluable Carrier-Linked Prodrugs
2012-08-10
2014-10-02
US2012156259 Biodegradable Polyethylene Glycol Based Water-Insoluble Hydrogels
2010-07-30
2012-06-21
US2009238867 Nanoparticulate Anidulafungin Compositions and Methods for Making the Same
2009-09-24
US2008103169 COMPOSITIONS COMPRISING ACID LABILE PROTON PUMP INHIBITING AGENTS, AT LEAST ONE OTHER PHARMACEUTICALLY ACTIVE AGENT AND METHODS OF USING SAME
2008-05-01
US8093294 Metallo-[beta]-lactamase inhibitors
2008-04-17
2012-01-10
Patent ID

Title

Submitted Date

Granted Date

US2017304388 NEW INDICATION OF CARDIOVASCULAR DRUGS FOR PREPARATION OF CANCER INHIBITION PHARMACEUTICAL COMPOSITION
2015-10-23
US9278091 COMPOUNDS FOR THE TREATMENT OF CLOSTRIDIUM DIFFICILE ASSOCIATED DISEASE
2015-02-12
2015-07-30
US2016082123 Hydrogel-Linked Prodrugs Releasing Tagged Drugs
2014-04-16
2016-03-24
US2015087688 PRODRUGS OF HYDROXYL-COMPRISING DRUGS
2013-04-24
2015-03-26
US2014243254 Polymeric Hyperbranched Carrier-Linked Prodrugs
2012-08-10
2014-08-28
Patent ID

Title

Submitted Date

Granted Date

US8987308 COMPOUNDS FOR THE TREATMENT OF CLOSTRIDIUM DIFFICILE-ASSOCIATED DISEASE
2012-11-30
2013-04-18
US9115079 NDM INHIBITOR
2012-07-26
2014-08-07
US8975416 ANTIBACTERIAL COMPOUNDS
2012-01-26
US9260375 METALLO-BETA-LACTAMASE INHIBITORS
2011-11-29
2012-03-22
US2016354315 DOSAGE FORMS AND USE THEREOF
2016-06-03
Tebipenem
Tebipenem pivoxil2DCSD.svg

Tebipenem pivoxil
Clinical data
Trade names Orapenem
Routes of
administration
Oral
Legal status
Legal status
  • Prescription-only in Japan; investigational elsewhere
Identifiers
CAS Number
KEGG
PDB ligand
Chemical and physical data
Formula C22H31N3O6S2
Molar mass 497.63 g/mol
3D model (JSmol)

/////////////////TEBIPENEM PIVOXIL, orapenem, テビペネムピボキシル  ,тебипенем пивоксил , تيبيبينام بيفوكسيل , L-084,  ME-1211, JAPAN 2009, SPR-994 , , Qualified infectious disease product designation

CC1C2C(C(=O)N2C(=C1SC3CN(C3)C4=NCCS4)C(=O)OCOC(=O)C(C)(C)C)C(C)O

Tesirine


Tesirine.png2D chemical structure of 1595275-62-9

Tesirine

Molecular Formula: C75H101N9O23
Molecular Weight: 1496.673 g/mol

UNII-8DVQ435K46;

CAS 1595275-62-9

(11S,11aS)-4-((2S,5S)-37-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5-isopropyl-2-methyl-4,7,35-trioxo-10,13,16,19,22,25,28,31-octaoxa-3,6,34-triazaheptatriacontanamido)benzyl 11-hydroxy-7-methoxy-8-((5-(((S)-7-methoxy-2-methyl-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)pentyl)oxy)-2-methyl-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate 

SG3249, Tesirine

[4-[[(2S)-2-[[(2S)-2-[3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]-3-methylbutanoyl]amino]propanoyl]amino]phenyl]methyl (6S,6aS)-3-[5-[[(6aS)-2-methoxy-8-methyl-11-oxo-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]pentoxy]-6-hydroxy-2-methoxy-8-methyl-11-oxo-6a,7-dihydro-6H-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate

PATENT

WO 2014057074

In 2012, tesirine (SG3249) was developed by Spirogen, as a drug linker combining a set of desired properties: fast and straightforward conjugation to antibody cysteines by maleimide Michael addition, good solubility in aqueous/DMSO (90/10) systems, and a traceless cleavable linker system delivering the highly potent pyrrolobenzodiazepine (PBD) DNA cross-linker SG3199

Image result for tesirine

Image result for tesirine

Image result for tesirine

CLIP

Image result for tesirine

CLIP

Scale-up Synthesis of Tesirine

 SpirogenQMB Innovation Centre42 New Road, E1 2AX London, United Kingdom
§ PharmaronNo. 6, Taihe Road, BDA, Beijing, 100176, People’s Republic of China
 Lonza AGRottenstrasse 6, CH – 3930 Visp, Switzerland
# Novasep Ltd1 Rue Démocrite, 72000 Le Mans, France
 Early Chemical Development, Pharmaceutical SciencesIMED Biotech UnitAstraZeneca, Macclesfield, United Kingdom
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00205
Abstract Image

This work describes the enabling synthesis of tesirine, a pyrrolobenzodiazepine antibody–drug conjugate drug-linker. Over the course of four synthetic campaigns, the discovery route was developed and scaled up to provide a robust manufacturing process. Early intermediates were produced on a kilogram scale and at high purity, without chromatography. Midstage reactions were optimized to minimize impurity formation. Late stage material was produced and purified using a small number of key high-pressure chromatography steps, ultimately resulting in a 169 g batch after 34 steps. At the time of writing, tesirine is the drug-linker component of eight antibody–drug conjugates in multiple clinical trials, four of them pivotal

 CLIP

Design and Synthesis of Tesirine, a Clinical Antibody–Drug Conjugate Pyrrolobenzodiazepine Dimer Payload

QMB Innovation Centre, Spirogen, 42 New Road, E1 2AX London, U.K.
ACS Med. Chem. Lett.20167 (11), pp 983–987
DOI: 10.1021/acsmedchemlett.6b00062
Publication Date (Web): May 24, 2016
Copyright © 2016 American Chemical Society
This article is part of the Antibody-Drug Conjugates and Bioconjugates special issue.
Abstract Image

Pyrrolobenzodiazepine dimers are an emerging class of warhead in the field of antibody–drug conjugates (ADCs). Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. One of the reactive imines was capped with a cathepsin B-cleavable valine-alanine linker. A robust synthetic route was developed to allow the production of tesirine on clinical scale, employing a flexible, convergent strategy. Tesirine was evaluated in vitro both in stochastic and engineered ADC constructs and was confirmed as a potent and versatile payload. The conjugation of tesirine to anti-DLL3 rovalpituzumab has resulted in rovalpituzumab-tesirine (Rova-T), currently under evaluation for the treatment of small cell lung cancer.

https://cdn-pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.6b00062/suppl_file/ml6b00062_si_001.pdf

SG3249 (tesirine) (860 mg, 73% over 2 steps). LC/MS, method 2, 2.65 min (ES+) m/z (relative intensity) 1496.78 ([M+H] +. , 20). [] 24 D = +262 (c = 0.056, CHCl3).

1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.20 (d, J = 7.0 Hz, 1H), 8.03 (t, J = 5.6 Hz, 1H), 7.97 – 7.84 (m, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.32 (s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.10 – 6.96 (m, 3H), 6.84 (s, 1H), 6.79 – 6.57 (m, 4H), 5.59 (d, J = 9.4 Hz, 1H), 5.16 (d, J = 12.7 Hz, 1H), 4.81 (d, J = 12.4 Hz, 1H), 4.38 (t, J = 7.1 Hz, 1H), 4.32 – 4.17 (m, 2H), 4.17 – 4.07 (m, 1H), 4.07 – 3.87 (m, 3H), 3.80 (d, J = 14.2 Hz, 6H), 3.74 – 3.62 (m, 1H), 3.59 (t, J = 7.2 Hz, 4H), 3.55 – 3.42 (m, 28H), 3.35 (d, J = 5.2 Hz, 2H), 3.21 – 3.11 (m, 2H), 3.11 – 2.98 (m, 2H), 2.98 – 2.83 (m, 1H), 2.49 – 2.28 (m, 5H), 2.03 – 1.88 (m, 1H), 1.87 – 1.65 (m, 10H), 1.64 – 1.47 (m, 2H), 1.29 (t, J = 5.9 Hz, 3H), 0.85 (dd, J = 17.1, 6.7 Hz, 6H).

13C NMR (126 MHz, DMSO-d6) δ 171.55, 171.29, 171.16, 170.78, 169.91, 164.80, 162.52, 155.03, 150.25, 139.27, 134.99, 128.84, 123.13, 122.67, 121.76, 119.28, 111.93, 110.93, 86.05, 70.21, 70.16, 70.02, 69.95, 69.46, 68.93, 68.79, 67.39, 57.94, 56.16, 54.03, 49.49, 38.97, 38.89, 36.39, 34.53, 34.40, 31.04, 28.69, 28.65, 22.72, 19.60, 18.55, 18.37, 13.88, 13.82. HRMS (ESI) m/z Calc. C75H101N9O23 1495.70831 found 1495.70444.

FT-IR (ATR, cm‐1 ) 3311, 2911, 2871, 1706, 1643, 1623, 1601, 1512, 1435, 1411, 1243, 1213, 1094, 1075, 946, 827, 747, 695, 664.

Patent ID

Title

Submitted Date

Granted Date

US2015297746 PYRROLOBENZODIAZEPINE-ANTIBODY CONJUGATES
2013-10-11
2015-10-22
US2017267778 HUMANIZED ANTI-TN-MUC1 ANTIBODIES AND THEIR CONJUGATES
2015-04-15
Patent ID

Title

Submitted Date

Granted Date

US2015283258 PYRROLOBENZODIAZEPINE – ANTI-PSMA ANTIBODY CONJUGATES
2013-10-11
2015-10-08
US2015283262 PYRROLOBENZODIAZEPINE-ANTIBODY CONJUGATES
2013-10-11
2015-10-08
US2015283263 PYRROLOBENZODIAZEPINE-ANTIBODY CONJUGATES
2013-10-11
2015-10-08
US2016106861 AXL ANTIBODY-DRUG CONJUGATE AND ITS USE FOR THE TREATMENT OF CANCER
2014-04-28
2016-04-21
US2014127239 PYRROLOBENZODIAZEPINES AND CONJUGATES THEREOF
2013-10-11
2014-05-08
Patent ID

Title

Submitted Date

Granted Date

US2017320960 NOVEL ANTI-MFI2 ANTIBODIES AND METHODS OF USE
2015-09-04
US2016015828 NOVEL ANTIBODY CONJUGATES AND USES THEREOF
2014-02-21
2016-01-21
US2015265722 PYRROLOBENZODIAZEPINE-ANTI-CD22 ANTIBODY CONJUGATES
2013-10-11
2015-09-24
US2015273077 PYRROLOBENZODIAZEPINE-ANTI-HER2 ANTIBODY CONJUGATES
2013-10-11
2015-10-01
US2015273078 PYRROLOBENZODIAZEPINE-ANTI-PSMA ANTIBODY CONJUGATES
2013-10-11
2015-10-01

.//////////Tesirine, SG3249, SG 3249

CC1=CN2C(C1)C=NC3=CC(=C(C=C3C2=O)OC)OCCCCCOC4=C(C=C5C(=C4)N(C(C6CC(=CN6C5=O)C)O)C(=O)OCC7=CC=C(C=C7)NC(=O)C(C)NC(=O)C(C(C)C)NC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCN8C(=O)C=CC8=O)OC

Evocalcet, エボカルセト , Эвокальцет , إيفوكالسيت , 依伏卡塞 ,


Evocalcet.pngImage result for EvocalcetEvocalcet.svg

Evocalcet

C24H26N2O2,  374.484 

Evocalcet; UNII-E58MLH082P; E58MLH082P; 870964-67-3; Evocalcet [INN]; Orkedia (TN)
エボカルセト

Эвокальцет [Russian] [INN]

إيفوكالسيت [Arabic] [INN]
依伏卡塞 [Chinese] [INN]
2-[4-[(3S)-3-[[(1R)-1-naphthalen-1-ylethyl]amino]pyrrolidin-1-yl]phenyl]acetic acid
KHK-7580
MT-4580
UNII:E58MLH082P
{4-[(3S)-3-{[(1R)-1-(1-Naphthyl)ethyl]amino}-1-pyrrolidinyl]phenyl}acetic acid
10098
870964-67-3 [RN]
Benzeneacetic acid, 4-[(3S)-3-[[(1R)-1-(1-naphthalenyl)ethyl]amino]-1-pyrrolidinyl]-
E58MLH082P
KHK-7580 / KHK7580 / MT-4580

Image result for Evocalcet

エボカルセト
Evocalcet

C24H26N2O2 : 374.48
[870964-67-3]

WP_000286

KHK 7580 …..example

3.008
Figure US20140080770A1-20140320-C00373
Figure US20140080770A1-20140320-C00374
Figure US20140080770A1-20140320-C00375
2HCl MS · APCI: 375[M + H]+

Figure imgb0350

in EP1757582

4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1- yl)phenylacetic acid

4-​[(3S)​-​3-​[[(1R)​-​1-​(1-​naphthalenyl)​ethyl]​amino]​-​1-​pyrrolidinyl]​-Benzeneacetic acid,

BASE ….870964-67-3

DI HCL SALT …….870856-31-8

MF C24 H26 N2 O2 BASE

MW 374.48 BASE

KHK-7580

KHK-7580; MT-4580

Mitsubishi Tanabe Pharma Corp… innovator

Kyowa Hakko Kirin Co Ltd.. licencee

4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid,

Evocalcet (trade name Orkedia) is a drug for the treatment of hyperparathyroidism.[1] It acts as a calcium-sensing receptor agonist.[2]

In 2018, it was approved in Japan for treatment of secondary hyperparathyroidism in patients on dialysis.[3]

useful as calcium-sensitive receptor (CaSR) agonists for treating hyperparathyroidism.  a CaSR agonist, being developed by Kyowa Hakko Kirin, under license from Mitsubishi Tanabe, for treating secondary hyperparathyroidism (phase 2 clinical, as of March 2015).

WO2005115975,/EP1757582

http://www.google.co.in/patents/EP1757582A1?cl=en

Example no

3.008
Figure US20140080770A1-20140320-C00373
Figure US20140080770A1-20140320-C00374
Figure US20140080770A1-20140320-C00375
2HCl MS · APCI: 375[M + H]+

Figure imgb0350

WO 2015034031A1

http://worldwide.espacenet.com/publicationDetails/biblio?DB=worldwide.espacenet.com&II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=20150312&CC=WO&NR=2015034031A1&KC=A1

Mitsubishi Tanabe Pharma Corporation

The present invention provides a novel crystal form of an arylalkylamine
compound. Specifically, a novel crystal form of
4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1- yl)phenylacetic acid has
excellent stability, and is therefore useful as an active ingredient for
a medicine. The present invention also provides an industrially
advantageous method for producing an arylalkylamine compound.

WP_000287

WO 2015034031A1

http://worldwide.espacenet.com/publicationDetails/biblio?DB=worldwide.espacenet.com&II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=20150312&CC=WO&NR=2015034031A1&KC=A1
Mitsubishi Tanabe Pharma Corporation

The present invention provides a novel crystal form of an arylalkylamine compound. Specifically, a novel crystal form of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1- yl)phenylacetic acid has excellent stability, and is therefore useful as an active ingredient for a medicine. The present invention also provides an industrially advantageous method for producing an arylalkylamine compound.

 

PATENT

http://www.google.co.in/patents/US20140080770?cl=und

Reference Example 3.001

Figure US20140080770A1-20140320-C00042

(1) To a mixed solution containing 33.5 g of 3-hydroxypiperidine and 62.7 ml of triethylamine dissolved in 250 ml of methylene chloride was added dropwise a solution of 55.7 ml of benzyloxycarbonyl chloride in 150 ml of methylene chloride, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous citric acid and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to obtain 75.5 g of benzyl 3-hydroxypiperidine-1-carboxylate.

MS•APCI (m/z): 236 [M+H]+

(2) 800 ml of a solution of 52.4 ml of oxalyl chloride in methylene chloride was cooled to −78° C., 53.2 ml of DMSO was added dropwise to the solution, and the mixture was stirred at −78° C. for 0.5 hour. A solution of 75.5 g of benzyl 3-hydroxypiperidine-1-carboxylate dissolved in 200 ml of methylene chloride was added dropwise to the mixture, and further 293 ml of triethylamine was added dropwise to the same, and the mixture was stirred for 16 hours while a temperature thereof was gradually raised to room temperature. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated to obtain 83.7 g of 1-benzyloxycarbonyl-3-piperidone. MS•APCI (m/z): 234 [M+H]+
(3) To a solution of 83.7 g of 1-benzyloxycarbonyl-3-piperidone dissolved in 1.2 liters of methylene chloride was added 55.0 g of (R)-(+)-1-(1-naphthyl)ethylamine, and after the mixture was stirred at room temperature for 2 hours, 69 ml of acetic acid and 160 g of sodium triacetoxy borohydride were added to the mixture, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added an aqueous sodium hydroxide to make the mixture basic, and then, chloroform was added to the mixture, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to obtain 98.7 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APCI (m/z): 389 [M+H]+
(4) To a solution of 40.95 g of triphosgene dissolved in 800 ml of methylene chloride was added dropwise a mixed solution containing 80.6 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate and 86.6 ml of triethylamine dissolved in 200 ml of methylene chloride at 0° C., and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added water, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was washed with 200 ml of diethyl ether, and the crystal collected by filtration was recrystallized from chloroform and diethyl ether to obtain 48.9 g of benzyl (R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate.

Further, the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=8:1→0:1) to obtain 5.82 g of benzyl (R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate and 14.5 g of benzyl (S)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate.

(5) To a solution containing 54.6 g of benzyl (R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate dissolved in 700 ml of tetrahydrofuran was added 350 ml of water, and the mixture was stirred under reflux for 15 hours. After tetrahydrofuran was evaporated, a saturated aqueous sodium bicarbonate solution and chloroform were added thereto, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to obtain 24.3 g of benzyl (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APCI (m/z): 389 [M+H]+
(6) To a solution containing 24.2 g of benzyl (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate dissolved in 250 ml of methanol was added 2.5 g of palladium carbon (10% wet), and the mixture was shaked under hydrogen atmosphere at 3 atm at room temperature for 40 hours. Palladium carbon was removed, and the solvent was evaporated, the residue was washed with ethyl acetate-chloroform (10:1), and collected by filtration to obtain 15.3 g of (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine (the following Reference example Table, Reference example 3.001(a)). MS•APCI (m/z): 255 [M+H]+
(7) By using 14.5 g of benzyl (S)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate, the same treatment was carried out as in the above-mentioned (5) to obtain 4.74 g of benzyl (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APCI (m/z): 389 [M+H]+

Moreover, by using 4.7 g of benzyl (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate, the same treatment was carried out as in the above-mentioned (6) to obtain 2.89 g of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine. MS•APCI (m/z): 255 [M+H]+

(8) To a solution of 3.46 g of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine dissolved in 15 ml of methanol was added dropwise 20 ml of a solution of 4M hydrochloric acid in ethyl acetate, and the mixture was stirred. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, washed and dried to obtain 3.33 g of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine dihydrochloride

3.008
Figure US20140080770A1-20140320-C00373
Figure US20140080770A1-20140320-C00374
Figure US20140080770A1-20140320-C00375
2HCl MS · APCI: 375[M + H]+
TABLE A3
Figure US20140080770A1-20140320-C00350
Example No. R1—X—
Figure US20140080770A1-20140320-C00351
—Ar Salt Physical properties, etc.

CLIP

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do not miss out on above click

 http://www.kyowa-kirin.com/research_and_development/pipeline/

KHK7580 -Secondary Hyperparathyroidism

JP

Company Mitsubishi Tanabe Pharma Corp.
Description Calcium receptor agonist
Molecular Target
Mechanism of Action Calcium-sensing receptor (CaSR) agonist
Therapeutic Modality Small molecule
Latest Stage of Development Phase II
Standard Indication Thyroid disease
Indication Details Treat hyperparathyroidism in patients receiving hemodialysis; Treat secondary hyperparathyroidism (SHPT)
Regulatory Designation
Partner

Kyowa Hakko Kirin Co. Ltd.

August 29, 2014

Kyowa Hakko Kirin Announces Commencement of Phase 2b Clinical Study of KHK7580 in Patients with Secondary Hyperparathyroidism in Japan

Tokyo, Japan, August 29, 2014 — Kyowa Hakko Kirin Co., Ltd. (Tokyo: 4151, President and CEO: Nobuo Hanai, “Kyowa Hakko Kirin”) today announced the initiation of a phase 2b clinical study evaluating KHK7580 for secondary hyperparathyroidism patients receiving hemodialysis in Japan.

This randomized, placebo-controlled, double-blind, parallel-group, multi-center study is designed to evaluate efficacy and safety in cohorts comprising KHK7580, its placebo and cinacalcet and initial dose of KHK7580 for secondary hyperparathyroidism patients receiving hemodialysis.

KHK7580 is a small molecular compound produced by Mitsubishi Tanabe Pharma Corporation (President & Representative Director, CEO: Masayuki Mitsuka, “Mitsubishi Tanabe Pharma”). Kyowa Hakko Kirin signed a license agreement of KHK7580 with Mitsubishi Tanabe Pharma for the rights to cooperative research, develop, market and manufacture the product in Japan and some part of Asia on March 2008.

The Kyowa Hakko Kirin Group is contributing to the health and prosperity of the world’s people by pursuing advances in life sciences and technology and creating new value.

Outline of this study

CLINICALTRIALS.GOV IDENTIFIER New window opensNCT02216656
TARGET POPULATION Secondary hyperparathyroidism patients receiving hemodialysis
TRIAL DESIGN Randomized, placebo-controlled, double-blind (included open arm of cinacalcet), parallel-group, multi-center study
ADMINISTRATION GROUP KHK7580, Placebo, cinacalcet
TARGET NUMBER OF SUBJECTS 150
PRIMARY OBJECTIVE Efficacy
TRIAL LOCATION Japan
TRIAL DURATION Jul. 2014 to Jun. 2015

Contact:

Kyowa Hakko Kirin
Media Contact:
+81-3-3282-1903
or
Investors:
+81-3-3282-0009

Update on march 2016

New comment waiting approval on New Drug Approvals

M.F. Balandrin commented on KHK 7580 structure cracked

KHK 7580 …..example 3.008 2HCl MS · APCI: 375[M + H]+ in …

The calcimimetic agent, KHK-7580, currently entering Phase III clinical trials, has now been given the INN (WHO) generic name, evocalcet. Its chemical structure has also now been published and it is, in fact, correct as proposed by Dr. Crasto (Well Done!!):

http://www.drugspider.com/drug/evocalcet

https://tripod.nih.gov/ginas/app/substance/f580b9fd

http://www.medkoo.com/products/6729

(Etymologically, in classical Latin, “evolutio” refers to “the unrolling of a scroll” and “evocare” refers to a “call out”…).

http://www.medkoo.com/products/6729

img

Name: Evocalcet
CAS#: 870964-67-3
Chemical Formula: C24H26N2O2
Exact Mass: 374.19943

Evocalcet is a calcium-sensing receptor agonist. The calcium-sensing receptor (CaSR) is a Class C G-protein coupled receptor which senses extracellular levels of calcium ion. The calcium-sensing receptor controls calcium homeostasis by regulating the release of parathyroid hormone (PTH). CaSR is expressed in all of the organs of the digestive system. CaSR plays a key role in gastrointestinal physiological function and in the occurrence of digestive disease. High dietary Ca2+ may stimulate CaSR activation and could both inhibit tumor development and increase the chemotherapeutic sensitivity of cancer cells in colon cancer tissues. (Last update: 12/15/2015).

Synonym: MT-4580; MT 4580; MT4580; KHK-7580; KHK7580; KHK 7580; Evocalcet

IUPAC/Chemical Name: 2-(4-((S)-3-(((R)-1-(naphthalen-1-yl)ethyl)amino)pyrrolidin-1-yl)phenyl)acetic acid

2

https://tripod.nih.gov/ginas/app/substance/f580b9fd

Structure of EVOCALCET

http://www.drugspider.com/drug/evocalcet

INN NAME
Evocalcet
LAB CODE(S)
MT-4580
KHK-7580
CHEMICAL NAME
{4-[(3S)-3-{[(1R)-1-(Naphthalen-1-yl)ethyl]amino}pyrrolidin-1-yl]phenyl}acetic acid
CHEMICAL STRUCTURE
MOLECULAR FORMULA
C24H26N2O2
SMILES
O=C(O)CC1=CC=C(N2C[C@@H](N[C@@H](C3=C4C=CC=CC4=CC=C3)C)CC2)C=C1
CAS REGISTRY NUMBER
870964-67-3
ORPHAN DRUG STATUS
No
ON FAST TRACK
No
NEW MOLECULAR ENTITY
Yes
ORIGINATOR
DEVELOPER(S)
CLASS
MECHANISM OF ACTION
WHO ATC CODE(S)
EPHMRA CODE(S)
CLINICAL TRIAL(S)
CONDITIONS INTERVENTIONS PHASES RECRUITMENT SPONSOR/COLLABORATORS
Secondary Hyperparathyroidism Drug: KHK7580 Phase 3 Recruiting Kyowa Hakko Kirin Company, Limited
Secondary Hyperparathyroidism Drug: KHK7580 Phase 3 Recruiting Kyowa Hakko Kirin Company, Limited
Secondary Hyperparathyroidism Drug: KHK7580|Drug: KRN1493 Phase 2|Phase 3 Recruiting Kyowa Hakko Kirin Company, Limited
Secondary Hyperparathyroidism Drug: Placebo|Drug: KHK7580 low dose|Drug: KHK7580 middle dose|Drug: KHK7580 high dose|Drug: KRN1493 Phase 2 Completed Kyowa Hakko Kirin Company, Limited
Hyperparathyroidism Drug: KHK7580 Phase 1|Phase 2 Completed Kyowa Hakko Kirin Company, Limited
Secondary Hyperparathyroidism Drug: KHK7580 Phase 1 Completed Kyowa Hakko Kirin Company, Limited
UPDATED ON
11 Oct 2015

CLIP

https://www.sciencedirect.com/science/article/pii/S0960894X18303676

Image result for Evocalcet

Scheme 1. Synthesis of key intermediates S4S5S9, and S10. Reagents and conditions: (a) Tf2O, i-Pr2NEt, CH2Cl2, −20 °C. Then, (R)-(+)-1-(1-naphthyl)ethylamine, −20 °C to rt (S1 57%); (b) triphosgene, Et3N, CH2Cl2, −20 °C to 5 °C. Then, i-Pr2NEt, tert-butanol, 70 °C; (c) separation via silica gel chromatography (S2 31%, S3 33% in 2 steps); (d) HClchloroform1,4-dioxane, rt (S4 > 94%, S5 > 94%); (e) (R)-(+)-1-(1-naphthyl)ethylamine, NaBH(OAc)3acetic acid, CH2Cl2, rt (S6 79%); (f) triphosgene, Et3N, CH2Cl2, 0 °C to rt; (g) separation via filtration and silica gel chromatography (S7 58%, S8 16% in 2 steps); (h) water, tetrahydrofuranreflux; (i) H2, Pd/C, methanol, rt (S9 50% in 2 steps); (j) HCl, ethyl acetate, methanol, rt (S10 31% in 3steps).

Scheme 2. Synthesis of 215 and evocalcet (16). Reagents and conditions: (a) aryl iodide or aryl bromide, palladium acetate, (rac)-BINAP, sodium tert-butoxide, toluene, 80 °C or reflux; (b) HCl, ethyl acetate or 1,4-dioxane, rt; (c) tert-butyl 4-fluorobenzoate, potassium carbonate, DMSO, 130 °C; (d) HCl, 1,4-dioxane, 45 °C; (e) 2-aminoethanol, EDC hydrochlorideHOBt, Et3N, DMF, rt; (f) 5-(4-bromophenyl)-2-(triphenylmethyl)–2H-tetrazole, Pd2(dba)3, (2-biphenyl)di-tert-butylphosphine, sodium tert-butoxide, toluene, rt; (g) HCl, water, 1,4-dioxane, rt; (h) tert-butyl 4-bromobenzoate, palladium acetate, (rac)-BINAP, sodium tert-butoxide, toluene, reflux; (i) trifluoroacetic acid, rt. Then, HCl, ethyl acetate or 1,4-dioxane, rt (2 23%, 3 21%, 4 44%, 5 34%, 620%, 7 55%, 8 29%, 9 21%, 10 19%, 11 40%, 13 26%, 14 69%, 15 69% in 2 steps); (j) 3-(trifluoromethoxy)phenylboronic acid, copper acetate, Et3N, CH2Cl2molecular sieve 4A, rt (S117%); (k) (COCl)2, DMSO, Et3N, CH2Cl2, −60 °C to rt (S12 was used in the next step without purification); (l) (R)-(+)-1-(1-naphthyl)ethylamine, NaBH(OAc)3acetic acid, CH2Cl2, rt. Then, separation of isomers; (m) HCl, ethyl acetate, rt (12 10% in 2 steps); (n) ethyl 4-bromophenylacetate, Pd2(dba)3, (2-biphenyl)di-tert-butylphosphine, sodium tert-butoxide, toluene, rt (S13 63%); (o) aqueous sodium hydroxide solution, ethanol, rt (evocalcet (16) 73%).

evocalcet as a white crystal. MS-APCI (m/z): 375 [M+H]+ .

1H NMR (400 MHz, DMSO-d6) δ 8.25-–8.37 (m, 1H), 7.88–7.97 (m, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 6.9 Hz, 1H), 7.39–7.57 (m, 3H), 7.01 (d, J = 8.6 Hz, 2H), 6.38 (d, J = 8.6 Hz, 2H), 4.74 (q, J = 6.4 Hz, 1H), 3.37 (s, 2H), 3.18–3.34 (m, 3H), 3.03–3.15 (m, 1H), 2.89–3.02 (m, 1H), 1.95–2.11 (m, 1H), 1.80–1.94 (m, 1H), 1.40 (d, J = 6.4 Hz, 3H).

Anal. Calcd for C24H26N2O2: C 76.98; H 7.00; N 7.48. Found: C 76.83; H 7.06; N 7.46.

HPLC 99.6% (25.4 min, Inertsil ODS-3V [5 μm, 4.6 × 250 mm], 0.05% TFA in H2O/0.05% TFA in CH3CN [95:5 to 0:100/60 min]).

References

  1. Jump up^ Kawata, Takehisa; Tokunaga, Shin; Murai, Miki; Masuda, Nami; Haruyama, Waka; Shoukei, Youji; Hisada, Yutaka; Yanagida, Tetsuya; Miyazaki, Hiroshi; Wada, Michihito; Akizawa, Tadao; Fukagawa, Masafumi (2018). “A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro”. PLOS ONE13 (4): e0195316. doi:10.1371/journal.pone.0195316PMID 29614098.
  2. Jump up^ Miyazaki, Hiroshi; Ikeda, Yousuke; Sakurai, Osamu; Miyake, Tsutomu; Tsubota, Rie; Okabe, Jyunko; Kuroda, Masataka; Hisada, Yutaka; Yanagida, Tetsuya; Yoneda, Hikaru; Tsukumo, Yukihito; Tokunaga, Shin; Kawata, Takehisa; Ohashi, Rikiya; Fukuda, Hajime; Kojima, Koki; Kannami, Ayako; Kifuji, Takayuki; Sato, Naoya; Idei, Akiko; Iguchi, Taku; Sakairi, Tetsuya; Moritani, Yasunori (2018). “Discovery of evocalcet, a next-generation calcium-sensing receptor agonist for the treatment of hyperparathyroidism”. Bioorganic & Medicinal Chemistry Letters28 (11): 2055–2060. doi:10.1016/j.bmcl.2018.04.055.
  3. Jump up^ “Kyowa Hakko Kirin Launches ORKEDIA® TABLETS (Evocalcet) for the Treatment of Secondary Hyperparathyroidism in Patients on Maintenance Dialysis in Japan” (Press release). Kyowa Hakko Kirin. May 22, 2018.
Evocalcet
Evocalcet.svg
Clinical data
Trade names Orkedia
Identifiers
CAS Number
PubChem CID
DrugBank
UNII
Chemical and physical data
Formula C24H26N2O2
Molar mass 374.48 g·mol−1

///////////////Evocalcet,  エボカルセト , Эвокальцет ,  إيفوكالسيت , 依伏卡塞 , JAPAN 2018, KHK-7580, MT-4580, UNII:E58MLH082P, ORKEDIA

SMILES Code: O=C(O)CC1=CC=C(N2C[C@@H](N[C@@H](C3=C4C=CC=CC4=CC=C3)C)CC2)C=C1

 C[C@H](c1cccc2c1cccc2)N[C@H]3CCN(C3)c4ccc(cc4)CC(=O)O

Patisiran


Patisiran

Sense strand:
GUAACCAAGAGUAUUCCAUdTdT
Anti-sense strand:
AUGGAAUACUCUUGGUUACdTdT
RNA, (A-U-G-G-A-A-Um-A-C-U-C-U-U-G-G-U-Um-A-C-dT-dT), complex with RNA (G-Um-A-A-Cm-Cm-A-A-G-A-G-Um-A-Um-Um-Cm-Cm-A-Um-dT-dT) (1:1),
ALN-18328, 6024128  , ALN-TTR02  , GENZ-438027  , SAR-438037  , 50FKX8CB2Y (UNII code)

 for RNA, (A-U-G-G-A-A-Um-A-C-U-C-U-U-G-G-U-Um-A-C-dT-dT), complex with RNA(G-Um-A-A-Cm-Cm-A-A-G-A-G-Um-A-Um-Um-Cm-Cm-A-Um-dT-dT) (1:1)

Nucleic Acid Sequence

Sequence Length: 42, 21, 2112 a 7 c 7 g 4 t 12 umultistranded (2); modified

CAS 1420706-45-1

Treatment of Amyloidosis,

SEE…..https://endpts.com/gung-ho-alnylam-lands-historic-fda-ok-on-patisiran-revving-up-the-first-global-rollout-for-an-rnai-breakthrough/

Lipid-nanoparticle-encapsulated double-stranded siRNA targeting a 3 untranslated region of mutant and wild-type transthyretin mRNA

Patisiran (trade name Onpattro®) is a medication for the treatment of polyneuropathy in people with hereditary transthyretin-mediated amyloidosis. It is the first small interfering RNA-based drug approved by the FDA. Through this mechanism, it is a gene silencing drug that interferes with the production of an abnormal form of transthyretin.

Chemical structure of Patisiran.

During its development, patisiran was granted orphan drug statusfast track designationpriority review and breakthrough therapy designation due to its novel mechanism and the rarity of the condition it is designed to treat.[1][2] It was approved by the FDA in August 2018 and is expected to cost around $345,000 to $450,000 per year.[3]

Patisiran was granted orphan drug designation in the U.S. and Japan for the treatment of familial amyloid polyneuropathy. Fast track designation was also granted in the U.S. for this indication. In the E.U., orphan drug designation was assigned to the compound for the treatment of transthyretin-mediated amyloidosis (initially for the treatment of familial amyloid polyneuropathy)

Hereditary transthyretin-mediated amyloidosis is a fatal rare disease that is estimated to affect 50,000 people worldwide. Patisiran is the first drug approved by the FDA to treat this condition.[4]

Patisiran is a second-generation siRNA therapy targeting mutant transthyretin (TTR) developed by Alnylam for the treatment of familial amyloid polyneuropathy. The product is delivered by means of Arbutus Biopharma’s (formerly Tekmira Pharmaceuticals) lipid nanoparticle technology

“A lot of peo­ple think it’s win­ter out there for RNAi. But I think it’s spring­time.” — Al­ny­lam CEO John Maraganore, NYT, Feb­ru­ary 7, 2011.

Patisiran — designed to silence messenger RNA and block the production of TTR protein before it is made — is number 6 on Clarivate’s list of blockbusters set to launch this year, with a 2022 sales forecast of $1.22 billion. Some of the peak sales estimates range significantly higher as analysts crunch the numbers on a disease that afflicts only about 30,000 people worldwide.

PATENT

WO 2016033326

https://patents.google.com/patent/WO2016033326A2

Transthyretin (TTR) is a tetrameric protein produced primarily in the liver.

Mutations in the TTR gene destabilize the protein tetramer, leading to misfolding of monomers and aggregation into TTR amyloid fibrils (ATTR). Tissue deposition results in systemic ATTR amyloidosis (Coutinho et al, Forty years of experience with type I amyloid neuropathy. Review of 483 cases. In: Glenner et al, Amyloid and Amyloidosis, Amsterdam: Excerpta Media, 1980 pg. 88-93; Hou et al., Transthyretin and familial amyloidotic polyneuropathy. Recent progress in understanding the molecular mechanism of

neurodegeneration. FEBS J 2007, 274: 1637-1650; Westermark et al, Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci USA 1990, 87: 2843-2845). Over 100 reported TTR mutations exhibit a spectrum of disease symptoms.

[0004] TTR amyloidosis manifests in various forms. When the peripheral nervous system is affected more prominently, the disease is termed familial amyloidotic

polyneuropathy (FAP). When the heart is primarily involved but the nervous system is not, the disease is called familial amyloidotic cardiomyopathy (FAC). A third major type of TTR amyloidosis is called leptomeningeal/CNS (Central Nervous System) amyloidosis.

[0005] The most common mutations associated with familial amyloid polyneuropathy

(FAP) and ATTR-associated cardiomyopathy, respectively, are Val30Met (Coelho et al, Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 2012, 79: 785-792) and Vall22Ile (Connors et al, Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin VI 221 amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J 2009, 158: 607-614). [0006] Current treatment options for FAP focus on stabilizing or decreasing the amount of circulating amyloidogenic protein. Orthotopic liver transplantation reduces mutant TTR levels (Holmgren et al, Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet 1991, 40: 242-246), with improved survival reported in patients with early-stage FAP, although deposition of wild-type TTR may continue (Yazaki et al, Progressive wild-type transthyretin deposition after liver transplantation preferentially occurs into myocardium in FAP patients. Am J Transplant 2007, 7:235-242; Adams et al, Rapid progression of familial amyloid polyneuropathy: a multinational natural history study Neurology 2015 Aug 25; 85(8) 675-82; Yamashita et al, Long-term survival after liver transplantation in patients with familial amyloid polyneuropathy. Neurology 2012, 78: 637-643; Okamoto et al., Liver

transplantation for familial amyloidotic polyneuropathy: impact on Swedish patients’ survival. Liver Transpl 2009, 15: 1229-1235; Stangou et al, Progressive cardiac amyloidosis following liver transplantation for familial amyloid polyneuropathy: implications for amyloid fibrillogenesis. Transplantation 1998, 66:229-233; Fosby et al, Liver transplantation in the Nordic countries – An intention to treat and post-transplant analysis from The Nordic Liver Transplant Registry 1982-2013. Scand J Gastroenterol. 2015 Jun; 50(6):797-808.

Transplantation, in press).

[0007] Tafamidis and diflunisal stabilize circulating TTR tetramers, which can slow the rate of disease progression (Berk et al, Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 2013, 310: 2658-2667; Coelho et al., 2012; Coelho et al, Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol 2013, 260: 2802-2814; Lozeron et al, Effect on disability and safety of Tafamidis in late onset of Met30 transthyretin familial amyloid polyneuropathy. Eur J Neurol 2013, 20: 1539-1545). However, symptoms continue to worsen on treatment in a large proportion of patients, highlighting the need for new, disease-modifying treatment options for FAP.

[0008] Description of dsRNA targeting TTR can be found in, for example,

International patent application no. PCT/US2009/061381 (WO2010/048228) and

International patent application no. PCT/US2010/05531 1 (WO201 1/056883). Summary

[0009] Described herein are methods for reducing or arresting an increase in a

Neuropathy Impairment Score (NIS) or a modified NIS (mNIS+7) in a human subject by administering an effective amount of a transthyretin (TTR)-inhibiting composition, wherein the effective amount reduces a concentration of TTR protein in serum of the human subject to below 50 μg/ml or by at least 80%. Also described herein are methods for adjusting a dosage of a TTR- inhibiting composition for treatment of increasing NIS or Familial Amyloidotic Polyneuropathy (FAP) by administering the TTR- inhibiting composition to a subject having the increasing NIS or FAP, and determining a level of TTR protein in the subject having the increasing NIS or FAP. In some embodiments, the amount of the TTR- inhibiting composition subsequently administered to the subject is increased if the level of TTR protein is greater than 50 μg/ml, and the amount of the TTR- inhibiting composition subsequently administered to the subject is decreased if the level of TTR protein is below 50 μg/ml. Also described herein are formulated versions of a TTR inhibiting siRNA.

Image result for Alnylam

PATENT

WO 2016203402

PAPERS

Annals of Medicine (Abingdon, United Kingdom) (2015), 47(8), 625-638.

Pharmaceutical Research (2017), 34(7), 1339-1363

Annual Review of Pharmacology and Toxicology (2017), 57, 81-105

CLIP

Image result for Alnylam

Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults
Aug 10,2018

− First and Only FDA-approved Treatment Available in the United States for this Indication –

− ONPATTRO Shown to Improve Polyneuropathy Relative to Placebo, with Reversal of Neuropathy Impairment Compared to Baseline in Majority of Patients –

− Improvement in Specified Measures of Quality of Life and Disease Burden Demonstrated Across Diverse, Global Patient Population –

− Alnylam to Host Conference Call Today at 3:00 p.m. ET. −

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Aug. 10, 2018– Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that the United States Food and Drug Administration (FDA) approved ONPATTRO™ (patisiran) lipid complex injection, a first-of-its-kind RNA interference (RNAi) therapeutic, for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. ONPATTRO is the first and onlyFDA-approved treatment for this indication. hATTR amyloidosis is a rare, inherited, rapidly progressive and life-threatening disease with a constellation of manifestations. In addition to polyneuropathy, hATTR amyloidosis can lead to other significant disabilities including decreased ambulation with the loss of the ability to walk unaided, a reduced quality of life, and a decline in cardiac functioning. In the largest controlled study of hATTR amyloidosis, ONPATTRO was shown to improve polyneuropathy – with reversal of neuropathy impairment in a majority of patients – and to improve a composite quality of life measure, reduce autonomic symptoms, and improve activities of daily living.

Image result for Alnylam

This press release features multimedia. View the full release here:https://www.businesswire.com/news/home/20180810005398/en/

ONPATTRO™ (patisiran) packaging and product vial (Photo: Business Wire)ONPATTRO™ (patisiran) packaging and product vial (Photo: Business Wire)

“Alnylam was founded on the vision of harnessing the potential of RNAi therapeutics to treat human disease, and this approval heralds the arrival of an entirely new class of medicines. We believe today draws us ever-closer to achieving our Alnylam 2020 goals of becoming a fully integrated, multi-product biopharmaceutical company with a sustainable pipeline,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. “With the potential for the sequential launches of several new medicines in the coming years, we believe we have the opportunity to meaningfully impact the lives of people around the world in need of new approaches to address serious diseases with significant unmet medical needs.”

“Today’s historic approval marks the arrival of a first-of-its kind treatment option for a rare and devastating condition with limited treatment options,” said Akshay Vaishnaw, M.D., Ph.D., President of R&D at Alnylam. “We extend our deepest gratitude to the patients who participated in the ONPATTRO clinical trials and their families and caregivers who supported them. We are also grateful for the tireless efforts of the investigators and study staff, without whom this important milestone would not have been possible. We also look forward to working with the FDA to potentially expand the ONPATTRO indication in the future.”

The FDA approval of ONPATTRO was based on positive results from the randomized, double-blind, placebo-controlled, global Phase 3 APOLLO study, the largest-ever study in hATTR amyloidosis patients with polyneuropathy. Results from the APOLLO study were published in the July 5, 2018, issue of The New England Journal of Medicine.

In APOLLO, the safety and efficacy of ONPATTRO were evaluated in a diverse, global population of hATTR amyloidosis patients in 19 countries, with a total of 39 TTR mutations. Patients were randomized in a 2:1 ratio to receive intravenous ONPATTRO (0.3 mg per kg of body weight) or placebo once every 3 weeks for 18 months. The study showed that ONPATTRO improved measures of polyneuropathy, quality of life, activities of daily living, ambulation, nutritional status and autonomic symptoms relative to placebo in adult patients with hATTR amyloidosis with polyneuropathy. The primary endpoint of the APOLLO study was the modified Neuropathy Impairment Score +7 (mNIS+7), which assesses motor strength, reflexes, sensation, nerve conduction and postural blood pressure.

  • Patients treated with ONPATTRO had a mean 6.0-point decrease (improvement) in mNIS+7 score from baseline compared to a mean 28.0-point increase (worsening) for patients in the placebo group, resulting in a mean 34.0-point difference relative to placebo, after 18 months of treatment.
  • While nearly all ONPATTRO-treated patients experienced a treatment benefit relative to placebo, 56 percent of ONPATTRO-treated patients at 18 months of treatment experienced reversal of neuropathy impairment (as assessed by mNIS+7 score) relative to their own baseline, compared to four percent of patients who received placebo.
  • Patients treated with ONPATTRO had a mean 6.7-point decrease (improvement) in Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) score from baseline compared to a mean 14.4-point increase (worsening) for patients in the placebo group, resulting in a mean 21.1-point difference relative to placebo, after 18 months of treatment.
  • As measured by Norfolk QoL-DN, 51 percent of patients treated with ONPATTRO experienced improvement in quality of life at 18 months relative to their own baseline, compared to 10 percent of the placebo-treated patients.
  • Over 18 months of treatment, patients treated with ONPATTRO experienced significant benefit vs. placebo for all other secondary efficacy endpoints, including measures of activities of daily living, walking ability, nutritional status, and autonomic symptoms.
  • The most common adverse events that occurred more frequently with ONPATTRO than with placebo were upper respiratory tract infections and infusion-related reactions. To reduce the risk of infusion-related reactions, patients received premedications prior to infusion.

“FDA approval of ONPATTRO represents an entirely new approach to treating patients with polyneuropathy in hATTR amyloidosis and shows promise as a new era in patient care,” said John Berk, M.D., Associate Professor of Medicine at Boston University School of Medicine and assistant director of the Amyloidosis Center at Boston University School of Medicine. “Given the strength of the APOLLO data, including data showing the possibility of halting or improving disease progression in many patients, ONPATTRO holds tremendous promise for people living with this disease.”

“For years I have witnessed the tragic impact of hATTR amyloidosis on generations of families. Today, we celebrate the FDA approval of ONPATTRO,” said Muriel Finkel, President of Amyloidosis Support Groups. “It’s extremely gratifying to see promising science translate into a treatment option that will allow patients to potentially experience an improvement in their disease and an improvement in their overall quality of life.”

“Today’s approval is significant in so many respects. It means the hATTR amyloidosis community of patients, families, caregivers and healthcare professionals in the United States now has a treatment option that offers renewed hope,” said Isabelle Lousada, Founder and Chief Executive Officer of the Amyloidosis Research Consortium. “With an FDA-approved treatment now available, I am more optimistic than ever that we can increase awareness of this rare disease and encourage more people to get tested and receive the proper diagnosis.”

ONPATTRO is expected to be available for shipment to healthcare providers in the U.S. within 48 hours.

Alnylam is committed to helping people access the medicines they are prescribed and will be offering comprehensive support services for people prescribed ONPATTRO through Alnylam Assist™. Visit AlnylamAssist.com for more information or call 1-833-256-2748.

ONPATTRO was reviewed by the FDA under Priority Review and had previously been granted Breakthrough Therapy and Orphan Drug Designations. On July 27, patisiran received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) for the treatment of hereditary transthyretin-mediated amyloidosis in adults with stage 1 or stage 2 polyneuropathy under accelerated assessment by the European Medicines Agency. The recommended Summary of Product Characteristics (SmPC) for the European Union (EU) includes data on secondary and exploratory endpoints. Expected in September, the European Commission will review the CHMP recommendation to make a final decision on marketing authorization, applicable to all 28 EU member states, plus Iceland, Liechtenstein and Norway. Regulatory filings in other markets, including Japan, are planned beginning in mid-2018.

Visit ONPATTRO.com for more information,

About ONPATTRO™ (patisiran) lipid complex injection
ONPATTRO was approved by the U.S. Food and Drug Administration (FDA) for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. ONPATTRO is the first and only RNA interference (RNAi) therapeutic approved by the FDA for this indication. ONPATTRO utilizes a novel approach to target and reduce production of the TTR protein in the liver via the RNAi pathway. Reducing the TTR protein leads to a reduction in the amyloid deposits that accumulate in tissues. ONPATTRO is administered through intravenous (IV) infusion once every 3 weeks following required premedication and the dose is based on actual body weight. Home infusion may be an option for some patients after an evaluation and recommendation by the treating physician, and may not be covered by all insurance plans. Regardless of the setting, ONPATTRO infusions should be performed by a healthcare professional. For more information about ONPATTRO, visit ONPATTRO.com.

About hATTR Amyloidosis
Hereditary transthyretin (TTR)-mediated amyloidosis (hATTR) is an inherited, progressively debilitating, and often fatal disease caused by mutations in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Mutations in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis represents a major unmet medical need with significant morbidity and mortality. The median survival is 4.7 years following diagnosis. Until now, people living with hATTR amyloidosis in the U.S. had no FDA-approved treatment options.

Alnylam Assist™
As part of Alnylam’s commitment to making therapies available to those who may benefit from them, Alnylam Assist will offer a wide range of services to guide patients through treatment with ONPATTRO, including financial assistance options for eligible patients, benefit verification and claims support, and ordering assistance and facilitation of delivery via specialty distributor or specialty pharmacy. Patients will have access to dedicated Case Managers who can provide personalized support throughout the treatment process and Patient Education Liaisons to help patients gain a better understanding of the disease. Visit AlnylamAssist.com for more information.

About RNAi
RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. RNAi therapeutics are a new class of medicines that harness the natural biological process of RNAi. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach in developing medicines to improve the care of patients with genetic and other diseases.

About Alnylam
Alnylam (Nasdaq: ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to improve the lives of people afflicted with rare genetic, cardio-metabolic, and hepatic infectious diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust discovery platform. ONPATTRO, available in the U.S. for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults, is Alnylam’s first U.S. FDA-approved RNAi therapeutic. Alnylam has a deep pipeline of investigational medicines, including three product candidates that are in late-stage development. Looking forward, Alnylam will continue to execute on its “Alnylam 2020” strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines to address the needs of patients who have limited or inadequate treatment options. Alnylam employs over 800 people worldwide and is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam or on LinkedIn.

Image result for patisiran

FDA approves first-of-its kind targeted RNA-based therapy to treat a rare disease

First treatment for the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adult patients

The U.S. Food and Drug Administration today approved Onpattro (patisiran) infusion for the treatment of peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adult patients. This is the first FDA-approved treatment for patients with polyneuropathy caused by hATTR, a rare, debilitating and often fatal genetic disease characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart and other organs. It is also the first FDA approval of a new class of drugs called small interfering ribonucleic acid (siRNA) treatment

Continue reading…

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM616518.htm?utm_campaign=08102018_PR_FDA%20approves%20new%20drug%20for%20rare%20disease%2C%20hATTR&utm_medium=email&utm_source=Eloqua

August 10, 2018

Release

The U.S. Food and Drug Administration today approved Onpattro (patisiran) infusion for the treatment of peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adult patients. This is the first FDA-approved treatment for patients with polyneuropathy caused by hATTR, a rare, debilitating and often fatal genetic disease characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart and other organs. It is also the first FDA approval of a new class of drugs called small interfering ribonucleic acid (siRNA) treatment.

“This approval is part of a broader wave of advances that allow us to treat disease by actually targeting the root cause, enabling us to arrest or reverse a condition, rather than only being able to slow its progression or treat its symptoms. In this case, the effects of the disease cause a degeneration of the nerves, which can manifest in pain, weakness and loss of mobility,” said FDA Commissioner Scott Gottlieb, M.D. “New technologies like RNA inhibitors, that alter the genetic drivers of a disease, have the potential to transform medicine, so we can better confront and even cure debilitating illnesses. We’re committed to advancing scientific principles that enable the efficient development and review of safe, effective and groundbreaking treatments that have the potential to change patients’ lives.”

RNA acts as a messenger within the body’s cells, carrying instructions from DNA for controlling the synthesis of proteins. RNA interference is a process that occurs naturally within our cells to block how certain genes are expressed. Since its discovery in 1998, scientists have used RNA interference as a tool to investigate gene function and its involvement in health and disease. Researchers at the National Institutes of Health, for example, have used robotic technologies to introduce siRNAs into human cells to individually turn off nearly 22,000 genes.

This new class of drugs, called siRNAs, work by silencing a portion of RNA involved in causing the disease. More specifically, Onpattro encases the siRNA into a lipid nanoparticle to deliver the drug directly into the liver, in an infusion treatment, to alter or halt the production of disease-causing proteins.

Affecting about 50,000 people worldwide, hATTR is a rare condition. It is characterized by the buildup of abnormal deposits of protein fibers called amyloid in the body’s organs and tissues, interfering with their normal functioning. These protein deposits most frequently occur in the peripheral nervous system, which can result in a loss of sensation, pain, or immobility in the arms, legs, hands and feet. Amyloid deposits can also affect the functioning of the heart, kidneys, eyes and gastrointestinal tract. Treatment options have generally focused on symptom management.

Onpattro is designed to interfere with RNA production of an abnormal form of the protein transthyretin (TTR). By preventing the production of TTR, the drug can help reduce the accumulation of amyloid deposits in peripheral nerves, improving symptoms and helping patients better manage the condition.

“There has been a long-standing need for a treatment for hereditary transthyretin-mediated amyloidosis polyneuropathy. This unique targeted therapy offers these patients an innovative treatment for their symptoms that directly affects the underlying basis of this disease,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research.

The efficacy of Onpattro was shown in a clinical trial involving 225 patients, 148 of whom were randomly assigned to receive an Onpattro infusion once every three weeks for 18 months, and 77 of whom were randomly assigned to receive a placebo infusion at the same frequency. The patients who received Onpattro had better outcomes on measures of polyneuropathy including muscle strength, sensation (pain, temperature, numbness), reflexes and autonomic symptoms (blood pressure, heart rate, digestion) compared to those receiving the placebo infusions. Onpattro-treated patients also scored better on assessments of walking, nutritional status and the ability to perform activities of daily living.

The most common adverse reactions reported by patients treated with Onpattro are infusion-related reactions including flushing, back pain, nausea, abdominal pain, dyspnea (difficulty breathing) and headache. All patients who participated in the clinical trials received premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) to reduce the occurrence of infusion-related reactions. Patients may also experience vision problems including dry eyes, blurred vision and eye floaters (vitreous floaters). Onpattro leads to a decrease in serum vitamin A levels, so patients should take a daily Vitamin A supplement at the recommended daily allowance.

The FDA granted this application Fast TrackPriority Review and Breakthrough Therapy designations. Onpattro also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

Approval of Onpattro was granted to Alnylam Pharmaceuticals, Inc.

References

  1. Jump up^ “FDA approves first-of-its kind targeted RNA-based therapy to treat a rare disease” (Press release). U.S. Food and Drug Administration. 10 August 2018. Retrieved 11 August 2018.
  2. Jump up^ Brooks, Megan (10 August 2018). “FDA OKs Patisiran (Onpattro) for Polyneuropathy in hAATR”Medscape. WebMD. Retrieved 10 August 2018.
  3. Jump up^ Lipschultz, Bailey; Cortez, Michelle (10 August 2018). “Rare-Disease Treatment From Alnylam to Cost $450,000 a Year”Bloomberg. Retrieved 11 August 2018.
  4. Jump up^ Loftus, Peter (10 August 2018). “New Kind of Drug, Silencing Genes, Gets FDA Approval”Wall Street Journal. Retrieved 10 August 2018.

////////////// Onpattro, patisiran, fda 2018, Fast TrackPriority Review, Breakthrough Therapy,  Orphan Drug designation, Alnylam Pharmaceuticals, ALN-18328,  6024128  , ALN-TTR02  , GENZ-438027  , SAR-438037  , 50FKX8CB2Y

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FDA approves new vaginal ring for one year of birth control


FDA approves new vaginal ring for one year of birth control

The U.S. Food and Drug Administration today approved Annovera (segesterone acetate and ethinyl estradiol vaginal system), which is a combined hormonal contraceptive for women of reproductive age used to prevent pregnancy and is the first vaginal ring contraceptive that can be used for an entire year. Annovera is a reusable donut-shaped (ring), non-biodegradable, flexible vaginal system that is placed in the vagina for three weeks followed by one week out of the vagina, at which time women may experience a period (a withdrawal bleed). This schedule is repeated every four weeks for one year (thirteen 28-day menstrual cycles).

August 10, 2018

Release

The U.S. Food and Drug Administration today approved Annovera (segesterone acetate and ethinyl estradiol vaginal system), which is a combined hormonal contraceptive for women of reproductive age used to prevent pregnancy and is the first vaginal ring contraceptive that can be used for an entire year. Annovera is a reusable donut-shaped (ring), non-biodegradable, flexible vaginal system that is placed in the vagina for three weeks followed by one week out of the vagina, at which time women may experience a period (a withdrawal bleed). This schedule is repeated every four weeks for one year (thirteen 28-day menstrual cycles).

“The FDA is committed to supporting innovation in women’s health and today’s approval builds on available birth control options,” states Victor Crentsil, M.D., acting deputy director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research.

Annovera is washed and stored in a compact case for the seven days not in use. Annovera does not require refrigeration prior to dispensing and can withstand storage temperatures up to 30°C (86°F).

The efficacy and safety of Annovera were studied in three, open label clinical trials with healthy women ranging from 18 to 40 years of age. Based on the results, about two to four women out of 100 women may get pregnant during the first year they use Annovera.

All hormonal contraception carries serious risks. Annovera carries a boxed warning relating to cigarette smoking and serious cardiovascular events. Women over 35 who smoke should not use Annovera. Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive use.

Annovera is contraindicated and should not be used in women with:

  • A high risk of arterial or venous thrombotic diseases;
  • Current or history of breast cancer or other estrogen- or progestin-sensitive cancer;
  • Liver tumors, acute hepatitis, or severe (decompensated) cirrhosis;
  • Undiagnosed abnormal uterine bleeding;
  • Hypersensitivity to any of the components of Annovera; and
  • Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir.

The most common side effects in women using Annovera are similar to those of other combined hormonal contraceptive products and include headache/migraine, nausea/vomiting, yeast infections, abdominal pain, dysmenorrhea (painful menstruation), breast tenderness, irregular bleeding, diarrhea and genital itching.

The FDA is requiring postmarketing studies to further evaluate the risks of venous thromboembolism, and the effects of CYP3A modulating drugs and tampon use on the pharmacokinetics of Annovera.

The FDA granted approval of Annovera to The Population Council, Inc.

/////////////fda 2018, Annovera, segesterone acetate, ethinyl estradiol, vaginal system

FDA approves first-of-its kind targeted RNA-based therapy Onpattro (patisiran) to treat a rare disease


Image result for patisiran

FDA approves first-of-its kind targeted RNA-based therapy to treat a rare disease

First treatment for the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adult patients

The U.S. Food and Drug Administration today approved Onpattro (patisiran) infusion for the treatment of peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adult patients. This is the first FDA-approved treatment for patients with polyneuropathy caused by hATTR, a rare, debilitating and often fatal genetic disease characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart and other organs. It is also the first FDA approval of a new class of drugs called small interfering ribonucleic acid (siRNA) treatment

Continue reading…

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM616518.htm?utm_campaign=08102018_PR_FDA%20approves%20new%20drug%20for%20rare%20disease%2C%20hATTR&utm_medium=email&utm_source=Eloqua

August 10, 2018

Release

The U.S. Food and Drug Administration today approved Onpattro (patisiran) infusion for the treatment of peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adult patients. This is the first FDA-approved treatment for patients with polyneuropathy caused by hATTR, a rare, debilitating and often fatal genetic disease characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart and other organs. It is also the first FDA approval of a new class of drugs called small interfering ribonucleic acid (siRNA) treatment.

“This approval is part of a broader wave of advances that allow us to treat disease by actually targeting the root cause, enabling us to arrest or reverse a condition, rather than only being able to slow its progression or treat its symptoms. In this case, the effects of the disease cause a degeneration of the nerves, which can manifest in pain, weakness and loss of mobility,” said FDA Commissioner Scott Gottlieb, M.D. “New technologies like RNA inhibitors, that alter the genetic drivers of a disease, have the potential to transform medicine, so we can better confront and even cure debilitating illnesses. We’re committed to advancing scientific principles that enable the efficient development and review of safe, effective and groundbreaking treatments that have the potential to change patients’ lives.”

RNA acts as a messenger within the body’s cells, carrying instructions from DNA for controlling the synthesis of proteins. RNA interference is a process that occurs naturally within our cells to block how certain genes are expressed. Since its discovery in 1998, scientists have used RNA interference as a tool to investigate gene function and its involvement in health and disease. Researchers at the National Institutes of Health, for example, have used robotic technologies to introduce siRNAs into human cells to individually turn off nearly 22,000 genes.

This new class of drugs, called siRNAs, work by silencing a portion of RNA involved in causing the disease. More specifically, Onpattro encases the siRNA into a lipid nanoparticle to deliver the drug directly into the liver, in an infusion treatment, to alter or halt the production of disease-causing proteins.

Affecting about 50,000 people worldwide, hATTR is a rare condition. It is characterized by the buildup of abnormal deposits of protein fibers called amyloid in the body’s organs and tissues, interfering with their normal functioning. These protein deposits most frequently occur in the peripheral nervous system, which can result in a loss of sensation, pain, or immobility in the arms, legs, hands and feet. Amyloid deposits can also affect the functioning of the heart, kidneys, eyes and gastrointestinal tract. Treatment options have generally focused on symptom management.

Onpattro is designed to interfere with RNA production of an abnormal form of the protein transthyretin (TTR). By preventing the production of TTR, the drug can help reduce the accumulation of amyloid deposits in peripheral nerves, improving symptoms and helping patients better manage the condition.

“There has been a long-standing need for a treatment for hereditary transthyretin-mediated amyloidosis polyneuropathy. This unique targeted therapy offers these patients an innovative treatment for their symptoms that directly affects the underlying basis of this disease,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research.

The efficacy of Onpattro was shown in a clinical trial involving 225 patients, 148 of whom were randomly assigned to receive an Onpattro infusion once every three weeks for 18 months, and 77 of whom were randomly assigned to receive a placebo infusion at the same frequency. The patients who received Onpattro had better outcomes on measures of polyneuropathy including muscle strength, sensation (pain, temperature, numbness), reflexes and autonomic symptoms (blood pressure, heart rate, digestion) compared to those receiving the placebo infusions. Onpattro-treated patients also scored better on assessments of walking, nutritional status and the ability to perform activities of daily living.

The most common adverse reactions reported by patients treated with Onpattro are infusion-related reactions including flushing, back pain, nausea, abdominal pain, dyspnea (difficulty breathing) and headache. All patients who participated in the clinical trials received premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) to reduce the occurrence of infusion-related reactions. Patients may also experience vision problems including dry eyes, blurred vision and eye floaters (vitreous floaters). Onpattro leads to a decrease in serum vitamin A levels, so patients should take a daily Vitamin A supplement at the recommended daily allowance.

The FDA granted this application Fast TrackPriority Review and Breakthrough Therapy designations. Onpattro also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

Approval of Onpattro was granted to Alnylam Pharmaceuticals, Inc.

////////////// Onpattro, patisiran, fda 2018, Fast TrackPriority Review, Breakthrough Therapy,  Orphan Drug designation

FDA approves new treatment Galafold (migalastat) for a rare genetic disorder, Fabry disease


FDA approves new treatment for a rare genetic disorder, Fabry disease

The U.S. Food and Drug Administration today approved Galafold (migalastat), the first oral medication for the treatment of adults with Fabry disease. The drug is indicated for adults with Fabry disease who have a genetic mutation determined to be responsive (“amenable”) to treatment with Galafold based on laboratory data. Fabry disease is a rare and serious genetic disease that results from buildup of a type of fat called globotriaosylceramide (GL-3) in blood vessels, the kidneys, the heart, the nerves and other organs.

August 10, 2018

Release

The U.S. Food and Drug Administration today approved Galafold (migalastat), the first oral medication for the treatment of adults with Fabry disease. The drug is indicated for adults with Fabry disease who have a genetic mutation determined to be responsive (“amenable”) to treatment with Galafold based on laboratory data. Fabry disease is a rare and serious genetic disease that results from buildup of a type of fat called globotriaosylceramide (GL-3) in blood vessels, the kidneys, the heart, the nerves and other organs.

“Thus far, treatment of Fabry disease has involved replacing the missing enzyme that causes the particular type of fat buildup in this disease. Galafold differs from enzyme replacement in that it increases the activity of the body’s deficient enzyme,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research.

Fabry disease is an inherited disorder caused by mutations (alterations) in the alpha-galactosidase A (GLA) gene located on the X-chromosome. Fabry disease is rare and affects both males and females. It is estimated that classic Fabry disease (the most severe type) affects approximately one in 40,000 males. The later-onset type is more frequent, and in some populations, may occur in one in 1,500 to 4,000 males. Patients with Fabry disease develop slowly progressive kidney disease, cardiac hypertrophy (enlargement of the heart), arrhythmias (abnormal heart rhythm), stroke and early death.

The efficacy of Galafold was demonstrated in a six-month, placebo-controlled clinical trial in 45 adults with Fabry disease. In this trial, patients treated with Galafold over six months had a greater reduction in globotriaosylceramide (GL-3) in blood vessels of the kidneys (as measured in kidney biopsy samples) as compared to patients on placebo.The safety of Galafold was studied in four clinical trials which included a total of 139 patients with Fabry disease.

The most common adverse drug reactions in patients taking Galafold in clinical trials were headache, nasal and throat irritation (nasopharyngitis), urinary tract infection, nausea, and fever (pyrexia).

Galafold was approved using the Accelerated Approval pathway, under which the FDA may approve drugs for serious conditions where there is an unmet medical need and where a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. A further study is required to verify and describe the clinical benefits of Galafold, and the sponsor will be conducting a confirmatory clinical trial of Galafold in adults with Fabry disease.

Galafold  was granted Priority Review designation, under which the FDA’s goal is to take action on an application within six months of application filing where the agency determines that the drug, if approved, would provide a significant improvement in treating, diagnosing or preventing a serious condition over available therapies. Galafold also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The FDA granted approval of Galafold to Amicus Therapeutics U.S., Inc.

///////////////fda 2018, Galafold, migalastat, Fabry disease, Amicus Therapeutics

Spiramycin, スピラマイシン


8025-81-8.pngSpiramycin I.svg

ChemSpider 2D Image | [(11E,13E)-6-({5-[(4,5-Dihydroxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy]-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl}oxy)-10-{[5-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy }-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxooxacyclohexadeca-11,13-dien-7-yl]acetaldehyde | C43H74N2O14Spiramycin.png2D chemical structure of 8025-81-8

ThumbChemSpider 2D Image | 033ECH6IFG | C43H74N2O14

Spiramycin

スピラマイシン

CAS: 8025-81-8

Sanofi INNOVATOR

Molecular Formula: C43H74N2O14
Molecular Weight: 843.065 g/mol

[(11E,13E)-6-({5-[(4,5-Dihydroxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy]-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl}oxy)-10-{[5-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy }-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxooxacyclohexadeca-11,13-dien-7-yl]acetaldehyde

2-[(11E,13E)-6-[5-(4,5-dihydroxy-4,6-dimethyloxan-2-yl)oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde

Leucomycin V, 9-O-[(2R,5S,6R)-5-(dimethylamino)tetrahydro-6-methyl-2H-pyran-2-yl]-

033ECH6IFG
24916-50-5 [RN]
Spiramycin I
[(4R,5S,6S,7R,9R,10R,11E,13E,16R)-6-{[(2S,3R,4R,5S,6R)-5-{[(2S,4R,5S,6S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy}-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-10-{[(2R,5S,6S)-5-(dimethylamino)-6
  • Provamycin
  • Rovamycin
  • RP 5337
  • Sequamycin
  • IL 5902
  • NSC-64393
  • ATC:J01FA02
  • Use:macrolide antibiotic
  • EINECS:232-429-6
  • LD50:130 mg/kg (M, i.v.); 2900 mg/kg (M, p.o.);
    170 mg/kg (R, i.v.); 3550 mg/kg (R, p.o.);
    5200 mg/kg (dog, p.o.)

2018/7/2 japan approved, UNII: 71ODY0V87H

Solubility

Slightly soluble in water

O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1621

Soluble in most organic solvents

O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1621

Spectral Properties

UV max (ethanol): 231nm

O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1621

Specific optical rotation: -80 deg at 20 deg C/D

O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1621
スピラマイシン
Spiramycin


スピラマイシン酢酸エステル JP17
Spiramycin Acetate

A macrolide antibiotic produced by Streptomyces ambofaciens. The drug is effective against gram-positive aerobic pathogens, N. gonorrhoeae, and staphylococci. It is used to treat infections caused by bacteria and Toxoplasma gondii.

Spiramycin is a macrolide antimicrobial agent with activity against gram-positive organisms, including Streptococcus pyogenes (group A beta-hemolytic streptococci), S. viridans, Corynebacterium diphtheriae, and methicillin-sensitive Staphylococcus aureus. Spiramycin is a 16-membered ring macrolide. It was discovered in 1952 as a product of Streptomyces ambofaciens. As a preparation for oral administration it has been used since 1955, in 1987 also the parenteral form was introduced into practice. The antibacterial spectrum comprises Gram-positive cocci and rods, Gram-negative cocci and also Legionellae, mycoplasmas, chlamydiae, some types of spirochetes, Toxoplasma gondii and Cryptosporidium species. Enterobacteria, pseudomonads and pathogenic moulds are resistant. Its action is mainly bacteriostatic, on highly sensitive strains it exerts a bactericide action.

Spiramycin is a macrolide antibiotic and antiparasitic It is used to treat toxoplasmosis and various other infections of soft tissues. Although used in Europe, Canada and Mexico,[1] spiramycin is still considered an experimental drug in the United States, but can sometimes be obtained by special permission from the FDA for toxoplasmosis in the first trimester of pregnancy.[2]

Spiramycin has been used in Europe since the year 2000 under the trade name “Rovamycine”, produced by Rhone-Poulenc Rorer and Famar Lyon, France and Eczacıbaşı İlaç, Turkey. It also goes under the name Rovamycine in Canada (distributed by OdanLaboratories), where it is mostly marketed to dentists for mouth infections.

Spiramycin is a 16-membered ring macrolide. It was discovered in 1952 as a product of Streptomyces ambofaciens. As a preparation for oral administration it has been used since 1955, in 1987 also the parenteral form was introduced into practice. The antibiotic action involves inhibition of protein synthesis in the bacterial cell during translocation. Resistance to spiramycin can develop by several mechanisms and its prevalence is to a considerable extent proportional to the frequency of prescription in a given area. The antibacterial spectrum comprises Gram-positive cocci and rods, Gram-negative cocci and also Legionellae, mycoplasmas, chlamydiae, some types of spirochetes, Toxoplasma gondii and Cryptosporidium species. Enterobacteria, pseudomonads and pathogenic moulds are resistant. Its action is mainly bacteriostatic, on highly sensitive strains it exerts a bactericide action. As compared with erythromycin, it is in vitro weight for weight 5 to 20 less effective, an equipotential therapeutic dose is, however, only double. This difference between the effectiveness in vitro and in vivo is explained above all by the great affinity of spiramycin to tissues where it achieves concentrations many times higher than serum levels. An important part is played also by the slow release of the antibiotic from the tissue compartment, the marked action on microbes in sub-inhibition concentrations and the relatively long persisting post-antibiotic effect. Its great advantage is the exceptionally favourable tolerance-gastrointestinal and general. It is available for parenteral and oral administration

Synthesis Path

  • From culture of Streptomyces ambofaciens.

Trade Names

Country Trade Name Vendor Annotation
D Rovamycine Teofarma
Selectomycin Grünenthal
F Bi Missilor Pierre Fabre
Birodogyl Sanofi-Aventis
Missilor Pierre Fabre comb.
Rodogyl Pierre Fabre
Rovamycine Grünenthal
I Rovamicina Sanofi-Aventis
Rovamycina Teofarma
Spiromix Pulitzer

Spiramycin

Title: Spiramycin
CAS Registry Number: 8025-81-8
Manufacturers’ Codes: RP-5337
Trademarks: Selectomycin (Grñenthal); Rovamicina (RPR); Rovamycin (RPR)
Literature References: Antibiotic substance classified in the erythromycin-carbomycin group and produced by Streptomyces ambofaciens from soil of northern France: Cosar et al., C.R. Seances Soc. Biol. Ses Fil. 234, 1498 (1952); Pinnert-Sindico et al.,Antibiot. Annu. 1954-1955, 724; Ninet, Verrier, US 2943023 (1960 to Rhône-Poulenc), see also US 3000785 (1961 to Rhône-Poulenc). Antibacterial activity and toxicity: H. Sous et al., Arzneim.-Forsch. 8, 386 (1958). Separation into 3 components named spiramycin I, II and III: Preud’homme, Charpentier, US 2978380 and US 3011947 (1961 to Rhône-Poulenc). Structure: Kuehne, Benson, J. Am. Chem. Soc. 87, 4660 (1965). Revised structure: Omura et al., ibid. 91, 3401 (1969); Mitscher et al., J. Antibiot. 26,55 (1973). Revised configuration at C-9: Freiberg et al., J. Org. Chem. 39, 2474 (1974). Symposium on pharmacology, antibacterial spectrum, and clinical efficacy: J. Antimicrob. Chemother. 22, Suppl. B, 1-213 (1988).
Properties: Amorphous base, slightly sol in water. [a]D20 -80° (methanol). uv max (ethanol): 231 nm. Sol in most organic solvents. Active on gram-positive bacteria and rickettsiae. Cross resistance between microorganisms resistant to erythromycin and carbomycin. LD50 in rats (mg/kg): 9400 orally; 1000 s.c.; 170 i.v. (Sous).
Optical Rotation: [a]D20 -80° (methanol)
Absorption maximum: uv max (ethanol): 231 nm
Toxicity data: LD50 in rats (mg/kg): 9400 orally; 1000 s.c.; 170 i.v. (Sous)
Derivative Type: Embonate
Trademarks: Spira 200 (RMB)
Derivative Type: Hexanedioate
Additional Names: Spiramycin adipate
Trademarks: Stomamycin (Chassot); Suanovil (Biokema)
Derivative Type: Spiramycin I
CAS Registry Number: 24916-50-5
Additional Names: Foromacidin A
Molecular Formula: C43H74N2O14
Molecular Weight: 843.05
Percent Composition: C 61.26%, H 8.85%, N 3.32%, O 26.57%
Properties: Crystals, mp 134-137°. [a]D20 -96°.
Melting point: mp 134-137°
Optical Rotation: [a]D20 -96°
Derivative Type: Spiramycin I triacetate
Properties: Crystals, mp 140-142°. [a]D20 -92.5°.
Melting point: mp 140-142°
Optical Rotation: [a]D20 -92.5°
Derivative Type: Spiramycin II
CAS Registry Number: 24916-51-6
Additional Names: Foromacidin B
Molecular Formula: C45H76N2O15
Molecular Weight: 885.09
Percent Composition: C 61.07%, H 8.65%, N 3.17%, O 27.11%
Properties: Crystals, mp 130-133°. [a]D20 -86°.
Melting point: mp 130-133°
Optical Rotation: [a]D20 -86°
Derivative Type: Spiramycin II diacetate
Properties: Crystals from cyclohexane, mp 156-160°. [a]D20 -98.4°.
Melting point: mp 156-160°
Optical Rotation: [a]D20 -98.4°
Derivative Type: Spiramycin III
CAS Registry Number: 24916-52-7
Additional Names: Foromacidin C
Molecular Formula: C46H78N2O15
Molecular Weight: 899.12
Percent Composition: C 61.45%, H 8.74%, N 3.12%, O 26.69%
Properties: Crystals, mp 128-131°. [a]D20 -83°.
Melting point: mp 128-131°
Optical Rotation: [a]D20 -83°
Derivative Type: Spiramycin III diacetate
Properties: Crystals from cyclohexane, mp 140-142°. [a]D20 -90.4°.
Melting point: mp 140-142°
Optical Rotation: [a]D20 -90.4°
Therap-Cat: Antibacterial.
Therap-Cat-Vet: Antibacterial; growth promotant.
Keywords: Antibacterial (Antibiotics); Macrolides.
Spiramycin
Spiramycin I.svg
Clinical data
Synonyms 2-[(4R,5S,6S,7R,9R,10R,11E,13E,16R)-6-{[(2S,3R,4R,5S,6R)-5-{[(2S,5S,6S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy}-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-10-{[(2R,5S,6R)-5-(dimethylamino)-6-methyloxan-2-yl]oxy}-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde
Routes of
administration
oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
E number E710 (antibiotics) Edit this at Wikidata
ECHA InfoCard 100.029.476 Edit this at Wikidata
Chemical and physical data
Formula C43H74N2O14
Molar mass 843.053 g/mol
3D model (JSmol)
Solubility in water Insoluble in water; Very soluble in acetonitrile and methanol; Almost completely(>99.5) in ethanol. mg/mL (20 °C)

References

  1. Jump up^ Spiramycin advanced consumer information | Drugs.com
  2. Jump up^ Toxoplasmosis at MayoClinic.com

References

    • Pinnert-Sindico, S. et al.: Antibiot. Annu. (ABANAE) 1954-1955, 724.
    • US 2 943 023 (Rhône-Poulenc; 28.6.1960; F-prior. 30.5.1956).
    • US 2 978 380 (Rhône-Poulenc; 4.4.1961; F-prior. 30.11.1955).
    • US 3 000 785 (Rhône-Poulenc; 19.9.1961; F-prior. 31.7.1953).
    • US 3 011 947 (Rhône-Poulenc; 5.12.1961; F-prior. 30.11.1955).
    • CN 107266512

      CN 107840864

DB06145.png

Spiramycin I)

///////////Spiramycin, スピラマイシン , japan 2018, Provamycin, Rovamycin, RP 5337, Sequamycin, IL 5902, NSC-64393, ATC:J01FA02, Use:macrolide antibiotic, EINECS:232-429-6

 

O=CCC4C(OC2OC(C(OC1OC(C)C(O)C(O)(C)C1)C(N(C)C)C2O)C)C(OC)C(O)CC(=O)OC(C)C\C=C\C=C\C(OC3OC(C)C(N(C)C)CC3)C(C)C4

FDA approves treatment Poteligeo (mogamulizumab-kpkc) for two rare types of non-Hodgkin lymphoma


 

FDA approves treatment for two rare types of non-Hodgkin lymphoma

The U.S. Food and Drug Administration today approved Poteligeo (mogamulizumab-kpkc) injection for intravenous use for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. This approval provides a new treatment option for patients with MF and is the first FDA approval of a drug specifically for SS.

August 8, 2018

Release

The U.S. Food and Drug Administration today approved Poteligeo (mogamulizumab-kpkc) injection for intravenous use for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. This approval provides a new treatment option for patients with MF and is the first FDA approval of a drug specifically for SS.

“Mycosis fungoides and Sézary syndrome are rare, hard-to-treat types of non-Hodgkin lymphoma and this approval fills an unmet medical need for these patients,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “We are committed to continuing to expedite the development and review of this type of targeted therapy that offers meaningful treatments for patients.”

Non-Hodgkin lymphoma is a cancer that starts in white blood cells called lymphocytes, which are part of the body’s immune system. MF and SS are types of non-Hodgkin lymphoma in which lymphocytes become cancerous and affect the skin. MF accounts for about half of all lymphomas arising from the skin. It causes itchy red rashes and skin lesions and can spread to other parts of the body. SS is a rare form of skin lymphoma that affects the blood and lymph nodes.

Poteligeo is a monoclonal antibody that binds to a protein (called CC chemokine receptor type 4 or CCR4) found on some cancer cells.

The approval was based on a clinical trial of 372 patients with relapsed MF or SS who received either Poteligeo or a type of chemotherapy called vorinostat. Progression-free survival (the amount of time a patient stays alive without the cancer growing) was longer for patients taking Poteligeo (median 7.6 months) compared to patients taking vorinostat (median 3.1 months).

The most common side effects of treatment with Poteligeo included rash, infusion-related reactions, fatigue, diarrhea, musculoskeletal pain and upper respiratory tract infection.

Serious warnings of treatment with Poteligeo include the risk of dermatologic toxicity, infusion reactions, infections, autoimmune problems (a condition where the immune cells in the body attack other cells or organs in the body), and complications of stem cell transplantation that uses donor stem cells (allogeneic) after treatment with the drug.

The FDA granted this application Priority Review and Breakthrough Therapydesignation. Poteligeo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted this approval to Kyowa Kirin, Inc.

///////////////// Poteligeo, mogamulizumab-kpkc, fda 2018, Kyowa Kirin, Priority Review, Breakthrough Therapy designation,  Orphan Drug designation
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