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Umeclidinium bromide, ウメクリジニウム臭化物

July 24, 2018 10:41 am / Leave a comment

ChemSpider 2D Image | Umeclidinium bromide | C29H34BrNO2 Umeclidinium bromide.png

Umeclidinium bromide

GSK-573719A, ウメクリジニウム臭化物

Molecular FormulaC₂₉H₃₄BrNO₂
Average mass508.490 Da

1-[2-(Benzyloxy)ethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide

1-Azoniabicyclo[2.2.2]octane, 4-(hydroxydiphenylmethyl)-1-[2-(phenylmethoxy)ethyl]-, bromide (1:1)

diphenyl-[1-(2-phenylmethoxyethyl)-1-azoniabicyclo[2.2.2]octan-4-yl]methanol;bromide

7AN603V4JV

869113-09-7 [RN]

9551

GSK573719A; UNII-7AN603V4JV

Umeclidinium bromide (trade name Incruse Ellipta) is a long-acting muscarinic antagonist approved for the maintenance treatment of chronic obstructive pulmonary disease (COPD).^[1] It is also approved for this indication in combination with vilanterol (as umeclidinium bromide/vilanterol).^[2]^[3]

In the 2014, the drug was also approved in the E.U. and in the U.S. for the maintenance treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). It was launched in the U.K. in October 2014 and in the U.S. in January 2015. In Japan, the product candidate was approved in 2015 as monotherapy for the maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD) and launched on October in the same year.

Image result for umeclidinium bromide synthesis

Umeclidinium bromide (Ellipta)
Umeclidinium bromide is a long-acting muscarinic acetylcholine antagonist developed by GlaxoSmithKline and approved by the US FDA at the end of 2013 for use in combination with vilanterol, a b2 agonist, for the treatment of chronic obstructive pulmonary disease.269 Due to umeclidinium’s poor oral bioavailability, the drug is administrated by inhalation as dry powder.269

The most likely scale preparation of the drug is described in Scheme .270
Commercially available ethyl isonipecotate (278) was alkylated with 1-bromo-2-chloroethane in the presence of K2CO3 in acetone to give ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (279). This material was then treated with lithium diisopropylamine (LDA) in THF to affect a transannular substitution reaction resulting in the cyclized quinuclidine 280 in 96% yield.270 Excess of phenyllithium was added to ester 280 in THF starting at low temperature then gradually warming to room temperature to give tertiary alcohol 281 in 61% yield. Amine 281 was finally alkylated with benzyl 2-bromoethyl ether (282) in MeCN/CHCl3 at elevated temperatures
to afford umeclidinium bromide (XXXV) in 69% yield.

269. Tal-Singer, R.; Cahn, A.; Mehta, R.; Preece, A.; Crater, G.; Kelleher, D.;Pouliquen, I. J. Eur. J. Pharmacol. 2013, 701, 40.
270. Laine, D. I.; McCleland, B.; Thomas, S.; Neipp, C.; Underwood, B.; Dufour, J.;Widdowson, K. L.; Palovich, M. R.; Blaney, F. E.; Foley, J. J.; Webb, E. F.;Luttmann, M. A.; Burman, M.; Belmonte, K.; Salmon, M. J. Med. Chem. 2009, 52, 2493.

FDA

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203975Orig1s000ChemR.pdf

1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-azoniabicyclo[2.2.2]octane bromide

PATENT

https://patents.google.com/patent/CN105461710A/en

umeclidinium bromide prepared patent US7439393, US RE44874, US 7488827, US 7498440, US7361787 and the like using phenyllithium prepared by reaction of intermediate 4 – [(diphenyl) hydroxymethyl] azabicyclo [2.2.2 ] octane.Specific methods: azabicyclo [2.2.2] octane-nucleophilic addition reaction with 4-carboxylate-fold amount of 2.02-2.5 phenyllithium occurs, the reaction temperature is controlled to -78 ° 0_15 ° C ο lithium Reagents expensive, difficult to store, use of harsh conditions, relatively high cost.

Example 1

Phenyl magnesium chloride: Under nitrogen atmosphere to 55g (2.3mol) of metallic magnesium sandpaper lit with 3 L of tetrahydrofuran was added dropwise 215g (1.91mol) chlorobenzene, micro-thermal reaction proceeds, controlled dropping, the reaction was kept boiling, dropwise for about 1.5 hours, after the dropping was heated slightly under reflux for 30min. Cool reserve.

[0008] Example 2

Phenyl magnesium bromide: The under argon 50.4g (2.lmol) sandpaper lit magnesium metal with 4.2 liters of anhydrous ethyl ether was added a solution of 300g (1.91mol) of bromobenzene, was added an iodine initiator, electrical hair fever reaction proceeds, controlled dropping, the reaction was kept boiling, about 1.5 hours dropwise was added dropwise to a gentle reflux heated 30min. Cool reserve.

[0009] Example 3

Preparation of crude product: azabicyclo [2.2.2] octane-4-carboxylate (135g, 0.736mo 1) was dissolved in 3L of tetrahydrofuran, under nitrogen, was cooled to -5~0 ° C, was added dropwise 300g preparation of benzyl bromide Grignard reagent. After incubation -5~0 ° C stirred for 1 hour (progress of the reaction was monitored by TLC sample). Adding 50ml of water quenching. Liquid separation, the aqueous phase was extracted twice with 500ml of tetrahydrofuran, and the combined organic phases were washed with water, dried and filtered. The solvent was partially removed under reduced pressure, the balance maintaining approximately 1L, the residue was stirred overnight at 20 ° C crystallization.Filtered, washed (petroleum ether 2 X 200 ml), the filter cake was dried at 40 ° C in vacuo to give a yellowish white crystals 121.2 g, yield 54.2%.

[0010] Example 4

Preparation of crude product: azabicyclo [2.2.2] octane-4-carboxylate (18.3g, 0.lOmo 1) was dissolved in 3L of tetrahydrofuran, under nitrogen, was cooled to 0~5 ° C, was added dropwise 0.25 mol phenyl magnesium chloride. After incubation 0~5 ° C stirred for 1 hour (progress of the reaction was monitored by TLC sample) o quenched with 10ml of water was added. Liquid separation, the aqueous phase was extracted twice with 100ml of tetrahydrofuran, and the combined organic phases were washed with water, dried and filtered. The solvent was partially removed under reduced pressure, the balance maintaining approximately 50mL, the residue was stirred overnight at 20 ° C crystallization.Filtered, washed (petroleum ether 2X20 ml), the filter cake was dried at 40 ° C in vacuo to give a yellowish white crystals 14.63 g, yield 48.1%.

[0011] Example 5

Preparation of crude product: azabicyclo [2.2.2] octane-4-carboxylate (18.38,0.1011101) ^ 31 was dissolved in tetrahydrofuran, under nitrogen, was cooled to 5~15 ° C, was added dropwise 0.30 mol of benzene bromide. After incubation 5~15 ° C stirred for 1 hour (progress of the reaction was monitored by TLC sample) o quenched with 10ml of water was added. Liquid separation, the aqueous phase was extracted twice with 100ml of tetrahydrofuran, and the combined organic phases were washed with water, dried and filtered. The solvent was partially removed under reduced pressure, the balance maintaining approximately 50mL, the residue was stirred overnight at 20 ° C crystallization.Filtered, washed (petroleum ether 2 X 20 ml), the filter cake was dried at 40 ° C in vacuo to yield 13.80 g of yellow-white crystals, yield 47.1%.

[0012] Example 6

Umeclidinium bromide purification: 100g crude product was dissolved in 320ml of water to 80 ° C a mixture of 640ml of acetone, add 5g active carbon, and filtered.The filtrate was cooled to 25 ° C, for 1 hour. Within 1 to 2 hours and cooled to 0~5 ° C for 3 hours. The filter cake with chilled 1: 2 acetone – washed twice with water (2x20ml). The filter cake was dried in vacuo at 60 ° C to give white crystalline solid (92 g, yield 92%). Purity (HPLC normalization method) 99.25%.

[0013] Example 7

Umeclidinium bromide purification: 100g crude product was dissolved in 180ml water at 50 ° C a mixture of 360ml of acetone, add 5g active carbon, and filtered.The filtrate was ~ 2 hours to 25 ° C, for 1 hour. Within 1 to 2 hours cooled to 0 ° C and left overnight protection. The filter cake with chilled 1: 2 acetone – washed twice with water (2x20ml). The filter cake was dried at 60 ° C in vacuo to give fine (98.3 g, yield 98.3%). Purity (HPLC normalization method) 97.75%.

PATENT

https://patents.google.com/patent/WO2014027045A1

International Patent Publication Number WO 2005/104745 (Glaxo Group Limited), filed 27^th April 2005, discloses muscarinic acetylcholine receptor antagonists. In particular, WO 2005/104745 discloses 4- [hydroxy(diphenyl)methyl]-l-{2-[(phenylmethyl)oxy]ethyl}-l-azoniabicyclo[2.2.2]octane bromide, of formula (I), and a process for the preparation of this compound (Example 84):

4-[Hydroxy(diphenyl)methyl]-l-{2-[(phenylmethyl)oxy]ethyl}-l-azoniabicyclo[2.2.2]octane bromide may also be referred to as umeclidinium bromide.

International Patent Publication Number WO 2011/029896 (Glaxo Group Limited), filed 10^th September 2010, discloses an alternative preparation for an early intermediate, ethyl-l-azabicyclo[2.2.2] octane-4-carboxylate, in the multi-step synthesis of umeclidinium bromide.

There exists a need for an alternative process for the preparation of umeclidinium bromide. In particular, a process that offers advantages over those previously disclosed in WO 2005/104745 and WO 2011/029896 is desired. Advantages may include, but are not limited to, improvements in safety, control (i.e of final product form and physical characteristics), yield, operability, handling, scalability, and efficiency.

Summary of the Invention

The present invention provides, in a first aspect, a process for the preparation of umeclidinium bromide, which comprises: a) reacting ((2-bromoethoxy)methyl)benzene, of formula (II)

in a dipolar aprotic solvent with a boiling point greater than about 90°C or an alcohol with a boiling point greater than about 80°C; and optionally

b) re-crystallising the product of step (a).

The present invention is further directed to intermediates used in the preparation of the compound of formula (III), and hence of umeclidinium bromide. The process disclosed herein provides a number of advantages over prior art processes of WO 2005/104745 and WO 2011/029896.

PATENT

EP 3248970

FORM A B AND AMORPHOUS

https://patents.google.com/patent/EP3248970A1/en

The invention relates to novel solid forms of umeclidinium bromide (I), chemically 1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-azabicyclo[2.2.2]octane bromide. In particular, to its novel crystalline forms, identified as form A and form B, as well as to an amorphous form, and to their characterization by means of analytic methods. The invention further relates to methods of their preparation and their use for the preparation of umeclidinium bromide in the API quality.

Umeclidinium bromide is indicated as an inhalation anticholinergic drug with an ultra-long-term effect in cooperating patients with the diagnosis of COPD (chronic obstructive pulmonary disease). COPD is defined as a preventable and treatable disease that is characterized by a persistent obstruction of air flow in the bronchi (bronchial obstruction), which usually progresses and is related to an intensified inflammatory response of the airways to harmful particles or gases. The main goal of the treatment of COPD is an improvement of the current control, i.e. elimination of symptoms, improvement of toleration of physical effort, improvement of the health condition and reduction of future risks, i.e. prevention and treatment of exacerbations, prevention of progression of the disease and mortality reduction

The structure of umeclidinium bromide, 1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-azabicyklo[2.2.2]octane bromide, is first mentioned in the general patent application WO2005009362 of 2003 .

Preparation of umeclidinium bromide is first disclosed in the patent EP 1 740 177B ( WO2005104745 ), where two methods (A and B) are mentioned, differing in the final processing and the product yield (method B included in Scheme 1). There, the last steps of the synthesis are described, the product being described by means of EI-MS, ¹H NMR and elementary analysis. There is no information concerning the chemical purity or polymorphic form.

Another preparation method of umeclidinium bromide is disclosed in the patent application WO 2014027045 , where three forms are also described (identified as forms 1 to 3), prepared using a method that is different from the procedure disclosed in the patent EP 1 740 177B .

Preparation of the amorphous form of umeclidinium bromide

1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-azabicyclo[2.2.2]octane bromide (100 mg, 0.197 mmol, purity UPLC 98.89%) is dissolved at the temperature of 25°C in a water: tert-butanol mixture in the volume ratio of 6:4 (total 70 ml). The clear solution is freeze-dried (a bath with a mixture of dry ice and ethanol, -70°C) and lyophilized (vacuum: 1.8 Pa for 72 h). An amorphous form of umeclidinium bromide was obtained (100 mg). This amorphous form was confirmed with DSC and X-ray powder diffraction. The X-ray powder diffraction pattern is shown in Fig. 8 and the DSC record in Fig. 9.

PAPER

Synthetic Communications An International Journal for Rapid Communication of Synthetic Organic Chemistry , Volume 48, 2018 – Issue 9, Convenient new synthesis of umeclidinium bromide

Umeclidinium bromide, a drug used for chronic obstructive pulmonary disease, is synthesized through a new intermediate of phenyl(quinuclidin-4-yl)methanone. This novel method with simple operation flow and cheap reagents, makes it suitable for scale up. The overall four-step process provides umeclidinium bromide in 29% yield and the purity up to 99.83%. The X-ray crystal structure of the drug molecule was first reported.

External links

Incruse Ellipta (umeclidinium inhalation powder) Official Site

References

^ Jump up to:^a ^b “Incruse Ellipta (umeclidinium inhalation powder) for Oral Inhalation Use. Full Prescribing Information” (PDF). GlaxoSmithKline, Research Triangle Park, NC 27709. Retrieved 22 February 2016.
Jump up^ Feldman, GJ; Edin, A (2013). “The combination of umeclidinium bromide and vilanterol in the management of chronic obstructive pulmonary disease: Current evidence and future prospects”. Therapeutic advances in respiratory disease. 7 (6): 311–9. doi:10.1177/1753465813499789. PMID 24004659.
Jump up^ “FDA Approves Umeclidinium and Vilanterol Combo for COPD”. Medscape. December 18, 2013.

Umeclidinium bromide
Clinical data

Trade names	Incruse Ellipta
Synonyms	GSK573719A
License data	EU EMA: by INN
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	Inhalation (DPI)
ATC code	R03BB07 (WHO) R03AL03 (WHO) (+vilanterol)
Legal status
Legal status	US: ℞-only In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding	~89%^[1]
Metabolism	Hepatic (CYP2D6)
Elimination half-life	11 hours
Excretion	Feces (58%) and urine(22%)
Identifiers
IUPAC name [show]
CAS Number	869113-09-7
PubChem CID	11519069
ChemSpider	9693857
KEGG	D10181
ChEBI	CHEBI:79040
ECHA InfoCard	100.166.375
Chemical and physical data
Formula	C₂₉H₃₄BrNO₂
Molar mass	508.49 g/mol
3D model (JSmol)	Interactive image

//////////////Umeclidinium bromide, Incruse Ellipta, ウメクリジニウム臭化物 , GSK573719A, UNII-7AN603V4JV, FDA 2014

C1C[N+]2(CCC1(CC2)C(C3=CC=CC=C3)(C4=CC=CC=C4)O)CCOCC5=CC=CC=C5.[Br-]

Synthesis

FDA Orange Book Patents: 1 of 15 (FDA Orange Book Patent ID)
Patent	9750726
Expiration	Nov 29, 2030
Applicant	GLAXOSMITHKLINE
Drug Application	N203975 (Prescription Drug: ANORO ELLIPTA. Ingredients: UMECLIDINIUM BROMIDE VILANTEROL TRIFENATATE)

from FDA Orange Book

FDA Orange Book Patents: 2 of 15 (FDA Orange Book Patent ID)
Patent	6759398
Expiration	Aug 3, 2021
Applicant	GLAXOSMITHKLINE
Drug Application	N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE UMECLIDINIUM BROMIDE VILANTEROL TRIFENATATE)

from FDA Orange Book

FDA Orange Book Patents: 3 of 15 (FDA Orange Book Patent ID)
Patent	7439393
Expiration	May 21, 2025
Applicant	GLAXOSMITHKLINE
Drug Application	N203975 (Prescription Drug: ANORO ELLIPTA. Ingredients: UMECLIDINIUM BROMIDE VILANTEROL TRIFENATATE)

from FDA Orange Book

FDA Orange Book Patents: 4 of 15 (FDA Orange Book Patent ID)
Patent	7629335
Expiration	Aug 3, 2021
Applicant	GLAXOSMITHKLINE
Drug Application	N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE UMECLIDINIUM BROMIDE VILANTEROL TRIFENATATE)

from FDA Orange Book

FDA Orange Book Patents: 5 of 15 (FDA Orange Book Patent ID)
Patent	7776895
Expiration	Sep 11, 2022
Applicant	GLAXOSMITHKLINE
Drug Application	N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE UMECLIDINIUM BROMIDE VILANTEROL TRIFENATATE)

from FDA Orange Book

FDA Orange Book Patents: 6 of 15 (FDA Orange Book Patent ID)
Patent	8161968
Expiration	Feb 5, 2028
Applicant	GLAXOSMITHKLINE
Drug Application	N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE UMECLIDINIUM BROMIDE VILANTEROL TRIFENATATE)

from FDA Orange Book

FDA Orange Book Patents: 7 of 15 (FDA Orange Book Patent ID)
Patent	8201556
Expiration	Feb 5, 2029
Applicant	GLAXO GRP ENGLAND
Drug Application	N205382 (Prescription Drug: INCRUSE ELLIPTA . Ingredients: UMECLIDINIUM BROMIDE)

from FDA Orange Book

FDA Orange Book Patents: 8 of 15 (FDA Orange Book Patent ID)
Patent	6537983
Expiration	Aug 3, 2021
Applicant	GLAXOSMITHKLINE
Drug Application	N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE UMECLIDINIUM BROMIDE VILANTEROL TRIFENATATE)

from FDA Orange Book

FDA Orange Book Patents: 9 of 15 (FDA Orange Book Patent ID)
Patent	7498440
Expiration	Apr 27, 2025
Applicant	GLAXOSMITHKLINE
Drug Application	N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE UMECLIDINIUM BROMIDE VILANTEROL TRIFENATATE)

from FDA Orange Book

FDA Orange Book Patents: 10 of 15 (FDA Orange Book Patent ID)
Patent	7488827
Expiration	Dec 18, 2027
Applicant	GLAXOSMITHKLINE
Drug Application	N203975 (Prescription Drug: ANORO ELLIPTA. Ingredients: UMECLIDINIUM BROMIDE VILANTEROL TRIFENATATE)

from FDA Orange Book

FDA Orange Book Patents: 11 of 15 (FDA Orange Book Patent ID)
Patent	8183257
Expiration	Jul 27, 2025
Applicant	GLAXOSMITHKLINE
Drug Application	N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE UMECLIDINIUM BROMIDE VILANTEROL TRIFENATATE)

from FDA Orange Book

FDA Orange Book Patents: 12 of 15 (FDA Orange Book Patent ID)
Patent	6878698
Expiration	Aug 3, 2021
Applicant	GLAXOSMITHKLINE
Drug Application	N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE UMECLIDINIUM BROMIDE VILANTEROL TRIFENATATE)

from FDA Orange Book

FDA Orange Book Patents: 13 of 15 (FDA Orange Book Patent ID)
Patent	8511304
Expiration	Jun 14, 2027
Applicant	GLAXOSMITHKLINE
Drug Application	N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE UMECLIDINIUM BROMIDE VILANTEROL TRIFENATATE)

from FDA Orange Book

FDA Orange Book Patents: 14 of 15 (FDA Orange Book Patent ID)
Patent	RE44874
Expiration	Mar 23, 2023
Applicant	GLAXOSMITHKLINE
Drug Application	N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE UMECLIDINIUM BROMIDE VILANTEROL TRIFENATATE)

from FDA Orange Book

FDA Orange Book Patents: 15 of 15 (FDA Orange Book Patent ID)
Patent	8309572
Expiration	Apr 27, 2025
Applicant	GLAXOSMITHKLINE
Drug Application	N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE UMECLIDINIUM BROMIDE VILANTEROL TRIFENATATE)

from FDA Orange Book

WO2005009362A22003-07-172005-02-03Glaxo Group LimitedMuscarinic acetylcholine receptor antagonists

WO2005104745A22004-04-272005-11-10Glaxo Group LimitedMuscarinic acetylcholine receptor antagonists

WO2014027045A12012-08-152014-02-20Glaxo Group LimitedChemical process

Vilanterol trifenatate, ビランテロールトリフェニル酢酸塩

July 23, 2018 8:32 am / Leave a comment

Vilanterol trifenatate.png

Image result for Vilanterol Trifenatate

Vilanterol trifenatate, ビランテロールトリフェニル酢酸塩

ビランテロールトリフェナテート

UNII-40AHO2C6DG; GW642444M; CAS 503070-58-4

free form, 503068-34-6

HY-14300A, CS-1679

444
642444
GSK-642444
GW-642444
GW-642444M

4-[(1R)-2-[6-[2-[(2,6-dichlorophenyl)methoxy]ethoxy]hexylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol;2,2,2-triphenylacetic acid

1,3-Benzenedimethanol, α¹-[[[6-[2-[(2,6-dichlorophenyl)methoxy]ethoxy]hexyl]amino]methyl]-4-hydroxy-, (α¹R)-

4-{(1R)-2-[(6-{2-[(2,6-Dichlorbenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol

Molecular Formula:	C₄₄H₄₉Cl₂NO₇
Molecular Weight:	774.776 g/mol

4-[(1R)-2-({6-[(2-{[(2,6-Dichlorophenyl)methyl]oxy}ethyl)oxy]hexyl}-amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol Acetate Salt

J. Med. Chem., 2010, 53 (11), pp 4522–4530

DOI: 10.1021/jm100326d

white crystalline solid: mp (DSC) 131.9−134.2 °C, [α]_D ²⁰ −14.6 (c 1.034 in MeOH). MS ES +ve m/z 289, 486/488 (M + H)⁺. ¹H NMR δ (500 MHz, CD₃OD) 7.47 (2H, m), 7.38 (8H, m), 7.28 (6H, tt, J 7.1, 1.8 Hz), 7.22 (4H, m), 6.86 (1H, d, J 7.9 Hz), 4.94 (1H, dd, J 9.7, 4.6 Hz), 4.91 (2H, s), 4.74 (2H, s), 3.79 (2H, m), 3.69 (2H, m), 3.56 (2H, t, J 6.1 Hz), 3.10 (2H, m), 2.99 (2H, m), 1.72 (2H, m), 1.65 (2H, m), 1.45 (4H, m). ¹³C NMR δ (125 MHz, CD₃OD) 180.1, 156.2, 147.7, 140.3, 137.9, 134.5, 133.0, 131.9, 131.6, 129.6, 128.9, 128.1, 127.1, 127.0, 126.7, 116.0, 72.1, 71.4, 71.3, 71.1, 70.1, 68.4, 60.9, 55.4, 48.9, 30.5, 27.4, 27.1, 26.8. Anal. found: C, H, N, Cl.

Vilanterol is a selective long-acting beta2-adrenergic agonist (LABA) with inherent 24-hour activity for once daily treatment of COPD and asthma. Its pharmacological effect is attributable to stimulation of intracellular adenylyl cyclase which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cAMP). Increases in cyclic AMP are associated with relaxation of bronchial smooth muscle and inhibition of release of hypersensitivity mediators from mast cells in the lungs.

Vilanterol is approved for use in several combination products such as with fluticasone furoate under the tradename Breo Ellipta and in combination with umeclidinium bromide as Anoro Ellipta. Approved by the FDA in 2013, use of Breo Ellipta is indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. It is also indicated for once-daily maintenance treatment of asthma in patients aged 18 or older with reversible obstructive airways disease.

Vilanterol (INN, USAN) is an ultra-long-acting β₂ adrenoreceptor agonist (ultra-LABA), which was approved in May 2013 in combination with fluticasone furoate for sale as Breo Ellipta by GlaxoSmithKline for the treatment of chronic obstructive pulmonary disease (COPD).^[1]

Vilanterol is available in following combinations:

with inhaled corticosteroid fluticasone furoate — fluticasone furoate/vilanterol (trade names Breo Ellipta (U.S.), Relvar Ellipta (EU,RU, JPN))
with muscarinic antagonist umeclidinium bromide — umeclidinium bromide/vilanterol (trade name Anoro Ellipta)

The other active component of BREO ELLIPTA is vilanterol trifenatate, a LABA with the chemical name triphenylacetic acid-4-{(1R)-2-[(6-{2-[2,6-dicholorobenzyl)oxy]ethoxy} hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol (1:1) and the following chemical structure:

Vilanterol trifenatate - Structural Formula Illustration

Vilanterol trifenatate is a white powder with a molecular weight of 774.8, and the empirical formula is C₂₄H₃₃Cl₂NO5•C₂₀H₁₆O₂. It is practically insoluble in water.

Image result for Vilanterol Trifenatate

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203975Orig1s000ChemR.pdf

PATENT

WO 2003024439

https://patents.google.com/patent/WO2003024439A1/ru

PAPER

Journal of Medicinal Chemistry (2010), 53(11), 4522-4530

A series of saligenin β₂ adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for β₂, β₁, and β₃ agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the β₂-receptor is presented.

Synthesis and Structure−Activity Relationships of Long-acting β₂Adrenergic Receptor Agonists Incorporating Metabolic Inactivation: An Antedrug Approach

Panayiotis A. Procopiou *†, Victoria J. Barrett‡, Nicola J. Bevan‡, Keith Biggadike†, Philip C. Box†, Peter R. Butchers‡, Diane M. Coe†, Richard Conroy†, Amanda Emmons‡, Alison J. Ford‡, Duncan S. Holmes†, Helen Horsley†, Fern Kerr†, Anne-Marie Li-Kwai-Cheung†, Brian E. Looker†, Inderjit S. Mann⊥, Iain M. McLay§, Valerie S. Morrison‡, Peter J. Mutch∥, Claire E. Smith∥ and Paula Tomlin†

^† Departments of Medicinal Chemistry

^‡ Respiratory Biology

^§ Computational Structural Chemistry

^∥ Drug Metabolism and Pharmacokinetics

Respiratory CEDD, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom

^⊥ Synthetic Chemistry, GlaxoSmithKline, Old Powder Mills, Near Leigh, Tonbridge, Kent TN11 9AN, United Kingdom

J. Med. Chem., 2010, 53 (11), pp 4522–4530

DOI: 10.1021/jm100326d

*To whom correspondence should be addressed. Phone: (+44)1438 762883. Fax: (+44)1438 768302. E-mail: pan.a.procopiou@gsk.com

https://pubs.acs.org/doi/full/10.1021/jm100326d

4-[(1R)-2-({6-[(2-{[(2,6-Dichlorophenyl)methyl]oxy}ethyl)oxy]hexyl}-amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol (13f) Triphenylacetate Salt

Triphenylacetic acid (1.81 g, 6.28 mmol) was added to a solution of 4-((R)-2-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexylamino}-1-hydroxyethyl)-2-hydroxymethyl-phenol (95% pure; 3.28 g, 6.41 mmol) in EtOH (20 mL), and the mixture heated to 80 °C to obtain a solution. The mixture was allowed to cool to ambient temperature, and the resulting product filtered, washed with a little ethanol, then dried in vacuo at 50 °C to afford 13f-triphenylacetate salt (4.3 g, 88%) as a white crystalline solid: mp (DSC) 131.9−134.2 °C, [α]_D²⁰ −14.6 (c 1.034 in MeOH). MS ES +ve m/z 289, 486/488 (M + H)⁺. ¹H NMR δ (500 MHz, CD₃OD) 7.47 (2H, m), 7.38 (8H, m), 7.28 (6H, tt, J 7.1, 1.8 Hz), 7.22 (4H, m), 6.86 (1H, d, J 7.9 Hz), 4.94 (1H, dd, J 9.7, 4.6 Hz), 4.91 (2H, s), 4.74 (2H, s), 3.79 (2H, m), 3.69 (2H, m), 3.56 (2H, t, J 6.1 Hz), 3.10 (2H, m), 2.99 (2H, m), 1.72 (2H, m), 1.65 (2H, m), 1.45 (4H, m). ¹³C NMR δ (125 MHz, CD₃OD) 180.1, 156.2, 147.7, 140.3, 137.9, 134.5, 133.0, 131.9, 131.6, 129.6, 128.9, 128.1, 127.1, 127.0, 126.7, 116.0, 72.1, 71.4, 71.3, 71.1, 70.1, 68.4, 60.9, 55.4, 48.9, 30.5, 27.4, 27.1, 26.8. Anal. found: C, H, N, Cl.

Patent

CN 103923058

https://patents.google.com/patent/CN103923058A/en

β 2- adrenergic receptor agonist is most widely used in clinical treatment of asthma and chronic obstructive pulmonary disease drugs. Currently available on the market β2_ adrenoceptor agonists longest duration of action of 12 hours, which resulted in the need twice daily dosing. Over the last decade, the development of high potency, high selectivity, rapid onset, long duration of action, is administered once daily β2- adrenoreceptor agonists caused great concern in the pharmaceutical industry. Triflate vilanterol by Glaxo Group Limited to develop a new type of ultra-long-acting β 2- adrenergic receptor agonist, on 18 December 2013 by the US FDA clearance to market its drugs name Anoro Ellipta0

vilanterol chemical name is 4 – {(lR) -2 – [(6- {2 _ [(2,6- dichlorobenzyl) oxy] ethoxy} hexyl) amino] -1 – hydroxyethyl} -2_ (hydroxymethyl) phenol, having the formula as follows:

At present the synthesis of chiral vilanterol reported mainly in the following two ways:

1, and references J.Med.Chem.2010,53,4522-4530 Patent W02003024439, synthetic routes such as

under:

1.2, and references J.Med.Chem.2010,53,4522-4530 Patent W02003024439, synthetic routes such as

under:

Two or more routes are carried over a key intermediate in the alkylation of the amine compound X and then deprotecting to give the target compound I. Use of highly toxic chiral oxazaborolidine key intermediate in the process for preparing a compound X as a catalyst is expensive, and serious environmental pollution can not be recycled, high production costs; while boron reducing agent used in the process alkoxy – tetrahydrofuran solution of dimethyl sulfide have high reactivity shortcomings need to use special equipment. Further, throughout the synthesis process used in amounts of sodium hydride, sodium hydride in the reaction process will emit a lot of heat, and the use of sodium hydride and stored under harsh conditions, there are security risks in industrial production, is not suitable for industrial production.

Laurus Labs Limited was improved synthesis process described above, Patent W02014041565, which scheme is as follows:

While this synthesis will replace potassium t-butoxide, sodium hydride, to reduce the security risks in industrial production, but the process for preparing a key intermediate compound using X is still toxic as chiral oxazaborolidine catalyst, and environmental pollution high production cost issues remain unresolved.

An epoxy compound IV (preparation described in Bioorganic & Medicinal Chemistry Letters, 23 (5), 2013,1548-1552 and Patent CN101684074A) amine VI with a chiral auxiliary to give the chiral compound V.

Wherein the amine is a chiral auxiliary or S- S- phenylethylamine naphthylethyl amine, amine chiral auxiliary used has S- (a) – methylbenzylamine, (S) -2_ A -1-phenylethylamine, S – (-) _ N- benzyl-1-phenylethylamine, S – (-) – l_ (l- naphthyl) ethylamine

Example a

(R) -1- (2,2- dimethyl–4H- benzo [d] [I, 3] dioxin-6-yl) _2_ (⑶-1- phenyl-ethylamino) ethanol, and the step of preparing a salt of I): 2, 2- dimethyl-6- ethylene prepared -4H- benzo [d] [I, 3] dioxane (compound of formula IV) burning

Was added to a three neck round bottom flask, 12.8 g of 2-bromo-1- (2,2-dimethyl -4H-1,3- benzodioxin-6-yl) (Compound of formula II) ethanone and 100 ml of methanol, stirred and dissolved it was cooled to -10 ° C, followed by the slow addition of 2.4 g of sodium borohydride addition was completed, the reaction at room temperature for 90 minutes. Was added to the reaction mixture quenched with 50 ml aqueous ammonium chloride solution, stirred and concentrated to remove most of the methanol for 10 minutes, then extracted with 50 ml of methylene chloride, the aqueous phase was repeatedly extracted three times with 50 ml dichloromethane and the combined organic phases . The organic phase was washed with 20 ml of distilled water and once with 20 ml of saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. Then a mixture of tetrahydrofuran and methanol in this step the resulting compound (about 12 g) was dissolved in a total volume of 200 ml (volume ratio of tetrahydrofuran to methanol is 1: 1), 20.8 g of potassium carbonate was added, and the reaction at room temperature for 18 hour. The reaction was concentrated to remove most of the organic solvent, 100 ml of distilled water was added to the concentrate, and then 60 ml of methylene chloride was separated out and the aqueous phase repeatedly extracted three times with 30 ml of methylene chloride, the organic phase was washed with 20 ml of distilled water once with 20 ml saturated brine once, dried over anhydrous sodium sulfate, and concentrated to give a white solid. Compound IV obtained in this step without further purification was used directly in the next reaction.

. [0012] Step 2): (R) -1- (2, 2 ~ _ methyl -4H- benzo [d] [I, 3] dioxo TK 6-yl) -2 – ((S preparation) -1-phenyl-ethylamino) ethanol

The 8.24 g of the epoxy compound IV dissolved in 30 ml dimethyl sulfoxide at room temperature was slowly added 5.8 g S- (a) – methylbenzylamine, and then controlling the reaction temperature at 60 ° C 3 hours, by TLC monitoring the reaction is complete. Wait until the reaction mixture was cooled, added to 90 ml saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (3 x 50 mL), the organic phase was dried over anhydrous sodium sulfate, then filtered and concentrated to give (R) -1- (2, 2-methyl–4H- benzo [d] [1,3] dioxin-6-yl) -2 – ((S) -1- phenylethyl) ethanol The crude product was 10.3 g, yield rate of 73%. The crude product obtained in this step without further purification was used directly in the next salt-forming reaction. [0013] 1H-NMR (500 MHz, CDCl3) δ 1.27 (d, J = 12.2 Hz, 3H), 1.49 (s, 6H), 2.94 (dd, J = 24.8 and 11.4 Hz, 1H), 3.21 (dd, J = 24.8 and 11.4 Hz, 1H), 4.32-4.39 (m, 1H), 4.59 (s, 2H), 4.84 – 4.89 (m, 1H), 6.82 (d, J = 15.0 Hz, 1H), 7.06 (d , J = 3.1 Hz, 1H), 7.25 – 7.35 (m, 6H).

[0014] LC-MS: m / z = 328.1 (C20H25NO3 + H +).

[0015] Chiral HPLC: R- configuration: 96.4%, S- configuration: 3.6%.

[0016] Step 3) (! R) -1- (2,2- dimethyl-benzo -41- [(1] [1,3] dioxin-6-yl) -2 – (( preparation of different salts of 1-phenyl-ethylamino) ethanol 5)

Step 2) The obtained crude product was equally divided into four parts, each of 20 ml of methanol are added to the solvent, stirring at 40 ° C under conditions to dissolve and camphorsulfonic acid were added to a solution of four parts, methanesulfonic acid , oxalic acid and benzoic acid is added in an amount of 1.5 equivalent of the crude product, after the addition was complete, stirring was continued for 2 hours, allowed to stand overnight and cooled at 0 ° C, filtered, to give the corresponding salt. The results shown in the following table.

[0017] Second Embodiment

(R) -1- (2,2- dimethyl–4H- benzo [d] [I, 3] dioxane _6_ yl) _2_ (⑶-2- methoxy-1-phenyl ethanol and salts thereof ethylamino)

Step I): (R) -1- (2, 2- dimethyl -4H- benzo [d] [I, 3] dioxin-6-yl) ~ 2 ~ (⑶-2- methoxy preparation of 1-phenyl-ethylamino) ethanol

The method of preparation of a Compound IV The procedure of Example I) the same embodiment.

[0018] The epoxy compound IV was added 8.24 g to 50 ml of acetonitrile solvent, stirring and dissolved slowly added

9.06 g S-2- methoxy-1-phenylethylamine, followed by stirring at 80 ° C for 6 hours. After completion of the reaction was monitored by TLC, the reaction mixture was concentrated. 30 ml of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (3×30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give (R) -1- (2, 2- dimethyl -4H- benzo [d] [1,3] dioxin-6-yl) -2 – ((S) -2_ gas-methoxy-1-phenylethyl-yl) ethanol 9.8 g crude was wide, wide rate of 68%. The crude product obtained in this step without further purification was used directly in the next salt-forming reaction.

[0019] 1H-NMR (500 MHz, CDCl3) δ 1.49 (s, 6H), 2.98 – 3.21 (m, 2H), 3.34 (s, 3H), 3.55 – 3.80 (m, 2H), 4.02 (dd, J = 12.4 and 2.3 Hz, 1H), 4.59 (s, 2H), 4.86 – 4.88 (m, 1H), 6.82 (d, J = 7.5 Hz, 1H), 7.06 (d, J = 1.4 Hz, 1H), 7.28 –

7.37 (m, 6H).

[0020] LC-MS: m / z = 358.0 (C21H27NO4 + H +).

[0021] Chiral HPLC: R- configuration: 97.1%, S- configuration: 2.9%.

[0022] Step 2) 😦 R) -l_ (2,2- dimethyl–4H- benzo [d] [l, 3] dioxin-6-yl) -2 – ((S) _2 preparation of different salts methoxy-1-phenyl-ethylamino) ethanol –

The procedure of Example I) thus-obtained crude product is equally divided into four parts, each mixed solvent was added 25 ml of ethanol and water (Vis: V # 1: 1) and stirred at 60 ° C under conditions so dissolved, then four solutions are each selected fumaric acid, malic acid, maleic acid and tartaric acid, acid is added in an amount 1.2 equivalents of crude product, after the addition was complete, stirring continued for 2 hours, allowed to stand between 5 ° C cooled overnight and filtered to give the corresponding salt. The results shown in the following table.

[0023] Example three

(R) -2- (benzyl ((S) -1-phenylethyl) amino) -1- (2, 2 – dimethyl – -4H- benzo [d] [I, 3] dioxane ethanol and salts of 6-yl)

Step I): (R) _2_ (benzyl ((S) -1-phenylethyl) atmosphere yl) -1- (2, 2 – dimethyl – -4H- benzo [d] [I, 3] preparation dioxin-6-yl) ethanol

The method of preparation of a Compound IV The procedure of Example I) the same embodiment.

[0024] 8.24 g of the epoxy compound IV were added to 50 ml of tetrahydrofuran solvent, and stirred to dissolve slowly added

10.97 g (i) S-benzyl-1-N- phenethylamine, the reaction was refluxed for 4 hours, the reaction was complete by TLC monitoring. Wait until the reaction solution was cooled, 30 ml of saturated aqueous ammonium chloride was added, stirred at room temperature for 10 minutes, then add 3 g of sodium chloride, stirring was continued for 30 minutes standing layer, the aqueous phase was extracted with ethyl acetate (3×30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give (R) -2_ (benzyl ((S) -1-phenylethyl) amino) -1- (2, 2 – dimethyl -4H- benzo [d] [1,3] dioxin-6-yl) ethanol The crude product was 9.3 g, 56% yield. The crude product obtained in this step without further purification was used directly in the next salt-forming reaction.

[0025] 1H-NMR (500 MHz, CDCl3) δ 1.27 (d, J = 12.4 Hz, 3H), 1.49 (s, 6H), 2.78 – 3.21 (m, 2H), 3.46 (s, 1H), 4.00 – 4.08 (m, 2H), 4.59 (s, 2H), 4.85 – 4.88 (m, 1H), 6.81 (d, J = 14.9 Hz, 1H), 7.05 – 7.37 (m, 12H).

[0026] LC-MS: m / z = 418.1 (C27H31NO3 + H +).

[0027] Chiral HPLC: R- configuration: 95.8%, S- configuration: 4.2%.

[0028] Step 2): (R) _2- (benzyl ((S) -1-phenylethyl) gas-yl) -1- (2, 2 – dimethyl – -4H- benzo [d] [ preparation I 3] dioxin-6-yl) ethanol of different salts

A mixed solvent of water -.V The procedure of Example I embodiment) of the obtained crude product was equally divided into four parts, each of which shall propanol and 30 ml of water is 3: 2) at 80 ° C for dissolution while stirring, and then was added to four parts, respectively, fumaric acid, citric acid, maleic acid and tartaric acid, the acid is added in an amount 1.2 equivalents of crude product, after the addition was complete, stirring continued for 2 hours, allowed to stand at 5 ° C for cooling overnight and filtered, to give the corresponding salt. The results shown in the following table.

[0029] Fourth Embodiment

(R) -1- (2,2- dimethyl–4Η- benzo [d] [I, 3] dioxane _6_-yl) -2- (S) -1- (naphthyl _1_ yl) ethanol and salts thereof ethylamino)

Step I): (R) -1- (2,2_ dimethyl -4H- benzo [d] [1,3] dioxin-6-yl) -2_

Preparation (S) _1_ (naphthalen-1-yl) ethylamino) ethanol Preparation of Compound IV in a procedure as in Example I) the same embodiment.

[0030] The 8.24 g of the epoxy compound IV were added to 40 ml _2_ N- methyl pyrrolidone was slowly added with stirring so that after dissolution 9.58 g S – (-) – 1- (1- naphthyl) ethylamine, temperature was controlled at 100 ° C for 6 hours, the reaction was complete by TLC monitoring. After the reaction was cooled, 60 ml of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (3X 50 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 00-1- (2,2-bis methyl-4! l-benzo [d] [l, 3] dioxin-6-yl) -2- (S) -1- (naphthalen-1-yl) ethylamino) ethanol The crude product 9.5 g, yield 63%. The crude product obtained in this step without further purification was used directly in the next salt-forming reaction.

[0031] 1H NMR (500 MHz, CDCl3) δ 1.40 (d, J = 11.9 Hz, 3H), 1.49 (s, 6H), 2.95 (dd, J = 24.7 and 11.0 Hz, 1H), 3.21 (dd, J = 24.9 and 11.0 Hz, 1H), 4.59 (s, 2H), 4.89 – 4.95 (m, 2H), 6.80 – 8.01 (m, I OH).

[0032] LC-MS: m / z = 378.2 (C24H27NO3 + H +).

[0033] Chiral HPLC: R- configuration: 97.8%, S- configuration: 2.3%.

[0034] Step 2): (R) -l_ (2,2- dimethyl–4H- benzo [d] [1,3] dioxin-6-yl) -2- (S) -1 preparation of (naphthalene-1-yl) ethylamino) ethanol salt of different –

The procedure of Example I embodiment) of the obtained crude product was equally divided into four parts, each of which shall solvent was added 25 ml of butanol was stirred at 80 ° C for the condition to be dissolved and then the mixture was four respective selection naphthalenesulfonic acid, camphorsulfonic acid, methanesulfonic acid and benzoic acid treatment, acid is added in an amount 1.5 equivalents crude product, after completion, stirring was continued for 2 hours, allowed to stand overnight and cooled at 0 ° C, filtered, to give the corresponding salt. The results shown in the following table.

[0035] Embodiment V

(S) – (2- (tert-butoxy quasi-yl) ((R) -2- (2, 2- dimethyl-benzo [d] [I, 3] dioxin-6-yl) – 2 preparation amino) phenylacetate -2_ their salts light ~ ethyl)

The I step) (2S) – Preparation of [(tert-butoxycarbonyl) amino] (phenyl) acetate Patent Documents US8455514 and CN102120724A prepared (2S) according to – [(tert-butoxycarbonyl) amino] (phenyl) acetic acid methyl ester.

[0036] 1H-NMR (500 MHz, CDCl3) δ 1.42 (s, 9H), 3.67 (s, 3H), 6.19 (s, 1H), 7.20 – 7.38 (m, 5H).

[0037] Step 2): (S) – (2- (tert-butoxy quasi-yl) ((R) -2- (2,2- dimethyl-benzo [d] [I, 3] dioxane ) -2-6-yl) -2-hydroxyethyl) aminophenyl acetate

The 8.24 g of the epoxy compound IV were added to 30 ml of dimethyl sulfoxide, added slowly with stirring to dissolve after

12.72 g (2S) – [(tert-butoxycarbonyl) amino] (phenyl) acetate, the reaction temperature is controlled at 70 ° C 4 h, monitoring by TLC the reaction was complete. Wait until the reaction solution was cooled, added 60 mL of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (3 x 50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give (S) – (2- (tert oxycarbonyl group) ((R) -2- (2, 2- dimethyl-benzo [d] [l, 3] dioxin-6-yl) -2-hydroxyethyl) amino) phenyl _2_ acetate The crude product was 11.2 g, yield 59%. The crude product obtained in this step without further purification was used directly in the next salt-forming reaction.

[0038] 1H-NMR (500 MHz, CDCl3) δ 1.42 (s, 9H), 1.49 (s, 6H), 3.48 (dd, J = 23.7and 7.5 Hz, 1H), 3.67 (s, 3H), 3.78 ( dd, J = 24.8 and 7.6 Hz, 1H), 4.59 (s, 2H), 5.52 – 5.55 (m, 1H), 6.41 (s, 1H), 6.80 – 7.32 (m, 8H).

[0039] LC-MS: m / z = 472.1 (C26H33NO7 + H +).

[0040] Chiral HPLC: R- configuration: 96.1%, S- configuration: 4.0%.

[0041] Step 3) (S) – (2_ (tert quasi-yl) ((R) _2_ (2,2_-dimethyl-benzo [d] [1,3] dioxin-6-yl) preparation of amino group) of different salts of methyl-2-phenyl-2-hydroxyethyl)

Step 2) The obtained crude product was equally divided into four parts, each solvent were added 20 ml of methanol was stirred at 40 ° C under conditions to dissolve, then the mixture was four respective selection acid, hydrochloric acid, naphthalenesulfonic acid, and methanesulfonic acid treatment, acid is added in an amount 1.5 equivalents crude product, after completion, stirring was continued for 2 hours, allowed to stand overnight and cooled at 0 ° C, filtered, to give the corresponding salt. The results shown in the following table.

PATENT

W02014041565

https://patents.google.com/patent/WO2014041565A2

Vilanterol is chemically described as 4-{(lR)-2-[6-{2-(2, 6-dichlorobenzyl) oxy] ethoxy} hexyl) amino]- l-hydroxyethyl}-2-(hydroxymethyl) phenol as represented by Formula I.

Formula I The compound 4-{(lR)-2-[(6-{2-[(2,6-dicUorobenzyl)oxy]emoxy}hexyl)amino]-l- hydroxy ethyl} -2-(hydroxymethyl)phenol is specifically described in WO2003/024439, as are pharmaceutically acceptable salts thereof, in particular the acetate, triphenylacetate, a-phenylcinnamate, 1-naphthoate and (R)-mandelate salts. More specifically the preferred pharmaceutically acceptable salt is triphenylacetate salt.

The PCT publication WO 2003/024439, the corresponding US equivalent US 7,361,787 (herein after the ‘787 patent) and J.Med.Chem, 2010, 53, 4522-4530 discloses the process for preparation of vilanterol along with pharmaceutically acceptable salt. The ‘787 patent reaction sequence is schematically represented as follows:

The process described in the ‘787 patent uses alcoholic solvent during the acetonide cleavage of Formula XIV, which tends to result in the formation of the corresponding ether impurities. This requires repetitive purifications, which can be tedious to practice during scale up process. Moreover the dibromo hexane used in the process contains the corresponding 1, 5-dibromo alkanes which tends to react in the same sequential manner to generate the corresponding analogues, which requires repetitive purifications to separate out from the final API. The ‘787 patent imply the use of column chromatographic procedures which are not feasible on the commercial scale.

The ‘787 patent further elucidates the process for preparing (5R)-5-(2, 2-dimethyl-4H-l,

isomeric impurities for the chiral intermediate would carry forward during the process 2013/000556

which results in the formation of various isomeric impurities which are difficult to separate and need more tedious procedures. Moreover reagents like sodium hydride are difficult to handle during the scale up process as it tends to generate high exothermicity, which can affect the yield and purity of the said compound.

The purity and the yield of vilanterol trifenatate as per the disclosed process are not satisfactory and also the said process involves chromatography techniques to isolate the intermediate compounds. The said techniques are tedious, labor intensive, time consuming process not suitable for industrial scale and which in turn result to an increase in the manufacturing cost. Moreover the said process involves the use of vilanterol trifenatate which degrades to form certain impurities and results in the formation of the final compound with a lesser purity.

In view of intrinsic fragility there is a need in the art to develop a simple, industrially feasible and scalable process for the synthesis of vilanterol that would avoid the aforementioned difficulties. Moreover it becomes necessary to prepare highly chiral pure oxazolidinone intermediate to prepare chirally pure vilanterol.

Examplel2: Preparation of 4-((R)-2-{6-[2-(2, 6-Dichlorobenzyloxy)-ethoxy]- hexylamino}-l-hydroxy ethyl)-2-hydroxymethyI-phenol (I-Vilanterol)

Compound XTV (1.0 eqt) was dissolved in acetone (10V) under nitrogen at ambient temperature. The reaction mass was cooled to 0-5°C and 0.5N HCl (12V) was added slowly. The reaction mass was allowed to stir for completion over one hour period. The reaction mass was diluted with dichloromethane and water, followed by addition of saturated sodium bicarbonate solution (lOv) at 0-5°C. The organic layer was separated then washed successively with water/saturated brine and dried over sodium sulfate the solution was concentrated to dryness under vacuum to obtain the residue, followed by column chromatography (MeOH-DCM as eluent). The pure fractions were concentrated under vacuum to afford the title compound as pale yellow color oil.

Yield: 77%; purity by HPLC: 99.15%; Chiral purity: R-isomer: 99.97%; S-isomer: 0.03%

Examplel3: Preparation of 4-((R)-2-{6-[2-(2, 6-Dichlorobenzyloxy)-ethoxy]- hexylamino}-l-hydroxy ethyI)-2-hydroxymethyl-phenol triphenyl acetate (IA: Vilanterol trifenatate)

Triphenyl acetic acid (l.Oeqt) was added to a solution of compound I (l.Oeqt) in acetone (20V) at ambient temperature and the mixture heated to 50-55°C to obtain a homogenous solution. The mixture was allowed to cool to ambient temperature; the resultant product was filtered, washed with chilled acetone, dried under vacuum at 50°C to afford the title compound as a white solid.

Yield: 69%; purity by HPLC: 99.79%; chiral purity-R-isomer: 99.96%; S-isomer: 0.049%

Patent

CN 102120724

Patent

CN 104744270

PATENT

CN 104744271

Patent

https://patents.google.com/patent/CN105646285A/en

β 2- adrenergic receptor agonist is most widely used in clinical treatment of asthma and chronic obstructive pulmonary disease drugs. Currently available on the market β 2- adrenoreceptor agonist longest duration of action of 12 hours, which resulted in the need twice daily dosing. Over the last decade, the development of high potency, high selectivity, rapid onset, long duration of action, once daily dosing of β 2- adrenoreceptor agonists caused great concern in the pharmaceutical industry. Three acid vilanterol by Glaxo Group Limited development of a new Ultralente β 2- adrenergic receptor agonists, having bronchodilatory action.

[0003] vilanterol chemical name is 4 – {(lR) -2 – [(6- {2 – [(2,6- dichlorobenzyl) oxy] ethoxy} hexyl) amino] – 1-hydroxyethyl} -2_ (hydroxymethyl) phenol, having the formula as follows:

[0005] vilanterol synthetic routes are:

[0007] (5R) -5- (2, 2- dimethyl -4H-1,3- benzodioxin-6-yl) -1,3-oxazolidin-2-one was prepared an important intermediate Whelan Castro. The synthesis of this intermediate are currently two main ways:

[0008] 1: Reference Laurus Labs Limited published patent W02014041565, its main synthetic routes are as follows:

[0009]

[0010] obvious drawback of this method, the starting material is 4-bromo-2-hydroxymethyl-phenol, expensive, the next two steps harsh reaction conditions, where low temperature -75 ° C, and the yield rate is not high. Obviously not suitable for large-scale industrial production.

[0011] 2: Reference J. Med Chem 2010, 53, 4522-4530, and patent W02003024439, scheme is as follows:

[0013]

The route salicylaldehyde as raw material, the final seven-step synthesis intermediates, but the reaction step, 2-bromo-1- (2,2-dimethyl -4H-1,3- benzodioxin en-6-yl) ethanone di-t-butyl imine and a dicarboxylic acid, a lower yield, only 58%; while the imine dicarboxylate and cesium carbonate expensive, more cost high; the next step and also acidolysis out a tert-butoxycarbonyl group, relatively low utilization atoms.

Synthetic Route [0046] The reaction is as follows:

[0047]

Preparation of 5- (2-bromoacetyl) -2-hydroxyphenyl 4-carbaldehyde: [0048] Example 1

[0049] Under nitrogen, the ice bath, the aluminum trichloride 164g (5eq) dispersed into 600mL (20-fold amount) in DCM was slowly added dropwise bromoacetyl bromide 99. 4g (2eq), 20min After completion of the dropwise addition, the temperature warmed to room temperature, the reaction LH, salicylaldehyde to this mixture was added dropwise 30g, 20min dropwise addition, dropwise, the reaction overnight at 35 ° C. To the reaction mixture was added ice-water, the organic layer was separated, washed with water, dried and concentrated to dryness in vacuo.With DCM and recrystallized from n-hexane, the product was filtered to give 36. 5g, about 61% yield. 4 bandit 1 (4001 hold, 0)? (: 13): Sll.52 (s, lH), 9.99 (s, lH), 8.30 (s, lH), 8.17 (d, lH, J = 8Hz), 7.10 (d, lH, J = 8Hz), 4.39 (s, 2H); MS (-ESI) m / z 240 [MH]

– 5 -phenyl-1-one Preparation of 2-bromo-1- [4-hydroxy-3- (hydroxymethyl): [0050] Example 2

[0051] 40. 0g of the compound 4 dissolved in 400mL of acetic acid (10 times the amount), under ice-cooling, sodium borohydride was added portionwise 6. 8g (1. leq), was added stirred at rt for lh, TLC showed the reaction complete.Concentrated in vacuo to remove most of acetic acid, diluted with water and neutralized with sodium bicarbonate, extracted with EA, the organic phase washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to crude off-white powder did. After laundering refluxed with DCM to give a white powder 32g, 80% yield.

[0052] ^ NMR (400MHz, DMS0-d6): δ 10. 53 (s, 1H), 7. 99 (s, 1H), 7. 79 (d, 1H, J = 8Hz), 6.87 (d, lH , J = 8Hz), 4.75 (s, 2H), 4.50 (s, 2H); MS (+ ESI) m / z 267 [m + Na] +

[0053] Example 3: 2-amino-1- [4-hydroxy-3- (hydroxymethyl) – phenyl-1-one hydrochloride (6)

[0054] 10. 0g of the compound 5 was added to 200mL of ethyl acetate, was added hexamethylenetetramine (1. leq) 6. 2g, room temperature lh, TLC showed complete reaction. After filtration the filter cake was dried in vacuo as a white powder 15. 6g.The above white powder was dissolved in 150mL of ethanol, concentrated hydrochloric acid (5eq) 17. 5mL, room temperature overnight, the reaction was concentrated to dryness in vacuo to give an off-white powder 16. 0g (mixture) administered directly in the next step.

[0055] ^ NMR (400MHz, DMS0-d6): δ 10. 89 (s, 1H), 8. 40 (s, 2H), 7. 98 (d, 1H, J = 2Hz), 7 · 70 (dd , 1H, J = 8Hz and 2Hz), 7 · 02 (d, 1H, J = 8Hz), 4 · 49 (s, 2H), 4 · 43 (s, 2H); MS (+ ESI) m / z 182 [M + H] +

Preparation of 2- (3-hydroxymethyl-4-hydroxyphenyl) -2-carbonyl-ethyl carbamate ⑵ of: [0056] Example 4

[0057] The product from the previous step, compound 6 (hydrochloride) 16. 0g added to 150mL of THF and 150mL water was added 20. 6gNaHC03 (5eq), dissolved 30mL THF was added dropwise to a solution of 9. 8g Boc20, 20min After dropping. Reaction at room temperature lh, TLC showed complete reaction. Water was added, extracted with EA, the organic phase was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to a crude solid powder did, then after 1-2 times the amount of reflux in DCM starched white powder 8. 7g, two step yield 76%.

[0058] ^ NMRQOOMHz, DMS0-d6):.. Δ 10. 35 (dr, 1H), 7 94 (s, 1H), 7 75 (d, 1H, J = 8Hz), 6 · 95 (t, 1H , J = 4Hz), 6 · 85 (t, 1H, J = 8Hz), 4 · 49 (s, 2H), 4 · 35 (d, 1H, J = 4Hz), L 39 (s, 9H); MS (ES +) m / z 304 [m + Na] +

[0059] Example 5: 2- (2,2-dimethyl -4H-1,3- benzodioxin-6-yl) -2-carbonyl-ethyl carbamate (7 ) preparation of

[0060] 7. 0g of the compound 2 was dissolved in 70mL of DCM (10-fold amount) was added a catalytic amount of p-toluenesulfonic acid (0. 05eq), was added dropwise 2-dimethoxyethane at reflux propane (2eq) was dissolved in 2-fold amount of DCM, 40min addition was complete, the reaction lh, TLC showed complete reaction. The reaction mixture was washed with saturated NaHC (V Sin three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated in vacuo to give a yellow oil. Of isopropyl ether and recrystallized from n-heptane to obtain a white powder 6. 7g, 83% yield.

[0061] iHNMRGOOMHz, CDC13):. Δ 7. 77 (dd, 1H, J = 8Hz and 2Hz), 7 65 (s, 1H), 6 86 (d, 1H, J = 8Hz), 5 51 (.. dr, 1H), 4 87 (s, 2H), 4 56 (d, 2H, J = 4Hz), 1 56 (s, 6H), 1 47 (s, 9H);…. MS (ES +) m / z 344 [M + Na] +

[0062] Example 6: (2R) -2- (2, 2- dimethyl -4H-1,3- benzodioxin-6-yl) -2-hydroxyethyl carbamate butyl ester (8)

[0063] The catalyst was added 0. 78mL to 10mL of anhydrous THF under nitrogen was added dropwise BH3 ice bath. THF, 20min addition was complete. Was added dropwise under ice-cooling 2. 5g of compound 7 was dissolved in 20mL of anhydrous THF, 50min dropwise addition, reaction was warmed to room temperature 0. 5h, TLC indicated complete reaction. After quenched with methanol under ice-cooling the reaction, the reaction solution was concentrated in vacuo, water was added, extracted with EA, the organic phase washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a pale yellow oil 2. 8g. After petroleum ether starched white powder 2. 2g, 88% yield.

[0064] iHNMRGOOMHz, CDC13):… Δ 7. 13 (dd, 1H, J = 8Hz and 2Hz), 6 99 (s, 1H), 6 79 (d, 1H, J = 8Hz), 4 92 ( dr, 1H), 4. 71-4. 74 (m, 1H), 3. 42 (d, 1H, J = 12Hz), 3. 20-3. 25 (m, 1H), 1.53 (s, 6H) , 1.44 (s, 9H); MS (+ ESI) m / z 346 [m + Na] +

[0065] Example 7: (5R) -5- (2, 2- dimethyl -4H-1,3- benzodioxin-6-yl) -1, 3 oxazolidin -2 – preparation of ⑴ -one

[0066] Under nitrogen, 8 dissolved in 15mL of DMF 1. 8g compound, at 10-15 ° C, potassium tert-butoxide was added 0. 7g (l. Leq), After completion of the reaction at room temperature lh, TLC the reaction was complete. Ice water was added, a white solid was precipitated, stirring at room temperature after 3h, filtered off with suction, the filter cake was dried to obtain a white powder l.Og, 72% yield (purity 99.6%, ee 99.2%).

[0067] iHNMRGOOMHz, CDC13): δ 7. 15 (dd, 1H, J = 8Hz and 4Hz), 7 · 02 (s, 1H), 6 · 83 (d, 1H, J = 8Hz), 6.09 (br, lH), 5.52 (t, lH, J = 8Hz), 4.84 (s, 2H), 3.92 (t, lH, J = 8Hz), 3.53 (t, lH, J = 8Hz), 1.53 (s, 6H); MS (+ ESI) m / z 250 [m + H] +.

PATENT

https://patents.google.com/patent/WO2017001907A1/en

onverting the formed alcohol, preferably Compound II, to Vilanterol trifenatate, according to the below scheme:

timarate

VII L-tait rate

Example 16: Vilanterol base

Compound VII (5 g, obtained by procedure in Example 10) was dissolved in 5 EtOH (50 mL), followed by addition of 1M HCI solution (50 mL). The mixture was

stirred at room temp, for 90 minutes. Afterwards, pH of the mixture was adjusted to

~9 by addition of 20 % K₂C0₃ solution (25 mL). The mixture was then extracted to dichloromethane (100 mL). Organic phase was washed with water (2 x 25 mL), dried over MgS0₄ and evaporated to dryness. The residue was purified by column 10 chromatography, elution with mixture of dichloromethane/ethanol/ammonia (50/8/1 ) to give title compound as brownish slightly yellowish oil .

Example 17: Vilanterol trifenatate

Vilanterol base (0.620 g) was dissolved in EtOH (6 mL). Triphenylacetic acid

(0.370 g) was added and the mixture was heated to 50° C and stirred at the same 15 temp, for 15 min. The mixture was then cooled to room temp., followed by cooling in ice-water bath for 90 minutes. The formed suspension was filtered, the filtration cake was washed with cold EtOH and dried at room temp, overnight.

Example 18: Preparation of Vilanterol base 20

( l/ )-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-l-(2,2-dimethyl- 4H-l,3-benzodioxin-6-yl)ethanol (15.5 g, obtained according to the procedure in US

2005/0075394, Example 77(iv)) was dissolved in EtOH (50 mL), followed by addition of 1M HCI solution (50 mL). The mixture was stirred at room temperature for 90 minutes.

Afterwards, the pH of the mixture was adjusted to ~9 by addition of 20 % K₂C0₃ 25 solution (25 mL). The mixture was then extracted to dichloromethane ( 100 mL). The organic phase was washed with water (2 x 25 mL), dried over MgS0₄ and evaporated to dryness.

The crude vilanterol base ( 14.5 g, 90.9 % purity) was dissolved in

dichloromethane and the solution was loaded on a column packed with 300 g Diol-silica 30 in dichloromethane. The column was eluted with dichloromethane with gradient of ethanol (2 – 20 %) . The chromatographic fractions were monitored by TLC. The

fractions containing relatively pure vilanterol were joined and evaporated to dryness, obtaining 11.0 g of vilanterol with purity 97.1 %.

Example 21: Preparation of Vilanterol L-tartrate

EtOH (700 mL) was mixed with 1 M aq. HCI acid (700 mL), the formed mixture 25 was cooled to 5 °C, followed by addition of compound VII L-tartrate ( 100 g, obtained by procedure in Example 15). The mixture was stirred at 5 °C for 15 hours. Afterwards, DCM (500 mL) was added, the mixture was cooled to 0 °C and aq. Solution of K₂C0₃ ( 130g of K₂C0₃ in 200 mL of water) was then added drop wise to the stirred reaction mixture until pH 9 – 9.5 was obtained. Temp, during the addition was kept below 5 °C. 30 The water phase was separated, and extracted with additional DCM (300 mL).

Combined organic extracts were warmed to temp. 20-25 °C and washed with water (2 x 500 mL), 1% brine (500 mL) and 24% brine (500 mL). Afterwards, organic extract was mixed with solution of L-Tartaric acid (26.6 g) in EtOH (210 mL). The mixture was stirred for 10 min. at temp. 20-25°C and then heated by setting the temp, of the 35 reactor jacket to 40°C. All DCM solvent was distilled off under vacuum to residual approximate 350 mL. The mixture was then cooled to 25°C, followed by addition of

EtOAc ( 1.5 L) . The mixture was stirred at 20-25 °C for 1 hour then cooled to -5 °C and stirred overnight. The product was separated by filtration, washed with cold EtOAc and dried under inert gas and room temp. Isolated yield 85%, chemical purity 99.8%, 5 optical purity 99.93%. The sample was analyzed by PXRD, the PXRD pattern is

presented in Figure 5.

Example 22: Preparation of Vilanterol trifenatate

Dichloromethane (256 mL) was mixed with water (256 mL), the formed mixture was cooled to 0 °C, followed by addition of Vilanterol L-tartrate (32 g, obtained by 10 procedure in Example 21 ) and EtOH (64 mL). Afterwards, 25% aq. solution of ammonia (34 mL) was then added drop wise to the stirred mixture. Temp, during the addition was kept below 5 °C. The water phase was separated, and extracted with additional

DCM (128 mL) . Combined organic extracts were warmed to temp. 20-25 °C mixed with MTBE (220 mL), EtOH (64 mL). The obtained mixture was then washed with water (3 x 15 220 mL). Afterwards, the obtained organic extract was mixed with triphenylacetic acid ( 14.5 g) and stirred until complete dissolution at temp. 20-25°C. Then EtOH (96 mL) was added and the mixture was heated by setting the temp, of the reactor jacket to

40°C. Part of DCM solvent was distilled off under vacuum to residual approximate volume 220 mL, The mixture was then cooled to 25°C, followed by addition of MTBE 20 (256 mL). The mixture was stirred at 20-25 °C for 1 hour then cooled to -5 °C and for additional 2 hours. The product was separated by filtration, washed with cold MTBE and dried under inert gas and room temp. Isolated yield 93%, chemical purity 99.8%, optical purity 99.93%.

CN102480971A *2009-09-042012-05-30葛兰素史密丝克莱恩有限责任公司Chemical compounds

WO2013183656A1 *2012-06-042013-12-12大日本住友製薬株式会社Conjugate of g-protein coupled receptor binding ligand and nucleic acid molecule

WO2014041565A2 *2012-09-132014-03-20Laurus Labs Private LimitedAn improved process for the preparation of vilanterol and intermediates thereof

CN103923058A *2014-05-062014-07-16上海鼎雅药物化学科技有限公司Method for synthesizing vilanterol intermediate and salt thereof

CN105646285A *2014-12-022016-06-08上海医药工业研究院Vilanterol intermediate, preparation method and application thereof

WO2017001907A12015-06-292017-01-05Teva Pharmaceuticals International Gmbh

References

Jump up^ “FDA approves Breo Ellipta to treat chronic obstructive pulmonary disease”. Retrieved 10 May 2013.

Harrell AW, Siederer SK, Bal J, Patel NH, Young GC, Felgate CC, Pearce SJ, Roberts AD, Beaumont C, Emmons AJ, Pereira AI, Kempsford RD: Metabolism and disposition of vilanterol, a long-acting beta(2)-adrenoceptor agonist for inhalation use in humans. Drug Metab Dispos. 2013 Jan;41(1):89-100. doi: 10.1124/dmd.112.048603. Epub 2012 Oct 4. [PubMed:23043183]
Spyratos D, Sichletidis L: Umeclidinium bromide/vilanterol combination in the treatment of chronic obstructive pulmonary disease: a review. Ther Clin Risk Manag. 2015 Mar 25;11:481-7. doi: 10.2147/TCRM.S67491. eCollection 2015. [PubMed:25848294]

Patent ID	Title	Submitted Date	Granted Date
US2012309725	COMBINATIONS OF A MUSCARINIC RECEPTOR ANTAGONIST AND A BETA-2 ADRENORECEPTOR AGONIST	2010-11-29	2012-12-06
US2014116434	Dry Powder Inhaler Compositions	2012-06-01	2014-05-01
US2013157991	Dry Powder Inhalation Drug Products Exhibiting Moisture Control Properties and Methods of Administering the Same	2011-08-31	2013-06-20
US2017189424	FLUTICASONE FUROATE IN THE TREATMENT OF COPD	2015-05-27
US9763965	AGGREGATE PARTICLES	2013-04-11	2015-03-26

Patent ID	Title	Submitted Date	Granted Date
US8309572	Muscarinic acetylcholine receptor antagonists	2012-02-22	2012-11-13
US8534281	Manifold for use in medicament dispenser	2006-12-11	2013-09-17
US8161968	Medicament dispenser	2004-07-21	2012-04-24
US8511304	Medicament dispenser	2003-01-22	2013-08-20
US2011319371	PHARMACEUTICAL FORMULATIONS COMPRISING 4-HEXYL)AMINO]-1-HYDROXYETHYL}-2-(HYDROXYMETHYL)PHENOL	2011-12-29

Patent ID	Title	Submitted Date	Granted Date
US6878698	Anti-inflammatory androstane derivatives	2003-05-15	2005-04-12
US6537983	Anti-inflammatory androstane derivatives	2003-03-06	2003-03-25
US7488827	Muscarinic Acetylcholine Receptor Antagonists	2007-10-25	2009-02-10
US6759398	Anti-inflammatory androstane derivative	2002-11-28	2004-07-06
US9750726	COMBINATIONS OF A MUSCARINIC RECEPTOR ANTAGONIST AND A BETA-2 ADRENORECEPTOR AGONIST	2015-12-16	2016-04-07

Patent ID	Title	Submitted Date	Granted Date
US8183257	Muscarinic Acetylcholine Receptor Antagonists	2009-05-14	2012-05-22
US7776895	Inhalation devices for delivering phenethanolamine derivatives for the treatment of respiratory diseases	2009-03-12	2010-08-17
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US7498440	Muscarinic acetylcholine receptor antagonists	2007-08-09	2009-03-03
US7629335	Anti-inflammatory androstane derivative	2007-02-01	2009-12-08

Vilanterol
Clinical data

License data	EU EMA: by INN
ATC code	R03AK10 (WHO) (+fluticasone) R03AL03 (WHO) (+umeclidinium)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only In general: ℞ (Prescription only)
Identifiers
IUPAC name [show]
CAS Number	503068-34-6
PubChem CID	10184665
ChemSpider	8360167
UNII	028LZY775B
KEGG	D09696
ChEBI	CHEBI:75037
ECHA InfoCard	100.217.751
Chemical and physical data
Formula	C₂₄H₃₃Cl₂NO₅
Molar mass	486.43 g/mol
3D model (JSmol)	Interactive image

/////////////Vilanterol trifenatate, HY-14300A, CS-1679, fda 2013, Breo Ellipta, Relvar Ellipta, 444 , 642444 , GSK-642444 , GW-642444 , GW-642444M , ビランテロール , ビランテロールトリフェニル酢酸塩 , ビランテロールトリフェナテート

C1=CC=C(C=C1)C(C2=CC=CC=C2)(C3=CC=CC=C3)C(=O)O.C1=CC(=C(C(=C1)Cl)COCCOCCCCCCNCC(C2=CC(=C(C=C2)O)CO)O)Cl

Ivosidenib, ивосидениб , إيفوزيدينيب , 艾伏尼布 ,

July 21, 2018 2:22 am / Leave a comment

Ivosidenib

AG-120; TIBSOVO

FDA approves first targeted treatment Tibsovo (ivosidenib) for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation

The U.S. Food and Drug Administration today approved Tibsovo (ivosidenib) tablets for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a specific genetic mutation. This is the first drug in its class (IDH1 inhibitors) and is approved for use with an FDA-approved companion diagnostic used to detect specific mutations in the IDH1 gene in patients with AML.

“Tibsovo is a targeted therapy that fills an unmet need for patients with relapsed or refractory AML who have an IDH1 mutation,” 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. “The use of Tibsovo is associated with a complete remission in some patients and a reduction in the need for both red cell and platelet transfusions.”

July 20, 2018

Release

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of abnormal white blood cells in the bloodstream and bone marrow. The National Cancer Institute at the National Institutes of Health estimates that approximately 19,520 people will be diagnosed with AML this year; approximately 10,670 patients with AML will die of the disease in 2018.

Tibsovo is an isocitrate dehydrogenase-1 inhibitor that works by decreasing abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to differentiation of malignant cells. If the IDH1 mutation is detected in blood or bone marrow samples using an FDA-approved test, the patient may be eligible for treatment with Tibsovo. Today the agency also approved the RealTime IDH1 Assay, a companion diagnostic that can be used to detect this mutation.

The efficacy of Tibsovo was studied in a single-arm trial of 174 adult patients with relapsed or refractory AML with an IDH1 mutation. The trial measured the percentage of patients with no evidence of disease and full recovery of blood counts after treatment (complete remission or CR), as well as patients with no evidence of disease and partial recovery of blood counts after treatment (complete remission with partial hematologic recovery or CRh). With a median follow-up of 8.3 months, 32.8 percent of patients experienced a CR orCRh that lasted a median 8.2 months. Of the 110 patients who required transfusions of blood or platelets due to AML at the start of the study, 37 percent went at least 56 days without requiring a transfusion after treatment with Tibsovo.

Common side effects of Tibsovo include fatigue, increase in white blood cells, joint pain, diarrhea, shortness of breath, swelling in the arms or legs, nausea, pain or sores in the mouth or throat, irregular heartbeat (QT prolongation), rash, fever, cough and constipation. Women who are breastfeeding should not take Tibsovo because it may cause harm to a newborn baby.

Tibsovo must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. The prescribing information for Tibsovo includes a boxed warning that an adverse reaction known as differentiation syndrome can occur and can be fatal if not treated. Signs and symptoms of differentiation syndrome may include fever, difficulty breathing (dyspnea), acute respiratory distress, inflammation in the lungs (radiographic pulmonary infiltrates), fluid around the lungs or heart (pleural or pericardial effusions), rapid weight gain, swelling (peripheral edema) or liver (hepatic), kidney (renal) or multi-organ dysfunction. At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor patients closely until symptoms go away.

Other serious warnings include a QT prolongation, which can be life-threatening. Electrical activity of the heart should be tested with an electrocardiogram during treatment. Guillain-Barré syndrome, a rare neurological disorder in which the body’s immune system mistakenly attacks part of its peripheral nervous system, has happened in people treated with Tibsovo, so patients should be monitored for nervous system problems.

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

The FDA granted the approval of Tibsovo to Agios Pharmaceuticals, Inc. The FDA granted the approval of the RealTime IDH1 Assay to Abbott Laboratories.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm614115.htm?utm_campaign=07202018_PR_FDA%20approves%20new%20AML%20drug&utm_medium=email&utm_source=Eloqua

ivosidenib

Molecular FormulaC₂₈H₂₂ClF₃N₆O₃
Average mass582.961 Da

1448347-49-6 [RN]

2-Pyrrolidinecarboxamide, N-[(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl]-1-(4-cyano-2-pyridinyl)-N-(5-fluoro-3-pyridinyl)-5-oxo-, (2S)-

AG-120

UNII:Q2PCN8MAM6

ивосидениб [Russian] [INN]

إيفوزيدينيب [Arabic] [INN]

艾伏尼布 [Chinese] [INN]

Ivosidenib is an experimental drug for treatment of cancer. It is a small molecule inhibitor of IDH1, which is mutated in several forms of cancer. The drug is being developed by Agios Pharmaceuticals and is in phase III clinical trials. The FDA awarded orphan drug statusfor acute myeloid leukemia and cholangiocarcinoma.^[1]^{[better source needed]}

It is in a phase III clinical trial for acute myeloid leukemia (AML) with an IDH1 mutation and a phase III clinical trial for cholangiocarcinoma with an IDH1 mutation.^[2]

OriginatorAgios Pharmaceuticals
DeveloperAbbVie; Agios Pharmaceuticals; University of Texas M. D. Anderson Cancer Center
ClassAntineoplastics; Cyclobutanes; Nitriles; Pyridines; Pyrrolidines; Small molecules
Mechanism of ActionIsocitrate dehydrogenase 1 inhibitors

Orphan Drug StatusYes – Acute myeloid leukaemia; Cholangiocarcinoma
New Molecular EntityYes

Highest Development Phases

PreregistrationAcute myeloid leukaemia
Phase IIICholangiocarcinoma
Phase IGlioma; Myelodysplastic syndromes; Solid tumours

Most Recent Events

28 Jun 2018Massachusetts General Hospital and Agios Pharmaceuticals plan a phase I trial for Acute myeloid leukaemia; Myelodysplastic syndromes and Chronic myelomonocytic leukaemia (Maintenance therapy) in USA (NCT03564821)
26 Jun 2018Ivosidenib licensed to CStone Pharmaceuticals in China, Hong Kong, Macau and Taiwan
14 Jun 2018Efficacy and adverse events data from a phase I trial in Acute myeloid leukaemia presented at the 23^rd Congress of the European Haematology Association (EHA-2018)

References

External links

Clinical trials registered for Ivosidenib

Ivosidenib
Clinical data

Routes of administration	Oral
ATC code	None
Legal status
Legal status	Investigational
Identifiers
IUPAC name [show]
CAS Number	1448347-49-6
PubChem CID	71657455
ChemSpider	38772333
UNII	Q2PCN8MAM6
Chemical and physical data
Formula	C₂₈H₂₂ClF₃N₆O₃
Molar mass	582.97 g·mol⁻¹
3D model (JSmol)	Interactive image

///////////////Tibsovo, ivosidenib, fda 2018, Fast Track, Priority Review , Orphan Drug designation, UNII:Q2PCN8MAM6, ивосидениб , إيفوزيدينيب , 艾伏尼布 ,

BMS-978587

July 19, 2018 10:30 am / Leave a comment

BMS-978587

Molecular Formula:	C₂₆H₃₅N₃O₃	CAS	1629125-65-0
Molecular Weight:	437.582

US9675571 PATENT

Inventor James Aaron Balog Audris Huang Bin Chen Libing Chen Steven P. Seitz Amy C. Hart Jay A. Markwalder

AssigneeBristol-Myers Squibb Co Priority date 2013-03-15

IDO-IN-4; 1629125-65-0; SCHEMBL17456163; AKOS030526622; ZINC521836543; CS-5086

(1R,2S)-2-[4-(Di-isobutylamino)-3-(3-(p-tolyl)ureido)phenyl] Cyclopropanecarboxylic Acid

(1R,2S)-2-[4-[bis(2-methylpropyl)amino]-3-[(4-methylphenyl)carbamoylamino]phenyl]cyclopropane-1-carboxylic acid

(lR,2S)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

BMS-978587 was discovered and developed within Bristol-Myers Squibb as a potent small molecule IDO inhibitor

Tryptophan is an amino acid which is essential for cell proliferation and survival. Indoleamine-2,3-dioxygenase is a heme-containing intracellular enzyme that catalyzes the first and rate-determining step in the degradation of the essential amino acid L-tryptophan to N-formyl-kynurenine. N-formyl-kynurenine is then metabolized by mutliple steps to eventually produce nicotinamide adenine dinucleotide (NAD+). Tryptophan catabolites produced from N-formyl-kynurenine, such as kynurenine, are known to be preferentially cytotoxic to T-cells. Thus an overexpression of IDO can lead to increased tolerance in the tumor microenvironment. IDO overexpression has been shown to be an independent prognostic factor for decreased survival in patients with melanoma, pancreatic, colorectal and endometrial cancers among others. Moreover, IDO has been found to be implicated in neurologic and psychiatric disorders including mood idsorders as well as other chronic diseases characterized by IDO activation and tryptophan depletiion, such as viral infections, for example AIDS, Alzheimer’s disease, cancers including T-cell leukemia and colon cancer, autimmune diseases, diseases of the eye such as cataracts, bacterial infections such as Lyme disease, and streptococcal infections.

Accordingly, an agent which is safe and effective in inhibiting production of IDO would be a most welcomed addition to the physician’s armamentarium

SYNTHESIS

PATENT

https://patents.google.com/patent/US9675571

Figure US09675571-20170613-C00026

Figure US09675571-20170613-C00027

Example 1 Method A Enantiomer 1 and Enantiomer 2 Enantiomer 1: (1R,2S)-2-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)cyclopropanecarboxylic acid

PATENT

WO2014/150677

https://patents.google.com/patent/WO2014150677A1/en

Example 1- Method A

Enantiomer 1 and Enantiomer 2

Enantiomer 1 : (lR,2S)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Enantiomer 2: (lS,2R)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

1A. 4-bromo-N,N-diisobutyl-2-nitroaniline

4-bromo-l-fluoro-2 -nitrobenzene (7 g, 31.8 mmol) and diisobutylamine (12.23 ml, 70.0 mmol) were heated at 130 °C for 3 h. It was then cooled to RT, purification via flash chromatography gave 1A (bright red solid, 8.19 g, 24.88 mmol, 78 % yield) LC-MS Anal. Calc’d for Ci₄H₂iBrN₂0₂ 328.08, found [M+3] 331.03, T_r = 2.63 min (Method A).

IB. N,N-diisobutyl-2-nitro-4-vinylaniline

To a solution of 1 A (1 g, 3.04 mmol) in ethanol (15.00 mL) and toluene (5 mL) (sonication to break up the solid) was added 2,4,6-trivinyl- 1 ,3 ,5 ,2,4,6-trioxatriborinane pyridine complex (0.589 g, 3.64 mmol) followed by K3PO₄ (1.289 g, 6.07 mmol) and water (2.000 mL). The reaction mixture was purged with Argon for 2 min and then Pd (PPh₃)₄(0.351 g, 0.304 mmol) was added. It was then heated at 80 °C in an oil bath for 8 h. LC-MS indicated completion. It was diluted with EtOAc (10 mL) and water (5 mL) and filtered through a pad of Celite, rinsed with EtOAc (2×30 mL). Aqueous layer was further extracted with EtOAc (2×30 mL), the combined extracts were washed with water, brine, dried over MgS0₄, filtered and concentrated. Purification via fiash chromatography gave IB (orange oil, 800 mg, 2.89 mmol, 95 % yield). LC-MS Anal. Calc’d for

Ci₆H₂₄N₂0₂ 276.18, found [M+H] 277.34, T_r = 2.41 min (Method A). 1H NMR

(400MHz, CHLOROFORM-d) δ 7.73 (d, J=2.2 Hz, 1H), 7.44 (dd, J=8.8, 2.2 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 6.60 (dd, J=17.5, 10.9 Hz, 1H), 5.63 (dd, J=17.6, 0.4 Hz, 1H), 5.20 (d, J=11.2 Hz, 1H), 3.00 – 2.89 (m, 4H), 1.99 – 1.85 (m, 2H), 0.84 (d, J=6.6 Hz, 12H) IC. Racemic (lR,2S)-ethyl 2-(4-(diisobutylamino)-3 nitrophenyl)

cyclopropanecarboxylate

To a solution of IB (800 mg, 2.61 mmol) in DCM (15 mL) was added rhodium(II) acetate dimer (230 mg, 0.521 mmol) followed by a slow addition of a solution of ethyl diazoacetate (0.811 mL, 7.82 mmol) in CH2CI2 (5.00 mL) over a period of 2 h via a syringe pump. The reaction mixture turned into a dark red solution and it was stirred at RT for extra 1 h. LC-MS indicated the appearance of two peaks with the desired molecular mass, the solvent was removed in vacuo and purification via flash

chromatography gave 1C (cis isomer) (yellow oil, 220 mg, 0.607 mmol, 23.30 % yield) and trans isomer (yellow oil, 300 mg, 0.828 mmol, 31.8 % yield). LC-MS Anal. Calc’d for C20H30N2O4 362.22, found [M+H] 363.27, T_r = 2.34 min (cis), 2.42 min (trans) (Method A), cis isomer: 1H NMR (400MHz, CHLOROFORM-d) δ 7.62 (d, J=1.8 Hz, 1H), 7.30 – 7.25 (m, 1H), 7.02 (d, J=8.6 Hz, 1H), 3.95 – 3.86 (m, 2H), 2.89 (d, J=7.3 Hz, 4H), 2.53 – 2.44 (m, 1H), 2.07 (ddd, J=9.2, 7.9, 5.7 Hz, 1H), 1.87 (dquin, J=13.5, 6.8 Hz, 2H), 1.67 (dt, J=7.3, 5.5 Hz, 1H), 1.37 – 1.30 (m, 1H), 0.99 (t, J=7.0 Hz, 3H), 0.82 (d, J=6.6 Hz, 12H) trans isomer: 1H NMR (400MHz, CHLOROFORM-d) δ 7.43 (d, J=2.2 Hz, 1H), 7.17 – 7.11 (m, 1H), 7.08 – 7.03 (m, 1H), 4.18 (q, J=7.3 Hz, 2H), 2.89 (d, J=7.3 Hz, 4H), 2.46 (ddd, J=9.2, 6.4, 4.2 Hz, 1H), 1.94 – 1.80 (m, 3H), 1.62 – 1.54 (m, 1H), 1.34 – 1.23 (m, 4H), 0.83 (d, J=6.6 Hz, 12H)

ID. Racemic (lR,2S)-ethyl 2-(3-amino-4-(diisobutylamino)phenyl) cyclopropanecarboxylate

To a stirred solution of 1C (cis isomer) (220 mg, 0.607 mmol) in EtOAc (6 mL) was added palladium on carbon (64.6 mg, 0.061 mmol) and the suspension was hydrogenated (1 atm, balloon) at RT for 1 h. LC-MS indicated completion. The suspension was filtered through a pad of Celite and the filter cake was rinsed with EtOAc (2×30 mL). Combined filtrate and rinses were evaporated in vacuo. Purification via flash chromatography gave ID (light yellow oil, 140 mg, 0.421 mmol, 69.4 % yield). LC-MS Anal. Calc’d for C20H32N2O2 332.25, found [M+H] 333.34, T_r= 2.22 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 6.95 (d, J=8.1 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 6.64 – 6.59 (m, 1H), 4.06 (s, 2H), 3.87 (qd, J=7.1, 0.9 Hz, 2H), 2.56 (d, J=7.0 Hz, 4H), 2.47 (q, J=8.6 Hz, IH), 2.01 (ddd, J=9.4, 7.8, 5.7 Hz, IH), 1.78 – 1.61 (m, 3H), 1.24 (ddd, J=8.6, 7.9, 5.1 Hz, IH), 0.92 (t, J=7.2 Hz, 3H), 0.89 (dd, J=6.6, 0.9 Hz, 12H)

Racemic example 1. Racemic (lR,2S)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

To a solution of ID (140 mg, 0.421 mmol) in THF (4mL) was added 1- isocyanato-4-methylbenzene (0.079 mL, 0.632 mmol). The resulting solution was stirred at RT for 3 h. LC-MS indicated completion. The reaction mixture was concentrated and used without purification in the next step. The crude ester (180 mg, 0.387 mmol) was dissolved in THF (4 mL), NaOH (IN aqueous) (1.160 mL, 1.160 mmol) was added. Then MeOH (1 mL) was added to dissolve the precipitate and it turned into a clear yellow solution. After 60 h, reaction was complete by LC-MS. Most MeOH and THF was removed in vacuo and the crude was diluted with 2 mL of water, the pH was adjusted to ca. 2 using IN aqueous HC1. The aqueous phase was then extracted with EtOAc (3×10 mL) and the combined organic phase was washed with brine, dried over Na₂S0₄ and concentrated. Purification via flash chromatography gave racemic example 1 (yellow foam, 110 mg, 0.251 mmol, 65.0 % yield), LC-MS Anal. Calc’d for CzeHssNsOs 437.27, found [M+H] 438.29, T_r = 4.22 min (Method A). 1H NMR (400MHz, CHLOROFORM- d) δ 10.15 (br. s., IH), 7.42 – 7.35 (m, 3H), 7.22 – 7.14 (m, 2H), 7.10 (d, J=8.1 Hz, 2H), 3.22 (d, J=6.6 Hz, 4H), 2.54 (q, J=8.6 Hz, IH), 2.31 (s, 3H), 2.16 – 1.98 (m, 3H), 1.61 (dt, J=7.3, 5.6 Hz, IH), 1.40 (td, J=8.3, 5.3 Hz, IH), 1.01 (br. s., 12H)

Example 1, Enantiomer 1 and Enantiomer 2. Chiral separation of racemic example 1 (Method H) gave enantiomer 1 T_r = 9.042 min (Method J). [a]²⁴ _D = -11.11 (c 7.02 mg/mL, MeOH) and enantiomer 2 T_r = 10.400 min (Method J). [a]²⁴ _D = + 11.17 (c 7.02 mg/mL, MeOH) as single enantiomers. Absolute stereochemistry was confirmed in example 1 method B.

Enantiomer 1 : LC-MS Anal. Calc’d for C26H35N3O3 437.27, found [M+H] 438.25, T_r= 4.19 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 8.12 (d, J=1.3 Hz, IH), 7.97 (s, IH), 7.20 (d, J=8.4 Hz, 2H), 7.14 – 7.07 (m, 2H), 7.02 (t, J=7.7 Hz, 2H),

6.89 (dd, J=8.1, 1.5 Hz, IH), 2.60 (q, J=8.6 Hz, IH), 2.50 (d, J=7.0 Hz, 4H), 2.32 (s, 3H), 2.13 – 2.04 (m, 1H), 1.71 – 1.55 (m, 3H), 1.35 (td, J=8.3, 5.1 Hz, 1H), 0.76 (dd, J=6.6, 2.2 Hz, 12H)

Enantiomer 2: LC-MS Anal. Calc’d for C26H35N3O3 437.27, found [M+H] 438.24, T_r= 4.18 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 8.11 (d, J=1.5 Hz, 1H), 7.96 (s, 1H), 7.23 – 7.16 (m, 2H), 7.13 – 7.07 (m, 2H), 7.05 – 6.98 (m, 2H), 6.89 (dd, J=8.3, 1.7 Hz, 1H), 2.59 (q, J=8.7 Hz, 1H), 2.49 (d, J=7.3 Hz, 4H), 2.32 (s, 3H), 2.12 – 2.03 (m, 1H), 1.70 – 1.53 (m, 3H), 1.34 (td, J=8.2, 5.0 Hz, 1H), 0.75 (dd, J=6.6, 2.0 Hz, 12H) Example 1 – Method B

Enantiomer 1 and Enantiomer 2

Enantiomer 2: (lS,2R)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

IE. 4-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-N,N-diisobutyl-2-nitroaniline

1A (10 g, 30.4 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(l,3,2-dioxaborinane) (7.55 g, 33.4 mmol), PdCl₂(dppf)- CH₂C1₂ adduct (0.556 g, 0.759 mmol) and potassium acetate

(8.94 g, 91 mmol) were combined in a round bottom flask, and DMSO (100 mL) was added. It was vacuated and back-filled with N₂ three times, then heated at 80 °C for 8 h. Reaction was complete by LC-MS. Cooled to RT and passed through a short plug of silica gel, rinsed with a mixture of Hexane/EtOAc (5: 1) (3×100 mL). After removing the solvent in vacuo, purification via flash chromatography gave IE (orange oil, 9 g, 22.36 mmol, 73.6 % yield), LC-MS Anal. Calc’d for C19H31BN2O4 362.24, found [M+H] 295.18 (mass of boronic acid), T_r = 3.65 min (Method A). 1H NMR (400MHz,

CHLOROFORM-d) δ 8.13 (d, J=1.8 Hz, 1H), 7.73 (dd, J=8.4, 1.5 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 3.75 (s, 4H), 3.00 – 2.92 (m, 4H), 1.93 (dquin, J=13.5, 6.8 Hz, 2H), 1.02 (s, 6H), 0.93 – 0.79 (m, 12H)

IF. (lS,2R)-ethyl 2-(4-(diisobutylamino)-3-nitrophenyl)

cyclopropanecarboxylate

To IE (9 g, 22.36 mmol) in a 500 mL round bottom flask was added 1,4-dioxane (60 mL). After it was dissolved, cesium carbonate (15.30 g, 47.0 mmol) was added. To the suspension was then added water (30 mL) slowly. It became an homogeneous solution. Enantiopure (lR,2R)-ethyl 2-iodocyclopropanecarboxylate (5.90 g, 24.59 mmol) (For synthesis see Organic Process Research & Development 2004, 8, 353-359 ) was then added. The resulting mixture was purged with nitrogen for 25 min. Then PdCl₂(dppf)-

CH₂C1₂ adduct (1.824 g, 2.236 mmol) was added. The reaction mixture was purged with nitrogen for another 10 min. It became dark brown colored solution. This mixture was then stirred under nitrogen at 87 °C for 22 h. LC-MS indicated product formation and depletion of starting material. It was then cooled to RT. After removing solvent under reduced pressure, it was diluted with EtOAc (50 mL) and water (50 mL). Organic layer was separated and the aqueous layer was further extracted with EtOAc (3x 30 mL). The combined organic layers were washed with brine, dried over MgS0₄, filtered and concentrated. Purification via flash chromatography gave IF (dark orange oil, 3.2 g, 8.83 mmol, 39.5 % yield), LC-MS Anal. Calc’d for C20H30N2O4 362.22, found [M+H] 363.3, T_r = 3.89 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) 57.65 – 7.60 (m, 1H), 7.29 (d, J=2.2 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 3.95 – 3.84 (m, 2H), 2.89 (d, J=7.3 Hz, 4H), 2.48 (q, J=8.6 Hz, 1H), 2.07 (ddd, J=9.2, 7.9, 5.7 Hz, 1H), 1.87 (dquin, J=13.5, 6.8 Hz, 2H), 1.67 (dt, J=7.3, 5.5 Hz, 1H), 1.38 – 1.28 (m, 1H), 0.99 (t, J=7.2 Hz, 3H), 0.82 (d, J=6.6 Hz, 12H

IG. (lS,2R)-ethyl 2-(3-amino-4-(diisobutylamino)phenyl)

cyclopropanecarboxylate

To a stirred solution of IF (5.5 g, 15.17 mmol) in EtOAc (150 mL) was added palladium on carbon (1.615 g, 1.517 mmol) and the suspension was hydrogenated (1 atm, balloon) for 1.5 h. LC-MS indicated completion. The suspension was filtered through a pad of Celite and the filter cake was rinsed with EtOAc (2×50 mL). Combined filtrate and rinses were concentrated under reduced pressure. Purification via flash chromatography gave 1G (yellow oil, 4.5 g, 13.53 mmol, 89 % yield). LC-MS Anal. Calc’d for

C20H32N2O2 332.25, found [M+H] 333.06, T_r = 2.88 min (Method A). 1H NMR

(400MHz, CHLOROFORM-d) δ 6.95 (d, J=7.9 Hz, 1H), 6.68 – 6.58 (m, 2H), 4.06 (s, 2H), 3.93 – 3.81 (m, 2H), 2.57 (d, J=7.3 Hz, 4H), 2.47 (q, J=8.6 Hz, 1H), 2.01 (ddd, J=9.4, 7.8, 5.5 Hz, 1H), 1.78 – 1.59 (m, 3H), 1.30 – 1.18 (m, 1H), 0.92 (t, J=7.2 Hz, 3H), 0.89 (dd, J=6.6, 0.9 Hz, 12H)

Example 1 enantiomer 2 was prepared following the reduction, urea formation and basic saponification procedures in racemic example 1 method A except that saponification was carried out at 50 °C for 8 h instead of at RT. Chiral analytical analysis verified it was enantiomer 2 T_r = 10.646 min (Method J). Absolute stereochemistry was confirmed by referring to reference: Organic Process Research & Development 2004, 8, 353-359.

Enantiomer 1 Method B: (lR,2S)-2-(4-(diisobutylamino)-3

tolyl)ureido)phenyl)cyclopropanecarboxylic acid

1H. Single enantiomer (lR,2S)-ethyl 2-(3-amino-4-(diisobutylamino)phenyl) cyclopropanecarboxylate

1H was prepared following procedures in example 1 enantiomer 2 method B utilizing enantiopure (l S,2S)-ethyl 2-iodocyclopropanecarboxylate. This was obtained through chiral resolution modifying the procedure in Organic Process Research & Development 2004, 8, 353-359, using (i?)-(+)-N-benzyl-a-methylbenzylamine instead of (S)-(-)-N-benzyl-a-methylbenzylamine). LC-MS Anal. Calc’d for C20H32N2O2 332.25, found [M+H] 333.06, T_r = 2.88 min (Method A). 1H NMR (400MHz, CHLOROFORM- d) δ 6.95 (d, J=7.9 Hz, 1H), 6.68 – 6.58 (m, 2H), 4.06 (s, 2H), 3.93 – 3.81 (m, 2H), 2.57 (d, J=7.3 Hz, 4H), 2.47 (q, J=8.6 Hz, 1H), 2.01 (ddd, J=9.4, 7.8, 5.5 Hz, 1H), 1.78 – 1.59 (m, 3H), 1.30 – 1.18 (m, 1H), 0.92 (t, J=7.2 Hz, 3H), 0.89 (dd, J=6.6, 0.9 Hz, 12H).

Note: 1H was also made through chiral separation (Method I) of racemic (1R,2S)- ethyl 2-(3-amino-4-(diisobutylamino)phenyl)cyclopropanecarboxylate. Chiral analytical analysis (Method K) showed 1H as a single enantiomer (99 % ee).

Example 1 enantiomer 1 was prepared following the reduction, urea formation and basic saponification procedures in racemic example 1 method A using 1H except that saponification was carried out at 50 °C for 8 h instead of at RT. Chiral analytical analysis verified it was enantiomer 1 with 97.8% ee (Method J).

Example 1 – Method C

Enantiomer 1

(lR,2S)-2-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)cyclopropanecarboxylic acid

II. Diastereomer 1: (R)-4-benzyl-3-((lR,2S)-2-(4-(diisobutylamino)-3- nitrophenyl)cyclopropanecarbonyl)oxazolidin-2-one

Diastereomer 2: (R)-4-benzyl-3-((l S,2R)-2-(4-(diisobutylamino)-3- nitrophenyl)cyclopropanecarbonyl)oxazolidin-2-one: 1C (1.2 g, 3.31 mmol) was dissolved in THF (20 mL), NaOH (IN aqueous) (8.28 mL, 8.28 mmol) was added. Saw precipitate formed, then MeOH (5.00 mL) was added and it turned into a clear yellow solution. The reaction was monitored by LC-MS. After 24 h, reaction was complete. Most MeOH and THF was removed in vacuo and the crude was diluted with 10 mL of water, the pH was adjusted to ca. 2 using IN aqueous HC1. The aqueous phase was then extracted with EtOAc (3×30 mL) and the combined organic phase was washed with brine, dried over Na₂S0₄ , filtered and concentrated to give 1.1 g of desired acid as an orange foam. This was used without purification in the subsequent step. To a solution of the crude acid from the previous step (1132 mg, 3.39 mmol) in THF (15 mL) cooled in an ice-water bath was added N-methylmorpholine (0.447 mL, 4.06 mmol) followed by slow addition of pivaloyl chloride (0.500 mL, 4.06 mmol). After stirring in an ice-water bath for 30 min, the reaction mixture was then cooled to -78 °C. In a separate reaction flask, ftBuLi (1.354 mL, 3.39 mmol) was added dropwise to a solution of (R)-4- benzyloxazolidin-2-one (600 mg, 3.39 mmol) in THF (15.00 mL). After 45 min at -78 °C, the solution was cannulated into the -78 °C anhydride mixture. After 30 min, the cooling bath was removed and the solution was allowed to warm to RT. After 1 h, LC-MS indicated completion. The reaction was quenched by addition of saturated aqueous NH₄C1. The solution was then partitioned between EtOAc and water. The organic phase was further extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water, brine, dried over MgS0₄, filtered and concentrated. Purification via flash chromatography gave II Diastereomer 1 (yellow oil, 600 mg, 1.216 mmol, 35.9 % yield). Diastereomer 2 (yellow oil, 450 mg, 0.912 mmol, 26.9 % yield) LC-MS Anal. Calc’d for C₂8H3₅N₃0₅ 493.26, found: [M+H] 494.23, T_r = 5.26 min (Diastereomer 1). T_r = 5.25 min (Diastereomer 2) (Method A). Diastereomer 1 : 1H NMR (400MHz,

CHLOROFORM-d) δ 7.56 (d, J=1.8 Hz, 1H), 7.35 – 7.23 (m, 4H), 7.18 – 7.12 (m, 2H), 7.03 (d, J=8.8 Hz, 1H), 4.37 (ddt, J=9.6, 7.3, 3.6 Hz, 1H), 4.11 – 4.06 (m, 2H), 3.48 – 3.40 (m, 1H), 3.22 (dd, J=13.4, 3.5 Hz, 1H), 2.89 (d, J=7.3 Hz, 4H), 2.77 – 2.66 (m, 2H), 1.97 – 1.81 (m, 3H), 1.52 – 1.44 (m, 1H), 0.82 (d, J=6.6 Hz, 12H); Diastereomer 2: 1H NMR (400MHz, CHLOROFORM-d) δ 7.62 (d, J=2.0 Hz, 1H), 7.36 – 7.19 (m, 4H), 7.09 – 6.97 (m, 3H), 4.45 (ddt, J=10.2, 7.2, 3.0 Hz, 1H), 4.14 – 4.05 (m, 2H), 3.45 – 3.36 (m, 1H), 2.80 (d, J=7.3 Hz, 4H), 2.52 (dd, J=13.3, 3.2 Hz, 1H), 2.19 (dd, J=13.2, 10.3 Hz, 1H), 2.03 (dt, J=7.2, 5.8 Hz, 1H), 1.72 (dquin, J=13.4, 6.8 Hz, 2H), 1.45 (ddd, J=8.3, 7.3, 5.3 Hz, 1H), 0.64 (dd, J=6.6, 2.0 Hz, 12H) 1 J. (lR,2S)-methyl 2-(4-(diisobutylamino)-3-nitrophenyl)

cyclopropanecarboxylate

To a solution of II Diastereomer 1 (460 mg, 0.932 mmol) in THF (6mL) at 0 °C was added hydrogen peroxide (0.228 mL, 3.73 mmol). Then a solution of lithium hydroxide monohydrate (44.6 mg, 1.864 mmol) in water (2.000 mL) was added to the cold THF solution and stirred for 6 h. LC-MS indicated completion, then 2 mL of saturated aqueous Na₂S0₃ was added followed by 3 mL of saturated aqueous NaHC0₃. The mixture was concentrated to remove most of the THF. The solution was then diluted with 5 mL of water. The aqueous solution was acidified with 1 N aqueous HC1 and extracted with EtOAc (3×20 mL). The combined organic extracts was washed with water, brine, dried over MgS0₄, filtered and concentrated to give 300 mg acid. To a solution of the crude acid from previous step (300 mg, 0.897 mmol) in MeOH (10 mL) was added 6 drops of concentrated H₂SO₄. The resulting solution was stirred at 50 °C for 6 h. After LC-MS indicated completion, solvent was removed under reduced pressure. It was then diluted with 5 mL of water, the aqueous layer was then extracted with EtOAc (3×20 mL) and the combined organic extracts were washed with water, brine, dried with Na₂S0₄, filtered and concentrated. Purification via flash chromatography gave 1J (orange oil, 260 mg, 0.746 mmol, 83 % yield). LC-MS Anal. Calc’d for Ci₉H₂₈N₂0₄ 348.20, found:

[M+H] 349.31 , T_r = 3.87 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ

7.66 – 7.61 (m, 1H), 7.31 – 7.25 (m, 1H), 7.04 (d, J=8.8 Hz, 1H), 3.47 (s, 3H), 2.90 (d, J=7.3 Hz, 4H), 2.54 – 2.44 (m, 1H), 2.14 – 2.04 (m, 1H), 1.89 (dquin, J=13.5, 6.8 Hz, 2H),

1.67 (dt, J=7.5, 5.5 Hz, 1H), 1.42 – 1.31 (m, 1H), 0.83 (dd, J=6.6, 1.1 Hz, 12H)

IK. (lR,2S)-methyl 2-(3-amino-4-(diisobutylamino)phenyl)

cyclopropanecarboxylate

To a stirred solution of 1 J (100 mg, 0.287 mmol) in EtOAc (5mL) was added palladium on carbon (30.5 mg, 0.029 mmol) and the suspension was hydrogenated (1 atm, balloon) for 2 h. LC-MS indicated completion. The suspension was filtered through a pad of Celite and the filter cake was rinsed with EtOAc (20 mL). Combined filtrate and rinses were concentrated. Purification via flash chromatography gave IK (yellow oil, 90 mg, 0.287 mmol, 99 % yield). LC-MS Anal. Calc’d for Ci₉H₃oN₂0₂ 318.23, found:

[M+H] 319.31 , T_r = 2.72 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 6.95 (d, J=8.1 Hz, 1H), 6.65 (d, J=1.8 Hz, 1H), 6.60 (dd, J=8.1 , 1.5 Hz, 1H), 4.08 (br. s., 2H), 3.42 (s, 3H), 2.58 (d, J=7.0 Hz, 4H), 2.52 – 2.42 (m, 1H), 2.09 – 1.98 (m, 1H), 1.79 – 1.59 (m, 3H), 1.32 – 1.22 (m, 1H), 0.94 – 0.84 (m, 12H)

Enantiomer 1 was prepared following the urea formation and saponification procedure in racemic example 1 method A. Chiral analytical analysis verified it was enantiomer 1 with 98.1% ee (Method J).

Example 1 – Method C Enantiomer 2

(lS,2R)-2-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Example 1 Enantiomer 2 was prepared following the procedure for Example 1 enantiomer 1 method C using diastereomer 2 instead of diastereomer 1. Chiral analytical analysis verified it was enantiomer 2 with 94.0% ee (Method J).

PAPER

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00171

Development of a Scalable Synthesis of BMS-978587 Featuring a Stereospecific Suzuki Coupling of a Cyclopropane Carboxylic Acid

Prantik Maity^†, V. V. Ramana Reddy^†, Jayaraj Mohan^†, Satish Korapati^†, Harishkumar Narayana^†, Nagesh Cherupally^†, Sathishkumar Chandrasekaran^†, Ravikumar Ramachandran^†, Chris Sfouggatakis^‡, Martin D. Eastgate^‡

, Eric M. Simmons^‡

, and Rajappa Vaidyanathan *^†

^† Chemical Development and API Supply, Biocon Bristol-Myers Squibb Research and Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore-560099, India

^‡ Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00171

*E-mail: vaidy@bms.com.

A modified synthetic route to BMS-978587 was developed featuring a chemoselective nitro reduction and a stereospecific Suzuki coupling as the key bond formation steps. A systematic evaluation of the reaction conditions led to the identification of a robust catalyst/ligand/base combination to reproducibly effect the Suzuki reaction on large scale. The modified route avoided several challenges with the original synthesis and furnished the API in high overall yield and purity without recourse to chromatography.

(1R,2S)-2-[4-(Di-isobutylamino)-3-(3-(p-tolyl)ureido)phenyl] Cyclopropanecarboxylic Acid (1)

………… afford 1 as a white solid (510 g, 99.05 HPLC area % purity, 96.0% potency, 60% yield; Pd content: <10 ppm).

¹H NMR (300 MHz, DMSO-d₆) 11.83 (br s, 1H), 9.30 (s, 1H), 7.90 (d, 1H, J = 1.5 Hz), 7.82 (s, 1H), 7.35–7.37 (d, 2H, J = 8.1 Hz), 7.06–7.10 (q, 3H, J = 2.1, 6.3, and 2.1 Hz), 6.78–6.80 (t, 1H, J = 6.3 and 1.8 Hz), 2.50–2.72 (m, 4H), 2.25 (s, 3H), 1.934–2.01 (m, 1H), 1.59–1.65 (m, 2H), 1.20–1.41 (m, 2H), 0.81(m, 13H);

¹³C NMR (100 MHz, DMSO-d₆) 172.2, 153.0, 139.0, 137.8, 135.2, 133.1, 131.2, 129.6, 123.0, 122.1, 121.4, 119.4, 63.6, 26.3, 25.3, 21.9, 21.6, 20.8, 11.4.

HRMS (ESI) m/zcalcd for C₂₆H₃₆N₃O₃ [M + H]⁺ 438.2757, found 438.2714.

REF

(a) Balog, J. A.; Huang, A.; Chen, B.; Chen, L.; Seitz, P.; Hart, A. C.; Markwalder, J. A. Preparation of cycloalkylaryl amide compounds as indoleamine 2,3-dioxygenase and therapeutic uses thereof, PCT Int. Appl. 2014, WO 2014150677A1 20140925.

(b) Balog, J. A.; Cherney, E. C.; Guo, W.; Huang, A.; Markwalder, J. A.; Seitz, S. P.; Shan, W.; Williams, D. K.; Murugesan, N.; Nara, S.Jethanand; Preparation of benzenediamine derivatives as inhibitors of indoleamine 2,3-dioxygenase for the treatment of cancer, PCT Int. Appl. 2016, WO 2016161269A1 20161006.

(c) Markwalder, J. A.; Seitz, S. P.; Hart, A.; Nation, A.; Balog, A.; Vite, G.; Borzilleri, R.; Jure-Kunkel, M.; Chen, B.; Chen, L.; Newitt, J.; Lu, H.; Abell, L.; Lin, T.-A.; Covello, K.; Hunt, J.; D’Arienzo, C.; Fargnoli, J.; Ranasinghe, A.; Traeger, S. C. Manuscript in preparation.

Swift, E. C.; Jarvo, E. R. Asymmetric transition metal-catalyzed cross-coupling reactions for the construction of tertiary stereocenters. Tetrahedron 2013, 69, 5799– 5817, DOI: 10.1016/j.tet.2013.05.001

Proceedings of the National Academy of Sciences of the United States of America2018vol. 115 13p. 3249 – 3254

////////////BMS-978587, IDO-IN-4, 1629125-65-0, CS-5086, BMS978587, BMS 978587

OC(=O)[C@@H]3C[C@@H]3c2cc(NC(=O)Nc1ccc(C)cc1)c(cc2)N(CC(C)C)CC(C)C

FDA approves first cancer drug Kisqali (ribociclib) through new oncology review pilot that enables greater development efficiency FDA expands the use of breast cancer drug

July 19, 2018 1:04 am / Leave a comment

FDA approves first cancer drug through new oncology review pilot that enables greater development efficiency FDA expands the use of breast cancer drug

The U.S. Food and Drug Administration today approved Kisqali (ribociclib) in combination with an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy. The FDA also approved Kisqali in combination with fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine based therapy or following disease progression on endocrine therapy.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm613801.htm?utm_campaign=07182018_PR_FDA%20expands%20the%20use%20of%20breast%20cancer%20drug&utm_medium=email&utm_source=Eloqua

July 18, 2018

Release

This is the first approval that FDA has granted as a part of two new pilot programs announced earlier this year that collectively aim to make the development and review of cancer drugs more efficient, while improving FDA’s rigorous standard for evaluating efficacy and safety. With this real-time review, the FDA was able to start evaluating the clinical data as soon as the trial results become available, enabling FDA to be ready to approve the new indication upon filing of a formal application with the Agency.

The first new program, called Real-Time Oncology Review, allows for the FDA to review much of the data earlier, after the clinical trial results become available and the database is locked, before the information is formally submitted to the FDA. This allows the FDA to begin its analysis of the data earlier, and provide feedback to the sponsor on how they can most effectively analyze the data to answer key regulatory questions. The pilot focuses on early submission of data that are the most relevant to assessing safety and effectiveness of the product. Then, when the sponsor submits the application with the FDA, the review team will already be familiar with the data and in a better position to conduct a more efficient, timely, and thorough review.

The second program is a new templated Assessment Aid that the applicant uses to organize its submission into a structured format to facilitate FDA’s review of the application. By using a structured template, the FDA is able to layer its assessment into the same file submitted by the sponsor, allowing this annotated application to serve as the document that contains the FDA review. This voluntary submission form provides for a more streamlined approach to reviewing data and illustrating FDA’s analysis. It allows for drug reviewers to focus on the key benefit-risk and labeling issues rather than administrative issues.

“With this approval, we’ve demonstrated some of the benefits of the new programs that we’re piloting for our review of cancer drugs, to improve regulatory efficiency while enhancing the process for evaluating the data submitted to us. This shows that, with smart policy approaches, we can gain efficiency while also improving the rigor of our process. These new programs were designed to reduce some of the administrative issues that can add to the time and cost of the review process, including the staffing burdens on the FDA. For example, by analyzing data earlier in the process, before formal submission to the FDA, and evaluating submissions in a structured template, we can make it easier to identify earlier when applications are missing key analysis or information that can delay reviews,” said FDA Commissioner Scott Gottlieb, M.D. “With today’s approval, the FDA used these new approaches to allow the review team to start analyzing data before the actual submission of the application and help guide the sponsor’s analysis of the top-line data to tease out the most relevant information. This enabled our approval less than one month after the June 28 submission date and several months ahead of the goal date.”

These new processes are good for patients, good for health care providers, good for product developers, and good for the FDA, by allowing our staff to have more time to engage with product developers and focus on the key aspects of drug reviews. We can improve efficiency and solidify our gold standard for review.”

Currently the two pilot programs are being used for supplemental applications for already-approved cancer drugs and could later be expanded to original drugs and biologics.

Kisqali was first approved in March 2017 for use with an AI to treat HR-positive, HER2-negative breast cancer in post-menopausal women whose cancer is advanced or has spread to other parts of the body.

“The approval adds a new treatment choice for patients with breast cancer,” 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 bring more treatment options to patients.”

Breast cancer is the most common form of cancer in the United States. The National Cancer Institute at the National Institutes of Health estimates approximately 266,120 women will be diagnosed with breast cancer this year and 40,920 will die of the disease. Approximately 72 percent of patients with breast cancer have tumors that are HR-positive and HER2-negative.

The efficacy of Kisqali in combination with an AI for pre/perimenopausal women was demonstrated in a clinical trial of 495 participants who received either Kisqali and an AI or placebo and an AI. All pre- or peri-menopausal patients on this study received ovarian suppression with goserelin. The trial measured progression-free survival (PFS), which is generally the amount of time after the start of this treatment during which the cancer does not substantially grow and the patient is alive. PFS was longer for patients taking Kisqali plus an AI (median PFS of 27.5 months) compared to patients who received placebo plus an AI (median PFS of 13.8 months).

The efficacy of Kisqali in combination with fulvestrant in treating advanced or metastatic breast cancer was demonstrated in a clinical trial that included 726 participants who received either Kisqali and fulvestrant or placebo and fulvestrant. The trial measured PFS, which was longer for patients taking Kisqali plus fulvestrant (median PFS of 20.5 months) compared to patients who received placebo plus fulvestrant (median PFS of 12.8 months).

The common side effects of Kisqali are infections, abnormally low count of a type of white blood cell (neutropenia), a reduction in the number of white cells in the blood (leukopenia), headache, cough, nausea, fatigue, diarrhea, vomiting, constipation, hair loss and rash.

Warnings include the risk of a heart problem known as QT prolongation that can cause an abnormal heartbeat and may lead to death, serious liver problems, low white blood cell counts that may result in infections that may be severe, and fetal harm.

The FDA granted Priority Review and Breakthrough Therapy designation for this indication.

The FDA granted this approval to Novartis Pharmaceuticals Corporation.

Mercaptamine bitartrate, システアミン , меркаптамин , 巯乙胺

July 18, 2018 10:43 am / Leave a comment

Cysteamine bitartrate.png Image result for mercaptamine bitartrate

Image result for mercaptamine bitartrate

Mercaptamine bitartrate

2-aminoethanethiol;2,3-dihydroxybutanedioic acid

Molecular Formula:	C₆H₁₃NO₆S
Molecular Weight:	227.231 g/mol

Cystagon; Cysteamine – Mylan/Orphan Europe; Cysteamine bitartrate

Procysbi; CYSTEAMINE BITARTRATE; 27761-19-9; CHEBI:50386; (+/-)-Tartaric Acid

INGREDIENT	UNII	CAS
Cysteamine Bitartrate	QO84GZ3TST	27761-19-9
Cysteamine Hydrochloride	IF1B771SVB	156-57-0

Cysteamine bitartrate is a mercaptoethylamine compound that is endogenously derived from the COENZYME A degradative pathway. The fact that cysteamine is readily transported into LYSOSOMES where it reacts with CYSTINE to form cysteine-cysteamine disulfide and CYSTEINE has led to its use in CYSTINE DEPLETING AGENTS for the treatment of CYSTINOSIS.

Cysteamine Bitartrate is an aminothiol salt used in the treatment of nephropathic cystinosis. Cysteamine bitartrate enters the cell and reacts with cystine producing cysteineand cysteine–cysteamine mixed disulfide compound, both of which, unlike cystine, can pass through the lysosomal membrane. This prevents the accumulation of cystinecrystals in the lysosomes of patients with cystinosis, which can cause considerable damage and eventual destruction of the cells, particularly in the kidneys. (NCI05)

Cysteamine is a simple aminothiol molecule that is used to treat nephropathic cystinosis, due to its ability to decrease the markedly elevated and toxic levels of intracellular cystine that occur in this disease and cause its major complications. Cysteamine has been associated with serum enzyme elevations when given intravenously in high doses, but it has not been shown to cause clinically apparent acute liver injury.

Given intravenously or orally to treat radiation sickness. The bitartrate salts (Cystagon® and Procysbi) have been used for the oral treatment of nephropathic cystinosis and cystinurea. The hydrochloride salt (Cystaran™) is indicated for the treatment of corneal cystine crystal accumulation in cystinosis patients.

OriginatorMylan
DeveloperAlphapharm; Mylan
ClassMercaptoethylamines; Small molecules; Sulfhydryl compounds
Mechanism of ActionGlutathione synthase stimulants

Highest Development Phases

MarketedNephropathic cystinosis
DiscontinuedUnspecified

Most Recent Events

09 Apr 2018Mercaptamine bitartrate licensed to Recordati worldwide
26 Oct 2017Chemical structure information added
31 Dec 2008Mercaptamine bitartrate oral is still in phase II/III trials for Undefined indication in European Union

DESCRIPTION: CYSTAGON® (cysteamine bitartrate) Capsules for oral administration, contain cysteamine bitartrate, a cystine depleting agent which lowers the cystine content of cells in patients with cystinosis, an inherited defect of lysosomal transport. CYSTAGON® is the bitartrate salt of cysteamine, an aminothiol, beta-mercaptoethylamine. Cysteamine bitartrate is a highly water soluble white powder with a molecular weight of 227 and the molecular formula C2H7NS · C4H6O6. It has the following chemical structure:

Cysteamine is a medication intended for a number of indications, and approved by the FDA to treat cystinosis.

It is stable aminothiol, i.e., an organic compound containing both an amine and a thiol functional groups. Cysteamine is a white, water-soluble solid. It is often used as salts of the ammonium derivative [HSCH₂CH₂NH₃]⁺^[1] including the hydrochloride, phosphocysteamine, and bitartrate.^[2]

Cysteamine molecule is biosynthesized in mammals, including humans, by the degradation of coenzyme A. The intermedia pantetheineis broken down into cysteamine and pantothenic acid.^[2] It is the biosynthetic precursor to the neurotransmitter hypotaurine.^[3]^[4]

Medical uses

Cysteamine is used to treat cystinosis. It is available by mouth (capsule and extended release capsule) and in eye drops.^[5]^[6]^[7]^[8]^[9]

Adverse effects

Topical use

The most important adverse effect related to topical use might be skin irritation.

Oral use

The label for oral formulations of cysteamine carry warnings about symptoms similar to Ehlers-Danlos syndrome, severe skin rashes, ulcers or bleeding in the stomach and intestines, central nervous symptoms including seizures, lethargy, somnolence, depression, and encephalopathy, low white blood cell levels, elevated alkaline phosphatase, and idiopathic intracranial hypertension that can cause headache, tinnitus, dizziness, nausea, double or blurry vision, loss of vision, and pain behind the eye or pain with eye movement.^[6]

The main side effects are Ehlers-Danlos syndrome, severe skin rashes, ulcers or bleeding in the stomach and intestines, central nervous symptoms, low white blood cell levels, elevated alkaline phosphatase, and idiopathic intracranial hypertension (IIH). IIH can cause headache, ringing in the ears, dizziness, nausea, blurry vision, loss of vision, and pain behind the eye or with eye movement.

Additional adverse effects of oral cysteamine include bad breath, skin odor, vomiting, nausea, stomach pain, diarrhea, and loss of appetite.^[6]

The drug is in pregnancy category C; the risks of cysteamine to a fetus are not known but it harms babies in animal models at doses less than those given to people.^[7]^[8]

For eye drops, the most common adverse effects are sensitivity to light, redness, and eye pain, headache, and visual field defects.^[8]

Interactions

There are no drug interactions for normal capsules or eye drops,^[7]^[8] but the extended release capsules should not be taken with drugs that affect stomach acid like proton pump inhibitors or with alcohol, as they can cause the drug to be released too quickly.^[6] It doesn’t inhibit any cytochrome P450 enzymes.^[6]

Pharmacology

People with cystinosis lack a functioning transporter (cystinosin) which transports cystine from the lysosome to the cytosol. This ultimately leads to buildup of cystine in lysosomes, where it crystallizes and damages cells.^[5] Cysteamine enters lysosomes and converts cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome.^[6]

Biological function

Cysteamine also promotes the transport of L-cysteine into cells, that can be further used to synthesize glutathione, which is one of the most potent intracellular antioxidants.^[4]

Cysteamine is used as a drug for the treatment of cystinosis; it removes cystine that builds up in cells of people with the disease.^[10]

History

First evidence regarding the therapeutic effect of cysteamine on cystinosis dates back to 1950s. Cysteamine was first approved as a drug for cystinosis in the US in 1994.^[6] An extended release form was approved in 2013.^[11]

Society and culture

It is approved by FDA and EMA.^[5]^[6]

In 2013, the regular capsule of cysteamine cost about $8,000 per year; the extended release form that was introduced that year was priced at $250,000 per year.^[11]

Research

It was studied in in vitro and animal models for radiation protection in the 1950s, and in similar models from the 1970s onwards for sickle cell anemia, effects on growth, its ability to modulate the immune system, and as a possible inhibitor of HIV.^[2]

In the 1970s it was tested in clinical trials for Paracetamol toxicity which it failed, and in clinical trials for systemic lupus erythematosus in the 1990s and early 2000s, which it also failed.^[2]

Clinical trials in Huntington’s disease were begun in the 1990s and were ongoing as of 2015.^[2]^[12]

As of 2013 it was in clinical trials for Parkinson’s disease, malaria, radiation sickness, neurodegenerative disorders, neuropsychiatric disorders, and cancer treatment.^[10]^[2]

It has been studied in clinical trials for pediatric nonalcoholic fatty liver disease^[13]

Horizon Pharma , following the acquisition of Raptor Pharmaceuticals (previously through its Bennu Pharmaceuticals subsidiary, and following its acquisition of Encode Pharmaceuticals , which licensed the drug from the University of California )) has developed and launched DR Cysteamine (EC Cysteamine; Procysbi), a methyl-CpG binding protein 2 (MECP2) gene modulating, oral delayed-release (DR), enteric-coated (EC), bitartrate salt formulation of mercaptamine (cysteamine).

PRODUCT PATENT, WO2007089670 ,

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007089670

hold SPC protection in most of the EU states until September 2028, and expire in the US in July 2037. In July 2018, the US FDA’s Orange Book was seen to list a patent covering product ( US8026284 and US9173851 ) of cysteamine bitartrate, that is due to expire in September 2027 and December 2034, respectively.

Cystinosis is a rare, autosomal recessive disease caused by intra-lysosomal accumulation of the amino acid cystine within various tissues, including the spleen, liver, lymph nodes, kidney, bone marrow, and eyes. Nephropathic cystinosis is associated with kidney failure that
necessitates kidney transplantation. To date, the only specific treatment for nephropathic cystinosis is the sulfhydryl agent, cysteamine. Cysteamine has been shown to lower intracellular cystine levels, thereby reducing the rate of progression of kidney failure in children.
[0004] Cysteamine, through a mechanism of increased gastrin and gastric acid production, is ulcerogenic. When administered orally to children with cystinosis, cysteamine has also been shown to cause a 3 -fold increase in gastric acid production and a 50% rise of serum gastrin levels. As a consequence, subjects that use cysteamine suffer
gastrointestinal (GI) symptoms and are often unable to take cysteamine regularly or at full dose .

[0005] To achieve sustained reduction of leukocyte cystine levels, patients are normally required to take oral cysteamine every 6 hours, which invariably means having to awaken from sleep. However, when a single dose of
cysteamine was administered intravenously the leukocyte cystine level remained suppressed for more than 24 hours, possibly because plasma cysteamine concentrations were higher and achieved more rapidly than when the drug is administered orally. Regular intravenous administration of cysteamine would not be practical. Accordingly, there is a need for formulations and delivery methods that would result in higher plasma, and thus intracellular, concentration as well as decrease the number of daily doses and therefore improve the quality of life for patients.

PATENT

US-20180193292

Process for the preparation of cysteamine bitartrate . Represents the first patenting to be seen from Lupin Limited on cysteamine bitartrate.

Cysteamine bitartrate (I) is a cystine depleting agent which lower the cystine content of cells in patients with cystinosis, an inherited defect of lysosomal transport, it is indicated for the management of nephropathic cystinosis in children and adults. Cysteamine bitartrate (I) is simplest stable aminothiol salt and has the following structural formula:

The application WO 2014204881 provides pharmaceutical composition of cysteamine bitrate and another application WO 2007089670 provides method of administrating cysteamine and pharmaceutically salts and method of treatment thereof.

Examples

1. Preparation of Cysteamine Bitartrate.

A mixture of ethanol (1000 ml), butylated hydroxy anisole (1 g) and cysteamine hydrochloride (100 g) was stirred and cooled to 5 to 10° C. To this mixture a solution of ethanol (500 ml) and sodium hydroxide (352 g) was added over a period of 30 minutes.

The mixture was stirred at a temperature of 10 to 15° C. for 45 minutes. The mixture was filtered through celite. The filtrate was added to a mixture of ethanol (1250 ml), butylated hydroxy anisole (1 g) and L-(+)-tartaric acid (132 g) at a temperature of 55-60° C. The reaction mixture was stirred at 70-75° C. for 45 minutes. The mixture was cooled to 20-30° C. The solid was filtered, washed with ethanol and dried under vacuum.

2. Purification of Cysteamine Bitartrate.

A mixture of cysteamine bitartrate (100 g) and ethanol (5000 ml) was heated to a temperature of 77-82° C. The solution was filtered and the filtrate was cooled to 20 to 30° C. and stirred for 40 minutes. The solid was filtered, washed with ethanol and dried under vacuum. Yield: 80 g; HPLC purity: 99.90%.

3. Preparation of Crystalline Form L1 of Cysteamine Bitartrate.

A mixture of cysteamine bitartrate (50 g) and methanol (600 ml) was heated to a temperature of 35-45° C. The solution was filtered and the filtrate was cooled to 5 to 10° C. Cysteamine bitartrate (0.25 g) seed material was added to the filtrate. The slurry was cooled to −5 to −25° C. and stirred for 40 minutes. The solid was filtered, washed with precooled methanol and dried under vacuum. Yield: 40 g. Cysteamine bitartrate with X-ray powder diffraction pattern as depicted in FIG. 1 was obtained.

4. Preparation of Crystalline Form L2 of Cysteamine Bitartrate.

A mixture of cysteamine bitartrate (50 g), butylated hydroxy anisole (1.3 g) and methanol (600 ml) was heated to a temperature of 35-45° C. The solution was filtered and the filtrate was cooled to 5 to 10° C. Cysteamine bitartrate (0.25 g) seed material was added to the filtrate. The slurry was cooled to −25 to −30° C. and stirred for 40 minutes. The solid was filtered, washed with precooled methanol and the solid was dried under 800-900 mm/Hg of vacuum at 35-40° C. for 5 hours. Yield: 40 g. Cysteamine bitartrate with X-ray powder diffraction pattern as depicted in FIG. 2 was obtained.

PATENT

WO 2014204881

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014204881

PATENTS

EP3308773A1 *2016-10-112018-04-18Recordati Industria Chimica E Farmaceutica SPAFormulations of cysteamine and cysteamine derivatives

Family To Family Citations

JP2016523364A *2013-06-172016-08-08ラプターファーマシューティカルズインコーポレイテッドシステアミン組成物の分析方法

WO2017087532A1 *2015-11-162017-05-26The Regents Of The University Of CaliforniaMethods of treating non-alcoholic steatohepatitis (nash) using cysteamine compounds

WO2017157922A12016-03-182017-09-21Recordati Industria Chimica E Farmaceutica S.P.A.Prolonged release pharmaceutical composition comprising cysteamine or salt thereof,

KR20167000255A2014-06-17서방성 시스테아민 비드 투약 형태

JP2016521489A2014-06-17

CN 2014800346472014-06-17延迟释放型半胱胺珠粒调配物，以及其制备及使用方法

EP201408131322014-06-17Delayed release cysteamine bead formulation

CA 29147702014-06-17Delayed release cysteamine bead formulation, and methods of making and using same

References

Jump up^ Reid, E. Emmet (1958). Organic Chemistry of Bivalent Sulfur. 1. New York: Chemical Publishing Company, Inc. pp. 398–399.
^ Jump up to:^a ^b ^c ^d ^e ^f Besouw, M; Masereeuw, R; van den Heuvel, L; Levtchenko, E (August 2013). “Cysteamine: an old drug with new potential”. Drug Discovery Today. 18 (15–16): 785–92. doi:10.1016/j.drudis.2013.02.003. PMID 23416144.
Jump up^ Singer, Thomas P (1975). “Oxidative Metabolism of Cysteine and Cystine”. In Greenberg, David M. Metabolic pathways Vol. 7. Metabolism of sulfur compounds (3rd ed.). New York: Academic Press. p. 545. ISBN 9780323162081.
^ Jump up to:^a ^b Besouw, Martine; Masereeuw, Rosalinde; van den Heuvel, Lambert; Levtchenko, Elena (August 2013). “Cysteamine: an old drug with new potential”. Drug Discovery Today. 18(15–16): 785–792. doi:10.1016/j.drudis.2013.02.003. ISSN 1878-5832. PMID 23416144.
^ Jump up to:^a ^b ^c Nesterova, Galina; Gahl, William A. (October 6, 2016). “Cystinosis”. GeneReviews. University of Washington, Seattle.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “US Label: Cysteamine bitartrate delayed-release capsules” (PDF). FDA. August 2015.
^ Jump up to:^a ^b ^c “US Label: Cysteamine bitartrate capsules” (PDF). FDA. June 2007.
^ Jump up to:^a ^b ^c ^d “US Label: Cysteamine ophthalmic solution” (PDF). FDA. October 2012.
Jump up^ Shams, F; Livingstone, I; Oladiwura, D; Ramaesh, K (10 October 2014). “Treatment of corneal cystine crystal accumulation in patients with cystinosis”. Clinical ophthalmology (Auckland, N.Z.). 8: 2077–84. doi:10.2147/OPTH.S36626. PMC 4199850 . PMID 25336909.
^ Jump up to:^a ^b Besouw, Martine; Masereeuw, Rosalinde; van den Heuvel, Lambert; Levtchenko, Elena (August 2013). “Cysteamine: an old drug with new potential”. Drug Discovery Today. 18(15–16): 785–792. doi:10.1016/j.drudis.2013.02.003. ISSN 1878-5832. PMID 23416144.
^ Jump up to:^a ^b Pollack, Andrew (30 April 2013). “F.D.A. Approves Raptor Drug for Form of Cystinosis”. The New York Times.
Jump up^ Shannon, KM; Fraint, A (15 September 2015). “Therapeutic advances in Huntington’s Disease”. Movement disorders : official journal of the Movement Disorder Society. 30 (11): 1539–46. doi:10.1002/mds.26331. PMID 26226924.
Jump up^ Mitchel, EB; Lavine, JE (November 2014). “Review article: the management of paediatric nonalcoholic fatty liver disease”. Alimentary pharmacology & therapeutics. 40 (10): 1155–70. doi:10.1111/apt.12972. PMID 25267322.

ysteamine
Clinical data

Skeletal formula (top) Ball-and-stick model of the cysteamine
Synonyms	2-Aminoethanethiol β-Mercaptoethylamine 2-Mercaptoethylamine Decarboxycysteine Thioethanolamine Mercaptamine
License data	EU EMA: by Mercaptamine bitartrate
Identifiers
IUPAC name [show]
CAS Number	60-23-1
PubChemCID	6058
IUPHAR/BPS	7440
DrugBank	DB00847
ChemSpider	5834
UNII	5UX2SD1KE2
KEGG	D03634
ChEBI	CHEBI:17141
ChEMBL	CHEMBL602
ECHA InfoCard	100.000.421
Chemical and physical data
Formula	C₂H₇NS
Molar mass	77.15 g·mol⁻¹
Melting point	95 to 97 °C (203 to 207 °F)

Title: Cysteamine

CAS Registry Number: 60-23-1

CAS Name: 2-Aminoethanethiol

Additional Names: mercaptamine; b-mercaptoethylamine; 2-aminoethyl mercaptan; thioethanolamine; decarboxycysteine; MEA; mercamine

Manufacturers’ Codes: L-1573

Trademarks: Becaptan (Labaz); Lambratene (formerly) (Cilag Italiano)

Molecular Formula: C2H7NS

Molecular Weight: 77.15

Percent Composition: C 31.14%, H 9.15%, N 18.16%, S 41.56%

Line Formula: HSCH2CH2NH2

Literature References: A sulfhydryl compound with a variety of biological effects. Prepn: Gabriel, Leupold, Ber. 31, 2837 (1898); Knorr, Rössler, ibid. 36, 1281 (1903); Mills, Jr., Bogart, J. Am. Chem. Soc. 62, 1173 (1940); Wenker, ibid. 57, 2328 (1935); D. A. Shirley, Preparation of Organic Intermediates (Wiley, New York, 1951) p 189. Use in treatment of paracetamol (acetaminophen) poisoning: L. F. Prescott et al., Lancet 2, 109 (1976); A. L. Harris, Br. Med. J. 284, 825 (1982). Effects in nephropathic cystinosis: M. Yudkoff et al., N. Engl. J. Med. 304, 141 (1981). Radioprotective effects: R. P. Bird, Radiat. Res. 72, 290 (1980); C. J. Koch, R. L. Howell, ibid. 87, 265 (1981). Cysteamine has been shown to be a duodenal ulcerogen in rats: H. Selye, S. Szabo, Nature 244,458 (1973); S. Szabo, Am. J. Pathol. 93, 273 (1978); P. Kirkegaard et al., Scand. J. Gastroenterol. 15, 621 (1980). Review: S. Szabo, Lab. Invest. 51, 121 (1984). It has also been found to deplete somatostatin concentration: S. Szabo, S. Reichlein, Endocrinology 109, 2255 (1981); S. M. Sagar et al., J. Neurosci. 2, 225 (1982). In pituitary tissue, cysteamine is a potent depletor of prolactin concentrations in vivo and in vitro: W. J. Millard et al., Science 217, 452 (1982). Toxicity studies: E. Beccari et al.,Arzneim.-Forsch. 5, 421 (1955); D. L. Klayman et al., J. Med. Chem. 12, 510 (1969); P. K. Srivastava, L. Field, ibid. 18, 798 (1975).

Properties: Crystals by sublimation in vacuo. Disagreeable odor. mp 97-98.5°. Oxidizes to cystamine on standing in air. Freely sol in water, alkaline reaction. LD50 in mice (mg/kg): 625 orally; 250 i.p. (Klayman); (Srivastava, Field).

Melting point: mp 97-98.5°

Toxicity data: LD50 in mice (mg/kg): 625 orally; 250 i.p. (Klayman); (Srivastava, Field)

Derivative Type: Hydrochloride

Molecular Formula: C2H7NS.HCl

Molecular Weight: 113.61

Percent Composition: C 21.14%, H 7.10%, N 12.33%, S 28.22%, Cl 31.21%

Properties: Crystals from alc, mp 70.2-70.7°. Sol in water, alcohol. LD50 (cg/kg): 23.19 i.p. in rats; 14.95 i.v. in rabbits (Beccari).

Melting point: mp 70.2-70.7°

Toxicity data: LD50 (cg/kg): 23.19 i.p. in rats; 14.95 i.v. in rabbits (Beccari)

Use: Experimentally as a radioprotective agent and to produce acute and chronic duodenal ulcers in rats.

Therap-Cat: Antidote to acetaminophen.

Keywords: Antidote (Acetaminophen Poisoning)

///////////Mercaptamine bitartrate, Cystagon, Cysteamine, Cysteamine bitartrate, Mercaptamine,, システアミン , меркаптамин , 巯乙胺

C(CS)N.C(C(C(=O)O)O)(C(=O)O)O

National award to Anthony Melvin Crasto for contribution to Pharma society from Times Network for Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai, India

July 14, 2018 2:18 pm / 4 Comments on National award to Anthony Melvin Crasto for contribution to Pharma society from Times Network for Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai, India

DR ANTHONY MEVIN CRASTO Conferred prestigious individual national award at function for contribution to Pharma society from Times Network, National Awards for Marketing Excellence ( For Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai India

////////////National award, contribution to Pharma society, Times Network, Excellence in HEALTHCARE, 5th July, 2018, Taj Lands End, Mumbai, India, ANTHONY CRASTO

#hotpersoninawheelchair
#worlddrugtracker

Tecovirimat

July 14, 2018 2:05 am / Leave a comment

ChemSpider 2D Image | Tecovirimat | C19H15F3N2O3

Tecovirimat

Molecular FormulaC₁₉H₁₅F₃N₂O₃
Average mass376.329 Da

816458-31-8 [RN]

869572-92-9 [RN]

UNII-F925RR824R

тековиримат [Russian]

تيكوفيريمات [Arabic]

替韦立马 [Chinese]

Benzamide, N-[(3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-

N-[(1R,2R,6S,7S,8S,10R)-3,5-Dioxo-4-azatetracyclo[5.3.2.0^2,6.0^8,10]dodec-11-en-4-yl]-4-(trifluoromethyl)benzamide

INGREDIENT	UNII	CAS	INCHI KEY
Tecovirimat monohydrate	SB96YO2BR8	1162664-19-8	QRHXYGPOQKLBJP-NPIFKJBVSA-N

Tecovirimat, sold under the brand name Tpoxx among others,^[6] is an antiviral medication with activity against orthopoxviruses such as smallpox and monkeypox.^[4]^[7]^[8] It is the first antipoxviral drug approved in the United States.^[9]^[10] It is an inhibitor of the orthopoxvirus VP37 envelope wrapping protein.^[4]

The drug works by blocking cellular transmission of the virus, thus preventing the disease.^[11] Tecovirimat has been effective in laboratory testing; it has been shown to protect animals from monkeypox and rabbitpox and causes no serious side effects in humans.^[6] Tecovirimat was first used for treatment in December 2018, after a laboratory-acquired vaccinia virus infection.^[12]

Two million doses of tecovirimat are stockpiled in the US Strategic National Stockpile should an orthopoxvirus-based bioterror attack occur.^[13]^[14] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[15]

The World Health Organization declared smallpox, a contagious and sometimes fatal infectious disease, eradicated in 1980. However, there have been longstanding concerns that smallpox may be used as a bioweapon.^2,5 Tecovirimat is an antiviral drug that was identified via a high-throughput screen in 2002.² It is effective against all orthopoxviruses, including vaccinia, cowpox, ectromelia, rabbitpox, monkeypox, and Variola (smallpox) virus.^1,4

Tecovirimat was approved by the FDA in July 2018 as the first drug ever approved to treat smallpox.^6,5 Tecovirimat was later approved by Health Canada in December 2021,⁷ followed by the approval from the European Commission in January 2022.⁹ Other than smallpox, tecovirimat is also indicated to treat complications due to replication of the vaccinia virus following vaccination against smallpox, and to treat monkeypox and cowpox in adults and children.⁸ Tecovirimat is available as both oral and intravenous formulations.¹⁰

Medical uses

In the United States, tecovirimat is indicated for the treatment of human smallpox disease.^[4] In the European Union it is indicated for the treatment of smallpox, monkeypox, and cowpox.^[5]

Mechanism of action

Tecovirimat inhibits the function of a major envelope protein required for the production of extracellular virus. The drug prevents the virus from leaving an infected cell, hindering the spread of the virus within the body.^[16]

Chemistry

The first synthesis of tecovirimat was published in a patent filed by scientists at Siga Technologies in 2004. It is made in two steps from cycloheptatriene.^[17]

A Diels–Alder reaction with maleic anhydride forms the main ring system^[18] and subsequent reaction with 4-trifluormethylbenzhydrazide gives the cyclic imide of the drug.^[17]^[19]

Synthesis

US 9,546,137 [2017, to SIGA TECH INC]

SYNTHESIS FROM SMARTCHEM

The scheme has taken from SmartChem a knowledgebase by ROW2 Technologies, Inc. (www.row2technologies.com)

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SYN 1

Synthetic Description

Reference: Dong, Ming-xin; Li, Hai-tao; Wang, Xiao-hua; Mao, Wen-xiang; Zhou, Shang-min; Dai, Qiu-yun. Preparation and structural determination of tecovirimat monohydrate crystal. Zhongguo Xinyao Zazhi. Volume 21. Issue 23. Pages 2736-2739. (2012).

SYN 2

Synthetic Description

Reference: Dai, Dongcheng. Process for the preparation of tecovirimat. Assignee Siga Technologies, Inc., USA. WO 2014028545. (2014).

SYN 3

Synthetic Description

Reference: Medical composition containing ST-246, its preparation and anti-poxvirus application. Assignee Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, PLA, Peop. Rep. China. CN 101912389. (2010).

EMA

Click to access tecovirimat-siga-epar-public-assessment-report_en.pdf

PATENT

https://patents.google.com/patent/US9546137B2/en

The present invention provides a process for making ST-246 outlined in Scheme 1

The present invention also provides a process for making ST-246 outlined in Scheme 2

The present invention further provides a process for making ST-246 outlined in Scheme 3

The present invention also provides a process for making ST-246 outlined in Scheme 4

The present invention further provides a process for making ST-246 outlined in Scheme 5

The present invention also provides the following compounds useful in the synthesis of ST-246:

EXAMPLE 1Synthetic Route I

Step A. Synthesis of Compound 6 (P=Boc)

To a mixture of compound 3 (5.0 g, 26.3 mmol, synthesized according to WO04112718) in EtOH (80 mL, EMD, AX0441-3) was added tert-butyl carbazate 5 (3.65 g, 27.6 mmol, Aldrich, 98%). The reaction mixture was heated to reflux for 4 h under nitrogen atmosphere. LC-MS analysis of the reaction mixture showed less than 5% of compound 3 remained. The reaction mixture was evaporated under reduced pressure. The residue was recrystallized from EtOAc-hexanes, the solid was filtered, washed with hexanes (50 mL) and dried under vacuum to afford compound 6 (3.1 g, 39% yield) as a white solid. The filtrate was concentrated and purified by column chromatography eluting with 25% EtOAc in hexanes to give an additional 3.64 g (46% yield) of compound 6 as a white solid. Total yield: 6.74 g (84% yield). ¹H NMR in CDCl₃: δ 6.30 (br s, 1H), 5.79 (t, 2H), 3.43 (s, 2H), 3.04 (s, 2H), 1.46 (s, 9H), 1.06-1.16 (m, 2H), 0.18-0.36 (m, 2H); Mass Spec: 327.2 (M+Na)⁺

Step B. Synthesis of Compound 7 (HCl Salt)

Compound 6 (3.6 g, 11.83 mmol) was dissolved in i-PrOAc (65 mL, Aldrich, 99.6%). 4M HCl in dioxane (10.4 mL, 41.4 mmol, Aldrich) was added drop-wise to the above solution keeping the temperature below 20° C. The reaction mixture was stirred at room temperature overnight (18 h) under nitrogen atmosphere. The resulting solid was filtered, washed with i-PrOAc (15 mL) and dried under vacuum to yield HCl salt of compound 7 (1.9 g, 67% yield) as a white solid. The filtrate was concentrated to ⅓ its volume and stirred at 10-15° C. for 30 min. The solid was filtered, washed with minimal volume of i-PrOAc and dried to afford additional 0.6 g (21% yield) of compound 7. Total yield: 2.5 g (88% yield). ¹H NMR in DMSO-d6: δ 6.72 (br s, 3H), 5.68 (m, 2H), 3.20 (s, 2H), 3.01 (s, 2H), 1.07-1.17 (m, 2H), 0.18-0.29 (m, 1H), −0.01-0.07 (m, 1H); Mass Spec: 205.1 (M+H)⁺

Step C. Synthesis of ST-246

To a mixture of compound 7 (0.96 g, 4 mmol) in dry dichloromethane (19 mL) was added triethylamine (1.17 mL, 8.4 mmol, Aldrich) keeping the temperature below 20° C. The resulting solution was stirred for 5 minutes at 15-20° C., to it was added drop-wise 4-(trifluoromethyl)benzoyl chloride 8 (0.63 mL, 4.2 mmol, Aldrich, 97%) and the reaction mixture was stirred at room temperature overnight (18 h). LC-MS and TLC analysis showed the correct molecular weight and R_fvalue of ST-246 but the reaction was not complete. Additional 0.3 mL (2 mmol, 0.5 eq) of 4-(trifluoromethyl)benzoyl chloride 8 was added to the reaction mixture at 15-20° C. The reaction was then stirred at room temperature overnight (19 h). LC-MS analysis indicated ca. 5% of starting material 7 still remained. The reaction was stopped and dichloromethane (30 mL) was added. The organic phase was washed with water (30 mL), saturated aqueous NH₄Cl (30 mL), water (15 mL) and saturated aqueous NaHCO₃(30 mL). The organic phase was separated, dried over Na₂SO₄, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 30-50% EtOAc in hexanes to afford ST-246 (0.34 g, 23% yield) as an off-white solid. Analytical data (¹H NMR, LC-MS and HPLC by co-injection) were matched with those of ST-246 synthesized according to WO04112718 and were consistent.

EXAMPLE 2Synthetic Route II

Step A. Synthesis of Compound 9

A mixture of compound 4 (2.0 g, 9.8 mmol) and maleic anhydride 2 (0.96 g, 9.8 mmol, Aldrich powder, 95%) in o-xylene (100 mL, Aldrich anhydrous, 97%) was heated to reflux using a Dean-Stark trap apparatus overnight. After 18 h, LC-MS analysis at 215 nm showed the desired product 9 (86%), an uncyclized product (2.6%) and a dimer by-product (11.6%).

The reaction mixture was cooled to 45° C. and evaporated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the insoluble solid (mostly uncyclized product) was removed by filtration. The filtrate was concentrated and purified by column chromatography eluting with 50% EtOAc in hexanes to yield compound 9 (1.5 g, 54% yield) as an off-white solid. ¹H NMR in CDCl₃: δ 8.44 (s, 1H), 7.91 (d, 2H), 7.68 (d, 2H), 6.88 (s, 2H); Mass Spec: 285.1 (M+H)⁺

Step B. Synthesis of ST-246 (Route II)

A mixture of compound 9 (0.97 g, 3.4 mmol) and cycloheptatriene 1 (0.51 mL, 4.42 mmol, distilled before use, Aldrich tech 90%) in toluene (50 mL, Aldrich anhydrous) was heated at 95° C. under nitrogen atmosphere. After 1.5 h at 95° C., LC-MS analysis at 254 nm showed 29% conversion to the desired product (endo:exo=94:6). The resulting solution was continued to be heated at same temperature overnight. After 18 h at 95° C., LC-MS analysis indicated 75% conversion with an endo:exo ratio of 94:6. The reaction temperature was increased to 110° C. and the reaction was monitored. After heating at 110° C. for 7 h, LC-MS analysis at 254 nm showed 96.4% conversion to the desired product (endo:exo=94:6). The volatiles were removed by evaporation under reduced pressure and the reside was purified by column chromatography eluting with 30% EtOAc in hexanes to afford ST-246 (0.29 g, 22.6% yield, HPLC area 99.7% pure and 100% endo isomer) as a white solid. Analytical data (¹H NMR, LC-MS and HPLC by co-injection) were matched with those of ST-246 synthesized according to WO04112718 and were consistent. An additional 0.5 g of ST-246 (38.9% yield, endo:exo=97:3) was recovered from column chromatography. Total Yield: 0.84 g (65.4% yield). ¹H NMR of ST-246 exo isomer in CDCl₃: δ 8.62 (s, 1H), 7.92 (d, 2H), 7.68 (d, 2H), 5.96 (m, 2H), 3.43 (s, 2H), 2.88 (s, 2H), 1.17 (s, 2H), 0.24 (q, 1H), 0.13 (m, 1H); Mass Spec: 377.1 (M+H)⁺

EXAMPLE 3Synthetic Route III

Step A. Synthesis of Compound 10

A mixture of maleic anhydride 2 (15.2 g, 155 mmol, Aldrich powder 95%) and tert-butyl carbazate 5 (20.5 g, 155 mmol, Aldrich, 98%) in anhydrous toluene (150 mL, Aldrich anhydrous) was heated to reflux using a Dean-Stark trap apparatus under nitrogen atmosphere. After refluxing for 2 h, no starting material 2 remained and LC-MS analysis at 254 nm showed the desired product 10 (20% by HPLC area), imine by-product (18%) and disubstituted by-product (56%). The reaction mixture was concentrated and purified by column chromatography eluting with 25% EtOAc in hexanes to afford compound 10 (5.98 g, 18% yield, HPLC area >99.5% pure) as a white solid. ¹H NMR in DMSO-d6: δ 9.61 (s, 1H), 7.16 (s, 2H), 1.42 (s, 9H); Mass Spec: 235.1 (M+Na)⁺.

Step B. Synthesis of Compound 11 (HCl salt)

Compound 10 (3.82 g, 18 mmol) was dissolved in i-PrOAc (57 mL, Aldrich, 99.6%). 4M HCl in dioxane (15.8 mL, 63 mmol, Aldrich) was added drop-wise to the above solution keeping the temperature below 20° C. The solution was stirred overnight (24 h) at room temperature under nitrogen atmosphere. The resulting solid was filtered, washed with i-PrOAc (10 mL) and dried at 45° C. under vacuum for 1 h to afford HCl salt of compound 11 (2.39 g, 89% yield) as a white solid. ¹H NMR in CD₃OD: δ 6.98 (s, 2H); Mass Spec: 113.0 (M+H)⁺

Step C. Synthesis of Compound 9 (Route III)

To a mixture of compound 11 (1.19 g, 8 mmol) in dry dichloromethane (24 mL) was added diisopropylethylamine (2.93 mL, 16.8 mmol, Aldrich redistilled grade) keeping the temperature below 20° C. The resulting solution was stirred for 5 minute at 15-20° C. and to it was added 4-(trifluoromethyl)benzoyl chloride 8 (1.31 mL, 8.8 mmol, Aldrich, 97%) drop-wise. The reaction was stirred at room temperature for 5 h. LC-MS analysis showed the correct MW but the reaction was not complete. Additional 0.48 mL (0.4 equiv) of 4-(trifluoromethyl)benzoyl chloride 8 was added to the reaction mixture at 15-20° C. and the reaction mixture was stirred at room temperature overnight (21 h). The reaction was stopped and dichloromethane (50 mL) was added. The organic phase was washed with water (50 mL), saturated aqueous NH₄Cl (50 mL), water (30 mL) and saturated aqueous NaHCO₃(30 mL). The organic phase was separated, dried over Na₂SO₄, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 30-35% EtOAc in hexanes to afford compound 9 (0.8 g, 35% yield) as a light pink solid. Analytical data (¹H NMR and LC-MS) were consistent with those of compound 9 obtained in Synthetic Route II.

Step D. Synthesis of ST-246 (Route III)

A mixture of compound 9 (0.5 g, 1.76 mmol) and cycloheptatriene 1 (0.33 mL, 3.17 mmol, distilled before to use, Aldrich tech 90%) in toluene (10 mL, Aldrich anhydrous) was heated at 110-115° C. under nitrogen atmosphere. After 6 h, LC-MS analysis at 254 nm showed 95% conversion to the desired product (endo:exo=94:6). The resulting solution was heated at same temperature overnight (22 h). LC-MS analysis at 254 nm showed no starting material 9 remained and the desired product (endo:exo=93:7). The reaction mixture was concentrated and purified by column chromatography eluting with 25-35% EtOAc in hexanes to afford ST-246 (0.39 g, HPLC area >99.5% pure with a ratio of endo:exo=99:1) as a white solid. Analytical data (¹H NMR, LC-MS and HPLC by co-injection) were compared with those of ST-246 synthesized according to WO04112718 and were found to be consistent. An additional 0.18 g of ST-246 (HPLC area >99.5% pure, endo:exo=91:9) was recovered from column chromatography. Total Yield: 0.57 g (86% yield).

EXAMPLE 4Synthetic Route IV

Step A. Synthesis of Compound 10

A mixture of maleic anhydride 2 (3.4 g, 34.67 mmol, Aldrich powder, 95%) and tert-butyl carbazate 5 (4.6 g, 34.67 mmol, Aldrich, 98%) in anhydrous toluene (51 mL, Aldrich) was heated to reflux using a Dean-Stark trap apparatus under nitrogen atmosphere. After refluxing for 2.5 h, no starting material 2 remained and LC-MS analysis at 254 nm showed the desired product 10 (19% HPLC area), imine by-product (18%) and another by-product (56%). The reaction mixture was concentrated and purified by column chromatography eluting with 30% EtOAc in hexanes to afford compound 10 (1.0 g, 13.6% yield, HPLC area >99% pure) as a white solid. Analytical data (¹H NMR and LC-MS) were consistent with those of compound 10 obtained in Synthetic Route III.

Step B. Synthesis of Compound 6

A mixture of compound 10 (4.4 g, 20.74 mmol) and cycloheptatriene 1 (3.22 mL, 31.1 mmol, distilled before to use, Aldrich tech 90%) in toluene (88 mL, 20 volume, Aldrich anhydrous) was heated at 95° C. under nitrogen atmosphere. After 15 h at 95° C., LC-MS analysis showed 83% conversion to the desired product. The reaction mixture was heated at 105° C. overnight. After total 40 h at 95-105° C., LC-MS analysis at 254 nm showed ˜99% conversion to the desired product (endo:exo=93:7). The reaction mixture was concentrated and the crude was purified by column chromatography eluting with 25-50% EtOAc in hexanes to afford compound 6 (2.06 g, 32.6% yield, HPLC area 99.9% pure and 100% endo isomer) as a white solid. ¹H NMR and LC-MS were consistent with those of compound 6 obtained in Synthetic Route I. An additional 4.0 g of 6 (63.4% yield, HPLC area 93% pure with a ratio of endo:exo=91:9) was recovered from column chromatography. Total Yield: 6.06 g (96% yield).

Step C. Synthesis of Compound 7 (HCl salt)

Compound 6 (2.05 g, 6.74 mmol) was dissolved in i-PrOAc (26 mL, Aldrich, 99.6%). 4M HCl in dioxane (5.9 mL, 23.58 mmol, Aldrich) was added drop-wise to the above solution keeping the temperature below 20° C. The solution was stirred overnight (18 h) at room temperature under nitrogen atmosphere. The resulting solid was filtered, washed with i-PrOAc (5 mL) and dried under vacuum to yield HCl salt of compound 7 (1.57 g, 97% yield) as a white solid. Analytical data (¹H NMR and LC-MS) were consistent with those of compound 7 in Synthetic Route I.

Step D. Synthesis of ST-246 (Route IV)

To a mixture of compound 7 (0.84 g, 3.5 mmol) in dichloromethane (13 mL) was added diisopropylethylamine (1.34 mL, 7.7 mmol) keeping the temperature below 20° C. and the resulting solution was stirred for 5-10 minutes. 4-(Trifluoromethyl)benzoyl chloride 8 (0.57 mL, 3.85 mmol, Aldrich, 97%) was added to above solution keeping the temperature below 20° C. The reaction mixture was stirred at room temperature for 2 h. Additional 0.2 mL (0.4 equiv) of 4-(trifluoromethyl)benzoyl chloride 8 was added to the reaction keeping the temperature below 20° C. The reaction was stirred at room temperature overnight (24 h). The reaction mixture was diluted with dichloromethane (20 mL). The organic phase was washed with water (20 mL), saturated aqueous NH₄Cl (20 mL), water (20 mL) and saturated aqueous NaHCO₃(20 mL). The organic phase was separated, dried over Na₂SO₄, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 30-35% EtOAc in hexanes to afford ST-246 (0.25 g, 19% yield, HPLC area >99.5% pure) as a white solid. Analytical data (¹H NMR and LC-MS) were consistent with those of ST-246 synthesized according to WO04112718.

EXAMPLE 5Synthetic Route V

Step A. Synthesis of Compound 13

To a mixture of compound 7 (1.6 g, 6.65 mmol, synthesized according to Synthetic Route I) in dichloromethane (80 mL,) was added triethylamine (2.04 mL, 14.63 mmol) keeping the temperature below 20° C. and the resulting solution was stirred for 5-10 minute. 4-Iodobenzoyl chloride 12 (1.95 g, 7.31 mmol, 1.1 equiv, Aldrich) was added portion-wise under nitrogen atmosphere to the above solution keeping the temperature below 20° C. The reaction mixture was stirred at room temperature overnight. After 17 h and 19 h, additional 0.35 g (0.2 equiv) of acid chloride 12 was added to the reaction keeping the temperature below 20° C. After 24 h, additional 0.18 g (0.1 equiv, used total 1.6 equiv) of acid chloride 12 was added and the reaction was continued to stir at room temperature overnight (total 43 h). LC-MS analysis at 215 nm showed 43% of the desired product (13) and ˜5% of compound 7. The reaction was diluted with dichloromethane (100 mL). The organic phase was washed with saturated aqueous NH₄Cl (100 mL), water (100 mL) and saturated aqueous NaHCO₃(100 mL). The organic phase was separated, dried over Na₂SO₄, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 25-50% EtOAc in hexanes to afford compound 13 (1.63 g, 57% yield, HPLC area 93% pure) as a white solid. ¹H NMR in DMSO-d6: δ 11.19 and 10.93 (two singlets with integration ratio of 1.73:1, total of 1H, same proton of two rotamers), 7.93 (d, 2H), 7.66 (d, 2H), 5.80 (s, 2H), 3.36 (s, 2H), 3.27 (s, 2H), 1.18 (s, 2H), 0.27 (q, 1H), 0.06 (s, 1H); Mass Spec: 435.0 (M+H)⁺

Step B. Synthesis of ST-246 (Route V)

Anhydrous DMF (6 mL) was added to a mixture of compound 13 (0.2 g, 0.46 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.44 mL, 3.45 mmol, Aldrich) and copper (I) iodide (90 mg, 0.47 mmol). The reaction mixture was stirred at −90° C. for 4 h. LC-MS analysis at 254 nm indicated no starting material 13 remained and showed 48% HPLC area of ST-246. The reaction mixture was cooled to 45° C. and DMF was removed under reduced pressure. The residue was slurried in EtOAc (30 mL) and insoluble solid was removed by filtration. The filtrate was concentrated and purified by column chromatography eluting with 25-35% EtOAc in hexanes to afford ST-246 (55 mg, 32% yield, 95% pure by HPLC at 254 nm) as off-white solid. Analytical data (¹H NMR and LC-MS) were consistent with those of ST-246 synthesized according to WO04112718.

PATENT

https://patents.google.com/patent/WO2014028545A1/en

Example 1 : Synthetic Route I:

P = Boc

Scheme 1

Step A. Synthesis of Compound 6 (P = Boc)

To a mixture of compound 3 (5.0 g, 26.3 mmol, synthesized according to WO041 12718) in EtOH (80 mL, EMD, AX0441 -3) was added terf-butyl carbazate 5 (3.65 g, 27.6 mmol, Aldrich, 98%). The reaction mixture was heated to reflux for 4 h under nitrogen atmosphere. LC-MS analysis of the reaction mixture showed less than 5% of compound 3 remained. The reaction mixture was evaporated under reduced pressure. The residue was recrystallized from EtOAc – hexanes, the solid was filtered, washed with hexanes (50 mL) and dried under vacuum to afford compound 6 (3.1 g, 39% yield) as a white solid. The filtrate was concentrated and purified by column chromatography eluting with 25% EtOAc in hexanes to give an additional 3.64 g (46% yield) of compound 6 as a white solid. Total yield: 6.74 g (84% yield). ¹H NMR in CDCI₃: δ 6.30 (br s, 1 H), 5.79 (t, 2H), 3.43 (s, 2H), 3.04 (s, 2H), 1 .46 (s, 9H), 1 .06-1 .16 (m, 2H), 0.18-0.36 (m, 2H); Mass Spec: 327.2 (M+Na)⁺

Step B. Synthesis of Compound 7 (HCI salt) Compound 6 (3.6 g, 1 1 .83 mmol) was dissolved in /^‘-PrOAc (65 mL, Aldrich, 99.6%). 4M HCI in dioxane (10.4 mL, 41 .4 mmol, Aldrich) was added drop-wise to the above solution keeping the temperature below 20 °C. The reaction mixture was stirred at room temperature overnight (18 h) under nitrogen atmosphere. The resulting solid was filtered, washed with /^‘-PrOAc (15 mL) and dried under vacuum to yield HCI salt of compound 7 (1 .9 g, 67% yield) as a white solid. The filtrate was concentrated to 1/3 its volume and stirred at 10 – 15 °C for 30 min. The solid was filtered, washed with minimal volume of /^‘-PrOAc and dried to afford additional 0.6 g (21 % yield) of compound 7. Total yield: 2.5 g (88% yield). ¹ H NMR in DMSO-d6: δ 6.72 (br s, 3H), 5.68 (m, 2H), 3.20 (s, 2H), 3.01 (s, 2H), 1 .07-1 .17 (m, 2H), 0.18-0.29 (m, 1 H), -0.01 -0.07 (m, 1 H); Mass Spec: 205.1 (M+H)⁺

Step C. Synthesis of ST-246

To a mixture of compound 7 (0.96 g, 4 mmol) in dry dichloromethane (19 mL) was added triethylamine (1 .17 mL, 8.4 mmol, Aldrich) keeping the temperature below 20 °C. The resulting solution was stirred for 5 minutes at 15 – 20 °C, to it was added drop-wise 4-(trifluoromethyl)benzoyl chloride 8 (0.63 mL, 4.2 mmol, Aldrich, 97%) and the reaction mixture was stirred at room temperature overnight (18 h). LC-MS and TLC analysis showed the correct molecular weight and R_f value of ST-246 but the reaction was not complete. Additional 0.3 mL (2 mmol, 0.5 eq) of 4-(trifluoromethyl)benzoyl chloride 8 was added to the reaction mixture at 15 – 20 °C. The reaction was then stirred at room temperature overnight (19 h). LC-MS analysis indicated ca. 5% of starting material 7 still remained. The reaction was stopped and dichloromethane (30 mL) was added. The organic phase was washed with water (30 mL), saturated aqueous NH CI (30 mL), water (15 mL) and saturated aqueous NaHCO3 (30 mL). The organic phase was separated, dried over Na₂SO₄, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 30 – 50% EtOAc in hexanes to afford ST-246 (0.34 g, 23% yield) as an off-white solid. Analytical data (¹H NMR, LC-MS and HPLC by co-injection) were matched with those of ST-246 synthesized according to WO041 12718 and were consistent. Example 2: Synthetic Route II

Scheme 2

Step A. Synthesis of Compound 9

Uncyclized product (MS = 303) Dimer by-product (MS = 489)

The reaction mixture was cooled to 45 °C and evaporated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the insoluble solid (mostly uncyclized product) was removed by filtration. The filtrate was concentrated and purified by column chromatography eluting with 50% EtOAc in hexanes to yield compound 9 (1 .5 g, 54% yield) as an off-white solid. ¹ H NMR in CDCI₃: δ 8.44 (s, 1 H), 7.91 (d, 2H), 7.68 (d, 2H), 6.88 (s, 2H); Mass Spec: 285.1 (M+H)⁺

Step B. Synthesis of ST-246 (Route II)

A mixture of compound 9 (0.97 g, 3.4 mmol) and cycloheptatriene 1 (0.51 mL, 4.42 mmol, distilled before use, Aldrich tech 90%) in toluene (50 mL, Aldrich anhydrous) was heated at 95 °C under nitrogen atmosphere. After 1 .5 h at 95 °C, LC-MS analysis at 254 nm showed 29% conversion to the desired product (endo:exo = 94:6). The resulting solution was continued to be heated at same temperature overnight. After 18 h at 95 °C, LC-MS analysis indicated 75% conversion with an endo:exo ratio of 94:6. The reaction temperature was increased to 1 10 °C and the reaction was monitored. After heating at 1 10 °C for 7 h, LC-MS analysis at 254 nm showed 96.4% conversion to the desired product (endo:exo = 94:6). The volatiles were removed by evaporation under reduced pressure and the reside was purified by column chromatography eluting with 30% EtOAc in hexanes to afford ST-246 (0.29 g, 22.6% yield, HPLC area 99.7% pure and 100% endo isomer) as a white solid. Analytical data (¹H NMR, LC-MS and HPLC by co- injection) were matched with those of ST-246 synthesized according to WO041 12718 and were consistent. An additional 0.5 g of ST-246 (38.9% yield, endo:exo = 97: 3) was recovered from column chromatography. Total Yield: 0.84 g (65.4% yield). ¹H NMR of ST-246 exo isomer in CDCI₃: δ 8.62 (s, 1 H), 7.92 (d, 2H), 7.68 (d, 2H), 5.96 (m, 2H), 3.43 (s, 2H), 2.88 (s, 2H), 1 .17 (s, 2H), 0.24 (q, 1 H), 0.13 (m, 1 H); Mass Spec: 377.1 (M+H)⁺

Example 3: Synthetic Route III

ST-246 9

P = Boc Scheme 3

Step A. Synthesis of Compound 10

A mixture of maleic anhydride 2 (15.2 g, 155 mmol, Aldrich powder 95%) and terf-butyl carbazate 5 (20.5 g, 155 mmol, Aldrich, 98%) in anhydrous toluene (150 mL, Aldrich anhydrous) was heated to reflux using a Dean-Stark trap apparatus under nitrogen atmosphere. After refluxing for 2 h, no starting material 2 remained and LC-MS analysis at 254 nm showed the desired product 10 (20% by HPLC area), imine byproduct (18%) and disubstituted by-product (56%). The reaction mixture was concentrated and purified by column chromatography eluting with 25% EtOAc in hexanes to afford compound 10 (5.98 g, 18% yield, HPLC area >99.5% pure) as a white solid. ¹ H NMR in DMSO-d6: δ 9.61 (s, 1 H), 7.16 (s, 2H), 1 .42 (s, 9H); Mass Spec: 235.1 (M+Na)⁺. duct

C₉H₁₂N₂0₄ C₁₄H₂₂N₄05

Mol. Wt.: 212.2 Mol. Wt.: 326.35

Step B. Synthesis of Compound 11 (HCI salt)

Compound 10 (3.82 g, 18 mmol) was dissolved in /^‘-PrOAc (57 mL, Aldrich, 99.6%). 4M HCI in dioxane (15.8 mL, 63 mmol, Aldrich) was added drop-wise to the above solution keeping the temperature below 20 °C. The solution was stirred overnight (24 h) at room temperature under nitrogen atmosphere. The resulting solid was filtered, washed with /^‘-PrOAc (10 mL) and dried at 45 °C under vacuum for 1 h to afford HCI salt of compound 11 (2.39 g, 89% yield) as a white solid. ¹ H NMR in CD₃OD: δ 6.98 (s, 2H); Mass Spec: 1 13.0 (M+H)⁺ Step C. Synthesis of Compound 9 (Route III)

To a mixture of compound 11 (1 .19 g, 8 mmol) in dry dichloromethane (24 mL) was added diisopropylethylannine (2.93 mL, 16.8 mmol, Aldrich redistilled grade) keeping the temperature below 20 °C. The resulting solution was stirred for 5 minute at 15 – 20 °C and to it was added 4-(trifluoromethyl)benzoyl chloride 8 (1 .31 mL, 8.8 mmol, Aldrich, 97%) drop-wise. The reaction was stirred at room temperature for 5 h. LC-MS analysis showed the correct MW but the reaction was not complete. Additional 0.48 mL (0.4 equiv) of 4-(trifluoromethyl)benzoyl chloride 8 was added to the reaction mixture at 15 – 20 °C and the reaction mixture was stirred at room temperature overnight (21 h). The reaction was stopped and dichloromethane (50 mL) was added. The organic phase was washed with water (50 mL), saturated aqueous NH₄CI (50 mL), water (30 mL) and saturated aqueous NaHCO3 (30 mL). The organic phase was separated, dried over Na₂SO₄, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 30 – 35% EtOAc in hexanes to afford compound 9 (0.8 g, 35% yield) as a light pink solid. Analytical data (¹H NMR and LC-MS) were consistent with those of compound 9 obtained in Synthetic Route II.

Step D. Synthesis of ST-246 (Route III)

A mixture of compound 9 (0.5 g, 1 .76 mmol) and cycloheptatriene 1 (0.33 mL, 3.17 mmol, distilled before to use, Aldrich tech 90%) in toluene (10 mL, Aldrich anhydrous) was heated at 1 10 – 1 15 °C under nitrogen atmosphere. After 6 h, LC-MS analysis at 254 nm showed 95% conversion to the desired product (endo:exo = 94:6). The resulting solution was heated at same temperature overnight (22 h). LC-MS analysis at 254 nm showed no starting material 9 remained and the desired product (endo:exo = 93:7). The reaction mixture was concentrated and purified by column chromatography eluting with 25 – 35% EtOAc in hexanes to afford ST-246 (0.39 g, HPLC area >99.5% pure with a ratio of endo:exo = 99:1 ) as a white solid. Analytical data (¹ H NMR, LC-MS and HPLC by co-injection) were compared with those of ST-246 synthesized according to WO041 12718 and were found to be consistent. An additional 0.18 g of ST-246 (HPLC area >99.5% pure, endo:exo = 91 : 9) was recovered from column chromatography. Total Yield: 0.57 g (86% yield).

Example 4 ; Synthetic Route IV:

P = Boc

Scheme 4

Step A. Synthesis of Compound 10

A mixture of maleic anhydride 2 (3.4 g, 34.67 mmol, Aldrich powder, 95%) and terf-butyl carbazate 5 (4.6 g, 34.67 mmol, Aldrich, 98%) in anhydrous toluene (51 ml_, Aldrich) was heated to reflux using a Dean-Stark trap apparatus under nitrogen atmosphere. After refluxing for 2.5 h, no starting material 2 remained and LC-MS analysis at 254 nm showed the desired product 10 (19% HPLC area), imine by-product (18%) and another by-product (56%). The reaction mixture was concentrated and purified by column chromatography eluting with 30% EtOAc in hexanes to afford compound 10 (1 .0 g, 13.6% yield, HPLC area >99% pure) as a white solid. Analytical data (¹H NMR and LC-MS) were consistent with those of compound 10 obtained in Synthetic Route III. Im ine by-product

Mol. Wt.: 212.2

Step B. Synthesis of Compound 6

A mixture of compound 10 (4.4 g, 20.74 mmol) and cycloheptatriene 1 (3.22 mL, 31 .1 mmol, distilled before to use, Aldrich tech 90%) in toluene (88 mL, 20 volume, Aldrich anhydrous) was heated at 95 °C under nitrogen atmosphere. After 15 h at 95 °C, LC-MS analysis showed 83% conversion to the desired product. The reaction mixture was heated at 105 °C overnight. After total 40 h at 95 – 105 °C, LC-MS analysis at 254 nm showed -99% conversion to the desired product (endo:exo = 93:7). The reaction mixture was concentrated and the crude was purified by column chromatography eluting with 25 – 50 % EtOAc in hexanes to afford compound 6 (2.06 g, 32.6% yield, HPLC area 99.9% pure and 100% endo isomer) as a white solid. ¹ H NMR and LC-MS were consistent with those of compound 6 obtained in Synthetic Route I. An additional 4.0 g of 6 (63.4% yield, HPLC area 93% pure with a ratio of endo:exo = 91 : 9) was recovered from column chromatography. Total Yield: 6.06 g (96% yield).

Step C. Synthesis of Compound 7 (HCI salt)

Compound 6 (2.05 g, 6.74 mmol) was dissolved in /^‘-PrOAc (26 mL, Aldrich, 99.6%). 4M HCI in dioxane (5.9 mL, 23.58 mmol, Aldrich) was added drop-wise to the above solution keeping the temperature below 20 °C. The solution was stirred overnight (18 h) at room temperature under nitrogen atmosphere. The resulting solid was filtered, washed with /^‘-PrOAc (5 mL) and dried under vacuum to yield HCI salt of compound 7 (1 .57 g, 97% yield) as a white solid. Analytical data (¹ H NMR and LC-MS) were consistent with those of compound 7 in Synthetic Route I.

Step D. Synthesis of ST-246 (Route IV) To a mixture of compound 7 (0.84 g, 3.5 mmol) in dichloromethane (13 mL) was added diisopropylethylamine (1 .34 mL, 7.7 mmol) keeping the temperature below 20 °C and the resulting solution was stirred for 5 – 10 minutes. 4-(Trifluoromethyl)benzoyl chloride 8 (0.57 mL, 3.85 mmol, Aldrich, 97%) was added to above solution keeping the temperature below 20 °C. The reaction mixture was stirred at room temperature for 2 h. Additional 0.2 mL (0.4 equiv) of 4-(trifluoromethyl)benzoyl chloride 8 was added to the reaction keeping the temperature below 20 °C. The reaction was stirred at room temperature overnight (24 h). The reaction mixture was diluted with dichloromethane (20 mL). The organic phase was washed with water (20 mL), saturated aqueous NH₄CI (20 mL), water (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic phase was separated, dried over Na₂SO₄, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 30 – 35% EtOAc in hexanes to afford ST-246 (0.25 g, 19% yield, HPLC area >99.5% pure) as a white solid. Analytical data (¹H NMR and LC-MS) were consistent with those of ST-246 synthesized according to WO041 12718.

Example 5: Synthetic Route V:

Scheme 5 Step A. Synthesis of Compound 13

To a mixture of compound 7 (1 .6 g, 6.65 mmol, synthesized according to Synthetic Route I) in dichloromethane (80 ml_,) was added triethylamine (2.04 ml_, 14.63 mmol) keeping the temperature below 20 °C and the resulting solution was stirred for 5 – 10 minute. 4-lodobenzoyl chloride 12 (1 .95 g, 7.31 mmol, 1 .1 equiv, Aldrich) was added portion-wise under nitrogen atmosphere to the above solution keeping the temperature below 20 °C. The reaction mixture was stirred at room temperature overnight. After 17 h and 19 h, additional 0.35 g (0.2 equiv) of acid chloride 12 was added to the reaction keeping the temperature below 20 °C. After 24 h, additional 0.18 g (0.1 equiv, used total 1 .6 equiv) of acid chloride 12 was added and the reaction was continued to stir at room temperature overnight (total 43 h). LC-MS analysis at 215 nm showed 43% of the desired product (13) and -5% of compound 7. The reaction was diluted with dichloromethane (100 ml_). The organic phase was washed with saturated aqueous NH₄CI (100 ml_), water (100 ml_) and saturated aqueous NaHCO₃ (100 ml_). The organic phase was separated, dried over Na2SO₄, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 25 – 50% EtOAc in hexanes to afford compound 13 (1 .63 g, 57% yield, HPLC area 93% pure) as a white solid. ¹ H NMR in DMSO-d6: δ 1 1 .19 and 10.93 (two singlets with integration ratio of 1 .73:1 , total of 1 H, same proton of two rotamers), 7.93 (d, 2H), 7.66 (d, 2H), 5.80 (s, 2H), 3.36 (s, 2H), 3.27 (s, 2H), 1 .18 (s, 2H), 0.27 (q, 1 H), 0.06 (s,1 H); Mass Spec: 435.0 (M+H)⁺

Step B. Synthesis of ST-246 (Route V)

Anhydrous DMF (6 ml_) was added to a mixture of compound 13 (0.2 g, 0.46 mmol), methyl 2, 2-difluoro-2-(fluorosulfonyl)acetate (0.44 ml_, 3.45 mmol, Aldrich) and copper (I) iodide (90 mg, 0.47 mmol). The reaction mixture was stirred at -90 °C for 4 h. LC-MS analysis at 254 nm indicated no starting material 13 remained and showed 48% HPLC area of ST-246. The reaction mixture was cooled to 45 °C and DMF was removed under reduced pressure. The residue was slurried in EtOAc (30 mL) and insoluble solid was removed by filtration. The filtrate was concentrated and purified by column chromatography eluting with 25 – 35% EtOAc in hexanes to afford ST-246 (55 mg, 32% yield, 95% pure by HPLC at 254 nm) as off-white solid. Analytical data (¹H NMR and LC-MS) were consistent with those of ST-246 synthesized according to WO041 12718.

History

Originally researched by the National Institute of Allergy and Infectious Diseases, the drug was owned by Viropharma and discovered in collaboration with scientists at the United States Army Medical Research Institute of Infectious Diseases.^[] It is owned and manufactured by Siga Technologies. Siga and Viropharma were issued a patent for tecovirimat in 2012.^[20]

Clinical trials

As of 2009, the results of clinical trials support its use against smallpox and other related orthopoxviruses. It shows potential for a variety of uses including preventive healthcare, as a post-exposure therapeutic, as a therapeutic, and an adjunct to vaccination.^[21]^[

Tecovirimat can be taken by mouth and as of 2008, was permitted for phase II trials by the U.S. Food and Drug Administration (FDA). In phase I trials, tecovirimat was generally well tolerated with no serious adverse events.^[22] Due to its importance for biodefense, the FDA designated tecovirimat for fast-track status, creating a path for expedited FDA review and eventual regulatory approval. On 13 July 2018, the FDA announced approval of tecovirimat.^[23]

Society and culture

Legal status

In November 2021, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product tecovirimat siga, intended for the treatment of orthopoxvirus disease (smallpox, monkeypox, cowpox, and vaccinia complications) in adults and in children who weigh at least 13 kilograms (29 lb)^[24] The applicant for this medicinal product is Siga Technologies Netherlands B.V.^[24] Tecovirimat was approved for medical use in the European Union in January 2022.^[5]^[25]

In December 2021, Health Canada approved oral tecovirimat for the treatment of smallpox in people weighing at least 13 kilograms (29 lb).^[26]^[27]

As of August 2022, Tpoxx is available in the US only through the Strategic National Stockpile as a Centers for Disease Control and Prevention investigational new drug.^[28]^[29] Intravenous Tpoxx has no lower weight cap and can be used in infants under the investigational new drug protocol.^[30]

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References

^ “Notice: Multiple Additions to the Prescription Drug List (PDL) [2022-01-24]”. Health Canada. 24 January 2022. Archived from the original on 29 May 2022. Retrieved 28 May 2022.
^ “New Medicines Approved in 2018”. Health Canada. 15 January 2020. Archived from the original on 29 May 2022. Retrieved 28 May 2022.
^ “Summary Basis of Decision (SBD) for Tpoxx”. Health Canada. 23 October 2014. Archived from the original on 29 May 2022. Retrieved 29 May 2022.
^ Jump up to:^a ^b ^c ^d “Tpoxx- tecovirimat monohydrate capsule”. DailyMed. 2 December 2021. Archived from the original on 23 April 2022. Retrieved 23 April 2022.
^ Jump up to:^a ^b ^c “Tecovirimat Siga EPAR”. European Medicines Agency. 10 November 2021. Archived from the original on 16 May 2022. Retrieved 23 April 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ Jump up to:^a ^b McNeil Jr DG (13 July 2018). “Drug to Treat Smallpox Approved by F.D.A., a Move Against Bioterrorism”. The New York Times. Archived from the original on 28 March 2019. Retrieved 16 July 2018.
^ Nakoune E, Olliaro P (May 2022). “Waking up to monkeypox”. BMJ. 377: o1321. doi:10.1136/bmj.o1321. PMID 35613732. S2CID 249047112.
^ Adler H, Gould S, Hine P, Snell LB, Wong W, Houlihan CF, et al. (May 2022). “Clinical features and management of human monkeypox: a retrospective observational study in the UK”. The Lancet. Infectious Diseases. 22 (8): 1153–1162. doi:10.1016/S1473-3099(22)00228-6. PMC 9300470. PMID 35623380. S2CID 249057804.
^ “FDA approves the first drug with an indication for treatment of smallpox”. U.S. Food and Drug Administration (FDA) (Press release). 13 July 2018. Archived from the original on 23 April 2019. Retrieved 1 August 2018.
^ “U.S. Food and Drug Administration Approves Siga Technologies’ Tpoxx (tecovirimat) for the Treatment of Smallpox”. Siga (Press release). Archived from the original on 21 September 2018. Retrieved 14 July 2018.
^ Grosenbach DW, Honeychurch K, Rose EA, Chinsangaram J, Frimm A, Maiti B, et al. (July 2018). “Oral Tecovirimat for the Treatment of Smallpox”. The New England Journal of Medicine. 379 (1): 44–53. doi:10.1056/NEJMoa1705688. PMC 6086581. PMID 29972742.
^ Whitehouse ER, Rao AK, Yu YC, Yu PA, Griffin M, Gorman S, et al. (October 2019). “Novel Treatment of a Vaccinia Virus Infection from an Occupational Needlestick – San Diego, California, 2019” (PDF). MMWR. Morbidity and Mortality Weekly Report. 68 (42): 943–946. doi:10.15585/mmwr.mm6842a2. PMC 6812835. PMID 31647789. Archived (PDF) from the original on 2 August 2022. Retrieved 2 August 2022.
^ Damon IK, Damaso CR, McFadden G (May 2014). “Are we there yet? The smallpox research agenda using variola virus”. PLOS Pathogens. 10 (5): e1004108. doi:10.1371/journal.ppat.1004108. PMC 4006926. PMID 24789223.
^ Cunningham A (13 July 2018). “FDA approves the first smallpox treatment”. Archived from the original on 12 July 2018. Retrieved 4 May 2018.
^ New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Archived from the original on 17 September 2020. Retrieved 16 September 2020.
^ Yang G, Pevear DC, Davies MH, Collett MS, Bailey T, Rippen S, et al. (October 2005). “An orally bioavailable antipoxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus Challenge”. Journal of Virology. 79 (20): 13139–13149. doi:10.1128/JVI.79.20.13139-13149.2005. PMC 1235851. PMID 16189015.
^ Jump up to:^a ^b AU patent 2004249250, Bailey, Thomas R.; Jordan, Robert & Rippin, Susan R., “Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases”, published 2004-12-29, assigned to Siga Pharmaceuticals Inc
^ Ishitobi, Hiroyuki; Tanida, Hiroshi; Tori, Kazuo; Tsuji, Teruji (1971). “Re-examination of the Cycloaddition of Cycloheptatriene with Maleic Anhydride”. Bulletin of the Chemical Society of Japan. 44 (11): 2993–3000. doi:10.1246/bcsj.44.2993.
^ Hughes, David L. (2019). “Review of the Patent Literature: Synthesis and Final Forms of Antiviral Drugs Tecovirimat and Baloxavir Marboxil”. Organic Process Research & Development. 23 (7): 1298–1307. doi:10.1021/acs.oprd.9b00144. S2CID 197172102.
^ U.S. Patent 8,124,643
^ “Siga Technologies”. Archived from the original on 20 February 2012. Retrieved 18 September 2009.
^ Jordan R, Tien D, Bolken TC, Jones KF, Tyavanagimatt SR, Strasser J, et al. (May 2008). “Single-dose safety and pharmacokinetics of ST-246, a novel orthopoxvirus egress inhibitor”. Antimicrobial Agents and Chemotherapy. 52 (5): 1721–1727. doi:10.1128/AAC.01303-07. PMC 2346641. PMID 18316519.
^ Commissioner, Office of the (24 March 2020). “Press Announcements – FDA approves the first drug with an indication for treatment of smallpox”. U.S. Food and Drug Administration (FDA). Archived from the original on 23 April 2019. Retrieved 14 July 2018.
^ Jump up to:^a ^b “Tecovirimat Siga: Pending EC decision”. European Medicines Agency. 11 November 2021. Archived from the original on 13 November 2021. Retrieved 13 November 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ “Summary of Product Characteristics” (PDF). European Medicines Agency. Archived (PDF) from the original on 21 May 2022. Retrieved 24 May 2022.
^ “Notice: Multiple Additions to the Prescription Drug List (PDL) [2022-01-24]”. Health Canada. 24 January 2022. Archived from the original on 29 May 2022. Retrieved 28 May 2022.
^ “Siga Announces Health Canada Regulatory Approval of Oral Tpoxx” (Press release). Siga Technologies. 1 December 2021. Archived from the original on 24 May 2022. Retrieved 24 May 2022.
^ “Information for Healthcare Providers on Obtaining and Using TPOXX (Tecovirimat) for Treatment of Monkeypox”. U.S. Centers for Disease Control and Prevention (CDC). 22 July 2022. Archived from the original on 31 July 2022. Retrieved 1 August 2022.
^ “Steps for Clinicians to Order Medication to Treat Monkeypox”. Coca Now. 19 July 2022. Archived from the original on 2 August 2022. Retrieved 24 July 2022.
^ “Monkeypox Outbreak: Updates on the Epidemiology, Testing, Treatment, and Vaccination” (PDF). U.S. Centers for Disease Control and Prevention. Archived (PDF) from the original on 2 August 2022. Retrieved 27 July 2022.

External links

“Tecovirimat”. Drug Information Portal. U.S. National Library of Medicine.
“Tecovirimat monohydrate”. Drug Information Portal. U.S. National Library of Medicine.

Tecovirimat
Clinical data

Trade names	Tpoxx
Other names	ST-246
AHFS/Drugs.com	Monograph
License data	US DailyMed: Tecovirimat
Routes of administration	By mouth, intravenous
ATC code	J05AX24 (WHO)
Legal status
Legal status	CA: ℞-only ^[1]^[2]^[3] US: ℞-only ^[4] EU: Rx-only ^[5]
Identifiers
show IUPAC name
CAS Number	869572-92-9
PubChem CID	16124688
DrugBank	DB12020
ChemSpider	17281586
UNII	F925RR824R
KEGG	D09390 as monohydrate: D11557
ChEMBL	ChEMBL1257073
Chemical and physical data
Formula	C₁₉H₁₅F₃N₂O₃
Molar mass	376.335 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI

FDA approves the first drug with an indication for treatment of smallpox

The U.S. Food and Drug Administration today approved TPOXX (tecovirimat), the first drug with an indication for treatment of smallpox. Though the World Health Organization declared smallpox, a contagious and sometimes fatal infectious disease, eradicated in 1980, there have been longstanding concerns that smallpox could be used as a bioweapon.

“To address the risk of bioterrorism, Congress has taken steps to enable the development and approval of countermeasures to thwart pathogens that could be employed as weapons. Today’s approval provides an important milestone in these efforts. This new treatment affords us an additional option should smallpox ever be used as a bioweapon,” said FDA Commissioner Scott Gottlieb, M.D. “This is the first product to be awarded a Material Threat Medical Countermeasure priority review voucher. Today’s action reflects the FDA’s commitment to ensuring that the U.S. is prepared for any public health emergency with timely, safe and effective medical products.”

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm613496.htm?utm_campaign=07132018_PR_FDA%20approves%20first%20drug%20with%20an%20indication%20for%20treatment%20of%20smallpox&utm_medium=email&utm_source=Eloqua

July 13, 2018

Release

Prior to its eradication in 1980, variola virus, the virus that causes smallpox, was mainly spread by direct contact between people. Symptoms typically began 10 to 14 days after infection and included fever, exhaustion, headache and backache. A rash initially consisting of small, pink bumps progressed to pus-filled sores before finally crusting over and scarring. Complications of smallpox could include encephalitis (inflammation of the brain), corneal ulcerations (an open sore on the clear, front surface of the eye) and blindness.

TPOXX’s effectiveness against smallpox was established by studies conducted in animals infected with viruses that are closely related to the virus that causes smallpox, and was based on measuring survival at the end of the studies. More animals treated with TPOXX lived compared to the animals treated with placebo. TPOXX was approved under the FDA’s Animal Rule, which allows efficacy findings from adequate and well-controlled animal studies to support an FDA approval when it is not feasible or ethical to conduct efficacy trials in humans.

The safety of TPOXX was evaluated in 359 healthy human volunteers without a smallpox infection. The most frequently reported side effects were headache, nausea and abdominal pain.

The FDA granted this application Fast Track and Priority Review designations. TPOXX also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases and a Material Threat Medical Countermeasure Priority Review Voucher, which provides additional incentives for certain medical products intended to treat or prevent harm from specific chemical, biological, radiological and nuclear threats.

The FDA granted approval of TPOXX to SIGA Technologies Inc.

TPOXX was developed in conjunction with the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA).

Tecovirimat

4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop(f)isoindol-2(1H)-yl)-benzamide

N- [(3aR,4R,4aR,5aS,6S, 6aS)- 3,3a,4,4a,5,5a,6,6a- octahydro-1,3-dioxo- 4,6- ethenocycloprop[f]iso- indol-2(1H)-yl]-4- (trifluoromethyl)- benzamide

4 -trifluoromethyl -N- (3, 3a, 4, 4a, 5, 5a, 6, 6a- octahydro-1, 3 -dioxo-4, 6 -ethenocycloprop [f] isoindol -2 ( 1H) -yl ) – benzamide

Details

NDA FILED IN US

2006 ORPHAN DRUG DESIGNATION IN US FOR SMALL POX

2010 ORPHAN DRUG DESIGNATION IN US FOR ORTHOPOX VIRUS

A core protein cysteine protease inhibitor potentially for treatment of smallpox infection.

SIGA TECHNOLOGIES INNOVATOR
SIGA-246; ST-246

CAS No. 869572-92-9

C19H15F3N2O3,

376.32921 g/mol

SYN

Tecovirimat (Tpoxx)
Tecovirimat is a drug used for the
treatment or prophylaxis of viral infections, particularly those caused by the
orthopoxvirus (Figure 12).
In 2015, Dai described a procedure
for the preparation of tecovirimat in a
US patent (Scheme 33).[57 ] The developed method started with a cycloaddition reaction of cycloheptatriene
with maleic anhydride in xylene to
yield adduct 192, which after reaction
with tert-butyl carbazate provided compound 193. Deprotection in acidic media gave rise to hydrazine derivative 194 and
subsequent reaction with p-trifluoromethylbenzoyl chloride afforded tecovirimat (191).

57 [57] D. Dai, US Patent 0322010, 2015.

This image has an empty alt attribute; its file name is str1-1.jpg

Synthesis

RAW MATERIAL

Key RM is, 4,6-Etheno-1H-cycloprop[f]isobenzofuran-1,3(3aH)-dione, 3a,4,4a,5,5a,6-hexahydro-, (3aR,4R,4aR,5aS,6S,6aS)-rel–

cas 944-41-2, [US7655688]

Molecular Formula:	C₁₁H₁₀O₃
Molecular Weight:	190.1953 g/mol

4,6-Etheno-1H-cycloprop[f]isobenzofuran-1,3(3aH)-dione, 4,4a,5,5a,6,6a-hexahydro-, (3aα,4β,4aα,5aα,6β,6aα)-
Tricyclo[3.2.2.0^2,4]non-8-ene-6,7-dicarboxylic anhydride, stereoisomer (8CI)
3,6-Cyclopropylene-Δ⁴-tetrahydrophthalic anhydride

MP 94-96 °C

Ref, Dong, Ming-xin; European Journal of Medicinal Chemistry 2010, V45(9), Pg 4096-4103

SMILES……….

O=C1OC(=O)[C@H]4[C@@H]1[C@H]3C=C[C@@H]4[C@@H]2C[C@@H]23

SYNTHESIS CONTINUED…….

ST-246

Patent

WO2014028545

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=B0F96581458D847AE213FF5A89020C1D.wapp1nA?docId=WO2014028545&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

The present invention provides a process for making ST-246 outlined in Scheme 1

P = Boc

Scheme 1

The present invention also provides a process for making ST-246 outlined in, Scheme 2

Scheme 2

The present invention further provides a process for making ST-246 outlined in Scheme 3

ST-246

P = Boc

Scheme 3

P = Boc

Scheme 4

The present invention further provides a process for making ST-246 outlined in

Scheme 5

Example 1 : Synthetic Route I:

P = Boc

Scheme 1

Step A. Synthesis of Compound 6 (P = Boc)

Step B. Synthesis of Compound 7 (HCI salt)

Compound 6 (3.6 g, 1 1 .83 mmol) was dissolved in /^‘-PrOAc (65 mL, Aldrich, 99.6%). 4M HCI in dioxane (10.4 mL, 41 .4 mmol, Aldrich) was added drop-wise to the above solution keeping the temperature below 20 °C. The reaction mixture was stirred at room temperature overnight (18 h) under nitrogen atmosphere. The resulting solid was filtered, washed with /^‘-PrOAc (15 mL) and dried under vacuum to yield HCI salt of compound 7 (1 .9 g, 67% yield) as a white solid. The filtrate was concentrated to 1/3 its volume and stirred at 10 – 15 °C for 30 min. The solid was filtered, washed with minimal volume of /^‘-PrOAc and dried to afford additional 0.6 g (21 % yield) of compound 7. Total yield: 2.5 g (88% yield). ¹ H NMR in DMSO-d6: δ 6.72 (br s, 3H), 5.68 (m, 2H), 3.20 (s, 2H), 3.01 (s, 2H), 1 .07-1 .17 (m, 2H), 0.18-0.29 (m, 1 H), -0.01 -0.07 (m, 1 H); Mass Spec: 205.1 (M+H)⁺

Step C. Synthesis of ST-246

To a mixture of compound 7 (0.96 g, 4 mmol) in dry dichloromethane (19 mL) was added triethylamine (1 .17 mL, 8.4 mmol, Aldrich) keeping the temperature below 20 °C. The resulting solution was stirred for 5 minutes at 15 – 20 °C, to it was added drop-wise 4-(trifluoromethyl)benzoyl chloride 8 (0.63 mL, 4.2 mmol, Aldrich, 97%) and the reaction mixture was stirred at room temperature overnight (18 h). LC-MS and TLC analysis showed the correct molecular weight and R_f value of ST-246 but the reaction was not complete. Additional 0.3 mL (2 mmol, 0.5 eq) of 4-(trifluoromethyl)benzoyl chloride 8 was added to the reaction mixture at 15 – 20 °C. The reaction was then stirred at room temperature overnight (19 h). LC-MS analysis indicated ca. 5% of starting material 7 still remained. The reaction was stopped and dichloromethane (30 mL) was added. The organic phase was washed with water (30 mL), saturated aqueous NH CI (30 mL), water (15 mL) and saturated aqueous NaHCO3 (30 mL). The organic phase was separated, dried over Na₂SO₄, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 30 -50% EtOAc in hexanes to afford ST-246 (0.34 g, 23% yield) as an off-white solid. Analytical data (¹H NMR, LC-MS and HPLC by co-injection) were matched with those of ST-246 synthesized according to WO041 12718 and were consistent.

Example 2: Synthetic Route II

Scheme 2

Step A. Synthesis of Compound 9

Uncyclized product (MS = 303) Dimer by-product (MS = 489)

Step B. Synthesis of ST-246 (Route II)

A mixture of compound 9 (0.97 g, 3.4 mmol) and cycloheptatriene 1 (0.51 mL, 4.42 mmol, distilled before use, Aldrich tech 90%) in toluene (50 mL, Aldrich anhydrous) was heated at 95 °C under nitrogen atmosphere. After 1 .5 h at 95 °C, LC-MS analysis at 254 nm showed 29% conversion to the desired product (endo:exo = 94:6). The resulting solution was continued to be heated at same temperature overnight. After 18 h at 95 °C, LC-MS analysis indicated 75% conversion with an endo:exo ratio of 94:6. The reaction temperature was increased to 1 10 °C and the reaction was monitored. After heating at 1 10 °C for 7 h, LC-MS analysis at 254 nm showed 96.4% conversion to the desired product (endo:exo = 94:6). The volatiles were removed by evaporation under reduced pressure and the reside was purified by column chromatography eluting with 30% EtOAc in hexanes to afford ST-246 (0.29 g, 22.6% yield, HPLC area 99.7% pure and 100% endo isomer) as a white solid. Analytical data (¹H NMR, LC-MS and HPLC by co-injection) were matched with those of ST-246 synthesized according to WO041 12718 and were consistent. An additional 0.5 g of ST-246 (38.9% yield, endo:exo = 97: 3) was recovered from column chromatography. Total Yield: 0.84 g (65.4% yield). ¹H NMR of ST-246 exo isomer in CDCI₃: δ 8.62 (s, 1 H), 7.92 (d, 2H), 7.68 (d, 2H), 5.96 (m, 2H), 3.43 (s, 2H), 2.88 (s, 2H), 1 .17 (s, 2H), 0.24 (q, 1 H), 0.13 (m, 1 H); Mass Spec: 377.1 (M+H)⁺

Example 3: Synthetic Route III

ST-246 9

P = Boc

Scheme 3

Step A. Synthesis of Compound 10

duct

C₉H₁₂N₂0₄ C₁₄H₂₂N₄05

Mol. Wt.: 212.2 Mol. Wt.: 326.35

C₉H₁₂N₂0₄ C₁₄H₂₂N₄05

Mol. Wt.: 212.2 Mol. Wt.: 326.35

Step B. Synthesis of Compound 11 (HCI salt)

Step C. Synthesis of Compound 9 (Route III)

Step D. Synthesis of ST-246 (Route III)

A mixture of compound 9 (0.5 g, 1 .76 mmol) and cycloheptatriene 1 (0.33 mL, 3.17 mmol, distilled before to use, Aldrich tech 90%) in toluene (10 mL, Aldrich anhydrous) was heated at 1 10 – 1 15 °C under nitrogen atmosphere. After 6 h, LC-MS analysis at 254 nm showed 95% conversion to the desired product (endo:exo = 94:6). The resulting solution was heated at same temperature overnight (22 h). LC-MS analysis at 254 nm showed no starting material 9 remained and the desired product (endo:exo = 93:7). The reaction mixture was concentrated and purified by column chromatography eluting with 25 – 35% EtOAc in hexanes to afford ST-246 (0.39 g, HPLC area >99.5% pure with a ratio of endo:exo = 99:1 ) as a white solid. Analytical data (¹ H NMR, LC-MS and HPLC by co-injection) were compared with those of ST-246 synthesized according to WO041 12718 and were found to be consistent. An additional 0.18 g of ST-246 (HPLC area >99.5% pure, endo:exo = 91 : 9) was recovered from column chromatography. Total Yield: 0.57 g (86% yield).

Example 4 ; Synthetic Route IV:

P = Boc

Scheme 4

Step A. Synthesis of Compound 10

Im ine by-product

Mol. Wt.: 212.2

Step B. Synthesis of Compound 6

A mixture of compound 10 (4.4 g, 20.74 mmol) and cycloheptatriene 1 (3.22 mL, 31 .1 mmol, distilled before to use, Aldrich tech 90%) in toluene (88 mL, 20 volume, Aldrich anhydrous) was heated at 95 °C under nitrogen atmosphere. After 15 h at 95 °C, LC-MS analysis showed 83% conversion to the desired product. The reaction mixture was heated at 105 °C overnight. After total 40 h at 95 – 105 °C, LC-MS analysis at 254 nm showed -99% conversion to the desired product (endo:exo = 93:7). The reaction mixture was concentrated and the crude was purified by column chromatography eluting with 25 – 50 % EtOAc in hexanes to afford compound 6 (2.06 g, 32.6% yield, HPLC area 99.9% pure and 100% endo isomer) as a white solid. ¹ H NMR and LC-MS were consistent with those of compound 6 obtained in Synthetic Route I. An additional 4.0 g of 6 (63.4% yield, HPLC area 93% pure with a ratio of endo:exo = 91 : 9) was recovered from column chromatography. Total Yield: 6.06 g (96% yield).

Step C. Synthesis of Compound 7 (HCI salt)

Step D. Synthesis of ST-246 (Route IV)

To a mixture of compound 7 (0.84 g, 3.5 mmol) in dichloromethane (13 mL) was added diisopropylethylamine (1 .34 mL, 7.7 mmol) keeping the temperature below 20 °C and the resulting solution was stirred for 5 – 10 minutes. 4-(Trifluoromethyl)benzoyl chloride 8 (0.57 mL, 3.85 mmol, Aldrich, 97%) was added to above solution keeping the temperature below 20 °C. The reaction mixture was stirred at room temperature for 2 h. Additional 0.2 mL (0.4 equiv) of 4-(trifluoromethyl)benzoyl chloride 8 was added to the reaction keeping the temperature below 20 °C. The reaction was stirred at room temperature overnight (24 h). The reaction mixture was diluted with dichloromethane (20 mL). The organic phase was washed with water (20 mL), saturated aqueous NH₄CI (20 mL), water (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic phase was separated, dried over Na₂SO₄, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 30 – 35% EtOAc in hexanes to afford ST-246 (0.25 g, 19% yield, HPLC area >99.5% pure) as a white solid. Analytical data (¹H NMR and LC-MS) were consistent with those of ST-246 synthesized according to WO041 12718.

Example 5: Synthetic Route V:

Scheme 5

Step A. Synthesis of Compound 13

Step B. Synthesis of ST-246 (Route V)

mg, 32% yield, 95% pure by HPLC at 254 nm) as off-white solid. Analytical data (¹H NMR and LC-MS) were consistent with those of ST-246 synthesized according to WO041 12718.

PAPER

N-(3,3a,4,4a,5,5a,6,6a-Octahydro-1,3-dioxo-4,6- ethenocycloprop[f]isoindol-2-(1H)-yl)carboxamides: Identification of Novel Orthopoxvirus Egress Inhibitors

ViroPharma Incorporated, 397 Eagleview Boulevard, Exton, Pennsylvania 19341, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, Maryland 21702, University of Alabama, Birmingham, Alabama 35294, and SIGA Technologies, Inc., 4575 SW Research Way, Corvallis, Oregon 97333

J. Med. Chem., 2007, 50 (7), pp 1442–1444

DOI: 10.1021/jm061484y

A series of novel, potent orthopoxvirus egress inhibitors was identified during high-throughput screening of the ViroPharma small molecule collection. Using structure−activity relationship information inferred from early hits, several compounds were synthesized, and compound 14was identified as a potent, orally bioavailable first-in-class inhibitor of orthopoxvirus egress from infected cells. Compound 14 has shown comparable efficaciousness in three murine orthopoxvirus models and has entered Phase I clinical trials.

http://pubs.acs.org/doi/suppl/10.1021/jm061484y

http://pubs.acs.org/doi/suppl/10.1021/jm061484y/suppl_file/jm061484ysi20070204_060607.pdf

General Procedure for synthesis of compounds 2-14, 16-18.

N-(3,3a,4,4a,5,5a,6,6aoctahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-4- (trifluoromethyl)benzamide (14).

A mixture of 2.00 g (9.8 mmol) of 4-(trifluoromethyl) benzoic acid hydrazide, 1.86 g (9.8 mmol) of 4,4a,5,5a,6,6a-hexahydro-4,6-etheno-1Hcycloprop[f]isobenzofuran-1,3(3aH)-dione, and one drop of diisopropylethylamine in 40 mL of absolute ethanol was refluxed for 4.5 h. Upon cooling to rt, 4 mL of water was added, and the product began to crystallize. The suspension was cooled in an ice bath, and the precipitate collected by filtration. The crystalline solid was air-dried affording 3.20 g (87%) of the product as a white solid;

Mp 194-195 ºC. 1 H NMR, (300 MHz, d6 -DMSO) δ 11.20, 11.09 (2 brs from rotamers, 1H), 8.06 (d, J= 7.8 Hz, 2H), 7.90 (d, J= 7.8 Hz, 2H), 5.78 (m, 2H), 3.26 (m, 4H), 1.15 (m, 2H), 0.24 (dd, J= 7.2, 12.9 Hz, 1H), 0.04 (m, 1H).

Anal. calcd. for C19H15F3N2O3● 0.25H2O: %C, 59.92; %H, 4.10; %F, 14.97; %N, 7.36; %O, 13.65. Found: %C, 59.97; %H, 4.02; %F, 14.94; %N, 7.36; %O, 13.71.

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PATENT

US20140316145

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http://www.google.com/patents/US8802714

Example 1

Preparation of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide

a. Preparation of Compounds 1(a) and 1(b).

A mixture of cycloheptatriene (5 g, 54.26 mmol) and maleic anhydride (6.13 g, 62.40 mmol) in xylenes (35 mL) was heated at reflux under argon overnight. The reaction was cooled to room temperature and a tan precipitate was collected by filtration and dried to give 2.94 grams (28%) of the desired product, which is a mixture of compounds 1(a) and 1(b). Compound 1(a) is normally predominant in this mixture and is at least 80% by weight. The purity of Compound 1(a) may be further enhanced by recrystallization if necessary. Compound 1(b), an isomer of compound 1(a) is normally less than 20% by weight and varies depending on the conditions of the reaction. Pure Compound 1(b) was obtained by concentrating the mother liquid to dryness and then subjecting the residue to column chromatography. Further purification can be carried out by recrystallization if necessary. ¹H NMR (500 MHz) in CDCl₃: δ 5.95 (m, 2H), 3.42 (m, 2H), 3.09 (m, 2H), 1.12 (m, 2H), 0.22 (m, 1H), 0.14 (m, 1H).

b. Preparation of N-[(3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide. desired

A mixture of compound 1(a) (150 mg, 0.788 mmol) and 4-trifluoromethylbenzhydrazide (169 mg, 0.827 mmol) in ethanol (10 mL) was heated under argon overnight. The solvent was removed by rotary evaporation. Purification by column chromatography on silica gel using 1/1 hexane/ethyl acetate provided 152 mg (51%) of the product as a white solid.

c. Preparation of N-[(3aR,4S,4aS,5aR,6R,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide. UNWANTED

N-[(3aR,4S,4aS,5aR,6R,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]4-(trifluoromethyl)-benzamide was prepared and purified in the same fashion as for N-[(3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide by replacing 1(a) with 1(b) and was obtained as a white solid. ¹H NMR (300 MHz) in CDCl₃: δ 8.62 (s, 1H), 7.92 (d, 2H), 7.68 (d, 2H), 5.96 (m, 2H), 3.43 (s, 2H), 2.88 (s, 2H), 1.17 (s, 2H), 0.24 (q, 1H), 0.13 (m, 1H); Mass Spec: 377.1 (M+H)⁺.

FINAL COMPD SYNTHESIS

TABLE 1

Example			**Mass
Number	R₆	*NMR	Spec	Name

1		¹H NMR in DMSO-d₆: δ 11.35 (d, 1H); 11.09 (d, 1H); 8.08 (d, 2H); 7.92 (d, 2H); 5.799 (s, 2H); 3.29 (brs, 4H); 1.17 (m, 2H); 0.26 (m, 1H); 0.078 (s, 1H)	375 (M − H)−	N-[(3aR,4R,4aR,5aS,6S, 6aS)-3,3a,4,4a,5,5a,6,6a- octahydro-1,3-dioxo- 4,6-ethenocycloprop[f] isoindol-2(1H)-yl]-4- (trifluoromethyl)- benzamide

TABLE 1 EXAMPLE 1

N- [(3aR,4R,4aR,5aS,6S, 6aS)- 3,3a,4,4a,5,5a,6,6a- octahydro-1,3-dioxo- 4,6- ethenocycloprop[f]iso- indol-2(1H)-yl]-4- (trifluoromethyl)- benzamide

¹H NMR in DMSO-d₆: δ 11.35 (d, 1H); 11.09 (d, 1H); 8.08 (d, 2H); 7.92 (d, 2H); 5.799 (s, 2H); 3.29 (brs, 4H); 1.17 (m, 2H); 0.26 (m, 1H); 0.078 (s, 1H), 375 (M − H)⁻

EXAMPLE 42 Characterization of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide (“ ”)

In the present application, ST-246 refers to: N-[(3aR,4R,4aR,5aS,65,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide.

Physico-Chemical Properties

Appearance: ST-246 is a white to off-white powder.

Melting Point: Approximately 196° C. by DSC.

Permeability: The calculated log P is 2.94. Based on the partition coefficient, ST-246 is expected to have good permeability.

Particle Size: The drug substance is micronized to improve its dissolution in the gastrointestinal fluids. The typical particle size of the micronized material is 50% less than 5 microns.

Solubility: The solubility of ST-246 is low in water (0.026 mg/mL) and buffers of the gastric pH range. Surfactant increases its solubility slightly. ST-246 is very soluble in organic solvents. The solubility data are given in Table 5.

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PATENT

http://www.google.com/patents/CN101445478A?cl=en

References

Damon, Inger K.; Damaso, Clarissa R.; McFadden, Grant (2014). “Are We There Yet? The Smallpox Research Agenda Using Variola Virus”. PLoS Pathogens 10 (5): e1004108.doi:10.1371/journal.ppat.1004108. PMID 24789223.
Siga Technologies
Jordan, R; Tien, D; Bolken, T. C.; Jones, K. F.; Tyavanagimatt, S. R.; Strasser, J; Frimm, A; Corrado, M. L.; Strome, P. G.; Hruby, D. E. (2008). “Single-Dose Safety and Pharmacokinetics of ST-246, a Novel Orthopoxvirus Egress Inhibitor”. Antimicrobial Agents and Chemotherapy 52 (5): 1721–1727. doi:10.1128/AAC.01303-07. PMC 2346641. PMID 18316519.
Yang, G; Pevear, D. C.; Davies, M. H.; Collett, M. S.; Bailey, T; Rippen, S; Barone, L; Burns, C; Rhodes, G; Tohan, S; Huggins, J. W.; Baker, R. O.; Buller, R. L.; Touchette, E; Waller, K; Schriewer, J; Neyts, J; Declercq, E; Jones, K; Hruby, D; Jordan, R (2005). “An Orally Bioavailable Antipoxvirus Compound (ST-246) Inhibits Extracellular Virus Formation and Protects Mice from Lethal Orthopoxvirus Challenge”. Journal of Virology 79 (20): 13139–13149. doi:10.1128/JVI.79.20.13139-13149.2005. PMC 1235851. PMID 16189015.

Referenced by
Citing Patent Filing date Publication date Applicant Title
CN101912389A * Aug 9, 2010 Dec 15, 2010 中国人民解放军军事医学科学院微生物流行病研究所 Pharmaceutical composition containing ST-246 and preparation method and application thereof
CN102406617A * Nov 30, 2011 Apr 11, 2012 中国人民解放军军事医学科学院生物工程研究所 Tecovirimat dry suspension and preparation method thereof
CN102406617B Nov 30, 2011 Aug 28, 2013 中国人民解放军军事医学科学院生物工程研究所 Tecovirimat dry suspension and preparation method thereof
CN103068232B * Mar 23, 2011 Aug 26, 2015 西佳科技股份有限公司多晶型物形式st-246和制备方法
US8530509 Jul 29, 2011 Sep 10, 2013 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US8802714 Aug 14, 2013 Aug 12, 2014 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US9045418 Jul 3, 2014 Jun 2, 2015 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of Orthopoxvirus infections and associated diseases

Patent Citations

Cited Patent	Filing date	Publication date	Applicant	Title
US20070287735 *	Apr 23, 2007	Dec 13, 2007	Siga Technologies, Inc.	Chemicals, compositions, and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US20090011037 *	Apr 23, 2008	Jan 8, 2009	Cydex Pharmaceuticals, Inc.	Sulfoalkyl Ether Cyclodextrin Compositions and Methods of Preparation Thereof
Citing Patent	Filing date	Publication date	Applicant	Title
US8530509	Jul 29, 2011	Sep 10, 2013	Siga Technologies, Inc.	Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US8802714	Aug 14, 2013	Aug 12, 2014	Siga Technologies, Inc.	Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US9045418	Jul 3, 2014	Jun 2, 2015	Siga Technologies, Inc.	Compounds, compositions and methods for treatment and prevention of Orthopoxvirus infections and associated diseases

//////////////////Tecovirimat, FDA 2018, ORPHAN DRUG DESIGNATION, TPOXX, SIGA Technologies Inc, Fast Track, Priority Review,

UNII-F925RR824R, тековиримат , تيكوفيريمات , 替韦立马 ,

FC(F)(F)c1ccc(cc1)C(=O)NN1C(=O)C2C(C3C=CC2C2CC32)C1=O

Acamprosate calcium, アカンプロセート

July 10, 2018 11:09 am / Leave a comment

ChemSpider 2D Image | Acamprosate | C5H11NO4S Image result for Acamprosate synthesis

Acamprosate calcium

Molecular Formula:	C₁₀H₂₀CaN₂O₈S₂
Molecular Weight:	400.474 g/mol

3-acetamidopropane-1-sulfonic acid

Campral [Trade name]

Ethanimidic acid, N-(3-sulfopropyl)-, (1Z)- [ACD/Index Name]

N4K14YGM3J

N-Acetylhomotaurine

アカンプロセート

INGREDIENT	UNII	CAS	fre form Cas 77337-76-9 181.21 C₅H₁₁NO₄S
Acamprosate Calcium	59375N1D0U	77337-73-6

INGREDIENT

UNII

CAS

fre form

Cas 77337-76-9

181.21

C₅H₁₁NO₄S

Acamprosate Calcium

59375N1D0U

77337-73-6

Acamprosate, sold under the brand name Campral, is a medication used along with counselling to treat alcohol dependence.^[1]^[2]

Acamprosate, also known by the brand name Campral™, is a drug used for treating alcohol dependence. Acamprosate is thought to stabilize the chemical balance in the brain that would otherwise be disrupted by alcoholism, possibly by blocking glutaminergic N-methyl-D-aspartate receptors, while gamma-aminobutyric acid type A receptors are activated. Reports indicate that acamprosate only works with a combination of attending support groups and abstinence from alcohol. Certain serious side effects include allergic reactions, irregular heartbeats, and low or high blood pressure, while less serious side effects include headaches, insomnia, and impotence. Acamprosate should not be taken by people with kidney problems or allergies to the drug.

Acamprosate is thought to stabilize chemical signaling in the brain that would otherwise be disrupted by alcohol withdrawal.^[3] When used alone, acamprosate is not an effective therapy for alcoholism in most individuals;^[4] however, studies have found that acamprosate works best when used in combination with psychosocial support since it facilitates a reduction in alcohol consumption as well as full abstinence.^[2]^[5]^[6]

Serious side effects include allergic reactions, abnormal heart rhythms, and low or high blood pressure, while less serious side effects include headaches, insomnia, and impotence.^[7] Diarrhea is the most common side-effect.^[8] Acamprosate should not be taken by people with kidney problems or allergies to the drug.^[9]

Until it became a generic in the United States, Campral was manufactured and marketed in the United States by Forest Laboratories, while Merck KGaA markets it outside the US.

Medical uses

Acamprosate is useful when used along with counselling in the treatment of alcohol dependence.^[2] Over three to twelve months it increases the number of people who do not drink at all and the number of days without alcohol.^[2] It appears to work as well as naltrexone.^[2]

Contraindications

Acamprosate is primarily removed by the kidneys and should not be given to people with severely impaired kidneys (creatinine clearance less than 30 mL/min). A dose reduction is suggested in those with moderately impaired kidneys (creatinine clearancebetween 30 mL/min and 50 mL/min).^[1]^[10] It is also contraindicated in those who have a strong allergic reaction to acamprosate calcium or any of its components.^[10]

Adverse effects

The US label carries warnings about increased of suicidal behavior, major depressive disorder, and kidney failure.^[1]

Adverse effects that caused people to stop taking the drug in clinical trials included diarrhea, nausea, depression, and anxiety.^[1]

Other frequent adverse effects include headache, stomach pain, back pain, muscle pain, joint pain, chest pain, infections, flu-like symptoms, chills, heart palpitations, high blood pressure, fainting, vomiting, upset stomach, constipation, increased appetite, weight gain, edema, sleepiness, decreased sex drive, impotence, forgetfulness, abnormal thinking, abnormal vision, distorted sense of taste, tremors, runny nose, coughing, difficulty breathing, sore throat, bronchitis, and rashes.^[1]

Pharmacology

Acamprosate calcium

Pharmacodynamics

The pharmacodynamics of acamprosate is complex and not fully understood;^[11]^[12]^[13] however, it is believed to act as an NMDA receptor antagonist and positive allosteric modulator of GABA_A receptors.^[12]^[13]

Ethanol and benzodiazepines act on the central nervous system by binding to the GABA_A receptor, increasing the effects of the inhibitory neurotransmitter GABA (i.e., they act as positive allosteric modulators at these receptors).^[12]^[4] In chronic alcohol abuse, one of the main mechanisms of tolerance is attributed to GABA_A receptors becoming downregulated (i.e. these receptors become less sensitive to GABA).^[4] When alcohol is no longer consumed, these down-regulated GABA_A receptor complexes are so insensitive to GABA that the typical amount of GABA produced has little effect, leading to physical withdrawal symptoms;^[4] since GABA normally inhibits neural firing, GABA_A receptor desensitization results in unopposed excitatory neurotransmission (i.e., fewer inhibitory postsynaptic potentialsoccur through GABA_A receptors), leading to neuronal over-excitation (i.e., more action potentials in the postsynaptic neuron). One of acamprosate’s mechanisms of action is the enhancement of GABA signaling at GABA_A receptors via positive allosteric receptor modulation.^[12]^[13] It has been purported to open the chloride ion channel in a novel way as it does not require GABA as a cofactor, making it less liable for dependence than benzodiazepines. Acamprosate has been successfully used to control tinnitus, hyperacusis, ear pain and inner ear pressure during alcohol use due to spasms of the tensor tympani muscle.^{[medical citation needed]}

In addition, alcohol also inhibits the activity of N-methyl-D-aspartate receptors (NMDARs).^[14]^[15] Chronic alcohol consumption leads to the overproduction (upregulation) of these receptors. Thereafter, sudden alcohol abstinence causes the excessive numbers of NMDARs to be more active than normal and to contribute to the symptoms of delirium tremensand excitotoxic neuronal death.^[16] Withdrawal from alcohol induces a surge in release of excitatory neurotransmitters like glutamate, which activates NMDARs.^[17] Acamprosate reduces this glutamate surge.^[18] The drug also protects cultured cells from excitotoxicity induced by ethanol withdrawal^[19] and from glutamate exposure combined with ethanol withdrawal.^[20]

Pharmacokinetics

Acamprosate is not metabolized by the human body.^[13] Acamprosate’s absolute bioavailability from oral administration is approximately 11%.^[13] Following administration and absorption of acamprosate, it is excreted unchanged (i.e., as acamprosate) via the kidneys.^[13]

History

Acamprosate was developed by Lipha, a subsidiary of Merck KGaA.^[21] and was approved for marketing in Europe in 1989.^{[citation needed]}

In October 2001 Forest Laboratories acquired the rights to market the drug in the US.^[21]^[22]

It was approved by the FDA in July 2004.^[23]

The first generic versions of acamprosate were launched in the US in 2013.^[24]

As of 2015 acamprosate was in development by Confluence Pharmaceuticals as a potential treatment for fragile X syndrome. The drug was granted orphan status for this use by the FDA in 2013 and by the EMA in 2014.^[25]

Society and culture

“Acamprosate” is the INN and BAN for this substance. “Acamprosate calcium” is the USAN and JAN. It is also technically known as N-acetylhomotaurine or as calcium acetylhomotaurinate.

It is sold under the brand name Campral.^[1]

Research

In addition to its apparent ability to help patients refrain from drinking, some evidence suggests that acamprosate is neuroprotective (that is, it protects neurons from damage and death caused by the effects of alcohol withdrawal, and possibly other causes of neurotoxicity).^[18]^[26]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m “Campral label” (PDF). FDA. January 2012. Retrieved 27 November2017. For label updates see FDA index page for NDA 021431
^ Jump up to:^a ^b ^c ^d ^e Plosker, GL (July 2015). “Acamprosate: A Review of Its Use in Alcohol Dependence”. Drugs. 75 (11): 1255–68. doi:10.1007/s40265-015-0423-9. PMID 26084940.
Jump up^ Williams, SH. (2005). “Medications for treating alcohol dependence”. American Family Physician. 72 (9): 1775–1780. PMID 16300039.
^ Jump up to:^a ^b ^c ^d Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). “Chapter 16: Reinforcement and Addictive Disorders”. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN 9780071827706. It has been hypothesized that long-term ethanol exposure alters the expression or activity of specific GABAA receptor subunits in discrete brain regions. Regardless of the underlying mechanism, ethanol-induced decreases in GABAA receptor sensitivity are believed to contribute to ethanol tolerance, and also may mediate some aspects of physical dependence on ethanol. … Detoxification from ethanol typically involves the administration of benzodiazepines such as chlordiazepoxide, which exhibit cross-dependence with ethanol at GABAA receptors (Chapters 5 and 15). A dose that will prevent the physical symptoms associated with withdrawal from ethanol, including tachycardia, hypertension, tremor, agitation, and seizures, is given and is slowly tapered. Benzodiazepines are used because they are less reinforcing than ethanol among alcoholics. Moreover, the tapered use of a benzodiazepine with a long half-life makes the emergence of withdrawal symptoms less likely than direct withdrawal from ethanol. … Unfortunately, acamprosate is not adequately effective for most alcoholics.
Jump up^ Mason, BJ (2001). “Treatment of alcohol-dependent outpatients with acamprosate: a clinical review”. The Journal of Clinical Psychiatry. 62 Suppl 20: 42–8. PMID 11584875.
Jump up^ Nutt, DJ (2014). “Doing it by numbers: A simple approach to reducing the harms of alcohol”. JOURNAL OF PSYCHOPHARMACOLOGY. 28: 3–7. doi:10.1177/0269881113512038. PMID 24399337.
Jump up^ “Acamprosate”. drugs.com. 2005-03-25. Archived from the original on 22 December 2006. Retrieved 2007-01-08.
Jump up^ Wilde, MI; Wagstaff, AJ (June 1997). “Acamprosate. A review of its pharmacology and clinical potential in the management of alcohol dependence after detoxification”. Drugs. 53(6): 1038–53. doi:10.2165/00003495-199753060-00008. PMID 9179530.
Jump up^ “Acamprosate Oral – Who should not take this medication?”. WebMD.com. Retrieved 2007-01-08.
^ Jump up to:^a ^b Saivin, S; Hulot, T; Chabac, S; Potgieter, A; Durbin, P; Houin, G (Nov 1998). “Clinical Pharmacokinetics of Acamprosate”. Clinical Pharmacokinetics. 35 (5): 331–345. doi:10.2165/00003088-199835050-00001. PMID 9839087.
Jump up^ “Acamprosate: Biological activity”. IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 26 November 2017. Due to the complex nature of this drug’s MMOA, and a paucity of well defined target affinity data, we do not map to a primary drug target in this instance.
^ Jump up to:^a ^b ^c ^d “Acamprosate: Summary”. IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 26 November 2017. Acamprosate is a NMDA glutamate receptor antagonist and a positive allosteric modulator of GABAA receptors.
Marketed formulations contain acamprosate calcium
^ Jump up to:^a ^b ^c ^d ^e ^f “Acamprosate”. DrugBank. University of Alberta. 19 November 2017. Retrieved 26 November 2017. Acamprosate is thought to stabilize the chemical balance in the brain that would otherwise be disrupted by alcoholism, possibly by blocking glutaminergic N-methyl-D-aspartate receptors, while gamma-aminobutyric acid type A receptors are activated. … The mechanism of action of acamprosate in maintenance of alcohol abstinence is not completely understood. Chronic alcohol exposure is hypothesized to alter the normal balance between neuronal excitation and inhibition. in vitro and in vivostudies in animals have provided evidence to suggest acamprosate may interact with glutamate and GABA neurotransmitter systems centrally, and has led to the hypothesis that acamprosate restores this balance. It seems to inhibit NMDA receptors while activating GABA receptors.
Jump up^ Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter 15: Reinforcement and Addictive Disorders”. In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 372. ISBN 9780071481274.
Jump up^ Möykkynen T, Korpi ER (July 2012). “Acute effects of ethanol on glutamate receptors”. Basic & Clinical Pharmacology & Toxicology. 111 (1): 4–13. doi:10.1111/j.1742-7843.2012.00879.x. PMID 22429661.
Jump up^ Tsai, G; Coyle, JT (1998). “The role of glutamatergic neurotransmission in the pathophysiology of alcoholism”. Annual Review of Medicine. 49: 173–84. doi:10.1146/annurev.med.49.1.173. PMID 9509257.
Jump up^ Tsai, GE; Ragan, P; Chang, R; Chen, S; Linnoila, VM; Coyle, JT (1998). “Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal”. The American Journal of Psychiatry. 155 (6): 726–32. doi:10.1176/ajp.155.6.726. PMID 9619143.
^ Jump up to:^a ^b De Witte, P; Littleton, J; Parot, P; Koob, G (2005). “Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action”. CNS Drugs. 19 (6): 517–37. doi:10.2165/00023210-200519060-00004. PMID 15963001.
Jump up^ Mayer, S; Harris, BR; Gibson, DA; Blanchard, JA; Prendergast, MA; Holley, RC; Littleton, J (2002). “Acamprosate, MK-801, and ifenprodil inhibit neurotoxicity and calcium entry induced by ethanol withdrawal in organotypic slice cultures from neonatal rat hippocampus”. Alcoholism: Clinical and Experimental Research. 26 (10): 1468–78. doi:10.1097/00000374-200210000-00003. PMID 12394279.
Jump up^ Al Qatari, M; Khan, S; Harris, B; Littleton, J (2001). “Acamprosate is neuroprotective against glutamate-induced excitotoxicity when enhanced by ethanol withdrawal in neocortical cultures of fetal rat brain”. Alcoholism: Clinical and Experimental Research. 25(9): 1276–83. doi:10.1111/j.1530-0277.2001.tb02348.x. PMID 11584146.
^ Jump up to:^a ^b Berfield, Susan (27 May 2002). “A CEO and His Son”. Bloomberg Businessweek.
Jump up^ “Press release: Forest Laboratories Announces Agreement For Alcohol Addiction Treatment”. Forest Labs via Evaluate Group. October 23, 2001.
Jump up^ “FDA Approves New Drug for Treatment of Alcoholism”. FDA Talk Paper. Food and Drug Administration. 2004-07-29. Archived from the original on 2008-01-17. Retrieved 2009-08-15.
Jump up^ “Acamprosate generics”. DrugPatentWatch. Retrieved 27 November 2017.
Jump up^ “Acamprosate – Confluence Pharmaceuticals – AdisInsight”. AdisInsight. Retrieved 27 November 2017.
Jump up^ Mann K, Kiefer F, Spanagel R, Littleton J (July 2008). “Acamprosate: recent findings and future research directions”. Alcohol. Clin. Exp. Res. 32 (7): 1105–10. doi:10.1111/j.1530-0277.2008.00690.x. PMID 18540918.

Title: Acamprosate Calcium

CAS Registry Number: 77337-73-6

CAS Name: 3-(Acetylamino)-1-propanesulfonic acid calcium salt (2:1)

Additional Names: calcium acetyl homotaurinate; Ca-AOTA; calcium bisacetyl homotaurine

Trademarks: Aotal (Merck KGaA); Campral (Merck Sant?

Molecular Formula: C10H20CaN2O8S2

Molecular Weight: 400.48

Percent Composition: C 29.99%, H 5.03%, Ca 10.01%, N 6.99%, O 31.96%, S 16.01%

Literature References: GABA (g-aminobutyric acid, q.v.) agonist. Prepn: J. P. Durlach, DE 3019350; idem, US 4355043 (1980, 1982 both to Lab. Meram). Physicochemical and pharmacological study: C. Chabenat et al., Methods Find. Exp. Clin. Pharmacol.10, 311 (1988). Pharmacology: J. Durlach et al., ibid. 437; A. Guiet-Bara et al., Alcohol 5, 63 (1988). Suppression of ethanol intake in rats: F. Boismare et al., Pharmacol. Biochem. Behav. 21, 787 (1984); J. Le Magnen et al., Alcohol 4, 97 (1987). Evaluation of abuse potential: K. A. Grant, W. L. Woolverton, Pharmacol. Biochem. Behav. 32, 607 (1989). HPLC determn in plasma: C. Chabenat et al., J. Chromatogr. 414, 417 (1987). Clinical evaluation in relapse prevention in weaned alcoholics: J. P. L’Huintre et al., Lancet 1, 1014 (1985); J. P. L’Huintre et al., Alcohol Alcohol. 25, 613 (1990). Review of clinical efficacy in maintenance of abstinence in alcoholics: L. J. Scott et al., CNS Drugs 19, 445-464 (2005); of mechanism of action: P. De Witte et al., ibid. 517-537.

Properties: Colorless crystalline powder, mp 270°. uv max (water): 192 nm (e 7360). Freely sol in water. Practically insol in absolute ethanol, dichloromethane. LD50 i.p. in male mice: 1.87 g/kg (Durlach, 1982).

Melting point: mp 270°

Absorption maximum: uv max (water): 192 nm (e 7360)

Toxicity data: LD50 i.p. in male mice: 1.87 g/kg (Durlach, 1982)

Therap-Cat: In treatment of alcoholism.

Keywords: Alcohol Dependence Treatment.

Acamprosate calcium

- ATC:N07BB03
Use:alcohol-abuse deterrent
Chemical name:3-(acetylamino)-1-propanesulfonic acid calcium salt (2:1)
Formula:C₁₀H₂₀CaN₂O₈S₂

MW:400.49 g/mol
CAS-RN:77337-73-6
EINECS:278-665-3
LD₅₀:>10 g/kg (M, p.o.)

Derivatives

free acid

Formula:C₅H₁₁NO₄S
MW:181.21 g/mol
CAS-RN:77337-76-9
EINECS:278-667-4

Substance Classes

Acetamides, acetylamino substituted acids and their amides
Amino sulfonic acids
Calcium salts

Synthesis Path

Substances Referenced in Synthesis Path

CAS-RN	Formula	Chemical Name	CAS Index Name
3687-18-1	C₃H₉NO₃S	3-aminopropane-1-sulfonic acid	1-Propanesulfonic acid, 3-amino-
156-87-6	C₃H₉NO	3-amino-1-propanol	1-Propanol, 3-amino-

Trade Names

Country	Trade Name	Vendor
D	Campral	Merck
F	Aotal	Merck Lipha
GB	Campral EC	Merck Serono
USA	Campral	Forest

Formulations

tabl. 50 mg, 100 mg, 333 mg

References

- DE 3 019 350 (Lab. Meram; appl. 21.5.1980; F-prior. 23.5.1979).
- US 4 355 043 (Lab. Meram; 19.10.1982; F-prior. 23.5.1979).

synthesis of 3-aminopropane-1-sulfonic acid:
- Fujii, A. et al.: J. Med. Chem. (JMCMAR) 18, 502 (1975).
- JP 46 002 012 (Kowa; appl. 19.1.1971).
- WO 8 400 958 (Mitsui; appl. 15.3.1984; J-prior. 7.9.1982, 19.7.1983, 8.9.1982).

Acamprosate
Clinical data


Trade names	Campral EC
Synonyms	N-Acetyl homotaurine, Acamprosate calcium (JAN JP), Acamprosate calcium (USANUS)
Pregnancy category	C^[1]> (US) B2 (AU)
Routes of administration	Oral ^[1]
ATC code	N07BB03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	11%^[1]
Protein binding	Negligible^[1]
Metabolism	Nil^[1]
Elimination half-life	20 h to 33 h^[1]
Excretion	Renal^[1]
Identifiers
IUPAC name [show]
CAS Number	77337-76-9
PubChem CID	155434
IUPHAR/BPS	7106
DrugBank	DB00659
ChemSpider	136929
UNII	N4K14YGM3J
KEGG	D07058
ChEBI	CHEBI:51042
ChEMBL	CHEMBL1201293
ECHA InfoCard	100.071.495
Chemical and physical data
Formula	C₅H₁₁NO₄S
Molar mass	181.211 g/mol
3D model (JSmol)	Interactive image
SMILES [hide] [Ca+2].O=C(NCCCS(=O)(=O)[O-])C.[O-]S(=O)(=O)CCCNC(=O)C
InChI [hide] InChI=1S/2C5H11NO4S.Ca/c21-5(7)6-3-2-4-11(8,9)10;/h22-4H2,1H3,(H,6,7)(H,8,9,10);/q;;+2/p-2 Key:BUVGWDNTAWHSKI-UHFFFAOYSA-L
(what is this?) (verify)

Open Babel bond-line chemical structure with annotated hydrogens.<br>Click to toggle size. Image result for Acamprosate nmr

////////////////Acamprosate calcium, アカンプロセート

CC(=O)NCCCS(O)(=O)=O

CC(=O)NCCCS(=O)(=O)[O-].CC(=O)NCCCS(=O)(=O)[O-].[Ca+2]

DOCONEXENT, доконексен, دوكونيكسانت , 二十二碳六烯酸

July 9, 2018 9:46 am / Leave a comment

ChemSpider 2D Image | Docosahexaenoic acid | C22H32O2 (4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexaenoic acid.png

Image result for doconexent Docosahexaenoic Acid

Doconexent

CAS 6217-54-5

WeightAverage: 328.4883
Chemical FormulaC₂₂H₃₂O₂

4,7,10,13,16,19-Docosahexaenoic acid, (4Z,7Z,10Z,13Z,16Z,19Z)-

Doconexent sodium

295P7EPT4C

81926-93-4

(4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexaenoic acid
22:6-4, 7,10,13,16,19
22:6(n-3)
4,7,10,13,16,19-docosahexaenoic acid
4,7,10,13,16,19-Docosahexaenoic acid
all-cis-4,7,10,13,16,19-docosahexaenoic acid
all-cis-DHA
cervonic acid
DHA
docosa-4,7,10,13,16,19-hexaenoic acid
Docosahexaenoic acid
Ropufa 60
S.Presso
all-Z-Docosahexaenoic acid
all-cis-4,7,10,13,16,19-Docosahexaenoic acid
Δ^{4,7,10,13,16,19}-Docosahexaenoic acid
4,7,10,13,16,19-Docosahexaenoic acid, (all-Z)- (8CI)
Docosahexaenoic acid (6CI)
- (4Z,7Z,10Z,13Z,16Z,19Z)-4,7,10,13,16,19-Docosahexaenoic acid
- (4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexaenoic acid
- (4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexenoic acid
- (all-Z)-4,7,10,13,16,19-Docosahexaenoic acid
- 4-cis,7-cis,10-cis,13-cis,16-cis,19-cis-Docosahexaenoic acid

Docosahexaenoic acid (22:6(n-3))

ZAD9OKH9JC

доконексент [Russian] [INN]

دوكونيكسانت [Arabic] [INN]

二十二碳六烯酸 [Chinese] [INN]

(4Z,7Z,10Z,13Z,16Z,19Z)-4,7,10,13,16,19-Docosahexaenoic acid [ACD/IUPAC Name]

(4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenoic acid

(4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexaenoic acid

(all-Z)- 4,7,10,13,16,19-Docosahexaenoic Acid

(all-Z)-4,7,10,13,16,19-Docosahexaenoic acid

4,7,10,13,16,19-Docosahexaenoic acid, (4Z,7Z,10Z,13Z,16Z,19Z)-

all-Z-Docosahexaenoic acid

cis-4, cis-7, cis-10, cis-13, cis-16, cis-19-docosahexaenoic acid

cis-4,7,10,13,16,19-Docosahexaenoic acid

D4,7,10,13,16,19-Docosahexaenoic Acid

A mixture of fish oil and primrose oil; used as a high-docosahexaenoic acid fatty acid supplement.

A mixture of fish oil and primrose oil, doconexent is used as a high-docosahexaenoic acid (DHA) supplement. DHA is a 22 carbon chain with 6 cis double bonds with anti-inflammatory effects. It can be biosythesized from alpha-linolenic acid or commercially manufactured from microalgae. It is an omega-3 fatty acid and primary structural component of the human brain, cerebral cortex, skin, and retina thus plays an important role in their development and function. The amino-phospholipid DHA is found at a high concentration across several brain subcellular fractions, including nerve terminals, microsomes, synaptic vesicles, and synaptosomal plasma membranes

Image result for doconexent

Synthesis , By Farmer, Ernest H.; Van den Heuvel, Frantz A., From Journal of the Chemical Society (1938), 427-30.

ALSO

Title: Docosahexaenoic Acid

CAS Registry Number: 6217-54-5

CAS Name: (4Z,7Z,10Z,13Z,16Z,19Z)-4,7,10,13,16,19-Docosahexaenoic acid

Additional Names: cervonic acid; doconexent; DHA

Molecular Formula: C22H32O2

Molecular Weight: 328.49

Percent Composition: C 80.44%, H 9.82%, O 9.74%

Literature References: Omega-3 fatty acid found in marine fish oils and in many phospholipids. Major structural component of excitable membranes of the retina and brain; synthesized in the liver from a-linolenic acid, q.v. Isoln from oil of Sardina ocellata J. and structure: J. M. Whitcutt, Biochem. J. 67, 60 (1957). Improved isoln from cod liver oil: S. W. Wright et al., J. Org. Chem. 52,4399 (1987). Effect on brain and behavioral development: P. E. Wainwright, Neurosci. Biobehav. Rev. 16, 193 (1992). Review of uptake and metabolism by retinal cells: N. G. Bazan, E. B. Rodriguez de Turco, J. Ocul. Pharmacol. 10, 591-603 (1994). Review of clinical studies in infant formula supplementation: M. Makrides et al., Lipids 31, 115-119 (1996).

Properties: Clear, faintly yellow oil, mp -44.7 to -44.5°. n26D 1.5017.

Melting point: mp -44.7 to -44.5°

Index of refraction: n26D 1.5017

Use: Nutritional supplement.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. It can be synthesized from alpha-linolenic acid or obtained directly from maternal milk (breast milk), fish oil, or algae oil.^[1]

DHA’s structure is a carboxylic acid (-oic acid) with a 22-carbon chain (docosa- derives from the Ancient Greek for 22) and six (hexa-) cis double bonds (-en-);^[2] with the first double bond located at the third carbon from the omega end.^[3] Its trivial name is cervonic acid, its systematic name is all-cis-docosa-4,7,10,13,16,19-hexa-enoic acid, and its shorthand name is 22:6(n−3) in the nomenclature of fatty acids.

Most of the DHA in fish and multi-cellular organisms with access to cold-water oceanic foods originates from photosynthetic and heterotrophic microalgae, and becomes increasingly concentrated in organisms the further they are up the food chain. DHA is also commercially manufactured from microalgae: Crypthecodinium cohnii and another of the genus Schizochytrium.^[4] DHA manufactured using microalgae is vegetarian.^[5]

In strict herbivores, DHA is manufactured internally from α-linolenic acid, a shorter omega-3 fatty acid manufactured by plants (and also occurring in animal products as obtained from plants), while omnivores and carnivores primarily obtain DHA from their diet.^[6] Limited amounts of eicosapentaenoic and docosapentaenoic acids are possible products of α-linolenic acid metabolism in young women^[7] and men.^[6] DHA in breast milk is important for the developing infant.^[8] Rates of DHA production in women are 15% higher than in men.^[9]

DHA is a major fatty acid in brain phospholipids and the retina. While the potential roles of DHA in the mechanisms of Alzheimer’s disease are under active research,^[10] studies of fish oil supplements, which contain DHA, have failed to support claims of preventing cardiovascular diseases.^[11]^[12]^[13]

Image result for doconexent

Central nervous system constituent

DHA is the most abundant omega-3 fatty acid in the brain and retina. DHA comprises 40% of the polyunsaturated fatty acids (PUFAs) in the brain and 60% of the PUFAs in the retina. Fifty percent of the weight of a neuron‘s plasma membraneis composed of DHA.^[14]

DHA modulates the carrier-mediated transport of choline, glycine, and taurine, the function of delayed rectifier potassium channels, and the response of rhodopsin contained in the synaptic vesicles, among many other functions.^[15]

DHA deficiency is associated with cognitive decline.^[16] Phosphatidylserine (PS) controls apoptosis, and low DHA levels lower neural cell PS and increase neural cell death.^[17] DHA levels are reduced in the brain tissue of severely depressed patients.^[18]^[19]

Image result for DOCONEXENT NMR

Metabolic synthesis

In humans, DHA is either obtained from the diet or may be converted in small amounts from eicosapentaenoic acid (EPA, 20:5, ω-3) via docosapentaenoic acid (DPA, 22:5 ω-3) as an intermediate.^[7]^[6] This synthesis had been thought to occur through an elongation step followed by the action of Δ4-desaturase.^[6] It is now considered more likely that DHA is biosynthesized via a C24 intermediate followed by beta oxidation in peroxisomes. Thus, EPA is twice elongated, yielding 24:5 ω-3, then desaturated to 24:6 ω-3, then shortened to DHA (22:6 ω-3) via beta oxidation. This pathway is known as Sprecher’s shunt.^[20]^[21]

In organisms such as microalgae, mosses and fungi, biosynthesis of DHA usually occurs as a series of desaturation and elongation reactions, catalyzed by the sequential action of desaturase and elongase enzymes. A common pathway in these organisms involves:

a desaturation at the sixth carbon of alpha-linolenic acid by a Δ6 desaturase to produce stearidonic acid,
elongation of the stearidonic acid by a Δ6 elongase to produce to eicosatetraenoic acid,
desaturation at the fifth carbon of eicosatetraenoic acid by a Δ5 desaturase to produce eicosapentaenoic acid,
elongation of eicosapentaenoic acid by a Δ5 elongase to produce docosapentaenoic acid, and
desaturation at the fourth carbon of docosapentaenoic acid by a Δ4 desaturase to produce DHA.^[22]

Metabolism

DHA can be metabolized into DHA-derived specialized pro-resolving mediators (SPMs), DHA epoxides, electrophilic oxo-derivatives (EFOX) of DHA, neuroprostanes, ethanolamines, acylglycerols, docosahexaenoyl amides of amino acids or neurotransmitters, and branched DHA esters of hydroxy fatty acids, among others.^[23]

The enzyme CYP2C9 metabolizes DHA to epoxydocosapentaenoic acids (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. 10,11-EDPs]).^[24]

Potential health effects

Neurological research

While one human trial of 402 subjects lasting 18 months concluded that DHA did not slow decline of mental function in elderly people with mild to moderate Alzheimer’s disease,^[25] a similar trial of 485 subjects lasting 6 months concluded that algal DHA of 900 mg per day taken decreased heart rate and improved memory and learning in healthy, older adults with mild memory complaints.^[26]

In another early-stage study, higher DHA levels in middle-aged adults was related to better performance on tests of nonverbal reasoning and mental flexibility, working memory, and vocabulary.^[27]

One study found that the use of DHA-rich fish oil capsules did not reduce postpartum depression in mothers or improve cognitive and language development in their offspring during early childhood.^[28] Another systematic review found that DHA had no significant benefits in improving visual field in individuals with retinitis pigmentosa.^[29] A 2017 pilot study found that fish oil supplementation reduced the depression symptoms emphasizing the importance of the target DHA levels.^[30]

Pregnancy and lactation

It has been recommended to eat foods which are high in omega-3 fatty acids for women who want to become pregnant or when nursing.^[31] A working group from the International Society for the Study of Fatty Acids and Lipids recommended 300 mg/day of DHA for pregnant and lactating women, whereas the average consumption was between 45 mg and 115 mg per day of the women in the study, similar to a Canadian study.^[32] Despite these recommendations, recent evidence from a trial of pregnant women randomized to receive supplementation with 800 mg/day of DHA versus placebo, showed that the supplement had no impact on the cognitive abilities of their children at up to seven years follow-up.^[33]

Other research

In one preliminary study, men who took DHA supplements for 6–12 weeks had lower blood markers of inflammation.^[34]

Nutrition

Algae-based DHA supplements

Ordinary types of cooked salmon contain 500–1500 mg DHA and 300–1000 mg EPA per 100 grams.^[35] Additional rich seafood sources of DHA include caviar (3400 mg per 100 grams), anchovies (1292 mg per 100 grams), mackerel (1195 mg per 100 grams), and cooked herring(1105 mg per 100 grams).^[35] Brains from mammals are also a good direct source, with beef brain, for example, containing approximately 855 mg of DHA per 100 grams in a serving.^[36]

Discovery of algae-based DHA

In the early 1980s, NASA sponsored scientific research on a plant-based food source that could generate oxygen and nutrition on long-duration space flights. Certain species of marine algae produced rich nutrients, leading to the development of an algae-based, vegetable-like oil that contains two polyunsaturated fatty acids, DHA and arachidonic acid,^[37] present in some health supplements.

Use as a food additive

DHA is widely used as a food supplement. It was first used primarily in infant formulas.^[38] In 2004, the US Food and Drug Administration endorsed qualified health claims for DHA.^[39]

Some manufactured DHA is a vegetarian product extracted from algae, and it competes on the market with fish oil that contains DHA and other omega-3s such as EPA. Both fish oil and DHA are odorless and tasteless after processing as a food additive.^[40]

Studies of vegetarians and vegans

Vegetarian diets typically contain limited amounts of DHA, and vegan diets typically contain no DHA.^[41] In preliminary research, algae-based supplements increased DHA levels.^[42]While there is little evidence of adverse health or cognitive effects due to DHA deficiency in adult vegetarians or vegans, breast milk levels remain a concern for supplying adequate DHA to the developing fetus.^[41]

DHA and EPA in fish oils

Fish oil is widely sold in capsules containing a mixture of omega-3 fatty acids, including EPA and DHA. Oxidized fish oil in supplement capsules may contain lower levels of EPA and DHA.^[43]^[44]

Hypothesized role in human evolution

An abundance of DHA in seafood has been suggested as being helpful in the development of a large brain,^[45] though other researchers claim a terrestrial diet could also have provided the necessary DHA.^[46]

Patent

CN 106190872

https://patents.google.com/patent/CN106190872A/zh

PATENT

WO 2017038860

https://patents.google.com/patent/WO2017038860A1/en

[Example 1]
The raw EPA ethyl ester 1 of Comparative Example 1 containing EPA 96.7%, except for changing the temperature of the alkaline hydrolysis in 6 ° C., in the same manner as in Comparative Example 1 was alkaline hydrolysis.
That is, the starting EPA ethyl ester 1 2.50 g, ethanol 6.25 mL (4.92 g, 14.11 equivalents relative fatty acid), water 1.00 mL, 48 wt% sodium hydroxide aqueous solution 0.76 g ( 1.20 equivalents of base) was added a sample solution 3 was prepared against fatty acids. In sample liquid 3, moisture 1.40 g, i.e., was 10.27 equivalents relative fatty acid. The sample liquid 3, stirred for 24 hours 6 ° C., was subjected to hydrolysis treatment. Confirmed the completion of the reaction of the hydrolysis treatment, returned to the sample liquid 3 after treatment at room temperature, after transferred to a separatory funnel, and hexane was added 3.13 mL, purified water 2.50mL the sample liquid 3. When further adding 2.25g of hydrochloric acid, the sample solution 3 was separated into two layers of hexane and aqueous layers. The pH of the aqueous layer was 1.0.

The sample liquid 3 was stirred, then the mixture was allowed to stand, after removing the aqueous layer from the sample liquid 3, was further stirred with purified water 3.75mL the sample liquid 3 after removal. Hydrochloric acid was added small amount to adjust the pH of the aqueous layer to 1.0. Thereafter, the aluminum plate was washed with the same amount of purified water as rinsing liquid. Rinsing liquid is recovered after washing with water was repeatedly washed with water until neutral pH 6.0 ~ 7.0. The hexane layer was recovered from the sample liquid 3 after washing with water, the recovered hexane layer, the hexane was removed with an evaporator and vacuum, the EPA3 a composition containing free EPA was obtained 2.14 g.
Against EPA3, it was evaluated in the same manner as EPA1. The results are shown in Table 1 and Table 4.
The recovery was 93.8%. The resulting Gardner color of EPA3 is 2-, AnV 1.3, ethyl ester (EE) content 2790Ppm, conjugated diene acid content was 0.47%. Conjugated unsaturated fatty acids other than the conjugated diene acid was not detected. These physical property values are shown in Table 1. Note that the conjugated unsaturated fatty acids, only the conjugated diene acid shown in Table 1.

PATENT

WO-2018120574

Process for production of docosahexaenoic acid (DHA), by microbial fermentation of Schizochytrium limacinum . Discloses use of DHA for treating cardiovascular diseases, infertility or neurological diseases. See CN106635405 , claiming method for separating DHA from powder DHA grease by supercritical extraction method. Kingdomway lists that it produces DHA by microorganism fermentation.

DHA, the full name doc-4,7,10,13,16,19-docosahexaenoic acid, DHA, is a polyunsaturated fatty acid. The human body is difficult to synthesize itself and must be taken from the outside world. DHA is one of the essential fatty acids in the human body. It has important physiological regulation functions and health care functions. When it is lacking, it will cause a series of diseases, including growth retardation, skin abnormalities, scales, infertility, mental retardation, etc. In addition, there are cardiovascular diseases. Special preventive and therapeutic effects. Studies have also shown that DHA can act on many different types of tissues and cells, inhibit inflammation and immune function, including reducing the production of inflammatory factors, inhibit lymphocyte proliferation, etc. DHA also has multiple effects in preventing Alzheimer’s disease and neurological diseases. .

The current commercial sources of DHA are mainly fish oil and microalgae. DHA extracted from traditional deep-sea fish oil is unstable due to the variety, season and geographical location of fish, and the content of cholesterol and other unsaturated fatty acids is high. The difference in length and degree of unsaturation of fatty acid chains is large, resulting in limited production and content of DHA. It is not high, it is difficult to separate and purify, and the cost is high. With the growing shortage of fish oil raw materials, it is difficult to achieve the widespread use of DHA, a high value-added product in the food and pharmaceutical industries. The production of DHA by microbial fermentation can overcome the defects of traditional fish oil extraction, can be used for mass production of DHA, continuously meet people’s needs, has broad application prospects, and has attracted the attention of scholars at home and abroad. The microbial fermentation method uses fermented microorganisms such as fungi and microalgae to produce DHA-containing algal oil, and refined to obtain essential oil with high DHA content. DHA-producing strains approved by the Ministry of Health include Schizochytrium sp., Ulkenia amoeboida, and Crypthecodinium cohnii.

The market share of DHA produced by microbial fermentation is increasing rapidly year by year. There is a trend to replace DHA of fish oil, improve the production technology and quality of microalgae DHA, and the prospect of entering the microalgae DHA market is broad.

The publication No. CN103882072A discloses a method for producing docosahexaenoic acid by using Schizochytrium, and the highest yield disclosed is a cell dry weight of 61.2 g/L, a DHA content of 55.07%, and a DHA yield of 22.17 g. /L. The publication No. CN101812484A discloses a method for fermenting DHA by high-density culture of Schizochytrium, which discloses a dry cell weight of 120-150 g/L and a DHA yield of 26-30 g/L, which is also reported. The highest production level of DHA produced by Schizochytrium sp. Although the DHA productivity has been greatly improved compared with the previous research, the industrial production of docosahexaenoic acid by using microalgae greatly reduces the production cost, increases the unit yield, and enables the method of microbial fermentation to produce DHA. Promotion and popularization are still far from enough.

There are three main methods for extracting DHA from the fermentation liquid of Schizochytrium, one is centrifugation, the other is organic solvent extraction, and the third is supercritical extraction. Centrifugation, such as the publication No. CN101817738B, discloses a method for extracting DHA from algae and fungal cells by separating the microalgae or fungal fermentation broth after fermentation by a separation system, and adjusting the pH of the sludge with an acid. 2.0-4.0, then control the temperature of the slime at 10 °C-20 °C, add anti-oxidant in the slime, and then carry out high-pressure homogenization and breaking through the high-pressure homogenizer; add the broken mud to the water, stir and feed The liquid was separated by a three-phase separator to obtain DHA grease. The invention adopts physical wall breaking and physical extraction methods, has simple process, high cell breakage, low temperature treatment of bacteria sludge and antioxidant treatment, can effectively protect the biological activity of algae and fungal cells, and the product is green and non-toxic. Residue. However, the quality of the oil layer after centrifugation of the invention is poor. In addition to the oil, it also contains impurities such as water, medium components and cell debris, which is not conducive to subsequent refining. In addition, the wastewater layer after centrifugation contains a large amount of slag and has a high COD. Difficult to handle or process is extremely costly. The organic solvent extraction method, such as the publication No. CN101824363B, discloses a method for extracting docosahexaenoic acid oil: the fermentation liquid containing docosahexaenoic acid is subjected to enzymatic breaking, and then an organic solvent is used first. The first stage water is divided, the cells are enriched, and the organic solvent is used for secondary extraction to obtain a crude oil. The method is simple in operation and low in equipment investment, but the method uses organic solvent for extraction, and the final product may have solvent residue, and the extraction process has safety hazards such as flammability and explosion. The supercritical extraction method, as disclosed in the publication No. CN102181320B, discloses a method for extracting bio-fermented DHA algae oil, comprising the following steps: a) drying the solid matter obtained by solid-liquid separation of the microalgae fermentation liquid to obtain a dried bacterial cell; b) extracting the dried cells with supercritical carbon dioxide as an extractant to obtain a carbon dioxide fluid; c) separating the carbon dioxide fluid under reduced pressure to obtain DHA algae oil. Experiments show that the DHA content of DHA algae oil obtained by the method provided by the invention is more than 40%, the extraction yield is only 85.23%, and the need to add ethanol as the extracting agent has certain safety risks and supercritical. The equipment is expensive and the extraction yield is not high.

In the prior art, the refining of DHA hair oil is mostly carried out by chemical refining technology, and the DHA hair oil is degummed, alkali refining, decolorized and deodorized to obtain DHA essential oil. Inevitably, there are some problems in the process technology. For example, in order to achieve the requirement of controlling low acid value, alkali refining usually adds excessive alkali, and some triglycerides are inevitably saponified; high COD wastewater produced by alkali refining will pollute the environment; Alkali refining requires high temperature treatment for a long time, which is easy to cause the product’s peroxide value and anisidine value to increase; the deodorization temperature is high, and the long time is easy to produce trans fatty acids.

Currently, there is still a need to develop new DHA production processes.

Fermentation culture

In the following Examples 1-13, unless otherwise specified, the seed medium formulations used were: glucose 3%, peptone 1%, yeast powder 0.5%, sea crystal 2%, and pH natural (the rest being water). The fermentation medium formula is: glucose 12%, peptone 1%, yeast powder 0.5%, sea crystal 2% (the rest is water).

Example 1

The Schizochytrium sp. ATCC 20888, Schizochytrium limacinum Honda et Yokochi ATCCMYA-1381, and Schizochytrium sp. CGMCC No. 6843 slope-preserved strains were respectively inserted into 400 mL of medium. The 2L shake flask was cultured at a temperature of 25 ° C at a rotation speed of 200 rpm for 24 hours to complete the activated culture of the strain. According to the inoculation amount of 0.4%, the shake flask seed solution was connected to the first-stage seed tank containing the sterilized medium, and the culture temperature was 28 ° C, the aeration amount was 1 vvm, the tank pressure was 0.02 MPa, and the stirring speed was 50 rpm for 30 hours to complete the first stage. Seeds are expanded and cultured. The seed liquid of the primary seed tank was connected to the secondary seed tank containing the sterilized medium according to the inoculation amount of 3%, and the culture temperature was 28 ° C, the aeration amount was 1 vvm, the tank pressure was 0.02 MPa, and the stirring speed was 75 rpm for 24 hours. Complete secondary seed expansion culture. The seed solution of the secondary seed tank was connected to a fermentor containing the sterilized medium according to a 3% inoculum.

The fermentation process has a culture temperature of 28 ° C, aeration of 1 vvm, a can pressure of 0.02 MPa, a stirring speed of 75 rpm, a carbon source containing 30% of the pretreated crude glycerin, a glucose concentration of 5 g/L, and a nitrogen source. Fermentation culture. During the fermentation process, the glucose concentration, pH, bacterial biomass, crude oil production and DHA yield of the fermentation broth were measured.

After 96 hours of culture, the fermentation was terminated. Table 1 below shows the biomass, crude oil production, DHA production and DHA productivity of the three strains cultured in the original culture mode. Table 2 below shows the mixed fat and fatty acid composition of the gas obtained after fermentation. Analysis results. The biomass, crude oil production and DHA production of CGMCC No.6843 are also shown in Figure 3.

Table 1: Fermentation results of different strains in the original culture mode

Table 2: 100m ³ fermenter original culture method

It can be seen from Table 1 and Table 2 that the yield and fatty acid composition of the three strains are different in the original culture mode, and the Schizochytrium sp. CGMCC No. 6843 is superior to the other two strains. Schizochytrid sp. (Schizochytrium sp. CGMCC No. 6843) was used as the starting strain to optimize the different culture methods.

PATENT

CN106635405

https://patents.google.com/patent/CN106635405A/zh

PATENT

WO2012153345

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012153345

PAPER

NMR

Organic Chemistry 2014 vol. 2014 21 pg. 4548 – 4561

Patent

WO 2015162265

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015162265&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

¹ H NMR (500 MHz; CDCI₃) δ_Η 5.43-5.30 (m, 12H, CH=CH), 2.85-2.80 (m, 10H, CH₂ bis-allylic), 2.42-2.40 (m, 4H, CH₂-C=0, CH₂ allylic), 2.07 (quint, J = 7.5 Hz, 2H, CH₂ allylic), 0.98 (t, J = 7.5 Hz, 3H, CH₃)

¹ H NMR (500 MHz; CDCI₃) δ_Η 5.43-5.30 (m, 12H, CH=CH), 2.85-2.80 (m, 10H, CH₂ bis-allylic), 2.42-2.40 (m, 4H, CH₂-C=0, CH₂ allylic), 2.07 (quint, J = 7.5 Hz, 2H, CH₂ allylic), 0.98 (t, J = 7.5 Hz, 3H, CH₃)

Image result for doconexent

Patent

Publication numberPriority datePublication dateAssigneeTitle

JPS60133094A *1983-12-211985-07-16Nisshin Oil Mills LtdManufacture of high purity eicosapentaenoic acid

JPH07242895A *1993-03-161995-09-19Ikeda Shiyotsuken KkEicosapentaenoic acid of high purity and isolation and purification of lower alcohol ester thereof

JPH09238693A *1996-03-071997-09-16Maruha CorpPurification of highly unsaturated fatty acid

JPH10139718A *1996-11-071998-05-26Kaiyo Bio Technol Kenkyusho:KkProduction of eicosapentaenoic acid

JP2004089048A *2002-08-302004-03-25National Institute Of Advanced Industrial & TechnologyNew labyrinthulacese microorganism and method for producing 4,7,10,13,16-docosapentaenoic acid therewith

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External links

DHA / EPA Omega-3 Institute – Recent studies, overviews, and objective science.
Docosahexaenoic acid (DHA) – University of Maryland Medical Center (UMMC)
Docosahexaenoic acid – DHA ChemSub Online

REFERENCE

Calder PC: Omega-3 fatty acids and inflammatory processes. Nutrients. 2010 Mar;2(3):355-74. doi: 10.3390/nu2030355. Epub 2010 Mar 18. [PubMed:22254027]
Kim HY: Novel metabolism of docosahexaenoic acid in neural cells. J Biol Chem. 2007 Jun 29;282(26):18661-5. Epub 2007 May 8. [PubMed:17488715]
Picq M, Chen P, Perez M, Michaud M, Vericel E, Guichardant M, Lagarde M: DHA metabolism: targeting the brain and lipoxygenation. Mol Neurobiol. 2010 Aug;42(1):48-51. doi: 10.1007/s12035-010-8131-7. Epub 2010 Apr 28. [PubMed:20422316]
Butovich IA, Lukyanova SM, Bachmann C: Dihydroxydocosahexaenoic acids of the neuroprotectin D family: synthesis, structure, and inhibition of human 5-lipoxygenase. J Lipid Res. 2006 Nov;47(11):2462-74. Epub 2006 Aug 9. [PubMed:16899822]
Serhan CN, Gotlinger K, Hong S, Lu Y, Siegelman J, Baer T, Yang R, Colgan SP, Petasis NA: Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes. J Immunol. 2006 Feb 1;176(3):1848-59. [PubMed:16424216]
Mas E, Croft KD, Zahra P, Barden A, Mori TA: Resolvins D1, D2, and other mediators of self-limited resolution of inflammation in human blood following n-3 fatty acid supplementation. Clin Chem. 2012 Oct;58(10):1476-84. Epub 2012 Aug 21. [PubMed:22912397]
Chen CT, Kitson AP, Hopperton KE, Domenichiello AF, Trepanier MO, Lin LE, Ermini L, Post M, Thies F, Bazinet RP: Plasma non-esterified docosahexaenoic acid is the major pool supplying the brain. Sci Rep. 2015 Oct 29;5:15791. doi: 10.1038/srep15791. [PubMed:26511533]
Pawlosky RJ, Hibbeln JR, Novotny JA, Salem N Jr: Physiological compartmental analysis of alpha-linolenic acid metabolism in adult humans. J Lipid Res. 2001 Aug;42(8):1257-65. [PubMed:11483627]
Pawlosky RJ, Hibbeln JR, Salem N Jr: Compartmental analyses of plasma n-3 essential fatty acids among male and female smokers and nonsmokers. J Lipid Res. 2007 Apr;48(4):935-43. Epub 2007 Jan 17. [PubMed:17234605]
Cederholm T, Salem N Jr, Palmblad J: omega-3 fatty acids in the prevention of cognitive decline in humans. Adv Nutr. 2013 Nov 6;4(6):672-6. doi: 10.3945/an.113.004556. eCollection 2013 Nov. [PubMed:24228198]
Guesnet P, Alessandri JM: Docosahexaenoic acid (DHA) and the developing central nervous system (CNS) – Implications for dietary recommendations. Biochimie. 2011 Jan;93(1):7-12. doi: 10.1016/j.biochi.2010.05.005. Epub 2010 May 15. [PubMed:20478353]
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Docosahexaenoic acid

Names

IUPAC name

(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid

Other names

cervonic acid
DHA
doconexent (INN)

Identifiers

CAS Number

6217-54-5

3D model (JSmol)

Interactive image

ChEBI

CHEBI:28125

ChEMBL

ChEMBL367149

ChemSpider

393183

ECHA InfoCard

100.118.398

IUPHAR/BPS

1051

PubChem CID

445580

UNII

ZAD9OKH9JC

Properties

C₂₂H₃₂O₂

328.488 g/mol

0.943 g/cm³

−44 °C (−47 °F; 229 K)

Boiling point

446.7 °C (836.1 °F; 719.8 K)

Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////////Docosahexaenoic acid (22:6(n-3)), ZAD9OKH9JC, доконексен, دوكونيكسانت , 二十二碳六烯酸 , Doconexent, 6217-54-5, cervonic acid, DHA, doconexent, 81926-93-4

all-Z-Docosahexaenoic acid
AquaGrow Advantage
CCRIS 7670
Cervonic acid
DHA
Doconexent
Doconexento
Doconexento [INN-Spanish]
Doconexentum
Doconexentum [INN-Latin]
Docosahexaenoic acid (all-Z)
Doxonexent
Efalex
Marinol D 50TG
Martek DHA HM
Monolife 50
Ropufa 60
UNII-ZAD9OKH9JC

CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O

Promega
308064-99-5

MW: 644.9746

4,7,10,13,16,19-Docosahexaenoic acid, (4E,7E,10E,13E,16E,19E)-
391921-09-8

MW: 328.4928

Algal DHA

MW: 328.4928

Omega-3 Fatty Acids

MW: 909.3808

4,7,10,13,16,19-Docosahexaenoic acid
2091-24-9

MW: 328.493

Doconexent [INN]
6217-54-5

MW: 328.4928

Docosahexaenoic acid, (Z,Z,Z,Z,Z,Z)-
32839-18-2

MW: 328.493

Doconexent sodium
81926-93-4

MW: 350.4749

(14C)Docosahexaenoic acid
93470-46-3

MW: 328.493

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Synthesis and Structure−Activity Relationships of Long-acting β₂Adrenergic Receptor Agonists Incorporating Metabolic Inactivation: An Antedrug Approach

Acamprosate is not metabolized by the human body.^[13] Acamprosate’s absolute bioavailability from oral administration is approximately 11%.^[13] Following administration and absorption of acamprosate, it is excreted unchanged (i.e., as acamprosate) via the kidneys.^[13]