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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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2,5-Bis(ethoxymethyl)furan, 6

1H NMR (CDCl3) = 6.20 (s, 2H), 4.36 (s, 4H), 3.47 (q, 4H, J = 7.1 Hz), 1.16 (t, 6H, J = 7.1 Hz);

13C NMR (CDCl3) = 150.9, 109.7, 65.7, 64.7, 15.1 ppm


Green Chem., 2017, Advance Article

DOI: 10.1039/C7GC02211E, Paper

F. A. Kucherov, K. I. Galkin, E. G. Gordeev, V. P. Ananikov

Efficient one-pot synthesis of tricyclic compounds from biobased 5-hydroxymethylfurfural (HMF) is described using a [4 + 2] cycloaddition reaction.

Efficient route for the construction of polycyclic systems from bioderived HMF

 Author affiliations


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ICH Q11 Q and A Document


Image result for ICH Q11

ICH Q11   Q and A Document

The topic of starting materials has been a vexed topic for some period. Indeed concerns relating to lack of clarity and issues pertaining to practical implementation led the EMA in Sept 2014 to publish a reflection paper—Reflection on the requirements for selection and justification of starting materials for the manufacture of chemical active substances.(10) The paper sought to outline key issues as well as authority expectations; specific areas of interest identified included the following:


Variance in interpretation between applicant and reviewer.


The registration of short syntheses that employ complex custom-made starting materials.


Lack of details preventing authorities being able to assess the suitability of a proposed registered starting material and its associated control strategy.

Image result for ICH Q11Image result for ICH Q11

While the consensus was that overall this provided a useful perspective of at least the EMA’s interpretation of ICH Q11(2) and requirements for starting…

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Solithromycin, солитромицин , سوليثروميسين , 索利霉素 ,


ChemSpider 2D Image | Solithromycin | C43H65FN6O10


  • Molecular Formula C43H65FN6O10
  • Average mass 845.009 Da
(3aS,4R,7S,9R,10R,11R,13R,15R,15aR)-1-{4-[4-(3-Aminophenyl)-1H-1,2,3-triazol-1-yl]butyl}-4-ethyl-7-fluoro-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4  ;,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranoside
2H-Oxacyclotetradecino[4,3-d]oxazole-2,6,8,14(1H,7H,9H)-tetrone, 1-[4-[4-(3-aminophenyl)-1H-1,2,3-triazol-1-yl]butyl]-4-ethyl-7-fluorooctahydro-11-methoxy-3a,7,9,11,13,15-hexamethyl-10-[[3,4,6-trideox  ;y-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-, (3aS,4R,7S,9R,10R,11R,13R,15R,15aR)-
3,4,6-Tridésoxy-3-(diméthylamino)-β-D-xylo-hexopyranoside de (3aS,4R,7S,9R,10R,11R,13R,15R,15aR)-1-{4-[4-(3-aminophényl)-1H-1,2,3-triazol-1-yl]butyl}-4-éthyl-7-fluoro-11-méthoxy-3a,7,9,11,13,15-hex améthyl-2,6,8,14-tétraoxotétradécahydro-2H-oxacyclotétradécino[4,3-d][1,3]oxazol-10-yle
CAS  760981-83-7 [RN]

Solithromycin (trade name Solithera) is a ketolide antibiotic undergoing clinical development for the treatment of community-acquired pneumonia (CAP)[1] and other infections.[2]

Solithromycin exhibits excellent in vitro activity against a broad spectrum of Gram-positive respiratory tract pathogens,[3][4] including macrolide-resistant strains.[5] Solithromycin has activity against most common respiratory Gram-(+) and fastidious Gram-(-) pathogens,[6][7] and is being evaluated for its utility in treating gonorrhea.

  • May 2011: Solithromycin is in a Phase 2 clinical trial for serious community-acquired bacterial pneumonia (CABP) and in a Phase 1 clinical trial with an intravenous formulation.[8]
  • September 2011 : Solithromycin demonstrated comparable efficacy to levofloxacin with reduced adverse events in Phase 2 trial in people with community-acquired pneumonia[9]
  • January 2015: In a Phase 3 clinical trial for community-acquired bacterial pneumonia (CABP), Solithromycin administered orally demonstrated statistical non-inferiority to the fluoroquinolone, Moxifloxacin.[10]
  • July 2015: Patient enrollment for the second Phase 3 clinical trial (Solitaire IV) for community-acquired bacterial pneumonia (CABP) was completed with results expected in Q4 2015.[11]
  • Oct 2015: IV to oral solithromycin demonstrated statistical non-inferiority to IV to oral moxifloxacin in adults with CABP.[12]
  • July 2016: Cempra Announces FDA Acceptance of IV and oral formulations of Solithera (solithromycin) New Drug Applications for in the Treatment of Community-Acquired Bacterial Pneumonia.[13]

Image result for Solithromycin

Image result for Solithromycin


X-ray crystallography studies have shown solithromycin, the first fluoroketolide in clinical development, has a third region of interactions with the bacterial ribosome,[14] as compared with two binding sites for other ketolides.

The only (previously) marketed ketolidetelithromycin, suffers from rare but serious side effects. Recent studies[15] have shown this to be likely due to the presence of the pyridineimidazole group of the telithromycin side chain acting as an antagonist towards various nicotinic acetylcholine receptors.

Macrolide antibiotics, such like erythromycin, azithromycin, and clarithromycin, have proven to be safe and effective for use in treating human infectious diseases such as community-acquired bacterial pneumonia (CABP), urethritis, and other infections.

Because of the importance of macrolide antibiotics, there has been growing recent interest in this area as exemplified by the new fourth-generation macrolide solithromycin , which is developed by Cempra Pharmaceuticals as the first fluoroketolide antibiotic that has recently completed phase III clinical trials and demonstrates potent activity against the pathogens associated with CABP, including macrolide- and penicillin-resistant isolates of S. pneumoniaeis

Summary of macrolide antibiotic development by semisynthesis.

To date, all macrolide antibiotics are produced by chemical modification (semisynthesis) of erythromycin, a natural product produced on the ton scale by fermentation. Depicted are erythromycin and the approved semisynthetic macrolide antibiotics clarithromycin, azithromycin and telithromycin along with the dates of their FDA approval and the number of steps for their synthesis from erythromycin. The previous ketolide clinical candidate cethromycin and the current clinical candidate solithromycin are also depicted. It is evident that increasingly lengthy sequences are being employed in macrolide discovery efforts.

Chemical differentiation of solithromycin from telithromycin





Scheme . Reported Route for the Synthesis of Solithromycin, FernandesP. B.ChapelH. ; Patent WO 2010/048599, 2009

WO 2016210239,


Figure 4: A convergent, fully synthetic route to solithromycin.

FromA platform for the discovery of new macrolide antibiotics

Nature, 533, 338–345 (19 May 2016), doi:10.1038/nature17967

residue was purified by column chromatography over silica gel (10% methanol–dichloromethane + 1% 30% aqueous ammonium hydroxide) to afford amine 49 as a pale yellow oil (1.11 g, 96%). TLC (10% methanol–dichloromethane + 1% 30% aqueous ammonium hydroxide): Rƒ = 0.12 (UV, anisaldehyde).

1H NMR (500 MHz, CD3OD) δ 8.26 (d, J = 6.5 Hz, 1H), 7.23 – 7.10 (m, 3H), 6.72 (ddd, J = 7.8, 2.3, 1.1 Hz, 1H), 4.47 (t, J = 7.1 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 2.05 – 1.95 (m, 2H), 1.57 – 1.47 (m, 2H).

13C NMR (126 MHz, CD3OD) δ 149.51, 149.15, 132.32, 130.72, 121.99, 116.32, 113.14, 51.20, 41.86, 30.64, 28.66.

FTIR (neat), cm-1 : 2424, 1612, 1587, 783, 694.

HRMS (ESI): Calculated for (C12H17N5 + H)+ : 232.1557; found: 232.1559.


The residue was purified by column chromatography (3% methanol–dichloromethane + 0.3% 30% aqueous ammonium hydroxide) to provide solithromycin (170 mg, 87%) as a white powder.

1H NMR (500 MHz, CDCl3) δ: 7.82 (s, 1H), 7.31 – 7.29 (m, 1H), 7.23 – 7.15 (m, 2H), 6.66 (dt, J = 7.2, 2.1 Hz, 1H), 4.89 (dd, J = 10.3, 2.0 Hz, 1H), 4.43 (td, J = 7.1, 1.5 Hz, 2H), 4.32 (d, J = 7.3 Hz, 1H), 4.08 (d, J = 10.6 Hz, 1H), 3.82 – 3.73 (m, 1H), 3.68 – 3.60 (m, 1H), 3.60 – 3.49 (m, 2H), 3.45 (s, 1H), 3.20 (dd, J = 10.2, 7.3 Hz, 1H), 3.13 (q, J = 6.9 Hz, 1H), 2.69 – 2.59 (m, 1H), 2.57 (s, 3H), 2.51 – 2.42 (m, 1H), 2.29 (s, 6H), 2.05 – 1.93 (m, 3H), 1.90 (dd, J = 14.5, 2.7 Hz, 1H), 1.79 (d, J = 21.4 Hz, 3H), 1.75 – 1.60 (m, 4H), 1.55 (d, J = 13.0 Hz, 1H), 1.52 (s, 3H), 1.36 (s, 3H), 1.32 (d, J = 7.0 Hz, 3H), 1.28 – 1.24 (m, 1H), 1.26 (d, J = 6.1 Hz, 3H), 1.20 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 7.0 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H).

13C NMR (125 MHz, CDCl3) δ 216.52, 202.79 (d, J = 28.0 Hz), 166.44 (d, J = 22.9 Hz), 157.19, 147.82, 146.82, 131.72, 129.63, 119.66, 116.14, 114.71, 112.36, 104.24, 97.78 (d, J = 206.2 Hz), 82.11, 80.72, 78.59, 78.54, 70.35, 69.64, 65.82, 61.05, 49.72, 49.22, 44.58, 42.77, 40.86, 40.22, 39.57, 39.20, 28.13, 27.59, 25.20 (d, J = 22.4 Hz). 24.28, 22.14, 21.15, 19.76, 17.90, 15.04, 14.70, 13.76, 10.47.

19F NMR (471 MHz, CDCl3) δ –163.24 (q, J = 11.2 Hz).

FTIR (neat), cm–1 : 3362 (br), 2976 (m), 1753 (s), 1460 (s), 1263 (s), 1078 (s), 1051 (s), 991 (s).

HRMS (ESI): Calcd for (C43H65FN6O10 + H)+ : 845.4819; Found: 845.4841.

Abstract Image

Potential causes for the formation of synthetic impurities that are present in solithromycin (1) during laboratory development are studied in the article. These impurities were monitored by HPLC, and their structures are identified on the basis of MS and NMR spectroscopy. In addition to the synthesis and characterization of these seven impurities, strategies for minimizing them to the level accepted by the International Conference on Harmonization (ICH) are also described.

Summary of macrolide antibiotic development by semisynthesis.


Identification, Characterization, Synthesis, and Strategy for Minimization of Potential Impurities Observed in the Synthesis of Solithromycin

 HEC Research and Development Center, HEC Pharm Group, Dongguan 523871, P. R. China
 State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Co., Ltd., Dongguan 523871, P. R. China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00201

Macrolide antibacterial agents are characterized by a large lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, are attached. The first generation macrolide, erythromycin, was soon followed by second generation macrolides clarithromycin and azithromycin. Due to widespread of bacterial resistance semi-synthetic derivatives, ketolides, were developed. These, third generation macrolides, to which, for example, belongs telithromycin, are used to treat respiratory tract infections. Currently, a fourth generation macrolide, solithromycin (also known as CEM-101 ) belonging to the fluoroketolide class is in the pre-registration stage. Solithromycin is more potent than third generation macrolides, is active against macrolide-resistant strains, is well-tolerated and exerts good PK and tissue distribution.


One route of synthesis of solithromycin is disclosed in WO2004/080391 A2. Said route is based on the synthetic strategy disclosed in Tetrahedron Letters, 2005, 46, 1483-1487. It is formally a 10 step linear synthesis starting from clarithromycin. Its characteristics are a late cleavage of cladinose, a hexose deoxy sugar which is in ketolides replaced with a keto group, and a 3-step building up of the side chain. Most intermediates are amorphous or cannot be purified by crystallization, hence chromatographic separations are required.

WO 2009/055557 A1 describes a process, in which the linker part of the side chain (azidobutyl) is synthesized separately thus making the synthesis more convergent. In addition, the benzoyl protection group instead of the acetyl is used to protect the 3-hydroxy group of the tetrahydropyran moiety. The linker part of the side chain is introduced using 4-azidobutanamine which is prepared through a selective Staudinger monoreduction of 1 ,4-diazidobutane.

WO 2014/145210 A1 discloses several routes of synthesis all based on the use of already fully constructed side chain building blocks, or its protected forms, which are reacted with an imidazoyl carbamate still containing the protected cladinose moiety. After the introduction of the side chain, the cladinose is cleaved and the aniline group protected for the oxidation of the hydroxy group and the fluorination. After fluorination and deprotection or unmasking of the aniline group, solithromycin is obtained.

Synthesis of crude solithromycin

A third aspect of the invention is a process for providing crude solithromycin (the compound of formula 5) through a convergent synthesis that combines both aforementioned building blocks, the macrolide building block (compound of formula 3) and the side chain building block 3-(1 -(4-aminobutyl)-1 H-1 ,2,3-triazol-4-yl)aniline prepared as discussed above.

As shown in Scheme 4, first, the compound of formula 3 and 3-(1-(4-aminobutyl)-1 H-1 ,2,3-triazol-4-yl)aniline are reacted in the presence of a strong base, for example, DBU, in a suitable solvent, for example, MeCN, to give the compound of formula 4. In the last step, the acetyl protecting group of the hydroxy group located on position β to the dimethylamino substituent is cleaved in methanol.

As discussed above, the fluorination is performed in the presence of acetyl group in the pyran part of the molecule and prior to the incorporation of the side chain, which allows that both exchanging the protection group in the pyran part of the molecule and masking or protecting the aniline moiety from oxidation caused under fluorinating conditions can be avoided.

Scheme 4: Representation of the specific embodiment of the present invention.

In another aspect of the present invention a process is provided for purification of crude solithromycin.

Purification of crude solithromycin

Due to its properties, solithromycin is very difficult to purify. The amorphous material obtained after various syntheses is truly a challenge for further processing.

Chromatographic separation is very difficult and of poor resolution. Due to the basic polar functional groups, the compound and its related impurities all tend to “trail” on typical normal stationary phases that are considered suitable for industrial use, such as silica and alumina. Purification by crystallization is just as difficult unless the material is already sufficiently pure. Impurities inhibit its crystallization to such an extent that solutions in alcohols can be stable even in concentrations of several-fold above the saturation levels of the pure material. Such solutions refuse to crystallize even after weeks of stirring or cooling. Seeding with crystalline solithromycin has no effect and the added seeds simply dissolve. In addition, only limited purification is achieved in most solvents. Lower primary alcohols, particularly ethanol, are most efficient for purification by crystallization when this is possible, but give low recovery and the crystallization is most sensitive toward impurities, thus still demanding prior chromatographic separation.

Clearly an alternative method of purification would be advantageous. For this reason we developed a process for purification employing an acidic salt formation, for example solithromycin oxalate salt, freebasing back to solithromycin, and crystallization from ethanol (Scheme 5).

Scheme 5: Representation of a particular embodiment of the present invention.

The formation of crystalline salts from crude solithromycin may be inhibited by impurities and is dependent on the solvent used. Only a limited number of acids gave useful precipitates from solutions of crude solithromycin. Of these, the precipitation of the oxalate salt from isopropyl acetate (‘PrOAc) or 2-methyltetrahydrofuran (MeTHF) was found to be most efficient in regard to yields, reaction times and purification ability. Precipitation of the citrate salt from MeTHF also significantly increased purity. However, impurities strongly inhibited crystal growth rates, the reaction thus required longer times compared to the oxalate salt formation. Crystallization of salts from solutions of impure solithromycin was also found possible with D-(-)-tartaric, dibenzoyl-d-tartaric, 2,4-dihydroxybenzoic, 3,5-dihydroxybenzoic, and (R)-(+)-2-pyrrolidinone-5-carboxylic acids using ethyl acetate, isopropyl acetate or MeTHF as solvents, or their mixtures with methyl f-butyl ether, but the efficiency and purification abilities were inferior to both the oxalate and the citrate salt.

Some acids, such as (R)-(-)-mandelic, L-(+)-tartaric, p-toluenesulfonic, benzoic, malonic, 4-hydroxybenzoic, (-)-malic, and (+)-camphor-10-sulfonic acid formed insoluble amorphous precipitates without improving purity. Many other acids were found unable of forming any precipitate from impure solithromycin under the conditions tested.

Example 1 : Synthesis of compound 2: (2R,3S,7R,9R, 10R, 1 1 R, 13R,Z)-10-(((2S,3R,4S,6R)-3- acetoxy-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-9- methoxy-3,5,7,9,1 1 , 13-hexamethyl-6,12, 14-trioxooxacyclotetradec-4-en-3-yl 1 H- imidazole-1 -carboxylate

A solution of (2S,3R,4S,6R)-4-(dimethylamino)-2-(((3R,5R,6R,7R,9R,13S,14R,Z)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxacyclotetradec-11-en-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl acetate, 1 (313 g) in dichloromethane (2.22 L) was cooled to -25 °C. DBU (115 mL) followed by CDI (125 g) were added and temperature of the reaction was raised to 0°C. The completion of the reaction was followed by HPLC. Upon the completion, the pH of the reaction mixture was adjusted to 6 using 10% aqueous acetic acid. Layers were separated and organic layer was washed twice with water, dried over sodium sulphate and concentrated to afford compound 2 as white foam (HPLC purity: 90 area%).

1H NMR (500 MHz, CDCI3) δ 8.00 (s, 1H), 7.28 (t, J = 1.5 Hz, 1H), 6.96 (dd, J = 1.6, 0.8 Hz, 1H), 6.70 (s, 1H), 5.58 (dd, J = 10.0, 3.2 Hz, 1H), 5.22 (s, 3H), 4.61 (dd, J = 10.5, 7.6 Hz, 1H), 4.25 (d, J = 7.6 Hz, 1H), 4.02 (d, J = 8.6 Hz, 1H), 3.67 (q, J = 6.8 Hz, 1H), 3.42-3.37 (m, 1H), 3.04 (brs, 1H), 2.93 (quintet, J =7.7 Hz, 1H), 2.67 (s, 3H), 2.58-2.52 (m, 1H), 2.13 (s, 6H), 1.94 (s, 3H), 1.77 (s, 3H), 1.72 (d, J = 0.8 Hz, 3H), 1.64-1.53 (m, 2H), 1.25 (d, J = 6.9, 3H), 1.19 (s, 3H), 1.13 (d, J = 6.2 Hz, 3H), 1.11 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 7.4 Hz, 3H), 0.84 (t, J = 7.4 Hz, 3H).

13C NMR (125 MHz, CDCI3) δ 204.84, 203.63, 169.64, 168.79, 145.85, 138.48, 137.94, 136.95, 130.75, 117.04, 101.78, 84.45, 80.77, 78.44, 76.89, 71.38, 69.02, 63.37, 50.91, 50.13, 47.31, 40.48, 40.48, 40.16, 38.81, 30.12, 22.53, 21.27, 20.84, 20.56, 20.06, 18.81, 14.98, 13.91, 13.14, 10.37.

Example 2: Synthesis of compound 3: (2R,3S,7R,9R, 10R, 11 R, 13S,Z)-10-(((2S,3R,4S,6R)-3- acetoxy-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-13- fluoro-9-methoxy-3,5,7,9, 11,13-hexamethyl-6, 12, 14-trioxooxacyclotetradec-4-en- 3-yl 1H-imidazole-1-carboxylate

A solution of (2R,3S,7R,9R,10R,11 R,13R,Z)-10-(((2S,3R,4S,6R)-3-acetoxy-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-9-methoxy-3,5,7,9,11,13-hexamethyl-6,12,14-trioxooxacyclotetradec-4-en-3-yl 1H-imidazole-1-carboxylate, 2 in THF (9 L) was cooled to 0 °C. DBU (115 mL) followed by NFSI (211 g) were added and reaction mixture was stirred at 0°C

until completion (followed by HPLC). The reaction mixture was quenched with cold, diluted NaHC03 (3 L). DCM (2.5 L) was added and layers were separated. Aqueous layer was washed with additional DCM (1.5 L). Combined organic layers were washed with brine (2 L), dried over sodium sulphate, filtrated and concentrated. Crude material was suspended in /PrOAc (2.5 L). Undissolved material was filtered-off and filtrate was concentrated in vacuo to afford compound 3 as pale yellow foam (475 g, HPLC purity: 85 area%).

19F NMR (470 MHz, CDCI3) δ -163.1 1.

13C NMR (125 MHz, CDCI3)5 204.81 , 202.27, 169.59, 165.51 (d, J = 22.9 Hz), 145.64, 138.02, 137.78, 136.85, 130.69, 1 16.95, 101 .57, 97.86 (d, J = 204.5 Hz), 84.23, 80.23, 78.95, 77.97, 71.24, 68.92, 63.1 1 , 49.05, 40.48, 40.48, 40.40, 40.08, 30.22, 24.18 (d, J = 16.8 Hz), 22.62, 21.64, 21 .18, 20.76, 19.97, 19.39, 14.37, 13.13, 10.32.

Synthesis of compound 3. (2R,3S,7R,9R, 10R, 1 1 R, 13S,Z)-10-(((2S,3R,4S,6R)-3- acetoxy-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-13- fluoro-9-methoxy-3,5,7,9, 1 1 , 13-hexamethyl-6, 12, 14-trioxooxacyclotetradec-4-en- 3-yl 1 H-imidazole-1 -carboxylate

A solution of (2S,3R,4S,6R)-4-(dimethylamino)-2-(((3R,5R,6R,7R,9R,13S,14R,Z)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,1 1 , 13-hexamethyl-2,4, 10-trioxooxacyclotetradec-1 1-en-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl acetate, 1 (2.45 g) in THF (17 mL) was cooled to 0 °C. DBU (0.9 mL) followed by CDI (0.97 g) were added. The completion of the reaction was followed by HPLC. Upon the completion, reaction was diluted by addition of THF (34 mL). Temperature of the reaction was lowered to -10 °C. DBU (0.72 mL) was added followed by solution of NFSI (1.51 g) in THF (14 mL). Upon completion of the reaction, mixture was diluted with the addition of water/ZPrOAc (1 :4) mixture and layers were separated. Organic phase was washed with water (3 x 25 mL), dried over Na2S04, filtered and concentrated to afford compound 3 as a white foam (3.1 g, HPLC purity: 70 area%).

Example 4: Synthesis of 3-(1 -(4-aminobutyl)-1 H-1 ,2,3-triazol-4-yl)aniline


1 moi% CuS04(aq)

2-(4-Chlorobutyl)isoindoline-1 ,3-dione. A mixture of phthalimide potassium salt (1 134 g, 6.00 mol), potassium carbonate (209 g, 1.50 mol), 1 ,4-dichlorobutane (1555 g, 12.00 mol), and potassium iodide (51 g, 0.30 mol, 5 mol%) in 2-butanone (4.80 L) was stirred 3 days at reflux conditions. The reaction mixture cooled to 40 °C was filtered and the insoluble materials washed with 2-butanone (1.00 L). The filtrate was evaporated at 80 °C under reduced pressure. 2-Propanol (1.00 L) was added to the residue and the solvent removed under reduced pressure. The residue was then crystallized from 2-propanol (4.30 L) at 25 °C. The product was isolated by filtration and washed with 2-propanol (1.00 L). After drying at 40 °C and approximately 50 mbar, there was obtained a white powder (1 1 1 1 g): 95% assay by quantitative 1H NMR; MS (ESI) m/z = 238 [MH]+.

2-(4-(4-(3-Aminophenyl)-1 H-1 ,2,3-triazol-l -yl)butyl)isoindoline-1 ,3-dione. To a solution of 2-(4-chlorobutyl)isoindoline-1 ,3-dione (950 g, 4.00 mol) in DMSO (2.80 L) was added sodium azide (305 g) and the mixture stirred 4 h at 70 °C. The reaction temperature was reduced to 25 °C and there was added in this order water (0.80 L), ascorbic acid (43 g, 0.24 mol, 6 mol%), 0.5M CuS04(aq) (160 ml_, 2 mol%) and m-aminophenylacetylene (493 g, 4.00 mol). The resulting mixture was stirred 18 h at 40 °C, forming a thick yellow slurry, which was then cooled to 0 °C and slowly diluted with water (2.40 L). The product was isolated by filtration, washing the filter cake with water (3 χ 2.00 L) and a 1 : 1 (vol.) mixture of methanol and water (2.00 L). After drying at 50 °C and approximately 50 mbar the product was obtained as a yellow powder (1405 g): 85% assay by quantitative 1H NMR; MS (ESI) m/z = 362 [MH]+.

3-(1-(4-Aminobutyl)-1H-1,2,3-triazol-4-yl)aniline. To a stirred suspension of 2-(4-(4-(3-Aminophenyl)-1 H-1 ,2,3-triazol-1 -yl)butyl)isoindoline-1 ,3-dione (659 g, 1 .55 mol) in 1 -butanol (3.26 L) was added hydrazine hydrate (50-60%, 174 ml_). After stirring for 18 h at 60 °C there was added toluene (0.72 L) and 1 M NaOH(aq) (5.00 L). After stirring for 20 min at 60 °C, the aqueous phase was removed and the organic phase washed at this same temperature with 1 M NaOH(aq) (1 .00 L), saturated NaCI(aq) (2 χ 2.00 L), and concentrated under reduced pressure to 2/3 of the initial quantity, dried over anhydrous sodium sulfate (300 g) in the presence of Fluorisil (30 g), filtered and evaporated under reduced pressure at 70 °C. The residual 1 -butanol is removed azotropically by adding toluene and evaporation under reduced pressure (2 χ 0.50 L). The residue was dissolved in tetrahydrofuran (0.50 L). To this solution kept stirring at 25 °C was slowly added methyl t-butyl ether (0.50 L) at which point the mixture was seeded. Additional methyl t-butyl ether (0.50 L) was slowly added and the product isolated by filtration, washed with methyl t-butyl ether (0.50 L), and dried at 35 °C and approximately 50 mbar to give an amber colored powder (321 g): mp = 70-73 °C (DSC);

1 H NMR (DMSO-d6, 500 MHz) 1 .30 (m, 2H), 1 .86 (m, 2H), 2.3-2.1 (bs, 2H), 2.53 (t, J = 6.0 Hz, 2H), 4.35 (t, J = 7.1 Hz, 2H), 5.17 (bs, 2H), 6.51 (ddd, J = 8.0, 2.3, 1 .0 Hz, 1 H), 6.92 (m, 1 H), 7.05 (t, J = 7.8 Hz, 1 H), 7.09 (t, J = 1 .9 Hz, 1 H), 8.39 (s, 1 H); 98% assay by quantitative 1 H NMR; MS (ESI) m/z = 232 [MH]+; I R (NaCI) 694, 789, 863, 1220, 1315, 1467, 1487, 1590, 2935 cm“1.

Example 5: Synthesis of compound 4: (2S,3R,4S,6R)-2-(((3aS,4R,7S,9R, 10R, 1 1 R, 13R,

15R)-1 -(4-(4-(3-aminophenyl)-1 H-1 ,2,3-triazol-1 -yl)butyl)-4-ethyl-7-fluoro-1 1 – methoxy-3a,7,9, 1 1 , 13, 15-hexamethyl-2,6,8, 14-tetraoxotetradecahydro-1 H- [1 ]oxacyclo-tetradecino[4,3-d]oxazol-10-yl)oxy)-4-(dimethylamino)-6-methyltetra- hydro-2H-pyran-3-yl acetate

A solution of (2R,3S,7R,9R,10R, 1 1 R, 13S,Z)-10-(((2S,3R,4S,6R)-3-acetoxy-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-13-fluoro-9-methoxy-3,5,7,9, 1 1 , 13-hexamethyl-6, 12,14-trioxooxacyclotetradec-4-en-3-yl 1 H-imidazole-1-carboxylate (425 g) in acetonitrile (3.1 L) was cooled to 0 °C. 4-(1-(4-aminobutyl)-1 H-1 ,2,3-triazol-4-yl)aniline, 3 (213 g) followed by DBU (83 ml.) were added. The mixture was stirred at 0° C until completion of the reaction (followed by HPLC). Mixture of DCM and water was added (4 L, 1 :1 ) and the pH was adjusted to 6 with 10% aqueous acetic acid. Layers were separated and organic layer was washed with water (2 x 2 L), dried over sodium sulphate and concentrated. The crude material was suspended in EtOAc (2.5 L). Undissolved material was filtered off and filtrate was concentrated in vacuo to afford compound 4 as yellow foam (470 g, HPLC purity: 75 area%).

19F NMR (470 MHz, CDCI3) δ -164.17 (q, J = 21.3 Hz).

13C NMR (125MHz, CDCI3) δ 216.67, 202.47 (d, J = 28.2 Hz), 169.88, 166.44 (d, J = 23.1 Hz), 157.28, 147.92, 147.00, 131 .81 , 129.73, 1 19.80, 1 16.16, 1 14.81 , 1 12.42, 101.90, 98.02 (d, J =205.9 Hz), 82.18, 79.74, 78.72, 71 .68, 69.33, 63.33, 61 .13, 49.80, 49.31 , 44.61 , 42.85, 40.71 , 39.37, 39.28, 31.97, 30.53, 29.1 1 , 27.69, 25.24 (d, J = 22.2 Hz), 24.36, 22.78, 22.24, 21.49, 21.04, 19.80, 18.04, 14.78, 14.70,14.21 , 13.83, 10.57.

Example 11 : Purification of crude solithromycin (compound 5) via oxalate (2)

To isopropyl acetate (5.77 L) crude solithromycin (192 g, 72 area%) was added, afterwards the mixture was stirred at reflux and filtered to remove any insoluble material. The filtrate was then stirred at 55 °C and oxalic acid (14.91 g, 164 mmol) was added in one batch. The suspension was cooled to 20 °C in the course of 1 h, stirred for additional 1 h and the product was isolated by filtration, washed with isopropyl acetate (0.5 L), and dried at 40 °C under reduced pressure to give the oxalate salt (106 g): 87.81 area% by HPLC (UV at 228 nm). The evaporation of the filtrate gave a resinous material containing solithromycin that can be recovered by reprocessing (88 g, 61.13 area%).

The above oxalate salt (106 g) was dissolved in water (2.40 L) and washed with MeTHF (2 χ 1.00 L) and ethyl acetate (0.50 L). Aqueous ammonia (25%; 37 mL) was then added to the filtrate while stirring at 25 °C. The precipitated product was extracted with ethyl acetate two times (3.00 L and 0.50 L). The combined extracts were washed with water (0.50 L), dried over Na2S04 and evaporated under reduced pressure. To the residue ethanol (2 χ 0.4 L) was added and again evaporated to affect the solvent exchange. The residue was then dissolved in ethanol (300 mL). After stirring for 24 h at 25 °C, the crystallized product was isolated by filtration and drying at 40 °C under reduced pressure to give solithromycin as an off-white crystalline solid (42 g): 98.61 area% by HPLC (UV at 228 nm).

The filtrate was evaporated under reduced pressure to give a yellowish foam (29 g: 68.65 area% by HPLC (UV at 228 nm) that was used for reprocessing.

Example 7: Purification of compound 5 (solithromycin): (3aS,4R,7S,9R, 10R, 1 1 R, 13R, 15R)-1 – (4-(4-(3-aminophenyl)-1 H-1 ,2,3-triazol-1 -yl)butyl)-10-(((2S,3R,4S,6R)-4- (dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-7- fluoro-1 1 -methoxy-3a,7,9, 1 1 , 13, 15-hexamethyloctahydro-1 H- [1 ]oxacyclotetradecino[4,3-d]oxazole-2,6,8, 14(7H, 9H)-tetraone

Crude solithromycin 5 (106 g, HPLC purity: 71 %) was suspended in /PrOAc (3 L) and heated to reflux, then filtered to remove undissolved material. Oxalic acid (8 g) was added to a filtrate at 60°C. Mixture was slowly cooled to RT and left stirring for additional 1 h. Precipitate was filtered off and dried in vacuo. Oxalate salt was suspended in water (1 .3 L) (if needed mixture was first filtered through Celite) then 25% aqueous ammonia (21 mL) was added and mixture was stirred additional 15 minutes. Precipitate was filtered off, rinsing with water. Wet solithromycin was dissolved it EtOAc (1 .8 L)/water (800 mL) solution. Layers were separated and organic phase was washed with water (2 x 250 mL), dried over Na2S04 and filtered. EtOAc was removed in vacuo to afford yellow foam.

Yellow foam was dissolved in EtOH (230 mL) and left stirring at RT until white precipitate fell out. White precipitate was dried in vacuo at room temperature to afford clean material (HPLC purity 97 area%).

19F NMR (470 MHz, CDCI3) δ -164.25 (q, J = 21 .3 Hz).

13C NMR (125 MHz, CDCI3) δ 216.64, 202.90 (d, J = 28.2 Hz), 166.53 (d, J = 23.2 Hz), 157.27, 147.88, 146.99, 131 .76, 129.70, 1 19.79, 1 16.1 1 , 1 14.79, 1 12.38, 104.31 , 97.84 (d, J = 206.1 Hz), 82.19, 80.77, 78.65, 78.58, 70.41 , 69.71 , 65.84, 61 .09, 49.77, 49.28, 44.64, 42.84, 40.92, 40.30, 39.61 , 39.26, 28.17, 27.66, 25.29 (d, J = 22.5 Hz), 24.32, 22.20, 21 .23, 19.82, 17.96, 15.12, 14.77, 13.83, 10.54.

Example 6: Synthesis of compound 5 (solithromycin): (3aS,4R,7S,9R, 10R, 1 1 R, 13R,15R)-1- (4-(4-(3-aminophenyl)-1 H-1 ,2,3-triazol-1-yl)butyl)-10-(((2S,3R,4S,6R)-4- (dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-7- fluoro-1 1 -methoxy-3a,7,9, 1 1 , 13, 15-hexamethyloctahydro-1 H- [1]oxacyclotetradecino[4,3-d]oxazole-2,6,8, 14(7H,9H)-tetraone

A solution of (2S,3R,4S,6R)-2-(((3aS,4R,7S,9R, 10R, 1 1 R, 13R, 15R)-1 -(4-(4-(3-aminophenyl)-1 H-1 ,2,3-triazol-1 -yl)butyl)-4-ethyl-7-fluoro-1 1 -methoxy-3a,7,9, 1 1 , 13,15-hexamethyl-2,6,8, 14-tetraoxotetradecahydro-1 H-[1 ]oxacyclotetradecino[4,3-d]oxazol-10-yl)oxy)-4-(dimethylamino)-6- methyltetrahydro-2H-pyran-3-yl acetate, 4 (470 g) in methanol (4.7 L) was stirred at room temperature and completion of the reaction was followed by HPLC. Upon completion, the reaction mixture was concentrated to afford crude solithromycin 5 as orange foam (402 g, HPLC purity: 73 area%).


  1. Jump up^ Reinert RR (June 2004). “Clinical efficacy of ketolides in the treatment of respiratory tract infections”. The Journal of Antimicrobial Chemotherapy53 (6): 918–27. PMID 15117934doi:10.1093/jac/dkh169.
  2. Jump up^
  3. Jump up^ Woolsey LN; Castaneira M; Jones RN. (May 2010). “CEM-101 activity against Gram-positive organisms”Antimicrobial Agents and Chemotherapy54 (5): 2182–2187. PMC 2863667Freely accessiblePMID 20176910doi:10.1128/AAC.01662-09.
  4. Jump up^ Farrell DJ; Sader HS; Castanheira M; Biedenbach DJ; Rhomberg PR; Jones RN. (June 2010). “Antimicrobial characterization of CEM-101 activity against respiratory tract pathogens including multidrug-resistant pneumococcal serogroup 19A isolates”. International Journal of Antimicrobial Agents35 (6): 537–543. PMID 20211548doi:10.1016/j.ijantimicag.2010.01.026.
  5. Jump up^ McGhee P; Clark C; Kosowska-Shick K; Nagai K; Dewasse B; Beachel L; Appelbaum PC. (January 2010). “In Vitro Activity of Solithromycin against Streptococcus pneumoniae andStreptococcus pyogenes with Defined Macrolide Resistance Mechanisms”Antimicrobial Agents and Chemotherapy54 (1): 230–238. PMC 2798494Freely accessiblePMID 19884376doi:10.1128/AAC.01123-09.
  6. Jump up^ Putnam, Shannon D.; Castanheira, Mariana; Moet, Gary J.; Farrell, David J.; Jones, Ronald N. (2010). “CEM-101, a novel fluoroketolide: antimicrobial activity against a diverse collection of Gram-positive and Gram-negative bacteria”. Diagnostic Microbiology and Infectious Disease66 (4): 393–401. PMID 20022192doi:10.1016/j.diagmicrobio.2009.10.013.
  7. Jump up^ Putnam, Shannon D.; Sader, Helio S.; Farrell, David J.; Biedenbach, Douglas J.; Castanheira, Mariana (2011). “Antimicrobial characterisation of solithromycin (CEM-101), a novel fluoroketolide: activity against staphylococci and enterococci”. International Journal of Antimicrobial Agents37 (1): 39–45. PMID 21075602doi:10.1016/j.ijantimicag.2010.08.021.
  8. Jump up^ “Intravenous (IV) Administration of Cempra Pharmaceutical’s Solithromycin (CEM-101) Demonstrates Excellent Systemic Tolerability in a Phase 1 Clinical Trial”. 7 May 2011.
  9. Jump up^ “Cempra antibiotic compound as effective, safer than levofloxacin”. 15 Sep 2011.
  10. Jump up^ 4 Jan 2015
  11. Jump up^ 7 July 2015
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  14. Jump up^ Llano-Sotelo B, Dunkle J, Klepacki D, Zhang W, Fernandes P, Cate JH, Mankin AS (2010). “Binding and Action of CEM-101, a New Fluoroketolide Antibiotic That Inhibits Protein Synthesis”Antimicrobial Agents and Chemotherapy54 (12): 4961–4970. PMC 2981243Freely accessiblePMID 20855725doi:10.1128/AAC.00860-10.
  15. Jump up^ Bertrand D, Bertrand S, Neveu E, Fernandes P (2010). “Molecular characterization of off-target activities of telithromycin: a potential role for nicotinic acetylcholine receptors”Antimicrobial Agents and Chemotherapy54 (12): 599–5402. PMC 2981250Freely accessiblePMID 20855733doi:10.1128/AAC.00840-10.

Further reading

Clinical data
Trade names Solithera
Routes of
Oral, intravenous
ATC code
Legal status
Legal status
  • Under FDA and EMA review for approval
Synonyms CEM-101; OP-1068
CAS Number
Chemical and physical data
Formula C43H65FN6O10
Molar mass 845.01 g/mol
3D model (JSmol)

/////////////Solithromycin, солитромицин سوليثروميسين 索利霉素 CEM-101,  OP-1068, UNII:9U1ETH79CK




Eravacycline structure.svg



1-Pyrrolidineacetamide, N-[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-7-(dimethylamino)-

1207283-85-9  CAS
1334714-66-7 dihydrochloride TP 434-046
1-Pyrrolidineacetamide, N-[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-7-(dimethylamino)-4-fluoro-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]


SPONSOR Tetraphase Pharmaceuticals, Inc.

Eravacycline (TP-434) is a synthetic fluorocycline antibiotic in development by Tetraphase Pharmaceuticals. It is closely related to the glycylglycine antibiotic tigecycline and the tetracycline class of antibiotics. It has a broad spectrum of activity including many multi-drug resistant strains of bacteria. Phase III studies in complicated intra-abdominal infections (cIAI) [1] and complicated urinary tract infections (cUTI)[2] were recently completed with mixed results. Eravacylcine has been designated as a Qualified Infectious Disease Product (QIDP), as well as for fast track approval by the FDA.[3]

ChemSpider 2D Image | Eravacycline | C27H31FN4O8


Inventors Jingye ZhouXiao-Yi XiaoLouis PlamondonDiana Katharine HuntRoger B. ClarkRobert B. Zahler
Applicant Tetraphase Pharmaceuticals, Inc.

Example 1. Synthesis of Compounds of Structural Formula (I).

The compounds of the invention can be prepared according the synthetic scheme shown in Scheme 1.

Figure imgf000048_0001

Compound 34

Figure imgf000063_0002

1H NMR (400 MHz, CD3OD) δ 8 22 (d, J= 1 1.0 Hz, 1 H), 4.33 (s, 2H), 4.10 (S3 1H), 3 83-3.72 (m, 2H), 3.25-2.89 (m, 12H), 2.32-2.00 (m, 6H), 1.69-1.56 (m, 1H); MS (ESI) m/z 559.39 (M+H).

Medical Uses

Eravacycline has shown broad spectrum of activity against a variety of Gram-positive and Gram-negative bacteria, including multi-drug resistant strains, such as methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Enterobacteriaceae.[4] It is currently being formulated as for intravenous and oral administration.

Image result for Eravacycline


WO 2016065290Image result for Eravacycline

Eravacylme is a tetracycline antibiotic that has demonstrated broad spectrum activity against a wide variety of multi-drug resistant Gram-negative, Gram-positive and anaerobic bacteria in humans. In Phase I and Phase II clinical trials, eravacycline also demonstrated a favorable safety and tolerability profile. In view of its attractive

pharmacological profile, synthetic routes to eravacycline and, in particular, synthetic routes that result in suitable quantities of eravacycline for drag development and manufacturing, are becoming increasingly important.

As described in International Publication No . WO 2010/017470, eravacycline is conveniently synthesized from 7-fluorosancycline, another tetracycline. 7-Fluorosancycline can be synthesized, in turn, from commercially available 7-ammosancycline or a protected derivative thereof. However, very few procedures for the conversion of (^-ammo-substituted tetracyclines, such as 7-aminosancycline, to C7-fiuoro-substituted tetracyclines, such as 7-fluorosancycline, have been reported, and those that have are not suitable to be deployed at production-scale.

Therefore, there is a need for improved processes, particularly improved production -scale processes, for converting C7-amino-substituted tetracyclines to C7-fluoro-substituted tetracyclines.

Example 3. Preparation of Eravacycline From 9-Aminosancycline Using a Photolytic Fluorination

[00158] Sancycline (0.414 g, 1.0 mmol) was dissolved in trifiuoroacetic acid (TFA). The solution was cooled to 0 °C. To the solution was added N-bromosuccinimide (NBS, 0.356 g, 2.1 mmol). The reaction was complete after stirring at 0 °C for 1 h. The reaction mixture was allowed to warm to rt. Solid NO3 (0.1 Ig, 0.11 mrnoi) was added and the reaction mixture was stirred at rt for 1 h. The reaction solution was added to 75 mL cold diethyl ether. The precipitate was collected by filtration and dried to give 0.46 g of compound 6. Compound 6 can then be reduced to compounds 7, 8, or 9 using standard procedures.


[00159] 9-Aminosancycline (7, 1 g, 0233 mmol) was dissolved in 20 mL sulfuric acid and the reaction was cooled using an ice bath. Potassium nitrate (235 mg, 0.233 mmol) was added in several portions. After stirring for 15 min, the reaction mixture was added to 400 mL MTBE followed by cooling using an ice bath. The solid was collected by filtration. The filter cake was dissolved in 10 mL water and the pH of the aqueous solution was adjusted to 5.3 using 25% aqueous NaOH. The resulting suspension was filtered, and the filter cake was dried to give 1 g compound 10: MS (ESI) m/z 475.1 (M+l).

[00160] Compound 10 (1.1 g) was dissolved in 20 mL of water and 10 mL of acetonitrile. To the solution was added acyl chloride 3 (in two portions: 600 mg and 650 mg). The pH of the reaction mixture was adjusted to 3.5 using 25% aqueous NaOH. Another portion of acyl chloride (800 mg) was added. The reaction was monitored by HPLC analysis. Product 11 was isolated from the reaction mixture by preparative HPLC. Lyophilization gave 1.1 g of compound 11: MS (ESI) m/z 586.3 (M+l).

[00161] Compound 11 (1.1 g) was dissolved in methanol. To the solution was added concentrated HC1 (0.5 mL) and 10% Pd-C (600 mg). The reaction mixture was stirred under a hydrogen atmosphere (balloon). After the reaction was completed, the catalyst was removed by filtration. The filtrate was concentrated to give 1 g of compound 12: ‘H NMR (400 MHz, DMSO), 8.37 (s, 1H), 4.38-4.33 (m, 3H), 3.70 (br s, 2H), 3.30-2.60 (m, 1211), 2.36-2.12 (m, 2H), 2.05-1.80 (m, 4H), 1.50-1.35 (m, 1H); MS (ESI) m/z 556.3 (M+l).

[00162] Compound 12 (150 mg) was dissolved in 1 mL of 48% HBF4. To the solution was added 21 mg of NaN02. After compound 12 was completely converted to compound 13 (LC/MS m/z 539.2), the reaction mixture was irradiated with 254 nm light for 6 h while being cooled with running water. The reaction mixture was purified by preparative HPLC using acetonitrile and 0.05 N aqueous HCl as mobile phases to yield the compound 4 (eravacyclme, 33 mg) as a bis-HCl salt (containing 78% of 4 and 10% of the 7-H byproduct, by HPLC): MS (ESI) m/z 559.3 (M+l).


Exploring the Boundaries of “Practical”: De Novo Syntheses of Complex Natural Product-Based Drug Candidates

Department of Chemistry and Biochemistry, University of California−Los Angeles, 607 Charles E. Young Drive East, Los Angeles, California 90095-1569, United States
Chem. Rev., Article ASAP
DOI: 10.1021/acs.chemrev.7b00126
Publication Date (Web): June 12, 2017
Copyright © 2017 American Chemical Society
This review examines the state of the art in synthesis as it relates to the building of complex architectures on scales sufficient to drive human drug trials. We focus on the relatively few instances in which a natural-product-based development candidate has been manufactured de novo, rather than semisynthetically. This summary provides a view of the strengths and weaknesses of current technologies, provides perspective on what one might consider a practical contribution, and hints at directions the field might take in the future.


Journal of Medicinal Chemistry (2012), 55(2), 597-605

Fluorocyclines. 1. 7-Fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: A Potent, Broad Spectrum Antibacterial Agent

Discovery Chemistry, Microbiology, and §Process Chemistry R&D, Tetraphase Pharmaceuticals, 480 Arsenal Street, Watertown, Massachusetts 02472, United States
J. Med. Chem.201255 (2), pp 597–605
DOI: 10.1021/jm201465w
Publication Date (Web): December 9, 2011
Copyright © 2011 American Chemical Society
*Phone: 617-715-3553. E-mail:
Abstract Image

This and the accompanying report (DOI: 10.1021/jm201467r) describe the design, synthesis, and evaluation of a new generation of tetracycline antibacterial agents, 7-fluoro-9-substituted-6-demethyl-6-deoxytetracyclines (“fluorocyclines”), accessible through a recently developed total synthesis approach. These fluorocyclines possess potent antibacterial activities against multidrug resistant (MDR) Gram-positive and Gram-negative pathogens. One of the fluorocyclines, 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline (17j, also known as TP434, 50th Interscience Conference on Antimicrobial Agents and Chemotherapy Conference, Boston, MA, September 12–15, 2010, poster F12157), is currently undergoing phase 2 clinical trials in patients with complicated intra-abdominal infections (cIAI).

(4S,4aS,5aR,12aS)-4-(Dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[2-(pyrrolidin-1-yl)acetamido]-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide (17j)

1H NMR (400 MHz, CD3OD) δ 8.22 (d, J = 11.0 Hz, 1 H), 4.33 (s, 2 H), 4.10 (s, 1 H), 3.83–3.72 (m, 2 H), 3.25–2.89 (m, 1 2 H), 2.32–2.00 (m, 6 H), 1.69–1.56 (m, 1 H).
MS (ESI) m/z 559.39 (M + H).


Journal of Organic Chemistry (2017), 82(2), 936-943

A Divergent Route to Eravacycline

Tetraphase Pharmaceuticals, Inc., 480 Arsenal Way, Suite 110, Watertown, Massachusetts 02472, United States
J. Org. Chem.201782 (2), pp 936–943
DOI: 10.1021/acs.joc.6b02442


Abstract Image

A convergent route to eravacycline (1) has been developed by employing Michael–Dieckmann cyclization between enone 3 and a fully built and protected left-hand piece (LHP, 2). After construction of the core eravacycline structure, a deprotection reaction was developed, allowing for the isoxazole ring opening and global deprotection to be achieved in one pot. The LHP is synthesized from readily available 4-fluoro-3-methylphenol in six steps featuring a palladium-catalyzed phenyl carboxylation in the last step.

Eravacycline di-HCl salt (1) as a yellow solid: purity 97.9%; mp 197–199 °C dec. The spectral data matched those from original sample as reported in our previous publication.(3)

3 RonnM.ZhuZ.HoganP. C.ZhangW.-Y.NiuJ.KatzC. E.DunwoodyN.GilickyO.DengY.;HuntD. K.HeM.ChenC.-L.SunC.ClarkR. B.XiaoX.-Y. Org. Process Res. Dev. 201317838845DOI: 10.1021/op4000219


WO 2016065290


Organic Process Research & Development (2013), 17(5), 838-845

 Abstract Image

Process research and development of the first fully synthetic broad spectrum 7-fluorotetracycline in clinical development is described. The process utilizes two key intermediates in a convergent approach. The key transformation is a Michael–Dieckmann reaction between a suitable substituted aromatic moiety and a key cyclohexenone derivative. Subsequent deprotection and acylation provide the desired active pharmaceutical ingredient in good overall yield.

Free base of 7. HPLC (248 nm) showed 97.1% purity with 0.80% of the corresponding impurity from 19, 1.2% of epimer of 7, and 0.80% the corresponding impurity from 20 (102g, 88.7% yield) product as a yellow solid.

1H NMR (CDCl3, 400 MHz, δ): 9.81 (d, 1H), 3.29 (s, 2H), 3.04 (m, 3H); 2.68 (bs, 4H), 2.62 (m, 1H), 2.44 (bs, 6H), 2.23 (t, 1H), 1.99 (s, 1H), 1.84 (bs, 4H), 1.5 (bs, 1H).

MS (ES) m/z calcd for +H: 559.2 (100.0), 560.2 (29.9), 561.2 (5.9); found: 559.3, 560.2, 561.3.

Give 7·2HCl (531 g containing 6.9% by weight water, ∼ 784 mmol). HPLC (248 nm) indicated a 96.6% purity with 0.64% of the corresponding impurity from 19, 1.3% of epimer of 7, and 1.3% the corresponding impurity from 20.

1H NMR, (d6-DMSO, 400 MHz, δ): 11.85 (s, 1H), 10.28 (s, 1H), 9.56 (s, 1H); 8.99 (s, 1H), 8.04 (d, J = 10.95 Hz, 1H), 4.32 (m, 1H), 4.30 (s, 1H), 3.58 (bs, 2H), 3.09 (bs, 2H), 3.007 (m, 1H); 2.94 (m, 2H), 2.8 (s, 6H), 2.15–2.32 (m, 2H), 1.92 (bd, 4H), 1.44 (m, 1H).

13C NMR (d6-DMSO, 100 MHz)193.74, 191.84, 187.45, 175.72, 171.88, 164.45, 152.12, 151.26, 148.93, 148.86, 125.13, 125.03, 122.79, 122.60, 116.00, 115.72, 115.25, 108.12, 95.38, 74.06, 67.78, 55.47, 53.91, 34.95, 33.98, 31.41, 26.45, 22.9.

MS (ES) m/zcalcd for +H: 559.2 (100.0), 560.2 (29.9), 561.2 (5.9); found: 559.3, 560.2, 561.3.


Natural product synthesis in the age of scalability – Natural …

RSC Publishing – Royal Society of Chemistry

… tetracycline analogues; B. Practical route to the key AB enone; C. Process route to the fully synthetic fluorocycline antibiotic eravacycline (11).


Natural product synthesis in the age of scalability

 Author affiliations

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Tetracycline (Myers/Tetraphase, 2005–2013). Myers’ convergent approach to the tetracyclines is a great example of how a scalable synthesis of a key intermediate en route to a natural product can fuel the discovery of entirely new drug candidates. These broad-spectrum polyketide antibiotics have been widely used in human and veterinary medicine, but, due to the development of tetracycline-resistant strains, there is an unmet need for novel tetracycline drugs. Pioneering work in this eld has been achieved by the Myers’ group, who published a landmark synthetic approach to the tetracycline class of antibiotics in 2005.16 Using this route, over 3,000 fully synthetic tetracyclines have been prepared to date. Central to their strategy was the synthesis of a highly versatile intermediate, AB enone 7, 17 which enabled the convergent construction of novel tetracycline antibiotics (Scheme 3, A).18 Naturally, the route to 7 had to be practical and amenable to large-scale synthesis and consequently, the synthetic approaches to this building block have become more and more practical and efficient with every new generation. In 2007, Myers published their rst practical and enantioselective approach to 7 (Scheme 3, B).17 The route started from 8, which can be accessed in multi-hundred gram amounts from commercially available 3-hydroxy-5-isoxazolecarboxylate (not shown) by O-benzylation followed by DIBAL reduction. In a three-step sequence, 8 was transformed into carbinol 9. In the key step of the sequence, 9 underwent an intramolecular Diels–Alder reaction to give a mixture of 4 diastereomeric cycloadducts, which, aer Swern oxidation, could be readily separated by ash column chromatography to afford 10. Finally, boron trichloride mediated opening of the oxabicyclic ring system and demethylation, followed by TBS protection of the tertiary hydroxyl-group, afforded 40 g of the AB enone 7 in 21% overall yield, over nine steps from commercial material. Slight modications of this route have allowed for the preparation of >20 kg batches of the AB enone. The availability of large-scale batches of 7 has both enabled the discovery and the development of eravacycline (11), the rst fully synthetic tetracycline analog in clinical development, from Tetraphase Pharmaceuticals. In their process route,19 the key Michael– Dieckmann cyclization between 7 and 12 was carried out on kg-scale and afforded 13 in 93.5% yield. This compound was transformed into eravacycline (11) in 3 more steps, including TBS-cleavage, hydrogenolysis and amide bond formation. Using this process, several kg of 11 have been prepared to date to support clinical studies. Finally, a third- and fourth-generation route to 7 has recently been published by Myers that is not only shorter than previous routes, but also amenable of structural modications of the AB-ring enone.20

16 M. G. Charest, C. D. Lerner, J. D. Brubaker, D. R. Siegel and A. G. Myers, Science, 2005, 308, 395–398. 17 J. D. Brubaker and A. G. Myers, Org. Lett., 2007, 9, 3523–3525. 18 (a) C. Sun, Q. Wang, J. D. Brubaker, P. M. Wright, C. D. Lerner, K. Noson, M. Charest, D. R. Siegel, Y.-M. Wang and A. G. Myers, J. Am. Chem. Soc., 2008, 130, 17913–17927; (b) X.-Y. Xiao, D. K. Hunt, J. Zhou, R. B. Clark, N. Dunwoody, C. Fyfe, T. H. Grossman, W. J. O’Brien, L. Plamondon, M. R¨onn, C. Sun, W.-Y. Zhang and J. A. Sutcliffe, J. Med. Chem., 2012, 55, 597–605; (c) R. B. Clark, M. He, C. Fyfe, D. Loand, W. J. O’Brien, L. Plamondon, J. A. Sutcliffe and X.-Y. Xiao, J. Med. Chem., 2011, 54, 1511–1528; (d) R. B. Clark, D. K. Hunt, M. He, C. Achorn, C.-L. Chen, Y. Deng, C. Fyfe, T. H. Grossman, P. C. Hogan, W. J. O’Brien, L. Plamondon, M. R¨onn, J. A. Sutcliffe, Z. Zhu and X.-Y. Xiao, J. Med. Chem., 2012, 55, 606–622; (e) C. Sun, D. K. Hunt, R. B. Clark, D. Loand, W. J. O’Brien, L. Plamondon and X.-Y. Xiao, J. Med. Chem., 2011, 54, 3704–3731. 19 M. Ronn, Z. Zhu, P. C. Hogan, W.-Y. Zhang, J. Niu, C. E. Katz, N. Dunwoody, O. Gilicky, Y. Deng, D. K. Hunt, M. He, C.-L. Chen, C. Sun, R. B. Clark and X.-Y. Xiao, Org. Process Res. Dev., 2013, 17, 838–845. 20 D. A. Kummer, D. Li, A. Dion and A. G. Myers, Chem. Sci., 2011, 2, 1710–1718. 21 (a) G. R. Pettit, Z. A. Chicacz, F. Gao, C. L. Herald, M. R. Boyd, J. M. Schmidt and J. N. A. Hooper, J. Org. Chem., 1993, 58, 1302–1304; (b) M. Kobayashi, S. Aoki, H. Sakai, K. Kawazoe, N. Kihara, T. Sasaki and I. Kitagawa, Tetrahedron Lett., 1993, 34, 2795–2798. 22 (a) J. Guo, K. J. Duffy, K. L. Stevens, P. I. Dalko, R. M. Roth, M. M. Hayward and Y. Kishi, Angew. Chem., Int. Ed., 1998, 37, 187–190; (b) M. M. Hayward, R. M. Roth, K. J. Duffy, P. I. Dalko, K. L. Stevens, J. Guo and Y. Kishi, Angew. Chem., Int. Ed., 1998, 37, 190–196; (c) I. Paterson, D. Y. K. Chen, M. J. Coster, J. L. Acena, J. Bach, ˜ K. R. Gibson, L. E. Keown, R. M. Oballa, T. Trieselmann, D. J. Wallace, A. P. Hodgson and R. D. Norcross, Angew. Chem., Int. Ed., 2001, 40, 4055–4060; (d) M. T. Crimmins, J. D. Katz, D. G. Washburn, S. P. Allwein and L. F. McAtee, J. Am. Chem. Soc., 2002, 124, 5661–5663; (e) M. Ball, M. J. Gaunt, D. F. Hook, A. S. Jessiman, S. Kawahara, P. Orsini, A. Scolaro, A. C. Talbot, H. R. Tanner, S. Yamanoi and S. V. Ley, Angew. Chem., Int. Ed., 2005, 44, 5433–5438. 23 A. B. Smith, T. Tomioka, C. A. Risatti, J. B. Sperry and C. Sfouggatakis, Org. Lett., 2008, 10, 4359–4362. 24 (a) U. Eder, G. Sauer and R. Wiechert, Angew. Chem., Int. Ed. Engl., 1971, 10, 496–497; (b) Z. G. Hajos and D. R. Parrish, J. Org. Chem., 1974, 39, 1615–1621; (c) B. List, Tetrahedron, 2002, 58, 5573–5590; (d) A. B. Northrup and D. W. C. MacMillan, Science, 2004, 305, 1752–1755; (e) A. B. Northrup, I. K. Mangion, F. Hettche and D. W. C. MacMillan, Angew. Chem., Int. Ed., 2004, 43, 2152– 2154. 25 A. B. Smith, C. Sfouggatakis, D. B. Gotchev, S. Shirakami, D. Bauer, W. Zhu and V. A. Doughty, Org. Lett., 2004, 6, 3637–3640. 26 A. B. Smith, C. A. Risatti, O. Atasoylu, C. S. Bennett, J. Liu, H. Cheng, K. TenDyke and Q. Xu, J. Am. Chem. Soc., 2011, 133, 14042–14053. 27 A. R. Carroll, E. Hyde, J. Smith, R. J. Quinn, G. Guymer and P. I. Forster, J. Org. Chem., 2005, 70, 1096–1099. 2W. J. O’Brien, L. Plamondon, M. R¨onn, C. Sun, W.-Y. Zhang and J. A. Sutcliffe, J. Med. Chem., 2012, 55, 597–605; (c) R. B. Clark, M. He, C. Fyfe, D. Loand, W. J. O’Brien, L. Plamondon, J. A. Sutcliffe and X.-Y. Xiao, J. Med. Chem., 2011, 54, 1511–1528; (d) R. B. Clark, D. K. Hunt, M. He, C. Achorn, C.-L. Chen, Y. Deng, C. Fyfe, T. H. Grossman, P. C. Hogan, W. J. O’Brien, L. Plamondon, M. R¨onn, J. A. Sutcliffe, Z. Zhu and X.-Y. Xiao, J. Med. Chem., 2012, 55, 606–622; (e) C. Sun, D. K. Hunt, R. B. Clark, D. Loand, W. J. O’Brien, L. Plamondon and X.-Y. Xiao, J. Med. Chem., 2011, 54, 3704–3731. 19 M. Ronn, Z. Zhu, P. C. Hogan, W.-Y. Zhang, J. Niu, C. E. Katz, N. Dunwoody, O. Gilicky, Y. Deng, D. K. Hunt, M. He, C.-L. Chen, C. Sun, R. B. Clark and X.-Y. Xiao, Org. Process Res. Dev., 2013, 17, 838–845. 20 D. A. Kummer, D. Li,


Applications of biocatalytic arene ipso,ortho cis-dihydroxylation in synthesis

 Author affiliations


Image result for Eravacycline

In 2005, Myers and co-workers reported the first use of 4 in complex natural product total synthesis.13 From their previously reported building block 43, tricyclic diketone 59 was accessible in a further 7 steps (10% overall yield from benzoate,   Scheme 7). Diketone 59 serves as a common precursor to the tetracycline AB-ring system and may be coupled with D-ring precursors such as 60 by a Michael–Dieckmann cascade cyclisation that forms the C-ring. Thus, after deprotection, the natural product ()-6-deoxytetracycline 61 is accessible in 14 steps and 7.0% overall yield from benzoate. Several points about the synthesis are noteworthy. The yield represents an improvement of orders of magnitude over the yields for all previously reported total syntheses of tetracyclines. Thus, for the first time, novel tetracycline analogues became accessible in useful quantities; union of 62 with 59 to access 63 is a representative example. Secondly, previous total syntheses of tetracyclines had been bedevilled by the difficulty of installing the C12a tertiary alcohol at a late stage.14c The Myers approach is conceptually distinct in that the C12a hydroxyl group is installed in the very first step, i.e. it is the hydroxyl group deriving from the microbial ipso hydroxylation. Finally, apart from the C12a stereocentre, all other stereocentres in the final tetracyclines are set under substrate control. Thus, all the stereochemical information in the final products may be considered ultimately to be of enzymatic origin. In the years following the Myers group’s initial disclosure, the methodology has been extended and improved to allow for the preparation of a greater diversity of novel tetracycline analogues.14 This has culminated in the development of eravacycline 65 (accessed from 59 and 64) by Tetraphase Pharmaceuticals.15 Eravacycline is indicated for treatment of multidrug-resistant infections and is currently in phase III trials.

13 (a) M. G. Charest, C. D. Lerner, J. D. Brubaker, D. R. Siegel and A. G. Myers, Science, 2005, 308, 395; (b) M. G. Charest, D. R. Siegel and A. G. Myers, J. Am. Chem. Soc., 2005, 127, 8292.

14 (a) J. D. Brubaker and A. G. Myers, Org. Lett., 2007, 9, 3523; (b) C. Sun, Q. Wang, J. D. Brubaker, P. M. Wright, C. D. Lerner, K. Noson, M. Charest, D. R. Siegel, Y.-M. Wang and A. G. Myers, J. Am. Chem. Soc., 2008, 130, 17913; (c) D. A. Kummer, D. Li, A. Dion and A. G. Myers, Chem. Sci., 2011, 2, 1710; (d) P. M. Wright and A. G. Myers, Tetrahedron, 2011, 67, 9853.

15 (a) R. B. Clark, M. He, C. Fyfe, D. Lofland, W. J. O’Brien, L. Plamondon, J. A. Sutcliffe and X.-Y. Xiao, J. Med. Chem., 2011, 54, 1511; (b) C. Sun, D. K. Hunt, R. B. Clark, D. Lofland, W. J. O’Brien, L. Plamondon and X.-Y. Xiao, J. Med. Chem., 2011, 54, 3704; (c) X.-Y. Xiao, D. K. Hunt, J. Zhou, R. B. Clark, N. Dunwoody, C. Fyfe, T. H. Grossman, W. J. O’Brien, L. Plamondon, M. Ro¨nn, C. Sun, W.-Y. Zhang and J. A. Sutcliffe, J. Med. Chem., 2012, 55, 597; (d) R. B. Clark, D. K. Hunt, M. He, C. Achorn, C.-L. Chen, Y. Deng, C. Fyfe, T. H. Grossman, P. C. Hogan, W. J. O’Brien, L. Plamondon, M. Ro¨nn, J. A. Sutcliffe, Z. Zhu and X.-Y. Xiao, J. Med. Chem., 2012, 55, 606; (e) M. Ronn, Z. Zhu, P. C. Hogan, W.-Y. Zhang, J. Niu, C. E. Katz, N. Dunwoody, O. Gilicky, Y. Deng, D. K. Hunt, M. He, C.-L. Chen, C. Sun, R. B. Clark and X.-Y. Xiao, Org. Process Res. Dev., 2013, 17, 838; ( f ) R. B. Clark, M. He, Y. Deng, C. Sun, C.-L. Chen, D. K. Hunt, W. J. O’Brien, C. Fyfe, T. H. Grossman, J. A. Sutcliffe, C. Achorn, P. C. Hogan, C. E. Katz, J. Niu, W.-Y. Zhang, Z. Zhu, M. Ro¨nn and X.-Y. Xiao, J. Med. Chem., 2013, 56, 8112.

WO 2017125557, Crystalline forms of eravacycline dihydrochloride or its solvates or hydrates. Also claims a process for the preparation of an eravacycline intended for oral or parenteral use, for the treatment of bacterial infections, preferably intra-abdominal and urinary tract infections caused by multidrug resistant gram negative pathogens. Follows on from WO2017097891 .

Tetraphase Pharmaceuticals is developing eravacycline, a fully synthetic fluorocycline antibiotic and the lead from a series of tetracycline analogs which includes TP-221 and TP-170, for treating bacterial infections.

Eravacycline is a tetracycline antibiotic chemically designated (4S,4aS,5aR,l2aS)-4-(Dimethylamino)-7-fluoro-3 ,10,12,12a-tetrahydroxy- 1,11 -dioxo-9-[2-(-pyrrolidin- 1 -yl)acetamido]-l,4,4a,5,5a,6,l l ,12a-octahydrotetracene-2-carboxamide and can be represented by the following chemical structure according to formula (I).


formula (I)

Eravacycline possesses antibacterial activity against Gram negative pathogens and Gram positive pathogens, in particular against multidrug resistant (MDR) Gram negative pathogens and is currently undergoing phase III clinical trials in patients suffering from complicated intraabdominal infections (cIAI) and urinary tract infections (cUTI).

WO 2010/017470 Al discloses eravacycline as compound 34. Eravacycline is described to be prepared according to a process, which is described in more detail only for related compounds.

The last step of this process involves column chromatography with diluted hydrochloric acid/ acetonitrile, followed by freeze drying.

WO 2012/021829 Al discloses pharmaceutically acceptable acid and base addition salts of eravacycline in general and a general process for preparing the same involving reacting eravacycline free base with the corresponding acids and bases, respectively. On page 15, lines 3 to 6, a lyophilized powder containing an eravacycline salt and mannitol is disclosed.

Xiao et. al. “Fluorocyclines. 1. 7-Fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: A Potent, Broad Spectrum Antibacterial Agent” J. Med. Chem. 2012, 55, 597-605 synthesized eravacycline following the procedure for compounds 17e and 17i on page 603. After preparative reverse phase HPLC, compounds 17e and 17i were both obtained as bis-hydrochloride salts in form of yellow solids.

Ronn et al. “Process R&D of Eravacycline: The First Fully Synthetic Fluorocycline in Clinical Development” Org. Process Res. Dev. 2013, 17, 838-845 describe a process yielding eravacycline bis-hydrochloride as the final product. The last step involves precipitation of eravacycline bis-hydrochloride salt by adding ethyl acetate as an antisolvent to a solution of eravacycline bis-hydrochloride in an ethanol/ methanol mixture. The authors describe in some detail the difficulties during preparation of the bis-hydrochloride salt of eravacycline. According to Ronn et al. “partial addition of ethyl acetate led to a mixture containing suspended salt and a gummy form of the salt at the bottom of the reactor. At this stage, additional ethanol was added, and the mixture was aged with vigorous stirring until the gummy material also became a suspended solid.” In addition, after drying under vacuum the solid contained “higher than acceptable levels of ethanol”. “The ethanol was then displaced by water by placing a tray containing the solids obtained in a vacuum oven at reduced pressure (…) in the presence of an open vessel of water.” At the end eravacycline bis-hydrochloride salt containing about 4 to 6% residual moisture was obtained. The authors conclude that there is a need for additional improvements to the procedure along with an isolation step suitable for large scale manufacturing.

It is noteworthy that eravacycline or its salts are nowhere described as being a crystalline solid and that the preparation methods used for the preparation of eravacycline are processes like lyophilization, preparative column chromatography and precipitation, which typically yield amorphous material.

The cumbersome process of Ronn et al. points towards problems in obtaining eravacycline bis-hydrochloride in a suitable solid state, problems with scaleability of the available production process as well as problems with the isolation and drying steps of eravacycline.

In addition, amorphous solids can show low chemical stability, low physical stability, hygroscopicity, poor isolation and powder properties, etc.. Such properties are drawbacks for the use as an active pharmaceutical ingredients.

Thus, there is a need in pharmaceutical development for solid forms of an active pharmaceutical ingredient which demonstrate a favorable profile of relevant properties for formulation as a pharmaceutical composition, such as high chemical and physical stability, improved properties upon moisture contact, low(er) hygroscopicity and improved powder properties.


WO 2017125557

The invention relates to crystalline eravacycline bis-hydrochloride and to a process for its preparation. Furthermore, the invention relates to the use of crystalline eravacycline bis-hydrochloride for the preparation of pharmaceutical compositions. The invention further relates to pharmaceutical compositions comprising an effective amount of crystalline eravacycline bis-hydrochloride. The pharmaceutical compositions of the present invention can be used as medicaments, in particular for treatment and/ or prevention of bacterial infections e.g. caused by Gram negative pathogens or Gram positive pathogens, in particular caused by multidrug resistant Gram negative pathogens. The pharmaceutical compositions of the present invention can thus be used as medicaments for e.g. the treatment of complicated intra-abdominal and urinary tract infection

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US2014194393 TETRACYCLINE COMPOSITIONS 2014-03-11 2014-07-10
US2013040918 TETRACYCLINE COMPOSITIONS 2012-10-17 2013-02-14
US8796245 C7-fluoro substituted tetracycline compounds 2012-12-18 2014-08-05
US8501716 C7-fluoro substituted tetracycline compounds 2012-08-09 2013-08-06
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  1. Jump up to:a b Solomkin, Joseph; Evans, David; Slepavicius, Algirdas; Lee, Patrick; Marsh, Andrew; Tsai, Larry; Sutcliffe, Joyce A.; Horn, Patrick (2016-11-16). “Assessing the Efficacy and Safety of Eravacycline vs Ertapenem in Complicated Intra-abdominal Infections in the Investigating Gram-Negative Infections Treated With Eravacycline (IGNITE 1) Trial: A Randomized Clinical Trial”. JAMA surgeryISSN 2168-6262PMID 27851857doi:10.1001/jamasurg.2016.4237.
  2. Jump up to:a b “Tetraphase Announces Top-Line Results From IGNITE2 Phase 3 Clinical Trial of Eravacycline in cUTI (NASDAQ:TTPH)” Retrieved 2016-11-20.
  3. Jump up^ “FDA Grants QIDP Designation to Eravacycline, Tetraphase’s Lead Antibiotic Product Candidate | Business Wire” Retrieved 2016-11-20.
  4. Jump up to:a b Zhanel, George G.; Cheung, Doris; Adam, Heather; Zelenitsky, Sheryl; Golden, Alyssa; Schweizer, Frank; Gorityala, Bala; Lagacé-Wiens, Philippe R. S.; Walkty, Andrew (2016-04-01). “Review of Eravacycline, a Novel Fluorocycline Antibacterial Agent”. Drugs76 (5): 567–588. ISSN 1179-1950PMID 26863149doi:10.1007/s40265-016-0545-8.
  5. Jump up^ Sutcliffe, J. A.; O’Brien, W.; Fyfe, C.; Grossman, T. H. (2013-11-01). “Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens”Antimicrobial Agents and Chemotherapy57 (11): 5548–5558. ISSN 1098-6596PMC 3811277Freely accessiblePMID 23979750doi:10.1128/AAC.01288-13.
  6. Jump up^ Solomkin, Joseph S.; Ramesh, Mayakonda Krishnamurthy; Cesnauskas, Gintaras; Novikovs, Nikolajs; Stefanova, Penka; Sutcliffe, Joyce A.; Walpole, Susannah M.; Horn, Patrick T. (2014-01-01). “Phase 2, randomized, double-blind study of the efficacy and safety of two dose regimens of eravacycline versus ertapenem for adult community-acquired complicated intra-abdominal infections”Antimicrobial Agents and Chemotherapy58 (4): 1847–1854. ISSN 1098-6596PMC 4023720Freely accessiblePMID 24342651doi:10.1128/AAC.01614-13.
  7. Jump up^ Abdallah, Marie; Olafisoye, Olawole; Cortes, Christopher; Urban, Carl; Landman, David; Quale, John (2015-03-01). “Activity of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including multidrug-resistant isolates, from New York City”Antimicrobial Agents and Chemotherapy59 (3): 1802–1805. ISSN 1098-6596PMC 4325809Freely accessiblePMID 25534744doi:10.1128/AAC.04809-14.
  8. Jump up^ Fyfe, Corey; LeBlanc, Gabrielle; Close, Brianna; Nordmann, Patrice; Dumas, Jacques; Grossman, Trudy H. (2016-08-22). “Eravacycline is active against bacterial isolates expressing the polymyxin resistance gene mcr-1”Antimicrobial Agents and Chemotherapy60: 6989–6990. ISSN 0066-4804PMC 5075126Freely accessiblePMID 27550359doi:10.1128/AAC.01646-16.
  9. Jump up^ “” Retrieved 2016-11-20. External link in |title= (help)
  10. Jump up to:a b “Tetraphase Pharmaceuticals Provides Update on Eravacycline Regulatory and Development Status (NASDAQ:TTPH)” Retrieved 2016-11-20.
  11. Jump up to:a b c “Tetraphase Announces Positive Top-Line Results from Phase 3 IGNITE4 Clinical Trial in Complicated Intra-Abdominal Infections (NASDAQ:TTPH)” Retrieved 2017-07-27.
  12. Jump up to:a b “Efficacy and Safety Study of Eravacycline Compared With Meropenem in Complicated Intra-abdominal Infections – Full Text View –” Retrieved 2017-07-27.
  13. Jump up^ “” Retrieved 2016-11-20. External link in |title= (help)
  14. Jump up to:a b “Efficacy and Safety Study of Eravacycline Compared With Ertapenem in Participants With Complicated Urinary Tract Infections – Full Text View –” Retrieved 2017-07-27.
  15. Jump up to:a b “Tetraphase Pharmaceuticals Doses First Patient in IGNITE3 Phase 3 Clinical Trial of Once-daily IV Eravacycline in cUTI (NASDAQ:TTPH)” Retrieved 2017-07-27.
  16. Jump up^ “Tetraphase reports 3Q loss”. Retrieved 2016-11-20.
  17. Jump up^ Feroldi, Brian (2016-11-20). “Why Tetraphase Pharmaceuticals Dropped 74% of Its Value in 2015 — The Motley Fool”The Motley Fool. Retrieved 2016-11-20.

External links


Eravacycline structure.svg
IUPAC name

3D model (JSmol)
PubChem CID
Molar mass 558.555



Tetraphase Pharmaceuticals Inc. (NASDAQ:TTPH) today announced that it will present two posters at IDWeek 2013 that examine the potential of its lead antibiotic candidate eravacycline to treat serious multi-drug resistant (MDR) infections. The first will highlight positive results of a Phase 1 study assessing the bronchopulmonary disposition safety and tolerability of eravacycline in healthy men and women; this study represents the first clinical assessment of eravacycline for potential use in treating pneumonia. The second poster will provide the results of a study that examined the activity of eravacycline in vitro against multiple Gram-negative and Gram-positive pathogens to set quality-control limits for monitoring eravacycline activity in future testing programs.

Eravacycline (TP-434) is a synthetic fluorocycline antibiotic in development.

Eravacycline (TP-434 or 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline) is a novel fluorocycline that was evaluated for antimicrobial activity against panels of recent aerobic and anaerobic Gram-negative and Gram-positive bacteria. Eravacycline showed potent broad spectrum activity against 90% of the isolates (MIC90) in each panel at concentrations ranging from ≤0.008 to 2 μg/mL for all species panels except Pseudomonas aeruginosa and Burkholderia cenocepacia (MIC90 values of 32 μg/mL for both organisms). The antibacterial activity of eravacycline was minimally affected by expression of tetracycline-specific efflux and ribosomal protection mechanisms in clinical isolates. Further, eravacycline was active against multidrug-resistant bacteria, including those expressing extended spectrum β-lactamases and mechanisms conferring resistance to other classes of antibiotics, including carbapenem resistance. Eravacycline has the potential to be a promising new IV/oral antibiotic for the empiric treatment of complicated hospital/healthcare infections and moderate-to-severe community-acquired infections.

Tetraphase’s lead product candidate, eravacycline, has also received an award from Biomedical Advanced Research and Development Authority (BARDA) that provides for funding  to develop eravacycline as a potential counter-measure to certain biothreat pathogens. It is worth up to USD 67 million.

Process R&D of Eravacycline: The First Fully Synthetic Fluorocycline in Clinical Development

Eravacycline (TP-434)

We are developing our lead product candidate, eravacycline, as a broad-spectrum intravenous and oral antibiotic for use as a first-line empiric monotherapy for the treatment of multi-drug resistant (MDR) infections, including MDR Gram-negative bacteria. We developed eravacycline using our proprietary chemistry technology. We completed a successful Phase 2 clinical trial of eravacycline with intravenous administration for the treatment of patients with complicated intra-abdominal infections (cIAI) and have initiated the Phase 3 clinical program.

Eravacycline is a novel, fully synthetic tetracycline antibiotic. We selected eravacycline for development from tetracycline derivatives that we generated using our proprietary chemistry technology on the basis of the following characteristics of the compound that we observed in in vitro studies of the compound:

  • potent antibacterial activity against a broad spectrum of susceptible and multi-drug resistant bacteria, including Gram-negative, Gram-positive, atypical and anaerobic bacteria;
  • potential to treat the majority of patients as a first-line empiric monotherapy with convenient dosing; and
  • potential for intravenous-to-oral step-down therapy.

In in vitro studies, eravacycline has been highly active against emerging multi-drug resistant pathogens like Acinetobacter baumannii as well as clinically important species ofEnterobacteriaceae, including those isolates that produce ESBLs or are resistant to the carbapenem class of antibiotics, and anaerobes.

Based on in vitro studies we have completed, eravacycline shares a similar potency profile with carbapenems except that it more broadly covers Gram-positive pathogens like MRSA and enterococci, is active against carbapenem-resistant Gram-negative bacteria and unlike carbapenems like Primaxin and Merrem is not active against Pseudomanas aeruginosa. Eravacycline has demonstrated strong activity in vitro against Gram-positive pathogens, including both nosocomial and community-acquired methicillin susceptible or resistantStaphylococcus aureus strains, vancomycin susceptible or resistant Enterococcus faecium andEnterococcus faecalis, and penicillin susceptible or resistant strains of Streptococcus pneumoniae. In in vitro studies for cIAI, eravacycline consistently exhibited strong activity against enterococci and streptococci. One of the most frequently isolated anaerobic pathogens in cIAI, either as the sole pathogen or often in conjunction with another Gram-negative bacterium, is Bacteroides fragilis. In these studies eravacycline demonstrated activity against Bacteroides fragilis and a wide range of Gram-positive and Gram-negative anaerobes.

Key Differentiating Attributes of Eravacycline
The following key attributes of eravacycline, observed in clinical trials and preclinical studies of eravacycline, differentiate eravacycline from other antibiotics targeting multi-drug resistant infections, including multi-drug resistant Gram-negative infections. These attributes will make eravacycline a safe and effective treatment for cIAI, cUTI and other serious and life-threatening infections for which we may develop eravacycline, such as ABSSSI and acute bacterial pneumonias.

  • Broad-spectrum activity against a wide variety of multi-drug resistant Gram-negative, Gram-positive and anaerobic bacteria. In our recently completed Phase 2 clinical trial of the intravenous formulation of eravacycline, eravacycline demonstrated a high cure rate against a wide variety of multi-drug resistant Gram-negative, Gram-positive and anaerobic bacteria. In addition, in in vitro studies eravacycline demonstrated potent antibacterial activity against Gram-negative bacteria, including E. coli; ESBL-producing Klebsiella pneumoniaeAcinetobacter baumannii; Gram-positive bacteria, including MSRA and vancomycin-resistant enterococcus, or VRE; and anaerobic pathogens. As a result of this broad-spectrum coverage, eravacycline has the potential to be used as a first-line empiric monotherapy for the treatment of cIAI, cUTI, ABSSSI, acute bacterial pneumonias and other serious and life-threatening infections.
  • Favorable safety and tolerability profile. Eravacycline has been evaluated in more than 250 subjects in the Phase 1 and Phase 2 clinical trials that we have conducted. In these trials, eravacycline demonstrated a favorable safety and tolerability profile. In our recent Phase 2 clinical trial of eravacycline, no patients suffered any serious adverse events, and safety and tolerability were comparable to ertapenem, the control therapy in the trial. In addition, in the Phase 2 clinical trial, the rate at which gastrointestinal adverse events such as nausea and vomiting that occurred in the eravacycline arms was comparable to the rate of such events in the ertapenem arm of the trial.
  • Convenient dosing regimen. In our recently completed Phase 2 clinical trial we dosed eravacycline once or twice a day as a monotherapy. Eravacycline will be able to be administered as a first-line empiric monotherapy with once- or twice-daily dosing, avoiding the need for complicated dosing regimens typical of multi-drug cocktails and the increased risk of negative drug-drug interactions inherent to multi-drug cocktails.
  • Potential for convenient intravenous-to-oral step-down. In addition to the intravenous formulation of eravacycline, we are also developing an oral formulation of eravacycline. If successful, this oral formulation would enable patients who begin intravenous treatment with eravacycline in the hospital setting to transition to oral dosing of eravacycline either in hospital or upon patient discharge for convenient home-based care. The availability of both intravenous and oral administration and the oral step-down will reduce the length of a patient’s hospital stay and the overall cost of care.

Additionally, in February 2012, Tetraphase announced a contract award from the Biomedical Advanced Research and Development Authority (BARDA) worth up to $67 million for the development of eravacycline, from which Tetraphase may receive up to approximately $40 million in funding. The contract includes pre-clinical efficacy and toxicology studies; clinical studies; manufacturing activities; and associated regulatory activities to position the broad-spectrum antibiotic eravacycline as a potential empiric countermeasure for the treatment of inhalational disease caused by Bacillus anthracisFrancisella tularensis and Yersinia pestis.\

PAPERAbstract Image

Process research and development of the first fully synthetic broad spectrum 7-fluorotetracycline in clinical development is described. The process utilizes two key intermediates in a convergent approach. The key transformation is a Michael–Dieckmann reaction between a suitable substituted aromatic moiety and a key cyclohexenone derivative. Subsequent deprotection and acylation provide the desired active pharmaceutical ingredient in good overall yield.

Process R&D of Eravacycline: The First Fully Synthetic Fluorocycline in Clinical Development

Tetraphase Pharmaceuticals Inc., 480 Arsenal Street, Suite 110, Watertown, Massachusetts, 02472, United States
Org. Process Res. Dev., 2013, 17 (5), pp 838–845
DOI: 10.1021/op4000219
Publication Date (Web): April 6, 2013
Copyright © 2013 American Chemical Society

FDA Grants QIDP Designation to Eravacycline, Tetraphase’s Lead Antibiotic Product Candidate

– Eravacycline designated as a QIDP for complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI) indications –

July 15, 2013 08:30 AM Eastern Daylight Time

WATERTOWN, Mass.–(BUSINESS WIRE)–Tetraphase Pharmaceuticals, Inc. (NASDAQ: TTPH) today announced that the U.S. Food and Drug Administration (FDA) has designated the company’s lead antibiotic product candidate, eravacycline, as a Qualified Infectious Disease Product (QIDP). The QIDP designation, granted for complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI) indications, will make eravacycline eligible to benefit from certain incentives for the development of new antibiotics provided under the Generating Antibiotic Incentives Now Act (GAIN Act). These incentives include priority review and eligibility for fast-track status. Further, if ultimately approved by the FDA, eravacycline is eligible for an additional five-year extension of Hatch-Waxman exclusivity.

/////////Tetraphase Pharmaceuticals,  TP-434,  1207283-85-9, eravacycline


GSK 2982772

str1Image result

CAS: 1622848-92-3 (free base),  1987858-31-0 (hydrate)

Chemical Formula: C20H19N5O3

Molecular Weight: 377.404


(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-4H-l,2,4- triazole-3-carboxamide

  • 3-(Phenylmethyl)-N-[(3S)-2,3,4,5-tetrahydro-5-methyl-4-oxo-1,5-benzoxazepin-3-yl]-1H-1,2,4-triazole-5-carboxamide
  • (S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

GSK2982772 is a potent and selective receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate for the Treatment of Inflammatory Diseases. GSK2982772 is, currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. GSK2982772 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. RIP1 has emerged as an important upstream kinase that has been shown to regulate inflammation through both scaffolding and kinase specific functions.

GSK-2982772, an oral receptor-interacting protein-1 (RIP1) kinase inhibitor, is in phase II clinical development at GlaxoSmithKline for the treatment of active plaque-type psoriasis, moderate to severe rheumatoid arthritis, and active ulcerative colitis. A phase I trial was also completed for the treatment of inflammatory bowel disease using capsule and solution formulations.

  • Originator GlaxoSmithKline
  • Class Antipsoriatics
  • Mechanism of Action Receptor-interacting protein serine-threonine kinase inhibitors

Highest Development Phases

  • Phase II Plaque psoriasis; Rheumatoid arthritis; Ulcerative colitis
  • Phase I Inflammatory bowel diseases

Most Recent Events

  • 15 Dec 2016 Biomarkers information updated
  • 01 Nov 2016 Phase-II clinical trials in Ulcerative colitis (Adjunctive treatment) in USA (PO) (NCT02903966)
  • 01 Oct 2016 Phase-II clinical trials in Rheumatoid arthritis in Poland (PO) (NCT02858492)

PHASE 2 Psoriasis, plaque GSK

Inflammatory Bowel Disease, Agents for
Rheumatoid Arthritis, Treatment of
Inventors Deepak BANDYOPADHYAYPatrick M. EidamPeter J. GOUGHPhilip Anthony HarrisJae U. JeongJianxing KangBryan Wayne KINGShah Ami LakdawalaJr. Robert W. MarquisLara Kathryn LEISTERAttiq RahmanJoshi M. RamanjuluClark A SehonJR. Robert SINGHAUSDaohua Zhang
Applicant Glaxosmithkline Intellectual Property Development Limited

Deepak Bandyopadhyay


Data Science and Informatics Leader | Innovation Advocate


 University of North Carolina at Chapel Hill

He is  a data scientist and innovator with experience in both early and late stages of drug development. his current role involves the late stage of drug product development. I’m leading a project to bring GSK’s large molecule process and analytical data onto our big data platform and develop new data analysis and modeling capabilities. Also, working within GSK’s Advanced Manufacturing Technology (AMT) initiative provides plenty of other opportunities to impact how we make medicines.

Previously as a computational chemist (i.e. a data scientist in drug discovery), he worked with scientists from many domains, including chemists, biologists, and other informaticians. he enjoys digging into all the computational aspects of life science research, and solving data challenges by exploiting adjacencies and connections – between diverse fields of knowledge, and the equally diverse scientists trained in them. 

He has supported multiple drug discovery projects at GSK starting from target identification (“how should we modulate disease X?”) through to candidate selection and early clinical development (“let’s see if what we discovered can become a medicine”). Deriving insight by custom data integration is one of my specialties; recently he designed and implemented a platform for integrating data sets from multiple experiments that will be used by GSK screening scientists to find and combine hits. 

A trained computer scientist and cheminformatician, he is  an active member of the algorithms, data science and internal innovation communities at GSK, leading many of these efforts. 

His Ph.D. work introduced new computational geometry techniques for structural bioinformatics and protein function prediction. I have touched on several other subject areas:

* data mining/machine learning (predictive modeling and graph mining), 
* computer graphics and augmented reality (one of the pioneers of projection mapping)
* robotics (keen current interest and future aspiration)

Receptor-interacting protein- 1 (RIP1) kinase, originally referred to as RIP, is a TKL family serine/threonine protein kinase involved in innate immune signaling. RIPl kinase is a RHIM domain containing protein, with an N-terminal kinase domain and a C-terminal death domain ((2005) Trends Biochem. Sci. 30, 151-159). The death domain of RIPl mediates interaction with other death domain containing proteins including Fas and TNFR-1 ((1995) Cell 81 513-523), TRAIL-Rl and TRAIL-R2 ((1997) Immunity 7, 821-830) and TRADD ((1996) Immunity 4, 387-396), while the RHIM domain is crucial for binding other RHFM domain containing proteins such as TRIF ((2004) Nat Immunol. 5, 503-507), DAI ((2009) EMBO Rep. 10, 916-922) and RIP3 ((1999) J. Biol. Chem. 274, 16871-16875); (1999) Curr. Biol. 9, 539-542) and exerts many of its effects through these interactions. RIPl is a central regulator of cell signaling, and is involved in mediating both pro-survival and programmed cell death pathways which will be discussed below.

The role for RIPl in cell signaling has been assessed under various conditions

[including TLR3 ((2004) Nat Immunol. 5, 503-507), TLR4 ((2005) J. Biol. Chem. 280,

36560-36566), TRAIL ((2012) J .Virol. Epub, ahead of print), FAS ((2004) J. Biol. Chem. 279, 7925-7933)], but is best understood in the context of mediating signals downstream of the death receptor TNFRl ((2003) Cell 114, 181-190). Engagement of the TNFR by TNF leads to its oligomerization, and the recruitment of multiple proteins, including linear K63-linked polyubiquitinated RIPl ((2006) Mol. Cell 22, 245-257), TRAF2/5 ((2010) J. Mol. Biol. 396, 528-539), TRADD ((2008) Nat. Immunol. 9, 1037-1046) and cIAPs ((2008) Proc. Natl. Acad. Sci. USA. 105, 1 1778-11783), to the cytoplasmic tail of the receptor. This complex which is dependent on RIPl as a scaffolding protein (i.e. kinase

independent), termed complex I, provides a platform for pro-survival signaling through the activation of the NFKB and MAP kinases pathways ((2010) Sci. Signal. 115, re4).

Alternatively, binding of TNF to its receptor under conditions promoting the

deubiquitination of RIPl (by proteins such as A20 and CYLD or inhibition of the cIAPs) results in receptor internalization and the formation of complex II or DISC (death-inducing signaling complex) ((2011) Cell Death Dis. 2, e230). Formation of the DISC, which contains RIPl, TRADD, FADD and caspase 8, results in the activation of caspase 8 and the onset of programmed apoptotic cell death also in a RIPl kinase independent fashion ((2012) FEBS J 278, 877-887). Apoptosis is largely a quiescent form of cell death, and is involved in routine processes such as development and cellular homeostasis.

Under conditions where the DISC forms and RJP3 is expressed, but apoptosis is inhibited (such as FADD/caspase 8 deletion, caspase inhibition or viral infection), a third RIPl kinase-dependent possibility exists. RIP3 can now enter this complex, become phosphorylated by RIPl and initiate a caspase-independent programmed necrotic cell death through the activation of MLKL and PGAM5 ((2012) Cell 148, 213-227); ((2012) Cell 148, 228-243); ((2012) Proc. Natl. Acad. Sci. USA. 109, 5322-5327). As opposed to apoptosis, programmed necrosis (not to be confused with passive necrosis which is not programmed) results in the release of danger associated molecular patterns (DAMPs) from the cell.

These DAMPs are capable of providing a “danger signal” to surrounding cells and tissues, eliciting proinflammatory responses including inflammasome activation, cytokine production and cellular recruitment ((2008 Nat. Rev. Immunol 8, 279-289).

Dysregulation of RIPl kinase-mediated programmed cell death has been linked to various inflammatory diseases, as demonstrated by use of the RIP3 knockout mouse (where RIPl -mediated programmed necrosis is completely blocked) and by Necrostatin-1 (a tool inhibitor of RIPl kinase activity with poor oral bioavailability). The RIP3 knockout mouse has been shown to be protective in inflammatory bowel disease (including Ulcerative colitis and Crohn’s disease) ((2011) Nature 477, 330-334), Psoriasis ((2011) Immunity 35, 572-582), retinal-detachment-induced photoreceptor necrosis ((2010) PNAS 107, 21695-21700), retinitis pigmentosa ((2012) Proc. Natl. Acad. Sci., 109:36, 14598-14603), cerulein-induced acute pancreatits ((2009) Cell 137, 1100-1111) and Sepsis/systemic inflammatory response syndrome (SIRS) ((2011) Immunity 35, 908-918). Necrostatin-1 has been shown to be effective in alleviating ischemic brain injury ((2005) Nat. Chem. Biol. 1, 112-119), retinal ischemia/reperfusion injury ((2010) J. Neurosci. Res. 88, 1569-1576), Huntington’s disease ((2011) Cell Death Dis. 2 el 15), renal ischemia reperfusion injury ((2012) Kidney Int. 81, 751-761), cisplatin induced kidney injury ((2012) Ren. Fail. 34, 373-377) and traumatic brain injury ((2012) Neurochem. Res. 37, 1849-1858). Other diseases or disorders regulated at least in part by RIPl -dependent apoptosis, necrosis or cytokine production include hematological and solid organ malignancies ((2013) Genes

Dev. 27: 1640-1649), bacterial infections and viral infections ((2014) Cell Host & Microbe 15, 23-35) (including, but not limited to, tuberculosis and influenza ((2013) Cell 153, 1-14)) and Lysosomal storage diseases (particularly, Gaucher Disease, Nature Medicine Advance Online Publication, 19 January 2014, doi: 10.1038/nm.3449).

A potent, selective, small molecule inhibitor of RIP1 kinase activity would block RIP 1 -dependent cellular necrosis and thereby provide a therapeutic benefit in diseases or events associated with DAMPs, cell death, and/or inflammation.



WO 2014125444

Example 12

Method H

(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-4H-l,2,4- triazole-3-carboxamide

A mixture of (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one, hydrochloride (4.00 g, 16.97 mmol), 5-benzyl-4H-l,2,4-triazole-3-carboxylic acid, hydrochloride (4.97 g, 18.66 mmol) and DIEA (10.37 mL, 59.4 mmol) in isopropanol (150 mL) was stirred vigorously for 10 minutes and then 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P) (50% by wt. in EtOAc) (15.15 mL, 25.5 mmol) was added. The mixture was stirred at rt for 10 minutes and then quenched with water and concentrated to remove isopropanol. The resulting crude material is dissolved in EtOAc and washed with 1M HC1, satd. NaHC03 and brine. Organics were concentrated and purified by column chromatography (220 g silica column; 20-90% EtOAc/hexanes, 15 min.; 90%, 15 min.) to give the title compound as a light orange foam (5.37 g, 83%). 1H NMR (MeOH-d4) δ: 7.40 – 7.45 (m, 1H), 7.21 – 7.35 (m, 8H), 5.01 (dd, J = 11.6, 7.6 Hz, 1H), 4.60 (dd, J = 9.9, 7.6 Hz, 1H), 4.41 (dd, J = 11.4, 9.9 Hz, 1H), 4.17 (s, 2H), 3.41 (s, 3H); MS (m/z) 378.3 (M+H+).

Alternative Preparation:

To a solution of (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one hydrochloride (100 g, 437 mmol), 5-benzyl-4H-l,2,4-triazole-3-carboxylic acid hydrochloride (110 g, 459 mmol) in DCM (2.5 L) was added DIPEA (0.267 L, 1531 mmol) at 15 °C. The reaction mixture was stirred for 10 min. and 2,4,6-tripropyl-l, 3, 5,2,4,6-trioxatriphosphinane 2,4,6-trioxide >50 wt. % in ethyl acetate (0.390 L, 656 mmol) was slowly added at 15 °C. After stirring for 60 mins at RT the LCMS showed the reaction was complete, upon which time it was quenched with water, partitioned between DCM and washed with 0.5N HCl aq (2 L), saturated aqueous NaHC03 (2 L), brine (2 L) and water (2 L). The organic phase was separated and activated charcoal (100 g) and sodium sulfate

(200 g) were added. The dark solution was shaken for 1 h before filtering. The filtrate was then concentrated under reduced pressure to afford the product as a tan foam (120 g). The product was dried under a high vacuum at 50 °C for 16 h. 1H MR showed 4-5% wt of ethyl acetate present. The sample was dissolved in EtOH (650 ml) and stirred for 30 mins, after which the solvent was removed using a rotavapor (water-bath T=45 °C). The product was dried under high vacuum for 16 h at RT (118 g, 72% yield). The product was further dried under high vacuum at 50 °C for 5 h. 1H NMR showed <1% of EtOH and no ethyl acetate. 1H NMR (400 MHz, DMSO-i¾) δ ppm 4.12 (s, 2 H), 4.31 – 4.51 (m, 1 H), 4.60 (t, J=10.36 Hz, 1 H), 4.83 (dt, 7=11.31, 7.86 Hz, 1 H), 7.12 – 7.42 (m, 8 H), 7.42 – 7.65 (m, 1 H), 8.45 (br. s., 1 H), 14.41 (br. s., 1 H). MS (m/z) 378 (M + H+).


(S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-4H-l,2,4-triazole-3-carboxamide (100 mg) was dissolved in 0.9 mL of toluene and 0.1 mL of methylcyclohexane at 60 °C, then stirred briskly at room temperature (20 °C) for 4 days. After 4 days, an off-white solid was recovered (76 mg, 76% recovery). The powder X-ray diffraction (PXRD) pattern of this material is shown in Figure 7 and the corresponding diffraction data is provided in Table 1.

The PXRD analysis was conducted using a PANanalytical X’Pert Pro

diffractometer equipped with a copper anode X-ray tube, programmable slits, and

X’Celerator detector fitted with a nickel filter. Generator tension and current were set to 45kV and 40mA respectively to generate the copper Ka radiation powder diffraction pattern over the range of 2 – 40°2Θ. The test specimen was lightly triturated using an agate mortar and pestle and the resulting fine powder was mounted onto a silicon background plate.

Table 1.


Discovery of a first-in-class receptor interacting protein 1 (RIP1) kinase specific clinical candidate (GSK2982772) for the treatment of inflammatory diseases
J Med Chem 2017, 60(4): 1247

RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.

J. Med. Chem. 2017, 60, 1247−1261

(S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b]- [1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (5).

EtOAc solvate. 1 H NMR (DMSO-d6) δ ppm 14.41 (br s, 1 H), 8.48 (br s, 1 H), 7.50 (dd, J = 7.7, 1.9 Hz, 1 H), 7.12−7.40 (m, 8 H), 4.83 (dt, J = 11.6, 7.9 Hz, 1 H), 4.60 (t, J = 10.7 Hz, 1 H), 4.41 (dd, J = 9.9, 7.8 Hz, 1 H), 4.12 (s, 2 H), 3.31 (s, 3 H). Anal. Calcd for C20H20N5O3·0.026EtOAc·0.4H2O C, 62.36; H, 5.17; N, 18.09. Found: C, 62.12; H, 5.05; N, 18.04.

Synthesis of (<it>S</it>)-3-amino-benzo[<it>b</it>][1,4]oxazepin-4-one via Mitsunobu and S<INF>N</INF>Ar reaction for a first-in-class RIP1 kinase inhibitor GSK2982772 in clinical trials
Tetrahedron Lett 2017, 58(23): 2306
Harris, P.A.
Identification of a first-in-class RIP1 kinase inhibitor in phase 2a clinical trials for immunoinflammatory diseases
ACS MEDI-EFMC Med Chem Front (June 25-28, Philadelphia) 2017, Abst 

Harris, P.
Identification of a first-in-class RIP1 kinase inhibitor in phase 2a clinical trials for immuno-inflammatory diseases
253rd Am Chem Soc (ACS) Natl Meet (April 2-6, San Francisco) 2017, Abst MEDI 313


////////////GSK 2982772, phase 2, Plaque psoriasis, Rheumatoid arthritis, Ulcerative colitis


Voxilaprevir, فوكسيلابريفير , 伏西瑞韦 , Воксилапревир

Voxilaprevir.svgUNII-0570F37359.pngChemSpider 2D Image | voxilaprevir | C40H52F4N6O9S

Figure imgf000410_0002


  • Molecular FormulaC40H52F4N6O9S
  • Average mass868.934 Da
 1535212-07-7 cas
(1R,18R,20R,24S,27S,28S)-N-[(1R,2R)-2-(Difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-28-ethyl-13,13-difluoro-7-methoxy-24-(2-methyl-2-propanyl)-22,25-dioxo-2,21-dioxa-4,11,2  ;3,26-tetraazapentacyclo[,12.05,10.018,20]nonacosa-3(12),4,6,8,10-pentaene-27-carboxamide
Cyclopropanecarboxamide, N-[[[(1R,2R)-2-[5,5-difluoro-5-(3-hydroxy-6-methoxy-2-quinoxalinyl)pentyl]cyclopropyl]oxy]carbonyl]-3-methyl-L-valyl-(3S,4R)-3-ethyl-4-hydroxy-L-prolyl-1-amino-2-(difluoromethyl)-N-[(1-methylcyclopropyl)sulfonyl]-, cyclic (1→2)-ether, (1R,2R)-
(laR,5S,8S,9S,10R,22aR)-5-teri-butyl- V-[(lR,2R)-2-(difluoromethyl)– 1-{ [(1-methylcyclopr opyl)sulfonyl] carbamoyl} cyclopropyl] -9-ethyl- 18,18- difluoro-14-methoxy-3,6-dioxo-l,la,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19] [1,10,3,6] dioxadiazacyclononadecino[ll,12-6]quinoxaline-8- carboxamide
(laR,5S,8S,9S,10R,22aR)-5-teri-butyl- V-[(lR,2R)-2-(difluoromethyl)- 1-{ [(1-methylcyclopr opyl)sulfonyl] carbamoyl} cyclopropyl] -9-ethyl- 18,18- difluoro-14-methoxy-3,6-dioxo-l,la,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19] [1,10,3,6] dioxadiazacyclononadecino[ll,12-6]quinoxaline-8- carboxamide

8H-7,10-Methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide, N-[(1R,2R)-2-(difluoromethyl)-1-[[[(1-methylcyclopropyl)sulfonyl]amino]carbonyl]cyclopropyl]-5-(1 ,1-dimethylethyl)-9-ethyl-18,18-difluoro-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-14-methoxy-3,6-dioxo-, (1aR,5S,8S,9S,10R,22aR)-

Воксилапревир [Russian] [INN]
فوكسيلابريفير [Arabic] [INN]
伏西瑞韦 [Chinese] [INN]

Voxilaprevir is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that is used in combination with sofosbuvirand velpatasvir. The combination has the trade name Vosevi and has received a positive opinion from the European Committee for Medicinal Products for Human Use in June 2017.[1]

In July 18, 2017, Vosevi was approved by Food and drug administration.[2]

The hepatitis C virus (HCV), a member of the hepacivirus genera within the Flaviviridae family, is the leading cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol. 2000, 32, 98-1 12). Consequently, a significant focus of current antiviral research is directed toward the development of improved methods for the treatment of chronic HCV infections in humans (Ciesek, S., von Hahn T., and Manns, MP., Clin. Liver Dis., 201 1 , 15, 597-609; Soriano, V. et al, J. Antimicrob. Chemother., 201 1 , 66, 1573-1686; Brody, H., Nature Outlook, 201 1 , 474, S1 -S7; Gordon, C. P., et al., J. Med. Chem. 2005, 48, 1 -20;

Maradpour, D., et al., Nat. Rev. Micro. 2007, 5, 453-463).

Virologic cures of patients with chronic HCV infection are difficult to achieve because of the prodigious amount of daily virus production in chronically infected patients and the high spontaneous mutability of HCV (Neumann, et al., Science 1998, 282, 103-7; Fukimoto, et al., Hepatology, 1996, 24, 1351 -4;

Domingo, et al., Gene 1985, 40, 1 -8; Martell, et al., J. Virol. 1992, 66, 3225-9). HCV treatment is further complicated by the fact that HCV is genetically diverse and expressed as several different genotypes and numerous subtypes. For example, HCV is currently classified into six major genotypes (designated 1 -6), many subtypes (designated a, b, c, and so on), and about 100 different strains (numbered 1 , 2, 3, and so on).

HCV is distributed worldwide with genotypes 1 , 2, and 3 predominate within the United States, Europe, Australia, and East Asia (Japan, Taiwan, Thailand, and China). Genotype 4 is largely found in the Middle East, Egypt and central Africa while genotype 5 and 6 are found predominantly in South Africa and South East Asia respectively (Simmonds, P. et al. J Virol. 84: 4597-4610, 2010).

The combination of ribavirin, a nucleoside analog, and interferon-alpha (a) (IFN), is utilized for the treatment of multiple genotypes of chronic HCV infections in humans. However, the variable clinical response observed within patients and the toxicity of this regimen have limited its usefulness. Addition of a HCV protease inhibitor (telaprevir or boceprevir) to the ribavirin and IFN regimen improves 12-week post-treatment virological response (SVR12) rates

substantially. However, the regimen is currently only approved for genotype 1 patients and toxicity and other side effects remain.

The use of directing acting antivirals to treat multiple genotypes of HCV infection has proven challenging due to the variable activity of antivirals against the different genotypes. HCV protease inhibitors frequently have compromised in vitro activity against HCV genotypes 2 and 3 compared to genotype 1 (See, e.g., Table 1 of Summa, V. et al., Antimicrobial Agents and Chemotherapy, 2012, 56, 4161 -4167; Gottwein, J. et al, Gastroenterology, 201 1 , 141 , 1067-1079).

Correspondingly, clinical efficacy has also proven highly variable across HCV genotypes. For example, therapies that are highly effective against HCV genotype 1 and 2 may have limited or no clinical efficacy against genotype 3.

(Moreno, C. et al., Poster 895, 61 st AASLD Meeting, Boston, MA, USA, Oct. 29 – Nov. 2, 2010; Graham, F., et al, Gastroenterology, 201 1 , 141 , 881 -889; Foster, G.R. et al., EASL 45th Annual Meeting, April 14-18, 2010, Vienna, Austria.) In some cases, antiviral agents have good clinical efficacy against genotype 1 , but lower and more variable against genotypes 2 and 3. (Reiser, M. et al.,

Hepatology, 2005, 41 ,832-835.) To overcome the reduced efficacy in genotype 3 patients, substantially higher doses of antiviral agents may be required to achieve substantial viral load reductions (Fraser, IP et al., Abstract #48, HEP DART 201 1 , Koloa, HI, December 201 1 .)

Antiviral agents that are less susceptible to viral resistance are also needed. For example, resistance mutations at positions 155 and 168 in the HCV protease frequently cause a substantial decrease in antiviral efficacy of HCV protease inhibitors (Mani, N. Ann Forum Collab HIV Res., 2012, 14, 1 -8;

Romano, KP et al, PNAS, 2010, 107, 20986-20991 ; Lenz O, Antimicrobial agents and chemotherapy, 2010, 54,1878-1887.)

In view of the limitations of current HCV therapy, there is a need to develop more effective anti-HCV therapies. It would also be useful to provide therapies that are effective against multiple HCV genotypes and subtypes.

Image result

Kyla BjornsonEda CanalesJeromy J. CottellKapil Kumar KARKIAshley Anne KatanaDarryl KatoTetsuya KobayashiJohn O. LinkRuben MartinezBarton W. PhillipsHyung-Jung PyunMichael SangiAdam James SCHRIERDustin SiegelJames G. TAYLORChinh Viet TranMartin Teresa Alejandra TrejoRandall W. VivianZheng-Yu YangJeff ZablockiSheila Zipfel
Applicant Gilead Sciences, Inc.

Kyla Ramey (Bjornson)

Kyla Ramey (Bjornson)

Senior CTM Associate at Gilead Sciences



WO 2014008285

26. A compound of Formula IVf:
Figure imgf000410_0002


Example 1. Preparation of (1 aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N- [(1 R,2R)-2-(difluoromethyl)-1 -{[(1 – methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo- 1 ,1 a,3,4,5,6,9,10,18,19,20,21 ,22,22a-tetradecahydro-8H-7,10- methanocyclopropa[18,19][1 ,10,3,6]dioxadiazacyclononadecino[1 1 ,12- b]quinoxaline-8-carboxamide.

Figure imgf000182_0001
Figure imgf000183_0001

Step 1 . Preparation of 1-1 : A mixture containing Intermediate B4 (2.03 g, 6.44 mmol), Intermediate E1 (1 .6 g, 5.85 mmol), and cesium carbonate (3.15 g, 9.66 mmol) in MeCN (40 mL) was stirred vigorously at rt under an atmosphere of Ar for 16 h. The reaction was then filtered through a pad of Celite and the filtrate concentrated in vacuo. The crude material was purified by silica gel

chromatography to provide 1-1 as a white solid (2.5 g). LCMS-ESI+ (m/z): [M- Boc+2H]+ calcd for C2oH27CIN3O4: 408.9; found: 408.6.

Step 2. Preparation of 1-2: To a solution 1 -1 (2.5 g, 4.92 mmol) in dioxane

(10 mL) was added hydrochloric acid in dioxane (4 M, 25 mL, 98.4 mmol) and the reaction stirred at rt for 5 h. The crude reaction was concentrated in vacuo to give 1-2 as a white solid (2.49 g) that was used in subsequently without further purification. LCMS-ESI+ (m/z): [M]+ calcd for C2oH26CIN3O4: 407.9; found: 407.9.

Step 3. Preparation of 1-3: To a DMF (35 mL) solution of 1-2 (2.49 g, 5.61 mmol), Intermediate D1 (1 .75 mg, 6.17 mmol) and DIPEA (3.9 mL, 22.44 mmol) was added COMU (3.12 g, 7.29 mmol) and the reaction was stirred at rt for 3 h. The reaction was quenched with 5% aqueous citric acid solution and extracted with EtOAc, washed subsequently with brine, dried over anhydrous MgSO , filtered and concentrated to produce 1 -3 as an orange foam (2.31 g) that was used without further purification. LCMS-ESI+ (m/z): [M]+ calcd for C35H49CIN4O7: 673.3; found: 673.7.

Step 4. Preparation of 1-4: To a solution of 1-3 (2.31 g, 3.43 mmol), TEA (0.72 mL, 5.15 mmol) and potassium vinyltrifluoroborate (0.69 mg, 5.15 mmol) in EtOH (35 mL) was added PdCI2(dppf) (0.25 g, 0.34 mmol, Frontier Scientific). The reaction was sparged with Argon for 15 min and heated to 80 °C for 2 h. The reaction was adsorbed directly onto silica gel and purified using silica gel chromatography to give 1 -4 as a yellow oil (1 .95 g). LCMS-ESI+ (m/z): [M+H]+ calcd for C37H53N4O7: 665.4; found: 665.3.

Step 5. Preparation of 1 -5: To a solution of 1 -4 (1 .95 g, 2.93 mmol) in

DCE (585 ml_) was added Zhan 1 B catalyst (0.215 g, 0.29 mmol, Strem) and the reaction was sparged with Ar for 15 min. The reaction was heated to 80 °C for 1 .5 h, allowed to cool to rt and concentrated. The crude product was purified by silica gel chromatography to produce 1 -5 as a yellow oil (1 .47 g; LCMS-ESI+ (m/z): [M+H]+ calcd for C35H49N4O7: 637.4; found: 637.3).

Step 6. Preparation of 1 -6: A solution of 1 -5 (0.97 g, 1 .52 mmol) in EtOH (15 ml_) was treated with Pd/C (10 wt % Pd, 0.162 g). The atmosphere was replaced with hydrogen and stirred at rt for 2 h. The reaction was filtered through Celite, the pad washed with EtOAc and concentrated to give 1 -6 as a brown foamy solid (0.803 g) that was used subsequently without further purification. LCMS-ESr (m/z): [M+H]+ calcd for C35H5i N4O7: 639.4; found: 639.3.

Step 7. Preparation of 1 -7: To a solution of 1 -6 (0.803 g, 1 .26 mmol) in DCM (10 ml_) was added TFA (5 ml_) and stirred at rt for 3 h. An additional 2 ml_ TFA was added and the reaction stirred for another 1 .5 h. The reaction was concentrated to a brown oil that was taken up in EtOAc (35 ml_). The organic solution was washed with water. After separation of the layers, sat. aqueous NaHCO3 was added with stirring until the aqueous layer reached a pH ~ 7-8. The layers were separated again and the aqueous extracted with EtOAc twice. The combined organics were washed with 1 M aqueous citric acid, brine, dried over anhydrous MgSO4, filtered and concentrated to produce 1 -6 as a brown foamy solid (0.719 g) that was used subsequently without further purification. LCMS-ESr (m/z): [M+H]+ calcd for C3i H43N4O7: 583.3; found: 583.4 .

Step 8. Preparation of Example 1 : To a solution of 1 -7 (0.200 g, 0.343 mmol), Intermediate A10 (0.157 g, 0.515 mmol), DMAP (0.063 g, 0.51 mmol) and DIPEA (0.3 ml_, 1 .72 mmol) in DMF (3 ml_) was added HATU (0.235 g, 0.617 mmol) and the reaction was stirred at rt o/n. The reaction was diluted with MeCN and purified directly by reverse phase HPLC (Gemini, 30-100% MeCN/H2O + 0.1 % TFA) and lyophilized to give Example 1 (1 18.6 mg) as a solid TFA salt. Analytic HPLC RetTime: 8.63 min. LCMS-ESI+ (m/z): [M+H]+ calcd for

C40H55F2N6O9S: 833.4; found: 833.5. 1H NMR (400 MHz, CD3OD) δ 9.19 (s, 1 H); 7.80 (d, J = 8.8 Hz, 1 H); 7.23 (dd, J = 8.8, 2.4 Hz, 1 H); 7.15 (d, J = 2.4 Hz, 1 H); 5.89 (d, J = 3.6 Hz, 1 H); 5.83 (td, JH-F = 55.6 Hz, J = 6.4 Hz, 1 H); 4.56 (d, J = 7.2 Hz, 1 H); 4.40 (s, 1 H) 4.38 (ap d, J = 7.2 Hz, 1 H); 4.16 (dd, J = 12, 4 Hz, 1 H); 3.93 (s, 3H); 3.75 (dt, J = 7.2, 4 Hz, 1 H); 3.00-2.91 (m, 1 H); 2.81 (td, J = 12, 4.4 Hz, 1 H); 2.63-2.54 (m, 1 H); 2.01 (br s, 2H); 1 .88-1 .64 (m, 3H); 1 .66-1 .33 (m, 1 1 H) 1 .52 (s, 3H); 1 .24 (t, J = 7.2 Hz, 3H); 1 .10 (s, 9H); 1 .02-0.96 (m, 2H); 0.96- 0.88 (m, 2H); 0.78-0.68 (m, 1 H); 0.55-0.46 (m, 1 H).


US 20150175625


US 20150175626;jsessionid=C6BE27513351D0F12E95BC8C04756872.wapp1nA?docId=WO2015100145&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

The hepatitis C virus (HCV), a member of the hepacivirus genera within the Flaviviridae family, is the leading cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol. 2000, 32, 98-112). Consequently, a significant focus of current antiviral research is directed toward the development of improved methods for the treatment of chronic HCV infections in humans (Ciesek, S., von Hahn T., and Manns, MP., Clin. Liver Dis., 2011, 15, 597-609; Soriano, V. et al, J. Antimicrob. Chemother., 2011, 66, 1573-1686; Brody, H., Nature Outlook, 2011, 474, S1-S7; Gordon, C. P., et al, J. Med. Chem. 2005, 48, 1-20; Maradpour, D., et al, Nat. Rev. Micro. 2007, 5, 453-463).

Virologic cures of patients with chronic HCV infection are difficult to achieve because of the prodigious amount of daily virus production in chronically infected patients and the high spontaneous mutability of HCV (Neumann, et al, Science 1998, 282, 103-7; Fukimoto, et al, Hepatology, 1996, 24, 1351-4; Domingo, et al, Gene 1985, 40, 1-8; Martell, et al, J. Virol. 1992, 66, 3225-9). HCV treatment is further complicated by the fact that HCV is genetically diverse and expressed as several different genotypes and numerous subtypes. For example, HCV is currently classified into six major genotypes (designated 1-6), many subtypes (designated a, b, c, and so on), and about 100 different strains (numbered 1, 2, 3, and so on).

HCV is distributed worldwide with genotypes 1, 2, and 3 predominate within the United States, Europe, Australia, and East Asia (Japan, Taiwan, Thailand, and China). Genotype 4 is largely found in the Middle East, Egypt and central Africa while genotype 5 and 6 are found predominantly in South Africa and South East Asia respectively (Simmonds, P. et al. J Virol. 84: [0006] There remains a need to develop effective treatments for HCV infections. Suitable compounds for the treatment of HCV infections are disclosed in U.S. Publication No. 2014-0017198, titled “Inhibitors of Hepatitis C Virus” filed on July 2, 2013 including the compound of formula I:

Example 1. Synthesis of (laR,5S,8S,9S,10R,22aR)-5-teri-butyl- V-[(lR,2R)-2-(difluoromethyl)- 1-{ [(1-methylcyclopr opyl)sulfonyl] carbamoyl} cyclopropyl] -9-ethyl- 18,18- difluoro-14-methoxy-3,6-dioxo-l,la,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19] [1,10,3,6] dioxadiazacyclononadecino[ll,12-6]quinoxaline-8- carboxamide (I) by route I

[0195] Compound of formula I was synthesized via route I as shown below:

Synthesis of intermediates for compound of formula I SEE PATENT

US  20150175626



Patent ID Patent Title Submitted Date Granted Date
US2014343008 HEPATITIS C TREATMENT 2014-01-30 2014-11-20
US2014017198 INHIBITORS OF HEPATITIS C VIRUS 2013-07-02 2014-01-16
US2015175626 SYNTHESIS OF AN ANTIVIRAL COMPOUND 2014-12-18 2015-06-25
US2015175646 SOLID FORMS OF AN ANTIVIRAL COMPOUND 2014-12-08 2015-06-25
US2015175655 INHIBITORS OF HEPATITIS C VIRUS 2013-07-02 2015-06-25
US2015361087 ANTIVIRAL COMPOUNDS 2015-06-09 2015-12-17
Patent ID Patent Title Submitted Date Granted Date
US2016130300 INHIBITORS OF HEPATITIS C VIRUS 2016-01-15 2016-05-12
Clinical data
Trade names Vosevi (combination with sofosbuvir and velpatasvir)
CAS Number
Chemical and physical data
Formula C40H52F4N6O9S
Molar mass 868.94 g·mol−1

FDA approves Vosevi for Hepatitis C

The U.S. Food and Drug Administration today approved Vosevi to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis.

The U.S. Food and Drug Administration today approved Vosevi to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis. Vosevi is a fixed-dose, combination tablet containing two previously approved drugs – sofosbuvir and velpatasvir – and a new drug, voxilaprevir. Vosevi is the first treatment approved for patients who have been previously treated with the direct-acting antiviral drug sofosbuvir or other drugs for HCV that inhibit a protein called NS5A.

“Direct-acting antiviral drugs prevent the virus from multiplying and often cure HCV. Vosevi provides a treatment option for some patients who were not successfully treated with other HCV drugs in the past,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. According to the Centers for Disease Control and Prevention, an estimated 2.7 to 3.9 million people in the United States have chronic HCV. Some patients who suffer from chronic HCV infection over many years may have jaundice (yellowish eyes or skin) and develop complications, such as bleeding, fluid accumulation in the abdomen, infections, liver cancer and death.

There are at least six distinct HCV genotypes, or strains, which are genetically distinct groups of the virus. Knowing the strain of the virus can help inform treatment recommendations. Approximately 75 percent of Americans with HCV have genotype 1; 20-25 percent have genotypes 2 or 3; and a small number of patients are infected with genotypes 4, 5 or 6.

The safety and efficacy of Vosevi was evaluated in two Phase 3 clinical trials that enrolled approximately 750 adults without cirrhosis or with mild cirrhosis.

The first trial compared 12 weeks of Vosevi treatment with placebo in adults with genotype 1 who had previously failed treatment with an NS5A inhibitor drug. Patients with genotypes 2, 3, 4, 5 or 6 all received Vosevi.

The second trial compared 12 weeks of Vosevi with the previously approved drugs sofosbuvir and velpatasvir in adults with genotypes 1, 2 or 3 who had previously failed treatment with sofosbuvir but not an NS5A inhibitor drug.

Results of both trials demonstrated that 96-97 percent of patients who received Vosevi had no virus detected in the blood 12 weeks after finishing treatment, suggesting that patients’ infection had been cured.

Treatment recommendations for Vosevi are different depending on viral genotype and prior treatment history.

The most common adverse reactions in patients taking Vosevi were headache, fatigue, diarrhea and nausea.

Vosevi is contraindicated in patients taking the drug rifampin.

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected adult patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. HBV reactivation in patients treated with direct-acting antiviral medicines can result in serious liver problems or death in some patients. Health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with Vosevi.

The FDA granted this application Priority Review and Breakthrough Therapydesignations.

The FDA granted approval of Vosevi to Gilead Sciences Inc

//////////Voxilaprevir, فوكسيلابريفير ,  伏西瑞韦 , Воксилапревир , fda 2017, GS 9857, gilead, 1535212-07-7


LOXO 195

CAS: 2097002-61-2
Chemical Formula: C20H21FN6O

Molecular Weight: 380.4274

2097002-59-8 (RS-isomer)   1350884-56-8 (R racemic)

Synonym: LOXO-195; LOXO 195; LOXO195.

IUPAC: (13E,14E,22R,6R)-35-fluoro-6-methyl-7-aza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina-2(1,2)-pyrrolidinacyclooctaphan-8-one

10H-5,7-Ethenopyrazolo[3,4-d]pyrido[2,3-k]pyrrolo[2,1-m][1,3,7]triazacyclotridecin-10-one, 17-fluoro-1,2,3,11,12,13,14,18b-octahydro-12-methyl-, (12R,18bR)-

SMILES Code: FC1=CN=C(CC[C@@H](C)NC(C2=C3N(C=CC4=N3)N=C2)=O)C([C@@H]5N4CCC5)=C1


Image result for LOXO 195

LOXO-195 is a potent and selective TRK inhibitor capable of addressing potential mechanisms of acquired resistance that may emerge in patients receiving larotrectinib (LOXO-101) or multikinase inhibitors with anti-TRK activity. LOXO-195 demonstrated potent inhibition of TRK fusions, including critical acquired resistance mutations, in enzyme and cellular assays, with minimal activity against other kinases. In diverse TRK fusion mouse models, LOXO-195 inhibited phospho-ERK and caused dramatic tumor growth inhibition, superior to first generation TRK inhibitors, without significant toxicity.

Tropomyosin-related kinase (TRK) is a receptor tyrosine kinase family of

neurotrophin receptors that are found in multiple tissues types. Three members of the TRK proto-oncogene family have been described: TrkA, TrkB, and TrkC, encoded by the NTRKI, NTRK2, and NTRK3 genes, respectively. The TRK receptor family is involved in neuronal development, including the growth and function of neuronal synapses, memory

development, and maintenance, and the protection of neurons after ischemia or other types of injury (Nakagawara, Cancer Lett. 169: 107-114, 2001).

TRK was originally identified from a colorectal cancer cell line as an oncogene fusion containing 5′ sequences from tropomyosin-3 (TPM3) gene and the kinase domain encoded by the 3′ region of the neurotrophic tyrosine kinase, receptor, type 1 gene (NTRKI) (Pulciani et al., Nature 300:539-542, 1982; Martin-Zanca et al., Nature 319:743-748, 1986). TRK gene fusions follow the well-established paradigm of other oncogenic fusions, such as those involving ALK and ROSl, which have been shown to drive the growth of tumors and can be successfully inhibited in the clinic by targeted drugs (Shaw et al., New Engl. J. Med. 371 : 1963-1971, 2014; Shaw et al., New Engl. J. Med. 370: 1189-1197, 2014). Oncogenic TRK fusions induce cancer cell proliferation and engage critical cancer-related downstream signaling pathways such as mitogen activated protein kinase (MAPK) and AKT (Vaishnavi et al., Cancer Discov. 5:25-34, 2015). Numerous oncogenic rearrangements involving

NTRK1 and its related TRK family members NTRK2 and NTRK3 have been described (Vaishnavi et al., Cancer Disc. 5:25-34, 2015; Vaishnavi et al., Nature Med. 19: 1469-1472, 2013). Although there are numerous different 5′ gene fusion partners identified, all share an in-frame, intact TRK kinase domain. A variety of different Trk inhibitors have been developed to treat cancer (see, e.g., U.S. Patent Application Publication No. 62/080,374,

International Application Publication Nos. WO 11/006074, WO 11/146336, WO 10/033941, and WO 10/048314, and U.S. Patent Nos. 8,933,084, 8,791, 123, 8,637,516, 8,513,263, 8,450,322, 7,615,383, 7,384,632, 6, 153,189, 6,027,927, 6,025,166, 5,910,574, 5,877,016, and 5,844,092).

LOXO-195 (TRK inhibitor)

LOXO-195 is a next-generation, selective TRK inhibitor capable of addressing potential mechanisms of acquired resistance that may emerge in patients receiving larotrectinib (LOXO-101) or multikinase inhibitors with anti-TRK activity.

Acquired resistance to targeted therapies has proven to be an important component of long-term cancer care and targeted therapy drug development. LOXO-195 was developed in anticipation of potential resistance to larotrectinib (LOXO-101), and in light of recent published literature regarding emerging mechanisms of resistance to TRK inhibition. With the LOXO-195 program, Loxo Oncology has an opportunity to clinically extend the duration of disease control for patients with TRK-driven cancers.

In May 2017, Loxo Oncology received clearance from the U.S. Food and Drug Administration for an Investigational New Drug (IND) application for LOXO-195. Loxo Oncology plans to initiate a multi-center Phase 1/2 study in mid-2017. The primary objective of the trial is to determine the maximum tolerated dose or recommended dose for further study. Key secondary objectives include measures of safety, pharmacokinetics, and anti-tumor activity (i.e. Objective Response Rate and Duration of Response, as determined by RECIST v1.1). The trial will include a dose escalation phase and dose expansion phase.


Data presented at the 2016 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics illustrated the potency, specificity, and favorable in vivo properties in animals of LOXO-195, our clinical candidate. Read the poster presented at AACR-NCI-EORTC here.

A research brief published in Cancer Discovery in June 2017 outlines the preclinical rationale for LOXO-195 and clinical proof-of-concept data from the first two patients treated. Read the publication here.



WO 2017075107

Can·cer, redefined
Lisa M. Jarvis
C&EN Global Enterp, 2017, 95 (27), pp 26–30
Publication Date (Web): July 3, 2017 (Article)
DOI: 10.1021/cen-09527-cover

Lisa M. JarvisC&EN201795 (27), pp 26–30July 3, 2017

Abstract Image

When Adrienne Skinner was diagnosed with ampullary cancer, a rare gastrointestinal tumor, in early 2013, it didn’t come as a complete surprise. For nearly a decade, she had known her genes were not in her favor. What she didn’t know was that her genes would also point the way to a cure. Skinner has Lynch syndrome, an inherited disorder caused by a defect in mismatch repair (MMR) genes, which encode for proteins that spot and fix mistakes occurring during DNA replication. People with Lynch syndrome have an up to 70% risk of developing colon cancer. Women with the disorder have similarly high chances of developing endometrial cancer at an early age. The first time Skinner heard about the syndrome was in late 2004, after her sister was diagnosed with colon, ovarian, and endometrial cancers, the telltale trifecta associated with Lynch syndrome. It turned out that Skinner, her sister, and their

/////////LOXO 195, 2097002-61-2

Cp2TiCl: An Ideal Reagent for Green Chemistry?

Green Chemistry International

 Abstract Image

The development of Green Chemistry inevitably involves the development of green reagents. In this review, we highlight that Cp2TiCl is a reagent widely used in radical and organometallic chemistry, which shows, if not all, at least some of the 12 principles summarized for Green Chemistry, such as waste minimization, catalysis, safer solvents, toxicity, energy efficiency, and atom economy. Also, this complex has proved to be an ideal reagent for green C–C and C–O bond forming reactions, green reduction, isomerization, and deoxygenation reactions of several functional organic groups as we demonstrate throughout the review.

Cp2TiCl: An Ideal Reagent for Green Chemistry?

 Department of Chemical Engineering, Escuela Politécnica Superior, University of…

View original post 2,879 more words


Lisdexamfetamine structure.svg


  • Molecular FormulaC15H25N3O
  • Average mass263.379 Da
608137-32-2 [RN]
Elvanse [Trade name]
Hexanamide, 2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]-, (2S)-
(2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanimidic acid
Image result for Lisdexamfetamine SYNTHESIS

CAS 608137-33-3

(2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide dimethanesulfonate

Image result

Applicants: NEW RIVER PHARMACEUTICALS INC. [US/US]; The Governor Tyler, 1881 Grove Avenue, Radford, VA 24141 (US) (For All Designated States Except US).
MICKLE, Travis [US/US]; (US) (For US Only).
KRISHNAN, Suma [US/US]; (US) (For US Only).
MONCRIEF, James, Scott [US/US]; (US) (For US Only).
LAUDERBACK, Christopher [US/US]; (US) (For US Only).
MILLER, Christal [US/US]; (US) (For US Only)
Inventors: MICKLE, Travis; (US).
MONCRIEF, James, Scott; (US).
LAUDERBACK, Christopher; (US).
MILLER, Christal; (US)

Image result for MICKLE, Travis

MICKLE, Travis
Dr. Travis Mickle founded KemPharm, Inc. in late 2006. Prior to KemPharm, from January 2003 to October 2005, Dr. Mickle was Director of Drug Discovery and Chemical Development at New River Pharmaceuticals where he also served in a variety of other senior research roles since joining the firm in 2001. During his tenure at New River, Dr. Mickle was responsible for creating a strong preclinical and clinical pipeline of drugs in the areas of ADHD, pain and thyroid dysfunction. His contributions included, as principal inventor, the discovery and development of lisdexamfetamine dimesylate, the highly successful therapy for the treatment of ADHD known as Vyvanse®. In addition, Dr. Mickle was an active participant in FDA and DEA meetings representing the company’s discovery/chemistry group and was also called in as a critical scientific resource during New River’s financings and strategic partnering discussions. Before his departure, Dr. Mickle played an integral part in New River’s development into a successful publicly-traded company which was subsequently acquired for $2.6 billion by its marketing partner, Shire PLC. Dr. Mickle is also the author of more than 150 US and international patents and patent applications, as well as several research papers. Dr. Mickle holds a Ph.D in Bio-Organic Chemistry from the University of Iowa.


Mrs. Krishnan has served as our Senior Vice President — Regulatory Affairs since 2012. From 2009 to 2011, Mrs. Krishnan served as Senior Vice President of Product Development at Pinnacle Pharmaceuticals, Inc. From 2007 to 2009, she served as Chief Financial Officer of Light Matters Foundation. Previously, Mrs. Krishnan was Vice President, Product Development at New River Pharmaceuticals Inc. from September 2002 until its acquisition by Shire plc in April 2007.

Mrs. Krishnan has 22 years’ experience in drug development. Prior to serving at New River Pharmaceuticals Inc., Mrs. Krishnan served in the following capacities: Director, Regulatory Affairs at Shire Pharmaceuticals, Inc., a specialty pharmaceutical company; Senior Project Manager at Pfizer, Inc., a multi-national pharmaceutical company; and a consultant at the Weinberg Group, a pharmaceutical and environmental consulting firm.

Mrs. Krishnan began her career as a discovery scientist for Janssen Pharmaceuticals, Inc., a subsidiary of Johnson & Johnson, a multi-national pharmaceutical company, in May 1991. Mrs. Krishnan received an M.S. in Organic Chemistry from Villanova University, an M.B.A. from Institute of Management and Research (India) and an undergraduate degree in Organic Chemistry from Ferguson University (India).

Senior Vice President, Regulatory Affairs

2012 – Current   (over 5 years)
Director, Regulatory Affairs
Senior Project Manager
May, 1991
Discovery Scientist
Senior Vice President of Product Development
Chief Financial Officer
Sep, 2002
Apr, 2007
Vice President, Product Development

Lisdexamfetamine (contracted from Llysinedextroamphetamine) is a prodrug of the central nervous system (CNS) stimulantdextroamphetamine, a phenethylamine of the amphetamine class that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and binge eating disorder.[4][5] Its chemical structure consists of dextroamphetamine coupled with the essential amino acid L-lysine. Lisdexamfetamine itself is inactive prior to its absorption and the subsequent rate-limited enzymaticcleavage of the molecule’s L-lysine portion, which produces the active metabolite (dextroamphetamine).

Lisdexamfetamine can be prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) in adults and children six and older, as well as for moderate to severe binge eating disorder in adults.[4] The safety and the efficacy of lisdexamfetamine dimesylate in children with ADHD three to five years old have not been established.[6]

Lisdexamfetamine is a Class B/Schedule II substance in the United Kingdom and a Schedule II controlled substance in the United States (DEA number 1205)[7] and the aggregate production quota for 2016 in the United States is 29,750 kilograms of anhydrous acid or base.[8] Lisdexamfetamine is currently in Phase III trials in Japan for ADHD.[9]



Lisdexamfetamine is used primarily as a treatment for attention deficit hyperactivity disorder (ADHD) and binge eating disorder;[4] it has similar off-label uses as those of other pharmaceutical amphetamines.[4][5] Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[10][11] but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth.[12][13][14] Reviews of magnetic resonance imaging (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus of the basal ganglia.[12][13][14]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.[15][16][17] Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning two years have demonstrated treatment effectiveness and safety.[15][17] Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing quality of life and academic achievement, and producing improvements in a large number of functional outcomes[note 1] across nine outcome categories related to academics, antisocial behavior, driving, non-medicinal drug use, obesity, occupation, self-esteem, service use (i.e., academic, occupational, health, financial, and legal services), and social function.[16][17] One review highlighted a nine-month randomized controlled trial in children with ADHD that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.[15] Another review indicated that, based upon the longest follow-up studies conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a substance use disorder as an adult.[17]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain’s neurotransmitter systems;[18] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projections from the locus coeruleus to the prefrontal cortex.[18]Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[19][18][20] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[21] Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans.[22][23] The Cochrane Collaboration‘s reviews[note 2] on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that while these drugs improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[25][26] A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.[27]

Individuals over the age of 65 were not commonly tested in clinical trials of lisdexamfetamine for ADHD.[4] Lisdexamfetamine is being investigated for possible treatment of cognitive impairment associated with schizophrenia and excessive daytime sleepiness.[28]


In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and some aspects of attention, in normal healthy adults;[29][30] these cognition-enhancing effects of amphetamine are known to be partially mediated through the indirect activation of both dopamine receptor D1 and adrenoceptor α2 in the prefrontal cortex.[19][29] A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.[31] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[19][32]Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[19][33][34] Stimulants such as amphetamine can improve performance on difficult and boring tasks and are used by some students as a study and test-taking aid.[19][34][35]Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for performance enhancement rather than as recreational drugs.[36][37][38] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[19][34]


Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;[39][40] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.[41][42] In healthy people at oral therapeutic doses, amphetamine has been shown to increase muscle strength, acceleration, athletic performance in anaerobic conditions, and endurance (i.e., it delays the onset of fatigue), while improving reaction time.[39][43][44] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[43][44][45] Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a “safety switch” that allows the core temperature limit to increase in order to access a reserve capacity that is normally off-limits.[44][46][47] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[39][43] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[48][49][43]

Available forms

Vyvanse capsules are available in doses of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg of the active ingredient, lisdexamfetamine dimesylate.[50] Vyvanse capsules contain several inactive ingredients, including microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.[50] The capsule shells contain gelatin and titanium dioxide, and may contain FD&C Red 3, FD&C Yellow 6, FD&C Blue 1, black iron oxide, and yellow iron oxide.[50]


Lisdexamfetamine dimesylate is approved and marketed in the United States for the treatment of attention-deficit hyperactivity disorder in pediatric patients. The active compound lisdexamfetamine contains D-amphetamine covalently linked to the essential amino acid L-lysine. Controlled release of D-amphetamine, a psychostimulant, occurs following administration of lisdexamfetamine to a patient. The controlled release has been reported to occur through hydrolysis of the amide bond linking D-amphetamine and L-lysine.

A procedure for making lisdexamfetamine hydrochloride is described in U.S. Pat. No. 7,223,735 to Mickle et al. (hereinafter Mickle). The procedure involves reacting D-amphetamine with (S)-2,5-dioxopyrrolidin-1-yl 2,6-bis(tert-butoxycarbonylamino)hexanoate to form a lysine-amphetamine intermediate bearing tert-butylcarbamate protecting groups. This intermediate is treated with hydrochloric acid to remove the tert-butylcarbamate protecting groups and provide lisdexamfetamine as its hydrochloride salt. However, this procedure suffers several drawbacks that are problematic when carrying out large scale reactions, such as manufacturing scale, to prepare lisdexamfetamine.

Lisdexamphetamine of formula I, is a conjugate of D-amphetamine and L-lysine and is chemically named as (2S)-2,6-diamino-N-[(lS)-methyl-2-phenylethyl]hexan amide.

Formula- I

Figure imgf000002_0001

Amphetamines stimulate central nervous system (CNS). Amphetamine is prescribed for treatment of various disorders, including attention deficit hyperactivity disorder (ADHD), obesity, nacrolepsy. It is approved as lisdextamphetamine dimesylate of formula IA and

Formula- IA

Figure imgf000002_0002

marketed under trade name Vyvanse for treatment of attention-deficit hyperactivity disorder in pediatric patients.

L-Lysine-D-amphetamine and its pharmaceutically acceptable salts were first disclosed in US patent 7,662,787 wherein it is exemplified as hydrochloride salt. Process for preparation of L- lysine-D-amphetamine includes reaction of BOC-Lys-(BOC)-hydroxysuccinimido ester with D-amphetamine in dioxane using diisopropyl ethyl amine (DIPEA) as a base to obtain BOC- protected lisdexamphetamine which is then purified using flash chromatography and further reacted with a mixture of 4M hydrochloric acid /dioxane to yield L-lysine-D-amphetamine hydrochloride. The process is as shown in following scheme:

Figure imgf000003_0001

4M HCI/dioxane

Figure imgf000003_0002

In equivalent patent US 7,659,253, process for preparation of mesylate salt is disclosed as shown below.

Figure imgf000003_0003


isopropyl acetate

-50°C, 2 hr

Figure imgf000003_0004

Process includes preparation of BOC-Lys-(BOC)-hydroxysuccinimido ester wherein use of reagents like N-hydroxy-succinimide (NHS) and Ν,Ν-dicyclohexyl- carbodimiide (DCC) is carried out, The above processes involve use of flash column chromatography to purify crude BOC- protected L-lysine-D-amphetamine intermediate. Use of column chromatography is very cumbersome, tedoius and time consuming, therefore not advisable at commercial scale. Further Ν,Ν-dicyclohexylcarbodimiide is known to be highly toxic and moisture sensitive compound, and its use leads to formation of a large amount of Ν,Ν-dicyclohexyl urea (DCU) as bye product which has to be removed from reaction mixture.. Therefore use of DCC is not advisable at industrial scale.

International patent publication WO 2010/042120 discloses a process for preparing L-lysine- D-amphetamine or its salts by reacting D-amphetamine with protected lysine or its salt by using an alkylphosphonic acid anhydride as coupling agent in presence of a base and solvent. The process is as shown in following scheme:

Figure imgf000004_0001

The application discloses use of alkylphosphonic acid anhydrides, which are expensive, and needs additional testing to show absence of phosphic impurities in intermediate or final compound to meet regulatory requirements. So it is not appealing to use alkylphosphonic anhydrides for scale up operations.

International patent publication WO2010/148305 discloses a process for preparation of lisdexamphetamine by removal of chlorine from Ν,Ν’-bistrifluoroacetyl-chloro- lisdexamphetamine by using hydrogenation catalyst like Pd/C, under hydrogen gas to form Ν,Ν’-bistrifluoroacetyl-lisdexamphetamine which on further deprotection by using deprotecting agent to form lisdexamphetamine. Alternatively first deprotection by using deprotecting agent and then chlorine is removed by using hydrogenation catalyst like Pd/C under hydrogen gas. The process involves additional steps of inserting chloro group and thereafter removing chloro group; further Pd/C is an expensive reagent, hence not attractive option from cost point of view.

It is therefore, necessary to overcome problems associated with prior art and to provide an efficient process for preparation of lisdexamphetamine and its pharmaceutically acceptable salts using easily available, less expensive, easy to handle raw materials and avoid use of column chromatography.


Figure US20120157706A1-20120621-C00005

Figure US20120157706A1-20120621-C00006

Figure US20120157706A1-20120621-C00007

Figure US20120157706A1-20120621-C00008

Figure US20120157706A1-20120621-C00009

      • Example IPreparation of N,N′-Biscarbobenzyloxy-Lisdexamfetamine (LDX-(Cbz)2)

Figure US20120157706A1-20120621-C00033

General Experimental Procedure: In an appropriately sized, inert jacketed reactor charge 378.3 g of Cbz-Lys(Cbz)-OSu and 2309 g of isopropyl acetate. Heat the stirred slurry to ˜50° C. In a second reactor mix 100.0 g of D-amphetamine into 165 g of isopropyl acetate. Add the D-amphetamine solution to the batch over 1.75-2.25 hours. After the addition is complete stir the heterogeneous mixture at 50-55° C. until the reaction is complete by HPLC analysis. Charge 1197 g of methanol and heat the batch at a vigorous reflux 1 hour. Cool the batch to 45-55° C. over 2 hours then hold at temperature for 14-16 hours. Cool the batch to 15-25° C. at a rate of 5-10° C. per hour. Filter the slurry. Rinse the wet cake with 449 g of methanol and dry on the filter under nitrogen. To a clean, dry reactor charge the crude solids and 1642 g of methanol. Stir the slurry and heat to a vigorous reflux for 2 hours. Cool the batch to 45-55° C. over 1-2 hours then hold at temperature 12-16 hours. Continue cooling to 15-25° C. at a rate of 5-10° C. per hour. Filter the slurry and wash the wet cake with 547 g of methanol. Vacuum dry the wet cake at ˜55° C. to give product as a white to off-white solid (332 g, 88 mol %).

The crude LDX-(Cbz)product isolated from the reaction mixture by crystallization had a purity of 99.96% according to HPLC analysis.1H NMR analysis of crude LDX-(Cbz)2product revealed the presence of 0.57% by weight N-hydroxysuccinimide. The purified LDX-(Cbz)2product obtained by re-crystallization from methanol had a purity of 99.99% according to HPLC analysis.1H NMR analysis of the purified LDX-(Cbz)2product obtained by re-crystallization from methanol revealed that the amount of N-hydroxysuccinimide in the purified LDX-(Cbz)2product was reduced to 0.05% by weight.

Example 2Preparation of Lisdexamfetamine Dimesylate

Figure US20120157706A1-20120621-C00034

General Experimental Procedure: In an appropriately sized, inert autoclave charge 100.0 g of LDX-(Cbz)2, 1 g of 10% (50% wet) palladium on carbon and 607.5 g of n-butanol. Stir the mixture under 100-150 psi of hydrogen at 80-85° C. until the reaction is complete by HPLC analysis. Heat the batch to 95-97° C. and hot filter. Transfer the product rich filtrate to an appropriately sized glass reactor. Charge 7.6 g of methanesulfonic acid maintaining a batch temperature of 32-38° C. To the resulting solution add 1.3 g of LDX-2MSA seed crystal. Stir the batch 4-16 hours at 32-38° C. Charge 30.4 g of methanesulfonic acid to the slurry over not less than 2 hours maintaining a batch temperature of 32-38° C. After the addition stir 1-2 hours at 32-38° C. Charge 436 g of isopropyl acetate over not less than 2 hours, then stir 1-2 hours at 32-38° C. Cool the batch to 15-25° C. and hold 1 hour. Filter the slurry. Wash the wet cake with a premixed combination of n-butanol (91.5 g) and isopropyl acetate (32.7 g) followed by a wash of isopropyl acetate (87.2 g). Vacuum dry the wet cake at ˜50° C. to give product as a white to off-white solid (78.8 g, 92 mol %).


WO 2017098533

Sun Pharmaceutical Industries Ltd

Process for preparation of lisdexamphetamine and its salts via a novel aziridine intermediate is claimed. Lisdexamphetamine attention deficit hyperactivity disorder (ADHD). Represents the first patenting to be seen from Sun pharmaceutical that focuses on lisdexamphetamine. At the time of publication Pawar and Patel are affiliated with Chattem chemicals .


WO 2005032474

IN 2011DE02040

WO 2013011526

IN 2009CH01986

WO 2010042120


Figure imgf000015_0002

Formula II A

Formula IV

Figure imgf000014_0001

Formula IVA

Figure imgf000015_0003


Examplel Preparation of 2,6-bis-tertiarvbutoxycarbonylamino hexanoic acid

To a solution of L-lysine monohydrochloride (25g, 0.14mol) and sodium hydroxide (15g) in water (250 ml), ditertiary butyl dicarbonate (70.0 g, 0.32 mol) was added at 15-25°C. The temperature was slowly raised to 55-60 °C and the reaction mixture was stirred for 12 hours.. After completion of reaction, ( monitored by TLC), the reaction mixture was cooled to 10-

15°C and pH was adjusted to 2.5-3.5 with 2N hydrochloric acid. The reaction mass’ was then extracted with dichloromethane (2 x 125 ml) and combined organic layer was successively washed with water (150 ml) and brine (150 ml). Dichloromethane layer was distilled under vacuum at 30-40 °C to obtain 29.7g of title compound as a viscous oily mass having purity 96.5% by HPLC.

Example 2: Preparation of (5-tert-butoxycarbonylamino-5-(l-methyl-2-phenyl- ethylcarba moyl)-pentyll-carbamic acid tert-butyl ester;

To a solution of 2,6-bis-tertbutoxy carbonylamino hexanoic acid (7.5g) in dichloromethane (150 ml) , triethyl amine (8.0 ml) was added at 25-30°C and the reaction mixture was stirred for 15 minutes. The solution was cooled to -15 to -10°C and isobutylchloroformate (4.35 g) was slowly added under nitrogen atmosphere and stirred for 30 minutes at -15°C to – 10°C. A solution of D-amphetamine (3.85 g) in dichloromethane (10 ml) was slowly added and. the reaction mixture was stirred at 15 to -10°C for 60 minutes. The reaction completion was checked by TLC. After completion of the reaction temperature was raised to 25-30°C and reaction mixture was successively washed with 0.5 N hydrochloric acid solution (2 x 75 ml), sodium bicarbonate solution (5%w/w 75ml), water (50 ml) and brine solution (50 ml). The combined dichloromethane layer was dried over sodium sulfate (10.0 g) and distilled at 30- 40°C to obtain a semisolid compound which was stirred with a mixture of n-heptane (85 ml) and ethyl acetate (5ml) at 25-30°C for 30 minutes. The solid, thus obtained, was filtered and dried to get 10.21 g of title compound having purity 89.77% by HPLC. The crude compound was dissolved in ethanol (45ml) at 50-55°C and water (50ml) was added. The reaction mixture was slowly cooled to 35-40°C, stirred for 30 minutes. The solid, thus obtained, was filtered and dried to get 7.35g of pure title compound as a white crystalline solid having purity 99.5 % by HPLC.

Example 3: Preparation of lisdexamphetamine dimesylate

(5-Tert-butoxycarbonylamino-5-( 1 -methyl-2-phenyl-ethylcarbamoyl)-pentyl]-carbamic acid tert-butyl ester (2.5g,) was dissolved in a mixture of isopropyl alcohol (10ml) and ethyl acetate (10ml) at 40-45°C and the reaction mass was cooled to 15-20°C. To this cold solution, methane sulphonic acid (2.5g) was added slowly and stirred for 12 hours at 15- 20°C. The reaction completion was checked by HPLC. The resulting solid was filtered, washed with a mixture of chilled isopropyl alcohol (5ml) and ethyl acetate (5ml) and dried under vacuum to obtain 1.68 g of title compound as a white crystalline solid having purity 99.72 % by HPLC.

Example 4: Preparation of lisdexamphetamine dimesylate:

(5-Tert-butoxycarbonylamino-5-( 1 -methyl-2-phenyl-ethylcarbamoyl)-pentyl]-carbamic acid tert-butyl ester (2.5 g,) was dissolved in ethanol (20 ml) at 25-30°C. To the reaction mixture, methane sulphonic acid (2.5 g) was slowly added and the reaction mixture was heated to 55- 60°C and stirred for 3 hours at 55-60°C. The reaction mixture was cooled to 25-30°C, stirred for 2 hours, filtered, washed with ethanol (10ml) and dried under vacuum to obtain 1.55g of lisdexamphetamine dimesylate having purity 99.61 % by HPLC.

Example 5: Purification of lisdexamphetamine dimesylate

Lisdexamphetamine dimesylate (1.40g,) was dissolved in ethanol (10 ml) at 50-55 °C and ethyl acetate (10 ml) was slowly added at 50-55 °C. The reaction mixture was cooled to 20- 25°C and stirred for 30 minutes. The resulting solid was filtered, washed with a mixture of ethanol and ethyl acetate (3 ml, 1: 1) and dried under vacuum at 55-60°C to obtain 1.28g of pure lisdexamphetamine dimesylate as a white crystalline solid having purity 99.90 % by HPLC.

Example 6: Preparation of lisdexamphetamine dimesylate

To a stirred solution of L-lysine monohydrochloride (50g) and sodium hydroxide (30 g) in water (500ml) at 15-25°C, ditertbutyl dicarbonate(140g) was added. The temperature was slowly raised to 55-60°C and reaction mixture was stirred for 12 hours. After completion of reaction, the reaction mixture was cooled to 10-15°C and pH was adjusted to 2.5-3.5 with 2N hydrochloric acid. The reaction mixture was then extracted with dichloromethane (2 x 250 ml) and combined dichloromethane layer was successively washed with water (300 ml) and brine (300 ml). To the organic layer triethyl amine (58g) in dichloromethane (500 ml) was added. The solution was cooled to -15 to -20°C and isobutylchloroformate (42.5 g) was slowly added at -15 to -20°C and stirred for 1 hour. A solution of D-amphetamine (41.85 g) in dichloromethane (100 ml) was slowly added to reaction mixture at -15 to -20 °C and stirred. After completion of the reaction, the reaction mixture was successively washed with 0.5 N hydrochloric solution (2 x 450 ml), sodium bicarbonate solution (5%w/w, 450 ml), water (450 ml) and brine solution (450 ml). The organic layer was dried over sodium sulfate and distilled under vacuum at 30-40°C to afford a residue. To this residue, ethanol (480 ml) was added followed by slow addition of methane sulphonic acid (55 g) under nitrogen atmosphere. The reaction temperature was raised 55-60°C and after completion of reaction, the reaction mixture was cooled to 20-25°C and stirred for 2 hours. The resulting solid was filtered, washed with ethanol (50 ml) and suck dried for 30 minutes, further washed with ethanol and dried to obtain lisdexamphetamine dimesylate.

Mechanism of action

Pharmacodynamics of amphetamine in a dopamine neuron
v · t · e
A pharmacodynamic model of amphetamine and TAAR1
via AADC
The image above contains clickable links

Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into the cytosol (light tan-colored area) through VMAT2. When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via potassium channels and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT. PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport. PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport. Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a CAMKIIα-dependent pathway, in turn producing dopamine efflux.

Lisdexamfetamine is an inactive prodrug that is converted in the body to dextroamphetamine, a pharmacologically active compound which is responsible for the drug’s activity.[119] After oral ingestion, lisdexamfetamine is broken down by enzymes in red blood cells to form L-lysine, a naturally occurring essential amino acid, and dextroamphetamine.[4] The conversion of lisdexamfetamine to dextroamphetamine is not affected by gastrointestinal pH and is unlikely to be affected by alterations in normal gastrointestinal transit times.[4][120]

The optical isomers of amphetamine, i.e., dextroamphetamine and levoamphetamine, are TAAR1 agonists and vesicular monoamine transporter 2 inhibitors that can enter monoamine neurons;[121][122] this allows them to release monoamine neurotransmitters (dopamine, norepinephrine, and serotonin, among others) from their storage sites in the presynaptic neuron, as well as prevent the reuptake of these neurotransmitters from the synaptic cleft.[121][122]

Lisdexamfetamine was developed with the goal of providing a long duration of effect that is consistent throughout the day, with reduced potential for abuse. The attachment of the amino acid lysine slows down the relative amount of dextroamphetamine available to the blood stream. Because no free dextroamphetamine is present in lisdexamfetamine capsules, dextroamphetamine does not become available through mechanical manipulation, such as crushing or simple extraction. A relatively sophisticated biochemical process is needed to produce dextroamphetamine from lisdexamfetamine.[120] As opposed to Adderall, which contains roughly equal parts of racemic amphetamine and dextroamphetamine salts, lisdexamfetamine is a single-enantiomer dextroamphetamine formula.[119][123] Studies conducted show that lisdexamfetamine dimesylate may have less abuse potential than dextroamphetamine and an abuse profile similar to diethylpropion at dosages that are FDA-approved for treatment of ADHD, but still has a high abuse potential when this dosage is exceeded by over 100%.[120]


The oral bioavailability of amphetamine varies with gastrointestinal pH;[118] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[124] Amphetamine is a weak base with a pKa of 9.9;[125]consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium.[125][118] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[125] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[126]

The half-life of amphetamine enantiomers differ and vary with urine pH.[125] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[125] An acidic diet will reduce the enantiomer half-lives to 8–11 hours; an alkaline diet will increase the range to 16–31 hours.[127][128] The biological half-life is longer and distribution volumes are larger in amphetamine dependent individuals.[128] The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively.[125] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[125] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[125] When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively.[125] Amphetamine is usually eliminated within two days of the last oral dose.[127]

The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract;[129] following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis.[129] The elimination half-life of lisdexamfetamine is generally less than one hour.[129]

CYP2D6, dopamine β-hydroxylase (DBH), flavin-containing monooxygenase 3 (FMO3), butyrate-CoA ligase (XM-ligase), and glycine N-acyltransferase (GLYAT) are the enzymes known to metabolize amphetamine or its metabolites in humans.[sources 9] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[125][127][134] Among these metabolites, the active sympathomimetics are 4‑hydroxyamphetamine,[138] 4‑hydroxynorephedrine,[139] and norephedrine.[140] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[125][127] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

Metabolic pathways of amphetamine in humans[sources 9]
Graphic of several routes of amphetamine metabolism
The image above contains clickable links

The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[134] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[125] The remaining 10–20% is excreted as the active metabolites.[125] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA,[136] which is then metabolized by GLYAT into hippuric acid.[137]


Comparison to other formulationsLisdexamfetamine dimesylate is a water-soluble (792 mg/mL) powder with a white to off-white color.[50]

Lisdexamfetamine dimesylate is one marketed formulation delivering dextroamphetamine. The following table compares the drug to other amphetamine pharmaceuticals.

Amphetamine base in marketed amphetamine medications
drug formula molecular mass
[note 8]
amphetamine base
[note 9]
amphetamine base
in equal doses
doses with
equal base
[note 10]
(g/mol) (percent) (30 mg dose)
total base total dextro- levo- dextro- levo-
dextroamphetamine sulfate[142][143] (C9H13N)2•H2SO4 368.49 270.41 73.38% 73.38% 22.0 mg 30.0 mg
amphetamine sulfate[144] (C9H13N)2•H2SO4 368.49 270.41 73.38% 36.69% 36.69% 11.0 mg 11.0 mg 30.0 mg
Adderall 62.57% 47.49% 15.08% 14.2 mg 4.5 mg 35.2 mg
25% dextroamphetamine sulfate[142][143] (C9H13N)2•H2SO4 368.49 270.41 73.38% 73.38%
25% amphetamine sulfate[144] (C9H13N)2•H2SO4 368.49 270.41 73.38% 36.69% 36.69%
25% dextroamphetamine saccharate[145] (C9H13N)2•C6H10O8 480.55 270.41 56.27% 56.27%
25% amphetamine aspartate monohydrate[146] (C9H13N)•C4H7NO4•H2O 286.32 135.21 47.22% 23.61% 23.61%
lisdexamfetamine dimesylate[147] C15H25N3O•(CH4O3S)2 455.49 135.21 29.68% 29.68% 8.9 mg 74.2 mg
amphetamine base suspension[note 11][56] C9H13N 135.21 135.21 100% 76.19% 23.81% 22.9 mg 7.1 mg 22.0 mg

History, society, and culture

Lisdexamfetamine was developed by New River Pharmaceuticals, who were bought by Shire Pharmaceuticals shortly before lisdexamfetamine began being marketed. It was developed for the intention of creating a longer-lasting and less-easily abused version of dextroamphetamine, as the requirement of conversion into dextroamphetamine via enzymes in the red blood cells increases its duration of action, regardless of the route of ingestion.[148] The drug lisdexamfetamine dimesylate is the first prodrug of its kind.

On 23 April 2008, Vyvanse received FDA approval for the adult population.[149] On 19 February 2009, Health Canada approved 30 mg and 50 mg capsules of lisdexamfetamine for treatment of ADHD.[150] On 8 February 2012, Vyvanse received FDA approval for maintenance treatment of adult ADHD.[151] In February 2014, Shire announced that two late-stage clinical trials had shown that Vyvanse was not an effective treatment for depression.[152] Lisdexamfetamine was granted approval in a number of European countries for the treatment of ADHD in children and adolescents over the age of 6 years, as well as adults who are continuing treatment from childhood, after a positive outcome of the regulatory procedure.[153] Shire also recently announced receipt of a positive result from a European decentralised procedure for lisdexamfetamine for adult patients with ADHD in the United Kingdom, Sweden and Denmark, expanding the indication of lisdexamfetamine to include newly diagnosed adult patients.[154]

In January 2015, lisdexamfetamine was approved by the U.S. Food and Drug Administration for treatment of binge eating disorder in adults.[28][155][156]

In January 2017, a new dosage form of lisdexamfetamine in the form of a chewable tablet (as opposed to a capsule) was approved by the FDA.[157]

Brand names

Lisdexamfetamine is sold as Tyvense (IE), Elvanse (UK), Venvanse (BR), Vyvanse (CA, US).[158]

Clinical research

Some clinical trials that used lisdexamfetamine as an add-on therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) for treatment-resistant depression indicated that this is no more effective than the use of an SSRI or SNRI alone.[159] Other studies indicated that psychostimulants potentiated antidepressants, and were under-prescribed for treatment resistant depression. In those studies patients showed significant improvement in energy, mood, and psychomotor activity.[160]


  1. Jump up^ The ADHD-related outcome domains with the greatest proportion of significantly improved outcomes from long-term continuous stimulant therapy include academics (~55% of academic outcomes improved), driving (100% of driving outcomes improved), non-medical drug use (47% of addiction-related outcomes improved), obesity (~65% of obesity-related outcomes improved), self esteem (50% of self-esteem outcomes improved), and social function (67% of social function outcomes improved).[16]The largest effect sizes for outcome improvements from long-term stimulant therapy occur in the domains involving academics (e.g., grade point average, achievement test scores, length of education, and education level), self-esteem (e.g., self-esteem questionnaire assessments, number of suicide attempts, and suicide rates), and social function (e.g., peer nomination scores, social skills, and quality of peer, family, and romantic relationships).[16]Long-term combination therapy for ADHD (i.e., treatment with both a stimulant and behavioral therapy) produces even larger effect sizes for outcome improvements and improves a larger proportion of outcomes across each domain compared to long-term stimulant therapy alone.[16]
  2. Jump up^ Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[24]
  3. Jump up^ The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.
  4. Jump up^ Transcription factors are proteins that increase or decrease the expression of specific genes.[93]
  5. Jump up^ In simpler terms, this necessary and sufficient relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always occur together and never occur alone.
  6. Jump up^ NMDA receptors are voltage-dependent ligand-gated ion channels that requires simultaneous binding of glutamate and a co-agonist (d-serine or glycine) to open the ion channel.[105]
  7. Jump up^ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[71] other forms of magnesium were not mentioned.
  8. Jump up^ For uniformity, molecular masses were calculated using the Lenntech Molecular Weight Calculator[141] and were within 0.01g/mol of published pharmaceutical values.
  9. Jump up^ Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
  10. Jump up^ dose = (1 / amphetamine base percentage) × scaling factor = (molecular masstotal / molecular massbase) × scaling factor. The values in this column were scaled to a 30 mg dose of dextroamphetamine sulfate. Due to pharmacological differences between these medications (e.g., differences in the release, absorption, conversion, concentration, differing effects of enantiomers, half-life, etc.), the listed values should not be considered equipotent doses.
  11. Jump up^ This product (Dyanavel XR) is an oral suspension (i.e., a drug that is suspended in a liquid and taken by mouth) that contains 2.5 mg/mL of amphetamine base.[56] The amphetamine base contains dextro- to levo-amphetamine in a ratio of 3.2:1,[56] which is approximately the ratio in Adderall. The product uses an ion exchange resin to achieve extended release of the amphetamine base.[56]

Cited Patent Filing date Publication date Applicant Title
US20050038121 * Jun 1, 2004 Feb 17, 2005 New River Pharmaceuticals Inc. Abuse resistant lysine amphetamine compounds
US20110196173 * Oct 9, 2008 Aug 11, 2011 Andreas Meudt Process for the Synthesis of Amphetamine Derivatives
DE1493824A1 * Nov 23, 1964 May 22, 1969 Hoffmann La Roche Verfahren zur Herstellung von Aminocarbonsaeureamiden
1 * Benzyl Chloroformate” in Handbook of Reagents for Organic Synthesis – Activating Agents and Protecting Groups ; Pearson et al., eds., 1999 John Wiley & Sons, pp. 46-50
2 * DATABASE CAPLUS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; Database Accession No. 1966:19805, Abstract NL 6414901, 28 July 1965
3 * Smith and March. Advanced Organic Chemistry 6th ed. (501-502)
Citing Patent Filing date Publication date Applicant Title
US8614346 Jun 18, 2010 Dec 24, 2013 Cambrex Charles City, Inc. Methods and compositions for preparation of amphetamine conjugates and salts thereof
WO2017003721A1 Jun 17, 2016 Jan 5, 2017 Noramco, Inc. Process for the preparation of lisdexamfetamine and related derivatives


  1. Jump up^ “Public Assessment Report Decentralised Procedure” (PDF). Shire Pharmaceuticals Contracts Limited. p. 14. Retrieved 23 August 2014.
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    Table 9.2 Dextroamphetamine formulations of stimulant medication
    Dexedrine [Peak:2–3 h] [Duration:5–6 h] …
    Adderall [Peak:2–3 h] [Duration:5–7 h]
    Dexedrine spansules [Peak:7–8 h] [Duration:12 h] …
    Adderall XR [Peak:7–8 h] [Duration:12 h]
    Vyvanse [Peak:3–4 h] [Duration:12 h]
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  13. ^ Jump up to:a b Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J (September 2013). “Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies”. J. Clin. Psychiatry. 74 (9): 902–917. PMC 3801446Freely accessible. PMID 24107764. doi:10.4088/JCP.12r08287.
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  15. ^ Jump up to:a b c Millichap JG (2010). “Chapter 9: Medications for ADHD”. In Millichap JG. Attention Deficit Hyperactivity Disorder Handbook: A Physician’s Guide to ADHD (2nd ed.). New York, USA: Springer. pp. 121–123, 125–127. ISBN 9781441913968.Ongoing research has provided answers to many of the parents’ concerns, and has confirmed the effectiveness and safety of the long-term use of medication.
  16. ^ Jump up to:a b c d e Arnold LE, Hodgkins P, Caci H, Kahle J, Young S (February 2015). “Effect of treatment modality on long-term outcomes in attention-deficit/hyperactivity disorder: a systematic review”. PLoS ONE. 10 (2): e0116407. PMC 4340791Freely accessible. PMID 25714373. doi:10.1371/journal.pone.0116407.The highest proportion of improved outcomes was reported with combination treatment (83% of outcomes). Among significantly improved outcomes, the largest effect sizes were found for combination treatment. The greatest improvements were associated with academic, self-esteem, or social function outcomes.
    Figure 3: Treatment benefit by treatment type and outcome group
  17. ^ Jump up to:a b c d Huang YS, Tsai MH (July 2011). “Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge”. CNS Drugs. 25 (7): 539–554. PMID 21699268. doi:10.2165/11589380-000000000-00000.Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. … In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.
  18. ^ Jump up to:a b c Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin”. In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 154–157. ISBN 9780071481274.
  19. ^ Jump up to:a b c d e f Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter 13: Higher Cognitive Function and Behavioral Control”. In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 318, 321. ISBN 9780071481274.Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. … stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks … through indirect stimulation of dopamine and norepinephrine receptors. …
    Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention.
  20. Jump up^ Bidwell LC, McClernon FJ, Kollins SH (August 2011). “Cognitive enhancers for the treatment of ADHD”. Pharmacol. Biochem. Behav. 99 (2): 262–274. PMC 3353150Freely accessible. PMID 21596055. doi:10.1016/j.pbb.2011.05.002.
  21. Jump up^ Parker J, Wales G, Chalhoub N, Harpin V (September 2013). “The long-term outcomes of interventions for the management of attention-deficit hyperactivity disorder in children and adolescents: a systematic review of randomized controlled trials”. Psychol. Res. Behav. Manag. 6: 87–99. PMC 3785407Freely accessible. PMID 24082796. doi:10.2147/PRBM.S49114.Only one paper53 examining outcomes beyond 36 months met the review criteria. … There is high level evidence suggesting that pharmacological treatment can have a major beneficial effect on the core symptoms of ADHD (hyperactivity, inattention, and impulsivity) in approximately 80% of cases compared with placebo controls, in the short term.
  22. Jump up^ Millichap JG (2010). “Chapter 9: Medications for ADHD”. In Millichap JG. Attention Deficit Hyperactivity Disorder Handbook: A Physician’s Guide to ADHD (2nd ed.). New York, USA: Springer. pp. 111–113. ISBN 9781441913968.
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  26. Jump up^ Punja S, Shamseer L, Hartling L, Urichuk L, Vandermeer B, Nikles J, Vohra S (February 2016). “Amphetamines for attention deficit hyperactivity disorder (ADHD) in children and adolescents”. Cochrane Database Syst. Rev. 2: CD009996. PMID 26844979. doi:10.1002/14651858.CD009996.pub2.
  27. Jump up^ Pringsheim T, Steeves T (April 2011). Pringsheim T, ed. “Pharmacological treatment for Attention Deficit Hyperactivity Disorder (ADHD) in children with comorbid tic disorders”. Cochrane Database Syst. Rev. (4): CD007990. PMID 21491404. doi:10.1002/14651858.CD007990.pub2.
  28. ^ Jump up to:a b
  29. ^ Jump up to:a b Spencer RC, Devilbiss DM, Berridge CW (June 2015). “The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex”. Biol. Psychiatry. 77 (11): 940–950. PMC 4377121Freely accessible. PMID 25499957. doi:10.1016/j.biopsych.2014.09.013.The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. … This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). … In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses.
  30. Jump up^ Ilieva IP, Hook CJ, Farah MJ (January 2015). “Prescription Stimulants’ Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis”. J. Cogn. Neurosci. 27: 1–21. PMID 25591060. doi:10.1162/jocn_a_00776.Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities. … The results of this meta-analysis … do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.
  31. Jump up^ Bagot KS, Kaminer Y (April 2014). “Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review”. Addiction. 109 (4): 547–557. PMC 4471173Freely accessible. PMID 24749160. doi:10.1111/add.12460.Amphetamine has been shown to improve consolidation of information (0.02 ≥ P ≤ 0.05), leading to improved recall.
  32. Jump up^ Devous MD, Trivedi MH, Rush AJ (April 2001). “Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers”. J. Nucl. Med. 42 (4): 535–542. PMID 11337538.
  33. Jump up^ Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu”. In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 266. ISBN 9780071481274.Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.
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  36. Jump up^ Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ (October 2006). “Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration”. Pharmacotherapy. 26 (10): 1501–1510. PMC 1794223Freely accessible. PMID 16999660. doi:10.1592/phco.26.10.1501.
  37. Jump up^ Weyandt LL, Oster DR, Marraccini ME, Gudmundsdottir BG, Munro BA, Zavras BM, Kuhar B (September 2014). “Pharmacological interventions for adolescents and adults with ADHD: stimulant and nonstimulant medications and misuse of prescription stimulants”. Psychol. Res. Behav. Manag. 7: 223–249. PMC 4164338Freely accessible. PMID 25228824. doi:10.2147/PRBM.S47013.misuse of prescription stimulants has become a serious problem on college campuses across the US and has been recently documented in other countries as well. … Indeed, large numbers of students claim to have engaged in the nonmedical use of prescription stimulants, which is reflected in lifetime prevalence rates of prescription stimulant misuse ranging from 5% to nearly 34% of students.
  38. Jump up^ Clemow DB, Walker DJ (September 2014). “The potential for misuse and abuse of medications in ADHD: a review”. Postgrad. Med. 126 (5): 64–81. PMID 25295651. doi:10.3810/pgm.2014.09.2801.Overall, the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications, with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study.
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    Physiologic and performance effects
    • Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
    • Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
    • Improved reaction time
    • Increased muscle strength and delayed muscle fatigue
    • Increased acceleration
    • Increased alertness and attention to task
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  44. ^ Jump up to:a b c Roelands B, de Koning J, Foster C, Hettinga F, Meeusen R (May 2013). “Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing”. Sports Med. 43 (5): 301–311. PMID 23456493. doi:10.1007/s40279-013-0030-4.In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo. … Dopaminergic drugs appear to override a safety switch and allow athletes to use a reserve capacity that is ‘off-limits’ in a normal (placebo) situation.
  45. Jump up^ Parker KL, Lamichhane D, Caetano MS, Narayanan NS (October 2013). “Executive dysfunction in Parkinson’s disease and timing deficits”. Front. Integr. Neurosci. 7: 75. PMC 3813949Freely accessible. PMID 24198770. doi:10.3389/fnint.2013.00075.Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or “clock,” activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft advances the start of responding during interval timing, whereas antagonists of D2 type dopamine receptors typically slow timing;… Depletion of dopamine in healthy volunteers impairs timing, while amphetamine releases synaptic dopamine and speeds up timing.
  46. Jump up^ Rattray B, Argus C, Martin K, Northey J, Driller M (March 2015). “Is it time to turn our attention toward central mechanisms for post-exertional recovery strategies and performance?”. Front. Physiol. 6: 79. PMC 4362407Freely accessible. PMID 25852568. doi:10.3389/fphys.2015.00079.Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009). … Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008)
  47. Jump up^ Roelands B, De Pauw K, Meeusen R (June 2015). “Neurophysiological effects of exercise in the heat”. Scand. J. Med. Sci. Sports. 25 Suppl 1: 65–78. PMID 25943657. doi:10.1111/sms.12350.This indicates that subjects did not feel they were producing more power and consequently more heat. The authors concluded that the “safety switch” or the mechanisms existing in the body to prevent harmful effects are overridden by the drug administration (Roelands et al., 2008b). Taken together, these data indicate strong ergogenic effects of an increased DA concentration in the brain, without any change in the perception of effort.
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  56. ^ Jump up to:a b c d e f “Dyanavel XR Prescribing Information” (PDF). Tris Pharmaceuticals. October 2015. pp. 1–16. Archived from the original (PDF) on 13 October 2016. Retrieved 23 November 2015.DYANAVEL XR contains d-amphetamine and l-amphetamine in a ratio of 3.2 to 1 … The most common (≥2% in the DYANAVEL XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted in 108 patients with ADHD (aged 6–12 years) were: epistaxis, allergic rhinitis and upper abdominal pain. …
    Extended-release oral suspension contains 2.5 mg amphetamine base per mL.
  57. Jump up^ Ramey JT, Bailen E, Lockey RF (2006). “Rhinitis medicamentosa” (PDF). J. Investig. Allergol. Clin. Immunol. 16 (3): 148–155. PMID 16784007. Retrieved 29 April 2015.Table 2. Decongestants Causing Rhinitis Medicamentosa
    – Nasal decongestants:
    – Sympathomimetic:
    • Amphetamine
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  59. Jump up^ Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, Murray KT, Quinn VP, Stein CM, Callahan ST, Fireman BH, Fish FA, Kirshner HS, O’Duffy A, Connell FA, Ray WA (November 2011). “ADHD drugs and serious cardiovascular events in children and young adults”. N. Engl. J. Med. 365 (20): 1896–1904. PMC 4943074Freely accessible. PMID 22043968. doi:10.1056/NEJMoa1110212.
  60. ^ Jump up to:a b “FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults”. United States Food and Drug Administration. 15 December 2011. Retrieved 4 November 2013.
  61. Jump up^ Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, Cheetham TC, Quinn VP, Dublin S, Boudreau DM, Andrade SE, Pawloski PA, Raebel MA, Smith DH, Achacoso N, Uratsu C, Go AS, Sidney S, Nguyen-Huynh MN, Ray WA, Selby JV (December 2011). “ADHD medications and risk of serious cardiovascular events in young and middle-aged adults”. JAMA. 306 (24): 2673–2683. PMC 3350308Freely accessible. PMID 22161946. doi:10.1001/jama.2011.1830.
  62. Jump up^ Montgomery KA (June 2008). “Sexual desire disorders”. Psychiatry (Edgmont). 5 (6): 50–55. PMC 2695750Freely accessible. PMID 19727285.
  63. Jump up^ O’Connor PG (February 2012). “Amphetamines”. Merck Manual for Health Care Professionals. Merck. Retrieved 8 May 2012.
  64. ^ Jump up to:a b c d Shoptaw SJ, Kao U, Ling W (January 2009). Shoptaw SJ, Ali R, ed. “Treatment for amphetamine psychosis”. Cochrane Database Syst. Rev. (1): CD003026. PMID 19160215. doi:10.1002/14651858.CD003026.pub3.A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention …
    About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) …
    Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.
  65. ^ Jump up to:a b Greydanus D. “Stimulant Misuse: Strategies to Manage a Growing Problem” (PDF). American College Health Association (Review Article). ACHA Professional Development Program. p. 20. Archived from the original (PDF) on 3 November 2013. Retrieved 2 November 2013.
  66. ^ Jump up to:a b Childs E, de Wit H (May 2009). “Amphetamine-induced place preference in humans”. Biol. Psychiatry. 65 (10): 900–904. PMC 2693956Freely accessible. PMID 19111278. doi:10.1016/j.biopsych.2008.11.016.This study demonstrates that humans, like nonhumans, prefer a place associated with amphetamine administration. These findings support the idea that subjective responses to a drug contribute to its ability to establish place conditioning.
  67. ^ Jump up to:a b 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. pp. 364–375. ISBN 9780071481274.
  68. ^ Jump up to:a b Spiller HA, Hays HL, Aleguas A (June 2013). “Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management”. CNS Drugs. 27 (7): 531–543. PMID 23757186. doi:10.1007/s40263-013-0084-8.Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin.
  69. Jump up^ Collaborators (2015). “Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013” (PDF). Lancet. 385 (9963): 117–171. PMC 4340604Freely accessible. PMID 25530442. doi:10.1016/S0140-6736(14)61682-2. Retrieved 3 March 2015.Amphetamine use disorders … 3,788 (3,425–4,145)
  70. Jump up^ Kanehisa Laboratories (10 October 2014). “Amphetamine – Homo sapiens (human)”. KEGG Pathway. Retrieved 31 October 2014.
  71. ^ Jump up to:a b c d e f Nechifor M (March 2008). “Magnesium in drug dependences”. Magnes. Res. 21 (1): 5–15. PMID 18557129.
  72. ^ Jump up to:a b c d e Ruffle JK (November 2014). “Molecular neurobiology of addiction: what’s all the (Δ)FosB about?”. Am. J. Drug Alcohol Abuse. 40 (6): 428–437. PMID 25083822. doi:10.3109/00952990.2014.933840.ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.
  73. ^ Jump up to:a b c d e Nestler EJ (December 2013). “Cellular basis of memory for addiction”. Dialogues Clin. Neurosci. 15 (4): 431–443. PMC 3898681Freely accessible. PMID 24459410.Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. … A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal’s sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement … Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. … Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
  74. Jump up^ Robison AJ, Nestler EJ (November 2011). “Transcriptional and epigenetic mechanisms of addiction”. Nat. Rev. Neurosci. 12 (11): 623–637. PMC 3272277Freely accessible. PMID 21989194. doi:10.1038/nrn3111.ΔFosB serves as one of the master control proteins governing this structural plasticity.
  75. ^ Jump up to:a b c d e f g h i j k l m n o p q r s t u v Olsen CM (December 2011). “Natural rewards, neuroplasticity, and non-drug addictions”. Neuropharmacology. 61 (7): 1109–1122. PMC 3139704Freely accessible. PMID 21459101. doi:10.1016/j.neuropharm.2011.03.010.Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). … In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).
  76. ^ Jump up to:a b c d Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (September 2013). “Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis”. Neurosci. Biobehav. Rev. 37 (8): 1622–1644. PMC 3788047Freely accessible. PMID 23806439. doi:10.1016/j.neubiorev.2013.06.011.These findings suggest that exercise may “magnitude”-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuroadaptive changes that develop during and following extended access to the drug. … Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes … Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.
  77. ^ Jump up to:a b c Zhou Y, Zhao M, Zhou C, Li R (July 2015). “Sex differences in drug addiction and response to exercise intervention: From human to animal studies”. Front. Neuroendocrinol. 40: 24–41. PMID 26182835. doi:10.1016/j.yfrne.2015.07.001.Collectively, these findings demonstrate that exercise may serve as a substitute or competition for drug abuse by changing ΔFosB or cFos immunoreactivity in the reward system to protect against later or previous drug use. … The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation.
  78. ^ Jump up to:a b c Linke SE, Ussher M (January 2015). “Exercise-based treatments for substance use disorders: evidence, theory, and practicality”. Am. J. Drug Alcohol Abuse. 41 (1): 7–15. PMC 4831948Freely accessible. PMID 25397661. doi:10.3109/00952990.2014.976708.The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published. … numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects.
  79. ^ Jump up to:a b 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, USA: McGraw-Hill Medical. p. 386. ISBN 9780071481274.Currently, cognitive–behavioral therapies are the most successful treatment available for preventing the relapse of psychostimulant use.
  80. Jump up^ Greene SL, Kerr F, Braitberg G (October 2008). “Review article: amphetamines and related drugs of abuse”. Emerg. Med. Australas. 20 (5): 391–402. PMID 18973636. doi:10.1111/j.1742-6723.2008.01114.x.
  81. Jump up^ Albertson TE (2011). “Amphetamines”. In Olson KR, Anderson IB, Benowitz NL, Blanc PD, Kearney TE, Kim-Katz SY, Wu AH. Poisoning & Drug Overdose (6th ed.). New York: McGraw-Hill Medical. pp. 77–79. ISBN 9780071668330.
  82. Jump up^ “Glossary of Terms”. Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015.
  83. Jump up^ Volkow ND, Koob GF, McLellan AT (January 2016). “Neurobiologic Advances from the Brain Disease Model of Addiction”. N. Engl. J. Med. 374 (4): 363–371. PMID 26816013. doi:10.1056/NEJMra1511480.Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
    Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
  84. 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. 368. ISBN 9780071481274.Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.
  85. Jump up^ Kollins SH (May 2008). “A qualitative review of issues arising in the use of psycho-stimulant medications in patients with ADHD and co-morbid substance use disorders”. Curr. Med. Res. Opin. 24 (5): 1345–1357. PMID 18384709. doi:10.1185/030079908X280707.When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD.
  86. Jump up^ Stolerman IP (2010). Stolerman IP, ed. Encyclopedia of Psychopharmacology. Berlin, Germany; London, England: Springer. p. 78. ISBN 9783540686989.
  87. Jump up^ Coghill DR, Caballero B, Sorooshian S, Civil R (June 2014). “A systematic review of the safety of lisdexamfetamine dimesylate”. CNS Drugs. 28 (6): 497–511. PMC 4057639Freely accessible. PMID 24788672. doi:10.1007/s40263-014-0166-2.The prodrug formulation of LDX may also lead to reduced abuse potential of LDX compared with immediate-release d-AMP.
  88. Jump up^ “Amphetamines: Drug Use and Abuse”. Merck Manual Home Edition. Merck. February 2003. Archived from the original on 17 February 2007. Retrieved 28 February 2007.
  89. Jump up^ Perez-Mana C, Castells X, Torrens M, Capella D, Farre M (September 2013). Pérez-Mañá C, ed. “Efficacy of psychostimulant drugs for amphetamine abuse or dependence”. Cochrane Database Syst. Rev. 9: CD009695. PMID 23996457. doi:10.1002/14651858.CD009695.pub2.
  90. Jump up^ Hyman SE, Malenka RC, Nestler EJ (July 2006). “Neural mechanisms of addiction: the role of reward-related learning and memory”. Annu. Rev. Neurosci. 29: 565–598. PMID 16776597. doi:10.1146/annurev.neuro.29.051605.113009.
  91. ^ Jump up to:a b c d e f g h Robison AJ, Nestler EJ (November 2011). “Transcriptional and epigenetic mechanisms of addiction”. Nat. Rev. Neurosci. 12 (11): 623–637. PMC 3272277Freely accdssible. PLID 21989194. doi:10.1038/nrn3111.
  92. ^ Jump up to:a b <` href=”″&gt;c d <` href=”httpr://″>e Rteiner H, Van Waes V (January 2013). “Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants”. Prog. Neurobiol. 100: 60–80. PMC 3525776Freely accessible. PMID 23085425. doi:10.1016/j.pneurobio.2012.10.001.
  93. Jump up^ Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter 4: Signal Transduction in the Brain”. In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 94. ISBN 9780071481274.
  94. Jump up^ Kanehisa Laboratories (29 October 2014). “Alcoholism – Homo sapiens (human)”. KEGG Pathway. Retrieved 31 October 2014.
  95. Jump up^ Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (February 2009). “Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens”. Proc. Natl. Acad. Sci. U.S.A. 106 (8): 2915–2920. PMC 2650365Freely accessible. PMID 19202072. doi:10.1073/pnas.0813179106.
  96. Jump up^ Nestler EJ (January 2014). “Epigenetic mechanisms of drug addiction”. Neuropharmacology. 76 Pt B: 259–268. PMC 3766384Freely accessible. PMID 23643695. doi:10.1016/j.neuropharm.2013.04.004.
  97. ^ Jump up to:a b Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (March 2012). “Sex, drugs, and rock ‘n’ roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms”. J. Psychoactive Drugs. 44 (1): 38–55. PMC 4040958Freely accessible. PMID 22641964. doi:10.1080/02791072.2012.662112.
  98. Jump up^ Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). “Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator”. J. Neurosci. 33 (8): 3434–3442. PMC 3865508Freely accessible. PMID 23426671. doi:10.1523/JNEUROSCI.4881-12.2013.
  99. Jump up^ Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM (February 2016). “Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats”. Neuropharmacology. 101: 154–164. PMID 26391065. doi:10.1016/j.neuropharm.2015.09.023.
  100. Jump up^ Stoops WW, Rush CR (May 2014). “Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research”. Expert Rev Clin Pharmacol. 7 (3): 363–374. PMC 4017926Freely accessible. PMID 24716825. doi:10.1586/17512433.2014.909283.Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved.
  101. Jump up^ Perez-Mana C, Castells X, Torrens M, Capella D, Farre M (September 2013). “Efficacy of psychostimulant drugs for amphetamine abuse or dependence”. Cochrane Database Syst. Rev. 9: CD009695. PMID 23996457. doi:10.1002/14651858.CD009695.pub2.To date, no pharmacological treatment has been approved for [addiction], and psychotherapy remains the mainstay of treatment. … Results of this review do not support the use of psychostimulant medications at the tested doses as a replacement therapy
  102. Jump up^ Forray A, Sofuoglu M (February 2014). “Future pharmacological treatments for substance use disorders”. Br. J. Clin. Pharmacol. 77 (2): 382–400. PMC 4014020Freely accessible. PMID 23039267. doi:10.1111/j.1365-2125.2012.04474.x.
  103. ^ Jump up to:a b Grandy DK, Miller GM, Li JX (February 2016). “”TAARgeting Addiction”-The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference”. Drug Alcohol Depend. 159: 9–16. PMID 26644139. doi:10.1016/j.drugalcdep.2015.11.014.When considered together with the rapidly growing literature in the field a compelling case emerges in support of developing TAAR1-selective agonists as medications for preventing relapse to psychostimulant abuse.
  104. ^ Jump up to:a b Jing L, Li JX (August 2015). “Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction”. Eur. J. Pharmacol. 761: 345–352. PMC 4532615Freely accessible. PMID 26092759. doi:10.1016/j.ejphar.2015.06.019.Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction.
  105. ^ Jump up to:a b Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter 5: Excitatory and Inhibitory Amino Acids”. In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 124–125. ISBN 9780071481274.
  106. ^ Jump up to:a b c Carroll ME, Smethells JR (February 2016). “Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments”. Front. Psychiatry. 6: 175. PMC 4745113Freely accessible. PMID 26903885. doi:10.3389/fpsyt.2015.00175.Physical Exercise
    There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction … In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse. … The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis. … Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon.
  107. ^ Jump up to:a b c d Shoptaw SJ, Kao U, Heinzerling K, Ling W (April 2009). Shoptaw SJ, ed. “Treatment for amphetamine withdrawal”. Cochrane Database Syst. Rev. (2): CD003021. PMID 19370579. doi:10.1002/14651858.CD003021.pub2.
  108. Jump up^ “Dexedrine Prescribing Information” (PDF). United States Food and Drug Administration. Amedra Pharmaceuticals LLC. October 2013. Retrieved 4 November 2013.
  109. Jump up^ “Adderall IR Prescribing Information” (PDF). United States Food and Drug Administration. Teva Pharmaceuticals USA, Inc. October 2015. Retrieved 18 May 2016.
  110. Jump up^ “Adderall XR Prescribing Information” (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. Retrieved 30 December 2013.
  111. Jump up^ Advokat C (July 2007). “Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD”. J. Atten. Disord. 11 (1): 8–16. PMID 17606768. doi:10.1177/1087054706295605.
  112. ^ Jump up to:a b c d Bowyer JF, Hanig JP (November 2014). “Amphetamine- and methamphetamine-induced hyperthermia: Implications of the effects produced in brain vasculature and peripheral organs to forebrain neurotoxicity”. Temperature (Austin). 1 (3): 172–182. PMC 5008711Freely accessible. PMID 27626044. doi:10.4161/23328940.2014.982049.Hyperthermia alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40°C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production. … The hyperthermia and the hypertension produced by high doses amphetamines are a primary cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional neurodegeneration and neuroinflammation in laboratory animals. … In animal models that evaluate the neurotoxicity of AMPH and METH, it is quite clear that hyperthermia is one of the essential components necessary for the production of histological signs of dopamine terminal damage and neurodegeneration in cortex, striatum, thalamus and hippocampus.
  113. Jump up^ “Amphetamine”. Hazardous Substances Data Bank. United States National Library of Medicine – Toxicology Data Network. Retrieved 26 February 2014.Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation.
  114. 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, USA: McGraw-Hill Medical. p. 370. ISBN 9780071481274.Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.
  115. Jump up^ Sulzer D, Zecca L (February 2000). “Intraneuronal dopamine-quinone synthesis: a review”. Neurotox. Res. 1 (3): 181–195. PMID 12835101. doi:10.1007/BF03033289.
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  117. Jump up^ Hofmann FG (1983). A Handbook on Drug and Alcohol Abuse: The Biomedical Aspects (2nd ed.). New York, USA: Oxford University Press. p. 329. ISBN 9780195030570.
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  119. ^ Jump up to:a b “Identification”. Lisdexamfetamine. DrugBank. University of Alberta. 16 September 2013. Retrieved 13 June 2014.
  120. ^ Jump up to:a b c Jasinski DR, Krishnan S (June 2009). “Abuse liability and safety of oral lisdexamfetamine dimesylate in individuals with a history of stimulant abuse”. J. Psychopharmacol. (Oxford). 23 (4): 419–427. PMID 19329547. doi:10.1177/0269881109103113.
  121. ^ Jump up to:a b Miller GM (January 2011). “The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity”. J. Neurochem. 116 (2): 164–176. PMC 3005101Freely accessible. PMID 21073468. doi:10.1111/j.1471-4159.2010.07109.x.
  122. ^ Jump up to:a b Eiden LE, Weihe E (January 2011). “VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse”. Ann. N. Y. Acad. Sci. 1216: 86–98. Bibcode:2011NYASA1216…86E. PMC 4183197Freely accessible. PMID 21272013. doi:10.1111/j.1749-6632.2010.05906.x.VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) … [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC).
  123. Jump up^ “Adderall XR Prescribing Information” (PDF). United States Food and Drug Administration. pp. 1–18. Retrieved 7 October 2013.
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  126. Jump up^ “Pharmacology”. Amphetamine. DrugBank. University of Alberta. 8 February 2013. Retrieved 5 November 2013.
  127. ^ Jump up to:a b c d “Pharmacology and Biochemistry”. Amphetamine. Pubchem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 12 October 2013.
  128. ^ Jump up to:a b “Metabolism/Pharmacokinetics”. AMPHETAMINE. United States National Library of Medicine – Toxicology Data Network. Hazardous Substances Data Bank. Retrieved 5 January 2014.Plasma protein binding, rate of absorption, & volumes of distribution of amphetamine isomers are similar. … The biological half-life of amphetamine is greater in drug dependent individuals than in control subjects, & distribution volumes are increased, indicating that greater affinity of tissues for the drug may contribute to development of amphetamine tolerance. … Concentrations of (14)C-amphetamine declined less rapidly in the plasma of human subjects maintained on an alkaline diet (urinary pH > 7.5) than those on an acid diet (urinary pH < 6). Plasma half-lives of amphetamine ranged between 16-31 hr & 8-11 hr, respectively, & the excretion of (14)C in 24 hr urine was 45 & 70%.
  129. ^ Jump up to:a b c “Vyvanse Prescribing Information” (PDF). United States Food and Drug Administration. Shire US Inc. January 2017. pp. 18–21. Retrieved 16 February 2017.
  130. Jump up^ Glennon RA (2013). “Phenylisopropylamine stimulants: amphetamine-related agents”. In Lemke TL, Williams DA, Roche VF, Zito W. Foye’s principles of medicinal chemistry (7th ed.). Philadelphia, USA: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. ISBN 9781609133450.The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). … The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. … Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. … Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
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Lisdexamfetamine structure.svg
Lisdexamfetamine ball-and-stick model.png
Clinical data
Trade names Tyvense, Elvanse, Venvanse, Vyvanse
AHFS/ Monograph
MedlinePlus a607047
License data
  • AU: B3
  • US: C (Risk not ruled out)
Physical: none
Psychological: moderate
Routes of
Oral (capsules)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 96.4%[1]
Metabolism Hydrolysis by enzymes in red blood cells initially.
Subsequent metabolism follows Amphetamine#Pharmacokinetics.
Onset of action 2 hours[2][3]
Biological half-life ≤1 hour (prodrug molecule)
9–11 hours (dextroamphetamine)
Duration of action 12 hours[2][3]
Excretion Renal: ~2%
Synonyms Vyvanse
CAS Number
PubChem CID
Chemical and physical data
Formula C15H25N3O
Molar mass 263.378 g/mol
3D model (Jmol)



FDA approves first subcutaneous C1 Esterase Inhibitor to treat rare genetic disease



The U.S. Food and Drug Administration today approved Haegarda, the first C1 Esterase Inhibitor (Human) for subcutaneous (under the skin) administration to prevent Hereditary Angioedema (HAE) attacks in adolescent and adult patients. The subcutaneous route of administration allows for easier at-home self-injection by the patient or caregiver, once proper training is received.

The U.S. Food and Drug Administration today approved Haegarda, the first C1 Esterase Inhibitor (Human) for subcutaneous (under the skin) administration to prevent Hereditary Angioedema (HAE) attacks in adolescent and adult patients. The subcutaneous route of administration allows for easier at-home self-injection by the patient or caregiver, once proper training is received.

HAE, which is caused by having insufficient amounts of a plasma protein called C1-esterase inhibitor (or C1-INH), affects approximately 6,000 to 10,000 people in the U.S. People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract or airway. These attacks of swelling can occur spontaneously, or can be triggered by stress, surgery or infection.

“The approval of Haegarda provides a new treatment option for adolescents and adults with Hereditary Angioedema,” said Peter Marks, M.D., Ph.D., director of FDA’s Center for Biologics Evaluation and Research. “The subcutaneous formulation allows patients to administer the product at home to help prevent attacks.”

Haegarda is a human plasma-derived, purified, pasteurized, lyophilized (freeze-dried) concentrate prepared from large pools of human plasma from U.S. donors. Haegarda is indicated for routine prophylaxis to prevent HAE attacks, but is not indicated for treatment of acute HAE attacks.

The efficacy of Haegarda was demonstrated in a multicenter controlled clinical trial. The study included 90 subjects ranging in age from 12 to 72 years old with symptomatic HAE. Subjects were randomized to receive twice per week subcutaneous doses of either 40 IU/kg or 60 IU/kg, and the treatment effect was compared to a placebo treatment period. During the 16 week treatment period, patients in both treatment groups experienced a significantly reduced number of HAE attacks compared to their placebo treatment period.

The most common side effects included injection site reactions, hypersensitivity (allergic) reactions, nasopharyngitis (swelling of the nasal passages and throat) and dizziness. Haegarda should not be used in individuals who have experienced life-threatening hypersensitivity reactions, including anaphylaxis, to a C1-INH preparation or its inactive ingredients.

Haegarda received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs to treat rare diseases or conditions.

The FDA granted approval of Haegarda to CSL Behring LLC.

///////////Haegarda, C1 Esterase inhibitor, CSL Behring LLC,  fda 2017, orphan drug

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