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GSK 2982772

July 20, 2017 9:21 am / Leave a comment

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

Chemical Formula: C20H19N5O3

Molecular Weight: 377.404

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

(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
Antipsoriatics

Inventors	Deepak BANDYOPADHYAY, Patrick M. Eidam, Peter J. GOUGH, Philip Anthony Harris, Jae U. Jeong, Jianxing Kang, Bryan Wayne KING, Shah Ami Lakdawala, Jr. Robert W. Marquis, Lara Kathryn LEISTER, Attiq Rahman, Joshi M. Ramanjulu, Clark A Sehon, JR. Robert SINGHAUS, Daohua Zhang
Applicant	Glaxosmithkline Intellectual Property Development Limited

Deepak Bandyopadhyay

Deepak BANDYOPADHYAY

Data Science and Informatics Leader | Innovation Advocate

GSK

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.

Patent

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⁺).

Crystallization:

(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.

Paper

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

http://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.6b01751

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

1H NMR AND 13C NMR PREDICT

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

CN3c4ccccc4OC[C@H](NC(=O)c2nnc(Cc1ccccc1)n2)C3=O

Voxilaprevir, فوكسيلابريفير , 伏西瑞韦 , Воксилапревир

July 19, 2017 10:44 am / Leave a comment

Voxilaprevir

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[24.2.1.0^3,12.0^5,10.0^18,20]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)-

GS-9857

UNII:0570F37359

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).

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).

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 45^th 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.

Kyla Bjornson, Eda Canales, Jeromy J. Cottell, Kapil Kumar KARKI, Ashley Anne Katana, Darryl Kato, Tetsuya Kobayashi, John O. Link, Ruben Martinez, Barton W. Phillips, Hyung-Jung Pyun, Michael Sangi, Adam James SCHRIER, Dustin Siegel, James G. TAYLOR, Chinh Viet Tran, Martin Teresa Alejandra Trejo, Randall W. Vivian, Zheng-Yu Yang, Jeff Zablocki, Sheila Zipfel,
Applicant	Gilead Sciences, Inc.

Kyla Ramey (Bjornson)

Senior CTM Associate at Gilead Sciences

……………………………………………………………………………….

PATENT

WO 2014008285

https://www.google.com/patents/WO2014008285A1?cl=en

26. A compound of Formula IVf:

RELATIVE SIMILAR EXAMPLE WITHOUT DIFLUORO GROUPS, BUT NOT SAME COMPD

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.

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, J_H-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).

PATENT

US 20150175625

PATENT

US 20150175626

https://patentscope.wipo.int/search/en/detail.jsf;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

References

“Summary of opinion: Vosevi” (PDF). European Medicines Agency. 22 June 2017.
FDA approves Vosevi for Hepatitis C

Patent ID	Patent Title	Submitted Date	Granted Date
US2014343008	HEPATITIS C TREATMENT	2014-01-30	2014-11-20
US2014212491	COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS	2014-01-30	2014-07-31
US2014017198	INHIBITORS OF HEPATITIS C VIRUS	2013-07-02	2014-01-16
US2015064253	COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS	2014-01-30	2015-03-05
US2015150897	METHODS OF TREATING HEPATITIS C VIRUS INFECTION IN SUBJECTS WITH CIRRHOSIS	2014-12-01	2015-06-04
US2015175625	CRYSTALLINE FORMS OF AN ANTIVIRAL COMPOUND	2014-12-18	2015-06-25
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
US2016120892	COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS	2015-09-28	2016-05-05
US2016130300	INHIBITORS OF HEPATITIS C VIRUS	2016-01-15	2016-05-12

Voxilaprevir
Clinical data

Trade names	Vosevi (combination with sofosbuvir and velpatasvir)
Identifiers
IUPAC name [show]
CAS Number	1535212-07-7
PubChemCID	89921642
ChemSpider	44209500
UNII	0570F37359
Chemical and physical data
Formula	C₄₀H₅₂F₄N₆O₉S
Molar mass	868.94 g·mol⁻¹

FDA approves Vosevi for Hepatitis C

07/18/2017

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

CCC1C2CN(C1C(=O)NC3(CC3C(F)F)C(=O)NS(=O)(=O)C4(CC4)C)C(=O)C(NC(=O)OC5CC5CCCCC(C6=NC7=C(C=C(C=C7)OC)N=C6O2)(F)F)C(C)(C)C

CC1(CC1)S(=O)(=O)NC(=O)[C@]2(C[C@H]2C(F)F)NC(=O)[C@@H]7[C@H](CC)[C@@H]3CN7C(=O)[C@@H](NC(=O)O[C@@H]6C[C@H]6CCCCC(F)(F)c4nc5ccc(OC)cc5nc4O3)C(C)(C)C

LOXO 195

July 12, 2017 11:06 am / Leave a comment

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.

1H NMR PREDICT

13C NMR PREDICT

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

http://pubs.acs.org/doi/full/10.1021/cen-09527-cover

Lisa M. JarvisC&EN, 2017, 95 (27), pp 26–30July 3, 2017

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?

July 6, 2017 1:10 am / Leave a comment

Green Chemistry International

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?

María Castro Rodríguez^†, Ignacio Rodríguez García^‡, Roman Nicolay Rodríguez Maecker^§, Laura Pozo Morales^†, J. Enrique Oltra^∥, and Antonio Rosales Martínez ^*^†^§⊥

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

View original post 2,879 more words

Lisdexamphetamine

June 28, 2017 10:35 am / Leave a comment

Lisdexamfetamine

Molecular FormulaC₁₅H₂₅N₃O
Average mass263.379 Da

608137-32-2 [RN]

Elvanse [Trade name]

Hexanamide, 2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]-, (2S)-

Lisdexamfetamine

L-lysine-d-amphetamine

(2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanimidic acid

H645GUL8KJ

L-lysine-(+)-amphetamine

NRP104|Vyvanse®

UNII:H645GUL8KJ

UNII-H645GUL8KJ

Vyvanse®

CAS 608137-33-3

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

https://www.google.com/patents/WO2005032474A2

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).
KRISHNAN, Suma; (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.

ABOUT SUMA KRISHNAN

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

Intrexon Corporation

2012 – Current (over 5 years)

Director, Regulatory Affairs

Shire

Senior Project Manager

Pfizer

May, 1991

Discovery Scientist

Janssen Pharmaceuticals

2009

2011

Senior Vice President of Product Development

Pinnacle Pharmaceuticals

2007

2009

Chief Financial Officer

Light Matters Foundation

Sep, 2002

Apr, 2007

Vice President, Product Development

New River Pharmaceuticals Inc

Lisdexamfetamine (contracted from L–lysine–dextroamphetamine) is a prodrug of the central nervous system (CNS) stimulant dextroamphetamine, 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 enzymatic cleavage 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]

Uses

Medical

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]

Cognitive

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]

Physical

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]

DESCRIPTION/SYNTHESIS

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

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

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:

4M HCI/dioxane

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

NHS;DCC;

isopropyl acetate

-50°C, 2 hr

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:

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.

PATENT

https://www.google.com/patents/US20120157706

Figure US20120157706A1-20120621-C00005

Figure US20120157706A1-20120621-C00007

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

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 %).

PATENT

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 .

PATENT

WO 2005032474

IN 2011DE02040

WO 2013011526

IN 2009CH01986

WO 2010042120

PATENT

https://www.google.com/patents/WO2013011526A1?cl=en

Figure imgf000015_0002

Formula II A

Formula IV

Formula IVA

EXAMPLES

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

via AADC

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]

Pharmacokinetics

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 pK_a 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]}

4-Hydroxyphenylacetone

4-Hydroxynorephedrine

Para-
Hydroxylation

CYP2D6

unidentified

Beta-
Hydroxylation

DBH

Oxidative
Deamination

FMO3

Oxidation

unidentified

Glycine
Conjugation

XM-ligase
GLYAT

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]

Chemistry

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 content ^{[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]

Notes

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]
Jump up^ Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.^[24]
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.
Jump up^ Transcription factors are proteins that increase or decrease the expression of specific genes.^[93]
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.
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]
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.
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.
Jump up^ Amphetamine base percentage = molecular mass_base / molecular mass_total. Amphetamine base percentage for Adderall = sum of component percentages / 4.
Jump up^ dose = (1 / amphetamine base percentage) × scaling factor = (molecular mass_total / molecular mass_base) × 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.
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]

PATENT CITATIONS

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

NON-PATENT CITATIONS

Reference
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

References

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^ Jump up to:^a ^b 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. p. 112. ISBN 9781441913968.
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]
^ Jump up to:^a ^b Brams M, Mao AR, Doyle RL (September 2008). “Onset of efficacy of long-acting psychostimulants in pediatric attention-deficit/hyperactivity disorder”. Postgrad. Med. 120 (3): 69–88. PMID 18824827. doi:10.3810/pgm.2008.09.1909.Onset of efficacy was earliest for d-MPH-ER at 0.5 hours, followed by d, l-MPH-LA at 1 to 2 hours, MCD at 1.5 hours, d, l-MPH-OR at 1 to 2 hours, MAS-XR at 1.5 to 2 hours, MTS at 2 hours, and LDX at approximately 2 hours. … MAS-XR, and LDX have a long duration of action at 12 hours postdose
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m “Vyvanse Prescribing Information” (PDF). United States Food and Drug Administration. Shire US Inc. January 2015. Retrieved 24 February 2015.
^ Jump up to:^a ^b Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). “Amphetamine, past and present – a pharmacological and clinical perspective”. J. Psychopharmacol. 27 (6): 479–496. PMC 3666194 . PMID 23539642. doi:10.1177/0269881113482532.
Jump up^ “Lisdexamfetamine dimesylate (generic).” Brown University Psychopharmacology Update 19.7 (2008): 1–2. Academic Search Premier. EBSCO. Web. 12 September 2010.
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^ Jump up to:^a ^b Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L (August 2012). “Toxicity of amphetamines: an update”. Arch. Toxicol. 86 (8): 1167–1231. PMID 22392347. doi:10.1007/s00204-012-0815-5.
Jump up^ Berman S, O’Neill J, Fears S, Bartzokis G, London ED (October 2008). “Abuse of amphetamines and structural abnormalities in the brain”. Ann. N. Y. Acad. Sci. 1141: 195–220. PMC 2769923 . PMID 18991959. doi:10.1196/annals.1441.031.
^ Jump up to:^a ^b Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K (February 2013). “Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects”. JAMA Psychiatry. 70 (2): 185–198. PMID 23247506. doi:10.1001/jamapsychiatry.2013.277.
^ 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 3801446 . PMID 24107764. doi:10.4088/JCP.12r08287.
^ Jump up to:^a ^b Frodl T, Skokauskas N (February 2012). “Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects.”. Acta psychiatrica Scand. 125 (2): 114–126. PMID 22118249. doi:10.1111/j.1600-0447.2011.01786.x.Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.
^ 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.
^ 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 4340791 . 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
^ 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.
^ 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.
^ 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.
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 3353150 . PMID 21596055. doi:10.1016/j.pbb.2011.05.002.
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 3785407 . 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.
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.
Jump up^ “Stimulants for Attention Deficit Hyperactivity Disorder”. WebMD. Healthwise. 12 April 2010. Retrieved 12 November 2013.
Jump up^ Scholten RJ, Clarke M, Hetherington J (August 2005). “The Cochrane Collaboration”. Eur. J. Clin. Nutr. 59 Suppl 1: S147–S149; discussion S195–S196. PMID 16052183. doi:10.1038/sj.ejcn.1602188.
^ Jump up to:^a ^b Castells X, Ramos-Quiroga JA, Bosch R, Nogueira M, Casas M (June 2011). Castells X, ed. “Amphetamines for Attention Deficit Hyperactivity Disorder (ADHD) in adults”. Cochrane Database Syst. Rev. (6): CD007813. PMID 21678370. doi:10.1002/14651858.CD007813.pub2.
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.
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.
^ Jump up to:^a ^b http://www.shire.com/shireplc/en/rd/pipeline
^ 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 4377121 . 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.
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.
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 4471173 . 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.
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.
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.
^ Jump up to:^a ^b ^c Wood S, Sage JR, Shuman T, Anagnostaras SG (January 2014). “Psychostimulants and cognition: a continuum of behavioral and cognitive activation”. Pharmacol. Rev. 66 (1): 193–221. PMID 24344115. doi:10.1124/pr.112.007054.
Jump up^ Twohey M (26 March 2006). “Pills become an addictive study aid”. JS Online. Archived from the original on 15 August 2007. Retrieved 2 December 2007.
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 1794223 . PMID 16999660. doi:10.1592/phco.26.10.1501.
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 4164338 . 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.
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.
^ Jump up to:^a ^b ^c Liddle DG, Connor DJ (June 2013). “Nutritional supplements and ergogenic AIDS”. Prim. Care. 40 (2): 487–505. PMID 23668655. doi:10.1016/j.pop.2013.02.009.Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training …
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
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s Westfall DP, Westfall TC (2010). “Miscellaneous Sympathomimetic Agonists”. In Brunton LL, Chabner BA, Knollmann BC. Goodman & Gilman’s Pharmacological Basis of Therapeutics (12th ed.). New York, USA: McGraw-Hill. ISBN 9780071624428.
Jump up^ Bracken NM (January 2012). “National Study of Substance Use Trends Among NCAA College Student-Athletes” (PDF). NCAA Publications. National Collegiate Athletic Association. Retrieved 8 October 2013.
Jump up^ Docherty JR (June 2008). “Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)”. Br. J. Pharmacol. 154 (3): 606–622. PMC 2439527 . PMID 18500382. doi:10.1038/bjp.2008.124.
^ Jump up to:^a ^b ^c ^d Parr JW (July 2011). “Attention-deficit hyperactivity disorder and the athlete: new advances and understanding”. Clin. Sports Med. 30 (3): 591–610. PMID 21658550. doi:10.1016/j.csm.2011.03.007.In 1980, Chandler and Blair⁴⁷ showed significant increases in knee extension strength, acceleration, anaerobic capacity, time to exhaustion during exercise, pre-exercise and maximum heart rates, and time to exhaustion during maximal oxygen consumption (VO2 max) testing after administration of 15 mg of dextroamphetamine versus placebo. Most of the information to answer this question has been obtained in the past decade through studies of fatigue rather than an attempt to systematically investigate the effect of ADHD drugs on exercise.
^ 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.
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 3813949 . 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.
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 4362407 . 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)
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.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Adderall XR Prescribing Information” (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. p. 11. Retrieved 30 December 2013.
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^ Jump up to:^a ^b ^c ^d “Vyvanse Prescribing Information” (PDF). Shire Inc. Retrieved 1 July 2014.
^ Jump up to:^a ^b ^c ^d ^e ^f Heedes G; Ailakis J. “Amphetamine (PIM 934)”. INCHEM. International Programme on Chemical Safety. Retrieved 24 June 2014.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Adderall XR Prescribing Information” (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 4–6. Retrieved 30 December 2013.
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^ Jump up to:^a ^b Vitiello B (April 2008). “Understanding the risk of using medications for attention deficit hyperactivity disorder with respect to physical growth and cardiovascular function”. Child Adolesc. Psychiatr. Clin. N. Am. 17 (2): 459–474. PMC 2408826 . PMID 18295156. doi:10.1016/j.chc.2007.11.010.
^ 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. …
DOSAGE FORMS AND STRENGTHS
Extended-release oral suspension contains 2.5 mg amphetamine base per mL.
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
^ Jump up to:^a ^b “FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children and young adults”. United States Food and Drug Administration. 20 December 2011. Retrieved 4 November 2013.
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 4943074 . PMID 22043968. doi:10.1056/NEJMoa1110212.
^ 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.
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 3350308 . PMID 22161946. doi:10.1001/jama.2011.1830.
Jump up^ Montgomery KA (June 2008). “Sexual desire disorders”. Psychiatry (Edgmont). 5 (6): 50–55. PMC 2695750 . PMID 19727285.
Jump up^ O’Connor PG (February 2012). “Amphetamines”. Merck Manual for Health Care Professionals. Merck. Retrieved 8 May 2012.
^ 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.
^ 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.
^ 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 2693956 . 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.
^ 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.
^ 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.
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 4340604 . PMID 25530442. doi:10.1016/S0140-6736(14)61682-2. Retrieved 3 March 2015.Amphetamine use disorders … 3,788 (3,425–4,145)
Jump up^ Kanehisa Laboratories (10 October 2014). “Amphetamine – Homo sapiens (human)”. KEGG Pathway. Retrieved 31 October 2014.
^ 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.
^ 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.
^ 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 3898681 . 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.
Jump up^ Robison AJ, Nestler EJ (November 2011). “Transcriptional and epigenetic mechanisms of addiction”. Nat. Rev. Neurosci. 12 (11): 623–637. PMC 3272277 . PMID 21989194. doi:10.1038/nrn3111.ΔFosB serves as one of the master control proteins governing this structural plasticity.
^ 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 3139704 . 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).
^ 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 3788047 . 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.
^ 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.
^ 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 4831948 . 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.
^ 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.
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.
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.
Jump up^ “Glossary of Terms”. Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015.
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.
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.
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.
Jump up^ Stolerman IP (2010). Stolerman IP, ed. Encyclopedia of Psychopharmacology. Berlin, Germany; London, England: Springer. p. 78. ISBN 9783540686989.
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 4057639 . 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.
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.
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.
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.
^ 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 3272277 . PLID 21989194 . doi :10.1038/nrn3111.
^ Jump up to:^a ^b <` href=”https://en.wikipedia.org/wiki/Lisdexamfetamine#cite_ref-@ddiction_genetics_101-2″>^{c d <` href=”httpr://en.wikipedia.org/wiki/Lisdexamfetamine#cite_ref-Addiction_genetics_101-4″>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 3525776 . PMID 23085425. doi:10.1016/j.pneurobio.2012.10.001.}
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.
Jump up^ Kanehisa Laboratories (29 October 2014). “Alcoholism – Homo sapiens (human)”. KEGG Pathway. Retrieved 31 October 2014.
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 2650365 . PMID 19202072. doi:10.1073/pnas.0813179106.
Jump up^ Nestler EJ (January 2014). “Epigenetic mechanisms of drug addiction”. Neuropharmacology. 76 Pt B: 259–268. PMC 3766384 . PMID 23643695. doi:10.1016/j.neuropharm.2013.04.004.
^ 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 4040958 . PMID 22641964. doi:10.1080/02791072.2012.662112.
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 3865508 . PMID 23426671. doi:10.1523/JNEUROSCI.4881-12.2013.
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.
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 4017926 . 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.
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
Jump up^ Forray A, Sofuoglu M (February 2014). “Future pharmacological treatments for substance use disorders”. Br. J. Clin. Pharmacol. 77 (2): 382–400. PMC 4014020 . PMID 23039267. doi:10.1111/j.1365-2125.2012.04474.x.
^ 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.
^ 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 4532615 . 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.
^ 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.
^ 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 4745113 . 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.
^ 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.
Jump up^ “Dexedrine Prescribing Information” (PDF). United States Food and Drug Administration. Amedra Pharmaceuticals LLC. October 2013. Retrieved 4 November 2013.
Jump up^ “Adderall IR Prescribing Information” (PDF). United States Food and Drug Administration. Teva Pharmaceuticals USA, Inc. October 2015. Retrieved 18 May 2016.
Jump up^ “Adderall XR Prescribing Information” (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. Retrieved 30 December 2013.
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.
^ 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 5008711 . 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.
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.
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.
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.
Jump up^ Miyazaki I, Asanuma M (June 2008). “Dopaminergic neuron-specific oxidative stress caused by dopamine itself” (PDF). Acta Med. Okayama. 62 (3): 141–150. PMID 18596830.
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.
^ Jump up to:^a ^b ^c ^d “Adderall XR Prescribing Information” (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 8–10. Retrieved 30 December 2013.
^ Jump up to:^a ^b “Identification”. Lisdexamfetamine. DrugBank. University of Alberta. 16 September 2013. Retrieved 13 June 2014.
^ 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.
^ 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 3005101 . PMID 21073468. doi:10.1111/j.1471-4159.2010.07109.x.
^ 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 4183197 . 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).
Jump up^ “Adderall XR Prescribing Information” (PDF). United States Food and Drug Administration. pp. 1–18. Retrieved 7 October 2013.
Jump up^ “Pharmacology”. Dextroamphetamine. DrugBank. University of Alberta. 8 February 2013. Retrieved 5 November 2013.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ “Adderall XR Prescribing Information” (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Retrieved 30 December 2013.
Jump up^ “Pharmacology”. Amphetamine. DrugBank. University of Alberta. 8 February 2013. Retrieved 5 November 2013.
^ 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.
^ 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%.
^ 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.
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.
Jump up^ Taylor KB (January 1974). “Dopamine-beta-hydroxylase. Stereochemical course of the reaction” (PDF). J. Biol. Chem. 249 (2): 454–458. PMID 4809526. Retrieved 6 November 2014.Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.
Jump up^ Krueger SK, Williams DE (June 2005). “Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism”. Pharmacol. Ther. 106 (3): 357–387. PMC 1828602 . PMID 15922018. doi:10.1016/j.pharmthera.2005.01.001.
Table 5: N-containing drugs and xenobiotics oxygenated by FMO
Jump up^ Cashman JR, Xiong YN, Xu L, Janowsky A (March 1999). “N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication”. J. Pharmacol. Exp. Ther. 288 (3): 1251–1260. PMID 10027866.
^ Jump up to:^a ^b ^c Santagati NA, Ferrara G, Marrazzo A, Ronsisvalle G (September 2002). “Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection”. J. Pharm. Biomed. Anal. 30 (2): 247–255. PMID 12191709. doi:10.1016/S0731-7085(02)00330-8.
Jump up^ Horwitz D, Alexander RW, Lovenberg W, Keiser HR (May 1973). “Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity”. Circ. Res. 32 (5): 594–599. PMID 4713201. doi:10.1161/01.RES.32.5.594.Subjects with exceptionally low levels of serum dopamine-β-hydroxylase activity showed normal cardiovascular function and normal β-hydroxylation of an administered synthetic substrate, hydroxyamphetamine.
^ Jump up to:^a ^b “Substrate/Product”. butyrate-CoA ligase. BRENDA. Technische Universität Braunschweig. Retrieved 7 May 2014.
^ Jump up to:^a ^b “Substrate/Product”. glycine N-acyltransferase. BRENDA. Technische Universität Braunschweig. Retrieved 7 May 2014.
Jump up^ “Compound Summary”. p-Hydroxyamphetamine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013.
Jump up^ “Compound Summary”. p-Hydroxynorephedrine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013.
Jump up^ “Compound Summary”. Phenylpropanolamine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013.
Jump up^ “Molecular Weight Calculator”. Lenntech. Retrieved 19 August 2015.
^ Jump up to:^a ^b “Dextroamphetamine Sulfate USP”. Mallinckrodt Pharmaceuticals. March 2014. Retrieved 19 August 2015.
^ Jump up to:^a ^b “D-amphetamine sulfate”. Tocris. 2015. Retrieved 19 August 2015.
^ Jump up to:^a ^b “Amphetamine Sulfate USP”. Mallinckrodt Pharmaceuticals. March 2014. Retrieved 19 August 2015.
Jump up^ “Dextroamphetamine Saccharate”. Mallinckrodt Pharmaceuticals. March 2014. Retrieved 19 August 2015.
Jump up^ “Amphetamine Aspartate”. Mallinckrodt Pharmaceuticals. March 2014. Retrieved 19 August 2015.
Jump up^ “Vyvanse Prescribing Information” (PDF). United States Food and Drug Administration. Shire US Inc. January 2015. pp. 12–16. Retrieved 24 February 2015.
Jump up^ Lisdexamfetamine Dimesylate: A Prodrug Stimulant for the Treatment of ADHD in Children and Adults
Jump up^ FDA Adult Approval of Vyvanse – FDA Label and Approval History
Jump up^ Health Canada Notice of Compliance – Vyvanse. 19 February 2009, retrieved on 9 March 2009.
Jump up^ [1]. 8 February 2012, retrieved on 9 February 2012.
Jump up^ Hirschler, Ben (7 February 2014). “UPDATE 2-Shire scraps Vyvanse for depression after failed trials”. Reuters. Retrieved 13 February 2014.
Jump up^ http://www.shire.com/shireplc/en/investors/irshirenews?id=684
Jump up^ http://www.shire.com/shireplc/en/investors/investorsnews/irshirenews?id=1055
Jump up^ http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm432543.htm
Jump up^ Cassels, Caroline. “FDA Okays Vyvanse for Binge Eating Disorder”. medscape.com. Retrieved 30 January 2015.
Jump up^ “Drugs@FDA: FDA Approved Drug Products”. http://www.accessdata.fda.gov. Retrieved 14 February 2017.
Jump up^ http://www.shire.com/shireplc/en/investors/investorsnews/irshirenews?id=684
Jump up^ Dale E, Bang-Andersen B, Sánchez C (May 2015). “Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs”. Biochem. Pharmacol. 95 (2): 81–97. PMID 25813654. doi:10.1016/j.bcp.2015.03.011.
Jump up^ “Psychostimulants in the therapy of treatment-resistant depression Review of the literature and findings from a retrospective study in 65 depressed patients”. Dialogues Clin Neurosci. 1: 165–74. 1999. PMC 3181580 . PMID 22034135.

Lisdexamfetamine
Clinical data


Trade names	Tyvense, Elvanse, Venvanse, Vyvanse
AHFS/Drugs.com	Monograph
MedlinePlus	a607047
License data	US FDA: Lisdexamfetamine
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Dependence liability	Physical: none Psychological: moderate
Addiction liability	Moderate
Routes of administration	Oral (capsules)
ATC code	N06BA12 (WHO)
Legal status
Legal status	AU: S8 (Controlled) CA: Schedule I DE: Anlage III (Special prescription form required) UK: Class B US: Schedule II In general: ℞ (Prescription only)
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%
Identifiers
IUPAC name [show]
Synonyms	Vyvanse
CAS Number	608137-32-2^[IUPHAR]
PubChem CID	11597698
IUPHAR/BPS	7213
DrugBank	DB01255
ChemSpider	9772458
UNII	H645GUL8KJ
ChEMBL	CHEMBL1201222
Chemical and physical data
Formula	C₁₅H₂₅N₃O
Molar mass	263.378 g/mol
3D model (Jmol)	Interactive image

////////

CC(CC1=CC=CC=C1)NC(=O)C(CCCCN)N

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

June 23, 2017 1:01 am / Leave a comment

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

06/22/2017

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

HNIW, CL 20, 六硝基六氮杂异伍兹烷

June 22, 2017 10:03 am / Leave a comment

ChemSpider 2D Image | HNIW | C6H6N12O12

HNIW, CL-20

Molecular FormulaC₆H₆N₁₂O₁₂
Average mass438.185 Da
1,3,4,7,8,10-hexanitrooctahydro-1H-5,2,6-(epiminomethanetriylimino)imidazo[4,5-b]pyrazine

CAS 135285-90-4

Hexanitrohexaazaisowurtzitane
2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane
Octahydro-1,3,4,7,8,10-hexanitro-5,2,6-(iminomethenimino)-1H-imidazo[4,5-b]pyrazine
HNIW
六硝基六氮杂异伍兹烷

ABOUT AUTHOR

Tomasz Gołofit

Warsaw University of Technolog… , Warsaw

Thermochemistry, Physical Chemistry, Materials Chemistry

Warsaw University of Technology

Department of Energized Materials

Warsaw, mazowieckie, Poland

Staff Paweł Maksimowski Wincenty Skupiński Wojciech Pawłowski Waldemar Tomaszewski Tomasz Gołofit Katarzyna Cieślak

Faculty of Chemistry, Division of High Energetic Materials, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland

Hexanitrohexaazaisowurtzitane /ˈhɛksɑːˈnaɪtroʊˈhɛksɑːˌæzɑːˌaɪsoʊˈvʊərtsɪteɪn/, also called HNIW and CL-20, is a nitroamine explosive with the formula C₆H₆N₁₂O₁₂. The structure of CL-20 was first proposed in 1979 by Dalian Institute of Chemical Physics.^[1]In 1980s, CL-20 was developed by the China Lake facility, primarily to be used in propellants. It has a better oxidizer-to-fuel ratio than conventional HMX or RDX. It releases 20% more energy than traditional HMX-based propellants, and is widely superior to conventional high-energy propellants and explosives.

Industrial production of CL-20 was achieved in China in 2011, and it was soon fielded in propellant of solid rockets.^[2] While most development of CL-20 has been fielded by the Thiokol Corporation, the US Navy (through ONR) has also been interested in CL-20 for use in rocket propellants, such as for missiles, as it has lower observability characteristics such as less visible smoke.^[3]

CL-20 has not yet been fielded in any production weapons system, but is undergoing testing for stability, production capabilities, and other weapons characteristics.

Synthesis

THEN CONVERTED TO CL20, HNIW

Synthesis of CL20, HNIW


505	Synthesis of CL-20: By oxidative debenzylation with cerium(IV) ammonium nitrate (CAN) IPC: Int.Cl.⁸ C07D	A simple debenzylation approach has been discussed for the synthesis of hexanitrohexaazaisowurtzitane (HNIW or CL-20) one of the most powerful high explosives of today with cerium ammonium (IV) nitrate.

	*G M Gore, R Sivabalan, U R Nair, A Saikia, S Venugopalan & B R Gandhe**

First, benzylamine (1) is condensed with glyoxal (2) under acidic and dehydrating conditions to yield the first intermediate compound.(3). Four benzyl groups selectively undergo hydrogenolysis using palladium on carbon and hydrogen. The amino groups are then acetylated during the same step using acetic anhydride as the solvent. (4). Finally, compound 4 is reacted with nitronium tetrafluoroborate and nitrosonium tetrafluoroborate, resulting in HNIW.^[4]

ChemSpider 2D Image | (3R,9R)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0~3,11~.0~5,9~]dodecane | C6H6N12O12

(3R,9R)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^3,11.0^5,9]dodecane

Molecular FormulaC₆H₆N₁₂O₁₂
Average mass438.185 Da
(3R,9R)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^3,11.0^5,9]dodecan

(3R,9R)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^3,11.0^5,9]dodecane

(3R,9R)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatétracyclo[5.5.0.0^3,11.0^5,9]dodécane

5,2,6-(Iminomethanetriylimino)-1H-imidazo[4,5-b]pyrazine, octahydro-1,3,4,7,8,10-hexanitro-, (5R,7aR)-

(3R,5S,9R,11S)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^3,11.0^5,9]dodecane

Molecular FormulaC₆H₆N₁₂O₁₂
Average mass438.185 Da
(3R,5S,9R,11S)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^3,11.0^5,9]dodecan

(3R,5S,9R,11S)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^3,11.0^5,9]dodecane

(3R,5S,9R,11S)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatétracyclo[5.5.0.0^3,11.0^5,9]dodécane

5,2,6-(Iminomethanetriylimino)-1H-imidazo[4,5-b]pyrazine, octahydro-1,3,4,7,8,10-hexanitro-, (3aR,5S,6R,7aS)

Cocrystal product with HMX

In August 2012, Onas Bolton et al. published results showing that a cocrystal of 2 parts CL-20 and 1 part HMX had similar safety properties to HMX, but with a greater firing power closer to CL-20. ^[5]^[6]

Cocrystal product with TNT

In August 2011, Adam Matzger and Onas Bolton published results showing that a cocrystal of CL-20 and TNT had

The synthesis of 2,4,6,8,10,12-hexabenzyl-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^5,9.0^3,11]-dodecane (HBIW) is the first stage in the production of 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.05,9.03,11] dodecane (CL-20), which is the most potent explosive known today. Because of the high performance characteristics of CL-20, a number of research projects are being conducted worldwide on CL-20 synthesis, properties and applications

Scale-Up Synthesis of Hexabenzylhexaazaisowurtzitane, an Intermediate in CL-20 Synthesis

Tomasz Gołofit ^*^†

, Paweł Maksimowski^†

, Piotr Szwarc^‡, Tomasz Cegłowski^‡, and Joanna Jefimczyk^†

^† Faculty of Chemistry, Division of High Energetic Materials, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland

^‡Chemical Works “NITRO−CHEM” S.A., Wojska Polskiego 65 A, 85−825 Bydgoszcz, Poland

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00101

*E-mail: tomgol@ch.pw.edu.pl.

http://pubs.acs.org/doi/full/10.1021/acs.oprd.7b00101

After successful synthesis of hexabenzylhexaazaisowurtzitane (HBIW) on a laboratory scale (0.25 L reactor), it was performed on a multilaboratory scale (10 L reactor) and subsequently in an experimental installation in which a 300 L reactor was built. Seven syntheses were carried out in the unit on a pilot scale to produce 250 kg of HBIW. The pilot-scale syntheses ran with a yield comparable to those observed for the processes conducted on a large-laboratory scale. Some modifications were suggested that allowed for reduction of the HBIW weight unit by approximately 50%

HBIW was 89%. FTIR υ (cm^–1): 3022, 2835, 1954, 1669, 1602, 1492, 1451, 1396, 1351, 1302, 1264, 1208, 1169, 1140, 1122, 1072, 1057, 1028, 1017, 986, 926, 896, 828, 792, 781, 749, 732, 698. ¹H NMR (CDCl₃, 400 MHz): δ 7.39–7.42 (m, 30 H, phenyl CH), 4.33 (s, 4 H, CH2), 4.26–4.27 (d, 8 H, CH2), 4.21 (s, 4 H, CH), 3.75 (s, 2, H, CH).

References

Jump up^ 王征, 和霄雯 (2016-04-19). “北理工的爆轰速度中国力量的可靠基石”. 北京理工大学新闻网.
Jump up^ 黎轩平 (2016-04-23). ““我们要在宇宙空间占一个位置！””. 北京理工大学新闻网.
Jump up^ Yirka, Bob (9 September 2011). “University chemists devise means to stabilize explosive CL-20”. Physorg.com. Retrieved 8 July 2012.
Jump up^ Nair, U. R.; Sivabalan, R.; Gore, G. M.; Geetha, M.; Asthana, S. N.; Singh, H. (2005). “Hexanitrohexaazaisowurtzitane (CL-20) and CL-20-based formulations (review)”. Combust. Explos. Shock Waves. 41 (2): 121–132. doi:10.1007/s10573-005-0014-2.
Jump up^ High Power Explosive with Good Sensitivity: A 2:1 Cocrystal of CL-20:HMX, Crystal Growth & Design (American Chemical Society), 2012, 12 (9), pp 4311–4314, DOI: 10.1021/cg3010882, Publication Date (Web): August 7, 2012, accessed 7 September 2012
Jump up^ Powerful new explosive could replace today’s state-of-the-art military explosive, SpaceWar.com, 6 September 2012, accessed 7 September 2012
Jump up^ Angewandte Chemie International Edition
Jump up^ Things I Won’t Work With: Hexanitrohexaazaisowurtzitane

TILOGLIPTIN

June 8, 2017 1:43 pm / Leave a comment

PRESENTING 2 MOLECULES………..I AM NOT SURE WHICH IS TITLE MOLECULE

EMAIL ME amcrasto@gmail.com

Molecular Formula:	C₂₅H₂₇N₇O
Molecular Weight:	441.539 g/mol

2-[(3R)-3alpha-Aminopiperidino]-3-(2-butynyl)-5-(4-methyl-2-quinazolinylmethyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-4-one

CAS 1428445-40-2

REF Bioorganic & Medicinal Chemistry (2013), 21(7), 1749-1755.

NEXT ONE………………

CID 71553372.png

CAS 1415912-31-0

1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-([1,2,5]thiadiazolo[3,4-b]pyridin-5-ylmethyl)-

8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-([1,2,5]thiadiazolo[3,4-b]pyridin-5-ylmethyl)-1H-purine-2,6-dione

8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-1-([1,2,5]thiadiazolo[3,4-b]pyridin-5-ylmethyl)purine-2,6-dione

Molecular Formula:	C₂₁H₂₃N₉O₂S
Molecular Weight:	465.536 g/mol

REF CN 102807568, CN 105315301, WO 2016019868

Salt………..

CAS 1874255-95-4

C₂₁ H₂₃ N₉ O₂ S . C₆ H₈ O₇

1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-([1,2,5]thiadiazolo[3,4-b]pyridin-5-ylmethyl)-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1)

TILOGLIPTIN

HWH-ZGC-2-143

Guangzhou Institutes of Biomedicine and Health

Image result for Guangzhou Institutes of Biomedicine and Health

Chia Tai Tianqing Pharmaceutical Group Co Ltd;

Image result for Chia Tai Tianqing Pharmaceutical Group Co Ltd;
Non-insulin dependent diabetes

Dipeptidyl peptidase IV inhibitor (oral, type 2 diabetes),

DPP-IV inhibitors (oral, type 2 diabetes), Guangzhou Institutes of Biomedicine and Health/Jiangsu Chia Tai Tianqing Pharmaceutical ; HWH-ZGC-2-143 ;

Novel polymorphic forms of thiadiazole derivatives, preferably aglucin, sitagliptin, saxagliptin, vildagliptin, levaratine, useful for treating type II diabetes. Guangzhou Institutes of Biomedicine and Health , in collaboration with Jiangsu Chia Tai Tianqing Pharmaceutical , is investigating tilogliptin , an oral dipeptidyl peptidase IV inhibitor and a pyrrolopyrimidine analog, for treating type 2 diabetes.

As of June 2017, Centaurus BioPharma is developing diabetes therapy, CT-1006 and CT-1005 (in preclinical development) for treating diabetes mellitus.

See WO2016019868, claiming novel citric acid salt of 8-((R)-3-amino-piperidin-1-yl)-1-([1,2,5]-thiadiazolo [3,4-b] pyridine-5methyl)-7-(2-butyn-1-yl)-3-methyl-xanthine, coassigned to Lianyungang Runzhong Pharmaceutical .

PATENT

WO2016019868

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016019868

Chinese Patent Application CN102807568 discloses the use of thiadiazole derivatives DPP-IV inhibitors and their use in the treatment and / or prophylaxis of diseases susceptible to DPP-IV inhibition, particularly in the treatment of type II diabetes. There is still a need for a good thiadiazole derivative DPP-IV inhibitor and a pharmaceutically acceptable salt thereof having good pharmacological and bioavailability.

The contents of the invention

In one aspect, the present application provides 8 – ((R) -3-amino-piperidin-1-yl) -1 – ([1,2,5] thiadiazolo [3,4-b] pyridine- Methyl) -7- (2-butyn-1-yl) -3-methyl-xanthine (having the structure of the following formula I, hereinafter referred to as the compound of formula I).

In another aspect, the present application provides monocarbamates of the compounds of formula I wherein the structural formula is as follows:

PATENT

WO 2017088790

Centaurus BioPharma Co Ltd; Chia Tai Tianqing Pharmaceutical Group Co Ltd

DPP-IV (dipeptidyl peptidase IV) is a serine protease that is expressed in various tissues (eg, liver, lung, intestine, kidney, etc.) in vivo, responsible for endogenous peptides (GLP-1 (7 -36)) metabolic cleavage. However, GLP-1 (7-36) has a variety of beneficial effects in the body, including stimulation of insulin secretion, inhibition of glucagon secretion, promotion of fullness and delayed gastric emptying. Thus, inhibition of DPP-IV can be used to prevent and / or treat diabetes, particularly type II diabetes. There are a variety of DPP-IV inhibitors listed, such as aglucin, sitagliptin, saxagliptin, vildagliptin, levaratine and so on.

Chinese Patent Application CN102807568 discloses a thiadiazole derivative DPP-IV inhibitor as shown in Formula I or Formula II wherein said compound of formula (especially compound 7) has a very good DPP-IV inhibitory activity. In addition, compound 7 also has a very good in vivo metabolic level and a very suitable in vivo half-life, particularly suitable as a DPP-IV inhibitor drug.

In addition to the therapeutic efficacy, the drug developer attempts to provide a suitable form of the active molecule having properties as a drug (e.g., processing, preparation, storage stability, etc.). Therefore, the discovery of the form of the desired nature of the drug development is also essential.

To a 30 L glass autoclave was added 5.5 L of ethanol, 550 g of an intermediate of 1,256 g of (R) 3-aminopiperidine dihydrochloride, 414 g of sodium bicarbonate, stirred and heated to a temperature of 75 ° C to 80 ° C ℃, stirring reaction 4h. TLC (254 nm UV light, methanol: dichloromethane: aqueous ammonia = 1: 10: 0.1, Rf intermediate 1 = 0.7, Rf product = 0.5) was monitored until intermediate 1 was complete, filtered, and ethanol washed. The filtrate 45 ± 5 ℃ under reduced pressure evaporated, add 5L of methylene chloride dissolved, 5L purified water washing; add 5L purified water, 288g citric acid extraction, 2.5L purified water extraction organic phase, combined with water; Methyl chloride and 10L ethanol; add 5L dichloromethane, the temperature control does not exceed 30 degrees, slowly adding sodium hydroxide solution, extraction and separation; organic phase washed with 5L purified water; anhydrous sodium sulfate drying organic phase. Filtered and the filtrate 30 ± 5 ° C evaporated to dryness under reduced pressure to give 372 g of the compound of formula 7 as an amorphous form

Paper

Bioorganic & Medicinal Chemistry (2013), 21(7), 1749-1755

Discovery of potent dipeptidyl peptidase IV inhibitors through pharmacophore hybridization and hit-to-lead optimization

^a Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou 510530, China
^b Jiangsu Chia-Tai Tianqing Pharmaceutical Co. Ltd, No. 8 Julong North Rd., Xinpu Lianyungang, Jiangsu 222006, China
^c State Key Laboratory of Respiratory Disease, Guangzhou 510120, China

https://doi.org/10.1016/j.bmc.2013.01.062

A novel dipeptidyl peptidase IV inhibitor hit (5, IC₅₀ = 0.86 μM) was structurally derived from our recently disclosed preclinical candidate 4 by replacing the cyanobenzyl with a butynyl based on pharmacophore hybridization. A hit-to-lead optimization effort was then initiated to improve its potency. Most N-substituted analogs exhibited good in vitro activity, and compound 18o (IC₅₀ = 1.55 nM) was identified to be a potent dipeptidyl peptidase IV inhibitor with a significantly improved pharmacokinetic properties (bioavailablity: 41% vs 82.9%; T_1/2: 2 h vs 4.9 h).

//////TILOGLIPTIN

N[C@@H]1CCCN(C1)C5=Nc4ccn(Cc3nc2ccccc2c(C)n3)c4C(=O)N5CC#CC

N[C@@H]1CCCN(C1)c5nc4c(C(=O)N(Cc2ccc3nsnc3n2)C(=O)N4C)n5CC#CC

TEGAFUR

June 1, 2017 11:39 am / Leave a comment

Tegafur

CAS 17902-23-7

2,4(1H,3H)-Pyrimidinedione, 5-fluoro-1-(tetrahydro-2-furanyl)-

Molecular Weight,200.17, MF C₈ H₉ F N₂ O₃
172-173 °C

Miyashita, Osamu; Chemical & Pharmaceutical Bulletin 1981, 29(11), PG 3181-90

Uracil, 5-fluoro-1-(tetrahydro-2-furyl)-

Utefos

Venoterpine

WY1559000

YR0450000

5-fluoro-1-tetrahydrofuran-2-ylpyrimidine-2,4(1H,3H)-dione

Carzonal

N1-(2′-Furanidyl)-5-fluorouracil

Synonyms:Ftorafur
ATC:L01BC03

EINECS:241-846-2
LD₅₀:800 mg/kg (M, i.v.); 775 mg/kg (M, p.o.);
685 mg/kg (R, i.v.); 930 mg/kg (R, p.o.);
34 mg/kg (dog, p.o.)

Derivatives, monosodium salt

Formula:C₈H₈FN₂NaO₃
MW:222.15 g/mol
CAS-RN:28721-46-2

Tegafur (INN, BAN, USAN) is a chemotherapeutic prodrug of 5-flourouracil (5-FU) used in the treatment of cancers. It is a component of the combination drug tegafur/uracil. When metabolised, it becomes 5-FU.^[1]

Medical uses

As a prodrug to 5-FU it is used in the treatment of the following cancers:^[2]

Stomach (when combined with gimeracil and oteracil)
Breast (with uracil)
Gallbladder
Lung (specifically adenocarcinoma, typically with uracil)
Colorectal (usually when combined with gimeracil and oteracil)
Head and neck
Liver (with uracil)^[3]
Pancreatic

It is often given in combination with drugs that alter its bioavailability and toxicity such as gimeracil, oteracil or uracil.^[2] These agents achieve this by inhibiting the enzyme dihydropyrimidine dehydrogenase (uracil/gimeracil) or orotate phosphoribosyltransferase (oteracil).^[2]

Image result for tegafur

Adverse effects

The major side effects of tegafur are similar to fluorouracil and include myelosuppression, central neurotoxicity and gastrointestinal toxicity (especially diarrhoea).^[2] Gastrointestinal toxicity is the dose-limiting side effect of tegafur.^[2] Central neurotoxicity is more common with tegafur than with fluorouracil.^[2]

Image result for tegafur

Pharmacogenetics

The dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes 5-fluorouracil, capecitabine, and tegafur.^[4] Genetic variations within the DPD gene (DPYD) can lead to reduced or absent DPD activity, and individuals who are heterozygous or homozygous for these variations may have partial or complete DPD deficiency; an estimated 0.2% of individuals have complete DPD deficiency.^[4]^[5] Those with partial or complete DPD deficiency have a significantly increased risk of severe or even fatal drug toxicities when treated with fluoropyrimidines; examples of toxicities include myelosuppression, neurotoxicity and hand-foot syndrome.^[4]^[5]

Mechanism of action

It is a prodrug to 5-FU, which is a thymidylate synthase inhibitor.^[2]

Pharmacokinetics

It is metabolised to 5-FU by CYP2A6.^[6]^[7]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.^{[§ 1]}

The interactive pathway map can be edited at WikiPathways: “FluoropyrimidineActivity_WP1601”.

Image result for tegafur

Image result for tegafur SYNTHESIS

MASS SPECTRUM

1H NMR

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(3R,9R)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.03,11.05,9]dodecane

(3R,5S,9R,11S)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.03,11.05,9]dodecane

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Cocrystal product with TNT

Scale-Up Synthesis of Hexabenzylhexaazaisowurtzitane, an Intermediate in CL-20 Synthesis

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(3R,9R)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^3,11.0^5,9]dodecane

(3R,5S,9R,11S)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^3,11.0^5,9]dodecane