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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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Development of an Efficient Manufacturing Process for a Key Intermediate in the Synthesis of Edoxaban

Abstract Image

Development of an Efficient Manufacturing Process for a Key Intermediate in the Synthesis of Edoxaban

Process Technology Research Laboratories (PTRL)Daiichi Sankyo Co., Ltd.1-12-1 Shinomiya, Hiratsuka-shi, Kanagawa 254-0014, Japan
Plant Management DepartmentDaiichi Sankyo Chemical Pharma Co., Ltd.477 Takada, Odawara-shi, Kanagawa 250-0216, Japan
§Global Supply Chain – Technology FunctionDaiichi Sankyo, Inc.211 Mt. Airy Road, Basking Ridge, New Jersey 07920, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00413
This article is part of the Japanese Society for Process Chemistry special issue

We report the development of a novel synthetic method to access a key intermediate in the synthesis of edoxaban. The main features of the new synthetic method are an improvement in the approach for the synthesis of a key chiral bromolactone, application of an interesting cyclization reaction utilizing neighboring group participation to construct a differentially protected 1,2-cis-diamine, and implementation of plug-flow reactor technology to enable the reaction of an unstable intermediate on multihundred kilogram scale. The overall yield for the preparation of edoxaban was significantly increased by implementing these changes and led to a more efficient and environmentally friendly manufacturing process.


Viloxazine, ヴィロキサジン;

Viloxazine structure.svg

ChemSpider 2D Image | Viloxazine | C13H19NO3


  • Molecular FormulaC13H19NO3
  • Average mass237.295 Da

update FDA APPROVED 2021/4/2, Qelbree, Viloxazine hydrochloride

C13H19NO3. HCl
Mol weight
256-281-7 [EINECS]
46817-91-8 free [RN], Hcl 35604-67-2
Emovit [Wiki]
Morpholine, 2-((2-ethoxyphenoxy)methyl)-
Morpholine, 2-[(2-ethoxyphenoxy)methyl]-
Viloxazine hydrochloride.png
Viloxazine hydrochloride OQW30I1332 35604-67-2


FORM A , B US226136693US2011032013




Viloxazine (trade names VivalanEmovitVivarint and Vicilan) is a morpholine derivative and is a selective norepinephrine reuptake inhibitor (NRI). It was used as an antidepressant in some European countries, and produced a stimulant effect that is similar to the amphetamines, except without any signs of dependence. It was discovered and brought to market in 1976 by Imperial Chemical Industries and was withdrawn from the market in the early 2000s for business reasons.

Image result for viloxazine synthesis


Image result for viloxazine synthesis


US 20180265482

 Viloxazine ((R,S)-2-[(2-ethoxyphenoxy)methyl]morpholine]) is a bicyclic morpholine derivative, assigned CAS No. 46817-91-8 (CAS No. 35604-67-2 for the HCl salt). It is characterized by the formula C 1319NO 3, with a molecular mass of 237.295 g/mol. Viloxazine has two stereoisomers, (S)-(−)- and (R)-(+)-isomer, which have the following chemical structures:
 (MOL) (CDX)
      Viloxazine is known to have several desirable pharmacologic uses, including treatment of depression, nocturnal enuresis, narcolepsy, sleep disorders, and alcoholism, among others. In vivo, viloxazine acts as a selective norepinephrine reuptake inhibitor (“NRI”).
      Between the two stereoisomers, the (S)-(−)-isomer is known to be five times as pharmacologically active as the (R)-(+)-isomer. See, e.g., “Optical Isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4 oxazine (viloxazine) and Related Compounds” (Journal of Medicinal Chemistry, Jan. 9, 1976, 19(8); 1074) in which it is disclosed that optical isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine (viloxazine) and 2-(3-methoxyphenoxymethyl)tetrahydro-1,4-oxazine were prepared and absolute configurations assigned. The synthesis of optical isomers of viloxazine analogs of known configuration was accomplished by resolution of the intermediate 4-benzyl-2-(p-toluenesulfonyloxymethyl)tetrahydro-1,4-oxazine isomers.
      Some unsatisfactory methods of synthesizing viloxazine are known in the art. For example, as disclosed in U.S. Pat. No. 3,714,161, viloxazine is prepared by reacting ethoxyphenol with epichlorohydrin to afford the epoxide intermediate 1-(2-ethoxyphenoxy)-2,3-epoxypropane. This epoxide intermediate is then treated with benzylamine followed with chloroacetyl chloride. The resulting morpholinone is then reduced by lithium aluminum hydride and then by Pd/C-catalyzed hydrogenation to yield viloxazine free base.
      Yet another unsatisfactory synthesis of viloxazine is disclosed in U.S. Pat. No. 3,712,890, which describes a process to prepare viloxazine HCl, wherein the epoxide intermediate, 1-(2-ethoxyphenoxy)-2,3-epoxypropane, is reacted with 2-aminoethyl hydrogen sulfate in ethanol in the presence of sodium hydroxide to form viloxazine free base. The product is extracted with diethyl ether from the aqueous solution obtained by evaporating the solvent in the reaction mixture then adding water to the residue. The ethereal extract is dried over a drying agent and the solvent is removed. Viloxazine HCl salt is finally obtained by dissolving the previous residue in isopropanol, concentrated aqueous HCl, and ethyl acetate followed by filtration.
      The foregoing methods of synthesizing viloxazine suffer from a number of deficiencies, such as low reaction yield and unacceptably large amount of impurities in the resulting product. Effective elimination or removal of impurities, especially those impurities possessing genotoxicity or other toxicities, is critical to render safe pharmaceutical products. For example, certain reagents traditionally utilized in viloxazine HCl preparation, such as epichlorohydrin and 2-aminoethyl hydrogen sulfate, present a special problem due to their toxicity. There is a need for effective methods to remove or limit harmful impurities down to a level that is appropriate and safe according to contemporary sound medical standards and judgment. Accordingly, a continuing and unmet need exists for new and improved methods of manufacturing viloxazine and its various salts to yield adequate quantities of pharmacologically desirable API with predictable and reliable control of impurities.
     Polymorph control is also an important aspect of producing APIs and their associated salts that are used in pharmaceutical products. However, no polymorphs of viloxazine HCl have previously been disclosed. A need therefore exists for new polymorphic forms of viloxazine that have improved pharmacological properties.


WO 2011130194


For the sake of convenience and without putting any limitations thereof, the methods of manufacture of viloxazine have been separated into several steps, each step being disclosed herein in a multiplicity of non-limiting embodiments. These steps comprise Step 1, during which 2-ethoxyphenol and epichlorhydrin are reacted to produce l-(2-ethoxyphenoxy)-2,3-epoxypropane (Epoxide 1); Step 2, during which l-(2-ethoxyphenoxy)-2,3-epoxypropane (Epoxide 1) is converted into viloxazine base which is further converted into viloxazine salt, and Step 3, during which viloxazine salt is purified/recrystallized, and various polymorphic forms of viloxazine salt are prepared.

The above-mentioned steps will be considered below in more details.

[0031] The process of the Step 1 may be advantageously carried out in the presence of a phase-transfer catalyst to afford near quantitative yield of l-(2-ethoxyphenoxy)-2,3-epoxypropane. Alternatively, the process may make use of a Finkelstein catalyst described in more details below. Additionally, the reaction may take place without the use of the catalyst.

 FIG. 1, depicted below, schematically illustrates the preparation of l-(2-ethoxyphenoxy)-2,3-epoxypropane (“Epoxide 1”) in accordance with Step I of an exemplary synthesis of viloxazine:


Epoxide 1

In one embodiment of the Step 1, the preparation of l-(2-ethoxyphenoxy)-2,3-epoxypropane (epoxide 1) can be effected by the use of a phase transfer catalyst in the presence of a solid or liquid base with a solution of a corresponding phenol and epichlorohydrin in one or more solvents (Fig. 1). The phase transfer catalyst can be selected from ammonium salts, such as benzyltriethylammonium salts, benzyltrimethylammonium salts, and tetrabutylammonium salts, phosphonium salts, guanidinium salts, crown ether, polyethylene glycol, polyethylene glycol ether, or polyethylene glycol ester, or other phase transfer catalysts know in the art. The solid or liquid base can be a carbonate such as alkali carbonate, NaOH, KOH, LiOH, LiOH/LiCl, amines such as mono-, di- or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine), DMAP, or other appropriate base. The solvents used in the solution of a corresponding phenol and epichlorohydrin include but are not limited to ethers such as methyl t-butyl ether, ketones, non-substituted or substituted aromatic solvents (xylene), halo-substituted hydrocarbons (e.g. CH2C12, CHC13), THF, DMF, dioxanes, non-substituted and substituted pyridines, acetonitrile, pyrrolidones, nitromethane , or other appropriate solvent. Additional catalyst, such as, for example, Finkelstein catalyst, can also be used in the process of this embodiment. This reaction preferably takes place at an elevated temperature. In one variation of the embodiment, the temperature is above 50°C. In another variation, epichlorohydrin, potassium carbonate, and a phase transfer catalyst are mixed with a solution of 2-ethoxyphenol in a solvent at an elevated temperature, such as 50 – 60°C. After the reaction is complete, the reaction mixture can be washed with water, followed by work-up procedures known in the art. Variations of this embodiment of the invention are further disclosed in Examples 1-8.

[0033] In one variation of the above embodiment of the Step 1 , Epoxide 1 is prepared by reacting 2-ethoxyphenol and epichlorohydrin in a solvent in the presence of two different catalysts, and a base in a solid state. The first catalyst is a phase transfer catalyst as described above; the second catalyst is a Finkelstein reaction catalyst. Without putting any limitation

hereon, metal iodide and metal bromide salts, such as potassium iodide, may be used as an example of a Finkelstein catalyst. The phase transfer catalyst and a solvent may be selected from any phase transfer catalysts and solvents known in the art. Potassium carbonate may be used as a non-limiting example of a solid base. Using the solid base in a powdered form may be highly beneficial due to the greatly enhanced interface and limiting the side reactions. This variation of the embodiment is further illustrated by Example 9. In another variation of the embodiment, liquid base such as triethylamine can be used to replace the solid base.

[0034] In a different embodiment of Step 1 , 2-ethoxyphenol and epichlorohydrin are reacted in a solvent-free system that comprises a solid or liquid base, a phase transfer catalyst as listed above and a Finkelstein catalyst.

[0035] FIG. 2, depicted below, schematically illustrates the preparation of l-(2-ethoxyphenoxy)-2,3-epoxypropane (“Epoxide 1”) in accordance with the Step I of another exemplary synthesis of viloxazine ( biphasic):

STEP I (alternative embodiment):

In this embodiment of Step 1, illustrated in Fig. 2, Epoxide 1 can be prepared by reacting epichlorohydrin with 2-ethoxyphenol in the presence of a catalytic amount of a phase transfer catalyst without the use of solvents at elevated temperatures in a two-stage process to afford near quantitative yield of l-(2-ethoxyphenoxy)-2,3-epoxypropane with very few side products. This embodiment of the invention is further illustrated by a non-limiting Example 12. The phase transfer catalyst for this embodiment can be selected from ammonium salts such as benzyltriethylammonium salts, benzyltrimethylammonium salts, tetrabutylammonium salts, etc; phosphonium salts, guanidinium salts, crown ether, polyethylene glycol, polyethylene glycol ether, or polyethylene glycol ester, or other phase transfer catalysts know in the art. The first stage of the process of this embodiment may take place without a solvent in a presence of a large excess of epichlorohydrin. This stage is followed by a de-chlorination stage, before or after

removal of excess epichlorohydrin, using a base and a solvent. The reaction produces l-(2-ethoxyphenoxy)-2,3-epoxypropane in high yield. Example of the bases used herein include but are not limited to NaOH, KOH, LiOH, LiOH/LiCl, K2C03, Na2C03, amines such as mono-, di-or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine etc.), DMAP. In one variation of this embodiment of Step 1, the phase transfer catalyst may be used only at the de-chlorination stage of the process. The de-chlorination stage can be carried out in a biphasic system or in a single phase system. For a biphasic system, it can be an organic-aqueous liquid biphasic system, or a liquid-solid biphasic system. Solvents that are useful for the process include but are not limited to non-substituted and substituted aromatic solvents (e.g. toluene, benzene, chlorobenzene, dimethylbenzene, xylene), halo-substituted hydrocarbons (e.g. CH2C12, CHC13), THF, dioxanes, DMF, DMSO, non-substituted and substituted pyridines, ketones, pyrrolidones, ethers, acetonitrile, nitromethane. As mentioned above, this process takes place at the elevated temperature. In one variation of the embodiment, the temperature is above 60°C. In another variation, 2-ethoxyphenol and epichlorohydrin are heated to 60 – 90°C for a period of time in the presence of phase transfer catalyst. Excess of epichlorohydrin is removed and the residue is dissolved in a solvent such as toluene or benzene treated with an aqueous base solution, such as NaOH, KOH, LiOH, LiOH/LiCl. In yet another variation of the embodiment, the residue after epichlorohydrin removal can be dissolved in one or more of the said solvent and treated with a base (solid or liquid but not an aqueous solution) and optionally a second phase transfer catalyst, optionally at elevated temperatures.

[0036] In yet another embodiment of Step 1 , Epoxide 1 can also be prepared by using a catalyst for a so-called Finkelstein reaction in the presence of a Finkelstein catalyst but without the need to use a phase transfer catalyst. Finkelstein catalysts useful herein include metal iodide salts and metal bromide salts, among others. In one variation of this embodiment, 2-ethoxyphenol and epichlorohydrin are dissolved in a polar aprotic solvent such as DMF, and a catalytic amount of an iodide such as potassium iodide and a base, as solid or liquid, are used. Preferably, the base is used as a solid, such as potassium carbonate powder. This embodiment is further illustrated by the Example 11.

[0037] In the alternative embodiment of Step 1 , Epoxide 1 can also be prepared by a different method that comprises reacting epichlorohydrin and the corresponding phenol in the presence of a base at a temperature lower than the ambient temperature, especially when a base solution is used, and without the use of a phase transfer catalyst. This embodiment is illustrated by the Example 10.

[0038] A very high, almost quantitative, yield of 1 -(2-ethoxyphenoxy)-2,3-epoxypropane can be obtained through realizing the above-described embodiments of Step 1 , with less impurities generated in Epoxide 1.

[0039] Epoxide 1 , produced in Step 1 as described above, is used to prepare viloxazine base (viloxazine), which is further converted into viloxazine salt through the processes of Step 2.

[0040] FIG. 3, depicted below, schematically illustrates the preparation of viloxazine

(“Step Ila”) and the preparation of viloxazine hydrochloride (“Step lib”), as well as their purification (“Step III”) in accordance with another example embodiment hereof:


Hydrogen Sulfate

STEP lib:

Step III:


Viloxazine free base ► Viloxazine salt

Wash/ raction


Purified viloxazine salt

In the embodiment of Step 2, illustrated in Fig. 3, the preparation of viloxazine base is achieved by reacting the Epoxide 1 intermediate prepared in Step 1 and aminoethyl hydrogen sulfate in presence of a large excess of a base as illustrated by the Examples 5-7 and 14. The base may be present as a solid or in a solution. Preferably, the molar ratio of the base to Epoxide 1 is more than 10. More preferably the ratio is more than 12. Even more preferably, the ratio is between 15 and 40. It was unexpectedly discovered that the use of a higher ratio of a base results in a faster reaction, less impurities, and lower reaction temperature.

[0041] Further advantages may be offered by a specific variation of this embodiment, wherein the base is added to the reaction mixture in several separate steps. For example, a third of the base is added to the reaction mixture, and the mixture is stirred for a period of time. Then the rest of the base is added followed by additional stirring. Alternatively, half of the base is added initially followed by the second half after some period of time, or the base is added in three different parts separated by periods of time. The bases used herein include but are not limited to NaOH, KOH, LiOH, LiOH/LiCl, K2C03, Na2C03, amines such as mono-, di- or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine), DMAP, and combinations thereof. . In one embodiment of the invention, the base is KOH. In another embodiment, the base is NaOH. In a further embodiment, the base is K2C03 powder. In yet further embodiment, the base is triethylamine. This embodiment is illustrated further by

Examples 13,15 and 16.

[0042] In another exemplary embodiment of Step 2, viloxazine is produced by cyclization of novel intermediate compound “Diol 1 ,” which is made from Epoxide 1 and N-benzyl-aminoethanol. This method allows one to drastically reduce the use of potentially toxic materials in the manufacturing process, completely eliminating some of them such as aminoethyl hydrogen sulfate. The first stage of the reaction results in the formation of an intermediate of Formula 3 (Diol 1), which is a new, previously unidentified compound.

[0043] Formula 3

Diol 1

FIG. 4, depicted below, schematically illustrates the preparation of viloxazine and its salts via “Diol 1” in accordance with another exemplary embodiment hereof (Bn = benzyl, Et = ethyl):

Viloxazine HCI

As illustrated in Fig. 4, Diol 1 is turned into N-benzyl viloxazine by cyclization. Removal of the benzyl protective group yields viloxazine base. Similarly, FIG. 5, depicted below, schematically illustrates the cyclization of Diol 1, as well as some side-reactions thereof.


Viloxazine hydrochloride was used in some European countries for the treatment of clinical depression.[4][5]

Side effects

Side effects included nausea, vomiting, insomnia, loss of appetite, increased erythrocyte sedimentation, EKG and EEG anomalies, epigastric pain, diarrhea, constipationvertigoorthostatic hypotensionedema of the lower extremities, dysarthriatremor, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminasesseizure, (there were three cases worldwide, and most animal studies (and clinical trials that included epilepsy patients) indicated the presence of anticonvulsant properties, so was not completely contraindicated in epilepsy,[6]) and increased libido.[7]

Drug interactions

Viloxazine increased plasma levels of phenytoin by an average of 37%.[8] It also was known to significantly increase plasma levels of theophylline and decrease its clearance from the body,[9] sometimes resulting in accidental overdose of theophylline.[10]

Mechanism of action

Viloxazine, like imipramine, inhibited norepinephrine reuptake in the hearts of rats and mice; unlike imipramine, it did not block reuptake of norepinephrine in either the medullae or the hypothalami of rats. As for serotonin, while its reuptake inhibition was comparable to that of desipramine (i.e., very weak), viloxazine did potentiate serotonin-mediated brain functions in a manner similar to amitriptyline and imipramine, which are relatively potent inhibitors of serotonin reuptake.[11] Unlike any of the other drugs tested, it did not exhibit any anticholinergic effects.[11]

It was also found to up-regulate GABAB receptors in the frontal cortex of rats.[12]

Chemical properties

It is a racemic compound with two stereoisomers, the (S)-(–)-isomer being five times as pharmacologically active as the (R)-(+)-isomer.[13]


Viloxazine was discovered by scientists at Imperial Chemical Industries when they recognized that some beta blockers inhibited serotonin reuptake inhibitor activity in the brain at high doses. To improve the ability of their compounds to cross the blood brain barrier, they changed the ethanolamine side chain of beta blockers to a morpholine ring, leading to the synthesis of viloxazine.[14]:610[15]:9 The drug was first marketed in 1976.[16] It was never approved by the FDA,[5] but the FDA granted it an orphan designation (but not approval) for cataplexy and narcolepsy in 1984.[17] It was withdrawn from markets worldwide in 2002 for business reasons.[14][18]

As of 2015, Supernus Pharmaceuticals was developing formulations of viloxazine as a treatment for ADHD and major depressive disorder under the names SPN-809 and SPN-812.[19][20]


Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bedwetting) in children, both of those times versus imipramine.[21][22] By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.[23]

In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM[24] without really improving daytime somnolence.[25]

In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy.[18]

Viloxazine has also been studied for the treatment of alcoholism, with some success.[26]

While viloxazine may have been effective in clinical depression, it did relatively poorly in a double-blind randomized controlled trial versus amisulpride in the treatment of dysthymia.[27]

It is also under investigation as a treatment for attention deficit hyperactivity disorder.[28]


  1. ^ Bouchard JM, Strub N, Nil R (October 1997). “Citalopram and viloxazine in the treatment of depression by means of slow drop infusion. A double-blind comparative trial”. Journal of Affective Disorders46 (1): 51–8. doi:10.1016/S0165-0327(97)00078-5PMID 9387086.
  2. ^ Case DE, Reeves PR (February 1975). “The disposition and metabolism of I.C.I. 58,834 (viloxazine) in humans”. Xenobiotica5 (2): 113–29. doi:10.3109/00498257509056097PMID 1154799.
  3. ^ “SID 180462– PubChem Substance Summary”. Retrieved 5 November 2005.
  4. ^ Pinder, RM; Brogden, RN; Speight, ™; Avery, GS (June 1977). “Viloxazine: a review of its pharmacological properties and therapeutic efficacy in depressive illness”. Drugs13 (6): 401–21. doi:10.2165/00003495-197713060-00001PMID 324751.
  5. Jump up to:a b Dahmen, MM, Lincoln, J, and Preskorn, S. NARI Antidepressants, pp 816-822 in Encyclopedia of Psychopharmacology, Ed. Ian P. Stolerman. Springer-Verlag Berlin Heidelberg, 2010. ISBN 9783540687061
  6. ^ Edwards JG, Glen-Bott M (September 1984). “Does viloxazine have epileptogenic properties?”Journal of Neurology, Neurosurgery, and Psychiatry47 (9): 960–4. doi:10.1136/jnnp.47.9.960PMC 1027998PMID 6434699.
  7. ^ Chebili S, Abaoub A, Mezouane B, Le Goff JF (1998). “Antidepressants and sexual stimulation: the correlation” [Antidepressants and sexual stimulation: the correlation]. L’Encéphale (in French). 24 (3): 180–4. PMID 9696909.
  8. ^ Pisani F, Fazio A, Artesi C, et al. (February 1992). “Elevation of plasma phenytoin by viloxazine in epileptic patients: a clinically significant drug interaction”Journal of Neurology, Neurosurgery, and Psychiatry55 (2): 126–7. doi:10.1136/jnnp.55.2.126PMC 488975PMID 1538217.
  9. ^ Perault MC, Griesemann E, Bouquet S, Lavoisy J, Vandel B (September 1989). “A study of the interaction of viloxazine with theophylline”. Therapeutic Drug Monitoring11 (5): 520–2. doi:10.1097/00007691-198909000-00005PMID 2815226.
  10. ^ Laaban JP, Dupeyron JP, Lafay M, Sofeir M, Rochemaure J, Fabiani P (1986). “Theophylline intoxication following viloxazine induced decrease in clearance”. European Journal of Clinical Pharmacology30 (3): 351–3. doi:10.1007/BF00541543PMID 3732375.
  11. Jump up to:a b Lippman W, Pugsley TA (August 1976). “Effects of viloxazine, an antidepressant agent, on biogenic amine uptake mechanisms and related activities”. Canadian Journal of Physiology and Pharmacology54 (4): 494–509. doi:10.1139/y76-069PMID 974878.
  12. ^ Lloyd KG, Thuret F, Pilc A (October 1985). “Upregulation of gamma-aminobutyric acid (GABA) B binding sites in rat frontal cortex: a common action of repeated administration of different classes of antidepressants and electroshock”The Journal of Pharmacology and Experimental Therapeutics235 (1): 191–9. PMID 2995646.
  13. ^ Danchev ND, Rozhanets VV, Zhmurenko LA, Glozman OM, Zagorevskiĭ VA (May 1984). “Behavioral and radioreceptor analysis of viloxazine stereoisomers” [Behavioral and radioreceptor analysis of viloxazine stereoisomers]. Biulleten’ Eksperimental’noĭ Biologii i Meditsiny (in Russian). 97 (5): 576–8. PMID 6326891.
  14. Jump up to:a b Williams DA. Antidepressants. Chapter 18 in Foye’s Principles of Medicinal Chemistry, Eds. Lemke TL and Williams DA. Lippincott Williams & Wilkins, 2012. ISBN 9781609133450
  15. ^ Wermuth, CG. Analogs as a Means of Discovering New Drugs. Chapter 1 in Analogue-based Drug Discovery. Eds.IUPAC, Fischer, J., and Ganellin CR. John Wiley & Sons, 2006. ISBN 9783527607495
  16. ^ Olivier B, Soudijn W, van Wijngaarden I. Serotonin, dopamine and norepinephrine transporters in the central nervous system and their inhibitors. Prog Drug Res. 2000;54:59-119. PMID 10857386
  17. ^ FDA. Orphan Drug Designations and Approvals: Viloxazine Page accessed August 1, 2-15
  18. Jump up to:a b Vignatelli L, D’Alessandro R, Candelise L. Antidepressant drugs for narcolepsy. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003724. Review. PMID 18254030
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  20. ^ Supernus. Psychiatry portfolio Page accessed August 1, 2015
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  22. ^ ^ Yurdakök M, Kinik E, Güvenç H, Bedük Y (1987). “Viloxazine versus imipramine in the treatment of enuresis”. The Turkish Journal of Pediatrics29 (4): 227–30. PMID 3332732.
  23. ^ Libert MH (1990). “The use of viloxazine in the treatment of primary enuresis” [The use of viloxazine in the treatment of primary enuresis]. Acta Urologica Belgica (in French). 58 (1): 117–22. PMID 2371930.
  24. ^ Guilleminault C, Mancuso J, Salva MA, et al. (1986). “Viloxazine hydrochloride in narcolepsy: a preliminary report”. Sleep9 (1 Pt 2): 275–9. PMID 3704453.
  25. ^ Mitler MM, Hajdukovic R, Erman M, Koziol JA (January 1990). “Narcolepsy”Journal of Clinical Neurophysiology7 (1): 93–118. doi:10.1097/00004691-199001000-00008PMC 2254143PMID 1968069.
  26. ^ Altamura AC, Mauri MC, Girardi T, Panetta B (1990). “Alcoholism and depression: a placebo controlled study with viloxazine”. International Journal of Clinical Pharmacology Research10 (5): 293–8. PMID 2079386.
  27. ^ León CA, Vigoya J, Conde S, Campo G, Castrillón E, León A (March 1994). “Comparison of the effect of amisulpride and viloxazine in the treatment of dysthymia” [Comparison of the effect of amisulpride and viloxazine in the treatment of dysthymia]. Acta Psiquiátrica Y Psicológica de América Latina (in Spanish). 40 (1): 41–9. PMID 8053353.
  28. ^ Mattingly, GW; Anderson, RH (December 2016). “Optimizing outcomes in ADHD treatment: from clinical targets to novel delivery systems”. CNS Spectrums21 (S1): 45–59. doi:10.1017/S1092852916000808PMID 28044946.
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Clinical data
Routes of
By mouthintravenous infusion[1]
ATC codeN06AX09 (WHO)
Legal status
Legal statusIn general: uncontrolled
Pharmacokinetic data
Elimination half-life2–5 hours
IUPAC name[show]
CAS Number46817-91-8  35604-67-2 (HCl salt)
PubChem CID5666
ECHA InfoCard100.051.148 
Chemical and physical data
Molar mass237.295 g/mol g·mol−1
3D model (JSmol)Interactive image
ChiralityRacemic mixture
InChI[hide]InChI=1S/C13H19NO3/c1-2-15-12-5-3-4-6-13(12)17-10-11-9-14-7-8-16-11/h3-6,11,14H,2,7-10H2,1H3 Key:YWPHCCPCQOJSGZ-UHFFFAOYSA-N 

/////////////////Viloxazine, ヴィロキサジン , Emovit, Vivalan, Emovit, Vivarint, Vicilan

Macimorelin acetate


ChemSpider 2D Image | Macimorelin | C26H30N6O3



  • Molecular FormulaC26H30N6O3
  • Average mass474.555 Da

CAS  381231-18-1

Chemical Formula: C26H30N6O3

Exact Mass: 474.23794

Molecular Weight: 474.55480

Elemental Analysis: C, 65.80; H, 6.37; N, 17.71; O, 10.11

381231-18-1 [RN]
D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-

CAS 945212-59-9 (Macimorelin acetate)

(2R)-2-(2-amino-2-methylpropanamido)-3-(1H-indol-3-yl)-N-[(1R)-2-(1H-indol-3-yl)-1-formamidoethyl]propanamide; acetic acid


USAN (ab-26)

ARD 07
D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-, acetate (1:1) [ACD/Index Name]
EP 1572

Diagnostic agent for adult growth hormone deficiency (AGHD)
1. D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-, acetate (1:1)
2. N2-(2-amino-2-methylpropanoyl-N1-[(1R)-1-formamido-2-(1H-indol-3-yl)ethyl]- D-tryptophanamide acetate


Aeterna Zentaris GmbH
D-87575, EP 1572, ARD 07

Macimorelin (also known as AEZS-130, EP-1572) is a novel synthetic small molecule, acting as a ghrelin agonist, that is orally active and stimulates the secretion of growth hormone (GH). Based on results of Phase 1 studies, AEZS-130 has potential applications for the treatment of cachexia, a condition frequently associated with severe chronic diseases such as cancer, chronic obstructive pulmonary disease and AIDS. In addition to the therapeutic application, a Phase 3 trial with AEZS-130 as a diagnostic test for growth hormone deficiencies in adults has been completed.

QUEBEC, Nov. 5, 2013 /PRNewswire/ – Aeterna Zentaris Inc. (the “Company”) today announced that it has submitted a New Drug Application (“NDA”) to the U.S. Food and Drug Administration (“FDA”) for its ghrelin agonist, macimorelin acetate (AEZS-130). Phase 3 data have demonstrated that the compound has the potential to become the first orally-approved product that induces growth hormone release to evaluate adult growth hormone deficiency (“AGHD”), with accuracy comparable to available intravenous and intramuscular testing procedures.  read at

macimorelin (JMV 1843), a ghrelin-mimetic growth hormone secretagogue in Phase III for adult growth hormone deficiency (AGHD)

Macimorelin, a growth hormone modulator, is currently awaiting registration in the U.S. by AEterna Zentaris as an oral diagnostic test of adult growth hormone deficit disorder. The company is also developing the compound in phase II clinical trials for the treatment of cancer related cachexia. The compound was being codeveloped by AEterna Zentaris and Ardana Bioscience; however, the trials underway at Ardana were suspended in 2008 based on a company strategic decision. AEterna Zentaris owns the worldwide rights of the compound. In 2007, orphan drug designation was assigned by the FDA for the treatment of growth hormone deficit in adults.

Macimorelin (INN), or Macrilen (trade name) is a drug being developed by Æterna Zentaris for use in the diagnosis of adult growth hormone deficiency. Macimorelin acetate, the salt formulation, is a synthetic growth hormone secretagogue receptor agonist.[1]Macimorelin acetate is described chemically as D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-acetate.

As of January 2014, it was in Phase III clinical trials.[2] The phase III trial for growth hormone deficiency is expected to be complete in December 2016.[3]

As of December 2017, it became FDA-approved as a method to diagnose growth hormone deficiency.[4] Traditionally, growth hormone deficiency was diagnosed via means of insulin tolerance test (IST) or glucagon stimulation test (GST). These two means are done parenterally, whereas Macrilen boasts an oral formulation for ease of administration for patients and providers.

Macimorelin is a growth hormone secretagogue receptor (ghrelin receptor) agonist causing release of growth hormone from the pituitary gland.[5][6][7]

Macimorelin, a novel and orally active ghrelin mimetic that stimulates GH secretion, is used in the diagnosis of adult GH deficiency (AGHD). More specifically, macimorelin is a peptidomimetic growth hormone secretagogue (GHS) that acts as an agonist of GH secretagogue receptor, or ghrelin receptor (GHS-R1a) to dose-dependently increase GH levels [3]. Growth hormone secretagogues (GHS) represent a new class of pharmacological agents which have the potential to be used in numerous clinical applications. They include treatment for growth retardation in children and cachexia associated with chronic disease such as AIDS and cancer.

Growth hormone (GH) is classically linked with linear growth during childhood. In deficiency of this hormone, AGHD is commonly associated with increased fat mass (particularly in the abdominal region), decreased lean body mass, osteopenia, dyslipidemia, insulin resistance, and/or glucose intolerance overtime. In addition, individuals with may be susceptible to cardiovascular complications from altered structures and function [5]. Risk factors of AGHD include a history of childhood-onset GH deficiency or with hypothalamic/pituitary disease, surgery, or irradiation to these areas, head trauma, or evidence of other pituitary hormone deficiencies [3]. While there are various therapies available such as GH replacement therapy, the absence of panhypopituitarism and low serum IGF-I levels with nonspecific clinical symptoms pose challenges to the detection and diagnosis of AGHD. The diagnosis of AGHD requires biochemical confirmation with at least 1 GH stimulation test [3]. Macimorelin is clinically useful since it displays good stability and oral bioavailability with comparable affinity to ghrelin receptor as its endogenous ligand. In clinical studies involving healthy subjects, macimorelin stimulated GH release in a dose-dependent manner with good tolerability [3].

Macimorelin, developed by Aeterna Zentaris, was approved by the FDA in December 2017 under the market name Macrilen for oral solution.

New active series of growth hormone secretagogues
J Med Chem 2003, 46(7): 1191

WO 2001096300

WO 2007093820


J Med Chem 2003, 46(7): 1191

Abstract Image


Synthetic Pathway for JMV 1843 and Analoguesa

a Reagents and conditions:  (a) IBCF, NMM, DME, 0 °C; (b) NH4OH; (c) H2, Pd/C, EtOH, HCl; (d) BOP, NMM, DMF, Boc-(d)-Trp-OH; (e) Boc2O, DMAP cat., anhydrous CH3CN; (f) BTIB, pyridine, DMF/H2O; (g) 2,4,5-trichlorophenylformate, DIEA, DMF; (h) TFA/anisole/thioanisole (8:1:1), 0 °C; (i) BOP, NMM, DMF, Boc-Aib-OH; (j) TFA/anisole/thioanisole (8:1:1), 0 °C; (k) RP preparative HPLC.

TFA, H-Aib-(d)-Trp-(d)-gTrp-CHO (7). 6 (1 g, 1.7 mmol) was dissolved in a mixture of trifluoroacetic acid (8 mL), anisole (1 mL), and thioanisole (1 mL) for 30 min at 0 °C. The solvents were removed in vacuo, the residue was stirred in ether, and the precipitated TFA, H-Aib-(d)-Trp-(d)-gTrp-CHO was filtered. 7 was purified by preparative HPLC and obtained in 52% yield. 1H NMR (400 MHz, DMSO-d6) + correlation 1H−1H:  δ 1.21 (s, 3H, CH3 (Aib)), 1.43 (s, 3H, CH3(Aib)), 2.97 (m, 2H, (CH2)β), 3.1 (m, 2H, (CH2)β), 4.62 (m, 1H, (CH)αA and (CH)αB), 5.32 (q, 0.4H, (CH)α‘B), 5.71 (q, 0.6H, (CH)α‘A), 7.3 (m, 4H, H5 and H6(2 indoles)), 7.06−7.2 (4d, 2H, H2A and H2B (2 indoles)), 7.3 (m, 2H, H4 or H7 (2 indoles)), 7.6−7.8 (4d, 2H, H4A and H4B or H7A and H7B), 7.97 (s, 3H, NH2 (Aib) and CHO (formyl)), 8.2 (d, 0.4H, NH1B (diamino)), 8.3 (m,1H, NHA and NHB), 8.5 (d, 0.6H, NH1A (diamino)), 8.69 (d, 0.6H, NH2A (diamino)), 8.96 (d, 0.4H, NH2B(diamino)), 10.8 (s, 0.6H, N1H1A (indole)), 10.82 (s, 0.4H, N1H1B (indole)), 10.86 (s, 0.6H, N1H2A (indole)), 10.91 (s, 0,4H, N1H2B (indole)). MS (ES), m/z:  475 [M + H]+, 949 [2M + H]+. HPLC tR:  16.26 min (conditions A).


The inventors have now found that the oral administration of growth hormone secretagogues (GHSs) EP 1572 and EP 1573 can be used effectively and reliably to diagnose GHD.

EP 1572 (Formula I) or EP 1573 (Formula II) are GHSs (see WO 01/96300, Example 1 and Example 58 which are EP 1572 and EP 1573, respectively) that may be given orally.

Figure US08192719-20120605-C00001

EP 1572 and EP 1573 can also be defined as H-Aib-D-Trp-D-gTrp-CHO and H-Aib-D-Trp-D-gTrp-C(O)NHCH2CH3. Wherein, His hydrogen, Aib is aminoisobutyl, D is the dextro isomer, Trp is tryptophan and gTrp is a group of Formula III:

Figure US08192719-20120605-C00002


H-Aib-D-Trp-D-gTrp-CHO: Figure US06861409-20050301-C00007

Example 1 H-Aib-D-Trp-D-gTrp-CHO

Total synthesis (percentages represent yields obtained in the synthesis as described below):

Figure US06861409-20050301-C00010


Z-D-Trp-OH (8.9 g; 26 mmol; 1 eq.) was dissolved in DME (25 ml) and placed in an ice water bath to 0° C. NMM (3.5 ml; 1.2 eq.), IBCF (4.1 ml; 1.2 eq.) and ammonia solution 28% (8.9 ml; 5 eq.) were added successively. The mixture was diluted with water (100 ml), and the product Z-D-Trp-NHprecipitated. It was filtered and dried in vacuo to afford 8.58 g of a white solid.


C19H19N3O3, 337 g.mol−1.

Rf=0.46 {Chloroform/Methanol/Acetic Acid (180/10/5)}.

1H NMR (250 MHZ, DMSO-d6): δ 2.9 (dd, 1H, Hβ, Jββ′=14.5 Hz; Jβα=9.8 Hz); 3.1 (dd, 1H, Hβ′, Jβ′β=14.5 Hz; Jβ′α=4.3 Hz); 4.2 (sextuplet, 1H, Hα); 4.95 (s, 2H, CH2(Z); 6.9-7.4 (m, 11H); 7.5 (s, 1H, H2); 7.65 (d, 1H, J=7.7 Hz); 10.8 (s, 1H, N1H).

Mass Spectrometry (Electrospray), m/z 338 [M+H]+, 360 [M+Na]+, 675 [2M+H]+, 697 [2M+Na]+.


Z-D-Trp-NH(3 g; 8.9 mmol; 1 eq.) was dissolved in DMF (100 ml). HCl 36% (845 μl; 1.1 eq.), water (2 ml) and palladium on activated charcoal (95 mg, 0.1 eq.) were added to the stirred mixture. The solution was bubbled under hydrogen for 24 hr. When the reaction went to completion, the palladium was filtered on celite. The solvent was removed in vacuo to afford HCl, H-D-Trp-NH2as a colorless oil.

In 10 ml of DMF, HCl, H-D-Trp-NH(8.9 mmol; 1 eq.), Boc-D-Trp-OH (2.98 g; 9.8 mmol; 1.1 eq.), NMM (2.26 ml; 2.1 eq.) and BOP (4.33 g; 1.1 eq.) were added successively. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (100 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo to afford 4.35 g of Boc-D-Trp-D-Trp-NHas a white solid.


C27H31N5O4, 489 g.mol−1.

Rf=0.48 {Chloroform/Methanol/Acetic Acid (85/10/5)}.

1H NMR (200 MHZ, DMSO-d6): δ 1.28 (s, 9H, Boc); 2.75-3.36 (m, 4H, 2 (CH2)β; 4.14 (m, 1H, CHα); 4.52 (m, 1H, CHα′); 6.83-7.84 (m, 14H, 2 indoles (10H), NH2, NH (urethane) and NH (amide)); 10.82 (d, 1H, J=2 Hz, N1H); 10.85 (d, 1H, J=2 Hz, N1H).

Mass Spectrometry (Electrospray), m/z 490 [M+H]+, 512 [M+Na]+, 979 [2M+H]+.


Boc-D-Trp-D-Trp-NH(3 g; 6.13 mmol; 1 eq.) was dissolved in acetonitrile (25 ml).

To this solution, di-tert-butyl-dicarbonate (3.4 g; 2.5 eq.) and 4-dimethylaminopyridine (150 mg; 0.2 eq.) were successively added. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane {5/5} to afford 2.53 g of Boc-D-(NiBoc)Trp-D-(NiBoc)Trp-NHas a white solid.


C37H47N5O8, 689 g.mol−1.

Rf=0.23 {ethyl acetate/hexane (5/5)}.

1H NMR (200 MHZ, DMSO-d6): δ 1.25 (s, 9H, Boc); 1.58 (s, 9H, Boc); 1.61 (s, 9H, Boc); 2.75-3.4 (m, 4H, 2 (CH2)β); 4.2 (m, 1H, CHα′); 4.6 (m, 1H, CHα); 7.06-8 (m, 14H, 2 indoles (10H), NH (urethane), NH and NH(amides)).

Mass Spectrometry (Electrospray), m/z 690 [M+H]+, 712 [M+Na]+, 1379 [2M+H]+, 1401 [2M+Na]+.


Boc-D-(NiBoc)Trp-D-(NiBoc)Trp-NH2 (3 g; 4.3 mmol; 1 eq.) was dissolved in the mixture DMF/water (18 ml/7 ml). Then, pyridine (772 μl; 2.2 eq.) and Bis(Trifluoroacetoxy)IodoBenzene (2.1 g; 1.1 eq.) were added. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and aqueous saturated sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. Boc-D-NiBoc)Trp-D-g(NiBoc)Trp-H was used immediately for the next reaction of formylation.

Rf=0.14 {ethyl acetate/hexane (7/3)}.

C36H47N5O7, 661 g.mol−1.

1H NMR (200 MHZ, DMSO-d6): δ 1.29 (s, 9H, Boc); 1.61 (s, 18H, 2 Boc); 2.13 (s, 2H, NH(amine)); 3.1-2.8 (m, 4H, 2 (CH2)β); 4.2 (m, 1H, CHα′); 4.85 (m, 1H, CHα); 6.9-8 (m, 12H, 2 indoles (10H), NH (urethane), NH (amide)).

Mass Spectrometry (Electrospray), m/z 662 [M+H]+, 684 [M+Na]+.


Boc-D-(NiBoc)Trp-D-g(NiBoc)Trp-H (4.3 mmol; 1 eq.) was dissolved in DMF (20 ml). Then, N,N-diisopropylethylamine (815 μl; 1.1 eq.) and 2,4,5-trichlorophenylformate (1.08 g; 1.1 eq.) were added. After 30 minutes, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane {5/5} to afford 2.07 g of Boc-D-(NiBoc)Trp-D-g(NiBoc)Trp-CHO as a white solid.


C37H47N5O8, 689 g.mol−1.

Rf=0.27 {ethyl acetate/hexane (5/5)}.

1H NMR (200 MHZ, DMSO-d6): δ 1.28 (s, 9H, Boc); 1.6 (s, 9H, Boc); 1.61 (s, 9H, Boc); 2.75-3.1 (m, 4H, 2 (CH2)β); 4.25 (m, 1H, (CH)αA&B); 5.39 (m, 0.4H, (CH)α′B); 5.72 (m, 0.6H, (CH)α′A); 6.95-8.55 (m, 14H, 2 indoles (10H), NH (urethane), 2 NH (amides), CHO (formyl)).

Mass Spectrometry (Electrospray), m/z 690 [M+H]+, 712 [M+Na]+, 1379 [2M+H]+.


Boc-D-(NiBoc)Trp-D-g(NiBoc)Trp-CHO (1.98 g; 2.9 mmol; 1 eq.) was dissolved in a -mixture of trifluoroacetic acid (16 ml), anisole (2 ml) and thioanisole (2 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, H-D-Trp-D-gTrp-CHO was filtered.

TFA, H-D-Trp-D-gTrp-CHO (2.9 mmol; 1 eq.), Boc-Aib-OH (700 mg; 1 eq.), NMM (2.4 ml; 4.2 eq.) and BOP (1.53 g; 1.2 eq.) were successively added in 10 ml of DMF. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to afford 1.16 g of Boc-Aib-D-Trp-D-gTrp-CHO as a white solid.


C31H38N6O5, 574 g.mol−1.

Rf=0.26 {Chloroform/Methanol/Acetic Acid (180/10/5)}.

1H NMR (200 MHZ, DMSO-d6): δ 1.21 (s, 6H, 2 CH3(Aib)); 1.31 (s, 9H, Boc); 2.98-3.12 (m, 4H, 2 (CH2)β); 4.47 (m, 1H, (CH)αA&B); 5.2 (m, 0.4H, (CH)α′B); 5.7 (m, 0.6H, (CH)α′A); 6.95-8.37 (m, 15H, 2 indoles (10H), 3 NH (amides), 1 NH (urethane) CHO (formyl)); 10.89 (m, 2H, 2 N1H (indoles)).

Mass Spectrometry (Electrospray), ml/z 575 [M+H]+, 597 [M+Na]+, 1149 [2M+H]+, 1171 [2M+Na]+.


Boc-Aib-D-Trp-D-gTrp-CHO (1 g; 1.7 nmmol) was dissolved in a mixture of trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole (1 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, H-Aib-D-Trp-D-gTrp-CHO was filtered.

The product TFA, H-Aib-D-Trp-D-gTrp-CHO was purified by preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm, 100 A).


C26H30N6O3, 474 g.mol−1.

1H NMR (400 MHZ, DMSO-d6)+1H/1H correlation: δ 1.21 (s, 3H, CH(Aib)); 1.43 (s, 3H, CH(Aib)); 2.97 (m, 2H, (CH2)β); 3.1 (m, 2H, (CH2)β′); 4.62 (m, 1H, (CH)αA&B); 5.32 (q, 0.4H, (CH)α′B); 5.71 (q, 0.6H, (CH)α′A); 7.3 (m, 4Hand H6(2 indoles)); 7.06-7.2 (4d, 2H, H2A et H2B (2 indoles)); 7.3 (m, 2H, Hor H(2 indoles)); 7.6-7.8 (4d, 2H, H4A and H4B or H7A et H7B); 7.97 (s, 3H, NH(Aib) and CHO (Formyl));8.2 (d, 0.4H, NH1B (diamino)); 8.3 (m,1H, NHA&B); 8.5 (d, 0.6H, NH1A (diamino)); 8.69 (d, 0.6H, NH2A (diamino)); 8.96 (d, 0.4H, NH2B (diamino)); 10.8 (s, 0.6H, N1H1A (indole)); 10.82 (s, 0.4H, N1H1B (indole)); 10.86 (s, 0.6H, N1H2A (indole)); 10.91 (s, 0.4, N1H2B (indole)).

Mass Spectrometry (Electrospray), m/z 475 [M+H]+, 949 [2M+H]+.





Aeterna Zentaris NDA for Macimorelin Acetate in AGHD Accepted for Filing by the FDA

Quebec City, Canada, January 6, 2014 – Aeterna Zentaris Inc. (NASDAQ: AEZS) (TSX: AEZS) (the “Company”) today announced that the U.S. Food and Drug Administration (“FDA”) has accepted for filing the Company’s New Drug Application (“NDA”) for its ghrelin agonist, macimorelin acetate, in Adult Growth Hormone Deficiency (“AGHD”). The acceptance for filing of the NDA indicates the FDA has determined that the application is sufficiently complete to permit a substantive review.

The Company’s NDA, submitted on November 5, 2013, seeks approval for the commercialization of macimorelin acetate as the first orally-administered product that induces growth hormone release to evaluate AGHD. Phase 3 data have demonstrated the compound to be well tolerated, with accuracy comparable to available intravenous and intramuscular testing procedures. The application will be subject to a standard review and will have a Prescription Drug User Fee Act (“PDUFA”) date of November 5, 2014. The PDUFA date is the goal date for the FDA to complete its review of the NDA.

David Dodd, President and CEO of Aeterna Zentaris, commented, “The FDA’s acceptance of this NDA submission is another significant milestone in our strategy to commercialize macimorelin acetate as the first approved oral product for AGHD evaluation. We are finalizing our commercial plan for this exciting new product. We are also looking to broaden the commercial application of macimorelin acetate in AGHD for use related to traumatic brain injury victims and other developmental areas, which would represent significant benefit to the evaluation of growth hormone deficiency, while presenting further potential revenue growth opportunities for the Company.”

About Macimorelin Acetate

Macimorelin acetate, a ghrelin agonist, is a novel orally-active small molecule that stimulates the secretion of growth hormone. The Company has completed a Phase 3 trial for use in evaluating AGHD, and has filed an NDA to the FDA in this indication. Macimorelin acetate has been granted orphan drug designation by the FDA for use in AGHD. Furthermore, macimorelin acetate is in a Phase 2 trial as a treatment for cancer-induced cachexia. Aeterna Zentaris owns the worldwide rights to this novel patented compound.

About AGHD

AGHD affects about 75,000 adults across the U.S., Canada and Europe. Growth hormone not only plays an important role in growth from childhood to adulthood, but also helps promote a hormonally-balanced health status. AGHD mostly results from damage to the pituitary gland. It is usually characterized by a reduction in bone mineral density, lean mass, exercise capacity, and overall quality of life.

About Aeterna Zentaris

Aeterna Zentaris is a specialty biopharmaceutical company engaged in developing novel treatments in oncology and endocrinology. The Company’s pipeline encompasses compounds from drug discovery to regulatory approval.


  1. ^ “Macrilen Prescribing Information” (PDF). Retrieved 2018-07-25.
  2. ^ “Aeterna Zentaris NDA for Macimorelin Acetate in AGHD Accepted for Filing by the FDA”. Wall Street Journal. January 6, 2014.
  3. ^
  4. ^ Research, Center for Drug Evaluation and. “Drug Approvals and Databases – Drug Trials Snapshots: Marcrilen” Retrieved 2018-07-25.
  5. ^ “Macimorelin”NCI Drug Dictionary. National Cancer Institute.
  6. ^ Koch, Linda (2013). “Growth hormone in health and disease: Novel ghrelin mimetic is safe and effective as a GH stimulation test”. Nature Reviews Endocrinology9 (6): 315. doi:10.1038/nrendo.2013.89.
  7. ^ Garcia, J. M.; Swerdloff, R.; Wang, C.; Kyle, M.; Kipnes, M.; Biller, B. M. K.; Cook, D.; Yuen, K. C. J.; Bonert, V.; Dobs, A.; Molitch, M. E.; Merriam, G. R. (2013). “Macimorelin (AEZS-130)-Stimulated Growth Hormone (GH) Test: Validation of a Novel Oral Stimulation Test for the Diagnosis of Adult GH Deficiency”Journal of Clinical Endocrinology & Metabolism98 (6): 2422. doi:10.1210/jc.2013-1157PMC 4207947.
Patent ID


Submitted Date

Granted Date

US8835444 Cyclohexyl amide derivatives as CRF receptor antagonists
Patent ID


Submitted Date

Granted Date

US7297681 Growth hormone secretagogues
US2012295942 Pyrazolo[5, 1b]oxazole Derivatives as CRF-1 Receptor Antagonists
US8349852 Quinazolinone Derivatives Useful as Vanilloid Antagonists
Patent ID


Submitted Date

Granted Date

US8614213 Organic compounds
US7994203 Organic compounds
US8273900 Organic compounds
Patent ID


Submitted Date

Granted Date

US6861409 Growth hormone secretagogues
US8192719 Methods and kits to diagnose growth hormone deficiency by oral administration of EP 1572 or EP 1573 compounds
US2014088105 Cyclohexyl Amide Derivatives and Their Use as CRF-1 Receptor Antagonists
IUPAC name

Other names

Aib-Trp-gTrp-CHO; AEZS-130; JMV 1843; Macimorelin acetate
3D model (JSmol)
PubChem CID
Molar mass 474.565 g·mol−1
V04CD06 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).


///////////macimorelin, FDA 2017, Aeterna Zentaris, AEZS-130, ARD-07, D-87875, EP-01572, EP-1572, JMV-1843, USAN (ab-26), MACIMORELIN ACETATE, orphan drug designation


Caplacizumab-yhdp, カプラシズマブ

FDA approves first therapy Cablivi (caplacizumab-yhdp) カプラシズマブ  , for the treatment of adult patients with a rare blood clotting disorder


February 6, 2019

The U.S. Food and Drug Administration today approved Cablivi (caplacizumab-yhdp) injection, the first therapy specifically indicated, in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), a rare and life-threatening disorder that causes blood clotting.

“Patients with aTTP endure hours of treatment with daily plasma exchange, which requires being attached to a machine that takes blood out of the body and mixes it with donated plasma and then returns it to the body. Even after days or weeks of this treatment, as well as taking drugs that suppress the immune system, many patients will have a recurrence of aTTP,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Cablivi is the first targeted treatment that inhibits the formation of blood clots. It provides a new treatment option for patients that may reduce recurrences.”

Patients with aTTP develop extensive blood clots in the small blood vessels throughout the body. These clots can cut off oxygen and blood supply to the major organs and cause strokes and heart attacks that may lead to brain damage or death. Patients can develop aTTP because of conditions such as cancer, HIV, pregnancy, lupus or infections, or after having surgery, bone marrow transplantation or chemotherapy.

The efficacy of Cablivi was studied in a clinical trial of 145 patients who were randomized to receive either Cablivi or a placebo. Patients in both groups received the current standard of care of plasma exchange and immunosuppressive therapy. The results of the trial demonstrated that platelet counts improved faster among patients treated with Cablivi, compared to placebo. Treatment with Cablivi also resulted in a lower total number of patients with either aTTP-related death and recurrence of aTTP during the treatment period, or at least one treatment-emergent major thrombotic event (where blood clots form inside a blood vessel and may then break free to travel throughout the body).The proportion of patients with a recurrence of aTTP in the overall study period (the drug treatment period plus a 28-day follow-up period after discontinuation of drug treatment) was lower in the Cablivi group (13 percent) compared to the placebo group (38 percent), a finding that was statistically significant.

Common side effects of Cablivi reported by patients in clinical trials were bleeding of the nose or gums and headache. The prescribing information for Cablivi includes a warning to advise health care providers and patients about the risk of severe bleeding.

Health care providers are advised to monitor patients closely for bleeding when administering Cablivi to patients who currently take anticoagulants.

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

The FDA granted the approval of Cablivi to Ablynx.


Cablivi is the first therapeutic approved in Europe, for the treatment of a rare blood-clotting disorder

On September 03, 2018, the European Commission has granted marketing authorization for Cablivi™ (caplacizumab) for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), a rare blood-clotting disorder. Cablivi is the first therapeutic specifically indicated for the treatment of aTTP   1. Cablivi was designated an ‘orphan medicine’ (a medicine used in rare diseases) on April 30, 2009. The approval of Cablivi in the EU is based on the Phase II TITAN and Phase III HERCULES studies in 220 adult patients with aTTP. The efficacy and safety of caplacizumab in addition to standard-of-care treatment, daily PEX and immunosuppression, were demonstrated in these studies. In the HERCULES study, treatment with caplacizumab in addition to standard-of-care resulted in a significantly shorter time to platelet count response (p<0.01), the study’s primary endpoint; a significant reduction in aTTP-related death, recurrence of aTTP, or at least one major thromboembolic event during study drug treatment (p<0.0001); and a significantly lower number of aTTP recurrences in the overall study period (p<0.001). Importantly, treatment with caplacizumab resulted in a clinically meaningful reduction in the use of PEX and length of stay in the intensive care unit (ICU) and the hospital, compared to the placebo group. Cablivi was developed by Ablynx, a Sanofi company. Sanofi Genzyme, the specialty care global business unit of Sanofi, will work with relevant local authorities to make Cablivi available to patients in need in countries across Europe.

About aTTP aTTP is a life-threatening, autoimmune blood clotting disorder characterized by extensive clot formation in small blood vessels throughout the body, leading to severe thrombocytopenia (very low platelet count), microangiopathic hemolytic anemia (loss of red blood cells through destruction), ischemia (restricted blood supply to parts of the body) and widespread organ damage especially in the brain and heart. About Cablivi Caplacizumab blocks the interaction of ultra-large von Willebrand Factor (vWF) multimers with platelets and, therefore, has an immediate effect on platelet adhesion and the ensuing formation and accumulation of the micro-clots that cause the severe thrombocytopenia, tissue ischemia and organ dysfunction in aTTP   2.

Note – Caplacizumab is a bivalent anti-vWF Nanobody that received Orphan Drug Designation in Europe and the United States in 2009, in Switzerland in 2017 and in Japan in 2018. The U.S. Food and Drug Administration (FDA) has accepted for priority review the Biologics License Application for caplacizumab for treatment of adults experiencing an episode of aTTP. The target action date for the FDA decision is February 6, 2019

Image result for Caplacizumab


(disulfide bridge: 22-96, 153-227)



EU 2018/8/31 APPROVED, Cablivi

Treatment of thrombotic thrombocytopenic purpura, thrombosis

Immunoglobulin, anti-(human von Willebrand’s blood-coagulation factor VIII domain A1) (human-Lama glama dimeric heavy chain fragment PMP12A2h1)

Other Names

  • 1: PN: WO2011067160 SEQID: 1 claimed protein
  • 98: PN: WO2006122825 SEQID: 98 claimed protein
  • ALX 0081
  • ALX 0681
  • Caplacizumab

Caplacizumab (ALX-0081) (INN) is a bivalent VHH designed for the treatment of thrombotic thrombocytopenic purpura and thrombosis.[1][2]

This drug was developed by Ablynx NV.[3] On 31 August 2018 it was approved in the European Union for the “treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), in conjunction with plasma exchange and immunosuppression”.[4]

It is an anti-von Willebrand factor humanized immunoglobulin.[5] It acts by blocking platelet aggregation to reduce organ injury due to ischemia.[5] Results of the phase II TITAN trial have been reported.[5]

In February 2019, caplacizumab-yhdp (CABLIVI, Ablynx NV) has been approved by the Food and Drug Administration for treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP). The drug is used in combination with plasma exchange and immunosuppressive therapy. [6]


WO 2006122825

WO 2009115614

WO 2011067160

WO 2011098518

WO 2011162831

WO 2013013228

WO 2014109927

WO 2016012285

WO 2016138034

WO 2016176089

WO 2017180587

WO 2017186928

WO 2018067987

Image result for Caplacizumab

Monoclonal antibody
Type Single domain antibody
Source Humanized
Target VWF
Clinical data
Synonyms ALX-0081
ATC code
CAS Number
  • none
Chemical and physical data
Formula C1213H1891N357O380S10
Molar mass 27.88 kg/mol


Caplacizumab (ALX-0081) is a humanized single-variable-domain immunoglobulin (Nanobody) that targets von Willebrand factor, and thereby inhibits the interaction between von Willebrand factor multimers and platelets. In a Phase 2 study (NCT01151423) of 75 patients with acquired thrombotic thrombocytopenic purpura who received SC caplacizumab (10 mg daily) or placebo during plasma exchange and for 30 d afterward, the time to a response was significantly reduced with caplacizumab compared with placebo (39% reduction in median time, P = 0.005).39Peyvandi FScully MKremer Hovinga JACataland SKnöbl PWu HArtoni AWestwood JPMansouri Taleghani MJilma B, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med 2016; 374(6):51122; PMID:26863353;[Crossref][PubMed][Web of Science ®][Google Scholar] The double-blind, placebo-controlled, randomized Phase 3 HERCULES study (NCT02553317) study will evaluate the efficacy and safety of caplacizumab treatment in more rapidly curtailing ongoing microvascular thrombosis when administered in addition to standard of care treatment in subjects with an acute episode of acquired thrombotic thrombocytopenic purpura. Patients will receive an initial IV dose of either caplacizumab or placebo followed by daily SC injections for a maximum period of 6 months. The primary outcome measure is the time to platelet count response. The estimated enrollment is 92 patients, and the estimated primary completion date of the study is October 2017. A Phase 3 follow-up study (NCT02878603) for patients who completed the HERCULES study is planned.


///////////////caplacizumab, Cablivi,  Ablynx, Priority Review, Orphan Drug designation,  fda 2019, eu 2018, Caplacizumab, nti-vWF Nanobody, Orphan Drug Designation, aTTP, Cablivi, Ablynx, Sanofi , ALX-0081, カプラシズマブ  , PEPTIDE, ALX 0081

Cannabidiol, カンナビジオール;



ChemSpider 2D Image | GWP42003-P | C21H30O2



Mol weight

FDA APPROVED, 2018/6/25, Epidiolex

(Greenwich Biosciences)

Anticonvulsant, Antiepileptic, Cannabinoid receptor agonist
Treatment of seizures
1,3-Benzenediol, 2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-3-cyclohexen-1-yl]-5-pentyl-
GW Research Ltd 


CAS Registry Number: 13956-29-1
CAS Name: 2-[(1R,6R)-3-Methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol
Additional Names:trans-(-)-2-p-mentha-1,8-dien-3-yl-5-pentylresorcinol
Molecular Formula: C21H30O2
Molecular Weight: 314.46
Percent Composition: C 80.21%, H 9.62%, O 10.18%
Literature References: Major nonpsychoactive constituent of cannabis, q.v. (Cannabis sativa L., Cannabinaceae). Exhibits multiple bioactivities including anticonvulsant, anxiolytic and anti-inflammatory effects. Isoln from wild hemp: R. Adams et al.,J. Am. Chem. Soc.62, 196, 2194 (1940); from hashish: A. Jacob, A. R. Todd, J. Chem. Soc.1940, 649. Structure: R. Mechoulam, Y. Shvo, Tetrahedron19, 2073 (1963). Crystal and molecular structure: T. Ottersen et al.,Acta Chem. Scand. B31, 807 (1977). Abs config: Y. Gaoni, R. Mechoulam, J. Am. Chem. Soc.93, 217 (1971). Synthesis of (±)-form: eidem, ibid.87, 3273 (1965); of (-)-form: T. Petrzilka et al.,Helv. Chim. Acta52, 1102 (1969); H. J. Kurth et al.,Z. Naturforsch.36B, 275 (1981). LC-IT-MS determn in cannabis products: A. A. M. Stolker et al.,J. Chromatogr. A1058, 143 (2004). Review of isoln, chemistry and metabolism: R. Mechoulam, L. Hanus, Chem. Phys. Lipids121, 35-43 (2002); of pharmacology and bioactivity: R. Mechoulam et al., J. Clin. Pharmacol.42, 11S-19S (2002).
Properties: Pale yellow resin or crystals, mp 66-67°. bp2 187-190° (bath temp 220°). bp0.001 130°. d440 1.040. nD20 1.5404. [a]D27 -125° (0.066 g in 5 ml 95% ethanol). [a]D18 -129° (c = 0.45 in ethanol). uv max (ethanol): 282, 274 nm (log e 3.10, 3.12). Practically insol in water or 10% NaOH. Sol in ethanol, methanol, ether, benzene, chloroform, petr ether.
Melting point: mp 66-67°
Boiling point: bp2 187-190° (bath temp 220°); bp0.001 130°
Optical Rotation: [a]D27 -125° (0.066 g in 5 ml 95% ethanol); [a]D18 -129° (c = 0.45 in ethanol)
Index of refraction:nD20 1.5404
Absorption maximum: uv max (ethanol): 282, 274 nm (log e 3.10, 3.12)
Density: d440 1.040
CAS Registry Number: 521-35-7
CAS Name: 6,6,9-Trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol
Additional Names: 3-amyl-1-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran; CBN
Molecular Formula: C21H26O2
Molecular Weight: 310.43
Percent Composition: C 81.25%, H 8.44%, O 10.31%
Literature References: Nonpsychoactive constituent of cannabis, q.v. (Cannabis sativa L. Cannabinaceae); weak cannabinoid receptor ligand. Isoln from cannabis resin: T. B. Wood et al.,J. Chem. Soc.69, 539 (1896); R. S. Cahn, J. Chem. Soc.1931, 630; T. S. Work et al.,Biochem. J.33, 123 (1939). Structural studies: R. S. Cahn, J. Chem. Soc.1932, 1342; 1933, 1400; F. Bergel, K. Vögele, Ann.493, 250 (1932). Structure and synthesis: R. Adams et al.,J. Am. Chem. Soc.62, 2204 (1940). Crystal structure: T. Ottersen et al.,Acta Chem. Scand. B31, 781 (1977). Improved syntheses: P. C. Meltzer et al.,Synthesis1981, 985; J. Novák, C. A. Salemink, Tetrahedron Lett.23, 253 (1982). Pharmacology: I. Yamamoto et al., Chem. Pharm. Bull.35, 2144 (1987); F. Petitet et al., Life Sci.63, 1 (1998). Review of chromatographic determn methods in biological samples: C. Staub, J. Chromatogr. B733, 119-126 (1999). Comparison of pharmacology with other cannabinoids: I. Yamamoto et al., J. Toxicol. Toxin Rev.22, 577-589 (2003).
Properties: Leaflets from petr ether, mp 76-77°. Sublimes at 4 mm with a bath temp of 180-190°. bp0.05 185°. Insol in water. Sol in methanol, ethanol, aq alkaline solns.
Melting point: mp 76-77°
Boiling point: bp0.05 185°
Additional Names: Hemp; Indian hemp
Literature References: Annual, dioecious plant, Cannabis sativa L. Cannabinaceae. Used since antiquity for its edible seed, fiber to produce rope and cloth, and medicinally as an analgesic, anti-emetic, hypnotic and intoxicant. Habit. Temporate to tropical regions, originally in central Asia, China and India. Constit. More than 60 known cannabinoids, primarily isomeric tetrahydrocannabinols, cannabidiol, cannabinol, q.q.v.; other constituents include alkaloids, proteins, sugars, steroids, flavonoids and vitamins. Seeds and seed oil contain fatty acids, including linoleic, oleic, stearic, and palmetic acids, vitamin E, phytosterols, carotenes. Pistillate plants secrete a cannabinoid containing resin from which hashish or charas is prepared. Preparations of dried flowering tops from these plants are known as bhangganja, or marijuana. Comprehensive description of constituents: C. E. Turner et al., J. Nat. Prod. 43, 169-234 (1980). Review of analytical methods: T. J. Raharjo, R. Verpoorte, Phytochem. Anal. 15, 79-94 (2004); of pharmacology and toxicology: I. B. Adams, B. R. Martin, Addiction 91, 1585-1614 (1996). Series of articles on psychiatric effects, pharmacology and therapeutic uses: Br. J. Psychiatry 178, 101-128 (2001). Book: Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential, F. Grotenhermen, E. Russo, Eds. (Haworth Press, New York, 2002) 439 pp.
Derivative Type: Extract
Manufacturers’ Codes: GW-1000
Trademarks: Sativex (GW Pharma)
Literature References: Medicinal preparation containing approximately equal amounts of D9-tetrahydrocannabinol and cannabidiol. Prepn of extracts from dried leaf and flowerhead: B. Whittle, G. Guy, WO 02064109 (2002 to GW Pharma); eidemUS04192760 (2004). Clinical evaluation for relief of neuropathic pain: J. S. Berman et al., Pain 112, 299 (2004); in multiple sclerosis: C. M. Brady et al., Mult. Scler. 10, 425 (2004). Review of development and clinical experience: P. F. Smith, Curr. Opin. Invest. Drugs 5, 748-754 (2004).
CAUTION: This is a controlled substance (hallucinogen): 21 CFR, 1308.11. Acute intoxication is frequently due to recreational use by ingestion or by inhalation of smoke. Psychological responses include euphoria, feelings of detachment and relaxation, visual and auditory hallucinations, anxiety, panic, paranoia, depression, drowsiness, psychotic symptoms. Other effects include impairment of cognitive and psychomotor performance, tachycardia, vasodilation, reddening of the conjuctivae, dry mouth, increased appetite. Chronic inhalation of smoke causes respiratory tract irritation and bronchoconstriction, and may be a significant risk factor for lung cancer. See Grotenhermen, Russo, loc. cit.
Therap-Cat: Analgesic.

Cannabidiol (CBD) is a phytocannabinoid discovered in 1940. It is one of some 113 identified cannabinoids in Cannabis plants, accounting for up to 40% of the plant’s extract.[6] As of 2018, preliminary clinical research on cannabidiol included studies of anxietycognitionmovement disorders, and pain.[7]

Cannabidiol can be taken into the body in multiple different ways, including by inhalation of cannabis smoke or vapor, as an aerosol spray into the cheek, and by mouth. It may be supplied as CBD oil containing only CBD as the active ingredient (no added THC or terpenes), a full-plant CBD-dominant hemp extract oil, capsules, dried cannabis, or as a prescription liquid solution.[2] CBD does not have the same psychoactivity as THC,[8][9][10] and may affect the actions of THC.[6][7][8][11] Although in vitro studies indicate CBD may interact with different biological targets, including cannabinoid receptors and other neurotransmitter receptors,[8][12] the mechanism of action for its possible biological effects has not been determined, as of 2018.[7][8]

In the United States, the cannabidiol drug Epidiolex has been approved by the Food and Drug Administration for treatment of two epilepsy disorders.[13] Side effects of long-term use listed on the Epidiolex label include somnolencedecreased appetitediarrheafatiguemalaiseweaknesssleeping problems, and others.[2]

The U.S. Drug Enforcement Administration has assigned Epidiolex a Schedule V classification while non-Epidiolex CBD remains a Schedule I drug prohibited for any use.[14] CBD is not scheduled under any United Nations drug control treaties, and in 2018 the World Health Organization recommended that it remain unscheduled.[15]

Medical uses


Medical reviews published in 2017 and 2018 incorporating numerous clinical trials concluded that cannabidiol is an effective treatment for certain types of childhood epilepsy.[16][17]

An orally administered cannabidiol solution (brand name Epidiolex) was approved by the US Food and Drug Administration in June 2018 as a treatment for two rare forms of childhood epilepsy, Lennox-Gastaut syndrome and Dravet syndrome.[13]

Other uses

Preliminary research on other possible therapeutic uses for cannabidiol include several neurological disorders, but the findings have not been confirmed by sufficient high-quality clinical research to establish such uses in clinical practice.[5][8][18][19][20][21]

Side effects

Preliminary research indicates that cannabidiol may reduce adverse effects of THC, particularly those causing intoxication and sedation, but only at high doses.[22] Safety studies of cannabidiol showed it is well-tolerated, but may cause tiredness, diarrhea, or changes in appetite as common adverse effects.[23] Epidiolex documentation lists sleepiness, insomnia and poor quality sleep, decreased appetite, diarrhea, and fatigue.[2]

Potential interactions

Laboratory evidence indicated that cannabidiol may reduce THC clearance, increasing plasma concentrations which may raise THC availability to receptors and enhance its effect in a dose-dependent manner.[24][25] In vitro, cannabidiol inhibited receptors affecting the activity of voltage-dependent sodium and potassium channels, which may affect neural activity.[26] A small clinical trial reported that CBD partially inhibited the CYP2C-catalyzed hydroxylation of THC to 11-OH-THC.[27]



Cannabidiol has very low affinity for the cannabinoid CB1 and CB2 receptors but is said to act as an indirect antagonist of these receptors.[28][29] At the same time, it may potentiate the effects of THC by increasing CB1 receptor density or through another CB1receptor-related mechanism.[30]

Cannabidiol has been found to act as an antagonist of GPR55, a G protein-coupled receptor and putative cannabinoid receptor that is expressed in the caudate nucleus and putamen in the brain.[31] It has also been found to act as an inverse agonist of GPR3GPR6, and GPR12.[12] Although currently classified as orphan receptors, these receptors are most closely related phylogenetically to the cannabinoid receptors.[12] In addition to orphan receptors, CBD has been shown to act as a serotonin 5-HT1A receptor partial agonist,[32] and this action may be involved in its antidepressant,[33][34] anxiolytic,[34][35] and neuroprotective effects.[36][37] It is an allosteric modulator of the μ- and δ-opioid receptorsas well.[38] The pharmacological effects of CBD have additionally been attributed to PPARγ agonism and intracellular calcium release.[6]

Research suggests that CBD may exert some of its pharmacological action through its inhibition of fatty acid amide hydrolase (FAAH), which may in turn increase the levels of endocannabinoids, such as anandamide, produced by the body.[6] It has also been speculated that some of the metabolites of CBD have pharmacological effects that contribute to the biological activity of CBD.[39]


The oral bioavailability of CBD is 13 to 19%, while its bioavailability via inhalation is 11 to 45% (mean 31%).[3][4] The elimination half-life of CBD is 18–32 hours.[5]

Cannabidiol is metabolized in the liver as well as in the intestines by CYP2C19 and CYP3A4 enzymes, and UGT1A7UGT1A9, and UGT2B7 isoforms.[2]

Pharmaceutical preparations

Nabiximols (brand name Sativex) is a patented medicine containing CBD and THC in equal proportions. The drug was approved by Health Canada in 2005 for prescription to treat central neuropathic pain in multiple sclerosis, and in 2007 for cancer related pain.[40][41]


Cannabidiol is insoluble in water but soluble in organic solvents such as pentane. At room temperature, it is a colorless crystalline solid.[42] In strongly basic media and the presence of air, it is oxidized to a quinone.[43] Under acidic conditions it cyclizes to THC,[44] which also occurs during pyrolysis (smoking).[45] The synthesis of cannabidiol has been accomplished by several research groups.[46][47][48]


Cannabidiol and THC biosynthesis[49]

Cannabis produces CBD-carboxylic acid through the same metabolic pathway as THC, until the next to last step, where CBDA synthase performs catalysis instead of THCA synthase.[50]


Cannabidiol numbering
Cannabidiol’s 7 double bond isomers and their 30 stereoisomers show


CBD was isolated from the cannabis plant in 1940, and its chemical structure was established in 1963.[7]

Society and culture


Cannabidiol is the generic name of the drug and its INN.[51]

Food and beverage

cbd-infused cold brew coffee and tea from kickback cold brew

An example of CBD-infused cold brew coffee & tea on a grocery store shelf.

Food and beverage products containing CBD were introduced in the United States in 2017.[52] Similar to energy drinks and protein barswhich may contain vitamin or herbal additives, food and beverage items can be infused with CBD as an alternative means of ingesting the substance.[53] In the United States, numerous products are marketed as containing CBD, but in reality contain little or none.[54] Some companies marketing CBD-infused food products with claims that are similar to the effects of prescription drugs have received warning lettersfrom the Food and Drug Administration for making unsubstantiated health claims.[55]

Plant sources

Selective breeding of cannabis plants has expanded and diversified as commercial and therapeutic markets develop. Some growers in the U.S. succeeded in lowering the proportion of CBD-to-THC to accommodate customers who preferred varietals that were more mind-altering due to the higher THC and lower CBD content.[56] Hemp is classified as any part of the cannabis plant containing no more than 0.3% THC in dry weight form (not liquid or extracted form).[57]

Legal status


CBD does not appear to have any psychotropic (“high”) effects such as those caused by ∆9-THC in marijuana, but may have anti-anxiety and anti-psychotic effects.[9] As the legal landscape and understanding about the differences in medical cannabinoids unfolds, it will be increasingly important to distinguish “medical marijuana” (with varying degrees of psychotropic effects and deficits in executive function) – from “medical CBD therapies” which would commonly present as having a reduced or non-psychoactive side-effect profile.[9][58]

Various strains of “medical marijuana” are found to have a significant variation in the ratios of CBD-to-THC, and are known to contain other non-psychotropic cannabinoids.[59] Any psychoactive marijuana, regardless of its CBD content, is derived from the flower (or bud) of the genus Cannabis. Non-psychoactive hemp (also commonly-termed industrial hemp), regardless of its CBD content, is any part of the cannabis plant, whether growing or not, containing a ∆-9 tetrahydrocannabinol concentration of no more than 0.3% on a dry-weight basis.[60] Certain standards are required for legal growing, cultivating, and producing the hemp plant. The Colorado Industrial Hemp Program registers growers of industrial hemp and samples crops to verify that the dry-weight THC concentration does not exceed 0.3%.[60]

United Nations

Cannabidiol is not scheduled under the Convention on Psychotropic Substances or any other UN drug treaty. In 2018, the World Health Organization recommended that CBD remain unscheduled.[15]

United States

In the United States, non-FDA approved CBD products are classified as Schedule I drugs under the Controlled Substances Act.[61] This means that production, distribution, and possession of non-FDA approved CBD products is illegal under federal law. In addition, in 2016 the Drug Enforcement Administration added “marijuana extracts” to the list of Schedule I drugs, which it defined as “an extract containing one or more cannabinoids that has been derived from any plant of the genus Cannabis, other than the separated resin (whether crude or purified) obtained from the plant.”[62] Previously, CBD had simply been considered “marijuana”, which is a Schedule I drug.[61][63]

In September 2018, following its approval by the FDA for rare types of childhood epilepsy,[13] Epidiolex was rescheduled (by the Drug Enforcement Administration) as a Schedule V drug to allow for its prescription use.[14] This change applies only to FDA-approved products containing no more than 0.1 percent THC.[14] This allows GW Pharmaceuticals to sell Epidiolex, but it does not apply broadly and all other CBD-containing products remain Schedule I drugs.[14] Epidiolex still requires rescheduling in some states before it can be prescribed in those states.[64][65]

CNN program that featured Charlotte’s Web cannabis in 2013 brought increased attention to the use of CBD in the treatment of seizure disorders.[66][67] Since then, 16 states have passed laws to allow the use of CBD products with a doctor’s recommendation (instead of a prescription) for treatment of certain medical conditions.[68] This is in addition to the 30 states that have passed comprehensive medical cannabis laws, which allow for the use of cannabis products with no restrictions on THC content.[68] Of these 30 states, eight have legalized the use and sale of cannabis products without requirement for a doctor’s recommendation.[68]

Some manufacturers ship CBD products nationally, an illegal action which the FDA has not enforced in 2018, with CBD remaining the subject of an FDA investigational new drugevaluation, and is not considered legal as a dietary supplement or food ingredient as of December 2018.[69][70] Federal illegality has made it difficult historically to conduct research on CBD.[71] CBD is openly sold in head shops and health food stores in some states where such sales have not been explicitly legalized.[72][73]

The 2014 Farm Bill[74] legalized the sale of “non-viable hemp material” grown within states participating in the Hemp Pilot Program.[75] This legislation defined hemp as cannabis containing less than 0.3% of THC delta-9, grown within the regulatory framework of the Hemp Pilot Program.[76] The 2018 Farm Bill allowed for interstate commerce of hemp derived products, though these products still fall under the purview of the FDA.[77][78]


Prescription medicine (Schedule 4) for therapeutic use containing 2 per cent (2.0%) or less of other cannabinoids commonly found in cannabis (such as ∆9-THC). A schedule 4 drug under the SUSMP is Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription.[79]

New Zealand

Cannabidiol is currently a class B1 controlled drug in New Zealand under the Misuse of Drugs Act. It is also a prescription medicine under the Medicines Act. In 2017 the rules were changed so that anyone wanting to use it could go to the Health Ministry for approval. Prior to this, the only way to obtain a prescription was to seek the personal approval of the Minister of Health.

Associate Health Minister Peter Dunne said restrictions would be removed, which means a doctor will now be able to prescribe cannabidiol to patients.[80]


On October 17, 2018, cannabidiol became legal for recreational and medical use.[81][82]


In 2019, the European Food Safety Authority (EFSA) announced that CBD and other cannabinoids would be classified as “novel foods“,[83] meaning that CBD products would require authorization under the EU Novel Food Regulation stating: because “this product was not used as a food or food ingredient before 15 May 1997, before it may be placed on the market in the EU as a food or food ingredient, a safety assessment under the Novel Food Regulation is required.”[84] The recommendation – applying to CBD extracts, synthesized CBD, and all CBD products, including CBD oil – was scheduled for a final ruling by the European Commission in March 2019.[83] If approved, manufacturers of CBD products would be required to conduct safety tests and prove safe consumption, indicating that CBD products would not be eligible for legal commerce until at least 2021.[83]

Cannabidiol is listed in the EU Cosmetics Ingredient Database (CosIng).[85] However, the listing of an ingredient, assigned with an INCI name, in CosIng does not mean it is to be used in cosmetic products or is approved for such use.[85]

Several industrial hemp varieties can be legally cultivated in Western Europe. A variety such as “Fedora 17” has a cannabinoid profile consistently around 1%, with THC less than 0.1%.[86]


CBD is classified as a medical product in Sweden.[87]

United Kingdom

Cannabidiol, in an oral-mucosal spray formulation combined with delta-9-tetrahydrocannabinol, is a product available (by prescription only until 2017) for relief of severe spasticity due to multiple sclerosis (where other anti-spasmodics have not been effective).[88]

Until 2017, products containing cannabidiol marketed for medical purposes were classed as medicines by the UK regulatory body, the Medicines and Healthcare products Regulatory Agency (MHRA) and could not be marketed without regulatory approval for the medical claims.[89][90] Cannabis oil is illegal to possess, buy, and sell.[91] In January 2019, the UK Food Standards Agency indicated it would regard CBD products, including CBD oil, as a novel food in the UK, having no history of use before May 1997, and indicating they must have authorization and proven safety before being marketed.[83][92]


While THC remains illegal, CBD is not subject to the Swiss Narcotic Acts because this substance does not produce a comparable psychoactive effect.[93] Cannabis products containing less than 1% THC can be sold and purchased legally.[94]


A 2016 literature review indicated that cannabidiol was under basic research to identify its possible neurological effects,[10] although as of 2016, there was limited high-quality evidence for such effects in people.[20][95][96] A 2018 meta-analysis compared the potential therapeutic properties of “purified CBD” with full-plant, CBD-rich cannabis extracts with regard to treating refractory (treatment-resistant) epilepsy, noting several differences.[97] The daily average dose of people using full-plant extracts was more than four times lower than of those using purified CBD, a possible entourage effect of CBD interacting with THC.[97]

Image result for cannabidiol synthesis





Cannabidiol: An overview of some chemical and pharmacological aspects. Part I: Chemical aspects


Image result for cannabidiol synthesis


Image result for cannabidiol synthesis


Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability

 KannaLife Sciences, 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States
 PharmaAdvance, Inc., 6 Dongsheng West Road, Building D1, Jiangyin, Jiangsu Province, P. R. China
ACS Med. Chem. Lett.20167 (4), pp 424–428
DOI: 10.1021/acsmedchemlett.6b00009
*E-mail: Phone: 215-630-5433.
Abstract Image

Cannabidiol is the nonpsychoactive natural component of C. sativa that has been shown to be neuroprotective in multiple animal models. Our interest is to advance a therapeutic candidate for the orphan indication hepatic encephalopathy (HE). HE is a serious neurological disorder that occurs in patients with cirrhosis or liver failure. Although cannabidiol is effective in models of HE, it has limitations in terms of safety and oral bioavailability. Herein, we describe a series of side chain modified resorcinols that were designed for greater hydrophilicity and “drug likeness”, while varying hydrogen bond donors, acceptors, architecture, basicity, neutrality, acidity, and polar surface area within the pendent group. Our primary screen evaluated the ability of the test agents to prevent damage to hippocampal neurons induced by ammonium acetate and ethanol at clinically relevant concentrations. Notably, KLS-13019 was 50-fold more potent and >400-fold safer than cannabidiol and exhibited an in vitro profile consistent with improved oral bioavailability.

Discovery of KLS-13019, a cannabidiol-derived neuroprotective agent, with improved potency, safety, and permeability
ACS Med Chem Lett 2016, 7(4): 424

Synthesis of cannabidiol by condensation of olivetol with 4(R)-isopropenyl-1(S)-methyl-2-cyclohexen-1-ol is described.

Cannabidiol is prepared by the condensation of olivetol with 4(R)-isopropenyl-1(S)-methyl-2-cyclohexen-1-ol  in the presence of p-TsOH in toluene .

A solution of olivetol (1-1) (0.40 g, 2.2 mol, 1 equiv.), p-TsOH (40 mg, 0.21 mmol, 0.1 equiv.) and compound 6 (0.47 g, 3.1 mmol, 1.4 equiv.) in toluene (28 mL) was stirred at RT for 1.5 hours. TLC analysis indicated ~70% conversion of the starting olivetol. The reaction was stopped at this point and EtOAc (30 mL) was added to dilute the reaction mixture, which was then washed by saturated NaHCO3 aqueous solution (3 x 50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give crude compound 1 (0.9 g). It was purified by column chromatography to give compound 1 (140 mg, yield 20%). HPLC purity: 97%. LC/MS (ESI): m/z 315 (M+1). 1H-NMR (300 MHz, CDCl3) δ 6.40-6.20 (br s, 2H), 6.10-5.90 (br s, 1H), 5.59 (s, 1H), 4.68 (s, 2H), 4.58 (s, 1H), 3.90-3.80 (m, 1H), 2.50-2.40 (m, 3H), 2.30-2.00 (m, 2H), 1.90-1.70 (m, 5H), 1.67 (s, 3H), 1.65-1.50 (m, 2H), 1.40-1.20 (m, 4H), 0.90 (t, J = 6.6 Hz, 3H). The analytical data are attached below. Optical Rotation of 1: [α]D 22= -121.4 (c 1.00, EtOH), the average of two measurements: -121.7 and -121.1 Literature: [α]D 22= -125 (Ben-Shabat, 2006).



J Am Chem Soc 1940, 62(1): 196

The red oil ethanolic extract from Minnesota wild hemp containing the carboxylated compound is submitted to a fractionated distillation with simultaneous thermal decarboxylation.

The fraction distilling at 190-210º C (2 mmHg) contains the desired compound as an intermediate oil, which is purified by treatment with 3,5-dinitrobenzoyl chloride  in pyridine to yield the crystalline bis(3,5-dinitrobenzoate) .

Finally this compound is treated with liq ammonia at room temperature in a high pressure bomb to obtain the FINAL cannabidiol.


Open Babel bond-line chemical structure with annotated hydrogens.<br>Click to toggle size.

<sup>1</sup>H NMR spectrum of C<sub>21</sub>H<sub>30</sub>O<sub>2</sub> in CDCL3 at 400 MHz.<br>Click to toggle size.

1H NMR spectrum of C21H30O2 in CDCL3 at 400 MHz.

R.J. Abraham, M. Mobli Modelling 1H NMR Spectra of Organic Compounds:
  Theory, Applications and NMR Prediction Software, Wiley, Chichester, 2008.



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  51. ^ “International Nonproprietary Names for Pharmaceutical Substances (INN)” (PDF)WHO Drug Information30 (2): 241. 2016.
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Further reading

Clinical data
Trade names Sativex (with THC), Epidiolex
Synonyms CBD
AHFS/ International Drug Names
Routes of
Inhalation (smokingvaping), buccal (aerosol spray), oral (solution)[1][2]
Drug class Cannabinoid
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only) or Dietary Supplement
  • US: Schedule I (except Epidiolex, Schedule V)
Pharmacokinetic data
Bioavailability • Oral: 13–19%[3]
• Inhaled: 31% (11–45%)[4]
Elimination half-life 18–32 hours[5]
CAS Number
PubChem CID
ECHA InfoCard 100.215.986 Edit this at Wikidata
Chemical and physical data
Formula C21H30O2
Molar mass 314.464 g/mol
3D model (JSmol)
Melting point 66 °C (151 °F)

/////////////////////Cannabidiol, カンナビジオール , FDA 2018, GW Research Ltd , APH-1501, BRCX-014, BTX-1204, BTX-1503, CBD, GW-42003, GWP-42003, GWP-42003-P, PLT-101, PTL-101, ZYN-002

Voretigene neparvovec , ボレチジーンネパルボベック;

Voretigene neparvovec
Voretigene neparvovec-rzyl;
Luxturna (TN)


DNA (synthetic adeno-associated virus 2 vector AAV2-hRPE65v2)

CAS: 1646819-03-5
2017/12/19, FDA  Luxturna, SPARK THERAPEUTICS

Vision loss treatment, Retinal dystrophy

2SPI046IKD (UNII code)

melting point (°C) 72-90ºC Rayaprolu V. et al. J. Virol. vol. 87. no. 24. (2013)



STN: 125610
Proper Name: voretigene neparvovec-rzyl
Trade Name: LUXTURNA
Manufacturer: Spark Therapeutics, Inc.

  • Is an adeno-associated virus vector-based gene therapy indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. Patients must have viable retinal cells as determined by the treating physician(s).

Product Information

Related Information

Voretigene neparvovec (Luxturna) is a novel gene therapy for the treatment of Leber’s congenital amaurosis.[1] It was developed by Spark Therapeutics and Children’s Hospital of Philadelphia.[2][3] It is the first in vivo gene therapy approved by the FDA.[4]

Leber’s congenital amaurosis, or biallelic RPE65-mediated inherited retinal disease, is an inherited disorder causing progressive blindness. Voretigene is the first treatment available for this condition.[5] The gene therapy is not a cure for the condition, but substantially improves vision in those treated.[6] It is given as an subretinal injection.

It was developed by collaboration between the University of Pennsylvania, Yale University, the University of Florida and Cornell University. In 2018, the product was launched in the U.S. by Spark Therapeutics for the treatment of children and adult patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The same year, Spark Therapeutics received approval for the product in the E.U. for the same indication.

Chemistry and production

Voretigene neparvovec is an AAV2 vector containing human RPE65 cDNA with a modified Kozak sequence. The virus is grown in HEK 293 cells and purified for administration.[7]


Married researchers Jean Bennett and Albert Maguire, among others, worked for decades on studies of congenital blindness, culminating in approval of a novel therapy, Luxturna.[8]

It was granted orphan drug status for Leber congenital amaurosis and retinitis pigmentosa.[9][10] A biologics license application was submitted to the FDA in July 2017 with Priority Review.[5] Phase III clinical trial results were published in August 2017.[11] On 12 October 2017, a key advisory panel to the Food and Drug Administration (FDA), composed of 16 experts, unanimously recommended approval of the treatment.[12] The US FDA approved the drug on December 19, 2017. With the approval, Spark Therapeutics received a pediatric disease priority review voucher.[13]

The first commercial sale of voretigene neparvovec — the first for any gene therapy product in the US — occurred in March 2018.[14][14][4] The price of the treatment has been announced at $425,000 per eye.[15]


LUXTURNA (voretigene neparvovec-rzyl) is an adeno-associated virus vector-based gene therapy indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy.

Patients must have viable retinal cells as determined by the treating physicians.


Warnings and Precautions

  • Endophthalmitis may occur following any intraocular surgical procedure or injection. Use proper aseptic injection technique when administering LUXTURNA, and monitor for and advise patients to report any signs or symptoms of infection or inflammation to permit early treatment of any infection.

  • Permanent decline in visual acuity may occur following subretinal injection of LUXTURNA. Monitor patients for visual disturbances.

  • Retinal abnormalities may occur during or following the subretinal injection of LUXTURNA, including macular holes, foveal thinning, loss of foveal function, foveal dehiscence, and retinal hemorrhage. Monitor and manage these retinal abnormalities appropriately. Do not administer LUXTURNA in the immediate vicinity of the fovea. Retinal abnormalities may occur during or following vitrectomy, including retinal tears, epiretinal membrane, or retinal detachment. Monitor patients during and following the injection to permit early treatment of these retinal abnormalities. Advise patients to report any signs or symptoms of retinal tears and/or detachment without delay.

  • Increased intraocular pressure may occur after subretinal injection of LUXTURNA. Monitor and manage intraocular pressure appropriately.

  • Expansion of intraocular air bubbles Instruct patients to avoid air travel, travel to high elevations or scuba diving until the air bubble formed following administration of LUXTURNA has completely dissipated from the eye. It may take one week or more following injection for the air bubble to dissipate. A change in altitude while the air bubble is still present can result in irreversible vision loss. Verify the dissipation of the air bubble through ophthalmic examination.

  • Cataract Subretinal injection of LUXTURNA, especially vitrectomy surgery, is associated with an increased incidence of cataract development and/or progression.

Adverse Reactions

  • In clinical studies, ocular adverse reactions occurred in 66% of study participants (57% of injected eyes), and may have been related to LUXTURNA, the subretinal injection procedure, the concomitant use of corticosteroids, or a combination of these procedures and products.

  • The most common adverse reactions (incidence ≥5% of study participants) were conjunctival hyperemia (22%), cataract (20%), increased intraocular pressure (15%), retinal tear (10%), dellen (thinning of the corneal stroma) (7%), macular hole (7%), subretinal deposits (7%), eye inflammation (5%), eye irritation (5%), eye pain (5%), and maculopathy (wrinkling on the surface of the macula) (5%).


Immune reactions and extra-ocular exposure to LUXTURNA in clinical studies were mild. No clinically significant cytotoxic T-cell response to either AAV2 or RPE65 has been observed.

In clinical studies, the interval between the subretinal injections into the two eyes ranged from 7 to 14 days and 1.7 to 4.6 years. Study participants received systemic corticosteroids before and after subretinal injection of LUXTURNA to each eye, which may have decreased the potential immune reaction to either AAV2 or RPE65.

Pediatric Use

Treatment with LUXTURNA is not recommended for patients younger than 12 months of age, because the retinal cells are still undergoing cell proliferation, and LUXTURNA would potentially be diluted or lost during the cell proliferation. The safety and efficacy of LUXTURNA have been established in pediatric patients. There were no significant differences in safety between the different age subgroups.

Please see US Full Prescribing Information for LUXTURNA.


1. LUXTURNA [package insert]. Philadelphia, PA: Spark Therapeutics, Inc; 2017. 2. Gupta PR, Huckfeldt RM. Gene therapy for inherited retinal degenerations: initial successes and future challenges. J Neural Eng. 2017;14(5):051002. 3. Kay C. Gene therapy: the new frontier for inherited retinal disease. Retina Specialist. March 2017. Accessed November 14, 2017 4. Polinski NK, Gombash SE, Manfredsson FP, et al. Recombinant adeno-associated virus 2/5-mediated gene transfer is reduced in the aged rat midbrain. Neurobiol Aging. 2015;36(2):1110-1120. 5. Moore T. Restoring retinal function in a mouse model of hereditary blindness. PLoS Med. 2005;2(11):e399. 6. McBee JK, Van Hooser JP, Jang GF, Palczewski K. Isomerization of 11-cis-retinoids to all-trans-retinoids in vitro and in vivo. J Biol Chem. 2001;276(51):48483-48493. 7. Thomas CE, Ehrhardt A, Kay MA. Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet. 2003;4(5):346-358. 8. Trapani I, Puppo A, Auricchio A. Vector platforms for gene therapy of inherited retinopathies. Prog Retin Eye Res. 2014;43:108-128. 9. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849-860.

Illustration of the RPE65 gene delivery method

Illustration of the RPE65 protein production cycle


Progress in Retinal and Eye Research (2018), 63, 107-131

Lancet (2017), 390(10097), 849-860.


  1. ^ “Luxturna (voretigene neparvovec-rzyl) label” (PDF). FDA. December 2017. Retrieved 31 December 2017. (for label updates, see FDA index page)
  2. ^ “Spark’s gene therapy for blindness is racing to a historic date with the FDA” 9 October 2017. Retrieved 9 October 2017.
  3. ^ Clarke,Reuters, Toni. “Gene Therapy for Blindness Appears Initially Effective, Says U.S. FDA”Scientific American. Retrieved 2017-10-12.
  4. Jump up to:a b “First Gene Therapy For Inherited Disease Gets FDA Approval” 19 Dec 2017.
  5. Jump up to:a b “Press Release – Investors & Media – Spark Therapeutics” Retrieved 9 October 2017.
  6. ^ McGinley, Laurie (19 December 2017). “FDA approves first gene therapy for an inherited disease”Washington Post.
  7. ^ Russell, Stephen; Bennett, Jean; Wellman, Jennifer A.; Chung, Daniel C.; Yu, Zi-Fan; Tillman, Amy; Wittes, Janet; Pappas, Julie; Elci, Okan; McCague, Sarah; Cross, Dominique; Marshall, Kathleen A.; Walshire, Jean; Kehoe, Taylor L.; Reichert, Hannah; Davis, Maria; Raffini, Leslie; George, Lindsey A.; Hudson, F Parker; Dingfield, Laura; Zhu, Xiaosong; Haller, Julia A.; Sohn, Elliott H.; Mahajan, Vinit B.; Pfeifer, Wanda; Weckmann, Michelle; Johnson, Chris; Gewaily, Dina; Drack, Arlene; et al. (2017). “Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65 -mediated inherited retinal dystrophy: A randomised, controlled, open-label, phase 3 trial”The Lancet390 (10097): 849–860. doi:10.1016/S0140-6736(17)31868-8PMC 5726391PMID 28712537.
  8. ^ “FDA approves Spark’s gene therapy for rare blindness pioneered at CHOP – Philly” Retrieved 2018-03-24.
  9. ^ “Voretigene neparvovec – Spark Therapeutics – AdisInsight”
  10. ^ Ricki Lewis, PhD (October 13, 2017). “FDA Panel Backs Gene Therapy for Inherited Blindness”Medscape.
  11. ^ Lee, Helena; Lotery, Andrew (2017). “Gene therapy for RPE65 -mediated inherited retinal dystrophy completes phase 3”. The Lancet390 (10097): 823–824. doi:10.1016/S0140-6736(17)31622-7PMID 28712536.
  12. ^ “Landmark Therapy to Treat Blindness Gets One Step Closer to FDA Approval” 2017-10-12. Retrieved 2017-10-12.
  13. ^ “Spark grabs FDA nod for Luxturna, a breakthrough gene therapy likely bearing a pioneering price”FiercePharma.
  14. Jump up to:a b “The anxious launch of Luxturna, a gene therapy with a record sticker price”STAT. 2018-03-21. Retrieved 2018-03-24.
  15. ^ Tirrell, Meg (3 January 2018). “A US drugmaker offers to cure rare blindness for $850,000”. CNBC. Retrieved 3 January 2018.

Further reading

Voretigene neparvovec
Gene therapy
Vector Adeno-associated virusserotype 2
Nucleic acid type DNA
Editing method RPE65
Clinical data
Trade names Luxturna
  • US: N (Not classified yet)
Routes of
subretinal injection
ATC code
Legal status
Legal status

//////////FDA 2017, Voretigene neparvovec , Voretigene neparvovec-rzyl, Luxturna, ボレチジーンネパルボベック, 1646819-03-5 , FDA  Luxturna, SPARK THERAPEUTICS, Vision loss treatment, Retinal dystrophy., AAV2-hRPE65v2, LTW-888, SPK-RPE65, Orphan drug,

TIABENDAZOLE, тиабендазол , تياباندازول , 噻苯达唑 , チアベンダゾール;

ChemSpider 2D Image | Tiabendazole | C10H7N3S



CAS: 148-79-8

  • Molecular FormulaC10H7N3S
  • Average mass201.248 Da
  • тиабендазол [Russian] [INN]
    تياباندازول [Arabic] [INN]
    噻苯达唑 [Chinese] [INN]
  • チアベンダゾール;
148-79-8 [RN]
1H-Benzimidazole, 2-(4-thiazolyl)-
205-725-8 [EINECS]
28558-32-9 [RN]
90507-06-5 [RN]
Arbotect [Trade name]
Benzimidazole, 2-(4-thiazolyl)-
Mintezol [Trade name]
MK 360 / MK-360 / NSC-525040 / NSC-90507

Tiabendazole (INNBAN), thiabendazole (AANUSAN), TBZ (and the trade names Mintezol, Tresaderm, and Arbotect) is a preservative[1]

2-Substituted benzimidazole first introduced in 1962. It is active against a variety of nematodes and is the drug of choice for strongyloidiasis. It has CNS side effects and hepatototoxic potential. (From Smith and Reynard, Textbook of Pharmacology, 1992, p919)

CAS Registry Number: 148-79-8
CAS Name: 2-(4-Thiazolyl)-1H-benzimidazole
Additional Names: 4-(2-benzimidazolyl)thiazole
Manufacturers’ Codes: MK-360
Trademarks: Equizole (Merial); Mertect (Syngenta); Mintezol (Merck & Co.); Tecto (Syngenta)
Molecular Formula: C10H7N3S
Molecular Weight: 201.25
Percent Composition: C 59.68%, H 3.51%, N 20.88%, S 15.93%
Literature References: Prepd by the reaction of 4-thiazolecarboxamide with o-phenylenediamine in polyphosphoric acid: H. D. Brown et al., J. Am. Chem. Soc. 83, 1764 (1961); L. H. Sarett, H. D. Brown, US 3017415 (1962 to Merck & Co.). Synthesis of labeled thiabendazole: D. J. Tocco et al., J. Med. Chem. 7, 399 (1964). Alternate route of synthesis: V. J. Grenda et al., J. Org. Chem. 30, 259 (1965). Anthelmintic props: H. D. Brown et al., loc. cit.; K. C. Kates et al., J. Parasitol. 57, 356 (1971). Fungicidal props: H. J. Robinson et al., J. Invest. Dermatol. 42, 479 (1966). Systemic props in plants: D. C. Erwin et al., Phytopathology 58,860 (1968). Toxicity: H. J. Robinson et al., Toxicol. Appl. Pharmacol. 7, 53 (1965). Residue analysis: IUPAC Appl. Chem. Div., Pure Appl. Chem. 52, 2567 (1980). Comprehensive description: V. K. Kapoor, Anal. Profiles Drug Subs. 16, 611-639 (1986).
Properties: Colorless crystals, mp 304-305°. uv max (methanol): 298 nm (e 23330). Fluorescence max in acid soln: 370 nm (310 nm excitation). Max soly in water at pH 2.2: 3.84%. Soluble in DMF, DMSO. Slightly soluble in alcohols, esters, chlorinated hydrocarbons. LD50 in mice, rats, rabbits (g/kg): 3.6, 3.1, >3.8 orally (Robinson).
Melting point: mp 304-305°
Absorption maximum: uv max (methanol): 298 nm (e 23330)
Toxicity data: LD50 in mice, rats, rabbits (g/kg): 3.6, 3.1, >3.8 orally (Robinson)
Derivative Type: Hypophosphite
CAS Registry Number: 28558-32-9
Trademarks: Arbotect (Syngenta)
Properties: Amber liquid. d25 1.103.
Density: d25 1.103
Use: Fungicide for spoilage control of citrus fruit; for treatment and prevention of Dutch elm disease in trees; for control of fungal diseases of seed potatoes.
Therap-Cat: Anthelmintic (Nematodes).
Therap-Cat-Vet: Anthelmintic, fungicide.
Keywords: Anthelmintic (Nematodes).

Thiabendazole, 2-(4′-thiazolyl)-benzimidazole (TBZ) (I) is an important anthelmintic and fungicidal agent widely used in pharmaceutical, agriculture and food industry. Owing to the commercial importance of thiabendazole, the various synthetic routes are disclosed in the literature for preparing this pharmacologically and fungicidally active compound.

The various literature discloses the synthesis of thiabendazole by using aniline, 4-cyanothiazole and hydrogen chloride in polychlorobenzene such as dichloro- or a trichlorobenzene solvent under high pressure reaction conditions to obtain N-phenyl-(thiazole-4-amidine)-hydrochloride (amidine hydrochloride). This amidine hydrochloride is then treated with hypohalites such as sodium or potassium hypochlorite, sodium hypobromite and calcium hypochlorite in presence of base such as alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide; or an alkali metal carbonate or bicarbonate such sodium carbonate, sodium bicarbonate to obtain thiabendazole.


The US patent no. US 3,274,208 discloses the process for preparation of amidine hydrochloride by reacting 4-cynothiazole and aniline in presence of aluminum chloride at 180 °C. The amidine hydrochloride is purified by acid base treatment.

The US patent no. US 3,299,081 (henceforth patent ‘081) discloses the process for preparation of N-phenyl-(thiazole-4-amidine)-hydrochloride (amidine hydrochloride) and thiabendazole by heating together 4-cyanothiazole and aniline hydrochloride and purging of excess dry hydrogen chloride gas under pressure (15 psig) reaction condition in a 1,2-dichlorobenzene solvent at 135 to 140 °C using closed reactor. The amidine hydrochloride is isolated by filtration and it is then cyclized to N-chloro-N’-phenyl-(thiazole-4-amidine) intermediate by reaction with sodium hypochlorite in water-methanol solvent, further the intermediate is then converted to thiabendazole by treatment with potassium hydroxide in ethanol. The preferred embodiment of the said patent discloses the use of excess hydrogen chloride in a polychlorobenzene medium to achieve higher yields of amidine hydrochloride. The reaction with gas under pressure is exothermic, so the reaction is unsafe.

As per the background of the patent ‘081, the prior art processes were disclosed that the N-aryl amidines could be prepared by reacting together a nitrile and an aromatic amine in the presence of a metal catalyst such as aluminum chloride or zinc chloride. The process involved the use of a metallic halide as an additional substance in the reaction mixture with the result that metal complexes are obtained which have to be decomposed and the metal removed before pure amidine compounds can be recovered. It was also known to prepare N-aryl amidines by reacting the nitrile and the aromatic amine hydrochloride in a solvent such as ether in the absence of metallic halide. The process referred to affords only poor yields of the desired amidine. Hence, neither of these methods are entirely satisfactory.


The US patent no. US 3,299,082 discloses the process for preparation of N-phenyl-(thiazole-4-amidine)-hydrochloride (amidine hydrochloride) by reacting aniline and 4-cyanothiazole in in the presence of a Friedel Crafts type catalyst such as aluminum chloride at temperature 180 °C. The amidine hydrochloride is reacted with hydroxylamine hydrochloride, in presence of base such as sodium bicarbonate and water as solvent to obtain N-phenyl-(thiazole-4-hydroxyamidine) which is then treated with alkyl or aryl sulfonyl halide such methane sulfonyl chloride in the presence of a base such as pyridine to obtain thiabendazole.

The US patent no. US 3,325,506 discloses the process for preparation of thiabendazole by reacting amidine hydrochloride with hypohalites such as sodium or potassium hypochlorite, sodium hypobromite and calcium hypochlorite in presence of base such as alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide; or an alkali metal carbonate or bicarbonate such sodium carbonate, sodium bicarbonate in water or mixtures of water and organic solvents to obtain thiabendazole.

The significance of by-products from reactions in process development work arises from the need to control or eliminate their formation which might affect product cost, process safety, product purity and environmental health. Very few reactions go to 100% completion in the desired sense. Even when conversion is 100% selectivity is not 100%. Most reactions are accompanied by by-products which arise as a direct consequence of a primary synthetic step including work-up and isolation and as a result of various types of side reactions. By-products from the latter type also include tars, polymeric materials, and coloring matters. The level of some by-products from side reactions depends frequently on the batch size.


In the pharmaceutical industry, an impurity is considered as any other inorganic or organic material, or residual solvents other than the drug substances, or ingredients, arise out of synthesis or unwanted chemicals that remains with APIs. Organic impurities are those substances which are formed in the drug substance during the process of synthesis of drug product or even formed during the storage of drug product. This type of impurity includes-intermediate, starting material, degradation product, reagents, ligands, catalyst and by product. Inorganic impurities present mainly include heavy metals, residual solvents, inorganic salts, filter aids, charcoal, reagent, ligands and catalyst.

Impurity profiling includes identification, structure elucidation and quantitative determination of impurities and degradation products in bulk drug materials and pharmaceutical formulations. Impurity profiling has gained importance in modern pharmaceutical analysis since an unidentified, potentially toxic impurities are hazardous to health and the presence of unwanted impurities may influence bioavailability, safety and efficacy of APIs. Now days, not only purity profile but also impurity profile has become mandatory according to various regulatory authorities. The International Conference on Harmonization (ICH) has published guidelines on impurities in new drug substances, products, and residual solvents.


The prior art processes for preparing thiabendazole suffer from inherent drawbacks and inconveniences, such as low yields, additional reaction steps, high-pressure and unsafe reaction conditions. Moreover, the prior art processes for preparation of thiabendazole are end up with surplus level of potential impurities such as 4-chloro thiabendazole (V) or 5-chloro thiabendazole (VI). Also, the prior processes are silent about these impurities. Since, the strict regulations of the regulatory authorities pertaining to the presence of impurities in the active ingredient, it is highly essential to align the research inline with the guidelines of the regulatory authorities in accordance to appropriate regulations and limits to register and commercialize the product in respective countries.

(V) (VI)

Hence, with objective of developing the short process, more direct and less expensive methods, significant improvement in the art for preparation of thiabendazole with controlled level of 4-chloro thiabendazole or 5-chloro thiabendazole impurities, residual solvents (methanol, benzene) and heavy metals (selenium, cobalt, molybdenum), the inventors of the instant invention are motivated to pursue the research to synthesize thiabendazole in under atmospheric conditions with high yield and high chemical purity for agricultural and pharmaceutical use.





It is used primarily to control moldblight, and other fungal diseases in fruits (e.g. oranges) and vegetables; it is also used as a prophylactic treatment for Dutch elm disease.

Use in treatment of aspergillosis has been reported.[2]

Used in anti-fungal Purple wallboards (optiSHIELD AT, mixture of azoxystrobin and thiabendazole).


As an antiparasitic, it is able to control roundworms (such as those causing strongyloidiasis),[3] hookworms, and other helminth species which attack wild animals, livestock and humans.[4]

Angiogenesis inhibitor

Genes responsible for the maintenance of cell walls in yeast have been shown to be responsible for angiogenesis in vertebrates. Tiabendazole serves to block angiogenesis in both frog embryos and human cells. It has also been shown to serve as a vascular disrupting agent to reduce newly established blood vessels. Tiabendazole has been shown to effectively do this in certain cancer cells.[5]


TBZ works by inhibition of the mitochondrial, helminth-specific enzyme, fumarate reductase, with possible interaction with endogenous quinone.[6]


Medicinally, thiabendazole is also a chelating agent, which means it is used medicinally to bind metals in cases of metal poisoning, such as leadmercury, or antimony poisoning.

In dogs and cats, thiabendazole is used to treat ear infections.

Thiabendazole is also used as a food additive,[7][8] a preservative with E number E233 (INS number 233). For example, it is applied to bananas to ensure freshness, and is a common ingredient in the waxes applied to the skins of citrus fruits. It is not approved as a food additive in the EU,[9] Australia and New Zealand.[10]


The substance appears to have a slight toxicity in higher doses, with effects such as liver and intestinal disorders at high exposure in test animals (just below LD50 level).[citation needed] Some reproductive disorders and decreasing weaning weight have been observed, also at high exposure. Effects on humans from use as a drug include nausea, vomiting, loss of appetite, diarrhea, dizziness, drowsiness, or headache; very rarely also ringing in the ears, vision changes, stomach pain, yellowing eyes and skin, dark urine, fever, fatigue, increased thirst and change in the amount of urine occur.[citation needed] Carcinogenic effects have been shown at higher doses.[11]


Thiabendazole synthesis:[12] L. H. Sarett, H. D. Brown, U.S. Patent 3,299,081 (1967 to Merck & Co.).

Intermediate arylamidine 2 is prepared by the dry HCl catalyzed addition of aniline to the nitrile function of 4-cyanothiazole (1). Amidine (2) is then converted to its N-chloro analog 3by means of NaOCl. On base treatment, this apparently undergoes a nitrene insertion reaction (4) to produce thiabendazole (5). Note the direction of the arrow is from the benzene to the nitrene since the nitrene is an electrophilic species.

Alternative route of synthesis: 4-thiazolecarboxamide with o-phenylenediamine in polyphosphoric acid.[13]

Synthesis of labeled thiabendazole:[14]


Cambendazole preparation and activity studies:[15][16]

Cambendazole (best of 300 agents in an extensive study),[17] is made by nitration of tiabendazole, followed by catalytic hydrogenation to 2, and acylation with Isopropyl chloroformate.

Additionally, tiabendazole was noted to exhibit moderate anti-inflammatory and analgesic activities, which led to the development of KB-1043.



The present invention relates to an improved process for preparing thiabendazole of formula (I) with high yield, high purity, in economical and commercially viable manner for agricultural and pharmaceutical use.

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Process for preparing thiabendazole with higher yield, purity, in an economical and commercially viable manner. Thiabendazole is an important anthelmintic and fungicidal agent widely used in pharmaceutical, agriculture and food industry. Represents the first filing from the Hikal Ltd and the inventors on thiabendazole.

The structural details of the 4-chloro thiabendazole (V) and 5-chloro thiabendazole (VI) impurities are as follow.

1. 4-Chloro thiabendazole:

(a) FT-IR study: The FT-IR spectrum was recorded in the KBr pellet using ABB FTLA-2000 FT-IR Spectrometer. The IR data is tabulated below.

Frequency (cm“1) Assignment (s)

1576.37 C=C stretching

1309.16 C-N stretching

3073.38 N-H stretching

(b) NMR spectral data:

NMR experiment was carried out on 400 MHz Bruker spectrometer using DMSO as solvent. The chemical shifts are reported on the δ scale in ppm relative DMSO at 2.5 ppm. The 1H spectra displayed in respectively. The NMR assignment of 4-chloro thiabendazole is shown below.

Proton assignments of 4-Chloro thiabendazole:

s-singlet, d-doublet, t -triplet, q- quartet, dd-doublet of doublet, br-broad, m-multiplet.

2. 5-Chloro thiabendazole:

(a) FT-IR study:

The FT-IR spectrum was recorded in the KBr pellet using ABB FTLA- 2000 Spectrometer. The IR data is tabulated below.

(b) NMR spectral data:

NMR experiment was carried out on 400 MHz Bruker spectrometer using DMSO-d6 as solvent. The chemical shifts are reported on the δ scale in ppm relative DMSO-d6 at 2.50

ppm. The 1H spectra displayed in respectively. The NMR assignment of 5-chloro thiabendazole is shown below.

Proton assignments 5-Chloro thiabendazole:

s-singlet, d-doublet, q-quartet m-multiplet, br-broad.


Example 1: Preparation of amidine hydrochloride (IV)

To the 4-neck, 1 lit RBF, fixed with thermo pocket, condenser and hydrogen chloride (HC1) gas inlet, 100 g (0.908 moles, 1.0 eq) of 4-cyanothiazole, 386 (3.86 V) ml of 1,2-dichlorobenzene and 86.02 (0.924 moles, 1.02 eq) g of aniline were charged. The reaction mass was heated to 55 to 60 °C and hydrogen chloride (HC1) gas was purged till exotherm ceased. Then the temperature of the reaction mass was raised to 135 to 140 °C and again dry HC1 gas was purged till 4-cyanothiazole was reduced to less than 0.2 % (w/w) analyzed by HPLC. The reaction mass was cooled to 45 to 50° C and 500 mL of water was charged and the reaction mass was stirred for half an hour. The pH of the reaction mass was adjusted between 3 to 5 using caustic lye. The reaction mass was filtered through hyflo bed, and bed was washed with 50 (0.5 V) mL of water. The organic layer was separated, and the aqueous layer was charged back to the RBF. 20 g of activated charcoal was added in aqueous layer under stirring at 45 to 50 °C. The reaction mass was heated to 55 to 60 °C and maintained under stirring for 1.0 hour. The reaction mass was filtered through the hyflo bed under

vacuum, and bed was washed with 50 mL of hot water and suck dried till no more filtrate collected. 300-400 mL of water was distilled from the aqueous layer at 55 °C under 50 m bar of vacuum. Then the reaction mass was cooled to 0 to 5 °C and maintained under stirring for 1 hour. The obtain amidine hydrochloride was filtered by using Buckner funnel and suck dried till no more filtrate collected from it. The wet cake was dried under vacuum at 55 to 60 °C to get 189 g (86.83% yield, HPLC purity 99.85%) of amidine hydrochloride.

Example 2: Preparation of thiabendazole (I)

The 5 lit RBF was fixed with over head stirrer, thermo pocket, condenser and addition funnel. 185 g (0.772 moles, 1.0 eq.) of amidine hydrochloride and 1536 mL (7.33V) of water were charged. The reaction mass was cooled to 0 to 5 °C. 1233 mL of methanol was added to the mass and the pH of the reaction mass was adjusted between 9 to 10 by using 5N sodium carbonate solution. The reaction mass was warmed to 10 to 15 °C and 415.35 g (12.57 % w/w, 0.91 eq.) sodium hypochlorite was slowly added by maintaining temperature between 10 to 15 °C. The reaction mass was stirred at same temperature for half an hour. Then the reaction mass was heated to 60 to 65 °C and 46.15 g (12.57 % w/w, 0.1 eq) sodium hypochlorite was added. The reaction mass was stirred at 60 to 65 °C for 1.0 hour and the reaction mass was cooled to 30 to 40 °C. The reaction mass was filtered, the bed was washed with 925 mL of water (5.0 V) and suck dried for 10 minutes to get 238 g (152 g on dry basis, 97.82 % yield, HPLC purity 99.77%) of thiabendazole.

Example 3: Purification of thiabendazole (I)

The 5 lit RBF was fixed with over head stirrer, thermo pocket, condenser and addition funnel. 224 g of wet crude thiabendazole (145 g on dry basis) was charged at 25 to 30 °C. 2392 mL (16.5 V) of water was charged and the reaction mass was heated to 75 to 80 °C. The pH of the reaction mass was adjusted between 1 to 2 by adding concentrated hydrochloride. Then 21.75 g (15 %, w/w) activated charcoal was added and the reaction mass was stirred for 1.0 hour at 75 to 80 °C. The reaction mass was filtered through hyflo bed and the bed was washed with 1445 mL (1.0 V) of hot water. The aqueous layer was charged back to clean RBF and cooled to 0 to 5 °C and stirred for 10 hours. The solid was filtered and suck dried under vacuum to get 224 g wet cake of thiabendazole hydrochloride (135 g on dry basis).

1261 niL (10 V w.r.t dry thiabendazole hydrochloride) was charged and then 224 g wet cake of thiabendazole hydrochloride was added. The reaction mass was heated to 70 to 80 °C and maintained under stirring for half an hour to get clear solution. The pH of the reaction mass was adjusted to 7 to 8 by using liquor ammonia. The reaction mass was cooled to 25 to 30 °C and stirred for 1.0 hour. The reaction mass was filtered, and the wet cake was slurry washed twice with 1350 mL (10V x 2 times). Then the bed was washed with 675 mL (5.0 V) water. The solid was dried under vacuum at 60 to 70 °C to afford 119 g (79.33% yield, HPLC purity 99.96%) of pure thiabendazole.


Fig. 5 Raman spectrum of solid thiabendazole, and SERS spectra of ethanol – water solutions on a re-used 3 m m thick Au woodpile array. Spurious bands from impurities are marked with asterisks.


Fig. 6 (A) Proton NMR spectrum of thiabendazole in DMSO-d 6 solution. (B) Plots of normalized selective relaxation rate enhancements of H1/ H2, H14, and H12. [TBZ] ¼ 2 Â 10 À3 mol L À1 , [DNA] ¼ 1, 2, 5, 10, 20 Â 10 À5 mol L À1 , pH ¼ 7.4, T ¼ 298 K. (C) Equilibrium constant of the TBZ-DNA system. [DNA] ¼ 2 Â 10 À5 mol L À1 , [TBZ] ¼ 2, 2.5, 3, 3.5, 4 Â 10 À3 mol L À1 , pH ¼ 7.4, T ¼ 298 K.


Thiabendazole has been prepared by heating thiazole-4-carboxamide and benzene-1,2-diamine in polyphosphoric acid (Scheme 13) (1961JA(83)1764). An alternative synthesis involves 4-carboxythiazole (CA 162 590253 (2015), CA 62 90958 (1964)) or 4-cyanothiazole (CA 130 110264 (1996), CA 121 57510 (1994)) as starting materials. A different approach to the synthesis of thiabendazole has been described starting from N-arylamidines; in the presence of sodium hypochlorite and a base, N-arylamidine hydrochlorides are transformed to benzimidazoles via formation of N-chloroamidine intermediate followed by ring closure in a stepwise or concerted mechanism (1965JOC(30)259).


One Pot Benzimidazole Synthesis.

A recent report (1) from workers at Chonnam National University (Gwangju, Korea)  describes a benzimidazole synthesis which:

  • produces good product yields (40-98%, for about 30 examples)
  • and proceeds in one pot from three readily available components: sodium azide, an aldehyde, and 2-haloanilines
  • shows good functional group tolerance(nitro-, ester-, chloro-, and various heterocyclic functionalities on the aldehyde or haloaniline component).


The Benzimidazole Synthesis of Lee and coworkers (1)

Naturally, there are many established ways to synthesize benzimidazoles, which are important substances used in the design of bioactive substances (2).  Recent work has sought to address specific drawbacks associated with these methods, which can include harsh reaction conditions and complicated product mixtures.

Further developments have focused on the use of 2-haloacetanilides, 2-haloarylamidines, arylamino oximes, and N-arylbenzimidamides (3).  This work notable due to the useful anthelmintic properties. Anthelmintic agents work to kill or repel intestinal worms. A review (3) discusses the synthesis of benzimidazoles, and cites the breakthrough discovery of thiabendazole by researchers at Merck in 1961.  Thiabendazole was found to have potent broad spectrum activity against gastrointestinal parasites.


Early thiabendazole synthesis (3)

The initial synthesis of thiabendazole occured via dehydrative cyclization of 1,2 diaminobenzenze in polyphosphoric acid (PPA). The commercialized process involved the conversion of N-arylamidines using hypochlorite (4). Although this process can be performed in ‘one-pot’ fashion it is more typically performed in two steps.

The ‘one-pot’ benzimidazole synthesis described by Lee et. Al. is showcased by its ability to produce thiabendazole in one step, from readily available starting materials (2-haloanilines, thiazole-4-carboxaldehyde) – in 97% yield.

Their work builds on the report of Driver and coworkers (5) that showed that benzimidazoles could be had from 2-azidoanilines in good yield. Indeed, Lee proposes a mechanism that produces an azidoaldimine intermediate, which foregoes the multistep preparation of 2-azidoaniline starting materials.

One proposed mechanistic pathway is shown, with the following steps:

  • initial in situ formation of an aldimine, via addition of aniline to an aldehyde;
  • Ar-X insertion of the copper catalyst;
  • Cu-azide association, with transfer of azide to the aromatic ring;
  • loss of nitrogen with concomitant ring formation, and catalyst regeneration

benzimidazolw-mechanism-Lee1One mechanistic explanation proposed by Lee and coworkers (1).

In developing their method, they investigated a number of factors:

  • Solvent.  DMSO outperformed other polar solvents (NMP, DMF, DMAc).  Less polar solvents failed (toluene, diglyme).
  • Source of Copper catalyst. The oxidation state of copper was not a factor, as Cu(I) and Cu(II) salts showed similar performance.
  • Ligand Evaluation. Ligand selection was not a large factor. Several were tested; ultimately TMEDA was selected.
  • Substituents on the aniline / pyridyl component. Base sensitive substituents were tolerated (benzoate ester) and 3-Cl groups were fine. The sensitivity to a broad range of substituents (the usual EWD- and ED-groups) was not rigorously determined
  • Nature of the haloaniline. Although both bromo- and iodoaniline examples were given, the predominance of iodoaniline examples suggests it was prefered by the authors for unstated reasons.
  • Reactivity of various aldehyde reactants. Aldehydes of varying classes were evaluated. Yields from aromatic substrates bearing ED groups(benzaldehyde, 4-Cl benzaldehyde, 4-methoxybenzaldehyde) produced the highest product yields.  Aliphatic aldehydes produced noticeably lower yields, with the curious exception of pivaldehyde. Several heterocyclic aldehydes (2- furyl- and 2-thionylaldehyde were tested and provided good results.

A synopsis of the Lee Procedure follows:

CuCl (0.1 mmol), haloaniline (2.0 mmol), TMEDA (0.1 mmol), NaN3 (4.0 mmol), aldehyde (2.4 mmol) were combined in DMSO  mL), The mixture was heated at 120 C for 12 hours. After cooling to room temperature the mixture was poured onto EtOAc (50 mL), washed with brine (25 mL) and water (25 mL). The organic phase was dried over Mg2SO4, and the residue from evaporation was purified by column chromatography (1:1 hexane / EtOAc mobile phase).

Artie McKim.

(1) Kim, Y.; Kumar, M.R.; Park, N.; Heo, Y.; Lee, S. J. Org. Chem. 201176, 9577-9583.
(2) Tumulty, D.; Cao, K.; Homes, C.P. Org Lett. 2001, 3, 83.; Wu, Z. Rea. P.; Wickham, G.; Tetrahedron Lett. 200041, 9871.;  Chari, M.A.; Shobha, P.S.D.;  Mukkanti, K. J. Heterocycl. Chem.201047, 153.
(3) Townsend, L.B.; Wise, D.S. Parasitology Today 6, 4 (1990) 107-112.
(4) Grenda, V. J.; Jones, R.E; Gal,G.; Sletzinger J. Org Chem. 30 (1965), 259-261.
(5) Shen, M.; Driver, T.G. Org Lett. 200810, 3367.


  1. ^ “E233 : E Number : Preservative” Retrieved 2018-08-28.
  2. ^ Upadhyay MP, West EP, Sharma AP (January 1980). “Keratitis due to Aspergillus flavus successfully treated with thiabendazole”Br J Ophthalmol64 (1): 30–2. doi:10.1136/bjo.64.1.30PMC 1039343PMID 6766732.
  3. ^ Igual-Adell R, Oltra-Alcaraz C, Soler-Company E, Sánchez-Sánchez P, Matogo-Oyana J, Rodríguez-Calabuig D (December 2004). “Efficacy and safety of ivermectin and thiabendazole in the treatment of strongyloidiasis”Expert Opin Pharmacother5 (12): 2615–9. doi:10.1517/14656566.5.12.2615PMID 15571478. Archived from the original on 2016-03-06.
  4. ^ Portugal R, Schaffel R, Almeida L, Spector N, Nucci M (June 2002). “Thiabendazole for the prophylaxis of strongyloidiasis in immunosuppressed patients with hematological diseases: a randomized double-blind placebo-controlled study”Haematologica87 (6): 663–4. PMID 12031927.
  5. ^ Cha, HJ; Byrom M; Mead PE; Ellington AD; Wallingford JB; et al. (August 2012). “Evolutionarily Repurposed Networks Reveal the Well-Known Antifungal Drug Thiabendazole to Be a Novel Vascular Disrupting Agent”PLoS Biology10 (8): e1001379. doi:10.1371/journal.pbio.1001379PMC 3423972PMID 22927795. Retrieved 2012-08-21.
  6. ^ Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990., p. 970
  7. ^ Rosenblum, C (March 1977). “Non-Drug-Related Residues in Tracer Studies”. Journal of Toxicology and Environmental Health2 (4): 803–14. doi:10.1080/15287397709529480PMID 853540.
  8. ^ Sax, N.I. Dangerous Properties of Industrial Materials. Vol 1-3 7th ed. New York, NY: Van Nostrand Reinhold, 1989., p. 3251
  9. ^ UK Food Standards Agency: “Current EU approved additives and their E Numbers”. Retrieved 2011-10-27.
  10. ^ Australia New Zealand Food Standards Code“Standard 1.2.4 – Labelling of ingredients”. Retrieved 2011-10-27.
  11. ^ “Reregistration Eligibility Decision THIABENDAZOLE” (PDF). Environmental Protection Agency. Retrieved 8 January 2013.
  12. ^ Setzinger, Meyer; Painfield, North; Gaines, Water A.; Grenda, Victor J. (1965). “Novel Preparation of Benzimidazoles from N-Arylamidines. New Synthesis of Thiabendazole1”. The Journal of Organic Chemistry30: 259–261. doi:10.1021/jo01012a061.
  13. ^ Brown, H. D.; Matzuk, A. R.; Ilves, I. R.; Peterson, L. H.; Harris, S. A.; Sarett, L. H.; Egerton, J. R.; Yakstis, J. J.; Campbell, W. C.; Cuckler, A. C. (1961). “Antiparasitic Drugs. Iv. 2-(4′-Thiazolyl)-Benzimidazole, A New Anthelmintic”. Journal of the American Chemical Society83 (7): 1764–1765. doi:10.1021/ja01468a052.
  14. ^ Tocco, D. J.; Buhs, R. P.; Brown, H. D.; Matzuk, A. R.; Mertel, H. E.; Harman, R. E.; Trenner, N. R. (1964). “The Metabolic Fate of Thiabendazole in Sheep1”. Journal of Medicinal Chemistry7 (4): 399–405. doi:10.1021/jm00334a002.
  15. ^ Hoff, Fisher, ZA 6800351 (1969 to Merck & Co.), C.A. 72, 90461q (1970).
  16. ^ Hoff, D. R.; Fisher, M. H.; Bochis, R. J.; Lusi, A.; Waksmunski, F.; Egerton, J. R.; Yakstis, J. J.; Cuckler, A. C.; Campbell, W. C. (1970). “A new broad-spectrum anthelmintic: 2-(4-Thiazolyl)-5-isopropoxycarbonylamino-benzimidazole”. Experientia26 (5): 550–551. doi:10.1007/BF01898506.
  17. ^ Chronicles of Drug Discovery, Book 1, pp 239-256.
Thiabendazole ball-and-stick.png
Clinical data
Trade names Mintezol, others
AHFS/ International Drug Names
Routes of
By mouthtopical
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability Сmax 1–2 hours (oral administration)
Metabolism GI tract
Elimination half-life 8 hours
Excretion Urine (90%)
CAS Number
PubChem CID
ECHA InfoCard 100.005.206 Edit this at Wikidata
Chemical and physical data
Formula C10H7N3S
Molar mass 201.249 g/mol
3D model (JSmol)
Density 1.103 g/cm3
Melting point 293 to 305 °C (559 to 581 °F)

Synthesis Reference

Lynn E. Applegate, Carl A. Renner, “Preparation of high purity thiabendazole.” U.S. Patent US5310923, issued October, 1977.


/////////////////MK 360MK-360NSC-525040,  NSC-90507, チアベンダゾール, TIABENDAZOLE, тиабендазол , تياباندازول , 噻苯达唑 , 

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