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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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LEUPRORELIN, リュープロレリン;



  • Molecular FormulaC59H84N16O12
  • Average mass1209.398 Da
53714-56-0 [RN]
For treatment of prostate cancer, endometriosis, uterine fibroids and premature puberty
Leuprolide acetate 37JNS02E7V 74381-53-6

Synthesis Reference, Daniel Kadzimirzs, Gerhard Jas, Volker Autze, “Solution-Phase Synthesis of Leuprolide and Its Intermediates.” U.S. Patent US20090005535, issued January 01, 2009.US20090005535

CAS Registry Number: 53714-56-0
CAS Name: 6-D-Leucine-9-(N-ethyl-L-prolinamide)-10-deglycinamideluteinizing hormone-releasing factor (pig)
Additional Names: leuprorelin; (D-Leu6)-des-Gly10-LH-RH-ethylamide
Molecular Formula: C59H84N16O12
Molecular Weight: 1209.40
Percent Composition: C 58.59%, H 7.00%, N 18.53%, O 15.88%
Literature References: Synthetic nonapeptide agonist analog of LH-RH, q.v. Prepn: M. Fujino et al., DE 2446005 (1975 to Takeda), C.A. 83, 10895y (1975); R. L. Gendrich et al., US 4005063 (1977 to Abbott). Synthesis: J. A. Vilchez-Martinez et al.,Biochem. Biophys. Res. Commun. 59, 1226 (1974); M. Fujino et al., ibid. 60, 406 (1974). Comparison of biological activity with natural LH-RH: D. H. Coy et al., ibid. 67, 576 (1975). Pharmacokinetics: L. T. Sennello et al., J. Pharm. Sci. 75, 158 (1986). Clinical efficacy in prostatic carcinoma: M. B. Garnick et al., N. Engl. J. Med. 311, 1281 (1984); in benign prostatic hypertrophy: L. M. Eri, K. J. Tveter, J. Urol. 150, 359 (1993). Clinical trial in endometriosis: J. M. Wheeler et al., Am. J. Obstet. Gynecol. 167, 1367 (1992).
Properties: Fluffy solid. [a]D25 -31.7° (c = 1 in 1% acetic acid).
Optical Rotation: [a]D25 -31.7° (c = 1 in 1% acetic acid)
Derivative Type: Monoacetate (salt)
CAS Registry Number: 74381-53-6
Additional Names: Leuprolide acetate
Manufacturers’ Codes: Abbott 43818; A-43818; TAP-144
Trademarks: Carcinil (Abbott); Eligard (Sanofi-Aventis); Enantone (Takeda); Leuplin (Takeda); Lucrin (Abbott); Lupron (TAP); Prostap (Wyeth); Viadur (Alza)
Molecular Formula: C59H84N16O12.C2H4O2
Molecular Weight: 1269.45
Percent Composition: C 57.71%, H 6.99%, N 17.65%, O 17.64%
Therap-Cat: Antineoplastic (hormonal); LH-RH agonist.
Keywords: Antineoplastic (Hormonal); LH-RH Analogs; LH-RH Agonist.
Leuprolide belongs to the general class of drugs known as hormones or hormone antagonists. It is a synthetic 9 residue peptide analog of gonadotropin releasing hormone. Leuprolide is used to treat advanced prostate cancer. It is also used to treat uterine fibroids and endometriosis. Leuprolide is also under investigation for possible use in the treatment of mild to moderate Alzheimer’s disease.

Jitsubo , a subsidiary of  Sosei , was investigating JIT-1007 , presumed to be a biosimilar version of an undisclosed peptide therapeutic, generated using its proprietary Molecular Hiving, for the treatment of an unidentified indication, however no development has been reported for some time, this program is assumed to be discontinued.

Leuprorelin, also known as leuprolide, is a manufactured version of a hormone used to treat prostate cancerbreast cancerendometriosisuterine fibroids, and early puberty.[1][2] It is given by injection into a muscle or under the skin.[1]

Common side effects include hot flashes, unstable mood, trouble sleepingheadaches, and pain at the site of injection.[1] Other side effects may include high blood sugarallergic reactions, and problems with the pituitary gland.[1] Use during pregnancy may harm the baby.[1] Leuprorelin is in the gonadotropin-releasing hormone (GnRH) analogue family of medications.[1] It works by decreasing gonadotropin and therefore decreasing testosterone and estradiol.[1]

Leuprorelin was patented in 1973 and approved for medical use in the United States in 1985.[1][3] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[4] In the United Kingdom a monthly dose costs the NHS about GB£75.24.[5] In the United States the equivalent dose has a wholesale cost of US$1,011.93.[6] It is sold under the brand name Lupron among others.[1]

Medical use

Leuprorelin may be used in the treatment of hormone-responsive cancers such as prostate cancer and breast cancer. It may also be used for estrogen-dependent conditions such as endometriosis[7] or uterine fibroids.

It may be used for precocious puberty in both males and females,[8] and to prevent premature ovulation in cycles of controlled ovarian stimulation for in vitro fertilization (IVF).

It may be used to reduce the risk of premature ovarian failure in women receiving cyclophosphamide for chemotherapy.[9]

Along with triptorelin and goserelin, it is has been used to delay puberty in transgender youth until they are old enough to begin hormone replacement therapy.[10] Researchers have recommended puberty blockers after age 12, when the person has developed to Tanner stages 2-3, and then cross-sex hormones treatment at age 16. This use of the drug is off-label, however, not having been approved by the Food and Drug Administration and without data on long-term effects of this use.[11]

They are also sometimes used as alternatives to antiandrogens like spironolactone and cyproterone acetate for suppressing testosterone production in transgender women.[citation needed]

It is considered a possible treatment for paraphilias.[12] Leuprorelin has been tested as a treatment for reducing sexual urges in pedophiles and other cases of paraphilia.[13][14]

Side effects

Common side effects of Lupron Injection include redness/burning/stinging/pain/bruising at the injection site, hot flashes (flushing), increased sweating, night sweats, tiredness, headache, upset stomach, nausea, diarrhea, constipation, stomach pain, breast swelling or tenderness, acne, joint/muscle aches or pain, trouble sleeping (insomnia), reduced sexual interest, vaginal discomfort/dryness/itching/discharge, vaginal bleeding, swelling of the ankles/feet, increased urination at night, dizziness, breakthrough bleeding in a female child during the first 2 months of leuprorelin treatment, weakness, chills, clammy skin, skin redness, itching, or scaling, testicle pain, impotence, depression, or memory problems.[15] The rates of gynecomastia with leuprorelin have been found to range from 3 to 16%.[16]

Mechanism of action

Leuprorelin is a gonadotropin-releasing hormone (GnRH) analogue acting as an agonist at pituitary GnRH receptors. Agonism of GnRH receptors initially results in the stimulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion by the anterior pituitary ultimately leading to increased serum estradiol and testosterone levels via the normal physiology of the hypothalamic–pituitary–gonadal axis (HPG axis); however, because propagation of the HPG axis is incumbent upon pulsatile hypothalamic GnRH secretion, pituitary GnRH receptors become desensitised after several weeks of continuous leuprorelin therapy. This protracted downregulation of GnRH receptor activity is the targeted objective of leuprorelin therapy and ultimately results in decreased LH and FSH secretion, leading to hypogonadism and thus a dramatic reduction in estradiol and testosterone levels regardless of sex.[17][18]

In the treatment of prostate cancer, the initial increase in testosterone levels associated with the initiation of leuprorelin therapy is counterproductive to treatment goals. This effect is avoided with concurrent utilisation of 5α-reductase inhibitors, such as finasteride, which function to block the downstream effects of testosterone.


The peptide sequence is Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt (Pyr = LPyroglutamyl).


Leuprorelin was discovered and first patented in 1973 and was introduced for medical use in 1985.[19][20] It was initially marketed only for daily injection, but a depot injectionformulation was introduced in 1989.[20]

Society and culture


Leuprorelin is the generic name of the drug and its INN and BAN, while leuprorelin acetate is its BANM and JANleuprolide acetate is its USAN and USPleuprorelina is its DCIT, and leuproréline is its DCF.[21][22][23][24] It is also known by its developmental code names A-43818Abbott-43818DC-2-269, and TAP-144.[21][22][23][24]

Leuprorelin is marketed by Bayer AG under the brand name Viadur, by Tolmar under the brand name Eligard, and by TAP Pharmaceuticals (1985–2008), by Varian Darou Pajooh under the brand name Leupromer and Abbott Laboratories (2008–present) under the brand name Lupron. It is available as a slow-release implant or subcutaneous/intramuscular injection.

In the UK and Ireland, leuprorelin is marketed by Takeda UK as Prostap SR (one-month injection) and Prostap 3 (three-month injection).


Available formsLupron injection was first approved by the FDA for treatment of advanced prostate cancer on April 9, 1985.

  • Lupron depot for monthly intramuscular injection was first approved by the FDA for palliative treatment of advanced prostate cancer on January 26, 1989, and subsequently in 22.5 mg/vial and 30 mg/vial for intramuscular depot injection every 3 and 4 months, respectively. 3.75 mg/vial and 11.25 mg/vial dosage forms were subsequently approved for subcutaneous depot injection every month and every 3 months, respectively for treatment of endometriosis or fibroids. 7.5 mg/vial, 11.25 mg/vial, and 15 mg/vial dosage forms were subsequently approved for subcutaneous depot injection for treatment of children with central precocious puberty.
  • Viadur (72 mg yearly subcutaneous implant) was first approved by the FDA for palliative treatment of advanced prostate cancer on March 6, 2000. Bayer will fulfill orders until current supplies are depleted, expected by the end of April 2008
  • Eligard (7.5 mg for monthly subcutaneous depot injection) was first approved by the FDA for palliative treatment of advanced prostate cancer on January 24, 2002, and subsequently in 22.5 mg, 30 mg, and 45 mg doses for subcutaneous depot injection every 3, 4, and 6 months, respectively.
  • Leupromer 7.5 (7.5 mg, one month depot for subcutaneous injection) is the second in situ-forming injectable drug in the world. It is used for palliative treatment of advanced prostate cancer, endometriosis, and uterine fibroids. It was approved by The Ministry of Health and Medical Education Of Iran.

Leuprorelin is available in the following forms, among others:[25][26][27]

  • Short-acting daily intramuscular injection (Lupron): 5 mg/mL (2.8 mL) used as 1 mg every day.
  • Long-acting depot intramuscular injection (Lupron Depot): 7.5 mg once a month, 22.5 mg every 3 months, or 30 mg every 4 months.
  • Long-acting depot subcutaneous injection (Eligard): 7.5 mg once a month, 22.5 mg every 3 months, 30 mg every 4 months, or 45 mg every 6 months.
  • Long-acting subcutaneous implant (Viadur): 65 mg pellet once every 12 months.

“Lupron protocol”

A 2005 paper in the controversial and non-peer reviewed journal Medical Hypotheses suggested leuprorelin as a possible treatment for autism,[28] the hypothetical method of action being the now defunct hypothesis that autism is caused by mercury, with the additional unfounded assumption that mercury binds irreversibly to testosterone and therefore leuprorelin can help cure autism by lowering the testosterone levels and thereby mercury levels.[29] However, there is no scientifically valid or reliable research to show its effectiveness in treating autism.[30] This use has been termed the “Lupron protocol”[31] and Mark Geier, the proponent of the hypothesis, has frequently been barred from testifying in vaccine-autism related cases on the grounds of not being sufficiently expert in that particular issue[32][33][34] and has had his medical license revoked.[31] Medical experts have referred to Geier’s claims as “junk science”.[35]

Veterinary use

Leuprorelin is frequently used in ferrets for the treatment of adrenal disease. Its use has been reported in a ferret with concurrent primary hyperaldosteronism,[36] and one with concurrent diabetes mellitus.[37]


As of 2006 leuprorelin was under investigation for possible use in the treatment of mild to moderate Alzheimer’s disease.[38]

by mouth formulation of leuprorelin is under development for the treatment of endometriosis.[39] It was also under development for the treatment of precocious pubertyprostate cancer, and uterine fibroids, but development for these uses was discontinued.[39] The formulation has the tentative brand name Ovarest.[39] As of July 2018, it is in phase II clinical trials for endometriosis.[39]



Process for producing leuprorelin as LH-RH (GnRH) agonist useful for treating endometriosis, uterine fibroids, premenopausal breast cancer and prostate cancer.





  1. Jump up to:a b c d e f g h i “Leuprolide Acetate”. The American Society of Health-System Pharmacists. Archived from the original on 23 December 2016. Retrieved 8 December2016.
  2. ^ “19th WHO Model List of Essential Medicines (April 2015)” (PDF). WHO. April 2015. Archived (PDF) from the original on May 13, 2015. Retrieved May 10, 2015.
  3. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 514. ISBN 9783527607495.
  4. ^ “WHO Model List of Essential Medicines (19th List)” (PDF)World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
  5. ^ British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 655. ISBN 9780857111562.
  6. ^ “NADAC as of 2016-12-07 |”Centers for Medicare and Medicaid ServicesArchived from the original on 21 December 2016. Retrieved 23 December 2016.
  7. ^ Crosignani PG, Luciano A, Ray A, Bergqvist A (January 2006). “Subcutaneous depot medroxyprogesterone acetate versus leuprolide acetate in the treatment of endometriosis-associated pain”. Human Reproduction21 (1): 248–56. doi:10.1093/humrep/dei290PMID 16176939.
  8. ^ Badaru A, Wilson DM, Bachrach LK, et al. (May 2006). “Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty”. The Journal of Clinical Endocrinology and Metabolism91 (5): 1862–7. doi:10.1210/jc.2005-1500PMID 16449344.
  9. ^ Clowse ME, Behera MA, Anders CK, Copland S, Coffman CJ, Leppert PC, Bastian LA (March 2009). “Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis”Journal of Women’s Health18 (3): 311–9. doi:10.1089/jwh.2008.0857PMC 2858300PMID 19281314.
  10. ^ David A. Wolfe; Eric J. Mash (9 October 2008). Behavioral and Emotional Disorders in Adolescents: Nature, Assessment, and Treatment. Guilford Press. pp. 556–. ISBN 978-1-60623-115-9Archived from the original on 2 July 2014. Retrieved 24 March 2012.
  11. ^ Dreger, A. (2009, Jan.-Feb.). Gender Identity Disorder in childhood: Inconclusive advice to parents. Hastings Center Report, pp. 26-29.
  12. ^ Saleh FM, Niel T, Fishman MJ (2004). “Treatment of paraphilia in young adults with leuprolide acetate: a preliminary case report series”. Journal of Forensic Sciences49 (6): 1343–8. doi:10.1520/JFS2003035PMID 15568711.
  13. ^ Schober JM, Byrne PM, Kuhn PJ (2006). “Leuprolide acetate is a familiar drug that may modify sex-offender behaviour: the urologist’s role”. BJU International97 (4): 684–6. doi:10.1111/j.1464-410X.2006.05975.xPMID 16536753.
  14. ^ Schober JM, Kuhn PJ, Kovacs PG, Earle JH, Byrne PM, Fries RA (2005). “Leuprolide acetate suppresses pedophilic urges and arousability”. Archives of Sexual Behavior34 (6): 691–705. doi:10.1007/s10508-005-7929-2PMID 16362253.
  15. ^ “Common Side Effects of Lupron (Leuprolide Acetate Injection) Drug Center”Archived from the original on 2015-07-29. Retrieved 2015-07-26.[full citation needed]
  16. ^ Di Lorenzo G, Autorino R, Perdonà S, De Placido S (December 2005). “Management of gynaecomastia in patients with prostate cancer: a systematic review”. Lancet Oncol6 (12): 972–9. doi:10.1016/S1470-2045(05)70464-2PMID 16321765.
  17. ^ Mutschler E, Schäfer-Korting M (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 372–3. ISBN 978-3-8047-1763-3.
  18. ^ Wuttke W, Jarry H, Feleder C, Moguilevsky J, Leonhardt S, Seong JY, Kim K (1996). “The neurochemistry of the GnRH pulse generator”Acta Neurobiologiae Experimentalis56(3): 707–13. PMID 8917899Archived from the original on 2015-12-08.
  19. ^ Jamil, George Leal (30 September 2013). Rethinking the Conceptual Base for New Practical Applications in Information Value and Quality. IGI Global. pp. 111–. ISBN 978-1-4666-4563-9.
  20. Jump up to:a b Hara T (1 January 2003). Innovation in the Pharmaceutical Industry: The Process of Drug Discovery and Development. Edward Elgar Publishing. pp. 106–107. ISBN 978-1-84376-566-0.
  21. Jump up to:a b J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 730–. ISBN 978-1-4757-2085-3.
  22. Jump up to:a b Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 599–. ISBN 978-3-88763-075-1.
  23. Jump up to:a b I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 164–. ISBN 978-94-011-4439-1.
  24. Jump up to:a b “Leuprorelin”.
  25. ^ Sara K. Butler; Ramaswamy Govindan (25 October 2010). Essential Cancer Pharmacology: The Prescriber’s Guide. Lippincott Williams & Wilkins. pp. 262–. ISBN 978-1-60913-704-5.
  26. ^ Richard A. Lehne; Laura Rosenthal (25 June 2014). Pharmacology for Nursing Care – E-Book. Elsevier Health Sciences. pp. 1296–. ISBN 978-0-323-29354-9.
  27. ^ Prostate Cancer. Demos Medical Publishing. 20 December 2011. pp. 503–. ISBN 978-1-935281-91-7.
  28. ^ Geier M, Geier D (2005). “The potential importance of steroids in the treatment of autistic spectrum disorders and other disorders involving mercury toxicity”. Med Hypotheses64 (5): 946–54. doi:10.1016/j.mehy.2004.11.018PMID 15780490.
  29. ^ Allen A (2007-05-28). “Thiomersal on trial: the theory that vaccines cause autism goes to court”SlateArchived from the original on 2008-02-03. Retrieved 2008-01-30.
  30. ^ “Testosterone regulation”. Research Autism. 2007-05-07. Archived from the original on 2015-04-18. Retrieved 2015-04-09.
  31. Jump up to:a b “Maryland medical board upholds autism doctor’s suspension”Chicago Tribune. May 11, 2011. Archived from the original on October 21, 2011.
  32. ^ John and Jane Doe v. Ortho-Clinical Diagnostics, Inc Archived 2008-03-06 at the Wayback Machine“, US District Court for the Middle District of North Carolina, July 6, 2006
  33. ^ Dr. Mark Geier Severely Criticized Archived 2016-12-02 at the Wayback Machine“, Stephen Barrett, M.D.,
  34. ^ Mills S, Jones T (2009-05-21). “Physician team’s crusade shows cracks”Chicago TribuneArchived from the original on 2009-05-25. Retrieved 2009-05-21.
  35. ^ ‘Miracle drug’ called junk science: Powerful castration drug pushed for autistic children, but medical experts denounce unproven claims Archived 2013-12-03 at the Wayback MachineChicago Tribune, May 21, 2009
  36. ^ Desmarchelier M, Lair S, Dunn M, Langlois I (2008). “Primary hyperaldosteronism in a domestic ferret with an adrenocortical adenoma”. Journal of the American Veterinary Medical Association233 (8): 1297–301. doi:10.2460/javma.233.8.1297PMID 19180717.
  37. ^ Boari A, Papa V, Di Silverio F, Aste G, Olivero D, Rocconi F (2010). “Type 1 diabetes mellitus and hyperadrenocorticism in a ferret”. Veterinary Research Communications34(Suppl 1): S107–10. doi:10.1007/s11259-010-9369-2PMID 20446034.
  38. ^ Doraiswamy PM, Xiong GL (2006). “Pharmacological strategies for the prevention of Alzheimer’s disease”. Expert Opinion on Pharmacotherapy7 (1): 1–10. doi:10.1517/14656566.7.1.S1PMID 16370917.
  39. Jump up to:a b c d “Leuprorelin oral – Enteris BioPharma – AdisInsight” Retrieved 16 July 2018.

External links

Leuprorelin ball-and-stick.png
Clinical data
Trade names Lupron, Eligard, Lucrin, others
Synonyms Leuprolide; Leuprolidine; A-43818; Abbott-43818; DC-2-269; TAP-144
AHFS/ Consumer Drug Information
MedlinePlus a685040
  • X
Routes of
Drug class GnRH analogueGnRH agonistAntigonadotropin
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life 3 hours
Excretion Kidney
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard 100.161.466 Edit this at Wikidata
Chemical and physical data
Formula C59H84N16O12
Molar mass 1209.421 g·mol−1
3D model (JSmol)

//////////LEUPRORELIN, リュープロレリン ,




  • Molecular FormulaC28H27ClF5NO
  • Average mass523.965 Da
CAS Registry Number: 26864-56-2
CAS Name: 1-[4,4-Bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol
Additional Names: 1-[4,4-bis(p-fluorophenyl)butyl]-4-(4-chloro-a,a,a-trifluoro-m-tolyl)-4-piperidinol; 1-(4,4-bis(4-fluorophenyl)butyl)-4-hydroxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidine
Manufacturers’ Codes: R-16341
MCN-JR-16,341 / R 16,341
Trademarks: Semap (Janssen)
Molecular Formula: C28H27ClF5NO
Molecular Weight: 523.97
Percent Composition: C 64.18%, H 5.19%, Cl 6.77%, F 18.13%, N 2.67%, O 3.05%
Literature References: Prepn: H. K. F. Hermans, C. J. E. Niemegeers, DE 2040231eidem, US 3575990 (both 1971 to Janssen); Sindelár et al., Collect. Czech. Chem. Commun. 38, 3879 (1973). Pharmacology and toxicology: Janssen et al., Eur. J. Pharmacol.11, 139 (1970). Crystal structure: Koch, Acta Crystallogr. 29B, 1538 (1973).
Properties: White, microcrystals, mp 105-107°. Slightly sol in water, dil HCl (<0.5 mg/ml). LD50 orally in mice (day 7): 86.8 mg/kg (Janssen).
Melting point: mp 105-107°
Toxicity data: LD50 orally in mice (day 7): 86.8 mg/kg (Janssen)
Therap-Cat: Antipsychotic.
Keywords: Antipsychotic.
Penfluridol (SemapMicefalLongoperidol) is a highly potent, first generation diphenylbutylpiperidine antipsychotic.[1] It was discovered at Janssen Pharmaceutica in 1968.[2] Related to other diphenylbutylpiperidine antipsychotics, pimozide and fluspirilene, penfluridol has an extremely long elimination half-life and its effects last for many days after single oral dose. Its antipsychotic potency, in terms of dose needed to produce comparable effects, is similar to both haloperidol and pimozide. It is only slightly sedative, but often causes extrapyramidal side-effects, such as akathisiadyskinesiae and pseudo-Parkinsonism. Penfluridol is indicated for antipsychotic treatment of chronic schizophrenia and similar psychotic disorders, it is, however, like most typical antipsychotics, being increasingly replaced by the atypical antipsychotics. Due to its extremely long-lasting effects, it is often prescribed to be taken orally as tablets only once a week (q 7 days). The once-weekly dose is usually 10–60 mg. A 2006 systematic review examined the use of penfluridol for people with schizophrenia:
Penfluridol compared to typical antipsychotics (oral) for schizophrenia[3]
Although there are shortcomings and gaps in the data, there appears to be enough overall consistency for different outcomes. The effectiveness and adverse effects profile of penfluridol are similar to other typical antipsychotics; both oral and depot. Furthermore, penfluridol is shown to be an adequate treatment option for people with schizophrenia, especially those who do not respond to oral medication on a daily basis and do not adapt well to depot drugs. One of the results favouring penfluridol was a lower drop out rate in medium term when compared to depot medications. It is also an option for people with long-term schizophrenia with residual psychotic symptoms who nevertheless need continuous use of antipsychotic medication. An additional benefit of penfluridol is that it is a low-cost intervention.[3]


    • ATC:N05AG03
  • Use:neuroleptic
  • Chemical name:1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol
  • Formula:C28H27ClF5NO
  • MW:523.97 g/mol
  • CAS-RN:26864-56-2
  • EINECS:248-074-5
  • LD50:87 mg/kg (M, p.o.);
    160 mg/kg (R, p.o.)



Late stage functionalization of secondary amines via a cobalt-catalyzed electrophilic amination of organozinc reagents
Org Lett 2019, 21(2): 494

Scheme 6

Scheme 6. A New Synthesis of Penfluridol 5
str1 str2

English: DE patent 2040231

US patent 3575990


File:Penfluridol synthesis.png



    • US 3 575 990 (Janssen; 20.4.1971; appl. 3.9.1969).
    • DOS 2 040 231 (Janssen; appl. 13.8.1970; USA-prior. 3.9.1969).
  • alternative synthesis:

    • FR-appl. 2 161 007 (Janssen; appl. 23.11.1972; J-prior. 25.11.1971).


Although Penfluridol listed for many years, but its chemical preparation technology abroad little studied in the earlier literature, there are several prepared as follows:

[0013] Process (a): 1971 Document Ger.0ffen [P], 2040231, (1971) Hermans.HKF first reported Penfluridol chemical synthesis, which process is as follows:


Figure CN106187863AD00101

[0015] The process of cyclopropyl methanol (ΙΠ) by 4,4, _-difluorophenyl-one ([pi) as a starting material, the reaction of cyclopropyl magnesium bromide-bis 4- (fluorophenyl), then the reaction with thionyl chloride to give 1,1_-bis (4-fluorophenyl) -4-chloro-butene (IV), obtained by catalytic hydrogenation 1,1_-bis (4-phenyl gas) burning chlorobutanol _4_ (V), and finally with 4-chloro-3-methylphenyl gas-4-piperidinol (X VH) in methyl isobutyl ketone was refluxed for three days the reaction to produce Penfluridol (the I), Document: al, Collect Czech.Chem.Commun [J], 38 (12): 3879-3901, (1973).

[0016] In the above process, starting material and documentation of cyclopropyl magnesium bromide hardly prepared each reaction were not reported preparation yield, and therefore Document Sindelar · K · et al, Collect Czech · Chem · Commun [ J], 38 (12):. 3879-3901, (1973) that this technology is not very good.

[0017] Process (b): 1973, Sindelar.K successful research and the following other technology, which process is as follows:


Figure CN106187863AD00111

[0019] The process consists of 4,4_-bis (4-fluorophenyl) butoxy alkyl iodide as a starting material, 4,4_ ethylenedioxythiophene condensing piperidone removal of generated hydrogen iodide in N-pentanone – [4,4-bis (4-fluorophenyl) butoxy group] -4,4-dioxo-condensing vinyl piperidone, N-then obtained by acid hydrolysis [4,4-bis (4-fluorophenyl ) azetidinyl] -4-piperidone (W), the compound (W) with 4-chloro-3-trifluoromethyl phenyl magnesium bromide reacted Penfluridol (I).

[0020] This process route may seem simple, but there are more desired to prepare intermediates, the process is more complex, with low yields reported in the literature.

[0021] Process (c): as follows:


Figure CN106187863AD00121

[0023] In this process, 4-chloro – (4-fluorophenyl) butyryl-one (Shan) starts, 4-fluorophenyl magnesium bromide reacts with 4-chloro – bis (4-fluorophenyl) butanol ( IX), and then boiling the reaction hydroiodic acid to give 4-iodo-in, red phosphorus catalyst – bis (4-fluorophenyl) butoxy left foot and finally burning ^^ – ^ – methyl ^ two gas – chlorophenyl Bu ‘piperidinol prepared products San ^ top five gas profitable ⑴.

[0024] This synthesis has the characteristics of high yield, but the intermediate (IX), (X) quality is not purified, many by-products, difficult to control the quality of products, and hydroiodic acid to be used, the source of raw material is difficult, therefore, not ideal technology.

[0025] Process (d), as follows:


Figure CN106187863AD00131

[0027] The process begins by Stobber reaction with 4,4 – fluorophenyl ketone reaction product diethyl succinate and compound (XI), and then generates bis (4-fluorophenyl) methine acid or base hydrolysis after succinic acid (M), by catalytic hydrogenation to give 4,4_-bis (4-fluorophenyl) butanoic acid after, the reaction with thionyl chloride without isolating the compound (XIV) with the compound directly (XW), by reduction after obtain the final product – Penfluridol. The disadvantage of this process is that, in the above reaction step, Stobber the reaction yield is low; hydrogenation catalyst manufacturing operation more difficult and unsafe; reaction with thionyl chloride, large air pollution, and other refractory.

[0028] The various preparation techniques Penfluridol other drug earlier British Patent Brit. 1141664 and German patent Ger. Off en. 2040231 has been reported, but no other foreign patent reports. In neither country has patent coverage, and no magazine reported.

 The reaction formula is as follows:


Figure CN106187863AD00151

[0059] Step (5), the preparation of compounds of formula (XW) as shown, may be employed a method reported in the literature, or prepared using a method specifically includes the following steps:


Figure CN106187863AD00161

0124] (6) Penfluridol drug (I) were prepared:


Figure CN106187863AD00221

[0126] In three 500ml reaction flask equipped with a mechanical stirrer, a condenser, a thermometer, a calcium chloride tube, was added 250ml of anhydrous diethyl ether, 2 · 4g (0 · 0631mol) tetrahydro lithium aluminum hydride, stirring was started, was added 20g (0 · 0372mol) amide (6), the addition was completed, 38 ° C for 6 hours.

[0127] completion of the reaction, water was added 4.2ml decomposition for 25 minutes, followed by addition of 5.4ml of 20% by weight concentration of sodium hydroxide solution decomposition for 20 minutes, 14.2ml decomposed with water for 15 minutes;

[0128] The decomposition was filtered, the filtrate (ethyl ether) and dried over anhydrous potassium carbonate. Filtered, the filter cake was washed with a little ether. The filtrate and the washings added to a distillation flask, recovery ether atmospheric distillation, vacuum drained, was added a mixed solvent l〇〇ml [chloroform: petroleum ether (60-90 ° C) = 1: 4, weight ratio, stirred and heated to reflux dissolution, filtered while hot, the filtrate was allowed to stand for crystallization at about 10 ° C, to be naturally deposited crystal after freezing -5 ° C overnight, filtered, the cake was washed with a mixed solvent, drain, ventilation pressure at 70 ° C dried to constant weight to give white crystalline product Penfluridol drug (I), mp 105-107 ° C, yield 81.5%.

[0129] Intermediate 4_ (3-trifluoromethyl-4-chlorophenyl) -4-piperidinol (XW) (referred piperidinol) Preparation:

[0130] (1) benzylamine (Beta) Preparation:


Figure CN106187863AD00222

[0132] equipped with a mechanical stirrer, a condenser, a thermometer 2000ml three reaction bottle, were added ammonium bicarbonate 240g (3.04mol), aqueous ammonia at a concentration of 20 wt %% of 15148 (17.812111〇1,

[0133] 1640ml), benzyl chloride 80g (0.632mol), reaction was stirred for 6 hours.Reaction to complete rested stratification. Aqueous layer was separated, and aqueous ammonia recovery bicarbonate atmospheric heating to 100 ° c, the water was distilled off under reduced pressure, with 50% sodium hydroxide PH12 above, extraction with benzene and dried solid sodium hydroxide. Recovery of benzene atmospheric distillation, vacuum distillation, collecting 33.4 g of the product obtained, yield 50.7%, content 99%,


Figure CN106187863AD00223

[0135] (3) N_ benzyl – bis ([beta] methoxycarbonyl-ethyl) amine (C) (referred to as diester thereof):


Figure CN106187863AD00231

[0137] The reaction flask equipped with a mechanical stirrer, a condenser, a thermometer three 250ml, 43g methyl acrylate (0.5111〇1) methanol 328 (401111), was added with stirring 21.48 benzylamine (0.2111〇1), The reaction was stirred for 7 hours. Completion of the reaction, recovery of excess methyl acrylate and methanol, water chestnut vacuum distillation until the internal temperature l〇〇-ll〇 ° C, to give the crude product as a yellow oil (C) 54g, yield 97%, content 94.3%.

[0138] (3) 1 – benzyl-4-piperidone (E) (referred to as the hydrolyzate) is prepared:


Figure CN106187863AD00232

[0140] In a reaction flask equipped with a 500ml three mechanical stirrer, thermometer, fractional distillation apparatus, was added 27% sodium methoxide 27g, crude diester was 33.4g (0.12mol), toluene 300ml, stirred and heated, the temperature reached 90 when ° C or more, additional 50ml toluene was reacted for 3 hours. Cooled to room temperature, and neutralized with acetic acid to PH6, standing layer. The toluene layer was separated and extracted with 150ml of 22% hydrochloric acid three times. Hydrochloric acid extracts were combined, heated with stirring for 4 hours. Recovered by distillation under reduced pressure and hydrochloric acid (about 120ml distilled dilute hydrochloric acid) was cooled to distillation l〇 ° C below, with 40% sodium hydroxide PH12 above. With 80ml ethyl acetate 3 times extracted with ethyl acetate extracts were combined, sub-net water, dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, recovering ethyl acetate atmospheric distillation, vacuum drained hydrolyzed to give (E) and the crude product 19g, yield 84%.

Figure CN106187863AD00233

[0141] (4) 1-ethoxycarbonyl-4-piperidone (F) (referred to as a carbonyl group-piperidone) Preparation:


Figure CN106187863AD00234

[0143] equipped with a mechanical stirrer, a condenser, 250ml three reaction flask thermometer, was added ethyl chloroformate 23.9g (0 · 22mo 1), benzene 100ml, stirring slowly added dropwise [The crude hydrolyzate (E ) 37 · 8g (0 · 2mo 1) + 20ml phenyl] solution dropwise, the reaction was heated with stirring for 5 hours.Water chestnut evaporated under reduced pressure and ethyl benzene chlorine, Li mechanical change stream distilled off under reduced pressure, low boiling point evaporated to give the product 268 was collected, yield 76%.

[0144] (5) 1 – ethoxycarbonyl-4- (3-trifluoromethyl-4-chlorophenyl) -4-piperidinol (G) (referred to as a carbonyl group-piperidinol) is:


Figure CN106187863AD00241

[0146] In three 500ml reaction flask equipped with a mechanical stirrer, a condenser, a thermometer, a dropping funnel and a calcium chloride drying tube over anhydrous anhydrous absolute, at room temperature was added magnesium metal shoulder 2.5g (0.103mol) 20ml of anhydrous ethyl ether and slowly stirring was started.

[0147] 2-chloro-5-bromo – trifluorotoluene (referred bromide) was dissolved under 27g (0.104mol) at room temperature in 130ml anhydrous diethyl ether and stirred to obtain a uniform liquid mass (W is);

[0148] When the liquid material taken (W) 15ml was added to the above reaction, a solution of iodine 0.13g, 1,2- dibromoethane 0.2g, initiated Grignard reaction was heated until the iodine color disappeared, the reaction slowed down, slow slow dropping liquid material (W). The addition was completed, refluxing was continued for 1 hour. Completion of the reaction, cooled to room temperature, slowly added dropwise at room temperature carbonyl piperidone (F) water solution was cooled at normal [carbonyl-piperidone 13.6g (0.0795mol) + 40ml dry ether], dropwise, the reaction was heated with stirring 1.5 hour. L〇〇ml ammonium chloride solution concentration of 20% by weight was added, refluxed for 15 minutes and allowed to stand 30 minutes at room temperature stratification. Discharged aqueous layer (lower layer), the residual liquid was distilled (upper layer) at an external temperature of 55 ° C atmospheric distillation recovery ether, discharge hot, refrigerated overnight, the precipitated solid. Filtered, washed with a small amount of time, drained, and dried to give the product (G) 24.1g, yield 85.7%, mp 118-126Γ.

[0149] (6) 4- (3-trifluoromethyl-4-chlorophenyl) -4-piperidinol (X VH) (referred piperidinol) Preparation:


Figure CN106187863AD00242

[0151] equipped with a mechanical stirrer, a condenser, 250ml three reaction flask thermometer, were added ethanol 40ml, 158 of sodium hydroxide (0.375111〇1), carbonyl piperidinol (6) 2 (^ (0.0569111〇1 ), heated to reflux, and the reaction stirred for 3.5 hours. the reaction was completed, 50ml of water was added, the reaction was refluxed for 10 minutes, the hot reaction solution was placed in 300g of crushed ice, stirred well, and the precipitated solid, -5 ° C frozen standing for 2 hours the above.

[0152] filtered, washed with water to pH 8-9, drained, and dried to give piperidinol (XVH) 15g, yield 94%, mp 137-144 ° C, ash content <5%.

[0153] Example 2

[0154] (a) 3- (4-fluorobenzoyl) propionic acid (2) (the acid) is prepared:


Figure CN106187863AD00251

[0156] The reaction flask equipped with a mechanical stirrer, a condenser, a thermometer three 500ml, was added 17.1g (0.171mol) of succinic anhydride, l〇5g (1 · 09mol) fluorobenzene, stirred and dissolved. Added in one portion 60g (0 · 306mol) in dry wrong trichloride, stirring, the reaction was stirred at 100 ° C for 2 hours, at a concentration of 10% by weight hydrochloric acid 165ml exploded 30 minutes;

[0157] Other embodiments with Example 1, the product, 111.? 105-107 ° (:, this step a yield of 81.5%, 46.7% overall yield.


  1. ^ van Praag HM, Schut T, Dols L, van Schilfgaarden R., Controlled trial of penfluridol in acute psychosis, Br Med J. 1971 December 18;4(5789):710-3
  2. ^ Janssen PA, Niemegeers CJ, Schellekens KH, Lenaerts FM, Verbruggen FJ, Van Nueten JM, Schaper WK., The pharmacology of penfluridol (R 16341) a new potent and orally long-acting neuroleptic drug, Eur J Pharmacol. 1970 July 15;11(2):139-54
  3. Jump up to:a b Soares, B; Silva de Lima, M (2006). “Penfluridol for schizophrenia”Cochrane Database of Systematic Reviews2: CD002923.pub2. doi:10.1002/14651858.CD002923.pub2.

Further reading

  • Benkert O, Hippius H.: Psychiatrische Pharmakotherapie, Springer-Verlag, 1976, 2. Auflage. ISBN3-540-07916-5
  • R Bhattacharyya, R Bhadra U Roy, S Bhattacharyya, J Pal S Sh Saha – Resurgence of Penfluridol:Merits and Demerits, Eastern Journal of Psychiatry, January-June 2015 vol 18, Issue 1 p 23 –29
Clinical data
AHFS/ International Drug Names
ATC code
CAS Number
CompTox Dashboard(EPA)
ECHA InfoCard 100.043.689Edit this at Wikidata
Chemical and physical data
Formula C28H27ClF5NO
Molar mass 523.965 g·mol−1
3D model (JSmol)

/////////Penfluridol, Antipsychotic, SemapMicefalLongoperidol, MCN-JR-16,341, R 16,341, MCN-JR-16,341 / R 16,341, 



ChemSpider 2D Image | elacridar | C34H33N3O5


C34H33N3O5, 563.6 g/mol

143664-11-3 [RN]
143851-84-7 (maleate salt(1:1))
143851-98-3 (monoHCl)
4-Acridinecarboxamide, N-[4-[2-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)ethyl]phenyl]-9,10-dihydro-5-methoxy-9-oxo-[ACD/Index Name]



Elacridar (GF120918)

GF-120918A (HCl)

GlaxoSmithKline  (previously  Glaxo Wellcome ) was developing elacridar, an inhibitor of the multidrug resistance transporter BCRP (breast cancer resistant protein), as an oral bioenhancer for the treatment of solid tumors.

Elacridar is an oral bioenhancer which had been in early clinical trials at GlaxoSmithKline for the treatment of cancer, however, no recent development has been reported. It is a very potent inhibitor of P-glycoprotein, an ABC-transporter protein that has been implicated in conferring multidrug resistance to tumor cells.


The condensation of 2-(4-nitrophenyl)ethyl bromide with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline by means of K2CO3 and KI in DMF at 100 C gives 6,7-dimethoxy-2-[2-(4-nitrophenyl)ethyl]-1,2,3,4-tetrahydroisoquinoline,

Which is reduced with H2 over Pd/C in ethanol to yield the corresponding amine . Finally, this compound is condensed with 5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid  by means of DCC and HOBt in DMF to afford the target carboxamide.

The intermediate 5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acidhas been obtained as follows: The condensation of 2-amino-3-methoxybenzoic acid  with 2-bromobenzoic acid  by means of K2CO3 and copper dust give the diphenylamine , which is cyclized to the target acridine Elacridar by means of POCl3 in refluxing acetonitrile.



Deuterated analogs of elacridar as P-gp/BCRP inhibitor by preventing efflux useful for treating cancer.

Elacridar, previously referred to as GF120918, is a compound with the structure of 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-(1 ,2,3,4-tetrahydro- 6,7-dimethoxy-2-isoquinolinyl)ethyl] phenyl]-4-acridine-carboxamide or, as sometimes written, N-4-[2-(1 ,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy- 9-oxo-4-acridine carboxamide. Elacridar was originally described as a P-gp selective inhibitor but is now recognized as a dual P-gp/BCRP inhibitor. (Matsson P, Pedersen JM, Norinder U, Bergstrom CA, and Artursson P 2009 Identification of novel specific and general inhibitors of the three major human ATP-binding cassette transporters P-gp, BCRP and MRP2 among registered drugs. Pharm Res 26:1816-1831 ).

003 Elacridar has been examined with some success both in vitro and in vivo as a P-gp and BCRP inhibitor. By way of example, in cancer patients, coadministration of elacridar with therapeutic agents such as paclitaxel (P-gp substrate) and topotecan (BCRP substrate) improved their oral absorption – presumably by preventing efflux into the intestinal lumen by P-gp/BCRP pumps located in the Gl tract. Similarly, in rodents, elacridar has been coadministered with some success with pump substrates such as morphine, amprenavir, imatinib, dasatinib, gefitinib, sorafenib, and sunitinib to increase drug levels in the brain (by blocking efflux mediated by P-gp and BCRP at the blood brain barrier). A summary of some of these studies can be found in a study report by Sane et al. (Drug Metabolism And Disposition 40:1612-1619, 2012).

004 Administration of elacridar has several limitations. By way of example, elacridar has unfavorable physicochemical properties; it is practically insoluble in water, making it difficult to formulate as, for example, either an injectable or oral dosage form. Elacridar’s poor solubility and high lipophilicity result in dissolution rate-limited absorption from the gut lumen.

005 A variety of approaches have been pursued in order to increase efficacy of elacridar. For example, United States Patent Application Publication 20140235631 discloses a nanoparticle formulation in order to increase oral bioavailability.

006 Sane et al. (Journal of Pharmaceutical Sciences, Vol. 102, 1343-1354 (2013)) report a micro-emulsion formulation of elacridar to try and overcome its dissolution-rate-limited bioavailability.

007 Sawicki et al. (Drug Development and Industrial Pharmacy, 2017 VOL. 43, NO. 4, 584-594) described an amorphous solid dispersion formulation of freeze dried elacridar hydrochloride-povidone K30-sodium dodecyl sulfate. However, when tested in healthy human volunteers, extremely high doses (e.g. 1000 mg) were required to achieve a Cmax of 326 ng/ml. (Sawicki et al. Drug Deliv. and Transl.

Res. Published online 18 Nov 2016).

008 Montesinos et al. (Mol Pharm. 2015 Nov 2; 12(11 ):3829-38) attempted several PEGylated liposome formulations of elacridar which resulted in a partial increase in half life, but without an increase in efficacy when co-administered with a therapeutic agent.

009 Because of the great unpredictability in the art and poor correlations in many cases between animal and human data, the value of such formulation attempts await clinical trial.

0010 Studies of the whole body distribution of a microdose of 11C elacridar after intravenous injection showed high level accumulation in the liver (Bauer et al. J Nucl Med. 2016;57:1265-1268). This has led some to suggest that systemic levels of elacridar are also substantially limited by clearance in the liver.

0011 A potentially attractive strategy for improving metabolic stability of some drugs is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the rate of formation of inactive metabolites by replacing one or more hydrogen atoms with deuterium atoms.

Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the absorption, distribution, metabolism, excretion and/or toxicity (‘ADMET’) properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

0012 Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, M I et al, J Pharm Sci, 1975, 64:367-91 ; Foster, A B, Adv Drug Res 1985, 14:1 -40 (“Foster”); Kushner, D J et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, M B et al, Curr Opin Drug Discov Devel, 2006, 9:101 -09 (“Fisher”)). The results have been variable and unpredictable. For some compounds, deuteration indeed caused decreased metabolic clearance in vivo. For others, no change in metabolism was observed. Still others demonstrated increased metabolic clearance. The great unpredictability and variability in deuterium effects has led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting metabolism (see Foster at p. 35 and Fisher at p. 101 ).

0013 The effects of deuterium modification on a drug’s metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem. 1991 , 34, 2871 -76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

0014 Considering elacridar’s challenging physicochemical and ADMET properties in humans, in spite of recent formulation advancements, there remains a need in the art for elacridar analogs that can achieve higher, less variable levels in the systemic circulation, at the blood-brain barrier, and elsewhere to optimize efflux inhibition.

Example 1 : Synthesis of Instant Analogs and Compositions

00179 This example demonstrates a synthetic method for making elacridar analogs, deuterium substitutions based upon the deuteration of the starting compounds. The synthesis and the analog numbers refer to Figure 4.

00180 Step 1

00181 A 12L three-neck flask was charged with compound 1 (270.5 g, 1.618 mol), compound 2 (357.8 g, 1.78 mol, 1.1 eq.), K2C03 (447 g, 3.236 mol, 2.0 eq), Cu (20.6 g, 0.324 mol, 0.2 eq.) and ethanol (2.7 L) and the resulting mixture was heated to reflux under nitrogen for 1 hour. The reaction mixture was cooled to room

temperature after the reaction progress was checked with LC-MS. Water (2.7 L) was added and the mixture was filtered through a pad of Celite. The Celite was washed with water (1.35L) and the combined filtrate was adjusted to pH~2 by addition of concentrated HCI (~410 mL) over 15 min. The resulting suspension was stirred at 10°C for 1.5 hours and the solid was filtered, washed with water (2.7 L) and dried at 45°C using a vacuum oven for 2 days to give compound 3 (465 g, ~100%) as a yellow solid.

00182 Step 2

00183 A suspension of compound 3 (498 g, 1.734 mol) in acetonitrile (4.0 L) was heated to reflux under stirring. To the suspension was added POCb (355.5 mL,

3.814 mol, 2.2 eq.) drop-wise over 2h. The mixture was heated at reflux for 2.5h and then cooled to 30 °C. To the mixture was slowly added water (3.0 L) and the resultant thick slurry was heated to reflux for 1 5h. The slurry was cooled to 10 °C and filtered. The solid was washed with water (2 X 1.0 L), acetonitrile (2 X 1.0 L) and dried using a vacuum oven overnight at 45 °C to afford compound 4 (426 g, 91.3%) as a yellow solid.

00184 Step 3:

00185 A 12L three-neck flask was charged with compound 5 (475g, 2.065 mol), compound 6 (474.8g, 2.065 mol), K2C03 (314g, 2.273 mol), Kl (68.6g, 0.413 moL) and DMF (2.5L) and the resulting mixture was heated to 70 °C and stirred for 2.5 hours. After LC-MS showed that the reaction was complete, the mixture was cooled to 50 °C and methanol (620 ml_) was added. Then the mixture was cooled to 30 °C and water (4.75 L) was added. The resulting suspension was cooled to 10 °C and for 1 hour. The solid was filtered, washed with water (2 X 2.5 L) and air dried for 2 days to afford the compound 7 (630 g, 89.1 %) as a yellow solid.

00186 Step 4

00187 To a solution of compound 7 (630 g, 1.84 mol) in THF/ethanol (8 L at 1 :1 ) was added Pd/C (10%, 50% wet, 30 g). The mixture was stirred under an

atmosphere of hydrogen (1 atm, balloon) at 15-20 °C for 4h. The reaction mixture was filtered through a pad of Celite and the pad was washed with TFIF (1.0 L). The filtrate was concentrated to 3 volumes under vacuum and hexanes (4.0 L) was added. The resulting slurry was cooled to 0 °C and stirred for 1 h. The solid was filtered and washed with hexanes (2 X 500 ml_) and air dried overnight to afford the compound 8 (522 g, 90.8%) as an off -white solid.

00188 Step 5

00189 A 5L three-neck flask was charged with compound 4 (250 g, 0.929 mol, 1 eq.), compound 8 (290 g, 0.929mol, 1 eq.) and DMF (2.5 L) and the resulting mixture was stirred at room temperature until it became a clear solution. To the solution was added TBTU (328 g, 1.021 mol, 1.1 eq.), followed by triethylamine (272 ml_, 1.95 mol, 2.1 eq.) and the resulting mixture was stirred at room temperature under nitrogen overnight. The mixture was poured slowly into water (7.5 L) with stirring and the resulting suspension was stirred for 1 hour at room temperature. The solid was filtered and washed with water (2 X 7 L). The solid thus obtained was dried using a vacuum oven at 50 °C for two days and 509.0 g (97.3%) of compound 9 was obtained as yellow solid.

00190 Step 6

00191 300.0 g (0.532 mol) of compound 9 was suspended in acetic acid (1.2 L) and heated to 70 °C. The resultant solution was hot filtered and heated to 70°C again. Preheated ethanol (70 °C, 3.6 L) was then added. To this solution was added concentrated HCI (66.0 ml_, 0.792 mol, 1.5 eq.) dropwise over 30 min. The resulting solution was stirred at 70°C until crystallization commenced (~about 20 min). The suspension was cooled to room temperature over 3h, filtered, washed with ethanol (2 X 1.8 L) and dried using a vacuum oven at 60°C over the weekend to afford compound 10 (253.0 g, 79.2%) as a brown solid.

Example 2 Manufacture of a Deuterated Elacridar analog EE60.

00192 EE60 is synthesized by the procedure shown in Figure 4 and as continued in Figure 5.

00193 The structure of EE60 is confirmed as follows: Samples of 5 pi are measured using an LC system comprising an UltiMate 3000 LC Systems (Dionex, Sunnyvale, CA) and an 2996 UV diode array detector (Waters). Samples are injected on to a 100 x 2mm (ID) 3.5 pm ZORBAX Extend-C18 column (Agilent, Santa Clara, CA). Elution is done at a flow rate of 0.4 mL/min using a 5 minute gradient from 20% to 95% B (mobile phase A was 0.1 % FICOOFI in water (v/v) and mobile phase B was methanol). 95% B is maintained for 1 min followed by re-equilibration at 20% B. Chromeleon (v6.8) is used for data acquisition and peak processing.

Example 3: Manufacture of a Deuterated Elacridar analog EE59

00194 EE59 was synthesized by the procedure shown in Figure 6.

00195 The resulting yellowish brown precipitate was removed by filtration and the filter cake was dried overnight (72 mg). Analysis of the filter cake by LCMS indicated the presence of a single peak at multiple wavelengths (215 nm, 220 nm, 254 nm,

280 nm); each peak confirmed the presence of the desired product (LC retention time, 5.3 min; m/z = 575 [(M+FI)+]).

00196 1H NMR of EE598 revealed 1H NMR (400 MHz, DMSO-d6) d 12.3 ( s , 1H), 10.6 (s, 1H), 8.51-8.46 (m, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.45-7.38 (m, 2H), 7.32-7.25 (m, 3H), 6.66 (d, J = 6.8 Hz, 2H), 3.62 (s, 2H), 2.86 (t, J = 6.8 Hz, 2H), 2.66 (m, 4H).

Example 4: Demonstration of superior properties of instant analogs and compositions: in vivo ADMET.

00197 Pharmacologic studies are performed according to Ward KW et al (2001 Xenobiotica 317783-797) and Ward and Azzarano (JPET 310:703-709, 2004).

Briefly, instant analogs are administered solutions in 10% aqueous polyethylene glycol-300 (PEG-300) or 6% Cavitron with 1 % dimethyl sulfoxide, or as well triturated suspensions in 0.5% aqueous HPMC containing 1 % Tween 80. Blood samples are collected at various times up to 48 h after drug administration; plasma samples are prepared and at “70°C until analysis.

00198 Mice. Instant analogs are administered to four groups of animals by oral gavage (10 ml/kg dose volume). Three groups receive instant analogs as a suspension at 3, 30, or 300 mg/kg, and the fourth group receive instant analogs as a solution in Cavitron at 3 mg/kg. Blood sampling in mice is performed via a tail vein at 0.5, 1 , 2, 4, 8, 24, and 32 h postdose.

00199 Rats. A total of seven groups of animals receive instant analogs by oral gavage (10 ml/kg). Three groups receive instant analogs as a suspension at 3, 30, or 300 mg/kg, and a fourth and fifth group each receive instant analogs as a solution in Cavitron or PEG-300, respectively, at 3 mg/kg. A sixth and seventh group of rats with indwelling hepatic portal vein catheters receive instant analogs by oral gavage (10 ml/kg) as a suspension at 3 or 30 mg/kg, respectively. Blood sampling in rats are performed via a lateral tail vein; samples are also obtained from the hepatic portal vein catheter. Blood samples are obtained before dosing and at 5, 15, 30, and 45 min, and 1 ,1.5, 2, 3, 4, 6, 8, 10, 24, and 32 h postdose.

00200 Dogs. Dogs receive instant analogs by lavage (4 ml/kg) on three separate occasions with dosages at 3 and 30 mg/kg as a suspension and 3 mg/kg as a solution in Cavitron. Blood samples are obtained from a cephalic vein and from the hepatic portal vein catheter before dosing and at 5, 15, 30, and 45 min and 1 , 1.5, 2, 3, 4, 6, 8, 10, 24, 32, and 48 h postdose.

00201 Monkeys. Monkeys receive instant analogs by oral gavage (8 ml/kg dose volume) on three separate occasions at dosages of 3 and 30 mg/kg as a suspension and 3 mg/kg as a solution in Cavitron. Blood samples are obtained from a femoral vein via an indwelling catheter and from the hepatic portal vascular access port

before dosing and at 5, 15, and 30 min and 1 , 1.5, 2, 4, 6, 8, 10, 24, 32, and 48 h postdose.

00202 Humans. Healthy volunteers receive instant analogs orally at doses ranging from 25 mg to 1000 mg. Blood samples are obtained and analyzed for analog concentrations at 0, 15 min, 30 min, 45 min, 60 min, 90 min, 120 min, 180 min, 2 hr, 4 hr, 6hr, 8 hr, 12 hr, 24 hr, and 48 h after administration .

Analytical Methods

00203 Instant analogs are isolated from samples by precipitation with acetonitrile and quantified by LC/MS/MS coupled with an atmospheric pressure chemical ionization interface (475°C). Internal standards [in acetonitrile/10 mM ammonium formate, pH 3.0; 95:5 (v/v)] are added to 50 pi samples and vortexed and centrifuged for 30 min at 4000 rpm. The supernatants are injected onto the LC/MS/MS system using an HTS PAL autosampler (CTC Analytics, Zwingen, Switzerland) coupled to an Aria TX2 high-throughput liquid chromatographic system using turbulent flow technology (Cohesive Technologies, Franklin, MA) in focus mode. The mobile phase consists of a mixture of 0.1 % formic acid in water and 0.1 % formic acid in

acetonitrile. The turbulent flow column is a 0.5 X 50-mm Cyclone P column

(Cohesive Technologies) in series to a 2 X 20 mm, 4 pm Polar RP (Phenomenex, Torrance, CA) analytical column. Positive-ion multiple reaction monitoring is used for the detection of instant analogs and internal standard and the selected precursor and product ions are mlz 564 and 252, respectively. Using a (1/x) weighted linear regression analysis of the calibration curve, linear responses in analyte/internal standard peak area ratios are observed for instant analog concentrations ranging from 2 to 10,000 ng/ml.

00204 Alternatively, useful analytical methods to demonstrate the surprising and superior properties of the instant elacridar analogs are the methods as described by Stokvis et al, J Mass Spectr 2004: 39: 1122-1130.



claiming nano-particle composition comprising breast cancer resistance protein inhibitor (eg elacridar).  Family member of the elacridar


J Med Chem 1995, 38(13): 2418


Product PATENT WO9212132



NMR includes d 2.60-2.95 (m,8H,CH2); 3.58 (s,2H,N–CH2 –Ph); 3.72 (s,6H,OMe); 4.05 (s,3H,OMe acridone); 6.78 (2s,2H,Ar.isoquinoline), 7.20-7.88 (m,8H,Ar.), 8.48 (t,2H,H1 and H8 acridone), 10.60 (s, 1H,CONH), 12.32 (s, 1H,NH acridone)

///////////Elacridar, GF-120918, GG-918 , GW-120918, GW-918, GF-120918A (HCl), solid tumors, GSK, GLAXO




Molecular Weight


CAS Number, 1187575-76-3




C32H38ClN3O2, 532.1 g/mol

CAS 603148-36-3




TTP-488; PF-04494700


MOA:RAGE inhibitor

Indication:Alzheimer’s disease (AD)

Status:Phase III (Active), Dementia, Alzheimer’s type
Company:vTv Therapeutics (Originator)


Azeliragon is in phase III clinical for the treatment of Alzheimer’s type dementia.

Azeliragon was originally by TransTech Pharma (now vTv Therapeutics), then licensed to Pfizer in 2006.

Pfizer discontinued the research in 2011, now vTv Therapeutics continues the further reaserch.

vTv Therapeutics  (previously TransTech Pharma) is developing azeliragon, an orally active antagonist of the receptor for advanced glycation end products (RAGE), for the treatment of Alzheimer’s disease (AD) in patients with diabetes.  In June 2019, this was still the case .

Azeliragon was originally developed at TransTech Pharma. In September 2006, Pfizer entered into a license agreement with the company for the development and commercialization of small- and large-molecule compounds under development at TransTech. Pursuant to the collaboration, Pfizer gained exclusive worldwide rights to develop and commercialize TransTech’s portfolio of RAGE modulators, including azeliragon.


1. WO03075921A2.

2. US2008249316A1.

US 20080249316

VTV Therapeutics

Azeliragon (TTP488) is an orally bioavailable small molecule that inhibits the receptor for advanced glycation endproducts (RAGE). A Phase 2 clinical trial to evaluate azeliragon as a potential treatment of mild-AD in patients with type 2 diabetes is ongoing.  The randomized, double-blind, placebo-controlled multicenter trial is designed as sequential phase 2 and phase 3 studies operationally conducted under one protocol. For additional information on the study, refer to NCT03980730 at

RAGE is an immunoglobulin-like cell surface receptor that is overexpressed in brain tissues of patients with AD. The multiligand nature of RAGE is highlighted by its ability to bind diverse ligands such as advanced glycation end-products (AGEs), linked to diabetic complications and β-amyloid fibrils, a hallmark of AD. The association between type 2 diabetes and AD is well documented. A linear correlation between circulating hemoglobin A1c (HbA1c) levels and cognitive decline has been demonstrated in the English Longitudinal Study of Ageing.



Novel crystalline forms of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine and its salt ( azeliragon ) (deignated as forms III and IV) as RAGE inhibitors useful for treating  psoriasis, rheumatoid arthritis and Alzheimer’s disease.

The Receptor for Advanced Glycation Endproducts (RAGE) is a member of the immunoglobulin super family of cell surface molecules. Activation of RAGE in different tissues and organs leads to a number of pathophysiological consequences. RAGE has been implicated in a variety of conditions including: acute and chronic inflammation (Hofmann et al., Cell 97:889-901 (1999)), the development of diabetic late complications such as increased vascular permeability (Wautier et al., J. Clin. Invest. 97:238-243 (1995)), nephropathy (Teillet et al., J. Am. Soc. Nephrol. 11 : 1488- 1497 (2000)), atherosclerosis (Vlassara et. al., The Finnish Medical Society DUODECIM, Ann. Med. 28:419-426 (1996)), and retinopathy (Hammes et al., Diabetologia 42:603-607 (1999)). RAGE has also been implicated in Alzheimer’s disease (Yan et al., Nature 382: 685-691 , (1996)), erectile dysfunction, and in tumor invasion and metastasis (Taguchi et al., Nature 405: 354-357, (2000)).

Binding of ligands such as advanced glycation endproducts (AGEs), S100/calgranulin/EN-RAGE, b-amyloid, CML (Ne-Carboxymethyl lysine), and amphoterin to RAGE has been shown to modify expression of a variety of genes. For example, in many cell types interaction between RAGE and its ligands generates oxidative stress, which thereby results in activation of the free radical sensitive transcription factor NF-kB, and the activation of NF-kB regulated genes, such as the cytokines IL- 1 b, TNF- a, and the like. In addition, several other regulatory pathways, such as those involving p21 ras.

MAP kinases, ERK1 and ERK2, have been shown to be activated by binding of AGEs and other ligands to RAGE. In fact, transcription of RAGE itself is regulated at least in part by NF-kB. Thus, an ascending, and often detrimental, spiral is fueled by a positive feedback loop initiated by ligand binding. Antagonizing binding of physiological ligands to RAGE, therefore, is our target, for down-regulation of the pathophysiological changes brought about by excessive concentrations of AGEs and other ligands for RAGE.

Pharmaceutically acceptable salts of a given compound may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, melting point, crystal shape, compaction behavior, flow properties, and/or solid state stability. These differences affect practical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability). Although U.S. Patent No. 7,884,219 discloses Form I and Form II of COMPOUND I as a free base, there is a need for additional drug forms that are useful for inhibiting RAGE activity in vitro and in vivo, and have properties suitable for large-scale manufacturing and formulation. Provided herein








Links to the following publications and presentations, which are located on outside websites, are provided for informational purposes only and do not constitute the opinions or views of vTv Therapeutics

Presentations and Posters

Links to the following publications and presentations, which are located on outside websites, are provided for informational purposes only and do not constitute the opinions or views of vTv Therapeutics

///////////Azeliragon, psoriasis, rheumatoid arthritis, Alzheimer’s disease, TTP-488,  PF-04494700, RAGE inhibitors, TransTech Pharma, PHASE 3, Dementia, Alzheimer’s type,


Afamelanotide, アファメラノチド , афамеланотид , أفاميلانوتيد , 阿法诺肽 ,


2D chemical structure of 75921-69-6

ChemSpider 2D Image | Afamelanotide | C78H111N21O19

Click here for structure editor


RN: 75921-69-6

Molecular Formula, C78-H111-N21-O19, Molecular Weight, 1646.8629


  • 75921-69-6
  • CUV1647
  • CUV-1647

alpha-Melanotropin, 4-L-norleucine-7-D-phenylalanine-

Prevention of Phototoxicity in Adults with Erythropoietic Protoporphyria (EPP)



афамеланотид [Russian] [INN]
أفاميلانوتيد [Arabic] [INN]
阿法诺肽 [Chinese] [INN]

Observations suggest that afamelanotide has beneficial effects in patients with erythropoietic protoporphyria, induces epidermal melanin formation.


Lensing, Cody J. et alFrom Journal of Medicinal Chemistry, 62(1), 144-158; 2019


oct 2019

FDA approves first treatment to increase pain-free light exposure in patients with a rare disorder

The U.S. Food and Drug Administration today granted approval to Scenesse (afamelanotide) to increase pain-free light exposure in adult patients with a history of phototoxic reactions (damage to skin) from erythropoietic protoporphyria.

For patients who are suffering from erythropoietic protoporphyria, a rare disorder, exposure to light may be extremely painful. Prior to today’s approval, there were no FDA-approved treatments to help erythropoietic protoporphyria patients increase their light exposure,” said Julie Beitz, M.D., director of FDA’s Center for Drug Evaluation and Research Office of Drug Evaluation III. “Today’s approval is one example of the FDA’s ongoing commitment to encourage industry innovation of therapies to treat rare diseases, and work with drug developers to make promising new therapies available to patients as safely and efficiently as possible.”

Erythropoietic protoporphyria is a rare disorder caused by mutations leading to impaired activity of ferrochelatase, an enzyme involved in heme production. Heme is an important component in hemoglobin, the oxygen carrying molecule in red blood cells. The decrease in ferrochelatase activity leads to an accumulation of protoporphyrin IX (PPIX) in the body. Light reaching the skin can react with PPIX causing intense skin pain and skin changes, such as redness and thickening. Scenesse (afamelanotide), a melanocortin-1 receptor (MC1-R) agonist, increases the production of eumelanin in the skin independent of exposure to sunlight or artificial light sources.  It is an implant that is administered subcutaneously (inserted under the skin).

The efficacy of Scenesse was established in two parallel group clinical trials with patients with erythropoietic protoporphyria who received Scenesse or placebo form of the implant subcutaneously every two months. The first clinical trial enrolled 93 subjects, of whom 48 received Scenesse, and were followed for 180 days. The primary endpoint was the total number of hours over 180 days spent in direct sunlight between 10 a.m. and 6 p.m. on days with no pain. The median total number of hours over 180 days spent in direct sunlight between 10 a.m. and 6 p.m. on days with no pain was 64 hours for patients receiving Scenesse and 41 hours for patients taking placebo.

The second clinical trial enrolled 74 patients, of whom 38 received Scenesse, and were followed for 270 days. The primary endpoint was the total number of hours over 270 days spent outdoors between 10 am and 3 pm on days with no pain for which “most of the day” was spent in direct sunlight. The analysis did not include sun exposure on days patients reported spending time in a combination of both direct sunlight and shade. The median total number of hours over 270 days spent outdoors between 10 am and 3 pm on days with no pain for which “most of the day” was spent in direct sunlight was six hours for patients receiving Scenesse and 0.75 hours for patients receiving placebo.

Scenesse’s most common side effects are implant site reaction, nausea, oropharyngeal (part of the throat just behind the mouth, where the oral cavity starts) pain, cough, fatigue, skin hyperpigmentation, dizziness, melanocytic nevus (moles), respiratory tract infection, somnolence (feeling drowsy), non-acute porphyria (build-up of normally occurring molecules created during heme production) and skin irritation. Scenesse should be administered by a health care professional who is proficient in the subcutaneous implantation procedure and has completed the applicant-provided training. Scenesse may induce skin darkening, and a full body skin examination is recommended for patients twice a year. In addition, patients are encouraged to maintain sun protection measures during treatment with Scenesse to prevent phototoxic reactions related to erythropoietic protoporphyria.

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

For more information:

Afamelanotide (melanotan ICUV1647; brand name Scenesse)[2] is a synthetic peptide and analogue of α-melanocyte stimulating hormone used to prevent skin damage from the sun in people with erythropoietic protoporphyria in Europe since January 2015. It is administered as an implant that is placed under the skin; the implant lasts for two months.

It is under development in other skin disorders in several jurisdictions. It causes skin to turn darker by causing the skin to make more melanin.

It was discovered at University of Arizona and initially developed there as a sunless tanning agent; the Australian company Clinuvel conducted further clinical trials in that and other indications, and brought the drug to market.

Unlicensed and untested powders sold as “melanotan” are found on the Internet marketed for tanning and other purposes, and multiple regulatory bodies have warned consumers that the peptides may be unsafe and ineffective.

Medical use

Afamelanotide is used in Europe to prevent phototoxicity in adults with erythropoietic protoporphyria (EPP).[1] It is an implant that is injected and placed under the skin; an implant lasts two months.[1]

People who have severe liver disease, liver impairment, or kidney impairment, should not use this drug. Pregnant women should not take it, and women who are active sexually should use contraception while they are taking it. It is not known if afamelanotide is secreted in breast milk.[1]

Adverse effects

Very common (up to 10% of people) adverse effects in people with EPP include headache and nausea. Common (between 1% and 10%) adverse effects include back pain, upper respiratory tract infections, decreased appetite, migraine, dizziness, weakness, fatigue, lethargy, sleepiness, feeling hot, stomach pain, diarrhea, vomiting, flushing and red skin, development of warts, spots, and freckles, itchy skin, and reactions at the injection site. There are many uncommon (less than 1%) adverse effects.[1]


Afamelanotide is thought to cause skin to darken by binding to the melanocortin 1 receptor which in turn drives melanogenesis.[1]

Afamelanotide has a half-life of 30 minutes. After the implant is injected, most of the drug is released within the first 2 days, with 90% released by the fifth day. By the tenth day no drug is detectable in plasma.[1]

Its metabolites, distribution, metabolism and excretion were not understood as of 2017.[1]


The amino acid sequence is Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2, and it is additionally known as [Nle4,D-Phe7]-α-MSH, which is sometimes abbreviated as NDP-MSH or NDP-α-MSH. Afamelanotide is the International Nonproprietary Name.[3]


The role of α-MSH in promoting melanin diffusion has been known since the 1960s.[4] In the 1980s, scientists at University of Arizona began attempting to develop α-MSH and analogs as potential sunless tanning agents, and synthesized and tested several analogs, including melanotan-I.[5]

To pursue the tanning agent, melanotan-I was licensed by Competitive Technologies, a technology transfer company operating on behalf of University of Arizona, to an Australian startup called Epitan,[6][5] which changed its name to Clinuvel in 2006.[7]

Early clinical trials showed that the peptide had to be injected about ten times a day due to its short half-life, so the company collaborated with Southern Research in the US to develop a depot formulation that would be injected under the skin, and release the peptide slowly. This was done by 2004.[6]

As of 2010, afamelanotide was in Phase III trials for erythropoietic protoporphyria and polymorphous light eruption, and was in Phase II trials for actinic keratosis and squamous cell carcinoma, and had been trialled in phototoxicity associated with systemic photodynamic therapy and solar urticaria.[8] Clinuvel had also obtained orphan drug status for afamelanotide in the US and the EU by that time.[8]

In May 2010 the Italian Medicines Agency (AIFA, or Agenzia Italiana del Farmaco) approved afamelanotide as a treatment for erythropoietic protoporphyria.[9]

In January 2015 afamelanotide was approved by the EMA in Europe for the treatment of phototoxicity in people with EPP.[1]

Society and culture


A number of products are sold online and in gyms and beauty salons as “melanotan” or “melanotan-1” which discuss afamelanotide in their marketing.[10][11] [12]

The products are not legal in any jurisdiction and are dangerous.[13][14][15][16]

Starting in 2007 health agencies in various counties began issuing warnings against their use.[17][18][19][20] [21][22]


Sawyer T K; Sanfilippo P J; Hruby V J; Engel M H; Heward C B; Burnett J B; Hadley M E

  • From Proceedings of the National Academy of Sciences of the United States of America (1980), 77(10), 5754-8.

2 Journal of Medicinal Chemistry (1982), 25(9), 1022-7.

3 Journal of medicinal chemistry (1984), 27(11), 1406-10.

4 Journal of Medicinal Chemistry (2019), 62(1), 144-158

5 Journal of Medicinal Chemistry (2018), 61(17), 7729-7740.

6 Journal of medicinal chemistry (2017), 60(2), 805-813.


US 4457864


  1. Jump up to:a b c d e f g h i “Scenesse: Summary of Product Characteristics” (PDF). EMA. 27 January 2016. Retrieved 6 April 2017. For updates see EMA Index page
  2. ^ “Afamelanotide”. AdisInsight. Retrieved 6 April 2017.
  3. ^ “International Nonproprietary Names for Pharmaceutical Substances (INN)” (PDF)World Health Organization. 2009. Retrieved 2009-03-02.
  4. ^ Baker, BI (31 May 1993). “The role of melanin-concentrating hormone in color change”. Annals of the New York Academy of Sciences680: 279–89. doi:10.1111/j.1749-6632.1993.tb19690.xPMID 8390154.
  5. Jump up to:a b Hadley, ME; Dorr, RT (April 2006). “Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization”. Peptides27 (4): 921–30. doi:10.1016/j.peptides.2005.01.029PMID 16412534.
  6. Jump up to:a b “EpiTan focuses on Melanotan, a potential blockbuster”The Pharma Letter. 1 November 2004.
  7. ^ “Epitan changes name to Clinuvel, announces new clinical program”LabOnline. 27 February 2006.
  8. Jump up to:a b Dean, Tim (3 May 2010). “Biotechnology profile: Bright future for Clinuvel (ASX:CUV)”Australian Life Scientist. Archived from the original on 6 April 2017.
  9. ^ “GAZZETTA UFFICIALE: SOMMARIO”Agenzia Nazionale Stampa Associata. 2010. Retrieved 2010-05-17.
  10. ^ “Believe It Or Not ‘Tanorexia’ A Very Real Problem”WCBS-TVCBS. 2009-05-20. Archived from the original on May 21, 2009. Retrieved 2009-07-23.
  11. ^ “Fools Gold”Cosmopolitan (Australia). 2009-06-14. Retrieved 2009-07-25.
  12. ^ Madrigal, Alexis (2009-01-29). “Suntan Drug Greenlighted for Trials”WiredArchivedfrom the original on 5 May 2009. Retrieved 2009-04-11.
  13. ^ “Tanning drug a health risk”Herald Sun. 2009-10-31. Retrieved 2009-10-31.
  14. ^ Ewan A Langan; Z. Nie; Lesley E Rhodes (June 2010). “Melanotropic peptides: More than just “Barbie drugs” and “sun tan jabs?“. British Journal of Dermatology163 (3): 451–5. doi:10.1111/j.1365-2133.2010.09891.xPMID 20545686.
  15. ^ Ewan A Langan; Denise Ramlogan; Lynne A Jamieson; Lesley E Rhodes (January 2009). “Change in moles linked to use of unlicensed “sun tan jab“. BMJ338: b277. doi:10.1136/bmj.b277PMID 19174439.
  16. ^ “Risky tan jab warnings ‘ignoredBBC. 2009-02-18. Archived from the original on 21 February 2009. Retrieved 2009-03-04.
  17. ^ “Warning against the product Melanotan”Danish Medicines Agency. 2008. Retrieved 2008-08-11.
  18. ^ Tan jab” is an unlicensed medicine and may not be safe”MHRA. 2008. Archived from the original on 2014-12-05. Retrieved 2008-11-17.
  19. ^ “US Lab Research Inc Warning letter”. U.S. Food and Drug Administration. 2009-01-29. Archived from the original on 10 July 2009. Retrieved 2009-07-23.
  20. ^ “Melanotan Powder for Injection”Notice Information: – Warning – 27 February 2009Irish Medicines Board. 2009. Retrieved 2009-02-02.
  21. ^ “Legemiddelverket advarer mot bruk av Melanotan”. Norwegian Medicines Agency. 2007-12-13. Archived from the original on 17 April 2009. Retrieved 2009-03-11.
  22. ^ “Melanotan – farlig og ulovlig brunfarge”Norwegian Medicines Agency. 2009-01-23. Archived from the original on 17 April 2009. Retrieved 2009-03-11.
Clinical data
Pronunciation /ˌæfəmɛˈlæntd/ (About this soundlisten)
Trade names Scenesse
Synonyms Melanotan; Melanotan-1; Melanotan I; CUV1647; EPT1647; NDP-MSH; NDP-α-MSH; [Nle4,D-Phe7]α-MSH
AHFS/ UK Drug Information
License data
Routes of
S.C.I.M.I.V.subcutaneous implantintranasal
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Elimination half-life 30 minutes[1]
CAS Number
PubChem CID
CompTox Dashboard (EPA)
Chemical and physical data
Formula C78H111N21O19
Molar mass 1646.845 g/mol g·mol−1
3D model (JSmol)

/////////////fda 2019, Scenesse, afamelanotide,  pain-free light exposure,  erythropoietic protoporphyria, アファメラノチド , афамеланотид أفاميلانوتيد 阿法诺肽 

Afamelanotide acetate [USAN]

MW: 1706.9145

2D chemical structure of 1566590-77-9

Valacyclovir HCl


ChemSpider 2D Image | Valaciclovir | C13H20N6O4


124832-26-4 [RN]
2-[(2-amino-6-hydroxy-9H-purin-9-yl)methoxy]ethyl L-valinate
2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl L-valinate [ACD/IUPAC Name]
2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl-L-valinat [German] [ACD/IUPAC Name]
2-{[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]oxy}ethyl L-valinate
L-Valinate de 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)méthoxy]éthyle [French] [ACD/IUPAC Name]
L-Valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester
L-valine ester with 9-[(2-hydroxyethoxy)methyl]guanine
L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester [ACD/Index Name]
L-valine, 2-[(2-amino-6-hydroxy-9H-purin-9-yl)methoxy]ethyl ester
CAS Registry Number: 124832-26-4
CAS Name: L-Valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester
Additional Names: L-valine ester with 9-[(2-hydroxyethoxy)methyl]guanine; valaciclovir; ValACV
Molecular Formula: C13H20N6O4
Molecular Weight: 324.34
Percent Composition: C 48.14%, H 6.22%, N 25.91%, O 19.73%
Literature References: L-Valine ester prodrug of acyclovir, q.v. Prepn: T. A. Krenitsky et al., EP 308065; L. M. Beauchamp, US4957924 (1989, 1990 both to Wellcome). Evaluation as prodrug: L. M. Beauchamp et al., Antiviral Chem. Chemother. 3, 157 (1992). Clinical pharmacokinetics: S. Weller et al., Clin. Pharmacol. Ther. 54, 595 (1993). Review of pharmacology and clinical efficacy in herpes virus infections: C. M. Perry, D. Faulds, Drugs 52, 754-772 (1996). Clinical trial to prevent cytomegalovirus disease in renal transplantation: D. Lowance et al., N. Engl. J. Med. 340, 1462 (1999); to prevent transmission of genital herpes: L. Corey et al., ibid. 350, 11 (2004).
Derivative Type: Hydrochloride
CAS Registry Number: 124832-27-5
Manufacturers’ Codes: 256U; BW-256U87; BW-256
Trademarks: Valtrex (GSK)
Properties: Crystalline solid, occurs as hydrate. uv max (water): 252.8 nm (e 8530). Soly in water: 174 mg/ml.
Absorption maximum: uv max (water): 252.8 nm (e 8530)
Therap-Cat: Antiviral.
Keywords: Antiviral; Purines/Pyrimidinones
Valaciclovir is the hydrochloride salt of L-valyl ester of the antiviral drug aciclovir (Zovirax[R]). It was first launched in 1995 by GlaxoSmithKline (GSK) for the oral treatment of recurrent genital herpes, varicella zoster virus (VZV) and herpes simplex virus (HSV) infection in immunocompetent adults.
Valaciclovir was originally developed by GSK and was subsequently licensed to Sigma-Tau and Sanofi (formerly known as sanofi-aventis). In March 2003, GSK and Shionogi signed a letter of intent to copromote both aciclovir and valaciclovir in Japan, where it has been marketed by GSK since 2000.

Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster(shingles).[1] It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases.[1] It is taken by mouth.[1]

Common side effects include headache and vomiting.[1] Severe side effects may include kidney problems.[1] Use in pregnancy appears to be safe.[1] It is a prodrug, which works after being converted to aciclovir in a person’s body.[1]

Valaciclovir was patented in 1987 and came into medical use in 1995.[2][3] It is available as a generic medication.[4] A month supply in the United Kingdom costs the NHS about £3 as of 2019.[4] In the United States the wholesale cost of this amount is about US$2.80.[5]In 2016 it was the 168th most prescribed medication in the United States with more than 3 million prescriptions.[6]

Medical uses

Valtrex brand valaciclovir 500mg tablets

Valaciclovir is used for the treatment of HSV and VZV infections, including:[7]

  • Oral and genital herpes simplex (treatment and prevention)
  • Reduction of HSV transmission from people with recurrent infection to uninfected individuals
  • Herpes zoster (shingles): the typical dosage for treatment of herpes is 1,000 mg orally three times a day for seven consecutive days.[8]
  • Prevention of cytomegalovirus following organ transplantation
  • Prevention of herpesviruses in immunocompromised people (such as those undergoing cancer chemotherapy)[9]
  • Chickenpox in children ages 2-18)[10]

It has shown promise as a treatment for infectious mononucleosis[11][12][13] and is preventively administered in suspected cases of herpes B virus exposure.[14]

Valaciclovir is not recommended in Bell’s palsy due to lack of benefit.[15]

Adverse effects

Common adverse drug reactions (≥1% of people) associated with valaciclovir are the same as for aciclovir, its active metabolite. They include: nausea, vomiting, diarrhea and headache. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo, confusion, dizziness, edemaarthralgia, sore throat, constipation, abdominal pain, rash, weakness and/or renal impairment. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenialeukopenia, tremor, ataxiaencephalopathy, psychotic symptoms, crystalluriaanorexia, fatigue, hepatitisStevens–Johnson syndrometoxic epidermal necrolysis and/or anaphylaxis.[7]


Valaciclovir belongs to a family of molecules. Valaciclovir is a prodrug, an esterified version of aciclovir that has greater oral bioavailability (about 55%) than aciclovir.[10] It is converted by esterases to the active drug, aciclovir, and the amino acidvaline, via hepatic first-pass metabolismAciclovir is selectively converted into a monophosphate form by viral thymidine kinase, which is more effective (3000 times) in phosphorylation of aciclovir than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into a disphosphate by cellular guanylate kinase and then into the active triphosphate form, aciclo-GTP, by cellular kinases.[10]

Mechanism of action

Aciclo-GTP, the active triphosphate metabolite of aciclovir, is a very potent inhibitor of viral DNA replication. Aciclo-GTP competitively inhibits and inactivates the viral DNA polymerase.[10] Its monophosphate form also incorporates into the viral DNA, resulting in chain termination. It has also been shown that the viral enzymes cannot remove aciclo-GMP from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolized within the cell, possibly by cellular phosphatases.[16]

Aciclovir is active against most species in the herpesvirus family. In descending order of activity:[17]

The drug is predominantly active against HSV and, to a lesser extent, VZV. It is only of limited efficacy against EBV and CMV. However, valacyclovir has recently been shown to lower or eliminate the presence of the Epstein–Barr virus in subjects afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms.[11][12][13] Although it can prevent the establishment of viral latency, acyclovir therapy has not proven effective at eradicating latent viruses in nerve ganglia.[17]

As of 2005, resistance to valaciclovir has not been significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase and mutations to viral thymidine kinase and/or DNA polymerase that alter substrate sensitivity.[18]

It also is used for herpes B virus postexposure prophylaxis.[14]


Valaciclovir was patented in 1987 and came into medical use in 1995.[2][3] It is available as a generic medication.[4] A month supply in the United Kingdom costs the NHS about £3 as of 2019.[4] In the United States the wholesale cost of this amount is about US$2.80.[5] In 2019, it was the 168th most prescribed medication in the United States with more than 3 million prescriptions.[6]


It is marketed by GlaxoSmithKline under the trade names Valtrex and Zelitrex. Valaciclovir has been available as a generic drug in the U.S. since November 25, 2009.[19]

Valtrex is offered in 500 mg and 1 gram tablets, with the active ingredient valacyclovir hydrochloride. The inactive ingredients include carnauba wax, colloidal silicon dioxide, crospovidoneFD&C Blue No. 2 Lakehypromellosemagnesium stearatemicrocrystalline cellulosepolyethylene glycolpolysorbate 80povidone, and titanium dioxide.[20]


Acyclovir (I) was coupled with N-Cbz-L-valine (II) in the presence of DCC and DMAP to afford the Cbz-protected valyl ester (III). The N-benzyloxycarbonyl group of (III) was then removed by either hydrogenation over Pd/C or by transfer hydrogenation in the presence of formic acid. AU 8820978; EP 0308065; EP 0596542; JP 1989068373; JP 1991115284; US 4957924; US 5061708


In an alternative procedure, condensation of L-valine (IV) with methyl acetoacetate (V) in the presence of NaOH produced the enamine-protected valine sodium salt (VI). Condensation of (VI) with the tosylate (VII), (prepared from acyclovir (I) and tosyl chloride) afforded ester (VIII). Then, acidic hydrolysis of the enaminoester moiety of (VIII) furnished the target valine ester. Similar procedures were also reported using omega-mesyl and omega-chloro acyclovir.


The esterification of acyclovir (I) with N-(tert-butoxycarbonyl)-L-valine (II) by means of EDC, TEA and DMAP in DMF gives the corresponding ester (III) which is finally deprotected by means of HCl in water to afford the target valacyclovir.


    • Synonyms:Valacyclovir, BW-256U, 256 U 87
    • ATC:J05AB11
  • Use:antiviral, prodrug of aciclovir
  • Chemical name:l-valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester
  • Formula:C13H20N6O4
  • MW:324.34 g/mol
  • CAS-RN:124832-26-4
  • InChI:InChI=1S/C13H20N6O4/c1-7(2)8(14)12(21)23-4-3-22-6-19-5-16-9-10(19)17-13(15)18-11(9)20/h5,7-8H,3-4,6,14H2,1-2H3,(H3,15,17,18,20)/t8-/m0/s1



  • Formula:C13H20N6O4 • HCl
  • MW:360.80 g/mol
  • CAS-RN:124832-27-5

Substance Classes

Synthesis Path


    • US 4 957 924 (Burroughs Wellcome; 18.9.1990; GB-prior. 15.8.1987).
    • EP 308 065 (Wellcome Found. Ltd; appl. 12.8.1988; GB-prior. 15.8.1987, 5.11.1987).
  • combination with lamotrigine:

    • WO 9 505 179 (Wellcome Found. Ltd; appl. 17.8.1994; GB-prior. 18.8.1993).
  • water-dispersible tablets:

    • WO 9 213 527 (Wellcome Found. Ltd; appl. 29.1.1992; GB-prior. 30.1.1991, 22.11.1991, 25.11.1991).
  • medical use for preventing post herpetic neuralgia:

    • GB 2 282 759 (SmithKline Beecham; appl. 14.10.1994; GB-prior. 16.10.1993).


  1. Jump up to:a b c d e f g “Valacyclovir Hydrochloride Monograph for Professionals” American Society of Health-System Pharmacists. Retrieved 17 March 2019.
  2. Jump up to:a b Long, Sarah S.; Pickering, Larry K.; Prober, Charles G. (2012). Principles and Practice of Pediatric Infectious Disease. Elsevier Health Sciences. p. 1502. ISBN 1437727026.
  3. Jump up to:a b Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 504. ISBN 9783527607495.
  4. Jump up to:a b c d British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 625–626. ISBN 9780857113382.
  5. Jump up to:a b “NADAC as of 2019-02-27”Centers for Medicare and Medicaid Services. Retrieved 3 March 2019. Cite error: The named reference “NADAC2019” was defined multiple times with different content (see the help page).
  6. Jump up to:a b “The Top 300 of 2019” Retrieved 22 December 2018. Cite error: The named reference “:1” was defined multiple times with different content (see the help page).
  7. Jump up to:a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3[page needed]
  8. ^ Lille, H. Martina; Wassilew, Sawko W. (2006). “Antiviral therapies of shingles in dermatology”. In Gross, Gerd; Doerr, H.W. (eds.). Herpes zoroster: recent aspects of diagnosis and control. Monographs in virology. 26. Basel (Switzerland): Karger Publishers. p. 124. ISBN 978-3-8055-7982-7. Retrieved January 1, 2012.
  9. ^ Elad S, Zadik Y, Hewson I, et al. (August 2010). “A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea”. Support Care Cancer18 (8): 993–1006. doi:10.1007/s00520-010-0900-3PMID 20544224.
  10. Jump up to:a b c d “VALTREX (valacyclovir hydrochloride) Caplets -GSKSource” Retrieved 2019-08-02.
  11. Jump up to:a b Balfour et al. (December 2005) A controlled trial of valacyclovir in infectious mononucleosis. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC., December 18, 2005. Abstract V1392
  12. Jump up to:a b Simon, Michael W.; Robert G. Deeter; Britt Shahan (March 2003). “The Effect of Valacyclovir and Prednisolone in Reducing Symptoms of EBV Illness In Children: A Double-Blind, Placebo-Controlled Study” (PDF)International Pediatrics18 (3): 164–169.[dead link]
  13. Jump up to:a b Balfour HH, Hokanson KM, Schacherer RM, et al. (May 2007). “A virologic pilot study of valacyclovir in infectious mononucleosis”. Journal of Clinical Virology39 (1): 16–21. doi:10.1016/j.jcv.2007.02.002PMID 17369082.
  14. Jump up to:a b “B Virus—First Aid and Treatment—Herpes B—CDC”. Retrieved June 6, 2015.
  15. ^ Baugh, Reginald F.; Basura, Gregory J.; Ishii, Lisa E.; Schwartz, Seth R.; Drumheller, Caitlin Murray; Burkholder, Rebecca; Deckard, Nathan A.; Dawson, Cindy; Driscoll, Colin (November 2013). “Clinical Practice Guideline: Bell’s Palsy”Otolaryngology–Head and Neck Surgery149 (3_suppl): S1–S27. doi:10.1177/0194599813505967ISSN 0194-5998In summary, antiviral therapy alone (acyclovir or valacyclovir) is not recommended in the treatment of Bell’s palsy due to lack of effectiveness of currently available drugs, unnecessary cost, and the potential for drug-related complications.
  16. ^[permanent dead link]
  17. Jump up to:a b O’Brien JJ, Campoli-Richards DM (March 1989). “Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy”. Drugs37 (3): 233–309. doi:10.2165/00003495-198937030-00002PMID 2653790.
  18. ^ Sweetman, Sean C., ed. (2005). Martindale: the complete drug reference (34th ed.). London: Pharmaceutical Press. ISBN 0-85369-550-4OCLC 56903116.[page needed]
  19. ^ Ahmed, Rumman (November 27, 2009). “Ranbaxy Launches Generic Valtrex in U.S.”The Wall Street Journal. Retrieved January 16, 2010.
  20. ^ “Valtrex Prescribing Information” (PDF)GlaxoSmithKline. September 2008. Retrieved May 7, 2009.

External links

Valaciclovir structure.svg
Clinical data
Trade names Valtrex, Zelitrex, others
AHFS/ Monograph
MedlinePlus a695010
License data
  • AU: B3
  • US: B (No risk in non-human studies)
Routes of
By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 55%
Protein binding 13–18%
Metabolism Liver (to aciclovir)
Elimination half-life <30 minutes (valaciclovir);
2.5–3.6 hours (aciclovir)
Excretion Kidney 40–50% (aciclovir),
faecal 47% (aciclovir)
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard 100.114.479 Edit this at Wikidata
Chemical and physical data
Formula C13H20N6O4
Molar mass 324.336 g/mol g·mol−1
3D model (JSmol)

//////////////Valacyclovir HCl,hydrochloride salt of L-valyl ester,  aciclovir, GlaxoSmithKline ,

Flecainide acetate

Skeletal formula of flecainide


54143-55-4 (free base)

200-659-6 [EINECS]
258-997-5 [EINECS]
54143-55-4 [RN]
Benzamide, N-(2-piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)-
  • Molecular FormulaC17H20F6N2O3
  • Average mass414.343 Da
CAS Registry Number: 54143-55-4
CAS Name: N-(2-Piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide
Molecular Formula: C17H20F6N2O3
Molecular Weight: 414.34
Percent Composition: C 49.28%, H 4.87%, F 27.51%, N 6.76%, O 11.58%
Literature References: Prepn: E. H. Banitt, W. R. Brown, US 3900481 (1975 to Riker); of the acetate: eidem, US 4005209 (1977 to Riker); E. H. Banitt et al., J. Med. Chem. 20, 821 (1977). Preliminary pharmacological study: J. R. Schmid et al., Fed. Proc. 34,775 (1975). In vitro electrophysiological study: A. B. Hodess et al., J. Cardiovasc. Pharmacol. 1, 427 (1979). Antiarrhythmic effects: P. Somani, Clin. Pharmacol. Ther. 27, 464 (1980). Use in acute exptl myocardial infarction: H. Gülker et al., Z. Cardiol. 70, 124 (1981). Clinical study in ventricular arrhythmias: J. L. Anderson et al., N. Engl. J. Med. 305, 473 (1981). Determn of acetate in human plasma by spectrophotofluorometry: S. F. Chang et al., Arzneim.-Forsch. 33, 251 (1983). Review of pharmacology and clinical efficacy: D. M. Roden, R. L. Woosley, N. Engl. J. Med. 315, 36-41 (1986). Symposium on clinical experience: Am. J. Cardiol. 62, Suppl., 1D-67D (1988). Comprehensive description: S. Alessi-Severini et al., Anal. Profiles Drug Subs. Excip. 21, 169-195 (1992).
Properties: uv max (ethanol): 205, 230, 300 nm (E1%1cm 521, 219, 59).
Absorption maximum: uv max (ethanol): 205, 230, 300 nm (E1%1cm 521, 219, 59)
White crystalline powder, m.p. 148-51 °C; hydrochloride, m.p. 228-9 °C
Derivative Type: Monoacetate
CAS Registry Number: 54143-56-5
Manufacturers’ Codes: R-818
Trademarks: Almarytm (Synthelabo); Apocard (Esteve); Ecrinal (Pharma Investi); Flécaine (3M Pharma); Tambocor (3M Pharma)
Molecular Formula: C17H20F6N2O3.C2H4O2
Molecular Weight: 474.39
Percent Composition: C 48.10%, H 5.10%, F 24.03%, N 5.91%, O 16.86%
Properties: White granular solid from isopropyl alcohol/isopropyl ether, mp 145-147°. Soly at 37° (mg/ml): water 48.4, alcohol 300.
Melting point: mp 145-147°
Therap-Cat: Antiarrhythmic (class IC).
Keywords: Antiarrhythmic.
Flecainide acetate is an antiarrhythmic that was first launched by 3M Pharmaceuticals in 1985 for the oral treatment of ventricular arrhythmias and supraventricular tachyarrhythmias
In 2007, the product was approved in Japan for the treatment of atrial fibrillation.
The compound was originally developed at 3M Pharmaceuticals. In January 1984, 3M signed a development and marketing agreement with Eisai for the Japanese market.
 3M’s pharmaceutical operations as well as regional marketing and intellectual property rights were acquired by Graceway in the U.S., Canada and Latin America, by Meda in Europe, and by Ironbridge Capital and Archer Capital in the Asia Pacific region, including Australia and South Africa. In 2011, Graceway’s active compounds were acquired by Medicis. In 2012, Medicis was acquired by Valeant (now Bausch Health).

Flecainide is a medication used to prevent and treat abnormally fast heart rates.[1] This includes ventricular and supraventricular tachycardias.[1] Its use is only recommended in those with dangerous arrhythmias or when significant symptoms cannot be managed with other treatments.[1] Its use does not decrease a person’s risk of death.[1] It is taken by mouth or injection into a vein.[1][2]

Common side effects include dizziness, problems seeing, shortness of breath, chest pain, and tiredness.[1] Serious side effects may include cardiac arrestarrhythmias, and heart failure.[1] It may be used in pregnancy, but has not been well studied in this population.[2][3] Use is not recommended in those with structural heart disease or ischemic heart disease.[1] Flecainide is a class Ic antiarrhythmic agent.[1] It works by decreasing the entry of sodium in heart cells, causing prolongation of the cardiac action potential.[1]

Flecainide was approved for medical use in the United States in 1985.[1] It is available as a generic medication.[2] A month supply in the United Kingdom costs the NHS about £7.68 as of 2019.[2] In the United States the wholesale cost of this amount is about 18.60 USD.[4]In 2016 it was the 273rd most prescribed medication in the United States with more than a million prescriptions.[5]

Medical uses

Flecainide is used in the treatment of many types of supraventricular tachycardias, including AV nodal re-entrant tachycardia (AVNRT) and Wolff-Parkinson-White syndrome (WPW).

It also has limited use in the treatment of certain forms of ventricular tachycardia (VT). In particular, flecainide has been useful in the treatment of ventricular tachycardias that are not in the setting of an acute ischemic event. It has use in the treatment of right ventricular outflow tract (RVOT) tachycardia[6] and in the suppression of arrhythmias in arrhythmogenic right ventricular dysplasia (ARVD).[7]Studies (notably the Cardiac Arrhythmia Suppression Trial) have shown an increased mortality when flecainide is used to suppress ventricular extrasystoles in the setting of acute myocardial infarction.[8][9]

In individuals suspected of having the Brugada syndrome, the administration of flecainide may help reveal the ECG findings that are characteristic of the disease process. This may help make the diagnosis of the disease in equivocal cases.[10]

Flecainide has been introduced into the treatment of arrhythmias in children.

In the long-term, flecainide seems to be safe in people with a healthy heart with no signs of left ventricular hypertrophyischemic heart disease, or heart failure.[11]

Side effects

Results of a medical study known as the Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that patients with structural heart disease (such as a history of MI (heart attack), or left ventricular dysfunction) and also patients with ventricular arrhythmias, should not take this drug. The results were so significant that the trial was stopped early and preliminary results were published.[12]

The dose may need to be adjusted in certain clinical scenarios. As with all other antiarrhythmic agents, there is a risk of proarrhythmiaassociated with the use of flecainide. This risk is probably increased when flecainide is co-administered with other class Ic antiarrhythmics, such as encainide. The risk of proarrhythmia may also be increased by hypokalemia.[13] The risk of proarrhythmia is not necessarily associated with the length of time an individual is taking flecainide, and cases of late proarrhythmia have been reported.[14] Because of the role of both the liver and the kidneys in the elimination of flecainide, the dosing of flecainide may need to be adjusted in individuals who develop either liver failure or renal failure.

Because of the negative inotropic effects of flecainide, it should be used with caution in individuals with depressed ejection fraction, and may worsen congestive heart failure in these individuals. It should be avoided in people with ischaemic heart disease and the elderly.[15]

As with all class I antiarrhythmic agents, Flecainide increases the capture thresholds of pacemakers.[16]


Due to the narrow therapeutic index of flecainide, physicians should be alert for signs of toxicity before life-threatening arrhythmias occur like torsades de pointes. While the toxic effects of flecainide are closely related to the plasma levels of the drug,[17] it is unfeasible to check the plasma concentration in an individual on a regular basis.

Signs of flecainide toxicity include marked prolongation of the PR interval and widening of the QRS duration on the surface ECG. There may be signs and symptoms attributable to overt heart failure secondary to sudden decreased myocardial contractility.


Treatment of flecainide cardiac toxicity involves increasing the excretion of flecainide, blocking its effects in the heart, and (rarely) institution of cardiovascular support to avoid impending lethal arrhythmias. Modalities that have had success include administration of a beta-sympathomimetic agent,[17] and administration of a sodium load[17](often in the form of hypertonic sodium bicarbonate). Placing the individual on cardiopulmonary bypass support may be necessary in order to temporarily remove the need for a beating heart and to increase blood flow to the liver.[18][19]


Flecainide has a very high affinity for lung tissue [20] and is associated with drug-induced interstitial lung disease.[21][22][23][24][25]


Flecainide has high bioavailability after an oral dose,[26] meaning that most of the drug that is ingested will enter the systemic blood stream. Peak serum concentrations can be seen 1 to 6 hours after ingestion of an oral dose. While the plasma half-life is about 20 hours, it is quite variable, and can range from 12 to 27 hours.[27] During oral loading with flecainide, a steady state equilibrium is typically achieved in 3 to 5 days.

The majority of flecainide is eliminated by the kidneys, with the remainder metabolized by the cytochrome P450 2D6 isoenzyme in the liver.[28] Therefore, alterations in renal function or urine pH will greatly affect the elimination of flecainide, as more is eliminated by the kidney than by the hepatic route.

Because of the dual elimination routes of flecainide and its tendency to decrease myocardial contractility,[15] flecainide interacts with numerous pharmaceuticals and can potentiate the effects of other myocardial depressants and AV node blocking agents. In addition, flecainide can decrease the metabolism or elimination of many (but not all) agents that use the cytochrome P450 enzyme system.

A full list of drug interactions with flecainide can be obtained from the manufacturer. Some important drug interactions with flecainide include:[citation needed]


Flecainide intoxication is rare but serious due to the cardiogenic shock that it provokes. Its diagnosis can be difficult in the lack of contributing anamnestic elements. Clinical and paraclinical signs are not specific. Treatment is primarily symptomatic, which gives good results thanks to the hypertonic solution of sodium salts. Organ donation is possible in the case of braindead patients who suffered a flecainide intoxication.[29]

Mechanism of action

Flecainide works by blocking the Nav1.5 sodium channel in the heart, slowing the upstroke of the cardiac action potential.[30] This thereby slows conduction of the electrical impulse within the heart, i.e. it “reduces excitability”. The greatest effect is on the His-Purkinje system and ventricular myocardium. The effect of flecainide on the ventricular myocardium causes decreased contractility of the muscle, which leads to a decrease in the ejection fraction.

The effect of flecainide on the sodium channels of the heart increases as the heart rate increases; This is known as use-dependence and is why that flecainide is useful to break a tachyarrhythmia.[31]

Flecainide also inhibits ryanodine receptor 2 (RyR2),[32] a major regulator of sarcoplasmic release of stored calcium ions. It can reduce calcium sparks and thus arrhythmogenic calcium waves in the heart.[33] While Flecainide therapy has been shown to suppress ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia(CPVT) and mouse models of this disease, the relative contribution from the inhibition of sodium channels and of RyR2 in this effect on CPVT is unclear.[34]

Brand names

Flecainide is sold under the trade name Tambocor (manufactured by 3M pharmaceuticals). Flecainide went off-patent on February 10, 2004. In addition to being marketed as Tambocor, it is also available in generic version and under the trade names Almarytm, Apocard, Ecrinal, and Flécaine.

Following is one of the synthesis routes: 2-Aminomethylpyridine (II) is condensed with 2,2,2-trifluoroethyl-2,5-bis(2,2,2-trifluoroethoxy)benzoate (I) in refluxing glyme to produce 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide (III), and the yielding product is then hydrogenated with H2 over Pd/C in acetic acid.

Systematic Method of Flecainide acetate


Flecainide acetate, 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate (I), is a drug for the treatment of arrhythmia. It and its neutral base are described in U.S. Pat. No. 3,900,481.

Figure US07196197-20070327-C00001

A key intermediate for the synthesis of Flecainide and its pharmaceutically acceptable salts is 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid (II). One prior method for the preparation of this intermediate, disclosed in British patent No. GB 2045760, is a multistep process which comprises the preparation of 1,4-bis(2,2,2-trifluoroethoxy)benzene from hydroquinone using the very expensive reagent trifluoroethyltriflate (CF3CH2OSO2CF3). 1,4-bis(2,2,2-trifluoroethoxy)benzene is then converted to 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid (II) through a multistep process. An alternative method described in the same patent begins from 1,4-dibromobenzene, which is then condensed with more than 8 equivalents of 2,2,2-trifluoroethanol, to furnish the 1,4-bis(2,2,2-trifluoroethoxy)benzene intermediate. 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid (II) is also be prepared starting from 1-bromo-4-fluorobenzene (PCT WO 02/066413) or from 2-bromo-5-chlorobenzoic acid (PCT WO 99/02498). All these approaches have limited commercial utility due to the cost of the reagents and the necessity for specialized equipment.

The method disclosed in British patent No. GB 2045760 for the preparation of the Flecainide base starts from 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid which is converted to its acid chloride and reacts either with 2-(aminomethyl)piperidine to form Flecainide in one step or with 2-(aminomethyl)pyridine, followed by catalytic hydrogenation of the pyridine ring, to form Flecainide base in two steps. The disadvantage of the one step process is that the acid chloride reacts non-selectively with both nitrogen atoms of the 2-(aminomethyl)piperidine, resulting in a mixture of the two acylated isomers.

Other preparations of Flecainide base are disclosed in WO 99/02498 and US2003/0032835. The process disclosed in WO 99/02498 starts from the cyanomethyl ester of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid, which selectively reacts with the primary amino group of 2-(aminomethyl)piperidine to furnish Flecainide. US 2003/032835 discloses a procedure which involves converting 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid to its activated 2,2,2-trifluoroethyl ester which then selectively reacts with the primary amino group of 2-(aminomethyl)piperidine to furnish Flecainide. Although activated esters of this type can be used for the formation of Flecainide, the reagents required to prepare them are expensive on the industrial scale. Moreover, the resulting cyanomethanol and 2,2,2-trifluoroethanol by-products are highly toxic. Esters from less expensive, non-toxic and readily available alcohols are still desired for commercial purposes. Based on the above deficiencies, a new process overcoming these deficiencies was required.

Figure US07196197-20070327-C00002

Figure US07196197-20070327-C00003

Figure US07196197-20070327-C00004

Figure US07196197-20070327-C00005

Figure US07196197-20070327-C00006


Preparation of 2-(2,2,2-trifluoroethoxy)benzoic acid

To a solution of 2,2,2-trifluoroethanol (40.0 g) and DMF (100 ml) was added sodium tert-butoxide (23.0 g) at 0° C. The solution was stirred at 20 to 25° C. for 1 hour at which point 2-chlorobenzoic acid (25.0 g) was added followed by cupric bromide (2.0 g). The mixture was stirred at 120° C. for 5 hours, cooled to 10° C., and water (30 ml) was added followed by 20% HCl solution (90 ml). The solution was extracted with dichloromethane (3×50 ml). The combined organic layers were washed with water (3×50 ml) and the volume was concentrated to 90 ml. Hexane (150 ml) was added to the residues, and the mixture was concentrated to volume of 120 ml and a further portion of hexane (30 ml) was added. The mixture was heated at 50° C. for 30 minutes and then stirred at room temperature for 1 hour. The solids were filtered to yield the crude product. This material was dissolved in ethyl acetate (50 ml), charcoal (1.7 g) was added and the mixture was stirred at room temperature a further 2 hours. The solution was filtered through Celite™ and crystallized from ethyl acetate/hexane to yield the pure product (30.9 g, yield 88.0%) as a white solid, m.p. 85–86° C.


Preparation of 5-bromo-2-(2,2,2-trifluoroethoxy)benzoic acid

To a solution of 2-(2,2,2-trifluoroethoxy)benzoic acid (22 g) in methylene chloride (100 ml), was added AlCl(13.3 g) at 0° C.followed by bromine (16.0 g, 0.1 mol). The reaction mixture was stirred at 0° C. for 1 hour and then at reflux for 2 hours. The solids were filtered and water (50 ml) and ethyl acetate (50 ml) were added to the filtrate. The aqueous layer was separated and extracted with ethyl acetate (2×60 ml) and the combined organic layers were washed with water (2×60 ml). The organic layer was concentrated under vacuum to dryness and hexane (100 ml) was added and the resulting suspension was stirred at 20 to 25° C. for 1 hour. The mixture was filtered and the cake was rinsed with heptanes (2×20 ml). The damp solids were dried in vacuum at 45° C. for 5–6 hours to give a white solid (28.3 g, yield 94.6%), m.p. 126–128° C.


Preparation of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid.

To a solution of 2,2,2-trifluoroethanol (14.7 g) and DMF (125 ml) was added sodium tert-butoxide (12.8 g) at 0° C. The solution was stirred at 20 to 25° C. for 1 hour at which point 5-bromo-2-(2,2,2-trifluoroethoxy)benzoic acid (20 g) was added followed by cupric bromide (2.0 g). The mixture was stirred at 100° C. for 10 hours, cooled to 10° C., and water (30 ml) was added followed by 20% HCl solution (90 ml). The solution was extracted with dichloromethane (3×80 ml), and the combined organic layers were washed with water (3×60 ml). The solution was concentrated to one-third of the original volume and hexane (200 ml) was added. The resulting suspension was stirred at room temperature for 2 hours, filtered and the damp cake was rinsed with hexane (2×40 ml). The damp cake was dried in vacuo at 40° C. for 5 hours to give the product as a white solid (16.02 g, yield 75.3%).


Preparation of methyl 2,5-bis(2,2,2-trifluoroethoxy)benzoate

A solution of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid (20 g) and thionyl chloride (15.0 g) in methanol (100 ml) was stirred at 80° C. for 2 hours. The solvents were evaporated under vacuum to give an oil residue. Toluene (100 ml) was added to the residue and the solution was washed with saturated NaHCO(30 ml) solution followed by water (3×30 ml). The organic layer was concentrated under reduced pressure to give the product as a white solid (20.5 g, yield 98.0%).


Preparation of Flecainide

A mixture of methyl 2,5-bis(2,2,2-trifluoroethoxy)benzoate (1.5 g), 2-(aminomethyl)piperidine (0.62 g) in toluene (3 ml) was stirred at reflux for 10 hours. After cooling to room temperature, water (10 ml) was added and two layers solution were separated. The aqueous layer was extracted with toluene (2×10 ml) and the combined organic layers were washed with water (3×10 ml). The organic layer was concentrated under reduced pressure to give Flecainide free base as a white solid (1.63 g, 85%).


Preparation of Flecainide acetate

To a solution of Flecainide free base (1.5 g) in isopropanol (7.5 ml) was added glacial acetic acid (0.3 g) and the solution was stirred under reflux for 2 hours. The solution was cooled to room temperature and hexane (15 ml) was added and solids began to precipitate. The resulting suspension was stirred at 20–25° C. for 2 hours and the solids were filtered and then rinsed with hexane (2×10 ml). The damp cake was dried in vacuum for 4 hours to give Flecainide acetate as a white solid (1.54 g, Yield 89%).


Publication numberPriority datePublication dateAssigneeTitle
US3900481A1974-04-011975-08-19Riker Laboratories IncDerivatives of pyrrolidine and piperidine
US4005209A *1974-04-011977-01-25Riker Laboratories, Inc.Antiarrhythmic method utilizing fluoroalkoxy-N-piperidyl and pyridyl benzamides
GB2045760A1979-03-191980-11-05Riker Laboratories IncProcess for the preparation of 2,5- bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl) benzamide (flecainide)
WO1999002498A11997-07-111999-01-21Finetech Ltd.Process and a novel intermediate for the preparation of flecainide
WO2002004419A22000-07-122002-01-17Geneva Pharmaceuticals, Inc.α,α-DIBROMO-α-CHLORO-ACETOPHENONES AS SYNTHONS
WO2002066413A12001-02-202002-08-29Narchem CorporationFlecainide synthesis
US20030032835A12001-08-102003-02-13Enrico ViganoProcess for the preparation of 2,5-bis-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide (FLECAINIDE)
US6593486B21997-04-212003-07-15Par Pharmaceutical, Inc.Process for making cyanomethyl ester precursors of flecainide


    • ATC:C01BC04
  • Use:antiarrhythmic
  • Chemical name:N-(2-piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide
  • Formula:C17H20F6N2O3
  • MW:414.35 g/mol
  • CAS-RN:54143-55-4
  • InChI:InChI=1S/C17H20F6N2O3/c18-16(19,20)9-27-12-4-5-14(28-10-17(21,22)23)13(7-12)15(26)25-8-11-3-1-2-6-24-11/h4-5,7,11,24H,1-3,6,8-10H2,(H,25,26)



  • Formula:C17H20F6N2O3 • C2H4O2
  • MW:474.40 g/mol
  • CAS-RN:54143-56-5

Synthesis Path


    • Banitt, E.H. et al.: J. Med. Chem. (JMCMAR) 18, 1130 (1975); 20, 821 (1977).
    • DE 2 513 916 (Riker; prior. 27.3.1975).
    • US 3 900 481 (Riker; 19.8.1975; prior. 1.4.1974).
    • US 4 005 209 (Riker; 25.1.1977; USA-prior. 1.4.1974, 27.5.1975).


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  12. ^ Cardiac Arrhythmia Suppression Trial (CAST) Investigators (1989). “Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction”. N Engl J Med321 (6): 406–12. doi:10.1056/NEJM198908103210629PMID 2473403.
  13. ^ Ohki R, Takahashi M, Mizuno O, Fujikawa H, Mitsuhashi T, Katsuki T, Ikeda U, Shimada K (2001). “Torsades de pointes ventricular tachycardia induced by mosapride and flecainide in the presence of hypokalemia”. Pacing Clin Electrophysiol24 (1): 119–21. doi:10.1046/j.1460-9592.2001.00119.xPMID 11227957.
  14. ^ Morganroth J (1992). “Early and late proarrhythmia from antiarrhythmic drug therapy”. Cardiovasc Drugs Ther6 (1): 11–14. doi:10.1007/BF00050910PMID 1533532.
  15. Jump up to:a b Santinelli V, Arnese M, Oppo I, Matarazzi C, Maione S, Palma M, Giunta A (1993). “Effects of flecainide and propafenone on systolic performance in subjects with normal cardiac function”. Chest103 (4): 1068–73. doi:10.1378/chest.103.4.1068PMID 8131440.
  16. ^ Fornieles-Pérez H, Montoya-García M, Levine P, Sanz O (2002). “Documentation of acute rise in ventricular capture thresholds associated with flecainide acetate”. Pacing Clin Electrophysiol25 (5): 871–72. doi:10.1046/j.1460-9592.2002.00871.xPMID 12049386.
  17. Jump up to:a b c Winkelmann B, Leinberger H (1987). “Life-threatening flecainide toxicity. A pharmacodynamic approach”. Annals of Internal Medicine106 (6): 807–14. doi:10.7326/0003-4819-106-6-807PMID 3107447.
  18. ^ Corkeron M, van Heerden P, Newman S, Dusci L (1999). “Extracorporeal circulatory support in near-fatal flecainide overdose”. Anaesth Intensive Care27 (4): 405–08. doi:10.1177/0310057×9902700413PMID 10470398.
  19. ^ Yasui R, Culclasure T, Kaufman D, Freed C (1997). “Flecainide overdose: is cardiopulmonary support the treatment?”. Annals of Emergency Medicine29 (5): 680–82. doi:10.1016/S0196-0644(97)70257-9PMID 9140253.
  20. ^ Latini R, Cavalli A, Maggioni AP, Volpi A (December 1987). “Flecainide distribution in human tissues”British Journal of Clinical Pharmacology24 (6): 820–22. doi:10.1111/j.1365-2125.1987.tb03252.xPMC 1386410PMID 3125854.
  21. ^ Ozkan M, Dweik RA, Ahmad M (September 2001). “Drug-induced lung disease”. Cleve Clin J Med68 (9): 782–85, 789–95. doi:10.3949/ccjm.68.9.782PMID 11563482.
  22. ^ Camus P, Fanton A, Bonniaud P, Camus C, et al. (2004). “Interstitial lung disease induced by drugs and radiation”. Respiration71 (4): 301–26. doi:10.1159/000079633PMID 15316202.
  23. ^ Pesenti S, Lauque D, Daste G, Boulay V, et al. (2002). “Diffuse Infiltrative Lung Disease Associated with Flecainide”. Respiration69 (2): 182–85. doi:10.1159/000056325PMID 11961436.
  24. ^ Haas M, Pérault MC, Bonnefoy P, Rodeau F, Caron F (2001). “[Interstitial pneumopathy due to flecainide]”. Presse Med30 (21): 1062. PMID 11471279.
  25. ^ Robain A, Perchet H, Fuhrman C (February 2000). “Flecainide-associated pneumonitis with acute respiratory failure in a patient with the LEOPARD syndrome”. Acta Cardiol55 (1): 45–57. doi:10.2143/ac.55.1.2005718PMID 10707759.
  26. ^ Smith G (1985). “Flecainide: a new class Ic antidysrhythmic”. Drug Intell Clin Pharm19(10): 703–07. doi:10.1177/106002808501901001PMID 3902429.
  27. ^ Padrini R, Piovan D, Busa M, al-Bunni M, Maiolino P, Ferrari M (1993). “Pharmacodynamic variability of flecainide assessed by QRS changes”. Clin Pharmacol Ther53 (1): 59–64. doi:10.1038/clpt.1993.9PMID 8422742.
  28. ^ Haefeli W, Bargetzi M, Follath F, Meyer U (1990). “Potent inhibition of cytochrome P450IID6 (debrisoquin 4-hydroxylase) by flecainide in vitro and in vivo”. J Cardiovasc Pharmacol15 (5): 776–79. doi:10.1097/00005344-199005000-00013PMID 1692938.
  29. ^ Abdelilah, Ghannam; et al. (2014). “Non-Accidental Flecainide Overdose, A Case Report”. International Journal of Medicine and Surgery1 (2): 53. doi:10.15342/ijms.v1i2.18.
  30. ^ Ramos E, O’leary M (2004). “State-dependent trapping of flecainide in the cardiac sodium channel”J Physiol560 (Pt 1): 37–49. doi:10.1113/jphysiol.2004.065003PMC 1665201PMID 15272045.
  31. ^ Wang Z, Fermini B, Nattel S (1993). “Mechanism of flecainide’s rate-dependent actions on action potential duration in canine atrial tissue”. J Pharmacol Exp Ther267 (2): 575–81. PMID 8246130.
  32. ^ Mehra D, Imtiaz MS, van Helden DF, Knollmann BC, Laver DR (2014). “Multiple modes of ryanodine receptor 2 inhibition by flecainide”Molecular Pharmacology86 (6): 696–706. doi:10.1124/mol.114.094623PMC 4244595PMID 25274603.
  33. ^ Hilliard FA, Steele DS, Laver D, Yang Z, Le Marchand SJ, Chopra N, Piston DW, Huke S, Knollmann BC (2010). “Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass”Journal of Molecular and Cellular Cardiology48 (2): 293–301. doi:10.1016/j.yjmcc.2009.10.005PMC 2813417PMID 19835880.
  34. ^ Smith GL, MacQuaide N (2015). “The direct actions of flecainide on the human cardiac ryanodine receptor: keeping open the debate on the mechanism of action of local anesthetics in CPVT”. Circulation Research116 (8): 1284–86. doi:10.1161/CIRCRESAHA.115.306298PMID 25858058.

External links

Skeletal formula of flecainide
Ball-and-stick model of the flecainide molecule
Clinical data
Pronunciation /flɛˈknd/flek-AY-nyde
Trade names Tambocor, others
AHFS/ Monograph
MedlinePlus a608040
  • C
ATC code
Pharmacokinetic data
Bioavailability 95%
Protein binding 40%
Metabolism CYP2D6 (limited)
Elimination half-life 20 hours (range 12–27 hours)
Excretion Kidney
CAS Number
CompTox Dashboard(EPA)
ECHA InfoCard 100.211.334Edit this at Wikidata
Chemical and physical data
Formula C17H20F6N2O3
Molar mass 414.343 g/mol g·mol−1
3D model (JSmol)
Chirality Racemic mixture

/////////Flecainide acetate, E-0735, R-818

Desvenlafaxine Succinate

Skeletal formula


Desvenlafaxine Succinate Monohydrate

93413-62-8 (free base, anhydrous)
448904-47-0 (anhydrous)
448904-48-1 (hemisuccinate)

WY-45233 (free base)

Name : Desvenlafaxine Succinate
Synonym : 1-(2-(Dimethylamino)-1-(4- hydroxyphenyl)ethyl)cyclohexanol butanedioate; O-Desmethylvenlafaxine Succinate
Mol Formula : C20H31NO6 / C16H25NO2.C4H6O4
CAS : 448904-47-0
Name : Desvenlafaxine Succinate Monohydrate
Synonym : 1-((1RS)-2-(Dimethylamino)-1-(4- hydroxyphenyl)ethyl)cyclohexanol hydrogen butanedioate monohydrate ; O-Desmethylvenlafaxine Succinate monohydrate; Desvenlafaxine Succinate
Mol Formula : C20H33NO7 / C16H25NO2.C4H6O4.H2O
CAS : 386750-22-7

Inventor/Developer – Wyeth Pharma Inc. 
Status/Comment – FDA approved

Desvenlafaxine Succinate Hydrate

Research Code:DVS-233

Trade Name:Pristiq®

MOA:Serotonin and norepinephrine reuptake inhibitor (SNRI)

Indication:Major depressive disorder (MDD)


Company:Pfizer (Originator)

Sales:$715 Million (Y2015); 
$737 Million (Y2014);;
$698 Million (Y2013);;
$630 Million (Y2012);;
$577 Million (Y2011);ATC Code:N06AX23

Desvenlafaxine succinate hydrate was approved by the U.S. Food and Drug Administration (FDA) on February 29, 2008.It was developed by Pfizer, then marketed as Pristiq® by Pfizer in the US.

The exact mechanism of the antidepressant action of Desvenlafaxine is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non-clinical studies have shown that Desvenlafaxine is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI). It is indicated for the treatment of major depressive disorder (MDD).

Pristiq® is available as extended release tablet for oral use, containing 50 mg or 100 mg of free Desvenlafaxine. The recommended dose is 50 mg once daily with or without food.

(desvenlafaxine) Extended-release Tablets



Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see WARNINGS AND PRECAUTIONS].

In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see WARNINGS AND PRECAUTIONS].

PRISTIQ is not approved for use in pediatric patients [ see Use in Specific Populations].


PRISTIQ is an extended-release tablet for oral administration that contains desvenlafaxine succinate, a structurally novel SNRI for the treatment of MDD. Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of the antidepressant venlafaxine, a medication used to treat major depressive disorder.

Desvenlafaxine is designated RS-4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol and has the empirical formula of C16H25NO2 (free base) and C16H25NO2 •C4H6O4•H2O (succinate monohydrate). Desvenlafaxine succinate monohydrate has a molecular weight of 399.48. The structural formula is shown below.

PRISTIQ® (desvenlafaxine) Structural Formula Illustration

Desvenlafaxine succinate is a white to off-white powder that is soluble in water. The solubility of desvenlafaxine succinate is pH dependent. Its octanol:aqueous system (at pH 7.0) partition coefficient is 0.21.

PRISTIQ is formulated as an extended-release tablet for once-a-day oral administration.

Each tablet contains 38 mg, 76 mg or 152 mg of desvenlafaxine succinate equivalent to 25 mg, 50 mg or 100 mg of desvenlafaxine, respectively.

Osmotica Pharmaceutical, Par Pharmaceutical and Pernix Therapeutics are marketing the product in the U.S. under the brand name Khedezla (TM) for the treatment of major depressive disorder.

In 2019, Pfizer and Mochida signed an agreement for joint development and commercialization of the product in Japan.

Desvenlafaxine, sold under the brand name Pristiq among others, is a medication used to treat major depressive disorder.[1] It is recommended that the need for further treatment be occasionally reassessed.[1] It appears less effective than its parent compound venlafaxine.[2] It is taken by mouth.[1]

Common side effects include dizziness, trouble sleeping, increased sweating, constipation, sleepiness, anxiety, and sexual problems.[1]Serious side effects may include suicide in those under the age of 25, serotonin syndrome, bleeding, mania, and high blood pressure.[1]withdrawal syndrome may occur if the dose is rapidly decreased.[1] It is unclear if use during pregnancy or breastfeeding is safe.[3] It is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class.[1]

Desvenlafaxine was approved for medical use in the United States in 2008.[1] Use in Europe was declined in 2009.[2] In the United States the wholesale cost is about 25.20 USD per month.[4] In 2016, it was the 272nd most prescribed medication in the United States, with more than a million prescriptions.[5]

Medical uses

Desvenlafaxine is primarily used as a treatment for major depressive disorder.[6] Use has only been studied up to 8 weeks.[1] It, however, appears less effective than venlafaxine.[2]

Doses of 50-400 mg/day appear effective for major depressive disorder, although no additional benefit was demonstrated at doses greater than 50 mg/day, and adverse events and discontinuations were more frequent at higher doses.[7]

Desvenlafaxine improves the HAM-D17 score[8] and measures of well being such as the Sheehan Disability Scale (SDS) and 5-item World Health Organization Well-Being Index (WHO-5).[9]

Adverse effects[edit]

Frequency of adverse effects:[6][10][11]

Very common adverse effects include:

  • Nausea
  • Headache
  • Dizziness
  • Dry mouth
  • Hyperhidrosis
  • Diarrhea
  • Insomnia
  • Constipation
  • Fatigue

Common adverse effects include:

  • Tremor
  • Blurred vision
  • Mydriasis
  • Decreased appetite
  • Sexual dysfunction
  • Insomnia
  • Anxiety
  • Elevated cholesterol and triglycerides
  • Proteinuria
  • Vertigo
  • Feeling jittery
  • Asthenia
  • Nervousness
  • Hot flush
  • Irritability
  • Abnormal dreams
  • Urinary hesitation
  • Yawning
  • Rash

Uncommon adverse effects include:

Rare adverse effects include:

Common however unknown intensity of adverse effects include:


Desvenlafaxine is a synthetic form of the isolated major active metabolite of venlafaxine, and is categorized as a serotonin-norepinephrine reuptake inhibitor (SNRI). When most normal metabolizers take venlafaxine, approximately 70% of the dose is metabolized into desvenlafaxine, so the effects of the two drugs are expected to be very similar.[12] It works by blocking the “reuptake” transporters for key neurotransmitters affecting mood, thereby leaving more active neurotransmitters in the synapse. The neurotransmitters affected are serotonin (5-hydroxytryptamine) and norepinephrine (noradrenaline). It is approximately 10 times more potent at inhibiting serotonin uptake than norepinephrine uptake.[13]

Transporter Ki[nM][13][14]
SERT 40.2
NET 558.4

Approval status

United States

Pristiq 50 mg tablets (US)

Wyeth announced on 23 January 2007 that it received an approvable letter from the Food and Drug Administration for desvenlafaxine. Final approval to sell the drug was contingent on a number of things, including:

  • A satisfactory FDA inspection of Wyeth’s Guayama, Puerto Rico facility, where the drug is to be manufactured;
  • Several postmarketing surveillance commitments, and follow-up studies on low-dose use, relapse, and use in children;
  • Clarity by Wyeth around the company’s product education plan for physicians and patients;
  • Approval of desvenlafaxine’s proprietary name, Pristiq.[15]

The FDA approved the drug for antidepressant use in February 2008, and was to be available in US pharmacies in May 2008.[16]

In March 2017, the generic form of the drug was made available in the US.


On February 4, 2009, Health Canada approved use of desvenlafaxine for treatment of depression.[17][18]

European Union

In 2009, an application to market desvenlafaxine for major depressive disorder in the European Union was declined.[2] In 2012, Pfizer received authorization in Spain to market desvenlafaxine for the disorder but it is not being sold.[19][20]


Desvenlafaxine is classified as a schedule 4 (prescription only) drug in Australia. It was listed on the PBS (Pharmaceutical Benefits Scheme) in 2008 for the treatment of major depressive disorders.


Sign succinic acid desvenlafaxine (Desvenlafaxinesuccinate, tradename Pristiq), chemical name RS-4- [2- dimethylamino-1- (1-hydroxycyclohexyl) ethyl] phenol succinic acid salt monohydrate; English name RS-4- (2 – (dimethylamino) -I- (1-hydroxycyclohexyl) ethyl) phenolsuccinatehydrate; formula C16H25NO2 · C4H6O · 4H20; relative molecular mass:. 399 48; CAS Registry number: 386750-22-7; of formula of formula I:


Figure CN104326923AD00041

[0004] The drug is produced by the US company Wyethphainsinc, February 29, 2008 listed by the US FDA approved, a serotonin – norepinephrine reuptake inhibitor is venlafaxine main active metabolite primarily for the treatment of major depressive disorder (MDD).

[0005] desvenlafaxine succinate is generally made with 0- desvenlafaxine succinate, aqueous salt synthesized, synthesized 0- desvenlafaxine earlier reports found in US Patent US4535186 discloses a method to 4-oxo-acetonitrile was synthesized from benzyl phenyl 0- desvenlafaxine, wherein the methylation step due to the use of formaldehyde as a methylating agent such that the reaction yield is very low, only 39 %, thereby affecting the overall yield of the overall reaction.

[0006] Currently many reported synthesis method of desvenlafaxine succinate is mostly based on the prior art (US4535186) Synthesis of venlafaxine, venlafaxine as a raw material to another, for which demethylation step reaction process improvement to synthesize 0- desmethylvenlafaxine, succinic acid and finally with water to a salt of desvenlafaxine succinate synthesis. The patent CN 1319934C, W0 0059851, CN101823969A venlafaxine are disclosed in as raw materials, the thiolate anion, lithium diphenylphosphide, HBr / HOAc as demethylating agent norepinephrine synthesis 0- venlafaxine oct, yields were> 73%. The reaction equation is as follows:


Figure CN104326923AD00042

[0008] In this class synthesis process, the raw material venlafaxine is synthesized by known techniques, the thiol compound used in the step of methylation away easily air pollution toxic, flammable irritant diphenyl compound and using a phosphine compound for corrosive HBr, increasing the difficulty of the operation and the post-treatment process such that the reaction unsuitable for industrial production.

[0009] Patent US7026508, US6689912 and US2005 / 0197392 each discloses a hydroxyphenyl acetonitrile as raw material, hydroxymethylated, α- ketone containing active hydrogen compound condensation, reducing the cyano group, an amino group and removal of methyl synthesis of methyl 〇- reaction desvenlafaxine, which synthetic route is shown below:

Figure CN104326923AD00051

[0011] In such processes, the raw materials used are expensive cyano reagent, wherein the reagent lithium tri-secondary butyl borohydride risk patents US7026508 and method disclosed in patent US 6689912 to use, the patent US2005 / 0197392 use flammable irritating to diphenylphosphine compound, in addition, such methods involve harsh reaction conditions the reduction step cyano.Therefore, this method does not meet the economy, and is not suitable for industrial production.

[0012] Chinese Patent CN101781221Α discloses a synthetic method for the synthesis of 0- hydroxyphenylacetic acid desvenlafaxine, the acid-halo – aminolysis cyclohexanone condensation, amide reduction Synthesis 〇- desvenlafaxine, which scheme is as follows:

Figure CN104326923AD00052

[0014] World Patent WO2008 / 093142 discloses a method similar to the above kind of oxygen acid as a raw material by benzyl, and finally debenzylation by synthesis 0- desvenlafaxine.

[0015] In such methods, the former are in a condensation reaction step with reduction of the amide using an unstable compound n-butyllithium, lithium tetrahydroaluminate; then using a compound unstable to hexamethyldisilazide amide, borane, this two-step reaction be carried out under an inert gas, dangerous reagents used twice, is not suitable for industrial operation.

Figure CN104326923AD00062

Example 1

Synthesis [0041] The compound of formula III

The [0042] room temperature, was added the compound of formula II (81.69g, 0. 60mol), 1200mL acetone 3L reaction flask, stirred and dissolved. To this was added 1〇) 3 (265.368,1.92111〇1) was slowly added dropwise (112.888,0.65111〇1) of benzyl bromide was heated at reflux for LH, starting material after the reaction was cooled to room temperature, filtered off with suction, the filter cake was washed with a suitable amount of acetone , the filtrate by rotary evaporation, 50 ° C to give a compound of formula blast drying ΠI134 7g, yield 99% ZHNMR (300MHz, DMS0):… δ7 50-7 22 (m, 7H), δ6.93 (d, 2H) , S5.03 (s, 2H), S2.53 (s, 3H); 13C-NMR:… S197.02, δ163 · 42, δ136 · 51, δ129 · 83, δ129 02, δ128 91, δ127 64 , δ127. 10, δ114. 29, δ70. 13, δ26. 6.

[0043] Example 2

[0044] following the experimental procedure of Example 1, benzyl bromide (112. 88g, 0. 65mol) is replaced with benzyl chloride (82. 28g, 0. 65mol), heated at reflux overnight, cooled to room temperature after completion of the reaction evacuated filter cake washed with a suitable amount of acetone, the filtrate by rotary evaporation, 50 ° C to give a compound of formula blast drying III103. 17g, yield 76%.

[0045] Example 3

Synthesis [0046] The compound of Formula IV

[0047] The compound of formula III is added to the 3L reaction flask (67. 9g, 0 · 30mol), Cufc2 (147. 4g, 0 · 65mol), 0 · 9L methylene chloride, I. 35LEA, heated to reflux, after completion of the reaction cooling suction filtered, the filter cake was washed with 200mL dichloromethane. The filtrates were combined, and the filtrate was washed with hydrochloric acid and then washed twice with water, dried, rotary evaporation, 50 ° C overnight blast drying. A compound of formula IV to give the crude 89.438, yield 98%.

[0048] 89. 43g was added the compound of formula IV (crude) was added to IL-neck round bottom flask, recrystallized from isopropanol, filtered off with suction, the filter cake was dried by blowing 45 ° C. Refined products 84. 9g, 95% yield. .. 1Hnmr (SoomhzJMSO-CI6): δ7 53-7 20 (m, 7H), 5 6. 95 (d, 2H), δ5 09 (s, 2H), δ4 69 (s, 2H); 13C-.. NMR:. δ190 83, 5 164.12, 5 136.71, δ129 96, δ128 91, δ128 31, δ127 00, δ126 73, δ114 37, δ70 82, δ32 45………

[0049] Example 4

Synthesis [0050] The compound of formula V

[0051] Add the compound of formula IV (36. 6g, 0. 12mol) A 250mL round bottom flask, 120mL of ethanol was stirred. Aqueous solution was slowly added dropwise thereto 39mL of dimethylamine (33%), dropwise, with stirring until completion of the reaction starting material. Rotary evaporation and water, to which ethanol was added, under ice-water bath, thereto was slowly added dropwise 12mL hydrobromic acid. After stirring 30min 25 ° C incubation rotary evaporation and water was added thereto and dissolved with 70mL of methylene chloride over anhydrous sodium sulfate, after rotary evaporation, and thereto was added 60mLEA refluxed 30min, 30min stirring ice-water bath. Filtered off with suction, 45 ° C blast drying to give the purified product compound of formula V41.lg, yield 98%.1H NMR (300MHz, DMS0-d6): δ7 · 55-7 · 24 (πι, 7Η), S6.97 (d, 2H), S5.13 (s, 2H), S3.79 (s, 2H), 5 2. 23 (s, 6H); 13C-NMR:….. δ195 45, 5 163.12, 5 136.53, 5 129.85, 5 128.96, 5 127.61, δ127 27, δ127 06, δ114 65, δ75 31, δ70 . 72, δ46. 55.

[0052] Example 5

Synthesis [0053] The compound of formula VI

[0054] Compound of formula V was added to 500mL round bottom flask (41g, 0. 12mol), 205mL of ethanol under ice-water bath, to which was added a likelihood of 0! 1 (9.368,0.23111〇1), after stirring for 11 ^ 301, to which was added portionwise like 8! 14 (8.888,0.23111〇1). The reaction was stirred for 4h at End material to room temperature. Rotary evaporation, and thereto was added 60mL of water, 120mL of methylene chloride, stirred, separated, the aqueous phase was extracted twice with 120mL dichloromethane. The organic phases were combined, spin dry.The crude 31. 0g, 98% yield.

[0055] The crude product 31g was dissolved in 180mL of ethanol, under ice-water bath, was slowly added dropwise thereto 16mL of concentrated hydrochloric acid to pH = 1-2, stirred at room temperature for 30 min. Rotary evaporation, 45 ° C blast drying. A compound of formula VI to give crude product 31. 2g, 89% yield.

[0056] To a 250mL round-bottom flask was added 31. 2g crude compound of formula VI, 78 mL ethyl acetate, heated to reflux to dissolve, cooled to room temperature naturally, filtered off with suction, the filter cake was washed with the amount of EA. Refined products 29. 3g, 94% yield. 1HNMR (300MHz, DMS0-d6):….. Δ7 45-7 24 (m, 7H), δ6 95 (d, 2H), δ5 07 (s, 2H), δ4 88 (br, 1H), δ4 . 60 (m, 1Η), δ2 48-2 27 (m, 2H), 52.19 (s, 6H); 13C-NMR:…. δ157 26, 5 137.21, 5 136.83, δ128 · 35, δ127 68, δ127. 52, δ127. 17, δ114. 19, δ69. 62, δ69. 13, δ67. 57,45.56.

[0057] Example 6

[0058] Following the procedure of Example 5 experiments embodiment, the shame 0! 1 (9.368,0.23111〇1) shame Alternatively 0! 1 (14.048,0.72111〇1), and NaBH4 (8. 88g, 0. 23mol) is replaced with NaBH4 (13. 32g, 0. 72mol), stirred Ih at room temperature the reaction was complete feed. Rotary evaporation, and thereto was added 60mL of water, burning 120mL dichloromethane, stirred, separated, the aqueous phase was extracted twice with 120mL dichloromethane. The organic phases were combined, spin dry. The crude 31. 33g, yield 99%.

[0059] Example 7

Synthesis [0060] The compound of formula VII

[0061] was added (24g, 0.078 mol) compound of formula VI to a 500mL round bottom flask, 240 mL of toluene, under ice-water bath, and thereto is added thionyl chloride (10. 2g, 0. 086mol), the reaction was heated to 60 ° C 4h, cooled, stirred for about 25 ° C 2h, filtered off with suction, the filter cake washed with 30mL toluene, and drying, the product compound of formula to give an off-white VII22. 4g, 88% yield. 1H NMR (300MHz, DMS〇-d6):… Δ7 44-7 29 (m, 7H), δ7 07 (d, 2Η), δ5 12 (s, 2Η), δ4 69 (m, 1Η).. , δ3 37-3 15 (m, 2H), δ2 80 (s, 6H); 13C-NMR:…. δ158 26, 5 137.33, 5 136.71, 5 128.31, δ127 72, δ127 47, δ127… 13, δ114. 21, δ69. 62, δ67. 57, δ59. 39, δ46. 74.

[0062] Example 8

Synthesis [0063] The compound of formula VIII

[0064] Add the compound of formula ¥ 11 (218,0.064 11〇1!) Was added to a round bottom flask, 2001 ^ toluene, triethylamine (7.21 8, 0.071mol), stirred for 3h, filtered off with suction, washed with a little toluene; the 500mL three-neck flask was added to the toluene solution, cooled to -80 ° C, n-butyllithium was slowly added dropwise 35mL (2. 5mol / L), dropwise with stirring incubated 0. 5h, 9. 48g was slowly added dropwise cyclohexanone, After dropping the reaction 4h, slowly warmed to room temperature, the reaction was quenched with saturated ammonium chloride, using lmol / L sodium hydroxide to adjust pH = about 9, EA extraction, rotary evaporation, the crude product was slurried with diethyl ether, dried to obtain a compound of formula VIII19. 56g, yield 86%. 1H bandit R (300MHz, DMS0-d6): δ7 · 45-7 · 23 (πι, 7Η), S6.87 (d, 2H), S5.09 (s, 2H), S3.05 (t, 1H) , S2.75 (t, lH), δ2 · 41-2 · 34 (πι, 1Η), S2.18 (s, 6H), Sl.58-0.92 (m, 10H); 13C-Mffi:. δ157 32 , δ136. 73, δ134. 73, δ129. 11, δ128. 90, δ127. 65, δ127. 16, δ114. 23, δ73. 42, δ70. 87, δ59. 85, δ48. 52, δ47. 35, δ38 . 95, δ26. 33, δ22. 30.

[0065] Example 9

After the [0066] following the experimental procedure of Example 8, the reaction temperature is added dropwise n-butyllithium was replaced _65 ° C, to give compound VIII crude, beaten with ether and drying to give pure 15. 33g, yield 67 %.

[0067] Example 10

Synthesis [0068] The compound of formula IX

[0069] The compound of formula ¥ 111 (1 (^, 0.028111〇1) was dissolved in ^ booklet 1,501,111, was added 18 10% wet palladium on carbon, into hydrogen, I.SMPa at room temperature for 5h, filtration, rotary evaporation as a white solid compound of formula 1X6 83g, yield 92% 1HNMR (300MHz, DMSO- (I6):… δ9 13 (br, 1H), 5 6.96 (d, 2H), 5 6.64 (d, 2H), 53.01 (t, 1H), S2.72 (t, lH), δ2 · 39-2 · 35 (πι, 1Η), S2.15 (s, 6H), Sl.57-0.90 (m, 10H); 13C, MR:. δ155 56, δ131 56, δ130 04, δ114 23, δ72 52, δ60 36, δ51 57, δ45 21, δ37 11, δ32 38, δ25 67, δ21 23〇………..

[0070] Example 11

Synthesis [0071] The compounds of formula I

Under [0072] nitrogen, the compound of formula IX is added to the three-necked flask (4g, 0. 015mol), succinic acid (1.85g, 0. 015mol), IOOmL acetone / water mixed solvent = 71/19 was heated at reflux for 3h proceeds down to room temperature to crystallization under ice-cooling, filtered off with suction, 40 ° C dried to give 5. 13g as a white solid compound of formula I, yield 85%.


Desvenlafaxine (Formula I, below) is an active pharmaceutical substance with an empirical formula of C16H25NO2 and a molecular weight of 263.38. Desvenlafaxine, which can also be referred to as desmethylvenlafaxine and/or O-desmethylvenlafaxine, is the major active metabolite of venlafaxine, an active pharmaceutical ingredient indicated for the treatment of major depressive disorder.

Figure imgf000002_0001

U.S. Patent No. 4,535, 186 discloses the first process for preparing desvenlafaxine. In U.S. Patent No.4,535,186, desvenlafaxine is synthesized by the process illustrated in Scheme 1:

Figure imgf000002_0002

Scheme 1 Additional alternative processes for preparing desvenlafaxine are described in the literature. These alternative processes generally proceed via the demethylation of venlafaxine, see, for example, U.S. Patent Application Publication No. 2005/197392, U.S. Patent Nos. 7,026,508, and 6,689,912, and International Patent Publication No. WO07/071404. These processes make use of different demethylating agents, such as lithium diphenylphosphide, alkali metal salts of trialkylborohydrides, high molecular weight thiolate anions, and metal sulfides. However, the use of the aforementioned demethylating agents presents several drawbacks, i.e., requires extensive purification procedures aimed to isolate desvenlafaxine from said demethylating agents and/or corresponding by-products, and involve odor workups, which make these processes unsuitable for industrial implementation.

In view of the foregoing, there is a need for an alternative process for preparing desvenlafaxine from venlafaxine including, for instance, an alternative process which avoids the drawbacks of current state of the art processes (e.g., makes use of simpler and shorter purification procedures, allows an essentially odorless workup, and which is well suited for industrial implementation).

Salts of O-desmethylvenlafaxine, including the fumarate, succinate and formate salts, have been described in the literature. For example, U.S. Patent No. 4,535,186 reports the preparation of O-desmethylvenlafaxine fumarate salt. More recently, the preparation of several polymorphic forms of the succinate salt have been reported in U.S. Patent No. 6,673,838 B2. Additionally, U.S. Patent Application Publication No. 2006/0058552 discloses the preparation of the formate salt.

HPLC Method

In the examples described below, the following analytical chromatographic HPLC method was used:

The chromatographic separation was carried out in a Kromasil C8, 5 μm, 25 cm x 4.6 mm. I. D column at room temperature.

The mobile phase was prepared by mixing 1,600 g of (NH4)H2P(It buffer solution pH = 4.4 and 313.2 g of acetonitrile HPLC grade. The pH of the mixture should be 4.9, adjust if necessary.

A (NH4)H2PO4 buffer solution (pH = 4.4) was prepared by dissolving 17 g of (NH4)H2PO4 in 1600 mL of water and adjusting the pH = 4.4 with HaPO4 or ammonium hydroxide.

The chromatograph was equipped with a 225 nm detector, and the flow rate was 1.2 mL per minute at room temperature. Test samples (20 μl) were prepared by dissolving the appropriate amount of sample to obtain 1 mg per mL concentration in the mobile phase.

In those conditions the retention time of desvanlafaxine, compound (I), is about 7 minutes, and the retention time of venlafaxine, compound (IV), is about 22 minutes.

EXAMPLE 1: Preparation of Desvenlafaxine (Le., Compound I).

This example illustrates a process for converting Compound IV into desvenlafaxine {i.e., Compound I) according to one aspect of the invention.

In a 100 mL flask 8 g (0.027 mol) of Venlafaxine free base, 13 mL of polyethylene glycol 400 (PEG400) and 6.9 g (0.041 mol) of 2-(diethylamino)ethanothiol were charged. 13.2 g (13.6 mL, 0.073 mol) of 30 % w/w solution of sodium methanolate in methanol were slowly added. The resulting suspension was heated to about 195° C and methanol was distilled off in the meantime. The stirring was continued for four hours at that temperature and then was cooled down to 20-25° C. 30 mL of 1 M hydrochloric acid were added to adjust pH to approx. 9.5. The resulting suspension was filtered at 20-25° C and the solid was dried at 50° C. The solid corresponded to desvenlafaxine (3.4 g; yield: 45 %; purity HPLC: 96.8 %).

EXAMPLE 2: Preparation of Desvenlafaxine Succinate Monohydrate.

This example illustrates a process for converting desvenlafaxine (i.e., Compound I) into desvenlafaxine succinate monohydrate according to one aspect of the invention.

Desvenlafaxine base (18.1 g, 0.069 mol) was charged into a 500 mL round bottomed flask under nitrogen atmosphere with 9.75 g (0.083 mol) of succinic acid, 135 g (170 mL) of acetone and 54 g of deionized water. The suspension was heated to reflux temperature and maintained at this temperature 30 minutes. The resulting solution was cooled to 50-55° C and filtered.

The filtered solution was cooled to 30-35° C in approximately 1 hour. In the interim, seeding was performed at approximately 40-45° C. The suspension was maintained for 3 hours at 30-35° C. Thereafter, the suspension was cooled to 20-25° C in approximately 1 hour, and maintained at this temperature for 2 hours. Then, the suspension was cooled to 10 ± 3° C in approximately 30 minutes and maintained at this temperature for 1 hour. Finally, the suspension was filtered and washed twice with 2 x 7.5 g (2 x 9.4 mL) of acetone. The wet solid was dried under vacuum at 60 ± 5° C to yield 22.96 g of desvenlafaxine succinate (yield: 83.6 %). Analytical data: HPLC Purity: 99.9 %; assay: 99.6 %.


    • Synonyms:metabolite of Venlafaxine, O-desmethylvenlafaxine, WY-45233, DVS-233
    • ATC:N06AX23
  • Use:antidepressant
  • Chemical name:4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol
  • Formula:C16H25NO2
  • MW:263.38 g/mol
  • CAS-RN:93413-62-8
  • InChI:InChI=1S/C16H25NO2/c1-17(2)12-15(13-6-8-14(18)9-7-13)16(19)10-4-3-5-11-16/h6-9,15,18-19H,3-5,10-12H2,1-2H3


succinate monohydrate

  • Formula:C20H33NO7
  • MW:399.48 g/mol
  • CAS-RN:386750-22-7

Synthesis Path

Trade Names

Country Trade Name Vendor Annotation
USA Pristiq Wyeth ,2008


  • tabl. 50 mg, 100 mg (as succinate)


    • a EP 1 973 866 (Synthon; 1.10.2008; appl. 19.12.2006; USA-prior. 20.12.2005).
    • b WO 2 008 090 465 (Medichem SA; 31.7.2008; appl. 22.1.2008; USA-prior. 22.1.2007).
    • c US 7 026 508 (Wyeth; 5.5.2005; appl. 10.11.2004; USA-prior. 12.2.2001).
    • d US 4 535 186 (American Home Products; 13.8.1985; appl. 26.10.1983; USA-prior. 19.4.1983).
  • new polymorph:

    • WO 2 008 110 338 (Synthon; 18.9.2008; appl. 6.3.2008; USA-prior. 9.3.2007).
  • crystalline polymorphs of Desvenlafaxine succinate:

    • CN 101 274 897 (Mai DE Ltd.; 1.10.2008; appl. 4.1.2008; USA-prior. 8.1.2007).
    • US 20 080 188 567 (Mai DE Ltd.; 8.7.2008; USA-prior. 8.1.2006).
  • enantiomers of Desvenlafaxine:

    • US 2 002 022 662 (American Home Products; 21.2.2002; appl. 21.9.2001; USA-prior. 15.6.1999).


  1. Jump up to:a b c d e f g h i “Desvenlafaxine Succinate Monograph for Professionals” American Society of Health-System Pharmacists. Retrieved 18 March 2019.
  2. Jump up to:a b c d “Withdrawal Assessment Report for Dessvenlafaxime” (PDF)EMA. p. 3. Retrieved 22 March 2019.
  3. ^ “Desvenlafaxine Pregnancy and Breastfeeding Warnings” Retrieved 19 March 2019.
  4. ^ “NADAC as of 2019-02-27”Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
  5. ^ “The Top 300 of 2019” Retrieved 22 December 2018.
  6. Jump up to:a b “PRODUCT INFORMATION PRISTIQ® desvenlafaxine (as succinate)” (PDF)TGA eBusiness Services. Pfizer Australia Pty Ltd. 10 December 2012. Retrieved 8 November2013.
  7. ^ Perry, Richard; Cassagnol, Manouchkathe (2009). “Desvenlafaxine: a new serotonin-norepinephrine reuptake inhibitor for the treatment of adults with major depressive disorder”. Clinical Therapeutics. 31 Pt 1: 1374–1404. doi:10.1016/j.clinthera.2009.07.012ISSN 1879-114XPMID 19698900.
  8. ^ Thase ME, Kornstein SG, Germain JM, Jiang Q, Guico-Pabia C, Ninan PT (March 2009). “An integrated analysis of the efficacy of desvenlafaxine compared with placebo in patients with major depressive disorder”. CNS Spectr14 (3): 144–54. PMID 19407711.
  9. ^ Soares CN, Kornstein SG, Thase ME, Jiang Q, Guico-Pabia CJ (October 2009). “Assessing the efficacy of desvenlafaxine for improving functioning and well-being outcome measures in patients with major depressive disorder: a pooled analysis of 9 double-blind, placebo-controlled, 8-week clinical trials”. J Clin Psychiatry70 (10): 1365–71. doi:10.4088/JCP.09m05133bluPMID 19906341.
  10. ^ “DESVENLAFAXINE tablet, extended release [Ranbaxy Pharmaceuticals Inc.]”DailyMed. Ranbaxy Pharmaceuticals Inc. March 2013. Retrieved 9 November 2013.
  11. ^ “desvenlafaxine (Rx) – Pristiq, Khedezla”Medscape Reference. WebMD. Retrieved 9 November 2013.
  12. ^ Lemke, Thomas L.; Williams, David A. (2012). Foye’s Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. p. 609. ISBN 978-1-60913-345-0.
  13. Jump up to:a b Deecher, DC; Beyer, CE; Johnston, G; Bray, J; Shah, S; Abou-Gharbia, M; Andree, TH (August 2006). “Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor” (PDF)The Journal of Pharmacology and Experimental Therapeutics318 (2): 657–665. doi:10.1124/jpet.106.103382PMID 16675639.
  14. ^ Roth, BL; Driscol, J (Dec 2012). “PDSP Ki Database”Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 7 July 2018.
  15. ^ “Wyeth Receives Approvable Letter From FDA For Pristiq (Desvenlafaxine Succinate) For The Treatment Of Major Depressive Disorder” (Press release). 2007-01-23. Retrieved 2007-04-04.
  16. ^ “FDA Approves Pristiq” (Press release). Wyeth. 2008-02-29. Archived from the original on 2008-03-05. Retrieved 2008-02-29.
  17. ^ Health Canada Notice of Compliance – Pristiq[permanent dead link]. February 4, 2009, retrieved on March 9, 2009.
  18. ^ “Summary Basis of Decision (SBD) PrPristiq™”. Health Canada. 2009-05-29. Retrieved 2016-12-30.
  19. ^ “Pristiq 100 mg Comprimidos de Liberacion Prolongada”. AEMPS Medicines Online Information Center – CIMA. Retrieved 2016-12-30.
  20. ^ “Pristiq 50 mg Comprimidos de Liberacion Prolongada”. AEMPS Medicines Online Information Center – CIMA. Retrieved 2016-12-30.

External links

Route 2

Reference:1. WO2008013990 / US20080183016.

Route 4

Reference:1. WO2008013993.

Route 5

Reference:1. WO2009084037.

Route 6

Reference:1. WO2008013994 / US20080177110.

Update Date:2015-08-31


Publication numberPriority datePublication dateAssigneeTitle
WO2008093142A1 *2007-01-312008-08-07Generics [Uk] LimitedProcess for the preparation of o-desmethyl venlafaxine
WO2010028130A2 *2008-09-032010-03-11Concert Pharmaceuticals, Inc.Antidepressant compounds
CN101781221A *2010-02-112010-07-21上海凯米侬医药科技有限公司Preparation method of O-desmethylvenlafaxine
CN102249936A *2010-05-192011-11-23江苏豪森医药研究院有限公司Hydrate of O-desmethylvenlafaxine hydrochloride and preparation method thereof

FUJII, TOZO等: “Quinolizidines. XXII. An extension of the “3-acetylpyridine route” to the syntheses of 9-hydroxy-10-methoxy- and 10-hydroxy-9-methoxybenzo[a]quinolizidine-type Alangium alkaloids”, 《CHEMICAL & PHARMACEUTICAL BULLETIN》, vol. 35, no. 9, 31 December 1987 (1987-12-31), XP002311646 *
周金培等: “抗抑郁药文拉法辛的合成研究”, 《中国药科大学学报》, vol. 30, no. 4, 31 December 1999 (1999-12-31) *
///////DVS-233 , PF-05212375  , WY-45233,    DESVENLAFAXINE SUCCINATE, WYETH


ChemSpider 2D Image | L-Methyldopa | C10H13NO4


  • Molecular FormulaC10H13NO4
  • Average mass211.214 Da
Name : Methyldopa
Synonym : 3-hydroxy-alpha-methyl-L-tyrosine
Mol Formula : C10H13NO4
CAS : 555-30-6
209-089-2 [EINECS]
555-30-6 [RN],
Alanine, 3- (3,4-dihydroxyphenyl)-2-methyl-, L-

Synthesis ReferenceVincenzo Cannata, Giancarlo Tamerlani, Mauro Morotti, “Process for the synthesis of the levodopa.” U.S. Patent US4962223, issued December, 1986.


Methyldopa USP is the L-isomer of alpha-methyldopa. Its chemical name is levo-3-(3,4-dihydroxyphenyl)- 2-methylalanine sesquihydrate. Its structural formula is:

Methyldopa structural formula

10H13NO4 • 1 1/2 H2O M.W. 238.24

Levodopa is a prodrug of dopamine that is administered to patients with Parkinson’s due to its ability to cross the blood-brain barrierLabel. Levodopa can be metabolised to dopamine on either side of the blood-brain barrier and so it is generally administered with a dopa decarboxylase inhibitor like carbidopa to prevent metabolism until after it has crossed the blood-brain barrierLabel,1. Once past the blood-brain barrier, levodopa is metabolized to dopamine and supplements the low endogenous levels of dopamine to treat symptoms of Parkinson’sLabel. The first developed drug product that was approved by the FDA was a levodopa and carbidopa combined product called Sinemet that was approved on May 2, 19751,7.

Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure.[1] It is one of the preferred treatments for high blood pressure in pregnancy.[1] For other types of high blood pressure including very high blood pressure resulting in symptoms other medications are typically preferred.[1] It can be given by mouth or injection into a vein.[1] Onset of effects is around 5 hours and they last about a day.[1]

Common side effects include sleepiness.[1] More severe side effects include red blood cell breakdown, liver problems, and allergic reactions.[1] Methyldopa is in the alpha-2 adrenergic receptor agonist family of medication.[1] It works by stimulating the brain to decrease the activity of the sympathetic nervous system.[1]

Methyldopa was discovered in 1960.[2] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[3] The wholesale cost in the developing world is about US$4.31–9.48 per month.[4] In the United States it costs less than $25 per month.[5]

Medical uses

Methyldopa is used in the clinical treatment of the following disorders:

Side effects

Methyldopa is capable of inducing a number of adverse side effects, which range from mild to severe. Nevertheless, they are generally mild when the dose is less than 1 gram per day.[6] Side effects may include:


Rebound hypertension via withdrawal on account of tolerance upon the abrupt discontinuation of methyldopa has been reported.[7]

Mechanism of action

Methyldopa has a dual mechanism of action:


Methyldopa exhibits variable absorption from the gastrointestinal tract. It is metabolized in the liver and intestines and is excreted in urine.


When methyldopa was first introduced, it was the mainstay of antihypertensive treatment, but its use has declined on account of relatively severe adverse side effects, with increased use of other safer and more tolerable agents such as alpha blockersbeta blockers, and calcium channel blockers. Additionally, it has yet to be associated with reducing adverse cardiovascular events including myocardial infarction and stroke, or overall all-cause mortality reduction in clinical trials.[8] Nonetheless, one of methyldopa’s still current indications is in the management of pregnancy-induced hypertension (PIH), as it is relatively safe in pregnancy compared to many other antihypertensives which may affect the fetus.


 L-methyldopa an α2 receptor agonistic cardiovascular drugs. The structural formula is as follows:


Figure CN105693541BD00031

[0004] The product produced methyl α- demethylated metabolite of norepinephrine, blockade of central α receptor, thereby inhibiting the heart, kidney and peripheral vascular sympathetic drive output at the same time, peripheral vascular resistance in vivo and plasma renin activity is reduced, and thus decrease blood pressure. It can be used for treating hypertension, nephropathy, including hypertension time.This product is safe, is the preferred treatment during pregnancy with hypertension drugs.

[0005] In the prior art, methyldopa synthesis are the following:

[0006] 1 to veratridine-one was synthesized by the synthesis of L-hydantoin intermediate methyldopa:


Figure CN105693541BD00032

[0008] 2 to veratridine-one was synthesized by the synthesis of L-amino nitrile intermediate methyldopa:


Figure CN105693541BD00033

[0010] 3, eugenol synthesized from L-methyldopa


Figure CN105693541BD00041

[0012] The plurality of reaction have their own advantages, but in general, the reaction need to use highly toxic cyanide, have a certain impact on the environment and operating conditions.


[0013] The present invention discloses a method for synthesizing methyldopa, the synthetic route without using highly toxic substances, the advantage of having a clean environment and efficient.

[00 M] methyldopa synthesis method disclosed in the present invention, is 3,4-dimethoxybenzaldehyde with 2-acetylamino-propionic acid methyl ester as a starting material synthesized by condensation, reduction, deprotection to give the crude product methyldopa, methyldopa and then purified to give pure product.Scheme with easy operation, high yield, etc. cleaning process.

[0015] The scheme is as follows:


Figure CN105693541BD00042

Example 1

[0034] (A) Weigh 3,4_-dimethoxybenzaldehyde 16.6g (0. Imol), sodium methoxide 5.4g (0. Imol), into dried dimethylformamide (150ml), stirring dissolution was complete, the reactor was placed in a cold water bath controlled at a temperature of about 20 ° C, weighed 2-acetamido-methyl 14.5g (0. Imol), successively portionwise added to the reactor, the reaction was stirred for at least 5 minutes plus complete. After all was added, maintaining the reaction temperature for 1.5h.After completion of the reaction, cold water was added Intermediate precipitated solid was filtered and washed several times with cold water.

[0035] (B) Intermediate (A) obtained was transferred to the reactor, 150ml of dichloromethane was added to dissolve, was added p-toluenesulfonyl chloride 19. Ig (0. Imol), triethylamine reactor after 10. Ig (0. Imol), the reaction was stirred for 2h, sodium boron hydride was added 4g, reaction was continued for lh. After completion of the reaction, cold water was added and sufficiently stirred, the aqueous layer was discarded liquid separation, the organic layer, the solvent was evaporated under reduced pressure to obtain an intermediate;

[0036] (C) Intermediate (B) obtained was transferred to the reactor was added 150ml 47% aqueous hydrobromic acid to the reactor, warmed to about 60 ° C, the reaction was stirred at reflux for 4h. Hydrobromic acid was distilled off under reduced pressure to about IlOml, filtered, the mother liquor was concentrated to dryness under reduced pressure, dissolve the solid with cold water, and ammonia to adjust the pH to 4.5 with a cold water bath, the precipitated white solid was large. Filtered and the solid washed with a little cold methylene chloride to give 20.8 g of crude product methyldopa, yield 98.5%.

[0037] (D) The crude product take methyldopa, add 30ml 0. Imo 1 / L dilute hydrochloric acid, an Ig activated carbon, heated, stirred until dissolution methyldopa, maintaining the temperature 〇.5h, filtered hot and allowed to cool to ammonia to adjust the pH to 4.5 to precipitate large amount of white solid was filtered, rinsed with a small amount of cold water, and dried to give 17.7 g methyldopa pure, a yield of 85.0%. Content was determined according to the “Chinese Pharmacopoeia” method and its content was 99.6%.

[0038] Example 2

[0039] (A) Weigh 166kg of 3,4-dimethoxybenzaldehyde, 54kg sodium methoxide, into dried dimethylformamide 500L stirred to dissolve completely, the reactor was placed in a cold water bath controlled temperature of about 20 ° C, 2-acetamido-Weigh 145kg methyl, successively portionwise added to the reactor, the reaction was stirred for at least 5 minutes the addition was completed. After all was added, maintaining the reaction temperature for 2 h. After completion of the reaction, cold water was added Intermediate precipitated solid was filtered and washed several times with cold water.

[0040] (B) Intermediate (A) obtained was transferred to the reactor, 500L of methylene chloride was added to dissolve, was added p-toluenesulfonyl chloride 19Ikg, triethylamine 10Ikg into the reactor, the reaction was stirred for 2.5h , sodium borohydride was added 4kg, reaction was continued for 1.3h. After completion of the reaction, cold water was added and sufficiently stirred, the aqueous layer was discarded liquid separation, the organic layer, the solvent was evaporated under reduced pressure to obtain an intermediate;

[0041] (C) Intermediate (B) obtained was transferred to the reactor, was added 500L 47% aqueous hydrobromic acid to the reactor, warmed to about 60 ° C, the reaction was stirred at reflux for 4h. Hydrobromic acid was distilled off under reduced pressure to about 375L, filtered, and the mother liquor was concentrated to dryness under reduced pressure, dissolve the solid with cold water, and ammonia to adjust the pH to 4.5 with a cold water bath, the precipitated white solid was large. Centrifuged, and the solid washed with a little cold water to give the crude product methyldopa 200kg, 94.7% yield.

[0042] (D) The crude product take methyldopa, add 300L O.lmol / L dilute hydrochloric acid, 10 kg activated carbon, heating and stirring until dissolved methyldopa, maintaining the temperature 〇.5h, filtered hot and allowed to cool to ammonia to adjust the pH to 4.5 to precipitate large amount of white solid was filtered, rinsed with a small amount of cold water, and dried to give pure methyldopa 177kg, 88.5% yield. Content was determined according to the “Chinese Pharmacopoeia” method and its content was 99.7%.


File:Methyldopa synthesis.svg

Exists as the sesquihydrate.

Prepn: Pfister, Stein, US 2868818 (1959 to Merck & Co.). D. F. Reinhold and M. Sletzinger, GB 936074 eidem U.S. Patent 3,344,023 (1963 to Merck and Co.)

Resolution: Jones et al., US 3158648 (1964 to Merck & Co.); cf. Slates et al., J. Org. Chem. 29, 1424 (1964). Resolution and configuration: Tristram, ibid. 2053.

Synthesis from asymmetric intermediates: Reinhold et al., J. Org. Chem. 33, 1209 (1968).

Prepn of the ethyl ester hydrochloride: FR M2153 (1963 to Merck & Co.);

of pharmaceutical dosage forms: Marcus, US 3230143 (1966 to Merck & Co.).


Reactions of D-glucose with phenolic amino acids: further insights into the competition between Maillard and Pictet-Spengler condensation pathways
Carbohydrate Research (2005), 340, (18), 2719-2727


    • ATC:C02AB01
  • Use:antihypertensive
  • Chemical name:3-hydroxy-α-methyl-l-tyrosine
  • Formula:C10H13NO4
  • MW:211.22 g/mol
  • CAS-RN:555-30-6
  • InChI:InChI=1S/C10H13NO4/c1-10(11,9(14)15)5-6-2-3-7(12)8(13)4-6/h2-4,12-13H,5,11H2,1H3,(H,14,15)/t10-/m0/s1
  • EINECS:209-089-2



    •  Tristram, E.W. et al.: J. Org. Chem. (JOCEAH) 29, 2053 (1964).
    • B Stein, G.A. et al.: J. Am. Chem. Soc. (JACSAT) 77, 700 (1955).
    •  Chem. Eng. from 8.11.1965; p. 247.
    • C Reinhold, D.F. et al.: J. Org. Chem. (JOCEAH) 33, 1209 (1968).
    • A US 2 868 818 (Merck & Co.; 13.1.1959; prior. 15.12.1953).
    •  GB 936 074 (Merck & Co.; appl. 18.10.1960; USA-prior. 8.4.1960, 24.8.1960).
    •  DE 1 171 931 (Merck & Co.; prior. 6.10.1960).
    •  US 3 158 648 (Merck & Co.; 24.11.1964; prior. 11.7.1961, 9.4.1962).
    •  FR 1 492 765 (Merck & Co.; appl. 10.10.1963; USA-prior. 11.10.1962, 19.9.1963).
  • similar method via l-α-acetylamino-α-vanillylpropionitrile:

    • GB 1 142 595 (Merck & Co.; appl. 23.5.1967, 12.2.1969).
  • alternative syntheses:

    • D a Steinetal, G.A.: J. Am. Chem. Soc. (JACSAT) 77, 700 (1955).
    • US 3 366 679 (Merck & Co.; 30.1.1968; prior. 11.10.1962, 19.9.1963).
    • DOS 2 302 937 (Tanabe; appl. 22.1.1973; J-prior. 22.1.1972).
    • US 3 517 057 (Merck & Co.; 23.6.1970; appl. 21.9.1967).
    • DE 1 235 946 (Boehringer Mannh.; appl. 8.8.1964).
    • DE 1 235 947 (Bayer; appl. 16.1.1963).
    • DE 1 258 416 (Knoll; appl. 9.10.1964).
    • DE 1 269 622 (Knoll; appl. 22.12.1966).
    • DOS 2 406 898 (BASF; appl. 14.2.1974).
    • AT 250 936 (Egyesült; appl. 3.11.1964; HU-prior. 18.11.1963).
    • FR 1 502 972 (Merck & Co.; appl. 21.10.1966; USA-prior. 22.10.1965).
    • FR 1 531 877 (Sankyo; appl. 18.7.1967; J-prior. 11.8.1966, 21.2.1967).
    • GB 1 321 802 (D.D.S.A.; appl. 5.2.1971).
    • b GB 2 059 955 (Merck & Co.; appl. 9.9.1980; USA-prior. 13.9.1979, 28.9.1979).
Skeletal formula of methyldopa
Ball-and-stick model of the methyldopa molecule
Clinical data
Trade names Aldomet, Aldoril, Dopamet, others
Synonyms L-α-Methyl-3,4-dihydroxyphenylalanine
AHFS/ Monograph
MedlinePlus a682242
  • AU: A
  • US: B (No risk in non-human studies)
Routes of
by mouth, IV
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability approximately 50%
Metabolism Liver
Onset of action 4 to 6 hrs[1]
Elimination half-life 105 minutes
Duration of action 10 to 48 hrs[1]
Excretion Kidney for metabolites
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard 100.008.264 Edit this at Wikidata
Chemical and physical data
Formula C10H13NO4
Molar mass 211.215 g/mol g·mol−1
3D model (JSmol)

Other Names

  • Alanine, 3-(3,4-dihydroxyphenyl)-2-methyl-, L- (8CI)
  • 3-Hydroxy-α-methyl-L-tyrosine
  • (-)-Methyldopa
  • (-)-α-Methyl-3,4-dihydroxyphenylalanine
  • (-)-α-Methyldopa
  • (2S)-2-Amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid
  • (S)-(-)-α-Methyldopa
  • (S)-α-Methyldopa
  • 2-Methyl-3-(3,4-dihydroxyphenyl)alanine
  • AMD
  • Aldochlor
  • Aldomet
  • Aldometil
  • Aldomin
  • Aldomine
  • Alpha medopa
  • Alphamethyldopa
  • Bayer 1440L
  • Baypresol
  • Dopamet
  • Dopatec
  • Dopegyt
  • Elanpres
  • Equibar
  • L-(-)-α-Methyl-β-(3,4-dihydroxyphenyl)alanine
  • L-(-)-β-(3,4-Dihydroxyphenyl)-α-methylalanine
  • L-2-Amino-2-methyl-3-(3,4-dihydroxyphenyl)propionic acid
  • L-3,4-Dihydroxy-α-methylphenylalanine
  • L-3,4-Dihydroxyphenyl-2-methylalanine
  • L-Methyldopa
  • L-α-Methyl-3,4-dihydroxyphenylalanine
  • L-α-Methyl-3-(3,4)-dihydroxyphenylalanine
  • L-α-Methyldopa
  • Lederdopa
  • Levo-3-(3,4-Dihydroxyphenyl)-2-methylalanine
  • MK 351
  • Medomet
  • Medopa
  • Medopren
  • Methoplain
  • Methyl-L-dopa
  • Methyldopa
  • NSC 169916
  • Nr.C 2294
  • Presinol
  • Presolisin
  • Sembrina
  • l-3-(3,4-Dihydroxyphenyl)-2-methylalanine
  • l-α-Methyldopa
  • α-Methyl-L-3,4-dihydroxyphenylalanine
  • α-Methyl-L-dopa
  • α-Methyldopa

General References

  1. Djamshidian A, Poewe W: Apomorphine and levodopa in Parkinson’s disease: Two revolutionary drugs from the 1950’s. Parkinsonism Relat Disord. 2016 Dec;33 Suppl 1:S9-S12. doi: 10.1016/j.parkreldis.2016.12.004. Epub 2016 Dec 22. [PubMed:28012951]
  2. Meiser J, Weindl D, Hiller K: Complexity of dopamine metabolism. Cell Commun Signal. 2013 May 17;11(1):34. doi: 10.1186/1478-811X-11-34. [PubMed:23683503]
  3. Elroby SA, Makki MS, Sobahi TR, Hilal RH: Toward the understanding of the metabolism of levodopa I. DFT investigation of the equilibrium geometries, acid-base properties and levodopa-water complexes. Int J Mol Sci. 2012;13(4):4321-39. doi: 10.3390/ijms13044321. Epub 2012 Apr 2. [PubMed:22605980]
  4. Robertson DR, Wood ND, Everest H, Monks K, Waller DG, Renwick AG, George CF: The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa. Br J Clin Pharmacol. 1989 Jul;28(1):61-9. [PubMed:2775615]
  5. Abrams WB, Coutinho CB, Leon AS, Spiegel HE: Absorption and metabolism of levodopa. JAMA. 1971 Dec 27;218(13):1912-4. [PubMed:5171067]
  6. Fanali G, Rampoldi V, di Masi A, Bolli A, Lopiano L, Ascenzi P, Fasano M: Binding of anti-Parkinson’s disease drugs to human serum albumin is allosterically modulated. IUBMB Life. 2010 May;62(5):371-6. doi: 10.1002/iub.317. [PubMed:20225277]
  7. FDA Approved Drug Products: Sinemet [Link]
  8. Sinemet FDA Label [File]

/////////Methyl-L-dopa, Methyldopa, NSC 169916




ChemSpider 2D Image | Vidofludimus | C20H18FNO4


2-[[2-fluoro-4-(3-methoxyphenyl)phenyl]carbamoyl]cyclopentene-1-carboxylic acid

1-Cyclopentene-1-carboxylic acid, 2-[[(3-fluoro-3′-methoxy[1,1′-biphenyl]-4-yl)amino]carbonyl]- [ACD/Index Name]
2-[(3-Fluoro-3′-methoxy-4-biphenylyl)carbamoyl]-1-cyclopentene-1-carboxylic acid
2-[(3-Fluoro-3′-methoxybiphenyl-4-yl)carbamoyl]cyclopent-1-ene-1-carboxylic acid

355.4 g/mol, C20H18FNO4

CAS 717824-30-1




2D chemical structure of 1354012-90-0

Vidofludimus calcium anhydrous
RN: 1354012-90-0


Molecular Formula, 2C20-H17-F-N-O4.Ca, Molecular Weight, 748.7886

1-Cyclopentene-1-carboxylic acid, 2-(((3-fluoro-3′-methoxy(1,1′-biphenyl)-4-yl)amino)carbonyl)-, calcium salt (2:1)

Inflammatory Bowel Disease,
Multiple Sclerosis,
Rheumatoid Arthritis,
Liver and Biliary Tract Disorders,
Systemic Lupus Erythematosus,

Dihydroorotate Dehydrogenase (DHODH) Inhibitors

phase II clinical development at Immunic (previously Immunic AG) as an induction and maintenance therapy for patients with moderate to severe ulcerative colitis, as well as for the treatment of patients with relapsed-remitting multiple sclerosis (RRMS). Immunic is also conducting early clinical evaluation of the drug as a potential treatment for Crohn’s disease, whereas a phase II clinical trial is ongoing at the Mayo Clinic in patients suffering from primary sclerosing cholangitis.

In 2016, Immunic acquired the product from 4SC.

Vidofludimus is under investigation in clinical trial NCT03722576 (Vidofludimus Calcium for Primary Sclerosing Cholangitis).

Ca salt of vidofludimus (designated as form A) as dihydroorotate dehydrogenase (DHODH) inhibitor eg graft versus host disease, rheumatoid arthritis and multiple sclerosis

Immunic AG  (a subsidiary of  Immunic Inc ), following an asset acquisition from 4SC, is developing vidofludimus an orally available, small molecule DHODH inhibitor and IL-17 blocker which inhibits pyrimidine biosynthesis, for the treatment of autoimmune and inflammatory disorders including ulcerative colitis, Crohn’s disease and multiple sclerosis


Bioorganic & Medicinal Chemistry Letters (2005), 15(21), 4854-4857


WO 03006424

SPC protection in most of the EU states until 2021 and expire in the US in January 2022 with US154 extension


WO2019101888 claiming composition comprising vidofludimus


WO 2012001151

WO 2016200778

WO 2018177151


WO2012001148 claiming similar compound (assigned to 4SC Ag ) naming the inventor Daniel Vitt. Immunic AG  (a subsidiary of  Immunic Inc ),;jsessionid=2957C3C97CE4063A06C879928DCA435C.wapp2nA?docId=WO2012001148&tab=PCTDESCRIPTION

Example 4: Preparation of the calcium salts

300.4 mg of Vidofludimus free acid was dissolved in 18 mL of DCM/MeOH (3:1) and sonicated for 8 minutes. 31.5 mg of calcium hydroxide was suspended in 3 mL of DCM/MeOH (3:1); this was slowly added to the Vidofludimus free acid solution. The slight suspension was stirred overnight at 25°C. The solvent was partially evaporated under nitrogen flow at 25°C. A thick light yellow suspension was observed. The solid was recovered by filtration and washed with DCM/MeOH (3:1). The material was dried for 15 min under vacuum at 25°C. The material was shown to be crystalline using the methods described in the following.

From elemental analysis, the ratio of fluorine to calcium was calculated. The elemental composition is essentially consistent with a hemi-calcium-salt.

The Raman spectrum of the newly formed compound demonstrated differences to that of the free acid (see Figure 3 for both spectra.). Note that a Raman spectrum that is not simply the superposition of the free acid, the salt former and the solvent spectra, e.g., a Raman spectrum where new peaks or shifted peaks are observed, may correspond to a salt.

However, from the Raman spectrum alone, it cannot be determined whether crystalline salt formation has occurred. Peak shifts could also be due, in principle, to complexation of the free acid and salt former as an amorphous product, to polymorphs of either the free acid or salt former, to impurities, or to degradation products. Therefore, the integrity of the molecular structure was confirmed by 1H-NMR.

In addition, the powder X-ray diffraction shown in Figure 5 show that crystalline material was obtained, however with a pattern different from that of the free acid (see Figure 6). With light microscopy the crystals were visualized (Figure 4), DSC (differential scanning calorimetry) demonstrated a melting point of about 155°C (indicating a melting of a solvate and of a non-solvated form), TG-FTIR (thermogravimetric analyzer-coupled Fourier-Transform Infrared) indicates that probably a methanol solvate and a hydrate were formed and dynamic vapor sorption revealed desolvation followed by 0.3% water uptake at about 85% r.h. and 0.4% water uptake at 95% r.h. (not reversible).



Novel white crystalline calcium salt of vidofludimus and its solvates and hydrates (designated as polymorph A), process for its preparation, composition comprising it and its use for the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis, amyotrophic lateral sclerosis, lupus erythematosus, fibrosis, uveitis, rhinitis and Pneumocystis carinii are claimed. Vidofludimus is known to be an IL-17 antagonist, immunosuppressant and dihydroorotate dehydrogenase inhibitor.

Novel calcium salt polymorphs as Anti-Inflammatory, Immunomodulatory and Anti- Proliferatory Agents

Subject matter of the present invention is a white crystalline polymorph A of the Ca salt of a compound according to formula I or a solvate and/or a hydrate thereof with a molar ratio of a compound according to formula 1 or a solvate and/or a hydrate thereof to calcium which is 2±0.3. Subject matter of the present invention is in particular a compound according to formula I or a solvate and/or a hydrate thereof which is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2theta at ±0.2 of the values shown below: 2 theta = 5.91°, 9.64°, 16.78°, 17.81°, 19.81°, 25.41° In particular the invention refers to new polymorphs of calcium salts of the Ca salt of a compound according to formula I or a solvate and/or a hydrate thereof which inhibits dihydroorotate dehydrogenase (DHODH), a process for their manufacture, pharmaceutical compositions containing them and to their use for the treatment and prevention of diseases, in particular their use in diseases where there is an advantage in inhibiting dihydroorotate dehydrogenase (DHODH). Examples of relevant diseases are given below.

Inflammatory Bowel Disease (IBD) is a group of inflammatory conditions of the colon and small intestine. With Crohn’s Disease and Ulcerative Colitis as principal types thereof. Crohn’s disease can affect the small intestine and large intestine, as well as the mouth, esophagus, stomach and the anus. Ulcerative colitis primarily affects the colon and the rectum.

Rheumatoid arthritis (RA) is a disease that is quite common especially among elder people. Its treatment with usual medications as for example non-steroid anti-inflammatory agents is not satisfactory. In view of the increasing ageing of the population, especially in the developed Western countries or in Japan the development of new medications for the treatment of RA is urgently required.

WO 2003/006425 describes certain specific compounds, which are reported to be useful for treatment and prevention of diseases where there is an advantage in inhibiting dihydroorotate dehydrogenase (DHODH). However, the specific salts according to the present invention are not disclosed. WO 2012/001148 describes the calcium salts of said compounds. However, the specific polymorphs according to the present invention are not disclosed.

WO 99/38846 and EP 0 646 578 disclose compounds which are reported to be useful for treatment of RA.

A medicament against rheumatoid arthritis with a new mechanism of action, leflunomide, was put on the market by the company Aventis under the tradename ARAVA [EP 780128, WO 97/34600]. Leflunomide has immunomodulatory as well as anti-inflammatory properties [EP 217206, DE 2524929]. The mechanism of action is based upon the inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme of the pyrimidine biosynthesis.

De Julian-Ortiz (J. Med. Chem. 1999, 42, 3308-3314) describes certain potential Anti-Herpes compounds with cyclopentenoic acid moieties.

DE 33 46 814 A1 describes certain carbonic acid amide derivatives for the treatment, prevention and amelioration of diseases connected to cerebral dysfunction and symptoms caused thereby.

In the human body, DHODH catalyzes the synthesis of pyrimidines, which are in particular necessary for cellular metabolism. An inhibition of DHODH leads to block of transcription of sensitive genes in metabolically activated cells, whereas cells with normal metabolic activity obtain their required pyrimidine building blocks from the pyrimidine salvage pathway and show normal transcriptional activity. Disease relevant activated lymphocytes rely on de novo pyrimidine syntheses and react particularly sensitively to DHODH inhibition. Some substances that inhibit DHODH are important medicaments for the treatment of chronic inflammatory and auto-immune diseases.

A compound named leflunomide (ARAVA) has been the first approved inhibitor of DHODH and is used for the treatment of human diseases, in particular rheumatoid arthritis. WO 99/45926 is a further reference that discloses compounds which act as inhibitors of DHODH. Another drug which is targeting DHODH is teriflunomide (AUBAGIO®) is the metabolite of leflunomide. Teriflunomide is approved for the treatment of multiple sclerosis in some countries.

JP-A-50-121428 discloses N-substituted cyclopentene-l,2-dicarboxylic acid monoamides as herbicides and their syntheses. For example, N-(4-chlorophenyl)-l-cyclopentene-l,2-dicarboxylic acid monoamide is produced by reacting l-cyclopentene-l,2-dicarboxylic anhydride with 4- chloroaniline.

In the Journal of Med. Chemistry, 1999, Vol. 42, pages 3308-3314, virtual combinatorial syntheses and computational screening of new potential Anti-Herpes compounds are described. In Table 3 on page 3313 experimental results regarding IC50 and cytotoxicity are presented for 2-(2,3-difluorophenylcarbamoyl)-l -cyclopentene- 1 -carboxylic acid, 2-(2,6-difluorophenylcarbamoyl)-l -cyclopentene-l -carboxylic acid and 2-(2,3,4-trifluorophenyl-carbamoyl)- 1 -cyclopentene- 1 -carboxylic acid.

DE 3346814 and US 4661630 disclose carboxylic acid amides. These compounds are useful for diseases attended with cerebral dysfunction and also have anti-ulcer, anti-asthma, anti-inflammatory and hypo-cholesterol activities.

In EP 0097056, JP 55157547, DE 2851379 and DE 2921002 tetrahydrophthalamic acid derivatives are described.

It is an object of the present invention to provide effective agents, specifically in the form of certain polymorphs of their calcium salts, which can be used for the treatment of diseases which require the inhibition of DHODH.

It was also an object of the present invention to provide compounds that inhibit DHODH in a range similar to the compounds disclosed in W02003/006425 and WO 2012/001148 and at the same time show a white colour in order to facilitate double blind placebo controlled clinical studies.

It was also an object of the present invention to provide compounds and composition comprising that compounds that inhibit DHODH in a range similar to the compounds disclosed in

W02003/006425 and WO 2012/001148 and are characterized by having a THF content below

720 ppm in order to be in compliance with guidelines of the European Medicines Agency (e.g. with the version 6 December 2016 ; EMA/CHMP/ICH/82260/2006)

Particularly, it has previously been found that certain compounds of the general formula (I) shown herein below, such as 2-(3-Fluoro-3′-methoxy-biphenyl-4-ylcarbamoyl)-cyclopent-l-enecarboxylic acid (INN Vidofludimus), exhibit good anti-inflammatory activity and their usability in the oral therapy for the treatment of autoimmune diseases such as for example rheumatoid arthritis or inflammatory bowel diseases had been addressed.

Accordingly, a novel white polymorph of Calcium- vidofludimus named polymorph A with an inhibitory effect on DHODH, in particular human DHODH, was provided. Furthermore, a composition was provided comprising said white polymorph of Calcium-vidofludimus named polymorph A characterized by having a Tetrahydroduran (THF) content below 720 ppm.
[I,I ‘ – biphenyl] – 4 – yl}carbamoyl)cyclopent – 1 – ene – 1 – carboxylic acid) according to formula (I) or a solvate and/or a hydrate thereof, CAS-No 717824-30-1white crystalline calcium salt of 2 – ({3 – fluoro – 3’ – methoxy –

Thus, subject matter of the present invention is a white crystalline calcium salt of vidofludimus with a molar ratio of vidofludimus to calcium is 2±0.3 or a solvate and/or a hydrate thereof. In contrast to the pale yellow polymorph as described in EP 2588446B1, e.g. example 4, subject matter of the present invention is of white color.

White crystal can be defined as crystals with pure white color similar to the RAL color code RAL9010 that is equal or similar to the US Federal Standard 595 color code“White 506”, #27885.

A solvate for all embodiments of the invention maybe selected from the group comprising ethanol, propanol, isopropanol, butanol, ΊΊ IF, water. In a preferred embodiment for all embodiments of the invention the solvate is a hydrate. In one preferred embodiment the solvate is a calcium dihydrate for all embodiments of the invention.

In particular, subject matter of the present invention is a white crystalline polymorph A of the Ca salt of a compound according to formula I (vidofludimus) or a solvate and/or a hydrate thereof thereof which is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2theta at ±0.2 of the values shown below:

2 theta = 5.91°, 9.64°, 16.78°, 17.81°, 19.81°, 25.41 °


/////////vidofludimus, PHASE 2, Inflammatory Bowel Disease,  (IBD),  Crohn’s Disease, Ulcerative Colitis, 4SC-101, UNII-8Y1PJ3VG81, SC12267, IM-90838, IMU-838, Immunic, 4SC,



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