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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 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, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, 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 30 year tenure till date Dec 2017, 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 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Mol weight


Chagas disease




Danong Chen, Glenn Rice. 2013. Novel formulations of nitrofurans including nifurtimox with enhanced activity with lower toxicity.US20150140089A1
  • OriginatorBayer
  • ClassAntiprotozoals; Nitrofurans; Small molecules; Thiamorpholines; Thiazines
  • Mechanism of ActionDNA damage modulators
  • RegisteredChagas disease
  • 07 Aug 2020Registered for Chagas disease (In adolescents, In children, In infants) in USA (PO)
  • 31 Jan 2020Preregistration for Chagas disease (In infants, In children, In adolescents) in USA (PO)
  • 29 Jan 2020Bayer completes a phase I trial in Chagas disease in Argentina (PO) (NCT03334838)
Title: Nifurtimox
CAS Registry Number: 23256-30-6
CAS Name: 3-Methyl-N-[(5-nitro-2-furanyl)methylene]-4-thiomorpholinamine 1,1-dioxide
Additional Names: 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide; tetrahydro-3-methyl-4-[(5-nitrofurfurylidene)amino]-2H-1,4-thiazine 1,1-dioxide; 1-[(5-nitrofurfurylidene)amino]-2-methyltetrahydro-1,4-thiazine 4,4-dioxide
Manufacturers’ Codes: Bay 2502
Trademarks: Lampit (Bayer)
Molecular Formula: C10H13N3O5S
Molecular Weight: 287.29
Percent Composition: C 41.81%, H 4.56%, N 14.63%, O 27.85%, S 11.16%
Literature References: Prepn from 5-nitrofurfural and 4-amino-3-methyltetrahydro-1,4-thiazine 1,1-dioxide: Herlinger et al., DE 1170957 corresp to US 3262930 (1964 and 1966 to Bayer). Series of articles on pharmacology and clinical findings: Arzneim.-Forsch. 22, 1563-1642 (1972). Toxicity data: K. Hoffmann, ibid. 1590.
Properties: Orange-red crystals from dil acetic acid, mp 180-182°. LD50 in mice, rats (mg/kg): 3720, 4050 by gavage (Hoffmann).
Melting point: mp 180-182°
Toxicity data: LD50 in mice, rats (mg/kg): 3720, 4050 by gavage (Hoffmann)
Therap-Cat: Antiprotozoal (Trypanosoma).
Keywords: Antiprotozoal (Trypanosoma).

Nifurtimox, sold under the brand name Lampit, is a medication used to treat Chagas disease and sleeping sickness.[1][4] For sleeping sickness it is used together with eflornithine in nifurtimox-eflornithine combination treatment.[4] In Chagas disease it is a second-line option to benznidazole.[5] It is given by mouth.[1]

Common side effects include abdominal pain, headache, nausea, and weight loss.[1] There are concerns from animal studies that it may increase the risk of cancer but these concerns have not be found in human trials.[5] Nifurtimox is not recommended in pregnancy or in those with significant kidney or liver problems.[5] It is a type of nitrofuran.[5]

Nifurtimox came into medication use in 1965.[5] It is on the World Health Organization’s List of Essential Medicines.[4] It is not available commercially in Canada.[1] It was approved for medical use in the United States in August 2020.[3] In regions of the world where the disease is common nifurtimox is provided for free by the World Health Organization (WHO).[6]

Chagas disease, caused by a parasite known as Trypanosoma cruzi (T.cruzi), is a vector-transmitted disease affecting animals and humans in the Americas. It is commonly known as American Trypanosomiasis.11

The CDC estimates that approximately 8 million people in Central America, South America, and Mexico are infected with T. cruzi, without symptoms. If Chagas disease is left untreated, life-threatening sequelae may result.11

Nifurtimox, developed by Bayer, is a nitrofuran antiprotozoal drug used in the treatment of Chagas disease. On August 6 2020, accelerated FDA approval was granted for its use in pediatric patients in response to promising results from phase III clinical trials. Continued approval will be contingent upon confirmatory data.10 A convenient feature of Bayer’s formulation is the ability to divide the scored tablets manually without the need for pill-cutting devices.10

Medical uses

Nifurtimox has been used to treat Chagas disease, when it is given for 30 to 60 days.[7][8] However, long-term use of nifurtimox does increase chances of adverse events like gastrointestinal and neurological side effects.[8][9] Due to the low tolerance and completion rate of nifurtimox, benznidazole is now being more considered for those who have Chagas disease and require long-term treatment.[5][9]

In the United States nifurtimox is indicated in children and adolescents (birth to less than 18 years of age and weighing at least 2.5 kilograms (5.5 lb) for the treatment of Chagas disease (American Trypanosomiasis), caused by Trypanosoma cruzi.[2]

Nifurtimox has also been used to treat African trypanosomiasis (sleeping sickness), and is active in the second stage of the disease (central nervous system involvement). When nifurtimox is given on its own, about half of all patients will relapse,[10] but the combination of melarsoprol with nifurtimox appears to be efficacious.[11] Trials are awaited comparing melarsoprol/nifurtimox against melarsoprol alone for African sleeping sickness.[12]

Combination therapy with eflornithine and nifurtimox is safer and easier than treatment with eflornithine alone, and appears to be equally or more effective. It has been recommended as first-line treatment for second-stage African trypanosomiasis.[13]

Pregnancy and breastfeeding

Use of nifurtimox should be avoided in pregnant women due to limited use.[5][8][14] There is limited data shown that nifurtimox doses up to 15 mg/kg daily can cause adverse effects in breastfed infants.[15] Other authors do not consider breastfeeding a contraindication during nifurtimox use.[15]

Side effects

Side effects occur following chronic administration, particularly in elderly people. Major toxicities include immediate hypersensitivity such as anaphylaxis and delayed hypersensitivity reaction involving icterus and dermatitis. Central nervous system disturbances and peripheral neuropathy may also occur.[8]


Nifurtimox is contraindicated in people with severe liver or kidney disease, as well as people with a background of neurological or psychiatric disorders.[5][16][20]

Mechanism of action

Nifurtimox forms a nitro-anion radical metabolite that reacts with nucleic acids of the parasite causing significant breakdown of DNA.[8] Its mechanism is similar to that proposed for the antibacterial action of metronidazole. Nifurtimox undergoes reduction and creates oxygen radicals such as superoxide. These radicals are toxic to T. cruzi. Mammalian cells are protected by presence of catalaseglutathioneperoxidases, and superoxide dismutase. Accumulation of hydrogen peroxide to cytotoxic levels results in parasite death.[8]

Manufacturing and availability

A bottle of nifurtimox

Nifurtimox is sold under the brand name Lampit by Bayer.[3] It was previously known as Bayer 2502.

Nifurtimox is only licensed for use in Argentina and Germany,[citation needed] where it is sold as 120-mg tablets. It was approved for medical use in the United States in August 2020.[3]


Nifurtimox is in a phase-II clinical trial for the treatment of pediatric neuroblastoma and medulloblastoma.[21]



Synthesis of Essential Drugs

2006, Pages 559-582

Nifurtimox, 1,1-dioxide 4-[(5-nitrofuryliden)amino]-3-methylthiomorpholine (37.4.7), is made by the following scheme. Interaction of 2-mercaptoethanol with propylene oxide in the presence of potassium hydroxide gives (2-hydroxyethyl)-(2-hydroxypropylsul-fide) (37.4.3), which undergoes intramolecular dehydration using potassium bisulfate to make 2-methyl-1,4-oxithiane (37.4.4). Oxidation of this using hydrogen peroxide gives 2-methyl-1,4-oxithian-4,4-dioxide (37.4.5), which when reacted with hydrazine transforms to 4-amino-3-methyltetrahydro-1,4-thiazin-1,1-dioxide (37.4.6). Reacting this with 5-nitrofurfurol gives the corresponding hydrazone—the desired nifurtimox [58,59].

58. H. Herlinger, K.H. Heinz, S. Petersen, M.Bock, Ger. Pat. 1.170.957 (1964).

59. H. Herlinger, K.H. Heinz, S. Petersen, M. Bock, U.S. Pat. 3.262.930 (1966)


  1. Jump up to:a b c d e f “Nifurtimox (Systemic)” 1995. Archived from the original on 20 December 2016. Retrieved 3 December 2016.
  2. Jump up to:a b “Lampit (nifurtimox) tablets, for oral use” (PDF)U.S. Food and Drug Administration(FDA). Bayer HealthCare Pharmaceuticals Inc. Retrieved 6 August 2020.
  3. Jump up to:a b c d “Lampit: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 6 August 2020.
  4. Jump up to:a b c World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. Jump up to:a b c d e f g h Bern, Caryn; Montgomery, Susan P.; Herwaldt, Barbara L.; Rassi, Anis; Marin-Neto, Jose Antonio; Dantas, Roberto O.; Maguire, James H.; Acquatella, Harry; Morillo, Carlos (2007-11-14). “Evaluation and Treatment of Chagas Disease in the United States”JAMA298 (18): 2171–81. doi:10.1001/jama.298.18.2171ISSN 0098-7484PMID 18000201.
  6. ^ “Trypanosomiasis, human African (sleeping sickness)”World Health Organization. February 2016. Archived from the original on 4 December 2016. Retrieved 7 December2016.
  7. ^ Coura JR, de Castro SL (2002). “A critical review of Chagas disease chemotherapy”Mem Inst Oswaldo Cruz97 (1): 3–24. doi:10.1590/S0074-02762002000100001PMID 11992141.
  8. Jump up to:a b c d e f g h “Nifurtimox Drug Information, Professional”http://www.drugs.comArchivedfrom the original on 2016-11-08. Retrieved 2016-11-09.
  9. Jump up to:a b Jackson, Yves; Alirol, Emilie; Getaz, Laurent; Wolff, Hans; Combescure, Christophe; Chappuis, François (2010-11-15). “Tolerance and Safety of Nifurtimox in Patients with Chronic Chagas Disease”Clinical Infectious Diseases51 (10): e69–e75. doi:10.1086/656917ISSN 1058-4838PMID 20932171.
  10. ^ Pepin J, Milord F, Mpia B, et al. (1989). “An open clinical trial of nifurtimox for arseno-resistant T. b. gambiense sleeping sickness in central Zaire”. Trans R Soc Trop Med Hyg83(4): 514–7. doi:10.1016/0035-9203(89)90270-8PMID 2694491.
  11. ^ Bisser S, N’Siesi FX, Lejon V, et al. (2007). “Equivalence Trial of Melarsoprol and Nifurtimox Monotherapy and Combination Therapy for the Treatment of Second-Stage Trypanosoma brucei gambiense Sleeping Sickness”J Infect Dis195 (3): 322–329. doi:10.1086/510534PMID 17205469.
  12. ^ Pepin J (2007). “Combination Therapy for Sleeping Sickness: A Wake-Up Call”J Infect Dis195 (3): 311–13. doi:10.1086/510540PMID 17205466.
  13. ^ Priotto G, Kasparian S, Mutombo W, et al. (July 2009). “Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiensetrypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial”. Lancet374(9683): 56–64. doi:10.1016/S0140-6736(09)61117-Xhdl:10144/72797PMID 19559476.
  14. ^ Schaefer, Christof; Peters, Paul W. J.; Miller, Richard K. (2014-09-17). Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment. Academic Press. ISBN 9780124079014Archived from the original on 2017-09-08.
  15. Jump up to:a b “Nifurtimox use while Breastfeeding |”http://www.drugs.comArchived from the original on 2016-11-08. Retrieved 2016-11-07.
  16. Jump up to:a b c “Parasites – American Trypanosomiasis (also known as Chagas Disease)”U.S. Centers for Disease Control and Prevention (CDC)Archived from the original on 2016-11-06. Retrieved 2016-11-09.
  17. Jump up to:a b Forsyth, Colin J.; Hernandez, Salvador; Olmedo, Wilman; Abuhamidah, Adieb; Traina, Mahmoud I.; Sanchez, Daniel R.; Soverow, Jonathan; Meymandi, Sheba K. (2016-10-15). “Safety Profile of Nifurtimox for Treatment of Chagas Disease in the United States”Clinical Infectious Diseases63 (8): 1056–1062. doi:10.1093/cid/ciw477ISSN 1537-6591PMC 5036918PMID 27432838.
  18. ^ Castro, José A.; de Mecca, Maria Montalto; Bartel, Laura C. (2006-08-01). “Toxic side effects of drugs used to treat Chagas’ disease (American trypanosomiasis)”. Human & Experimental Toxicology25 (8): 471–479. doi:10.1191/0960327106het653oaISSN 0960-3271PMID 16937919.
  19. Jump up to:a b Estani, Sergio Sosa; Segura, Elsa Leonor (1999-09-01). “Treatment of Trypanosoma cruzi infection in the undetermined phase. Experience and current guidelines of treatment in Argentina”Memórias do Instituto Oswaldo Cruz94: 363–365. doi:10.1590/S0074-02761999000700070ISSN 0074-0276PMID 10677756.
  20. ^ “Chagas disease”World Health OrganizationArchived from the original on 2014-02-27. Retrieved 2016-11-08.
  21. ^ Clinical trial number NCT00601003 for “Study of Nifurtimox to Treat Refractory or Relapsed Neuroblastoma or Medulloblastoma” at Retrieved on July 10, 2009.

External links

  • “Nifurtimox”Drug Information Portal. U.S. National Library of Medicine.
Nifurtimox 3D.png
Clinical data
Trade names Lampit[1]
Other names Bayer 2502[1]
AHFS/ archive
License data
Routes of
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Low
Metabolism Liver (Cytochrome P450 oxidase (CYP) involved)
Elimination half-life 2.95 ± 1.19 hours
Excretion Kidney, very low
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard 100.041.377 Edit this at Wikidata
Chemical and physical data
Formula C10H13N3O5S
Molar mass 287.29 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
Melting point 180 to 182 °C (356 to 360 °F)

///////////Nifurtimox, LAMPIT, 2020 APPROVALS, FDA 2020, ニフルチモックス, CHAGAS DISEASE, ANTI PROTOZOAL



ChemSpider 2D Image | trans-N-{(1S)-1-[6-(4-Fluoro-1H-pyrazol-1-yl)-3-pyridinyl]ethyl}-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl}cyclohexanecarboxamide | C27H32FN9O2


Mol weight
Cyclohexanecarboxamide, N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)-3-pyridinyl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]-, cis
2097132-94-8 [RN]

Other Names

  • cis-N-[(1S)-1-[6-(4-Fluoro-1H-pyrazol-1-yl)-3-pyridinyl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]cyclohexanecarboxamide
  • BLU 123244
  • BLU 667
  • Pralsetinib
  • X 581238
  • cis-N-{(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl}-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}cyclohexane-1-carboxamide



Pralsetinib, sold under the brand name Gavreto, is a medication for the treatment of metastatic RET fusion-positive non-small cell lung cancer (NSCLC).[1] Pralsetinib is a tyrosine kinase inhibitor. It is taken by mouth.[1]

The most common adverse reactions include increased aspartate aminotransferase (AST), decreased hemoglobin, decreased lymphocytes, decreased neutrophils, increased alanine aminotransferase (ALT), increased creatinine, increased alkaline phosphatase, fatigue, constipation, musculoskeletal pain, decreased calcium, hypertension, decreased sodium, decreased phosphate, and decreased platelets.[1]

Pralsetinib was approved for medical use in the United States in September 2020.[1][2][3][4]

Medical uses

Pralsetinib is indicated for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test.[1][4]


Efficacy was investigated in a multicenter, open-label, multi-cohort clinical trial (ARROW, NCT03037385) with 220 participants aged 26-87 whose tumors had RET alterations.[1][4] Identification of RET gene alterations was prospectively determined in local laboratories using either next generation sequencing, fluorescence in situ hybridization, or other tests.[1] The main efficacy outcome measures were overall response rate (ORR) and response duration determined by a blinded independent review committee using RECIST 1.1.[1] The trial was conducted at sites in the United States, Europe and Asia.[4]

Efficacy for RET fusion-positive NSCLC was evaluated in 87 participants previously treated with platinum chemotherapy.[1] The ORR was 57% (95% CI: 46%, 68%); 80% of responding participants had responses lasting 6 months or longer.[1] Efficacy was also evaluated in 27 participants who never received systemic treatment.[1] The ORR for these participants was 70% (95% CI: 50%, 86%); 58% of responding participants had responses lasting 6 months or longer.[1]

The US Food and Drug Administration (FDA) granted the application for pralsetinib priority revieworphan drug, and breakthrough therapy designations[1]and granted approval of Gavreto to Blueprint Medicines.[1]


US 20170121312

    • Step 7: Synthesis of (1R,4S)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-carboxamide (Compound 129) and (1S,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide (Compound 130)

    • [0194]
      Figure US20170121312A1-20170504-C00094
    • [0195]
      The title compounds were prepared from methyl 1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxylate (192 mg, 0.53 mmol) using the same two-step procedure (hydrolysis and amide coupling) outlined in Synthetic Protocols 1 and 2, with PyBOP as the amide coupling reagent instead of HATU. The products were initially isolated as a mixture of diastereomers (190 mg), which was then dissolved in 6 mL methanol and purified by SFC (ChiralPak AD-H 21×250 mm, 40% MeOH containing 0.25% DEA in CO2, 2.5 mL injections, 70 mL/min). Peak 1 was concentrated to give (1R,4S)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide (29 mg, 10%) as a white solid. Peak 2 was concentrated to give (1s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-carboxamide (130 mg, 46%) as a white solid.

Example 6. Synthesis of Compound 149Step 1: Synthesis of Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate

    • [0196]
      Figure US20170121312A1-20170504-C00095
    • [0197]
      Methyl 4-iodo-1-methoxycyclohexanecarboxylate (3.37 g, 11.3 mmol) was dissolved in dimethylacetamide (38 mL) in a pressure vessel under a stream of N2. Rieke Zinc (17.7 mL of a 50 mg/mL suspension in THF, 13.6 mmol) was added quickly via syringe, and the vessel was capped and stirred at ambient temperature for 15 minutes. The vessel was opened under a stream of Nand 2,4-dichloro-6-methylpyrimidine (1.84 g, 11.3 mmol) was added followed by PdCl2dppf (826 mg, 1.13 mmol). The vessel was capped and heated to 80° C. for one hour, then cooled to room temperature. The reaction mixture was diluted with EtOAc, filtered through celite, and the filtrate was washed with H2O (3×), brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 50% EtOAc-hexanes) to give methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate (74 mg, 2.2%) as a colorless oil. MS (ES+) C14H19ClN2Orequires: 298, found: 299 [M+H]+.

Step 2: Synthesis of tert-Butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate

    • [0198]
      Figure US20170121312A1-20170504-C00096
    • [0199]
      Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate (70.5 mg, 0.236 mmol), tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (69.8 mg, 0.354 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (20.0 mg, 0.2 equiv.), Pd2(dba)(21.6 mg, 0.1 equiv.), and potassium acetate (70 mg, 0.71 mmol) were combined in a vial under nitrogen and 0.98 mL dioxane was added. The reaction mixture was heated to 115° C. for 2 h, then cooled to ambient temperature. The reaction mixture was diluted with EtOAc, filtered through celite, concentrated onto silica gel, and the resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-hexanes) to give tert-butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate (48 mg, 44%) as a yellow oil. MS (ES+) C23H33N5Orequires: 459, found: 460 [M+H]+.

Step 3: Synthesis of 1-Methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid

    • [0200]
      Figure US20170121312A1-20170504-C00097
    • [0201]
      Lithium hydroxide monohydrate (13 mg, 0.31 mmol) was added to a solution of tert-butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate (47.7 mg, 0.104 mmol) in THF/MeOH/H2O (17:1:1, 1.8 mL). The reaction mixture was heated to 60° C. and stirred for 16 h. The reaction mixture was then cooled to ambient temperature and concentrated to give crude 1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid (57 mg, crude) which was used in the subsequent amide coupling without any further purification. MS (ES+) C17H23N5Orequires: 345, found: 346 [M+H]+.

Step 4: Synthesis of (1s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide (Compound 149)

    • [0202]
      Figure US20170121312A1-20170504-C00098
    • [0203]
      The title compound was prepared from 1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid (57 mg, 0.104 mmol) using the same procedured (amide coupling) outlined in Synthetic Protocols 1 and 2, with PyBOP as the amide coupling reagent instead of HATU. The products were initially isolated as a mixture of diastereomers (36 mg), which was then dissolved in 6 mL methanol-DCM (1:1) and purified by SFC (ChiralPak IC-H 21×250 mm, 40% MeOH containing 0.25% DEA in CO2, 1.0 mL injections, 70 mL/min). Peak 1 was an undesired isomer, and Peak 2 was concentrated to give (1 s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide (13.4 mg, 24%) as a white solid.

Synthesis of IntermediatesExample 7. Synthesis of Ketone and Boronate IntermediatesA. Methyl 1-methoxy-4-oxocyclohexane-1-carboxylate

    • [0204]
      Figure US20170121312A1-20170504-C00099
    • [0205]
      The title compound was prepared as described in WO 2014/130810 A1 page 86.

B. Ethyl 1-ethoxy-4-oxocyclohexane-1-carboxylate

    • [0206]
      Figure US20170121312A1-20170504-C00100

Step 1: Synthesis of ethyl 8-ethoxy-1,4-dioxaspiro[4.5]decane-8-carboxylate

    • [0207]
      A solution of 1,4-dioxaspiro[4.5]decan-8-one (20.0 g, 128 mmol) in CHBr(3234 g, 1280 mmol) was cooled to 0° C. and potassium hydroxide (57.5 g, 1024 mmol) in EtOH (300 mL) was added dropwise over 2.5 hrs. After stirring the mixture for 23 h, the mixture was concentrated, and the residue was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude product, which was purified by flash column chromatography on silica gel (gradient elution, PE:EA=15:1 to 10:1) to obtain the title compound (18.0 g).

Step 2: Synthesis of ethyl 1-ethoxy-4-oxocyclohexane-1-carboxylate

    • [0208]
      To a solution of ethyl 8-ethoxy-1,4-dioxaspiro[4.5]decane-8-carboxylate (10 g, 43 mmol) in 1,4-dioxane (250 mL) was added aqueous HCl (6 M, 92.5 mL), and the mixture was stirred for 23 h at ambient temperature. The mixture was then diluted with H2O and extracted with EtOAc.
    • [0209]
      The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography on silica gel (PE:EA=15:1) to obtain the product (8.0 g). 1H NMR (400 MHz, DMSO) δ 4.20-4.13 (m, 2H), 3.43 (q, J=6.9 Hz, 1H), 2.48-2.39 (m, 1H), 2.24-2.12 (m, 2H), 2.10-2.01 (m, 1H), 1.22 (t, J=7.1 Hz, 2H), 1.17 (t, J=7.0 Hz, 2H).

C. Ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate

    • [0210]
      Figure US20170121312A1-20170504-C00101

Step 1: Synthesis of ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate

    • [0211]
      A solution of methylmagnesium bromide (3M, 109.8 mL, 329.4 mmol) was added dropwise to a suspension of CuCN (14.75 g, 164.7 mmol) in diethyl ether (50 mL) at 0° C. The mixture was stirred for 30 min at 0° C. and then cooled to −78° C. The solution of ethyl 2-methyl-4-oxocyclohex-2-ene-1-carboxylate (10 g, 54.9 mmol) in diethyl ether (10 mL) was then added dropwise. The mixture was stirred between −40° C. to −20° C. for 2 h, then was warmed to ambient temperature for 16 h. The reaction mixture was carefully added to a saturated solution of ammonium chloride. The aqueous layer was extracted twice with diethyl ether, and the organic layers were combined. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (PE:EA=10:1) to give ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate (1.16 g).

Step 2: Synthesis of ethyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate

    • [0212]
      Ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate (1.16 g, 5.85 mmol) and DIPEA (3.03 g, 23.4 mmol) were dissolved in dry toluene (2 mL) and heated at 45° C. for 10 minutes. Trifluoromethanesulfonic anhydride (6.61 g, 23.4 mmol) in DCM (20 mL) was added dropwise over 10 min and the mixture was heated at 45° C. for 2 h. The mixture was allowed to cool to room temperature, concentrated, diluted with water (60 mL) and extracted with DCM (2×40 mL). The organic layer was washed with saturated sodium bicarbonate solution (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-petroleum ether) to afford ethyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (1 g).

Step 3: Synthesis of ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate

    • [0213]
      Ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (1 g, 3.03 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.15 g, 4.54 mmol), Pd(dppf)Cl(73.5 mg, 0.09 mmol) and potassium acetate (891 mg, 9.08 mmol) were suspended in 1,4-dioxane (20 mL). The reaction mixture was flushed with nitrogen, then heated to 100° C. for 2 h. The mixture was cooled to room temperature, filtered, and concentrated, and the resulting brown oil was purified by flash column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-petroleum ether) to afford ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (618 mg).

D. Ethyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate

    • [0214]
      Figure US20170121312A1-20170504-C00102
    • [0215]
      Ethyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate was prepared using the same synthetic protocol as described above using ethyl 2-methyl-4-oxocyclohexane-1-carboxylate as the starting material.

E. Methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate

    • [0216]
      Figure US20170121312A1-20170504-C00103

Step 1: Synthesis of methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate

    • [0217]
      A mixture of acrylaldehyde (120 g, 2.14 mol), methyl methacrylate (200 g, 2.00 mol) and hydroquinone (2.2 g, 20 mmol) were heated in a sealed steel vessel at 180° C. for one h. The mixture was then cooled to ambient temperature and concentrated. The residue was purified by silica gel column chromatography (gradient elution, petroleum ether:ethyl acetate=100:1 to 80:1) to give methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate (70 g, 22% yield) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3): δ 6.38 (d, J=6.4 Hz, 1H), 4.73-4.70 (m, 1H), 3.76 (s, 3H), 2.25-2.22 (m, 1H), 1.99-1.96 (m, 2H), 1.79-1.77 (m, 1H), 1.49 (s, 3H).

Step 2: Synthesis of methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate

    • [0218]
      To a solution of methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate (20.0 g, 128 mmol) in anhydrous tetrahydrofuran (200 mL) was added borane (67 mL, 1 M in tetrahydrofuran) dropwise at −5° C. The reaction mixture was stirred at 0° C. for 3 hours. This reaction was monitored by TLC. The mixture was quenched by a solution of sodium acetate (10.5 g, 128 mmol) in water (15 mL). Then the mixture was treated with 30% hydrogen peroxide solution (23.6 g, 208.2 mmol) slowly at 0° C. and stirred at 30° C. for 3 h. The mixture was then partitioned between saturated sodium sulfite solution and tetrahydrofuran. The aqueous layer was further extracted with tetrahydrofuran (2×). The combined organic layers were washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (gradient elution, petroleum ether:ethyl acetate=10:1 to 1:1) to give crude methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate (18 g, crude) as a pale yellow oil, which used directly for next step.

Step 3: Synthesis of methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate

    • [0219]
      To a solution of methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate (18.0 g, 103 mmol) in anhydrous dichloromethane (200 mL) was added PCC (45.0 g, 209 mmol) in portions. The reaction mixture was stirred at ambient temperature until TLC indicated the reaction was completed. Petroleum ether (500 mL) was then added and the mixture was filtered. The filter cake was washed with petroleum ether (100 mL), and the filtrate was concentrated under vacuum to give methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate (15 g, 84% yield) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3): δ 4.25 (d, J=17.6 Hz, 1H), 4.07 (d, J=17.6 Hz, 1H), 3.81 (s, 3H), 2.52-2.44 (m, 3H), 2.11-2.04 (m, 1H), 1.53 (s, 3H).

Example 8. Synthesis of Iodide IntermediatesA. Methyl 1-methoxy-4-iodocyclohexane-1-carboxylate

    • [0220]
      Figure US20170121312A1-20170504-C00104

Step 1: Synthesis of methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate

    • [0221]
      Methyl 1-methoxy-4-oxocyclohexanecarboxylate (4.00 g, 21.5 mmol) was dissolved in methanol (100 mL) and the solution was cooled to 0° C. Sodium borohydride (2.03 g, 53.7 mmol) was added in portions over 20 min. The reaction mixture was stirred for 30 min, then was quenched by addition of aqueous saturated NH4Cl solution. The quenched reaction mixture was evaporated to remove the MeOH, then the aqueous suspension was extracted with DCM (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to yield a residue that was purified by flash-column chromatography on silica gel (gradient elution, 5% to 100% ethyl acetate-hexanes) to afford methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate (2.00 g, 49.5%) as a colorless oil. MS (ES+) C9H16Orequires: 188, found: 211 [M+Na]+.

Step 2: Synthesis of methyl 1-methoxy-4-iodocyclohexane-1-carboxylate

    • [0222]
      Methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate (2.00 g, 10.6 mmol) was dissolved in THF (20 mL) and imidazole (723 mg, 10.6 mmol) and triphenylphosphine (3.34 g, 12.8 mmol) were added. The mixture was cooled to 0° C., and then a solution of iodine (3.24 g, 12.8 mmol) in THF (10 mL) was added dropwise over 15 min. The reaction mixture was allowed to warm to ambient temperature and was then stirred for 2 days, after which it was poured over saturated sodium thiosulfate solution and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, concentrated, and the residue was triturated with hexane (40 mL, stir for 20 min). The mixture was filtered, and the filtrate was evaporated to provide a residue that was purified by flash-column chromatography on silica gel (gradient elution, 0 to 30% ethyl acetate-hexanes) to give the title compound (2.37 g, 75%) as a pale yellow oil. MS (ES+) C9H15IOrequires: 298, found: 299 [M+H]+.

B. Ethyl 1-ethoxy-4-iodocyclohexane-1-carboxylate

    • [0223]
      Figure US20170121312A1-20170504-C00105
    • [0224]
      The title compound was prepared as described above using ethyl 1-ethoxy-4-oxocyclohexane-1-carboxylate as a starting material. C11H19IOrequires: 326, found: 327 [M+H].

Example 9. Synthesis of Amine IntermediatesA. (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine

    • [0225]
      Figure US20170121312A1-20170504-C00106

Step 1: Synthesis of 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one

    • [0226]
      4-Fluoro-1H-pyrazole (4.73 g, 55 mmol) and potassium carbonate (17.27 g, 125 mmol) were combined and stirred in N,N-dimethylformamide (41.7 mL) for 10 minutes in an open sealed tube before addition of 2-bromo-5-acetylpyridine (10 g, 50 mmol). The reaction tube was sealed and stirred for 20 hours at 100° C. The reaction mixture was then cooled to room temperature and poured into water (˜700 mL). The mixture was sonicated and stirred for 20 minutes, after which a beige solid was isolated by filtration, washed with small amounts of water, and dried to yield 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one (9.81 g, 96% yield). MS: M+1=206.0.

Step 2: Synthesis of (R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

    • [0227]
      To a stirred room temperature solution of 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one (9.806 g, 47.8 mmol) in THF (96 mL) was added (R)-(+)-t-Butylsulfinamide (5.79 g, 47.8 mmol) followed by titanium (IV) ethoxide (21.8 g, 96 mmol). The solution was stirred at 75° C. on an oil bath for 15 hours. The reaction solution was cooled to room temperature and then to −78° C. (external temperature) before the next step. To the −78° C. solution was added dropwise over nearly 55 minutes L-Selectride (143 mL of 1N in THF, 143 mmol). During addition, some bubbling was observed. The reaction was then stirred after the addition was completed for 15 minutes at −78° C. before warming to room temperature. LC-MS of sample taken during removal from cold bath showed reaction was completed. The reaction was cooled to −50° C. and quenched slowly with methanol (˜10 mL), then poured into water (600 mL) and stirred. An off-white precipitate was removed by filtration, with ethyl acetate used for washes. The filtrate was diluted with ethyl acetate (800 mL), the layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated down. The crude was purified by silica gel chromatography to yield (R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (10.5 g, 99% purity, 70.3% yield) as a light yellow solid. MS: M+1=311.1.

Step 3: Synthesis of (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine

  • [0228]
    A solution of (R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (10.53 g, 33.9 mmol)) in methanol (79 mmol) and 4N HCl/dioxane (85 mL, 339 mmol) was stirred for 2.5 hours, at which point LC-MS showed reaction was complete. The reaction solution was poured into diethyl ether (300 mL) and a sticky solid was formed. The mixture was treated with ethyl acetate (200 mL) and sonicated. The solvents were decanted, and the sticky solid was treated with more ethyl acetate (˜200 mL), sonicated and stirred. The bulk of the sticky solid was converted to a suspension. A light yellow solid was isolated by filtration, washed with smaller amounts of ethyl acetate, and dried to yield (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine (7.419 g, 78% yield). LC-MS confirmed desired product in high purity. MS: M+1=207.1.


CN 111440151


CN 111362923


  1. Jump up to:a b c d e f g h i j k l m n “FDA approves pralsetinib for lung cancer with RET gene fusions”U.S. Food and Drug Administration (FDA). 4 September 2020. Retrieved 8 September 2020.  This article incorporates text from this source, which is in the public domain.
  2. ^ “Blueprint Medicines Announces FDA Approval of Gavreto (pralsetinib) for the Treatment of Adults with Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer” (Press release). Blueprint Medicines. 4 September 2020. Retrieved 8 September 2020 – via PR Newswire.
  3. ^ “Roche announces FDA approval of Gavreto (pralsetinib) for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer”Roche (Press release). 7 September 2020. Retrieved 8 September 2020.
  4. Jump up to:a b c d “Drug Trial Snapshot: Gavreto”U.S. Food and Drug Administration. 4 September 2020. Retrieved 16 September 2020.  This article incorporates text from this source, which is in the public domain.

External links

Clinical data
Trade names Gavreto
Other names BLU-667
License data
  • US: N (Not classified yet)
Routes of
By mouth
Drug class Tyrosine kinase inhibitor
ATC code
  • None
Legal status
Legal status
CAS Number
PubChem CID
Chemical and physical data
Formula C27H32FN9O2
Molar mass 533.612 g·mol−1
3D model (JSmol)

Roche buys into Blueprint’s RET inhibitor

The deal positions pralsetinib to compete against Lilly’s Retevmo

by Lisa M. Jarvis

Roche is investing $775 million in cash and equity for access to Blueprint Medicines’ oncology drug candidate pralsetinib, which is under review by the US Food and Drug Administration.

Pralsetinib is a small-molecule inhibitor of RET alterations—rare genetic fusions or mutations that occur at low levels across lung, thyroid, and many other cancers.

The drug will go up against Eli Lilly and Company’s Retevmo, an RET inhibitor that received FDA approval in May for certain lung and thyroid cancers. Lilly acquired Retevmo in its $8 billion purchase of Loxo Oncology in 2019, a deal to obtain Loxo’s pipeline of small molecules for genetically defined tumors.

But SVB Leerink analyst Andrew Berens points out that Retevmo has side effects: it can cause an irregular heart rhythm called QT prolongation and hemorrhagic events. That leaves room for pralsetinib, which Roche will be better able to get in front of oncologists, Berens argues. In addition to a vast commercial network, Roche brings diagnostic tools to help identify cancer patients whose tumors feature RET alterations.

The FDA has a deadline of Nov. 23 to decide on approving the drug for lung cancer.

Roche’s move lowers the likelihood of a takeover of Blueprint, which had appeared on many investors’ short lists of acquisition targets. “We were surprised by the profuse language framing this deal as ensuring Blueprint’s independence,” Piper Sandler stock analyst Christopher J. Raymond told investors in a note.

//////////Pralsetinib, GAVRETO, 2020 APPROVALS, FDA 2020



Cortexolone 17α-propionate.svg


(1R,3aS,3bR,9aR,9bS,11aS)-1-(2-hydroxyacetyl)-9a,11a-dimethyl-7-oxo-1H,2H,3H,3aH,3bH,4H,5H,7H,8H,9H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-1-yl propanoate

Mol weight

FDA APPROVED, 2020/8/26, Winlevi


Anti-acne, Androgen receptor antagonist

Clascoterone, sold under the brand name Winlevi, is an antiandrogen medication which is used topically in the treatment of acne.[1][2][3] It is also under development for the treatment of androgen-dependent scalp hair loss.[2] The medication is used as a cream by application to the skin, for instance the face and scalp.[3]

Clascoterone is an antiandrogen, or antagonist of the androgen receptor (AR), the biological target of androgens such as testosterone and dihydrotestosterone.[4][5] It shows no systemic absorption when applied to skin.[3]

The medication, developed by Cassiopea and Intrepid Therapeutics,[2] was approved by the US Food and Drug Administration (FDA) for acne in August 2020.[6][7]

Medical uses

Clascoterone is indicated for the topical treatment of acne vulgaris in females and males age 12 years and older.[1][8] It is applied to the affected skin area in a dose of 1 mg cream (or 10 mg clascoterone) twice per day, once in the morning and once in the evening.[1] The medication should not be used ophthalmicallyorally, or vaginally.[1]

Available forms

Clascoterone is available in the form of a 1% (10 mg/g) cream for topical use.[1]


Clascoterone has no contraindications.[1]

Side effects

The incidences of local skin reactions with clascoterone were similar to placebo in two large phase 3 randomized controlled trials.[1][9] Suppression of the hypothalamic–pituitary–adrenal axis (HPA axis) may occur during clascoterone therapy in some individuals due to its cortexolone metabolite.[1][8] HPA axis suppression as measured by the cosyntropin stimulation test was observed to occur in 3 of 42 (7%) of adolescents and adults using clascoterone for acne.[1][8] HPA axis function returned to normal within 4 weeks following discontinuation of clascoterone.[1][8] Hyperkalemia (elevated potassium levels) occurred in 5% of clascoterone-treated individuals and 4% of placebo-treated individuals.[1]



Clascoterone is an steroidal antiandrogen, or antagonist of the androgen receptor (AR), the biological target of androgens such as testosterone and dihydrotestosterone (DHT).[1][4][5] In a bioassay, the topical potency of the medication was greater than that of progesteroneflutamide, and finasteride and was equivalent to that of cyproterone acetate.[10] Likewise, it is significantly more efficacious as an antiandrogen than other AR antagonists such as enzalutamide and spironolactone in scalp dermal papilla cells and sebocytes in vitro.[5]\


Steady-state levels of clascoterone occur within 5 days of twice daily administration.[1] At a dosage of 6 g clascoterone cream applied twice daily, maximal circulating levels of clascoterone were 4.5 ± 2.9 ng/mL, area-under-the-curve levels over the dosing interval were 37.1 ± 22.3 h*ng/mL, and average circulating levels of clascoterone were 3.1 ± 1.9 ng/mL.[1] In rodents, clascoterone has been found to possess strong local antiandrogenic activity, but negligible systemic antiandrogenic activity when administered via subcutaneous injection.[10] Along these lines, the medication is not progonadotropic in animals.[10]

The plasma protein binding of clascoterone is 84 to 89% regardless of concentration.[1]

Clascoterone is rapidly hydrolyzed into cortexolone (11-deoxycortisol) and this compound is a possible primary metabolite of clascoterone based on in-vitro studies in human liver cells.[1][8] During treatment with clascoterone, cortexolone levels were detectable and generally below or near the low limit of quantification (0.5 ng/mL).[1] Clascoterone may also produce other metabolites, including conjugates.[1]

The elimination of clascoterone has not been fully characterized in humans.[1]


Clascoterone, also known as cortexolone 17α-propionate or 11-deoxycortisol 17α-propionate, as well as 17α,21-dihydroxyprogesterone 17α-propionate or 17α,21-dihydroxypregn-4-en-3,20-dione 17α-propionate, is a synthetic pregnane steroid and a derivative of progesterone and 11-deoxycortisol (cortexolone).[11] It is specifically the C17α propionate ester of 11-deoxycortisol.[10]

An analogue of clascoterone is 9,11-dehydrocortexolone 17α-butyrate (CB-03-04).[12]


C17α esters of 11-deoxycortisol were unexpectedly found to possess antiandrogenic activity.[10] Clascoterone, also known as cortexolone 17α-propionate, was selected for development based on its optimal drug profile.[10] The medication was approved by the US Food and Drug Administration (FDA) for the treatment of acne in August 2020.[6]

Two large phase 3 randomized controlled trials evaluated the effectiveness of clascoterone for the treatment of acne over a period of 12 weeks.[1][8][9] Clascoterone decreased acne symptoms by about 8 to 18% more than placebo.[1][9] The defined treatment success endpoint was achieved in about 18 to 20% of individuals with clascoterone relative to about 7 to 9% of individuals with placebo.[1][8][9] The comparative effectiveness of clascoterone between males and females was not described.[1][9]

A small pilot randomized controlled trial in 2011, found that clascoterone cream decreased acne symptoms to a similar or significantly greater extent than tretinoin 0.05% cream.[8][13] No active comparator was used in the phase III clinical trials of clascoterone for acne.[8] Hence, it’s unclear how clascoterone compares to other therapies used in the treatment of acne.[8]

The FDA approved clascoterone based on evidence from two clinical trials (Trial 1/NCT02608450 and Trial 2/NCT02608476) of 1440 participants 9 to 58 years of age with acne vulgaris.[14] The trials were conducted at 99 sites in the United States, Poland, Romania, Bulgaria, Ukraine, Georgia, and Serbia.[14]

Participants applied clascoterone or vehicle (placebo) cream twice daily for 12 weeks.[14] Neither the participants nor the health care providers knew which treatment was being given until after the trial was completed.[14] The benefit of clascoterone in comparison to placebo was assessed after 12 weeks of treatment using the Investigator’s Global Assessment (IGA) score that measures the severity of disease (on a scale from 0 to 4) and a decrease in the number of acne lesions.[14]

Society and culture


Clascoterone is the generic name of the drug and its INN and USAN.[11][15]


Clascoterone has been suggested as a possible treatment for hidradenitis suppurativa (acne inversa), an androgen-dependent skin condition.[16]


  • Cortexolone derivatives in which the hydroxyl group at position C-17α is esterified with short chain aliphatic or aromatic acids and the derivatives of the corresponding 9,11-dehydro derivative, are known to have an antiandrogenic effect.
  • [0002]
    EP 1421099 describes cortexolone 17α-propionate and 9,11-dehydro-cortexolone-17-α-butanoate regarding a high antiandrogenic biological activity demonstrated both “in vitro” and “in vivo” on the animal.
  • [0003]
    US3530038 discloses the preparation of a crystalline form of cortexolone-17α-propionate having a melting point of 126-129 °C and an IR spectrum with bands at (cm-1): 3500, 1732, 1713, 1655 and 1617.
  • [0004]
    A method for obtaining the above mentioned derivatives is described by Gardi et al. (Gazz. Chim. It. 63, 43 1,1963) and in the United States patent US3152154 providing for the transformation of cortexolone, or transformation of 9,11-dehydrocortexolone, in the intermediate orthoester using orthoesters available in the market as a mixture of aprotic solvents such as cyclohexane and DMF, in presence of acid catalysis (ex. PTSA.H20). The intermediate orthoester thus obtained can be used as is or upon purification by suspension in a solvent capable of solubilising impurities, preferably in alcohols. The subsequent hydrolysis in a hydroalcoholic solution, buffered to pH 4-5 preferably in acetate buffer, provides the desired monoester.
  • [0005]

    Such synthesis is indicated in the diagram 1 below

    Figure imgb0001
  • [0006]
    However, the monoesters thus obtained were, in the reaction conditions, unstable and, consequently hard to manipulate and isolate (R. Gardi et al Tetrahedron Letters, 448, 1961). The instability is above all due to the secondary reaction of migration of the esterifying acyl group from position 17 to position 21.
  • [0007]
    It is thus known that in order to obtain the above mentioned monoesters with a chemical purity in such a manner to be able to proceed to the biological tests, it is necessary to use, at the end of the synthesis, a purification process which is generally performed by means of column chromatography.
  • [0008]
    Furthermore, US3152154 describes how the hydrolysis of the diester in a basic environment is not convenient due to the formation of a mixture of 17α,21-diol, of 17- and 21 -monoesters, alongside the initial non-reacted product.
  • [0009]
    Now, it has been surprisingly discovered that an alcoholysis reaction using a lipase from Candida as a biocatalyst can be usefully applied during the preparation of 17α monoesters of cortexolone, or its 9,11-dehydroderivatives.
  • [0010]

    As a matter of fact, it has been discovered that such enzymatic alcoholysis of the 17,21-diester of the cortexolone, or of its derivative 9,11-dehydro, selectively occurs in position 21 moving to the corresponding monoester in position 17, as shown in diagram 2 below:

    Figure imgb0002
  • [0011]
    The chemoselectivity of the special enzymatic reaction in alcoholysis conditions, according to the present invention, opens new perspectives for preparation, at industrial level with higher yields, of 17α-monoesters with respect to the methods already indicated in literature.
  • [0012]
    The diesters serving as a substrate for the reaction of the invention can be prepared according to the prior art, for example following the one described in B.Turner, (Journal of American Chemical Society, 75, 3489, 1953) which provides for the esterification of corticosteroids with a linear carboxylic acid in presence of its anhydride and PTSA monohydrate.


    • Example 1

Alcoholysis with CCL of cortexolone 17α, 21-dipropionate

      • [0055]
        Add butanol (0.4g, 5.45 mmoles) and CCL (17.4g, 3.86 U/mg, FLUKA) to a solution of cortexolone-17α,21-dipropionate (0.5g, 1.09 mmoles) in toluene (50ml). Maintain the mixture under stirring, at 30 °C, following the progress of the reaction in TLC (Toluene/ethyl acetate 6/4) until the initial material is dissolved (24h). Remove the enzyme by means of filtration using a Celite layer. Recover the cortexolone 17α-propionate (0.437, 99%) after evaporation under low pressure. Through crystallisation, from diisopropyl ether you obtain a product with a purity >99% in HPLC.
      • [0056]
        1H-NMR (500MHz, CDCl3) relevant signals δ (ppm) 5.78 (br s, 1 H, H-4), 4.32 (dd, 1 H, H-21), 4.25 (dd, 1H, H-21), 1.22 (s, 3H, CH3-19), 1.17 (t, 3H, CH3), 0.72 (s, 3H, CH3-18). P.f. 114 °C

Example 2 (comparative)

      • [0057]
        According to the method described in example 1 prepare cortexolone-17α-butanoate.
      • [0058]
        1H-NMR relevant signals δ (ppm) 5.78 (br s, 1H, H-4), 4.32 (dd, 1H, H-21), 4.26 (dd, 1H, H-21), 1.23 (s, 3H, CH3-19), 0.97 (t, 3H, CH3), 0.73 (s, 3H. CH3-18). P.F. 134-136 °C

Example 3 (comparative)

According to the method described in the example prepare cortexolone-17α-valerate.

      • [0059]
        1H-NMR relevant signals δ (ppm) 5.77 (br s, 1H, H-4), 4.32 (dd, 1H, H-21), 4.26 (dd, 1H, H-21), 1.22 (s, 3H, CH3-19), 0.95 (t, 3H, CH3), 0.72 (s, 3H, CH3-18). P.f. 114 °C (diisopropyl ether).

Example 4 (comparative)

According to the method described in the example prepare 9, 11-dehydro-cortexolone-17α-butanoate.

      • [0060]
        1H-NMR relevant signals δ (ppm) 5.77 (br s, 1H, H-4), 5.54 (m, 1H, H-9), 4.29 (dd, 1H, H-21), 4.24 (dd, 1H, H-21), 1.32 (s, 3H, CH3-19), 0.94(t, 3H, CH3), 0.68 (s, 3H, CH3-18). P.f. 135-136 °C (acetone/hexane).

Example 5

Alcoholysis with CALB of cartexolone-17α, 21-dipropionate

      • [0061]
        Dissolve cortexolone, 17α, 2-dipropionate (0.5g, 1.09 mmoles) in acetonitrile (40ml), add CALB (2.3g, 2.5 U/mg Fluka) and octanol (0.875ml). Leave the mixture under stirring, at 30 °C, for 76 hrs. Remove the enzyme by means of filtration using a paper filter. Once the solvents evaporate, recover a solid (0.4758) which upon analysis 1H-NMR shall appear made up of cortexolone-17α-propionate at 91%.

Example 6


      • [0062]
        Add the solvent (t-butylmethylether or diisopropylether) to the sample according to the ratios indicated in Table 3. Heat the mixture to the boiling temperature of the solvent, under stirring, until the sample dissolves completely. Cool to room temperature and leave it at this temperature, under stirring, for 6 hours. Filter using a buchner funnel and maintain the solid obtained, under low pressure, at a room temperature for 15 hours and then, at 40°C, for 5 hours.

Example 7 (comparative)


      • [0063]
        Disslove the sample in the suitable solvent (dichloromethane, acetone, ethyl acetate or ethanol) according to the ratios indicated in table 3 and then add the solvent, hexane or water, according to the ratios indicated in table 3, maintaining the mixture, under stirring, at room temperature. Recover the precipitate by filtration using a buchner funnel and desiccate as in example 6.

Example 8.

Obtaining a pharmaceutical form containing the medication in a defined crystalline form.

  • [0064]
    Prepare a fluid cream containing 2 % cetylic alcohol, 16% glyceryl monostearate, 10% vaseline oil, 13 % propylene glycol, 10% polyethylenglycol with low polymerization 1.5% polysorbate 80 and 47.5 % purified water. Add 1 g of cortexolone 17α-propionate of crystalline form III to 100 g of this cream and subject the mixture to homogenisation by means of a turbine agitator until you obtain homogeneity. You obtain a cream containing a fraction of an active ingredient dissolved in the formulation vehicle and a non-dissolved fraction of an active ingredient, present as a crystal of crystalline form III. This preparation is suitable for use as a formulation vehicle for skin penetration tests on Franz cells, where a coefficient of penetration in the range of 0.04 to 0.03 cm/h is observed on the preparation.


  1. Jump up to:a b c d e f g h i j k l m n o p q r s t u v w “Winlevi (clascoterone) cream, for topical use”(PDF). Cassiopea. Retrieved 9 September 2020.
  2. Jump up to:a b c
  3. Jump up to:a b c Kircik LH (July 2019). “What’s new in the management of acne vulgaris”Cutis104(1): 48–52. PMID 31487336.
  4. Jump up to:a b Rosette C, Rosette N, Mazzetti A, Moro L, Gerloni M (February 2019). “Cortexolone 17α-Propionate (Clascoterone) is an Androgen Receptor Antagonist in Dermal Papilla Cells In Vitro”. J Drugs Dermatol18 (2): 197–201. PMID 30811143.
  5. Jump up to:a b c Rosette C, Agan FJ, Mazzetti A, Moro L, Gerloni M (May 2019). “Cortexolone 17α-propionate (Clascoterone) Is a Novel Androgen Receptor Antagonist that Inhibits Production of Lipids and Inflammatory Cytokines from Sebocytes In Vitro”. J Drugs Dermatol18 (5): 412–418. PMID 31141847.
  6. Jump up to:a b “Cassiopea Receives FDA Approval for Winlevi (clascoterone cream 1%), First-in-Class Topical Acne Treatment Targeting the Androgen Receptor”Cassiopea (Press release). Retrieved 2020-08-30.
  7. ^ “Winlevi: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 9 September 2020.
  8. Jump up to:a b c d e f g h i j Barbieri, John S. (2020). “A New Class of Topical Acne Treatment Addressing the Hormonal Pathogenesis of Acne”. JAMA Dermatology156 (6): 619–620. doi:10.1001/jamadermatol.2020.0464ISSN 2168-6068PMID 32320045.
  9. Jump up to:a b c d e Hebert A, Thiboutot D, Stein Gold L, Cartwright M, Gerloni M, Fragasso E, Mazzetti A (April 2020). “Efficacy and Safety of Topical Clascoterone Cream, 1%, for Treatment in Patients With Facial Acne: Two Phase 3 Randomized Clinical Trials”JAMA Dermatol156 (6): 621–630. doi:10.1001/jamadermatol.2020.0465PMC 7177662PMID 32320027.
  10. Jump up to:a b c d e f Celasco G, Moro L, Bozzella R, Ferraboschi P, Bartorelli L, Quattrocchi C, Nicoletti F (2004). “Biological profile of cortexolone 17alpha-propionate (CB-03-01), a new topical and peripherally selective androgen antagonist”. Arzneimittelforschung54 (12): 881–6. doi:10.1055/s-0031-1297043PMID 15646372.
  11. Jump up to:a b
  12. ^ Celasco G, Moroa L, Bozzella R, Ferraboschi P, Bartorelli L, Di Marco R, Quattrocchi C, Nicoletti F (2005). “Pharmacological profile of 9,11-dehydrocortexolone 17alpha-butyrate (CB-03-04), a new androgen antagonist with antigonadotropic activity”. Arzneimittelforschung55 (10): 581–7. doi:10.1055/s-0031-1296908PMID 16294504.
  13. ^ Trifu V, Tiplica GS, Naumescu E, Zalupca L, Moro L, Celasco G (2011). “Cortexolone 17α-propionate 1% cream, a new potent antiandrogen for topical treatment of acne vulgaris. A pilot randomized, double-blind comparative study vs. placebo and tretinoin 0·05% cream”. Br. J. Dermatol165 (1): 177–83. doi:10.1111/j.1365-2133.2011.10332.xPMID 21428978S2CID 38404925.
  14. Jump up to:a b c d e “Drug Trial Snapshot: Winlevi”U.S. Food and Drug Administration (FDA). 26 August 2020. Retrieved 10 September 2020.  This article incorporates text from this source, which is in the public domain.
  15. ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82”. WHO Drug Information33 (3): 106. hdl:10665/330879.
  16. ^ Der Sarkissian SA, Sun HY, Sebaratnam DF (August 2020). “Cortexolone 17 α-proprionate for hidradenitis suppurativa”. Dermatol Ther: e14142. doi:10.1111/dth.14142PMID 32761708.

External links

  • “Clascoterone”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02608450 for “A Study to Evaluate the Safety and Efficacy of CB-03-01 Cream, 1% in Subjects With Facial Acne Vulgaris (25)” at
  • Clinical trial number NCT02608476 for “A Study to Evaluate the Safety and Efficacy of CB-03-01 Cream, 1% in Subjects With Facial Acne Vulgaris (26)” at
Cortexolone 17α-propionate.svg
Clinical data
Trade names Winlevi
Other names CB-03-01; Breezula; 11-Deoxycortisol 17α-propionate; 17α-(Propionyloxy)-
deoxycorticosterone; 21-Hydroxy-3,20-dioxopregn-4-en-17-yl propionate
License data
Routes of
Topical (cream)
ATC code
  • None
Legal status
Legal status
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard 100.210.810 Edit this at Wikidata
Chemical and physical data
Formula C24H34O5
Molar mass 402.531 g·mol−1
3D model (JSmol)

/////////Clascoterone, クラスコステロン , FDA 2020, 2020 APPROVALS, ANTI ACNE


Somapacitan, ソマパシタン;

(Disulfide bridge: 53-165, 182-189)


2D chemical structure of 1338578-34-9



Growth hormone (GH) receptor agonist

CAS: 1338578-34-9

(2S)-5-[2-[2-[2-[[(2S)-1-amino-6-[[2-[(2R)-2-amino-2-carboxyethyl]sulfanylacetyl]amino]-1-oxohexan-2-yl]amino]-2-oxoethoxy]ethoxy]ethylamino]-2-[[(4S)-4-carboxy-4-[[2-[2-[2-[4-[16-(2H-tetrazol-5-yl)hexadecanoylsulfamoyl]butanoylamino]ethoxy]ethoxy]acetyl]amino]butanoyl]amino]-5-oxopentanoic acid

Mol weight
JAP ソマパシタン;

Treatment of growth hormone dificiency
albumin-binding growth hormone






Somapacitan, also known as NNC0195-0092,3 is a growth hormone analog indicated to treat adults with growth hormone deficiency.2,6 This human growth hormone analog differs by the creation of an albumin binding site, and prolonging the effect so that it requires weekly dosing rather than daily.5

Somapacitan was granted FDA approval on 28 August 2020.7


Somapacitan, sold under the brand name Sogroya, is a growth hormone medication.[2] Somapacitan is a human growth hormone analog.[1] Somapacitan-beco is produced in Escherichia coli by recombinant DNA technology.[1]

The most common side effects include: back pain, joint paint, indigestion, a sleep disorder, dizziness, tonsillitis, swelling in the arms or lower legs, vomiting, adrenal insufficiency, hypertension, increase in blood creatine phosphokinase (a type of enzyme), weight increase, and anemia.[2]

It was approved for medical use in the United States in August 2020.[2][3][4]

Somapacitan (Sogroya) is the first human growth hormone (hGH) therapy that adults only take once a week by injection under the skin; other FDA-approved hGH formulations for adults with growth hormone deficiency must be administered daily.[2]

Medical uses

Somapacitan is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency.[2]


Somapacitan should not be used in people with active malignancy, any stage of diabetic eye disease in which high blood sugar levels cause damage to blood vessels in the retina, acute critical illness, or those with acute respiratory failure, because of the increased risk of mortality with use of pharmacologic doses of somapacitan in critically ill individuals without growth hormone deficiency.[2]


Somapacitan was evaluated in a randomized, double-blind, placebo-controlled trial in 300 particpants with growth hormone deficiency who had never received growth hormone treatment or had stopped treatment with other growth hormone formulations at least three months before the study.[2] Particpants were randomly assigned to receive injections of weekly somapacitan, weekly placebo (inactive treatment), or daily somatropin, an FDA-approved growth hormone.[2] The effectiveness of somapacitan was determined by the percentage change of truncal fat, the fat that is accumulated in the trunk or central area of the body that is regulated by growth hormone and can be associated with serious medical issues.[2]

At the end of the 34-week treatment period, truncal fat decreased by 1.06%, on average, among particpants taking weekly somapacitan while it increased among particpants taking the placebo by 0.47%.[2] In the daily somatropin group, truncal fat decreased by 2.23%.[2] Particpants in the weekly somapacitan and daily somatropin groups had similar improvements in other clinical endpoints.[2]

It was approved for medical use in the United States in August 2020.[2][4] The U.S. Food and Drug Administration (FDA) granted the approval of Sogroya to Novo Nordisk, Inc.[2][4]


  1. Jump up to:a b c d “Sogroya (somapacitan-beco) injection, for subcutaneous use” (PDF). Retrieved 1 September 2020.
  2. Jump up to:a b c d e f g h i j k l m n o “FDA approves weekly therapy for adult growth hormone deficiency”U.S. Food and Drug Administration (FDA) (Press release). 1 September 2020. Retrieved 1 September 2020.  This article incorporates text from this source, which is in the public domain.
  3. ^ “FDA approves once-weekly Sogroya for the treatment of adult growth hormone deficiency”Novo Nordisk (Press release). 28 August 2020. Retrieved 1 September 2020.
  4. Jump up to:a b c “Sogroya: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 2 September 2020.

External links

Clinical data
Trade names Sogroya
Other names somapacitan-beco, NNC0195-0092
License data
Routes of
Drug class Human growth hormone analog
ATC code
  • None
Legal status
Legal status
CAS Number
PubChem CID
Chemical and physical data
Formula C1038H1609N273O319S9
Molar mass 23305.42 g·mol−1

CTID Title Phase Status Date
NCT01706783 A Trial Investigating the Safety, Tolerability, Availability and Distribution in the Body of Once-weekly Long-acting Growth Hormone (Somapacitan) Compared to Once Daily Norditropin NordiFlex® in Adults With Growth Hormone Deficiency Phase 1 Completed 2018-05-25
NCT01973244 A Trial Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a Single Dose of Long-acting Growth Hormone (Somapacitan) Compared to Daily Dosing of Norditropin® SimpleXx® in Children With Growth Hormone Deficiency Phase 1 Completed 2018-05-25
NCT02962440 A Trial Investigating the Absorption, Metabolism and Excretion of Somapacitan After Single Dosing in Healthy Male Subjects Phase 1 Completed 2017-06-07
CTID Title Phase Status Date
NCT02616562 Investigating Efficacy and Safety of Once-weekly NNC0195-0092 (Somapacitan) Treatment Compared to Daily Growth Hormone Treatment (Norditropin® FlexPro®) in Growth Hormone Treatment naïve Pre-pubertal Children With Growth Hormone Deficiency Phase 2 Recruiting 2020-03-25
NCT03075644 A Trial to Evaluate the Safety of Once Weekly Dosing of Somapacitan (NNC0195-0092) and Daily Norditropin® FlexPro® for 52 Weeks in Previously Human Growth Hormone Treated Japanese Adults With Growth Hormone Deficiency Phase 3 Completed 2019-10-18
NCT03905850 A Study to Compare the Uptake Into the Blood of Two Strengths of Somapacitan After Injection Under the Skin in Healthy Subjects Phase 1 Completed 2019-08-06
NCT03212131 Investigation of Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Multiple Doses of Somapacitan in Subjects With Mild and Moderate Degrees of Hepatic Impairment Compared to Subjects With Normal Hepatic Function. Phase 1 Completed 2019-05-24
NCT01514500 First Human Dose Trial of NNC0195-0092 (Somapacitan) in Healthy Subjects Phase 1 Completed 2018-05-25
CTID Title Phase Status Date
NCT03811535 A Research Study in Children With a Low Level of Hormone to Grow. Treatment is Somapacitan Once a Week Compared to Norditropin® Once a Day Phase 3 Recruiting 2020-09-03
NCT03878446 A Research Study in Children Born Small and Who Stayed Small. Treatment is Somapacitan Once a Week Compared to Norditropin® Once a Day Phase 2 Recruiting 2020-08-27
NCT02382939 A Trial to Compare the Safety of Once Weekly Dosing of Somapacitan With Daily Norditropin® FlexPro® for 26 Weeks in Previously Human Growth Hormone Treated Adults With Growth Hormone Deficiency Phase 3 Completed 2020-07-09
NCT02229851 Trial to Compare the Efficacy and Safety of NNC0195-0092 (Somapacitan) With Placebo and Norditropin® FlexPro® (Somatropin) in Adults With Growth Hormone Deficiency. Phase 3 Completed 2020-07-07
NCT03186495 Investigation of Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Multiple Doses of Somapacitan in Subjects With Various Degrees of Impaired Renal Function Compared to Subjects With Normal Renal Function Phase 1 Completed 2020-04-17

EU Clinical Trials Register

EudraCT Title Phase Status Date
2018-000232-10 A dose-finding trial evaluating the effect and safety of once-weekly treatment of somapacitan compared to daily Norditropin® in children with short stature born small for gestational age with no catch-up growth by 2 years of age or older Phase 2 Ongoing, Prematurely Ended 2019-05-15
2015-000531-32 A randomised, multinational, active-controlled,(open-labelled), dose finding, (double-blinded), parallel group trial investigating efficacy and safety of once-weekly NNC0195-0092 treatment compared to daily growth hormone treatment (Norditropin® FlexPro®) in growth hormone treatment naïve pre-pubertal children with growth hormone deficiency Phase 2 Ongoing, Completed 2015-12-10
2014-000290-39 A multicentre, multinational, randomised, open-labelled, parallel-group, active-controlled trial to compare the safety of once weekly dosing of NNC0195-0092 with daily Norditropin® FlexPro® for 26 weeks in previously human growth hormone treated adults with growth hormone deficiency Phase 3 Completed 2014-11-07
2013-002892-16 A multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) and active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of NNC0195-0092 with once weekly dosing of placebo and daily Norditropin® FlexPro® in adults with growth hormone deficiency for 35 weeks, followed by a 53-week open-label extension period Phase 3 Completed 2014-10-07
2018-000231-27 A trial comparing the effect and safety of once weekly dosing of somapacitan with daily Norditropin® in children with growth hormone deficiency Phase 3 Ongoing

EU Clinical Trials Register

EudraCT Title Phase Status Date
2013-000013-20 A randomised, open-labelled, active-controlled, multinational, dose-escalation trial investigating safety, tolerability, pharmacokinetics and pharmacodynamics of a single dose of long-acting growth hormone (NNC0195-0092) compared to daily dosing of Norditropin® SimpleXx® in children with growth hormone deficiency Phase 1 Ongoing, Completed 2013-12-09

///////////Somapacitan, PEPTIDE.2020 APPROVALS, FDA 2020, ソマパシタン, NN8640


Copper Cu 64 dotatate, 銅(Cu64)ドータテート;

Copper dotatate Cu-64.png

2D chemical structure of 1426155-87-4

Figure imgf000004_0001

Copper Cu 64 dotatate




Copper 64-DOTA-tate

Copper Cu-64 dotatate

Copper dotatate Cu-64

Diagnostic (neuroendocrine tumors), Radioactive agent

C65H86CuN14O19S2. 2H
Mol weight

FDA APPROVED 2020. 2020/9/3. Detectnet


Cuprate(2-)-64Cu, (N-(2-(4,10-bis((carboxy-kappaO)methyl)-7-(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl-kappaN1,kappaN4,kappaN7,kappaN10)acetyl)-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-threonyl-L-cysteinyl-L-threoni

Copper Cu 64 dotatate, sold under the brand name Detectnet, is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adults.[1]

Common side effects include nausea, vomiting and flushing.[2]

It was approved for medical use in the United States in September 2020.[1][2]


The U.S. Food and Drug Administration (FDA) approved copper Cu 64 dotatate based on data from two trials that evaluated 175 adults.[3]

Trial 1 evaluated adults, some of whom had known or suspected NETs and some of whom were healthy volunteers.[3] The trial was conducted at one site in the United States (Houston, TX).[3] Both groups received copper Cu 64 dotatate and underwent PET scan imaging.[3] Trial 2 data came from the literature-reported trial of 112 adults, all of whom had history of NETs and underwent PET scan imaging with copper Cu 64 dotatate.[3] The trial was conducted at one site in Denmark.[3] In both trials, copper Cu 64 dotatate images were compared to either biopsy results or other images taken by different techniques to detect the sites of a tumor.[3] The images were read as either positive or negative for presence of NETs by three independent image readers who did not know participant clinical information.[3]



  • Known imaging techniques with tremendous importance in medical diagnostics are positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), single photon computed tomography (SPECT) and ultrasound (US). Although today’s imaging technologies are well developed they rely mostly on non-specific, macroscopic, physical, physiological, or metabolic changes that differentiate pathological from normal tissue.
  • [0003]
    Targeting molecular imaging (MI) has the potential to reach a new dimension in medical diagnostics. The term “targeting” is related to the selective and highly specific binding of a natural or synthetic ligand (binder) to a molecule of interest (molecular target) in vitro or in vivo.
  • [0004]
    MI is a rapidly emerging biomedical research discipline that may be defined as the visual representation, characterization and quantification of biological processes at the cellular and sub-cellular levels within intact living organisms. It is a novel multidisciplinary field, in which the images produced reflect cellular and molecular pathways and in vivo mechanism of disease present within the context of physiologically authentic environments rather than identify molecular events responsible for disease.
  • [0005]
    Several different contrast-enhancing agents are known today and their unspecific or non-targeting forms are already in clinical routine. Some examples listed below are reported in literature.
  • [0006]
    For example, Gd-complexes could be used as contrast agents for MRI according to “Contrast Agents I” by W. Krause (Springer Verlag 2002, page one and following pages). Furthermore, superparamagnetic particles are another example of contrast-enhancing units, which could also be used as contrast agents for MRI (Textbook of Contrast Media, Superparamagnetic Oxides, Dawson, Cosgrove and Grainger Isis Medical Media Ltd, 1999, page 373 and following pages). As described in Contrast Agent II by W. Krause (Springer Verlag 2002, page 73 and following pages), gas-filled microbubbles could be used in a similar way as contrast agents for ultrasound. Moreover “Contrast Agents II” by W. Krause (Springer Verlag, 2002, page 151 and following pages) reports the use of iodinated liposomes or fatty acids as contrast agents for X-Ray imaging.
  • [0007]
    Contrast-enhancing agents that can be used in functional imaging are mainly developed for PET and SPECT.
  • [0008]
    The application of radiolabelled bioactive peptides for diagnostic imaging is gaining importance in nuclear medicine. Biologically active molecules which selectively interact with specific cell types are useful for the delivery of radioactivity to target tissues. For example, radiolabelled peptides have significant potential for the delivery of radionuclides to tumours, infarcts, and infected tissues for diagnostic imaging and radiotherapy.
  • [0009]
    DOTA (1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10tetraazacyclododecane) and its derivatives constitute an important class of chelators for biomedical applications as they accommodate very stably a variety of di- and trivalent metal ions. An emerging area is the use of chelator conjugated bioactive peptides for labeling with radiometals in different fields of diagnostic and therapeutic nuclear oncology.
  • [0010]
    There have been several reports in recent years on targeted radiotherapy with radiolabeled somatostatin analogs.
  • [0011]
    US2007/0025910A1 discloses radiolabled somatostatin analogs primarily based on the ligand DOTA-TOC. The radionucleotide can be (64)Copper and the somatostatin analog may be octreotide, lanreotide, depreotide, vapreotide or derivatives thereof. The compounds of US2007/0025910A1 are useful in radionucleotide therapy of tumours.
  • [0012]
    US2007/0025910A1 does not disclose (64)Cu-DOTA-TATE. DOTA-TATE and DOTA-TOC differ clearly in affinity for the 5 known somatostatin receptors (SST1-SST2). Accordingly, the DOTA-TATE has a 10-fold higher affinity for the SST2 receptor, the receptor expressed to the highest degree on neuroendocrine tumors. Also the relative affinity for the other receptor subtypes are different. Furthermore, since 177Lu-DOTATATE is used for radionuclide therapy, only 64Cu-DOTATATE and not 64Cu-DOTATOC can be used to predict effect of such treatment by a prior PET scan.
  • [0013]
    There exists a need for further peptide-based compounds having utility for diagnostic imaging techniques, such as PET.

Figure US20140341807A1-20141120-C00001

  • [0033]
    Preparation of “Cu-Dotatate-DOTA-TATE
  • [0034]
    64Cu was produced using a GE PETtrace cyclotron equipped with a beamline. The 64Cu was produced via the 64Ni (p,n) 64Cu reaction using a solid target system consisting of a water cooled target mounted on the beamline. The target consisted of 64Ni metal (enriched to >99%) electroplated on a silver disc backing. For this specific type of production a proton beam with the energy of 16 MeV and a beam current of 20 uA was used. After irradiation the target was transferred to the laboratory for further chemical processing in which the 64Cu was isolated using ion exchange chromatography. Final evaporation from aq. HCl yielded 2-6 GBq of 64Cu as 64CuCl2 (specific activity 300-3000 TBq/mmol; RNP >99%). The labeling of 64Cu to DOTA-TATE was performed by adding a sterile solution of DOTA-TATE (0.3 mg) and Gentisic acid (25 mg) in aq Sodium acetate (1 ml; 0.4M, pH 5.0) to a dry vial containing 64CuCl2 (˜1 GBq). Gentisic acid was added as a scavenger to reduce the effect of radiolysis. The mixture was left at ambient temperature for 10 minutes and then diluted with sterile water (1 ml). Finally, the mixture was passed through a 0.22 μm sterile filter (Millex GP, Millipore). Radiochemical purity was determined by RP-HPLC and the amount of unlabeled 64Cu2+ was determined by thin-layer chromatography. All chemicals were purchased from Sigma-Aldrich unless specified otherwise. DOTA-Tyr3-Octreotate (DOTA-TATE) was purchased from Bachem (Torrance, Calif.). Nickel-64 was purchased in +99% purity from Campro Scientific Gmbh. All solutions were made using Ultra pure water (<0.07 μSimens/cm). Reversed-phase high pressure liquid chromatography was performed on a Waters Alliance 2795 Separations module equipped with at Waters 2489 UV/Visible detector and a Caroll Ramsey model 105 S-1 radioactivity detector—RP-HPLC column was Luna C18, HST, 50×2 mm, 2.5 μm, Phenomenex. The mobile phase was 5% aq. acetonitrile (0.1% TFA) and 95% aq. acetonitrile (0.1% TFA).
  • [0035]
    Thin layer chromatography was performed with a Raytest MiniGita Star TLC-scanner equipped with a Beta-detector. The eluent was 50% aq methanol and the TLC-plate was a Silica60 on Al foil (Fluka). Ion exchange chromatography was performed on a Dowex 1×8 resin (Chloride-form, 200-400 mesh).


  1. Jump up to:a b “FDA approval letter” (PDF). 3 September 2020. Retrieved 5 September 2020.  This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b “RadioMedix and Curium Announce FDA Approval of Detectnet (copper Cu 64 dotatate injection) in the U.S.” (Press release). Curium. 8 September 2020. Retrieved 9 September 2020 – via GlobeNewswire.
  3. Jump up to:a b c d e f g h “Drug Trials Snapshots: Detectnet”U.S. Food and Drug Administration (FDA). 3 September 2020. Retrieved 10 September 2020.  This article incorporates text from this source, which is in the public domain.

External links

Coppers Coming | Cu 64 dotatate injection is coming soonThe emerging role of copper-64 radiopharmaceuticals as cancer theranostics  - ScienceDirect

The emerging role of copper-64 radiopharmaceuticals as cancer theranostics  - ScienceDirect

The FDA has approved copper Cu 64 dotatate injection (Detectnet) for the localization of somatostatin receptor–positive neuroendocrine tumors (NETs), according to an announcement from RadioMedix Inc. and Curium Pharma.1

The positron emission tomography (PET) diagnostic agent is anticipated to launch immediately, according to Curium. Doses will be accessible through several nuclear pharmacies or through the nuclear medicine company.

“Detectnet brings an exciting advancement in the diagnosis of NETs for healthcare providers, patients, and their caregivers,” Ebrahim Delpassand MD, CEO of RadioMedix, stated in a press release. “The phase 3 results demonstrate the clinical sensitivity and specificity of Detectnet which will provide a great aid to clinicians in developing an accurate treatment approach for their [patients with] NETs.”

Copper Cu 64 dotatate adheres to somatostatin receptors with highest affinity for subtype 2 receptors (SSTR2). Specifically, the agent binds to somatostatin receptor–expressing cells, including malignant neuroendocrine cells; these cells overexpress SSTR2. The agent is a positron-producing radionuclide that possesses an emission yield that permits PET imaging.

“Perhaps most exciting is that the 12.7-hour half-life allows Detectnet to be produced centrally and shipped to sites throughout the United States,” added Delpassand. “This will help alleviate shortages or delays that have been experienced with other somatostatin analogue PET agents.”

Two single-center, open-label studies confirmed the efficacy of the diagnostic agent, according to Curium.2 In Study 1, investigators conducted a prospective analysis of 63 patients, which included 42 patients with known or suspected NETs according to histology, conventional imaging, or clinical evaluations, and 21 healthy volunteers. The majority of the participants, or 88% (n = 37) had a history of NETs at the time that they underwent imaging. Just under half of patients (44%; n = 28) were men and the majority were white (86%). Moreover, patients had a mean age of 54 years.

Images produced by the PET agent were interpreted to be either positive or negative for NET via 3 independent readers who had been blinded to the clinical data and other imaging information. Moreover, the results from the diagnostic agent were compared with a composite reference standard that was comprised of 1 oncologist’s blinded evaluation of patient diagnosis based on available histopathology results, reports of conventional imaging that had been done within 8 weeks before the PET imaging, as well as clinical and laboratory findings, which involved chromogranin A and serotonin levels.

Additionally, the percentage of patients who tested positive for disease via composite reference as well as through PET imaging was used to quantify positive percent agreement. Conversely, the percentage of participants who did not have disease per composite reference and who were determined to be negative for disease per PET imaging was used to quantify negative percent agreement.

Results showed that the percent reader agreement for positive detection in 62 scans was 91% (95% CI, 75-98) and negative detection was 97% (95% CI, 80-99). For reader 2, these percentages were 91% (95% CI, 75-98) and 80% (95% CI, 61-92), respectively, for 63 scans. Lastly, the percent reader agreement for reader 3 in 63 scans was 91% (95% CI, 75-98) positive and 90% (95% CI, 72-97) negative.

Study 2 was a retrospective analysis in which investigators examined published findings collected from 112 patients; 63 patients were male, while 43 were female. The mean age of patients included in the analysis was 62 years. All patients had a known history of NETs. Results demonstrated similar performance with the PET imaging agent.

In both safety and efficacy trials, a total of 71 patients were given a single dose of the diagnostic agent; the majority of these patients had known or suspected NETs and 21 were healthy volunteers. Adverse reactions such as nausea, vomiting, and flushing were reported at a rate of less than 2%. In all clinical experience that has been published, a total of 126 patients with a known history of NETs were given a single dose of the PET diagnostic agent. A total of 4 patients experienced nausea immediately after administration.

“Curium is excited to bring the first commercially available Cu 64 diagnostic agent to the US market,” Dan Brague, CEO of Curium, North America, added in the release. “Our unique production capabilities and distribution network allow us to deliver to any nuclear pharmacy, hospital, or imaging center its full dosing requirements first thing in the morning, to provide scheduling flexibility to the institution and its patients. We look forward to joining with healthcare providers and our nuclear pharmacy partners to bring this highly efficacious agent to the market.”

1. RadioMedix and Curium announce FDA approval of Detectnet (copper Cu 64 dotatate injection) in the US. News release. RadioMedix Inc and Curium. September 8, 2020. Accessed September 9, 2020.
2. Detectnet. Prescribing information. Curium Pharma; 2020. Accessed September 9, 2020.

///////////////Copper Cu 64 dotatate, 銅(Cu64)ドータテート , FDA 2020, 2020 APPROVALS, Diagnostic, neuroendocrine tumors, Radioactive agent,


Lactitol, ラクチトール

Chemical structure of lactitol




Mol weight

To treat chronic idiopathic constipation (CIC) in adults

FDA 2/12/2020, APPROVED, Pizensy

Lactitol, NS-4, Portolac, Importal

CAS Registry Number: 585-86-4
CAS Name: 4-O-b-D-Galactopyranosyl-D-glucitol
Additional Names: b-galactoside sorbitol; lactit; lactit M; lactite; lactobiosit; lactosit; lactositol
Molecular Formula: C12H24O11
Molecular Weight: 344.31
Percent Composition: C 41.86%, H 7.03%, O 51.11%
Literature References: Polyol sweetener; relative sweetness compared to sucrose is 36%. Prepd by hydrogenation of lactose, q.v.: M. J. B. Senderens, Compt. Rend. 170, 47 (1920); M. L. Wolfrom et al., J. Am. Chem. Soc. 60, 571 (1938). Pharmacology: D. H. Patil et al., Br. J. Nutr. 57, 195 (1987). Crystal structure: J. A. Kanters et al., Acta Crystallogr. C46, 2408 (1990); J. Kivikoski et al., Carbohydr. Res. 223, 45 (1992). Toxicology: E. J. Sinkeldam et al., J. Am. Coll. Toxicol. 11, 165 (1992). Clinical trial in chronic hepatic encephalopathy: O. Riggio et al., Hepatogastroenterology 37, 524 (1990); as a laxative: L. Goovaerts, G. P. Ravelli, Acta Ther. 19, 61 (1993). Review of properties and applications: J. A. van Velthuijsen, J. Agric. Food Chem. 27, 680-686 (1979); of chemistry and use in foods: C. H. den Uyl, Dev. Sweeteners 3, 65-81 (1987).
Properties: Crystals from absolute ethanol, mp 146°. [a]D23 +14° (c = 4 in water). Sol in water, dimethyl sulfoxide, N,N-dimethylformamide; slightly sol in ethanol, ether. Strongly hygroscopic.
Melting point: mp 146°
Optical Rotation: [a]D23 +14° (c = 4 in water)
Derivative Type: Monohydrate
CAS Registry Number: 81025-04-9
Trademarks: Importal (Novartis); Portolac (Zyma)
Properties: White, sweet, odorless, crystalline solid. Non-hygroscopic. mp 94-97° (van Velthuijsen), water of crystallization evaporates 145°-185°; also reported as mp 120° (den Uyl). [a]D22 +12.3°. Soly at 25° (g/100 g solvent): water 206; ethanol 0.75; ether 0.4; DMSO 233; DMF 39; at 50°: water 512; ethanol 0.88; at 75°: water 917.
Melting point: mp 94-97° (van Velthuijsen); mp 120° (den Uyl)
Optical Rotation: [a]D22 +12.3°
Derivative Type: Dihydrate
CAS Registry Number: 81025-03-8
Trademarks: Lacty (CCA Biochem)
Properties: White, sweet, odorless, crystalline powder. Data for food grade, mp 75°. [a]D25 +13.5-15.0°. pH of 10% solution 4.5 – 8.5. 140 g will dissolve in 100 ml water at 25°.
Melting point: mp 75°
Optical Rotation: [a]D25 +13.5-15.0°
Use: Sweetener in food.
Therap-Cat: Laxative. In treatment of hepatic encephalopathy.
Keywords: Laxative/Cathartic

Lactitol is a sugar alcohol used as a replacement bulk sweetener for low calorie foods with approximately 40% of the sweetness of sugar. It is also used medically as a laxative. Lactitol is produced by two manufacturers, Danisco and Purac Biochem.


MedicalLactitol is used in a variety of low food energy or low fat foods. High stability makes it popular for baking. It is used in sugar-freecandiescookies (biscuits)chocolate, and ice cream. Lactitol also promotes colon health as a prebiotic. Because of poor absorption, lactitol only has 2.4 kilocalories (9 kilojoules) per gram, compared to 4 kilocalories (17 kJ) per gram for typical saccharides. Hence, lactitol is about 60% as caloric as typical saccharides.

Lactitol is listed as an excipient in some prescription drugs.[1][2]

Lactitol is a laxative and is used to prevent or treat constipation,[3] e.g., under the trade name Importal.[4][5]

In February 2020, Lactitol was approved for use in the United States as an osmotic laxative for the treatment of chronic idiopathic constipation (CIC) in adults.[6][7][8]

Lactitol in combination with Ispaghula husk is an approved combination for idiopathic constipation as a laxative and is used to prevent or treat constipation.[medical citation needed]

Safety and health

Lactitol, erythritolsorbitolxylitolmannitol, and maltitol are all sugar alcohols.[medical citation needed] The U.S. Food and Drug Administration (FDA) classifies sugar alcohols as “generally recognized as safe” (GRAS). They are approved as food additives, and are recognized as not contributing to tooth decay or causing increases in blood glucose.Lactitol is also approved for use in foods in most countries around the world.

Like other sugar alcohols, lactitol causes cramping, flatulence, and diarrhea in some individuals who consume it. This is because humans lack a suitable beta-galactosidase in the upper gastrointestinal (GI) tract, and a majority of ingested lactitol reaches the large intestine,[9] where it then becomes fermentable to gut microbes (prebiotic) and can pull water into the gut by osmosis.{[medical citation needed] Those with health conditions should consult their GP or dietician prior to consumption.{[medical citation needed]


The U.S. Food and Drug Administration (FDA) approved Pizensy based on evidence from a clinical trial (Trial 1/ NCT02819297) of 594 patients with CIC conducted in the United States.[8] The FDA also considered other supportive evidence including data from Trial 2 (NCT02481947) which compared Pizensy to previously approved drug (lubiprostone) for CIC, and Trial 3 (NCT02819310) in which patients used Pizensy for one year as well as data from published literature.[8]

The benefit and side effects of Pizensy were evaluated in a clinical trial (Trial 1) of 594 patients with CIC.[8] In this trial, patients received treatment with either Pizensy or placebo once daily for 6 months.[8] Neither the patients nor the health care providers knew which treatment was being given until after the trials were completed.[8]

In the second trial (Trial 2) of three months duration, improvement in CSBMs was used to compare Pizensy to the drug lubiprostonewhich was previously approved for CIC.[8] The third trial (Trial 3) was used to collect the side effects in patients treated with Pizensy for one year.[8]


Lactitol (CAS NO.: 585-86-4), with its other name of 4-O-beta-D-Galactopyranosyl-D-glucitol, could be produced through many synthetic methods.

Following is one of the synthesis routes: Lactitol is obtained by catalytic hydrogenation of lactose (I) in the presence of either, nickel catalysts such as Raney nickel (1-9), or ruthenium catalysts (10). Alternatively, lactose (I) is reduced by employing NaBH(9).

Production Method of Lactitol







  1. ^ “Lactitol (Inactive Ingredient)” 23 September 2018. Retrieved 24 February 2020.
  2. ^ “Lactitol Monohydrate (Inactive Ingredient)” 3 October 2018. Retrieved 24 February 2020.
  3. ^ Miller LE, Tennilä J, Ouwehand AC (2014). “Efficacy and tolerance of lactitol supplementation for adult constipation: a systematic review and meta-analysis”Clin Exp Gastroenterol7: 241–8. doi:10.2147/CEG.S58952PMC 4103919PMID 25050074.
  4. ^ “Importal” 3 February 2020. Retrieved 24 February 2020.
  5. ^ (the Swedish Medicines Information Engine). Revised 2003-02-12.
  6. ^ “Pizensy: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 24 February 2020.
  7. ^ “Pizensy- lactitol powder, for solution”DailyMed. 21 February 2020. Retrieved 24 February 2020.
  8. Jump up to:a b c d e f g h “Drug Trial Snapshot: Pizensy”U.S. Food and Drug Administration (FDA). 12 February 2020. Retrieved 4 March 2020. This article incorporates text from this source, which is in the public domain.
  9. ^ Grimble GK, Patil DH, Silk DB (1988). “Assimilation of lactitol, an unabsorbed disaccharide in the normal human colon”Gut29 (12): 1666–1671. doi:10.1136/gut.29.12.1666PMC 1434111PMID 3220306.

External links

  •  Media related to Lactitol at Wikimedia Commons
  • “Lactitol”Drug Information Portal. U.S. National Library of Medicine.
Chemical structure of lactitol
IUPAC name

Other names

3D model (JSmol)
ECHA InfoCard 100.008.698
E number E966 (glazing agents, …)
PubChem CID
Molar mass 344.313 g·mol−1
Melting point 146 °C (295 °F; 419 K)
A06AD12 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒ verify (what is ☑☒ ?)
Infobox references
Clinical data
Trade names Importal, Pizensy
Other names Lactitol Hydrate (JANJP)
License data
Routes of
By mouth
ATC code
Legal status
Legal status
CAS Number
PubChem CID
E number E966 (glazing agents, …) Edit this at Wikidata
CompTox Dashboard(EPA)
ECHA InfoCard 100.008.698 Edit this at Wikidata
Chemical and physical data
Formula C12H24O11
Molar mass 344.313 g·mol−1
3D model (JSmol)


Click to View Image


4-OD-Galactopyranosyl-D-glucitol [585-86-4].
Monohydrate. 362.34 [81025-04-9].
Dihydrate. 380.35 [81025-03-8].
» Lactitol contains not less than 98.0 percent and not more than 101.0 percent of C12H24O11, calculated on the anhydrous basis.
Packaging and storage— Preserve in well-closed containers.
Labeling— Label it to indicate whether it is the monohydrate, the dihydrate, or the anhydrous form.
Water, Method I 921 between 4.5% and 5.5% (monohydrate); between 9.5% and 10.5% (dihydrate); and not more than 0.5% for the anhydrous form.
Residue on ignition 281: not more than 0.5%.
Heavy metals 231 Dissolve 4 g of it in 25 mL of water: the limit is 5 µg per g.
Reducing sugars— Dissolve 500 mg of it in 2.0 mL of water in a 10-mL conical flask. Into a similar flask, pipet 2 mL of a dextrose solution containing 0.5 mg per mL. Concomitantly add 1 mL of alkaline cupric tartrate TS to each solution, heat to boiling, and cool: the lactitol solution shows no more turbidity than that produced in the dextrose solution, in which a reddish brown precipitate forms (0.2%, as dextrose).

Related compounds—

Standard solution— Dissolve an accurately weighed quantity of USP Lactitol RS in water to obtain a solution having a known concentration of about 0.3 mg per mL.
Chromatographic system— Proceed as directed in the Assay, except to chromatograph the Standard solution instead of the Standard preparation.
Test solution— Use the Assay preparation, prepared as directed in the Assay.

Procedure— Separately inject equal volumes (about 25 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the peak responses. The relative retention times are about 0.53 for lactose, 0.58 for glucose, 0.67 for galactose, 0.72 for lactulitol, 1.0 for lactitol, 1.55 for galactitol, and 1.68 for sorbitol. Calculate the percentages of galactitol, sorbitol, lactulitol, lactose, glucose, and galactose in the portion of Lactitol taken by the formula:

100(CV/W)(rU / rS)

in which C is the concentration, in mg per mL, of USP Lactitol RS in the Standard solution; V is the volume, in mL, of the Test solution; W is the weight, in mg, of Lactitol in the Test solution; rU is the peak response of the relevant related compound, if observed, obtained from the Test solution; and rS is the lactitol peak response obtained from the Standard solution. The total of the percentages of all related compounds is not more than 1.5%.


Mobile phase— Use water.
Standard preparation— Dissolve an accurately weighed quantity of USP Lactitol RS in water to obtain a solution having a known concentration of about 10.0 mg per mL.
Assay preparation— Transfer about 1000 mg of Lactitol, accurately weighed, to a 100-mL volumetric flask, dissolve in and dilute with water to volume, and mix.
Chromatographic system (see Chromatography 621)—The liquid chromatograph is equipped with a refractive index detector and a 7.8-mm × 30-cm column that contains packing L34. The column is maintained at 85, and the flow rate is about 0.7 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the relative standard deviation for replicate injections is not more than 1.0% for lactitol.

Procedure— Separately inject equal volumes (about 25 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the peak responses. Calculate the quantity, in mg, of C12H24O11 in the portion of Lactitol taken by the formula:

100C(rU / rS)

in which C is the concentration, in mg per mL, of USP Lactitol RS in the Standard preparation, and rU and rS are the lactitol peak responses obtained from the Assay preparation and the Standard preparation, respectively.

Auxiliary Information— Please check for your question in the FAQs before contacting USP.

Topic/Question Contact Expert Committee
Monograph Elena Gonikberg, Ph.D.
Senior Scientist
(MDGRE05) Monograph Development-Gastrointestinal Renal and Endocrine
Reference Standards Lili Wang, Technical Services Scientist
USP32–NF27 Page 1263

Pharmacopeial Forum: Volume No. 31(4) Page 1143

Chromatographic Column—

Chromatographic columns text is not derived from, and not part of, USP 32 or NF 27.

//////////////////Lactitol, ラクチトール , APPROVALS 2020, FDA 2020,  NS-4, Portolac, Importal

Eptinezumab エプチネズマブ;

Fig. 4.7



(Heavy chain)
(Light chain)
(Disulfide bridge: H22-H95, H138-H194, H214-L219, H220-H’220, H223-H’223, H255-H315, H361-H419, H’22-H’95, H’138-H’194, H’214-L’219, H’255-H’315, H’361-H’419, L22-L89, L139-L199, L’22-L’89, L’139-L’199)

Mol weight

Antimigraine, Anti-calcitonin gene-related peptide (GCRP) antibody

Immunoglobulin G1, anti-(calcitonin gene-related peptide) (human-oryctolagus cuniculus monoclonal ALD403 heavy chain), disulfide with human-oryctolagus cuniculus monoclonal ALD403 kappa-chain, dimer

Approved 2020 fda

ALD403, UNII-8202AY8I7H

Humanized anti-calcitonin gene-related peptide (CGRP) IgG1 antibody for the treatment of migraine.

Eptinezumab, sold under the brand name Vyepti, is a medication for the preventive treatment of migraine in adults.[2] It is a monoclonal antibody that targets calcitonin gene-related peptides (CGRP) alpha and beta.[3][4] It is administered by intravenous infusion every three months.[2]

Image result for Eptinezumab

Eeptinezumab-jjmr was approved for use in the United States in February 2020.[5]

Image result for Eptinezumab


  1. ^ “Alder BioPharmaceuticals Initiates PROMISE 2 Pivotal Trial of Eptinezumab for the Prevention of Migraine”. Alder Biopharmaceuticals. 28 November 2016.
  2. Jump up to:a b “Vyeptitm (eptinezumab-jjmr) injection, for intravenous use” (PDF). U.S. Food and Drug Administration (FDA). Retrieved 24 February2020.
  3. ^ Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, et al. (November 2014). “Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial”. The Lancet. Neurology13 (11): 1100–1107. doi:10.1016/S1474-4422(14)70209-1PMID 25297013.
  4. ^ “International Nonproprietary Names for Pharmaceutical Substances (INN)” (PDF)WHO Drug Information. WHO. 31 (1). 2017.
  5. ^ “Vyepti: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 24 February 2020.

External links

Image result for Eptinezumab

Monoclonal antibody
Type Whole antibody
Source Humanized
Clinical data
Trade names Vyepti
Other names ALD403,[1] eeptinezumab-jjmr
License data
Routes of
Drug class Calcitonin gene-related peptide antagonist
ATC code
  • None
Legal status
Legal status
CAS Number
  • none
Chemical and physical data
Formula C6352H9838N1694O1992S46
Molar mass 143283.20 g·mol−1

Biologics license application submitted for eptinezumab, an anti-CGRP antibody for migraine prevention

Alder BioPharmaceuticals has submitted a biologics license application (BLA) for eptinezumab, a humanized IgG1 monoclonal antibody that targets calcitonin gene-related peptide (CGRP), for migraine prevention. If the US Food and Drug Administration grants approval, Alder will be on track to launch the drug in Q1 2020. The BLA included data from the PROMISE 1 and PROMISE 2 studies, which evaluated the effects of eptinezumab in episodic migraine patients (n=888) or chronic migraine patients (n=1,072), respectively.  In PROMISE 1, the primary and key secondary endpoints were met, and the safety and tolerability were similar to placebo, while in PROMISE 2, the primary and all key secondary endpoints were met, and the safety and tolerability was consistent with earlier eptinezumab studies.

Alder announced one-year results from the PROMISE 1 study in June 2018, which indicated that, following the first quarterly infusion, episodic migraine patients treated with 300 mg eptinezumab experienced 4.3 fewer monthly migraine days (MMDs) from a baseline of 8 MMDs, compared to 3.2 fewer MMDs for placebo from baseline (p= 0.0001). At one year after the third and fourth quarterly infusions, patients treated with 300 mg eptinezumab experienced further gains in efficacy, with a reduction of 5.2 fewer MMDs compared to 4.0 fewer MMDs for placebo-treated patients.  In addition, ~31% of episodic migraine patients achieved, on average per month, 100% reduction of migraine days from baseline compared to ~ 21% for placebo. New 6-month results from the PROMISE 2 study were also released in June 2018.  These results indicated that, after the first quarterly infusion, chronic migraine patients dosed with 300 mg of eptinezumab experienced 8.2 fewer MMDs, from a baseline of 16 MMDs, compared to 5.6 fewer MMDs for placebo from baseline (p <.0001). A further reduction in MMDs was seen following a second infusion; 8.8 fewer MMDs for patients dosed with 300 mg compared to 6.2 fewer MMDs for those with placebo. In addition, ~ 21% of chronic migraine patients achieved, on average, 100% reduction of MMDs from baseline compared to 9% for placebo after two quarterly infusions of 300 mg of eptinezumab.

If approved, eptinezumab would become the fourth antibody therapeutic for migraine prevention on the US market, following the approval of erenumab-aooe (Aimovig; Novartis), galcanezumab-gnlm (Emgality; Eli Lilly & Company) and fremanezumab-vfrm (Ajovy; Teva Pharmaceuticals) in 2018.

//////////Eptinezumab, Monoclonal antibody, Peptide, エプチネズマブ  , fda 2020, approvals 2020

Amisulpride, アミスルプリド ,


ChemSpider 2D Image | Amisulpride | C17H27N3O4S



FDA 2020, Barhemsys APPROVED, 2020/2/27

Amisulpride (INN);
Deniban (TN);
Solian (TN)
Mol weight

Antipsychotic, Dopamine receptor antagonist, Neuropsychiatric agent


275-831-7 [EINECS]
Synthesis ReferenceUS4401822
CAS Registry Number: 71675-85-9
CAS Name: 4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide
Additional Names: 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-o-anisamide; aminosultopride
Manufacturers’ Codes: DAN-2163
Trademarks: Deniban (Synthelabo); Socian (Synthelabo); Solian (Synthelabo); Sulamid (Baldacci)
Molecular Formula: C17H27N3O4S
Molecular Weight: 369.48
Percent Composition: C 55.26%, H 7.37%, N 11.37%, O 17.32%, S 8.68%
Literature References: Dopamine receptor antagonist. Prepn: M. Thominet et al., BE 872585eidem, US 4401822 (1979, 1983 both to Soc. d’Etudes Sci. Ind. de l’Ile-de-France).
Crystal structure: H. L. DeWinter et al., Acta Crystallogr. C46, 313 (1990). Psychopharmacology: G. Perrault et al., J. Pharmacol. Exp. Ther. 280, 73 (1997). HPLC determn in plasma and urine: B. Malavasi et al., J. Chromatogr. B 676, 107 (1996). Series of articles on pharmacology and clinical efficacy in schizophrenia: Int. Clin. Psychopharmacol. 12, Suppl. 2, S11-S36 (1997).
Properties: Crystals from acetone, mp 126-127°. LD50 in male mice (mg/kg): 56-60 i.v.; 175-180 i.p.; 224-250 s.c.; 1024-1054 orally (Thominet).
Melting point: mp 126-127°
Toxicity data: LD50 in male mice (mg/kg): 56-60 i.v.; 175-180 i.p.; 224-250 s.c.; 1024-1054 orally (Thominet)
Therap-Cat: Antipsychotic.
Keywords: Antipsychotic; Benzamides; Dopamine Receptor Antagonist.
Amisulpride (trade name Solian) is an antipsychotic drug sold by Sanofi-Aventis.  but is approved for use in Europe and Australia for the treatment of psychoses and schizophrenia. Additionally, it is approved in Italy for the treatment of dysthymia (under the brand name Deniban). Amisulpride is a selective dopamine antagonist.

Amisulpride is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses orally and intramuscularly to treat schizophrenia and acute psychotic episodes. It is sold under the brandnames Barhemsys[6] (as an antiemetic) and Solian, Socian, Deniban and others (as an antipsychotic).[2] It is also used to treat dysthymia.[7]

It is usually classed with the atypical antipsychotics. Chemically it is a benzamide and like other benzamide antipsychotics, such as sulpiride, it is associated with a high risk of elevating blood levels of the lactation hormone, prolactin (thereby potentially causing the absence of the menstrual cycle, breast enlargement, even in males, breast milk secretion not related to breastfeeding, impaired fertility, impotence, breast pain, etc.), and a low risk, relative to the typical antipsychotics, of causing movement disorders.[8][9][10] It has also been found to be modestly more effective in treating schizophrenia than the typical antipsychotics.[9]

Amisulpride is approved for use in the United States in adults for the prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class; and to treat PONV in those who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis.[6]

Amisulpride is believed to work by blocking, or antagonizing, the dopamine D2 receptor, reducing its signalling. The effectiveness of amisulpride in treating dysthymia and the negative symptoms of schizophrenia is believed to stem from its blockade of the presynapticdopamine D2 receptors. These presynaptic receptors regulate the release of dopamine into the synapse, so by blocking them amisulpride increases dopamine concentrations in the synapse. This increased dopamine concentration is theorized to act on dopamine D1 receptors to relieve depressive symptoms (in dysthymia) and the negative symptoms of schizophrenia.[7]

It was introduced by Sanofi-Aventis in the 1990s. Its patent expired by 2008, and generic formulations became available.[11] It is marketed in all English-speaking countries except for Canada and the United States.[10] A New York City based company, LB Pharmaceuticals, has announced the ongoing development of LB-102, also known as N-methyl amisulpride, an antipsychotic specifically targeting the United States.[12][13] A poster presentation at European Neuropsychopharmacology[14] seems to suggest that this version of amisulpride, known as LB-102 displays the same binding to D2, D3 and 5HT7 that amisulpride does.[15][16]

Medical uses


In a 2013 study in a comparison of 15 antipsychotic drugs in effectiveness in treating schizophrenic symptoms, amisulpride was ranked second and demonstrated high effectiveness. 11% more effective than olanzapine (3rd), 32-35% more effective than haloperidolquetiapine, and aripiprazole, and 25% less effective than clozapine (1st).[9] Although according to other studies it appears to have comparable efficacy to olanzapine in the treatment of schizophrenia.[17][18] Amisulpride augmentation, similarly to sulpirideaugmentation, has been considered a viable treatment option (although this is based on low-quality evidence) in clozapine-resistant cases of schizophrenia.[19][20] Another recent study concluded that amisulpride is an appropriate first-line treatment for the management of acute psychosis.[21]


Amisulpride’s use is contraindicated in the following disease states[2][22][8]

Neither is it recommended to use amisulpride in patients with hypersensitivities to amisulpride or the excipients found in its dosage form.[2]

Adverse effects

Very Common (≥10% incidence)[1]
  • Extrapyramidal side effects (EPS; including dystonia, tremor, akathisiaparkinsonism). Produces a moderate degree of EPS; more than aripiprazole (not significantly, however), clozapine, iloperidone (not significantly), olanzapine (not significantly), quetiapine (not significantly) and sertindole; less than chlorpromazine (not significantly), haloperidol, lurasidone (not significantly), paliperidone (not significantly), risperidone (not significantly), ziprasidone (not significantly) and zotepine (not significantly).[9]
Common (≥1%, <10% incidence)[1][2][23][22][8]
  • Hyperprolactinaemia (which can lead to galactorrhoea, breast enlargement and tenderness, sexual dysfunction, etc.)
  • Weight gain (produces less weight gain than chlorpromazine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, zotepine and more (although not statistically significantly) weight gain than haloperidol, lurasidone, ziprasidone and approximately as much weight gain as aripiprazole and asenapine)[9]
  • Anticholinergic side effects (although it does not bind to the muscarinic acetylcholine receptors and hence these side effects are usually quite mild) such as
– constipation
– dry mouth
– disorder of accommodation
– Blurred vision
Rare (<1% incidence)[1][2][23][22][8]

Hyperprolactinaemia results from antagonism of the D2 receptors located on the lactotrophic cells found in the anterior pituitary gland. Amisulpride has a high propensity for elevating plasma prolactin levels as a result of its poor blood-brain barrier penetrability and hence the resulting greater ratio of peripheral D2 occupancy to central D2 occupancy. This means that to achieve the sufficient occupancy (~60–80%[24]) of the central D2 receptors in order to elicit its therapeutic effects a dose must be given that is enough to saturate peripheral D2receptors including those in the anterior pituitary.[25][26]

  • Somnolence. It produces minimal sedation due to its absence of cholinergic, histaminergic and alpha adrenergic receptor antagonism. It is one of the least sedating antipsychotics.[9]


The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[27] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[28] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[28] Less commonly there may be a felling of the world spinning, numbness, or muscle pains.[28] Symptoms generally resolve after a short period of time.[28]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[29] It may also result in reoccurrence of the condition that is being treated.[30] Rarely tardive dyskinesia can occur when the medication is stopped.[28]


Torsades de pointes is common in overdose.[31][32] Amisulpride is moderately dangerous in overdose (with the TCAs being very dangerous and the SSRIs being modestly dangerous).[33][34]


Amisulpride should not be used in conjunction with drugs that prolong the QT interval (such as citalopramvenlafaxinebupropionclozapinetricyclic antidepressantssertindoleziprasidone, etc.),[33] reduce heart rate and those that can induce hypokalaemia. Likewise it is imprudent to combine antipsychotics due to the additive risk for tardive dyskinesia and neuroleptic malignant syndrome.[33]



Amisulpride and its relatives sulpiridelevosulpiride, and sultopride have been shown to bind to the high-affinity GHB receptor at concentrations that are therapeutically relevant (IC50 = 50 nM for amisulpride).[37]Amisulpride functions primarily as a dopamine D2 and D3 receptor antagonist. It has high affinity for these receptors with dissociation constantsof 3.0 and 3.5 nM, respectively.[36] Although standard doses used to treat psychosis inhibit dopaminergic neurotransmission, low doses preferentially block inhibitory presynaptic autoreceptors. This results in a facilitation of dopamine activity, and for this reason, low-dose amisulpride has also been used to treat dysthymia.[2]

Amisulpride, sultopride and sulpiride respectively present decreasing in vitro affinities for the D2 receptor (IC50 = 27, 120 and 181 nM) and the D3 receptor (IC50 = 3.6, 4.8 and 17.5 nM).[39]

Though it was long widely assumed that dopaminergic modulation is solely responsible for the respective antidepressant and antipsychoticproperties of amisulpride, it was subsequently found that the drug also acts as a potent antagonist of the serotonin 5-HT7 receptor (Ki = 11.5 nM).[36] Several of the other atypical antipsychotics such as risperidone and ziprasidone are potent antagonists at the 5-HT7 receptor as well, and selective antagonists of the receptor show antidepressant properties themselves. To characterize the role of the 5-HT7 receptor in the antidepressant effects of amisulpride, a study prepared 5-HT7 receptor knockout mice.[36] The study found that in two widely used rodent models of depression, the tail suspension test, and the forced swim test, those mice did not exhibit an antidepressant response upon treatment with amisulpride.[36] These results suggest that 5-HT7 receptor antagonism mediates the antidepressant effects of amisulpride.[36]

Amisulpride also appears to bind with high affinity to the serotonin 5-HT2B receptor (Ki = 13 nM), where it acts as an antagonist.[36] The clinical implications of this, if any, are unclear.[36] In any case, there is no evidence that this action mediates any of the therapeutic effects of amisulpride.[36]

Society and culture

Brand names

Brand names include: Amazeo, Amipride (AU), Amival, Solian (AUIERUUKZA), Soltus, Sulpitac (IN), Sulprix (AU), Midora (RO) and Socian (BR).[40][41]


Amisulpride was not approved by the Food and Drug Administration for use in the United States until February 2020, but it is used in Europe,[41]Israel, Mexico, India, New Zealand and Australia[2] to treat psychosis and schizophrenia.[42][43]

Amisulpride was approved for use in the United States in February 2020.[44][6]


Dopamine receptor antagonist. Prepn: M. Thominet et al., BE 872585; eidem, U.S. Patent 4,401,822 (1979, 1983 both to Soc. d’Etudes Sci. Ind. de l’Ile-de-France).


4-Amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl)-o-anisamide, could be produced through many synthetic methods.

Following is one of the synthesis routes:
Firstly, the acetylation of 5-aminosalicylic acid (I) with acetic anhydride in hot acetic acid affords 5-acetaminosalicylic acid (II), which is methylated with dimethyl sulfate and K2CO3 in refluxing acetone producing methyl 2-methoxy-5-acetaminobenzoate (III). Secondly, nitration of (III) with HNOin acetic acid affords methyl 2-methoxy-4-nitro-5-acetaminobenzoate (IV), which is deacetylated with H2SO4 in refluxing methanol to give methyl 2-methoxy-4-nitro-5-aminobenzoate (V). Next, the diazotation of (V) with NaNO2-HCl, followed by reaction with sodium ethylmercaptide, oxidation with H2O2 and hydrolysis with NaOH in ethanol yields 2-methoxy-4-nitro-5-(ethylsulfonyl)benzoic acid (VI), which is condensed with N-ethyl-2-aminomethylpyrrolidine (VII) in the presence of ethyl chloroformate and triethylamine in dioxane affording 2-methoxy-4-nitro-N-[(1-ethyl-2-pyrrolidinyl) methyl]-5-(ethylsulfonyl)benzamide (VIII). At last, this compound is reduced with H2 over Raney-Ni in ethanol.

Production Route of Amisulpride


BE 0872585; ES 476755; FR 2415099; GB 2083458; JP 54145658; US 4294828; US 4401822

Alkylation of 2-methoxy-4-amino-5-mercaptobenzoic acid (X) with diethyl sulfate acid Na2CO3 gives 2-methoxy-4-amino-5-ethylthiobenzoic acid (XI), which is oxidized with H2O2 in acetic acid yielding 2-methoxy-4-amino-5-(ethylsulfonyl)benzoic acid (XII). Finally, this compound is condensed with (VII) by means of ethyl chloroformate.


FR 2460930

Acetylation of 5-aminosalicylic acid (I) with acetic anhydride in hot acetic acid gives 5-acetaminosalicylic acid (II), which is methylated with dimethyl sulfate and K2CO3 in refluxing acetone yielding methyl 2-methoxy-5-acetaminobenzoate (III). Nitration of (III) with HNO3 in acetic acid affords methyl 2-methoxy-4-nitro-5-acetaminobenzoate (IV), which is deacetylated with H2SO4 in refluxing methanol to give methyl 2-methoxy-4-nitro-5-aminobenzoate (V). The diazotation of (V) with NaNO2-HCl, followed by reaction with sodium ethylmercaptide, oxidation with H2O2 and hydrolysis with NaOH in ethanol yields 2-methoxy-4-nitro-5-(ethylsulfonyl)benzoic acid (VI), which is condensed with N-ethyl-2-aminomethylpyrrolidine (VII) by means of ethyl chloroformate and triethylamine in dioxane affording 2-methoxy-4-nitro-N-[(1-ethyl-2-pyrrolidinyl) methyl]-5-(ethylsulfonyl)benzamide (VIII). Finally, this compound is reduced with H2 over Raney-Ni in ethanol.


Treatment of thiourea (I) with iodomethane provided S-methylthiouronium iodide (II). This was further condensed with N-methylpiperazine (III) to afford the intermediate piperazine-1-carboxamidine (IV)


Regioselective lithiation of 1,2,4-trichlorobenzene (V) with n-BuLi at -60 C, followed by quenching of the resultant organolithium compound (VI) with N,N-dimethylformamide yielded 2,3,5-trichlorobenzaldehyde (VII) (1), which was then reduced with NaBH4 to provide alcohol (VIII). Bromination of (VIII) using PBr3 afforded compound (IX), whose bromide atom was displaced with KCN to give the trichlorophenylacetonitrile (X). Claisen condensation of (X) with ethyl formate in the presence of NaOEt furnished the oxo nitrile sodium enolate (XI), which was subsequently O-alkylated with iodomethane yielding the methoxy acrylonitrile (XII). Finally, cyclization of (XII) with the piperazine-1-carboxamidine (IV) in EtOH gave rise to the target pyrimidine derivative


Amisulpride is represented by the formula (I) as given below.

Figure US20130096319A1-20130418-C00001

The product patent U.S. Pat. No. 4,401,822 describes preparation of amisulpride as shown in scheme (I)

Figure US20130096319A1-20130418-C00002

The synthesis of amisulpride involves oxidation of 2-methoxy-4-amino-5-ethyl-thio benzoic acid (III) using acetic acid and hydrogen peroxide at 40-45° C. for few hours to obtain 2-methoxy-4-amino-5-ethyl-sulfonyl benzoic acid (IV). In our attempt to repeat this reaction, we found that almost 22 hours were required for completion and the purity of compound (IV) was 87.6%.

    • [0006]
      Thus, the product patent method suffers from the disadvantages such as high reaction time, low yield and low purity.
    • [0007]
      Liu Lie et al, Jingxi Huagong Zhongjianti 2008, 38 (3), 29-32 describes the process for the preparation of 2-methoxy-4-amino-5-ethyl-sulfonyl benzoic acid (IV) as shown in scheme (II).
    • Figure US20130096319A1-20130418-C00003
    • [0008]
      4-amino salicylic acid (VI) is treated with dimethyl sulphate in the presence of potassium hydroxide and acetone to give 4-amino-2-methoxy-methyl benzoate in 4 hours, which is further treated with potassium thiocynate to give compound of formula (VIII). 4-Amino-2-,methoxy-5-thiocyanatobenzoate (VIII) is treated with bromoethane to give 4-amino-5-ethylthio-2-methoxy benzoic acid (IX) which is further converted to 2-methoxy-4-amino-5-ethyl-sulfonyl benzoic acid (IV) via oxidation with hydrogen peroxide and acetic acid.
    • [0009]
      The yield of conversion of compound (VIII) to compound (IX) is 57% and the overall yield of compound (IV) from compound (VI) is 24% only. Thus, the above process suffers from the disadvantages such as low yield and in that it uses bromoethane which is skin and eye irritant and has carcinogenic effects.
    • [0010]
      Therefore, there is, an unfulfilled need to provide industrially feasible process for the preparation of 2-methoxy-4-amino-5-ethyl-sulfonyl benzoic acid (IV) and amisulpride (I) with higher purity and yield, since it is one of the key intermediates in the manufacture of amisulpride.


The present invention is related to a novel process for the preparation of amisulpride (I) that involves: (i) methylation of 4-amino-salicylic-acid (VI) with dimethyl sulphate and base, optionally in presence of TBAB to obtain 4-amino-2-methoxy methyl benzoate (VII) and (ii) oxidation of 4-amino-2-methoxy-5-ethyl thio benzoic acid (IX) or 4-amino-2-methoxy-5-ethyl thio methyl benzoate (X) with oxidizing agent in the presence of sodium tungstate or ammonium molybdate to give 2-methoxy-4-amino-5-ethyl-sulfonyl benzoic acid (IV) or 2-methoxy-4-amino-5-ethyl-sulfonyl methyl benzoate (XI) respectively.
    • Example 13

    • [0097]
      Preparation of crude amisulpride
    • [0098]
      To a stirring mixture of 4-amino-2-methoxy-5-ethyl sulphonyl benzoic acid (IV) and acetone (5.0 L) at 0-5° C., triethyl amine (0.405 Kg) was added and stirred followed by addition of ethyl chloroformate (0.368 Kg). N-ethyl-2-amino methyl pyrrolidine (0.627 Kg) was added to the reaction mass at 5-10° C. Temperature of reaction mass was raised to 25-30° C. and stirred for 120 min. To the same reaction mass triethyl amine (0.405 Kg) and ethyl chloroformate (0.368 Kg) was added with maintaining the temperature. Reaction mass was stirred for 120 min. After completion of reaction, water (4.0 L) was added. Reaction mass was filtered and washed with water (2.0 L). Filtrate was collected and water was added (9.0 L). pH of the reaction mass was adjusted to 10.8-11.2 by using 20% NaOH solution. Reaction mass was stirred for 240-300 min, filtered and washed with water. Solid was dried under vacuum
    • [0099]
      Yield : 70%
    • [0100]
      Purity: 98%

Example 14

  • [0101]
    Purification of amisulpride
  • [0102]
    Amisulpride (1 kg) was charged in acetone (6 liters) and the reaction mixture was heated till a clear solution was obtained. Slurry of activated carbon (0.1 kg in 1 liter) was added in acetone. The reaction mass was stirred at 50-55 ° C. for 60 minutes and filtered hot. The filtrate was concentrated and further heated to dissolve the solid. The reaction mass was cooled to 0-5° C., stirred and filtered. The precipitated solid was washed with acetone and dried.
  • [0103]
    Yield: 750 gm (75%)
  • [0104]
    HPLC purity: 99.8% (quantitative)
  • [0105]
    M.P.: 125° C.
  • [0106]
    DSC: shows endotherm at 133° C.
  • [0107]
    Particle size: d10=0.637, d50=6.0, d90=13.325 microns



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  32. ^ Joy, JP; Coulter, CV; Duffull, SB; Isbister, GK (August 2011). “Prediction of Torsade de Pointes From the QT Interval: Analysis of a Case Series of Amisulpride Overdoses”. Clinical Pharmacology & Therapeutics90 (2): 243–245. doi:10.1038/clpt.2011.107PMID 21716272.
  33. Jump up to:a b c Taylor, D; Paton, C; Shitij, K (2012). Maudsley Prescribing Guidelines in Psychiatry(11th ed.). West Sussex: Wiley-Blackwell. ISBN 978-0-47-097948-8.
  34. ^ Levine, M; Ruha, AM (July 2012). “Overdose of atypical antipsychotics: clinical presentation, mechanisms of toxicity and management”. CNS Drugs26 (7): 601–611. doi:10.2165/11631640-000000000-00000PMID 22668123.
  35. ^ Roth, BL; Driscol, J. “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 14 August 2017.
  36. Jump up to:a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar asat au av aw Abbas AI, Hedlund PB, Huang XP, Tran TB, Meltzer HY, Roth BL (2009). “Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo”Psychopharmacology205 (1): 119–28. doi:10.1007/s00213-009-1521-8PMC 2821721PMID 19337725.
  37. Jump up to:a b Maitre, M.; Ratomponirina, C.; Gobaille, S.; Hodé, Y.; Hechler, V. (April 1994). “Displacement of [3H] gamma-hydroxybutyrate binding by benzamide neuroleptics and prochlorperazine but not by other antipsychotics”. European Journal of Pharmacology256(2): 211–214. doi:10.1016/0014-2999(94)90248-8PMID 7914168.
  38. ^ Schoemaker H, Claustre Y, Fage D, Rouquier L, Chergui K, Curet O, Oblin A, Gonon F, Carter C, Benavides J, Scatton B (1997). “Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity”. J. Pharmacol. Exp. Ther280 (1): 83–97. PMID 8996185.
  39. ^ Blomme, Audrey; Conraux, Laurence; Poirier, Philippe; Olivier, Anne; Koenig, Jean-Jacques; Sevrin, Mireille; Durant, François; George, Pascal (2000), “Amisulpride, Sultopride and Sulpiride: Comparison of Conformational and Physico-Chemical Properties”, Molecular Modeling and Prediction of Bioactivity, Springer US, pp. 404–405, doi:10.1007/978-1-4615-4141-7_97ISBN 9781461368571
  40. ^ “Amisulpride international” 3 February 2020. Retrieved 26 February 2020.
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External links

Clinical data
Trade names Solian, Barhemsys, others
Other names APD421
AHFS/ International Drug Names
License data
  • AU: C
Routes of
By mouthintravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 48%[3][2]
Protein binding 16%[2]
Metabolism Hepatic (minimal; most excreted unchanged)[2]
Elimination half-life 12 hours[3]
Excretion Renal[3] (23–46%),[4][5]Faecal[2]
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard 100.068.916 Edit this at Wikidata
Chemical and physical data
Formula C17H27N3O4S
Molar mass 369.48 g/mol g·mol−1
3D model (JSmol)

  1. Rosenzweig P, Canal M, Patat A, Bergougnan L, Zieleniuk I, Bianchetti G: A review of the pharmacokinetics, tolerability and pharmacodynamics of amisulpride in healthy volunteers. Hum Psychopharmacol. 2002 Jan;17(1):1-13. [PubMed:12404702]
  2. Moller HJ: Amisulpride: limbic specificity and the mechanism of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1101-11. [PubMed:14642970]
  3. Weizman T, Pick CG, Backer MM, Rigai T, Bloch M, Schreiber S: The antinociceptive effect of amisulpride in mice is mediated through opioid mechanisms. Eur J Pharmacol. 2003 Oct 8;478(2-3):155-9. [PubMed:14575800]
  4. Leucht S, Pitschel-Walz G, Engel RR, Kissling W: Amisulpride, an unusual “atypical” antipsychotic: a meta-analysis of randomized controlled trials. Am J Psychiatry. 2002 Feb;159(2):180-90. [PubMed:11823257]
  5. Rehni AK, Singh TG, Chand P: Amisulpride-induced seizurogenic effect: a potential role of opioid receptor-linked transduction systems. Basic Clin Pharmacol Toxicol. 2011 May;108(5):310-7. doi: 10.1111/j.1742-7843.2010.00655.x. Epub 2010 Dec 22. [PubMed:21176108]


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WO2019113084A1 *2017-12-052019-06-13Sunovion Pharmaceuticals Inc.Crystal forms and production methods thereof
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CN102807516A *2012-08-162012-12-05四川省百草生物药业有限公司Intermediate in amisulpride and method for preparing amisulpride by using intermediate
CN103819383A *2012-11-192014-05-28上海美迪西生物医药有限公司Synthesis method for amisulpride
CN103319385B *2013-06-182015-07-08苏州诚和医药化学有限公司Method for synthesizing 2-methoxy-4-amino-5-ethylsulfonyl benzoic acid
CN103450058B *2013-09-182015-10-14广安凯特医药化工有限公司A kind of preparation method of amisulpride acid
CN103553989B *2013-11-082015-03-11苏州诚和医药化学有限公司Synthetic method of 2-methoxyl-4-amino-5-ethyl sulfuryl methyl benzoate
CN104725292B *2015-03-232017-07-25湖北荆江源制药股份有限公司A kind of preparation method of (S) () Amisulpride
CN105237422A *2015-09-062016-01-13南京理工大学Synthetic method of 4-amino-5-chloro-2-methoxyl benzoic acid

///////////////Amisulpride, アミスルプリド , 标准品 , FDA 2020, 2020 APPROVALS, Barhemsys, SOLIAN,  Antipsychotic, Benzamides,  Dopamine Receptor Antagonist,


Rimegepant sulfate, リメゲパント硫酸塩;

ChemSpider 2D Image | Rimegepant | C28H28F2N6O3



  • Molecular FormulaC28H28F2N6O3
  • Monoisotopic mass534.219116 Da
1289023-67-1 [RN]
1-Piperidinecarboxylic acid, 4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-1-yl)-, (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester
BMS 927711

Antimigraine, Calcitonin receptor-like receptor antagonist

Treatment of migraine

Rimegepant sulfate.png



Rimegepant sulfate (USAN)


(C28H28F2N6O3)2. H2SO4. 3H2O
Mol weight

Nurtec ODT, FDA 2020, 2020/2/27 fda approved

Biohaven Pharmaceuticals developed Rimegepant, also known as BMS-927711, acquired in 2016 from Bristol-Myers Squibb, Rimegepant, also known as BMS-927711. Rimegepant is a potent, selective, competitive and orally active calcitonin gene-related peptide (CGRP) antagonist in clinical trials for treating migraine. Rimegepant has shown in vivo efficacy without vasoconstrictor effect; it is superior to placebo at several different doses (75 mg, 150 mg, and 300 mg) and has an excellent tolerability profile.

Rimegepant is a medication for the treatment of an acute migraine with or without aura (a sensory phenomenon or visual disturbance) in adults. However, it is not to be used prophylactically. In the US, it is marketed under the brand name, Nurtec ODT.[1]

It is not indicated for the preventive treatment of migraine.[1] It is taken by mouth, to dissolve on the tongue.[1] It takes effect within an hour and can provide relief for up to 48 hours, according to Biohaven. It is not a narcotic and has no addictive potential, and consequently will not be designated a controlled substance. It works by blocking CGRP receptors. 86% of patients did not require additional rescue medication within 24 hours of a single dose of Nurtec. All this info was obtained from a press release from Biohaven. (

Rimegepant was approved for use in the United States as of February 27th, 2020 by the U.S. Food and Drug Administration (FDA) to be produced and marketed by Biohaven Pharmaceuticals.[2]

Charlie Conway

Charlie Conway, Chief Scientific Officer at Biohaven Pharmaceuticals

Vlad Coric, M.D.

Vlad Coric, M.D., CEO at Biohaven

No alternative text description for this image



– First and only calcitonin gene-related peptide (CGRP) receptor antagonist available in a fast-acting orally disintegrating tablet (ODT)- A single oral dose of NURTEC ODT 75 mg can provide fast pain relief and return patients to normal function within one hour, and deliver sustained efficacy that lasts up to 48 hours for many patients- 86 percent of patients treated with a single dose of NURTEC ODT did not use a migraine rescue medication within 24 hours- Biohaven to host investor conference call on Friday, February 28, 2020 at 8:00 am ET

NEW HAVEN, Conn., Feb. 27, 2020 /PRNewswire/ — Biohaven Pharmaceutical Holding Company Ltd. (NYSE: BHVN) today announced that the U.S. Food and Drug Administration (FDA) has approved NURTEC™ ODT (rimegepant) for the acute treatment of migraine in adults. NURTEC ODT is the first FDA-approved product for Biohaven, a company dedicated to advancing innovative therapies for neurological diseases.

Nurtec™ ODT convenient 8-count package

NURTEC™ ODT Convenient 8-count Package

 NURTEC™ ODT zoom in showing one individual quick-dissolving tablet (not actual size)

A single quick-dissolving tablet of NURTEC ODT can provide fast pain relief and return patients to normal function within one hour, and deliver sustained efficacy that lasts up to 48 hours for many patients. NURTEC ODT disperses almost instantly in a person’s mouth without the need for water, offering people with migraine a convenient, discreet way to take their medication anytime and anywhere they need it. NURTEC ODT is not indicated for the preventive treatment of migraine. Biohaven expects topline results from its prevention of migraine trial later this quarter.

Vlad Coric, M.D., CEO of Biohaven commented, “The FDA approval of NURTEC ODT marks an important milestone for the migraine community and a transformative event for Biohaven. Millions of people suffering from migraine are often not satisfied with their current acute treatment, at times having to make significant tradeoffs because of troublesome side effects and reduced ability to function. NURTEC ODT is an important new oral acute treatment for migraine that offers patients the potential to quickly reduce and eliminate pain and get back to their lives.” Dr. Coric added, “We believe NURTEC ODT will be the first of many innovative Biohaven medicines to become available to treat devastating neurological diseases, a therapeutic category many other companies have abandoned. We are dedicated to helping patients with these conditions, who often have limited or no treatment options, live better, more productive lives.”

NURTEC ODT, with its novel quick-dissolve oral tablet formulation, works by blocking CGRP receptors, treating a root cause of migraine. NURTEC ODT is not an opioid or narcotic, does not have addiction potential and is not scheduled as a controlled substance by the U.S. Drug Enforcement Administration.

NURTEC ODT may offer an alternative treatment option, particularly for patients who experience inadequate efficacy, poor tolerability, or have a contraindication to currently available therapies. More than 3,100 patients have been treated with rimegepant with more than 113,000 doses administered in clinical trials, including a one-year long-term safety study. In the pivotal Phase 3 trial, NURTEC ODT was generally well tolerated; the most common adverse reaction was nausea (2%) in patients who received NURTEC ODT compared to 0.4% of patients who received placebo.

Mary Franklin, Executive Director of the National Headache Foundation commented, “Everyone knows someone living with migraine, yet it remains an invisible disease that is often overlooked and misunderstood. Almost all people with migraine need an acute treatment to stop a migraine attack as it occurs, which can happen without warning. The approval of NURTEC ODT is exciting for people with migraine as it provides a new treatment option to help people regain control of their attacks and their lives.”

Peter Goadsby, M.D., Ph.D., Professor of Neurology and Director of the King’s Clinical Research Facility, King’s College Hospital commented, “I see many patients in my practice whose lives are disrupted by migraine, afraid to go about everyday life in case of a migraine attack. Many feel unsure if their acute treatment will work and if they can manage the side effects. With the FDA approval of NURTEC ODT, there is renewed hope for people living with migraine that they can get back to living their lives without fear of the next attack.”

The FDA approval of NURTEC ODT is based on results from the pivotal Phase 3 clinical trial (Study 303) and the long-term, open-label safety study (Study 201). In the Phase 3 trial, NURTEC ODT achieved statistical significance on the regulatory co-primary endpoints of pain freedom and freedom from most bothersome symptom (MBS) at two hours post dose compared to placebo. NURTEC ODT also demonstrated statistical superiority at one hour for pain relief (reduction of moderate or severe pain to no pain or mild pain) and return to normal function. The benefits of pain freedom, pain relief, return to normal function and freedom from MBS were sustained up to 48 hours for many patients. Importantly, these benefits were seen with only a single dose of NURTEC ODT. Eighty-six percent of patients treated with NURTEC ODT did not require rescue medication (e.g. NSAIDS, acetaminophen) within 24 hours post dose. The long-term safety study assessed the safety and tolerability of rimegepant with multiple doses used over up to one year. The study evaluated 1,798 patients, who used rimegepant 75 mg as needed to treat migraine attacks, up to one dose per day. The study included 1,131 patients who were exposed to rimegepant for at least six months, and 863 who were exposed for at least one year, all of whom treated an average of at least two migraine attacks per month. The safety of treating more than 15 migraines in a 30-day period has not been established.

NURTEC ODT is contraindicated in patients with a history of hypersensitivity to rimegepant, NURTEC ODT, or to any of its components. Hypersensitivity reactions with dyspnea and severe rash, including delayed serious hypersensitivity days after administration, occurred in less than 1% of subjects taking NURTEC ODT in clinical studies.

Biohaven Conference Call Information
Biohaven is hosting a conference call and webcast on Friday, February 28, 2020, at 8:00 a.m. ET.  Participants are invited to join the conference by dialing 877-407-9120 (toll-free) or 412-902-1009 (international). To access the audio webcast with slides, please visit the “Events & Presentations” page in the Investors section of the Company’s website.

Biohaven’s Commitment to Patient Access 
Biohaven is committed to supporting the migraine community by eliminating barriers to medication access. The company has launched a patient support program. For more information and to enroll, please call 1-833-4-NURTEC or visit

NURTEC ODT will be available in pharmacies in early March 2020 in packs of eight tablets. Each eight tablet pack covers treatment of eight migraine attacks with one dose, as needed, up to once daily.  Sample packs containing two tablets will also be made available to healthcare providers. Patients with migraine should discuss with their primary care provider or neurologist whether NURTEC ODT is appropriate for them.

NURTEC™ ODT (rimegepant) is the first and only calcitonin gene-related peptide (CGRP) receptor antagonist available in a quick-dissolve ODT formulation that is approved by the U.S. Food and Drug Administration (FDA) for the acute treatment of migraine in adults. The activity of the neuropeptide CGRP is thought to play a causal role in migraine pathophysiology. NURTEC ODT is a CGRP receptor antagonist that works by reversibly blocking CGRP receptors, thereby inhibiting the biologic activity of the CGRP neuropeptide. The recommended dose of NURTEC ODT is 75 mg, taken as needed, up to once daily. For more information about NURTEC ODT, visit

About Migraine
Nearly 40 million people in the U.S. suffer from migraine and the World Health Organization classifies migraine as one of the 10 most disabling medical illnesses. Migraine is characterized by debilitating attacks lasting four to 72 hours with multiple symptoms, including pulsating headaches of moderate to severe pain intensity that can be associated with nausea or vomiting, and/or sensitivity to sound (phonophobia) and sensitivity to light (photophobia). There is a significant unmet need for new acute treatments as more than 90 percent of migraine sufferers are unable to work or function normally during an attack.

About CGRP Receptor Antagonism
Small molecule CGRP receptor antagonists represent a novel class of drugs for the treatment of migraine. This unique mode of action potentially offers an alternative to current agents, particularly for patients who have contraindications to the use of triptans, or who have a poor response to triptans or are intolerant to them.

What is NURTEC ODT? 
NURTEC™ ODT (rimegepant) is indicated for the acute treatment of migraine with or without aura in adults.

No alternative text description for this image

Raising the “flag of freedom from migraine” over Biohaven headquarters in New Haven CT

Mechanism of action

Rimegepant is a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist.[3]


WO 2011046997


WO 2012050764

The disclosure generally relates to a synthetic process for preparing compounds of formula I including the preparation of chemical intermediates useful in this process. CGRP inhibitors are postulated to be useful in pathophysiologic conditions where excessive CGRP receptor activation has occurred. Some of these include neurogenic vasodilation, neurogenic inflammation, migraine, cluster headache and other headaches, thermal injury, circulatory shock, menopausal flushing, and asthma. CGRP antagonists have shown efficacy in human clinical trials. See Davis CD, Xu C. Curr Top Med Chem. 2008 8(16):1468-79; Benemei S, Nicoletti P, Capone JG, Geppetti P. Curr Opin Pharmacol 2009 9(1):9-14. Epub 2009 Jan 20; Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, Leibensperger H, Froman S, Assaid C, Lines C, Koppen H, Winner PK. Lancet. 2008 372:2115. Epub 2008 Nov 25; Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, Lines CR, Rapoport AM; Neurology 2008 70: 1304. Epub 2007 Oct 3.

CGRP receptor antagonists have been disclosed in PCT publications WO 2004/092166, WO 2004/092168, and WO 2007/120590. The compound (5S,6S,9R)- 5-amino-6-(2,3-difluorophenyl)-6,7,8!9-tetrahydiO-5H-cyclohepta[b]pyridin-9-yl 4- (2-oxo-2,3-dihydiO-lH-imidazo[4,5-b]pyridin-l-yl)piperidine-l-carboxylate is an inhibitor of the calcitonin gene-related peptide (CGRP) receptor.

Figure imgf000004_0001
Figure imgf000005_0001

cheme 1 illustrates a synthesis of formula I compounds. heme 1,

Figure imgf000011_0001


Figure imgf000012_0001

( 6S, 9R)-6~ (2, 3 -difluorophenyl)-9-(triisopropylsiIyloxy) – 6, 7, 8, 9-tetrahydro-5H- cyclohepta[b]pyridin-5 -amine. To a 100 mL hastelloy autoclave reactor was charged (6S,9R)-6-(2,3-difluorophenyl)-9-(triisopiOpylsilyloxy)-6,7,8,9-tetrahydi -5H- cyclohepta[b]pyridin-5-one (5.00 g, 1 1.22 mmol), 1,4-dioxane (50 mL) and titanium tetra(isopropoxide) (8.33 mL, 28.11 mmol). The reactor was purged three times with nitrogen and three times with ammonia. After the purge cycle was completed, the reactor was pressurized with ammonia to 100 psig. The reaction mixture was heated to 50°C (jacket temperature) and stirred at a speed to ensure good mixing. The reaction mixture was aged at 100 psig ammonia and 50°C for 20 h. The mixture was then cooled to 20°C then 5 % Pd/Alumina (1.0 g, 20 wt%) was charged to the autoclave reactor. The reactor was purged three times with nitrogen and three times with hydrogen. After the purged cycle completed, the reactor was pressurized with hydrogen to 100 psig and mixture was heated to 50°C (jacket temperature) and stirred at a speed to ensure good mixing. The reaction mixture was aged at 100 psig H2 and 50°C for 23h (reactor pressure jumped to -200 psig due to soluble ammonia in the mixture). The mixture was then cooled to 20 °C then filtered then transferred to a 100 ml 3-necked flask. To the mixture water (0.55 mL) was added drop wise, which resulted in yellow slurry. The resulting slurry was stirred for 30 mm then filtered, then the titanium dioxide cake was washed with 1,4-dioxane (30 mL). The filtrate was collected and the solvent was removed. The resulting oil was dissolved in isopropanol (40 mL). To the solution ~5N HC1 in isopropanol (9.0 ml) was added drop wise resulting in a thick slurry. To the slurry isopropyi acetate (60 ml) was added and heated to 45 °C for 10 min and then cooled to 22 °C over approximately 3 h to afford a white solid (3.0 g, 51.5 %). Ή NMR (500 MHz, CD3OD)

δ ppm 8.89 (d, J= 5.3, 1H), 8,42 (bs, 1H), 8.05 (bs, 1H), 7.35 (dd, J= 8.19 , 16.71), 7.2 (bs, 2H), 7.22 (m, 1H) 7.15 (m, 1H), 5.7 (dd, J = 1.89, J = 8.51), 5.4 (m, 1H), 3.5 ( m, 1H), 1.9-2.5 (B, 4h) 1.4 (sept, J = 15.13,3H), 1.2 (t, J= Ί.5Ί 18H); 13C NMR (125 MHz, CD3OD) δ 153.5, 151.6, 151.5, 151.3, 149.4, 143.4, 135.03, 129.8, 129.8, 127.8, 126.8, 126.4, 118.6, 72.4, 54.1, 41.4, 34.3, 32.3, 25.4, 18.6, 18.5, 13.7, 13.6, 13.5, 13.3.

Example 2

Figure imgf000013_0001

(6S,9R)-5-cmino-6-(2 -difluorophenyl)-6, 7,8,9-tetrahydro~5H-cyclohepta[b^ 9-o To a 250 ml flask was charged (6S,9R)-6-(253-difluoiOphenyl)-9-

(tnisopiOpylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-amine di HC1 salt (15 g, 25.88 mtnol) and a solution of isopropanol: water (45 mL : 15 mL). The mixture was heated to 82 °C for 6h then dried via azeotropic distillation at atmospheric pressure using isopropanol until the KF was less than < 3 %. After fresh isopropanol (25 ml) was added, the mixture was heated to 70 °C and then isopropyl acetate (45 ml) was added that resulting in a white slurry. The slurry cooled to 22 °C for 15 min to afford a white solid (9.33 g, 99%). 1H NMR (500 MHz CD3OD) δ 8.77 (d, J= 5.7 Hz, 1H), 8.47 (d, J= 7.9 Hz, 1H), 8.11 (dd, J= 6.0, 8.2 Hz, 1H), 7.21-7.32 (m, 3H), 5.53 (dd, J= 3.8, 9.8 Hz, 1H) 5.33 (d, J = 9.8 Hz, 1H), 3.5 (bm, 1H), 2.25- 2.40 (m, 2H), 2.15 (bm, 1H), 1.90 (bm, 1H); 13C NMR (125 MHz, MeOD) δ 159.4, 153.9, 151.9 and 151.8, 149.7, 143.6, 141.8, 135.7, 130.6, 127.7, 126.8, 1 18.9, 70.0, 54.9, 42.2, 34.5, 33.4. Example 3

Figure imgf000014_0001

(5S, 6S, 9R)-5-amino-6-(2, 3-difluorophenyl)-6, 7>8,9-tetrahydro-5H- cyclohepta[b ]pyridin-9~yl~4-(2-oxo-2, 3-dihydro-lH-imidazo[4, 5-b ]pyridin-l- yl)piperidine-l-carboxylate. To a round bottom flask was charged (5S,6S,9R)-5- amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol dihydrochloride (1.00 g, 2.73 mmol) and dichloromethane (15 mL). A solution of sodium carbonate (0.58 g, 5.47 mmol), 20 wt% aqueous sodium chloride (5 mL), and water (10 mL) was added and the biphasic mixture was aged for 30 min. The phases were allowed to separate and the organic stream was retained. The dichloromethane solvent was then switched with azeotropic drying to tetrahydrofuran, with a final volume of (15 mL). At 20 °C was added, l-(l-(lH~imidazole-l-carbonyl)piperidin- 4-yl)-lH-imidazo[4,5-b]pyridin-2(3H)-one (0.95 g, 3.01 mmol), followed by a 20 wt% potassium ter/-butoxide solution in THF (4 mL, 6.20 mmol). The thin slurry was aged for lh, and then the reaction was quenched with the addition of 20 wt% aqueous sodium chloride (5 mL) and 20 wt% aqueous citric acid (2.5 mL). The layers were allowed to separate and the organic rich layer was retained. The organic layer was washed with 20 wt% aqueous sodium chloride (1 mL). The organic tetrahydrofuran stream was then concentrated in vacuo to afford an oil which was resuspended in dichloromethane (20 mL) and dried with MgS04. The

dichloromethane stream was concentrated in vacuo to afford an oil, which was crystallized from ethanohheptane to afford a white solid (1.14 g, 78.3%). LCMS: [M+H] = 535: 1H MR (600 MHz, 6-DMSO) δ 11.58 (IH, bs), 8.45 (IH, bd), 8.03 (IH, d, J= 7.3 Hz), 7.91 (IH, bs), 7.54 (IH, bd), 7.36 (IH, bm), 7.34 (IH, bm), 7.28 (IH, m), 7.21 (IH, m), 7.01 (IH, bs), 6.01 (IH, dd, J= 3.2, 9.8 Hz), 4.48 (IH, d, J= 9.5 Hz), 4.43 (IH, bm), 4.38 (IH, bm), 4.11 (IH, bm), 3.08 (IH, bm), 2.93 (IH, bm), 2.84 (IH, m), 2.62 (IH, bm), 2.20 (2H, bm), 2.13 (IH, bm), 2.12 (IH, bm), 1.75 (IH, bm), 1.72 (1H, bm), 1.66 (1H, bm); C NMR (125 MHz, i/6-DMSO) δ 156.6, 154.2, 153.0, 149.8, 148.1, 146.4, 143.5, 139.6, 137.4, 134.0, 132.8, 124.7, 124.5, 123.3, 122.2, 116.3, 115.0, 114.3, 73.7, 52.8, 50.0, 43.8, 43.3, 32.0, 30.3, 28.6; nip 255°C.

Example 4

Figure imgf000015_0001


To a round bottom flask was added, Ι,Γ-carbonyldiimidazole (8.59 g, 51.4 mmoi), diisopropylethylamine (12.6 mL, 72.2 mmol) and tetrahydrofuran (100 niL). This mixture was warmed to 40°C and aged for 10 min, after which l-(piperidin-4-yl)-lH- imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (10 g, 34,3 mmol) was added. The slurry was aged at 40 °C for 3 h, and then upon reaction completion, the solvent was swapped to acetonitrile which afforded an off white solid (9.19 g, 85.9%). LCMS: [M+H] = 313; Ή NMR (400 MHz, 6-DMSO) δ 11.58 (1H, s), 8.09 (1H, s), 7.97 (1H, d, J= 8.0 Hz), 7.73 (1H, d, J= 4.0 Hz), 7.53 (1H, s), 7.05 (1H, s), 7.00 (1H, dd, J= 4.0, 8.0 Hz), 4.52, (1H, dd, J= 8.0, 12.0 Hz), 4.05 (2H, bd, J= 8,0 Hz), 3.31 (2H, m), 2.34 (2H, m), 1.82 (2H, bd, J = 12.0 Hz); 13C NMR (100 MHz, i/6~DMSO) δ 153.0, 150.4, 143.4, 139.8, 137.2, 128.9, 123.0, 1 18.7, 116.4, 115.2, 49.3, 45.1 , 28.5; mp 226°C.

Example 5

Figure imgf000015_0002


To a 250 ml round bottom flask was added 3-N-piperidin-4-ylpyridine-2, 3 -diamine dihydrochloride (10 g, 52 mmol) and acetonitrile (100 mL). Triethyl amine (11.44 g, 1 13 mmol) and 1 , -Carbonyldiimidazole (18.34 g, 113 mmol) were added at ambient temperature and the mixture was stirred for 2 h. The solvent was evaporated under vacuum to—30 ml reaction volume and isopropyl acetate (50 mL) was added into the resulting sluny at 40°C. The slurry was cooled to 10-15 °C and then stirred for 1 h to afford an off white solid (10 g, 85%).


US 20130225636

EP 2815749


 Journal of Medicinal Chemistry (2012), 55(23), 10644-10651.

Calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated clinical efficacy in the treatment of acute migraine. Herein, we describe the design, synthesis, and preclinical characterization of a highly potent, oral CGRP receptor antagonist BMS-927711 (8). Compound 8 has good oral bioavailability in rat and cynomolgus monkey, attractive overall preclinical properties, and shows dose-dependent activity in a primate model of CGRP-induced facial blood flow. Compound 8 is presently in phase II clinical trials.


Organic letters (2015), 17(24), 5982-5.

An asymmetric synthesis of novel heterocyclic analogue of the CGRP receptor antagonist rimegepant (BMS-927711, 3) is reported. The cycloheptane ring was constructed by an intramolecular Heck reaction. The application of Hayashi–Miyaura and Ellman reactions furnished the aryl and the amine chiral centers, while the separable diastereomeric third chiral center alcohols led to both carbamate and urea analogues. This synthetic approach was applicable to both 6- and 5-membered heterocycles as exemplified by pyrazine and thiazole derivatives.


Originally discovered at Bristol-Myers Squibb,[4] it was under development by Biohaven Pharmaceuticals and is now also being marketed in the US by the same company after receiving FDA approval late February 2020.[5]


  1. Jump up to:a b c “Nurtec ODT (rimegepant) orally disintegrating tablets, for sublingual or oral use” (PDF). February 2020. Retrieved 27 February 2020.
  2. ^ “Nurtec ODT: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 28 February 2020.
  3. ^ Diener HC, Charles A, Goadsby PJ, Holle D (October 2015). “New therapeutic approaches for the prevention and treatment of migraine”. The Lancet. Neurology14 (10): 1010–22. doi:10.1016/S1474-4422(15)00198-2PMID 26376968.
  4. ^ “Rimegepant – Biohaven Pharmaceuticals Holding Company”Adis Insight. Springer Nature Switzerland AG.
  5. ^ “Rimegepant (BHV-3000) – for acute treatment of Migraine”. Biohaven Pharmaceuticals.

External links

Clinical data
Trade names Nurtec ODT
Other names BHV-3000, BMS-927711
License data
Routes of
By mouth
Drug class calcitonin gene-related peptide receptor antagonist
ATC code
  • none
Legal status
Legal status
CAS Number
PubChem CID
CompTox Dashboard(EPA)
Chemical and physical data
Formula C28H28F2N6O3
Molar mass 534.568 g·mol−1
3D model (JSmol)

//////////Rimegepant , リメゲパント硫酸塩, Rimegepant sulfate,  migraine, BMS-927711, fda 2020


Image result for teprotumumab-trbw

Tepezza (teprotumumab-trbw)

Company: Horizon Therapeutics plc
Date of Approval: January 21, 2020
Treatment for: Thyroid Eye Disease


CAS number1036734-93-6

R-1507 / R1507 / RG-1507 / RG1507 / RO-4858696 / RO-4858696-000 / RO-4858696000 / RO4858696 / RO4858696-000 / RV-001 / RV001

Tepezza (teprotumumab-trbw) is a fully human monoclonal antibody (mAb) and a targeted inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) for the treatment of active thyroid eye disease (TED).

FDA Approves Tepezza (teprotumumab-trbw) for the Treatment of Thyroid Eye Disease (TED) – January 21, 2020

Today, the U.S. Food and Drug Administration (FDA) approved Tepezza (teprotumumab-trbw) for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis). Today’s approval represents the first drug approved for the treatment of thyroid eye disease.

“Today’s approval marks an important milestone for the treatment of thyroid eye disease. Currently, there are very limited treatment options for this potentially debilitating disease. This treatment has the potential to alter the course of the disease, potentially sparing patients from needing multiple invasive surgeries by providing an alternative, non surgical treatment option,” said Wiley Chambers, M.D., deputy director of the Division of Transplant and Ophthalmology Products in the FDA’s Center for Drug Evaluation and Research. “Additionally, thyroid eye disease is a rare disease that impacts a small percentage of the population, and for a variety of reasons, treatments for rare diseases are often unavailable. This approval represents important progress in the approval of effective treatments for rare diseases, such as thyroid eye disease.”

Thyroid eye disease is associated with the outward bulging of the eye that can cause a variety of symptoms such as eye pain, double vision, light sensitivity or difficulty closing the eye. This disease impacts a relatively small number of Americans, with more women than men affected. Although this condition impacts relatively few individuals, thyroid eye disease can be incapacitating. For example, the troubling ocular symptoms can lead to the progressive inability of people with thyroid eye disease to perform important daily activities, such as driving or working.

Tepezza was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive Tepezza or a placebo. Of the patients who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than 2 millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.

The most common adverse reactions observed in patients treated with Tepezza are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache. Tepezza should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for 6 months following the last dose of Tepezza.

The FDA granted this application Priority Review, in addition to Fast Track and Breakthrough Therapy Designation. Additionally, Tepezza received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases or conditions. Development of this product was also in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and efficacy of products for use in rare diseases or conditions.

The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.

Teprotumumab (RG-1507), sold under the brand name Tepezza, is a medication used for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis).[1]

The most common adverse reactions observed in people treated with teprotumumab-trbw are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache.[1] Teprotumumab-trbw should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for six months following the last dose of teprotumumab-trbw.[1]

It is a human monoclonal antibody developed by Genmab and Roche. It binds to IGF-1R.

Teprotumumab was first investigated for the treatment of solid and hematologic tumors, including breast cancer, Hodgkin’s and non-Hodgkin’s lymphomanon-small cell lung cancer and sarcoma.[2][3] Although results of phase I and early phase II trials showed promise, research for these indications were discontinued in 2009 by Roche. Phase II trials still in progress were allowed to complete, as the development was halted due to business prioritization rather than safety concerns.

Teprotumumab was subsequently licensed to River Vision Development Corporation in 2012 for research in the treatment of ophthalmic conditions. Horizon Pharma (now Horizon Therapeutics, from hereon Horizon) acquired RVDC in 2017, and will continue clinical trials.[4] It is in phase III trials for Graves’ ophthalmopathy (also known as thyroid eye disease (TED)) and phase I for diabetic macular edema.[5] It was granted Breakthrough TherapyOrphan Drug Status and Fast Track designations by the FDA for Graves’ ophthalmopathy.[6]

In a multicenter randomized trial in patients with active Graves’ ophthalmopathy Teprotumumab was more effective than placebo in reducing the clinical activity score and proptosis.[7] In February 2019 Horizon announced results from a phase 3 confirmatory trial evaluating teprotumumab for the treatment of active thyroid eye disease (TED). The study met its primary endpoint, showing more patients treated with teprotumumab compared with placebo had a meaningful improvement in proptosis, or bulging of the eye: 82.9 percent of teprotumumab patients compared to 9.5 percent of placebo patients achieved the primary endpoint of a 2 mm or more reduction in proptosis (p<0.001). Proptosis is the main cause of morbidity in TED. All secondary endpoints were also met and the safety profile was consistent with the phase 2 study of teprotumumab in TED.[8] On 10th of July 2019 Horizon submitted a Biologics License Application (BLA) to the FDA for teprotumumab for the Treatment of Active Thyroid Eye Disease (TED). Horizon requested priority review for the application – if so granted (FDA has a 60-day review period to decide) it would result in a max. 6 month review process.[9]


Teprotumumab-trbw was approved for use in the United States in January 2020, for the treatment of adults with thyroid eye disease.[1]

Teprotumumab-trbw was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive teprotumumab-trbw or a placebo.[1] Of the subjects who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than two millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.[1]

The U.S. Food and Drug Administration (FDA) granted the application for teprotumumab-trbw fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation.[1] The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.[1]


  1. Jump up to:a b c d e f g h “FDA approves first treatment for thyroid eye disease”U.S. Food and Drug Administration (FDA) (Press release). 21 January 2020. Retrieved 21 January 2020.  This article incorporates text from this source, which is in the public domain.
  2. ^
  3. ^
  4. ^
  5. ^
  6. ^
  7. ^ Smith, TJ; Kahaly, GJ; Ezra, DG; Fleming, JC; Dailey, RA; Tang, RA; Harris, GJ; Antonelli, A; Salvi, M; Goldberg, RA; Gigantelli, JW; Couch, SM; Shriver, EM; Hayek, BR; Hink, EM; Woodward, RM; Gabriel, K; Magni, G; Douglas, RS (4 May 2017). “Teprotumumab for Thyroid-Associated Ophthalmopathy”The New England Journal of Medicine376 (18): 1748–1761. doi:10.1056/NEJMoa1614949PMC 5718164PMID 28467880.
  8. ^ “Horizon Pharma plc Announces Phase 3 Confirmatory Trial Evaluating Teprotumumab (OPTIC) for the Treatment of Active Thyroid Eye Disease (TED) Met Primary and All Secondary Endpoints”Horizon Pharma plc. Retrieved 22 March 2019.
  9. ^ “Horizon Therapeutics plc Submits Teprotumumab Biologics License Application (BLA) for the Treatment of Active Thyroid Eye Disease (TED)”Horizon Therapeutics plc. Retrieved 27 August 2019.

External links

Monoclonal antibody
Type Whole antibody
Source Human
Target IGF-1R
Clinical data
Other names teprotumumab-trbw, RG-1507
ATC code
  • none
Legal status
Legal status
CAS Number
  • none
ECHA InfoCard 100.081.384 Edit this at Wikidata
Chemical and physical data
Formula C6476H10012N1748O2000S40
Molar mass 145.6 kg/mol g·mol−1

/////////Teprotumumab-trbw, APPROVALS 2020, FDA 2020, ORPHAN, BLA, fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation, Tepezza,  Horizon Therapeutics, MONOCLONAL ANTIBODY, 2020 APPROVALS,  active thyroid eye disease, Teprotumumab

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