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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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 amcrasto@gmail.com, 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......https://newdrugapprovals.wordpress.com/ , 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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AZITHROMYCIN, アジスロマイシン;


Azithromycin

Azithromycin structure.svg

ChemSpider 2D Image | Azithromycin | C38H72N2O12

AZITHROMYCIN

C38H72N2O12,

748.9845

アジスロマイシン;

CAS: 83905-01-5
PubChem: 51091811
ChEBI: 2955
ChEMBL: CHEMBL529
DrugBank: DB00207
PDB-CCD: ZIT[PDBj]
LigandBox: D07486
NIKKAJI: J134.080H
CAS Registry Number: 83905-01-5
CAS Name: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl-a-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-b-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one
Additional Names: N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A; 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A
Molecular Formula: C38H72N2O12
Molecular Weight: 748.98
Percent Composition: C 60.94%, H 9.69%, N 3.74%, O 25.63%
Literature References: Semi-synthetic macrolide antibiotic; related to erythromycin A, q.v. Prepn: BE 892357; G. Kobrehel, S. Djokic, US 4517359 (1982, 1985 both to Sour Pliva); of the crystalline dihydrate: D. J. M. Allen, K. M. Nepveux, EP 298650eidemUS 6268489 (1989, 2001 both to Pfizer). Antibacterial spectrum: S. C. Aronoff et al., J. Antimicrob. Chemother. 19, 275 (1987); and mode of action: J. Retsema et al., Antimicrob. Agents Chemother. 31, 1939 (1987). Series of articles on pharmacology, pharmacokinetics, and clinical experience: J. Antimicrob. Chemother. 31, Suppl. E, 1-198 (1993). Clinical trial in prevention of Pneumocystis carinii pneumonia in AIDS patients: M. W. Dunne et al., Lancet 354, 891 (1999). Review of pharmacology and clinical efficacy in pediatric infections: H. D. Langtry, J. A. Balfour, Drugs 56, 273-297 (1998).
Properties: Amorphous solid, mp 113-115°. [a]D20 -37° (c = 1 in CHCl3).
Melting point: mp 113-115°
Optical Rotation: [a]D20 -37° (c = 1 in CHCl3)
Derivative Type: Dihydrate
CAS Registry Number: 117772-70-0
Manufacturers’ Codes: CP-62993; XZ-450
Trademarks: Azitrocin (Pfizer); Ribotrex (Fabre); Sumamed (Pliva); Trozocina (Sigma-Tau); Zithromax (Pfizer); Zitromax (Pfizer)
Properties: White crystalline powder. mp 126°. [a]D26 -41.4° (c = 1 in CHCl3).
Melting point: mp 126°
Optical Rotation: [a]D26 -41.4° (c = 1 in CHCl3)
Therap-Cat: Antibacterial.

Azithromycin is an antibiotic used for the treatment of a number of bacterial infections.[3] This includes middle ear infectionsstrep throatpneumoniatraveler’s diarrhea, and certain other intestinal infections.[3] It can also be used for a number of sexually transmitted infections, including chlamydia and gonorrhea infections.[3] Along with other medications, it may also be used for malaria.[3] It can be taken by mouth or intravenously with doses once per day.[3]

Common side effects include nauseavomitingdiarrhea and upset stomach.[3] An allergic reaction, such as anaphylaxisQT prolongation, or a type of diarrhea caused by Clostridium difficile is possible.[3] No harm has been found with its use during pregnancy.[3] Its safety during breastfeeding is not confirmed, but it is likely safe.[4] Azithromycin is an azalide, a type of macrolide antibiotic.[3] It works by decreasing the production of protein, thereby stopping bacterial growth.[3]

Azithromycin was discovered 1980 by Pliva, and approved for medical use in 1988.[5][6] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[7] The World Health Organization classifies it as critically important for human medicine.[8] It is available as a generic medication[9] and is sold under many trade names worldwide.[2] The wholesale cost in the developing world is about US$0.18 to US$2.98 per dose.[10] In the United States, it is about US$4 for a course of treatment as of 2018.[11] In 2016, it was the 49th most prescribed medication in the United States with more than 15 million prescriptions.[12]

Medical uses

Azithromycin is used to treat many different infections, including:

  • Prevention and treatment of acute bacterial exacerbations of chronic obstructive pulmonary disease due to H. influenzaeM. catarrhalis, or S. pneumoniae. The benefits of long-term prophylaxis must be weighed on a patient-by-patient basis against the risk of cardiovascular and other adverse effects.[13]
  • Community-acquired pneumonia due to C. pneumoniaeH. influenzaeM. pneumoniae, or S. pneumoniae[14]
  • Uncomplicated skin infections due to S. aureusS. pyogenes, or S. agalactiae
  • Urethritis and cervicitis due to C. trachomatis or N. gonorrhoeae. In combination with ceftriaxone, azithromycin is part of the United States Centers for Disease Control-recommended regimen for the treatment of gonorrhea. Azithromycin is active as monotherapy in most cases, but the combination with ceftriaxone is recommended based on the relatively low barrier to resistance development in gonococci and due to frequent co-infection with C. trachomatis and N. gonorrhoeae.[15]
  • Trachoma due to C. trachomatis[16]
  • Genital ulcer disease (chancroid) in men due to H. ducrey
  • Acute bacterial sinusitis due to H. influenzaeM. catarrhalis, or S. pneumoniae. Other agents, such as amoxicillin/clavulanate are generally preferred, however.[17][18]
  • Acute otitis media caused by H. influenzaeM. catarrhalis or S. pneumoniae. Azithromycin is not, however, a first-line agent for this condition. Amoxicillin or another beta lactam antibiotic is generally preferred.[19]
  • Pharyngitis or tonsillitis caused by S. pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy[20]

Bacterial susceptibility

Azithromycin has relatively broad but shallow antibacterial activity. It inhibits some Gram-positive bacteria, some Gram-negative bacteria, and many atypical bacteria.

A strain of gonorrhea reported to be highly resistant to azithromycin was found in the population in 2015. Neisseria gonorrhoeae is normally susceptible to azithromycin,[21] but the drug is not widely used as monotherapy due to a low barrier to resistance development.[15] Extensive use of azithromycin has resulted in growing Streptococcus pneumoniae resistance.[22]

Aerobic and facultative Gram-positive microorganisms

Aerobic and facultative Gram-negative microorganisms

Anaerobic microorganisms

Other microorganisms

Pregnancy and breastfeeding[edit source]

No harm has been found with use during pregnancy.[3] However, there are no adequate well-controlled studies in pregnant women.[23]

Safety of the medication during breastfeeding is unclear. It was reported that because only low levels are found in breast milk and the medication has also been used in young children, it is unlikely that breastfed infants would suffer adverse effects.[4] Nevertheless, it is recommended that the drug be used with caution during breastfeeding.[3]

Airway diseases

Azithromycin appears to be effective in the treatment of COPD through its suppression of inflammatory processes.[24] And potentially useful in asthma and sinusitis via this mechanism.[25] Azithromycin is believed to produce its effects through suppressing certain immune responses that may contribute to inflammation of the airways.[26][27]

Adverse effects

Most common adverse effects are diarrhea (5%), nausea (3%), abdominal pain (3%), and vomiting. Fewer than 1% of people stop taking the drug due to side effects. Nervousness, skin reactions, and anaphylaxis have been reported.[28] Clostridium difficile infection has been reported with use of azithromycin.[3] Azithromycin does not affect the efficacy of birth control unlike some other antibiotics such as rifampin. Hearing loss has been reported.[29]

Occasionally, people have developed cholestatic hepatitis or delirium. Accidental intravenous overdose in an infant caused severe heart block, resulting in residual encephalopathy.[30][31]

In 2013 the FDA issued a warning that azithromycin “can cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm.” The FDA noted in the warning a 2012 study that found the drug may increase the risk of death, especially in those with heart problems, compared with those on other antibiotics such as amoxicillin or no antibiotic. The warning indicated people with preexisting conditions are at particular risk, such as those with QT interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or those who use certain drugs to treat abnormal heart rhythms.[32][33][34]

Pharmacology

Mechanism of action

Azithromycin prevents bacteria from growing by interfering with their protein synthesis. It binds to the 50S subunit of the bacterial ribosome, thus inhibiting translation of mRNA. Nucleic acid synthesis is not affected.[23]

Pharmacokinetics

Azithromycin is an acid-stable antibiotic, so it can be taken orally with no need of protection from gastric acids. It is readily absorbed, but absorption is greater on an empty stomach. Time to peak concentration (Tmax) in adults is 2.1 to 3.2 hours for oral dosage forms. Due to its high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations are released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma due to ion trapping and its high lipid solubility.[citation needed] Azithromycin’s half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days.[35]

Following a single dose of 500 mg, the apparent terminal elimination half-life of azithromycin is 68 hours.[35] Biliary excretion of azithromycin, predominantly unchanged, is a major route of elimination. Over the course of a week, about 6% of the administered dose appears as unchanged drug in urine.

History

A team of researchers at the pharmaceutical company Pliva in ZagrebSR CroatiaYugoslavia, — Gabrijela Kobrehel, Gorjana Radobolja-Lazarevski, and Zrinka Tamburašev, led by Dr. Slobodan Đokić — discovered azithromycin in 1980.[6] It was patented in 1981. In 1986, Pliva and Pfizer signed a licensing agreement, which gave Pfizer exclusive rights for the sale of azithromycin in Western Europe and the United States. Pliva put its azithromycin on the market in Central and Eastern Europe under the brand name Sumamed in 1988. Pfizer launched azithromycin under Pliva’s license in other markets under the brand name Zithromax in 1991.[36] Patent protection ended in 2005.[37]

Society and culture

Zithromax (azithromycin) 250 mg tablets (CA)

Cost

It is available as a generic medication.[9] The wholesale cost is about US$0.18 to US$2.98 per dose.[10] In the United States it is about US$4 for a course of treatment as of 2018.[11] In India, it is about US$1.70 for a course of treatment.[citation needed]

Available forms

Azithromycin is commonly administered in film-coated tablet, capsule, oral suspensionintravenous injection, granules for suspension in sachet, and ophthalmic solution.[2]

Usage

In 2010, azithromycin was the most prescribed antibiotic for outpatients in the US,[38] whereas in Sweden, where outpatient antibiotic use is a third as prevalent, macrolides are only on 3% of prescriptions.[39]

Solved: Using Push Arrows To Show Mechanisms, Show How To ...
Antibiotics | Free Full-Text | From Erythromycin to Azithromycin ...

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References

  1. Jump up to:ab “Azithromycin Use During Pregnancy”Drugs.com. 2 May 2019. Retrieved 24 December 2019.
  2. Jump up to:abcdef “Azithromycin International Brands”. Drugs.com. Archived from the original on 28 February 2017. Retrieved 27 February 2017.
  3. Jump up to:abcdefghijklm “Azithromycin”. The American Society of Health-System Pharmacists. Archived from the original on 5 September 2015. Retrieved 1 August 2015.
  4. Jump up to:ab “Azithromycin use while Breastfeeding”Archived from the original on 5 September 2015. Retrieved 4 September 2015.
  5. ^ Greenwood, David (2008). Antimicrobial drugs : chronicle of a twentieth century medical triumph (1. publ. ed.). Oxford: Oxford University Press. p. 239. ISBN9780199534845Archived from the original on 5 March 2016.
  6. Jump up to:ab Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 498. ISBN9783527607495.
  7. ^ 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.
  8. ^ World Health Organization (2019). Critically important antimicrobials for human medicine (6th revision ed.). Geneva: World Health Organization. hdl:10665/312266ISBN9789241515528. License: CC BY-NC-SA 3.0 IGO.
  9. Jump up to:ab Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. ISBN9781284057560.
  10. Jump up to:ab “Azithromycin”International Drug Price Indicator Guide. Retrieved 4 September 2015.
  11. Jump up to:ab “NADAC as of 2018-05-23”Centers for Medicare and Medicaid Services. Retrieved 24 May 2018.
  12. ^ “The Top 300 of 2019”clincalc.com. Retrieved 22 December2018.
  13. ^ Taylor SP, Sellers E, Taylor BT (2015). “Azithromycin for the Prevention of COPD Exacerbations: The Good, Bad, and Ugly”. Am. J. Med128 (12): 1362.e1–6. doi:10.1016/j.amjmed.2015.07.032PMID26291905.
  14. ^ Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM, Musher DM, Niederman MS, Torres A, Whitney CG (2007). “Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults”. Clin. Infect. Dis. 44 Suppl 2: S27–72. doi:10.1086/511159PMID17278083.
  15. Jump up to:ab “Gonococcal Infections – 2015 STD Treatment Guidelines”Archived from the original on 1 March 2016.
  16. ^ Burton M, Habtamu E, Ho D, Gower EW (2015). “Interventions for trachoma trichiasis”Cochrane Database Syst Rev11 (11): CD004008. doi:10.1002/14651858.CD004008.pub3PMC4661324PMID26568232.
  17. ^ Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, Brook I, Ashok Kumar K, Kramper M, Orlandi RR, Palmer JN, Patel ZM, Peters A, Walsh SA, Corrigan MD (2015). “Clinical practice guideline (update): adult sinusitis”. Otolaryngol Head Neck Surg152 (2 Suppl): S1–S39. doi:10.1177/0194599815572097PMID25832968.
  18. ^ Hauk L (2014). “AAP releases guideline on diagnosis and management of acute bacterial sinusitis in children one to 18 years of age”. Am Fam Physician89 (8): 676–81. PMID24784128.
  19. ^ Neff MJ (2004). “AAP, AAFP release guideline on diagnosis and management of acute otitis media”. Am Fam Physician69 (11): 2713–5. PMID15202704.
  20. ^ Randel A (2013). “IDSA Updates Guideline for Managing Group A Streptococcal Pharyngitis”. Am Fam Physician88 (5): 338–40. PMID24010402.
  21. ^ The Guardian newspaper: ‘Super-gonorrhoea’ outbreak in Leeds, 18 September 2015Archived 18 September 2015 at the Wayback Machine
  22. ^ Lippincott Illustrated Reviews : Pharmacology Sixth Edition. p. 506.
  23. Jump up to:ab “US azithromycin label”(PDF). FDA. February 2016. Archived(PDF) from the original on 23 November 2016.
  24. ^ Simoens, Steven; Laekeman, Gert; Decramer, Marc (May 2013). “Preventing COPD exacerbations with macrolides: A review and budget impact analysis”. Respiratory Medicine107 (5): 637–648. doi:10.1016/j.rmed.2012.12.019PMID23352223.
  25. ^ Gotfried, Mark H. (February 2004). “Macrolides for the Treatment of Chronic Sinusitis, Asthma, and COPD”CHEST125 (2): 52S–61S. doi:10.1378/chest.125.2_suppl.52SISSN0012-3692PMID14872001.
  26. ^ Zarogoulidis, P.; Papanas, N.; Kioumis, I.; Chatzaki, E.; Maltezos, E.; Zarogoulidis, K. (May 2012). “Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases”. European Journal of Clinical Pharmacology68 (5): 479–503. doi:10.1007/s00228-011-1161-xISSN1432-1041PMID22105373.
  27. ^ Steel, Helen C.; Theron, Annette J.; Cockeran, Riana; Anderson, Ronald; Feldman, Charles (2012). “Pathogen- and Host-Directed Anti-Inflammatory Activities of Macrolide Antibiotics”Mediators of Inflammation2012: 584262. doi:10.1155/2012/584262PMC3388425PMID22778497.
  28. ^ Mori F, Pecorari L, Pantano S, Rossi M, Pucci N, De Martino M, Novembre E (2014). “Azithromycin anaphylaxis in children”. Int J Immunopathol Pharmacol27 (1): 121–6. doi:10.1177/039463201402700116PMID24674687.
  29. ^ Dart, Richard C. (2004). Medical Toxology. Lippincott Williams & Wilkins. p. 23.
  30. ^ Tilelli, John A.; Smith, Kathleen M.; Pettignano, Robert (2006). “Life-Threatening Bradyarrhythmia After Massive Azithromycin Overdose”. Pharmacotherapy26 (1): 147–50. doi:10.1592/phco.2006.26.1.147PMID16506357.
  31. ^ Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 132–133.
  32. ^ Denise Grady (16 May 2012). “Popular Antibiotic May Raise Risk of Sudden Death”The New York TimesArchived from the original on 17 May 2012. Retrieved 18 May 2012.
  33. ^ Ray, Wayne A.; Murray, Katherine T.; Hall, Kathi; Arbogast, Patrick G.; Stein, C. Michael (2012). “Azithromycin and the Risk of Cardiovascular Death”New England Journal of Medicine366(20): 1881–90. doi:10.1056/NEJMoa1003833PMC3374857PMID22591294.
  34. ^ “FDA Drug Safety Communication: Azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms”. FDA. 12 March 2013. Archived from the original on 27 October 2016.
  35. Jump up to:ab “Archived copy”Archived from the original on 14 October 2014. Retrieved 10 October 2014.
  36. ^ Banić Tomišić, Z. (2011). “The Story of Azithromycin”Kemija U Industriji60 (12): 603–617. ISSN0022-9830Archived from the original on 8 September 2017.
  37. ^ “Azithromycin: A world best-selling Antibiotic”http://www.wipo.int. World Intellectual Property Organization. Retrieved 18 June 2019.
  38. ^ Hicks, LA; Taylor TH, Jr; Hunkler, RJ (April 2013). “U.S. outpatient antibiotic prescribing, 2010”. The New England Journal of Medicine368 (15): 1461–1462. doi:10.1056/NEJMc1212055PMID23574140.
  39. ^ Hicks, LA; Taylor TH, Jr; Hunkler, RJ (September 2013). “More on U.S. outpatient antibiotic prescribing, 2010”. The New England Journal of Medicine369 (12): 1175–1176. doi:10.1056/NEJMc1306863PMID24047077.

External links

Keywords: Antibacterial (Antibiotics); Macrolides.

Azithromycin
Azithromycin structure.svg
Azithromycin 3d structure.png
Clinical data
Trade names Zithromax, Azithrocin, others[2]
Other names 9-deoxy-9α-aza-9α-methyl-9α-homoerythromycin A
AHFS/Drugs.com Monograph
MedlinePlus a697037
License data
Pregnancy
category
  • AU: B1 [1]
  • US: B (No risk in non-human studies) [1]
Routes of
administration
By mouth (capsule, tablet or suspension), intravenouseye drop
Drug class Macrolide antibiotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 38% for 250 mg capsules
Metabolism Liver
Elimination half-life 11–14 h (single dose) 68 h (multiple dosing)
Excretion Biliarykidney (4.5%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.126.551 Edit this at Wikidata
Chemical and physical data
Formula C38H72N2O12
Molar mass 748.984 g·mol−1 g·mol−1
3D model (JSmol)

/////////AZITHROMYCIN, Antibacterial, Antibiotics,  Macrolides, CORONA VIRUS, COVID 19, アジスロマイシン ,

CHLOROQUINE, クロロキン;Хлорохин , クロロキン , كلوروكين


Chloroquine

Chloroquine.svg

CHLOROQUINE

N4-(7-Chloroquinolin-4-yl)-N1,N1-diethylpentane-1,4-diamine
Хлорохин [Russian] [INN]
クロロキン [Japanese]
كلوروكين [Arabic] [INN]
Formula
C18H26ClN3
CAS
54-05-7
Mol weight
319.8721
CAS Registry Number: 54-05-7
CAS Name: N4-(7-Chloro-4-quinolinyl)-N1,N1-diethyl-1,4-pentanediamine
Additional Names: 7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline
Manufacturers’ Codes: SN-7618; RP-3377
Molecular Formula: C18H26ClN3
Molecular Weight: 319.87
Percent Composition: C 67.59%, H 8.19%, Cl 11.08%, N 13.14%
Literature References: Prepd by the condensation of 4,7-dichloroquinoline with 1-diethylamino-4-aminopentane: DE 683692 (1939); H. Andersag et al., US 2233970 (1941 to Winthrop); Surrey, Hammer, J. Am. Chem. Soc. 68, 113 (1946). Review: Hahn in Antibiotics vol. 3, J. W. Corcoran, F. E. Hahn, Eds. (Springer-Verlag, New York, 1975) pp 58-78. Comprehensive description: D. D. Hong, Anal. Profiles Drug Subs. 5, 61-85 (1976). Comparative clinical trial with dapsone in rheumatoid arthritis: P. D. Fowler et al., Ann. Rheum. Dis. 43, 200 (1984); with penicillamine: T. Gibson et al., Br. J. Rheumatol. 26, 279 (1987).
Properties: mp 87°.
Melting point: mp 87°
Image result for CHLOROQUINE
Derivative Type: Diphosphate
CAS Registry Number: 50-63-5
Trademarks: Arechin (Polfa); Avloclor (AstraZeneca); Malaquin (Ahn Gook); Resochin (Bayer)
Molecular Formula: C18H26ClN3.2H3PO4
Molecular Weight: 515.86
Percent Composition: C 41.91%, H 6.25%, Cl 6.87%, N 8.15%, P 12.01%, O 24.81%
Properties: Bitter, colorless crystals. Dimorphic. One modification, mp 193-195°; the other, mp 215-218°. Freely sol in water; pH of 1% soln about 4.5; less sol at neutral and alkaline pH. Stable to heat in solns of pH 4.0 to 6.5. Practically insol in alcohol, benzene, chloroform, ether.
Melting point: mp 193-195°; mp 215-218°
Derivative Type: Sulfate
CAS Registry Number: 132-73-0
Trademarks: Aralen (Sanofi-Synthelabo); Nivaquine (Aventis)
Molecular Formula: C18H26ClN3.H2SO4
Molecular Weight: 417.95
Percent Composition: C 51.73%, H 6.75%, Cl 8.48%, N 10.05%, S 7.67%, O 15.31%
Therap-Cat: Antimalarial; antiamebic; antirheumatic. Lupus erythematosus suppressant.
Keywords: Antiamebic; Antiarthritic/Antirheumatic; Antimalarial; Lupus Erythematosus Suppressant.

Chloroquine is a medication used primarily to prevent and to treat malaria in areas where that parasitic disease is known to remain sensitive to its effects.[1] A benefit of its use in therapy, when situations allow, is that it can be taken by mouth (versus by injection).[1] Controlled studies of cases involving human pregnancy are lacking, but the drug may be safe for use for such patients.[verification needed][1][2] However, the agent is not without the possibility of serious side effects at standard doses,[1][3] and complicated cases, including infections of certain types or caused by resistant strains, typically require different or additional medication.[1] Chloroquine is also used as a medication for rheumatoid arthritislupus erythematosus, and other parasitic infections (e.g., amebiasis occurring outside of the intestines).[1] Beginning in 2020, studies have proceeded on its use as a coronavirus antiviral, in possible treatment of COVID-19.[4]

Chloroquine, otherwise known as chloroquine phosphate, is in the 4-aminoquinoline class of drugs.[1] As an antimalarial, it works against the asexual form of the malaria parasite in the stage of its life cycle within the red blood cell.[1] In its use against rheumatoid arthritis and lupus erythematosus, its activity as a mild immunosuppressive underlies its mechanism.[1] Antiviral activities, established and putative, are attributed to chloroquines inhibition of glycosylation pathways (of host receptor sialylation or virus protein post-translational modification), or to inhibition of virus endocytosis (e.g., via alkalisation of endosomes), or other possible mechanisms.[5] Common side effects resulting from these therapeutic uses, at common doses, include muscle problems,[clarification needed] loss of appetite, diarrhea, and skin rash.[clarification needed][1] Serious side effects include problems with vision (retinopathy), muscle damage, seizures, and certain anemias.[1][6]

Chloroquine was discovered in 1934 by Hans Andersag.[7][8] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[9] It is available as a generic medication.[1] The wholesale cost in the developing world is about US$0.04.[10] In the United States, it costs about US$5.30 per dose.[1]

Medical uses

Malaria

Distribution of malaria in the world:[11]
♦ Elevated occurrence of chloroquine- or multi-resistant malaria
♦ Occurrence of chloroquine-resistant malaria
♦ No Plasmodium falciparum or chloroquine-resistance
♦ No malaria

Chloroquine has been used in the treatment and prevention of malaria from Plasmodium vivaxP. ovale, and P. malariae. It is generally not used for Plasmodium falciparum as there is widespread resistance to it.[12][13]

Chloroquine has been extensively used in mass drug administrations, which may have contributed to the emergence and spread of resistance. It is recommended to check if chloroquine is still effective in the region prior to using it.[14] In areas where resistance is present, other antimalarials, such as mefloquine or atovaquone, may be used instead. The Centers for Disease Control and Prevention recommend against treatment of malaria with chloroquine alone due to more effective combinations.[15]

Amebiasis

In treatment of amoebic liver abscess, chloroquine may be used instead of or in addition to other medications in the event of failure of improvement with metronidazole or another nitroimidazole within 5 days or intolerance to metronidazole or a nitroimidazole.[16]

Rheumatic disease

As it mildly suppresses the immune system, chloroquine is used in some autoimmune disorders, such as rheumatoid arthritis and lupus erythematosus.[1]

Side effects

Side effects include blurred vision, nausea, vomiting, abdominal cramps, headache, diarrhea, swelling legs/ankles, shortness of breath, pale lips/nails/skin, muscle weakness, easy bruising/bleeding, hearing and mental problems.[17][18]

  • Unwanted/uncontrolled movements (including tongue and face twitching) [17]
  • Deafness or tinnitus.[17]
  • Nausea, vomiting, diarrhea, abdominal cramps[18]
  • Headache.[17]
  • Mental/mood changes (such as confusion, personality changes, unusual thoughts/behavior, depression, feeling being watched, hallucinating)[17][18]
  • Signs of serious infection (such as high fever, severe chills, persistent sore throat)[17]
  • Skin itchiness, skin color changes, hair loss, and skin rashes.[18][19]
    • Chloroquine-induced itching is very common among black Africans (70%), but much less common in other races. It increases with age, and is so severe as to stop compliance with drug therapy. It is increased during malaria fever; its severity is correlated to the malaria parasite load in blood. Some evidence indicates it has a genetic basis and is related to chloroquine action with opiate receptors centrally or peripherally.[20]
  • Unpleasant metallic taste
    • This could be avoided by “taste-masked and controlled release” formulations such as multiple emulsions.[21]
  • Chloroquine retinopathy
  • Electrocardiographic changes[22]
    • This manifests itself as either conduction disturbances (bundle-branch block, atrioventricular block) or Cardiomyopathy – often with hypertrophy, restrictive physiology, and congestive heart failure. The changes may be irreversible. Only two cases have been reported requiring heart transplantation, suggesting this particular risk is very low. Electron microscopy of cardiac biopsies show pathognomonic cytoplasmic inclusion bodies.
  • Pancytopeniaaplastic anemia, reversible agranulocytosislow blood plateletsneutropenia.[23]

Pregnancy

Chloroquine has not been shown to have any harmful effects on the fetus when used for malarial prophylaxis.[24] Small amounts of chloroquine are excreted in the breast milk of lactating women. However, this drug can be safely prescribed to infants, the effects are not harmful. Studies with mice show that radioactively tagged chloroquine passed through the placenta rapidly and accumulated in the fetal eyes which remained present five months after the drug was cleared from the rest of the body.[23][25] Women who are pregnant or planning on getting pregnant are still advised against traveling to malaria-risk regions.[24]

Elderly

There is not enough evidence to determine whether chloroquine is safe to be given to people aged 65 and older. Since it is cleared by the kidneys, toxicity should be monitored carefully in people with poor kidney functions.[23]

Drug interactions

Chloroquine has a number of drug-drug interactions that might be of clinical concern:[citation needed]

Overdose

Chloroquine is very dangerous in overdose. It is rapidly absorbed from the gut. In 1961, a published compilation of case reports contained accounts of three children who took overdoses and died within 2.5 hours of taking the drug. While the amount of the overdose was not stated, the therapeutic index for chloroquine is known to be small.[26] One of the children died after taking 0.75 or 1 gram, or twice a single therapeutic amount for children. Symptoms of overdose include headache, drowsiness, visual disturbances, nausea and vomiting, cardiovascular collapse, seizures, and sudden respiratory and cardiac arrest.[23]

An analog of chloroquine – hydroxychloroquine – has a long half-life (32–56 days) in blood and a large volume of distribution (580–815 L/kg).[27] The therapeutic, toxic and lethal ranges are usually considered to be 0.03 to 15 mg/l, 3.0 to 26 mg/l and 20 to 104 mg/l, respectively. However, nontoxic cases have been reported up to 39 mg/l, suggesting individual tolerance to this agent may be more variable than previously recognised.[27]

Pharmacology

Chloroquine’s absorption of the drug is rapid. It is widely distributed in body tissues. It’s protein binding is 55%.[ It’s metabolism is partially hepatic, giving rise to its main metabolite, desethylchloroquine. It’s excretion os ≥50% as unchanged drug in urine, where acidification of urine increases its elimination It has a very high volume of distribution, as it diffuses into the body’s adipose tissue.

Accumulation of the drug may result in deposits that can lead to blurred vision and blindness. It and related quinines have been associated with cases of retinal toxicity, particularly when provided at higher doses for longer times. With long-term doses, routine visits to an ophthalmologist are recommended.

Chloroquine is also a lysosomotropic agent, meaning it accumulates preferentially in the lysosomes of cells in the body. The pKa for the quinoline nitrogen of chloroquine is 8.5, meaning—in simplified terms, considering only this basic site—it is about 10% deprotonated at physiological pH (per the Henderson-Hasselbalch equation) This decreases to about 0.2% at a lysosomal pH of 4.6.Because the deprotonated form is more membrane-permeable than the protonated form, a quantitative “trapping” of the compound in lysosomes results.

Mechanism of action

Medical quinolines

Malaria

Hemozoin formation in P. falciparum: many antimalarials are strong inhibitors of hemozoin crystal growth.

The lysosomotropic character of chloroquine is believed to account for much of its antimalarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes. Its lysosomotropic properties further allow for its use for in vitro experiments pertaining to intracellular lipid related diseases,[28][29] autophagy, and apoptosis.[30]

Inside red blood cells, the malarial parasite, which is then in its asexual lifecycle stage, must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasitic cell.[citation needed]

Hemoglobin is composed of a protein unit (digested by the parasite) and a heme unit (not used by the parasite). During this process, the parasite releases the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a nontoxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.[citation needed]

Chloroquine enters the red blood cell by simple diffusion, inhibiting the parasite cell and digestive vacuole. Chloroquine then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form the FP-chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion. [31] Parasites that do not form hemozoin are therefore resistant to chloroquine.[32]

Resistance in malaria[edit source]

Since the first documentation of P. falciparum chloroquine resistance in the 1950s, resistant strains have appeared throughout East and West Africa, Southeast Asia, and South America. The effectiveness of chloroquine against P. falciparum has declined as resistant strains of the parasite evolved. They effectively neutralize the drug via a mechanism that drains chloroquine away from the digestive vacuole. Chloroquine-resistant cells efflux chloroquine at 40 times the rate of chloroquine-sensitive cells; the related mutations trace back to transmembrane proteins of the digestive vacuole, including sets of critical mutations in the P. falciparum chloroquine resistance transporter (PfCRT) gene. The mutated protein, but not the wild-type transporter, transports chloroquine when expressed in Xenopus oocytes (frog’s eggs) and is thought to mediate chloroquine leak from its site of action in the digestive vacuole.[33] Resistant parasites also frequently have mutated products of the ABC transporter P. falciparum multidrug resistance (PfMDR1) gene, although these mutations are thought to be of secondary importance compared to PfcrtVerapamil, a Ca2+ channel blocker, has been found to restore both the chloroquine concentration ability and sensitivity to this drug. Recently, an altered chloroquine-transporter protein CG2 of the parasite has been related to chloroquine resistance, but other mechanisms of resistance also appear to be involved.[34] Research on the mechanism of chloroquine and how the parasite has acquired chloroquine resistance is still ongoing, as other mechanisms of resistance are likely.[citation needed]

Other agents which have been shown to reverse chloroquine resistance in malaria are chlorpheniraminegefitinibimatinibtariquidar and zosuquidar.[35]

Antiviral

Chloroquine has antiviral effects.[36] It increases late endosomal or lysosomal pH, resulting in impaired release of the virus from the endosome or lysosome – release requires a low pH. The virus is therefore unable to release its genetic material into the cell and replicate.[37][38]

Chloroquine also seems to act as a zinc ionophore, that allows extracellular zinc to enter the cell and inhibit viral RNA-dependent RNA polymerase.[39][40]

Other

Chloroquine inhibits thiamine uptake.[41] It acts specifically on the transporter SLC19A3.

Against rheumatoid arthritis, it operates by inhibiting lymphocyte proliferation, phospholipase A2, antigen presentation in dendritic cells, release of enzymes from lysosomes, release of reactive oxygen species from macrophages, and production of IL-1.

History

In Peru the indigenous people extracted the bark of the Cinchona plant[42] trees and used the extract (Chinchona officinalis) to fight chills and fever in the seventeenth century. In 1633 this herbal medicine was introduced in Europe, where it was given the same use and also began to be used against malaria.[43] The quinoline antimalarial drug quinine was isolated from the extract in 1820, and chloroquine is an analogue of this.

Chloroquine was discovered in 1934, by Hans Andersag and coworkers at the Bayer laboratories, who named it “Resochin”.[44] It was ignored for a decade, because it was considered too toxic for human use. During World War II, United States government-sponsored clinical trials for antimalarial drug development showed unequivocally that chloroquine has a significant therapeutic value as an antimalarial drug. It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.[45]

Society and culture

Resochin tablet package

Formulations

Chloroquine comes in tablet form as the phosphate, sulfate, and hydrochloride salts. Chloroquine is usually dispensed as the phosphate.[46]

Names

Brand names include Chloroquine FNA, Resochin, Dawaquin, and Lariago.[47]

Other animals

Chloroquine is used to control the aquarium fish parasite Amyloodinium ocellatum.[48]

Research

COVID-19

In late January 2020 during the 2019–20 coronavirus outbreak, Chinese medical researchers stated that exploratory research into chloroquine and two other medications, remdesivir and lopinavir/ritonavir, seemed to have “fairly good inhibitory effects” on the SARS-CoV-2 virus, which is the virus that causes COVID-19. Requests to start clinical testing were submitted.[49] Chloroquine had been also proposed as a treatment for SARS, with in vitro tests inhibiting the SARS-CoV virus.[50][51]

Chloroquine has been recommended by Chinese, South Korean and Italian health authorities for the treatment of COVID-19.[52][53] These agencies noted contraindications for people with heart disease or diabetes.[54] Both chloroquine and hydroxychloroquine were shown to inhibit SARS-CoV-2 in vitro, but a further study concluded that hydroxychloroquine was more potent than chloroquine, with a more tolerable safety profile.[55] Preliminary results from a trial suggested that chloroquine is effective and safe in COVID-19 pneumonia, “improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course.”[56] Self-medication with chloroquine has caused one known fatality.[57]

On 24 March 2020, NBC News reported[58] a fatality due to misuse of a chloroquine product used to control fish parasites.[59]

Other viruses

In October 2004, a group of researchers at the Rega Institute for Medical Research published a report on chloroquine, stating that chloroquine acts as an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro.[60]

Chloroquine was being considered in 2003, in pre-clinical models as a potential agent against chikungunya fever.[61]

Other

The radiosensitizing and chemosensitizing properties of chloroquine are beginning to be exploited in anticancer strategies in humans.[62][63] In biomedicinal science, chloroquine is used for in vitro experiments to inhibit lysosomal degradation of protein products.

 

 

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  54. ^ “Plaquenil (hydroxychloroquine sulfate) dose, indications, adverse effects, interactions… from PDR.net”http://www.pdr.netArchivedfrom the original on 18 March 2020. Retrieved 19 March 2020.
  55. ^ Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. (March 2020). “In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)”. Clinical Infectious Diseasesdoi:10.1093/cid/ciaa237PMID 32150618.
  56. ^ Gao J, Tian Z, Yang X (February 2020). “Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies”Bioscience Trends14: 72–73. doi:10.5582/bst.2020.01047PMID 32074550Archived from the original on 19 March 2020. Retrieved 19 March 2020.
  57. ^ Edwards, Erika; Hillyard, Vaughn (23 March 2020). “Man dies after ingesting chloroquine in an attempt to prevent coronavirus”NBC News. Retrieved 24 March 2020.
  58. ^ “A man died after ingesting a substance he thought would protect him from coronavirus”NBC News. Retrieved 25 March 2020.
  59. ^ “Banner Health experts warn against self-medicating to prevent or treat COVID-19”Banner Health (Press release). 23 March 2020. Retrieved 25 March 2020.
  60. ^ Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M (October 2004). “In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine”. Biochemical and Biophysical Research Communications323 (1): 264–8. doi:10.1016/j.bbrc.2004.08.085PMID 15351731.
  61. ^ Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R (November 2003). “Effects of chloroquine on viral infections: an old drug against today’s diseases?”. The Lancet. Infectious Diseases3(11): 722–7. doi:10.1016/S1473-3099(03)00806-5PMID 14592603.
  62. ^ Savarino A, Lucia MB, Giordano F, Cauda R (October 2006). “Risks and benefits of chloroquine use in anticancer strategies”. The Lancet. Oncology7 (10): 792–3. doi:10.1016/S1470-2045(06)70875-0PMID 17012039.
  63. ^ Sotelo J, Briceño E, López-González MA (March 2006). “Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial”. Annals of Internal Medicine144 (5): 337–43. doi:10.7326/0003-4819-144-5-200603070-00008PMID 16520474.
    “Summaries for patients. Adding chloroquine to conventional chemotherapy and radiotherapy for glioblastoma multiforme”. Annals of Internal Medicine144 (5): I31. March 2006. doi:10.7326/0003-4819-144-5-200603070-00004PMID 16520470.

External links

“Chloroquine”Drug Information Portal. U.S. National Library of Medicine.

Chloroquine
Chloroquine.svg
Chloroquine 3D structure.png
Clinical data
Pronunciation /ˈklɔːrəkwɪn/
Trade names Aralen, other
Other names Chloroquine phosphate
AHFS/Drugs.com Monograph
License data
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Liver
Elimination half-life 1-2 months
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.175 Edit this at Wikidata
Chemical and physical data
Formula C18H26ClN3
Molar mass 319.872 g·mol−1
3D model (JSmol)

//////////////CHLOROQUINE,, クロロキン, ANTIMALARIAL, COVID 19, CORONA VIRUS, Хлорохинクロロキン كلوروكين

Niclosamide, ニクロサミド , никлосамид , نيكلوساميد , 氯硝柳胺 , 


 

Niclosamide.svg

Niclosamide

ChemSpider 2D Image | Niclosamide | C13H8Cl2N2O4

Niclosamide

ニクロサミド;

Formula
C13H8Cl2N2O4
cas
50-65-7
Mol weight
327.1196
никлосамид [Russian] [INN]
نيكلوساميد [Arabic] [INN]
氯硝柳胺 [Chinese] [INN]
Niclosamide [BSI] [INN] [ISO] [USAN] [Wiki]
1532
2′,5-Dichlor-4′-nitro-salizylsaeureanilid [German]
2′,5-Dichloro-4′-nitrosalicylanilide
200-056-8 [EINECS]
2820605
50-65-7 [RN]
]
5-Chlor-N-(2-chlor-4-nitrophenyl)-2-hydroxybenzolcarboxamid
5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide

CAS Registry Number: 50-65-7

CAS Name: 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide
Additional Names: 2¢,5-dichloro-4¢-nitrosalicylanilide; 5-chloro-N-(2¢-chloro-4¢-nitrophenyl)salicylamide; 5-chlorosalicyloyl-(o-chloro-p-nitranilide); N-(2¢-chloro-4¢-nitrophenyl)-5-chlorosalicylamide
Manufacturers’ Codes: Bayer 2353
Trademarks: Cestocide (Bayer); Niclocide (Miles); Ruby (Spencer); Trédémine (RPR); Yomesan (Bayer)
Molecular Formula: C13H8Cl2N2O4
Molecular Weight: 327.12
Percent Composition: C 47.73%, H 2.47%, Cl 21.68%, N 8.56%, O 19.56%
Literature References: Prepn: GB 824345 (1959 to Bayer), C.A. 54, 15822b (1960). See also: E. Schraufstätter, R. Gönnert, US 3079297; R. Strufe et al., US 3113067 (both 1963 to Bayer); Bekhli et al., Med. Prom. SSSR 1965, 25.
Properties: Pale yellow crystals, mp 225-230°. Practically insol in water. Sparingly sol in ethanol, chloroform, ether.
Melting point: mp 225-230°
Derivative Type: Ethanolamine salt
CAS Registry Number: 1420-04-8
Additional Names: Clonitrilide
Trademarks: Bayluscid (Bayer)
Molecular Formula: C13H8Cl2N2O4.C2H7NO
Molecular Weight: 388.20
Percent Composition: C 46.41%, H 3.89%, Cl 18.27%, N 10.82%, O 20.61%
Properties: Yellow-brown solid, mp 204°.
Melting point: mp 204°
Use: The ethanolamine salt as a molluscicide.
Therap-Cat: Anthelmintic (Cestodes).
Therap-Cat-Vet: Anthelmintic (Cestodes).
Keywords: Anthelmintic (Cestodes).

Niclosamide, sold under the brand name Niclocide among others, is a medication used to treat tapeworm infestations.[2] This includes diphyllobothriasishymenolepiasis, and taeniasis.[2] It is not effective against other worms such as pinworms or roundworms.[3] It is taken by mouth.[2]

Side effects include nausea, vomiting, abdominal pain, and itchiness.[2] It may be used during pregnancy and appears to be safe for the baby.[2] Niclosamide is in the anthelmintic family of medications.[3] It works by blocking the uptake of sugar by the worm.[4]

Niclosamide was discovered in 1958.[5] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[6] The wholesale cost in the developing world is about 0.24 USD for a course of treatment.[7] It is not commercially available in the United States.[3] It is effective in a number of other animals.[4]

Side effects

Side effects include nausea, vomiting, abdominal pain, constipation, and itchiness.[2] Rarely, dizziness, skin rash, drowsiness, perianal itching, or an unpleasant taste occur. For some of these reasons, praziquantel is a preferable and equally effective treatment for tapeworm infestation.[citation needed]

Mechanism of action

Niclosamide inhibits glucose uptake, oxidative phosphorylation, and anaerobic metabolism in the tapeworm.[8]

Other applications

Niclosamide’s metabolic effects are relevant to wide ranges of organisms, and accordingly it has been applied as a control measure to organisms other than tapeworms. For example, it is an active ingredient in some formulations such as Bayluscide for killing lamprey larvae,[9][10] as a molluscide,[11] and as a general purpose piscicide in aquaculture. Niclosamide has a short half-life in water in field conditions; this makes it valuable in ridding commercial fish ponds of unwanted fish; it loses its activity soon enough to permit re-stocking within a few days of eradicating the previous population.[11] Researchers have found that niclosamide is effective in killing invasive zebra mussels in cool waters.[12]

Research

Niclosamide is being studied in a number of types of cancer.[13] Niclosamide along with oxyclozanide, another anti-tapeworm drug, was found in a 2015 study to display “strong in vivo and in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA)”.[14]

syn

https://www.sciencedirect.com/science/article/pii/S0099542805320028

Image result for niclosamide

References

  1. Jump up to:a b c d e f World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. pp. 81, 87, 591. hdl:10665/44053ISBN 9789241547659.
  2. Jump up to:a b c “Niclosamide Advanced Patient Information – Drugs.com”http://www.drugs.comArchived from the original on 20 December 2016. Retrieved 8 December 2016.
  3. Jump up to:a b Jim E. Riviere; Mark G. Papich (13 May 2013). Veterinary Pharmacology and Therapeutics. John Wiley & Sons. p. 1096. ISBN 978-1-118-68590-7Archived from the original on 10 September 2017.
  4. ^ Mehlhorn, Heinz (2008). Encyclopedia of Parasitology: A-M. Springer Science & Business Media. p. 483. ISBN 9783540489948Archived from the original on 2016-12-20.
  5. ^ 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.
  6. ^ “Niclosamide”International Drug Price Indicator GuideArchived from the original on 10 May 2017. Retrieved 1 December 2016.
  7. ^ Weinbach EC, Garbus J (1969). “Mechanism of action of reagents that uncouple oxidative phosphorylation”. Nature221 (5185): 1016–8. doi:10.1038/2211016a0PMID 4180173.
  8. ^ Boogaard, Michael A. Delivery Systems of Piscicides “Request Rejected”(PDF)Archived (PDF) from the original on 2017-06-01. Retrieved 2017-05-30.
  9. ^ Verdel K.Dawson (2003). “Environmental Fate and Effects of the Lampricide Bayluscide: a Review”. Journal of Great Lakes Research29 (Supplement 1): 475–492. doi:10.1016/S0380-1330(03)70509-7.
  10. Jump up to:a b “WHO Specifications And Evaluations. For Public Health Pesticides. Niclosamide” (PDF).[dead link]
  11. ^ “Researchers find new methods to combat invasive zebra mussels”The Minnesota Daily. Retrieved 2018-11-19.
  12. ^ “Clinical Trials Using Niclosamide”NCI. Retrieved 20 March 2019.
  13. ^ Rajamuthiah R, Fuchs BB, Conery AL, Kim W, Jayamani E, Kwon B, Ausubel FM, Mylonakis E (April 2015). Planet PJ (ed.). “Repurposing Salicylanilide Anthelmintic Drugs to Combat Drug Resistant Staphylococcus aureus”PLoS ONE10 (4): e0124595. doi:10.1371/journal.pone.0124595ISSN 1932-6203PMC 4405337PMID 25897961.

External links

 

Niclosamide

Niclosamide
Niclosamide.svg
Clinical data
Trade names Niclocide, Fenasal, Phenasal, others[1]
AHFS/Drugs.com Micromedex Detailed Consumer Information
Routes of
administration
By mouth
ATC code
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.052 Edit this at Wikidata
Chemical and physical data
Formula C13H8Cl2N2O4
Molar mass 327.119 g/mol g·mol−1
3D model (JSmol)
Melting point 225 to 230 °C (437 to 446 °F)

//////////Niclosamide ニクロサミド , никлосамидنيكلوساميد氯硝柳胺 , covid 19, corona virus

Nitazoxanide ニタゾキサニド;


Nitazoxanide

Image result for nitazoxanide SYNTHESIS

Nitazoxanide

Formula
C12H9N3O5S
Exact mass
307.0263
Mol weight
307.282
Nitazoxanide
CAS Registry Number: 55981-09-4
CAS Name: 2-(Acetyloxy)-N-(5-nitro-2-thiazolyl)benzamide
Additional Names: N-(5-nitro-2-thiazolyl)salicylamide acetate (ester); 2-(2¢-acetoxy)benzamido-5-nitrothiazole
Manufacturers’ Codes: PH-5776
Trademarks: Alinia (Romark); Cryptaz (Romark)
Molecular Formula: C12H9N3O5S
Molecular Weight: 307.28
Percent Composition: C 46.90%, H 2.95%, N 13.67%, O 26.03%, S 10.44%
Literature References: Broad spectrum antiparasitic agent; inhibits pyruvate ferredoxin oxidoreductase. Prepn: J. F. Rossignol, R. Cavier, DE 2438037eidem, US 3950351 (1975, 1976 both to S.P.R.L. Phavic); and antiparasitic activity: R. Cavier et al., Eur. J. Med. Chem. – Chim. Ther. 13, 539 (1978). Antibacterial spectrum in vitro: L Dubreuil et al., Antimicrob. Agents Chemother. 40, 2266 (1996). Toxicology: J. R. Murphy, J.-C. Friedmann, J. Appl. Toxicol. 5, 49 (1985). Clinical pharmacokinetics: A. Stockis et al., Int. J. Clin. Pharmacol. Ther. 34, 349 (1996). Clinical trial in intestinal protozoan and helminthic infections: H. Abaza et al., Curr. Ther. Res. 59, 116 (1998). Review of mechanism of action and clinical experience: H. M. Gilles, P. S. Hoffman, Trends Parasitol. 18, 95-97 (2002).
Properties: Light yellow crystalline powder. Crystals from methanol, mp 202°. Poorly sol in ethanol. Practically insol in water. LD50 orally in male, female mice: 1350, 1380 mg/kg; in rats: >10 g/kg (Murphy, Friedmann).
Melting point: mp 202°
Toxicity data: LD50 orally in male, female mice: 1350, 1380 mg/kg; in rats: >10 g/kg (Murphy, Friedmann)
Therap-Cat: Anthelmintic (cestodes); antiprotozoal (Cryptosporidium).
Keywords: Anthelmintic (Cestodes); Antiprotozoal (Cryptosporidium).

Nitazoxanide is a broad-spectrum antiparasitic and broad-spectrum antiviral drug that is used in medicine for the treatment of various helminthicprotozoal, and viral infections.[4][5][6] It is indicated for the treatment of infection by Cryptosporidium parvum and Giardia lamblia in immunocompetent individuals and has been repurposed for the treatment of influenza.[1][6] Nitazoxanide has also been shown to have in vitro antiparasitic activity and clinical treatment efficacy for infections caused by other protozoa and helminths;[4][7] emerging evidence suggests that it possesses efficacy in treating a number of viral infections as well.[6]

Chemically, nitazoxanide is the prototype member of the thiazolides, a class of drugs which are synthetic nitrothiazolyl-salicylamide derivatives with antiparasitic and antiviral activity.[4][6][8] Tizoxanide, an active metabolite of nitazoxanide in humans, is also an antiparasitic drug of the thiazolide class.[4][9]

Uses

Nitazoxanide is an effective first-line treatment for infection by Blastocystis species[10][11] and is indicated for the treatment of infection by Cryptosporidium parvum or Giardia lamblia in immunocompetent adults and children.[1] It is also an effective treatment option for infections caused by other protozoa and helminths (e.g., Entamoeba histolytica,[12] Hymenolepis nana,[13] Ascaris lumbricoides,[14] and Cyclospora cayetanensis[15]).[7]

As of September 2015, it is in phase 3 clinical trials for the treatment influenza due to its inhibitory effect on a broad range of influenza virus subtypes and efficacy against influenza viruses that are resistant to neuraminidase inhibitors like oseltamivir.[6][16] Nitazoxanide is also being researched as a potential treatment for chronic hepatitis B, chronic hepatitis Crotavirus and norovirus gastroenteritis.[6]

Chronic hepatitis B

Nitazoxanide alone has shown preliminary evidence of efficacy in the treatment of chronic hepatitis B over a one-year course of therapy.[17] Nitazoxanide 500 mg twice daily resulted in a decrease in serum HBV DNA in all of 4 HBeAg-positive patients, with undetectable HBV DNA in 2 of 4 patients, loss of HBeAg in 3 patients, and loss of HBsAg in one patient. Seven of 8 HBeAg-negative patients treated with nitazoxanide 500 mg twice daily had undetectable HBV DNA and 2 had loss of HBsAg. Additionally, nitazoxanide monotherapy in one case and nitazoxanide plus adefovir in another case resulted in undetectable HBV DNA, loss of HBeAg and loss of HBsAg.[18] These preliminary studies showed a higher rate of HBsAg loss than any currently licensed therapy for chronic hepatitis B. The similar mechanism of action of interferon and nitazoxanide suggest that stand-alone nitazoxanide therapy or nitazoxanide in concert with nucleos(t)ide analogs have the potential to increase loss of HBsAg, which is the ultimate end-point of therapy. A formal phase Ⅱ study is being planned for 2009.[19]

Chronic hepatitis C

Romark initially decided to focus on the possibility of treating chronic hepatitis C with nitazoxanide.[20] The drug garnered interest from the hepatology community after three phase II clinical trials involving the treatment of hepatitis C with nitazoxanide produced positive results for treatment efficacy and similar tolerability to placebo without any signs of toxicity.[20] A meta-analysis from 2014 concluded that the previous held trials were of low-quality and with held with a risk of bias. The authors concluded that more randomized trials with low risk of bias are needed to give any determine if Nitazoxanide can be used as an effective treatment for chronic hepatitis C patients.[21]

Clinical trials

Nitazoxanide has gone through Phase II clinical trials for the treatment of hepatitis C, in combination with peginterferon alfa-2a and ribavirin.[22][23]Romark Laboratories has announced encouraging results from international Phase I and II clinical trials evaluating a controlled release version of nitazoxanide in the treatment of chronic hepatitis C virus infection. The company used 675 mg and 1,350 mg twice daily doses of controlled release nitazoxanide showed favorable safety and tolerability throughout the course of the study, with mild to moderate adverse events. Primarily GI-related adverse events were reported.

A randomised double-blind placebo-controlled study published in 2006, with a group of 38 young children (Lancet, vol 368, page 124-129)[24] concluded that a 3-day course of nitazoxanide significantly reduced the duration of rotavirus disease in hospitalized pediatric patients. Dose given was “7.5 mg/kg twice daily” and the time of resolution was “31 hours for those given nitazoxanide compared with 75 hours for those in the placebo group.” Rotavirus is the most common infectious agent associated with diarrhea in the pediatric age group worldwide.

Teran et al.. conducted a study at the Pediatric Center Albina Patinö, a reference hospital in the city of Cochabamba, Bolivia, from August 2007 to February 2008. The study compared nitazoxanide and probiotics in the treatment of acute rotavirus diarrhea. They found Small differences in favor of nitazoxanide in comparison with probiotics and concluded that nitazoxanide is an important treatment option for rotavirus diarrhea.[17]

Lateef et al.. conducted a study in India that evaluated the effectiveness of nitazoxanide in the treatment of beef tapeworm (Taenia saginata) infection. They concluded that nitazoxanide is a safe, effective, inexpensive, and well-tolerated drug for the treatment of niclosamide- and praziquantel-resistant beef tapeworm (Taenia saginata) infection.[18]

A retrospective review of charts of patients treated with nitazoxanide for trichomoniasis by Michael Dan and Jack D. Sobel demonstrated negative result. They reported three case studies; two of which with metronidazole-resistant infections. In Case 3, they reported the patient to be cured with high divided dose tinidazole therapy. They used a high dosage of the drug (total dose, 14–56 g) than the recommended standard dosage (total dose, 3 g) and observed a significant adverse reaction (poorly tolerated nausea) only with the very high dose (total dose, 56 g). While confirming the safety of the drug, they showed nitazoxanide is ineffective for the treatment of trichomoniasis.[25]

Contraindications

Nitazoxanide is contraindicated only in individuals who have experienced a hypersensitivity reaction to nitazoxanide or the inactive ingredients of a nitazoxanide formulation.[1]

Adverse effects

The side effects of nitazoxanide do not significantly differ from a placebo treatment for giardiasis;[1] these symptoms include stomach pain, headache, upset stomach, vomiting, discolored urine, excessive urinating, skin rash, itching, fever, flu syndrome, and others.[1][26] Nitazoxanide does not appear to cause any significant adverse effects when taken by healthy adults.[1][2]

Overdose

Information on nitazoxanide overdose is limited. Oral doses of 4 grams in healthy adults do not appear to cause any significant adverse effects.[1][2] In various animals, the oral LD50 is higher than 10 g/kg.[1]

Interactions

Due to the exceptionally high plasma protein binding (>99.9%) of nitazoxanide’s metabolite, tizoxanide, the concurrent use of nitazoxanide with other highly plasma protein-bound drugs with narrow therapeutic indices (e.g., warfarin) increases the risk of drug toxicity.[1] In vitro evidence suggests that nitazoxanide does not affect the CYP450 system.[1]

Pharmacology

Pharmacodynamics

The anti-protozoal activity of nitazoxanide is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction which is essential to anaerobic energy metabolism.[1][8] PFOR inhibition may also contribute to its activity against anaerobic bacteria.[27]

It has also been shown to have activity against influenza A virus in vitro.[28] The mechanism appears to be by selectively blocking the maturation of the viral hemagglutinin at a stage preceding resistance to endoglycosidase H digestion. This impairs hemagglutinin intracellular trafficking and insertion of the protein into the host plasma membrane.

Nitazoxanide modulates a variety of other pathways in vitro, including glutathione-S-transferase and glutamate-gated chloride ion channels in nematodes, respiration and other pathways in bacteria and cancer cells, and viral and host transcriptional factors.[27]

Pharmacokinetics

Following oral administration, nitazoxanide is rapidly hydrolyzed to the pharmacologically active metabolite, tizoxanide, which is 99% protein bound.[1][9] Tizoxanide is then glucuronide conjugated into the active metabolite, tizoxanide glucuronide.[1] Peak plasma concentrations of the metabolites tizoxanide and tizoxanide glucuronide are observed 1–4 hours after oral administration of nitazoxanide, whereas nitazoxanide itself is not detected in blood plasma.[1]

Roughly ​23 of an oral dose of nitazoxanide is excreted as its metabolites in feces, while the remainder of the dose excreted in urine.[1] Tizoxanide is excreted in the urinebile and feces.[1] Tizoxanide glucuronide is excreted in urine and bile.[1]

Chemistry

History

Nitazoxanide is the prototype member of the thiazolides, which is a drug class of structurally-related broad-spectrum antiparasitic compounds.[4] Nitazoxanide is a light yellow crystalline powder. It is poorly soluble in ethanol and practically insoluble in water.

Nitazoxanide was originally discovered in the 1980s by Jean-François Rossignol at the Pasteur Institute. Initial studies demonstrated activity versus tapewormsIn vitro studies demonstrated much broader activity. Dr. Rossignol co-founded Romark Laboratories, with the goal of bringing nitazoxanide to market as an anti-parasitic drug. Initial studies in the USA were conducted in collaboration with Unimed Pharmaceuticals, Inc. (Marietta, GA) and focused on development of the drug for treatment of cryptosporidiosis in AIDS. Controlled trials began shortly after the advent of effective anti-retroviral therapies. The trials were abandoned due to poor enrollment and the FDA rejected an application based on uncontrolled studies.

Subsequently, Romark launched a series of controlled trials. A placebo-controlled study of nitazoxanide in cryptosporidiosis demonstrated significant clinical improvement in adults and children with mild illness. Among malnourished children in Zambia with chronic cryptosporidiosis, a three-day course of therapy led to clinical and parasitologic improvement and improved survival. In Zambia and in a study conducted in Mexico, nitazoxanide was not successful in the treatment of cryptosporidiosis in advanced infection with human immunodeficiency virus at the doses used. However, it was effective in patients with higher CD4 counts. In treatment of giardiasis, nitazoxanide was superior to placebo and comparable to metronidazole. Nitazoxanide was successful in the treatment of metronidazole-resistant giardiasis. Studies have suggested efficacy in the treatment of cyclosporiasisisosporiasis, and amebiasis.[29] Recent studies have also found it to be effective against beef tapeworm(Taenia saginata).[30]

Research

Nitazoxanide is also under investigation for the treatment of COVID-19.[31]

Pharmaceutical products

Dosage forms

Nitazoxanide is currently available in two oral dosage forms: a tablet (500 mg) and an oral suspension (100 mg per 5 ml when reconstituted).[1]

An extended release tablet (675 mg) has been used in clinical trials for chronic hepatitis C; however, this form is not currently marketed and available for prescription.[20]

Brand names

Nitazoxanide is sold under the brand names Adonid, Alinia, Allpar, Annita, Celectan, Colufase, Daxon, Dexidex, Diatazox, Kidonax, Mitafar, Nanazoxid, Parazoxanide, Netazox, Niazid, Nitamax, Nitax, Nitaxide, Nitaz, Nizonide, NT-TOX, Pacovanton, Paramix, Toza, and Zox.

SYN

Image result for nitazoxanide SYNTHESIS

https://www.sciencedirect.com/science/article/pii/S0960894X11002848

CLIP

Image result for nitazoxanide SYNTHESIS

Image result for nitazoxanide SYNTHESIS

CLIP

Image result for nitazoxanide SYNTHESIS

PATENT

Image result for nitazoxanide SYNTHESIS

https://patents.google.com/patent/CN105175352A/zh

 

References

  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 “Nitazoxanide Prescribing Information” (PDF). Romark Pharmaceuticals. August 2013. pp. 1–5. Archived from the original (PDF) on 16 January 2016. Retrieved 3 January 2016.
  2. Jump up to:a b c d e Stockis A, Allemon AM, De Bruyn S, Gengler C (May 2002). “Nitazoxanide pharmacokinetics and tolerability in man using single ascending oral doses”. Int J Clin Pharmacol Ther40 (5): 213–220. doi:10.5414/cpp40213PMID 12051573.
  3. ^ “Nitazoxanide”PubChem Compound. National Center for Biotechnology Information. Retrieved 3 January 2016.
  4. Jump up to:a b c d e Di Santo N, Ehrisman J (2013). “Research perspective: potential role of nitazoxanide in ovarian cancer treatment. Old drug, new purpose?”Cancers (Basel)5 (3): 1163–1176. doi:10.3390/cancers5031163PMC 3795384PMID 24202339Nitazoxanide [NTZ: 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide] is a thiazolide antiparasitic agent with excellent activity against a wide variety of protozoa and helminths.  … Nitazoxanide (NTZ) is a main compound of a class of broad-spectrum anti-parasitic compounds named thiazolides. It is composed of a nitrothiazole-ring and a salicylic acid moiety which are linked together by an amide bond … NTZ is generally well tolerated, and no significant adverse events have been noted in human trials [13]. … In vitro, NTZ and tizoxanide function against a wide range of organisms, including the protozoal species Blastocystis hominis, C. parvum, Entamoeba histolytica, G. lamblia and Trichomonas vaginalis [13]
  5. ^ White CA (2004). “Nitazoxanide: a new broad spectrum antiparasitic agent”. Expert Rev Anti Infect Ther2 (1): 43–9. doi:10.1586/14787210.2.1.43PMID 15482170.
  6. Jump up to:a b c d e f Rossignol JF (October 2014). “Nitazoxanide: a first-in-class broad-spectrum antiviral agent”. Antiviral Res110: 94–103. doi:10.1016/j.antiviral.2014.07.014PMID 25108173Originally developed and commercialized as an antiprotozoal agent, nitazoxanide was later identified as a first-in-class broad-spectrum antiviral drug and has been repurposed for the treatment of influenza. … From a chemical perspective, nitazoxanide is the scaffold for a new class of drugs called thiazolides. These small-molecule drugs target host-regulated processes involved in viral replication. … A new dosage formulation of nitazoxanide is presently undergoing global Phase 3 clinical development for the treatment of influenza. Nitazoxanide inhibits a broad range of influenza A and B viruses including influenza A(pH1N1) and the avian A(H7N9) as well as viruses that are resistant to neuraminidase inhibitors. … Nitazoxanide also inhibits the replication of a broad range of other RNA and DNA viruses including respiratory syncytial virus, parainfluenza, coronavirus, rotavirus, norovirus, hepatitis B, hepatitis C, dengue, yellow fever, Japanese encephalitis virus and human immunodeficiency virus in cell culture assays. Clinical trials have indicated a potential role for thiazolides in treating rotavirus and norovirus gastroenteritis and chronic hepatitis B and chronic hepatitis C. Ongoing and future clinical development is focused on viral respiratory infections, viral gastroenteritis and emerging infections such as dengue fever.
  7. Jump up to:a b Anderson, V. R.; Curran, M. P. (2007). “Nitazoxanide: A review of its use in the treatment of gastrointestinal infections”. Drugs67(13): 1947–1967. doi:10.2165/00003495-200767130-00015PMID 17722965Nitazoxanide is effective in the treatment of protozoal and helminthic infections … Nitazoxanide is a first-line choice for the treatment of illness caused by C. parvum or G. lamblia infection in immunocompetent adults and children, and is an option to be considered in the treatment of illnesses caused by other protozoa and/or helminths.
  8. Jump up to:a b Sisson G1, Goodwin A, Raudonikiene A, Hughes NJ, Mukhopadhyay AK, Berg DE, Hoffman PS. (July 2002). “Enzymes associated with reductive activation and action of nitazoxanide, nitrofurans, and metronidazole in Helicobacter pylori”Antimicrob. Agents Chemother46 (7): 2116–23. doi:10.1128/aac.46.7.2116-2123.2002PMC 127316PMID 12069963Nitazoxanide (NTZ) is a redox-active nitrothiazolyl-salicylamide
  9. Jump up to:a b Korba BE, Montero AB, Farrar K, et al. (January 2008). “Nitazoxanide, tizoxanide and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication”. Antiviral Res77 (1): 56–63. doi:10.1016/j.antiviral.2007.08.005PMID 17888524.
  10. ^ “Blastocystis: Resources for Health Professionals”. United States Centers for Disease Control and Prevention. 2017-05-02. Retrieved 4 January 2016.
  11. ^ Roberts T, Stark D, Harkness J, Ellis J (May 2014). “Update on the pathogenic potential and treatment options for Blastocystis sp”Gut Pathog6: 17. doi:10.1186/1757-4749-6-17PMC 4039988PMID 24883113Blastocystis is one of the most common intestinal protists of humans. … A recent study showed that 100% of people from low socio-economic villages in Senegal were infected with Blastocystis sp. suggesting that transmission was increased due to poor hygiene sanitation, close contact with domestic animals and livestock, and water supply directly from well and river [10]. …
    Table 2: Summary of treatments and efficacy for Blastocystis infection
  12. ^ Muñoz P, Valerio M, Eworo A, Bouza E (2011). “Parasitic infections in solid-organ transplant recipients”Curr Opin Organ Transplant16 (6): 565–575. doi:10.1097/MOT.0b013e32834cdbb0PMID 22027588. Retrieved 7 January 2016Nitazoxanide: intestinal amoebiasis: 500 mg po bid x 3 days
  13. ^ “Hymenolepiasis: Resources for Health Professionals”. United States Centers for Disease Control and Prevention. 2017-05-02. Retrieved 4 January 2016.
  14. ^ Hagel I, Giusti T (October 2010). “Ascaris lumbricoides: an overview of therapeutic targets”Infectious Disorders – Drug Targets10 (5): 349–67. doi:10.2174/187152610793180876PMID 20701574new anthelmintic alternatives such as tribendimidine and Nitazoxanide have proved to be safe and effective against A. lumbricoides and other soil-transmitted helminthiases in human trials.
  15. ^ Shoff WH (5 October 2015). Chandrasekar PH, Talavera F, King JW (eds.). “Cyclospora Medication”Medscape. WebMD. Retrieved 11 January 2016Nitazoxanide, a 5-nitrothiazole derivative with broad-spectrum activity against helminths and protozoans, has been shown to be effective against C cayetanensis, with an efficacy 87% by the third dose (first, 71%; second 75%). Three percent of patients had minor side effects.
  16. ^ Li TC, Chan MC, Lee N (September 2015). “Clinical Implications of Antiviral Resistance in Influenza”Viruses7 (9): 4929–4944. doi:10.3390/v7092850PMC 4584294PMID 26389935Oral nitazoxanide is an available, approved antiparasitic agent (e.g., against cryptosporidium, giardia) with established safety profiles. Recently, it has been shown (together with its active metabolite tizoxanide) to possess anti-influenza activity by blocking haemagglutinin maturation/trafficking, and acting as an interferon-inducer [97]. … A large, multicenter, Phase 3 randomized-controlled trial comparing nitazoxanide, oseltamivir, and their combination in uncomplicated influenza is currently underway (NCT01610245).
    Figure 1: Molecular targets and potential antiviral treatments against influenza virus infection
  17. Jump up to:a b Teran, C. G.; Teran-Escalera, C. N.; Villarroel, P. (2009). “Nitazoxanide vs. Probiotics for the treatment of acute rotavirus diarrhea in children: A randomized, single-blind, controlled trial in Bolivian children”. International Journal of Infectious Diseases13(4): 518–523. doi:10.1016/j.ijid.2008.09.014PMID 19070525.
  18. Jump up to:a b Lateef, M.; Zargar, S. A.; Khan, A. R.; Nazir, M.; Shoukat, A. (2008). “Successful treatment of niclosamide- and praziquantel-resistant beef tapeworm infection with nitazoxanide”. International Journal of Infectious Diseases12 (1): 80–82. doi:10.1016/j.ijid.2007.04.017PMID 17962058.
  19. ^ World Journal of Gastroenterology 2009 April 21, Emmet B Keeffe MD, Professor, Jean-François Rossignol The Romark Institute for Medical Research, Tampa
  20. Jump up to:a b c Keeffe, E. B.; Rossignol, J. F. (2009). “Treatment of chronic viral hepatitis with nitazoxanide and second generation thiazolides”World Journal of Gastroenterology15 (15): 1805–1808. doi:10.3748/wjg.15.1805PMC 2670405PMID 19370775.
  21. ^ Nikolova, Kristiana; Gluud, Christian; Grevstad, Berit; Jakobsen, Janus C (2014). “Nitazoxanide for chronic hepatitis C”. Cochrane Database of Systematic Reviews (4): CD009182. doi:10.1002/14651858.CD009182.pub2ISSN 1465-1858PMID 24706397.
  22. ^ “Romark Initiates Clinical Trial Of Alinia For Chronic Hepatitis C In The United States” (Press release). Medical News Today. August 16, 2007. Retrieved 2007-10-11.
  23. ^ Franciscus, Alan (October 2, 2007). “Hepatitis C Treatments in Current Clinical Development”. HCV Advocate. Archived from the original on September 6, 2003. Retrieved 2007-10-11.
  24. ^ Rossignol, Jean-François; Abu-Zekry, Mona; Hussein, Abeer; Santoro, M Gabriella (2006). “Effect of nitazoxanide for treatment of severe rotavirus diarrhoea: randomised double-blind placebo-controlled trial”. The Lancet368 (9530): 124–9. CiteSeerX 10.1.1.458.1597doi:10.1016/S0140-6736(06)68852-1PMID 16829296.
  25. ^ Dan, M.; Sobel, J. D. (2007). “Failure of Nitazoxanide to Cure Trichomoniasis in Three Women”. Sexually Transmitted Diseases34 (10): 813–4. doi:10.1097/NMD.0b013e31802f5d9aPMID 17551415.
  26. ^ “Nitazoxanide”MedlinePlus. Retrieved 9 April 2014.
  27. Jump up to:a b Shakya, A; Bhat, HR; Ghosh, SK (2018). “Update on Nitazoxanide: A Multifunctional Chemotherapeutic Agent”. Current Drug Discovery Technologies15 (3): 201–213. doi:10.2174/1570163814666170727130003PMID 28748751.
  28. ^ Rossignol, J. F.; La Frazia, S.; Chiappa, L.; Ciucci, A.; Santoro, M. G. (2009). “Thiazolides, a New Class of Anti-influenza Molecules Targeting Viral Hemagglutinin at the Post-translational Level”Journal of Biological Chemistry284 (43): 29798–29808. doi:10.1074/jbc.M109.029470PMC 2785610PMID 19638339.
  29. ^ White Jr, AC (2003). “Nitazoxanide: An important advance in anti-parasitic therapy”. Am. J. Trop. Med. Hyg68 (4): 382–383. doi:10.4269/ajtmh.2003.68.382PMID 12875283.
  30. ^ Lateef, M.; Zargar, S. A.; Khan, A. R.; Nazir, M.; Shoukat, A. (2008). “Successful treatment of niclosamide- and praziquantel-resistant beef tapeworm infection with nitazoxanide”. International Journal of Infectious Diseases12 (1): 80–2. doi:10.1016/j.ijid.2007.04.017PMID 17962058.
  31. ^ Cynthia Liu, Qiongqiong Zhou, Yingzhu Li, Linda V. Garner, Steve P. Watkins, Linda J. Carter, Jeffrey Smoot, Anne C. Gregg, Angela D. Daniels, Susan Jervey, Dana Albaiu. Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases. ACS Central Science 2020; doi:10.1021/acscentsci.0c00272

External links

Nitazoxanide
Nitazoxanide.svg
Clinical data
Trade names Alinia, Nizonide, and others
AHFS/Drugs.com Monograph
MedlinePlus a603017
License data
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration
Oral
Drug class Antiprotozoal
Broad-spectrum antiparasitic
Broad-spectrum antiviral
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding Nitazoxanide: ?
Tizoxanide: over 99%[1][2]
Metabolism Rapidly hydrolyzed to tizoxanide[1]
Metabolites tizoxanide[1][2]
tizoxanide glucuronide[1][2]
Elimination half-life 3.5 hours[3]
Excretion Renalbiliary, and fecal[1]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.054.465 Edit this at Wikidata
Chemical and physical data
Formula C12H9N3O5S
Molar mass 307.283 g/mol g·mol−1
3D model (JSmol)

//////////////nitazoxanide, corona virus, covid 19

Hydroxychloroquine, ヒドロキシクロロキン, гидроксихлорохин , هيدروكسيكلوروكين , 羟氯喹 ,


ChemSpider 2D Image | hydroxychloroquine | C18H26ClN3O

 

Hydroxychloroquine
ヒドロキシクロロキン;
Formula
C18H26ClN3O
cas
118-42-3
sulphate 747-36-4
Mol weight
335.8715

 

гидроксихлорохин [Russian] [INN]
هيدروكسيكلوروكين [Arabic] [INN]
羟氯喹 [Chinese] [INN]
Oxychlorochin, Plaquenil Plaquenil®, 

Hydroxychloroquine (HCQ), sold under the brand name Plaquenil among others, is a medication used for the prevention and treatment of certain types of malaria.[2] Specifically it is used for chloroquine-sensitive malaria.[3] Other uses include treatment of rheumatoid arthritislupus, and porphyria cutanea tarda.[2] It is taken by mouth.[2] It is also being used as an experimental treatment for coronavirus disease 2019 (COVID-19).[4]

Common side effects include vomitingheadache, changes in vision and muscle weakness.[2] Severe side effects may include allergic reactions.[2] Although all risk cannot be excluded it remains a treatment for rheumatic disease during pregnancy.[5] Hydroxychloroquine is in the antimalarial and 4-aminoquinoline families of medication.[2]

Hydroxychloroquine was approved for medical use in the United States in 1955.[2] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[6] The wholesale cost in the developing world is about US$4.65 per month as of 2015, when used for rheumatoid arthritis or lupus.[7] In the United States the wholesale cost of a month of treatment is about US$25 as of 2020.[8] In the United Kingdom this dose costs the NHS about £ 5.15.[9] In 2017, it was the 128th most prescribed medication in the United States with more than five million prescriptions.[10]

Medical use

Hydroxychloroquine treats malaria, systemic lupus erythematosus, rheumatic disorders like rheumatoid arthritisporphyria cutanea tarda, and Q fever.[2]

In 2014, its efficacy to treat Sjögren syndrome was questioned in a double-blind study involving 120 patients over a 48-week period.[11]

Hydroxychloroquine is widely used in the treatment of post-Lyme arthritis. It may have both an anti-spirochaete activity and an anti-inflammatory activity, similar to the treatment of rheumatoid arthritis.[12]

Contraindications

The drug label advises that hydroxychloroquine should not be prescribed to individuals with known hypersensitivity to 4-Aminoquinoline compounds.[13] There are a range of other contraindications[14] [15] and caution is required if patients have certain heart conditions, diabetes, psoriasis etc.

Side effects[

The most common adverse effects are a mild nausea and occasional stomach cramps with mild diarrhea. The most serious adverse effects affect the eye, with dose-related retinopathy as a concern even after hydroxychloroquine use is discontinued.[2] For short-term treatment of acute malaria, adverse effects can include abdominal cramps, diarrhea, heart problems, reduced appetite, headache, nausea and vomiting.[2]

For prolonged treatment of lupus or rheumatoid arthritis, adverse effects include the acute symptoms, plus altered eye pigmentation, acneanemia, bleaching of hair, blisters in mouth and eyes, blood disorders, convulsions, vision difficulties, diminished reflexes, emotional changes, excessive coloring of the skin, hearing loss, hives, itching, liver problems or liver failureloss of hair, muscle paralysis, weakness or atrophy, nightmares, psoriasis, reading difficulties, tinnitus, skin inflammation and scaling, skin rash, vertigoweight loss, and occasionally urinary incontinence.[2] Hydroxychloroquine can worsen existing cases of both psoriasis and porphyria.[2]

Children may be especially vulnerable to developing adverse effects from hydroxychloroquine.[2]

Eyes

One of the most serious side effects is retinopathy (generally with chronic use).[2][16] People taking 400 mg of hydroxychloroquine or less per day generally have a negligible risk of macular toxicity, whereas the risk begins to go up when a person takes the medication over 5 years or has a cumulative dose of more than 1000 grams. The daily safe maximum dose for eye toxicity can be computed from one’s height and weight using this calculator. Cumulative doses can also be calculated from this calculator. Macular toxicity is related to the total cumulative dose rather than the daily dose. Regular eye screening, even in the absence of visual symptoms, is recommended to begin when either of these risk factors occurs.[17]

Toxicity from hydroxychloroquine may be seen in two distinct areas of the eye: the cornea and the macula. The cornea may become affected (relatively commonly) by an innocuous cornea verticillata or vortex keratopathy and is characterized by whorl-like corneal epithelial deposits. These changes bear no relationship to dosage and are usually reversible on cessation of hydroxychloroquine.

The macular changes are potentially serious. Advanced retinopathy is characterized by reduction of visual acuity and a “bull’s eye” macular lesion which is absent in early involvement.

Overdose

Due to rapid absorption, symptoms of overdose can occur within a half an hour after ingestion. Overdose symptoms include convulsions, drowsiness, headache, heart problems or heart failure, difficulty breathing and vision problems.

Hydroxychloroquine overdoses are rarely reported, with 7 previous cases found in the English medical literature. In one such case, a 16-year-old girl who had ingested a handful of hydroxychloroquine 200mg presented with tachycardia (heart rate 110 beats/min), hypotension (systolic blood pressure 63 mm Hg), central nervous system depression, conduction defects (ORS = 0.14 msec), and hypokalemia (K = 2.1 meq/L). Treatment consisted of fluid boluses and dopamine, oxygen, and potassium supplementation. The presence of hydroxychloroquine was confirmed through toxicologic tests. The patient’s hypotension resolved within 4.5 hours, serum potassium stabilized in 24 hours, and tachycardia gradually decreased over 3 days.[18]

Interactions

The drug transfers into breast milk and should be used with care by pregnant or nursing mothers.[citation needed]

Care should be taken if combined with medication altering liver function as well as aurothioglucose (Solganal), cimetidine (Tagamet) or digoxin (Lanoxin). HCQ can increase plasma concentrations of penicillamine which may contribute to the development of severe side effects. It enhances hypoglycemic effects of insulin and oral hypoglycemic agents. Dose altering is recommended to prevent profound hypoglycemiaAntacids may decrease the absorption of HCQ. Both neostigmine and pyridostigmine antagonize the action of hydroxychloroquine.[19]

While there may be a link between hydroxychloroquine and hemolytic anemia in those with glucose-6-phosphate dehydrogenase deficiency, this risk may be low in those of African descent.[20]

Specifically, the FDA drug label for hydroxychloroquine lists the following drug interactions [13]:

  • Digoxin (wherein it may result in increased serum digoxin levels)
  • Insulin or antidiabetic drugs (wherein it may enhance the effects of a hypoglycemic treatment)
  • Drugs that prolong QT interval and other arrhythmogenic drugs (as Hydroxychloroquine prolongs the QT interval and may increase the risk of inducing ventricular arrhythmias if used concurrently)
  • Mefloquine and other drugs known to lower the convulsive threshold (co-administration with other antimalarials known to lower the convulsion threshold may increase risk of convulsions)
  • Antiepileptics (concurrent use may impair the antiepileptic activity)
  • Methotrexate (combined use is unstudied and may increase the frequency of side effects)
  • Cyclosporin (wherein an increased plasma cylcosporin level was reported when used together).

Pharmacology[

Pharmacokinetics

Hydroxychloroquine has similar pharmacokinetics to chloroquine, with rapid gastrointestinal absorption and elimination by the kidneys. Cytochrome P450 enzymes (CYP2D62C83A4 and 3A5) metabolize hydroxychloroquine to N-desethylhydroxychloroquine.[21]

Pharmacodynamics

Antimalarials are lipophilic weak bases and easily pass plasma membranes. The free base form accumulates in lysosomes (acidic cytoplasmic vesicles) and is then protonated,[22] resulting in concentrations within lysosomes up to 1000 times higher than in culture media. This increases the pH of the lysosome from 4 to 6.[23] Alteration in pH causes inhibition of lysosomal acidic proteases causing a diminished proteolysis effect.[24] Higher pH within lysosomes causes decreased intracellular processing, glycosylation and secretion of proteins with many immunologic and nonimmunologic consequences.[25] These effects are believed to be the cause of a decreased immune cell functioning such as chemotaxisphagocytosis and superoxide production by neutrophils.[26] HCQ is a weak diprotic base that can pass through the lipid cell membrane and preferentially concentrate in acidic cytoplasmic vesicles. The higher pH of these vesicles in macrophages or other antigen-presenting cells limits the association of autoantigenic (any) peptides with class II MHC molecules in the compartment for peptide loading and/or the subsequent processing and transport of the peptide-MHC complex to the cell membrane.[27]

Mechanism of action

Hydroxychloroquine increases[28] lysosomal pH in antigen-presenting cells. In inflammatory conditions, it blocks toll-like receptors on plasmacytoid dendritic cells (PDCs).[citation needed] Hydroxychloroquine, by decreasing TLR signaling, reduces the activation of dendritic cells and the inflammatory process. Toll-like receptor 9 (TLR 9) recognizes DNA-containing immune complexes and leads to the production of interferon and causes the dendritic cells to mature and present antigen to T cells, therefore reducing anti-DNA auto-inflammatory process.

In 2003, a novel mechanism was described wherein hydroxychloroquine inhibits stimulation of the toll-like receptor (TLR) 9 family receptors. TLRs are cellular receptors for microbial products that induce inflammatory responses through activation of the innate immune system.[29]

As with other quinoline antimalarial drugs, the mechanism of action of quinine has not been fully resolved. The most accepted model is based on hydrochloroquinine and involves the inhibition of hemozoin biocrystallization, which facilitates the aggregation of cytotoxic heme. Free cytotoxic heme accumulates in the parasites, causing their deaths.[citation needed]

Brand names

It is frequently sold as a sulfate salt known as hydroxychloroquine sulfate.[2] 200 mg of the sulfate salt is equal to 155 mg of the base.[2]

Brand names of hydroxychloroquine include Plaquenil, Hydroquin, Axemal (in India), Dolquine, Quensyl, Quinoric.[30]

Research

COVID-19

Hydroxychloroquine and chloroquine have been recommended by Chinese and South Korean health authorities for the experimental treatment of COVID-19.[31][32] In vitro studies in cell cultures demonstrated that hydroxychloroquine was more potent than chloroquine against SARS-CoV-2.[33]

On 17 March 2020, the AIFA Scientific Technical Commission of the Italian Medicines Agency expressed a favorable opinion on including the off-label use of chloroquine and hydroxychloroquine for the treatment of SARS-CoV-2 infection.[34]

 

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Image result for hydroxychloroquine

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https://d-nb.info/1166863441/34

white solid (0.263 g, 78%). 1H NMR
(600 MHz, CDCl3
) δ 8.48 (d, J = 5.4 Hz, 1H), 7.93 (d, J = 5.4 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.34 (dd, J = 8.8, 7.3 Hz, 1H), 6.39 (d, J = 5.4 Hz, 1H), 4.96 (d, J = 7.5 Hz, 1H), 3.70 (sx,J = 6.8 Hz, 1H), 3.55 (m, 2H), 2.57 (m, 5H), 2.49 (m, 2H),
1.74–1.62 (m, 1H), 1.65–1.53 (m, 3H), 1.31 (d, J = 6.9 Hz, 3H),
1.24 (d, J = 7.2 Hz, 2H);

13C NMR (125 MHz, CDCl3) δ 152.2,
149.5, 149.2, 135.0, 129.0, 125.4, 121.2, 117.4, 99.4, 58.6, 54.9,
53.18, 48.5, 47.9, 34.5, 24.1, 20.6, 11.9. Spectra were obtained
in accordance with those previously reported [38,39].

38. Cornish, C. A.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1985,
2585–2598. doi:10.1039/P19850002585
39. Münstedt, R.; Wannagat, U.; Wrobel, D. J. Organomet. Chem. 1984,
264, 135–148. doi:10.1016/0022-328X(84)85139-6

 

 

References

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  12. ^ Steere, AC; Angelis, SM (October 2006). “Therapy for Lyme Arthritis: Strategies for the Treatment of Antibiotic-refractory Arthritis”. Arthritis and Rheumatism54 (10): 3079–86. doi:10.1002/art.22131PMID 17009226.
  13. Jump up to:a b “Plaquenil- hydroxychloroquine sulfate tablet”DailyMed. 3 January 2020. Retrieved 20 March 2020.
  14. ^ “Plaquenil (hydroxychloroquine sulfate) dose, indications, adverse effects, interactions”pdr.net. Retrieved 19 March 2020.
  15. ^ “Drugs & Medications”webmd.com. Retrieved 19 March 2020.
  16. ^ Flach, AJ (2007). “Improving the Risk-benefit Relationship and Informed Consent for Patients Treated with Hydroxychloroquine”Transactions of the American Ophthalmological Society105: 191–94, discussion 195–97. PMC 2258132PMID 18427609.
  17. ^ Marmor, MF; Kellner, U; Lai, TYY; Lyons, JS; Mieler, WF (February 2011). “Revised Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy”. Ophthalmology118 (2): 415–22. doi:10.1016/j.ophtha.2010.11.017PMID 21292109.
  18. ^ Marquardt, Kathy; Albertson, Timothy E. (1 September 2001). “Treatment of hydroxychloroquine overdose”The American Journal of Emergency Medicine19 (5): 420–424. doi:10.1053/ajem.2001.25774ISSN 0735-6757PMID 11555803.
  19. ^ “Russian Register of Medicines: Plaquenil (hydroxychloroquine) Film-coated Tablets for Oral Use. Prescribing Information” (in Russian). Sanofi-Synthelabo. Archived from the original on 16 August 2016. Retrieved 14 July 2016.
  20. ^ Mohammad, Samya; Clowse, Megan E. B.; Eudy, Amanda M.; Criscione-Schreiber, Lisa G. (March 2018). “Examination of Hydroxychloroquine Use and Hemolytic Anemia in G6PDH-Deficient Patients”. Arthritis Care & Research70 (3): 481–485. doi:10.1002/acr.23296ISSN 2151-4658PMID 28556555.
  21. ^ Kalia, S; Dutz, JP (2007). “New Concepts in Antimalarial Use and Mode of Action in Dermatology”. Dermatologic Therapy20 (4): 160–74. doi:10.1111/j.1529-8019.2007.00131.xPMID 17970883.
  22. ^ Kaufmann, AM; Krise, JP (2007). “Lysosomal Sequestration of Amine-containing Drugs: Analysis and Therapeutic Implications”. Journal of Pharmaceutical Sciences96 (4): 729–46. doi:10.1002/jps.20792PMID 17117426.
  23. ^ Ohkuma, S; Poole, B (1978). “Fluorescence Probe Measurement of the Intralysosomal pH in Living Cells and the Perturbation of pH by Various Agents”Proceedings of the National Academy of Sciences of the United States of America75 (7): 3327–31. doi:10.1073/pnas.75.7.3327PMC 392768PMID 28524.
  24. ^ Ohkuma, S; Chudzik, J; Poole, B (1986). “The Effects of Basic Substances and Acidic Ionophores on the Digestion of Exogenous and Endogenous Proteins in Mouse Peritoneal Macrophages”The Journal of Cell Biology102 (3): 959–66. doi:10.1083/jcb.102.3.959PMC 2114118PMID 3949884.
  25. ^ Oda, K; Koriyama, Y; Yamada, E; Ikehara, Y (1986). “Effects of Weakly Basic Amines on Proteolytic Processing and Terminal Glycosylation of Secretory Proteins in Cultured Rat Hepatocytes”The Biochemical Journal240 (3): 739–45. doi:10.1042/bj2400739PMC 1147481PMID 3493770.
  26. ^ Hurst, NP; French, JK; Gorjatschko, L; Betts, WH (1988). “Chloroquine and Hydroxychloroquine Inhibit Multiple Sites in Metabolic Pathways Leading to Neutrophil Superoxide Release”. The Journal of Rheumatology15 (1): 23–27. PMID 2832600.
  27. ^ Fox, R (1996). “Anti-malarial Drugs: Possible Mechanisms of Action in Autoimmune Disease and Prospects for Drug Development”. Lupus5: S4–10. doi:10.1177/096120339600500103PMID 8803903.
  28. ^ Waller; et al. Medical Pharmacology and Therapeutics (2nd ed.). p. 370.
  29. ^ Takeda, K; Kaisho, T; Akira, S (2003). “Toll-Like Receptors”. Annual Review of Immunology21: 335–76. doi:10.1146/annurev.immunol.21.120601.141126PMID 12524386.
  30. ^ “Hydroxychloroquine trade names”Drugs-About.com. Retrieved 18 June 2019.
  31. ^ “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia”China Law Translate. 3 March 2020. Retrieved 18 March 2020.
  32. ^ “Physicians work out treatment guidelines for coronavirus”Korea Biomedical Review. 13 February 2020. Retrieved 18 March2020.
  33. ^ Yao, Xueting; Ye, Fei; Zhang, Miao; Cui, Cheng; Huang, Baoying; Niu, Peihua; Liu, Xu; Zhao, Li; Dong, Erdan; Song, Chunli; Zhan, Siyan (9 March 2020). “In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)”. Clinical Infectious Diseasesdoi:10.1093/cid/ciaa237ISSN 1537-6591PMID 32150618.
  34. ^ “Azioni intraprese per favorire la ricerca e l’accesso ai nuovi farmaci per il trattamento del COVID-19”Italian Medicines Agency (AIFA) (in Italian). 17 March 2020. Retrieved 18 March2020.

External links

 

Hydroxychloroquine
Hydroxychloroquine.svg
Hydroxychloroquine.png

Hydroxychloroquine freebase molecule
Clinical data
Trade names Plaquenil, others
Other names Hydroxychloroquine sulfate
AHFS/Drugs.com Monograph
MedlinePlus a601240
License data
Pregnancy
category
  • AU: D [1]
  • US: N (Not classified yet) [1]
Routes of
administration
By mouth (tablets)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability Variable (74% on average); Tmax = 2–4.5 hours
Protein binding 45%
Metabolism Liver
Elimination half-life 32–50 days
Excretion Mostly Kidney (23–25% as unchanged drug), also biliary (<10%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.003.864 Edit this at Wikidata
Chemical and physical data
Formula C18H26ClN3O
Molar mass 335.872 g/mol g·mol−1
3D model (JSmol)

 

///////////Hydroxychloroquine, Hydroxy chloroquine, HCQ, ヒドロキシクロロキン , covid 19, coronavirus, antimalarial, гидроксихлорохинهيدروكسيكلوروكين羟氯喹Oxychlorochin, Plaquenil Plaquenil®, 

Arbidol, Umifenovir,


Arbidol.svg

ChemSpider 2D Image | Umifenovir | C22H25BrN2O3S

Umifenovir

  • Molecular FormulaC22H25BrN2O3S
  • Average mass477.414 Da
Арбидол [Russian]
阿比朵尔 [Chinese]
131707-25-0 [RN]
1H-Indole-3-carboxylic acid, 6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl-2-[(phenylthio)methyl]-, ethyl ester
9271
Arbidol
Ethyl 6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl-2-[(phenylsulfanyl)methyl]-1H-indole-3-carboxylate

Umifenovir[2] (trade names Arbidol RussianАрбидолChinese阿比朵尔) is an antiviral treatment for influenza infection used in Russia[3] and China. The drug is manufactured by Pharmstandard (RussianФармстандарт). Although some Russian studies have shown it to be effective, it is not approved for use in other countries. It is not approved by FDA for the treatment or prevention of influenza.[4] Chemically, umifenovir features an indole core, functionalized at all but one positions with different substituents. The drug is claimed to inhibit viral entry into target cells and stimulate the immune response. Interest in the drug has been renewed as a result of the SARS-CoV-2 outbreak.

Umifenovir is manufactured and made available as tabletscapsules and syrup.

Image result for Arbidol

Arbidol Hydrochloride

  • Molecular FormulaC22H28BrClN2O4S
  • Average mass531.891 Da
  • 868364-57-2 [RN]

Status

Testing of umifenovir’s efficacy has mainly occurred in China and Russia,[5][6] and it is well known in these two countries.[7] Some of the Russian tests showed the drug to be effective[5] and a direct comparison with Tamiflu showed similar efficiency in vitro and in a clinical setting.[8] In 2007, Arbidol (umifenovir) had the highest sales in Russia among all over-the-counter drugs.

Mode of action

Biochemistry

Umifenovir inhibits membrane fusion.[3] Umifenovir prevents contact between the virus and target host cells. Fusion between the viral envelope (surrounding the viral capsid) and the cell membrane of the target cell is inhibited. This prevents viral entry to the target cell, and therefore protects it from infection.[9]

Some evidence suggests that the drug’s actions are more effective at preventing infections from RNA viruses than infections from DNA viruses.[10]

As well as specific antiviral action against both influenza A and influenza B viruses, umifenovir exhibits modulatory effects on the immune system. The drug stimulates a humoral immune response, induces interferon-production, and stimulates the phagocytic function of macrophages.[11]

Clinical application

Umifenovir is used primarily as an antiviral treatments for influenza. The drug has also been investigated as a candidate drug for treatment of hepatitis C.[12]

More recent studies indicate that umifenovir also has in vitro effectiveness at preventing entry of Ebolavirus Zaïre Kikwit, Tacaribe arenavirus and human herpes virus 8 in mammalian cell cultures, while confirming umifenovir’s suppressive effect in vitro on Hepatitis B and poliovirus infection of mammalian cells when introduced either in advance of viral infection or during infection.[13][14]

Research

In February 2020, Li Lanjuan, an expert of the National Health Commission of China, proposed using Arbidol (umifenovir) together with darunavir as a potential treatment during the 2019–20 coronavirus pandemic.[15] Chinese experts claim that preliminary tests had shown that arbidol and darunavir could inhibit replication of the virus.[16][17] So far without additional effect if added on top of recombinant human interferon α2b spray.[18]

Side effects

Side effects in children include sensitization to the drug. No known overdose cases have been reported and allergic reactions are limited to people with hypersensitivity. The LD50 is more than 4 g/kg.[19]

Criticism

In 2007, the Russian Academy of Medical Sciences stated that the effects of Arbidol (umifenovir) are not scientifically proven.[20]

Russian media criticized lobbying attempts by Tatyana Golikova (then-Minister of Healthcare) to promote umifenovir,[21] and the unproven claim that Arbidol can speed up recovery from flu or cold by 1.3-2.3 days.[22] They also debunked claims that the efficacy of umifenovir is supported by peer-reviewed studies.[23][24]

 

Clip

https://www.sciencedirect.com/science/article/pii/S0960894X1730687X

Image result for Arbidol

 

CLIP

1,2-Dimethyl-5-hydroxyindole-3-acetic acid ethyl ester (I) is acetylated with acetic anhydride affording the O-acyl derivative (II) , which is brominated to the corresponding dibromide compound (III) . The reaction of (III) with thiophenol in KOH yields (IV) , which is then submitted to a conventional Mannich condensation with formaldehyde and dimethylamine in acetic acid, giving the free base of arbidol (V), which is treated with aqueous hydrochloric acid .

Image result for Arbidol

References

  1. ^ “Full Prescribing Information: Arbidol® (umifenovir) film-coated tablets 50 and 100 mg: Corrections and Additions”State Register of Medicines (in Russian). Open joint-stock company “Pharmstandard-Tomskchempharm”. Retrieved 3 June 2015.
  2. ^ Recommended INN: List 65., WHO Drug Information, Vol. 25, No. 1, 2011, page 91
  3. Jump up to:a b Leneva IA, Russell RJ, Boriskin YS, Hay AJ (February 2009). “Characteristics of arbidol-resistant mutants of influenza virus: implications for the mechanism of anti-influenza action of arbidol”. Antiviral Research81 (2): 132–40. doi:10.1016/j.antiviral.2008.10.009PMID 19028526.
  4. ^ “FDA Approved Drugs for Influenza”U.S. Food and Drug Administration.
  5. Jump up to:a b Leneva IA, Fediakina IT, Gus’kova TA, Glushkov RG (2005). “[Sensitivity of various influenza virus strains to arbidol. Influence of arbidol combination with different antiviral drugs on reproduction of influenza virus A]”Terapevticheskii Arkhiv (Russian translation). ИЗДАТЕЛЬСТВО “МЕДИЦИНА”. 77 (8): 84–8. PMID 16206613.
  6. ^ Wang MZ, Cai BQ, Li LY, Lin JT, Su N, Yu HX, Gao H, Zhao JZ, Liu L (June 2004). “[Efficacy and safety of arbidol in treatment of naturally acquired influenza]”. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae26 (3): 289–93. PMID 15266832.
  7. ^ Boriskin YS, Leneva IA, Pécheur EI, Polyak SJ (2008). “Arbidol: a broad-spectrum antiviral compound that blocks viral fusion”. Current Medicinal Chemistry15 (10): 997–1005. doi:10.2174/092986708784049658PMID 18393857.
  8. ^ Leneva IA, Burtseva EI, Yatsyshina SB, Fedyakina IT, Kirillova ES, Selkova EP, Osipova E, Maleev VV (February 2016). “Virus susceptibility and clinical effectiveness of anti-influenza drugs during the 2010-2011 influenza season in Russia”. International Journal of Infectious Diseases43: 77–84. doi:10.1016/j.ijid.2016.01.001PMID 26775570.
  9. ^ Boriskin YS, Pécheur EI, Polyak SJ (July 2006). “Arbidol: a broad-spectrum antiviral that inhibits acute and chronic HCV infection”Virology Journal3: 56. doi:10.1186/1743-422X-3-56PMC 1559594PMID 16854226.
  10. ^ Shi L, Xiong H, He J, Deng H, Li Q, Zhong Q, Hou W, Cheng L, Xiao H, Yang Z (2007). “Antiviral activity of arbidol against influenza A virus, respiratory syncytial virus, rhinovirus, coxsackie virus and adenovirus in vitro and in vivo”. Archives of Virology152 (8): 1447–55. doi:10.1007/s00705-007-0974-5PMID 17497238.
  11. ^ Glushkov RG, Gus’kova TA, Krylova LIu, Nikolaeva IS (1999). “[Mechanisms of arbidole’s immunomodulating action]”. Vestnik Rossiiskoi Akademii Meditsinskikh Nauk (in Russian) (3): 36–40. PMID 10222830.
  12. ^ Pécheur EI, Lavillette D, Alcaras F, Molle J, Boriskin YS, Roberts M, Cosset FL, Polyak SJ (May 2007). “Biochemical mechanism of hepatitis C virus inhibition by the broad-spectrum antiviral arbidol”Biochemistry46 (20): 6050–9. doi:10.1021/bi700181jPMC 2532706PMID 17455911.
  13. ^ Pécheur EI, Borisevich V, Halfmann P, Morrey JD, Smee DF, Prichard M, Mire CE, Kawaoka Y, Geisbert TW, Polyak SJ (January 2016). “The Synthetic Antiviral Drug Arbidol Inhibits Globally Prevalent Pathogenic Viruses”Journal of Virology90 (6): 3086–92. doi:10.1128/JVI.02077-15PMC 4810626PMID 26739045.
  14. ^ Hulseberg CE, Fénéant L, Szymańska-de Wijs KM, Kessler NP, Nelson EA, Shoemaker CJ, Schmaljohn CS, Polyak SJ, White JM. Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses. J Virol. 2019 Apr 3;93(8). pii: e02185-18. doi:10.1128/JVI.02185-18 PMID 30700611
  15. ^ Ng E (4 February 2020). “Coronavirus: are cocktail therapies for flu and HIV the magic cure?”South China Morning PostBangkok and Hangzhou hospitals put combination remedies to the test.
  16. ^ Zheng W, Lau M (4 February 2020). “China’s health officials say priority is to stop mild coronavirus cases from getting worse”South China Morning Post.
  17. ^ Lu H (January 2020). “Drug treatment options for the 2019-new coronavirus (2019-nCoV)”. Bioscience Trendsdoi:10.5582/bst.2020.01020PMID 31996494.
  18. ^ “Efficacies of lopinavir/ritonavir and abidol in the treatment of novel coronavirus pneumonia”. 4 February 2020. Retrieved 24 February 2020.
  19. ^ “АРБИДОЛ® (ARBIDOL)”Vidal. Archived from the originalon 4 February 2009.
  20. ^ “Resolution”Meetings of the Presidium of the Formulary Committee. Russian Academy of Medical Sciences. 16 March 2007.
  21. ^ “How do we plant federal ministers”MKRU. 21 April 2011.
  22. ^ Golunov I (23 December 2013). “13 most popular flu cures: do they work?”Professional Journalism Platform.
  23. ^ Reuters S. “Stick in the wheel”Esquire.
  24. ^ “Repetition – the mother of learning”Esquire.

External links

Umifenovir
Arbidol.svg
Umifenovir ball-and-stick model.png
Clinical data
Trade names Arbidol
Pregnancy
category
  • C
Routes of
administration
Oral (hard capsulestablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 40%
Metabolism Hepatic
Elimination half-life 17–21 hours
Excretion 40% excrete as unchanged umifenovir in feces (38.9%) and urine (0.12%)[1]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.247.800 Edit this at Wikidata
Chemical and physical data
Formula C22H25BrN2O3S
Molar mass 477.41 g/mol g·mol−1
3D model (JSmol)

Umifenovir is an indole-based, hydrophobic, dual-acting direct antiviral/host-targeting agent used for the treatment and prophylaxis of influenza and other respiratory infections.13 It has been in use in Russia for approximately 25 years and in China since 2006. Its invention is credited to a collaboration between Russian scientists from several research institutes 40-50 years ago, and reports of its chemical synthesis date back to 1993.13 Umifenovir’s ability to exert antiviral effects through multiple pathways has resulted in considerable investigation into its use for a variety of enveloped and non-enveloped RNA and DNA viruses, including Flavivirus,2 Zika virus,3 foot-and-mouth disease,4 Lassa virus,6 Ebola virus,6 herpes simplex,8, hepatitis B and C viruses, chikungunya virus, reovirus, Hantaan virus, and coxsackie virus B5.13,9 This dual activity may also confer additional protection against viral resistance, as the development of resistance to umifenovir does not appear to be significant.13

Umifenovir is currently being investigated as a potential treatment and prophylactic agent for COVID-19 caused by SARS-CoV2 infections in combination with both currently available and investigational HIV therapies.1,16,17

 

Indication

Umifenovir is currently licensed in China and Russia for the prophylaxis and treatment of influenza and other respiratory viral infections.13 It has demonstrated activity against a number of viruses and has been investigated in the treatment of Flavivirus,2 Zika virus,3 foot-and-mouth disease,4 Lassa virus,6 Ebola virus,6 and herpes simplex.8 In addition, it has shown in vitro activity against hepatitis B and C viruses, chikungunya virus, reovirus, Hantaan virus, and coxsackie virus B5.13,9

Umifenovir is currently being investigated as a potential treatment and prophylactic agent for the prevention of COVID-19 caused by SARS-CoV-2 infections.1,16

Pharmacodynamics

Umifenovir exerts its antiviral effects via both direct-acting virucidal activity and by inhibiting one (or several) stage(s) of the viral life cycle.13 Its broad-spectrum of activity covers both enveloped and non-enveloped RNA and DNA viruses. It is relatively well-tolerated and possesses a large therapeutic window – weight-based doses up to 100-fold greater than those used in humans failed to produce any pathological changes in test animals.13

Umifenovir does not appear to result in significant viral resistance. Instances of umifenovir-resistant influenza virus demonstrated a single mutation in the HA2 subunit of influenza hemagglutinin, suggesting resistance is conferred by prevention of umifenovir’s activity related to membrane fusion. The mechanism through which other viruses may become resistant to umifenovir requires further study.13

Mechanism of action

Umifenovir is considered both a direct-acting antiviral (DAA) due to direct virucidal effects and a host-targeting agent (HTA) due to effects on one or multiple stages of viral life cycle (e.g. attachment, internalization), and its broad-spectrum antiviral activity is thought to be due to this dual activity.13 It is a hydrophobic molecule capable of forming aromatic stacking interactions with certain amino acid residues (e.g. tyrosine, tryptophan), which contributes to its ability to directly act against viruses. Antiviral activity may also be due to interactions with aromatic residues within the viral glycoproteins involved in fusion and cellular recognition,5,7 with the plasma membrane to interfere with clathrin-mediated exocytosis and intracellular trafficking,10 or directly with the viral lipid envelope itself (in enveloped viruses).13,12 Interactions at the plasma membrane may also serve to stabilize it and prevent viral entry (e.g. stabilizing influenza hemagglutinin inhibits the fusion step necessary for viral entry).13

Due to umifenovir’s ability to interact with both viral proteins and lipids, it may also interfere with later stages of the viral life cycle. Some virus families, such as Flaviviridae, replicate in a subcellular compartment called the membranous web – this web requires lipid-protein interactions that may be hindered by umifenovir. Similarly, viral assembly of hepatitis C viruses is contingent upon the assembly of lipoproteins, presenting another potential target.13

Absorption

Umifenovir is rapidly absorbed following oral administration, with an estimated Tmax between 0.65-1.8 hours.14,15,13 The Cmax has been estimated as 415 – 467 ng/mL and appears to increase linearly with dose,14,15 and the AUC0-inf following oral administration has been estimated to be approximately 2200 ng/mL/h.14,15

Volume of distribution

Data regarding the volume of distribution of umifenovir are currently unavailable.

Protein binding

Data regarding protein-binding of umifenovir are currently unavailable.

Metabolism

Umifenovir is highly metabolized in the body, primarily in hepatic and intestinal microsomess, with approximately 33 metabolites having been observed in human plasma, urine, and feces.14 The principal phase I metabolic pathways include sulfoxidation, N-demethylation, and hydroxylation, followed by phase II sulfate and glucuronide conjugation. In the urine, the major metabolites were sulfate and glucuronide conjugates, while the major species in the feces was unchanged parent drug (~40%) and the M10 metabolite (~3.0%). In the plasma, the principal metabolites are M6-1, M5, and M8 – of these, M6-1 appears of most importance given its high plasma exposure and long elimination half-life (~25h), making it a potentially important player in the safety and efficacy of umifenovir.14

Enzymes involved in the metabolism of umifenovir include members of the cytochrome P450 family (primarily CYP3A4), flavin-containing monooxygenase (FMO) family, and UDP-glucuronosyltransferase (UGT) family (specifically UGT1A9 and UGT2B7).14,11

  1. Lu H: Drug treatment options for the 2019-new coronavirus (2019-nCoV). Biosci Trends. 2020 Jan 28. doi: 10.5582/bst.2020.01020. [PubMed:31996494]
  2. Haviernik J, Stefanik M, Fojtikova M, Kali S, Tordo N, Rudolf I, Hubalek Z, Eyer L, Ruzek D: Arbidol (Umifenovir): A Broad-Spectrum Antiviral Drug That Inhibits Medically Important Arthropod-Borne Flaviviruses. Viruses. 2018 Apr 10;10(4). pii: v10040184. doi: 10.3390/v10040184. [PubMed:29642580]
  3. Fink SL, Vojtech L, Wagoner J, Slivinski NSJ, Jackson KJ, Wang R, Khadka S, Luthra P, Basler CF, Polyak SJ: The Antiviral Drug Arbidol Inhibits Zika Virus. Sci Rep. 2018 Jun 12;8(1):8989. doi: 10.1038/s41598-018-27224-4. [PubMed:29895962]
  4. Herod MR, Adeyemi OO, Ward J, Bentley K, Harris M, Stonehouse NJ, Polyak SJ: The broad-spectrum antiviral drug arbidol inhibits foot-and-mouth disease virus genome replication. J Gen Virol. 2019 Sep;100(9):1293-1302. doi: 10.1099/jgv.0.001283. Epub 2019 Jun 4. [PubMed:31162013]
  5. Kadam RU, Wilson IA: Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol. Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):206-214. doi: 10.1073/pnas.1617020114. Epub 2016 Dec 21. [PubMed:28003465]
  6. Hulseberg CE, Feneant L, Szymanska-de Wijs KM, Kessler NP, Nelson EA, Shoemaker CJ, Schmaljohn CS, Polyak SJ, White JM: Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses. J Virol. 2019 Apr 3;93(8). pii: JVI.02185-18. doi: 10.1128/JVI.02185-18. Print 2019 Apr 15. [PubMed:30700611]
  7. Zeng LY, Yang J, Liu S: Investigational hemagglutinin-targeted influenza virus inhibitors. Expert Opin Investig Drugs. 2017 Jan;26(1):63-73. doi: 10.1080/13543784.2017.1269170. Epub 2016 Dec 14. [PubMed:27918208]
  8. Li MK, Liu YY, Wei F, Shen MX, Zhong Y, Li S, Chen LJ, Ma N, Liu BY, Mao YD, Li N, Hou W, Xiong HR, Yang ZQ: Antiviral activity of arbidol hydrochloride against herpes simplex virus I in vitro and in vivo. Int J Antimicrob Agents. 2018 Jan;51(1):98-106. doi: 10.1016/j.ijantimicag.2017.09.001. Epub 2017 Sep 7. [PubMed:28890393]
  9. Pecheur EI, Borisevich V, Halfmann P, Morrey JD, Smee DF, Prichard M, Mire CE, Kawaoka Y, Geisbert TW, Polyak SJ: The Synthetic Antiviral Drug Arbidol Inhibits Globally Prevalent Pathogenic Viruses. J Virol. 2016 Jan 6;90(6):3086-92. doi: 10.1128/JVI.02077-15. [PubMed:26739045]
  10. Blaising J, Levy PL, Polyak SJ, Stanifer M, Boulant S, Pecheur EI: Arbidol inhibits viral entry by interfering with clathrin-dependent trafficking. Antiviral Res. 2013 Oct;100(1):215-9. doi: 10.1016/j.antiviral.2013.08.008. Epub 2013 Aug 25. [PubMed:23981392]
  11. Song JH, Fang ZZ, Zhu LL, Cao YF, Hu CM, Ge GB, Zhao DW: Glucuronidation of the broad-spectrum antiviral drug arbidol by UGT isoforms. J Pharm Pharmacol. 2013 Apr;65(4):521-7. doi: 10.1111/jphp.12014. Epub 2012 Dec 24. [PubMed:23488780]
  12. Teissier E, Zandomeneghi G, Loquet A, Lavillette D, Lavergne JP, Montserret R, Cosset FL, Bockmann A, Meier BH, Penin F, Pecheur EI: Mechanism of inhibition of enveloped virus membrane fusion by the antiviral drug arbidol. PLoS One. 2011 Jan 25;6(1):e15874. doi: 10.1371/journal.pone.0015874. [PubMed:21283579]
  13. Blaising J, Polyak SJ, Pecheur EI: Arbidol as a broad-spectrum antiviral: an update. Antiviral Res. 2014 Jul;107:84-94. doi: 10.1016/j.antiviral.2014.04.006. Epub 2014 Apr 24. [PubMed:24769245]
  14. Deng P, Zhong D, Yu K, Zhang Y, Wang T, Chen X: Pharmacokinetics, metabolism, and excretion of the antiviral drug arbidol in humans. Antimicrob Agents Chemother. 2013 Apr;57(4):1743-55. doi: 10.1128/AAC.02282-12. Epub 2013 Jan 28. [PubMed:23357765]
  15. Liu MY, Wang S, Yao WF, Wu HZ, Meng SN, Wei MJ: Pharmacokinetic properties and bioequivalence of two formulations of arbidol: an open-label, single-dose, randomized-sequence, two-period crossover study in healthy Chinese male volunteers. Clin Ther. 2009 Apr;31(4):784-92. doi: 10.1016/j.clinthera.2009.04.016. [PubMed:19446151]
  16. Wang Z, Chen X, Lu Y, Chen F, Zhang W: Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment. Biosci Trends. 2020 Feb 9. doi: 10.5582/bst.2020.01030. [PubMed:32037389]
  17. Nature Biotechnology: Coronavirus puts drug repurposing on the fast track [Link]

 

/////////////////Arbidol, umifenovir, covid 19, corona virus, Арбидол阿比朵尔 

CCOC(=O)C1=C(CSC2=CC=CC=C2)N(C)C2=CC(Br)=C(O)C(CN(C)C)=C12

 

Image result for ARBIDOL DRUG FUTURE

https://eurekalert.org/pub_releases/2020-02/nuos-edm022620.php

LANRAPRENIB


Lanraplenib Chemical Structure

2D chemical structure of 1800046-95-0

LANRAPLENIB

GS-9876

Phase II, GILEAD

Phase II Gilead Cutaneous lupus erythematosus

Rheumatoid arthritis

Sjogren syndrome

GS-9876
 LANRAPLENIB

Imidazo(1,2-a)pyrazin-8-amine, 6-(6-amino-2-pyrazinyl)-N-(4-(4-(3-oxetanyl)-1-piperazinyl)phenyl)-

6-(6-Aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo|1,2-a]pyrazin-8-amine

6-(6-Amino-2-pyrazinyl)-N-(4-(4-(3-oxetanyl)-1-piperazinyl)phenyl)imidazo(1,2-a)pyrazin-8-amine

Molecular Weight

443.50

Formula

C₂₃H₂₅N₉O

CAS No.

1800046-95-0

Lanraplenib (GS-9876) is a highly selective and orally active SYK inhibitor (IC50=9.5 nM) in development for the treatment of inflammatory diseases. Lanraplenib (GS-9876) inhibits SYK activity in platelets via the glycoprotein VI (GPVI) receptor without prolonging bleeding time (BT) in monkeys or humans.

Description

Lanraplenib (GS-9876) is a highly selective and orally active SYK inhibitor (IC50=9.5 nM) in development for the treatment of inflammatory diseases. Lanraplenib (GS-9876) inhibits SYK activity in platelets via the glycoprotein VI (GPVI) receptor without prolonging bleeding time (BT) in monkeys or humans[1][2][3].

IC50 & Target

IC50: 9.5 nM (SYK)[1]

In Vitro

Lanraplenib (GS-9876) inhibits anti-IgM stimulated phosphorylation of AKT, BLNK, BTK, ERK, MEK, and PKCδ in human B cells with EC50 values of 24-51 nM. Lanraplenib (GS-9876) inhibits anti-IgM mediated CD69 and CD86 expression on B-cells (EC50=112±10 nM and 164±15 nM, respectively) and anti-IgM /anti-CD40 co-stimulated B cell proliferation (EC50=108±55 nM). In human macrophages, Lanraplenib (GS-9876) inhibits IC-stimulated TNFα and IL-1β release (EC50=121±77 nM and 9±17 nM, respectively)[1].
Lanraplenib (GS-9876) inhibits glycoprotein VI (GPVI)-induced phosphorylation of linker for activation of T cells and phospholipase Cγ2, platelet activation and aggregation in human whole blood, and platelet binding to collagen under arterial flow[2].

Lanraplenib succinate.png

Lanraplenib succinate

1800047-00-0

UNII-QJ2PS903VZ

QJ2PS903VZ

GS-SYK Succinate

1241.3 g/mol, C58H68N18O14

6-(6-aminopyrazin-2-yl)-N-[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]imidazo[1,2-a]pyrazin-8-amine;butanedioic acid

PAPER

https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00621

https://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.9b00621/suppl_file/ml9b00621_si_001.pdf

Abstract Image

Spleen tyrosine kinase (SYK) is a critical regulator of signaling in a variety of immune cell types such as B-cells, monocytes, and macrophages. Accordingly, there have been numerous efforts to identify compounds that selectively inhibit SYK as a means to treat autoimmune and inflammatory diseases. We previously disclosed GS-9973 (entospletinib) as a selective SYK inhibitor that is under clinical evaluation in hematological malignancies. However, a BID dosing regimen and drug interaction with proton pump inhibitors (PPI) prevented development of entospletinib in inflammatory diseases. Herein, we report the discovery of a second-generation SYK inhibitor, GS9876 (lanraplenib), which has human pharmacokinetic properties suitable for once-daily administration and is devoid of any interactions with PPI. Lanraplenib is currently under clinical evaluation in multiple autoimmune indications.

Step 6. 6-(6-Aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo|1,2-a]pyrazin-8-amine (39). To a solution of tert-butyl(6-(6-(bis(tert-butoxycarbonyl)amino)pyrazm-2-yl)imidazo[1,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin1yl)phenyl)carbamate 45 (200 mg, 0.269 mmol) in DCM (2 ml) was added TFA (0.5 ml, 6.578 mmol). The reaction was stirred at room temperature for 16h, treated with saturated sodium bicarbonate, extracted with EtOAc, and purified on silica gel, eluting with 5%MeOH / EtOAc to 20%MeOH / EtOAc. The desired fractions were combined and concentrated to provide 100 mg (83% yield) of the title compound 39. m/z calcd for C23H25N9O [M+H] + 444.23, found LCMS-ESI+ (m/z): [M+H] + 444.20. 1H NMR (300 MHz d6-DMSO) δ: 9.5 (s,lH), 8.588 (s, 1H), 8.47 (s, 1H), 8.12 (d, 1H), 7.95-7.92 (d5 2H), 7.88 (s, 1H), 7.62 (s, 1H), 6.99-6.96 (d, 2H), 6.46 (s, 2H), 4.57- 4.53 (m, 2H), 4.48-4.44 (m, 2H), 3.43 (m, 1H), 3.15-3.12 (m, 4H), 2.41- 2.38 (m, 4H).

MORE SYNTHESIS COMING, WATCH THIS SPACE…………………..

 

SYNTHESIS

PATENT

WO 2015100217

WO 2016010809

PATENT

WO 2016172117

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016172117

Protein kinases, the largest family of human enzymes, encompass well over 500 human proteins. Spleen Tyrosine Kinase (Syk) is a member of the Syk family of tyrosine kinases, and is a regulator of early B-cell development as well as mature B-cell activation, signaling, and survival.

Acute Graft Versus Host Disease (aGVHD), also known as fulminant Graft Versus Host Disease, generally presents symptoms within the first 100 days following allogenic hematopoietic stem cell transplantation and is generally characterized by selective damage to the skin, liver, mucosa, and gastrointestinal tract. Chronic Graft Versus Host Disease (cGVHD) occurs in recipients of allogeneic hematopoietic stem cell transplant (HSCT). GVHD is considered chronic when it occurs >100 days post-transplant, though aspects of cGVHD may manifest themselves prior to the 100 day point and overlap with elements of aGVHD. The disease has a cumulative incidence of 35-70% of transplanted patients, and has an annual incidence of approximately 3,000-5,000 and a prevalence of approximately 10,000 in the US. cGVHD is difficult to treat and is associated with worse outcomes compared to those without cGVHD. Current standard of care includes a variety of approaches including systemic corticosteroids often combined with calcineurin inhibitors, mTOR inhibitors, mycophenylate mofetil, or rituximab. Despite treatment, response rates are poor (40-50%) and cGVHD is associated with significant morbidity such as serious infection and impaired quality of life; the 5-year mortality is 30-50% (Blazar et al., Nature Reviews Immunology 12, 443-458, June 2012).

Human and animal models have demonstrated that aberrant B-lymphocyte signaling and survival is important in the pathogenesis of cGVHD. B-cell targeted drugs, including SYK inhibitors (fostamatinib – Sarantopoulos et al, Biology of Blood and Marrow Transplantation, 21(2015) S 11 -S 18) and BTK inhibitors (ibrutinib – Nakasone et al, Int. J. HematoL- 27 March 2015), have been shown to selectively reduce the function and frequency of aberrant GVHD B-cell populations ex vivo.

There remains a need for new methods, pharmaceutical compositions, and regimens for the treatment of GVHD, including aGVHD and cGVHD.

Example 2. Preparation of 6-(6-aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)imid azo [ 1,2-a] pyrazin-8-amine (2)

2-Bis(tert-butoxycarbonyl)amino-6-bromopyrazine XIV: To a mixture of 6-bromopyrazin-2-amine (5 g, 28.7 mmol) and di-tert-butyl dicarbonate (25.09 g, 1 14.94 mmol) was added DCM (10 ml) followed by DMAP (0.351 g, 29 mmol). The reaction was heated to 55 °C for lh, cooled to RT, the reaction was partitioned between water and DCM, purified on silica gel and concentrated to provide of 2-bis(tert-butoxycarbonyl)amino-6-bromopyrazine XIV. LCMS-ESI+ (m/z): [M+H]+: 374.14. XH NMR (DMSO) δ: 8.84(d, 2H), 1.39 (s, 18H).

tert-Butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[l,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)carbamate XVI – CHEMISTRY A route: tert-Butyl 4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl(6-(tributylstannyl)imidazo[l,2-a]pyrazin-8-yl)carbamate V (215 mg, 0.291 mmol), was combined with 2-bis(tert-butoxycarbonyl)amino-6-bromopyrazine XIV (217.58 mg, 0.581 mmol),

bis(triphenylphosphine)palladium(II) dichloride(30.61 mg, 0.044 mmol) and 1,4-dioxane (5ml). The reaction mixture was stirred in a microwave reactor at 120 °C for 30 min. The reaction mixture was quenched with saturated KF, extracted with EtOAc, purified on silica gel, eluted with EtOAc. The desired fractions were combined and concentrated to provide 100 mg (46% yield) of tert-butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[l,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)carbamate XVI. LCMS-ESI+ (m/z): [M+H]+: 744.4. lH NMR (300 MHz d6-DMSO) δ: 9.37 (s, 1H), 9.18 (s, 1H), 8.77 (s, 1H), 8.33 (d, 1H), 7.87 (d, 1H), 7.28-7.25 (d, 2H), 6.92-6.89 (d, 2H), 4.55-4.41 (m, 4H), 3.4 (m, lH), 3.14-3. 11 (m,4H), 2,37-2.34 (m, 4H), 1.37 (s, 18H), 1.3 (s, 9H).

tert-Butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[l,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)carbamate XVI – CHEMISTRY B route: Step 1 : To a dry 250 mL round-bottomed flask was added 2-bis(tert-butoxycarbonyl)amino-6-bromopyrazine XIV (l .Og, l .Oequiv, 2.67mmol), KOAc (790mg, 8.02mmol, 3.0equiv), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(l ,3,2-dioxaborolane) (750mg, 2.94mmol, l . l equiv), Pd(dba) (171mg, 0.187mmol, 0.07equiv) and X-phos (128mg, 0.267mmol, O. lequiv) followed by 1,4-dioxane (25mL) and the solution was sonicated for 5 min and then purged with N2 gas for 5 min. The flask with contents was then placed under N2 atmosphere and heated at 1 10 °C for 90 min. Once full conversion to the pinacolboronate was achieved by LCMS, the reaction was removed from heat and allowed to cool to RT. Once cool, the reaction contents were filtered through Celite and the filter cake was washed 3 x 20 mL EtOAc. The resultant solution was then concentrated down to a deep red-orange

syrup providing N, N-BisBoc 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazin-2-amine XV, which was used directly in the next step.

Step 2: The freshly formed N, N-BisBoc 6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrazin-2-amine XV (2.67 mmol based on 100% conversion, 2.0 equiv based on bromide) was dissolved in 20 Ml of 1,2-dimethoxy ethane and to that solution was added tert-butyl (6-bromoimidazo[l,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)carbamate IV (707mg, 1.34mmol, l .Oequiv), Na2CC>3 (283mg, 2.67mmol, 2.0equiv), Pd(PPh3)4 (155mg, 0.134mmol, 0.1 equiv) and water (l OmL) and the solution was degassed for 5 min using N2 gas. The reaction was then placed under N2 atmosphere and heated at 110 °C for 90 min. LCMS showed complete consumption of the bromide starting material and the reaction was removed from heat and allowed to cool to RT. The reaction was diluted with 100 mL water and 100 mL 20% MeOH/DCM and the organic layer was recovered, extracted 1 x sat. NaHCCb, 1 x sat brine and then dried over Na2SC>4. The solution was then filtered and concentrated down to an orange-red solid. The sample was then slurried in warm MeOH, sonicated then filtered, washing 2 x 20 mL with cold MeOH and then the cream-colored solid was dried on hi-vacuum overnight to yield 905 mg of tert-butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[l,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin- 1 -yl)phenyl)carbamate XVI.

6-(6-Aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)imidazo[l,2-a]pyrazin-8-amine (2): To a solution of tert-butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[l,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-l -yl)phenyl)carbamate XVI (200 mg, 0.269 mmol) in DCM (2 ml) was added TFA (0.5 ml, 6.578 mmol). The reaction was stirred at rt for 16h, saturated sodium bicarbonate was added, extracted with EtOAC and purified on silica gel, eluted with 5%MeOH / EtOAc, 20%MeOH / EtOAc. The desired fractions were combined and concentrated to provide the title compound 2. LCMS-ESI+(m/z): [M+H]+: 444.2. lH NMR (300 MHz d6-DMSO) δ: 9.5 (s, lH), 8.588 (s, IH), 8.47 (s, IH), 8. 12 (d, IH), 7.95-7.92 (d, 2H), 7.88 (s, IH), 7.62 (s, IH), 6.99-6.96 (d, 2H), 6.46 (s, 2H), 4.57-4.53 (m, 2H), 4.48-4.44 (m, 2H), 3.43 (m, IH), 3.15-3.12 (m, 4H), 2.41 -2.38 (m, 4H).

Example 2 – Alternate Synthesis

H2S04, water 

Di-feri-butyl {6-[8-({4-[4-(oxetan-3-yl)piperazin-l-yl]phenyl}amino)imidazo[l,2-fl]pyrazin-6-yl]pyrazin-2-yl}imidodicarbonate:

To a 720 L reactor, was added di-fer/-butyl (6-bromopyrazin-2-yl)imidodicarbonate (18.5 kg, 1.41 equiv, 49 mol), bis(pinacolato)diboron (13.8 kg, 1.56 equiv, 54 mol), potassium propionate (11.9 kg, 3.02 equiv, 106 mol), and bis(di-fer/-butyl(4-dimethylaminophenyl) phosphine)dichloropalladium (1.07 kg, 0.0043 equiv, 1.5 mol), followed by degassed toluene (173 L). The mixture was degassed then heated at 65 °C until the reaction was deemed complete (0% tert-butyl 2-((6-bromopyrazin-2-yl)(tert-butoxycarbonyl)amino)-2-oxoacetate) by UPLC. Upon completion, the reaction was cooled to 23 °C. Once cooled, 6-bromo-N-(4-(4-(oxetan-3-yl)piperazin-l -yl)phenyl)imidazo[l ,2-a]pyrazin-8-amine (15.0 kg, 1.00 equiv, 35 mol) was added and the mixture was degassed. A degassed aqueous potassium carbonate solution prepared using water (54 L) and potassium carbonate (20.6 g, 4.26 equiv, 149 mol) was then added to the reaction mixture and the reactor contents was degassed. The reactor contents was heated at 65 °C until reaction was deemed complete (1% 6-bromo-N-(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)imidazo[l,2-a]pyrazin-8-amine) by UPLC. Upon completion, the reaction was cooled to 24 °C.

The cooled mixture was concentrated and then diluted with dichloromethane (300 L), transferred to a 1900 L reactor and rinsed forward with dichloromethane (57 L). N-acetyl-L-cysteine (3.8 kg) was charged and the mixture was agitated for 15 h. Water (135 L) was then added and the mixture was filtered and rinsed forward with dichloromethane (68 L). The organic layer was recovered and washed with a brine solution prepared using water (68 L) and sodium chloride (7.5 kg).

The resultant organic layer was polish filtered then concentrated and fert-butyl methyl ether (89.9 kg) was slowly charged keeping the temperature at 31 °C. The contents was cooled to 0 °C and aged, then filtered and rinsed with tert-butyl methyl ether (32.7 kg) and dried at 40 °C to give 17.2 kg of di-tert-butyl {6-[8-({4-[4-(oxetan-3-yl)piperazin-l-yl]phenyl} amino)imidazo[l,2-a]pyrazin-6-yl]pyrazin-2-yl}imidodicarbonate.

LCMS-ESf (m/z): [M+H]+: 644.3. ΧΗ ΝΜΚ (400 MHz, CDC13) δ: 9.43 (s, 1H), 8.58 (s, 1H), 8.53 (s, 1H), 8.02 (s, 1H), 7.84 (m, 2H), 7.63 (d, 1H), 7.61 (d, 1H), 7.04 (m, 2H), 4.71 (m,4H), 3.59 (m, lH), 3.27 (m, 4H), 2.55 (m, 4H), 1.46 (s, 18H).

6-(6-Aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)imidazo[l,2-a]pyrazin-8-amine succinate (Example 2):

To a slurry of di-tert-butyl {6-[8-({4-[4-(oxetan-3-yl)piperazin-l -yl]phenyl} amino)imidazo[l,2-a]pyrazin-6-yl]pyrazin-2-yl}imidodicarbonate (225 g, 0.35 mol, 1 mol eq.) in water (12 parts) was added a solution of sulfuric acid (3.1 parts, 6.99 mol, 20 mol eq.) in water (5 parts). The reaction was heated to ca. 40 °C and stirred at this temperature for ca. 4 h at which point the reaction is deemed complete. The reaction mixture was cooled to ca. 22 °C, acetone (3 parts) was charged and a solution of sodium carbonate (4.1 parts, 8.75 mol, 25.0 mol eq.) in water (15 parts) was added. The resulting slurry was filtered and the wet cake was washed with water in portions (4 x 1 parts), then with fert-butyl methyl ether (4 parts). The wet cake (Example 2 free base) was dried at ca. 60 °C. To the slurry of dry Example 2 free base in 2-propanol (2.3 parts) was added a solution of succinic acid (Based on the isolated Example 2 free base: 0.43 parts, 1.6 mol eq.) in 2-propanol (15 parts). The resulting slurry was heated to ca. 40 °C and stirred at this temperature for ca. 2 h and then cooled to ca. 22 °C, followed by a stir period of ca. 16 h. The slurry was filtered at ca. 22 °C and the wet cake was washed with 2-propanol (5 parts) and dried at ca. 60 °C to afford the product.

LCMS-ESI+ (m/z): [M+H]+: 620.65. ¾ NMR (400 MHz d6-DMSO) δ: 12.2 (broad s, 1.5H), 9.58 (s, IH), 8.63 (s, IH), 8.50 (s, IH), 8.15 (s, IH), 7.95 (d, 2H), 7.90 (s, IH), 7.64 (s, IH), 7.00 (d, 2H), 6.50 (s, 2H), 4.52 (dd, 4H), 3.45 (m, IH), 3.19 (m, 4H), 2.40 (m, 10H).

REF

[1]. Di Paolo J, et al. FRI0049 Preclinical Characterization of GS-9876, A Novel, Oral SYK Inhibitor That Shows Efficacy in Multiple Established Rat Models of Collagen-Induced Arthritis.Annals of the Rheumatic Diseases 2016;75:443-444.

[2]. Clarke AS, et al. Effects of GS-9876, a novel spleen tyrosine kinase inhibitor, on platelet function and systemic hemostasis. Thromb Res. 2018 Oct;170:109-118.

[3]. Kivitz AJ, et al. GS-9876, a Novel, Highly Selective, SYK Inhibitor in Patients with Active Rheumatoid Arthritis: Safety, Tolerability and Efficacy Results of a Phase 2 Study [abstract]. Arthritis Rheumatol.2018; 70 (suppl 10).

/////////////LANRAPLENIB, GS-9876, SYK inhibitor

NC1=CN=CC(C2=CN3C(C(NC4=CC=C(N5CCN(C6COC6)CC5)C=C4)=N2)=NC=C3)=N1

TRANILAST


Tranilast.svg

ChemSpider 2D Image | Tranilast | C18H17NO5

Tranilast

  • Molecular FormulaC18H17NO5
  • Average mass327.331 Da
2-{[(2E)-3-(3,4-Dimethoxyphenyl)prop-2-enoyl]amino}benzoic acid
3,4-DAA
5070
53902-12-8 [RN]

Tranilast (INN, brand name Rizaben) is an antiallergic drug. It was developed by Kissei Pharmaceuticals and was approved in 1982 for use in Japan and South Korea for bronchial asthma. Indications for keloid and hypertrophic scar were added in the 1980s.

Kissei  has developed and launched tranilast in Japan and South Korea for the treatment of allergic rhinitis, asthma and atopic dermatitis. Kissei, in collaboration with  GlaxoSmithKline  was additionally developing tranilast for the prevention of restenosis following percutaneous transluminal coronary angioplasty.

Medical uses

It is used Japan, South Korea, and China to treat asthma, keloid scars, and hypertrophic scars, and as an ophthalmic solution for allergic pink eye.[1]

It should not be taken women who are or might become pregnant, and it is secreted in breast milk.[1]

Interactions

People who are taking warfarin should not also take tranilast, as they interact.[1] It appears to inhibit UGT1A1 so will interfere with metabolism of drugs that are affected by that enzyme.[1]

Adverse effects

When given systemically, tranilast appears to cause liver damage; in a large well-conducted clinical trial it caused elevated transaminases three times the upper limit of normal in 11 percent of patients, as well as anemia, kidney failure, rash, and problems urinating.[1]

Given systemically it inhibits blood formation, causing leukopeniathrombocytopenia, and anemia.[1]

Society and culture

As of March 2018 it was marketed in Japan, China, and South Korea under the brand names Ao Te Min, Arenist, Brecrus, Garesirol, Hustigen, Krix, Lumios, Rizaben, Tramelas, Tranilast and it was marketed as a combination drug with salbutamol under the brand name Shun Qi.[2]

In 2016 the FDA proposed that tranilast be excluded from the list of active pharmaceutical ingredients that compounding pharmacies in the US could formulate with a prescription.[1]

Pharmacology

It appears to work by inhibiting the release of histamine from mast cells; it has been found to inhibit proliferation of fibroblasts but its biological target is not known.[3] It has been shown to inhibit the release of many cytokines in various cell types, in in vitro studies.[3] It has also been shown to inhibit NALP3 inflammasome activation and is being studied as a treatment for NALP3-driven inflammatory diseases.[4]

Chemistry

Tranilast is an analog of a metabolite of tryptophan, and its chemical name is 3′,4′-dimethoxycinnamoyl) anthranilic acid (N-5′).[3]

It is almost insoluble in water, easily soluble in dimethylsulfoxide, soluble in dioxane, and very slightly soluble in ether. It is photochemically unstable in solution.[3]

File:Tranilast synthesis.svg

Orally active anti-allergic agent. Prepn: K. Harita et al., DE 2402398; idem, US 3940422 (1974, 1976 both to Kissei).

Y. Kamijo, M. Kobayashi, and A. Ajisawa, Jpn. Kokai, 77/83,428 (1977) via Chem. Abstr.,

88:6,569f (1978).

Research

After promising results in three small clinical trials, tranilast was studied in a major clinical trial (the PRESTO trial) by SmithKline Beecham in partnership with Kissei for prevention of restenosis after percutaneous transluminal coronary revascularization,[5] but was not found effective for that application.[1][6]

As of 2016, Altacor was developing a formulation of tranilast to prevent of scarring following glaucoma surgery and had obtained an orphan designation from the EMA for this use.[7][8]

History

It was developed by Kissei and first approved in Japan and South Korea for asthma in 1982, and approved uses for keloid and hypertrophic scars were added later in the 1980s.[3]

PATENT

tranilast product case US03940422 , expired in all the regional territories.

PATENT

WO2013144916 claiming tranilast complexes and cocrystals with nicotinamide, saccharin, gentisic acid, salicylic acid, urea, 4-aminobenzoic acid and 2,4-dihydroxybenzoic acid

Patent

WO-2020035546

Nuformix Ltd

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020035546&tab=PCTDESCRIPTION&_cid=P11-K75NGV-11408-1

Novel crystalline forms of tranilast or its salts as histamine H1 receptor antagonist useful for treating allergy, allergic rhinitis and atopic dermatitis.

Tranilast, (2-[[3-(3,4-dimethoxyphenyl)-l-oxo-2-propenyl]amino] benzoic acid, shown below), was originally developed as an anti-allergy drug due to its ability to inhibit the release of inflammatory mediators, such as histamine, from mast cells and basophils (P. Zampini. IntJ Immunopharmacol. 1983;

Tranilast

Tranilast has been marketed in Japan, China and South Korea by Kissei Pharmaceutical Co. Ltd, for allergic conditions such as allergic conjunctivitis, bronchial asthma, allergic rhinitis and atopic dermatitis, under the Rizaben® brand name for more than thirty years. More recently tranilast has also been shown to have anti-proliferative properties. Tranilast was shown to inhibit the proliferation of fibroblasts and suppress collagen synthesis (M. Isaji. Biochem Pharmacol. 1987; 36: 469-474) and also to inhibit the transformation of fibroblasts to myofibroblasts and their subsequent contraction (M. Isaji. Life Sci. 1994; 55: 287-292). This additional behaviour led to tranilast gaining additional approval for the treatment of keloids and hypertrophic scars.

[004] Over recent years many researchers have explored the anti-proliferative effects of tranilast to assess its potential in fibrotic and cancerous conditions. Its anti-proliferative action is believed to be due to its ability to inhibit transforming growth factor beta (TGF-b) (H. Suzawa. Jpn J Pharmacol. 1992 Oct; 60(2): 91-96). Fibrosis is a condition that can affect most organs of the body and fibroblast proliferation, differentiation and collagen synthesis are known to be key factors in the progression of most types of fibrosis. Tranilast has been shown in-vivo to have potential beneficial effects in

numerous fibrotic conditions. Tranilast has been shown in-vivo to have potential in lung fibrosis (M. Kato. Eur RespirJ. 2013; 42(57): 2330), kidney fibrosis (DJ Kelly, J Am Soc Nephrol. 2004; 15(10): 2619-29), cardiac fibrosis (J Martin, Cardiovasc Res. 2005; 65(3): 694-701), ocular fibrosis (M J Moon, BMC Opthalmol. 2016; 16: 166) and liver fibrosis (M Uno, Hepatology. 2008; 48(1): 109-18.

[005] Tranilast’s anti-tumor action has also recently been demonstrated, in-vitro and in-vivo. Tranilast has been shown to inhibit the proliferation, apoptosis and migration of several cell lines including breast cancer (R. Chakrabarti. Anticancer Drugs. 2009 Jun; 20(5): 334-45) and prostate cancer (S. Sato. Prostate. 2010 Feb; 70(3): 229-38) cell lines. In a study of mammary carcinoma in mice tranilast was found to produce a significant reduction in metastasis (R. Chakrabarti. Anticancer Drugs. 2009 Jun; 20(5): 334-45). In a pilot study in humans, tranilast was shown to have the potential to improve the prognosis of patients with advanced castration-resistant prostate cancer (K. Izumi. Anticancer Research. 2010 Jul; 30: 73077-81). In-vitro studies also showed the therapeutic potential of tranilast in glioma (M Platten. IntJ Cancer. 2001; 93:53-61), pancreatic cancer (M Hiroi, J Nippon Med Sch. 2002; 69: 224-234) and gastric carcinoma (M Yashiro, Anticancer Res. 2003; 23: 3899-3904).

[006] Given the wide range of fibrotic conditions and cancers for which tranilast could have a potential therapeutic benefit, as well as the different patient types and specific areas of the body requiring treatment, it is anticipated that patients would benefit from having multiple delivery methods for the administration of tranilast so as to best suit the patient’s needs. The pharmaceutical compositions could include, for example, a solid oral dosage, a liquid oral dosage, an injectable composition, an inhalable composition, a topical composition or a transdermal composition.

[007] Kissei Pharmaceutical Co. Ltd explored the anti-proliferative effect of tranilast in the prevention of restenosis associated with coronary intervention. In a Phase II clinical study Kissei found that the current approved dose of tranilast (300 mg/day) was insufficient to prevent restenosis and that a higher dose of 600 mg/day was needed to achieve a decrease in restenosis rates (H. Tamai, Am Heart J.1999; 138(5): 968-75). However, it was found that a 600 mg daily dosage can result in a ten-fold inter-patient variation in plasma concentrations of the drug (30-300 pmol/L) (H Kusa ma. Atherosclerosis. 1999; 143: 307-313) and in the Phase III study of tranilast for the prevention of restenosis the dose was further increased to 900mg daily (D Holmes, Circulation. 2002; 106(10): 1243-1250).

[008] The marketed oral form of tranilast (Rizaben®) contains tranilast in its pure crystalline form. Crystalline tranilast has extremely low aqueous solubility (solubility of 14.5 pg/ml in water and 0.7 pg/ml in pH 1.2 buffer solution (Society of Japanese Pharmacopoeia. 2002)). Whilst, high energy amorphous forms are often used as a means of improving the solubility of poorly soluble drug

compounds, literature shows that an amorphous form of tranilast is not completely photostable in the solid state and that it undergoes photodegradation on storage when exposed to light (S. Onoue. EurJ Pharm Sci. 2010; 39: 256-262).

[009] It is expected that the very low solubility of tranilast is a limiting factor in the oral bioavailability of the drug. Given the limited time any drug has to firstly dissolve in the

gastrointestinal tract and then be absorbed into the bloodstream, this issue will become even more limiting as the oral dose of tranilast is increased. The poor solubility of tranilast is also possibly a key factor in the high inter-patient variability reported for higher dose tranilast pharmacokinetics. As a BCS class II drug (low solubility/high permeability) it is expected that absorption from the gastrointestinal tract is hampered by the dissolution rate of the drug in gastrointestinal media as well as its overall solubility. For treatment of chronic proliferative diseases such as fibrosis and cancer it is vital for the delivery method of a drug to produce consistent, predictable plasma levels that are maintained above the minimum effective concentration. To achieve efficacious oral delivery of tranilast at higher doses there is a need for new solid forms of the drug with both high solubility and rapid dissolution rates.

[010] Given the severity of conditions involving cancer or fibrosis there is also a need for systemic treatment options by which tranilast can be delivered by healthcare specialists that do not require the patient to swallow solid oral dosage forms. Alternative dosage forms suitable for these needs could include, for example, injectable compositions, liquid oral formulations or nebulized inhaled formulations. These would require a liquid formulation of tranilast suitable for systemic delivery. [Oil] Given the potential of tranilast to treat ocular diseases, such as allergic conjunctivitis, Kissei Pharmaceutical Co. Ltd recognised the need to develop an eye drop formulation of tranilast for localised treatment. However, as well as having very low aqueous solubility, tranilast is also photochemically unstable when stored in solution, resulting in significant degradation (N Hori, Chem. Pharm. Bull. 1999; 47(12): 1713-1716). Therefore, the only way Kissei were able to achieve an eye drop liquid composition of tranilast was to use both solubilising and stabilising agents in the formulation (US Patent 5356620). The resulting 0.5% (w/v) eye drop formulation is currently also marketed under the Rizaben® brand name. However, the focus of this formulation and of the subsequent research that has attempted to produce alternative solution formulations of tranilast has always been solely on external delivery of tranilast using compositions such as eye drops and skin ointments etc. None of the liquid formulations of tranilast previously described have been produced for systemic delivery such as for oral or IV delivery. Excipients used in the previously reported external preparations are not suitable for systemic delivery. Also, despite the successful

development of an eye drop formulation of tranilast, the package insert of the marketed Rizaben® eye drops states that the product should not be stored in a refrigerator as crystals may precipitate.

[012] Thus, there remains a need for aqueous pharmaceutical compositions of tranilast suitable for systemic delivery. Given the potential photochemical degradation issue of long term storage of tranilast in solution and also the disadvantage of the larger storage facilities needed to store bulkier solution based formulations it would also be advantageous to develop a stable highly soluble solid form of tranilast that can be quickly dissolved at the time of treatment by the patient or healthcare provider to produce the required liquid formulation.

[013] Following efforts to make a liquid formulation of tranilast, Kissei made the statement that tranilast and pharmaceutically acceptable salts thereof are too insoluble in water to prepare an aqueous solution (US Patent 5356620). Since that US patent the only crystalline pharmaceutically acceptable salt to have been published is the sodium salt (N Geng, Cryst. Growth Des. 2013; 13: 3546-3553). In line with the findings of Kissei the authors of this paper stated that the apparent solubility of the crystalline tranilast sodium salt is even less than that of pure tranilast. Also, when they performed a dissolution study of tranilast in a sodium containing media they found that as the tranilast dissolved it gradually precipitated out of solution as its sodium salt indicating that the sodium salt has a lower thermodynamic solubility than the pure drug. The authors of this paper also successfully prepared the non-pharmaceutically acceptable crystalline cytosine salt of tranilast. Despite this crystalline cytosine salt showing approximately a two-fold solubility improvement over pure crystalline tranilast, not only would this crystalline cytosine salt not be suitable for systemic delivery to a patient due to cytosine not having FDA acceptability but this improvement in solubility would not be great enough to produce high dose tranilast liquid formulations such as an injectable formulation.

[014] Patent application EP1946753 discloses an attempt to prepare an external preparation of tranilast and claims the preparation of ionic liquid salts of tranilast with organic amines. The inventors claim that blending tranilast with the organic amine results in a liquid form. This application does not disclose the formation of any solid state, crystalline tranilast salts with organic amines. They demonstrate that these ionic liquid forms of tranilast have higher solubility in solvents suitable for external application to the skin and that these preparations have higher photostability than pure tranilast in the same formulation. However, this improved photostability still results in a significant proportion of the tranilast being photo-degraded and would not be suitable for long term storage. Also, the solvents used for preparation of these ionic liquid salt formulations are not suitable for internal delivery of tranilast. Moreover, there is no mention in EP1946753 of improved solubility in aqueous or bio-relevant media.

PATENT

US20150119428

https://patents.google.com/patent/US20150119428

  • Tranilast, (2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid), shown below, is a therapeutic agent that exhibits an anti-allergic effect. It has been shown to inhibit the release of inflammatory mediators, such as histamine, from mast cells and basophils (P. Zampini. Int J Immunopharmacol. 1983; 5(5): 431-5). Tranilast has been used as an anti-allergic treatment, for several years in Japan and South Korea, for conditions such as allergic conjunctivitis, bronchial asthma, allergic rhinitis and atopic dermatitis.
  • Figure US20150119428A1-20150430-C00001
  • [0004]
    Tranilast is currently marketed in Japan and South Korea by Kissei Pharmaceutical Co. Ltd under the Rizaben® brand name. As well as displaying an anti-allergic effect tranilast has been shown to possess anti-proliferative properties. Tranilast was found to inhibit the proliferation of fibroblasts and suppress collagen synthesis (M. Isaji. Biochem Pharmacol. 1987; 36: 469-474) and also to inhibit the transformation of fibroblasts to myofibroblasts and their subsequent contraction (M. Isaji. Life Sci. 1994; 55: 287-292). On the basis of these effects tranilast is now also indicated for the treatment of keloids and hypertrophic scars. Its anti-fibrotic action is believed to be due to its ability to inhibit transforming growth factor beta (TGF-β) (H. Suzawa. Jpn J Pharmacol. 1992 October; 60(2): 91-96). TGF-β induced fibroblast proliferation, differentiation and collagen synthesis are known to be key factors in the progression of idiopathic pulmonary fibrosis and tranilast has been shown in-viva to have potential in the treatment of this chronic lung disease (T. Jiang. Afr J Pharm Pharmaco. 2011; 5(10): 1315-1320). Tranilast has also been shown in-vivo to be have potential beneficial effects in the treatment of airway remodelling associated with chronic asthma (S. C. Kim. J Asthma 2009; 46(9): 884-894.
  • [0005]
    It has been reported that tranilast also has activity as an angiogenesis inhibitor (M. Isaji. Br. J Pharmacol. 1997; 122(6): 1061-1066). The results of this study suggested that tranilast may be beneficial for the treatment of angiogenic diseases such as diabetic retinopathy and age related macular degeneration. As well as showing inhibitory effects on mast cells and fibroblasts, tranilast has also demonstrated an ability to diminish tumor necrosis factor-alpha (TNF-α) from cultured macrophages (H. O. Pae. Biochem Biophys Res Commun. 371: 361-365) and T-cells (M. Platten. Science. 310: 850-855), and inhibited NF-kB-dependent transcriptional activation in endothelial cells (M. Spieker. Mol Pharmacol. 62: 856-863). Recent studies have revealed that tranilast attenuates inflammation and inhibits bone destruction in collagen induced arthritis in mice suggesting the possible usefulness of tranilast in the treatment of inflammatory conditions such as arthritis (N. Shiota. Br. Pharmacol. 2010; 159 (3): 626-635).
  • [0006]
    As has recently been demonstrated, in-vitro and in-vivo, tranilast also possesses an anti-tumor action. Tranilast has been shown to inhibit the proliferation, apoptosis and migration of several cell lines including breast cancer (R. Chakrabarti. Anticancer Drugs. 2009 June; 20(5): 334-45) and prostate cancer (S. Sato. Prostate. 2010 February; 70(3): 229-38) cell lines. In a study of mammary carcinoma in mice tranilast was found to produce a significant reduction in metastasis (R. Chakrabarti. Anticancer Drugs. 2009 June; 20(5): 334-45). In a pilot study in humans, tranilast was shown to have the potential to improve the prognosis of patients with advanced castration-resistant prostate cancer (K. Izurni. Anticancer Research. 2010 July; 30: 73077-81).
  • [0007]
    It has been reported that tranilast has the ability to induce or enhance neurogenesis and, therefore, could be used as an agent to treat neuronal conditions such as cerebral ischernia, glaucoma, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s disease, neurodegenerative trinucleotide repeat disorders, neurodegenerative lyosomal storage diseases, spinal cord injury and trauma, dementia, schizophrenia and peripheral neuropathy (A. Schneider. EP2030617).
  • [0008]
    Tranilast’s beneficial properties have been reported to have utility in several ocular conditions. Tranilast is currently approved in Japan and Korea far the treatment of allergic conjunctivitis. WO2010137681 claims the use of tranilast as a prophylactic or therapeutic agent for the treatment of retinal diseases. The anti-fibrotic properties of tranilast have been reported to be of benefit in maintaining the filtering blob during glaucoma surgery and this has been demonstrated in a pilot study in humans (E. Chihara.J Glaucoma. 1999; 11(2): 127-133). There have also been several reported cases of the beneficial use of tranilast in the prevention of postoperative recurrence of pterygium (C. Fukui. Jap J Opthalmol. 1999; 12: 547-549). Tsuji recently reported that tranilast may be beneficial not only in the prevention of ptergium recurrence, but also for the inhibition of symblepharon and granuloma formation (A. Tsuji. Tokai J Exp Clin Med. 2011; 36(4): 120-123). Collectively it has been demonstrated that tranilast possesses anti-allergic, anti-fibrotic, anti-inflammatory, anti-tumor, neurogenesis enhancing end angiogenesis inhibitory properties and as such may be useful for the treatment of diseases associated with such properties.
  • [0009]
    Tranilast occurs as a yellow crystalline powder that is identified by CAS Registry Number: 53902-12-8. As is typical of cinnamic acid derivatives (G. M. J. Schmidt J Chem. Soc. 1964: 2000) tranilast is photochemically unstable when in solution, tranforming into cis-isomer and dimer forms on exposure to light (N. Hori. Cehm Pharm Bull. 1999; 47: 1713-1716). Although pure crystalline tranilast is photochemically stable in the solid state it is practically insoluble in water (14.5 μg/ml) and acidic media (0.7 μg/ml in pH 1.2 buffer solution) (Society of Japanese Pharmacopoeia. 2002). Although tranilast has shown activity in various indications, it is possible that the therapeutic potential of the drug is currently limited by its poor solubility and photostability. High energy amorphous forms are often used as a means of improving the solubility of poorly soluble APIs, however, literature shows that amorphous solid dispersions of tranilast are not completely photostable in the solid state and that they undergo photodegradation on storage when exposed to light (S. Onoue. Eur J Pharm Sci. 2010; 39: 256-262). US20110136835 describes a combination of tranilast and allopurinol and its use in the treatment of hyperuricemia associated with gout and has one mention of a “co-crystal form”, but lacks any further description or characterization.

Patent

Publication numberPriority datePublication dateAssigneeTitle
Family To Family Citations
JP2001072605A *1999-09-032001-03-21Lion CorpTransdermal and transmucosal absorption-promoting agent composition
JP2001187728A *1999-12-282001-07-10Lion CorpOphthalmic composition
JP2011225626A *2001-02-012011-11-10Rohto Pharmaceutical Co LtdEye lotion
US6585997B22001-08-162003-07-01Access Pharmaceuticals, Inc.Mucoadhesive erodible drug delivery device for controlled administration of pharmaceuticals and other active compounds
CA2548281C2003-12-092013-11-12Medcrystalforms, LlcMethod of preparation of mixed phase co-crystals with active agents
JP2005314229A *2004-03-312005-11-10Rohto Pharmaceut Co LtdTranilast-containing medicine composition
JP4843824B22004-08-182011-12-21株式会社 メドレックスTopical preparation
JP2007051089A *2005-08-182007-03-01Medorekkusu:KkPreparation for external use
WO2007046544A1 *2005-10-212007-04-26Medrx Co., Ltd.Preparation for external application comprising salt of mast cell degranulation inhibitor having carboxyl group with organic amine
WO2008078730A1 *2006-12-262008-07-03Translational Research, Ltd.Preparation for transnasal application
EP2030617A12007-08-172009-03-04Sygnis Bioscience GmbH & Co. KGUse of tranilast and derivatives thereof for the therapy of neurological conditions
CN101683330A *2008-09-232010-03-31沈阳三川医药科技有限公司Oral compound pharmaceutic preparation containing tranilast and salbutamol
US20110136835A1 *2009-09-142011-06-09Nuon Therapeutics, Inc.Combination formulations of tranilast and allopurinol and methods related thereto
EP2429495A4 *2009-05-152014-01-22Shin Nippon Biomedical Lab LtdIntranasal pharmaceutical compositions with improved pharmacokinetics
WO2010137681A12009-05-292010-12-02参天製薬株式会社Prophylactic or therapeutic agent for retinal diseases comprising tranilast, method for prevention or treatment of retinal diseases, and tranilast or pharmaceutically acceptable salt thereof and use thereof
JP2011093849A *2009-10-302011-05-12Kissei Pharmaceutical Co LtdEasily dissolvable powder inhalant composed of tranilast
JPWO2011096241A1 *2010-02-022013-06-10テルモ株式会社Bioabsorbable stent
AU2013239114B2 *2012-03-302017-07-20Nuformix LimitedTranilast compositions and cocrystals

Family To Family Citations
AU2013239114B2 *2012-03-302017-07-20Nuformix LimitedTranilast compositions and cocrystals
US10155757B22015-03-102018-12-18Vectura LimitedCrystalline form of a JAK3 kinase inhibitor
CN106344550A *2016-09-282017-01-25江苏省人民医院Application of tranilast to preparation of medicines for treating pneumoconiosis
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References

  1. Jump up to:a b c d e f g h “FDA Proposed Rules” (PDF)Federal Register81 (242): 91071–91082. December 16, 2016. Another version of same published at here
  2. ^ “International brands for Tranilast”. Drugs.com. Retrieved 10 March 2018.
  3. Jump up to:a b c d e Darakhshan, S; Pour, AB (January 2015). “Tranilast: a review of its therapeutic applications”. Pharmacological Research91: 15–28. doi:10.1016/j.phrs.2014.10.009PMID 25447595.
  4. ^ Y. Huang et al, “Tranilast directly targets NLRP3 to treat inflammasome-driven diseases.”EMBO Mol Med., 10(4), 2018
  5. ^ “Kissei’s existing business flat but R&D pipeline should lead to growth”The Pharma Letter. 8 September 2000.
  6. ^ Holmes, D. R; Savage, M; Lablanche, J. M; Grip, L; Serruys, P. W; Fitzgerald, P; Fischman, D; Goldberg, S; Brinker, J. A; Zeiher, A. M; Shapiro, L. M; Willerson, J; Davis, B. R; Ferguson, J. J; Popma, J; King Sb, 3rd; Lincoff, A. M; Tcheng, J. E; Chan, R; Granett, J. R; Poland, M (2002). “Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) Trial”. Circulation106 (10): 1243–50. doi:10.1161/01.CIR.0000028335.31300.DAPMID 12208800.
  7. ^ “Tranilast – Altacor: ALT-401”AdisInsight. Retrieved 10 March 2018.
  8. ^ “EU/3/10/756 Orphan Designation”. European Medicines Agency. 6 August 2010. Retrieved 10 March 2018.
Tranilast
Tranilast.svg
Clinical data
AHFS/Drugs.com International Drug Names
Routes of
administration
Oral
ATC code
  • none
Legal status
Legal status
  • US: Not FDA approved
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.150.125 Edit this at Wikidata
Chemical and physical data
Formula C18H17NO5
Molar mass 327.336 g·mol−1
3D model (JSmol)

///////////////Tranilast,  Rizaben, antiallergic,  Kissei Pharmaceuticals,  Japan, South Korea,  bronchial asthma,  keloid,  hypertrophic scar

ENCORAFENIB, エンコラフェニブ


LGX818 structure.svg

2D chemical structure of 1269440-17-6

Encorafenib.png

ENCORAFENIB, エンコラフェニブ

UNII:8L7891MRB6

Formula:C22H27ClFN7O4S, Average: 540.01

1269440-17-6

  • BRAFTOVI
  • NVP-LGX818
  • NVP-LGX-818-NXA
  • NVP-LGX818-NXA
  • ENCORAFENIB [USAN]
  • ENCORAFENIB [WHO-DD]
  • ENCORAFENIB
  • ENCORAFENIB [INN]
  • METHYL N-((2S)-1-((4-(3-(5-CHLORO-2-FLUORO-3-(METHANESULFONAMIDO)PHENYL)(-1-(PROPAN-2-YL)-1H-PYRAZOL-4-YL(PYRIMIDIN-2-YL)AMINO)PROPAN-2-YL)CARBAMATE
  • CARBAMIC ACID, N-((1S)-2-((4-(3-(5-CHLORO-2-FLUORO-3-((METHYLSULFONYL)AMINO)PHENYL)-1-(1-METHYLETHYL)-1H-PYRAZOL-4-YL)-2-PYRIMIDINYL)AMINO)-1-METHYLETHYL)-, METHYL ESTER
  • LGX818
  • LGX-818

Encorafenib, also known as BRAFTOVI, is a kinase inhibitor. Encorafenib inhibits BRAF gene, which encodes for B-raf protein, which is a proto-oncogene involved in various genetic mutations Label. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which impacts cell division, differentiation, and secretion. Mutations in this gene, most frequently the V600E mutation, are the most commonly identified cancer-causing mutations in melanoma, and have been isolated in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of the lung 6.

On June 27, 2018, the Food and Drug Administration approved encorafenib and Binimetinib(BRAFTOVI and MEKTOVI, Array BioPharma Inc.) in combination for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test Label.

Array Biopharma  (a wholly owned subsidiary of  Pfizer ), under license from  Novartis , and licensees  Pierre Fabre  and  Ono Pharmaceutical  have developed and launched the B-Raf kinase inhibitor encorafenib . In January 2020, the US FDA’s Orange Book was seen to list encorafenib patents such as US8946250 , US8501758 , US9314464 and US9763941 , expiring in the range of 2029-2032. At that time Orange Book also reported that encorafenib as having NCE exclusivity expiring on July 27, 2023.

Encorafenib (trade name Braftovi) is a drug for the treatment of certain melanomas. It is a small molecule BRAF inhibitor [1] that targets key enzymes in the MAPK signaling pathway. This pathway occurs in many different cancers including melanoma and colorectal cancers.[2] The substance was being developed by Novartis and then by Array BioPharma. In June 2018, it was approved by the FDA in combination with binimetinib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma.[3][4]

The most common (≥25%) adverse reactions in patients receiving the drug combination were fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia.[3]

Indication

Used in combination with Binimetinib in metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test 5.

Associated Conditions

Pharmacodynamics

Encorafenib has shown improved efficacy in the treatment of metastatic melanoma 3.

Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis 7.

Once-daily dosing of single-agent encorafenib has a distinct tolerability profile and shows varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic stage melanoma 7.

Mechanism of action

Encorafenib is a kinase inhibitor that specifically targets BRAF V600E, as well as wild-type BRAF and CRAF while tested with in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, including BRAF V600E, result in activated BRAF kinases that mahy stimulate tumor cell growth. Encorafenib is able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and significantly reduce ligand binding to these kinases at clinically achievable concentrations (≤ 0.9 μM) Label.

In efficacy studies, encorafenib inhibited the in vitro cell growth of tumor cell lines that express BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing the BRAF V600E mutation, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression Label.

Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, co-administration of encorafenib and binimetinib result in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. In addition to the above, the combination of encorafenib and binimetinib acted to delay the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared with the administration of either drug alone Label.

Image result for ENCORAFENIB

Pharmacology

Encorafenib acts as an ATP-competitive RAF kinase inhibitor, decreasing ERK phosphorylation and down-regulation of CyclinD1.[5]This arrests the cell cycle in G1 phase, inducing senescence without apoptosis.[5] Therefore it is only effective in melanomas with a BRAF mutation, which make up 50% of all melanomas.[6] The plasma elimination half-life of encorafenib is approximately 6 hours, occurring mainly through metabolism via cytochrome P450 enzymes.[7]

Clinical trials

Several clinical trials of LGX818, either alone or in combinations with the MEK inhibitor MEK162,[8] are being run. As a result of a successful Phase Ib/II trials, Phase III trials are currently being initiated.[9]

History

Approval of encorafenib in the United States was based on a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453) in 577 patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma.[3] Patients were randomized (1:1:1) to receive binimetinib 45 mg twice daily plus encorafenib 450 mg once daily, encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily.[3] Treatment continued until disease progression or unacceptable toxicity.[3]

The major efficacy measure was progression-free survival (PFS) using RECIST 1.1 response criteria and assessed by blinded independent central review.[3] The median PFS was 14.9 months for patients receiving binimetinib plus encorafenib, and 7.3 months for the vemurafenib monotherapy arm (hazard ratio 0.54, 95% CI: 0.41, 0.71, p<0.0001).[3] The trial was conducted at 162 sites in Europe, North America and various countries around the world.[4]

SYN

PATENT

WO2010010154 , expiry , EU states,  2029,  US in 2030 with US154 extension.

WO 2011025927

WO 2016089208

Patent

WO-2020011141

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020011141&tab=FULLTEXT&_cid=P20-K5QFFQ-43376-1

Novel deuterated analogs of diarylpyrazole compounds, particularly encorafenib are B-RAF and C-RAF kinase inhibitors, useful for treating proliferative diseases such as melanoma and colorectal cancer. Family members of the product case, WO2010010154 , expire in most of the EU states until 2029 and will expire in the US in 2030 with US154 extension. In January 2020, the US FDA’s Orange Book was seen to list encorafenib patents such as US8946250 , US8501758 , US9314464 and US9763941 , expiring in the range of 2029-2032. At that time Orange Book also reported that encorafenib as having NCE exclusivity expiring on July 27, 2023.

The mitogen-activated protein kinase (MAPK) pathway mediates the activity of many effector molecules that coordinately control cell proliferation, survival, differentiation, and migration. Cells are bound by plasma factors such as growth factors, cytokines, or hormones to plasma membrane-associated Ras and GTP and thereby activated to recruit Raf. This interaction induces Raf’s kinase activity, resulting in direct phosphorylation of MAPK / ERK (MEK), which in turn phosphorylates extracellular signal-related kinase (ERK). Activated ERK phosphorylates a range of effector molecules, such as kinases, phosphatases, transcription factors, and cytoskeleton proteins. Therefore, the Ras-Raf-MEK-ERK signaling pathway transmits signals from cell surface receptors to the nucleus and is essential for cell proliferation and survival.

[0003]
According to Raf’s ability to interact with upstream regulator Ras, Raf has three different isoforms, namely A-Raf, B-Raf, and C-Raf. An activating mutation of one of the Ras genes can be observed in about 20% of all tumors, and the Ras-Raf-MEK-ERK pathway is activated in about 30% of all tumors. Activation mutations in the B-Raf kinase domain occur in approximately 70% of melanoma, 40% of papillary cancer, 30% of low-grade ovarian cancer, and 10% of colorectal cancer. Most B-Raf mutations are found in the kinase domain, with a single substitution (V600E) accounting for 80%. The mutated B-Raf protein activates the Raf-MEK-ERK pathway by increasing kinase activity against MEK or by activating C-Raf. B-Raf inhibitors inhibit cells involved in B-Raf kinase by blocking the signal cascade in these cancer cells and eventually inducing cell arrest and / or death.

[0004]
Encorafenib (aka LGX-818, chemical name is (S)-(1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1-iso Propyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) prop-2-yl) methyl carbamate, which has the following structural formula) is a new oral BRAF jointly developed by Novartis and Array Pharmaceuticals Inhibitors can inhibit the activation of the MAPK pathway caused by B-Raf kinase mutations (such as V600 mutations, that is, glutamate mutations at amino acid 600). Encorafenib alone or in combination with MEK inhibitor Binimetinib is used to treat patients with advanced BRAF v600 mutant melanoma. On June 27, 2018, the FDA approved Encorafenib (commercial name BRAFTOVI) capsules in combination with Binimetinib (commercial name: MEKTOVI) tablets for treating melanoma patients with BRAF V600E or BRAFV 600K mutations.
It is known that poor absorption, distribution, metabolism, and / or excretion (ADME) properties are the main cause of the failure of many candidate drug clinical trials. Many drugs currently on the market also limit their scope of application due to poor ADME properties. The rapid metabolism of drugs will cause many drugs that could be highly effective in treating diseases to be difficult to make because they are metabolized from the body too quickly. Although frequent or high-dose medication may solve the problem of rapid drug removal, this method will bring problems such as poor patient compliance, side effects caused by high-dose medication, and rising treatment costs. In addition, rapidly metabolizing drugs may also expose patients to adverse toxic or reactive metabolites.

[0007]
Although Encoratenib as a BRAF inhibitor can effectively treat BRAF V600 mutant melanoma, there are still serious clinical unmet needs in this field, and the Encoratenib compound is a class II BCS with poor water solubility at weakly acidic and neutral pH Compounds have poor oral availability, so finding new compounds that have a therapeutic effect on BRAF kinase mutations, have good oral bioavailability, and have pharmaceutical properties is still a challenging task. Therefore, there remains a need in the art to develop compounds that have selective inhibitory activity and / or better pharmacodynamics / pharmacokinetics for use as BRAF inhibitors, and the present invention provides such compounds.

PAPER

European journal of cancer (Oxford, England : 1990) (2018), 88, 67-76.

References

  1. ^ Koelblinger P, Thuerigen O, Dummer R (March 2018). “Development of encorafenib for BRAF-mutated advanced melanoma”Current Opinion in Oncology30 (2): 125–133. doi:10.1097/CCO.0000000000000426PMC 5815646PMID 29356698.
  2. ^ Burotto M, Chiou VL, Lee JM, Kohn EC (November 2014). “The MAPK pathway across different malignancies: a new perspective”Cancer120 (22): 3446–56. doi:10.1002/cncr.28864PMC 4221543PMID 24948110.
  3. Jump up to:a b c d e f g “FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations”U.S. Food and Drug Administration (FDA)(Press release). 27 June 2018. Archived from the original on 18 December 2019. Retrieved 28 June 2018.  This article incorporates text from this source, which is in the public domain.
  4. Jump up to:a b “Drug Trial Snapshot: Braftovi”U.S. Food and Drug Administration (FDA). 16 July 2018. Archived from the original on 19 December 2019. Retrieved 18 December 2019. This article incorporates text from this source, which is in the public domain.
  5. Jump up to:a b Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, Piao Y, Liu J, Cheng W, Bi X, Gong P, Song Z, Meng S (January 2016). “Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells”. Cancer Letters370 (2): 332–44. doi:10.1016/j.canlet.2015.11.015PMID 26586345.
  6. ^ Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. (July 2012). “A landscape of driver mutations in melanoma”Cell150 (2): 251–63. doi:10.1016/j.cell.2012.06.024PMC 3600117PMID 22817889.
  7. ^ Koelblinger P, Thuerigen O, Dummer R (March 2018). “Development of encorafenib for BRAF-mutated advanced melanoma”Current Opinion in Oncology30 (2): 125–133. doi:10.1097/CCO.0000000000000426PMC 5815646PMID 29356698.
  8. ^ “18 Studies found for: LGX818”Clinicaltrials.gove.
  9. ^ Clinical trial number NCT01909453 for “Study Comparing Combination of LGX818 Plus MEK162 and LGX818 Monotherapy Versus Vemurafenib in BRAF Mutant Melanoma (COLUMBUS)” at ClinicalTrials.gov

External links

  1. Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, Piao Y, Liu J, Cheng W, Bi X, Gong P, Song Z, Meng S: Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. Cancer Lett. 2016 Jan 28;370(2):332-44. doi: 10.1016/j.canlet.2015.11.015. Epub 2015 Nov 14. [PubMed:26586345]
  2. Koelblinger P, Thuerigen O, Dummer R: Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol. 2018 Mar;30(2):125-133. doi: 10.1097/CCO.0000000000000426. [PubMed:29356698]
  3. Moschos SJ, Pinnamaneni R: Targeted therapies in melanoma. Surg Oncol Clin N Am. 2015 Apr;24(2):347-58. doi: 10.1016/j.soc.2014.12.011. Epub 2015 Jan 24. [PubMed:25769717]
  4. Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion-Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT: Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):603-615. doi: 10.1016/S1470-2045(18)30142-6. Epub 2018 Mar 21. [PubMed:29573941]
  5. FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations [Link]
  6. BRAF B-Raf proto-oncogene, serine/threonine kinase [ Homo sapiens (human) ] [Link]
  7. Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma [Link]
  8. Encorafenib FDA label [File]
  9. Encorafenib review [File]
Encorafenib
LGX818 structure.svg
Clinical data
Trade names Braftovi
Other names LGX818
AHFS/Drugs.com Monograph
MedlinePlus a618040
License data
Routes of
administration
Oral
Drug class Antineoplastic Agents
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C22H27ClFN7O4S
Molar mass 540.011 g/mol g·mol−1
3D model (JSmol)

///////////ENCORAFENIB, 1269440-17-6, BRAFTOVI, NVP-LGX818, LGX818, LGX 818, エンコラフェニブ  ,

COC(=O)N[C@@H](C)CNc1nccc(n1)c2cn(nc2c3cc(Cl)cc(NS(=O)(=O)C)c3F)C(C)C

patent

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020011141&tab=FULLTEXT&_cid=P20-K5QFFQ-43376-1

Method for preparing compounds of the invention

[0165]
The compounds of the invention, including their salts, can be prepared using known organic synthesis techniques, and can be synthesized according to any of a number of possible synthetic routes, such as those in the schemes below. The reaction for preparing the compound of the present invention can be performed in a suitable solvent, and a person skilled in the art of organic synthesis can easily select a solvent. Suitable solvents may be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is performed (e.g., a temperature ranging from the solvent freezing temperature to the solvent boiling point temperature). A given reaction may be performed in one solvent or a mixture of more than one solvent. The skilled person can select a solvent for a specific reaction step depending on the specific reaction step.

[0166]
The preparation of the compounds of the invention may involve the protection and removal of different chemical groups. Those skilled in the art can easily determine whether protection and removal of protection are needed and the choice of an appropriate protecting group. The chemical nature of the protecting group can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.

[0167]
The compound of the present invention can be prepared into a single stereo by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomer isomer. Enantiomeric resolution can be performed using diastereomeric derivatives of the compounds of the present invention, with preferentially dissociable complexes (e.g., crystalline diastereomeric salts). Diastereomers have significantly different physical properties (eg, melting points, boiling points, solubility, reactivity, etc.) and can be easily separated by the advantages of these dissimilarities. Diastereomers can be separated by chromatography, preferably by separation / resolution techniques based on differences in solubility. The optically pure enantiomer is then recovered, along with the resolving reagent, by any practical means that does not allow racemization. A more detailed description of techniques suitable for resolution of stereoisomers of compounds starting from racemic mixtures can be found in Jean Jacques, Andre Collet, Samue1H. Wilen, “Enantiomers, Racemates and Resolution” (“Enantiomers, Racemates and Resolutions “), John Wiley And Sons, Inc., 1981.

[0168]
The reaction can be monitored according to any suitable method known in the art. For example, it may be by spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g. 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g. UV-visible light), mass spectrometry (MS)) or by chromatography Methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) to monitor product formation.

[0169]
The compound of formula (I) of the present invention can be prepared by the following reaction scheme 1:

[0170]
Reaction Flowchart 1

[0171]
WO2020011141 / pic / XxJADXdTFKEoDNpTEyy19bUgmH96fty917ouhkO5VZ8DxAcnBrNNXgNmrPfLZTkbnfDDV8tm_ImJg2inA4pPj9gRdLA4C4Y4C4Y4C4Y4C4R4A4

[0172]
Wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 and X 5 are as defined in the present invention. The compound of formula (I) can be obtained by using a compound of formula (I-1) and a sulfonating agent X 5 SO 2 Cl at a suitable base (for example, pyridine, triethylamine, 4- (N, N-dimethylamino) pyridine, etc.) Reaction with a suitable solvent (e.g., dichloromethane, THF, etc.). The reaction is performed at a temperature ranging from about 0 ° C to about 1000 ° C, and may take up to about 20 hours to complete. The reaction mixture is optionally further reacted to remove any protecting groups.

[0173]
The compound of formula (I-1) can be prepared by the following reaction scheme 2:

[0174]
Reaction Flowchart 2

[0175]
WO2020011141 / pic / 0j7t4gaakD7jifc_-mXUo7X65c8la3xpUvQQUfnz6tLaRlcSBbtBx_ehky4qNV0PICK_GRydD0JIoErMNKGqXAa-Pdt7Mtw-IlvJllyprtNJlkwQFY2QFKYFQFY2F2F2F-A

[0176]
Wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 and X 5 are as defined in the present invention, M is a leaving group (for example, iodine, bromine, chlorine, trifluoromethanesulfonyloxy, etc.), each Z may be, for example, hydrogen, methyl, etc., or two Z groups may be connected to form a boric acid ester. Both P groups can be H, or two P groups taken together represent a suitable nitrogen protecting group (eg, one P can be hydrogen and the other can be Boc). The compound of formula (I-2) can be obtained by using a compound of formula (I-4) and a compound of formula (I-3) in a suitable transition metal catalyst (for example, Pd (PPh 3 ) 4 or PdCl 2(dppf)), a suitable solvent (for example, DME, dioxane, toluene, ethanol, etc.) and a suitable base (for example, anhydrous potassium carbonate or sodium carbonate, etc.) are reacted. The reaction is carried out at a temperature ranging from about 20 ° C to 120 ° C, and may take about 2 hours to complete. Compounds of formula (I) can be synthesized by leaving the protecting group P from compounds of formula (I-2) (eg, by treatment with a strong acid such as hydrogen chloride in the presence of DME and dioxane).

[0177]
Compounds of formula (I-4) can be prepared by the following reaction scheme 3:

[0178]
Reaction Flowchart 3

[0179]
WO2020011141 / pic / H1aXUHL0cjl3M_4rpEpbJjUXM5MVl8eWmRAYSGnBPikn5V42NDHXIWwphroHiMSaKEOQI2xHvuG9rOZ0TmtIGAgEd55PYww1WwLNWYpYGOjx5MePjrwW1

[0180]
Wherein Y 1 , Y 2 , R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 and X 4 are as defined in the present invention, and M is a leaving group (for example, iodine, Bromine, chlorine, trifluoromethanesulfonyloxy, etc.), and V is a leaving group (eg, iodine, bromine, chlorine, trifluoromethanesulfonyloxy, etc.). Compounds of formula (I-4) can be prepared by reacting an amine compound of formula (I-5) and a compound of formula (I-6). The reaction is performed in a suitable solvent (for example, DMSO, NMP, dioxane, or isopropanol) in the presence of a suitable base (for example, sodium carbonate or potassium carbonate, etc.) at a temperature ranging from about 25 ° C to about 120 ° C.

[0181]
Examples

[0182]
The present invention will be further described below with reference to specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions in the following examples are generally based on conventional conditions or conditions recommended by the manufacturer. Unless stated otherwise, parts and percentages are parts by weight and percent by weight.

[0183]
The abbreviations used in this article have the following meanings:

[0184]

[TABLE 0001]

APCI Atmospheric pressure chemical dissociation
HPLC High performance liquid chromatography
TLC TLC
h hour
DMF N, N-dimethylformamide
2 CO 3 Potassium carbonate
DCM Dichloromethane
THF Tetrahydrofuran
CH 3 MgBr Methyl magnesium bromide
PTSA p-Toluenesulfonic acid
TFA Trifluoroacetate
NMP N-methylpyrrolidone
Diguanidinium carbonate Guanidine carbonate
MTBE Methyl tert-butyl ether
POCl 3 Phosphorus oxychloride
DMSO Dimethyl sulfoxide
Pd (dppf) Cl 2 [1,1′-Bis (diphenylphosphino) ferrocene] Palladium dichloride
Dioxane Dioxane
TsCl 4-toluenesulfonyl chloride
Boc Tert-butoxy carbon
DIPEA N, N-diisopropylethylamine
CDCl 3 Deuterated chloroform
TEA Triethylamine
DMAP 4-dimethylaminopyridine
Na 2 CO 3 Sodium carbonate
HCl hydrochloric acid

[0185]

[表 0002]

MsCl Methanesulfonyl chloride
Tol Toluene

[0186]
Preparation of intermediate A 2-chloro-4- (3-iodo-1- (prop-2-yl-d 7) -1H-pyrazol-4-yl) pyrimidine.

[0188]
Use the following route for synthesis:

[0189]

[0187]
WO2020011141 / pic / FNMs_XnbU3RObeg6K-VT91xnEa9pD4CszLQIShhoBrnGwf4vFDH7dAkcn-3inZ_bWfKR2ST5u0v_zJNop7mFw4GGCQQ-n-KUOLKt_hScUwRV00GBR1

[0188]
Use the following route for synthesis:

[0189]
WO2020011141 / pic / X5sd0-Eb1TIYnP9Ih5i8tod2iaKSm99ccdy8emg0txiLBrTHdVUkygjUPWlzRjkQFaUW8mpEfWyY68vXxmmbEdx1Q3ZQZFZ1ZYZFZ5ZFJ2

[0190]
Step 1 Synthesis of Compound A-2

[0191]
Compound 1 (5.0 g, 73.4 mmol) was added to a 47% solution of hydrobromic acid (20 ml). The reaction solution was reacted at 80 ° C for 3 hours, and distilled under normal pressure. The 60-70 ° C fraction was collected to obtain a colorless liquid. 6.2g, yield 65%.

[0192]
Step 2 Synthesis of Compound A-4

[0193]
Compound A-3 (3.0 g, 27.8 mmol) was added to a DMF (20 ml) solution, the solution was lowered to 0 ° C, K 2 CO 3 (4.6 g, 33.3 mmol, 10 ml) was added, and the mixture was stirred at low temperature for 0.5 h. Then compound A-2 (4.3g, 33.3mmol) was slowly added dropwise. After the dropwise addition, the temperature was raised to 90 ° C for 10 hours. The reaction solution was extracted with DCM (50ml × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 1: 1) to obtain 3.1 g of a white solid in a yield of 72%. LC-MS (APCI): m / z = 158.21.06 (M + 1) + .

[0194]
Step 3 Synthesis of Compound A-5

[0195]
Under nitrogen protection, compound A-4 (3.0 g, 19.1 mmol) was added to a solution of anhydrous THF (40 ml), and the temperature was lowered to -5 ° C, and CH 3 MgBr (19.1 ml, 57.3 mmol, 3 ml / L) was added dropwise . Anhydrous THF solution. After the dropwise addition was completed, the temperature was gradually raised to reflux for 4 h. The reaction was quenched with saturated ammonium chloride, then the pH was adjusted to neutral with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (50 ml × 3). The phases were dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 2: 3) to obtain 2.0 g of a yellow solid with a yield of 61%. LC-MS (APCI): m / z = 175.21.06 (M + 1) + .

[0196]
Step 4 Synthesis of Compound A-6

[0197]
Compound A-5 (2.0g, 11.5mmol), PTSA (4.2g, 23.0mmol) were added to the acetonitrile (15ml) solution, and after dropping to 0 ° C, sodium nitrite (1.43g, 20.7mmol) and Aqueous solution (5 ml) of potassium iodide (3.82 g, 23.0 mmol). The reaction solution was reacted at room temperature for 3 hours, and extracted with ethyl acetate (30 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to obtain 2.5 g of an orange solid with a yield of 75%.

[0198]
Step 5 Synthesis of Compound A-8

[0199]
Under nitrogen protection, compound A-6 (2.0 g, 7.01 mmol) was added to a DMF (15 ml) solution, and the temperature was raised to 120 ° C. Then compound A-7 (1.9 g, 10.5 mmol, 10 ml) was added at 120 ° C. The reaction was stirred for 0.5h. Dichloromethane (30ml × 3) was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was separated by column. ) To obtain 1.9 g of the product in a yield of 80%. LC-MS (APCI): m / z = 341.06 (M + 1) + .

[0200]
Step 6 Synthesis of Compound A-9

[0201]
Under nitrogen protection, compound A-8 (1.9 g, 5.6 mmol) and guanidine carbonate (1.6 g, 12.8 mmol) were sequentially added to the NMP (20 ml) solution. At the same time, a water separation device was set up to raise the solution to 130 ° C. The reaction was stirred at 130 ° C for 10 hours. After the reaction was completed, dichloromethane (30ml × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was separated by column (eluent: petroleum ether / ethyl acetate (v / v) = 2: 3), 1.5 g of product was obtained with a yield of 81%. LC-MS (APCI): m / z = 336.86 (M + 1) + .

[0202]
Step 7 Synthesis of Compound A-10

[0203]
Compound A-9 (1.5 g, 4.5 mmol) was added to the TFA (15 ml) solution. After reducing to 0 ° C, sodium nitrite (0.93 g, 13.4 mmol) was added as a solid. The reaction solution was reacted at room temperature for 1 h. Extract with ethyl acetate (30ml × 3), combine the organic phases, dry over anhydrous sodium sulfate, spin dry the oil with MTBE (10ml), and filter to obtain 1.3g of white solid, 87% yield, LC-MS (APCI) : m / z = 338.15 (M + 1) + .

[0204]
Step 8 Synthesis of intermediate compound A

[0205]
Compound A-10 (1.3 g, 3.86 mmol) was added to a solution of POCl 3 (15 ml), and the temperature was raised to 110 ° C., and the reaction was refluxed at this temperature for 10 h. After the reaction was completed, the reaction solution was spin-dried and dichloromethane (30 ml × 2) Extraction, combined organic phases, dried over anhydrous sodium sulfate, and column separation of the concentrated solution (eluent: petroleum ether / ethyl acetate (v / v) = 4: 1), 1.0 g of product was obtained, yield 73% . LC-MS (APCI): m / z = 356.32 (M + 1) + .

[0206]
Preparation of intermediate B (S)-(methyl-d 3) (1-aminoprop-2-yl) aminocarbonate.

[0208]
Use the following route for synthesis:

[0209]

[0207]
WO2020011141 / pic / -0strXxact6b2WUIRF3g-qYghbCelI38aof_aRxWyEeaR72see_zBNkAfrwxU-jzi8mdXg4_x4dVwb8bvcLmC0ELLoGLnitco1K2i6cFdUmLPY-LVCRcRcRiOsrQrCsIrOc

[0208]
Use the following route for synthesis:

[0209]
WO2020011141 / pic / luvqF_emaX_eXgTd5ug-arAL8ywwxiu1gGgclql8FZMllvX_6O0eC2cCrB0EEspypcf5ZTRPbOib3MqPf8rPV8752UgYWY2ZwOYZY

[0210]
Step 1 Synthesis of Compound B-2

[0211]
Compound B-1 (1.3 g, 4.5 mmol) was dissolved in a toluene (15 ml) solution, the temperature was lowered to 0 ° C, and CD 3 OD (0.5 g, 15 mmol) and triethylamine (1.7 g, 17 mmol) in toluene were added dropwise . (10ml) solution, reacted at room temperature for 2h after the dropwise addition, washed three times with ice water, dried over anhydrous sodium sulfate, filtered to obtain a toluene solution of compound B-2, and directly used in the next step.

[0212]
Step 2 Synthesis of Compound B-4

[0213]
At 0 ° C, the hydrochloride (0.5 g, 2.4 mmol) and triethylamine (0.73 g, 7.2 mmol) of compound B-3 were added to a solution of dichloromethane (10 ml) in this order, and one step of compound B was added dropwise. -2 toluene solution, reacted for 5 hours at room temperature after the addition, quenched by adding water (10ml), extracted with dichloromethane (20ml × 3), combined organic phases, dried over anhydrous sodium sulfate, and concentrated the column for separation (elution Agent: petroleum ether / ethyl acetate (v / v) = 4: 1), 0.45 g of white solid product was obtained with a yield of 80%.

[0214]
Step 3 Synthesis of intermediate compound B

[0215]
At 0 ° C, a solution of 4M hydrochloric acid in dioxane (4ml) was slowly added to a solution of compound B-4 (0.45g, 1.9mmol) in dichloromethane (10ml), and the reaction was continued at room temperature for 6h. After the reaction was completed, the solution was spin-dried, petroleum ether (10 ml) was slurried, and 0.2 g of the product was obtained by suction filtration with a yield of 77%.

[0216]
Preparation of intermediate C (1-aminoprop-2-yl-1,1,3,3,3-d 5) carbamate.

[0218]
Use the following route for synthesis:

[0219]

[0217]
WO2020011141 / pic / bZLBsYoBZtulvxpYYI8e5PX_miQYNGkgLgTUstJSMH5SqupQ2PJkQONEOn2GgxHGWmCDZMa-2G5AAvETeF0Qc5Isx_T67ZCJL4_fm2

[0218]
Use the following route for synthesis:

[0219]
WO2020011141 / pic / NoYKNLy2Fhdd3EaVaPfdnESILNKxV3p8R23Zhj7ewo2iRP1aX1fafA7EijayZQiw1sBGSuhkSMC5kcA3OJoo4VaSIpow2Qpww2wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwzw

[0220]
Step 1 Synthesis of compound C-3

[0221]
A mixture of compound C-2 (4.6 g, 61.8 mmol), compound C-1 (11.5 g, 67.6 mmol) and sodium hydroxide (7.16 g, 67.7 mmol) in water (60 ml) was stirred and reacted at 0 ° C for 3 h. After the reaction was completed, water (60 ml) was added, and the mixture was extracted with ethyl acetate (60 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 10: 1), 11.2 g of an oily substance was obtained, and the yield was 88%.

[0222]
Step 2 Synthesis of Compound C-4

[0223]
Under a nitrogen atmosphere, DMSO (4.8 g, 61.5 mmol) was slowly added to a solution of oxalyl chloride (6.0 g, 47.2 mmol) in DCM (60 ml) at -78 ° C, and the mixture was stirred at -78 ° C for half an hour. Then, a solution of compound C-3 (8.0 g, 38.2 mmol) in DCM (20 ml) was added to the mixture, and the mixture was further stirred at -78 ° C for 1 h, and then triethylamine (16 ml) was added to the mixture, and the mixture was raised to At room temperature, it was washed with 1N hydrochloric acid (50ml) and sodium bicarbonate aqueous solution (50ml) successively. The organic phase was dried over anhydrous sodium sulfate, heat-shrinked, and then slurried with a volume ratio of PE: EA = 8: 1 to obtain 5.3g of a white solid product. The rate is 87%.

[0224]
Step 3 Synthesis of Compound C-5

[0225]
1,5,7-Triazabicyclo [4.4.0] dec-5-ene (0.27 g, 1.9 mmol) was added to a solution of compound C-4 (4.0 g, 19.3 mmol) in deuterated chloroform (30 ml) After the reaction solution was stirred at room temperature for 30 hours, water (10 ml) was added to quench the reaction, and the organic phase was separated and washed with saturated sodium chloride. The organic phase was dried and spin-dried to obtain 3.9 g of an oil with a yield of 98%.

[0226]
Step 4 Synthesis of compound C-6

[0227]
Under a nitrogen atmosphere, compound C-5 (4.0 g, 18.9 mmol) and tert-butylsulfinamide (2.7 g, 22.6 mmol) were added to the THF (60 ml) solution, and tetraisopropyl titanate was added at room temperature. Ester (11.8 g, 41.5 mmol), and then heated to 60 ° C for 3 h. The reaction solution was cooled to room temperature, quenched by adding water, and extracted with ethyl acetate (60 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate ( v / v) = 4: 1), 3.5 g of product was obtained with a yield of 58%. LC-MS (APCI): m / z = 315.80 (M + 1) + .

[0228]
Step 5 Synthesis of compound C-7

[0229]
At -50 ° C, NaBH 4 (0.73 g, 19.1 mmol) was added to a solution of compound C-6 (2.0 g, 6.3 mmol) in methanol (20 ml), and then the reaction was continued at low temperature for 1 h. 1M hydrochloric acid was added to quench the reaction, and the mixture was extracted with dichloromethane (30 ml × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain 2.1 g of an oily product.

[0230]
Step 6 Synthesis of compound C-8

[0231]
A solution of 4M hydrochloric acid in dioxane (10 ml) was slowly added to a solution of compound C-7 (2.0 g, 6.3 mmol) in dichloromethane (20 ml) at 0 ° C, and the reaction was continued at 0 ° C for 6 h. After the reaction is completed, the solvent is spin-dried and directly used in the next step without further processing.

[0232]
Step 7 Synthesis of compound C-9

[0233]
Triethylamine (1.43 g, 14.1 mmol) was added to a solution of compound C-8 (1.5 g, 7.0 mmol) in dichloromethane (20 ml) at 0 ° C, and methyl chloroformate was added dropwise to the mixture. (0.8g, 8.5mmol), and react at room temperature for 5 hours after the addition. After the reaction is complete, water (10ml) is added to quench the reaction. The reaction solution is extracted with dichloromethane (20ml × 2). Sodium was dried, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 4: 1) to obtain 1.1 g of a white solid product with a yield of 58%.

[0234]
Step 8 Synthesis of intermediate compound C

[0235]
Under a hydrogen atmosphere, Pd-C (0.2g, 10%) was added to the compound C-9 (1.0g, 3.7mmol) in ethanol (5ml) and a 1N hydrochloric acid solution (5ml), and the reaction was stirred for 5h. After the reaction was completed, It was filtered and the filtrate was directly concentrated to obtain 0.4 g of the product.

[0236]
Example 1 (S) -methyl- (1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- (propan-2-yl -d 7) Preparation of 1H-pyrazol-4-yl) pyrimidin-2-yl) amino) propan-2-yl) carbamate (compound L-1).

[0238]
Use the following route for synthesis:

[0239]

[0237]
WO2020011141 / pic / 3xtiuTx657XV12_fky8oaKP_xXwX4wCXzmrOFYj-6WrLGfn7RokqPCy3lz6vK0t_oUjqoYktURzPEI8R4Z4fga0Yw0QXQQWYQZYUZTYWYQT

[0238]
Use the following route for synthesis:

[0239]
WO2020011141 / pic / kZCwkP7P-x1L3nCmUBMv9tcq80zMDMHYE9GLLB13iwjtMkE58H7GHYCHtBFrk_OoAPcX1xuC9dLyLTpjsyBA2GaUqv2D2XU2C2R2C2R2C2R2C2B2C2D2C2C2B2

[0240]
Step 1 Synthesis of Compound 2

[0241]
Under nitrogen protection, intermediate compound A (1.0 g, 2.8 mmol), compound 1 (0.52 g, 3.1 mmol), and sodium carbonate (1.2 g, 11.2 mmol) were sequentially added to the DMSO (20 ml) solution, and the temperature was raised to 90 ° C. The reaction was stirred at this temperature for 16h. After the reaction was completed, DCM (30ml × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was separated by column (eluent: petroleum ether / ethyl acetate (v / v) = 1: 2), 0.8 g of product was obtained with a yield of 63%. LC-MS (APCI): m / z = 452.33 (M + 1) + .

[0242]
Step 2 Synthesis of Compound 4

[0243]
Under nitrogen protection, compound 2 (0.5 g, 1.11 mmol), compound 3 (0.5 g, 1.33 mmol), sodium carbonate (0.47 g, 4.43 mmol), and Pd (dppf) Cl2 (0.09 g, 0.11 mmol) were added in this order. Into a mixed solution of toluene (20 ml) and water (4 ml), heated to 80 ° C. for 2 h. The reaction solution was cooled to room temperature, extracted with ethyl acetate (30 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 1: 1) 0.2 g of product was obtained with a yield of 31%. LC-MS (APCI): m / z = 569.09 (M + 1) + .

[0244]
Step 3 Synthesis of Compound 5

[0245]
At 0 ° C, a solution of 4M hydrochloric acid in dioxane (4ml) was slowly added to a solution of compound 4 (0.2g, 0.35mmol) in DCM (10ml), and the reaction mixture was warmed to room temperature for 6h. After the reaction is complete, the solution is spin-dried and directly sent to the next step without further processing. LC-MS (APCI): m / z = 469.27 (M + 1) + .

[0246]
Step 4 Synthesis of Compound L-1

[0247]
Compound 5 (0.15 g, 0.32 mmol) and triethylamine (0.16 g, 1.6 mmol) were sequentially added to the DCM (10 ml) solution. After the temperature was lowered to 0 ° C, MsCl (0.11 g, 1.0 mmol) was slowly added dropwise. After the addition was completed, the reaction temperature was raised to room temperature for 5 hours. After the reaction was completed, the reaction solution was spin-dried to obtain a residue. Toluene (9 ml), methanol (1 ml), water (10 ml), and sodium carbonate (2 g) were sequentially added to the residue. The reaction temperature was raised to 85 ° C for 10 hours, cooled to room temperature, and extracted with ethyl acetate (20ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: dichloromethane / methanol (v / v) = 20: 1), 50 mg of product was obtained with a yield of 35%. LC-MS (APCI): m / z = 547.31 (M + 1) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.08 (d, J = 11.4 Hz, 2H), 7.61 (d, J = 6.3 Hz, 1H), 7.42 (d, J = 5.6 Hz, 1H), 6.48 (d , J = 5.1 Hz, 1H), 5.32 (d, J = 18.8 Hz, 1H), 5.17 (s, 1H), 4.59 (d, J = 13.2 Hz, 1H), 3.79 (s, 1H), 3.61 (s , 3H), 3.24 (s, 1H), 2.98 (d, J = 16.6Hz, 3H), 2.01 (s, 1H), 1.31 (s, 3H).

[0248]
Example 2 (S)-(methyl-d 3)-(1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1-iso Preparation of propyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) propan-2-yl) carbamate (compound L-2).

[0249]
WO2020011141 / pic / tVDfDEoOqWI5X7v8Kaju3q5h9JqkTve6llLuavobFC_1bh4Bp_PcG7AbdlZy5eFwRexqa8OY2mQ_WQBTMQu5Ce-x7qWisFmuvIijUJGQ7JhMqHf6vDSCLDW8ySQjx0v3LUA6YMGFZwOYZJznC59drnUBFfVdu6tdIqqvonWRiGg “>

[0250]
Use the following route for synthesis:

[0251]
WO2020011141 / pic / m9mXD-mrSGFj20R47ROzFF6keVQ70kCzBace3esKjuDXwTUrjQQweunbgPzPIPpGrRj1It6FgZXqv5ywjyC2eHI6VD0F0D0f0FJ1DKfY1D1KVFY1D1F1D1F2D2F2D2F2D2D2D2F2D2D2D2D2D2D2D2D2D2D2D2D2D2D2D2D2D2D2D2d2d2d2d2d2ddffd1d2d2dffd2d2dffd2ddfffd1d2d2dffd1ddffj1nKixYeQ2ohmGYVDVF7F7R2

[0252]
Step 1 Synthesis of compound 7

[0253]
Under nitrogen protection, compound 6 (0.5 g, 1.5 mmol), intermediate compound B (0.2 g, 1.5 mmol), and sodium carbonate (0.63 g, 6.0 mmol) were sequentially added to the DMSO (20 ml) solution, and the temperature was raised to 90 ° C. The reaction was stirred at this temperature for 16h. After the reaction was completed, DCM (30ml × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was separated by column (eluent: petroleum ether / ethyl acetate (v / v) = 1: 2), 0.42 g of product was obtained in a yield of 65%. LC-MS (APCI): m / z = 447.80 (M + 1) + .

[0254]
Step 2 Synthesis of Compound 8

[0255]
Under nitrogen protection, compound 7 (0.4 g, 0.90 mmol), compound 3 (0.4 g, 1.07 mmol), sodium carbonate (0.38 g, 3.6 mmol), and Pd (dppf) Cl2 (0.07 g, 0.09 mmol) were added in this order. Into a mixed solution of toluene (20 ml) and water (4 ml), the mixture was heated to 80 ° C. and reacted for 2 h. The reaction solution was cooled to room temperature, extracted with ethyl acetate (30 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 1: 1) 0.2 g of product was obtained with a yield of 40%. LC-MS (APCI): m / z = 565.03 (M + 1) + .

[0256]
Step 3 Synthesis of Compound 9

[0257]
At 0 ° C, a solution of 4M hydrochloric acid in dioxane (4 ml) was slowly added to a solution of compound 8 (0.2 g, 0.35 mmol) in DCM (10 ml), and the reaction mixture was warmed to room temperature and continued to react for 6 h. After the reaction is complete, the solution is spin-dried and directly sent to the next step without further processing. LC-MS (APCI): m / z = 465.27 (M + 1) + .

[0258]
Step 4 Synthesis of Compound L-2

[0259]
Compound 9 (0.2 g, 0.43 mmol) and triethylamine (0.22 g, 2.1 mmol) were sequentially added to the DCM (10 ml) solution. After lowering to 0 ° C, MsCl (0.15 g, 1.3 mmol) was slowly added dropwise. After the addition was completed, the reaction temperature was raised to room temperature for 5 hours. After the reaction was completed, the reaction solution was spin-dried to obtain a residue. Toluene (9 ml), methanol (1 ml), water (10 ml), and sodium carbonate (2 g) were sequentially added to the residue. The reaction temperature was raised to 85 ° C for 10 hours, cooled to room temperature, and extracted with ethyl acetate (20ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: dichloromethane / methanol (v / v) = 20: 1), 70 mg of product was obtained with a yield of 30%. LC-MS (APCI): m / z = 543.21 (M + 1) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.01 (d, J = 11.4 Hz, 2H), 7.63 (d, J = 6.3 Hz, 1H), 7.40 (d, J = 5.8 Hz, 1H), 6.58 (d , J = 6.1 Hz, 1H), 5.47 (d, J = 18.8 Hz, 1H), 5.17 (s, 1H), 4.59 (d, J = 12.2, Hz, 1H), 3.80 (s, 1H), 3.61 ( s, 1H) 3.24 (s, 1H), 3.10 (d, J = 16.6 Hz, 3H), 2.21 (s, 1H), 1.35 (s, 3H), 1.27 (d, 6H).

[0260]
Example 3 (S)-(methyl-d 3)-(1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- ( Preparation of prop-2-yl-d 7) -1H-pyrazol-4 -yl) pyrimidin-2-yl) amino) prop-2-yl) carbamate (compound L-3).

[0261]
WO2020011141 / pic / iqj6pvdjjM4HOwS5mON3pOQ9HR7saOazmNYNpzaiXojjcGBiI6WDlFm3cKezb4yS-LlWgLP3UOsiRLU-U82AHxNXxfErtH82vSuy7aRZyypOhFxSIKcmsU1IrgUTfZfHvHyV7GUrqgilmX3Uhs5HqB4J8lAtCQzt3Usg8oMeezs “>

[0262]
Take the following synthetic route:

[0263]
WO2020011141 / pic / YwVS_N4uouPkEHjeYuqZOHrNDrfCXIg0xzYvgPjs2CnKzWkQFiTy2WMm9EsgMfhElppKsKCS5sgXcDsnhYWWYWWYWWYVWYWYWW

[0264]
Step 1 Synthesis of compound 10

[0265]
Under nitrogen protection, intermediate compound A (0.6 g, 1.7 mmol), intermediate compound B (0.23 g, 1.7 mmol), and sodium carbonate (0.71 g, 6.8 mmol) were added to the DMSO (20 ml) solution in this order, and the temperature was raised to The reaction was stirred at 90 ° C for 16h at this temperature. After the reaction was completed, DCM (30ml × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate ( v / v) = 1: 2), 0.65 g of product was obtained with a yield of 84%. LC-MS (APCI): m / z = 454.92 (M + 1) + .

[0266]
Step 2 Synthesis of Compound 11

[0267]
Under nitrogen protection, compound 10 (0.6 g, 1.3 mmol), compound 3 (0.59 g, 1.6 mmol), sodium carbonate (0.56 g, 5.3 mmol), and Pd (dppf) Cl2 (0.10 g, 0.13 mmol) were added in this order. Into a mixed solution of toluene (20 ml) and water (4 ml), heated to 80 ° C. for 2 h. The reaction solution was cooled to room temperature, extracted with ethyl acetate (30 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 1: 1) 0.32 g of the product was obtained with a yield of 43%. LC-MS (APCI): m / z = 572.10 (M + 1) + .

[0268]
Step 3 Synthesis of Compound 12

[0269]
At 0 ° C, a solution of 4M hydrochloric acid in dioxane (4 ml) was slowly added to a solution of compound 11 (0.3 g, 0.52 mmol) in DCM (10 ml), and the reaction mixture was warmed to room temperature and continued to react for 6 h. After the reaction is complete, the solution is spin-dried and directly sent to the next step without further processing. LC-MS (APCI): m / z = 472.09 (M + 1) + .

[0270]
Step 4 Synthesis of Compound L-3

[0271]
Compound 12 (0.25 g, 0.53 mmol) and triethylamine (0.27 g, 2.6 mmol) were sequentially added to the DCM (10 ml) solution. After dropping to 0 ° C, MsCl (0.18 g, 1.6 mmol) was slowly added dropwise. After the addition was completed, the reaction temperature was raised to room temperature for 5 hours. After the reaction was completed, the reaction solution was spin-dried to obtain a residue. Toluene (9 ml), methanol (1 ml), water (10 ml), and sodium carbonate (2 g) were sequentially added to the residue. The reaction temperature was raised to 85 ° C for 10 hours, cooled to room temperature, and extracted with ethyl acetate (20ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: dichloromethane / methanol (v / v) = 20: 1), 75 mg of product was obtained with a yield of 26%. LC-MS (APCI): m / z = 550.29 (M + 1) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (d, J = 11.4 Hz, 2 H), 7.63 (d, J = 6.3 Hz, 1 H), 7.40 (d, J = 5.8 Hz, 1 H), 6.65 (d , J = 6.1 Hz, 1H), 5.47 (d, J = 18.8 Hz, 1H), 5.17 (s, 1H), 4.63 (d, J = 12.2, Hz, 1H), 3.70 (s, 1H), 3.54 ( s, 1H), 3.16 (d, J = 16.6 Hz, 3H), 2.11 (s, 1H), 1.38 (s, 3H).

[0272]
Example 4 (1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- (prop-2-yl) -1H-pyrazole- 4- yl) pyrimidin-2-yl) amino ) propan-2-yl -1,1,3,3,3-d 5) carbamate (compound L-4),

[0273]
(S)-(1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- (prop-2-yl) -1H-pyrazole 4-yl) pyrimidin-2-yl) amino) propan-2- yl-1,1,3,3,3-d 5) methyl carbamate (compound L-4-S) and

[0274]
(R)-(1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- (prop-2-yl) -1H-pyrazole 4-yl) pyrimidin-2-yl) amino) propan-2- yl-1,1,3,3,3-d 5) Preparation of methyl carbamate (compound L-4-R).

[0275]
WO2020011141 / pic / m0IN31dnhItfm5H-dGFizFalHv9quUKvHfmY4zFpAaHFgTp-0iUzxdHuZwlvRxqTStKdio_PlNaIPfHi8pthED3hbMalT8GyFmZ1tCDOIKmutZCiuLJ4FJW4WY

[0276]
Take the following synthetic route:

[0277]
WO2020011141 / pic / fjV2PIKmugqfUgshQfiVwrkjSTGfhIl9ZWz96JIiDMEhwjAlTOxFStuhxFFooUqAr0FVv7GXsyKUDxeLYZl-uQQWMt1C9_9Zi9U9U9Zi9U9U

[0278]
Step 1 Synthesis of compound 13

[0279]
Under nitrogen protection, compound 6 (0.4 g, 1.1 mmol), intermediate compound C (0.16 g, 1.1 mmol), and sodium carbonate (0.50 g, 4.6 mmol) were sequentially added to the DMSO (15 ml) solution, and the solution was raised to The reaction was stirred at 90 ° C at this temperature for 16 hours. After the reaction was completed, the reaction solution was extracted with dichloromethane (30 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether). / Ethyl acetate (v / v) = 1: 2) to obtain 0.40 g of the product in a yield of 75%. LC-MS (APCI): m / z = 449.53 (M + 1) + .

[0280]
Step 2 Synthesis of Compound 14

[0281]
Under a nitrogen atmosphere, compound 13 (0.4 g, 0.9 mmol), compound 3 (0.5 g, 1.4 mmol), sodium carbonate (0.40 g, 3.56 mmol), and Pd (dppf) Cl 2 (0.08 g, 0.1 mmol) were added in this order. Into a mixed solution of toluene (20 ml) and water (4 ml), heated to 80 ° C. for 2 h. The reaction solution was cooled to room temperature, and then extracted with ethyl acetate (30 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 1: 1), 0.28 g of product was obtained with a yield of 55%. LC-MS (APCI): m / z = 567.12 (M + 1) + .

[0282]
Step 3 Synthesis of Compound 15

[0283]
At 0 ° C, a solution of 4M hydrochloric acid in dioxane (2ml) was slowly added to a solution of compound 14 (0.28g, 0.50mmol) in dichloromethane (10ml), and the reaction was continued at room temperature for 6h. After the reaction is completed, the solution is directly spin-dried and directly sent to the next step without further processing. LC-MS (APCI): m / z = 467.29 (M + 1) + .

[0284]
Step 4 Synthesis of compound L-4

[0285]
Triethylamine (0.13 g, 1.28 mmol) was added to a solution of compound 15 (0.2 g, 0.43 mmol) in dichloromethane (10 ml). After the solution was lowered to 0 ° C, methanesulfonyl chloride (0.15 g, 1.3 mmol) was slowly added dropwise to the upper solution. The reaction solution was reacted at room temperature for 5 hours. After the reaction was completed, the reaction solution was spin-dried. To the residue were added toluene (9 ml), methanol (1 ml), and water (10 ml). Sodium carbonate (2g), the solution was reacted at 85 ° C for 10h, the reaction solution was cooled to room temperature, and then extracted with ethyl acetate (20ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation ( Eluent: dichloromethane / methanol (v / v) = 20: 1) to obtain 65 mg of the product with a yield of 27%. LC-MS (APCI): m / z = 545.08 (M + 1) + . 1 H NMR (400MHz, CDCl 3 ) δ8.05 (d, 2H), 7.61 (d, 1H), 7.45 (d, 1H), 6.40 (d, 1H), 5.29 (d, 1H), 5.18 (s, 1H), 4.62 (d, 1H), 3.89 (d, 1H), 3.58 (s, 3H), 3.10 (d, 3H), 2.05 (s, 1H), 1.29 (d, 6H).

[0286]
Step 5 Synthesis of compounds L-4-S and L-4-R

[0287]
The racemic compound L-4 was separated using a chiral preparative column to obtain compounds L-4-S and L-4-R.

[0288]
Example 5 (1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- (prop-2-yl-d 7))-1H -Pyrazol-4-yl) pyrimidin-2-yl) amino) propan-2-yl-1,1,3,3,3-d 5) methyl carbamate (compound L-5),

[0289]
(S)-(1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- (prop-2-yl-d 7))- 1H-pyrazol-4-yl) pyrimidin-2-yl) amino) propan-2-yl-1,1,3,3,3-d 5) methyl carbamate (compound L-5-S) and

[0290]
(R)-(1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- (prop-2-yl-d 7))- 1H-pyrazol-4-yl) pyrimidin-2-yl) amino) propan-2-yl-1,1,3,3,3-d 5) Preparation of methyl carbamate (compound L-5-R) .

[0291]
WO2020011141 / pic / 4br07jLUTScNPUcnWdxxTyAAMGS9P15P0yXUsyhcCny-ABv5BZExa5YOY-Hj3wTZWdByUUB-EQbGG-h4QuoddgCTRMClBcl1WY1TjnTsnDDYTZxC6-taMQZYW1Z1WY

[0292]
WO2020011141 / pic / By6lfXwpBcoklf-47-VujG_XNVWV7ZjYOo73wMiKwo9v4cKff0K2As3lqLKG1kFOYG87EWp6SIobdq2gtEFMnxfVVVJVYVZGYZFYZVYG-ZVY-ZFY-ZF

[0293]
Take the following synthetic route:

[0294]
WO2020011141 / pic / dMfm7g9kIiR87Eo-VsdQ2-2wcdHuYsfKuUWOyKuR4SUJ3Kmoy907w2C1tLHvEDhc4vBBT2l48TSysgdivcFJmRqGQNZWYQZNYWQD

[0295]
Step 1 Synthesis of compound 16

[0296]
Under nitrogen protection, intermediate compound A (0.5 g, 1.5 mmol), intermediate compound C (0.2 g, 1.5 mmol), and sodium carbonate (0.63 g, 6.0 mmol) were added to the DMSO (20 ml) solution in this order. The temperature was raised to 90 ° C, and the reaction was stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was extracted with dichloromethane (30ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: Petroleum ether / ethyl acetate (v / v) = 1: 2) to obtain 0.45 g of the product with a yield of 68%. LC-MS (APCI): m / z = 456.68 (M + 1) + .

[0297]
Step 2 Synthesis of Compound 17

[0298]
Under a nitrogen atmosphere, compound 16 (0.45 g, 0.98 mmol), compound 3 (0.55 g, 1.54 mmol), sodium carbonate (0.42 g, 3.95 mmol), and Pd (dppf) Cl 2 (0.08 g, 0.1 mmol) were sequentially added Into a mixed solution of toluene (20 ml) and water (4 ml), heated to 80 ° C. for 2 h. The reaction solution was cooled to room temperature, and then extracted with ethyl acetate (30 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 1: 1), 0.40 g of the product was obtained in a yield of 70%. LC-MS (APCI): m / z = 574.16 (M + 1) + .

[0299]
Step 3 Synthesis of Compound 18

[0300]
A solution of 4M hydrochloric acid in dioxane (2 ml) was slowly added to a solution of compound 17 (0.40 g, 0.70 mmol) in dichloromethane (10 ml) at 0 ° C, and the reaction was allowed to proceed to room temperature for 6 h. After the reaction is completed, the solution is directly spin-dried and directly sent to the next step without further processing. LC-MS (APCI): m / z = 474.21 (M + 1) + .

[0301]
Step 4 Synthesis of Compound L-5

[0302]
Triethylamine (0.23 g, 2.21 mmol) was added to a solution of compound 18 (0.35 g, 0.74 mmol) in dichloromethane (10 ml). After the solution was lowered to 0 ° C, methanesulfonyl chloride (0.25 g, 2.2 mmol) was slowly added dropwise to the upper solution. The reaction solution was reacted at room temperature for 5 hours. After the reaction was completed, the reaction solution was spin-dried. To the residue were added toluene (9 ml), methanol (1 ml), and water (10 ml). Sodium carbonate (2g), the solution was reacted at 85 ° C for 10h, the reaction solution was cooled to room temperature, and then extracted with ethyl acetate (20ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation Eluent: dichloromethane / methanol (v / v) = 20: 1) to obtain 120 mg of the product in a yield of 30%. LC-MS (APCI): m / z = 552.33 (M + 1) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.02 (d, 2H), 7.61 (d, 1H), 7.45 (d, 1H), 6.40 (d, 1H), 5.22 (d, 1H), 5.18 (s, 1H), 4.59 (d, 1H), 3.58 (s, 3H), 2.98 (d, 3H), 2.05 (s, 1H).

[0303]
Step 5 Synthesis of compounds L-5-S and L-5-R

[0304]
The racemic compound L-4 was separated using a chiral preparative column to obtain compounds L-5-S and L-5-R.

Fluorodopa F 18, フルオロドパ (18F), флуородопа (18F) , فلورودوبا (18F) , 氟[18F]多巴 ,


92812-82-3.png

ChemSpider 2D Image | Fluorodopa F 18 | C9H1018FNO4

Fluorodopa F 18

2019/10/10, fda 2019,

Formula
C9H10FNO4
Cas
92812-82-3
Mol weight
215.1784

Diagnostic aid (brain imaging), Radioactive agent, for use in positron emission tomography (PET)

CAS 92812-82-3

フルオロドパ (18F)

L-6-(18F)Fluoro-DOPA
L-Tyrosine, 2-fluoro-18F-5-hydroxy- [ACD/Index Name]
флуородопа (18F) [Russian] [INN]
فلورودوبا (18F) [Arabic] [INN]
氟[18F]多巴 [Chinese] [INN]
((18)F)FDOPA
2-(fluoro-(18)F)-5-hydroxy-L-tyrosine
2-(Fluoro-18F)-5-hydroxy-L-tyrosine
2-(Fluoro-18F)-L-DOPA
2C598205QX
6-((18)F)fluoro-L-DOPA
6-(18F)Fluoro-L-DOPA
6692
(18F)FDOPA
2-((18)F)fluoro-5-hydroxy-L-tyrosine

Fluorodopa, also known as FDOPA, is a fluorinated form of L-DOPA primarily synthesized as its fluorine-18isotopologue for use as a radiotracer in positron emission tomography (PET).[1] Fluorodopa PET scanning is a valid method for assessing the functional state of the nigrostriatal dopaminergic pathway. It is particularly useful for studies requiring repeated measures such as examinations of the course of a disease and the effect of treatment

In October 2019, Fluorodopa was approved in the United States for the visual detection of certain nerve cells in adult patients with suspected Parkinsonian Syndromes (PS).[2][3]

The U.S. Food and Drug Administration (FDA) approved Fluorodopa F 18 based on evidence from one clinical trial of 56 patients with suspected PS.[2] The trial was conducted at one clinical site in the United States.[2]

PAPER

 Organic & Biomolecular Chemistry (2019), 17(38), 8701-8705

A one-pot two-step synthesis of 6-[18F]fluoro-L-DOPA ([18F]FDOPA) has been developed involving Cu-mediated radiofluorination of a pinacol boronate ester precursor. The method is fully automated, provides [18F]FDOPA in good activity yield (104 ± 16 mCi, 6 ± 1%), excellent radiochemical purity (>99%) and high molar activity (3799 ± 2087 Ci mmol−1), n = 3, and has been validated to produce the radiotracer for human use.

Graphical abstract: One-pot synthesis of high molar activity 6-[18F]fluoro-l-DOPA by Cu-mediated fluorination of a BPin precursor
Radiosynthesis of [ 18F]6F-l-DOPA The synthesis of [ 18F]6F-l-DOPA was fully-automated using a General Electric (GE) TRACERLab FXFN synthesis module (Figure S1) loaded as follows: V1: 500 µL 15mg/mL TBAOTf + 0.2 mg/mL Cs2CO3 in water; V2: 1000 µL acetonitrile; V3: 4 µmol Bpin precursor, 20 µmol Cu2+ , 500 µmol pyridine in 1 mL DMF; V4: 0.2 mL 0.25 M ascorbic acid + 0.6 mL 12.1 N HCl; V6: 3 mL acetonitrile; V7: 10 mL 0.9% saline, USP; V8: 2 mL ethanol, USP; Dilution flask: 100 mL acetonitrile ; F18 separation port: QMA cartridge ; C18 port: Strata cartridge.

PATENT

KR 2019061368

The present invention relates to an L-dopa precursor compd., a method for producing the same, and a method for producing 18F-labeled L-dopa using the same.  The method of prepg. 18F-labeled L-dopa I using the L-dopa precursor II [A = halogen-(un)substituted alkyl; W, X, Y = independently protecting group] can improve the labeling efficiency of 18F.  After the labeling reaction, sepn. and purifn. steps of the product can be carried out continuously and it can be performed with on-column labeling (a method of labeling through the column).  The final product I, 18 F-labeled L-dopa, can be obtained at a high yield relative to conventional methods.  Further, it has an advantage that it is easy to apply various methods such as bead labeling.

PAPER

Science (Washington, DC, United States) (2019), 364(6446), 1170-1174.

PAPER

European Journal of Organic Chemistry (2018), 2018(48), 7058-7065.

PATENT

WO 2018115353

CN 107311877

References

  1. ^ Deng WP, Wong KA, Kirk KL (June 2002). “Convenient syntheses of 2-, 5- and 6-fluoro- and 2,6-difluoro-L-DOPA”. Tetrahedron: Asymmetry13 (11): 1135–1140. doi:10.1016/S0957-4166(02)00321-X.
  2. Jump up to:a b c “Drug Trials Snapshots: Fluorodopa F 18”U.S. Food and Drug Administration (FDA). 27 November 2019. Archived from the original on 27 November 2019. Retrieved 27 November 2019. This article incorporates text from this source, which is in the public domain.
  3. ^ “Drug Approval Package: Fluorodopa F18”U.S. Food and Drug Administration (FDA). 20 November 2019. Archived from the original on 27 November 2019. Retrieved 26 November 2019. This article incorporates text from this source, which is in the public domain.
Fluorodopa
Fluorodopa.png
Clinical data
Other names 6-fluoro-L-DOPA, FDOPA
License data
Legal status
Legal status
Identifiers
CAS Number
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C9H10FNO4
Molar mass 215.18 g/mol g·mol−1
3D model (JSmol)

//////////////////Fluorodopa F 18, フルオロドパ (18F), FDA 2019, флуородопа (18F) فلورودوبا (18F) 氟[18F]多巴 , radio labelled

N[C@@H](CC1=CC(O)=C(O)C=C1[18F])C(O)=O

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