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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

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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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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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References

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  29. ^ Kurup P, Zhang Y, Xu J, Venkitaramani DV, Haroutunian V, Greengard P, et al. (April 2010). “Abeta-mediated NMDA receptor endocytosis in Alzheimer’s disease involves ubiquitination of the tyrosine phosphatase STEP61”The Journal of Neuroscience30(17): 5948–57. doi:10.1523/JNEUROSCI.0157-10.2010PMC 2868326PMID 20427654.
  30. ^ Kim EL, Wüstenberg R, Rübsam A, Schmitz-Salue C, Warnecke G, Bücker EM, et al. (April 2010). “Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells”Neuro-Oncology12 (4): 389–400. doi:10.1093/neuonc/nop046PMC 2940600PMID 20308316.
  31. ^ Hempelmann E (March 2007). “Hemozoin biocrystallization in Plasmodium falciparum and the antimalarial activity of crystallization inhibitors”. Parasitology Research100 (4): 671–6. doi:10.1007/s00436-006-0313-xPMID 17111179.
  32. ^ Lin JW, Spaccapelo R, Schwarzer E, Sajid M, Annoura T, Deroost K, et al. (June 2015). “Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance” (PDF)The Journal of Experimental Medicine212(6): 893–903. doi:10.1084/jem.20141731PMC 4451122PMID 25941254Archived (PDF) from the original on 22 September 2017. Retrieved 4 November 2018.
  33. ^ Martin RE, Marchetti RV, Cowan AI, Howitt SM, Bröer S, Kirk K (September 2009). “Chloroquine transport via the malaria parasite’s chloroquine resistance transporter”. Science325 (5948): 1680–2. Bibcode:2009Sci…325.1680Mdoi:10.1126/science.1175667PMID 19779197.
  34. ^ Essentials of medical pharmacology fifth edition 2003, reprint 2004, published by-Jaypee Brothers Medical Publisher Ltd, 2003, KD Tripathi, pages 739,740.
  35. ^ Alcantara LM, Kim J, Moraes CB, Franco CH, Franzoi KD, Lee S, et al. (June 2013). “Chemosensitization potential of P-glycoprotein inhibitors in malaria parasites”. Experimental Parasitology134 (2): 235–43. doi:10.1016/j.exppara.2013.03.022PMID 23541983.
  36. ^ 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.
  37. ^ Al-Bari MA (February 2017). “Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases”Pharmacology Research & Perspectives5 (1): e00293. doi:10.1002/prp2.293PMC 5461643PMID 28596841.
  38. ^ Fredericksen BL, Wei BL, Yao J, Luo T, Garcia JV (November 2002). “Inhibition of endosomal/lysosomal degradation increases the infectivity of human immunodeficiency virus”Journal of Virology76 (22): 11440–6. doi:10.1128/JVI.76.22.11440-11446.2002PMC 136743PMID 12388705.
  39. ^ Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ (1 October 2014). “Chloroquine is a zinc ionophore”PloS One9(10): e109180. doi:10.1371/journal.pone.0109180PMC 4182877PMID 25271834.
  40. ^ te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ (November 2010). “Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture”PLoS Pathogens6 (11): e1001176. doi:10.1371/journal.ppat.1001176PMC 2973827PMID 21079686.
  41. ^ Huang Z, Srinivasan S, Zhang J, Chen K, Li Y, Li W, et al. (2012). “Discovering thiamine transporters as targets of chloroquine using a novel functional genomics strategy”PLOS Genetics8 (11): e1003083. doi:10.1371/journal.pgen.1003083PMC 3510038PMID 23209439.
  42. ^ Fern, Ken (2010–2020). “Cinchona officinalis – L.” Plans for a FutureArchived from the original on 25 August 2017. Retrieved 2 February 2020.
  43. ^ V. Kouznetsov, Vladímir (2008). “Antimalarials: construction of molecular hybrids based on chloroquine” (PDF)Universitas Scientiarum: 1. Archived (PDF) from the original on 22 February 2020. Retrieved 22 February 2020 – via scielo.
  44. ^ Krafts K, Hempelmann E, Skórska-Stania A (July 2012). “From methylene blue to chloroquine: a brief review of the development of an antimalarial therapy”. Parasitology Research111 (1): 1–6. doi:10.1007/s00436-012-2886-xPMID 22411634.
  45. ^ “The History of Malaria, an Ancient Disease”. Centers for Disease Control. 29 July 2019. Archived from the original on 28 August 2010.
  46. ^ “Chloroquine”nih.gov. National Institutes of Health. Retrieved 24 March 2020.
  47. ^ “Ipca Laboratories: Formulations – Branded”Archived from the original on 6 April 2019. Retrieved 14 March 2020.
  48. ^ Francis-Floyd, Ruth; Floyd, Maxine R. “Amyloodinium ocellatum, an Important Parasite of Cultured Marine Fish” (PDF)agrilife.org.
  49. ^ “Could an old malaria drug help fight the new coronavirus?”asbmb.orgArchived from the original on 6 February 2020. Retrieved 6 February 2020.
  50. ^ 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.
  51. ^ Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020 Mar 11:105938. doi:10.1016/j.ijantimicag.2020.105938 PMID 32171740
  52. ^ “Physicians work out treatment guidelines for coronavirus”m.koreabiomed.com (in Korean). 13 February 2020. Archivedfrom the original on 17 March 2020. Retrieved 18 March 2020.
  53. ^ “Azioni intraprese per favorire la ricerca e l’accesso ai nuovi farmaci per il trattamento del COVID-19”aifa.gov.it (in Italian). Retrieved 18 March 2020.
  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

Galidesivir


BCX4430.svg

ChemSpider 2D Image | Galidesivir | C11H15N5O3

Galidesivir

  • Molecular FormulaC11H15N5O3
  • Average mass265.268 Da
Immucillin-A
OLF97F86A7
UNII:OLF97F86A7
галидесивир [Russian] [INN]
غاليديسيفير [Arabic] [INN]
加利司韦 [Chinese] [INN]
Galidesivir [INN]
(2S,3S,4R,5R)-2-(4-amino- 5H-pyrrolo[3,2-d]pyrimidin- 7-yl)-5-(hydroxymethyl) pyrrolidine-3,4-diol
(2S,3S,4R,5R)-2-(4-Amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)-3,4-pyrrolidinediol [ACD/IUPAC Name]
10284
222631-44-9 [RN]
249503-25-1 [RN]
3,4-Pyrrolidinediol, 2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)-, (2S,3S,4R,5R)- [ACD/Index Name]
BCX4430 [Wiki]

Galidesivir

249503-25-1

222631-44-9, BCX-4430 (HCL salt form of galidesivir)

2-(4-Amino-5H-pyrrolo(3,2-d)pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol.png

Galidesivir (BCX4430Immucillin-A) is an antiviral drug, an adenosine analog[1] (a type of nucleoside analog).[2] It is developed by BioCryst Pharmaceuticals with funding from NIAID, originally intended as a treatment for hepatitis C, but subsequently developed as a potential treatment for deadly filovirus infections such as Ebola virus disease and Marburg virus disease.

It also shows broad-spectrum antiviral effectiveness against a range of other RNA virus families, including bunyavirusesarenavirusesparamyxovirusescoronavirusesflaviviruses and phleboviruses.[3] BCX4430 has been demonstrated to protect against both Ebola and Marburg viruses in both rodents and monkeys, even when administered up to 48 hours after infection,[1] and development for use in humans was then being fast-tracked due to concerns about the lack of treatment options for the 2013-2016 Ebola virus epidemic in West Africa.[4]

BCX4430 later showed efficacy against Zika virus in a mouse model, though there are no plans for human trials at this stage.[5]

Galidesivir is one of several antiviral drugs being tested for coronavirus disease 2019.[6]

Image result for Galidesivir SYNTHESIS

CLIP

https://www.sciencedirect.com/science/article/pii/S0040402017305926

Image result for Galidesivir SYNTHESIS

CLIP

https://cen.acs.org/sections/coronavirus/biological-chemistry/infectious-disease/coronavirus-drug-repurposing.html

coronavirus-scheme.jpg

When any new virus emerges, drug and vaccine developers spring into action, searching for products to stop it in its tracks. Drug discovery campaigns launch, vaccine development efforts ramp up, and everyone mobilizes to get it all into the clinic as quickly as possible.

The current pandemic, driven by a coronavirus known as SARS-CoV-2, is no different. Already, a Phase I study of an mRNA-based vaccine developed by Moderna has begun, and major pharma companies and small biotechs are working on other types of vaccines. But even if they work, the most optimistic timelines put a vaccine a year to 18 months away.

The more immediate approach to an outbreak is to scour the medicine cabinet for existing molecules that could be repurposed against a new virus. The most advanced potential treatment is Gilead Sciences’ remdesivir, an antiviral discovered during the 2014 Ebola epidemic. The compound is already being tested in four, Phase III trials—two in China and two in the US—against the respiratory disease COVID-19. Gilead expects the first dataset from those studies to come out in April.

A new paper from CAS explored remdesivir and other possible options the cabinet might contain (ACS Cent. Sci. 2020, DOI: 10.1021/acscentsci.0c00272). CAS, a division of the American Chemical Society, which publishes C&EN, looked at the landscape of patent and journal articles covering small molecules, antibodies, and other therapeutic classes to identify therapies with potential activity against COVID-19.

SARS-CoV-2, belongs to the same family as two coronaviruses responsible for earlier outbreaks, Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). Because all three feature structurally similar proteins that allow entry into and replication inside host cells, CAS searched for patent data related to those more well-studied coronaviruses.

C&EN has assembled the relevant small molecules identified by CAS, which can be explored by the stage in the viral life cycle they aim to disrupt.

Patents

Patent ID Title Submitted Date Granted Date
US7390890 Inhibitors of nucleoside metabolism 2007-08-23 2008-06-24
US7211653 Inhibitors of nucleoside metabolism 2005-02-03 2007-05-01
US6803455 Inhibitors of nucleoside metabolism 2003-05-22 2004-10-12
US6492347 Inhibitors of nucleoside metabolism 2002-05-23 2002-12-10
US6228847 Inhibitors of nucleoside metabolism 2001-05-08
Patent ID Title Submitted Date Granted Date
EP1023308 INHIBITORS OF NUCLEOSIDE METABOLISM 2000-08-02 2005-09-07
US6066722 Inhibitors of nucleoside metabolism 2000-05-23

References

  1. Jump up to:a b Warren TK, Wells J, Panchal RG, Stuthman KS, Garza NL, Van Tongeren SA, et al. (April 2014). “Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430” (PDF)Nature508 (7496): 402–5. Bibcode:2014Natur.508..402Wdoi:10.1038/nature13027PMID 24590073.
  2. ^ Kamat SS, Burgos ES, Raushel FM (October 2013). “Potent inhibition of the C-P lyase nucleosidase PhnI by Immucillin-A triphosphate”Biochemistry52 (42): 7366–8. doi:10.1021/bi4013287PMC 3838859PMID 24111876.
  3. ^ Westover JB, et al. Galidesivir limits Rift Valley fever virus infection and disease in Syrian golden hamsters. Antiviral Res. 2018 Aug;156:38-45. Westover, J. B.; Mathis, A.; Taylor, R.; Wandersee, L.; Bailey, K. W.; Sefing, E. J.; Hickerson, B. T.; Jung, K. H.; Sheridan, W. P.; Gowen, B. B. (2018). “Galidesivir limits Rift Valley fever virus infection and disease in Syrian golden hamsters”Antiviral Research156: 38–45. doi:10.1016/j.antiviral.2018.05.013PMC 6035881PMID 29864447.
  4. ^ Rodgers P (8 April 2014). “BioWar Lab Helping To Develop Treatment For Ebola”Forbes Magazine.
  5. ^ Julander JG, Siddharthan V, Evans J, Taylor R, Tolbert K, Apuli C, et al. (January 2017). “Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model”Antiviral Research137: 14–22. doi:10.1016/j.antiviral.2016.11.003PMC 5215849PMID 27838352.
  6. ^ Praveen Duddu. Coronavirus outbreak: Vaccines/drugs in the pipeline for Covid-19. clinicaltrialsarena.com 19 February 2020.

 

Galidesivir
BCX4430.svg
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C11H15N5O3
Molar mass 265.268 g·mol−1
3D model (JSmol)

//////////////Galidesivir, Immucillin-A, OLF97F86A7, UNII:OLF97F86A7, галидесивирغاليديسيفير加利司韦 , BCX4430, BCX 4430, CORONAVIRUS, COVID 19

 

nitazoxanide

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]

 

clip

Image result for hydroxychloroquine

clip

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

  1. Jump up to:a b “Hydroxychloroquine Use During Pregnancy”Drugs.com. 28 February 2020. Retrieved 21 March 2020.
  2. Jump up to:a b c d e f g h i j k l m n o p “Hydroxychloroquine Sulfate Monograph for Professionals”. The American Society of Health-System Pharmacists. 20 March 2020. Archived from the original on 20 March 2020. Retrieved 20 March 2020.
  3. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia. Jones & Bartlett Learning. p. 463. ISBN 9781284057560.
  4. ^ Cortegiani, Andrea; Ingoglia, Giulia; Ippolito, Mariachiara; Giarratano, Antonino; Einav, Sharon (10 March 2020). “A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19”Journal of Critical Caredoi:10.1016/j.jcrc.2020.03.005ISSN 0883-9441.
  5. ^ Flint, Julia; Panchal, Sonia; Hurrell, Alice; van de Venne, Maud; Gayed, Mary; Schreiber, Karen; Arthanari, Subha; Cunningham, Joel; Flanders, Lucy; Moore, Louise; Crossley, Amy (1 September 2016). “BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding – Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids”Rheumatology55 (9): 1693–1697. doi:10.1093/rheumatology/kev404ISSN 1462-0324.
  6. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ^ “Single Drug Information | International Medical Products Price Guide”. Retrieved 31 December 2019.[dead link]
  8. ^ “NADAC as of 2019-08-07”Centers for Medicare and Medicaid Services. Retrieved 19 March 2020Typical dose is 600mg per day. Costs 0.28157 per dose. Month has about 30 days.
  9. ^ British national formulary: BNF 69 (69 ed.). British Medical Association. 2015. p. 730. ISBN 9780857111562.
  10. ^ “The Top 300 of 2020”ClinCalc. Retrieved 18 March 2020.
  11. ^ Effects of Hydroxychloroquine on Symptomatic Improvement in Primary Sjögren Syndrome, Gottenberg, et al. (2014) “Archived copy”Archived from the original on 11 July 2015. Retrieved 10 July 2015.
  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

FAVIPIRAVIR, ファビピラビル


 

FAVIPIRAVIR
Toyama (Originator)
RNA-Directed RNA Polymerase (NS5B) Inhibitors
Chemical Formula: C5H4FN3O2
CAS #: 259793-96-9
Molecular Weight: 157.1

ANTI-INFLUENZA COMPOUND

clinical trials  http://clinicaltrials.gov/search/intervention=Favipiravir
Chemical Name: 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
Synonyms: T-705, T705, Favipiravir

ChemSpider 2D Image | favipiravir | C5H4FN3O2

  • Molecular FormulaC5H4FN3O2
  • Average mass157.103 Da
259793-96-9 [RN]
2-Pyrazinecarboxamide, 6-fluoro-3,4-dihydro-3-oxo-
6-Fluoro-3-hydroxypyrazine-2-carboxamide
6-Fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide
8916
Avigan

ファビピラビル
Favipiravir

6-Fluoro-3-hydroxypyrazine-2-carboxamide

C5H4FN3O2 : 157.1
[259793-96-9]

https://www.pmda.go.jp/files/000210319.pdf

The drug substance is a white to light yellow powder. It is sparingly soluble in acetonitrile and in methanol, and slightly soluble in water and in ethanol (99.5). It is slightly soluble at pH 2.0 to 5.5 and sparingly soluble at pH 5.5 to 6.1. The drug substance is not hygroscopic at 25°C/51% to 93%RH. The melting point is 187°C to 193°C, and the dissociation constant (pKa) is 5.1 due to the hydroxyl group of favipiravir. Measurement results on the partition ratio of favipiravir in water/octanol at 25°C indicate that favipiravir tends to be distributed in the 1-octanol phase at pH 2 to 4 and in the water phase at pH 5 to 13.

Any batch manufactured by the current manufacturing process is in Form A. The stability study does not show any change in crystal form over time; and a change from Form A to Form B is unlikely.

Experimental Properties

PROPERTY VALUE SOURCE
melting point (°C) 187℃ to 193℃ https://www.pmda.go.jp/files/000210319.pdf
water solubility slightly soluble in water https://www.pmda.go.jp/files/000210319.pdf
pKa 5.1 https://www.pmda.go.jp/files/000210319.pdf
T-705 is an RNA-directed RNA polymerase (NS5B) inhibitor which has been filed for approval in Japan for the oral treatment of influenza A (including avian and H1N1 infections) and for the treatment of influenza B infection.
The compound is a unique viral RNA polymerase inhibitor, acting on viral genetic copying to prevent its reproduction, discovered by Toyama Chemical. In 2005, Utah State University carried out various studies under its contract with the National Institute of Allergy and Infectious Diseases (NIAID) and demonstrated that T-705 has exceptionally potent activity in mouse infection models of H5N1 avian influenza.
T-705 (Favipiravir) is an antiviral pyrazinecarboxamide-based, inhibitor of of the influenza virus with an EC90 of 1.3 to 7.7 uM (influenza A, H5N1). EC90 ranges for other influenza A subtypes are 0.19-1.3 uM, 0.063-1.9 uM, and 0.5-3.1 uM for H1N1, H2N2, and H3N2, respectively. T-705 also exhibits activity against type B and C viruses, with EC90s of 0.25-0.57 uM and 0.19-0.36 uM, respectively. (1) Additionally, T-705 has broad activity against arenavirus, bunyavirus, foot-and-mouth disease virus, and West Nile virus with EC50s ranging from 5 to 300 uM.
Studies show that T-705 ribofuranosyl triphosphate is the active form of T-705 and acts like purines or purine nucleosides in cells and does not inhibit DNA synthesis
In 2012, MediVector was awarded a contract from the U.S. Department of Defense’s (DOD) Joint Project Manager Transformational Medical Technologies (JPM-TMT) to further develop T-705 (favipiravir), a broad-spectrum therapeutic against multiple influenza viruses.
Several novel anti-influenza compounds are in various phases of clinical development. One of these, T-705 (favipiravir), has a mechanism of action that is not fully understood but is suggested to target influenza virus RNA-dependent RNA polymerase. We investigated the mechanism of T-705 activity against influenza A (H1N1) viruses by applying selective drug pressure over multiple sequential passages in MDCK cells. We found that T-705 treatment did not select specific mutations in potential target proteins, including PB1, PB2, PA, and NP. Phenotypic assays based on cell viability confirmed that no T-705-resistant variants were selected. In the presence of T-705, titers of infectious virus decreased significantly (P < 0.0001) during serial passage in MDCK cells inoculated with seasonal influenza A (H1N1) viruses at a low multiplicity of infection (MOI; 0.0001 PFU/cell) or with 2009 pandemic H1N1 viruses at a high MOI (10 PFU/cell). There was no corresponding decrease in the number of viral RNA copies; therefore, specific virus infectivity (the ratio of infectious virus yield to viral RNA copy number) was reduced. Sequence analysis showed enrichment of G→A and C→T transversion mutations, increased mutation frequency, and a shift of the nucleotide profiles of individual NP gene clones under drug selection pressure. Our results demonstrate that T-705 induces a high rate of mutation that generates a nonviable viral phenotype and that lethal mutagenesis is a key antiviral mechanism of T-705. Our findings also explain the broad spectrum of activity of T-705 against viruses of multiple families.

Favipiravir, also known as T-705Avigan, or favilavir is an antiviral drug being developed by Toyama Chemical (Fujifilm group) of Japan with activity against many RNA viruses. Like certain other experimental antiviral drugs (T-1105 and T-1106), it is a pyrazinecarboxamide derivative. In experiments conducted in animals Favipiravir has shown activity against influenza virusesWest Nile virusyellow fever virusfoot-and-mouth disease virus as well as other flavivirusesarenavirusesbunyaviruses and alphaviruses.[1]Activity against enteroviruses[2] and Rift Valley fever virus has also been demonstrated.[3] Favipiravir has showed limited efficacy against Zika virus in animal studies, but was less effective than other antivirals such as MK-608.[4] The agent has also shown some efficacy against rabies,[5] and has been used experimentally in some humans infected with the virus.[6]

In February 2020 Favipiravir was being studied in China for experimental treatment of the emergent COVID-19 (novel coronavirus)disease.[7][8] On March 17 Chinese officials suggested the drug had been effective in treating COVID in Wuhan and Shenzhen.[9][10]

Discovered by Toyama Chemical Co., Ltd. in Japan, favipiravir is a modified pyrazine analog that was initially approved for therapeutic use in resistant cases of influenza.7,9 The antiviral targets RNA-dependent RNA polymerase (RdRp) enzymes, which are necessary for the transcription and replication of viral genomes.7,12,13

Not only does favipiravir inhibit replication of influenza A and B, but the drug shows promise in the treatment of influenza strains that are resistant to neuramidase inhibitors, as well as avian influenza.9,19 Favipiravir has been investigated for the treatment of life-threatening pathogens such as Ebola virus, Lassa virus, and now COVID-19.10,14,15

Mechanism of action

The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase.[11] Other research suggests that favipiravir induces lethal RNA transversion mutations, producing a nonviable viral phenotype.[12] Favipiravir is a prodrug that is metabolized to its active form, favipiravir-ribofuranosyl-5′-triphosphate (favipiravir-RTP), available in both oral and intravenous formulations.[13][14] Human hypoxanthine guanine phosphoribosyltransferase (HGPRT) is believed to play a key role in this activation process.[15] Favipiravir does not inhibit RNA or DNA synthesis in mammalian cells and is not toxic to them.[1] In 2014, favipiravir was approved in Japan for stockpiling against influenza pandemics.[16] However, favipiravir has not been shown to be effective in primary human airway cells, casting doubt on its efficacy in influenza treatment.[17]

Approval status

In 2014, Japan approved Favipiravir for treating viral strains unresponsive to current antivirals.[18]

In March 2015, the US Food and Drug Administration completed a Phase III clinical trial studying the safety and efficacy of Favipiravir in the treatment of influenza.[19]

Ebola virus trials

Some research has been done suggesting that in mouse models Favipiravir may have efficacy against Ebola. Its efficacy against Ebola in humans is unproven.[20][21][22] During the 2014 West Africa Ebola virus outbreak, it was reported that a French nurse who contracted Ebola while volunteering for MSF in Liberia recovered after receiving a course of favipiravir.[23] A clinical trial investigating the use of favipiravir against Ebola virus disease was started in Guéckédou, Guinea, during December 2014.[24] Preliminary results showed a decrease in mortality rate in patients with low-to-moderate levels of Ebola virus in the blood, but no effect on patients with high levels of the virus, a group at a higher risk of death.[25] The trial design has been criticised by Scott Hammer and others for using only historical controls.[26] The results of this clinical trial were presented in February 2016 at the annual Conference on Retroviruses and Opportunistic Infections (CROI) by Daouda Sissoko[27] and published on March 1, 2016 in PLOS Medicine.[28]

SARS-CoV-2 virus disease

In March 2020, Chinese officials suggested Favipiravir may be effective in treating COVID-19.[29]

SYN

https://link.springer.com/article/10.1007/s11696-018-0654-9

Image result for FAVIPIRAVIR SYNTHESIS

Image result for FAVIPIRAVIR SYNTHESIS

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 1315 kb)

Ref

https://pdfs.semanticscholar.org/be8e/cb882b99204983d2f60077c7ab8b53f4d62c.pdf

Drug Discoveries & Therapeutics. 2014; 8(3):117-120.

As a RNA polymerase inhibitor, 6-fluoro-3-hydroxypyrazine-2-carboxamide commercially named favipiravir has been proved to have potent inhibitory activity against RNA viruses in vitro and in vivo. A four-step synthesis of the compound is described in this article, amidation, nitrification, reduction and fluorination with an overall yield of about 8%. In addition, we reported the crystal structure of the title compound. The molecule is almost planar and the intramolecular O−H•••O hydrogen bond makes a 6-member ring. In the crystal, molecules are packing governed by both hydrogen bonds and stacking interactions.

2.2.1. Preparation of 3-hydroxypyrazine-2-carboxamide To a suspension of 3-hydroxypyrazine-2-carboxylic acid (1.4 g, 10 mmol) in 150 mL MeOH, SOCl2 was added dropwise at 40°C with magnetic stirring for 6 h resulting in a bright yellow solution. The reaction was then concentrated to dryness. The residue was dissolved in 50 mL 25% aqueous ammonia and stirred overnight to get a suspension. The precipitate was collected and dried. The solid yellow-brown crude product was recrystallization with 50 mL water to get the product as pale yellow crystals (1.1 g, 78%). mp = 263-265°C. 1 H-NMR (300 MHz, DMSO): δ 13.34 (brs, 1H, OH), 8.69 (s, 1H, pyrazine H), 7.93-8.11 (m, 3H, pyrazine H, CONH2). HRMS (ESI): m/z [M + H]+ calcd for C5H6N3O2 + : 140.0460; found: 140.0457.

2.2.2. Preparation of 3-hydroxy-6-nitropyrazine-2- carboxamide In the solution of 3-hydroxypyrazine-2-carboxamide (1.0 g, 7 mmol) in 6 mL concentrate sulfuric acid under ice-cooling, potassium nitrate (1.4 g, 14 mmol) was added. After stirring at 40°C for 4 h, the reaction mixture was poured into 60 mL water. The product was collected by fi ltration as yellow solid (0.62 g, 48%). mp = 250-252°C. 1 H-NMR (600 MHz, DMSO): δ 12.00- 15.00 (br, 1H, OH), 8.97 (s, 1H, pyrazine H), 8.32 (s, 1H, CONH2), 8.06 (s, 1H, CONH2). 13C-NMR (75 MHz, DMSO): δ 163.12, 156.49, 142.47, 138.20, 133.81. HRMS (ESI): m/z [M + H]+ calcd for C5H5N4O4 + : 185.0311; found: 185.0304.

2.2.3. Preparation of 6-amino-3-hydroxypyrazine-2- carboxamide 3-Hydroxy-6-nitropyrazine-2-carboxamide (0.6 g, 3.3 mmol) and a catalytic amount of raney nickel were suspended in MeOH, then hydrazine hydrate was added dropwise. The resulting solution was refl uxed 2 h, cooled, filtered with diatomite, and then MeOH is evaporated in vacuo to get the crude product as dark brown solid without further purification (0.4 g, 77%). HRMS (ESI): m/z [M + H]+ calcd for C5H7N4O2 + : 155.0569; found:155.0509.

2.2.4. Preparation of 6-fluoro-3-hydroxypyrazine-2- carboxamide To a solution of 6-amino-3-hydroxypyrazine-2- carboxamide (0.4 g, 2.6 mmol) in 3 mL 70% HFpyridine aqueous at -20°C under nitrogen atmosphere, sodium nitrate (0.35 g, 5.2 mmol) was added. After stirring 20 min, the solution was warmed to room temperature for another one hour. Then 20 mL ethyl acetate/water (1:1) were added, after separation of the upper layer, the aqueous phase is extracted with four 20 mL portions of ethyl acetate. The combined extracts are dried with anhydrous magnesium sulfate and concentrated to dryness to get crude product as oil. The crude product was purified by chromatography column as white solid (0.12 g, 30%). mp = 178-180°C. 1 H-NMR (600 MHz, DMSO): δ 12.34 (brs, 1H, OH), 8.31 (d, 1H, pyrazine H, J = 8.0 Hz), 7.44 (s, 1H, CONH2), 5.92 (s, 1H, CONH2). 13C-NMR (75 MHz, DMSO): δ 168.66, 159.69, 153.98, 150.76, 135.68. HRMS (ESI): m/z [M + H]+ calcd for C5H5FN3O2 + : 158.0366; found: 158.0360.

SEE

Chemical Papers (2019), 73(5), 1043-1051.

PAPER

Medicinal chemistry (Shariqah (United Arab Emirates)) (2018), 14(6), 595-603

http://www.eurekaselect.com/158990/article

PATENT

CN 107641106

PAPER

Chemical Papers (2017), 71(11), 2153-2158.

https://link.springer.com/article/10.1007%2Fs11696-017-0208-6

Image result for A practical and step-economic route to Favipiravir

Image result for A practical and step-economic route to Favipiravir

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Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 514 kb)

References

  1.  Furuta, Y.; Takahashi, K.; Shiraki, K.; Sakamoto, K.; Smee, D. F.; Barnard, D. L.; Gowen, B. B.; Julander, J. G.; Morrey, J. D. (2009). “T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections”. Antiviral Research 82 (3): 95–102. doi:10.1016/j.antiviral.2009.02.198PMID 19428599edit
  2. WO 2000010569
  3. WO 2008099874
  4. WO 201009504
  5. WO 2010104170
  6. WO 2012063931

Process route
OH
OH
hydrolysis
CLIP
Influenza virus is a central virus of the cold syndrome, which has attacked human being periodically to cause many deaths amounting to tens millions. Although the number of deaths shows a tendency of decrease in the recent years owing to the improvement in hygienic and nutritive conditions, the prevalence of influenza is repeated every year, and it is apprehended that a new virus may appear to cause a wider prevalence.
For prevention of influenza virus, vaccine is used widely, in addition to which low molecular weight substances such as Amantadine and Ribavirin are also used

CLIP

Synthesis of Favipiravir
ZHANG Tao1, KONG Lingjin1, LI Zongtao1,YUAN Hongyu1, XU Wenfang2*
(1. Shandong Qidu PharmaceuticalCo., Ltd., Linzi 255400; 2. School of Pharmacy, Shandong University, Jinan250012)
ABSTRACT: Favipiravir was synthesized from3-amino-2-pyrazinecarboxylic acid by esterification, bromination with NBS,diazotization and amination to give 6-bromo-3-hydroxypyrazine-2-carboxamide,which was subjected to chlorination with POCl3, fluorination with KF, andhydrolysis with an overall yield of about 22%.

PATENT
US6787544

Figure US06787544-20040907-C00005

subs            G1 G2 G3 G4 R2
    compd 32 N CH C—CF3 N H

…………………
EP2192117
Figure US20100286394A1-20101111-C00001
Example 1-1

Figure US20100286394A1-20101111-C00002

To a 17.5 ml N,N-dimethylformamide solution of 5.0 g of 3,6-difluoro-2-pyrazinecarbonitrile, a 3.8 ml water solution of 7.83 g of potassium acetate was added dropwise at 25 to 35° C., and the solution was stirred at the same temperature for 2 hours. 0.38 ml of ammonia water was added to the reaction mixture, and then 15 ml of water and 0.38 g of active carbon were added. The insolubles were filtered off and the filter cake was washed with 11 ml of water. The filtrate and the washing were joined, the pH of this solution was adjusted to 9.4 with ammonia water, and 15 ml of acetone and 7.5 ml of toluene were added. Then 7.71 g of dicyclohexylamine was added dropwise and the solution was stirred at 20 to 30° C. for 45 minutes. Then 15 ml of water was added dropwise, the solution was cooled to 10° C., and the precipitate was filtered and collected to give 9.44 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyradinecarbonitrile as a lightly yellowish white solid product.
1H-NMR (DMSO-d6) δ values: 1.00-1.36 (10H, m), 1.56-1.67 (2H, m), 1.67-1.81 (4H, m), 1.91-2.07 (4H, m), 3.01-3.18 (2H, m), 8.03-8.06 (1H, m), 8.18-8.89 (1H, broad)
Example 1-2
4.11 ml of acetic acid was added at 5 to 15° C. to a 17.5 ml N,N-dimethylformamide solution of 5.0 g of 3,6-difluoro-2-pyrazinecarbonitrile. Then 7.27 g of triethylamine was added dropwise and the solution was stirred for 2 hours. 3.8 ml of water and 0.38 ml of ammonia water were added to the reaction mixture, and then 15 ml of water and 0.38 g of active carbon were added. The insolubles were filtered off and the filter cake was washed with 11 ml of water. The filtrate and the washing were joined, the pH of the joined solution was adjusted to 9.2 with ammonia water, and 15 ml of acetone and 7.5 ml of toluene were added to the solution, followed by dropwise addition of 7.71 g of dicyclohexylamine. Then 15 ml of water was added dropwise, the solution was cooled to 5° C., and the precipitate was filtered and collected to give 9.68 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile as a slightly yellowish white solid product.
Examples 2 to 5
The compounds shown in Table 1 were obtained in the same way as in Example 1-1.

TABLE 1
Figure US20100286394A1-20101111-C00003
Example No. Organic amine Example No. Organic amine
2 Dipropylamine 4 Dibenzylamine
3 Dibutylamine 5 N-benzylmethylamine

Dipropylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
1H-NMR (DMSO-d6) 6 values: 0.39 (6H, t, J=7.5 Hz), 1.10 (4H, sex, J=7.5 Hz), 2.30-2.38 (4H, m), 7.54 (1H, d, J=8.3 Hz)
Dibutylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
1H-NMR (DMSO-d6) 6 values: 0.36 (6H, t, J=7.3 Hz), 0.81 (4H, sex, J=7.3 Hz), 0.99-1.10 (4H, m), 2.32-2.41 (4H, m), 7.53 (1H, d, J=8.3 Hz)
Dibenzylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
1H-NMR (DMSO-d6) δ values: 4.17 (4H, s), 7.34-7.56 (10H, m), 8.07 (1H, d, J=8.3 Hz)
N-benzylmethylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
1H-NMR (DMSO-d6) δ values: 2.57 (3H, s), 4.14 (2H, s), 7.37-7.53 (5H, m), 8.02-8.08 (1H, m)
Preparation Example 1

Figure US20100286394A1-20101111-C00004

300 ml of toluene was added to a 600 ml water solution of 37.5 g of sodium hydroxide. Then 150 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile was added at 15 to 25° C. and the solution was stirred at the same temperature for 30 minutes. The water layer was separated and washed with toluene, and then 150 ml of water was added, followed by dropwise addition of 106 g of a 30% hydrogen peroxide solution at 15 to 30° C. and one-hour stirring at 20 to 30° C. Then 39 ml of hydrochloric acid was added, the seed crystals were added at 40 to 50° C., and 39 ml of hydrochloric acid was further added dropwise at the same temperature. The solution was cooled to 10° C. the precipitate was filtered and collected to give 65.6 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a slightly yellowish white solid.
1H-NMR (DMSO-d6) δ values: 8.50 (1H, s), 8.51 (1H, d, J=7.8 Hz), 8.75 (1H, s), 13.41 (1H, s)

CLIP
jan 2014

Investigational flu treatment drug has broad-spectrum potential to fight multiple viruses
First patient enrolled in the North American Phase 3 clinical trials for investigational flu treatment drug
BioDefense Therapeutics (BD Tx)—a Joint Product Management office within the U.S. Department of Defense (DoD)—announced the first patient enrolled in the North American Phase 3 clinical trials for favipiravir (T-705a). The drug is an investigational flu treatment candidate with broad-spectrum potential being developed by BD Tx through a contract with Boston-based MediVector, Inc.
Favipiravir is a novel, antiviral compound that works differently than anti-flu drugs currently on the market. The novelty lies in the drug’s selective disruption of the viralRNA replication and transcription process within the infected cell to stop the infection cycle.
“Favipiravir has proven safe and well tolerated in previous studies,” said LTC Eric G. Midboe, Joint Product Manager for BD Tx. “This first patient signifies the start of an important phase in favipiravir’s path to U.S. Food and Drug Administration (FDA) approval for flu and lays the groundwork for future testing against other viruses of interest to the DoD.”
In providing therapeutic solutions to counter traditional, emerging, and engineered biological threats, BD Tx chose favipiravir not only because of its potential effectiveness against flu viruses, but also because of its demonstrated broad-spectrum potential against multiple viruses.  In addition to testing favipiravir in the ongoing influenzaprogram, BD Tx is testing the drug’s efficacy against the Ebola virus and other viruses considered threats to service members. In laboratory testing, favipiravir was found to be effective against a wide variety of RNA viruses in infected cells and animals.
“FDA-approved, broad-spectrum therapeutics offer the fastest way to respond to dangerous and potentially lethal viruses,” said Dr. Tyler Bennett, Assistant Product Manager for BD Tx.
MediVector is overseeing the clinical trials required by the  FDA  to obtain drug licensure. The process requires safety data from at least 1,500 patients treated for flu at the dose and duration proposed for marketing of the drug. Currently, 150 trial sites are planned throughout the U.S.
SOURCE BioDefense Therapeutics
Malpani Y, Achary R, Kim SY, Jeong HC, Kim P, Han SB, Kim M, Lee CK, Kim JN, Jung YS.
Eur J Med Chem. 2013 Apr;62:534-44. doi: 10.1016/j.ejmech.2013.01.015. Epub 2013 Jan 29.

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  16. Delang L, Abdelnabi R, Neyts J: Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. Antiviral Res. 2018 May;153:85-94. doi: 10.1016/j.antiviral.2018.03.003. Epub 2018 Mar 7. [PubMed:29524445]
  17. Nature Biotechnology: Coronavirus puts drug repurposing on the fast track [Link]
  18. Pharmaceuticals and Medical Devices Agency: Avigan (favipiravir) Review Report [Link]
  19. World Health Organization: Influenza (Avian and other zoonotic) [Link]
Favipiravir
Favipiravir.svg
Names
IUPAC name

5-Fluoro-2-hydroxypyrazine-3-carboxamide
Other names

T-705; Avigan; favilavir
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
PubChem CID
UNII
Properties
C5H4FN3O2
Molar mass 157.104 g·mol−1
Pharmacology
J05AX27 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

////////////FAVIPIRAVIR, ファビピラビル , 8916, Avigan, T-705, favilavir, COVID-19,  coronavirus, antiinfluenza

 

ANTHONY MELVIN CRASTO

Want to know everything on vir series

click

http://drugsynthesisint.blogspot.in/p/vir-series-hep-c-virus-22.html

AND

http://medcheminternational.blogspot.in/p/vir-series-hep-c-virus.html

 

Camostat Mesilate, カモスタットメシル酸塩 日局収載


Camostat.svg

ChemSpider 2D Image | Camostat | C20H22N4O5

Camostat

  • Molecular FormulaC20H22N4O5
  • Average mass398.413 Da
4-[[4-[(Aminoiminomethyl)amino]benzoyl]oxy]benzeneacetic Acid 2-(Dimethylamino)-2-oxoethyl Ester
4-{2-[2-(Dimethylamino)-2-oxoethoxy]-2-oxoethyl}phenyl 4-carbamimidamidobenzoate
59721-28-7 [RN]
Benzeneacetic acid, 4-[[4-[(aminoiminomethyl)amino]benzoyl]oxy]-, 2-(dimethylamino)-2-oxoethyl ester
Camostat Mesilate

Camostat Mesilate

カモスタットメシル酸塩 日局収載

Trypsin-like protease inhibitor CAS 59721-29-8

C20H22N4O5.CH4O3S

494.52

MP 194, methanol, diethyl ether, Chemical and Pharmaceutical Bulletin2005, vol. 53, 8, pg. 893 – 898

カモスタットメシル酸塩 日局収載
Camostat Mesilate

Dimethylcarbamoylmethyl 4-(4-guanidinobenzoyloxy)phenylacetate monomethanesulfonate

C20H22N4O5▪CH4O3S : 494.52
[59721-29-8]

Launched – 1985, in Japan by Ono for the oral treatment of postoperative reflux esophagitis and chronic pancreatitis.

Camostat mesilate is a synthetic serine protease inhibitor that has been launched in Japan by Ono for the oral treatment of postoperative reflux esophagitis and chronic pancreatitis. It has been demonstrated that the drug has the ability to inhibit proteases such as trypsin, kallikrein, thrombin, plasmin, and C1 esterase, and that it decreases inflammation by directly suppressing the activity of monocytes and pancreatic stellate cells (PSCs).

In 2011, orphan drug designation was received in the U.S. by Stason Pharmaceuticals for the treatment of chronic pancreatitis. In 2017, Kangen Pharmaceuticals acquired KC Specialty Therapeutics (formerly a wholly-owned subsidiary of Stason Pharmaceuticals).

Camostat (INN; development code FOY-305) is a serine protease inhibitor. Serine protease enzymes have a variety of functions in the body, and so camostat has a diverse range of uses. It is used in the treatment of some forms of cancer and is also effective against some viral infections, as well as inhibiting fibrosis in liver or kidney disease or pancreatitis.[1][2][3][4][5] It is approved in Japan for the treatment of pancreatitis.[6][7]

An in vitro study shows that Camostat reduces significantly the infection of Calu-3 lung cells by SARS-CoV-2, the virus responsible for COVID-19.[8]

SYN

DE 2548886; FR 2289181; GB 1472700; JP 76054530; US 4021472

The reaction of p-hydrophenylacetic acid (I) with N,N-dimethylbromoacetamide (II) by means of triethylamine in reftuxing acetonitrile gives N,N-dimethylcarbamoylmethyl-p-hydroxyphenylacetate (III), which is then condensed with p-guanidinobenzoyl chloride (IV) [obtained from the corresponding acid p-guanidinobenzoic acid (V) and thionyl chloride] in pyridine.

By reaction of N,N-dimethylcarbamoylmethyl-p-(p-aminobenzoyloxy)phenylacetate (VI) with cyanamide (VII).

PATENT

DE 2548886

JP 52089640

JP 54052052

PATENT

CN 104402770

https://patents.google.com/patent/CN104402770A/en

Camostat mesilate, chemical name is 4-(4-guanidine radicals benzoyloxy group) toluylic acid-N, N-dimethyl carbamoyl methyl esters mesylate, be the non-peptide proteinoid enzyme inhibitors of Japanese little Ye medicine Co., Ltd. exploitation, first in January, 1985 go on the market with trade(brand)name Foipan in Japan.Pharmacological evaluation shows: camostat mesilate has very strong restraining effect to trypsinase, kallikrein, Tryptase, zymoplasm, C1 esterase, oral rear kassinin kinin generation system, fibrinolytic system, blood coagulation system and the complement system acting on rapidly body, suppress the exception of the enzymic activity of these systems hyperfunction, thus control the symptom of chronic pancreatitis, alleviating pain, reduce amylase value, the clinical alleviation for chronic pancreatitis acute symptom.In addition, this product is also used for the treatment of diffusivity blood vessel blood coagulation disease.Pharmacological evaluation also finds, camostat mesilate also has the effects such as anticancer, antiviral, and effectively can reduce proteinuria, and play the effect of preliminary conditioning, further research is still underway.Current this product not yet in Discussion on Chinese Listed, also without the report succeeded in developing.

A preparation method for camostat mesilate, comprises the steps:

(1), by 160g methylene dichloride DCM join stirring in reaction vessel, cooling, be cooled to start when 0–10 DEG C to drip 51g 50% dimethylamine agueous solution, drip 30g chloroacetyl chloride simultaneously; Drip process control temp 5–10 DEG C, system pH controls 4-7, at 5–10 DEG C, react 1h after dripping off, reaction process pH controls 5-7, and reaction terminates rear standing 20min, separatory, water layer is with 54g dichloromethane extraction, and organic layer is concentrating under reduced pressure below 80 DEG C, obtains 3-pyrrolidone hydrochloride, crude, 3-pyrrolidone hydrochloride, crude carries out underpressure distillation within 130 DEG C, obtains 3-pyrrolidone hydrochloride distillation product; Output is 31g;

(2), the 3-pyrrolidone hydrochloride of 30.6g, 9g triethylamine TEA, 0.4g sodium bisulfite and 40g p-hydroxyphenylaceticacid p-hydroxyphenylaceticacid drop in order in reaction vessel and carry out stirring at low speed, and then drip the triethylamine of 17.6g, dropping temperature 40-95 DEG C, drip off rear maintenance 80-95 DEG C reaction 3h, after reaction terminates, add aqueous solution of sodium bisulfite (0.05gNaHSO3+90gH2O), add and start more than temperature 70 C, add finishing temperature more than 48 DEG C, after adding, cool, crystal seed is added when 40 DEG C, keep cooling temperature 0-5 DEG C, crystallization 2h, filter after crystallization, filter cake 100g purified water is washed, camostat mesilate crude product is obtained after draining, camostat mesilate crude product, 50mL ethyl acetate are joined heating for dissolving in aqueous solution of sodium bisulfite (0.2g NaHSO3+20g H2O), after having dissolved, cooling crystallization, keep recrystallization temperature 0-5 DEG C, crystallization time 1h, suction filtration after crystallization, filter cake, with 10mL water washing, washs with 20mL ethyl acetate after draining again, again at 60 ± 3 DEG C of drying under reduced pressure 2h after draining, obtain camostat mesilate refined silk, output is about 47g,

(3), the camostat mesilate refined silk of 47g is joined heating for dissolving in 30mL acetonitrile, after dissolving terminates, cooling temperature is to 0-5 DEG C, crystallization 1h, after crystallization terminates, suction filtration, filter cake with 17mL acetonitrile wash, drain, drying under reduced pressure 2h at 60 ± 3 DEG C, obtain camostat mesilate product, output is about 45g.

PATENT

https://patents.google.com/patent/CN104402770B/en

Clip

https://www.pharmaceutical-technology.com/news/german-researchers-covid-19-drug/

German researchers identify potential drug for Covid-19

Covid-19

Scientists at the German Primate Center – Leibniz Institute for Primate Research have found that an existing drug may help treat Covid-19.

As well as Charité – Universitätsmedizin Berlin, the scientists worked with researchers at the University of Veterinary Medicine Hannover Foundation, the BG-Unfallklinik Murnau, the LMU Munich, the Robert Koch Institute and the German Center for Infection Research.

The research aimed to understand the entry of the novel coronavirus, SARS-CoV-2, into host cells, as well as determine approaches to block the process.

Research findings showed that SARS-CoV-2 requires cellular protein TMPRSS2 to enter hosts’ lung cells.

German Primate Center Infection Biology Unit head Stefan Pöhlmann said: “Our results show that SARS-CoV-2 requires the protease TMPRSS2, which is present in the human body, to enter cells. This protease is a potential target for therapeutic intervention.”

CLIP

https://neurosciencenews.com/tmprss2-coronavirus-treatment-15873/

Potential drug to block coronavirus identified

Summary: A clinically proven drug known to block an enzyme essential for the viral entry of Coronavirus into the lungs blocks the COVID 19 (SARS-CoV-2) infection. The drug, Camostat mesilate, is a drug approved in Japan to treat pancreatic inflammation. Results suggest this drug may also protect against COVID 19. Researchers call for further clinical trials.

Viruses must enter cells of the human body to cause disease. For this, they attach to suitable cells and inject their genetic information into these cells. Infection biologists from the German Primate Center – Leibniz Institute for Primate Research in Göttingen, together with colleagues at Charité – Universitätsmedizin Berlin, have investigated how the novel coronavirus SARS-CoV-2 penetrates cells. They have identified a cellular enzyme that is essential for viral entry into lung cells: the protease TMPRSS2. A clinically proven drug known to be active against TMPRSS2 was found to block SARS-CoV-2 infection and might constitute a novel treatment option.

The findings have been published in Cell.

Several coronaviruses circulate worldwide and constantly infect humans, which normally caused only mild respiratory disease. Currently, however, we are witnessing a worldwide spread of a new coronavirus with more than 101,000 confirmed cases and almost 3,500 deaths. The new virus has been named SARS coronavirus-2 and has been transmitted from animals to humans. It causes a respiratory disease called COVID-19 that may take a severe course. The SARS coronavirus-2 has been spreading since December 2019 and is closely related to the SARS coronavirus that caused the SARS pandemic in 2002/2003. No vaccines or drugs are currently available to combat these viruses.

Stopping virus spread

A team of scientists led by infection biologists from the German Primate Centre and including researchers from Charité, the University of Veterinary Medicine Hannover Foundation, the BG-Unfallklinik Murnau, the LMU Munich, the Robert Koch Institute and the German Center for Infection Research, wanted to find out how the new coronavirus SARS-CoV-2 enters host cells and how this process can be blocked. The researchers identified a cellular protein that is important for the entry of SARS-CoV-2 into lung cells. “Our results show that SARS-CoV-2 requires the protease TMPRSS2, which is present in the human body, to enter cells,” says Stefan Pöhlmann, head of the Infection Biology Unit at the German Primate Center. “This protease is a potential target for therapeutic intervention.”

This shows the coronavirus

The SARS coronavirus-2 has been spreading since December 2019 and is closely related to the SARS coronavirus that caused the SARS pandemic in 2002/2003. No vaccines or drugs are currently available to combat these viruses. The image is credited to CDC.

Promising drug

Since it is known that the drug camostat mesilate inhibits the protease TMPRSS2, the researchers have investigated whether it can also prevent infection with SARS-CoV-2. “We have tested SARS-CoV-2 isolated from a patient and found that camostat mesilate blocks entry of the virus into lung cells,” says Markus Hoffmann, the lead author of the study. Camostat mesilate is a drug approved in Japan for use in pancreatic inflammation. “Our results suggest that camostat mesilate might also protect against COVID-19,” says Markus Hoffmann. “This should be investigated in clinical trials.”

References

  1. ^ Okuno, M.; Kojima, S.; Akita, K.; Matsushima-Nishiwaki, R.; Adachi, S.; Sano, T.; Takano, Y.; Takai, K.; Obora, A.; Yasuda, I.; Shiratori, Y.; Okano, Y.; Shimada, J.; Suzuki, Y.; Muto, Y.; Moriwaki, Y. (2002). “Retinoids in liver fibrosis and cancer”. Frontiers in Bioscience7 (4): d204-18. doi:10.2741/A775PMID 11779708.
  2. ^ Hsieh, H. P.; Hsu, J. T. (2007). “Strategies of development of antiviral agents directed against influenza virus replication”. Current Pharmaceutical Design13 (34): 3531–42. doi:10.2174/138161207782794248PMID 18220789.
  3. ^ Kitamura, K.; Tomita, K. (2012). “Proteolytic activation of the epithelial sodium channel and therapeutic application of a serine protease inhibitor for the treatment of salt-sensitive hypertension”. Clinical and Experimental Nephrology16 (1): 44–8. doi:10.1007/s10157-011-0506-1PMID 22038264.
  4. ^ Zhou, Y.; Vedantham, P.; Lu, K.; Agudelo, J.; Carrion Jr, R.; Nunneley, J. W.; Barnard, D.; Pöhlmann, S.; McKerrow, J. H.; Renslo, A. R.; Simmons, G. (2015). “Protease inhibitors targeting coronavirus and filovirus entry”Antiviral Research116: 76–84. doi:10.1016/j.antiviral.2015.01.011PMC 4774534PMID 25666761.
  5. ^ Ueda, M.; Uchimura, K.; Narita, Y.; Miyasato, Y.; Mizumoto, T.; Morinaga, J.; Hayata, M.; Kakizoe, Y.; Adachi, M.; Miyoshi, T.; Shiraishi, N.; Kadowaki, D.; Sakai, Y.; Mukoyama, M.; Kitamura, K. (2015). “The serine protease inhibitor camostat mesilate attenuates the progression of chronic kidney disease through its antioxidant effects”. Nephron129 (3): 223–32. doi:10.1159/000375308PMID 25766432.
  6. ^ “Covid-19 potential drug identified by German researchers”http://www.pharmaceutical-technology.com. Retrieved 2020-03-14.
  7. ^ “Camostat”drugs.com.
  8. ^ Hoffman, Markus (2020-03-05). “SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor”Cell. Retrieved 2020-03-05.

External links

  • Kunze H, Bohn E (May 1983). “Effects of the serine protease inhibitors FOY and FOY 305 on phospholipase A1 (EC 3.1.1.32) activity in rat – liver lysosomes”. Pharmacol Res Commun15 (5): 451–9. doi:10.1016/S0031-6989(83)80065-4PMID 6412250.
  • Göke B, Stöckmann F, Müller R, Lankisch PG, Creutzfeldt W (1984). “Effect of a specific serine protease inhibitor on the rat pancreas: systemic administration of camostate and exocrine pancreatic secretion”. Digestion30 (3): 171–8. doi:10.1159/000199102PMID 6209186.
Camostat
Camostat.svg
Clinical data
Trade names Foipan
AHFS/Drugs.com International Drug Names
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • US: Not FDA approved
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C20H22N4O5
Molar mass 398.419 g·mol−1
3D model (JSmol)

/////////////Camostat, SARS-CoV-2COVID-19,  coronavirus, SARS-CoV-2COVID-19, FOY305,  FOY-S980, カモスタットメシル酸塩 日局収載 , Japan,  Ono, oral treatment of postoperative reflux esophagitis, chronic pancreatitis.

CN(C)C(=O)COC(=O)CC1=CC=C(C=C1)OC(=O)C2=CC=C(C=C2)N=C(N)N.CS(=O)(=O)O

Remdesivir, レムデシビル , ремдесивир , ريمديسيفير , 瑞德西韦 ,


Remdesivir (USAN.png

GS-5734 structure.png

ChemSpider 2D Image | remdesivir | C27H35N6O8P

Remdesivir

Formula
C27H35N6O8P
CAS
1809249-37-3
Mol weight
602.576

レムデシビル

UNII:3QKI37EEHE
ремдесивир [Russian] [INN]
ريمديسيفير [Arabic] [INN]
瑞德西韦 [Chinese] [INN]
2-Ethylbutyl (2S)-2-{[(S)-{[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydro-2-furanyl]methoxy}(phenoxy)phosphoryl]amino}propanoate (non-preferred name)

L-Alanine, N-((S)-hydroxyphenoxyphosphinyl)-, 2-ethylbutyl ester, 6-ester with 2-C-(4-aminopyrrolo(2,1-f)(1,2,4)triazin-7-yl)-2,5-anhydro-D-altrononitrile

2-Ethylbutyl (2S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo(2,1-f)(1,2,4)triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

  • 2-Ethylbutyl (2S)-2-[[(S)-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo(2,1-f)(1,2,4)triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl]methoxy]phenoxyphosphoryl]amino]propanoate
  • 2-Ethylbutyl (2S)-2-[[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo(2,1-f)(1,2,4)triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl]methoxy]phenoxyphosphoryl]amino]propanoate
  • 2-Ethylbutyl N-[(S)-[2-C-(4-aminopyrrolo(2,1-f)(1,2,4)triazin-7-yl)-2,5-anhydro-D-altrononitril-6-O-yl]phenoxyphosphoryl]-L-alaninate
  • GS 5734
  • L-Alanine, N-[(S)-hydroxyphenoxyphosphinyl)-, 2-ethylbutyl ester,6-ester with 2-C-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,5-anhydro-D-altrononitrile
GS-5734

Treatment of viral infections

Phase III, clinical trials for the treatment of hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19). National Institute of Allergy and Infectious Diseases (NIAID) is evaluating remdesivir in phase II/III clinical trials for the treatment of Ebola virus infection.

The compound has been evaluated in preclinical studies for the potential treatment of Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) infections.

Remdesivir is a nucleoside analogue, with effective antiviral activity, with EC50s of 74 nM for ARS-CoV and MERS-CoV in HAE cells, and 30 nM for murine hepatitis virus in delayed brain tumor cells.

Remdesivir (development code GS-5734) is a novel antiviral drug in the class of nucleotide analogs. It was developed by Gilead Sciences as a treatment for Ebola virus disease and Marburg virus infections,[1] though it has subsequently also been found to show antiviral activity against other single stranded RNA viruses such as respiratory syncytial virusJunin virusLassa fever virusNipah virus, Hendra virus, and the coronaviruses (including MERS and SARS viruses).[2][3] It is being studied for SARS-CoV-2 and Nipah and Hendra virus infections.[4][5][6] Based on success against other coronavirus infections, Gilead provided remdesivir to physicians who treated an American patient in Snohomish County, Washington in 2020, infected with SARS-CoV-2[7] and is providing the compound to China to conduct a pair of trials in infected individuals with and without severe symptoms.[8]

Research usage

Laboratory tests suggest remdesivir is effective against a wide range of viruses, including SARS-CoV and MERS-CoV. The medication was pushed to treat the West African Ebola virus epidemic of 2013–2016. Although the drug turned out to be safe, it was not particularly effective against filoviruses such as the Ebola virus.

Ebola virus

Remdesivir was rapidly pushed through clinical trials due to the West African Ebola virus epidemic of 2013–2016, eventually being used in at least one human patient despite its early development stage at the time. Preliminary results were promising and it was used in the emergency setting during the Kivu Ebola epidemic that started in 2018 along with further clinical trials, until August 2019, when Congolese health officials announced that it was significantly less effective than monoclonal antibody treatments such as mAb114 and REGN-EB3. The trials, however, established its safety profile.[9][10][11][12][13][14][15][16]

SARS-CoV-2

In response to the 2019–20 coronavirus outbreak induced by coronavirus SARS-CoV-2, Gilead provided remdesivir for a “small number of patients” in collaboration with Chinese medical authorities for studying its effects.[17]

Gilead also started laboratory testing of remdesivir against SARS-CoV-2. Gilead stated that remdesivir was “shown to be active” against SARS and MERS in animals.[3][18]

In late January 2020, remdesivir was administered to the first US patient to be confirmed to be infected by SARS-CoV-2, in Snohomish County, Washington, for “compassionate use” after he progressed to pneumonia. While no broad conclusions were made based on the single treatment, the patient’s condition improved dramatically the next day,[7] and he was eventually discharged.[19]

Also in late January 2020, Chinese medical researchers stated to the media that in exploratory research considering a selection of 30 drug candidates. Remdesivir and two other drugs, chloroquine and lopinavir/ritonavir, seemed to have “fairly good inhibitory effects” on SARS-CoV-2 at the cellular level. Requests to start clinical testing were submitted,[20][21]. On February 6, 2020, a clinical trial of remdesivir began in China.[22]

Other viruses

The active form of remdesivir, GS-441524, shows promise for treating feline coronavirus.[23]

Mechanism of action and resistance

Remdesivir is a prodrug that metabolizes into its active form GS-441524. GS-441524 is an adenosine nucleotide analog that confuses viral RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production. It was unknown whether it terminates RNA chains or causes mutations in them.[24]However, it has been learned that the RNA dependent RNA polymerase of ebolavirus is inhibited for the most part by delayed chain termination.[25]

Mutations in the mouse hepatitis virus RNA replicase that cause partial resistance were identified in 2018. These mutations make the viruses less effective in nature, and the researchers believe they will likely not persist where the drug is not being used.[24]

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

 

SYNTHESIS

Remdesivir can be synthesized in multiple steps from ribose derivatives. The figure below is one of the synthesis route of remdesivir invented by Chun et al. from Gilead Sciences.[26]In this method, intermediate a is firstly prepared from L-alanine and phenyl phosphorodichloridate in presence of triethylamine and dichloromethane; triple benzyl-protected ribose is oxidized by dimethyl sulfoxide with acetic anhydride and give the lactone intermediate b; pyrrolo[2,1-f][1,2,4]triazin-4-amine is brominated, and the amine group is protected by excess trimethylsilyl chloriden-Butyllithium undergoes a halogen-lithium exchange reaction with the bromide at -78 °C to yield the intermediate c. The intermediate b is then added to a solution containing intermediate c dropwise. After quenching the reaction in a weakly acidic aqueous solution, a mixture of 1: 1 anomers was obtained. It was then reacted with an excess of trimethylsilyl cyanide in dichloromethane at -78 °C for 10 minutes. Trimethylsilyl triflate was added and reacts for an additional 1 hour, and the mixture was quenched in an aqueous sodium hydrogen carbonate. A nitrile intermediate was obtained. The protective group, benzyl, was then removed with boron trichloride in dichloromethane at -20 °C. The excess of boron trichloride was quenched in a mixture of potassium carbonate and methanol. A benzyl-free intermediate was obtained. The isomers were then separated via reversed-phase HPLC. The optically pure compound and intermediate a are reacted with trimethyl phosphate and methylimidazole to obtain a diastereomer mixture of remdesivir. In the end, optically pure remdesivir can be obtained through methods such as chiral resolution.

The synthesis of Remdesivir was invented by Byoung Kwon Chun et al. from Gilead Sciences, Inc. and claimed in the patent, WO2016069826A1.
中文: 瑞德西韋的合成方法是由吉利德科學公司的 Byoung Kwon Chun等人所發明,並在WO2016069826A1中聲明專利。

Synthesis of Remdesivir

PATENT

WO 2018204198

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=E7724EB6CA3959303E18B3D392E0219F.wapp1nA?docId=WO2018204198&tab=PCTDESCRIPTION

Prevention and treatment methods for some Arenaviridae , Coronaviridae , Filoviridae, Flaviviridae, and Paramyxoviridae viruses present challenges due to a lack of vaccine or post-exposure treatment modality for preventing or managing these infections. In some cases, patients only receive supportive and resource intensive therapy such as electrolyte and fluid balancing, oxygen, blood pressure maintenance, or treatment for secondary infections. Thus, there is a need for antiviral therapies having a potential for broad antiviral activity.

[0004] The compound (S)-2-ethylbutyl 2-(((S)-(((2R,3 S,4R,5R)-5-(4-aminopyrrolo[2, 1-f][l,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate, referred herein as Compound 1 or Formula I, is known to exhibit antiviral properties against Arenaviridae, Coronaviridae, Filoviridae, and

Paramyxoviridae viruses as described in Warren, T. et al., Nature (2016) 531 :381-385 and antiviral activities against Flaviviridae viruses as described in co-pending United States provisional patent application no. 62/325,419 filed April 20, 2016.

[0005] (S)-2-Ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2, l-f][l,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)

propanoate or 2-ethylbutyl ((S)-(((2R,3 S,4R,5R)-5-(4-aminopyrrolo[2, l-f][l,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate, (Formula I), has the following structure:

Formula I

PATENT

WO 2017184668

https://patents.google.com/patent/WO2017184668A1/en

A. Preparation of Compounds

Example 1. (2S)-ethyl 2-(chloro(phenoxy)phosphorylamino)pro anoate (Chloridate A)

Figure imgf000086_0001

[0246] Ethyl alanine ester hydrochloride salt (1.69 g, 11 mmol) was dissolved in anhydrous CH2CI2 (10 mL) and the mixture stirred with cooling to 0 °C under N2(g). Phenyl dichlorophosphate (1.49 mL, 10 mmol) was added followed by dropwise addition of Et3N over 10 min. The reaction mixture was then slowly warmed to RT and stirred for 12 h. Anhydrous Et20 (50 mL) was added and the mixture stirred for 30 min. The solid that formed was removed by filtration, and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluting with 0-50% EtOAc in hexanes to provide intermediate A (1.13 g, 39%). H NMR (300 MHz, CDC13) δ 7.39-7.27 (m, 5H), 4.27 (m, 3H), 1.52 (m, 3H), 1.32 (m, 3H). 31P NMR (121.4 MHz, CDC13) δ 8.2, 7.8.

Example 2. (2S)-2-ethylbutyl 2-(chloro(phenoxy)phosphorylamino)propanoate

(Chloridate B

Figure imgf000087_0001

[0247] The 2-ethylbutyl alanine chlorophosphoramidate ester B was prepared using the same procedure as chloridate A except substituting 2-ethylbutyl alanine ester for ethyl alanine ester. The material is used crude in the next reaction. Treatment with methanol or ethanol forms the displaced product with the requisite LCMS signal.

Example 3. (2S)-isopropyl 2-(chloro(phenoxy)phosphorylamino)propanoate

(Chloridate C)

Figure imgf000087_0002

C

[0248] The isopropyl alanine chlorophosphoramidate ester C was prepared using the same procedure as chloridate A except substituting isopropyl alanine ester for the ethyl alanine ester. The material is used crude in the next reaction. Treatment with methanol or ethanol forms the displaced product with the requisite LCMS signal.

Example 4. (2S)-2-ethylbutyl 2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[l,2-firi,2,41triazin- 7-yl)-5-cvano-3,4-dihvdroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphorylamino)propanoate (Compound 9)

[0249] Compound 9 can be prepared by several methods described below. Procedure 1

Figure imgf000088_0001

[0250] Prepared from Compound 1 and chloridate B according to the same method as for the preparation of compound 8 as described in PCT Publication no. WO 2012/012776. 1H NMR (300 MHz, CD3OD) δ 7.87 (m, 1H), 7.31-7.16 (m, 5H), 6.92-6.89 (m, 2H), 4.78 (m, 1H), 4.50-3.80 (m, 7H), 1.45-1.24 (m, 8H), 0.95-0.84 (m, 6H). 31P NMR (121.4 MHz, CD3OD) δ 3.7. LCMS m/z 603.1 [M+H], 601.0 [M-H].

Procedure 2

Figure imgf000088_0002

9

[0251] (2S)-2-ethylbutyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7- yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino) propanoate. (2S)-2-ethylbutyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (1.08 g, 2.4 mmol) was dissolved in anhydrous DMF (9 mL) and stirred under a nitrogen atmosphere at RT. (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (350 mg, 1.2 mmol) was added to the reaction mixture in one portion. A solution of i-butylmagnesium chloride in THF (1M, 1.8 mL, 1.8 mmol) was then added to the reaction drop wise over 10 minutes. The reaction was stirred for 2 h, at which point the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (3 x 15 mL) followed by saturated aqueous sodium chloride solution (15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil was purified with silica gel column chromatography (0-10% MeOH in DCM) to afford (2S)-2- ethylbutyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2, l-f][l,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino) propanoate (311 mg, 43%, 1 :0.4 diastereomeric mixture at phosphorus) as a white solid. H NMR (400 MHz, CD3OD) δ 7.85 (m, 1H), 7.34 – 7.23 (m, 2H), 7.21 – 7.09 (m, 3H), 6.94 – 6.84 (m, 2H), 4.78 (d, / = 5.4 Hz, 1H), 4.46 – 4.33 (m, 2H), 4.33 – 4.24 (m, 1H), 4.18 (m, 1H), 4.05 – 3.80 (m, 3H), 1.52 – 1.39 (m, 1H), 1.38 – 1.20 (m, 7H), 0.85 (m, 6H). 31P NMR (162 MHz, CD3OD) δ 3.71, 3.65. LCMS m/z 603.1 [M+H], 600.9 [M-H]. HPLC (2-98% MeCN-H20 gradient with 0.1% TFA modifier over 8.5 min, 1.5mL/min, Column: Phenomenex Kinetex C18, 2.6 um 100 A, 4.6 x 100 mm ) tR = 5.544 min, 5.601 min

Separation of the (S) and (R) Diastereomers

[0252] (2S)-2-ethylbutyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)- 5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino) propanoate was dissolved in acetonitrile. The resulting solution was loaded onto Lux Cellulose-2 chiral column, equilibrated in acetonitrile, and eluted with isocratic

acetonitrile/methanol (95 :5 vol/vol). The first eluting diastereomer had a retention time of 17.4 min, and the second eluting diastereomer had a retention time of 25.0 min.

[0253] First Eluting Diastereomer is (S)-2-ethylbutyl 2-(((R)-(((2R,3S,4R,5R)-5-(4- aminopyrrolo[2, 1 -f] [ 1 ,2,4]triazin-7-yl)-5-cyano-3 ,4-dihydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phos horyl)amino)propanoate:

Figure imgf000089_0001

!HNMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 7.36 (d, / = 4.8 Hz, 1H), 7.29 (br t, J = 7.8 Hz, 2H), 7.19 – 7.13 (m, 3H), 7.11 (d, / = 4.8 Hz, 1H), 4.73 (d, / = 5.2 Hz, 1H), 4.48 – 4.38 (m, 2H), 4.37 – 4.28 (m, 1H), 4.17 (t, / = 5.6 Hz, 1H), 4.08 – 3.94 (m, 2H), 3.94 – 3.80 (m, 1H), 1.48 (sep, / = 12.0, 6.1 Hz, 1H), 1.34 (p, / = 7.3 Hz, 4H), 1.29 (d, / = 7.2 Hz, 3H), 0.87 (t, / = 7.4 Hz, 6H). 31PNMR (162 MHz, CD3OD) δ 3.71 (s). HPLC (2-98% MeCN-H20 gradient with 0.1 % TFA modifier over 8.5 min, 1.5mL/min, Column: Phenomenex Kinetex C18, 2.6 um 100 A, 4.6 x 100 mm ) is = 5.585 min. [0254] Second Eluting Diastereomer is (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4- aminopyrrolo[2, 1 -f] [ 1 ,2,4]triazin-7-yl)-5-cyano-3 ,4-dihydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate:

Figure imgf000090_0001

HNMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.36 – 7.28 (m, 3H), 7.23 – 7.14 (m, 3H), 7.08 (d, 7 = 4.8 Hz, 1H), 4.71 (d, 7 = 5.3 Hz, 1H), 4.45 – 4.34 (m, 2H), 4.32 – 4.24 (m, 1H), 4.14 (t, / = 5.8 Hz, 1H), 4.08 – 3.94 (m, 2H), 3.93 – 3.85 (m, 1H), 1.47 (sep, / = 6.2 Hz, 1H), 1.38 – 1.26 (m, 7H), 0.87 (t, / = 7.5 Hz, 6H). 31PNMR (162 MHz, CD3OD) δ 3.73 (s). HPLC (2- 98% MeCN-H20 gradient with 0.1% TFA modifier over 8.5 min, 1.5mL/min, Column: Phenomenex Kinetex C18, 2.6 urn 100 A, 4.6 x 100 mm ) tR = 5.629 min.

Example 5. (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolor2J- f|[l,2,41triazin-7-yl)-5-cvano-3,4-dihvdroxytetrahvdrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (32)

Figure imgf000090_0002

[0255] The preparation of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l f][l,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate is described below.

Preparation of (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)- one.

Figure imgf000090_0003

[0256] (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol (15.0g) was combined with MTBE (60.0 mL), KBr (424.5 mg), aqueous K2HP04solution (2.5M, 14.3 mL), and TEMPO (56 mg). This mixture was cooled to about 1 °C. Aqueous bleach solution (7.9%wt.) was slowly charged in portions until complete consumption of starting material as indicated through a starch/iodide test. The layers were separated, and the aqueous layer was extracted with MTBE. The combined organic phase was dried over MgS04 and concentrated under reduced pressure to yield the product as a solid.

Preparation (4-amino-7-iodopyrrolor2,l-fl ri,2,41triazine)

Figure imgf000091_0001

[0257] To a cold solution of 4-aminopyrrolo[2, l-f][l,2,4]-triazine (10.03 g; 74.8 mmol) in N,N-dimethylformamide (70.27 g), N-iodosuccinimide (17.01g; 75.6 mmol) was charged in portions, while keeping the contents at about 0 °C. Upon reaction completion (about 3 h at about 0 °C), the reaction mixture was transferred into a 1 M sodium hydroxide aqueous solution (11 g NaOH and 276 mL water) while keeping the contents at about 20-30 °C. The resulting slurry was agitated at about 22 °C for 1.5 h and then filtered. The solids are rinsed with water (50 mL) and dried at about 50 °C under vacuum to yield 4-amino-7- iodopyrrolo[2,l-f] [l,2,4]triazine as a solid. !H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.78 (br s, 2H), 6.98 (d, J = 4.4 Hz, 1H), 6.82 (d, J = 4.4 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 155.7, 149.1, 118.8, 118.1, 104.4, 71.9. MS m/z = 260.97 [M+H].

Preparation (3R,4R,5R)-2-(4-aminopyrrolor2, l-firi,2,41triazin-7-yl)-3,4-bis(benzyloxy)-5- ((benzyloxy)methyl)tetrahvdrofuran-2-ol via (4-amino-7-iodopyrrolor2,l-fl ri,2,41triazine)

Figure imgf000091_0002

[0258] To a reactor under a nitrogen atmosphere was charged iodobase 2 (81 g) and THF (1.6 LV). The resulting solution was cooled to about 5 °C, and TMSC1 (68 g) was charged. PhMgCl (345mL, 1.8 M in THF) was then charged slowly while maintaining an internal temperature at about < 5°C. The reaction mixture was stirred at about 0°C for 30 min, and then cooled to about -15 °C. zPrMgCl-LiCl (311 mL, 1.1 M in THF) was charged slowly while maintaining an internal temperature below about -12 °C. After about 10 minutes of stirring at about -15 °C, the reaction mixture was cooled to about -20 °C, and a solution of lactone 1 (130 g) in THF (400 mL) was charged. The reaction mixture was then agitated at about -20 °C for about 1 h and quenched with AcOH (57 mL). The reaction mixture was warmed to about 0 °C and adjusted to pH 7-8 with aqueous NaHCC>3 (5 wt%, 1300 mL). The reaction mixture was then diluted with EtOAc (1300 mL), and the organic and aqueous layers were separated. The organic layer was washed with IN HC1 (1300 mL), aqueous NaHCC>3 (5 wt%, 1300 mL), and brine (1300 mL), and then dried over anhydrous Na2S04 and concentrated to dryness. Purification by silica gel column chromatography using a gradient consisting of a mixture of MeOH and EtOAc afforded the product.

Preparation ((2S)-2-ethylbutyl 2- (((perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate) (mixture of Sp and Rp):

1 ) phenyl dichlorophosphate

CH2CI2, -78 °C to ambient

2) pentafluorophenol

Et3N, 0 °C to ambient

Figure imgf000092_0001

[0259] L- Alanine 2-ethylbutyl ester hydrochloride (5.0 g, 23.84 mmol) was combined with methylene chloride (40 mL), cooled to about -78 °C, and phenyl dichlorophosphate (3.65 mL, 23.84 mmol) was added. Triethylamine (6.6 mL, 47.68 mmol) was added over about 60 min at about -78 °C and the resulting mixture was stirred at ambient temperature for 3h. The reaction mixture was cooled to about 0 °C and pentafluorophenol (4.4 g, 23.84 mmol) was added. Triethylamine (3.3 mL, 23.84 mmol) was added over about 60 min. The mixture was stirred for about 3h at ambient temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with an aqueous sodium carbonate solution several times, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of EtOAc and hexanes (0 to 30%). Product containing fractions were concentrated under reduced pressure to give (2S)-2-ethylbutyl 2-(((perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate as a solid. H NMR (400 MHz, Chloroform-d) δ 7.41 – 7.32 (m, 4H), 7.30 – 7.17 (m, 6H), 4.24 – 4.16 (m, 1H), 4.13 – 4.03 (m, 4H), 4.01 – 3.89 (m, 1H), 1.59 – 1.42 (m, 8H), 1.40 – 1.31 (m, 8H), 0.88 (t, J = 7.5 Hz, 12H). 31P NMR (162 MHz, Chloroform-d) δ – 1.52. 19F NMR (377 MHz, Chloroform-d) δ – 153.63, – 153.93 (m), – 160.05 (td, J = 21.9, 3.6 Hz), – 162.65 (qd, J = 22.4, 20.5, 4.5 Hz). MS m/z = 496 [M+H]. Preparation of Title Compound (mixture of Sp and Rp):

Figure imgf000093_0001

[0260] The nucleoside (29 mg, 0.1 mmol) and the phosphonamide (60 mg, 0.12 mmol) and N,N-dimethylformamide (2 mL) were combined at ambient temperature. 7¾ri-Butyl magnesiumchloride (1M in THF, 0.15 mL) was slowly added. After about lh, the reaction was diluted with ethyl acetate, washed with aqueous citric acid solution (5%wt.), aqueous saturated NaHC03 solution and saturated brine solution. The organic phase was dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of methanol and CH2CI2 (0 to 5%). Product containing fractions were concentrated under reduced pressure to provide the product.

Preparation of (3aR,4R,6R,6aR)-4-(4-aminopyrrolor2, l-firi,2,41triazin-7-yl)-6- (hvdroxymethyl)-2,2-dimethyltetrahydrofuror3,4-diri,31dioxole-4-carbonitrile:

Figure imgf000093_0002

[0261] To a mixture of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2, l-f] [l,2,4]triazin-7-yl)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (5.8g, 0.02 mol), 2,2- dimethoxypropane (11.59 mL, 0.09 mol) and acetone (145 mL) at ambient temperature was added sulfuric acid (18M, 1.44 mL). The mixture was warmed to about 45 °C. After about 30 min, the mixture was cooled to ambient temperature and sodium bicarbonate (5.8 g) and water 5.8 mL) were added. After 15 min, the mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate (150 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure to give crude (2R,3R,4S,5R)-2-(4-aminopyrrolo[2, l-f] [l,2,4]triazin-7-yl)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-carbonitrile. !H NMR (400 MHz, CD3OD) δ 7.84 (s, 1H), 6.93 (d, / = 4.6 Hz, 1H), 6.89 (d, / = 4.6 Hz, 1H), 5.40 (d, / = 6.7 Hz, 1H), 5.00 (dd, / = 6.7, 3.3 Hz, 1H), 4.48 – 4.40 (m, 1H), 3.81 – 3.72 (m, 2H), 1.71 (s, 3H), 1.40 (s, 3H). MS m/z = 332.23 [M+l].

Preparation of (2S)-2-ethylbutyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolor2,l-firi,2,41triazin- 7-yl)-5-cvano-3,4-dihvdroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate:

Figure imgf000094_0001

[0262] Acetonitrile (100 mL) was combined with (2S)-2-ethylbutyl 2-(((4- nitrophenoxy)(phenoxy)phosphoryl)-amino)propanoate (9.6 g, 21.31 mmol), the substrate alcohol (6.6 g, 0.02 mol), magnesium chloride (1.9 g, 19.91 mmol) at ambient temperature. The mixture was agitated for about 15 min and N,N-diisopropylethylamine (8.67 mL, 49.78 mmol) was added. After about 4h, the reaction was diluted with ethyl acetate (100 mL), cooled to about 0 °C and combined with aqueous citric acid solution (5%wt., 100 mL). The organic phase was washed with aqueous citric acid solution (5%wt., 100 mL) and aqueous saturated ammonium chloride solution (40 mL), aqueous potassium carbonate solution

(10%wt., 2 x 100 mL), and aqueous saturated brine solution (100 mL). The organic phase was dried with sodium sulfate and concentrated under reduced pressure to provide crude product. !H NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.31 – 7.22 (m, 2H), 7.17 – 7.09 (m, 3H), 6.93 – 6.84 (m, 2H), 5.34 (d, / = 6.7 Hz, 1H), 4.98 (dd, / = 6.6, 3.5 Hz, 1H), 4.59 – 4.50 (m, 1H), 4.36 – 4.22 (m, 2H), 4.02 (dd, / = 10.9, 5.7 Hz, 1H), 3.91 (dd, / = 10.9, 5.7 Hz, 1H), 3.83 (dq, / = 9.7, 7.1 Hz, 1H), 1.70 (s, 3H), 1.50 – 1.41 (m, 1H), 1.39 (s, 3H), 1.36 – 1.21 (m, 7H), 0.86 (t, / = 7.4 Hz, 6H). MS m/z = 643.21 [M+l]. Preparation of (S)-2-ethylbutyl 2-(((S)-(((2R.3S.4R.5R)-5-(4-aminopyrrolor2.1- firi,2,41triazin-7-yl)-5-cvano-3,4-ditivdroxytetratiydrofuran-2- yl)methoxy)( henoxy)phosphoryl)amino)propanoate (Compound 32)

Figure imgf000095_0001

Compound 32

[0263] The crude acetonide (12.85 g) was combined with tetrahydrofuran (50 mL) and concentrated under reduced pressure. The residue was taken up in tetrahydrofuran (100 mL), cooled to about 0 °C and concentrated HC1 (20 mL) was slowly added. The mixture was allowed to warm to ambient temperature. After consumption of the starting acetonide as indicated by HPLC analysis, water (100 mL) was added followed by aqueous saturated sodium bicarbonate solution (200 mL). The mixture was extracted with ethyl acetate (100 mL), the organic phase washed with aqueous saturated brine solution (50 mL), dried over sodium sulfated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of methanol and ethyl acetate (0 to 20%).

Product containing fractions were concentrated under reduced pressure to provide the product.

PATENT

US 20170071964

US 20160122374

PAPER

Journal of Medicinal Chemistry (2017), 60(5), 1648-1661.

https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.6b01594

The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded in history with over 28,000 cases, resulting in >11,000 deaths including >500 healthcare workers. A focused screening and lead optimization effort identified 4b (GS-5734) with anti-EBOV EC50 = 86 nM in macrophages as the clinical candidate. Structure activity relationships established that the 1′-CN group and C-linked nucleobase were critical for optimal anti-EBOV potency and selectivity against host polymerases. A robust diastereoselective synthesis provided sufficient quantities of 4b to enable preclinical efficacy in a non-human-primate EBOV challenge model. Once-daily 10 mg/kg iv treatment on days 3–14 postinfection had a significant effect on viremia and mortality, resulting in 100% survival of infected treated animals [ Nature 2016531, 381−385]. A phase 2 study (PREVAIL IV) is currently enrolling and will evaluate the effect of 4b on viral shedding from sanctuary sites in EBOV survivors.

(S)-2-Ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (4b)

Compound 4b was prepared from 4 and 22b as described previously.(17)1H NMR (400 MHz, methanol-d4): δ 7.86 (s, 1H), 7.33–7.26 (m, 2H), 7.21–7.12 (m, 3H), 6.91 (d, J = 4.6 Hz, 1H), 6.87 (d, J = 4.6 Hz, 1H), 4.79 (d, J = 5.4 Hz, 1H), 4.43–4.34 (m, 2H), 4.28 (ddd, J = 10.3, 5.9, 4.2 Hz, 1H), 4.17 (t, J = 5.6 Hz, 1H), 4.02 (dd, J = 10.9, 5.8 Hz, 1H), 3.96–3.85 (m, 2H), 1.49–1.41 (m, 1H), 1.35–1.27 (m, 8H), 0.85 (t, J = 7.4 Hz, 6H).
13C NMR (100 MHz, methanol-d4): δ 174.98, 174.92, 157.18, 152.14, 152.07, 148.27, 130.68, 126.04, 125.51, 121.33, 121.28, 117.90, 117.58, 112.29, 102.60, 84.31, 84.22, 81.26, 75.63, 71.63, 68.10, 67.17, 67.12, 51.46, 41.65, 24.19, 20.56, 20.50, 11.33, 11.28.
 31P NMR (162 MHz, methanol-d4): δ 3.66 (s).
HRMS (m/z): [M]+ calcd for C27H35N6O8P, 602.2254; found, 602.2274.
[α]21D – 21 (c 1.0, MeOH).

PAPER

Nature (London, United Kingdom) (2016), 531(7594), 381-385.

https://www.nature.com/articles/nature17180

Remdesivir
GS-5734 structure.png
Clinical data
Other names GS-5734
Routes of
administration
By mouthinsufflation
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C27H35N6O8P
Molar mass 602.585 g·mol−1
3D model (JSmol)
Remdesivir
GS-5734 structure.png
Clinical data
Other names GS-5734
Routes of
administration
By mouthinsufflation
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C27H35N6O8P
Molar mass 602.585 g·mol−1
3D model (JSmol)

//////////////Remdesivir, レムデシビル , UNII:3QKI37EEHE, ремдесивир ريمديسيفير 瑞德西韦 , GS-5734 , GS 5734, PHASE 3 , CORONOVIRUS, COVID-19

CCC(CC)COC(=O)[C@H](C)N[P@](=O)(OC[C@H]1O[C@](C#N)([C@H](O)[C@@H]1O)c2ccc3c(N)ncnn23)Oc4ccccc4

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

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